Toxicological Profile for

Bromomethane

March 2020
BROMOMETHANE ii

DISCLAIMER

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

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

Services.
BROMOMETHANE iii

FOREWORD

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

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

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

and republished as necessary.

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

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

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

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

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

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

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

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

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

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

public health are identified by ATSDR.

Each profile includes the following:

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

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

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

exposures;

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

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

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

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

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

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

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

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

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

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

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

this toxicological profile resides with ATSDR.

Patrick N. Breysse, Ph.D., CIH

Director, National Center for Environmental Health and

Agency for Toxic Substances and Disease Registry

Centers for Disease Control and Prevention
BROMOMETHANE iv

*Legislative Background

The toxicological profiles are developed under the Comprehensive Environmental Response, 

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

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

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

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

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

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

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

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

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

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

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

VERSION HISTORY

Date Description

March 2020 Final toxicological profile released

April 2018 Draft for public comment toxicological profile released

September 1992 Final toxicological profile released
BROMOMETHANE vi

CONTRIBUTORS & REVIEWERS

CHEMICAL MANAGER TEAM

Sam Keith, M.S., C.H.P. (Lead) Lisa Ingerman, Ph.D., D.A.B.T.

Obaid Faroon, D.V.M., Ph.D. Julie M. Klotzbach, Ph.D.

Mike Fay, Ph.D. Christina Coley, B.S.

ATSDR, Division of Toxicology and Human Health 

Sciences, Atlanta, GA

SRC, Inc., North Syracuse, NY

REVIEWERS

Interagency Minimal Risk Level Workgroup:

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

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

Toxicology Program (NTP).

Additional reviews for science and/or policy: 

ATSDR, Division of Community Health Investigations; ATSDR, Office of Science; NCEH, Division of 

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

PEER REVIEWERS

1. Kelly A. Reynolds, Ph.D., Zuckerman College of Public Health Program, The University of 

Arizona, Tucson, Arizona

2. Kyle Steenland, Ph.D., Rollins School of Public Health at Emory, Atlanta, Georgia

3. Prakash Mulay, MBBS, MPH, Florida Department of Health, Tallahassee, Florida

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

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

Compensation, and Liability Act, as amended.

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

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

the administrative record for this compound.

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

content. The responsibility for the content of this profile lies with ATSDR.
BROMOMETHANE vii

CONTENTS

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

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

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

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

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

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

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

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

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

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

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................6

CHAPTER 2. HEALTH EFFECTS..............................................................................................................9

2.1 INTRODUCTION..........................................................................................................................9

2.2 DEATH ........................................................................................................................................37

2.3 BODY WEIGHT..........................................................................................................................38

2.4 RESPIRATORY ..........................................................................................................................39

2.5 CARDIOVASCULAR.................................................................................................................41

2.6 GASTROINTESTINAL...............................................................................................................41

2.7 HEMATOLOGICAL ...................................................................................................................43

2.8 MUSCULOSKELETAL..............................................................................................................43

2.9 HEPATIC.....................................................................................................................................44

2.10 RENAL ........................................................................................................................................44

2.11 DERMAL.....................................................................................................................................45

2.12 OCULAR .....................................................................................................................................46

2.13 ENDOCRINE...............................................................................................................................46

2.14 IMMUNOLOGICAL ...................................................................................................................47

2.15 NEUROLOGICAL.......................................................................................................................47

2.16 REPRODUCTIVE .......................................................................................................................54

2.17 DEVELOPMENTAL...................................................................................................................55

2.18 CANCER......................................................................................................................................56

2.19 GENOTOXICITY........................................................................................................................58

2.20 MECHANISMS OF TOXICITY .................................................................................................60

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS.................................................................................................................62

3.1 TOXICOKINETICS.....................................................................................................................62

3.1.1 Absorption.............................................................................................................................62

3.1.2 Distribution ...........................................................................................................................63

3.1.3 Metabolism............................................................................................................................64

3.1.4 Excretion ...............................................................................................................................65

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models.............66

3.1.6 Animal-to-Human Extrapolations.........................................................................................67

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.....67

3.3 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................68

3.3.1 Biomarkers of Exposure........................................................................................................69
BROMOMETHANE viii

3.3.2 Biomarkers of Effect ............................................................................................................. 70

3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 71

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 72

4.1 CHEMICAL IDENTITY ............................................................................................................. 72

4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 72

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ......................................................................... 74

5.1 OVERVIEW ................................................................................................................................ 74

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .................................................. 76

5.2.1 Production ............................................................................................................................. 76

5.2.2 Import/Export ........................................................................................................................ 79

5.2.3 Use ........................................................................................................................................ 80

5.2.4 Disposal ................................................................................................................................. 81

5.3 RELEASES TO THE ENVIRONMENT ..................................................................................... 81

5.3.1 Air ......................................................................................................................................... 82

5.3.2 Water ..................................................................................................................................... 85

5.3.3 Soil ........................................................................................................................................ 86

5.4 ENVIRONMENTAL FATE ........................................................................................................ 86

5.4.1 Transport and Partitioning ..................................................................................................... 86

5.4.2 Transformation and Degradation .......................................................................................... 89

5.5 LEVELS IN THE ENVIRONMENT ........................................................................................... 93

5.5.1 Air ......................................................................................................................................... 94

5.5.2 Water ..................................................................................................................................... 98

5.5.3 Sediment and Soil ................................................................................................................. 99

5.5.4 Other Media .......................................................................................................................... 99

5.6 GENERAL POPULATION EXPOSURE.................................................................................. 100

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 101

CHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 103

6.1 INFORMATION ON HEALTH EFFECTS ............................................................................... 103

6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 103

6.3 ONGOING STUDIES ................................................................................................................ 111

CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 112

CHAPTER 8. REFERENCES .................................................................................................................. 114

APPENDICES

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

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR BROMOMETHANE ........................ B-1 

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

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

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

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .................................................. F-1 
BROMOMETHANE ix

LIST OF FIGURES

1-1. Health Effects in Animals Following Inhalation Exposure to Bromomethane ....................................3

1-2. Health Effects in Animals Following Oral Exposure to Bromomethane .............................................4

1-3. Summary of Sensitive Targets of Bromomethane – Inhalation............................................................8

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

2-2. Levels of Significant Exposure to Bromomethane – Inhalation.........................................................25

2-3. Levels of Significant Exposure to Bromomethane – Oral..................................................................34

5-1. Number of NPL Sites with Bromomethane Contamination ...............................................................74

6-1. Summary of Existing Health Effects Studies on Bromomethane by Route and Endpoint...............104
BROMOMETHANE x

LIST OF TABLES

1-1. Minimal Risk Levels (MRLs) for Bromomethane ...............................................................................7

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

2-2. Levels of Significant Exposure to Bromomethane – Oral..................................................................31

2-3. Genotoxicity of Bromomethane In Vitro............................................................................................58

2-4. Genotoxicity of Bromomethane In Vivo.............................................................................................59

4-1. Chemical Identity of Bromomethane..................................................................................................72

4-2. Physical and Chemical Properties of Bromomethane.........................................................................72

5-1. Facilities that Produce, Process, or Use Bromomethane ....................................................................76

5-2. U.S. Companies Manufacturing Bromomethane................................................................................77

5-3. Bromomethane Inventory in the United States from 2003 to 2014....................................................79

5-4. Releases to the Environment from Facilities that Produce, Process, or Use Bromomethane.............82

5-5. Estimated Anthropogenic and Natural Sources of Bromomethane (Gg/Year) 1996–1998 and 

2008 ....................................................................................................................................................84

5-6. Lowest Limit of Detection Based on Standards.................................................................................93

5-7. Summary of Environmental Levels of Bromomethane ......................................................................94

5-8. Bromomethane Levels in Water, Soil, and Air of National Priorities List (NPL) Sites.....................94

5-9. Percentile Distribution of Annual Mean Bromomethane Concentrations (ppbv) Measured in 

Ambient Air at Locations Across the United States...........................................................................95

5-10. Ambient Air Concentrations in Parts per Billion Near Areas of Bromomethane Use .....................96

5-11. Bromomethane Levels Following Fumigation .................................................................................97

7-1. Regulations and Guidelines Applicable to Bromomethane..............................................................112
BROMOMETHANE 1

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

Bromomethane is a gas at room temperatures, but can be liquified under sufficient pressure, and is a 

liquid below 38°F (Piccirillo and Piccirillo 2010). Bromomethane is primarily used in the form of a gas, 

compressed liquid, or in solution as a fumigant for the control of insects, fungi, and rodents. Under the 

U.S. Environmental Protection Agency (EPA) Clean Air Act, production and most uses of bromomethane 

in the United States were phased out in 2005; however, bromomethane is still allowed to be used under 

two critical use exemptions—to eliminate quarantine pests and for agricultural use where there are no 

technically or financially feasible alternatives. 

Bromomethane naturally occurs in oceans, from which it is released into the atmosphere. Bromomethane 

in the atmosphere breaks down slowly, with a half-life of 11 months. Bromomethane in water and soil is 

likely to volatilize at a faster rate than it would break down. Bromomethane levels in ambient air are 

relatively low. The maximum annual mean 24-hour bromomethane concentration at 104 sites across the 

United States was 0.15 ppbv in 2018 (EPA 2019a). 

The most likely route of human exposure is by inhalation because bromomethane exists as a gas at room 

temperature. Bromomethane has very little odor at concentrations that may produce toxicity; therefore, 

exposure to hazardous levels may occur without awareness of exposure. However, tracer amounts of 

acrolein have been added to help facilitate odor recognition. Exposure to inhaled bromomethane is more 

likely to occur in workers than in the general population. The general population is not likely to be 

exposed to bromomethane via the oral route; however, exposure to a small amount of bromomethane 

could occur via contaminated water or food.

1.2 SUMMARY OF HEALTH EFFECTS

As noted in Section 1.1, because bromomethane exists as a gas at room temperature, inhalation is the 

most likely exposure route. However, it is possible that humans could be exposed to very small amounts 

in food or water. Given the predominance of the inhalation exposure route, most animal toxicity studies 

have examined effects of inhaled bromomethane, with few studies evaluating effects of oral exposure. In 

addition to animal studies, some information is available from studies of exposed workers to 

bromomethane vapor, although reliable quantitative estimates of exposure have not been reported in these 
BROMOMETHANE 2

1. RELEVANCE TO PUBLIC HEALTH

studies. The available data in humans and animals provide strong evidence that the respiratory tract and 

the nervous system are the most sensitive targets of bromomethane toxicity following inhalation exposure

(Figure 1-1). There is some evidence of developmental effects following inhalation exposure of rats, 

although this has not been substantiated in other studies. Other effects observed in inhalation studies 

include cardiovascular, reproductive, hepatic, and renal effects; however, these effects occur at higher 

exposures. Based on the small number of oral studies in animals, the primary target of gavage exposure 

to bromomethane is damage to the stomach (Figure 1-2). However, chronic-duration oral studies did not 

identify target organ systems for bromomethane. Dermal and ocular exposure to bromomethane vapor or 

liquid produces damage at the site of contact. 

Respiratory Effects. In humans, the lungs appear to be the primary target of toxicity in the respiratory 

tract; cough, edema, hemorrhagic lesions, and dyspnea have been reported following acute exposure

(Akca et al. 2009; Greenberg 1971; O'Neal 1987; Prain and Smith 1952). In laboratory animals, most of 

the observed damage to the respiratory tract is confined to the nasal cavity, although some studies have 

reported thrombi or hemorrhagic lesions, congestion, or pneumonia in the lungs (Eustis et al. 1988; Irish 

et al. 1940; Kato et al. 1986). Within the nasal cavity, the bromomethane-induced damage is limited to 

the olfactory epithelium; the observed effects include degeneration, hyperplasia, metaplasia, and loss of 

sensory cells (Eustis et al. 1988; Gotoh et al. 1994; Hastings et al. 1991; Hurtt et al. 1987, 1988; NTP 

1992; Reuzel et al. 1987, 1991; Youngentob and Schwob 2006). Comparison of LOAEL values from 

intermediate- and chronic-duration studies suggests that the nasal effects are exposure duration-related

(NTP 1992).

Neurological Effects. Neurological effects have been observed in fumigators, other workers exposed 

post-fumigation, and non-workers accidentally exposed to bromomethane. The initial neurological 

effects observed in humans exposed to high levels of bromomethane occur within a few hours of exposure 

and include headache, weakness, and nausea and vomiting (Akca et al. 2009; Deschamps and Turpin 

1996; Marraccini et al. 1983; Wyers 1945). Depending on the exposure level, these symptoms may 

progress into ataxia, tremors, paralysis, and clonic seizures (Balagopal et al. 2011; Deschamps and Turpin 

1996; Hine 1969; Hustinx et al. 1993; Prain and Smith 1952; Prockop and Smith 1986). The neurological 

effects typically begin to wane after several days, but recovery may not be complete even after many 

months (Bishop 1992; Deschamps and Turpin 1996; Longley and Jones 1965; O’Neal 1987; Rathus and 

Landy 1961). Only limited information is available on the effects of long-term inhalation exposure of 

humans to low levels of bromomethane. Headache, weakness, and increased prevalence of neurological 

signs such as muscle ache, fatigue, and dizziness have been noted in workers exposed repeatedly or for 
BROMOMETHANE 3

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-1. Health Effects in Animals Following Inhalation Exposure to 

Bromomethanea
BROMOMETHANE 4

1. RELEVANCE TO PUBLIC HEALTH

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

30

Dose (mg/kg/day) Effects in Animals

Intermediate: Histological alterations 

in forestomach

Acute: Histological alterations in nonglandular stomach

1-5

Chronic: Decreased body weight 

gain and decreased food consumption

10-15
BROMOMETHANE 5

1. RELEVANCE TO PUBLIC HEALTH

extended periods in the workplace (Anger et al. 1986; Hine 1969; Kantarjian and Shaheen 1963; Kishi et 

al. 1988). A variety of concentration-related neurological effects ranging from alterations in 

neurotransmitter levels to cerebral and cerebellar degeneration have been observed in laboratory animals. 

Mild and transient neurobehavioral signs (decreased locomotor activity in mice) are the most sensitive 

effects of inhaled bromomethane; it is noted that impaired performance on neurobehavioral tests have not 

been consistently found at all testing durations. As exposure levels increase, overt signs of neurotoxicity 

such as abnormal gait, tremors, ataxia, hind-limb paralysis, and convulsions have been reported in rats, 

mice, rabbits, and monkeys (Breslin et al. 1990; Eustis et al. 1988; Irish et al. 1940; NTP 1992). At 

higher concentrations, histological damage, particularly necrosis and degeneration, was observed in the 

cerebrum and cerebellum of rats and mice exposed to bromomethane for ≥2 weeks (Eustis et al. 1988; 

Kato et al. 1986; NTP 1992); increases in mortality were also observed at these concentrations.

Developmental Effects. There is some evidence that inhaled bromomethane is a developmental toxicant. 

Increased incidences of gallbladder agenesis and fused sternebrae (a minor variation) and decreases in 

fetal weight have been observed in the offspring of rabbits exposed to a maternally toxic concentration 

(80 ppm) (Breslin et al. 1990). However, other inhalation studies in rats and rabbits respectively using 

similar or lower exposure levels (Hardin et al. 1981; NIOSH 1980) and an oral exposure study in rats and 

rabbits (Kaneda et al. 1998) have not reported developmental effects.

Gastrointestinal Effects. For oral exposure, damage to the epithelium of the forestomach has been 

observed in rats administered bromomethane in oil via gavage. However, no adverse gastrointestinal 

effects were associated with oral exposure of dogs exposed to dietary bromomethane in 

microencapsulated form at higher doses for up to 2 years. There is some question as to whether the 

forestomach effects in rats are due to the bolus administration of a very reactive chemical and whether 

gavage administration is an appropriate model for human exposure to bromomethane. Thus, there is 

uncertainty regarding the relevance of this effect to humans.

Other Targets. Other targets of bromomethane toxicity that have been observed in laboratory animal 

inhalation studies include the heart (myocardial fibrosis and degeneration and cardiomyopathy) (Eustis et 

al. 1988; Kato et al. 1986; NTP 1992), liver (necrosis) (Hurrt et al. 1987), kidneys (nephrosis) (Eustis et 

al. 1988), and the male reproductive system (decreased sperm density and testicular degeneration) (EPA 

1988a; Eustis et al. 1988; Kato et al. 1986); these effects are typically observed at higher concentrations 

that are near-lethal or lethal. 
BROMOMETHANE 6

1. RELEVANCE TO PUBLIC HEALTH

Dermal Effects. Erythema, edema, and blisters have been observed in humans dermally exposed to 

liquefied bromomethane or bromomethane vapor. A study in animals found histological damage to the 

epidermis and dermis following a very brief (≤5 minutes) direct dermal contact to liquefied 

bromomethane. In addition, the temperature of liquidized bromomethane can be below -93°C; therefore, 

exposed tissue can freeze and develop erythema, edema, and blisters (Vivas et al. 2015). This could be a 

possible contributor to dermal effects of bromomethane.

Ocular Effects. In humans exposed to bromomethane vapor, conjunctivitis, erythema, and edema of the 

eyelids have been reported (Langard et al. 1996; O’Neal 1987; Prain and Smith 1952; Wyers 1945).

Cancer Effects. There are limited data on the carcinogenic potential of bromomethane in humans. 

Several studies of agricultural workers (Alavanja et al. 2003; Barry et al. 2012) and a study of workers 

exposed to a variety of brominated chemicals (Wong et al. 1984) have found increases in specific types of 

cancer; however, the workers were exposed to numerous chemicals and none of the studies established 

that bromomethane was the causative agent. No evidence of carcinogenic effects was observed in rats or 

mice exposed via inhalation to bromomethane for at least 2 years (NTP 1992; Reuzel et al. 1987, 1991) or 

in rats administered bromomethane via gavage (Danse et al. 1984; IRIS 2002).

The U.S. Department of Health and Human Services (NTP 2016) has not categorized the carcinogenicity 

of bromomethane. The International Agency for Research on Cancer (IARC 2016) classified 

bromomethane as a Group 3 carcinogen (not classifiable as to its carcinogenicity to humans). EPA (IRIS 

2002) has determined that bromomethane is classified as a Group D carcinogen (not classifiable as to 

human carcinogenicity).

1.3 MINIMAL RISK LEVELS (MRLs)

ATSDR develops MRLs, which are substance-specific guidelines intended to serve as screening levels by 

ATSDR health assessors and other responders to identify contaminants and potential health effects that 

may be of concern at hazardous waste sites. See Appendix A for detailed information on the MRLs for 

bromomethane.

MRLs for bromomethane are summarized Table 1-1. As noted in Section 1.1, the most likely route of 

human exposure is by inhalation because bromomethane exists as a gas at room temperature. Numerous 

studies have been conducted in laboratory animals for acute, intermediate, and chronic exposure 
BROMOMETHANE 7

1. RELEVANCE TO PUBLIC HEALTH

durations, with sufficient data to derive intermediate- and chronic-duration inhalation MRLs. 

Neurotoxicity and lesions of the upper respiratory tract are the most sensitive effects of inhalation 

exposure to bromomethane (Figure 1-3). The general population is not likely to be exposed to 

bromomethane via the oral route; thus, very few animal studies on the oral toxicity of bromomethane 

have been conducted. One acute- and one intermediate-duration gavage studies show that the most 

sensitive effect of oral exposure to bromomethane is stomach lesions; however, these studies administered

bromomethane by gavage. As discussed in Section 1.2, there is uncertainty as to whether the observed 

forestomach lesions in animals are unique to gavage administration of bromomethane, and how these 

effects are related to humans who have no forestomach. Chronic-duration oral studies did not identify 

target organs for bromomethane; the only effect observed in chronic-duration oral studies is decreased 

body weight.

Table 1-1. Minimal Risk Levels (MRLs) for Bromomethanea

Exposure 

duration MRL Critical effect

Point of 

departure

Uncertainty 

factor Reference

Inhalation exposure (ppm)

Acute Insufficient data for MRL derivation

Intermediate 0.02 Neurobehavioral 

effects

1.8 ppm

(LOAELHEC)

90 NTP 1992

Chronic 0.001 Nasal lesions 0.11

(LOAELHEC)

90 Reuzel et al. 

1991

Oral exposure (mg/kg/day)

Acute Insufficient data for MRL derivation

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

aSee Appendix A for additional information. 

LOAELHEC = lowest-observed-adverse-effect level, human equivalent concentration
BROMOMETHANE 8

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-3. Summary of Sensitive Targets of Bromomethane – Inhalation

The respiratory tract and neurological system are the most sensitive target of bromomethane

inhalation exposure.
BROMOMETHANE 9

CHAPTER 2. HEALTH EFFECTS

2.1 INTRODUCTION 

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and 

other interested individuals and groups with an overall perspective on the toxicology of bromomethane. It 

contains descriptions and evaluations of toxicological studies and epidemiological investigations and 

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

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

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

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

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

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

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

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

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

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

literature. 

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

in Table 2-2 and Figure 2-3; available dermal data for bromomethane examined skin effects only.

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

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. 

LOAELs have been classified into "less serious" or "serious" effects. "Serious" effects are those that 

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

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

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

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

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be 
BROMOMETHANE 10

2. HEALTH EFFECTS

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

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

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

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

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

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

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

effects to human health.

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

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

Bromomethane exists as a gas at room temperature; therefore, inhalation is the predominant route of 

exposure. Oral exposure is unlikely, but it could occur due to small amounts of bromomethane in food or 

water. Given the importance of the inhalation route, most toxicity studies have examined effects of 

inhaled bromomethane, with animal studies conducted for acute, intermediate, and chronic exposure 

durations, as illustrated in Figure 2-1. In addition, some information is available from studies or case 

reports of exposed workers to bromomethane vapor, although reliable quantitative estimates of exposure 

have not been reported in these studies. Epidemiological studies conducted in bromomethane workers 

have been conducted, but worker populations were exposed to numerous chemicals. A few animal 

studies have examined the toxicity of oral exposure, and no information on humans exposed to oral 

bromomethane was identified.

Available studies in humans and animals provide evidence that adverse effects to the neurological system 

and respiratory tract are the most sensitive effects of inhalation exposure. Other adverse effects of 

inhalation exposure include developmental, reproductive, renal, hepatic, and cardiovascular effects; 

however, these effects occur at exposure levels that are near or above levels causing lethality. Available 

acute- and intermediate-duration oral studies show that the gastrointestinal system is the primary target of 

gavage exposure in rats; however, gastrointestinal effects were not observed in a study of dogs

administered bromomethane in a microencapsulated form in the diet. There is some question as to 

whether the forestomach effects in rats are due to the bolus administration of a very reactive chemical and 

whether gavage administration is an appropriate model for human exposure to bromomethane. Available 

chronic-duration oral studies did not identify targets for bromomethane. Dermal and ocular exposure to 
BROMOMETHANE 11

2. HEALTH EFFECTS

bromomethane vapor or liquid bromomethane can cause erythema and blisters to skin, and damage to 

eyes.

• Respiratory Endpoints: Studies in humans and animals provide evidence that inhalation of 

bromomethane produces damage to the respiratory tract. Acute exposure of humans has been 

reported to cause cough, edema, hemorrhagic lesions, and dyspnea. In animals, the most 

sensitive effect of inhaled bromomethane is damage to the olfactory epithelium.

• Neurological Endpoints: Neurological effects have been observed in humans and animals 

exposed to inhaled bromomethane. In humans, effects include headache, weakness, ataxia, 

tremors, paralysis, and seizures. Neurological effects in animals exhibit dose and duration 

dependence, with effects ranging from alterations in neurotransmitter levels to cerebral and 

cerebellar degeneration. The most sensitive effects of inhaled bromomethane in animals is 

decreased locomotor activity.

• Developmental Endpoints: In animal studies, increased incidences of gallbladder agenesis and

fused sternebrae, and decreased fetal weight have been observed in the offspring of rabbits

exposed to inhaled bromomethane. However, these effects have not been observed in inhalation 

studies in other species or in oral exposure studies in animals.

• Gastrointestinal Endpoints: Gavage administration of bromomethane to rats produces damage 

to the gastric epithelium in rats.

• Other Endpoints: Inhalation studies in laboratory animals have reported effects to the heart 

(myocardial fibrosis and degeneration and cardiomyopathy), liver (necrosis), kidneys (nephrosis),

and male reproductive system (decreased sperm density and testicular degeneration). However, 

these effects do not appear to be sensitive targets of bromomethane.
BROMOMETHANE 12

2. HEALTH EFFECTS

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

Most studies examined the potential respiratory and neurological effects of bromomethane

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

*Includes studies discussed in Chapter 2. A total of 109 studies (including those finding no effect) have examined toxicity; most studies examined multiple 

endpoints.
BROMOMETHANE 13

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

ACUTE EXPOSURE

1 Rat (CD) 

15 M, 15 F

6 hours 0, 30, 

100, 350

CS, BW, 

NX, GN, HP

Neuro 100 350 Decreases in motor activity and alterations in 

FOB performance

EPA 1993

2 Rat 

(Fischer344) 5 M, 

5 F

2 weeks

5 days/week

6 hours/day

0, 160 BC, HE, HP Resp 160 Minimal-mild olfactory epithelium 

degeneration; loss of olfactory sensory cells

Eustis et al. 1988

3 Rat (LongEvans) 

15–30 M

2 weeks

4 days/week

4 hours/day

0, 200 CS, HP, OF Resp 200 M Marked damage to olfactory epithelium

Neuro 200 M Impaired olfactory function

Hastings et al. 1991

4 Rat (NS) 

5 M

8 hours 

(1 exposure)

0, 16, 31, 

63, 125, 

250

BI Neuro 16 M 31 M Decreased brain neurotransmitters

Honma 1987

5 Rat (NS) 

5 M

8 hours 

(1 exposure)

0, 63, 

125, 188, 

250

CS, LE Death 302 M LC50

Neuro 63 M Impaired reflexes

Honma et al. 1985

6 Rat (NS) 

10 M

5 days

6 hours/day

0, 200 HP, OW Repro 200 M

Hurtt and Working 1988

7 Rat

(Fischer344) 

10 M

5 days

6 hours/day

0, 90, 

175, 250, 

325

HP, LE, CS Death 325 M 3/5 died

Resp 90 M 175 M 325 M Nasal olfactory epithelial degeneration; severe 

and extensive damage to nasal olfactory 

epithelium

Hepatic 250 M 325 M Focal hepatocellular coagulative necrosis

Renal 325 M

Endocr 90 M 175 M Microvacuolization of spongiocytes in adrenal 

cortex
BROMOMETHANE 14

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Neuro 175 M 250 M Ataxia, cerebellar degeneration

Repro 250 M 325 M Delayed spermiation

Hurtt et al. 1987

8 Rat (NS) 

5 M

1–5 days

6 hours/day

0, 90, 

200

HP, OF Resp 90 200 Loss of olfactory epithelium

Hurtt et al. 1988

9 Rat

40 NS

22 hours 

(1 exposure)

100–

13,000

NS Death 260

Irish et al. 1940

10 Rat (NS) 

5–10 M

4 hours 500–900 NS Death 767 M 25% lethality

Kato et al. 1986

11 Rat (LongEvans) M6 hours 0, 330 HP Neuro 330 M Degeneration of neurons in olfactory bulb

Schwob et al. 1999

12 Rat (LongEvans) M6 hours 0, 330 HP, OF Resp 330 M Severe damage to nasal olfactory epithelium

Neuro 330 M Impaired performance on test of olfactory 

function

Youngentob and Schwob 2006

13 Mouse

(NS) 6 M

1 hour 

(1 exposure)

0, 220–

1,530

OW, HP, 

CS

Death 980 M 1/6 died at 980 ppm; LC50=1,160 ppm

Neuro 560 M 700 M Hyperactivity

Alexeeff et al. 1985

14 Mouse 

(NS) 20 M, 

20 F

2 weeks

5 days/week

6 hours/day

0, 160 HP, BC, HE, 

BW, LE

Death 160 >50% lethality after eight and six exposures in 

males and females, respectively

Bd wt 160 26 and 18% decrease in terminal body 

weights in males and females, respectively

Resp 160 Congestion, hemorrhage, and thrombi in 

lungs, nasal olfactory epithelial degeneration 

and atrophy

Cardio 160 Cardiomyopathy
BROMOMETHANE 15

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Hemato 160 Decreased RBCs, hemoglobin, hematocrit, 

and increased WBCs; splenic hematopoiesis 

and red pulp cellular depletion

Renal 160 Nephrosis

Endocr 160 F Adrenal gland x-zone atrophy

Immuno 160 Thymus atrophy and splenic lymphoid 

depletion

Neuro 160 Overt signs of neurotoxicity; neuronal necrosis 

in the cerebral cortex and cerebellum

Repro 160 M Minimal testicular degeneration

Eustis et al. 1988

15 Mouse 

(B6C3F1) 

10 M, 10 F

2 weeks

5 days/week

6 hours/day

0, 12, 25, 

50, 100, 

200

CS, BW, 

HP, LE

Death 200 Deaths in 90% males and 60% females

NTP 1992

16 Dog 

(Beagle) 

2–3 M, 2–

3 F

2–4 days, 

7 hours/day

55, 156, 

268, 283

CS, BW, 

HE, OW, 

GN, HP

Bd wt 283 Weight loss

Resp 55 156 268 Labored breathing at 156 ppm; pulmonary 

edema/rales at 268 ppm

Neuro 55 156 268 Decreased activity, irregular gait post 

exposure at 156 ppm; extreme or severe 

delirium at 268 ppm

EPA 2001a

17 Rabbit

(NS) 26 F

13 days

GDs 7–19

6 hours/day

0, 20, 40, 

80

CS, TG, DX Neuro 40 F 80 F Ataxia, lethargy

Develop 40 F 80 F Gallbladder agenesis, fused sternebrae

Breslin et al. 1990

INTERMEDIATE EXPOSURE

18 Monkey

(NS) 4–

6 NS

6 months

5 days/week

8 hours/day

33, 66 CS Neuro 33 66 Paralysis

Irish et al. 1940
BROMOMETHANE 16

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

19 Rat

(SpragueDawley) 

NS

4 weeks

4 days/week

7.5 hours/day

0, 65 NX Neuro 65

Anger et al. 1981

20 Rat

(SpragueDawley) 

NS

36 weeks

5 days/week

6 hours/day

0, 55 NX Neuro 55

Anger et al. 1981

21 Rat (NS) 

25 M, 25 F

2 generations

5 days/week

6 hours/day

0, 3, 30, 

90

OW Repro 3

Develop 3 F

30 M

30 F

90 M

Reduced pup weights

Mayhew et al. 1986, as cited in EPA 1986a

22 Rat (CD) 

15 M, 15 F

6 hours/day, 

5 days/week, 

13 weeks

0, 30, 70, 

140

BW, CS, FI, 

GN, HP, LE, 

NX, OW

Death 140 M 2/15 deaths in males exposed to 140 ppm

Bd wt 30 F

70 M

70 F

140 M

23% decrease in terminal body weight gain 

along with 9% decrease in food consumption

in females, and 37% decrease in terminal 

body weight gain and 13% decrease in body 

weight in males

Resp 70 140 Minimal dysplasia of the olfactory epithelium

Neuro 30 F

70 M

70 F

140 M

Decreased locomotor activity in females at 

70 ppm and 10% decrease in absolute brain 

weight at 140 ppm; increased landing foot 

splay, ataxia, and histopathological changes 

in brain tissue (vacuolization, axonal 

degeneration, and necrosis in brain tissue) in 

males that developed convulsions or died

EPA 1994a
BROMOMETHANE 17

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

23 Rat 

(SpragueDawley) 

10 F

6 hours/day 

28 days

0, 20, 60, 

120

CS, BW, 

OW, GN, IX

Bd wt 60 F 120 F 12% decrease in terminal body weight

Immuno 120 F

EPA 2011

24 Rat (CD) 

24 F

6 hours/day, 

GDs 6–20 and 

LDs 5–20

0, 5, 25, 

50

CS, BW, 

GN, HP, LE, 

NX, OW

Bd wt 5 25 Decreased body weight gain (11–18%) for 

females on PNDs 7–17; 17% for males on 

PNDs 13–17

Neuro 50 No neurological effects in dams (FOB tests)

Develop 5 25 Decreased motor activity in pups on PND 21; 

effects were not statistically significant 

possibly due to high variability in the data

EPA 2019b

25 Rat

(Fischer344) 5 M, 

5 F

3–6 weeks

5 days/week

6 hours/day

0, 160 BW, HE, 

LE, HP

Death 160 >50% lethality in males after 14 exposures

Bd wt 160 Decreased terminal body weight, 32% in 

males and 18% in females

Resp 160 Olfactory epithelial degeneration and atrophy

Cardio 160 F Myocardial degeneration

Hemato 160 F Splenic hemosiderosis

Hepatic 160 Minimal necrosis

Renal 160

Endocr 160 Cytoplasmic vacuolization in adrenal glands

Immuno 160 Thymus necrosis and atrophy

Neuro 160 Overt signs of neurotoxicity; neuronal necrosis 

in cerebral cortex, thalamus, hippocampus

Repro 160 M Testicular degeneration

Eustis et al. 1988

26 Rat (NS) 

30 F

19 days

GDs 1–19

6 hours/day

20, 70 FX, MX, DX, 

TG

Repro 70 F

Develop 70 F

Hardin et al. 1981
BROMOMETHANE 18

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

27 Rat 5 M 3 weeks 

(continuous)

1, 5, 10 BI Neuro 5 M 10 M Decreased neurotransmitters

Honma et al. 1982

28 Rat (NS) 

12 M

3 weeks

5 days/week

4 hours/day

0, 200, 

300

CS, HP, 

BW, NX

Death 300 M

Neuro 200 M Altered behavior

Ikeda et al. 1980

29 Rat (NS) 

20–30 NS

6 months

5 days/week

8 hours/day

33, 66, 

100, 200

HP, CS Death 100 25/30 sacrificed due to morbidity

Resp 66 100 Mild congestion

Irish et al. 1940

30 Rat (NS) 

10–12 M

6 weeks

5 days/week

4 hours/day

150, 200, 

300, 400

HP, BC, 

BW, CS

Bd wt 150 M 200 M Decreased body weight (approximately 10% 

less than control)

Resp 300 M Small hemorrhagic lesions in the lung

Cardio 150 M Focal fibrosis

Hemato 400 M

Hepatic 300 M Fatty degeneration

Renal 400 M

Neuro 200 M 300 M Paralysis

Develop 300 M 400 M Testicular atrophy

Kato et al. 1986

31 Rat

(albino) 

40 F

6 weeks

5 day/week

7 hours/day

20, 70 DX, TG, OF, 

MX

Develop 70 F

NIOSH 1980

32 Rat (F344) 

8 M, 8 F

3 weeks

5 days/week

6 hours/day

0, 30, 60, 

120

CS, NX Neuro 30 60 Decreased startle amplitude

NTP 1992

33 Rat (F344) 

8 M, 8 F

9 weeks

5 days/week

6 hours/day

0, 30, 60, 

120

CS, NX Neuro 120

NTP 1992
BROMOMETHANE 19

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

34 Rat (F344) 

10 M, 10 F

13 weeks

5 days/week

6 hours/day

0, 30, 60, 

120

CS, BW, 

HP, HE, NX

Bd wt 60 120 12–13% decrease body weight gain

Resp 60 120 Olfactory epithelial dysplasia and cysts

Cardio 120

Hemato 30 F 60 F Decreased erythrocyte levels

Hepatic 120

Renal 120

Neuro 60 120 Altered performance in neurobehavioral tests

NTP 1992

35 Rat

(SpragueDawley) 

5 M

3 weeks

(continuous)

0, 1, 5, 

10

HP, BI Death 10 M

Sato et al. 1985

36 Mouse

10 M, 10 F

13 weeks 

5 days/week 

6 hours/day

0, 10, 20, 

40, 80, 

120

NS Death 120

Hemato 120

Neuro 40 80 120 Mild limb crossing at twitching at 80 ppm; 

severe limb crossing and twitching at 120 ppm

Repro 80 120 M Decreased sperm density

EPA 1988a

37 Mouse

(B6C3F1) 

50 M, 50 F

20 weeks

5 days/week

6 hours/day

100 BW, BC, CS Death 100 48% of males died

Bd wt 100 Severe body weight loss

Hemato 100

Neuro 100 Tremors, paralysis

NTP 1987

38 Mouse

(B6C3F1) 

8 M, 8 F

13 weeks

5 days/week

6 hours/day

0, 20, 40, 

80

CS, NX Neuro 40 80 Increased activity latency and hotplate latency

NTP 1992

39 Mouse

(B6C3F1) 

10 M, 10 F

13 weeks

5 days/week

6 hours/day

0, 10, 20, 

40, 80, 

120

CS, BW, 

HE, HP

Bd wt 80 M 120 M 12% decreased body weight gain

Resp 120

Cardio 120
BROMOMETHANE 20

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Hemato 20 M 40 M Increased RBCs, decreased mean cell 

volume and mean cell hemoglobin

Hepatic 120

Renal 120

Neuro 80 120 Severe curling and crossing of hindlimbs and 

twitching of forelimbs

NTP 1992

40 Mouse

(B6C3F1) 

10 M, 10 F

3 months

5 days/week

6 hours/day

0, 10, 30, 

33, 100

CS, BW, 

HE, HP, NX

Neuro 33 M 100 M Decreased locomotor activity; increased 

activity and hot plate latency

NTP 1992

41 Mouse

(B6C3F1) 

6–13 M, 

6–16 F

6 months

5 days/week

6 hours/day

0, 10, 33, 

100

CS, BW, 

HE, HP, NX

Neuro 10b Decreased locomotor activity

NTP 1992

42 Guinea pig

(NS) 11–

16 NS

6 months

5 days/week

8 hours/day

17, 33, 

66, 100, 

220

NS Death 100

Resp 100 220 Pulmonary congestion, edema, leukocyte 

infiltration, hemorrhage

Hepatic 220

Renal 220

Irish et al. 1940

43 Dog

(Beagle) 

4 M, 4 F

7 hours/day 

5 days/week 

5 or 7 weeks

0, 5.3, 

11.0/158, 

26.0, 

53.1, 

102.7c

CS, BW, FI, 

HE, BC, 

UR, OW, 

HP

Bd wt 102.7 M

11/158c

F

11/158c M Weight loss (24% less than controls)

Resp 102.7

Cardio 102.7

Gastro 102.7

Hemato 102.7

Musc/skel 102.7

Renal 102.7
BROMOMETHANE 21

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Hepatic 5.3 M

11/158c

F

11/158c M Increased urinary bilirubin

Dermal 102.7

Ocular 102.7

Endocr 102.7

Neuro 26 53.1 158 Ataxia, intention tremor, nystagmus, 

convulsions, minimal vacuoles in cerebellum

Repro 102.7

EPA 2001b

44 Dog 

(Beagle) 4 

M, 4 F

7 hours/day, 

5 days/week, 

6 weeks

0, 5.3, 

10, 20

BW, CS, FI, 

GN, HP, LE, 

NX, OW

Bd wt 20

Resp 20

Cardio 20

Gastro 20

Musc/skel 20

Hepatic 20

Renal 20

Endocr 20

Immuno 20

Neuro 10 F

5.3 M

20 F

10 M

Absence of proprioceptive placing

Repro 20

EPA 2002

45 Rabbit

(NS) 15 F

15 days

GDs 1–15

6 hours/day

20, 70 DX, TG Death 70 F

Develop 20 F No information reported on developmental 

effects at 70 ppm

Hardin et al. 1981

46 Rabbit

(NS) 42–

58 NS

6 months

5 days/week

8 hours/day

17, 33, 

66

HP, CS Death 66 14/42 died

Resp 17 33 Pneumonia

Cardio 66

Hepatic 66
BROMOMETHANE 22

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Renal 66

Neuro 17 33 Paralysis

Irish et al. 1940

47 Rabbit

(NS) 24 F

24 days 

GDs 1–24

7 hours/day

20, 70 TG, FX Repro 20 F

Develop 20 F

NIOSH 1980

48 Rabbit

(NS) 6 M

8 months

4 days/week

7.5 hours/day

27 NX Neuro 27 M No decrease in nerve conduction velocity

Russo et al. 1984

CHRONIC EXPOSURE

49 Rat

(F344/DuC

rj) 50 M, 

50 F

2 years

5 days/week

6 hours/day

0, 4, 20, 

100

CS, BW, HP Resp 4 20 Inflammation of nasal epithelium

Cardio 100

Hepatic 100

Renal 100

Neuro 100

Gotoh et al. 1994

50 Rat (NS) 

90 M, 90 F

128 weeks

5 days/week

6 hours/day

0, 3.1, 

29.6, 

89.1

HP, GN, 

BC, UR

Death 89.1 Early mortality

Bd wt 89.1

Resp 3.1d Very slight or slight basal cell hyperplasia of 

nasal olfactory epithelium

Cardio 29.6 89.1 Thrombi in heart, cartilaginous metaplasia, 

moderate-severe myocardial degeneration

Gastro 29.6 89.1 Hyperkeratosis of esophagus

Hemato 89.1

Renal 89.1

Reuzel et al. 1987, 1991
BROMOMETHANE 23

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

51 Mouse 

(Crj:BDF1) 

50 M, 50 F

2 years

5 days/week

6 hours/day

0, 4, 16, 

64

CS, BW, HP Resp 64

Cardio 64

Hepatic 64

Renal 64

Neuro 16 64 Cerebellum atrophy

Gotoh et al. 1994

53 Mouse

(B6C3F1) 

50 M, 50 F

103 weeks

5 days/week

6 hours/day

0, 10, 33 BC, CS Hemato 33

Neuro 10 33 Abnormal posture

NTP 1987

53 Mouse

(B6C3F1) 

86 M, 86 F

12–18 months 

5 days/week 

6 hours/day

0, 10, 33, 

100

CS, BW, 

HP, OF

Neuro 10 F Decreased locomotor activity

NTP 1992 (Animals in the 100 ppm group were exposed for 20 weeks and allowed to recover until the end of the study.)

54 Mouse

(B6C3F1) 

86 M, 86 F

2 years

5 days/week

6 hours/day

0, 10, 33, 

100

CS, BW, 

HP, OF

Death 100 Decreased survival

Bd wt 33 100 Decreased body weight gain

Resp 33 100 Olfactory epithelial necrosis and metaplasia

Cardio 33 100 Myocardial degeneration and cardiomyopathy

Musc/skel 33 100 Sternum dysplasia

Hepatic 33

Renal 33
BROMOMETHANE 24

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effects

Neuro 10 33 100 Overt signs of neurotoxicity at 33 ppm; 

cerebellar and cerebral degeneration at 

100 ppm

NTP 1992 (Animals in the 100 ppm group were exposed for 20 weeks and allowed to recover until the end of the study.)

aThe number corresponds to entries in Figure 2-2; differences in levels of health effects and cancer effects between male and females are not indicated in Figure 2-2. 

Where such differences exist, only the levels of effect for the most sensitive gender are presented.

bUsed to derive an intermediate-duration inhalation Minimal Risk Level (MRL) of 0.02 ppm based on a minimal LOAEL adjusted for intermittent exposure (LOAELadj), and 

converted to a human equivalent concentration (LOAELHEC) for extrarespiratory effects by multiplying the LOAELadj by the default blood:gas partition coefficient of 1. The 

LOAELHEC of 1.8 ppm was divided by a total uncertainty factor of 90 (3 for the use of a minimal LOAEL, 3 for extrapolation from animals to humans with dosimetric 

adjustments and 10 for human variability).

cThe following dosing protocol was used (all exposures were 7 hours/day, 5 days/week). Control (0 ppm): half of the group was exposed for 5 weeks and the remaining 

half was exposed for 2 additional weeks; 5.3 ppm: exposure for 7 weeks; 11/158 ppm: 5-week exposure to 11 ppm, followed by exposure to 158 ppm for 6 days followed 

by a 2-day recovery (no rationale was provided for the change in dose after 5 weeks of exposure); 26.0, 53.1, and 102.7 ppm: 5-week exposure. dUsed to derive a chronic-duration inhalation MRL of 0.001 ppm based on a minimal LOAEL of 3 ppm adjusted for intermittent exposure (LOAELadj), and converted to a 

human equivalent concentration (LOAELHEC) by multiplying the LOAELadj by the RGDR for extrathoracic respiratory effects. The LOAELHEC of 0.108 ppm was divided by a 

total uncertainty factor of 90 (3 for use of a minimal LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments and 10 for human variability).

Bd wt or BW = body weight; BC = blood chemistry; BI = biochemical changes; Cardio = cardiovascular; CEL = cancer effect level; CS = clinical signs; 

Develop = developmental; DX = developmental toxicity; Endocr = endocrine; F = female(s); FI = food intake; FOB = functional observational battery; FX = fetal toxicity; 

Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; HE = hematology; Hemato = hematological; HP = histopathology; Immuno = immunological; 

IX = immune function; LC50 = lethal concentration, 50% kill; LD = lactation day; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); 

Musc/skel = musculoskeletal; MX = maternal toxicity; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; NX = neurotoxicity; OF = organ 

function; OW = organ weight; PND = postnatal day; RBC = red blood cell; Repro = reproductive; Resp = respiratory; RGDR = regional gas dose ration; TG = teratogenicity; 

UR = urinalysis; WBC = white blood cell
BROMOMETHANE 25

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMOMETHANE 26

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMOMETHANE 27

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMOMETHANE 28

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMOMETHANE 29

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMOMETHANE 30

2. HEALTH EFFECTS

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

Chronic (≥365 days)
BROMOMETHANE 31

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effects

ACUTE EXPOSURE

1 Rat

(Crj:CD 

(SD)) 

24 F

GDs 6–15

(GO)

0, 3, 10, 30 DX Gastro 10 F 30 F Erosion and thickened wall of the nonglandular portion of the stomach

Develop 30 F

Kaneda et al. 1998

2 Rabbit

(Kbl:JW)

GDs 6–18

(GO)

0, 1, 3, 10 DX Develop 10 F

Kaneda et al. 1998

INTERMEDIATE EXPOSURE

3 Rat (NS) 

9–14 M

13–25 weeks

5 days/week

(G)

0, 50 HP Gastro 50 M Fibrosis, inflammation, hyperplasia

Boorman et al. 1986

4 Rat (NS) 

10 M, 

10 F

13 weeks

5 days/week

(G)

0, 0.4, 2, 10, 

50

GN, HP, BC Resp 50

Gastro 0.4 2 50 Hyperplasia and focal hyperemia at 

2 mg/kg/day; ulcers at 50 mg/kg/day

Hemato 10 50 Slight anemia

Hepatic 50

Neuro 50

Danse et al. 1984

5 Rat

(SpragueDawley) 

15 M, 

15 F

4 weeks ad 

libitum

(F)

0, 0.009, 

0.085, 

0.835, 7.98

BC, BW, 

CS, FI, GN, 

HE, HP, LE, 

OW

Bd wt 7.98 Decreased body weight gain was 

observed, but is not considered adverse 

because food consumption was also 

decreased

Resp 7.98

Cardio 7.98

Gastro 7.98

Hemato 7.98

Musc/skel 7.98

Hepatic 7.98

Renal 7.98
BROMOMETHANE 32

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effects

Endocr 7.98

Neuro 7.98

Repro 7.98

EPA 1996

CHRONIC EXPOSURE

6 Rat 

(SpragueDawley) 

50 M, 

50 F

24 months

(F)

M: 0.02, 

0.11, 2.20, 

11.1; F: 0, 

0.03, 0.15, 

2.92, 15.12

CS, BW, FI, 

HE, BC, 

UR, OW, 

GN, HP

Bd wt 11.1 M Decreased body weight gain was 

observed, but is not considered adverse 

because food consumption was also 

decreased

Resp 11.1 M

Cardio 11.1 M

Hemato 11.1 M

Musc/skel 11.1 M

Renal 11.1 M

Ocular 11.1 M

Endocr 11.1 M

EPA 1999

7 Dog

(Beagle) 

4 or 8 M, 

4 or 8 F

1 year ad 

libitum

(F)

M: 0, 0.06, 

0.15, 2.28; 

F: 0, 0.07, 

0.12, 0.27

BC, BW, FI, 

GN, HE, 

HP, OP, UR

Resp 0.27

Cardio 0.27

Gastro 0.27

Musc/skel 0.27

Hepatic 0.27

Dermal 0.27

Ocular 0.27

Endocr 0.27

Immuno 0.27
BROMOMETHANE 33

2. HEALTH EFFECTS

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

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses 

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effects

Neuro 0.27

Repro 0.27

Wilson et al. 2000

aThe number corresponds to entries in Figure 2-3; differences in levels of health effects and cancer effects between male and females are not indicated in Figure 2-3. 

Where such differences exist, only the levels of effect for the most sensitive gender are presented.

BC = blood chemistry; Bd wt or BW = body weight; Cardio = cardiovascular; CS = clinical signs; Develop = developmental; DX = developmental effects; 

Endocr = endocrine; (F) = feed; F = female(s); FI = food intake; (G) = gavage; (GO) = gavage in oil; Gastro = gastrointestinal; GD = gestation day; GN = gross necropsy; 

HE = hematology; Hemato = hematological; HP = histopathology; Immuno = immunological; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); 

Musc/skel = muscular/skeletal; Neuro = neurological; NOAEL = no-observed-adverse-effect level; NS = not specified; OP = ophthalmological; OW = organ weight; 

Repro = reproductive; Resp = respiratory; UR = urinalysis
BROMOMETHANE 34

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMOMETHANE 35

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMOMETHANE 36

2. HEALTH EFFECTS

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

Chronic (≥365 days)
BROMOMETHANE 37

2. HEALTH EFFECTS

2.2 DEATH

There are many reports of humans who have died following acute inhalation exposure to bromomethane. 

Most cases involved accidental exposures associated with manufacturing or packaging operations, use of 

or leaking fire extinguishers containing bromomethane, or fumigation activities (Alexeeff and Kilgore 

1983). Death is not immediate, but usually occurs within 1–2 days of exposure (Langard et al. 1996; 

Marraccini et al. 1983; Prain and Smith 1952); deaths have also been reported a number of days after the 

exposure (Behrens and Dukes 1986). The cause of death is not certain, but is probably due to 

neurological and lung injury. Fatal exposure levels in humans are usually not known, but limited data 

suggest that the value depends, in part, on exposure duration. No studies were located regarding lethality 

in humans after oral exposure to bromomethane. 

Inhalation studies in animals indicate that acute inhalation exposures to levels of 160–980 ppm may be 

lethal (Alexeeff et al. 1985; Eustis et al. 1988; Honma et al. 1985; Hurtt et al. 1987; Irish et al. 1940; Kato 

et al. 1986; NTP 1992). Several studies reveal that there is an extremely narrow margin between lethal 

and nonlethal exposures. For example, Kato et al. (1986) found no deaths in rats exposed to 700 ppm for 

4 hours, but 100% lethality in animals exposed to 800 ppm, with 25% lethality at 767 ppm. Similarly, 

Irish et al. (1940) found 100% survival in rats exposed to 100 ppm for 24 hours and 100% lethality at 

220 ppm. In repeated inhalation exposure studies, no deaths were observed in rats exposed to 120 ppm 

bromomethane for 13 weeks (NTP 1992), but 50% mortality was observed following 3 weeks of exposure 

to 160 ppm (Eustis et al. 1988). Species and sex differences in the lethality of bromomethane have been 

found (Eustis et al. 1988). Deaths were observed in 50% of the male mice, female mice, and male rats 

after 8, 6, or 14 exposures to 160 ppm, respectively; no deaths were observed in similarly exposed female 

rats. Intermediate-duration inhalation exposures of animals can lead to death after exposure to levels at 

concentrations of 70–300 ppm in rats, mice, and/or rabbits (EPA 1988a; Eustis et al. 1988; Hardin et al. 

1981; Ikeda et al. 1980; Irish et al. 1940; NTP 1987, 1992; Reuzel et al. 1987; Sato et al. 1985).

No deaths or alterations in survival were observed in rats chronically exposed to 15.12 mg/kg/day 

microencapsulated bromomethane in the diet (EPA 1999) or in dogs exposed to bromomethane in feed at 

doses up to 0.28 mg/kg/day for 1 year (Wilson et al. 2000). 
BROMOMETHANE 38

2. HEALTH EFFECTS

2.3 BODY WEIGHT

Several inhalation studies in animals indicate that exposure to bromomethane decreases body weight gain

or produces weight loss. In acute exposure studies, decreases in body weight gain were observed in mice 

exposed to 160 ppm for 2 weeks (Eustis et al. 1988) and 13% weight loss was observed in dogs exposed 

to 283 ppm for 2 days associated with extreme toxicity, emesis, heavy salivation, and dehydration (EPA 

2001b). No alterations in body weight gain were observed in mice exposed to 100 ppm for 2 weeks (NTP 

1992). In intermediate-duration studies, body weight decreases were observed in rats and mice. In rats, 

terminal body weights were decreased in by 37% in males exposed to 140 ppm and by 23% in females 

exposed to 70 ppm for 13 weeks (EPA 1994a). Small decreases in body weight gain and/or terminal body 

weights were observed in rats exposed to 200 ppm for 3 or 6 weeks (Ikeda et al. 1980; Kato et al. 1986), 

in rats exposed to 120 ppm for 4 weeks (EPA 2011), in rats and mice exposed to 120 ppm for 13 weeks 

(NTP 1992), and in mice exposed to 100 ppm for 20 weeks and allowed to recover for over 80 weeks 

(NTP 1992). In contrast, weight loss was noted in mice exposed to 100 ppm for 13 weeks (NTP 1992),

100 ppm for 20 weeks (NTP 1987), and in dogs exposed to 102.7 ppm for 5 weeks (EPA 2001b); 

additionally, a 32% decrease in body weight gain was observed in rats exposed to 160 ppm for 3–6 weeks 

(Eustis et al. 1988). A decrease in maternal body weight gain was observed in rabbits exposed to 80 ppm 

on gestation days 7–19; this concentration was also associated with severe neurological effects and likely 

a decrease in food intake (Breslin et al. 1990); however, no decreases in maternal weight gain were 

observed when the experiment was repeated. In chronic-duration studies, decreases in body weight gain 

were observed in mice exposed to 100 ppm for 2 years (NTP 1992), but were not observed in rats exposed 

to concentrations as high as 89.1 ppm for 128 weeks (Reuzel et al. 1987, 1991). 

Dietary exposure studies in rats observed decreased body weight gain; however, because these decreases 

were accompanied by decreased food consumption, they are not considered adverse. In a 4-week study of 

rats exposed to 7.98 mg/kg/day in the diet as microencapsulated bromomethane, mean body weight gain 

was decreased by 14% in males during the first week of exposure and by 33% in females during weeks 1–

2, but not during other weeks (EPA 1996). These changes were accompanied by decreased food intake.

Decreases in body weight gain were observed in the first 12–18 months of exposure to 11.1 and 

15.12 mg/kg/day microencapsulated bromomethane in male and female rats, respectively, in the diet for 

2 years; however, decreased food consumption was also decreased during that time (EPA 1999). No 

effects on body weight were observed in male or female beagle dogs given bromomethane in the diet for 

52 weeks at doses up to 0.28 mg/kg/day (Wilson et al. 2000). 
BROMOMETHANE 39

2. HEALTH EFFECTS

2.4 RESPIRATORY

Observations in humans exposed to inhaled bromomethane indicate that the respiratory tract, particularly 

the lungs, is a target of bromomethane toxicity. The human data do not allow for a concentrationresponse assessment since most reports did not include exposure levels; however, it can be assumed that 

the severity of the lesions increased with exposure concentration. Lung edema is the most common 

effect, and is often accompanied by focal hemorrhagic lesions (Greenberg 1971; Marraccini et al. 1983; 

Miller 1943; Prain and Smith 1952; Wyers 1945). This injury can severely impair respiratory function 

and lead to hypoxia, cyanosis, and complete respiratory failure (Greenberg 1971; Hine 1969; O'Neal 

1987). There is also evidence that bromomethane is a respiratory irritant based on reports of sore throat 

and a burning sensation in the nose and throat (Bishop 1992; Hine 1969); this likely occurs at lower 

concentrations than the severe lung effects. A study of bromomethane applicators (69% did not use 

protective equipment) reported a 36% incidence of dyspnea, cough, and phlegm (Akca et al. 2009). 

Inhalation studies in laboratory animals suggested that the nasal cavity, particularly the olfactory 

epithelium, is the most sensitive target in the respiratory tract. In acute exposure studies, degeneration of 

the olfactory epithelium was observed in rats exposed to ≥160 ppm (Eustis et al. 1988; Hastings et al. 

1991; Hurtt et al. 1987, 1988; Reed et al. 1995; Youngentob and Schwob 2006) and in mice at 160 ppm 

(Eustis et al. 1988). These studies demonstrate that the severity and extent of the damage increased with 

concentration. A 5-day exposure to 175 ppm resulted in moderate olfactory epithelium degeneration in 

50–80% of the tissue and exposure to 325 or 330 ppm resulted in severe degeneration in 80–95% of the 

olfactory epithelium (Hurtt et al. 1987; Youngentob and Schwob 2006). Although the severity of the 

olfactory epithelial degeneration appears to decrease with exposure duration in acute studies, there is 

some evidence of a shift in the type of lesions. Moderate to marked olfactory epithelium degeneration 

was observed after a 3-day exposure to 160 ppm. After 10 days, the severity of the degeneration was 

scored as minimal to mild; however, there was a loss of olfactory sensory cells and respiratory epithelial 

metaplasia (Eustis et al. 1988). Several studies demonstrated that the marked damage to the olfactory 

epithelium can occur in mice and rats after a single 4–8-hour exposure to ≥180 ppm bromomethane 

(Hastings et al. 1991; Holbrook et al. 2014; Huard et al. 1998; Hurtt et al. 1988; Reed et al. 1995). With 

continued exposure, there is evidence of regeneration of the olfactory epithelium after 3 or 4 days of 

exposure (Hastings et al. 1991; Hurtt et al. 1988) and recovery 10 weeks post-exposure (Hastings et al. 

1991; Hurtt et al. 1988). Upon examination of the type of olfactory epithelial cells damaged by 

bromomethane, Huard et al. (1998) found that neurons and sustentacular cells were completely destroyed 

by exposure to 330 ppm bromomethane for 6 hours; most of the Bowman’s ducts were also eliminated. 
BROMOMETHANE 40

2. HEALTH EFFECTS

However, three proliferative cell populations—Bowman’s duct/gland cells, horizontal basal cells, and 

globose basal cells—were spared and could regenerate the olfactory epithelium. 

Intermediate- and chronic-duration inhalation studies suggest that rats may be more sensitive to the nasal 

effects of bromomethane than mice. A 13-week exposure to 120 ppm resulted in increases in the 

incidence of olfactory epithelium dysplasia and cysts in rats, but no nasal effects in mice (NTP 1992). 

Dysplasia of the olfactory epithelium due to local irritation was also observed in male and female rats 

exposed to 140 ppm bromomethane for 13 weeks (EPA 1994a). In rats, a 29-month exposure resulted in

basal cell hyperplasia in the olfactory epithelium (Reuzel et al. 1987, 1991); the severity of the lesion was 

scored as very slight at 3.1 ppm, slight at 29.6 ppm, and slight to moderate at 89.1 ppm. This study did 

not find nasal lesions in rats exposed for 12 or 24 months. Another study (Gotoh et al. 1994) reported no 

nasal lesions in rats exposed to 4 ppm for 2 years, inflammation in males at 20 ppm and in females at 

100 ppm, and necrosis and metaplasia of the olfactory epithelium in males at 100 ppm. In contrast, no 

nasal effects were observed in mice exposed to 33 or 100 ppm for 2 years (Gotoh et al. 1994; NTP 1992). 

In the NTP (1992) study, olfactory epithelium necrosis (males only) and metaplasia were observed in 

mice exposed to 100 ppm for 20 weeks and allowed to recover for the remainder of the 2-year study (NTP 

1992). Degeneration of the olfactory epithelium was also observed in dogs exposed to 11.0 ppm for 

4 weeks followed by 158 ppm for 6 days, followed by a 2-day recovery (EPA 2001b); no lesions were 

observed in dogs exposed to 102.7 ppm for 4 weeks (EPA 2001b). In addition to the lesions observed in 

the olfactory epithelium, several studies have also reported focal or multifocal loss of olfactory sensory 

cells (Eustis et al. 1988; Hurtt et al. 1988) and a loss of olfactory function. 

Labored breathing was observed in dogs exposed to 156 ppm for 4 days and pulmonary edema and rales 

were observed at 268 ppm (EPA 2001a). Lung congestion, hemorrhage, and thrombi were observed in 

mice acutely exposed to a 160 ppm bromomethane (Eustis et al. 1988); this concentration also resulted in 

deaths. Intermediate-duration exposure in rats resulted in pulmonary hemorrhage at 10 ppm (Sato et al. 

1985) and hemorrhagic lesions at 400 ppm (Kato et al. 1986). Lung congestion was noted in rats exposed 

to 100 ppm and rabbits exposed to 66 ppm (Irish et al. 1940); however, the study provided limited 

incidence data. However, other intermediate-duration studies in rats and mice did not find lung effects at 

exposure levels as high as 120 ppm (NTP 1992) and chronic exposure studies in rats and mice have not 

reported lung effects at 89.1–100 or 33–64 ppm, respectively (Gotoh et al. 1994; NTP 1992; Reuzel et al. 

1987).
BROMOMETHANE 41

2. HEALTH EFFECTS

Oral exposure of animals to bromomethane does not appear to produce adverse effects in the respiratory 

tract. In animals, no histological evidence of lung injury was detected in rats exposed to oral doses of 

50 mg/kg/day for 13 weeks (Danse et al. 1984). Slight atelectasis and interstitial pneumonia were 

observed in some animals exposed to oral doses of 10 or 50 mg/kg/day, but this was judged to be due to 

inadvertent inhalation exposure that occurred during oral dosing (Danse et al. 1984). In a 2-year study in 

rats (EPA 1999) and 1-year study in beagle dogs (Wilson et al. 2000), doses up to 11.1 in males and 

15.12 in females (equivalent to 0.28 mg/kg/day bromomethane), respectively, did not result in alterations 

in lung weight or histopathology of nasopharyngeal tissues, trachea, or lung. Similarly, a dose of 

7.98 mg/kg/day for 4 weeks in rats resulted in no exposure-associated findings (EPA 1996).

2.5 CARDIOVASCULAR

Some cardiovascular effects, such as high blood pressure and minute myocardial hemorrhages, have been 

reported in cases of individuals exposed to inhaled bromomethane (Bishop 1992; O’Neal 1987; Prockop 

and Smith 1986; Viner 1945); the effects have not been consistently found and it is not known if these 

effects are related to the bromomethane exposure or were pre-existing conditions. However, the findings 

are supported by several studies in mice and rats that indicate that the heart is susceptible to injury. 

Effects that have been reported at exposure levels of 89.1–150 ppm include fibrosis (Kato et al. 1986), 

myocardial degeneration (Eustis et al. 1988; NTP 1992; Reuzel et al. 1987, 1991), cardiomyopathy (NTP 

1992), and cardiac thrombi (Reuzel et al. 1987). No histological alterations were observed in the hearts of 

dogs exposed to 102.7 ppm for 5 weeks (EPA 2001b).

Neither heart weight nor histopathology of heart or abdominal aorta were altered by treatment of beagle 

dogs with bromomethane in feed at doses up to 0.28 mg/kg/day for 1 year (Wilson et al. 2000), or rats 

exposed to 7.98 mg/kg/day for 4 weeks (EPA 1996) or male and female rats exposed to doses of 11.1 and 

15.12 mg/kg/day, respectively, as microencapsulated bromomethane in the diet for 2 years (EPA 1999).

2.6 GASTROINTESTINAL

Several case reports have noted nausea, vomiting, and/or diarrhea in individuals acutely exposed to 

inhaled bromomethane (Deschamps and Turpin 1996; Herzstein and Cullen 1990; Hustinx et al. 1993; 

Kulkarni et al. 2015; Langard et al. 1996; O’Malley et al. 2011; Yamano et al. 2001); it is not known if 

the nausea and vomiting were neurological effects or due to gastrointestinal irritation. 
BROMOMETHANE 42

2. HEALTH EFFECTS

In animals, exposure to inhaled bromomethane typically is not associated with gastrointestinal effects; 

however, oral exposure studies show that bromomethane produces damage to the gastrointestinal tract. 

Gastrointestinal effects have not been noted in most inhalation studies in animals, but Alexeeff et al. 

(1985) reported an unusual increase in hemorrhagic lesions of the colon in mice exposed to high, lethal 

concentrations (1,490 ppm) of bromomethane, Hurtt et al. (1987) reported diarrhea in rats exposed to 

250 ppm, and Reuzel et al. (1987, 1991) noted an increased incidence of hyperkeratosis of the esophagus 

and stomach in rats exposed to 89.1 ppm. This effect is probably mediated by transport of bromomethane 

from the lungs to the throat by mucociliary clearance (Reuzel et al. 1987).

Studies in gavaged animals show that repeated administration of bromomethane to rats can result in 

irritation and hyperplasia of the epithelium in the forestomach (Boorman et al. 1986; Danse et al. 1984; 

Kaneda et al. 1998). In rats exposed to 30 mg/kg/day bromomethane in corn oil by gavage on days 6–

15 of gestation, erosion and thickening of the wall of the non-glandular stomach or adhesion of the 

stomach to the spleen, liver, or diaphragm were observed (Kaneda et al. 1998). These effects were not 

observed in rabbits similarly exposed at doses up to 10 mg/kg/day (Kaneda et al. 1998). Adhesion of the 

stomach to the liver, spleen, or diaphragm and frank ulceration of the stomach were also observed in rats 

exposed to 50 mg/kg/day bromomethane by gavage for 5 days/week for 13–25 weeks (Boorman et al. 

1986). Microscopic evaluation showed inflammation, fibrosis, acanthosis, and pseudoepitheliomatous 

hyperplasia of the forestomach. Following a 4-week recovery period in rats exposed for 13 weeks, 

epithelial hyperplasia had regressed, although fibrotic lesions or adhesions, which developed during

exposure, remained. As compared to rats exposed for 13 weeks, the severity and incidence of hyperplasia 

was increased in rats exposed for 25 weeks; the incidence of fibrosis was increased, although the severity 

was decreased.

Dose-dependent gastrointestinal lesions were observed in rats administered bromomethane at doses of 2, 

10, and 50 mg/kg/day by gavage for 90 days (Danse et al. 1984). In the 2 mg/kg/day group, mild focal 

hyperemia of the forestomach was observed. In rats administered 10 and 50 mg/kg/day, hyperkeratosis 

and decreased surface area due to adhesions were observed, with severity increasing with dose. At 

50 mg/kg/day, frank ulcerations were observed in the forestomach. Lesions appeared to be the result of a 

direct irritant effect of bromomethane on the epithelium. Boorman et al. (1986) conducted a response 

study with the observations that epithelial hyperplasia increased with exposure duration from 13 to 

25 weeks, but regressed when exposure through 13 weeks was stopped, although fibrotic lesions or 

adhesions that developed during exposure remained. The possible relationship between this hyperplastic 

response and cancer of the forestomach is discussed in Section 2.18. In contrast, dietary exposure to 
BROMOMETHANE 43

2. HEALTH EFFECTS

bromomethane did not result in gastrointestinal lesions in beagle dogs exposed to 0.28 mg/kg/day 

bromomethane for 1 year (Wilson et al. 2000) or rats exposed to 7.98 mg/kg/day for 4 weeks (EPA 1996) 

or male and female rats exposed to up to 11.1 and 15.12 mg/kg/day microencapsulated bromomethane, 

respectively, for 2 years (EPA 1999).

2.7 HEMATOLOGICAL

Hematological effects have not been observed in humans exposed to inhaled bromomethane (Johnstone 

1945; Kantarjian and Shaheen 1963; Longley and Jones 1965; O'Neal 1987; Viner 1945; Wyers 1945). 

Inconsistent results have been observed regarding hematological effects in animals following inhalation 

exposure. Decreased erythrocyte, hematocrit, and hemoglobin levels and increased leukocyte levels were 

observed in female mice exposed to 160 ppm for 8 days; no effects were observed in males (Eustis et al. 

1988). A 13-week study found decreases in erythrocyte levels in female rats exposed to 60 or 120 ppm 

and decreases in hematocrit and hemoglobin levels in female rats exposed to 120 ppm; however, only 

minimal decreases were observed (approximately 5%) (NTP 1992). A related effect of splenic 

hemosiderosis was observed in rats exposed to 160 ppm bromomethane for 6 weeks (Eustis et al. 1988). 

In contrast, a 13-week mouse study found increases in erythrocyte levels and decreases in mean cell 

volume and mean cell hemoglobin in males exposed to ≥40 ppm and increases in hemoglobin levels in 

males at 120 ppm (NTP 1992). The biological significance of these findings is not clear. Other studies 

have not found significant hematological effects (EPA 1988a, 1994; Kato et al. 1986; Reuzel et al. 1987, 

1991). 

Oral exposure of animals does not appear to produce adverse effects to the hematological system. Slight 

anemia was observed in rats exposed to doses of 50 mg/kg/day for 13 weeks, but this was judged to be 

secondary to the pronounced lesions of the forestomach (Danse et al. 1984). No evidence of other 

hematological effects was detected at doses up to 10 mg/kg/day. Bromomethane in feed at doses up to 

0.28 mg/kg/day for 1 year in dogs, or 7.98 mg/kg/day for 4 weeks in rats or 11.1 and 15.12 mg/kg/day in 

male and female rats, respectively, for 2 years did not result in effects on hematological alterations in 

dogs or rats, respectively (EPA 1996, 1999; Wilson et al. 2000).

2.8 MUSCULOSKELETAL

There are limited data on the toxicity of bromomethane to the musculoskeletal system. NTP (1992) 

reported a dose-related increase in the incidence of dysplasia in the sternum of mice exposed to inhaled 
BROMOMETHANE 44

2. HEALTH EFFECTS

bromomethane at a concentration of 100 ppm for 20 weeks. Bromomethane in feed at doses up to 

0.28 mg/kg/day for 1 year (Wilson et al. 2000) or 7.98 mg/kg/day for 4 weeks (EPA 1996) did not result 

in microscopic lesions in bone or skeletal muscle.

2.9 HEPATIC

Case reports of humans exposed to bromomethane vapors indicated that the liver may become swollen 

and tender in some cases (Hine 1969); more severe liver effects, including congestion, fatty degeneration, 

or atrophy, have been reported in lethal cases (Miller 1943; O’Neal 1987; Prain and Smith 1952). In 

other cases, no significant liver injury was detected (Greenberg 1971; Hine 1969; Marraccini et al. 1983). 

Similar results have been reported in rats and mice exposed to inhaled bromomethane, with mild signs of 

liver injury (edema, focal hemorrhages, minimal necrosis) being noted in some studies at levels of 160–

1,200 ppm (Alexeeff et al. 1985; Eustis et al. 1988; Hurtt et al. 1987; Irish et al. 1940; Kato et al. 1986); 

no hepatocellular lesions were observed at 66 ppm (Irish et al. 1940). No liver effects were observed in 

rat and mouse chronic exposure studies at concentrations as high as 120 ppm (Gotoh et al. 1994; NTP 

1992; Reuzel et al. 1987, 1991) or in dogs exposed to ≤102.7 ppm for 5 weeks (EPA 2001b).

In animals exposed to oral bromomethane, histological signs of liver damage were not detected in rats 

given doses up to 50 mg/kg/day for 90 days (Danse et al. 1984) or to 7.98 mg/kg/day for 4 weeks (EPA 

1996). Exposure of beagle dogs to 0.28 mg/kg/day bromomethane in feed for 1 year or of male and 

female rats to 11.1 and15.12 mg/kg/day microencapsulated bromomethane in feed, respectively, for 

2 years did not result in treatment-related serum chemistry changes or effects on liver weight or 

histopathology (EPA 1999; Wilson et al. 2000).

2.10 RENAL

Adverse renal effects are often reported in humans exposed to high levels of bromomethane vapor. 

Common effects noted in case reports include congestion, anuria or oliguria, proteinuria, and histological 

alterations in the kidney (Hine 1969; Marraccini et al. 1983; O'Neal 1987; Prain and Smith 1952; Viner 

1945; Wyers 1945). However, there are many cases where renal effects were minimal or absent (Hine 

1969; Johnstone 1945; Longley and Jones 1965). Although two laboratory animal studies reported 

kidney effects—enlarged and paled kidney in mice exposed to 900 ppm for 1 hour (Alexeeff et al. 1985); 

and nephrosis in mice exposed to 160 ppm for 2 weeks (Eustis et al. 1988) and minimal nephrosis in rats 

exposed for 3–6 weeks (Eustis et al. 1988), most intermediate- and chronic-duration studies in rats and 
BROMOMETHANE 45

2. HEALTH EFFECTS

mice did not find renal effects (EPA 2001b; Gotoh et al. 1994; NTP 1992). A developmental study in 

rats, with inhalation exposure of dams for 6 weeks, showed a slightly increased incidence of interstitial 

nephritis at 70 ppm, the highest concentration tested (Sikov et al. 1981 [MRID00102990], as cited in EPA 

2018a). However, the incidence did not reach statistical significance and EPA (2018a) did not consider 

the incidence during gestation to be “significant enough to determine a LOAEL,” but it might be a 

threshold effect. Renal effects reported by Sikov et al. (1981 [MRID00102990], as cited in EPA 2018a) 

are not included in Table 2-1 (Levels of Significant Exposure to Bromomethane – Inhalation) because the 

primary study report was not available for review. 

Decreased absolute, but not relative, kidney weights were observed in beagle dogs given bromomethane 

in feed at doses up to 0.28 mg/kg/day for 52 weeks, but there were no treatment-related effects on serum 

chemistry, urinalysis, or kidney histopathology (Wilson et al. 2000). No renal effects were observed in 

rats exposed to 7.98 mg/kg/day for 4 weeks (EPA 1996) or male and female rats exposed to 11.1 and 

15.12 mg/kg/day, respectively, in the diet for 2 years (EPA 1999).

2.11 DERMAL

Dermal effects are associated with direct exposure of skin to bromomethane vapor or liquid, but not with 

oral exposure. Bromomethane vapor is irritating to the skin, and humans who are exposed to 

bromomethane in air may experience signs of skin irritation. Direct dermal contact with bromomethane 

can lead to severe injury to the skin. Symptoms usually do not appear immediately, but develop a few 

hours after exposure termination. Early signs typically include a burning, tingling, or itching sensation, 

with erythema, edema, numbness, pain, and large blisters that resemble second-degree burns developing 

somewhat later (Butler et al. 1945; Hezemans-Boer et al. 1988; Horiuchi et al. 2008; Watrous 1942; 

Wyers 1945). Injury is usually mild on exposed skin areas where rapid evaporation can occur and is more 

severe in moist or covered regions where evaporation is retarded and the liquid can remain on the skin 

longer (Watrous 1942; Zwaveling et al. 1987). Effects generally begin to subside within 5–10 days after 

exposure termination (Watrous 1942), and recovery is usually complete within about 1 month postexposure (Butler et al. 1945; Zwaveling et al. 1987).

The exposure levels leading to dermal effects of this sort are rarely known. Most cases involve people 

doused with liquid bromomethane (Longley and Jones 1965; Watrous 1942) or exposed to very high 

vapor levels (Hezemans-Boer et al. 1988; Zwaveling et al. 1987). Numerous case reports of humans 

exposed to lower levels of airborne bromomethane did not include descriptions of dermal effects, even 
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though the level of inhalation exposure caused profound or even fatal neurological or respiratory effects 

(e.g., Greenberg 1971; Hine 1969; Marraccini et al. 1983).

In rats, a 30-second exposure to liquefied bromomethane applied to a 12 cm2 area of shaved skin resulted 

in slight edema and small ecchymoses (Yamamoto et al. 2000). A 1–5-minute exposure resulted in 

necrotic changes 12 hours postexposure. Histological examination of the skin showed a necrotized 

epidermis 6–72 hours postexposure and complete re-epithelialization 1 week postexposure. In all layers 

of the dermis, degeneration of the vascular wall, which progressed to necrosis and hemorrhaging, was 

observed. The severity of the epidermal and dermal damage was exposure duration-related.

No studies were located regarding dermal or ocular effects following systemic absorption of 

bromomethane in animals or humans. No microscopic lesions were noted in the skin of beagle dogs 

exposed to bromomethane in the diet (up to 0.28 mg/kg/day) for 52 weeks (Wilson et al. 2000).

2.12 OCULAR

Bromomethane vapor is irritating to the eyes, and humans who are exposed to bromomethane in air may

experience conjunctivitis, erythema, rashes, edema of the eyelids, exfoliation, lesions, or even blisters 

(Langard et al. 1996; O'Neal 1987; Prain and Smith 1952; Wyers 1945). However, eye irritation has not 

been observed in animals exposed to bromomethane vapor or dietary bromomethane. Ophthalmoscopic 

examination did not reveal alterations in dogs exposed to 102.7 ppm bromomethane for 5 weeks (EPA 

2001b). In beagle dogs given bromomethane in feed at doses up to 0.28 mg/kg/day for 52 weeks, there 

were no effects on ophthalmology or histopathology of eyes (with optic nerves) (Wilson et al. 2000). No 

alterations were noted in the ophthalmoscopic examination in male and female rats exposed to up to 

11.1 and 15.12 mg/kg/day, respectively, in the diet for 2 years (EPA 1999).

2.13 ENDOCRINE

A cohort study evaluated potential associations between occupational pesticide exposure and subclinical 

hypothyroidism in 679 male pesticide workers residing in Iowa and North Carolina (Lerro et al. 2018). 

Exposures to pesticides were self-reported, with exposures reported as “intensity-weighted days;”

however, no quantitative estimates of exposure were reported. It is likely that workers were exposed to 

multiple chemicals, although this was not explicitly stated in the study report; results were not adjusted 

for multiple exposures. The risk of subclinical hypothyroidism was not increased in bromomethane 
BROMOMETHANE 47

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workers, with an odds ratio (OR) of 0.45 (95% confidence interval [CI] 0.11, 1.81) for the highest 

intensity exposure. No additional information regarding potential endocrine effects of bromomethane in 

humans was identified.

In rats, histological alterations consisting of microvacuolation of spongiocytes were noted in the adrenal 

cortex following exposure to 175 or 250 ppm bromomethane for 4–5 days (Hurtt et al. 1987); at 350 ppm, 

lipid droplet accumulation in the parenchymal cells and intrasinusoidal accumulation of erythrocytes were 

observed. Minimal to slight intracytoplasmic vacuoles were also observed in the zona fasciculata of the 

adrenal glands in dogs exposed to 11.0 ppm for 5 weeks and 159 ppm for 5 days, but not in dogs exposed 

to 102.7 ppm for 5 weeks (EPA 2001b).

Exposure of rats to bromomethane in feed at 7.98 mg/kg/day for 4 weeks (EPA 1996) or of beagle dogs to 

0.28 mg/kg/day bromomethane in feed for 1 year did not result in endocrine changes (as measured by 

weight of thyroid and parathyroid and histopathology of thyroid, parathyroid, adrenal glands, pancreas, 

and pituitary gland) (EPA 1996; Wilson et al. 2000).

2.14 IMMUNOLOGICAL

No studies were located regarding immunological or lymphoreticular effects in humans after inhalation or 

oral exposure to bromomethane. Data from animal studies are limited to inhalation exposure. Eustis et 

al. (1988) reported thymus necrosis and atrophy in rats and mice exposed to 160 ppm for 6 or 2 weeks, 

respectively; splenic lymphoid depletion was also observed in mice. In a study submitted to EPA, no 

alterations in sheep red blood cell antibody formation were observed in rats exposed to concentrations as 

high as 120 ppm for 28 days (EPA 2011).

2.15 NEUROLOGICAL

Adverse effects on the neurological system occur following inhalation exposure of humans and animals; 

however, there is no evidence of neurological toxicity following oral exposure of animals. Inhalation 

exposure to bromomethane frequently leads to a spectrum of neurological effects in humans. Initial 

symptoms typically include headache, dizziness, nausea/vomiting, confusion, weakness, numbness, 

slurred speech, and visual disturbances (Akca et al. 2009; Anger et al. 1986; Deschamps and Turpin 1996; 

Herzstein and Cullen 1990; Hine 1969; Hustinx et al. 1993; Johnstone 1945; Kantarjian and Shaheen 

1963; Kulkarni et al. 2015; Marraccini et al. 1983; O’Neal 1987; Prain and Smith 1952; Rathus and 
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Landy 1961; Watrous 1942). Other effects that can develop include slurred speech, lack of inhibition, 

agitation, and confusion (Bishop 1992; Greenberg 1971; Hustinx et al. 1993; Johnstone 1945; Kulkarni et 

al. 2015; O’Neal 1987; Prain and Smith 1952). In severe cases, these effects may progress to ataxia, 

tremor, seizures, and coma (Balagopal et al. 2011; Behrens and Dukes 1986; Bishop 1992; de Souza et al. 

2013; Deschamps and Turpin 1996; Geyer et al. 2005; Greenberg 1971; Hustinx et al. 1993; Johnstone 

1945; Kulkarni et al. 2015; Longley and Jones 1965; Marraccini et al. 1983; O’Neal 1987; Prain and 

Smith 1952; Prockop and Smith 1986; Rathus and Landy 1961; Viner 1945; Wyers 1945; Yamano and 

Nakadate 2006; Yamano et al. 2001). In most cases of acute exposure, the effects did not occur 

immediately, but developed after a lag of several hours (Clarke et al. 1945); some cases have reported 

effects developing several weeks after exposure (Herzstein and Cullen 1990). If death does not ensue, 

symptoms usually decrease in severity over the course of several weeks to several months post-exposure, 

although frequently, they do not disappear completely (Bishop 1992; Chavez et al. 1985; de Souza et al. 

2013; Greenberg 1971; Hine 1969; Johnstone 1945; Kantarjian and Shaheen 1963; Longley and Jones 

1965; Prockop and Smith 1986). A study of fumigators involved in fumigation jobs using sulfuryl 

fluoride or bromomethane for at least 6 months did not find significant alterations in nerve conduction 

velocity tests or neurobehavioral tests among workers with high bromomethane exposure, as compared to 

a referent group (Calvert et al. 1998a); exposure levels were not reported. Because there were only 

28 workers with high bromomethane exposure, the statistical power of this study was fairly low. 

Quantitative data on the exposure levels leading to neurological effects in humans are limited. A single 

exposure study reported neurological effects in workers exposed to 4,400 ppm bromomethane for 

approximately 1 hour (Deschamps and Turpin 1996); although the workers wore respirators, the 

bromomethane saturated the respirator cartridge within a few minutes. Early studies indicated that 

workplace exposure to concentrations of 100–500 ppm could lead to visual disturbances, speech 

disturbances, mental confusion, and numbness of extremities (Johnstone 1945) and exposure to <35 ppm 

resulted in headache, nausea/vomiting, numbness, and vertigo (Watrous 1942). Anger et al. (1986) 

reported an increased incidence of neurological symptoms (muscle ache, muscle fatigue) and poorer 

performance on tests of memory and finger sensitivity in a group of fumigators who used bromomethane 

for at least 1 year. Although the study authors estimated an exposure level of 2.3 ppm, exposure levels 

were not determined for these workers; the value of 2.3 ppm was taken from personal monitoring data 

collected in different populations of fumigators. The study authors estimated exposures to be 2.3 ppm for 

field fumigators and 169 ppm for study structural fumigators; however, actual exposures in this study are 

unknown. Therefore, the outcomes observed cannot quantitatively be related to exposure levels. In 

addition, several confounding issues complicate interpretation of study results: (1) workers were also 
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exposed to sulfuryl fluoride and chloropicrin; (2) the control group was comprised of workers who were 

more sedentary than fumigators; (3) it was not clear how many workers were involved in structural 

fumigation versus field fumigation; (4) several demographic differences were noted between groups, 

including racial/ethnic mix, physical demands of job-related activities, and self-reported alcohol 

consumption, prescription drug use, and illegal drug use; and (5) workers self-selected for participation in 

the study. It is noted that the study accounted for potential confounders by dividing workers into separate 

groups based on the percentage of time they used bromomethane or sulfuryl fluoride and statistical 

adjustments were made for some variables including age, alcohol consumption, and race.

Two studies evaluated potential associations between neurodevelopment in children and exposure to 

bromomethane. A longitudinal birth cohort study examined the relationship between residential 

proximity to four agricultural fumigants (bromomethane, chloropicrin, metam sodium, and 

1,3-dichloropropene) and IQ and behavior in 285 children at age 7 years (Gunier et al. 2017). Participants 

lived in the Salinas Valley, California, and lived within 8 km of fumigant use. Quantitative estimates of 

exposure were not reported. In children residing in the area from birth to age 7 years, a 10-fold increase 

in bromomethane use was associated with a 2.6-point decrease (95% CI: -5.2, 0.0) in Full-Scale IQ. No 

association was observed between bromomethane exposure and attention problems or hyperactivity, as 

assessed by both parents and teachers. A population-based, case-control study examining associations 

between prenatal and infant exposure to pesticides and autism spectrum disorder in children did not find 

an association for bromomethane (von Ehrenstein et al. 2019). The study was conducted in 2,961 

children with a diagnosis of autism spectrum disorder, identified through records from the California 

Department of Developmental Services. Exposure data were obtained from the data from the California 

state mandated Pesticide Use Report. Participants were considered as exposed based on proximity to 

pesticide application. No quantitative exposure estimates were reported. ORs (95% Cis) for autism 

spectrum disorder during pregnancy and the first year of life were 1.12 (0.88, 1.42) and 1.09 (0.86, 1.39), 

respectively.

Inhalation studies in animals confirm that the central nervous system is a sensitive target of 

bromomethane toxicity; the effects include alterations in neurotransmitter levels, impaired performance 

on neurobehavioral tests, overt signs of toxicity, and histological lesions. A series of studies conducted 

by Honma and associates measured neurotransmitter levels in a number of sections of the brains of rats 

following a single 8-hour exposure (Honma 1987; Honma et al. 1987) or 3-week continuous exposure 

(Honma et al. 1982). An 8-hour exposure to 31 ppm resulted in significant decreases in norepinephrine 

levels in the hypothalamus (Honma 1987; Honma et al. 1987); at 100 ppm, decreases in dopamine and 
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serotonin were observed in the striatum, and norepinephrine levels were decreased in the striatum, 

hypothalamus, frontal cortex, and midbrain. Continuous exposure to 10 ppm for 3 weeks also resulted in 

decreases in norepinephrine levels in the hypothalamus (Honma et al. 1982). 

Several studies have reported alterations in neurological function in rats, mice, and rabbits exposed for 

acute, intermediate, and chronic durations. An 8-hour exposure to bromomethane resulted in decreased 

locomotor activity at 188 ppm, decreased body temperature at 125 ppm, and increased sleep potency of 

thiopental at 63 ppm (Honma et al. 1985). In rats exposed to 350 ppm for 6 hours, a decrease in motor 

activity and a number of alterations in performance on functional observational battery (FOB) tests were 

observed; FOB alterations included inactivity, decreased rearing, uncoordinated righting response, and 

decreased hindlimb grip strength (EPA 1993). These alterations were observed 1-day post-exposure, but 

were not observed 8 or 15 days post-exposure. Intermediate- and chronic-duration studies reported 

alterations in performance on neurobehavioral performance tests (NTP 1992). The observed effects 

included decreases in locomotor activity, increases in hotplate latency, decreases in startle response

latency and amplitude, decreases in forelimb grip strength, increases in hindlimb grip strength, and 

impaired performance on the rotarod test (Ikeda et al. 1980; NTP 1992). NTP (1992) classified the 

severity of neurobehavioral effects as mild. Of these effects, exposure-related decreases in locomotor 

activity was the most sensitive effect, with a LOAEL value of 10 ppm in male and female mice exposed 

for 6 months and in female mice exposed for 9 months; a NOAEL was not identified (NTP 1992). 

Decreased locomotor activity was observed in female rats exposed to 70 ppm for 13 weeks, with a 

NOAEL of 30 ppm; at week 13, total cumulative movements were significantly decreased by 37 and 34% 

at exposures of 70 and 140 ppm, respectively. EPA (1994a) noted that the largest decreases in locomotor 

activity were observed during the first half of the 90-minute testing session, but that no statistically 

significant differences were observed when epoch data were compared. In males, convulsions with death, 

altered FOB tests (increased landing foot splay and incidence of uncoordinated righting), and 

histopathological alterations in the brain (vacuolization, axonal degeneration, and necrosis) accompanied 

by convulsions and death were observed at 140 ppm, with a NOAEL of 70 ppm (EPA 1994a). A study in 

rabbits also found decreases in sciatic and ulnar nerve conduction velocity and decreases in eye blink 

reflex following a 4-week exposure to 65 ppm (Anger et al. 1981); no alterations in nerve conduction 

velocity were observed in rats similarly exposed to 65 ppm for 4 weeks or to 55 ppm for 36 weeks (Anger 

et al. 1981) or in rabbits exposed to 27 ppm for 8 months (Russo et al. 1984). A 6-week dog study (EPA 

2002) did not find alterations in performance on FOB tests or locomotor activity. 
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Numerous studies have reported overt signs of neurotoxicity in rats, mice, dogs, rabbits, and monkeys 

following acute, intermediate, or chronic exposure to bromomethane. Commonly reported effects 

included decreased locomotor activity, abnormal gait, tremors, paralysis, convulsions, delirium, and limb 

crossing and twitching (Alexeeff et al. 1985; Breslin et al. 1990; EPA 1988a, 2001a; Eustis et al. 1988; 

Hurtt et al. 1987; Irish et al. 1940; NTP 1992). The lowest LOAELs for overt signs of neurotoxicity in 

mice following acute-, intermediate-, and chronic-duration exposure were 12 ppm (NTP 1992), 53.1 ppm 

(EPA 2001b), and 33 ppm (NTP 1992), respectively. Although 12 ppm was identified as a LOAEL for 

neurological signs in mice following acute exposure, there is some uncertainty due to the vague reporting 

of the clinical signs; NTP (1992) reported that trembling, jumpiness, and paralysis were observed in all 

groups and that the effects were most pronounced at ≥50 ppm. However, no incidence data were 

provided and it is not known if all of these effects were observed at all bromomethane concentrations. 

Neurological signs (lack of interest when approached, considered to be decreased activity) were observed 

in 2/8 dogs exposed to 53.1 ppm 7 hours/day, 5 days/week for 5 weeks, with more rapidly appearing and 

severe neurological effects (tremor) at 103 ppm (Newton et al. 1994a, 1994b [MRID 443386801 and 

443386802, respectively], as cited in EPA 2001b). After lower and longer exposures of 5 ppm for 

34 exposures over 7 weeks, during a neurological examination, 2/8 female dogs were unresponsive and 

motionless and another dog appeared depressed, no effects were noted in the remaining six dogs exposed 

to 5.3 ppm for 7 weeks. Following the same protocol using 11 ppm exposures for 7 weeks and then 

increasing to 158 ppm resulted in rapid onset of severe neurological effects (two exposures produced 

decreased activity; six exposures resulted in tremors, prostration, ataxia, intention tremor, nystagmus, 

marked depression, opisthotonus, paddling gait of all limbs, vacuolization of the cerebellar granular layer 

in 8/8 dogs, olfactory epithelial degeneration in 8/8 dogs, and intracytoplasmic vacuolization of the 

adrenals in 4/4 dogs) (EPA 2001b). In a subsequent study, no overt signs of neurotoxicity were observed 

in eight dogs exposed to 20 ppm for 6 weeks (EPA 2002). Histological examinations of the brain found 

cerebellar degeneration in rats exposed to 250 ppm for 5 days (Hurtt et al. 1987), neuronal necrosis in the 

cerebrum and cerebellum in mice exposed to 160 ppm for 2 weeks and in rats exposed to 160 ppm for 

2.5 weeks (Eustis et al. 1988), edema, congestion/hyperemia, and necrosis in the cortex in rats exposed to 

400 ppm for 6 weeks (Kato et al. 1986), vacuoles in the granular layer of the cerebellum of dogs exposed 

to 11.0 ppm for 5 weeks followed by 158 ppm for 5 days (EPA 2001b), and cerebellar and cerebral

degeneration in rats exposed to 325 ppm for 4 days (Hurtt et al. 1987) and in mice exposed to 100 ppm 

for 20 weeks and allowed to recover for the remaining duration of the 2-year study (NTP 1992). The 

histological alterations observed in the intermediate-duration studies occurred at or near lethal 

concentrations. In chronic-duration studies, slight atrophy in the cerebellum was observed in mice 
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exposed to 64 ppm for 2 years (nonlethal concentration) (Gotoh et al. 1994), but not in rats exposed to 

89.1 or 100 ppm (Gotoh et al. 1994; Reuzel et al. 1987, 1991).

A developmental study in rats indicates that bromomethane produces neurotoxicity in offspring (Beck 

2004 [MRID 46665001], as cited in EPA 2019b). Dams were exposed to 0, 5, 25, or 50 ppm 

bromomethane on gestation days 6–20 and again on lactation days 5–20; neurotoxicity assessments (FOB 

testing, acoustic startle response, locomotor activity, and learning and memory testing) were conducted in 

offspring on postnatal days 21, 26, 62, and 72. The only adverse neurological effects observed were

decreases in total and ambulatory activities in the 25 and 50 ppm exposure group on postnatal day 21. 

EPA (2019b) noted that these decreases did not reach statistical significance, possibly due to high 

variability in the data. In the 25 ppm group, total and ambulatory activities were reduced 26 and 31% 

from control values, respectively. In the 50 ppm group, total and ambulatory activities were 40 and 45% 

from control values, respectively. EPA (2019b) noted that these reductions were not statistically 

significant, reportedly due to large variability in the data.

Several studies have also examined the effect of bromomethane on the olfactory system. As discussed in 

Section 2.4 (Respiratory), exposure to bromomethane can result in significant damage to the nasal 

olfactory epithelium. Bromomethane exposure can also result in damage to the neurons in the olfactory 

bulb; a 6-hour exposure to 330 ppm bromomethane resulted in death of 90–98% of the neurons (Schwob 

et al. 1999; Youngentob and Schwob 2006). As with the nasal olfactory epithelium, damage to the 

olfactory bulb was repaired. Glial cell proliferation was observed 1 day post-exposure and new olfactory 

neurons appeared by post-exposure day 3; at 6–8 weeks post-exposure, the population of reinnervated 

fibers was similar to controls (Schwob et al. 1999). Damage to the olfactory epithelium and neurons in 

the olfactory bulb resulted in severe impairment of olfaction in rats exposed to 200 ppm for 4 hours 

(Hastings et al. 1991) and rats exposed to 330 ppm for 6 hours (Youngentob and Schwob 2006). 

Although there was continued exposure in the Hastings et al. (1991) study, olfactory performance 

improved and was similar to controls by exposure day 4; the investigators noted that the recovery of 

olfactory function did not appear to be correlated with regeneration of the olfactory epithelium, which 

occurred at a much slower rate. Youngentob and Schwob (2006) showed that rats were still able to 

perceive odors (rats were able to correctly identify 45% of the odors compared to 20% chance 

performance), but there was a significant shift in odor quality perception, which was not correlated with a 

decrease in identification performance. These results suggest that a few neurons for some odor receptors 

are retained, allowing the animal to identify an odor, whereas some odor receptors may be completely 

eliminated. The study also found that there was a large degree of variation in the location of the damaged
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tissue between individual rats and that there was a significant relationship between individual odorant 

identification performance and the extent and location of the damaged tissue. In a study examining the 

recovery of olfactory neurons after bromomethane damage in mice exposed for 8 hours to 180 ppm, 

regenerated olfactory sensory neurons remained functionally impaired when observed 3 months later, 

because the innervation of the olfactory bulb by regenerated P2 olfactory sensory neurons was erroneous 

(Holbrook et al. 2014). Instead of one receptor innervating one glomerulus (as in normal epithelium), 

several P2 axons innervated multiple glomeruli, and these axons were not believed to be synaptically 

connected to the glomeruli (Holbrook et al. 2014).

An oral dietary study that exposed rats to 7.98 mg/kg/day bromomethane for 4 weeks reported no 

neurological effects based on brain weight and pathological assessment of the brain, peripheral nerves, 

spinal cord, pituitary, and optic nerve (EPA 1996).

Several mechanisms have been proposed to explain the neurotoxicity of bromomethane. One possible 

mechanism involves binding to proteins involved in oxidative reactions and energy production (reviewed 

by de Souza et al. 2013). Humans exposed to high levels of bromomethane exhibit MRI abnormalities 

that are characteristic of energy deprivation syndrome (e.g., de Souza et al. 2013; Geyer et al. 2005); the 

alterations included T2 signal abnormalities and fluid-attenuated inversion recovery sequences in the 

cerebellar dentate nuclei, periaqueductal region, dorsal midbrain and pons, and inferior olives 

symmetrically. These abnormalities consist of strikingly symmetric changes in the periventricular, 

cerebellar, and brainstem areas of the brain, locations that are particularly susceptible to damage from 

energy deprivation (reviewed by de Souza et al. 2013). In addition, several metabolites of 

bromomethane, including methanethiol and formaldehyde, are highly reactive compounds capable of 

inhibiting cellular respiration (reviewed by de Souza et al. 2013). Bromomethane has also been shown to 

rapidly inhibit creatine kinase in the brain (Hyakudo et al. 2001). Creatine kinase maintains cellular 

energy homeostasis by catalyzing the conversion of creatine and ATP to phosphocreatine and ADP 

(reviewed by de Souza et al. 2013). Inhibition of tyrosine hydroxylase activity by bromomethane may be 

the mechanism by which the dopaminergic system is perturbed (reviewed by de Souza et al. 2013). 

Furthermore, S-methylcysteine formed during the metabolism of bromomethane is structurally analogous 

to the neurotransmitter γ-amino butyric acid, and has been shown to exert neurotoxic effects on the rat 

hippocampus (reviewed by Bulathsinghala and Shaw 2014).

Glutathione depletion induced by bromomethane could also contribute to neurotoxicity. Lower 

glutathione levels and reduced glutathione-S-transferase activity were observed in the brains of rats 
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exposed to bromomethane by inhalation for 5 days (Davenport et al. 1992). Under conditions of acuteduration, high-level exposures, however, glutathione appears to detoxify bromomethane. For example, 

when glutathione levels were depleted with buthionine sulfoximine prior to exposing rats to 

bromomethane, an increase in toxicity was observed (reviewed by WHO 1995). In addition, Tanaka et al. 

(1988) observed an alleviation of bromomethane effects on sleep and wakefulness as well as an increase 

in the subcutaneous LD50 of bromomethane when rats were pretreated with glutathione. Further, humans 

with a congenital deficiency in glutathione transferase suffered more severe effects of bromomethane 

exposure, further supporting a detoxifying action of glutathione conjugation under conditions of acute 

exposure (reviewed by de Souza et al. 2013).

Bromomethane also alters neurotransmitter levels in the brain. Reduced levels of dopamine and 

norepinephrine were observed in the brains of rats after exposure to bromomethane (Honma et al. 1987). 

In addition, tyrosine hydroxylase activity was inhibited by exposure to bromomethane (Honma 1987). 

Inhibition of tyrosine hydroxylase activity by bromomethane may be the mechanism by which the 

dopaminergic system is perturbed (reviewed by de Souza et al. 2013). Furthermore, S-methylcysteine 

formed during the metabolism of bromomethane is structurally analogous to the neurotransmitter,

γ-amino butyric acid, and has been shown to exert neurotoxic effects on the rat hippocampus (reviewed 

by Bulathsinghala and Shaw 2014).

2.16 REPRODUCTIVE

No studies were located regarding reproductive effects of bromomethane in humans after inhalation or 

oral exposure, or in animals following oral exposure. In male animals, effects on the testes (delayed 

spermiation, minimal tubular degeneration, atrophy) have been observed in rats and mice exposed to 160–

405 ppm for 1–6 weeks (Eustis et al. 1988; Hurtt et al. 1987; Kato et al. 1986) and decreases in sperm 

density were observed in mice exposed to 120 ppm for 13 weeks (EPA 1988a). However, exposure of 

male rats to 70 ppm for 5 days did not interfere with normal reproductive function and impregnation 

success (NIOSH 1981), and no histopathological alterations were observed in male rats exposed to 

200 ppm for 5 days (Hurtt and Working 1988). No effects on reproductive function in females have been 

observed in rats or rabbits exposed to levels up to 70 ppm before and during gestation (NIOSH 1980), 

even though these levels produced maternal toxicity. No histological alterations were observed in 

reproductive tissues of dogs exposed to ≤102.7 ppm for 5 weeks (EPA 2001b). No organ weight or 

histological changes in reproductive tissues of rats were observed following dietary exposure to 

7.99 mg/kg/day for 4 weeks (EPA 1996).
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2.17 DEVELOPMENTAL

One epidemiology study evaluated the potential association between residential proximity to 

bromomethane application and developmental outcomes (Gemmill et al. 2013). Moderate or high 

bromomethane use during the second trimester was inversely associated with birth weight (not significant 

in moderate use group), birth length, and head circumference (not significant in high use group). These 

associations were found in women living within a 3-, 5-, or 8-km radius from the source. Two additional 

epidemiology studies in children examining neurodevelopmental outcomes are reviewed in Section 2.15 

(Neurological).

An inhalation developmental study in rats reported slight, but statistically significant, delays in sexual 

maturation (Beck 2004 [MRID 46665001], as cited in EPA 2019b). In offspring of dams exposed to 

50 ppm bromomethane for 6 hours/day on gestation days 6–20 and lactational days 5–20, preputial 

separation and vaginal opening were delayed by 1.4 and 1.6 days, respectively. No effects were 

observed following exposure to 5 ppm. Increased incidences of a malformation (gallbladder agenesis) 

and a minor variation (fused sternebrae) and decreased fetal body weights were observed in offspring 

from rabbits exposed to 80 ppm during gestation (Breslin et al. 1990); marked maternal toxicity (lethargy, 

ataxia, lateral recumbency, and decreased body weight) were also observed at this exposure level and the 

observed developmental effects may have been secondary to the maternal toxicity. No decreased weights 

were observed in F0 generation females or in F1 generation pups in a multigeneration study in rats 

exposed up to 90 ppm, but a 21% non-dose-related reduction was reported for F2 generation female pups 

exposed to either 30 or 90 ppm, and pup weight was decreased in F2 generation males exposed to 90 ppm

(Mayhew et al. 1986, as cited in EPA 1986a). In contrast, studies in rats and rabbits indicate that 

inhalation exposure to levels up to 70 or 20 ppm, respectively, for 7 hours/day during gestation does not 

result in any statistically significant developmental effects, (Hardin et al. 1981; Sikov et al. 1980, as 

summarized in NIOSH 1980). For rabbits, inhalation exposure up to 20 ppm for 15 days also produced 

no developmental effects; however, developmental toxicity could not be assessed in the 70 ppm group 

due to extreme maternal mortality starting on gestation day 15 (Hardin et al. 1981). 

Developmental toxicity was assessed in rats and rabbits administered bromomethane via gavage in corn 

oil on gestation days 6–15 or 6–18, respectively (Kaneda et al. 1998). No significant alterations in 

resorptions or fetal deaths, number of live fetuses, sex ratio, or fetal body weights were observed in rats 

exposed to ≤30 mg/kg/day or rabbits exposed to ≤10 mg/kg/day. An increase in fetuses having 
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25 presacral vertebrae was observed in rats exposed to 30 mg/kg/day; however, there were no significant 

differences in the number of litters with this variation and it was not considered exposure-related. No 

alterations in the occurrence of external, visceral, or skeletal malformations or variations were observed in 

the rabbits.

2.18 CANCER

The U.S. Department of Health and Human Services (NTP 2016) has not categorized the carcinogenicity 

of bromomethane. IARC (2016) classified bromomethane as a Group 3 carcinogen (not classifiable as to 

its carcinogenicity to humans). EPA (IRIS 2002) has determined that bromomethane is classified as a 

Group D carcinogen (not classifiable as to human carcinogenicity).

The carcinogenic potential of bromomethane has not been formally investigated in epidemiological 

studies of occupationally-exposed workers; however, some information is available from epidemiological 

studies. Wong et al. (1984) studied the incidence of cancer in a cohort of workers exposed to a wide 

variety of brominated chemicals, and noted that two men who died of testicular cancer had both been 

exposed to organic bromides, including bromomethane. However, since there are numerous risk factors 

for testicular cancer, and since the workers may have been exposed to other chemicals, this observation is 

not sufficient to indicate that bromomethane is carcinogenic. Several studies have evaluated the potential 

association between bromomethane and increased risk of prostate cancer. Utilizing the Agricultural 

Health Study cohort of male pesticide applicators, Alavanja et al. (2003) found elevated ORs for prostate 

cancer (adjusted for age and family history of prostate cancer) among applicators with the two highest 

cumulative exposure quintiles for bromomethane (OR 2.73, 95% CI 1.18–6.33 and OR 3.47, 95% CI 

1.37–8.76, respectively). A nested case-control study of predominantly Hispanic farm workers did not 

find an association between bromomethane exposure and prostate cancer (Mills and Yang 2003). For the 

highest estimated exposure quartile (estimate not reported), the OR was 1.59 (95% CI 0.77–3.30); no 

trend was observed over increasing exposure quartiles (p=0.25). A second case control study examined 

residents in California’s Central Valley and assessed potential exposure to bromomethane using pesticide 

use near the subject’s residence (Cockburn et al. 2011). An increase in the risk of prostate cancer was 

observed among exposed residents (OR 1.62; 95% CI 1.02–2.59). However, when the cases were 

categorized based on low and high exposure, no significant differences were found between the two 

groups (p=0.10). In a follow-up study of the Agricultural Health Study cohort, no significant association 

between increasing bromomethane exposure and increasing risk of prostate cancer was found (Barry et al. 

2012); the relative risk (RR) for workers with the highest intensity weight lifetime days of exposure was 
BROMOMETHANE 57

2. HEALTH EFFECTS

0.99 (95% CI 0.72–1.36). However, there was a nonsignificant increase in the relative risk among 

bromomethane applicators with a family history of prostate cancer (RR 1.46, 95% CI 0.97–2.20). The 

Barry et al. (2012) study found an increased risk of stomach cancer among applicators with high 

bromomethane use (RR 3.13; 95% CI 1.25–7.80; RR 3.33, 95% CI 1.30–8.51 with a 15-year lag), as 

compared to applicators with no use of bromomethane. A nested case-control study of Hispanic 

agricultural workers did not find an association between ever using bromomethane and gastric cancer (OR 

1.01; 95% CI 0.57–1.74) (Mills and Yang 2007). However, among workers with the highest potential 

exposure, there was an increased risk (OR 2.38; 95% CI 1.06–5.37) when compared to workers with the 

lowest risk, but not with workers with no bromomethane exposure (OR 1.33; 95% CI 0.67–2.67). 

Although these occupational studies provide some suggestive associations between increased cancer risk 

and exposure to bromomethane, the studies are inadequate for establishing causality; none of the studies 

measured actual bromomethane exposure levels and workers were likely exposed to multiple pesticides.

The potential carcinogenesis of bromomethane has been evaluated in laboratory animals following 

inhalation and oral exposure. No evidence of carcinogenic effects was detected in mice exposed to 

33 ppm for 2 years (NTP 1992), in mice exposed to 100 ppm for 20 weeks and allowed to recover for the 

remainder of the 2-year study (NTP 1992), or in rats exposed to 89.1 ppm for 29 months (Reuzel et al. 

1987, 1991). No tumors were identified in beagle dogs exposed to bromomethane in feed for 1 year 

(Wilson et al. 2000). Danse et al. (1984) reported an increased incidence of forestomach lesions, which 

were interpreted as squamous cell carcinomas, in rats administered 50 mg/kg bromomethane via gavage 

5 days/week for 13 weeks. However, histological diagnosis of epithelial carcinomas in the presence of

marked hyperplasia is difficult (Wester and Kroes 1988). After reevaluation of the histological slides, a 

panel of scientists from the National Toxicology Program (NTP) concluded that there was no evidence of

a neoplastic response in this study, but rather only hyperplasia and inflammation (IRIS 2002). This is 

consistent with the observation that the hyperplasia of the forestomach produced by 13 weeks of exposure 

to bromomethane regressed when exposure ended (Boorman et al. 1986). Longer-term (25 weeks) oral 

exposure of rats to 50 mg/kg/day of bromomethane led to a severely dysplastic and hypermetabolic

forestomach lesion in 1 rat (out of 15 exposed) that was judged to be a very early carcinoma; however, the 

regression of hyperplasia after exposure ended argued against the carcinogenic potential of 

bromomethane.
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2. HEALTH EFFECTS

2.19 GENOTOXICITY

Bromomethane has produced positive results in a number of mutagenicity test systems, both in vitro

(Table 2-3) and in vivo (Table 2-4). This effect does not appear to require metabolic activation, which is 

consistent with the fact the bromomethane is a direct-acting alkylating agent that can methylate DNA 

(Ikawa et al. 1986; Starratt and Bond 1988). This property suggests that bromomethane might be 

carcinogenic, but this has not been established.

Table 2-3. Genotoxicity of Bromomethane In Vitro

Species (test system) Endpoint

Results

Reference

With 

activation

Without 

activation

Prokaryotic organisms:

Escherichia coli Sd-4 Gene mutation No data + Djalali-Behzad et al. 1981

E. coli WP2 her

(gene reversion)

Gene mutation + + Moriya et al. 1983

Salmonella typhimurium

(TA100, TA1535)

(gene reversion)

Gene mutation + + Moriya et al. 1983

S. typhimurium

(TA98, TA1537, TA1538)

(gene reversion)

Gene mutation – – Moriya et al. 1983

S. typhimurium

(TA100)

(desiccator system)

Gene mutation No data – Simmon and Tardiff 1978

S. typhimurium

(TA100)

(desiccator system)

Gene mutation + + NTP 1992

S. typhimurium

(TA98)

(plate test)

Gene mutation – – Kramers et al. 1985

S. typhimurium

(TA100)

(plate test)

Gene mutation + + Kramers et al. 1985

Klebsiella pneumonia

(ur- pro-)

(fluctuation test)

Gene mutation No data + Kramers et al. 1985

Eukaryotic organisms:

Mouse lymphoma cells

(L5178YTK+/-)

(forward mutation)

Gene mutation No data + Kramers et al. 1985

Syrian hamster embryo 

cells

Enhanced 

transformation by 

Sa7 adenovirus

No data – Hatch et al. 1983
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Table 2-3. Genotoxicity of Bromomethane In Vitro

Species (test system) Endpoint

Results

Reference

With 

activation

Without 

activation

Human peripheral 

lymphocytes

Sister chromatid 

exchanges

No data + Tucker et al. 1986

Rat liver cells Unscheduled DNA 

synthesis

No data – Kramers et al. 1985

Human embryonic 

intestinal cells

Unscheduled DNA 

synthesis

– – NIOSH 1981

– = negative result; ± = weakly positive; DNA = deoxyribonucleic acid

Table 2-4. Genotoxicity of Bromomethane In Vivo

Species (test system) Endpoint Results Reference

Nonmammals

Drosophila melanogaster

Berlin-K wild type

(sex linked recessive lethal test)

Gene mutation + Kramers et al. 1985

D. melanogaster

(somatic wing spot assay)

Recombinogenic activity + Katz 1987

D. melanogaster

Oregon-K wild type

(sex-linked recessive lethal test)

Gene mutation – NIOSH 1981

Mammals

Human (lymphocytes) Gene (hprt) mutation – Calvert et al. 1998b

Human (lymphocytes) Kinetochore-negative 

micronuclei induction

– Calvert et al. 1998b

Human (lymphocytes) Kinetochore-positive 

micronuclei induction

– Calvert et al. 1998b

Human (oropharyngeal cells) Micronuclei inductions + Calvert et al. 1998b

Sprague-Dawley rat (bone 

marrow cells) 

Chromosomal aberrations − NIOSH 1981

B6C3F1 mouse (bone marrow 

cells)

Sister chromatid exchange + NTP 1992

Sprague-Dawley rat Dominant lethal – NIOSH 1981

B6C3F1 mouse Sperm abnormality − NIOSH 1981

F344 rat (testes) DNA alkylation + MRID4318201, as cited in 

EPA 2018a

CBA mouse (liver and spleen 

cells) 

DNA alkylation + Djalali-Behzad et al. 1981

F344 rats (liver, lung, stomach, 

and forestomach)

DNA adduct formation + Gansewendt et al. 1991

F344 rat (bone marrow cells) Micronuclei inductions + Ikawa et al. 1986
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Table 2-4. Genotoxicity of Bromomethane In Vivo

Species (test system) Endpoint Results Reference

BDF1 mouse (bone marrow 

cells) 

Micronuclei inductions + Ikawa et al. 1986

B6C3F1 mouse (peripheral 

erythrocytes)

Micronuclei inductions + NTP 1992

+ = positive results; – = negative results; (+) = weakly positive

The in vivo genotoxicity of bromomethane was evaluated in bromomethane fumigation workers (Calvert 

et al. 1998b). Increases in micronuclei were observed in oropharyngeal cells (p=0.08). Increases in 

kinetochore-positive micronucleated lymphocytes (p=0.06 in smokers and 0.08 in nonsmokers) were 

found, but this association was not found when workers were divided into two groups based on the 

number of hours since recent bromomethane exposure. No alterations in lymphocyte hrpt Vf formation 

were observed (p=0.73). In animals, the frequency of bone marrow cells with chromosomal aberrations 

was not increased in rats exposed to 70 ppm for 5 days (NIOSH 1981), but was increased several-fold in 

rats exposed to 140 ppm for 14 days (Ikawa et al. 1986). Inhalation exposure of rats to 250 ppm 

bromomethane 6 hours/day for 5 days resulted in DNA alkylation in testicular cells; mortality and 

neurotoxicity were also observed at this exposure level (MRID4318201, as cited in EPA 2018a). DjalaliBehzad et al. (1981) found that inhalation exposure of mice to bromomethane for 4 hours led to alkylation 

of DNA in liver and spleen, although the levels were quite low. In contrast to these positive findings, no 

genotoxic effects could be detected in sperm from rats or mice exposed to 70 ppm bromomethane for 

5 days, using either the dominant lethal or recessive lethal tests, or by direct examination of the sperm 

(NIOSH 1981). These studies indicate that bromomethane does have genotoxic potential, but that effects 

may be minimal and difficult to measure following brief or low dose exposure.

Additionally, inhalation and oral studies in rats (Gansewendt et al. 1991) and inhalation and 

intraperitoneal studies in mice (Djalali-Behzad et al. 1981) demonstrate that bromomethane is an 

alkylating agent resulting in the formation of DNA adducts: 3-methyl-adenine, 7-methyl-guanine, and 

O6

-methyl-guanine. In the rats, the methylated guanines were preferentially found in the stomach and 

forestomach following inhalation or oral exposure.

2.20 MECHANISMS OF TOXICITY

Several mechanisms have been proposed regarding the neurotoxicity of bromomethane; these are 

discussed in Section 2.15. 
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Little information is available regarding the mechanisms of toxicity for bromomethane. However, 

general cellular mechanisms may play a role in the toxicity of bromomethane. Bromomethane may be 

directly toxic to cells via its ability to bind lipids and proteins (reviewed by de Souza et al. 2013). In 

addition, bromomethane has been shown to deplete glutathione in several tissues (reviewed by WHO 

1995). In rats exposed to bromomethane by inhalation, increased glutathione-S-transferase activity was 

observed in the lungs (Jaskot et al. 1988). 
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CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, 

BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

• Absorption:

o Respiratory tract: Bromomethane is well absorbed from the respiratory tract. A small study 

in humans estimated that approximately 52–55% of the inhaled dose was absorbed. Studies 

in animals estimate a fractional absorption from the respiratory tract of 27–48%.

o Gastrointestinal tract: The estimated fractional absorption of oral bromomethane in a single 

study in rats was ≥97%.

o Dermal: Bromomethane is absorbed following dermal exposure, although quantitative 

estimates of absorption were not identified.

• Distribution: Based on inhalation exposure studies in laboratory animals, bromomethane 

undergoes wide distribution throughout the body, including the central nervous system.

• Metabolism: Bromomethane undergoes extensive metabolism. Metabolites include bromide ion, 

methanol (which can be further metabolized to formaldehyde, formate, and carbon dioxide), 

S-methyl derivatives, and glutathione conjugates.

• Excretion: Excretion of bromomethane occurs mainly by expiration of carbon dioxide or by 

urinary excretion of nonvolatile metabolites (Bond et al. 1985; Jaskot et al. 1988; Medinsky et al. 

1985). Small amounts of bromomethane undergo biliary excretion and are excreted in the feces. 

3.1.1 Absorption 

In a small human study, bromomethane uptake was 55.4% and 52.1% when the subjects inhaled 

0.018 ppm bromomethane through the nose or mouth, respectively (ARB 1988). A study in nine 

fumigators accidentally exposed to bromomethane found elevated serum bromide levels 4 hours after 

exposure (Hustinx et al. 1993). Studies in rats suggest that exposure to airborne bromomethane is rapidly 

absorbed and distributed (Andersen et al. 1980; Bond et al. 1985; Gargas and Andersen 1982; Jaskot et al. 

1988; Medinsky et al. 1985). Andersen et al. (1980) and Gargas and Andersen (1982) suggested that 

bromomethane absorption followed a rapid first-order uptake kinetics with no measurable saturable 

kinetics based on studies in rats exposed to 100–10,000 ppm bromomethane for 2 hours. Gas uptake 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

constants of 0.44 (kg-hour)-1 (Andersen et al. 1980) and 0.55 (kg-hour)-1 (Gargas and Andersen 1982) 

were calculated from these data. Gargas and Andersen (1982) estimated a first-order rate constant of 

0.32 (kg-hour)-1

. In contrast, Medinsky et al. (1985) reported nonlinear uptakes, with saturation at 

≥170 ppm. Fractional absorption was 48% at 1.6 and 9.0 ppm, 38% at 170 ppm, and 27% at 310 ppm in 

rats exposed for 6 hours. At high bromomethane levels (310 ppm), the total amount absorbed appears to 

reach a maximum (62 mg/kg), suggesting that some aspect of uptake (perhaps glutathione availability) 

becomes limiting (see Section 3.1.3). The first-order rate constant for bromomethane was estimated to be 

1.6 (kg-hour)-1

. Medinsky et al. (1985) suggested that the higher concentrations tested in the Gargas and 

Andersen (1982) study may have resulted in glutathione depletion shortly after exposure was initiated and 

that the glutathione availability was a rate-limiting factor in bromomethane uptake; this is supported by 

the much higher rate constant estimated in the Medinsky et al. (1985) study compared to the Gargas and 

Andersen (1982) study. In dogs, an uptake of 39.5% was estimated following a 3-hour exposure to 

0.174–0.361 ppm bromomethane (ARB 1986).

No studies were located regarding bromomethane absorption after oral exposure of humans. In rats given 

a single oral dose of 14C-labeled bromomethane dissolved in corn oil, only about 3% of the label was 

excreted in the feces (Medinsky et al. 1984). This indicates that at least 97% of the dose was absorbed 

from the gastrointestinal tract.

No quantitative studies were located regarding bromomethane absorption across the skin of humans. 

Yamamoto et al. (2000) reported a rapid increase in plasma bromide levels in rats dermally exposed to 

liquid bromomethane for 0.5–5 minutes.

3.1.2 Distribution 

Most information regarding distribution of bromomethane was obtained from inhalation exposure studies 

in laboratory animals. In rats exposed to 14C-bromomethane in air, radioactive label was widely 

distributed throughout the body (Bond et al. 1985; Jaskot et al. 1988; Medinsky et al. 1985). Levels were 

somewhat higher in lungs, adrenals, liver, and kidneys than in other tissues (Bond et al. 1985; Jaskot et al. 

1988). The form of the label was not studied by these researchers, but is probably mostly metabolites. 

However, Honma et al. (1985) showed that low levels of parent bromomethane can be detected for up to 

24 hours after an 8-hour exposure to 250 ppm bromomethane. The study found that the highest levels of 

bromomethane were in the adipose tissue, followed by the blood, muscles, brain, kidneys, and liver. 

Bromomethane levels in the adipose tissue and blood rapidly declined post-exposure; the levels were 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

decreased by half within the first 30 minutes. The elimination of bromomethane from the brain and liver 

was slower. A similar distribution pattern was found when bromine (rather than bromomethane) levels 

were measured. A similar tissue distribution pattern was observed in rats exposed to 250–1,000 ppm 

bromomethane for 2 hours (Honma et al. 1985), with the exception that bromomethane levels were higher 

in the liver than in the brain immediately following exposure. Kato et al. (1986) noted concentrationspecific differences in bromine tissue distribution in rats 5 days following a 6-week exposure to 200–

400 ppm (4 hours/day, 5 days/week). At 200 ppm, the ratio of bromine concentrations in the kidneys, 

spleen, and liver was 1:0.87:0.16; at 400 ppm, the ratio was 1:0.76:0.56.

In rats exposed to a very high bromomethane concentration (2,000 ppm for 1 hour), there was a rapid 

increase in relative plasma bromine levels and then a rapid decrease. Using a two-compartment model, a

half-time of 9.1 days was calculated for plasma bromine levels (Hori et al. 2002). In rats exposed to 

300 ppm bromomethane 6 hours/day for 3 days, a plasma bromine half-time of 5.4 days was calculated 

(Hori et al. 2002).

Bromomethane’s relative hydrophobicity suggests that it can cross the blood-brain barrier (de Souza et al. 

2013), which is supported by the elevated brain bromomethane levels measured in the Honma et al. 

(1985) rat study.

In rats given oral doses of 14C-bromomethane, label was distributed widely throughout the body, with 

highest levels in liver and kidneys (Medinsky et al. 1984).

In rats dermally exposed to liquid bromomethane, plasma bromide levels rapidly increased in proportion 

to the exposure duration with peak levels observed 1 hour after a 0.5-, 1-, 3-, or 5-minute exposure 

(Yamamoto et al. 2000). The plasma bromide levels gradually decreased and returned to baseline levels 

4–8 weeks postexposure. Yamamoto et al. (2000) estimated plasma bromide ion half-times (assuming a 

two-compartment model) of 6.3, 6.5, 5.3, and 5.0 days following the 0.5-, 1-, 3-, and 5-minute exposures, 

respectively.

3.1.3 Metabolism 

Bromomethane undergoes initial metabolism primarily by nucleophilic displacement of the bromide ion. 

When the attacking species is water, the products are methanol and bromide ion:
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

HOH + CH3Br -> CH3OH + H+ + BrThe amount of bromomethane broken down by this reaction in the body is not known, but increased 

levels of both methanol and bromide have been detected in exposed animals (Gargas and Andersen 1982; 

Honma et al. 1985). Elevated bromine levels were found in the blood, kidneys, and liver of rats shortly 

after termination of an 8-hour exposure to 250 ppm (Honma et al. 1985). The peak levels of bromine 

occurred 4–8 hours after exposure, as compared to the peak levels of bromomethane, which occurred after 

1 hour of exposure. Oxidation of methanol leads to formaldehyde and formate, which may enter the onecarbon metabolic pool, be oxidized to carbon dioxide and water, or undergo further reactions in the 

oxalate or tricarboxylic acid cycles to form amino acids such as cysteine or homocysteine (Bulathsinghala

and Shaw 2014). Bromomethane may also react with organic thiols (R-SH) to yield S-methyl derivatives:

R-SH + CH3

Br -> R-SCH3 + H+ + BrThis has been shown to result in formation of S-methylcysteine derivatives in hemoglobin of mice 

exposed to bromomethane (Iwasaki 1988b), and by analogy with methyl chloride (Kornbrust and Bus 

1983), is likely to result in formation of S-methyl glutathione (Medinsky et al. 1985). Conjugation with 

glutathione is supported by the finding of decreased glutathione concentrations in the liver, kidneys, 

lungs, and brains of mice exposed to bromomethane for 1 hour (Alexeeff et al. 1985). Further 

metabolism of S-methyl derivatives such as those mentioned above produces methanethiol via 

intermediates S-methylcysteine and methylthioacetic acid (Bulathsinghala and Shaw 2014). Methanethiol 

undergoes additional metabolism to formaldehyde and formate, subsequently following the pathways 

described above. Ultimately, the formation of carbon dioxide accounts for 40–50% of the administered 

dose and other unidentified nonvolatile metabolites account for about 20–25% of the administered dose 

(Bond et al. 1985; Jaskot et al. 1988; Medinsky et al. 1985).

3.1.4 Excretion 

No studies were located regarding excretion of bromomethane in humans after inhalation or oral 

exposure. In animals exposed to bromomethane vapors, excretion occurs mainly by expiration of carbon 

dioxide or by urinary excretion of nonvolatile metabolites (Bond et al. 1985; Jaskot et al. 1988; Medinsky 

et al. 1985). Only small amounts are excreted in the feces. Very little parent bromomethane is exhaled 

(Jaskot et al. 1988; Medinsky et al. 1985), and tissue levels of parent bromomethane decrease with a halflife of only about 15–30 minutes (Honma et al. 1985; Jaskot et al. 1988). Half-lives for clearance of 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

metabolites from the body and most tissues range from 2 to 10 hours (Honma et al. 1985; Jaskot et al. 

1988).

A significant fraction (about 25–30%) of 14C-radiolabeled bromomethane (14CH3

Br) remains in tissues 

after 24–72 hours and a small portion is excreted (7% via exhaled air in 32 hours). The greater excretion 

rate of 14CO2 (43% in exhaled air, 21% in urine, and 2% in feces) indicates rapid metabolism and longerterm retention of bromide ion (Jaskot et al. 1988; Medinsky et al. 1985). This rapid excretion of 14CO2

presumably represents turnover of various intracellular metabolites or adducts, although this has not been 

established. The half-life of bromine in the blood, kidneys, and liver was approximately 5 days in rats 

exposed to 250 ppm bromomethane for 8 hours (Honma et al. 1985). Following a 1-hour exposure to 

220–1,530 ppm bromomethane, 95% of the bromide was eliminated from the blood, kidneys, liver, lungs, 

and brain of mice after 2.5 days. Saturation of the detoxification mechanism by inhaled bromomethane 

(which can affect excretion) was proposed by the study authors (Alexeeff et al. 1985).

One study in animals indicates that the rate and pattern of excretion of 14C-label following oral exposure 

to 14C-bromomethane is similar to that following inhalation exposure: 32% was exhaled as carbon 

dioxide, 43% was excreted in the urine, 4% of unmetabolized parent compound was exhaled, 2% was 

excreted in the feces, and 14% remained in the body after 72 hours (95% of the radiolabel was recovered) 

(Medinsky et al. 1984). In rats with cannulated bile ducts, 46% of the administered dose was excreted in 

the bile, with much lower amounts exhaled as CO2 (12%) and excreted in urine (7%) (Medinsky et al. 

1984). Given the low fecal excretion seen in rats without bile duct cannulation, these experiments suggest 

that bromomethane metabolite(s) excreted in bile are reabsorbed and further metabolized prior to 

excretion in urine or as exhaled CO2.

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

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

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

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

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

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

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

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

between target tissue dose and toxic endpoints. 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

No PBPK models were identified for bromomethane.

3.1.6 Animal-to-Human Extrapolations 

In several species, including humans, similar target tissues have been found, namely the respiratory tract 

and the nervous system. Although the target tissues were similar across species, dose-response 

differences were noted in several animal studies. Irish et al. (1940) exposed rats, rabbits, and monkeys to 

the same bromomethane concentrations for 6 months. The respective NOAEL and LOAEL values for 

neurotoxicity were 66 and 100 ppm (convulsions) for rats, 17 and 33 ppm (paralysis) for rabbits, and 

33 and 66 ppm (paralysis) for monkeys. NTP (1992) also noted species-differences in the neurotoxicity 

of bromomethane; exposure to 120 ppm resulted in alterations in performance on neurobehavioral tests 

without overt signs of toxicity in rats and severe curling and crossing of hindlimbs and twitching of 

forelimbs in mice. Although mice were more sensitive to the neurotoxicity of bromomethane, the 

respiratory tract was more sensitive in rats than in mice. Olfactory epithelial dysplasia was observed in 

rats exposed to 120 ppm for 13 weeks; no nasal effects were observed in mice also exposed to 120 ppm 

for 13 weeks (NTP 1992). Reliable dose-response data are not available for humans that would allow for 

a comparison of adverse effect levels with animal data. In the absence of these data, it is assumed that 

humans would be as sensitive as animals to the neurological and respiratory toxicity of bromomethane.

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental 

germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal 

exposure during gestation and lactation. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

Populations at greater exposure risk to unusually high exposure levels to bromomethane are discussed in 

Section 5.7, Populations with Potentially High Exposures.

There are limited data on the toxicity of bromomethane in children. One case report discussed effects 

observed in an infant accidentally exposed to bromomethane (Langard et al. 1996). Vomiting and severe 

diarrhea were reported in the infant who died; the cause of death was determined to be acute pneumonia 

due to aspiration. Vomiting, as well as eye, throat, and mouth irritation, was reported in the parents. 

A study in rabbits found increased incidences of a minor malformation and minor variation and decreases 

in body weights in the offspring of rabbits exposed via inhalation (Breslin et al. 1990). However, other 

studies in rats and rabbits have not reported developmental effects following inhalation exposure during 

gestation (Hardin et al. 1981; NIOSH 1980) or oral exposure (Kaneda et al. 1998).

It may be expected that the young, the elderly, and people with lung, kidney, or neurological disease 

might be more readily affected than healthy adults. In addition, humans with a congenital deficiency in 

glutathione transferase suffered more severe effects of bromomethane exposure, further supporting a 

detoxifying action of glutathione conjugation under conditions of acute exposure (reviewed by de Souza 

et al. 2013). Studies in animals reveal that there are differences in sensitivity between species (such as 

respiratory toxicity, neurotoxicity, and mortality) (e.g., Gotoh et al. 1994; Irish et al. 1940), and some 

studies have noted small differences in sensitivity between males and females (Eustis et al. 1988). It is 

not known if these differences apply to humans.

3.3 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility 

(NAS/NRC 1989).

A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

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

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. Biomarkers of 

exposure to bromomethane are discussed in Section 3.3.1. The National Report on Human Exposure to 

Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable sample of 
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

the U.S. population to environmental chemicals using biomonitoring; see CDC (2018),

http://www.cdc.gov/exposurereport/. If available, biomonitoring data for bromomethane from this report

are discussed in Section 5.6, General Population Exposure. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that (depending on magnitude) can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

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

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effect caused 

by bromomethane are discussed in Section 3.3.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.2, Children and Other Populations that are Unusually Susceptible.

3.3.1 Biomarkers of Exposure

Measurement of parent bromomethane (e.g., in expired air, blood, or urine) has not been investigated as a 

possible biomarker of exposure in humans, mainly because studies in animals suggest that bromomethane 

is cleared so rapidly (half-lives of 15–30 minutes) that this is unlikely to be useful for monitoring 

environmental exposures. Similarly, methanol and other organic metabolites are also cleared with short 

half-lives (Honma et al. 1985; Jaskot et al. 1988), so they are also unlikely to be useful in biomonitoring.

In contrast, the bromide ion level in blood or serum has been used as a biomarker of bromomethane 

exposure. The relationship between bromide ion concentrations and the severity of effects in exposed 

people was investigated by Alexeeff and Kilgore (1983), who assembled and evaluated data from a large 

number of case reports. Serum bromide levels are usually below 15 ppm in unexposed people. In 

bromomethane-exposed people, levels up to 80 ppm may occur without any obvious clinical signs, while 

levels of 150–400 ppm are observed in people with moderate to severe symptoms. Bromide is cleared 

from blood with a half-life of about 12 days in healthy people, and half-lives of 3–15 days have been 
BROMOMETHANE 70

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

observed in bromomethane-exposed people (Alexeeff and Kilgore 1983). Consequently, the correlation 

between serum bromide levels and severity of effects is most apparent within the first 1–2 days of 

exposure, and there may be little correlation later. Bromide ion is cleared mainly by excretion in the 

urine, and may be a candidate biomarker of bromomethane exposure. Tanaka et al. (1991) observed a 

significant correlation (r=0.596, p<0.01) between bromine levels in urine and personal air samples for 

bromomethane (concentrations ranging up to 390 ppm) in a group of 41 plant fumigators wearing gas 

masks with respirator canisters. The authors postulated three potential routes of exposure to 

bromomethane in the workers, including dermal absorption, leakage through an incomplete seal of the gas

mask, and breakthrough in the respiratory canister (Tanaka et al. 1991). Further investigation is needed to 

better establish whether urinary bromine is a reliable biomarker of exposure to bromomethane.

Formation of stable methylated adducts such as S-methylcysteine in hemoglobin is known to occur in 

animals following inhalation exposure to bromomethane (Iwasaki 1988a, 1988b), and has been 

demonstrated in vitro using both human and mouse hemoglobin (Bamgbose and Bamgbose 2008), but the 

potential use of this endpoint for biomonitoring in humans has not been fully explored.

Neither elevated serum bromide levels nor formation of methylated adducts are, by themselves, specific 

for bromomethane exposure. For example, increased bromide levels could result from exposure to 

bromide in the diet or ingestion of bromate- or bromide-containing medicines, and increased methyl 

adducts might result from exposure to other methyl halides, various methyl nitrosamines, or other 

alkylating agents. However, the combination of these two methods (i.e., a finding of increased bromide 

and increased methylation) would strongly indicate that bromomethane exposure had occurred.

3.3.2 Biomarkers of Effect

As discussed in Chapter 2, the effects that are most often observed in humans exposed to bromomethane 

vapor are central nervous system injury (disturbed vision, tremor, convulsions, coma), lung irritation 

(edema, impaired respiration), and renal injury (oliguria or anuria). Of these, neurological or 

neurobehavioral signs often appear to be the most sensitive indication of effect, since preclinical 

symptoms can be observed in humans exposed to low levels of bromomethane in the workplace (Anger et 

al. 1986; Kishi et al. 1988; Verberk et al. 1979). Of course, positive findings for endpoints of this sort 

(headache, weakness, ataxia, nausea, double vision, abnormal electroencephalogram) are not specific 

indicators of bromomethane exposure, since other chemicals or diseases may produce similar 

neurological changes.
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3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

3.4 INTERACTIONS WITH OTHER CHEMICALS

No studies were located regarding the interaction of bromomethane with other chemicals. Since it seems 

likely that cellular glutathione may serve a protective function by reacting with bromomethane (Kornbrust 

and Bus 1983), other chemicals (electrophilic xenobiotics, reactive intermediates) that lead to decreases in 

glutathione levels might increase the toxicity of bromomethane, but this has not been investigated. 

Similarly, bromomethane might be expected to have additive or synergistic interactions with other 

alkylating agents, but this has not been investigated.
BROMOMETHANE 72

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Table 4-1 lists common synonyms, trade names, and other pertinent identification information for 

bromomethane.

Table 4-1. Chemical Identity of Bromomethane

Characteristic Information Reference

Chemical name Bromomethane Windholz 1983

Synonym(s) and registered 

trade name(s)

Methyl bromide; monobromomethane; 

methyl fume; Embafume; Terabol

EPA 1986b; IRIS 2002

Chemical formula CH3Br Windholz 1983

Chemical structure Windholz 1983

CAS Registry Number 74-83-9 Sax and Lewis 1987

CAS = Chemical Abstracts Service 

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Table 4-2 lists important physical and chemical properties of bromomethane.

Table 4-2. Physical and Chemical Properties of Bromomethane

Property Information Reference

Molecular weight 94.94 HSDB 2014

Color Colorless HSDB 2014

Physical state Gas HSDB 2014

Melting point -93.68°C HSDB 2014

Boiling point 3.5°C HSDB 2014

Density at 20°Ca 3.97 at 20°C (gas); 1.73 at 0°C (liquid) HSDB 2014

Odor Usually odorless; sweetish chloroform-like odor at 

high concentrations

HSDB 2014

Odor threshold:

Water No data

Air 80 mg/m3 (20 ppm) Ruth 1986

H C Br

H

H
BROMOMETHANE 73

4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Bromomethane

Solubility:

Water at 20°C 15.2 g/L at 25°C

18.5 g/L at 20°C

13.4 g/L at 25°C

HSDB 2014

Organic solvents Readily soluble in lower alcohols, ethers, esters, 

ketones, halogenated hydrocarbons, aromatic 

hydrocarbons, and carbon disulfide; freely soluble 

in benzene, carbon tetrachloride, and carbon 

disulfide; miscible in ethanol and chloroform

HSDB 2014

Partition coefficients:

Log Kow 1.19 HSDB 2014

Log Koc 0.95–1.3 Yates et al. 2003

Vapor pressure at 20°C 1,420 mmHg HSDB 2014

Henry's law constant at 25°C 0.00734 atm m3/mole HSDB 2014

Autoignition temperature Nonflammable EPA 1986b

Flashpoint Nonflammable EPA 1986b

Flammability limits Nonflammable EPA 1986b

Conversion factorsb 1 ppm=3.88 mg/m3

1 mg/m3=0.26 ppm

Explosive limits Nonflammable EPA 1986b

aDensity of vapor relative to air.

bBased on the following formulas: ppm = (mg/m3) (24.45)/ (molecular weight), and mg/m3 = (ppm) (molecular 

weight)/ 24.45.
BROMOMETHANE 74

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Bromomethane has been identified in at least 94 of the 1,854 hazardous waste sites that have been 

proposed for inclusion on the EPA National Priorities List (NPL) (ATSDR 2017). However, the number 

of sites in which bromomethane has been evaluated is not known. The number of sites in each state is 

shown in Figure 5-1. 

Figure 5-1. Number of NPL Sites with Bromomethane Contamination

• The most likely route of human exposure is by inhalation because bromomethane exists as a gas 

at room temperature. Exposure to higher levels of inhaled bromomethane is more likely to occur 

in occupational settings; exposure of the general population is by bromomethane in ambient air. 

• The general population is not likely to be exposed to bromomethane via the oral route; however, 

exposure to a small amount of bromomethane could occur via contaminated water or food.
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5. POTENTIAL FOR HUMAN EXPOSURE

• Bromomethane is a naturally occurring component of the environment, with oceans representing 

the largest natural source.

• Anthropogenic emissions of bromomethane recently have been markedly reduced due to 

restriction of bromomethane as a fumigant. Currently, the largest anthropogenic emission sources 

of bromomethane are biomass burning in agriculture and the use of biofuels.

• Bromomethane readily volatilizes into air from water and soil, with volatilization increasing with 

temperature.

• In air, the main degradation pathway for bromomethane is reaction with photochemicallygenerated hydroxyl radicals.

• Bromomethane degrades in water through a combination of abiotic (e.g., hydrolysis) and biotic 

processes.

• In soil, bromomethane degrades by three principle mechanisms: hydrolysis, methylation by 

organic matter, and biological oxidation by soil microorganisms.

Bromomethane is a naturally occurring component of the environment, with oceans representing the 

largest natural source (Butler and Rodriguez 1996). In the past, the primary anthropogenic source of 

bromomethane in the environment was from its use as a fumigant in fields and greenhouses to control a 

variety of pests and, to a lesser extent, by automobile exhaust. From 1995 to 1998, the use of 

bromomethane as a fumigant accounted for approximately 40% of all identified sources; however, by 

2012, this use accounted for only about 10% of all sources of bromomethane (UNEP 2015). The use of 

bromomethane as a fumigant has declined about 80% since the mid-1990s. Today, the largest source of 

anthropogenically generated bromomethane arises from biomass burning and the use of biofuels (UNEP 

2015). 

Bromomethane has a high potential for volatilization and tends to partition to the atmosphere where it is 

slowly degraded. Bromomethane that has not degraded in the troposphere will gradually diffuse into the 

stratosphere where it will slowly degrade due to direct photolysis from high-energy UV radiation, which 

releases free bromine radicals, and contributes to the catalytic removal of stratospheric ozone. Because of 
BROMOMETHANE 76

5. POTENTIAL FOR HUMAN EXPOSURE

its ozone-depletion and global warming potential, the United States and most other nations have gradually 

phased out its agricultural use as a fumigant. Bromomethane may only currently be used in the United 

States for two critical use exemptions and for quarantine and preshipment (QPS) purposes (EPA 2016a). 

Levels of bromomethane in the troposphere have been decreasing at a rate of approximately 0.2–0.4 ppt 

per year due to the phase out of its use as an agricultural fumigant (WMO 2011). The 2008 annual mean 

levels of bromomethane were estimated to range from 7.3 to 7.5 ppt (WMO 2011). Prior to the 

widespread use of bromomethane as a fumigant, it was estimated that natural background levels in the 

atmosphere were approximately 5.3 ppt (UNEP 2015). Levels can be several orders of magnitude greater 

where it was applied as a fumigant. For example, bromomethane levels >12 mg/m3 (3 ppm) were 

observed 4 hours postapplication above a field located in California in which it was applied (Yates et al. 

1997). 

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

Bromomethane is produced by reaction of methanol with hydrobromic acid, followed by distillation of 

the product (IARC 1986; Windholz 1983). Table 5-1 summarizes information on U.S. companies that 

reported the manufacture or use of bromomethane in 2017 (TRI17 2019). Toxics Release Inventory 

(TRI) data should be used with caution since only certain types of industrial facilities are required to 

report. This is not an exhaustive list.

Table 5-1. Facilities that Produce, Process, or Use Bromomethane

Statea

Number of 

facilities

Minimum amount on 

site in poundsb

Maximum amount on site 

in poundsb Activities and usesc

AL 2 1,000 9,999 1, 12, 13

AR 1 1,000,000 9,999,999 1, 2, 3, 4, 5, 9

CA 2 10,000 9,999,999 2, 3, 4, 7, 9

FL 1 100,000 999,999 7, 9

GA 1 100,000 999,999 7, 9

IL 1 100 999 1, 5

LA 1 1,000 9,999 1, 5, 13

MO 2 1,000 999,999 1, 5, 6

NC 1 100,000 999,999 7, 9

ND 1 1,000 9,999 12
BROMOMETHANE 77

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Facilities that Produce, Process, or Use Bromomethane

Statea

Number of 

facilities

Minimum amount on 

site in poundsb

Maximum amount on site 

in poundsb Activities and usesc

NE 1 1,000 9,999 12

OH 1 1,000 9,999 12

SC 2 0 9,999 1, 5

TN 1 0 99 1, 5

TX 1 0 99 1, 5, 12

aPost office state abbreviations used. bAmounts on site reported by facilities in each state. cActivities/Uses:

1. Produce

2. Import

3. Used Processing

4. Sale/Distribution

5. Byproduct

6. Reactant

7. Formulation Component

8. Article Component

9. Repackaging

10. Chemical Processing Aid

11. Manufacture Aid

12. Ancillary

13. Manufacture Impurity

14. Process Impurity

Source: TRI17 2019 (Data are from 2017)

According to the National Pesticide Information Retrieval System, there are nine companies in the United 

States manufacturing bromomethane (NPIRS 2016). Several of these products are mixtures of 

bromomethane with another pesticide. The companies, their bromomethane containing products, and the 

active ingredients are provided in Table 5-2. EPA also monitors the amount of bromomethane produced 

and used annually in the United States and releases data regarding its inventory for that calendar year. 

Because not all of the bromomethane that is produced is consumed annually, there may be a surplus at the 

end of the year. Data from 2003 to 2014 are provided in Table 5-3. Numerous countries have also phased 

out the use of bromomethane. Global production of bromomethane for all uses was estimated at

24,866 metric tons in 2013, which is nearly a 70% decrease in production from the early 1990s (UNEP 

2015). 

Table 5-2. U.S. Companies Manufacturing Bromomethane

Company Registered product Active ingredients

Albermerle Corp. M-B-R 98 Technical. EPA registration number 3377-27 98% bromomethane

Great Lakes 

Chemical Corp.

MEH-O-GAS 100. EPA registration number 5785-11 100% bromomethane

TERR-O-GAS 70 preplant soil fumigant. EPA 

registration number 5785-19

70% bromomethane, 

30% chloropicrin

TERR-O-GAS 98. EPA registration number 5785-22 98% bromomethane, 2% 

chloropicrin

TERR-O-GAS 67. EPA registration number 5785-24 67% bromomethane, 

33% chloropicrin
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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-2. U.S. Companies Manufacturing Bromomethane

Company Registered product Active ingredients

TERR-O-GAS 57. Preplant soil fumigant. EPA 

registration number 5785-28

57% bromomethane, 

43% chloropicrin

TERR-O-GAS 75. EPA registration number 5785-40 75% bromomethane, 

25% chloropicrin

METH-O-GAS Q. EPA registration number 5785-41 100% bromomethane

TERR-O-GAS 80. EPA registration number 5785-47 80% bromomethane, 

20% chloropicrin

TERR-O-GAS 50. EPA registration number 5785-48 50% bromomethane, 

50% chloropicrin

Methyl bromide. EPA registration number 5785-51 100% bromomethane

67-63 EPA registration number 5785-52 67% bromomethane, 

33% chloropicrin

98-2 EPA registration number 5785-56 98% bromomethane

Soil Chemicals Corp. PIC-BROM 33. EPA registration number 8536-5 67% bromomethane, 

32.8% chloropicrin

PIC-BROM 55. EPA registration number 8536-6 45% bromomethane, 

54.7% chloropicrin

PIC-BROM 43. EPA registration number 8536-7 43% bromomethane, 

56.7% chloropicrin

PIC-BROM 59. EPA registration number 8536-9 50% bromomethane, 

49.7% chloropicrin

PIC-BROM 25. EPA registration number 8536-11 75% bromomethane, 

24.9% chloropicrin

Methyl bromide 100. EPA registration number 8536-15 100% bromomethane

Methyl bromide 98. EPA registration number 8536-19 98% bromomethane

PIC-BROM 67. EPA registration number 8536-20 33% bromomethane, 

66% chloropicrin

Methyl bromide quarantine fumigant. EPA registration 

number 8536-29 

100% bromomethane

ICP-IL America, Inc. METABROM 100. EPA registration number 8622-16 100% bromomethane

METABROM Q. EPA registration number 8622-55 100% bromomethane

Trical Inc. TRI-CON 57/43. EPA registration number 11220-4 57% bromomethane, 

43% chloropicrin

TRI-CON 67/33. EPA registration number 11220-7 67% bromomethane, 

33% chloropicrin

TRI-CON 75/25. EPA registration number 11220-8 75% bromomethane, 

25% chloropicrin

TRI-CON 50/50. EPA registration number 11220-10 50% bromomethane, 

50% chloropicrin

TRI-CON 45/55. EPA registration number 11220-11 45% bromomethane, 

54.7% chloropicrin

Methyl bromide 89.5. EPA registration number 

11220-17

89.5% bromomethane, 

10.5% chloropicrin

MBC concentrate soil fumigant. EPA registration 

number 11220-32

98% bromomethane
BROMOMETHANE 79

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-2. U.S. Companies Manufacturing Bromomethane

Company Registered product Active ingredients

Bromine Compounds 

LTD

Methyl bromide 100. EPA registration number 15298-4 100% bromomethane

Shadow Mountain 

Products Corp.

TRI-CON 80/20. EPA registration number 58266-1 80% bromomethane, 

19.9% chloropicrin

Triest AG Group, Inc. MBC soil fumigant. EPA registration number 87994-1 68.6% bromomethane

MBC-33. EPA registration number 87994-2 67% bromomethane, 

32.8% chloropicrin

Mebrom Corp. MEBROM 100. EPA registration number 89816-2 100% bromomethane

MEBROM 70-30. EPA registration number 89816-3 70% bromomethane, 

30% chloropicrin

Source: NPIRS 2016

Table 5-3. Bromomethane Inventory in the United States from 2003 to 2014

Year Amount of inventory at the end of the year (metric tons)

2003 16,422

2004 12,994

2005 9,974

2006 7,941

2007 6,458

2008 4,271

2009 3,064

2010 1,803

2011 1,249

2012 627

2013 357

2014 158

Source EPA 2016c

5.2.2 Import/Export

In 1990, the world consumption of bromomethane was >6.7x107 kg (WHO 1994). Global bromomethane 

sales for 1984 to 1990 totaled 389,814 tons, ca. 3.9x108 kg (WHO 1995). According to Chemical Data 

Reporting Submissions Database (EPA 2016e), one reporting facility, a confidential manufacturing 

company, reported 0 pounds of imports for 2012. Two reporting facilities, Albemarle Corporation and 

Chemtura Corporation, reported import volumes as ‘withheld’ for 2012 through 2015 (EPA 2016e).

More detailed data regarding the import and export of bromomethane were not located.
BROMOMETHANE 80

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Use

In the past, the primary use of bromomethane was as a soil or space fumigant for the control of insects 

(insecticide), fungi (fungicide), and rodents (EPA 1986b; IARC 1986). It also had previous applications 

as an acaricide, antimicrobial, herbicide, and nematicide. Space fumigation was usually performed by 

enclosing the structure in a sealed tent and releasing bromomethane gas inside, while soil fumigation was 

usually performed by injecting bromomethane into the soil underneath a nonporous covering. 

Bromomethane was used in pre-planting soil fumigation, quarantine and commodity fumigation, and 

structural fumigation (WHO 1995). Bromomethane is classified as an 8A fumigant by the Insecticide 

Resistance Action Committee; it is a non-specific (multi-site) inhibitor (IRAC 2019). Bromomethane 

was also used in fire extinguishers in Europe from the 1920s through the 1940s (WHO 1995; IARC 1986; 

O’Neil et al. 2014), but never gained widespread use as a fire extinguishing agent in the United States 

(Alexeeff and Kilgore 1983). In the 1960s, use of bromomethane in fire extinguishers was stopped after 

causing fatal accidents (WHO 1995). Bromomethane has been used in ionization chambers; wool 

degreasing; oil extraction of nuts, seeds, and flowers; as a soil or space fumigant for insects, fungi, and 

rodents; and as a methylating agent in the chemical industry (Larrañaga et al. 2016; O’Neil et al. 2014). 

Bromomethane has also been used for the disinfection of potatoes, tomatoes, and other crops (Larrañaga

et al. 2016). EPA has restricted the use of bromomethane to critical uses (EPA 2016a).

Because bromomethane is considered an ozone-depleting substance, the EPA phased out its use under the 

Clean Air Act in 2005; however, some critical use exemptions are still allowed to eliminate quarantine 

pests and for agricultural use where there are no technically or financially feasible alternatives (EPA 

2014a, 2016a). The application of bromomethane is deemed critical if two strict criteria are met: a lack 

of bromomethane availability would result in a significant market disruption and no feasible alternative 

substances are available (EPA 2016a). Only two critical use exemptions were approved by the EPA for 

2016: strawberry farmers in the state of California and dry cure pork producers (EPA 2016a, 2016b). 

The EPA denied critical use exemptions in 2016 for Michigan cucurbit, eggplant, pepper, and tomato 

growers; Florida eggplant, pepper, strawberry, and tomato growers; the California Association of Nursery 

and Garden Centers; California stone fruit, table and raisin grape, walnut, and almond growers; 

ornamental growers in California and Florida; and the U.S. Golf Course Superintendents Association 

(EPA 2015a). For 2016, the EPA is allowing the production and import of 141 metric tons of 

bromomethane for these two critical uses (EPA 2016b). A separate exemption under the Clean Air Act 

exists for the production and consumption of bromomethane for QPS purposes in order to prevent the 
BROMOMETHANE 81

5. POTENTIAL FOR HUMAN EXPOSURE

spread of quarantine pests that may cause disease or result in significant environmental problems (e.g., 

fumigation of logs to control wood-boring pests from imported wood products). Since 1999, global 

consumption of bromomethane for QPS has remained steady at approximately 10,000 metric tons 

annually; however, non-QPS consumption of bromomethane has decreased from approximately 

50,000 metric tons in 1999 to <3,000 metric tons in 2013 (UNEP 2015).

5.2.4 Disposal

National or local regulations must be observed when disposing of bromomethane (WHO 1994). For large 

quantities, controlled incineration is recommended; incineration is hazardous for untrained personnel and 

therefore, only minimal amounts should be released into well-ventilated outdoor air (WHO 1994).

Incineration requires dilution with additional fuel. Safe, efficient methods for loading this toxic gas into 

the combustion chamber must be employed. If an appropriate combustion chamber is unavailable, clearly 

labeled waste containers must be returned to the supplier (UN Hazard Class 2.3, UN Subsidiary Risks 6.1; 

National Fire Protection Association Code: Health 3; Flammability 1; Instability 0) (NOAA 2019; WHO 

1994). Spills may accumulate in lowered spaces as this gas is heavier than air; disposal of spills by 

trained experts includes personal protection requiring complete protective clothing and self-contained 

breathing apparatus; ventilation is critical, and a direct water jet should never be used on spills containing 

bromomethane (WHO 2009). Disposal of fumigant products containing bromomethane, equipment washwaters, or rinsate must not contaminate or be released to water as this pesticide is toxic to mammals and 

birds (EPA 2008a).

5.3 RELEASES TO THE ENVIRONMENT

The Toxics Release Inventory (TRI) data should be used with caution because only certain types of 

facilities are required to report (EPA 2005). This is not an exhaustive list. Manufacturing and processing 

facilities are required to report information to the TRI only if they employ ≥10 full-time employees; if 

their facility is included in Standard Industrial Classification (SIC) Codes 10 (except 1011, 1081, and 

1094), 12 (except 1241), 20–39, 4911 (limited to facilities that combust coal and/or oil for the purpose of 

generating electricity for distribution in commerce), 4931 (limited to facilities that combust coal and/or 

oil for the purpose of generating electricity for distribution in commerce), 4939 (limited to facilities that 

combust coal and/or oil for the purpose of generating electricity for distribution in commerce), 4953 

(limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 5169, 5171, and 

7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities primarily engaged in 
BROMOMETHANE 82

5. POTENTIAL FOR HUMAN EXPOSURE

solvents recovery services on a contract or fee basis); and if their facility produces, imports, or processes 

≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI chemical in a calendar 

year (EPA 2005).

5.3.1 Air

Estimated releases of 294,930 pounds (~133.78 metric tons) of bromomethane to the atmosphere from 

19 domestic manufacturing and processing facilities in 2017, accounted for about 99.98% of the estimated 

total environmental releases from facilities required to report to the TRI (TRI17 2019). These releases are 

summarized in Table 5-4.

Table 5-4. Releases to the Environment from Facilities that Produce, Process, or 

Use Bromomethanea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and offsite

AK 1 41,653 0 0 0 0 41,653 0 41,653 

AL 2 20,000 0 10 0 0 20,010 0 20,010 

CA 2 639 0 0 0 0 639 0 639 

FL 1 608 0 0 0 0 608 0 608 

GA 1 10,601 0 0 0 0 10,601 0 10,601 

IL 1 11,345 0 0 0 0 11,345 0 11,345 

LA 1 0 0 0 0 0 0 0 0 

MO 2 891 0 0 0 0 891 0 891 

NC 1 3,000 0 0 0 0 3,000 0 3,000 

ND 1 2,383 0 0 0 0 2,383 0 2,383 

NE 1 7,350 0 0 0 0 7,350 0 7,350 

OH 1 0 0 0 0 0 0 0 0 

SC 2 102,966 0 0 0 0 102,966 0 102,966 

TN 1 93,494 15 0 31 0 93,540 0 93,540 
BROMOMETHANE 83

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-4. Releases to the Environment from Facilities that Produce, Process, or 

Use Bromomethanea

Reported amounts released in pounds per yearb

Statec RFd Aire Waterf UIg Landh Otheri

Total release

On-sitej Off-sitek

On- and offsite

TX 1 0 0 0 0 0 0 0 0 

Total 19 294,930 15 10 31 0 294,986 0 294,986 

aThe TRI data should be used with caution since only certain types of facilities are required to report. This is not an 

exhaustive list. Data are rounded to nearest whole number.

bData in TRI are maximum amounts released by each facility.

cPost office state abbreviations are used. dNumber of reporting facilities.

eThe sum of fugitive and point source releases are included in releases to air by a given facility. f

Surface water discharges, waste water treatment-(metals only), and publicly owned treatment works (POTWs) 

(metal and metal compounds).

gClass I wells, Class II-V wells, and underground injection. hResource Conservation and Recovery Act (RCRA) subtitle C landfills; other onsite landfills, land treatment, surface 

impoundments, other land disposal, other landfills.

i

Storage only, solidification/stabilization (metals only), other off-site management, transfers to waste broker for 

disposal, unknown

j

The sum of all releases of the chemical to air, land, water, and underground injection wells.

kTotal amount of chemical transferred off-site, including to POTWs.

RF = reporting facilities; UI = underground injection

Source: TRI17 2019 (Data are from 2017)

Since bromomethane is highly volatile, nearly all environmental releases of bromomethane are into the

air. EPA’s National Emission Inventory (NEI) database contains data regarding sources that emit criteria 

air pollutants and their precursors, and hazardous air pollutants (HAPs) for the 50 United States, 

Washington DC, Puerto Rico, and the U.S. Virgin Islands. The NEI database derives emission data from 

multiple sources, including state and local environmental agencies; the TRI database; computer models 

for on- and off-road emissions; and databases related to EPA's Maximum Achievable Control Technology 

(MACT) programs to reduce emissions of HAPs. In 2011, approximately 5,596 metric tons of 

bromomethane were emitted to the environment in the United States according to data submitted to the 

NEI (EPA 2015b). For 2013, the United Nations Environmental Program (UNEP) estimated that total 

anthropogenic global emissions of bromomethane from non-QPS usage (e.g., agricultural soil fumigation 

practices) amounted to 1,673 metric tons and QPS emissions were 7,108 metric tons (UNEP 2015). The 

largest QPS emission (3,874 metric tons) was estimated to arise from usage on timber and wood 

packaging, followed by emissions on durable goods, preplant fumigation, and perishable items (UNEP 

2015).
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5. POTENTIAL FOR HUMAN EXPOSURE

Use of bromine-containing additives (ethylene dibromide) in leaded gasoline results in the release of 

bromomethane in exhaust fumes (about 70–220 μg/m3 of exhaust) (Harsch and Rasmussen 1977), and 

this may have been a significant source of bromomethane release in the past. Combustion of unleaded 

gasoline releases much less bromomethane (about 4–5 μg/m3

), so current emissions from this source are

presumably much lower than previously, and are likely to decrease further as leaded gasoline continues to 

be phased out.

Due to the phase-out of leaded gasoline and the restrictions on bromomethane use as a fumigant, 

anthropogenic emissions of bromomethane are lower than the amount produced from natural sources. 

Currently, the largest estimated anthropogenic emission sources of bromomethane are biomass burning in 

agriculture and the use of biofuels (UNEP 2015). The ocean is both a major source and a sink for 

bromomethane. Estimates suggest that about 56 Gg (56,000 metric tons) of bromomethane are emitted 

from the ocean and uptake is about 77 Gg (77,000 metric tons) annually, resulting in a net sink of about 

21 Gg (21,000 metric tons) (Baker et al. 1999). Others have offered slightly different estimates, but still 

concluded that the ocean acts as a net sink for bromomethane (Butler and Rodriguez 1996; WMO 2011). 

Approximately 10–40 Gg (10,000–40,000 metric tons) of bromomethane are released each year from the 

burning of biomass (Butler and Rodriguez 1996; WMO 2011). Coastal salt marshes have also been 

identified as a natural terrestrial source of bromomethane, with emissions of about 14 Gg (14,000 metric 

tons) annually, and the production of bromomethane and methyl chloride was demonstrated in laboratory 

studies using a variety of terrestrial plants and wood rot fungi (Rhew et al. 2003). A summary of all of 

the different sources and sinks of bromomethane were presented by the World Meteorological 

Organization in its 2010 Scientific Assessment of Ozone Depletion. The UNEP (2015) Report of the 

Methyl Bromide Technical Options Committee also provides a comprehensive review on the emissions of

this substance from both anthropogenic and natural sources. Estimates of the various sources for two 

different temporal periods are provided in Table 5-5.

Table 5-5. Estimated Anthropogenic and Natural Sources of Bromomethane 

(Gg/Year) 1996–1998 and 2008

Sourcesa 1996–1998 (Gg/year) Range (Gg/year) 2008 (Gg/year) Range (Gg/year)

Fumigationdispersive (soils)41.5 28.1–55.6 6.7 4.6–9.0

Fumigation 

quarantine and 

preshipment

7.9 7.4–8.5 7.6 7.1–8.1
BROMOMETHANE 85

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Table 5-5. Estimated Anthropogenic and Natural Sources of Bromomethane 

(Gg/Year) 1996–1998 and 2008

Sourcesa 1996–1998 (Gg/year) Range (Gg/year) 2008 (Gg/year) Range (Gg/year)

Ocean 42 34–49 42 34–49

Biomass burning 29 10–40 29 10–40

Leaded gasoline 5.7 4.0–7.4 <5.7 No data

Temperate 

peatlands

0.6 -0.1–1.3 0.6 -0.1–1.3

Rice paddies 0.7 0.1–1.7 0.7 0.1–1.7

Coastal salt 

marshes

7 0.6–14 7 0.6–14

Based on California 

salt marshes

14 7–29 14 7–29

Based on Scottish 

salt marshes

1 0.5–3.0 1 0.5–3.0

Based on Tasmania 

salt marshes

0.6 0.2–1.0 0.6 0.2–1.0

Mangroves 1.3 1.2–1.3 1.3 1.2–1.3

Shrublands 0.2 0–1 0.2 0 to 1

Rapeseed 4.9 3.8–5.8 5.1 4.0–6.1

Fungus (litter 

decay)

1.7 0.5–5.2 1.7 0.5–5.2

Fungus (leaf-cutter 

ants)

0.5 No data 0.5 No data

aPotential terrestrial sources (tropical trees, temperate woodlands, tropical ferns, and abiotic decomposition) were 

not quantified.

Source: WMO 2011

5.3.2 Water

Estimated releases of 15 pounds (~0.01 metric tons) of bromomethane to surface water from 19 domestic 

manufacturing and processing facilities in 2017, accounted for <1% of the estimated total environmental 

releases from facilities required to report to the TRI (TRI17 2019). This estimate includes releases to 

waste water treatment and publicly owned treatment works (POTWs) (TRI17 2019). These releases are 

summarized in Table 5-4.

Some bromomethane may leach from fumigated soil into surface water (EPA 1986b; IARC 1986). Most 

of this would be expected to quickly volatilize into air, although some could migrate downward into 

groundwater where evaporation is not significant.
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5. POTENTIAL FOR HUMAN EXPOSURE

5.3.3 Soil

Estimated releases of 31 pounds (~0.02 metric tons) of bromomethane to soil from 19 domestic 

manufacturing and processing facilities in 2017, accounted for <1% of the estimated total environmental 

releases from facilities required to report to the TRI (TRI17 2019). An additional 10 pounds 

(~0.005 metric tons), accounted for <1% of the total environmental emissions, were released via 

underground injection (TRI17 2019). These releases are summarized in Table 5-4.

Soil fumigation was the primary use of bromomethane in the United States, historically accounting for 

approximately 65% of total consumption (EPA 1987; IARC 1986). However, the use of bromomethane 

applied to soils as a fumigant has been decreasing rapidly since the late 1990s. Soil fumigation of 

California strawberry crops is still allowed for 2016 and the EPA is allowing 141 metric tons of 

bromomethane to be used for this and one other critical use exemption (EPA 2016b). 

5.4 ENVIRONMENTAL FATE

5.4.1 Transport and Partitioning

Bromomethane is a readily volatile compound, with a boiling point of 3.6°C (Windholz 1983) and a 

vapor pressure at 20°C of 1,420 mmHg (EPA 1982). Consequently, bromomethane has a strong 

tendency to volatilize into air from other media (soil, water). Because bromomethane is quite soluble in 

water (approximately 13–18 g/L) (EPA 1986b), some bromomethane in air may partition into clouds and 

rain, where it may be redeposited to the earth by wet deposition. 

Anderson et al. (1996) used soil column studies to assess the volatilization rate of bromomethane applied 

as a pressurized liquid to the surface of a sandy clay loam (53% sand, 29% silt, 17% clay, 3.1% organic 

matter, pH 6.6) as a function of temperature and moisture content. The results indicated that 

volatilization of bromomethane from the soil surface was rapid and positively correlated with increasing 

temperature and moisture content. At a constant soil moisture tension of 0.3 bar, 27.3, 30.4, and 50.9% of 

the applied bromomethane was volatilized after 3 hours at temperatures of 15, 25, and 35°C, respectively. 

After 119 hours, 32.2, 35.2, and 54.4% of the applied bromomethane was lost to volatilization at 15, 25, 

and 35°C, respectively. At a constant incubation temperature of 25°C, 4.0, 28.7, 28.0, and 66.3% of the 

applied bromomethane was volatilized at 3, 1, 0.3, and 0.03 bar tension, respectively, after 2 hours. After 

72 hours, 4.1, 28.9, 34.7, and 66.7% was volatilized at 3, 1, 0.3, and 0.03 bar tension, respectively 
BROMOMETHANE 87

5. POTENTIAL FOR HUMAN EXPOSURE

(Anderson et al. 1996). Volatilization of bromomethane from three soils consisting of different organic 

matter content showed large variations in the amounts volatilized versus the amounts degraded (Gan et al. 

1996, 1997). Forty mL of bromomethane gas was injected to a depth of 30 cm into packed columns of 

low organic matter containing soils: a Greenfield sandy loam (0.92% organic matter) or a Carsitas loamy 

sand (0.22% organic matter). Similar experiments were conducted using Linne clay loam with greater 

organic matter content (2.99% organic matter). Cumulative volatilization losses from the two low organic 

matter containing soils were approximately 90%; however, only 44% of the applied bromomethane was 

volatilized from the Linne clay loam, with about half being degraded. Only about 10% degradation 

occurred in the two low organic matter containing soils. Additional experiments were conducted to 

determine the effect of moisture content on the rate of volatilization. Increasing the volumetric moisture 

content of the Greenfield sandy loam from 0.058 to 0.180 cm3

/cm3 resulted in a 17% decrease in the 

amount of bromomethane that was volatilized (Gan et al. 1996). It was concluded that as the moisture 

content increased, the effective diffusion coefficient of bromomethane in the soil decreased, resulting in a 

lower surface volatilization flux and greater degradation (Gan et al. 1996, 1997); these results are in 

contrast to the findings of Anderson et al. (1996). Similarly, it was observed that soils with higher bulk 

density tended to have lower volatilization rates since the effective diffusion coefficient of bromomethane 

and other gasses in these soils are lower as compared to soils with lower bulk density. 

It is common practice to cover treated fields with tarps immediately following fumigation in order to limit 

volatilization loss of the fumigant and maximize the impact of fumigant vapors on the treated soils. 

Historically, high-density polyethylene (HDPE) tarps were used in agriculture as the standard barrier film; 

however, HDPE is semi-permeable to gases such as bromomethane and other fumigants. The 

development of high barrier totally impermeable film tarps (TIF) (HDPE-based films containing 

multilayer polymers composed of ethylene vinyl alcohol) or virtually impermeable films (VIF) (HDPE or 

low-density polyethylene [LDPE] films containing nylon or vinyl polymers) have shown better 

performance at reducing volatilization losses of bromomethane and other fumigants (Fennimore and Ajwa 

2011; Freeman 2015). Volatilization losses from soil columns treated with bromomethane and methyl 

iodide were monitored using HDPE tarps or high-barrier TIF tarps, or left completely uncovered 

following fumigation (Gan and Yates 1996; Gan et al. 1997). In each experiment, it was observed that 

greater volatilization losses occurred in soils that were left uncovered and contained the lowest amounts 

of organic matter. The authors also observed that under similar conditions, a greater percentage of methyl 

iodide was volatilized as compared to bromomethane due to the relatively slow rate of degradation of 

methyl iodide when compared to bromomethane (Gan and Yates 1996; Gan et al. 1997). Using a 

Greenfield sandy loam with approximately 0.92% organic matter, the cumulative volatilization loss of 
BROMOMETHANE 88

5. POTENTIAL FOR HUMAN EXPOSURE

bromomethane injected as a cooled liquid to a depth of 30 cm below the surface was 75, 68, and 45% for 

an uncovered soil column, a soil column covered with HDPE, and a soil column covered with a TIF tarp, 

respectively (Gan et al. 1997). Volatilization was significantly decreased in similar experiments using 

soils containing a higher percentage of organic matter. For example, only 30% of the applied 

bromomethane was volatilized from a nursery potting soil containing 9.60% organic matter and covered 

with a HDPE film. Packed soil column experiments using a low organic Arlington sandy loam (0.92% 

organic matter, pH 7.2) indicated that approximately 88% of the injected bromomethane was volatilized if 

the soil surface was left uncovered (Gan et al. 2000). Volatilization losses were 83 and 55% of the 

nominal concentration when the soil columns were covered with a HDPE tarp and a high-barrier TIF tarp, 

respectively (Gan et al. 2000). The addition of soil amendments rich in organic matter was also shown to 

reduce volatilization losses of bromomethane by enhancing the rate of degradation (Gan et al. 1998). 

Applying 5% composted manure to soil columns treated with bromomethane reduced volatilization 

approximately 12% as compared to unamended soil columns (Gan et al. 1998).

Majewski et al. (1995) monitored postapplication volatilization losses of a bromomethane/chloropicrin 

(67%/33%) fumigant in field experiments in Monterey County, California in which bromomethane was 

injected into the soil and then the fields were either left uncovered or were covered with tarps (Majewski 

et al. 1995). The fumigant was injected to a depth of 25–30 cm in pressurized liquid form at an 

application rate of 392 kg/ha to fields located approximately 6 km away from one another. One field was 

immediately covered with a high-barrier TIF plastic tarp, while the other field was left uncovered. Both

fields were Salinas clay loam with similar physical properties and moisture content. The primary 

difference between the properties of the soils was that the non-tarped field contained a greater content of 

organic carbon (2.30%) than the tarped field (1.40%) and possessed higher clay content, but a lower silt 

content. Cumulative volatilization losses of bromomethane were approximately 22 and 32% at 5 and 

9 days postapplication, respectively, for the tarp-covered field, while the cumulative volatilization loss of 

bromomethane from the uncovered field was about 89% 5 days postapplication (Majewski et al. 1995). 

The maximum volatilization flux of bromomethane from the covered field occurred about 20 hours 

postapplication and was 91 μg/m2

-second, while the maximum volatilization flux from the uncovered 

field was about 4 times greater and occurred at <3 hours postapplication. 

Field studies conducted in California demonstrated the effectiveness of deep injection depths, irrigation, 

and postapplication tarping practices at reducing bromomethane volatilization from treated fields (Wang 

et al. 1997). Bromomethane was injected into Arlington fine sandy loam (64% sand, 29% silt, 7% clay) 

in experimental plots constructed at the University of California Agricultural Experimental Station in 
BROMOMETHANE 89

5. POTENTIAL FOR HUMAN EXPOSURE

Riverside, California. When bromomethane was applied as a gas at an injection depth of 25 cm, 

cumulative volatilization losses were 87, <42, and 59% for uncovered plots, plots that were immediately 

irrigated and covered by HDPE tarps, and non-irrigated plots covered by HDPE tarpaulins, respectively. 

At a deeper injection depth of 60 cm, the volatilization losses decreased to 60, 15, and <15% for 

uncovered plots, HDPE covered plots, and plots covered by a Hytibar plastic tarp, respectively.

Bromomethane, either as a gas or dissolved in water, has relatively low affinity for soils (Brown and 

Rolston 1980; Fuhr et al. 1948). Koc values in the ranges of 1–10 (EPA 1986b; Roy and Griffin 1985) and 

9–22 (Yates et al. 2003) suggest that this compound possesses high mobility and could ultimately leach 

into groundwater. However, the rapid volatilization and degradation rates of bromomethane in soil will 

reduce the potential of this chemical to leach. The lack of detection of bromomethane in groundwater 

(see Section 5.5.2 water monitoring data) strongly suggests that although bromomethane is very mobile in 

soils, it is either volatilized or degraded before migrating to lower soil horizons and contaminating 

groundwater. 

Bromomethane is not expected to bioconcentrate in aquatic organisms because of its low octanol/water 

partition coefficient (Kow) (estimated to be about 13) (EPA 1979a). The bioconcentration factor (BCF) 

for bromomethane has not been measured experimentally. However, based on an empirical relation 

between the BCF and the Kow (Neely et al. 1974), the estimated BCF for bromomethane is about 3. This 

low estimated BCF indicates that bromomethane is not likely to bioconcentrate in aquatic organisms 

(EPA 1986b).

5.4.2 Transformation and Degradation

Air. The main degradation pathway for bromomethane in the troposphere is reaction with 

photochemically-generated hydroxyl radicals. The rate constant for this reaction has been measured to be 

4.02x10-14 cm3

/molecule-second at 25°C (Atkinson 1989), which corresponds to an atmospheric half-life 

of about 266 days, assuming a hydroxyl radical concentration of 1.5x106 molecules/cm3 and a 12-hour 

day. Due to the long atmospheric half-life, some bromomethane will gradually diffuse into the 

stratosphere above the ozone layer where it will slowly degrade due to direct photolysis from high-energy 

UV radiation and contribute to the catalytic removal of stratospheric ozone. The direct photolysis halflife in the stratosphere is estimated to be about 35 years (Butler and Rodriguez 1996). The total lifetime 

of atmospheric bromomethane is calculated by summing its reciprocal lifetime due to each major sink as 

shown in the equation below (Butler and Rodriguez 1996; WMO 2011; Yvon and Butler 1996):
BROMOMETHANE 90

5. POTENTIAL FOR HUMAN EXPOSURE

where ttotal is the total lifetime of atmospheric bromomethane, tp is the lifetime in the troposphere and 

stratosphere, to is the lifetime due to ocean uptake, and ts represents the lifetime due to terrestrial uptake. 

Using lifetimes of 1.7, 2.7, and 3.4 years for tp, to, and ts, the total atmospheric lifetime of bromomethane 

(ttotal) was estimated as 0.8 years (Shorter et al. 1995; Yvon and Butler 1996). There is a great deal of 

uncertainty in this estimate, however, since all of the sources and sinks of bromomethane are not 

thoroughly understood; therefore, this lifetime can only be considered a best estimate for the global 

lifetime of atmospheric bromomethane. 

Water. Bromomethane degrades in water through a combination of abiotic and biotic processes. 

Hydrolysis of bromomethane takes place by SN2 nucleophilic substitution reaction, yielding methanol, the 

bromide anion, and the hydrogen ion as hydrolysis products. At neutral pH and a temperature of 25°C, 

the half-life of bromomethane in nonsterile purified deionized water was reported as 20 days (Papiernik et 

al. 2000). The hydrolysis half-life of bromomethane was studied in distilled water over a pH range of 3–

8, and at temperatures of 18 and 30°C (Gentile et al. 1989). At 18°C, the hydrolysis half-lives of

bromomethane were reported as 29, 19, 12, and 9 days at pH 3, 5, 7, and 8, respectively. When the 

temperature was increased to 30°C, the observed half-lives were 28, 18, 10, and 8 days at pH 3, 5, 7, and 

8, respectively, in the distilled water. Slightly longer hydrolysis half-lives were observed in groundwater 

with a pH of 7.5–7.8. Half-lives ranging from 36 to 50 days were observed at 18°C, and half-lives 

ranging from 15 to 19 days were observed in the groundwater at 30°C (Gentile et al. 1989). A 6–7-fold 

increase in the rate of hydrolysis was observed when an aqueous solution of bromomethane maintained at 

neutral pH was irradiated with UV light at 254 nm (Castro and Belser 1981). The enhanced degradation 

was attributed to hydrolysis of an excited state of bromomethane, but since this compound has only weak 

absorption above 290 nm, it is uncertain whether this enhanced hydrolysis rate is important under 

environmental conditions. 

Goodwin et al. (1998) studied the microbial oxidation of bromomethane in freshwater, estuary water, 

coastal seawater, and hypersaline-alkaline water by monitoring the production of 14CO2 from samples of 

14CH3Br incubated in the different water types. Calculated half-lives were approximately 5, 36, 82, and 

298 days for the freshwater, estuary water, coastal seawater, and hypersaline-alkaline water samples, 

total p o s

τ τ t τ

1 1 1 1

= + +
BROMOMETHANE 91

5. POTENTIAL FOR HUMAN EXPOSURE

respectively (Goodwin et al. 1998). No 14CO2 production was observed for sterilized controls. These 

data suggest that biotic degradation processes will occur at a rate similar to the hydrolysis rate in 

freshwater, but microbial degradation appears to be slower in seawater given these results. 

Bromomethane was shown to be oxidized using water samples obtained at different depths from Mono 

Lake, California (Connell et al. 1997). Oxidation only occurred in nonsterilized lake water samples, 

suggesting microbial-induced degradation as opposed to abiotic degradation mechanisms. 

Sediment and Soil. Bromomethane degrades in soil by three principle mechanisms: hydrolysis, 

methylation by organic matter, and biological oxidation by microorganisms in the soil. For soils rich in 

organic matter, degradation by reaction with nucleophilic sites in the organic matter is thought to be the 

primary mechanism responsible for the consumption of bromomethane, whereas hydrolysis and 

microbially mediated oxidation are the main degradation mechanisms for soils of low organic matter 

content. 

Evidence suggests that bromomethane undergoes nucleophilic substitution with sites in soil organic 

matter, resulting in the methylation of the organic matter and the release of the bromide anion (Papiernik 

et al. 2000). To study its abiotic degradation mechanisms, bromomethane was incorporated in an 

Arlington sandy loam (74.6% sand, 18.0% silt, 7.4% clay, 9.2 g/kg organic carbon, pH 6.73) and a Linne 

clay loam (36.7% sand, 32.0% silt, 31.3% clay, 25.1 g/kg organic carbon, pH 6.80) under sterile and 

nonsterile conditions (Papiernik et al. 2000). The half-lives of bromomethane in the Arlington sandy 

loam were approximately 38.5 and 46.2 days in non-autoclaved and autoclaved samples, respectively. 

Shorter half-lives of approximately 3.6 and 4.2 days were observed in non-autoclaved and autoclaved 

Linne clay loam samples, respectively. Because the rates of degradation were similar in the autoclaved 

and the non-autoclaved soil experiments, the authors concluded that abiotic processes were largely 

responsible for the observed loss rather than microbial activity. The greater content of organic matter in 

the Linne clay loam also resulted in much greater degradation rates as compared to the lower organic 

containing Arlington sandy loam. This observation is consistent with the data of Gan and Yates (1996), 

which observed a similar correlation between the consumption of bromomethane and soil organic matter 

content. In four soils containing 0.92, 2.51, 2.99, and 9.60% organic matter, the half-lives of 

bromomethane were reported as 22, 6, 6, and 6 days, respectively, and there was no statistically 

significant difference in degradation rates in sterilized versus nonsterilized soils, which again suggests the 

importance of abiotic transformations rather than microbially mediated degradation (Gan and Yates 

1996). 
BROMOMETHANE 92

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Gan et al. (1994) studied the degradation of bromomethane in four California surface soils: Greenfield 

sandy loam (9.5% clay, 0.921% organic matter, pH 7.39), Wasco sandy loam (4.3% clay, 0.646% organic 

matter, pH 6.98), Linne clay loam (25.1% clay, 2.989% organic matter, pH 7.23), and Carsetas loamy 

sand (0.1% clay, 0.222% organic matter, pH 8.02) under moist, air-dried, and oven-dried conditions (Gan 

et al. 1994). The authors determined that the degradation of bromomethane was highly correlated with 

the amount of organic matter and nitrogen content contained in moist and air-dried soils, but not ovendried soils. Half-lives of approximately 11–33 and 6–39 days were calculated for the four soils under 

moist and air-dried conditions, respectively, while half-lives of roughly 27–59 days were estimated in the 

oven-dried soil experiments. 

Accelerated rates of bromomethane degradation were observed in experiments conducted employing six 

soils used to grow strawberries in California (Trikey-Dotan and Ajwa 2014). A bromomethane 

(67%)/chloropicrin (33%) mixture was applied at a rate of 100 mg/kg to 100 g of soil from the six 

different plots in sealed glass vials. In order to test the dissipation rates after repeated applications, soils

were chosen from three locations (Oxnard, Salinas, and Watsonville) that either had been previously 

fumigated with chloropicrin or had never been fumigated. Half-lives ranged from under an hour to 

approximately 15 hours in the six soils. The half-lives of bromomethane in the Salinas and Watsonville 

soils were significantly shorter in the nontreated soils as compared to the previously fumigated soils. In 

contrast, a slightly longer half-life (14.5 hours) was observed in the nontreated soil from Oxnard as 

compared to the previously treated soil (half-life 11.6 hours). Unlike other studies, the authors did not 

find any significant correlation between soil properties and the degradation rate of bromomethane in these 

soils and surmised that the accelerated degradation rates of bromomethane observed in these soils was the 

result of biotic processes.

The bacterial oxidation of bromomethane under aerobic conditions in methanotrophic soils (soils 

containing bacteria that readily oxidize methane) has been demonstrated (Ou 1998). Using an application 

rate of 1,000 mg/g, bromomethane was completely degraded within 40–90 hours under aerobic conditions 

in methanotrophic soils. At an application rate of 10 mg/g, bromomethane was completely degraded in 

5 hours under aerobic conditions, but degraded very slowly under anaerobic conditions (Ou 1998). 

Formaldehyde and the free bromide anion were reported as the primary degradation products (Ou 1998). 

The authors remarked that the majority of agricultural soils in the United States are not methanotrophic 

and have low methane oxidizing capabilities, so this may not be a particularly important environmental 

fate process. Low levels of bromomethane were shown to be rapidly degraded by an agricultural (corn 

field) soil and highly organic forest soil obtained from southern New Hampshire under aerobic conditions 
BROMOMETHANE 93

5. POTENTIAL FOR HUMAN EXPOSURE

(Hines et al. 1998). Bromomethane applied to vials of soil at 10 ppb was completely consumed in the 

forest soil in a matter of minutes, and in the agricultural soil in a matter of hours. Almost no degradation 

occurred in autoclaved soils or soils that had previously been sterilized by the addition of antibiotics 

12 hours earlier, confirming that the source of degradation was biological. Experiments conducted using 

high levels of bromomethane (10–10,000 ppm) resulted in toxicity to the microbes and much slower 

degradation rates. Experiments conducted under a nitrogen-rich environment also showed little 

degradation of bromomethane for any of the soils tested, suggesting that biodegradation is very slow 

under anaerobic conditions. Although biodegradation under anaerobic conditions is considered to occur 

slowly in the environment, Oremland et al. (1994) demonstrated that bromomethane may react with free 

sulfide commonly found in anaerobic sediments and salt marshes, resulting in the production of 

methylated sulfur reaction products, which in turn are degraded by sulfate-reducing bacteria. 

5.5 LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to bromomethane depends, in part, on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of bromomethane in unpolluted atmospheres and in pristine surface waters are often so 

low as to be near the limits of current analytical methods. In reviewing data on bromomethane levels 

monitored or estimated in the environment, it should also be noted that the amount of chemical identified 

analytically is not necessarily equivalent to the amount that is bioavailable.

Table 5-6 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. An overview summary of the range of concentrations detected in environmental media is 

presented in Table 5-7.

Table 5-6. Lowest Limit of Detection Based on Standardsa

Media Detection limit Reference

Air 0.2 ppb LeFevre et al. 1989

Drinking water 0.01 μg/L EPA 1988c

Surface water and groundwater 0.01 μg/L EPA 1988c

Whole blood 3 ng/mL blood Pellizzari et al. 1985

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.
BROMOMETHANE 94

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Table 5-7. Summary of Environmental Levels of Bromomethane

Media Low High For more information

Outdoor air (ppbv)a Not reported 0.46b Section 5.5.1

Outdoor (ppbv)c 0.04 8.7 Section 5.5.1

Surface water (ppb) Not detected Section 5.5.2

Ground water (ppb) 0.50 6.4 Section 5.5.2

Drinking water (ppb) Detected but not quantified Section 5.5.2

Food (ppb) Not detected Section 5.5.4

Soil No data No data Section 5.5.3

aAmbient air, non-agricultural areas. bData collected 2015 (EPA 2019a); median: 0.007 ppbv. cAgricultural areas near bromomethane use.

Detections of bromomethane in air, water, and soil at NPL sites are summarized in Table 5-8.

Table 5-8. Bromomethane Levels in Water, Soil, and Air of National Priorities List 

(NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

quantitative 

measurements NPL sites

Water (ppb) 7.00 11.5 10.9 10 10

Soil (ppb) 10.9 11.8 2.68 4 4

Air (ppbv) 0.700 0.325 10.4 4 4

aConcentrations found in ATSDR site documents from 1981 to 2017 for 1,854 NPL sites (ATSDR 2017). Maximum 

concentrations were abstracted for types of environmental media for which exposure is likely. Pathways do not 

necessarily involve exposure or levels of concern.

5.5.1 Air

The global annual mean mixing ratio of bromomethane in the troposphere for 2008 was reported to range 

from about 7.3 to 7.5 pptv (0.0073–0.0075 ppbv), which is a decrease of about 20% from the estimates 

from 1996 to 1998, prior to the large-scale phase-out of bromomethane’s use as an agricultural fumigant 

(WMO 2011). Background atmospheric levels of bromomethane were estimated to be approximately 

5.3 pptv (0.0053 ppbv) prior to the introduction of this substance as a fumigant in the 1940s (UNEP 

2015).
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Data from the EPA Air Quality System (AQS) database are consistent with current estimates for levels of 

bromomethane in the atmosphere provided by the WMO and UNEP. Table 5-9 shows the annual mean 

24-hour percentile distributions of bromomethane from multiple monitoring locations across the nation 

for the years 2010–2018 (EPA 2019a). 

Table 5-9. Percentile Distribution of Annual Mean Bromomethane 

Concentrations (ppbv) Measured in Ambient Air at Locations 

Across the United States

Year

Number of U.S. 

locations 25th 50th 75th 95th Maximum

2010 257 0.0046 0.0088 0.013 0.043 0.14

2011 231 0.0028 0.0068 0.011 0.039 0.21

2012 231 0.00 0.0081 0.011 0.027 0.14

2013 217 0.00 0.0040 0.0089 0.021 0.13

2014 197 0.00 0.0090 0.011 0.024 0.90

2015 175 0.00 0.0034 0.012 0.026 0.40

2016 159 0.00 0.005 0.018 0.049 0.26

2017 124 0.00 0.00 0.00 0.022 0.31

2018 105 0.00 0.00 0.00 0.017 0.14

Source: EPA Air Quality System (AQS) annual summaries (EPA 2019a)

The 2013 National Monitoring Program sponsored by the EPA compiled 24-hour air sample data from 

66 monitoring sites located in 26 states across the United States (EPA 2015c). Samples from 34 sites 

were assessed for volatile organic compounds, including bromomethane. Bromomethane was detected 

above the detection limits in 1,404 out of 1,883 samples collected at a maximum concentration of 

3.37 ppbv (EPA 2015c). The arithmetic mean was reported as 0.014 ppbv and the median value was 

0.011 ppbv. 

In agricultural areas where bromomethane is applied as a fumigant, ambient air levels are often higher 

than in non-agricultural areas. Average concentrations at five monitoring sites in Ventura County, 

California were 0.02–0.39 ppbv with a highest 1-day concentration of 3.90 ppbv at one location over the 

monitoring period August 22 to September 30, 2005, which coincided with high bromomethane usage for

this county (Cal EPA 2008). Average concentrations of 0.22–0.88 ppbv with a highest 1-day 

concentration of 5.92 ppbv were reported for Ventura County for sampling period June 14 to August 6, 

2006 (Cal EPA 2008). Bromomethane was detected in all 23 samples of air obtained from urban 

communities in California that had high use of 1,3-dichloropropene and secondary use of bromomethane 
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at a mean concentration of 0.69 μg/m3 (0.17 ppbv) and in all 30 samples of air from urban communities 

that had high use of bromomethane and secondary use of 1,3-dichloropropene at a mean concentration of 

5.2 μg/m3 (1.3 ppbv) (Lee et al. 2002). In rural communities that had high use of 1,3-dichloropropene 

and secondary use of bromomethane, bromomethane was detected in 117 out of 118 air samples at a mean 

concentration of 2.5 μg/m3 (0.63 ppbv) and in rural communities with high bromomethane usage and 

secondary usage of 1,3-dichloropropene, it was detected in 149 out of 149 air samples at a mean of 

12 μg/m3 (3.0 ppbv) (Lee et al. 2002). Table 5-10 shows some monitoring data for bromomethane at 

various communities in California where it was applied as a fumigant. 

Table 5-10. Ambient Air Concentrations in Parts per Billion Near Areas of 

Bromomethane Use

Concentration (ppbv) Location (California) Date Sampling details Reference

0.2–8.7 Camarillo/Oxnard 2010–2014 Data represents the highest 

1-day concentration for each 

of the years

Cal EPA 2015

0.1–1.8 Watsonville 2010–2014 Data represents the highest 

1-day concentration for each 

of the years

Cal EPA 2015

0.6–3.8 Santa Maria 2010–2014 Data represents the highest 

1-day concentration for each 

of the years

Cal EPA 2015

0.13 Watsonville 2012 1-Year overall average 

concentration

Cal EPA 2014

0.45 Watsonville 2013 1-Year overall average 

concentration

Cal EPA 2014

0.26 Salinas 2011 1-Year overall average 

concentration

Cal EPA 2014

0.09 Salinas 2012 1-Year overall average 

concentration

Cal EPA 2014

0.39 Salinas 2013 1-Year overall average 

concentration

Cal EPA 2014

0.20 Santa Maria 2011 1-Year overall average 

concentration

Cal EPA 2014

0.09 Santa Maria 2012 1-Year overall average 

concentration

Cal EPA 2014

0.15 Santa Maria 2013 1-Year overall average 

concentration

Cal EPA 2014

0.17 Ripon 2011 1-Year overall average 

concentration

Cal EPA 2014

0.08 Ripon 2012 1-Year overall average 

concentration

Cal EPA 2014

0.11 Ripon 2013 1-Year overall average 

concentration

Cal EPA 2014
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Table 5-10. Ambient Air Concentrations in Parts per Billion Near Areas of 

Bromomethane Use

Concentration (ppbv) Location (California) Date Sampling details Reference

0.23 Camarillo/Oxnard 2011 1-Year overall average 

concentration

Cal EPA 2014

0.10 Camarillo/Oxnard 2012 1-Year overall average 

concentration

Cal EPA 2014

0.06 Camarillo/Oxnard 2013 1-Year overall average 

concentration

Cal EPA 2014

0.11 Shafter 2011 1-Year overall average 

concentration

Cal EPA 2014

0.06 Shafter 2012 1-Year overall average 

concentration

Cal EPA 2014

0.04 Shafter 2013 1-Year overall average 

concentration

Cal EPA 2014

0.631 Parlier 2006 Highest 1-day concentration Wofford et al. 

2014

1.02 Monterey 1986 Mean concentration Baker et al. 

1996

1.10 Monterey 1986 Maximum concentration Baker et al. 

1996

Highest air levels of bromomethane are usually observed locally at field sites shortly following its 

application or at facilities where it is used as a fumigant. These situations appear to be the greatest acute 

exposure scenarios for humans. Bromomethane peak concentrations of 12.4 and 13.4 mg/m3 (3.14 and 

3.39 ppmv) were observed 4 hours postapplication above a field located in Moreno Valley, California in 

which bromomethane was injected at a depth of 25 cm (Yates et al. 1997). At a deeper injection depth 

(68 cm), the maximum concentration measured at 0.5 m above the field was 0.625 mg/m3 (0.158 ppmv) 

and occurred roughly 12 hours postapplication. Bromomethane levels as high as 20 ppmv were observed 

in sealed trailers used to transport grapes that had been fumigated with bromomethane and 7 ppmv inside 

the refrigerated area at a facility (O’Malley et al. 2011). Table 5-11 summarizes bromomethane levels 

under high exposure scenarios.

Table 5-11. Bromomethane Levels Following Fumigation

Concentration (ppmv) Sampling details Reference

10–20 Inside trailer transporting grapes fumigated 

with bromomethane with vent doors closed

O’Malley et al. 2011

2.0–4.0 Enclosed refrigerated building storing 

fumigated grapes

O’Malley et al. 2011
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Table 5-11. Bromomethane Levels Following Fumigation

Concentration (ppmv) Sampling details Reference

3.14–3.39 Peak concentration above a treated field 

when bromomethane was injected at a 

shallow 25 cm depth

Yates et al. 1997

~45 Peak concentration inside of a greenhouse 

shortly after fumigation

De Vreede et al. 1998

5.5.2 Water

Bromomethane occurs in ocean waters at a concentration of about 1–2 ng/L (0.001–0.002 μg/L) 

(Lovelock 1975; Singh et al. 1983), but is not a common contaminant in fresh waters in the United States. 

It was not detected in storm water runoff from 15 U.S. cities (Cole et al. 1984) or in influents to sewage 

treatment plants in four cities (EPA 1979b), and was detected in only 1.4% of >900 surface

water samples recorded in the STORET database (Staples et al. 1985). The median concentration in these 

positive samples was <10 μg/L. Bromomethane was not detected in 297 surface water samples for which 

it was analyzed for in 2015 in the STORET database (EPA 2016d). Bromomethane has been identified, 

but not quantified, in drinking water supplies of several U.S. cities (Coleman et al. 1976; EPA 1975; Kool 

et al. 1982; Kopfler et al. 1977; EPA 1976). Bromomethane in drinking water is presumably generated as 

an inadvertent byproduct following chlorination. Bromomethane was monitored as part of the 

Unregulated Contaminant Monitoring Rule (UCMR-3) program to collect data for contaminants 

suspected to be present in drinking water, but that do not have health-based standards set under the Safe 

Drinking Water Act (SDWA). Bromomethane was detected above its minimum reporting level 

(0.2 μg/L) but not above its reference concentration (140 μg/L) in 115 out of 36,848 samples of drinking 

water obtained from public water systems (PWSs) (EPA 2017). It was detected above its minimum 

reporting level but not above its reference concentration in 49 out of 4,916 PWSs that reported results. 

Observation of bromomethane in groundwater is somewhat more likely than in surface water, since 

evaporation is restricted. Bromomethane was detected at a concentration of 0.50 μg/L in groundwater at 

1 out of 1,831 sites sampled by the U.S. Geological Survey (USGS) in monitoring studies conducted from 

1992 to 1996 (Kolpin et al. 2000). Bromomethane was not detected in any of the 40 principal aquifers in 

the United States that are used for drinking water during a USGS assessment from 1991 to 2010. 

However, it was detected in 1 of the 22 urban aquifers (0.09% of total) at 0.29 μg/L. The laboratory 

reporting levels ranged from 0.1 to 0.4 μg/L (USGS 2015). A review of the EPA Pesticides in 

Groundwater Database showed that bromomethane was detected in only 2 out of 20,429 groundwater 
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wells sampled from 1971 to 1991 (EPA 1992). Both detections occurred at sampling locations in 

California at levels of 1.5 and 6.4 μg/L. There were no detections of bromomethane in 15,119 wells 

sampled in Florida and no detections in 93 wells sampled in Hawaii over the 2-decade study period. 

Plumb (1992) analyzed the occurrence of bromomethane and other contaminants in wells at active and 

abandoned hazardous waste sites for different regions of the country. Bromomethane was not detected in 

any wells covering EPA Regions 1, 2, 4, 5, 6, 7, 8, and 10; however, it was detected in 3.2% of 

groundwater wells in EPA Region 3 (Pennsylvania, West Virginia, Maryland, District of Columbia, and 

Delaware) and 0.8% of the groundwater wells in EPA Region 9 (California, Nevada, Utah, Hawaii, 

Guam, Samoa, Northern Mariana Islands, and Trust Territories). Bromomethane was not detected in 

1,174 community wells or 617 private wells located in Wisconsin (Krill and Sonzogni 1986). 

5.5.3 Sediment and Soil

No data were found on bromomethane levels in soil. Bromomethane is not expected to be a stable 

constituent of soil, since it either evaporates or reacts with organic soil components releasing the bromide 

ion. The background bromide content of soils normally is about ≤10 mg/kg depending upon the soil type 

(WHO 1995). Bromide ion concentrations were measured in greenhouse soil before and after the 

application of bromomethane at a rate of 80 g/m2

. Prior to fumigation, bromide levels were about 

5 mg/kg. Two months post treatment, bromide levels of >30 mg/kg were observed; however, these levels 

decreased to <10 mg/kg 3 months later. The total bromide ion concentrations in two soils containing 

2.81 and 0.93% organic carbon were 9 and 5 mg/kg, respectively, before application of bromomethane 

(IARC 1986). Following the application of bromomethane at a rate of 500 mg/kg to both soils, the

bromide ion concentration increased to 63 mg/kg for the soil containing 2.81% organic carbon and 

25 mg/kg for the soil containing 0.93% organic carbon after 24 hours (IARC 1986).

5.5.4 Other Media

Although bromomethane was used extensively as a fumigant for grains and other food products, it is 

rarely detected unchanged as a residue in foods. Most of the fumigant is rapidly lost to the atmosphere, 

and the remaining portion reacts with the food components, producing residues of inorganic bromide 

(IARC 1986; NAS 1978). Daft (1987, 1988, 1989) reported that bromomethane was not detected in 

hundreds of tested food products. The tolerances for residues on agricultural commodities and processed 

foods that have been set by EPA and FDA are for bromide ion, not bromomethane (EPA 2014b). 

Bromide ion is a frequently detected component in food samples. For example, it was detected in 27.9% 
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of lettuce samples, 27% of tomato samples, and 37.3% of rye tested in a European Union report on 

pesticide residues in food (EFSA 2015); however, bromide ion is a naturally occurring component in 

plants and it is not a unique indicator for bromomethane usage.

5.6 GENERAL POPULATION EXPOSURE

Inhalation of bromomethane in ambient air is the predominant exposure route for most people in the 

United States. Singh et al. (1981) calculated that average daily doses of bromomethane from air in 

three U.S. cities ranged from 4.5 to 24.5 μg/day, based on total air intake of 23 m3

/day by an adult. These 

estimates were based on 1979 monitoring data in urban areas that had mean concentrations well above 

current levels. Using the same air intake rate and ambient air levels of 7.3–7.5 pptv from the WMO for 

2008 (WMO 2011), current intake is roughly 0.66–0.68 μg/day. Based on the very low levels of 

bromomethane in water and the negligible levels in food, it appears that exposure of the general 

population to bromomethane from sources other than air is likely to be insignificant under normal 

circumstances.

The Fourth National Report on Human Exposures to Environmental Chemicals, published and updated by 

the Centers for Disease Control and Prevention reporting biomonitoring data from the National Health 

and Nutrition Examination Survey (NHANES) for survey years 2005–2012 does not include data for 

bromomethane or the bromide ion (CDC 2018). 

Exposure of workers to bromomethane is highly variable, depending on conditions. The highest 

exposures are most likely to occur during fumigation activities, especially when bromomethane is first 

released to the environment after fumigation ends. Exposure levels under these conditions could reach

from 25 to 2,500 ppmv (IARC 1986; NIOSH 1984; Van Den Oever et al. 1982), which would correspond 

to a dose of 100–10,000 mg/hour for an exposed worker. 

Occupational exposure to bromomethane was examined in a 17-year study of 124 employees at a 

chemical factory primarily manufacturing bromomethane (Yamano et al. 2011). Workers aged 18–

64 years were grouped based upon their responsibilities: synthesis group, filling group, and other group. 

The geometric mean workplace levels in the synthesis and filling areas were 0.68 and 0.77 ppmv, 

respectively. The median urinary concentration of bromide ion for all employees over the 17-year period 

was 11 μg/mg CRE (creatinine corrected). The synthesis group had urinary concentrations of bromide 

ion ranging from 2.5 to 51.8 μg/mg, with a median of 13.0 μg/mg. The filling group and other group had 
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median values of 11.9 and 7.2 μg/mg, respectively. Levels were ≥30 μg/mg in 16.3% of the workers in 

the synthesis group, 6.9% of the workers in the filling group, and in none of the workers of the other 

group. Exposure to bromomethane may have occurred during work procedures, such as the exchange of 

reaction equipment for maintenance or cleaning, during operations to adjust weights after filling canisters, 

or during canister recycling.

Concentrations of bromide in blood samples from six storage room workers (four females, two males) 

ages 32–54 years were examined (Baur et al. 2015; Kloth et al. 2014). The workers were accidentally 

exposed to fumigant offgassing while unloading and unpacking at a European company importing goods 

from overseas. Exposure incidents were reported 3 times during a 2-year period (2010–2012). 

Bromomethane was found in ambient air of the storage room at concentrations ranging from 2.5 to 

200 ppmv (mean 125 ppmv) measured after the occurrence of the first incident, and also detected in the 

air after the second incident (concentration not reported). Serum bromide levels in the analyzed samples 

were similar to background levels; however, low levels of bromomethane were detected in the serum of 

one worker (0.24 μg/L) 5 days following the second incident.

Data were not located on the exposure of children to bromomethane. Children are likely to be exposed to 

low levels of bromomethane from inhalation of ambient air. Children residing in agricultural areas where 

a critical use exemption for bromomethane has been granted may be exposed to slightly greater levels.

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

Members of the general population are not likely to be exposed to high levels of bromomethane except in 

the immediate vicinity of industrial facilities that release the gas into air, or near locations where 

bromomethane is being used as a soil or a space fumigant. This includes individuals returning to work or 

living in locations that have recently been fumigated, especially if insufficient time has been allowed for 

the chemical to disperse. Individuals living near waste sites that contain bromomethane might also be 

exposed, although the level of exposure is not known. Individuals involved in the production of 

bromomethane and those licensed to use it as a fumigant may be exposed to high levels if proper safety 

precautions are not followed; these individuals should check the label of specific products and follow the 

guidelines and instructions provided on the product labels for the proper use, disposal, application, and 

storage of each specific product.
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Although bromomethane has been banned for use in homes or residential settings, a pest control company 

fumigated a resort in the U.S. Virgin Islands in the spring of 2015 with bromomethane, resulting in severe 

illness for a family of four persons staying at the resort (Kulkarni et al. 2015). Sampling of the housing 

units detected bromomethane at levels of 0.59–1.12 ppmv several days after the initial fumigation. In 

addition to the four individuals of the family who became ill, 37 individuals were identified who had 

potentially been exposed to bromomethane after the fumigation in the spring of 2015 or from a previous 

fumigation in the fall of 2014.

Two produce inspectors became ill when they were intermittently exposed to high levels of 

bromomethane while performing routine inspections of fumigated grapes inside a cold storage unit at a 

produce facility located in California (O’Malley et al. 2011). The measured serum bromide level for one 

worker was 4.4 mg/dL 5 days after working in the cold storage unit. A peak serum bromide level of 

58 mg/dL was estimated on his last day of potential exposure by assuming a 12-day half-life for inorganic 

bromide. A second inspector had measured bromide levels of 1.5 mg/dL more than a month after his last 

day of work at the facility, which corresponded to a peak estimated level of approximately 85 mg/dL 

1 month prior. Air samples obtained at three locations that either stored or transported the grapes showed 

median levels of bromomethane ranging from <0.4 to 15 ppmv, with a maximum level of 20 ppmv in 

trailers responsible for transporting the grapes. 

The exposure to workers using bromomethane for quarantine purposes was evaluated by measuring 

ambient air levels during the fumigation process and monitoring urinary bromine levels of 251 employees 

involved in the fumigation of logs and grain products (Tanaka et al. 1991). Workers fumigated logs both 

inside the sealed holds of a transport ship and in sealed polyvinyl sheets at the shipyard. Additionally, 

other workers fumigated grains in a closed warehouse and a silo. Exposure periods for both the 

dispersion and degassing processes were roughly 120 minutes/day over a 6-day work week. Ambient 

concentrations during the bromomethane dispersion process averaged 1.1–3.8 ppmv and ambient levels 

averaged 0.5–74.6 ppmv during the degassing process. Urinary bromine levels of workers engaged in the 

fumigation activities ranged from 7.8 to 9.0 mg/L (0.78–0.90 mg/dL) and a control group of 379 workers 

who were not involved in the use of bromomethane averaged 6.3 mg/L (0.63 mg/dL) (Tanaka et al. 1991). 

Even though workers used full facepiece gas masks with a respiratory canister to limit inhalation 

exposure during the fumigation process, bromomethane was detected in the exhaled breath of a sampling 

of workers who fumigated logs aboard the ship and in the shipyard and fumigated grains in the closed 

warehouse.
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Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of bromomethane is available. Where adequate information is 

not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of 

research designed to determine the adverse health effects (and techniques for developing methods to 

determine such health effects) of bromomethane.

Data needs are defined as substance-specific informational needs that, if met, would reduce the 

uncertainties of human health risk assessment. This definition should not be interpreted to mean that all 

data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

6.1 INFORMATION ON HEALTH EFFECTS

Studies evaluating the health effects of inhalation, oral, and dermal exposure of humans and animals to 

bromomethane that are discussed in Chapter 2 are summarized in Figure 6-1. The purpose of this figure 

is to illustrate the information concerning the health effects of bromomethane. The number of human and 

animal studies examining each endpoint is indicated regardless of whether an effect was found and the 

quality of the study or studies. 

6.2 IDENTIFICATION OF DATA NEEDS

Missing information in Figure 6-1 should not be interpreted as a “data need.” A data need, as defined in 

ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological 

Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public 

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature.
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Figure 6-1. Summary of Existing Health Effects Studies on Bromomethane by 

Route and Endpoint* 

Potential respiratory and neurological effects were the most studied endpoints 

The majority of the studies examined inhalation exposure in animals (versus humans)

*Includes studies discussed in Chapter 2; the number of studies include those finding no effect. Studies 

may have examined multiple health effects. No dermal studies in humans or animals were located.
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Acute-Duration MRLs. The acute-duration inhalation database was not considered suitable for 

derivation of an MRL for bromomethane. Acute inhalation studies identify the neurological and 

respiratory systems as the primary targets of acute inhalation of bromomethane in humans; however, 

information on these effects was obtained from case reports and, therefore, is not adequate for the basis of 

an acute MRL. Several targets for acute exposure to bromomethane have been identified in animal

studies, including respiratory system, neurological system, liver, kidneys, heart, reproductive system, and 

the developing fetus. The most sensitive endpoint identified is a duration-adjusted LOAEL of 2.14 ppm; 

however, there is considerable uncertainty associated with classifying this concentration as a 

LOAEL. NTP (1992) reported that “neurological signs including trembling, jumpiness, and paralysis 

were observed in all groups but were most pronounced in the three highest dose groups (50, 100, 

200 ppm).” However, the NTP report did not include incidence data for these effects and it is unclear 

whether any or all of the effects were observed at the lowest concentration tested (12 ppm). Additional 

acute-duration inhalation studies using low exposure levels (duration adjusted concentrations ≤5 ppm) are 

need to reliably define NOAEL and LOAEL values for neurological effects.

An acute-duration oral MRL was not derived. The only effect observed in acute-duration oral studies is 

damage to the glandular stomach (Kaneda et al. 1998). As noted earlier in Sections 1.2 and 2.1, there is 

some question as to whether the forestomach effects in rats are due to the bolus administration of a very 

reactive chemical and whether gavage administration is an appropriate model for human exposure to 

bromomethane. Longer duration exposure studies using dietary exposure did not observe damage to the 

gastrointestinal tract (Wilson et al. 2000). Additional acute-duration dietary oral exposures studies are 

important to determine if gastrointestinal tract damage is only observed when bromomethane is 

administered by gavage.

Intermediate-Duration MRLs. The database for intermediate-duration inhalation exposure to 

bromomethane was considered adequate for derivation of an MRL. The intermediate-duration oral 

database was not sufficient to derive an MRL. The most sensitive effect observed from oral gavage 

exposure was hyperplasia and focal hyperemia of the forestomach (Danse et al. 1984). As discussed 

above under Acute-Duration MRLs and in Sections 1.2 and 2.1, in this study, bromomethane was 

administered by gavage; therefore, there is uncertainty regarding the relevance of gastrointestinal damage 

to human health. Additional acute-duration dietary exposures studies are important to determine if 

gastrointestinal tract damage is only observed when bromomethane is administered by gavage.
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Chronic-Duration MRLs. The database for chronic-duration inhalation exposure to bromomethane 

was considered adequate for derivation of an MRL. The chronic-duration oral database was not sufficient 

to derive an MRL. The two chronic-duration oral studies did not identify targets for bromomethane (EPA 

1999; Wilson et al. 2000). Additional studies examining the effects of chronic-duration dietary 

bromomethane over a wide range of doses may provide information on potential targets of exposure.

Health Effects. 

Neurotoxicity. There is clear evidence from studies in humans and animals that the nervous 

system is adversely affected by inhalation exposure to bromomethane. This includes evidence of 

clinical neurological signs and behavioral changes (Akca et al. 2009; Alexeeff et al. 1985; Anger 

et al. 1986; Balagopal et al. 2011; Behrens and Dukes 1986; Bishop 1992; Breslin et al. 1990; 

Clarke et al. 1945; Deschamps and Turpin 1996; Eustis et al. 1988; Greenberg 1971; Herzstein 

and Cullen 1990; Hine 1969; Hustinx et al. 1993; Irish et al. 1940; Kantarjian and Shaheen 1963; 

Longley and Jones 1965; Marraccini et al. 1983; O'Neal 1987; Prain and Smith 1952; Prockop 

and Smith 1986; Rathus and Landy 1961; Viner 1945; Wyers 1945; Yamano and Nakadate 2006; 

Yamano et al. 2001), as well as biochemical changes and histological lesions in the brain 

(Alexeeff et al. 1985; Eustis et al. 1988; Honma 1987; Honma et al. 1982; Hurtt et al. 1987; Kato 

et al. 1986; NTP 1992). Although quantitative exposure information from humans is limited, the 

thresholds for acute, intermediate, and chronic inhalation exposures are known with reasonable 

precision. No information is available on humans exposed by the oral route, but two oral studies 

in rats (Boorman et al. 1986; Danse et al. 1984) did not produce any visible neurological signs. It 

is not known if this apparent route specificity is due simply to differences in dose, or to 

differences in absorption, distribution, or metabolism between routes. For this reason, additional 

oral dose-response studies in animals that focus specifically on histological, biochemical, or 

functional tests of nervous system injury would be valuable. If these tests indicate that the 

nervous system is not injured following oral exposure, additional toxicokinetic studies would be 

helpful in understanding the basis for the distinction between inhalation and oral effects.

Reproductive Toxicity. No information was located regarding reproductive effects in 

humans. Intermediate-duration inhalation studies in animals (Eustis et al. 1988; Kato et al. 1986) 

indicate that the testes may undergo degeneration and atrophy at high exposure levels, but the 

dose-response curve is not well defined. Further studies in animals to identify the threshold for 

this endpoint would be helpful. Two studies in female animals (Hardin et al. 1981; NIOSH 1980) 
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6. ADEQUACY OF THE DATABASE

have not detected reproductive effects even at doses that produced maternal toxicity. Additional 

studies to confirm this in several different animal species would be helpful.

No information exists on reproductive effects in humans or animals after oral exposure. Based on 

the inhalation studies in animals that indicate that the testes are a target tissue, it would be 

valuable to include histological examination of the testes in any intermediate- or chronic-duration 

oral studies in animals. In addition, tests of male reproductive success would be valuable in 

assessing the functional significance of any testicular lesions.

Developmental Toxicity. There is no information on developmental effects in humans 

exposed to bromomethane. One study in rabbits found minor fetal malformations and variations 

at maternally toxic concentrations (Breslin et al. 1990). In contrast, no developmental effects 

were observed in a study in rats and rabbits (Hardin et al. 1981; NIOSH 1980). A summary of a 

neurodevelopmental study in rats reported neurological effects (decreased total and ambulatory 

activities) in high-dose male and mid-dose female offspring on postnatal day 21 (Beck 1994 

[MRID46665001], as cited in EPA 2018a). Unfortunately, the study report is not available for 

review. Neurological effects have been well characterized in multiple species (rat, mouse, rabbit, 

and dog) and there is indication that protection factors for adults will be sufficient for infants and 

children. Therefore, it is considered that additional neurodevelopmental studies are not needed in 

determining the potential for adverse neurodevelopmental effects associated with gestational 

exposure to bromomethane. An oral exposure in rats and rabbits did not find developmental 

effects (Kaneda et al. 1998). 

Gastrointestinal Toxicity. Gastrointestinal toxicity has not been reported in inhalation studies 

in animals. In oral toxicity studies, damage to the stomach has been observed in rats exposed for 

acute (Kaneda et al. 1998) and intermediate durations (Danse et al. 1984); however, in these 

studies, bromomethane was administered by gavage. In a chronic-duration oral study of dietary 

bromomethane, no gastrointestinal effects were observed (Wilson et al. 2000). Although oral 

exposure to bromomethane to humans is unlikely, if it occurs, exposure would be to small 

amounts in food or water. Therefore, there is uncertainty regarding the relevance of 

gastrointestinal damage of gavage administration to human health. Additional acute- and 

intermediate-duration dietary studies could provide information to determine if dietary exposure 

to bromomethane is relevant to human health.
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Epidemiology and Human Dosimetry Studies. As noted previously, there are many reports on the 

adverse effects of bromomethane in humans. Most studies involve people with accidental acute highlevel exposures in air, but there are also several studies of workers with repeated low-level exposures 

(Calvert et al. 1998a; Kishi et al. 1988; Verberk et al. 1979). These studies are sufficient to identify the 

main health effects of concern and to estimate the exposure levels that lead to effects. However, further 

studies of workers who are exposed to low levels during manufacture or use of bromomethane would be 

helpful, if reliable current and past exposure data are available. These additional quantitative human data 

would be valuable in increasing the confidence in the estimated safe exposure levels in the workplace and 

the environment. This would improve the ability to evaluate potential risk to humans exposed to low 

levels of bromomethane in air near waste sites.

Biomarkers of Exposure and Effect. The most common biomarker of exposure to bromomethane is 

serum bromide concentration. Studies in humans have established an association between bromide levels 

and severity of effect (Alexeeff and Kilgore 1983), although the quantitative relation between exposure 

level and bromide concentration has not been established. Since bromide is cleared from the blood with a 

half-life of 3–15 days, this test is best suited for detecting relatively recent exposures. Because bromide is 

a normal component of blood, and because bromide levels may be increased by other chemicals or drugs, 

increased serum bromide is not specific for bromomethane. Other possible biomarkers available include 

direct measurement of parent bromomethane or methanol in expired air or blood (Honma et al. 1985; 

Jaskot et al. 1988), and measurement of methylated adducts such as S-methylcysteine in hemoglobin 

(Iwasaki 1988a). Measurement of parent bromomethane or methanol is not likely to be helpful except in 

the interval immediately following an acute exposure, while measurement of stable methylated adducts, 

although not specific for bromomethane, could be useful for longer periods. Further studies in humans or 

animals would be helpful in determining the sensitivity of these biomarkers and evaluating their 

usefulness in monitoring people exposed to low levels of bromomethane near waste sites.

The most sensitive biomarkers of bromomethane effects appear to be changes in the nervous system. 

These can be detected in groups of exposed people by measuring the incidence of signs and symptoms 

such as weakness, nausea, ataxia, and vision problems. However, it is obvious that these are not specific 

for bromomethane-induced effects, and because of the large variation between people, these tests are not 

reliable for identifying preclinical effects in potentially exposed individuals. Studies to develop more 

specific and more objective biomarkers of bromomethane-induced effects would be useful in assessing 

the potential health significance of low-level bromomethane exposure near waste sites.
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6. ADEQUACY OF THE DATABASE

Absorption, Distribution, Metabolism, and Excretion. The toxicokinetics of bromomethane have 

not been thoroughly investigated in humans, but there is good information from studies in animals on 

uptake, distribution, and excretion following inhalation exposure (Bond et al. 1985; Gargas and Andersen 

1982; Honma et al. 1985; Jaskot et al. 1988; Medinsky et al. 1985), and there is one study on 

toxicokinetics following oral exposure (Medinsky et al. 1984). Available data indicate that the 

toxicokinetics of bromomethane absorption are mainly first-order except at very high doses. While the 

metabolism of related compounds such as chloromethane has been studied in detail (Kornbrust and Bus 

1983), the metabolism of bromomethane has not been thoroughly investigated. Additional studies on the 

rate and extent of bromomethane hydrolysis and alkylation reactions in vivo would be valuable in

understanding the basis of bromomethane toxicity, and in assessing the utility of various biomarkers of 

exposure (e.g., parent compound, bromide, methanol, adducts).

Comparative Toxicokinetics. Available studies indicate that bromomethane affects the same target 

tissues in humans and animals, although there are apparent differences in sensitivity between species, 

with rabbits being more sensitive than rats or mice (Irish et al. 1940). However, quantitative toxicokinetic 

data on absorption, distribution, and excretion are primarily available for rats (Bond et al. 1985; Gargas 

and Andersen 1982; Honma et al. 1985; Jaskot et al. 1988; Medinsky et al. 1984, 1985). Additional 

toxicokinetic studies would be helpful in understanding the basis of the differences in species sensitivity, 

and in determining which animal species is the most appropriate model for human exposure.

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. There are limited data on the toxicity of bromomethane in 

children; a report of an accidental exposure suggests that infants and adults would have similar toxic 

effects (Langard et al. 1996).

Physical and Chemical Properties. The physical and chemical properties of bromomethane are 

sufficiently well known to allow estimation of environmental fate. Although there is some disparity in 

reported values for the solubility in water and Henry’s law constant for bromomethane (see Table 4-1), 

further studies to define these parameters more precisely are not essential, since volatilization from water 

is so rapid.

Production, Import/Export, Use, Release, and Disposal. According to the Emergency Planning 

and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit 
BROMOMETHANE 110

6. ADEQUACY OF THE DATABASE

substance release and off-site transfer information to the EPA. The TRI, which contains this information 

for 2014, became available in October of 2016. This database is updated yearly and should provide a list 

of industrial production facilities and emissions.

Environmental Fate. The fate of bromomethane in the environment is dominated by rapid evaporation 

into air, where it is quite stable (EPA 1986b). The rates of volatilization from soil and water have been 

studied and are known with reasonable precision (although such rates are typically site-specific) 

(Anderson et al. 1996; Gan et al. 1996, 1997). The rates of breakdown by hydrolysis, reaction with 

hydroxyl radical, and direct photolysis in the stratosphere have also been estimated (Atkinson 1989; 

Castro and Belser 1981; Davis et al. 1976; Robbins 1976; WMO 2011; UNEP 2015). Further studies to 

improve the accuracy of available rate constants for these processes would be helpful, but are not 

essential to understanding the basic behavior of bromomethane in the environment.

Bioavailability from Environmental Media. Bromomethane is known to be well absorbed 

following inhalation and oral contact (Gargas and Andersen 1982; Medinsky et al. 1984). Small amounts 

may also be absorbed across the skin, but this has not been quantified. No information was located 

regarding the relative bioavailability of bromomethane from media such as food or soil. However, since

bromomethane has a low Koc value (EPA 1982), it is not likely that bioavailability would be much 

reduced by these media. Moreover, since bromomethane is rarely found in these media, research on this 

subject does not appear essential.

Food Chain Bioaccumulation. Although the bioconcentration, bioaccumulation, and 

biomagnification of bromomethane have not been formally investigated, it seems clear that these are not 

of significant concern. This is the result of several factors, including the high volatility and high water 

solubility of the compound, its low Kow, and its relatively rapid metabolism by reaction with organic 

materials (EPA 1982; Medinsky et al. 1985). On this basis, it does not appear that research in this area is 

essential.

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of 

bromomethane in contaminated media at hazardous waste sites are needed so that the information 

obtained on levels of bromomethane in the environment can be used in combination with the known body 

burden of bromomethane to assess the potential risk of adverse health effects in populations living in the 

vicinity of hazardous waste sites.
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6. ADEQUACY OF THE DATABASE

Bromomethane levels in ambient air are decreasing since the phase out of this substance in 2005 (EPA 

2019a; WMO 2011; UNEP 2015). Detections of bromomethane in water are rare. Bromomethane has 

been analyzed for, but rarely detected, in foods (Daft 1987, 1988, 1989). The EPA RED (EPA 2008b) for 

bromomethane provides estimates of human exposure levels to handlers, workers, and bystanders 

associated with its use as a soil fumigant. An exposure assessment for the general population would be 

helpful.

Exposure Levels in Humans. Bromomethane is not normally measured in human tissues such as 

blood or urine, even in people exposed to high levels. This is because bromomethane is removed from 

the body very quickly after exposure ceases. Consequently, this is not likely to be a useful means of 

monitoring exposure of humans to low levels of bromomethane. Increased levels of bromide have been 

detected in blood of persons exposed to bromomethane in accidents or in the workplace, but no studies 

were located regarding bromide levels in persons potentially exposed to bromomethane near waste sites. 

Since bromide is a normal component of serum, and since the serum bromide level is quite variable, it 

does not seem that broad surveys of blood bromide levels in persons living near waste sites would be 

useful. However, site-specific studies at locations where bromomethane exposure is likely might prove 

helpful.

Exposures of Children. Data on the exposures of children to bromomethane were not 

located. Because humans are most likely to be exposed to bromomethane in air, studies that are tailored 

to assessing exposure of children to bromomethane in ambient air would be useful given the tendency for 

children to spend more time outdoors than many adults.

6.3 ONGOING STUDIES

No ongoing studies of bromomethane were identified by NIH RePORTER (2019).
BROMOMETHANE 112

CHAPTER 7. REGULATIONS AND GUIDELINES

Pertinent international and national regulations, advisories, and guidelines regarding bromomethane in air, 

water, and other media are summarized in Table 7-1. This table is not an exhaustive list, and current 

regulations should be verified by the appropriate regulatory agency.

Table 7-1. Regulations and Guidelines Applicable to Bromomethane

Agency Description Information Reference

Air

EPA RfC 5x10-3 mg/m3 a IRIS 2002

WHO Air quality guidelines Not listed WHO 2010

Water & Food

EPA Drinking water standards and health 

advisories 

EPA 2018b

1-Day health advisory (10-kg child) 0.1 mg/L

10-Day health advisory (10-kg child) 0.1 mg/L

DWEL 0.05 mg/L

Lifetime health advisory 0.01 mg/L

10-4 Cancer risk No data

National primary drinking water regulations Not listed EPA 2009

RfD 1.4x10-3 mg/kg/dayb IRIS 2002

WHO Drinking water quality guidelines No data WHO 2017

FDA Substances Added to Food Not listedc FDA 2018

Cancer

HHS Carcinogenicity classification No data NTP 2016

EPA Carcinogenicity classification Group Dd IRIS 2002

IARC Carcinogenicity classification Group 3e IARC 1999

Occupational

OSHA Ceilingf PEL for general industry, shipyards 

and construction

20 ppmg OSHA 2018a, 2018b, 

2018c

NIOSH REL (up to 10-hour TWA) None establishedh NIOSH 2018

IDLH 250 ppm NIOSH 1994

Emergency Criteria

EPA AEGLs-air No data EPA 2016f

AEGL-1i

10-minute NRj

30-minute NRj

60-minute NRj

4-hour NRj

8-hour NRj
BROMOMETHANE 113

7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Bromomethane

Agency Description Information Reference

AEGL-2i

10-minute 940 ppm

30-minute 380 ppm

60-minute 210 ppm

4-hour 67 ppm

8-hour 67 ppm

AEGL-3i

10-minute 3,300 ppm

30-minute 1,300 ppm

60-minute 740 ppm

4-hour 230 ppm

8-hour 130 ppm

DOE PACs-air DOE 2018b

PAC-1k 19 ppm

PAC-2k 210 ppm

PAC-3k 740 ppm

aThe RfC is based on a LOAEL(HEC) of 0.48 mg/m3 for degenerative and proliferative lesions of the olfactory

epithelium of the nasal cavity in rats. bThe RfD is based on a NOAEL of 1.4 mg/kg/day for epithelial hyperplasia of the forestomach in rats. cThe Substances Added to Food inventory replaces EAFUS and contains the following types of ingredients: food and 

color additives listed in FDA regulations, flavoring substances evaluated by FEMA or JECFA, GRAS substances 

listed in FDA regulations, substances approved for specific uses in food prior to September 6, 1958, substances that 

are listed in FDA regulations as prohibited in food, delisted color additives, and some substances "no longer FEMA 

GRAS." dGroup D: not classifiable as to human carcinogenicity. eGroup 3: not classifiable as to its carcinogenicity to humans. f

An employee's exposure will at no time exceed the exposure limit given for that substance. If instantaneous 

monitoring is not feasible, then the ceiling will be assessed as a 15-minute TWA exposure, which will not be 

exceeded at any time over a working day.

gSkin designation. hPotential occupational carcinogen. i

Definitions of AEGL terminology are available from EPA (2018c). j

NR: not recommended due to insufficient data.

kDefinitions of PAC terminology are available from U.S. DOE (2018a).

AEGL = acute exposure guideline levels; DOE = Department of Energy; DWEL = drinking water equivalent level; 

EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; FDA = Food and 

Drug Administration; FEMA = Flavor and Extract Manufacturers Association; GRAS = generally recognized as safe; 

HEC = human equivalent concentration; HHS = Department of Health and Human Services; IARC = International 

Agency for Research on Cancer; IDLH = immediately dangerous to life or health; IRIS = Integrated Risk Information 

System; JECFA = Joint Expert Committee on Food Additives; LOAEL = lowest-observed-adverse-effect level; 

NIOSH = National Institute for Occupational Safety and Health; NOAEL = no-observed-adverse-effect level; 

NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; PAC = protective 

action criteria; PEL = permissible exposure limit; REL = recommended exposure limit; RfC = inhalation reference 

concentration; RfD = oral reference dose; TWA = time-weighted average; WHO = World Health Organization
BROMOMETHANE 114

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BROMOMETHANE A-1

APPENDIX A. ATSDR MINIMAL RISK LEVEL WORKSHEETS

MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the 

most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an 

estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk 

of adverse noncancer health effects over a specified route and duration of exposure. MRLs are based on 

noncancer health effects only; cancer effects are not considered. These substance-specific estimates, 

which are intended to serve as screening levels, are used by ATSDR health assessors to identify 

contaminants and potential health effects that may be of concern at hazardous waste sites. It is important 

to note that MRLs are not intended to define clean-up or action levels.

MRLs are derived for hazardous substances using the NOAEL/uncertainty factor approach. They are 

below levels that might cause adverse health effects in the people most sensitive to such chemicalinduced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and chronic 

(≥365 days) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal 

route of exposure are not derived because ATSDR has not yet identified a method suitable for this route 

of exposure. MRLs are generally based on the most sensitive substance-induced endpoint considered to 

be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or 

birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not 

mean that adverse health effects will occur.

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals.
BROMOMETHANE A-2

APPENDIX A

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Human Health Sciences, expert panel peer reviews, and agency-wide MRL 

Workgroup reviews, with participation from other federal agencies and comments from the public. They 

are subject to change as new information becomes available concomitant with updating the toxicological 

profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published MRLs. 

For additional information regarding MRLs, please contact the Division of Toxicology and Human 

Health Sciences, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road NE, Mailstop 

S102-1, Atlanta, Georgia 30329-4027.
BROMOMETHANE A-3

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Bromomethane

CAS Numbers: 74-83-9

Date: March 2020

Profile Status: Final

Route: Inhalation

Duration: Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL.

Rationale for Not Deriving an MRL: Neurological and respiratory systems are the primary targets of 

acute inhalation of bromomethane in humans. Studies in laboratory animals identify several organ 

systems (respiratory tract, cardiovascular system, liver, kidneys, immunological system, reproductive 

system, neurological system, and the developing fetus) as targets of acute exposure to inhaled 

bromomethane, with neurotoxicity identified as the most sensitive effect. A 2-week study in mice 

identified neurological effects at an exposure level of 12 ppm (NTP 1992). However, there is 

considerable uncertainty associated with classifying this concentration as a LOAEL. NTP (1992) 

reported that “neurological signs including trembling, jumpiness, and paralysis were observed in all 

groups but were most pronounced in the three highest dose groups (50, 100, 200 ppm).” However, the 

NTP report did not include incidence data for these effects and it is unclear whether any or all of the 

effects were observed at the lowest concentration tested (12 ppm). At this time, the database is not 

considered suitable for identifying a point of departure (POD) for derivation of an acute-duration 

inhalation MRL because of the uncertainty in establishing the NOAEL and/or LOAEL values in the NTP 

(1992) study based on the information provided in the study report. 

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE A-4

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

MRL:

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

LSE Graph Key:

Species:

Bromomethane 

74-83-9

March 2020

Final

Inhalation

Intermediate

0.02 ppm

Decreased locomotor activity

NTP 1992

LOAEL[HEC] of 1.8 ppm

90

41

Mouse

MRL Summary: The intermediate-duration inhalation MRL for bromomethane was derived based on 

neurobehavioral effects (temporary decreased locomotor activity in male mice) observed at the 6-month 

(but not at the 0-, 3-, 9-, 12-, 15-, 18-, 21-, or 24-month) evaluation period of a 2-year cancer bioassay 

(NTP 1992). In this study, various neurological effects were sporadically observed in male and female 

mice, but effects did not exhibit temporal- or exposure-related dependence. The MRL of 0.02 ppm was 

derived from a minimal LOAEL of 10 ppm, adjusted for intermittent exposure, converted to a human 

equivalent concentration [HEC] of 1.8 ppm, and divided by a total uncertainty factor of 90 (3 for the use 

of a minimal LOAEL, 3 for extrapolation from animals to humans with dosimetric adjustments, and 

10 for human variability).

Selection of the Principal Study: The NTP (1992) study in rats and mice was selected as the principal 

study for deriving the intermediate-duration inhalation MRL because this study identified the lowest 

LOAEL value for neurological effects. The study conducted extensive evaluations of neurobehavioral 

and neurological endpoints using functional observational battery (FOB) testing at numerous intermittent 

exposure durations and exposure levels. In addition, the study evaluated comprehensive toxicological 

endpoints. 

Selection of the Critical Effect: The MRL was based on a minimal LOAEL of 10 ppm for decreased 

locomotor activity in male mice. The 10 ppm concentration was considered a minimal LOAEL because 

of the small magnitude of change (16%) in locomotor activity. 

Alterations in performance on neurobehavioral tests were observed in rats and mice throughout the 

exposure period. However, statistically significant alterations in neurobehavioral effects were not 

observed at all time points (see Table A-1 for an overview of the statistically significant alterations). The 

earliest effect was an increased startle response latency in male rats exposed to 120 ppm for 3 weeks and 

the lowest LOAEL was 10 ppm for decreased locomotor activity in male mice and altered exploratory 

behavior (decreased novel side crossings and decreased novel side duration) in female mice exposed for 

6 months. It is noted that the decreases in locomotor activity were not statistically significant at 9 

months, but were significant at ≥10 ppm in female mice exposed for 12 months. There is extensive 

evidence in humans and laboratory animals that the nervous system in general and motor function 

specifically is a sensitive target of bromomethane toxicity. Ataxia has been reported in some severe cases 

of bromomethane poisoning in humans (Balagopal et al. 2011; Behrens and Dukes 1986). Ataxia, gait 

disturbances, paralysis, and limb crossing and twitching have been observed in laboratory animals 

exposed to lethal concentrations (Alexeeff et al. 1985; EPA 1988a; Eustis et al. 1988; Hurtt et al. 1987; 
BROMOMETHANE A-5

APPENDIX A

NTP 1992). Cerebellar and cerebral degeneration or necrosis have also been observed in rats and mice 

exposed to ≥100 ppm (Eustis et al. 1988; Kato et al. 1986; NTP 1992). 

Although the alterations were not observed at all time points, the decrease in locomotor activity observed 

in male and female mice exposed for 6 months was selected as the critical effect for the MRL.

Table A-1. Alterations in Performance on Neurobehavioral Tests in Rats and 

Mice Exposed to Inhaled Bromomethane for Intermediate Durationsa 

Test and exposure duration Male rats Female rats Male mice Female mice

Startle response latency

3 weeks — 120 ppm ↑ No assessment No assessment

6 weeks — —

9 weeks — — No assessment No assessment

12 weeks 120 ppm ↑

3 months Not evaluated Not evaluated 100 ppm ↓ 100 ppm ↑

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —

Startle response amplitude

3 weeks — — No assessment No assessment

6 weeks 60 ppm ↓

120 ppm ↓

— — —

9 weeks — — No assessment No assessment

12 weeks — 120 ppm ↓ — —

3 months Not evaluated Not evaluated 100 ppm ↑ 100 ppm ↑

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —

Activity latency

3 weeks — — No assessment No assessment

6 weeks — — 80 ppm ↑ —

9 weeks — — No assessment No assessment

12 weeks — — — 80 ppm ↓

3 months Not evaluated Not evaluated 100 ppm ↑ —

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —

Novel side time

3 weeks — — No assessment No assessment

6 weeks — — — —

9 weeks — — No assessment No assessment
BROMOMETHANE A-6

APPENDIX A

Table A-1. Alterations in Performance on Neurobehavioral Tests in Rats and 

Mice Exposed to Inhaled Bromomethane for Intermediate Durationsa

Test and exposure duration Male rats Female rats Male mice Female mice

12 weeks — — — —

3 months Not evaluated Not evaluated 100 ppm ↓ 100 ppm ↑

6 months Not evaluated Not evaluated — 10 ppm ↓

33 ppm ↓

100 ppm ↑

9 months Not evaluated Not evaluated — —

Novel side crossings

3 weeks — — No assessment No assessment

6 weeks — — — —

9 weeks — — No assessment No assessment

12 weeks 120 ppm ↑ — —

3 months Not evaluated Not evaluated 100 ppm ↓

6 months Not evaluated Not evaluated — 10 ppm ↓

33 ppm ↓

100 ppm ↑

9 months Not evaluated Not evaluated — —

Locomotor activity

3 weeks — — No assessment No assessment

6 weeks — — — —

9 weeks — — No assessment No assessment

12 weeks — — — —

3 months Not evaluated Not evaluated 100 ppm ↓ —

6 months Not evaluated Not evaluated 10 ppm ↓

33 ppm ↓

33 ppm ↓

100 ppm ↓

9 months Not evaluated Not evaluated — —

Hindlimb foot splay

3 weeks — — No assessment No assessment

6 weeks — — — —

9 weeks — — No assessment No assessment

12 weeks — 120 ppm ↓ — —

3 months Not evaluated Not evaluated — —

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —
BROMOMETHANE A-7

APPENDIX A

Table A-1. Alterations in Performance on Neurobehavioral Tests in Rats and 

Mice Exposed to Inhaled Bromomethane for Intermediate Durationsa 

Test and exposure duration Male rats Female rats Male mice Female mice

Hindlimb grip strength

3 weeks — — No assessment No assessment

6 weeks 120 ppm ↓ — — —

9 weeks — — No assessment No assessment

12 weeks — — — —

3 months Not evaluated Not evaluated 100 ppm ↑ 100 ppm ↑

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated 33 ppm ↓ —

Forelimb grip strength

3 weeks — — No assessment No assessment

6 weeks — — — —

9 weeks — — No assessment No assessment

12 weeks — 120 ppm ↓ — —

3 months Not evaluated Not evaluated — —

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —

Hot plate latency

3 weeks — — No assessment No assessment

6 weeks — — 80 ppm ↑ —

9 weeks — — No assessment No assessment

12 weeks — — — —

3 months Not evaluated Not evaluated — 100 ppm ↑

6 months Not evaluated Not evaluated — —

9 months Not evaluated Not evaluated — —

— = no significant alterations; ↓ = decreased response; ↑ = increased response

aSee Table A-2 for magnitude of the alteration.

Source: NTP 1992

Selection of the Principal Study: The NTP (1992) study was selected as the principal study for deriving 

an intermediate-duration inhalation MRL for bromomethane because it identified the lowest reliable 

LOAEL for acute effects.
BROMOMETHANE A-8

APPENDIX A

Summary of the Principal Study:

NTP. 1992. Toxicology and carcinogenesis studies of methyl bromide (CAS No. 74-83-9) in B6C3F1 

mice (inhalation studies). National Toxicology Program. Technical report series No. 385. 

http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr385.pdf. May 27, 2015 

NTP (1992) conducted the following series of studies: (1) groups of 10 male and 10 female B6C3F1 

mice exposed to 0, 10, 20, 40, 80, or 120 ppm, 6 hours/day, 5 days/week for 13 weeks; (2) groups of 

10 male and 10 female F344/N rats exposed to 0, 30, 60, or 120 ppm, 6 hours/day, 5 days/week for 

13 weeks; (3) groups of 8 male and 8 female F344/N rats exposed to 0, 30, 60, or 120 ppm, 6 hours/day, 

5 days/week for 13 weeks; (4) groups of 8 male and 8 female B6C3F1 mice exposed to 0, 20, 40, or 

80 ppm, 5 days/week for 13 weeks; (5) interim neurobehavioral and histopathological assessments 

(conducted at 3, 6, and 9 months) in groups of 6–13 male and 6–16 female B6C3F1 mice exposed to 0, 

10, 33, and 100 ppm bromomethane for 6 hours/day, 5 days/week as part of a 2-year cancer bioassay, and 

(6) groups of 15 male and female B6C3F1 mice exposed to 0 or 160 ppm, 6 hours/day, 5 days/week for

up to 6 weeks (the data for this study are reported in detail in Eustis et al. 1988). In the 13-week studies

involving eight animals/sex/species, neurobehavioral assessment were conducted at weeks 3 (rats only),

6, 9, 12 (rats only), and 13 (mice only). Other evaluations at the end of the 13-week treatment period

(10 animals/sex/species) included body weight, hematology, clinical chemistry, organ weights, and

histopathology of comprehensive tissues. In the 6-week study, histopathology of selected tissues,

including brain, was assessed at the end of the treatment period, which was the duration in which

mortality was >50% (14 exposures for male rats, 30 exposures female rats, 8 exposures in male mice, and

14 exposures in female mice). In the 2-year cancer bioassay, neurobehavioral effects were evaluated at 3,

6, and 9 months, and histopathology of comprehensive tissues was conducted at 6 months.

Adverse neurological effects of inhaled bromomethane and LOAEL values, with associated NOAELs, for 

each exposure level and assessment time-point are summarized in Table A-2. Neurobehavioral effects 

were observed in mice throughout the 6-week to 6-month assessment period. The study authors classified 

the severity of neurobehavioral effects as mild. In rats, neurobehavioral effects were observed at 3, 6, and 

12 weeks, but not at 9 weeks. The study authors classified the severity of neurobehavioral effects as 

minor. Microscopic evaluation of brain tissues showed neuronal necrosis of the cerebral cortex (mice and 

rats), cerebellum (mice), and thalamus (rats) following 6 weeks of exposure to 160 ppm. However, no 

histopathological changes to the brain were observed in mice and rats exposed to ≤120 ppm for 13 weeks. 

Comparison of LOAEL values for rats and mice in the 6-week exposure study with exposure 

concentrations up to 120 ppm suggests that mice are more sensitive than rats; the NOAEL and LOAEL 

values for neurological effects were 80 and 120 ppm in rats, respectively, and 40 and 60 ppm in mice, 

respectively.

In addition to neurological effects, decreased body weight and histopathological alterations in several 

tissue types were observed. In rats and mice exposed to 160 ppm for up to 6 weeks (exposures levels that

produced substantial mortality), histopathological changes were observed in the nasal cavity, heart, 

spleen, liver, adrenal glands, and testes. Decreased body weight gain was observed in male and female 

mice and rats exposed to 160 ppm for up to 6 weeks and to 120 ppm for 13 weeks. In female rats exposed 

for 13 weeks, decreased erythrocyte count was observed at 60 and 120 ppm, and decreased hematocrit 

and hemoglobin were observed at 120 ppm (NTP 1992). Additional details on non-neurological adverse 

effects reported in NTP (1992) are provided in Table 2-1 in Chapter 2.
BROMOMETHANE A-9

APPENDIX A

Table A-2. Neurological Effects Observed in Mice and Rats Exposed to Inhaled 

Bromomethane for Intermediate-Duration Exposures

Time of observation Effects in rats Effects in mice

13-Week exposure study (6 hours/day, 5 days/week)

3 Weeks

0, 30, 60, or 120 ppm

No death at any exposure

60 ppm: decreased startle 

response amplitude (males; 15%;

p≤0.05)

120 ppm: decreased startle 

response amplitude (males; 28%; 

p≤0.01); increased startle response 

latency (females; 12%; p≤0.05)

NOAEL/LOAEL: 30 ppm/60 ppm

No assessment in mice 

6 Weeks

Mice: 0, 20, 40, 80, or 

120 ppm

Rats: 0, 30, 60, or 

120 ppm

No death at any exposure

120 ppm: decreased hindlimb 

strength (males: 32%; p≤0.05)

NOAEL/LOAEL: 80 ppm/120 ppm

No death at any exposure

80 ppm: increased activity latency 

(males: 156%, p≤0.01); increased hot

plate latency (males: 80%, p≤0.05)

120 ppm: severe curling and crossing of 

the hindlimbs and twitching of the 

forelimbs

NOAEL/LOAEL: 40 ppm/80 ppm

9 Weeks

0, 30, 60, or 120 ppm

No death at any exposure

No neurobehavioral effects 

observed (increased hot plate 

latency in females at 120 ppm was 

<0.5% and was not considered 

toxicologically relevant)

NOAEL/LOAEL: 120 ppm/X

No assessment in mice

12 Weeks (rats), 

13 weeks (mice)

Mice: 0, 10, 20, 40, 80, 

or 120 ppm 

Rats: 0, 30, 60, or 

120 ppm

No death at any exposure

120 ppm: increased novel side 

crossing frequency (males: 480%; 

p≤0.05); decreased hindlimb foot

splay (females: 20%; p≤0.05); 

decreased forelimb grip strength 

(females: 25%; p≤0.05); increased 

startle response latency (females: 

17%; p≤0.05); decreased startle 

response amplitude (females: 22%, 

p≤0.05)

NOAEL/LOAEL: 80 ppm/120 ppm

No death at any exposure

80 ppm: decreased activity latency 

(females 76%, p<0.05) 

120 ppm: severe curling and crossing of 

hindlimbs and twitching of forelimbs

NOAEL/LOAEL: 80 ppm/120 ppm
BROMOMETHANE A-10

APPENDIX A

Table A-2. Neurological Effects Observed in Mice and Rats Exposed to Inhaled 

Bromomethane for Intermediate-Duration Exposures

Time of observation Effects in rats Effects in mice

6-Week exposure study (6 hours/day, 5 days/week) (detailed report of this study is presented in 

Eustis et al. 1988)

Rats and mice: 0 or 

160 ppm

Male rats and male 

mice were sacrificed 

after 14 exposures due 

to high mortality; female 

mice were sacrificed 

after 8 exposures

Substantial mortality was observed 

in both sexesa. 

Lethargy and neurological signs 

(curling and crossing of the 

hindlimbs, forelimb twitching and 

tremors); the study authors noted 

that severity was less than in mice

Neuronal necrosis of cerebral cortex

(males and females) and thalamus 

(females)

NOAEL/LOAEL: not applicable 

(serious LOAEL at 160 ppm)

Substantial mortality was observed in 

both sexesa

Lethargy and neurological signs (curling 

and crossing of the hindlimbs, forelimb 

twitching and tremors)

Neuronal necrosis of cerebral cortex 

(males) and cerebellum (males and 

females)

NOAEL/LOAEL: not applicable 

(serious LOAEL at 160 ppm)

24-Month exposure study (6 hours/day, 5 days/week)

3 Months

0, 10, 33, or 100 ppm 

– 10 ppm: no mortality

33 ppm: no mortality

100 ppm: 10/86 deaths in males; 

1/86 deaths in females; decreased 

startle response latency (males: 32%, 

p≤0.01; females; 38%, p≤0.01); 

increases startle response amplitude 

(males: 62%, p≤0.01; females: 66%, 

p≤0.01); increased activity latency 

(males: 370%; p≤0.01); decreased 

novel side time (males: 44%, p≤0.05); 

increased novel side time (females: 

19%, p≤0.05), decreased novel side 

crossing (males: 67%, p≤0.01); 

decreased locomotor activity (males: 

39%; p≤0.01); increased hind limb grip 

strength (males: 30%, p≤0.05; females: 

32%, p≤0.01); increased hot plate 

latency (females: 39%; p≤0.01)

NOAEL/LOAEL: 33 ppm/100 ppm

6 Months

0, 10, 33, or 100 ppm 

– 10 ppm: 1/86 deaths in males; no 

deaths in females; decreased novel side 

crossings (females: 37%, p≤0.05); 

decreased locomotor activity (males: 

16%, p≤0.01; females: 10%, p≤0.05)

33 ppm: no mortality; decreased novel 

side crossings (females: 28%, p≤0.05); 
BROMOMETHANE A-11

APPENDIX A

Table A-2. Neurological Effects Observed in Mice and Rats Exposed to Inhaled 

Bromomethane for Intermediate-Duration Exposures

Time of observation Effects in rats Effects in mice

deceased locomotor activity (males: 

14%, p≤0.01; females: 11%, p≤0.05)

100 ppm: 45/86 deaths in males; 

14/86 deaths in females; increased 

novel side crossings (females: 31%, 

p≤0.01), decreased novel side crossings 

(females: 55%, p≤0.01); deceased 

locomotor activity (females: 28%, 

p≤0.01) (no assessment in males due to 

excessive mortality)

NOAEL/LOAEL: X/10 ppm

9 Months

0, 10, 33, or 100 ppm 

– Control: 18/86 deaths in males; 

23/85 deaths in females

10 ppm: 22/85 deaths in males;

18/86 deaths in females

33 ppm: 18/85 deaths in males; 

18/86 deaths in females decreased 

hindlimb grip strength (males: 21%, 

p≤0.01)

100 ppm: 55/86 deaths in males;

22/86 deaths in females; no assessment 

due to excessive mortality (males)

NOAEL/LOAEL: 10 ppm/33 ppm

aIncidence data for mortality were not reported.

LOAEL = lowest observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; X = NOAEL or LOAEL 

value not identified

Source: NTP 1992

Selection of the Point of Departure for the MRL: In selecting the POD for derivation of the 

intermediate-duration inhalation MRL, an important consideration is that death was observed in rats 

continuously exposed to 10 ppm bromomethane for 3 weeks; no mortality was observed at 0, 1, or 5 ppm 

(Sato et al. 1985). Therefore, adverse effects associated with LOAELadj values >5 ppm (adjusted for 

intermittent exposure) were not considered as the basis of the intermediate-duration inhalation MRL. The 

LOAELadj value of 1.8 ppm for decreased locomotor activity in mice (a NOAEL value was not identified) 

is the only LOAELadj value ≤5 ppm (NTP 1992); therefore, this was selected as the critical effect.

To determine the POD for derivation of the intermediate-duration inhalation MRL, data sets for decreased 

locomotor activity in male and female mice (summarized in Table A-3) were analyzed by continuous 

variable models in the EPA Benchmark Dose Software (BMDS, version 3.1.1). The benchmark response 

(BMR) for continuous models is defined as a change equal to 1 standard deviation (SD) from the control 
BROMOMETHANE A-12

APPENDIX A 

mean. Adequate model fit is judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the 

dose-response curve, and scaled residual at the data point (except the control) closest to the predefined 

BMR. Among all of the models providing adequate fit to the data, the lowest BMCL (the lower limit of a 

one-sided 95% CI on the BMC) is selected as a reasonably conservative POD when differences between 

the BMCLs estimated from these models are >3-fold; otherwise, the BMCL from the model with the 

lowest Akaike’s information criterion (AIC) is chosen.

For male and female mice, none of the BMC models provided adequate fit to the locomotor activity data. 

Therefore, the minimal LOAEL of 10 ppm in male mice was selected as the POD for derivation of the 

intermediate-duration inhalation MRL. 

Table A-3. Decreased Locomotor Activity in Male and Female Mice Exposed to 

Inhaled Bromomethane for 6 Months

Exposure level (ppm) Number Mean activity (in instrument units) SE SD

Male mice

0 13 184 4.3 15.5

10 16 155a 10.8 43.2

33 16 158a 4.2 16.8

100 X X X X

Female mice

0 12 187 3.5 12.1

10 15 168b 5.0 19.4

33 16 166b 8.5 34

100 10 135a 9.5 30

ap≤0.01.

bp≤0.05.

SD = standard deviation; SE = standard error; X = due to significant mortality in male mice, neurobehavioral 

assessments were not conducted

Source: NTP 1992

Calculations 

Intermittent Exposure: The LOAEL of 10 ppm identified in male mice was adjusted for intermediate 

exposure: 

LOAELadj = [(LOAEL of 10 ppm) (6 hours/24 hours) (5 days/7 days) = 1.8 ppm

Human Equivalent Concentration: The HEC for mice for extrathoracic effects (RGDRET) was calculated 

by multiplying the LOAELadj by the regional gas dose ratio (RGDR) for extrarespiratory effects. In the 

absence of available blood:gas partition coefficients for humans and mice, the default ratio for the 

RGDRET of 1 was used: 

LOAELadj x RGDR = LOAELHEC

1.8 ppm x 1 = 1.8 ppm

Uncertainty Factor: The total uncertainty factor was 90 (3 for the use of a minimal LOAEL, 3 for 

extrapolation from animals to humans with dosimetric adjustments, and 10 for human variability): 
BROMOMETHANE A-13

APPENDIX A

LOAELadjHEC/total uncertainty factor = intermediate-duration inhalation MRL

1.8 ppm/90 = 0.02 ppm

Other Additional Studies or Pertinent Information that Lend Support to this MRL: Specific 

information regarding effects of intermediate-duration inhalation exposure of humans is limited to a case 

report of two workers; no exposure data were reported (O’Malley et al. 2011). Signs and symptoms of 

neurotoxicity (difficulty with concentration and memory, dizziness, visual disturbances, difficulty with 

speech, ataxia, and abnormal gait) were reported. Although available data on intermediate-duration 

exposure of humans is limited, it is well established that exposure to inhaled bromomethane is neurotoxic 

to humans (Bulathsinghala and Shaw 2014; de Souza et al. 2013). 

Several animal studies have evaluated the effects of intermediate-duration inhalation exposure to 

bromomethane. Results show that bromomethane affects several organ systems, with adverse effects 

observed in the respiratory tract (Eustis et al. 1988; Irish et al. 1940; Kato et al. 1986; NTP 1992), heart 

(Eustis et al. 1988; Kato et al. 1986), liver (Eustis et al. 1988; Kato et al. 1986), immunological system 

(Eustis et al. 1988), nervous system (EPA 1988a; Eustis et al. 1988; Honma et al. 1982; Ikeda et al. 1980; 

Irish et al. 1940; Kato et al. 1986; NTP 1992), reproductive system (EPA 1988a; Eustis et al. 1988), and 

the developing fetus (Mayhew et al. 1986, as cited in EPA 1986a; Kato et al. 1986). The lowest effect 

levels adjusted for intermittent exposure (LOAELadj) identified for each outcome were 10 ppm for 

pulmonary hemorrhage (Sato et al. 1985), 17.9 ppm for focal fibrosis of the heart (Kato et al. 1986), 

28.6 ppm for thymus inflammation and atrophy (Eustis et al. 1988), 1.79 ppm for decreased locomotor 

activity (NTP 1992), 21.4 ppm for decreased sperm density (EPA 1984), and 5.36 ppm for decreased pup 

weight (Mayhew et al. 1986, as cited in EPA 1986a). 

Numerous studies in laboratory animals support identifying the nervous system as a critical target of 

toxicity. Overt signs of neurological effects have been observed in animals, including paralysis, tremors, 

and curling and crossing of limb in monkeys exposed to ≥66 ppm (Irish et al. 1940), rats exposed to 

300 ppm (Kato et al. 1986), mice exposed to ≥80 ppm (EPA 1988a), and rabbits exposed to ≥33 ppm 

(Irish et al. 1940). A dog study reported that during a neurological examination, one dog appeared 

depressed and one dog was unresponsive and motionless (EPA 2001b). Both dogs were exposed to 

5.3 ppm 7 hours/day, 5 days/week for 7 weeks; these symptoms were not observed in the remaining six 

dogs in this group. The investigators considered the significance of this finding as unclear. However, in 

a subsequent study, no overt signs of neurotoxicity were observed in eight dogs exposed to 5.3 ppm (EPA 

2002); alterations in proprioceptive placing were sporadically observed in dogs exposed to 10 or 20 ppm. 

Although there is some uncertainty regarding the toxicological significance of the findings in the two 

dogs exposed to 5.3 ppm for 7 weeks (EPA 2001b), the findings were not confirmed in a subsequent 

6-week dog study (EPA 2002) and the MRL is 250 times lower than this exposure concentration and is

likely to be protective of the effect.

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE A-14

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

MRL:

Critical Effect:

Reference:

Point of Departure:

Uncertainty Factor:

LSE Graph Key:

Species:

Bromomethane 

74-83-9

March 2020

Final

Inhalation

Chronic

0.001 ppm

Respiratory effects (basal cell hyperplasia of the olfactory epithelium)

Reuzel et al. 1991

LOAEL(HEC) of 0.110 ppm

90

50

Rat

MRL Summary: The chronic-duration inhalation MRL for bromomethane was derived from a minimal 

LOAEL value of 3.1 ppm (adjusted for intermittent exposure and converted to a LOAEL(HEC) of 

0.108 ppm) for basal cell hyperplasia of the olfactory epithelium. A total uncertainty factor of 90 was 

applied (3 for use of a minimal LOAEL, 3 for extrapolation from animals to humans with dosimetric 

adjustments, and 10 for human variability). 

Selection of the Critical Effect: The most sensitive effects of chronic exposure of animals to inhaled 

bromomethane are lesions of the respiratory epithelium in male and female rats (Reuzel et al. 1987, 1991) 

and mild neurotoxicity in female mice (NTP 1992). Basal cell hyperplasia of the olfactory epithelium 

was selected as the critical effect because the LOAELadj of 0.55 ppm (a NOAEL was not identified) for 

respiratory lesions is lower than the LOAELadj of 1.79 ppm (a NOAEL was not identified) for 

neurotoxicity reported by NTP (1992). 

Selection of the Principal Study: The Reuzel et al. (1991) study was selected as the principal study 

because it reported the lowest LOAELadj value of 0.55 ppm (a NOAEL was not identified) for lesions of 

the olfactory epithelium in male and female rats. In addition, the study demonstrated exposure-related 

increases of hyperplasia of the olfactory epithelium in both male and female rats after 128 weeks of 

exposure. Severity of nasal lesions increased with exposure concentration and duration. 

Summary of the Principal Study:

Reuzel PG, Dreef-van der Meulen HC, Hollanders VM, et al. 1991. Chronic inhalation toxicity and 

carcinogenicity study of methyl bromide in Wistar rats. Food Chem Toxicol 29(1):31-39. (Data also 

reported in Reuzel PG, Kuper CF, Dreef-Van Der Meulen HC, et al. 1987. Initial submission: Chronic 

(29-month) inhalation toxicity and carcinogenicity study of methyl bromide in rats with cover letter dated 

081092. DuPont Chem Co. Submitted to the U.S. EPA under TSCA Section 8ECP. EPA Document No. 

88-920008788.OTS0546338.)

Groups of 60 male and female Wistar rats were exposed to target concentrations of 0, 3, 60, or 90 ppm 

(actual concentrations were 3.1, 29.6, and 89.1 ppm) bromomethane for 6 hours/day, 5 days/week for 

128 weeks (males) and 129 weeks (females). Animals were examined daily for clinical signs and 

mortality, and rats were weighed weekly for the first 12 weeks of the study, then monthly for the 

remainder of the study. Assessments for hematology, clinical chemistry, and urinalysis were conducted at 

weeks 12–14 and 52–53. Gross pathological examination was performed on all animals at the end of 
BROMOMETHANE A-15

APPENDIX A

treatment or upon early death. At the end of the treatment period, organ weights were recorded for 

selected tissues and histopathological examination was conducted on comprehensive tissues. 

Cumulative mortality was significantly increased in the 89.1 ppm group at exposure week 114 in male 

rats (36/60; p<0.05) and at exposure week 121 in female rats (38/50; p<0.05); significant increases were 

not observed at other time points. Body weights were also decreased throughout the study in males and 

females exposed to 89.1 ppm. No treatment-related effects were observed for hematology, clinical 

chemistry, or urinalysis. Significant, exposure-related histopathological changes were observed in the 

nasal cavity (basal cell hyperplasia of the olfactory epithelium) at all bromomethane concentrations 

tested, with changes classified as very slight or slight at 3.1 ppm, slight at 29.6 ppm, and slight to 

moderate at 89.1 ppm. Hyperkeratosis of the esophagus was observed in male rats in the 89.1 ppm group. 

Microscopic examination of the heart showed cartilaginous metaplasia in males, thrombi in males and 

females, and moderate to severe myocardial degeneration in females exposed to 89.1 ppm. The 

incidences of neoplastic lesions in treatment groups were similar to controls. 

Selection of the Point of Departure for the MRL: The most sensitive effect identified in the Reuzel et al. 

(1991) study is nasal lesions (basal cell hyperplasia of the olfactory epithelium) in male and female rats, 

with a LOAEL of 3.1 ppm at the lowest concentration tested; data are summarized in Table A-4. To 

determine the POD to derive the chronic-duration inhalation MRL, incidence data were fit to all available 

dichotomous models in EPA’s BMDS (version 3.1.1) using the extra risk option. Adequate model fit is 

judged by three criteria: goodness-of-fit (p>0.1), visual inspection of the dose-response curve, and scaled 

residual at the data point (except the control) closest to the predefined BMR. Among all of the models 

providing adequate fit to the data, the lowest BMCL (the lower limit of a one-sided 95% CI on the BMC) 

is selected as a reasonably conservative POD when differences between the BMCLs estimated from these 

models are >3-fold; otherwise, the BMCL from the model with the lowest AIC is chosen (EPA 2012). 

Table A-4. Incidence and Severity Data for Basal Cell Hyperplasia of the 

Olfactory Epithelium in Male and Female Rats Exposed to Inhaled 

Bromomethane for 29 Months

Exposure level (ppm)

Number of rats affected/number 

of rats examined Severity (number of rats)

Male rats

0 4/46 Very slight: 2

Slight: 2

Moderate: 0

3.1 13/48a Very slight: 9

Slight: 3

Moderate: 1

29.6 23/48b Very slight: 7

Slight: 12

Moderate: 4

89.1 31/48b Very slight: 8

Slight:14

Moderate: 9
BROMOMETHANE A-16

APPENDIX A

Table A-4. Incidence and Severity Data for Basal Cell Hyperplasia of the 

Olfactory Epithelium in Male and Female Rats Exposed to Inhaled 

Bromomethane for 29 Months

Exposure level (ppm)

Number of rats affected/number 

of rats examined Severity (number of rats)

Female rats

0 9/58 Very slight: 7

Slight: 2

Moderate: 0

3.1 19/58a Very slight: 17

Slight: 2

Moderate: 0

29.6 25/59a Very slight: 13

Slight: 9

Moderate: 3

89.1 42/59b Very slight: 10

Slight: 23

Moderate: 9

ap≤0.05

bp≤0.01

Source: Reuzel et al. 1987, 1991

Only the LogLogistic model provided adequate fit to the incidence data for basal cell hyperplasia of the 

olfactory epithelium in male rats (BMC10 5.81 ppm; BMCL10 3.65 ppm) (Table A-5). The goodness of fit 

(p-value) was <0.1 for all other models. The selected model fit is shown in Figure A-1. For basal cell 

hyperplasia of the olfactory epithelium in female rats, dichotomous models provided adequate fit to the 

incidence data, except for the Hill and probit models (Table A-6). Using the criteria for model selection, 

the LogLogistic model (BMC10 6.41 ppm; BMCL10 4.13 ppm) was selected as the best fit model. The 

selected model fit is shown in Figure A-2. None of the models provided adequate fit for the combined 

male and female data sets.

Table A-5. Benchmark Dose Model (Version 3.1.1) Predictions for 

Bromomethane, Incidence of Basal Cell Hyperplasia of the Olfactory Epithelium 

in Male Rats Following Chronic Inhalation Exposure (Reuzel et al. 1991)

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMC10

(ppm)

BMCL10

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

All doses

Gammac 2 5.47 0.06 1.25 1.03 -1.50 221.83 ND-0.10 ND-0.10

Hill 1 0.11 0.74 -0.02 -0.12 0.17 218.22 ND-10 ND-10

Logistic 2 8.65 0.01 0.73 1.71 -2.11 225.61 ND-0.10 ND-0.10

LogLogisticd,e 2 3.56 0.17 1.35 0.29 1.35 219.68 5.67 3.56

LogProbitd 1 0.14 0.71 -0.02 0.12 -0.29 218.25 ND-10 ND-10
BROMOMETHANE A-17

APPENDIX A

Table A-5. Benchmark Dose Model (Version 3.1.1) Predictions for 

Bromomethane, Incidence of Basal Cell Hyperplasia of the Olfactory Epithelium 

in Male Rats Following Chronic Inhalation Exposure (Reuzel et al. 1991)

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMC10

(ppm)

BMCL10

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Multistage (1-degree)f 2 5.47 0.06 1.25 1.03 -1.61 221.83 ND-0.10 ND-0.10

Multistage (2-degree)f 2 5.47 0.06 1.25 1.03 -1.61 221.83 ND-0.10 ND-0.10

Multistage (3-degree)f 2 5.47 0.06 1.25 1.03 -1.61 221.83 ND-0.10 ND-0.10

Probit 2 8.48 0.01 1.78 -2.08 -2.08 225.31 ND-0.10 ND-0.10

Weibullc 2 5.47 0.06 1.25 1.03 -1.50 221.83 ND-0.10 ND-0.10

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMC; also the largest residual at any dose. cPower restricted to ≥1.

dSlope restricted to ≥1.

eSelected model. The only model that provided adequate fit to the data was the Log-Logistic. f

Betas restricted to ≥0.

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 10 = exposure concentration associated with 10% extra risk); DF = degrees of freedom; 

ND-0.10 = not determined, goodness-of-fit criteria, p<0.10; ND-10 = not determined, BMDL is 10-fold lower than the 

lowest non-zero dose; Hill model BMCL10 = 0.028; LobProbit model BMCL10 = 0.043

Figure A-1. Selected Model (LogLogistic) for Incidence of Basal Cell Hyperplasia 

of the Olfactory Epithelium in Male Rats Following Chronic Inhalation Exposure

(Reuzel et al. 1991)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70 80

Response

Concentration (ppm)

Estimated Probability Response at BMD Data BMD BMDL
BROMOMETHANE A-18

APPENDIX A

Table A-6. Benchmark Dose Model (Version 3.1.1) Predictions for 

Bromomethane, Incidence of Basal Cell Hyperplasia of the Olfactory Epithelium 

in Female Rats Following Chronic Inhalation Exposure (Reuzel et al. 1991)

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMC10

(ppm)

BMCL10

(ppm)

Dose 

below 

BMC

Dose 

above 

BMC

Overall 

largest

Gammac 2 3.53 0.17 1.44 -0.24 1.44 282.22 9.44 7.00

Hill 1 3.16 0.07 0.83 -1.31 0.83 283.86 ND-0.10 ND-0.10

Logistic 2 4.24 0.12 1.22 0.48 -1.57 283.12 15.94 13.01

LogLogisticd,e 2 3.75 0.15 1.42 -0.80 1.42 282.39 6.41 4.13

LogProbitd 1 3.40 0.06 1.48 0.20 -1.56 284.11 ND-0.10 ND-0.10

Multistage (1-degree)f 2 3.53 0.17 1.44 -0.24 1.44 282.22 9.44 7.00

Multistage (2-degree)f 2 3.53 0.17 1.44 -0.24 1.44 282.22 9.44 7.00

Multistage (3-degree)f 2 3.53 0.17 1.44 -0.24 1.44 282.22 9.44 7.00

Probit 2 4.19 0.12 1.24 0.47 -1.55 283.06 15.56 12.83

Weibullc 2 3.53 0.17 1.44 -0.24 1.44 282.22 9.44 7.00

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMC; also the largest residual at any dose.

cPower restricted to ≥1.

dSlope restricted to ≥1.

eSelected model. All models provided adequate fit to the data. BMCLs for models providing adequate fit were not 

sufficiently close (differed by >2–3-fold). Therefore, the model with lowest BMCL was selected (Log-Logistic). f

Betas restricted to ≥0.

AIC = Akaike Information Criterion; BMC = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMCL = 95% lower confidence limit on the BMC (subscripts denote 

benchmark response: i.e., 10 = exposure concentration associated with 10% extra risk); DF = degrees of freedom; 

ND-0.10 = not determined, goodness-of-fit criteria, p<0.10

Figure A-2. Selected Model (LogLogistic) for Incidence of Basal Cell Hyperplasia 

of the Olfactory Epithelium in Female Rats Following Chronic Inhalation 

Exposure (Reuzel et al. 1991)

0

0.2

0.4

0.6

0.8

1

0 10 20 30 40 50 60 70 80

Response

Concentration (ppm)

Estimated Probability Response at BMD Data BMD BMDL
BROMOMETHANE A-19

APPENDIX A

The BMCL10 values of 3.56 and 4.13 ppm for olfactory epithelial basal cell hyperplasia in male and 

female rats, respectively, which are theoretical no-effect levels, are higher than the empirical LOAEL of 

3.1 ppm, suggesting that the BMD models are not predictive of low-concentration effects. Therefore, to 

determine the POD for derivation of the chronic inhalation MRL, LOAELadj value for olfactory epithelial 

hyperplasia was converted to a HEC (LOAELHEC) by multiplying the LOAELadj by the RGDR values for 

extrathoracic effects, as shown in Table A-7. 

Table A-7. Possible PODs for the Chronic-Duration Inhalation MRL

Species Exposure Effect

LOAEL 

(ppm)

LOAELadj

(ppm)a RGDR

LOAELHEC

(ppm)b Reference

Male rats 29 Months,

6 hours/day, 

5 days/week

Basal cell 

hyperplasia of 

the olfactory 

epithelium

3.1 0.55 0.280c 0.154 Reuzel et al. 

1991

Female 

rats

29 Months,

6 hours/day, 

5 days/week

Basal cell 

hyperplasia of 

the olfactory 

epithelium

3.1 0.55 0.200c 0.110 Reuzel et al. 

1991

aAdjusted for intermittent exposure. See details below under Calculations. bHEC: LOAELadj-HEC = (LOAELadj)(RGDR). See details below under Calculations. cRGDR for rats for extrathoracic respiratory effects (RGDRET). See details below under Calculations. 

HEC = human equivalent concentration; LOAEL = lowest observed-adverse-effect level; NOAEL = no-observedadverse-effect level; POD = point of departure; RGDR = regional gas dose ratio

Calculations 

Intermittent Exposure: The LOAEL of 3.1 ppm in female rats was adjusted for intermittent exposure 

(6 hours/day, 5 days/week): 

LOAELadj = [(LOAEL of 3.1 ppm) (6 hours/24 hours) (5 days/7 days) = 0.55 ppm

Human Equivalent Concentration: The RGDR for rats for extrathoracic respiratory effects (RGDRET) 

was calculated using the following equation (EPA 1994b):

where VE is the ventilation rate (m3

/day; humans: 20; male Wistar rats: 0.42; female Wistar rats: 0.30; 

EPA 1988b), and SAET is surface are of the extrathoracic region of the respiratory tract (cm2

; humans: 

200; male and female rats: 15) (EPA 1994b). 

LOAELadj x RGDR = LOAELHEC

0.55 ppm x 0.20 = 0.110 ppm

Uncertainty Factor: The total uncertainty factor was 90 (3 for the use of a minimal LOAEL, 3 for 

extrapolation from animals to humans with dosimetric adjustments, and 10 for human variability): 
BROMOMETHANE A-20

APPENDIX A

LOAELadjHEC/total uncertainty factor = Chronic-duration inhalation MRL

0.11 ppm/90 = 0.001 ppm

Other Additional Studies or Pertinent Information that Lend Support to this MRL: Information 

regarding effects of chronic-duration inhalation exposure of humans is limited to occupational survey 

studies (Akca et al. 2009; Anger et al. 1986) and case reports (Geyer et al. 2005; Greenberg 1971; Hine 

1969) in bromomethane workers. Results show that chronic inhalation exposure to bromomethane 

produces signs and symptoms of neurotoxicity (headache, dizziness, decreased upper extremity sensation, 

decreased recall, uncoordinated movements, ataxia, seizures, confusion), respiratory effects (nasal 

irritation, dyspnea, cough, increased phlegm), nausea, and vomiting. The Anger et al. (1986) survey 

study conducted in 32 bromomethane workers employed as fumigators showed increased muscle ache 

and fatigue and mild neurotoxic effects (headache, dizziness, decreased upper extremity sensation, and 

decreased recall). However, exposure levels were not determined for these workers. The reported mean 

exposure level of 2.3 ppm was determined from personal monitoring data collected in different 

populations of fumigators. However, since exposures of workers in the survey study are unknown, the 

outcomes observed cannot quantitatively be related to exposure levels.

Results of animal studies show that chronic exposure to bromomethane produces toxicity to the 

respiratory tract in rats (Gotoh et al. 1994; Reuzel et al. 1987, 1991) and mice (NTP 1992;), heart in rats 

(Reuzel et al. 1987, 1991) and mice (NTP 1992), gastrointestinal tract in rats (Reuzel et al. 1987, 1991), 

skeleton in mice (NTP 1992), and neurological system in mice (NTP 1992). In addition, decreased body 

weight gain was observed in rats (Reuzel et al. 1987, 1991) and mice (NTP 1992). The lowest effect 

levels adjusted for continuous exposure (LOAELadj) were 1.79 ppm for decreased locomotor activity 

(NTP 1992), 17.9 ppm for dysplasia of the sternum (NTP 1992), 0.54 ppm for basal cell hyperplasia of 

the olfactory epithelium (Reuzel et al. 1987, 1991), 16.1 ppm for myocardial degeneration (Reuzel et al. 

1987, 1991), and 16.1 ppm for hyperkeratosis of the esophagus (Reuzel et al. 1987, 1991).

Identification of the respiratory tract as one of the most sensitive targets of toxicity is supported by 

findings of nasal irritation and cough noted in cases reports and a rat study by Gotoh et al. (1994). Nonneoplastic lesions of the nasal cavity were observed in a 2-year study in male and female F344 rats 

exposed to 0, 4, 20, or 100 ppm bromomethane 6 hours/day, 5 days/week (Gotoh et al. 1994). 

Inflammation of the nasal cavity was observed in males exposed to 4, 20, and 100 ppm and in females 

exposed to 100 ppm, and necrosis of the olfactory epithelium was observed in males exposed to 100 ppm.

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE A-21

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Bromomethane

CAS Numbers: 74-83-9

Date: March 2020

Profile Status: Final

Route: Oral

Duration: Acute

MRL Summary: There are insufficient data for derivation of an acute-duration oral MRL.

Rationale for Not Deriving an MRL: The oral toxicity of this compound has not been thoroughly 

studied because bromomethane tends to volatilize and exists mainly as a gas at room temperature. One 

acute-duration oral study was identified (Kaneda et al. 1998). This study exposed pregnant rats to 0, 3, 

10, or 30 mg/kg/day and pregnant rabbits to 0, 1, 3, or 10 mg/kg/day bromomethane in corn oil by gavage 

on gestation days 6–15. In rats, erosion and thickening of the wall of the non-glandular stomach or 

adhesion of the stomach to the spleen, liver, or diaphragm was seen in all rats in the 30 mg/kg/day dose 

group. No clinical signs of toxicity, effects on reproductive function, or developmental effects in fetuses 

were observed. The only effects observed in rabbits were significant decreases in body weight and 

decreased food consumption in the 10 mg/kg/day group. Effects on body weight gain in rats and rabbits 

were considered to be secondary to the decreased food consumption.

It is unclear if effects observed in the glandular stomach are due to the bolus administration of a very 

reactive chemical, and if gavage administration would be an appropriate model for human exposure to 

bromomethane. In chronic-duration dietary studies, no gastrointestinal lesions were observed in rats 

(EPA 1999) or dogs (Wilson et al. 2000). The general population is not likely to be exposed to 

bromomethane via the oral route; however, exposure to a small amount of bromomethane could occur via 

contaminated water or food and, therefore, would not mimic the gavage exposure in animal studies. 

Given the uncertainty of whether the observed forestomach lesions are unique to gavage administration of 

bromomethane, an acute-duration oral MRL was not derived. 

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE A-22

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Bromomethane

CAS Numbers: 74-83-9

Date: March 2020

Profile Status: Final

Route: Oral

Duration: Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration oral MRL.

Rationale for Not Deriving an MRL: The oral toxicity of this compound has not been thoroughly 

studied because bromomethane tends to volatilize and exists mainly as a gas at room temperature. Two 

intermediate-duration gavage studies conducted male rats were identified (Boorman et al. 1986; Danse et 

al. 1984). These studies administer bromomethane by gavage at doses of 0, 0.4, 2, 10, or 50 mg/kg/day 

(Boorman et al. 1986) for 13 weeks and 0 or 50 mg/kg/day for 13–25 weeks (Danse et al. 1984). Mild 

focal hyperemia in the forestomach was observed at 2 mg/kg/day (Danse et al. 1984) and forestomach 

ulceration was observed at 50 mg/kg/day (Boorman et al. 1986; Danse et al. 1984). A 4-week feeding 

study in rats did not identify any adverse effects of dietary exposure to microencapsulated bromomethane 

at doses up to 7.98 mg/kg/day (EPA 1996). Although mean body weight gain was decreased by 14% in 

males during the first week of exposure and by 33% in females during weeks 1–2, but not during other 

weeks (EPA 1996). These changes were accompanied by decreased food intake and, therefore, are not 

considered adverse. 

It is unclear if effects observed in the forestomach of rats are due to the bolus administration of a very 

reactive chemical, and if gavage administration would be an appropriate model for human exposure to 

bromomethane. The general population is not likely to be exposed to bromomethane via the oral route; 

however, exposure to a small amount of bromomethane could occur via contaminated water or food and, 

therefore, would not mimic the gavage exposure in animal studies. Given the uncertainty of whether the 

observed forestomach lesions are unique to gavage administration of bromomethane, an acute-duration 

oral MRL was not derived. 

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE A-23

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: Bromomethane

CAS Numbers: 74-83-9

Date: March 2020

Profile Status: Final

Route: Oral

Duration: Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration oral MRL.

Rationale for Not Deriving an MRL: The oral toxicity of this compound has not been thoroughly 

studied because bromomethane tends to volatilize and exists mainly as a gas at room temperature. Two 

chronic-duration oral studies were identified: one study exposing dogs to dietary bromomethane at doses 

up to in 0.28 mg/kg/day in males and 0.27 mg/kg/day in females for 1 year (Wilson et al. 2000) and one 

study exposing rats to microencapsulated bromomethane at doses up to 11.10 and 15.12 mg/kg/day in 

males and females, respectively, for 12–24 months (EPA 1999). No adverse effects were observed in the 

study in dogs (Wilson et al. 2000). In rats, decreases in body weight gain were observed in the first 12–

18 months at the highest dose levels. However, decreased food consumption were also observed at these 

doses during the same time period; therefore, decreased body weight gain is not considered adverse (EPA 

1999). No other compound-related effects were observed.

This database was not considered adequate for derivation of a chronic-duration oral MRL because the 

targets of toxicity have not been established.

Agency Contacts (Chemical Managers): Sam Keith
BROMOMETHANE B-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR 

BROMOMETHANE

The objective of the toxicological profile is to evaluate the potential for human exposure and the potential 

health hazards associated with inhalation, oral, or dermal/ocular exposure to bromomethane. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen were conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for bromomethane. ATSDR primarily focused on peer-reviewed articles without 

publication date or language restrictions. Non-peer-reviewed studies that were considered relevant to the 

assessment of the health effects of bromomethane have undergone peer review by at least three ATSDRselected experts who have been screened for conflict of interest. The inclusion criteria used to identify 

relevant studies examining the health effects of bromomethane are presented in Table B-1.

Table B-1. Inclusion Criteria for the Literature Search and Screen

Health Effects

Species

Human

Laboratory mammals

Route of exposure

Inhalation

Oral

Dermal (or ocular)

Parenteral (these studies will be considered supporting data)

Health outcome

Death

Systemic effects

Body weight effects 

Respiratory effects

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects
BROMOMETHANE B-2

APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen

Other noncancer effects

Cancer

Toxicokinetics

Absorption

Distribution

Metabolism

Excretion

PBPK models

Biomarkers

Biomarkers of exposure

Biomarkers of effect

Interactions with other chemicals

Potential for human exposure

Releases to the environment

Air

Water

Soil

Environmental fate

Transport and partitioning

Transformation and degradation

Environmental monitoring

Air

Water

Sediment and soil

Other media

Biomonitoring

General populations

Occupation populations

B.1.1 Literature Search

The current literature search was intended to update the draft toxicological profile for bromomethane 

released for public comment in 2018. The following main databases were searched in May 2019:

• PubMed 

• National Library of Medicine’s TOXLINE

• Scientific and Technical Information Network’s TOXCENTER

The search strategy used the chemical names, Chemical Abstracts Service (CAS) numbers, 

synonyms, Medical Subject Headings (MeSH) headings, and keywords for bromomethane. The 

query strings used for the literature search are presented in Table B-2. 

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures 
BROMOMETHANE B-3

APPENDIX B

and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases 

were searched in the creation of various tables and figures, such as the TRI Explorer, the Substance 

Priority List (SPL) resource page, and other items as needed. Regulations applicable to bromomethane

were identified by searching international and U.S. agency websites and documents.

Review articles were identified and used for the purpose of providing background information and 

identifying additional references. ATSDR also identified reports from the grey literature, which included 

unpublished research reports, technical reports from government agencies, conference proceedings and 

abstracts, and theses and dissertations. 

Table B-2. Database Query Strings 

Database

search date Query string

PubMed

05/2019 (74-83-9[rn] OR "methyl bromide"[nm] OR "Bercema"[tw] OR "Brom-O-Gas"[tw] OR "BromO-Sol"[tw] OR "BROMO METHANE"[tw] OR "Bromomethane"[tw] OR "Celfume"[tw] OR 

"Curafume"[tw] OR "Dawson 100"[tw] OR "Detia gas EX-M"[tw] OR "Dowfume MC-2"[tw] 

OR "Dowfume MC-2R"[tw] OR "Dowfume MC-33"[tw] OR "Drexel Plant Bed Gas"[tw] OR 

"Edco"[tw] OR "Embafume"[tw] OR "F 40B1"[tw] OR "Halon 1001"[tw] OR "Haltox"[tw] OR 

"Iscobrome"[tw] OR "Kayafume"[tw] OR "M-B-C Fumigant"[tw] OR "M-B-R 98"[tw] OR 

"MBC Soil Fumigant"[tw] OR "Mbc-33 Soil Fumigant"[tw] OR "MBX"[tw] OR "Metafume"[tw] 

OR "Meth-O-Gas"[tw] OR "Methane, bromo"[tw] OR "Methogas"[tw] OR "Methybrom"[tw] 

OR "Methyl bromide"[tw] OR "Methyl fume"[tw] OR "Methylbromide"[tw] OR 

"Monobromomethane"[tw] OR "Pestmaster"[tw] OR "Profume"[tw] OR "R 40B1"[tw] OR 

"Terabol"[tw] OR "Terr-O-Cide II"[tw] OR "Terr-O-Gas"[tw] OR "Tri-Brom"[tw] OR 

"Zytox"[tw]) AND (2014/12/01 : 3000[dp] OR 2015/12/01 : 3000[edat] OR 2015/12/01 : 

3000[crdt] OR 2015/12/01 : 3000[mhda])

Toxline

05/2019 (74-83-9[rn] OR "Bercema" OR "Brom-O-Gas" OR "Brom-O-Sol" OR "BROMO METHANE" 

OR "Bromomethane" OR "Celfume" OR "Curafume" OR "Dawson 100" OR "Detia gas EXM" OR "Dowfume MC-2" OR "Dowfume MC-2R" OR "Dowfume MC-33" OR "Drexel Plant 

Bed Gas" OR "Edco" OR "Embafume" OR "F 40B1" OR "Halon 1001" OR "Haltox" OR 

"Iscobrome" OR "Kayafume" OR "M-B-C Fumigant" OR "M-B-R 98" OR "MBC Soil 

Fumigant" OR "Mbc-33 Soil Fumigant" OR "MBX" OR "Metafume" OR "Meth-O-Gas" OR 

"Methane, bromo" OR "Methogas" OR "Methybrom" OR "Methyl bromide" OR "Methyl 

fume" OR "Methylbromide" OR "Monobromomethane" OR "Pestmaster" OR "Profume" OR 

"R 40B1" OR "Terabol" OR "Terr-O-Cide II" OR "Terr-O-Gas" OR "Tri-Brom" OR "Zytox") 

AND ( ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR DART [org] OR EMIC [org] OR 

EPIDEM [org] OR HEEP [org] OR HMTC [org] OR IPA [org] OR RISKLINE [org] OR 

MTGABS [org] OR NIOSH [org] OR NTIS [org] OR PESTAB [org] OR PPBIB [org] ) AND 

NOT PubMed [org] AND NOT pubdart [org]

Year of Publication 2015 through 2019

Toxcenter

05/2019 FILE 'TOXCENTER' ENTERED AT 14:16:04 ON 01 MAY 2019

CHARGED TO COST=EH011.10.LB.01.05

L1 5026 SEA FILE=TOXCENTER 74-83-9 

L2 4155 SEA FILE=TOXCENTER L1 NOT PATENT/DT 

L3 4039 SEA FILE=TOXCENTER L2 NOT TSCATS/FS 

L4 243 SEA FILE=TOXCENTER L3 AND ED>=20150101 

 ACT TOXQUERY/Q

 ---------
BROMOMETHANE B-4

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

L5 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR 

 BIOMARKER? OR NEUROLOG?) 

L6 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR 

EPIDEMIOLOGY/ST,CT,

 IT) 

L7 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L8 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT 

L9 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?) 

L10 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?) 

L11 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS 

OR 

 DIETARY OR DRINKING(W)WATER?) 

L12 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR 

PERMISSIBLE))

L13 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L14 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? 

OR 

 OVUM?) 

L15 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L16 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

L17 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR 

SPERMAS? OR 

 SPERMATOB? OR SPERMATOC? OR SPERMATOG?) 

L18 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR 

SPERMATOX? OR 

 SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?) 

L19 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR 

DEVELOPMENTAL?) 

L20 QUE (ENDOCRIN? AND DISRUPT?) 

L21 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR 

INFANT?) 

L22 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?) 

L23 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?) 

L24 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? 

OR 

 NEOPLAS?) 

L25 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR 

CARCINOM?) 

L26 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR 

GENETIC(W)TOXIC?)

L27 QUE (NEPHROTOX? OR HEPATOTOX?) 

L28 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L29 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L30 QUE L5 OR L6 OR L7 OR L8 OR L9 OR L10 OR L11 OR L12 OR L13 OR 

 L14 OR L15 OR L16 OR L17 OR L18 OR L19 OR L20 OR L21 OR L22 OR 

 L23 OR L24 OR L25 OR L26 OR L27 OR L28 OR L29 
BROMOMETHANE B-5

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

L31 QUE (RAT OR RATS OR MOUSE OR MICE OR GUINEA(W)PIG? OR 

MURIDAE 

 OR DOG OR DOGS OR RABBIT? OR HAMSTER? OR PIG OR PIGS OR 

SWINE 

 OR PORCINE OR MONKEY? OR MACAQUE?) 

L32 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR 

LAGOMORPHA 

 OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE) 

L33 QUE L30 OR L31 OR L32 

L34 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? 

OR 

 PRIMATES OR PRIMATE?) 

L35 QUE L33 OR L34 

 ---------

L36 146 SEA FILE=TOXCENTER L4 AND L35 

L37 133 DUP REM L36 (13 DUPLICATES REMOVED)

 ANSWERS '1-133' FROM FILE TOXCENTER

L*** DEL 146 S L4 AND L35

L*** DEL 146 S L4 AND L35

L38 133 SEA FILE=TOXCENTER L37 

L39 17 SEA FILE=TOXCENTER L38 AND MEDLINE/FS 

 D SCAN L37

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATSa

05/2019 Compounds searched: 74-83-9

NTP

05/2019 "74-83-9" "Methyl bromide" "Methylbromide" "Bromomethane" 

"Monobromomethane" "BROMO METHANE" "Bercema" "Methane, bromo" 

"Edco" "MBX" "Terabol" "Halon 1001" "Brom-O-Gas" "Brom-O-Sol" "Celfume" 

"Curafume" "Dawson 100" "Detia gas EX-M" "Dowfume MC-2" "Dowfume MC-2R" 

"Dowfume MC-33" "Drexel Plant Bed Gas" "Embafume" "F 40B1" "Haltox" "Iscobrome" 

"Kayafume" "M-B-C Fumigant" "M-B-R 98" "MBC Soil Fumigant" "Mbc-33 Soil 

Fumigant" "Metafume" "Meth-O-Gas" "Methogas" "Methybrom" "Methyl fume" 

"Pestmaster" "Profume" "R 40B1" "Terr-O-Cide II" "Terr-O-Gas" "Tri-Brom" "Zytox"

Regulations.gov

05/2019 74-83-9 "Methyl bromide" "Methylbromide" "Bromomethane" "Monobromomethane"

NIH RePORTER

05/2019 Text Search: "Bercema" OR "Brom-O-Gas" OR "Brom-O-Sol" OR "BROMO 

METHANE" OR "Bromomethane" OR "Celfume" OR "Curafume" OR "Dawson 100" 

OR "Detia gas EX-M" OR "Dowfume MC-2" OR "Dowfume MC-2R" OR "Dowfume MC33" OR "Drexel Plant Bed Gas" OR "Edco" OR "Embafume" OR "F 40B1" OR "Halon 

1001" OR "Haltox" OR "Iscobrome" OR "Kayafume" OR "M-B-C Fumigant" OR "M-B-R 

98" OR "MBC Soil Fumigant" OR "Mbc-33 Soil Fumigant" OR "MBX" OR "Metafume" 
BROMOMETHANE B-6

APPENDIX B

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

OR "Meth-O-Gas" OR "Methane, bromo" OR "Methogas" OR "Methybrom" OR "Methyl 

bromide" OR "Methyl fume" OR "Methylbromide" OR "Monobromomethane" OR 

"Pestmaster" OR "Profume" OR "R 40B1" OR "Terabol" OR "Terr-O-Cide II" OR "TerrO-Gas" OR "Tri-Brom" OR "Zytox" (Advanced), Search in: Projects AdminIC: All, 

Fiscal Year: Active Projects

Other Identified throughout the assessment process

aSeveral versions of the TSCATS database were searched, as needed, by CASRN including TSCATS1 via Toxline 

(no date limit), TSCATS2 via https://yosemite.epa.gov/oppts/epatscat8.nsf/ReportSearch?OpenForm (date restricted 

by EPA receipt date), and TSCATS via CDAT (date restricted by ‘Mail Received Date Range’), as well as google for 

recent TSCA submissions.

The 2019 results were: 

• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate 

removal): 335

• Number of records identified from other strategies: 47

• Total number of records to undergo literature screening: 382

B.1.2 Literature Screening 

A two-step process was used to screen the literature search to identify relevant studies on bromomethane: 

• Title and abstract screen

• Full text screen

Title and Abstract Screen. Within the reference library, titles and abstracts were screened manually for 

relevance. Studies that were considered relevant (see Table B-1 for inclusion criteria) were moved to the

second step of the literature screening process. Studies were excluded when the title and abstract clearly 

indicated that the study was not relevant to the toxicological profile. 

• Number of titles and abstracts screened: 382

• Number of studies considered relevant and moved to the next step: 52

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 52

• Number of studies cited in the pre-public draft of the toxicological profile: 218

• Total number of studies cited in the profile: 262

A summary of the results of the literature search and screening is presented in Figure B-1.
BROMOMETHANE B-7

APPENDIX B

Figure B-1. April 2018 Literature Search Results and Screen for Bromomethane
BROMOMETHANE C-1

APPENDIX C. USER'S GUIDE

Chapter 1. Relevance to Public Health

This chapter provides an overview of U.S. exposures, a summary of health effects based on evaluations of 

existing toxicologic, epidemiologic, and toxicokinetic information, and an overview of the minimal risk 

levels. This is designed to present interpretive, weight-of-evidence discussions for human health 

endpoints by addressing the following questions:

1. What effects are known to occur in humans?

2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites?

Minimal Risk Levels (MRLs)

Where sufficient toxicologic information is available, ATSDR derives MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans.

MRLs should help physicians and public health officials determine the safety of a community living near 

a hazardous substance emission, given the concentration of a contaminant in air or the estimated daily 

dose in water. MRLs are based largely on toxicological studies in animals and on reports of human 

occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based. 

Section 1.2, Summary of Health Effects, contains basic information known about the substance. Other 

sections, such as Section 3.2 Children and Other Populations that are Unusually Susceptible and 

Section 3.4 Interactions with Other Substances, provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to 

protect sensitive subpopulations (people who are most susceptible to the health effects caused by the 

substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, 

these individual uncertainty factors are multiplied together. The product is then divided into the 

inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a 
BROMOMETHANE C-2

APPENDIX C

substance-specific MRL are provided in the footnotes of the levels of significant exposure (LSE) tables

that are provided in Chapter 2. Detailed discussions of the MRLs are presented in Appendix A.

Chapter 2. Health Effects

Tables and Figures for Levels of Significant Exposure (LSE)

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species and MRLs to humans for noncancer 

endpoints. The LSE tables and figures can be used for a quick review of the health effects and to locate 

data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction 

with the text. All entries in these tables and figures represent studies that provide reliable, quantitative 

estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE tables and figures follow. The numbers in the left column of the legends correspond to 

the numbers in the example table and figure.

TABLE LEGEND

See Sample LSE Table (page C-5)

(1) Route of exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. 

Typically, when sufficient data exist, three LSE tables and two LSE figures are presented in the 

document. The three LSE tables present data on the three principal routes of exposure

(i.e., inhalation, oral, and dermal). LSE figures are limited to the inhalation and oral routes. Not 

all substances will have data on each route of exposure and will not, therefore, have all five of the 

tables and figures. Profiles with more than one chemical may have more LSE tables and figures.

(2) Exposure period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and 

chronic (≥365 days)—are presented within each relevant route of exposure. In this example, two

oral studies of chronic-duration exposure are reported. For quick reference to health effects 

occurring from a known length of exposure, locate the applicable exposure period within the LSE 

table and figure.

(3) Figure key. Each key number in the LSE table links study information to one or more data points 

using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 51 identified NOAELs and less serious LOAELs (also see the three

"51R" data points in sample LSE Figure 2-X).

(4) Species (strain) No./group. The test species (and strain), whether animal or human, are identified 

in this column. The column also contains information on the number of subjects and sex per 

group. Chapter 1, Relevance to Public Health, covers the relevance of animal data to human 

toxicity and Section 3.1, Toxicokinetics, contains any available information on comparative 

toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated 

to equivalent human doses to derive an MRL.

(5) Exposure parameters/doses. The duration of the study and exposure regimens are provided in 

these columns. This permits comparison of NOAELs and LOAELs from different studies. In 

this case (key number 51), rats were orally exposed to “Chemical X” via feed for 2 years. For a 
BROMOMETHANE C-3

APPENDIX C

more complete review of the dosing regimen, refer to the appropriate sections of the text or the 

original reference paper (i.e., Aida et al. 1992).

(6) Parameters monitored. This column lists the parameters used to assess health effects. Parameters 

monitored could include serum (blood) chemistry (BC), behavioral (BH), biochemical changes 

(BI), body weight (BW), clinical signs (CS), developmental toxicity (DX), enzyme activity (EA), 

food intake (FI), fetal toxicity (FX), gross necropsy (GN), hematology (HE), histopathology 

(HP), lethality (LE), maternal toxicity (MX), organ function (OF), ophthalmology (OP), organ 

weight (OW), teratogenicity (TG), urinalysis (UR), and water intake (WI).

(7) Endpoint. This column lists the endpoint examined. The major categories of health endpoints 

included in LSE tables and figures are death, body weight, respiratory, cardiovascular, 

gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, ocular, endocrine, 

immunological, neurological, reproductive, developmental, other noncancer, and cancer. "Other

noncancer" refers to any effect (e.g., alterations in blood glucose levels) not covered in these 

systems. In the example of key number 51, three endpoints (body weight, hematological, and 

hepatic) were investigated.

(8) NOAEL. A NOAEL is the highest exposure level at which no adverse effects were seen in the 

organ system studied. The body weight effect reported in key number 51 is a NOAEL at

25.5 mg/kg/day. NOAELs are not reported for cancer and death; with the exception of these two 

endpoints, this field is left blank if no NOAEL was identified in the study.

(9) LOAEL. A LOAEL is the lowest dose used in the study that caused an adverse health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific endpoint used to 

quantify the adverse effect accompanies the LOAEL. Key number 51 reports a less serious 

LOAEL of 6.1 mg/kg/day for the hepatic system, which was used to derive a chronic exposure, 

oral MRL of 0.008 mg/kg/day (see footnote "c"). MRLs are not derived from serious LOAELs. 

A cancer effect level (CEL) is the lowest exposure level associated with the onset of 

carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious 

effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report 

doses not causing measurable cancer increases. If no LOAEL/CEL values were identified in the 

study, this field is left blank.

(10) Reference. The complete reference citation is provided in Chapter 8 of the profile.

(11) Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. For example, footnote "c" indicates that the LOAEL of 6.1 mg/kg/day in key 

number 51 was used to derive an oral MRL of 0.008 mg/kg/day.

FIGURE LEGEND

See Sample LSE Figure (page C-6)

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods.

(13) Exposure period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the chronic exposure period are illustrated.
BROMOMETHANE C-4

APPENDIX C

(14) Endpoint. These are the categories of health effects for which reliable quantitative data exist. 

The same health effect endpoints appear in the LSE table.

(15) Levels of exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in 

mg/kg/day.

(16) LOAEL. In this example, the half-shaded circle that is designated 51R identifies a LOAEL

critical endpoint in the rat upon which a chronic oral exposure MRL is based. The key number 

51 corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 6.1 mg/kg/day (see entry 51 in the sample LSE table) to 

the MRL of 0.008 mg/kg/day (see footnote "c" in the sample LSE table).

(17) CEL. Key number 59R is one of studies for which CELs were derived. The diamond symbol 

refers to a CEL for the test species (rat). The number 59 corresponds to the entry in the LSE 

table.

(18) Key to LSE figure. The key provides the abbreviations and symbols used in the figure.
BROMOMETHANE

C-5

APPENDIX C
BROMOMETHANE C-6 

APPENDIX C
BROMOMETHANE D-1 

APPENDIX D. QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances may find the following information helpful for fast 

answers to often-asked questions.

Primary Chapters/Sections of Interest

Chapter 1: Relevance to Public Health: The Relevance to Public Health Section provides an overview 

of exposure and health effects and evaluates, interprets, and assesses the significance of toxicity 

data to human health. A table listing minimal risk levels (MRLs) is also included in this chapter.

Chapter 2: Health Effects: Specific health effects identified in both human and animal studies are 

reported by type of health effect (e.g., death, hepatic, renal, immune, reproductive), route of 

exposure (e.g., inhalation, oral, dermal), and length of exposure (e.g., acute, intermediate, and 

chronic). 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. 

Pediatrics: 

Section 3.2 Children and Other Populations that are Unusually Susceptible

Section 3.3 Biomarkers of Exposure and Effect

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) 

Internet: http://www.atsdr.cdc.gov 

The following additional materials are available online: 

Case Studies in Environmental Medicine are self-instructional publications designed to increase primary 

health care providers’ knowledge of a hazardous substance in the environment and to aid in the 

evaluation of potentially exposed patients (see https://www.atsdr.cdc.gov/csem/csem.html). 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident (see https://www.atsdr.cdc.gov/MHMI/index.asp). Volumes I and II are planning guides 

to assist first responders and hospital emergency department personnel in planning for incidents 

that involve hazardous materials. Volume III—Medical Management Guidelines for Acute 

Chemical Exposures—is a guide for health care professionals treating patients exposed to 

hazardous materials.

Fact Sheets (ToxFAQsTM) provide answers to frequently asked questions about toxic substances (see 

https://www.atsdr.cdc.gov/toxfaqs/Index.asp).
BROMOMETHANE D-2 

APPENDIX D

Other Agencies and Organizations

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, GA

30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015 • Web Page: 

https://www.cdc.gov/nceh/. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 395 E Street, S.W., Suite 9200, 

Patriots Plaza Building, Washington, DC 20201 • Phone: 202-245-0625 or 1-800-CDC-INFO 

(800-232-4636) • Web Page: https://www.cdc.gov/niosh/. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212 • Web Page: 

https://www.niehs.nih.gov/. 

Clinical Resources (Publicly Available Information) 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266 • Web Page: 

http://www.acoem.org/. 

The American College of Medical Toxicology (ACMT) is a nonprofit association of physicians with 

recognized expertise in medical toxicology. Contact: ACMT, 10645 North Tatum Boulevard, 

Suite 200-111, Phoenix AZ 85028 • Phone: 844-226-8333 • FAX: 844-226-8333 • Web Page: 

http://www.acmt.net. 

The Pediatric Environmental Health Specialty Units (PEHSUs) is an interconnected system of specialists 

who respond to questions from public health professionals, clinicians, policy makers, and the 

public about the impact of environmental factors on the health of children and reproductive-aged 

adults. Contact information for regional centers can be found at http://pehsu.net/findhelp.html. 

The American Association of Poison Control Centers (AAPCC) provide support on the prevention and 

treatment of poison exposures. Contact: AAPCC, 515 King Street, Suite 510, Alexandria VA 

22314 • Phone: 701-894-1858 • Poison Help Line: 1-800-222-1222 • Web Page: 

http://www.aapcc.org/. 
BROMOMETHANE E-1

APPENDIX E. GLOSSARY

Absorption—The process by which a substance crosses biological membranes and enters systemic 

circulation. Absorption can also refer to the taking up of liquids by solids, or of gases by solids or liquids.

Acute Exposure—Exposure to a chemical for a duration of ≤14 days, as specified in the Toxicological 

Profiles.

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact.

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment.

Benchmark Dose (BMD) or Benchmark Concentration (BMC)—is the dose/concentration 

corresponding to a specific response level estimate using a statistical dose-response model applied to 

either experimental toxicology or epidemiology data. For example, a BMD10 would be the dose

corresponding to a 10% benchmark response (BMR). The BMD is determined by modeling the doseresponse curve in the region of the dose-response relationship where biologically observable data are 

feasible. The BMDL or BMCL is the 95% lower confidence limit on the BMD or BMC. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period.

Biomarkers—Indicators signaling events in biologic systems or samples, typically classified as markers 

of exposure, effect, and susceptibility.

Cancer Effect Level (CEL)—The lowest dose of a chemical in a study, or group of studies, that 

produces significant increases in the incidence of cancer (or tumors) between the exposed population and 

its appropriate control.

Carcinogen—A chemical capable of inducing cancer.

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-control study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without the outcome.

Case Report—A report that describes a single individual with a particular disease or exposure. These 

reports may suggest some potential topics for scientific research, but are not actual research studies.

Case Series—Reports that describe the experience of a small number of individuals with the same 

disease or exposure. These reports may suggest potential topics for scientific research, but are not actual 

research studies.
BROMOMETHANE E-2

APPENDIX E

Ceiling Value—A concentration that must not be exceeded.

Chronic Exposure—Exposure to a chemical for ≥365 days, as specified in the Toxicological Profiles.

Clastogen—A substance that causes breaks in chromosomes resulting in addition, deletion, or 

rearrangement of parts of the chromosome.

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome, and who are disease-free at start of follow-up. Often, at 

least one exposed group is compared to one unexposed group, while in other cohorts, exposure is a 

continuous variable and analyses are directed towards analyzing an exposure-response coefficient.

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at a specific point in time.

Data Needs—Substance-specific informational needs that, if met, would reduce the uncertainties of 

human health risk assessment.

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism.

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the response or amount of the response.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

effect occurs. Effects include malformations and variations, altered growth, and in utero death.

Epidemiology—The investigation of factors that determine the frequency and distribution of disease or 

other health-related conditions within a defined human population during a specified period. 

Excretion—The process by which metabolic waste products are removed from the body.

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome.

Half-life—A measure of rate for the time required to eliminate one-half of a quantity of a chemical from 

the body or environmental media.

Health Advisory—An estimate of acceptable drinking water levels for a chemical substance derived by 

EPA and based on health effects information. A health advisory is not a legally enforceable federal 

standard, but serves as technical guidance to assist federal, state, and local officials.

Immediately Dangerous to Life or Health (IDLH)—A condition that poses a threat of life or health, or 

conditions that pose an immediate threat of severe exposure to contaminants that are likely to have 

adverse cumulative or delayed effects on health.
BROMOMETHANE E-3

APPENDIX E

Immunotoxicity—Adverse effect on the functioning of the immune system that may result from 

exposure to chemical substances. 

Incidence—The ratio of new cases of individuals in a population who develop a specified condition to 

the total number of individuals in that population who could have developed that condition in a specified 

time period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles.

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.

In Vivo—Occurring within the living organism.

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals.

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for

a specific length of time is expected to cause death in 50% of a defined experimental animal population.

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population.

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical

is expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control.

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus.

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function.

Metabolism—Process in which chemical substances are biotransformed in the body that could result in 

less toxic and/or readily excreted compounds or produce a biologically active intermediate.

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure.

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1.
BROMOMETHANE E-4

APPENDIX E

Morbidity—The state of being diseased; the morbidity rate is the incidence or prevalence of a disease in 

a specific population.

Mortality—Death; the mortality rate is a measure of the number of deaths in a population during a 

specified interval of time.

Mutagen—A substance that causes mutations, which are changes in the DNA sequence of a cell’s DNA. 

Mutations can lead to birth defects, miscarriages, or cancer.

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

hazardous substance.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Although effects may be produced at this dose, they 

are not considered to be adverse.

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution.

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An odds ratio that is greater than 1 is considered to indicate greater risk of 

disease in the exposed group compared to the unexposed group.

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

regulatory limit on the amount or concentration of a substance not to be exceeded in workplace air 

averaged over any 8-hour work shift of a 40-hour workweek.

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests (insects or other organisms harmful to cultivated plants or animals).

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body.

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body.

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic 

endpoints. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
BROMOMETHANE E-5

APPENDIX E

Physiologically Based Pharmacokinetic (PBPK) Model—A type of physiologically based doseresponse model that is comprised of a series of compartments representing organs or tissue groups with 

realistic weights and blood flows. These models require a variety of physiological information, including

tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates, and possibly 

membrane permeabilities. The models also utilize biochemical information, such as blood:air partition 

coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry 

models.

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which a group is followed over time and the pertinent 

observations are made on events occurring after the start of the study. 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek.

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. 

The inhalation RfC is expressed in units of mg/m3 or ppm.

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily oral exposure of the human population to a potential hazard that is likely to be without risk of 

deleterious noncancer health effects during a lifetime. The oral RfD is expressed in units of mg/kg/day. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). RQs are 

(1) ≥1 pound or (2) for selected substances, an amount established by regulation either under CERCLA or 

under Section 311 of the Clean Water Act. Quantities are measured over a 24-hour period.

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a hazardous substance. The toxicity may be directed to the reproductive organs and/or 

the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual 

behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the 

integrity of this system.

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort.

Risk—The possibility or chance that some adverse effect will result from a given exposure to a hazardous 

substance.

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, existing health 

condition, or an inborn or inherited characteristic that is associated with an increased occurrence of 

disease or other health-related event or condition.
BROMOMETHANE E-6

APPENDIX E

Risk Ratio/Relative Risk—The ratio of the risk among persons with specific risk factors compared to the 

risk among persons without risk factors. A risk ratio that is greater than 1 indicates greater risk of disease 

in the exposed group compared to the unexposed group.

Short-Term Exposure Limit (STEL)—A STEL is a 15-minute TWA exposure that should not be 

exceeded at any time during a workday. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population.

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen—A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which it is believed that nearly all workers may be repeatedly 

exposed, day after day, for a working lifetime without adverse effect. The TLV may be expressed as a 

Time-Weighted Average (TLV-TWA), as a Short-Term Exposure Limit (TLV-STEL), or as a ceiling 

limit (TLV-C).

Time-Weighted Average (TWA)—An average exposure within a given time period. 

Toxicokinetic—The absorption, distribution, metabolism, and elimination of toxic compounds in the 

living organism.

Toxics Release Inventory (TRI)—The TRI is an EPA program that tracks toxic chemical releases and 

pollution prevention activities reported by industrial and federal facilities. 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL),

Reference Dose (RfD), or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis (3 being the approximate logarithmic 

average of 10 and 1).

Xenobiotic—Any substance that is foreign to the biological system.
BROMOMETHANE F-1

APPENDIX F. ACRONYMS, ABBREVIATIONS, AND SYMBOLS

AAPCC American Association of Poison Control Centers

ACGIH American Conference of Governmental Industrial Hygienists

ACOEM American College of Occupational and Environmental Medicine

ACMT American College of Medical Toxicology

ADI acceptable daily intake

ADME absorption, distribution, metabolism, and excretion

AEGL Acute Exposure Guideline Level

AIC Akaike’s information criterion 

AIHA American Industrial Hygiene Association

ALT alanine aminotransferase

AOEC Association of Occupational and Environmental Clinics

AP alkaline phosphatase

AST aspartate aminotransferase

atm atmosphere

ATSDR Agency for Toxic Substances and Disease Registry

AWQC Ambient Water Quality Criteria

BCF bioconcentration factor

BMD/C benchmark dose or benchmark concentration

BMDX dose that produces a X% change in response rate of an adverse effect

BMDLX 95% lower confidence limit on the BMDX

BMDS Benchmark Dose Software

BMR benchmark response

BUN blood urea nitrogen 

C centigrade

CAA Clean Air Act

CAS Chemical Abstract Services

CDC Centers for Disease Control and Prevention

CEL cancer effect level

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act

CFR Code of Federal Regulations

Ci curie

CI confidence interval

cm centimeter

CPSC Consumer Products Safety Commission

CWA Clean Water Act

DNA deoxyribonucleic acid

DOD Department of Defense

DOE Department of Energy

DWEL drinking water exposure level

EAFUS Everything Added to Food in the United States

ECG/EKG electrocardiogram

EEG electroencephalogram

EPA Environmental Protection Agency

ERPG emergency response planning guidelines

F Fahrenheit

F1 first-filial generation

FDA Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FR Federal Register
BROMOMETHANE F-2

APPENDIX F

FSH follicle stimulating hormone

g gram

GC gas chromatography

gd gestational day

GGT γ-glutamyl transferase 

GRAS generally recognized as safe

HEC human equivalent concentration 

HED human equivalent dose 

HHS Department of Health and Human Services

HPLC high-performance liquid chromatography

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer

IDLH immediately dangerous to life and health

IRIS Integrated Risk Information System

Kd adsorption ratio

kg kilogram

kkg kilokilogram; 1 kilokilogram is equivalent to 1,000 kilograms and 1 metric ton

Koc organic carbon partition coefficient

Kow octanol-water partition coefficient

L liter

LC liquid chromatography

LC50 lethal concentration, 50% kill

LCLo lethal concentration, low

LD50 lethal dose, 50% kill

LDLo lethal dose, low

LDH lactic dehydrogenase

LH luteinizing hormone

LOAEL lowest-observed-adverse-effect level

LSE Level of Significant Exposure

LT50 lethal time, 50% kill

m meter

mCi millicurie

MCL maximum contaminant level

MCLG maximum contaminant level goal

MF modifying factor

mg milligram

mL milliliter

mm millimeter

mmHg millimeters of mercury

mmol millimole

MRL Minimal Risk Level

MS mass spectrometry

MSHA Mine Safety and Health Administration

Mt metric ton

NAAQS National Ambient Air Quality Standard

NAS National Academy of Science

NCEH National Center for Environmental Health

ND not detected

ng nanogram

NHANES National Health and Nutrition Examination Survey

NIEHS National Institute of Environmental Health Sciences
BROMOMETHANE F-3

APPENDIX F

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

QPS quarantine and preshipment

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time-weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey
BROMOMETHANE

F-4

APPENDIX F

USNRC U.S. Nuclear Regulatory Commission

VOC volatile organic compound

WBC white blood cell

WHO World Health Organization > greater than ≥ greater than or equal to = equal to < less than ≤ less than or equal to % percent α alpha β beta γ gamma δ delta

μm micrometer

μg microgram q1* cancer slope factor – negative + positive

(+) weakly positive result (–) weakly negative result