Toxicological Profile for

Bromodichloromethane 

March 2020 
BROMODICHLOROMETHANE 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.
BROMODICHLOROMETHANE 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
BROMODICHLOROMETHANE 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.
BROMODICHLOROMETHANE v 

VERSION HISTORY 

Date Description

Final toxicological profile released

Draft for public comment toxicological profile released

March 2020 

April 2018 

December 1989 Final toxicological profile released
BROMODICHLOROMETHANE vi

CONTRIBUTORS & REVIEWERS

CHEMICAL MANAGER TEAM

Susan Zells Ingber, A.B., M.S.P.P. (Lead) Lisa Ingerman, Ph.D., D.A.B.T.

Melanie Buser, M.P.H. Christina Coley, B.S.

Mario Citra, Ph.D.

Fernando Llados, Ph.D.

Laura A. McIlroy, B.A.

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 Health and Safety (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; EPA, National 

Center for Environmental Assessment.

PEER REVIEWERS

1. Bill L. Lasley, Ph.D., Center for Health and Environment, University of California, Davis, 

California;

2. David Savitz, Ph.D., Brown University, Providence, Rhode Island; and

3. June K. Dunnick, Ph.D., NIEHS, Research Triangle Park, North Carolina.

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.
BROMODICHLOROMETHANE 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...........................................................................................2

1.3 MINIMAL RISK LEVELS (MRLs)..............................................................................................4

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

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

2.2 DEATH ........................................................................................................................................56

2.3 BODY WEIGHT..........................................................................................................................56

2.4 RESPIRATORY ..........................................................................................................................57

2.5 CARDIOVASCULAR.................................................................................................................57

2.6 GASTROINTESTINAL...............................................................................................................58

2.7 HEMATOLOGICAL ...................................................................................................................58

2.8 MUSCULOSKELETAL..............................................................................................................58

2.9 HEPATIC.....................................................................................................................................59

2.10 RENAL ........................................................................................................................................61

2.11 DERMAL.....................................................................................................................................62

2.12 OCULAR .....................................................................................................................................62

2.13 ENDOCRINE...............................................................................................................................63

2.14 IMMUNOLOGICAL ...................................................................................................................63

2.15 NEUROLOGICAL.......................................................................................................................64

2.16 REPRODUCTIVE .......................................................................................................................64

2.17 DEVELOPMENTAL...................................................................................................................65

2.18 OTHER NONCANCER...............................................................................................................70

2.19 CANCER......................................................................................................................................70

2.20 GENOTOXICITY........................................................................................................................72

CHAPTER 3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL 

INTERACTIONS.................................................................................................................77

3.1 TOXICOKINETICS ....................................................................................................................77

3.1.1 Absorption.............................................................................................................................77

3.1.2 Distribution ...........................................................................................................................78

3.1.3 Metabolism............................................................................................................................79

3.1.4 Excretion ...............................................................................................................................80

3.1.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models.............81

3.1.6 Animal-to-Human Extrapolations.........................................................................................82

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.....82

3.3 BIOMARKERS OF EXPOSURE AND EFFECT.......................................................................83

3.3.1 Biomarkers of Exposure........................................................................................................84
BROMODICHLOROMETHANE viii

3.3.2 Biomarkers of Effect ............................................................................................................. 85

3.4 INTERACTIONS WITH OTHER CHEMICALS ....................................................................... 86

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION ............................................................. 87

4.1 CHEMICAL IDENTITY ............................................................................................................. 87

4.2 PHYSICAL AND CHEMICAL PROPERTIES .......................................................................... 87

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE ......................................................................... 89

5.1 OVERVIEW ................................................................................................................................ 89

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL .................................................. 90

5.2.1 Production ............................................................................................................................. 90

5.2.2 Import/Export ........................................................................................................................ 90

5.2.3 Use ........................................................................................................................................ 91

5.2.4 Disposal ................................................................................................................................. 91

5.3 RELEASES TO THE ENVIRONMENT ..................................................................................... 91

5.3.1 Air ......................................................................................................................................... 92

5.3.2 Water ..................................................................................................................................... 92

5.3.3 Soil ........................................................................................................................................ 93

5.4 ENVIRONMENTAL FATE ........................................................................................................ 94

5.4.1 Transport and Partitioning ..................................................................................................... 94

5.4.2 Transformation and Degradation .......................................................................................... 95

5.5 LEVELS IN THE ENVIRONMENT ........................................................................................... 96

5.5.1 Air ......................................................................................................................................... 98

5.5.2 Water ................................................................................................................................... 101

5.5.3 Sediment and Soil ............................................................................................................... 108

5.5.4 Other Media ........................................................................................................................ 108

5.6 GENERAL POPULATION EXPOSURE.................................................................................. 111

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .............................................. 116

CHAPTER 6. ADEQUACY OF THE DATABASE ................................................................................ 121

6.1 INFORMATION ON HEALTH EFFECTS ............................................................................... 121

6.2 IDENTIFICATION OF DATA NEEDS .................................................................................... 121

6.3 ONGOING STUDIES ................................................................................................................ 127

CHAPTER 7. REGULATIONS AND GUIDELINES ............................................................................. 128

CHAPTER 8. REFERENCES .................................................................................................................. 130

APPENDICES

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

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

APPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF HEALTH EFFECTS 

DATA FOR BROMODICHLOROMETHANE ............................................................. C-1 

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

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

APPENDIX F. GLOSSARY .................................................................................................................... F-1 

APPENDIX G. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ................................................. G-1 
BROMODICHLOROMETHANE ix

LIST OF FIGURES 

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

1-2. Summary of Sensitive Targets of Bromodichloromethane – Inhalation .............................................. 6

1-3. Summary of Sensitive Targets of Bromodichloromethane – Oral........................................................ 7

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

2-2. Levels of Significant Exposure to Bromodichloromethane – Inhalation............................................ 23

2-3. Levels of Significant Exposure to Bromodichloromethane – Oral ..................................................... 50

5-1. Number of NPL Sites with Bromodichloromethane Contamination .................................................. 89

6-1. Summary of Existing Health Effects Studies on Bromodichloromethane By Route and

Endpoint ........................................................................................................................................... 122
BROMODICHLOROMETHANE x 

LIST OF TABLES 

1-1. Minimal Risk Levels (MRLs) for Bromodichloromethane .................................................................. 8

2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM) .......................................... 13

2-2. Levels of Significant Exposure to Bromodichloromethane – Inhalation............................................ 21

2-3. Levels of Significant Exposure to Bromodichloromethane – Oral ..................................................... 25

2-4. Genotoxicity of Bromodichloromethane In Vitro ............................................................................... 72

2-5. Genotoxicity of Bromodichloromethane In Vivo................................................................................ 74

3-1. Tissue to Blood Ratios of Radioactivity 24-Hours After Gavage Administration of 

[

14C]-Bromodichloromethane to Male Rats ........................................................................................ 79

4-1. Chemical Identity of Bromodichloromethane .................................................................................... 87

4-2. Physical and Chemical Properties of Bromodichloromethane ........................................................... 88

5-1. Lowest Limit of Detection Based on Standards ................................................................................. 97

5-2. Summary of Environmental Levels of Bromodichloromethane ......................................................... 97

5-3. Bromodichloromethane Levels in Water, Soil, and Air of National Priorities List (NPL) Sites ........ 97

5-4. Percentile Distribution of Annual Mean Bromodichloromethane Concentrations (ppbv) 

Measured in Ambient Air at Locations Across the United States ...................................................... 98

5-5. Statistical Summary of Bromodichloromethane Concentrations from the 2012 and 2013 

National Monitoring Program ............................................................................................................ 99

5-6. Outdoor Air Monitoring Data for Bromodichloromethane ................................................................ 99

5-7. Indoor Air Monitoring Data for Bromodichloromethane ................................................................. 100

5-8. Water-Related Activities and Indoor Air Monitoring Data for Bromodichloromethane.................. 101

5-9. Surface Water Monitoring Data for Bromodichloromethane ........................................................... 102

5-10. Groundwater Monitoring Data for Bromodichloromethane ........................................................... 104

5-11. Drinking Water Monitoring Data for Bromodichloromethane ....................................................... 105

5-12. Swimming Pool Water Monitoring Data for Bromodichloromethane ........................................... 107

5-13. Bromodichloromethane Detections in Food from the U.S. Food and Drug Administration 

(FDA) 1991–2003 Market Basket Survey ...................................................................................... 108

5-14. Bromodichloromethane in Food ..................................................................................................... 110

5-15. Blood Bromodichloromethane Levels in the NHANES U.S. Population ...................................... 113
BROMODICHLOROMETHANE xi

5-16. Exposure and Blood Concentrations ..............................................................................................117

5-17. Exposure and Breath (Alveolar Air) Concentrations......................................................................119

5-18. Exposure and Urine Concentrations...............................................................................................120
BROMODICHLOROMETHANE 1

CHAPTER 1. RELEVANCE TO PUBLIC HEALTH

1.1 OVERVIEW AND U.S. EXPOSURES

Bromodichloromethane (CHBrCl2; Chemical Abstracts Service [CAS] Registry Number 75-27-4) belongs 

to a group of chemicals referred to as trihalomethanes; the other chemicals in this group are chloroform, 

bromoform, and dibromochloromethane. The major source of bromodichloromethane in the environment 

is its formation as a byproduct during the chlorination of water containing organic matter and bromide. 

Approximately 86% of the population in the United States are served by public water systems that use 

chlorine or chlorine-containing compounds to disinfectant water supplies; the disinfection helps protect 

against microbial contaminants that might otherwise cause serious water-borne diseases when exposure 

occurs (EPA 2016, 2015d; USGS 2010a). 

The most likely source of exposure to bromodichloromethane is from chlorinated waters supplied to 

homes, work, and public places. Exposure can occur through ingestion, inhalation of vapors during 

showering or bathing, and dermal absorption during water-related activities. Bromodichloromethane 

levels in drinking water in the United States have been reported to range from below the detection limit to 

183 μg/L (EPA 2005b). Another survey reported mean concentrations ranging from 1.0 to 20.3 μg/L 

(Savitz et al. 2006). Ingestion of food sources contaminated with bromodichloromethane is not an 

important exposure pathway because it is not frequently detected in foodstuffs and levels are typically 

very low. Very low levels of bromodichloromethane have been detected in ambient air, and this is not 

likely an exposure route of concern for the general population. The maximum arithmetic mean 

concentration of bromodichloromethane in outdoor air samples at 83 locations across the United States 

was 0.033 ppbv in 2018 (EPA 2019). 

Blood bromodichloromethane level is the most commonly used biomarker of exposure; alveolar air and 

urine levels of bromodichloromethane are also reliable biomarkers. Studies comparing the relative 

contribution of different activities to blood bromodichloromethane levels found that showering was the 

largest contributor, followed by bathing, and then consumption of drinking water (Backer et al. 2000; 

Nuckols et al. 2005).
BROMODICHLOROMETHANE 2 

1. RELEVANCE TO PUBLIC HEALTH

1.2 SUMMARY OF HEALTH EFFECTS

Information on the toxicity of bromodichloromethane comes primarily from oral studies in laboratory 

animals. Although a large number of epidemiology studies have examined the toxicity of 

trihalomethanes, only a small percentage have analyzed the risks associated with exposure to 

bromodichloromethane. These studies evaluated hepatic, reproductive, developmental, and cancer 

endpoints. Over 60 laboratory animal toxicity studies have been identified. More than 90% of them 

involve oral exposure, and no dermal studies were identified. In general, the effects observed in 

laboratory animal studies occurred at exposure levels that are much higher than levels typically associated 

with residential or environmental exposures to bromodichloromethane. 

As illustrated in Figure 1-1, the most sensitive effects appear to be liver damage, kidney damage, 

decreases in sperm velocity, impaired immune response, and increases in resorptions. A systematic 

review of these endpoints resulted in the following hazard identification conclusions:

• Hepatic effects are a presumed health effect for humans

• Renal effects are a suspected health effect for humans

• Immunological effects are a suspected health effect for humans

• The data are inadequate to conclude whether reproductive effects will occur in humans 

• Developmental effects are a presumed health effect for humans

Hepatic Effects. Results from numerous inhalation and oral animal studies support the identification of 

the liver as a presumed target in humans. Oral studies in rats and mice have found marked increases in 

serum enzymes (e.g., alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase) 

and centrilobular hepatocellular vacuolar degeneration in rats following acute exposure (Condie et al. 

1983; Keegan et al. 1998; Lilly et al. 1994, 1996; Thornton-Manning et al. 1994). Intermediate- and 

chronic-duration exposures have resulted in hepatocellular fatty degeneration or metamorphosis (Aida et 

al. 1992; NTP 1987). Hepatocellular degeneration was also observed in an acute-duration mouse 

inhalation study (Torti et al. 2001). Bile duct damage (proliferation, cholangiofibrosis, hyperplasia) has 

also been observed in rats following intermediate and chronic exposure (Aida et al. 1992; NTP 1987); 

these effects occur at higher doses than the hepatocellular effects. Animal studies found oral routespecific differences in toxicity. The available data suggest a higher toxicity when bromodichloromethane 

was administered via gavage in an oil vehicle compared to an aqueous vehicle (Lilly et al. 1994) and was 

greater when administered via gavage compared to dietary exposure (bromodichloromethane was 
 

BROMODICHLOROMETHANE 3 

1. RELEVANCE TO PUBLIC HEALTH

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

Bromodichloromethane 
BROMODICHLOROMETHANE 4

1. RELEVANCE TO PUBLIC HEALTH

microencapsulated and added to the diet) (Aida et al. 1992). Only one epidemiology study examined 

hepatic outcomes and did not find a significant association between blood bromodichloromethane levels 

and alterations in serum alanine aminotransferase levels (Burch et al. 2015). 

Renal Effects. Identification of the kidney as a suspected target in humans comes from the results of 

inhalation and oral studies in rats and mice. Renal tubular degeneration has been observed in mice 

following acute- and intermediate-duration inhalation exposure (Torti et al. 2001) and following acute-, 

intermediate-, and chronic-duration oral exposure (George et al. 2002; Lilly et al. 1994, 1996; NTP 1987). 

Acute oral studies at relatively high doses also reported increases in blood urea nitrogen, urinary glucose, 

and urinary protein levels (Lilly et al. 1996). No human studies examined this endpoint.

Immune Effects. Several studies have reported impaired immune responses in rats orally administered 

bromodichloromethane for acute or intermediate durations. Decreased immune responses to humoral and 

cell-mediated immune stimulants were observed in animals receiving gavage doses of bromodichloromethane (French et al. 1999; Munson et al. 1982). A comparison of lowest-observed-adverse-effect level 

(LOAEL) values identified in rats and mice suggest that rats may be more sensitive than mice to the 

immunotoxicity of bromodichloromethane. One epidemiological study examined immune endpoints and 

found inverse associations between bromodichloromethane levels in exhaled breath and several 

biomarkers of immune function (Vlaanderen et al. 2017). 

Reproductive Effects. Three epidemiology studies evaluated potential reproductive targets. A decrease 

in menstrual cycle length, specifically the follicular phase length, was significantly associated with 

bromodichloromethane drinking water levels (Windham et al. 2003). Another epidemiology study found 

a significant association between a shorter time-to-pregnancy and an estimate of bromodichloromethane 

levels intake from tap water (MacLehose et al. 2008). The third study did not find an association between 

alterations in sperm parameters and blood bromodichloromethane levels (Zeng et al. 2013).

Although several laboratory animal studies have examined potential reproductive endpoints, additional 

data are needed to evaluate the adversity of the observed effects. A diminished response to luteinizing 

hormone levels in pregnant rats (Bielmeier et al. 2001, 2004, 2007) and decreased sperm velocity (with 

no change in the percentage of motile or progressive motile sperm) (Klinefelter et al. 1995) were 

observed in rats. It is unclear if these effects would result in a decrease in reproductive function. A 

2-generation study did not find alterations in fertility in rats (Christian et al. 2001b). 
BROMODICHLOROMETHANE 5

1. RELEVANCE TO PUBLIC HEALTH

Developmental Effects. Epidemiology and laboratory animal studies have reported developmental effects 

associated with bromodichloromethane exposure. Inconsistent results have been observed in 

epidemiology studies with some studies finding decreases in birth weight and increased risk of small for 

gestational age (Summerhayes et al. 2012; Rivera-Núñez and Wright 2013; Wright et al. 2004) and other 

studies not finding these effects (Cao et al. 2016; Danileviciute et al. 2012; Hoffman et al. 2008). 

Epidemiology studies have also found increases in the risk of stillbirth (King et al. 2000) and spontaneous 

abortions (Waller et al. 1998). Other studies have found no associations with the risk of stillbirths 

(Rivera-Núñez et al. 2018) or cardiovascular defects (Wright et al. 2017).

In rats, increases in the occurrence of full-litter resorptions have been found following early gestational 

gavage administration of bromodichloromethane (Bielmeier et al. 2001; Narotsky et al. 1997). A delay in 

skeletal ossification was observed in rats exposed to bromodichloromethane in drinking water (Christian 

et al. 2001a; Ruddick et al. 1983). 

Cancer Effects. The carcinogenic potential of bromodichloromethane has been evaluated in three 

epidemiological study and several chronic-duration oral studies in rats and mice. Epidemiological studies 

did not find an increased risk of colorectal cancer (Bove et al. 2007) or colon cancer (Jones et al. 2019) 

associated with bromodichloromethane levels in public water supplies; Jones et al. (2019) did find an 

association for rectal cancer. The third study did not find an association between blood bromodichloromethane levels and total cancer deaths (Min and Min 2016). Gavage administration of relatively high 

doses has resulted in increases in neoplastic lesions in the large intestine and kidneys of rats (NTP 1987) 

and livers of mice (NTP 1987). No increases in tumor incidences were observed in drinking water studies 

testing lower doses (George et al. 2002; NTP 2006) or at slightly higher doses in a dietary exposure study 

(Aida et al. 1992).

The U.S. Department of Health and Human Services categorized bromodichloromethane as reasonably 

anticipated to be a human carcinogen (NTP 2016), EPA categorized it as a probable human carcinogen 

(Group B2) (IRIS 2002), and the International Agency for Research on Cancer categorized it as possibly 

carcinogenic to humans (IARC 2016).

1.3 MINIMAL RISK LEVELS (MRLs)

The inhalation database was not considered adequate for deriving inhalation MRLs. As presented in

Figure 1-2, the limited available inhalation data for bromodichloromethane suggest that the liver and 
BROMODICHLOROMETHANE 6 

1. RELEVANCE TO PUBLIC HEALTH

kidney are sensitive targets of toxicity. However, other potentially sensitive endpoints, particularly 

developmental toxicity, have not been examined for this exposure route. 

The oral database was considered adequate for derivation of acute- and chronic-duration oral MRLs for 

bromodichloromethane. As with inhalation exposure, the liver and kidney are sensitive targets following 

oral exposure to bromodichloromethane. Developmental, immunological, and reproductive endpoints 

also have relatively low LOAEL values, as illustrated in Figure 1-3. The MRL values are summarized in 

Table 1-1 and discussed in greater detail in Appendix A. 

Figure 1-2. Summary of Sensitive Targets of Bromodichloromethane – Inhalation 

The kidney is the most sensitive target of bromodichloromethane inhalation exposure. 

Numbers in circles are the lowest LOAELs for all health effects in animals; no human data were identified.
BROMODICHLOROMETHANE 7

1. RELEVANCE TO PUBLIC HEALTH

Figure 1-3. Summary of Sensitive Targets of Bromodichloromethane – Oral

The liver is the most sensitive target of bromodichloromethane oral exposure. 

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

No reliable dose response data were available for humans.
 

 

BROMODICHLOROMETHANE 8 

1. RELEVANCE TO PUBLIC HEALTH

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

Exposure Point of Uncertainty 

duration MRL Critical effect departure factor Reference 

Inhalation exposure

Acute Insufficient data for MRL derivation 

Intermediate Insufficient data for MRL derivation

Chronic Insufficient data for MRL derivation

Oral exposure (mg/kg/day)

Acute 0.07 Full-litter resorption in 7.15 (BMDL05) 100 Narotsky et al. 

rats 1997

Intermediate Insufficient data for MRL derivation; chronic MRL considered protective for 

intermediate duration exposure

Chronic 0.008 Hepatocellular fatty 0.78 (BMDL10) 100 Aida et al. 

degeneration in rats 1992

aSee Appendix A for additional information.
BROMODICHLOROMETHANE 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 bromodichloromethane. It contains descriptions and evaluations of toxicological studies and epidemiological 

investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic 

data to public health. When available, mechanisms of action are discussed along with the health effects 

data; toxicokinetic mechanistic data are discussed in Section 3.1.

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

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

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

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

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

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

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

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

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

body of literature. A systematic review of the scientific evidence of the health effects associated with 

exposure to bromodichloromethane was also conducted; the results of this review are presented in 

Appendix C.

Summaries of the human observational studies are presented in Table 2-1. Animal inhalation studies are 

presented in Table 2-2 and Figure 2-2, and animal oral studies are presented in Table 2-3 and Figure 2-3; 

no dermal data were identified for bromodichloromethane.

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 
BROMODICHLOROMETHANE 10

2. HEALTH EFFECTS

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 

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. Levels of exposure associated with cancer (Cancer Effect Levels, CELs) of 

bromodichloromethane are indicated in Table 2-3 and Figure 2-3.

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

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

The health effects of bromodichloromethane have been evaluated in epidemiological and laboratory 

animal studies. As illustrated in Figure 2-1, most of the health effects data come from oral exposure 

studies in animals. Animal data are available for each health effect category and exposure duration 

category. The most examined endpoints were body weight (approximately 70% of the animal studies 

examined this endpoint), hepatic (approximately 50%), and renal (approximately 50%). Only five animal 

studies evaluated toxicity following inhalation exposure and these studies examined a limited number of 

endpoints (body weight, hepatic, renal, ocular, and other noncancer). The small number of available 

observational epidemiological studies only examined hepatic, immunological, reproductive, 

developmental, and cancer endpoints. Although some epidemiological studies suggest associations 

between bromodichloromethane exposure and an adverse health outcome, most of the studies are crosssectional in design and do not establish causality. The epidemiological studies used several biomarkers of 

exposure including levels of bromodichloromethane measured in municipal water, blood bromodichloromethane levels, and levels of bromodichloromethane in exhaled breath. These biomarkers assess recent 

exposure, particularly the blood and exhaled breath since bromodichloromethane is rapidly excreted; most 

studies did not evaluate historical exposures. Another limitation of the epidemiological studies is that 

they involve co-exposure to other disinfection byproducts, which have similar targets of toxicity. Most 
BROMODICHLOROMETHANE 11

2. HEALTH EFFECTS

studies did not statistically adjust for co-exposure to other compounds (e.g., chloroform, dibromochloromethane); thus, it is difficult to evaluate whether the observed effect was related to bromodichloromethane exposure or total exposure to disinfection byproducts, including other trihalomethanes. 

The human and animal studies suggest several sensitive targets of bromodichloromethane toxicity: 

• Hepatic Endpoints: Hepatic effects are a presumed health effect for humans based on limited 

evidence in humans and strong evidence in mice following acute inhalation exposure and in rats 

and mice following acute, intermediate, and chronic oral exposure. The liver effects include 

increases in serum enzymes, increases in liver weight, hepatocellular degeneration, and bile duct 

damage.

• Developmental Endpoints. Developmental effects are a presumed health effect for humans 

based on strong evidence from acute and intermediate oral exposures in rats. The most sensitive 

developmental endpoint was full-litter resorption in rats acutely administered bromodichloromethane via gavage. Inconsistent results have been observed in epidemiology studies, with some 

studies finding decreases in birth weight and increased risk of small for gestational age, and other 

studies not finding developmental effects. 

• Renal Endpoints: Renal effects are a suspected health effect for humans based on moderate 

evidence in rats and mice following inhalation and oral exposure. The main effect observed was 

renal tubular degeneration; high acute oral doses also reported increases in blood urea nitrogen, 

urinary glucose, and urinary protein levels.

• Immune Endpoints. Immunological effects are a suspected health effect for humans based on 

moderate evidence in rats following acute and intermediate oral exposure. Decreased immune 

responses to stimulants were observed in rats. 

• Reproductive Endpoints. Data are inadequate to conclude whether reproductive effects will 

occur in humans. Inconsistent results have been observed in animal studies examining potential 

reproductive endpoints, with some studies reporting effects (alterations in reproductive hormone 

levels and decreases in sperm velocity) and others reporting no effects (no alterations in 

histopathology, no changes in sperm motility, and no alterations in fertility in a 2-generation rat 

study).

• Other Endpoints. Alterations in body weight and gastrointestinal, hematological, ocular, 

endocrine, and neurological effects have also been observed in inhalation and/or oral exposure 

studies in laboratory animals; however, these do not appear to be sensitive targets of bromodichloromethane toxicity.
BROMODICHLOROMETHANE 12

2. HEALTH EFFECTS

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

Most studies examined the potential body weight, hepatic, and renal effects of bromodichloromethane

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

*Includes studies discussed in Chapter 2. A total of 84 studies (including those finding no effect) have examined toxicity; most studies examined multiple 

endpoints.
BROMODICHLOROMETHANE 13

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

Bove et al. 2007

Case-control study of residents living 

in Monroe County, New York; 

128 cases and 253 controls

Exposure: Mean and median BDCM in 

sampled tap water were 8.72 and 8.48 μg/L.

Logistic regression adjustments: alcohol 

consumption, beta carotene, total calories

Cancer effects: No association between BDCM 

concentrations in water samples and the risk of rectal 

cancer (OR 1.15, 95% CI 1.00–1.32).

Burch et al. 2015

Cross-sectional study of 2,781 1999–

2006 NHANES adult participants 

(average age of 40 years, 53% 

women)

Exposure: Median BDCM in blood was 

1.5 pg/mL (range of 0.2–86 pg/mL); median 

BDCM level in tap water was 4 μg/L (range of 

0.03–52 μg/L).

Logistic regression adjustments: age, race, 

smoking, body mass index, alcohol 

consumption, self-reported high blood 

pressure, diastolic blood pressure, total 

cholesterol, albumin, C-reactive protein

Hepatic effects: No association between blood BDCM 

levels above the median and the risk of elevated alanine 

aminotransferase levels were found (OR 1.01; 95% CI 

0.67–1.51).

No significant correlation (p=0.429) between blood BDCM 

levels and alanine aminotransferase activity.

Cao et al. 2016

Retrospective cohort study of 

1,184 pregnant women in China

Exposure: Geometric mean BDCM levels in 

blood during late pregnancy was 1.5 ng/L 

(95% CI 1.4–1.6).

Logistic regression adjustments: prenatal 

BMI, weight gain during pregnancy, infant’s 

gender, parity, study city, maternal age, 

gestational age, education, birth length, SGA, 

household income

Developmental effects: BDCM was inversely 

associated with birth length. The estimated mean 

decrease was 0.15 cm (95% CI -0.29 to -0.01) for the 

highest (>4.8 ng/L) vs. lowest (<0.5 ng/L) exposure group 

(p=0.04 for trend).

No association with birth weight or gestational age 

(p=0.18 and 0.93, respectively, for trend).

Chen et al. 2019

Longitudinal study of 451 motherneonate pairs in China

Exposure: maternal blood BDCM measured 

in early pregnancy; mean of 1.1 ng/L

Statistical analysis adjustments: 

gestational age, infant’s sex, maternal age, 

pre-pregnancy BMI, maternal education, 

secondhand smoking, alcohol consumption

Developmental effects: Inverse association between 

maternal BDCM levels and neonatal neurological 

assessment test scores (measured at 3 days of age) in 

male and female infants combined (β -0.47, 

95%CI -0.89 to -0.05) and males only (β -0.88, 

95%CI -1.52 to -0,24); no associations in females only 

(β -0.11, 95%CI -0.66–0.44).
BROMODICHLOROMETHANE 14

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

Danileviciute et al. 2012

Nested case-control study of 

682 pregnant women in Lithuania

Exposure: Internal dose of trihalomethane 

(μg/day) estimated from daily water ingestion, 

showering, and bathing recollection data; daily 

uptake range of 0.0001–0.34 μg/day.

Logistic regression adjustments: marital 

status, square gestational age, parity, 

maternal education, maternal and paternal 

smoking, alcohol consumption, BMI, blood 

pressure, ethnic group, pregnancy history, 

infant gender, birth year

Developmental effects: BDCM intake (entire pregnancy 

or individual trimesters) was not associated with low birth 

weight (OR 1.26, 95% CI 0.58–2.72) or SGA (OR 1.31, 

95% CI 0.82–2.09).

Non-conjugator phenotype for glutathione S-transferase 

increased risk for low birth weight, but not significantly.

Dodds and King 2001

Retrospective cohort study of 

49,842 women in Canada

Exposure: BDCM in municipal water; 

concentration range categorized by quartile: 

- Q1: <5 μg/L

- Q2: 5–9 μg/L

- Q3: 10–19 μg/L

- Q4: ≥20 μg/L

Logistic regression adjustments: maternal 

age, parity, maternal smoking, neighborhood 

family income

Developmental effects: BDCM concentrations ≥20 μg/L 

were associated with increased risk of neural tube defects 

based on 10 cases; the relative risk (RR) was 2.5 (95% 

CI 1.2–5.1).

The risk for cardiovascular anomalies at BDCM ≥20 μg/L 

was decreased (RR 0.3. 95% CI 0.2–0.7); there was no 

association between BDCM and risk of cleft defects (RR 

0.6, 95%CI 0.2–1.9) at ≥20 μg/L.

Grazuleviciene et al. 2013

Prospective cohort study of 

3,074 women in Lithuania 

Exposure: Internal dose of trihalomethanes 

(μg/day) estimated from daily water ingestion, 

showering, and bathing recollection data 

during the first trimester of pregnancy. BDCM 

intake categorized by tertiles: 

- T1: 0.000–0.013 μg/day

- T2: 0.013–0.051 μg/day

- T3: 0.051–0.436 μg/day

Logistic regression adjustments: age, BMI, 

chronic disease, alcohol consumption, fetus 

number, previous premature birth, infant sex

Developmental effects: Exposure to BDCM during the 

first month of pregnancy increased the risk of congenital 

heart anomalies (OR 2.16, 95% CI, 1.05–4.46 for T3).

No association during second (OR 1.54, 95% CI 0.78–

3.04) or third (OR 1.32, 95% CI 0.68–2.56) month of 

pregnancy or during the first trimester as a whole (OR 

1.82., 95% CI 0.89–3.69).
BROMODICHLOROMETHANE 15

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

No association with congenital musculoskeletal or 

urogenital anomalies were found. The ORs for the T3 

groups:

Musculoskeletal anomalies 

first month OR 0.73. 95% CI 0.29–1.84

second month OR 0.92, 95% CI 0.39–2.17

third month OR 1.70, 95% CI 0.78–3.71

first trimester OR 1.29, 95% CI 0.57–2.92

Urogenital anomalies 

first month OR 2.27. 95% CI 0.69–7.43

second month OR 1.81, 95% CI 0.66–4.96

third month OR 1.85, 95% CI 0.68–5.07

first trimester OR 2.87, 95% CI 00.92–8.99

Hoffman et al. 2008

Cross-sectional study of 

2,766 pregnant women from three 

U.S. communities

Exposure: Average residential BDCM 

concentration in community with moderate 

levels of chlorinated disinfection byproducts:

- T1: 8.2–11.8 μg/L

- T2: 11.9–14.1 μg/L

- T3: 14.2–28.5 μg/L

Average residential BDCM concentration in 

community with moderate levels of brominated 

disinfection byproducts:

- T1: 15.8–20.1 μg/L

- T2: 20.2–22.9 μg/L

- T3: 23–29.2 μg/L

Bayesian adjustments: other disinfection 

byproducts, maternal age, race/ethnicity, 

income, education, employment status, prepregnancy BMI, parity, caffeine intake

Developmental effects: No association between 

average residential BDCM concentration and risk of SGA 

in the community with moderate levels of chlorinated 

disinfection byproducts (OR 1.5, 95% CI 0.6–3.7 for T3) 

or moderate levels of brominated disinfection byproducts 

(OR 0.9, 95% CI 0.4–2.4 for T3).
BROMODICHLOROMETHANE 16

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

Iszatt et al. 2011

Case-control study of 468 cases with 

hypospadias and 485 controls in 

England 

Exposure: Trihalomethanes intake based on 

estimates of individual water consumption and 

use. BDCM intake categorized by quartiles: 

- Q1: 0 μg/day

- Q2: >0–1.0 μg/day

- Q3: 2–5 μg/day

- Q4: 6–50 μg/day

Logistic regression adjustments: family 

income, birth weight, folate supplement use 

during pregnancy, maternal smoking during 

weeks 6 through 18 of pregnancy, maternal 

occupational exposure to phthalates

Developmental effects: After adjustment, intake of

≥6 μg/day BDCM was associated with an increased the 

risk of hypospadias (OR 1.65, 95% CI 1.02–2.69). 

However, there was no dose-response relationship 

(p=0.13 for trend).

Concentration of BDCM in water was not associated with 

hypospadias for OR 1.05 (95% CI 0.65–1.68) for Q4. 

However, elevated risk of hypospadias was associated 

with consumption of cold tap water at home, total water, 

bottled water, and total fluid suggesting other factors may 

have influenced the risk.

Jones et al. 2019

Prospective cohort study of 

15,53 women reporting public water 

source for >10 years and participating 

in the Iowa Woman’s Health Study

Exposure: BDCM in municipal water; 

concentration range categorized by quartile:

- Q1: <0.25 μg/L

- Q2: 0.25–1.16 μg/L

- Q3: 1.17–3.78 μg/L

- Q4: >3.78 μg/L

Statistical analysis adjustments: age, 

physical activity, smoking status, NO3-N level

Cancer effects: Association between BDCM 

concentration in municipal water and risk of rectal cancer 

in Q2 (HR 1.76, 95%CI 1.10–2.84), Q3 (HR 1.99, 95%CI 

1.22–3.25), and Q3 (HR 1.87, 95%CI 1.17–3.00).

No association between BDCM concentration in 

municipal water and the risk of colon cancer (Q4 HR 1.16, 

95%CI 0.94–1.45).

King et al. 2000

Retrospective cohort study of 

49,756 women in Canada

Exposure: BDCM in municipal water; 

concentration range categorized by quartile: 

- Q1: <5 μg/L

- Q2: 5–9 μg/L

- Q3: 10–19 μg/L

- Q4: ≥20 μg/L

Logistic regression adjustments: maternal 

age, parity, maternal smoking, infant’s sex, 

neighborhood family income

Developmental effects: Exposure to ≥20 μg/L BDCM 

almost doubled the risk of stillbirth (RR 1.98, 95% CI, 

1.23–3.49).

Analysis of continuous data showed a 29% increase in 

risk for stillbirth with each 10 μg/L BDCM (95% CI 1.10–

1.53).

Risk of unexplained stillbirth was not associated with 

BDCM (Q4 RR 1.35, 95% CI 0.57–3.19) but risk of 

stillbirth caused by asphyxia was increased 32% per 

10 μg/L BDCM (95% 1.00–1.74).
BROMODICHLOROMETHANE 17

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

MacLehose et al. 2008

Prospective cohort study of 

1,315 women in three metropolitan 

areas

Exposure: Brominated disinfection 

byproducts measured in water samples were 

used to estimate four exposure metrics: tap 

water concentration, amount ingested through 

drinking, quantity that reached the 

bloodstream through inhalation and dermal 

exposure while showering or bathing, and 

integrated measure of the amount in the 

bloodstream through ingestion and 

showering/bathing. 

Statistical analysis adjustments: maternal 

age, race, ethnicity, education, marital status, 

income, smoking, alcohol use, caffeine 

consumption, BMI, age at menarche, 

employment status, diabetes, vitamin use, and 

total water consumption (total ounces of tap 

water plus bottled water)

Reproductive effects: For the ingested metric, an 

association between time to pregnancy and BDCM levels 

were found; the OR at highest concentration 

(≥12.8 μg/day) was 1.5 (95% CI 1.2–1.9); this would be 

indicative of a shorter time to pregnancy.

No associations between time to pregnancy and BDCM 

exposure were found for the other three metrics; the 

adjusted ORs in the highest exposure groups were 

1.1 (95% CI 0.9–1.4), 1.1 (95%CI 0.9–1.3), and 1.1 (0.9–

1.4) for the tap water, showering/bathing, and integrated 

exposure metrics, respectively.

Min and Min 2016

Cross-sectional study of 933 1999–

2004 NHANES adult participants; not 

diagnosed with cancer and 19 died 

from cancer 

Exposure: Blood bromodichloromethane 

levels:

- T1: <1.00 μg/L

- T2: 1.00–2.70 μg/L

- T3: >2.71 μg/L

Statistical analysis adjustments: age, sex, 

race/ethnicity, education family income, 

smoking status, alcohol consumption status, 

moderate physical activity, BMI, total 

cholesterol, hypertension, diabetes

Cancer effects: No association between total cancer 

mortality and BDCM levels (p=0.0869).
BROMODICHLOROMETHANE 18

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

Rivera-Núñez and Wright 2013

Retrospective cohort study of 

672,120 live births in the United 

States

Exposure: BDCM in public water systems 

during the second and third trimesters. Mean 

BDCM concentration by trimester: 6 μg/L in 

second trimester and 6.1 μg/L in 3rd trimester.

Logistic regression adjustments: maternal 

age, race/ethnicity, education, smoking, parity, 

adequacy of prenatal care, prenatal source of 

payment, income, marital status, maternal 

medical and reproductive health factors, 

season, sum of four trihalomethanes, sum of 

five haloacetic acids

Developmental effects: BDCM in 3rd trimester 

associated with reductions in mean birth weight (49–63 g) 

in unadjusted models, but there was no dose-response 

relationship; associations remained in adjusted models 

but the magnitudes of reductions were considerably 

lower.

3rd trimester BDCM was not associated with increased 

SGA (OR 0.91, 95% CI 0.83–1.00).

2nd trimester BDCM was not associated with increased 

preterm delivery (OR 1.09, 95% CI 0.97–1.23).

Rivera-Núñez et al. 2018

Case control study of 2,460 stillbirth 

cases and 24,600 controls; mothers 

lived in a Massachusetts town with 

complete public water source and 

disinfection type data

Exposure: BDCM in public water systems 

during the second trimester. Mean BDCM 

concentration was 6.4 μg/L. BDCM 

concentration categorized into tertiles:

- T1: ≤4.1 μg/L

- T2: >4.1–7.2 μg/L

- T3: >7.2–49.5 μg/L

Statistical analysis adjustments: maternal 

race, education, marital status, source of 

water, sum of four trihalomethanes, sum of 

five haloacetic acids

Developmental effects: No associations between 

BDCM and all causes of stillbirths.

Associations between BDCM and unexplained stillbirths 

for T2 (OR 1.78, 95%CI 1.20–2.63) and T3 (OR 1.51, 

95%CI 1.01–2.27).

Summerhayes et al. 2012

Retrospective cohort study of 

314,982 births in Australia

Exposure: BDCM in water distributed by 

public utility company. BDCM concentration 

range for third trimester categorized by 

deciles:

- D1: 2.95–9.78 μg/L

- D10: 21.96–52.55 μg/L

Logistic binomial adjustments: infant’s sex, 

year of birth, season of birth, duration of 

pregnancy at first prenatal care visit, maternal 

smoking during pregnancy, maternal age, 

indigenous mother, maternal country of birth, 

previous pregnancy, preexisting diabetes, 

preexisting hypertension, gestational diabetes, 

preeclampsia, socioeconomic status

Developmental effects: SGA associated with 

interquartile range increase in 3rd trimester BDCM of 

5 μg/L (RR 1.02, 95% CI, 1.01–1.04).

3rd trimester analysis by deciles showed associations only 

for D9 (19.05–21.96 μg/L) (RR 1.06, 95% CI, 1.00–1.12) 

and D10 (RR 1.10, 95% CI, 1.04–1.16).

In general, larger associations were seen in nonsmokers 

than in smokers.
BROMODICHLOROMETHANE 19

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

Vlaanderen et al. 2017

Experimental study of 29 men and 

30 women swimming in a chlorinated 

pool for 40 minutes

Exposure: Concentration of BDCM in 

exhaled breath after swimming was 2.2 μg/m3.

Statistical analysis adjustments: sex, age, 

BMI

Immunological effects: Inverse associations between 

BDCM in exhaled breath and serum levels of C-X-C motif 

chemokine 10, C-C motif chemokine 22, C-reactive 

protein, and vascular endothelial growth factor.

Association between exhaled breath BDCM and 

interleukin-1rA levels.

Waller et al. 1998

Prospective cohort study of 

5,144 pregnant women in California

Exposure: BDCM levels in water distributed 

by public utility companies and reported 

intakes (glasses cold water and hot water per 

day) at 8 weeks of gestation. High personal 

exposure to BDCM was defined as drinking 

≥5 glasses of cold tap water per day and first 

trimester BDCM water level of ≥18 μg/L.

Logistic regression model adjustments: 

gestational age at interview, maternal age, 

history of pregnancy loss, maternal race, 

employment during pregnancy, cigarette 

smoking

Developmental effects: Association between high 

personal exposure to BDCM and spontaneous abortion, 

OR of 2.0 (95% CI 1.2–3.5). The OR adjusted for 

exposure to other trihalomethanes (chloroform, 

bromoform, chlorodibromomethane) was 3.0 (95% CI 

1.4–6.6)

Windham et al. 2003

Prospective cohort study of 

401 women

Exposure: Estimated BDCM levels based on 

reported daily water consumption, number and 

duration of showers taken per week, and 

average levels of BDCM in tap water; 

estimated BDCM exposure levels were not 

reported 

Statistical analysis adjustments: Age, race, 

BMI, income, pregnancy history, caffeine and 

alcohol consumption, smoking

Reproductive effects: Decrease in the length of the 

menstrual cycle with increasing exposures; the adjusted 

OR was -0.74 (95% CI -1.5 to -0.02) for the highest 

quartile of exposure (≥16 μg/L). 

Decrease in follicular phase length observed (-0.80, 95% 

CI -1.5 to -0.08) for the highest quartile of exposure.

Wright et al. 2004

Retrospective cohort study of 

196,000 births in the United States

Exposure: BDCM in public water systems 

and private wells during the third trimester 

Linear and logistic regression adjustments: 

diabetes, median household income, infant 

sex, adequacy of prenatal care, maternal race, 

maternal education, maternal cigarette 

smoking, maternal age, parity, previous infant 

Developmental effects: Exposure to >5 μg/L BDCM 

was associated with reductions in birth weight (12 g) and 

longer gestational age (0.5–0.6 days).

Association between BDCM and risk of SGA; OR 1.1 

(95% CI 1.07–1.14) for subjects with BDCM levels of >5–

13 μg/L and OR 1.15, (95% CI 1.08–1.22) for subjects 

with BDCM levels of 14–46 μg/L. 
BROMODICHLOROMETHANE 20

2. HEALTH EFFECTS

Table 2-1. Health Effects in Humans Exposed to Bromodichloromethane (BDCM)

Reference and study population Exposure Outcomes

weighing ≥4,000 g, previous preterm delivery, 

maternal medical history Inverse association for preterm delivery; OR 0.89 (95% CI 

0.85–1.10) for >5–13 μg/L and OR 0.92 (95% CI 0.85–

0.99) for 14–46 μg/L.

Wright et al. 2017

Case-control study of 904 infants born 

with nonchromosomal congenital 

anomalies of the heart and circulatory 

system and 9,040 matched controls

Exposure: Public water supply BDCM levels, 

mean concentration 6.85 μg/L.

Conditional logistic regression 

adjustments: type of water sources and 

treatment, health index, infant birth weight, 

town-level income, number of prenatal visits, 

maternal reproductive risk factors

Developmental effects: No associations between 

maternal BDCM exposure and risk of all cardiovascular 

defects, conotruncal heart defects, transposition of the 

great arteries, tetralogy of Fallot, arterial septal defects, 

ventricular septal defects, or pulmonary stenosis. 

Zeng et al. 2013

Cross-sectional study of 401 men in 

China seeking semen examinations

Exposure: Mean and median blood BDCM 

levels were 1.98 and 1.69 ng/L.

Statistical analysis adjustments: age, BMI, 

abstinence time, alcohol use, smoking status

Reproductive effect: No dose-related correlations 

between blood bromodichloromethane levels and sperm 

concentration (p for trend=0.61), sperm count (p for 

trend=0.44), or sperm motility (p for trend=0.76).

No association between blood BDCM levels and serum 

testosterone levels were found (p=0.70).

BDCM = bromodichloromethane; BMI = body mass index; CI = confidence interval; NHANES = National Health and Nutrition Examination Survey; OR = odds 

ratio; SGA = small for gestational age
BROMODICHLOROMETHANE 21

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Bromodichloromethane – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

ACUTE EXPOSURE

1 Mouse

(C57BL/6)

6 M

6 hours/day

7 days/week

1 week

1, 10, 

30, 100, 

150 

LE, BW, OW, 

HP

Death 30 2/6, 1/6, 3/6 deaths in wild type strain at 

30, 100, and 150 ppm, respectively 

Bd wt 10 30 Decreased body weight gain

Hepatic 10 30 Centrilobular hepatocellular 

degeneration at ≥30 ppm and 

hepatocellular necrosis at ≥100 ppm

Renal 1 10 Tubular degeneration and nephrosis 

Ocular 10 30 Mild eye irritation

Other noncancer 

(urinary bladder)

150

Torti et al. 2001

2 Mouse

(FVB/N)

6 M

6 hours/day

7 days/week

1 week

1, 10, 

30, 100, 

150 

LE, BW, OW, 

HP

Death 30 2/6, 4/6, 6/6 deaths at 30, 100, and 

150 ppm, respectively 

Bd wt 100

Hepatic 1 10 Centrilobular hepatocellular 

degeneration at ≥10 ppm and 

hepatocellular necrosis at ≥100 ppm

Renal 1 10 Tubular degeneration and nephrosis

Other noncancer 

(urinary bladder)

150

Torti et al. 2001
BROMODICHLOROMETHANE 22

2. HEALTH EFFECTS

Table 2-2. Levels of Significant Exposure to Bromodichloromethane – Inhalation

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(ppm)

Parameters 

monitored Endpoint

NOAEL 

(ppm)

Less 

serious 

LOAEL 

(ppm)

Serious 

LOAEL 

(ppm) Effect

INTERMEDIATE EXPOSURE

3 Mouse

(C57BL/6)

6 NS

6 hours/day

7 days/week

3 weeks

0, 0.3, 

1, 3, 10, 

30 

LE, BW, OW, 

HP

Bd wt 30

Hepatic 30 Centrilobular hepatocellular 

degeneration was observed at ≥10 ppm 

in heterozygous strains

Renal 3 10 Tubular degeneration; investigators 

provided severity scores but did not 

provide incidence data

Other noncancer 

(urinary bladder)

30

Torti et al. 2001

4 Mouse

(FVB/N)

6 NS

6 hours/day

7 days/week

3 weeks

0, 0.3, 

1, 3, 10, 

30 

LE, BW, OW, 

HP

Death 30 4/6 deaths in wild-type strain 

Bd wt 30

Hepatic 30

Renal 3 10 Tubular degeneration at ≥10 ppm; 

investigators provided severity scores 

for these lesions but did not provide 

incidence data

Other noncancer 

(urinary bladder)

30

Torti et al. 2001

aThe number corresponds to entries in Figure 2-2.

BW or Bd wt = body weight; HP = histopathology; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); NOAEL = no-observed-adverseeffect level; NS = not specified; OW = organ weight
BROMODICHLOROMETHANE 23

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMODICHLOROMETHANE 24

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMODICHLOROMETHANE 25

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

ACUTE EXPOSURE

1 Rat

(F344)

14 F

GDs 6–10

(GW)

0, 75 CS, BW, 

OF, DX

Bd wt 75 Body weight on GD 20 

reduced 35% 

Develop 75 62% full-litter resorption rate

Bielmeier et al. 2001

2 Rat

(F344)

10–11 F

GDs 8 or 9; 

or 9

(GW)

0, 75, 100 CS, DX Repro 75 Reduced serum 

progesterone

Develop 75 64% full-litter resorptions

Bielmeier et al. 2001

3 Rat

(SpragueDawley)

13 F

GDs 6–10

(GW)

0, 75, 100 CS, BW, 

OF, DX

Develop 100 Full-litter resorption rate was 

0%; no information was 

provided regarding pup 

weight

Bielmeier et al. 2001 

4 Rat

(F344)

10–13 F

GDs 6–10, 

GDs 6–15, 

or GDs 11–

15

(GW)

0, 75 CS, DX Develop 75 Full-litter resorption in rats 

dosed on GDs 6–10 and 6–

15

Bielmeier et al. 2001

5 Rat

(F344)

9–13 F

GDs 6–10

(GW)

0, 75, 100 CS, OF, DX Repro 75 Decreased serum 

progesterone and luteinizing 

hormone on GD 10

Develop 75 Full-litter resorptions (80%) 

on GDs 6–10

Bielmeier et al. 2004 
BROMODICHLOROMETHANE 26

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

6 Rat

(F344)

NS-F

GDs 6–10

(GW)

0, 100 CS, OF, BI Repro 100 Significant reductions in 

serum progesterone and 

luteinizing hormone on 

GD 10

Bielmeier et al. 2007

7 Rat

(SpragueDawley)

10 M, 

10 F

Once

(GO)

390, 546, 

765, 1,071, 

1,500 

CS, LE Death 916 M

969 F

LD50 values 

Chu et al. 1980

8 Rat

(SpragueDawley)

10 M, 

10 F

Once

(GO) 

390, 546, 

765, 1,071, 

1,500 

CS, LE Bd wt 546 M 765 M Decreases in body weight 

gain were in males at 

765 mg/kg (36% of controls) 

and 1,071 mg/kg (45%); no 

alterations were observed in 

females

Hemato 390 F Decreases in hematocrit and 

red blood cell count in 

females at ≥390 mg/kg and 

hemoglobin level at 

≥546 mg/kg

Other noncancer 

(blood glucose)

1,500

Chu et al. 1982
BROMODICHLOROMETHANE 27

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

9 Rat

(F344)

6 F

5 days

(GW)

0, 75, 150, 

300 

IX Immuno 75 Decreased response to the 

T-cell stimulant, 

phytohemagglutinin (PHA), 

in mesenteric lymph node 

lymphocytes at 

75 mg/kg/day

Decreased response to 

concanavalin A (Con A) in 

mesenteric lymph node 

lymphocytes at 

150 mg/kg/day 

Decreased response to 

Con A and PHA in the 

splenic lymphocytes and to 

S. typhimurium in the 

mesenteric lymph node 

lymphocytes at 

300 mg/kg/day 

Impaired humoral immunity 

(response to sheep red 

blood cells) at 

300 mg/kg/day

French et al. 1999 
BROMODICHLOROMETHANE 28

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

10 Rat

(Fischer 

344)

12 M

Once

(G) 

0, 20.5, 

30.7, 41.0, 

81.9, 122.9, 

163.8, 

245.7 

BW, BC, 

OW

Bd wt 245.7

Hepatic 163.8 245.7 Increases in ALT (239%), 

AST (130%), and sorbitol 

dehydrogenase (378%); 

significant increases at 81.9, 

122.9, and 163.8 mg/kg, but 

were not considered 

biologically significant

Keegan et al. 1998 

11 Rat

(Fischer 

344)

6 M

Once

(GW) 

0, 200, 400 BW, BC, 

OW, HP

Bd wt 400

Hepatic 200 400 Vacuolar degeneration and 

necrosis and alterations in 

serum enzyme levels

Renal 200 400 Tubule degeneration 24 and 

48 hours post-exposure and 

tubule necrosis 48 hours 

post-exposure, increases in 

urinary glucose and protein 

levels and decreases in 

urinary pH and osmolarity; 

urinary pH and osmolarity 

decreased at 200 mg/kg

Other noncancer 

(blood glucose)

400

Lilly et al. 1994
BROMODICHLOROMETHANE 29

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

12 Rat

(Fischer 

344)

6 M

Once

(GO) 

0, 200, 400 BW, BC, 

OW, HP

Bd wt 400

Hepatic 200 400 Vacuolar degeneration and 

necrosis and alterations in 

serum enzyme levels

Renal 200 400 Tubule degeneration 24 and 

48 hours post-exposure and 

tubule necrosis 48-hours 

post-exposure, increases in 

urinary glucose and protein 

levels and decreases in 

urinary pH and osmolarity; 

urinary pH and osmolarity 

were also decreased at 

200 mg/kg

Other noncancer 

(blood glucose)

400

Lilly et al. 1994

13 Rat

(Fischer 

344)

6 M

Once

(GW) 

0, 200, 400 BW, BC, 

OW, HP

Bd wt 200 400 12% decrease in body 

weight 

Hepatic 200 400 Minimal centrilobular 

necrosis and mild vacuolar 

degeneration 

Renal 200 Mild to marked proximal 

tubule necrosis

Other noncancer 

(blood glucose)

400

Lilly et al. 1996

Note: Animals were killed 48-hours post exposure. 
BROMODICHLOROMETHANE 30

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

14 Rat

(Fischer 

344)

10 M

Once

(GW) 

0, 122.8, 

163.8, 

245.7, 

327.7, 

491.5 

BW, BC, 

UR, OW

Bd wt 327.7 491.5 13% decrease in body 

weight 48 hours postexposure

Lilly et al. 1997

15 Rat

(F344)

12–14 F

GDs 6–15 

(GO), (GW)

0, 25, 50, 

75 

CS, BW, 

MX, DX, OF

Bd wt 25 50 Decreased weight gain on 

GDs 6–8 at 25 mg/kg/day; 

weight loss at 50 mg/kg/day

Develop 25b 50 Full-litter resorptions; no 

alterations in gestation 

length, postnatal viability, or 

pup weight on PND 1 or 6 in 

surviving litters

BMDL05 of 7.15 mg/kg/day

Narotsky et al. 1997

16 Rat

(F344/N)

5 M, 5 F

Once

(GO)

0, 150, 300, 

600, 1,250, 

2,500 

LE, CS Death 600 Deaths occurred in 

2/5 males and 1/5 females 

at 600 mg/kg and in all 

males and females at 

1,250 or 2,500 mg/kg

NTP 1987

17 Rat

(F344/N)

5 M, 5 F

14 days

(GO)

0, 38, 75, 

150, 300, 

600 

LE, CS, BW Bd wt 150 300 600 21% decrease in terminal 

body weights in males at 

300 mg/kg/day and weight 

loss or no weight gain in 

males and females at 

600 mg/kg/day

NTP 1987
BROMODICHLOROMETHANE 31

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

18 Rat

(SpragueDawley)

15 F

GDs 6–15

(GO)

0, 50, 100, 

200 

CS, BW, 

HP, MX, DX

Bd wt 100 200 Maternal body weight gain 

reduced by 38%

Resp 200

Cardio 200

Gastro 200

Hemato 200

Musc/skel 200

Hepatic 200

Renal 200

Endocr 200

Immuno 200

Neuro 200

Repro 200

Develop 100 200 Delayed ossification of the 

sternebrae

Ruddick et al. 1983

19 Rat

(Fischer 

344)

6 F

5 days

(GW)

0, 75, 150, 

300 

BW, BC, 

OW, HP

Death 300 2/6 rats died on day 5 

Bd wt 150 300 16.8% decrease in body 

weight

Hepatic 75 150 Hepatocellular vacuolar 

degeneration 
BROMODICHLOROMETHANE 32

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Renal 75 150 Tubule vacuolar 

degeneration and tubular 

degeneration at 

≥150 mg/kg/day; tubular 

necrosis and 8- and 12-fold 

increases in serum 

creatinine and urea nitrogen 

at 300 mg/kg/day

Thornton-Manning et al. 1994

20 Mouse

(ICR)

6 M

Once

(GW) 

Not reported NX Neuro 524 ED50 on the screen test was 

524 mg/kg

Balster and Borzelleca 1982

21 Mouse

(ICR)

8 M

14 days

(GW)

0, 1.2, 11.6 NX Neuro 11.6 No significant alteration in 

performance on a swimming 

endurance test

Balster and Borzelleca 1982

22 Mouse

(ICR 

Swiss)

NR, M,F

Once

(GW) 

500–4,000 CS, LE Death 450 M

900 F

LD50 values 

Bowman et al. 1978
BROMODICHLOROMETHANE 33

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

23 Mouse

(CD-1)

10 M

14 days

(GO) 

0, 37, 74, 

148 

CS, BW, 

BC, HP

Bd wt 148

Hepatic 37 74 Centrilobular pallor at 

≥74 mg/kg/day, focal 

inflammation at 

148 mg/kg/day 

Renal 74 148 Intratubular mineralization, 

epithelial hyperplasia, and 

cytomegaly 

Condie et al. 1983 

24 Mouse

(C57BL/6)

6 F

14 days

(W) 

0, 10, 37, 

62 

IX Immuno 62 No alterations in the 

response to T-lymphocyte or 

B-lymphocyte stimulants

French et al. 1999

25 Mouse

(CD-1)

8–9 M,F

14 day

(GW) 

0, 50, 125, 

250 

BW, HE, 

BC, OW, IX

Bd wt 125 250 20–22% decrease in body 

weight gain

Hemato 50 125 Decreases in fibrinogen at 

125 (females only) and 

250 mg/kg/day

Hepatic 125 250 Increases in (>800%) in ALT 

and AST 

Renal 125 250 41% increase in serum urea 

nitrogen levels

Immuno 125 250 Alterations in humoral 

immunity (decreases in 

antibody forming cells and 

hemagglutination) 
BROMODICHLOROMETHANE 34

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Other noncancer 

(blood glucose)

125 250 30% decrease in blood 

glucose levels in males

Munson et al. 1982

26 Mouse

(B6C3F1)

5 M, 5 F

Once

(GO) 

0, 150, 300, 

600, 1,250, 

2,500 

CS, LE Death 600 100 and 40% mortality in 

males and females at 

600 mg/kg; 100% mortality 

in males and females at 

1,250 and 2,500 mg/kg

NTP 1987

27 Mouse

(B6C3F1)

5 M, 5 F

14 days

(GO) 

0, 19, 38, 

75, 150, 

300 

CS, LE, 

BW

Death 150 100% mortality in males at 

150 and 300 mg/kg; no 

deaths related to BDCM 

exposure in females

NTP 1987

28 Mouse

(C57BLl/6

J)

6 F

5 days

(GW) 

0, 75, 150 BW, BC, 

OW, HP

Bd wt 150

Hepatic 150

Renal 150

Thornton-Manning et al. 1994

INTERMEDIATE EXPOSURE

29 Rat

(Wistar)

7 M

1 month

(F) 

0, 20, 60, 

180 

BW, OW, 

HE, BC, HP

Bd wt 60 180 19% decrease in body 

weight gain 

Resp 180

Cardio 180

Gastro 180

Hemato 180

Hepatic 60 180 Decrease in absolute liver 

weight, vacuolization, 

swelling, and necrosis
BROMODICHLOROMETHANE 35

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Renal 180

Endocr 180

Aida et al. 1989

Note: BDCM was microencapsulated and added to the diet.

30 Rat

(Wistar)

7 M

1 month

(GO) 

0, 20, 60, 

180 

BW, OW, 

HE, BC, HP

Bd wt 60 180 15% decrease in body 

weight gain 

Resp 180

Cardio 180

Gastro 180

Hemato 180

Hepatic 20 60 Increases in relative liver 

weight at 180 mg/kg/day 

and vacuolization at 

≥60 mg/kg/day

Renal 180

Endocr 180

Aida et al. 1989 

31 Rat

(Wistar)

6 M, 6 F

6 months

(F) 

M: 0, 6.1, 

25.5, 138.0 

F: 0, 8.0, 

31.7, 168.4 

CS, WI, 

BW, OW, 

HE, BC, HP

Bd wt 25.5 138.0 Decreased body weight gain 

in males (32%) and females 

(24%)

Resp 138.0

Cardio 138.0

Gastro 138.0

Hemato 138.0
BROMODICHLOROMETHANE 36

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Hepatic 6.1 Increases in absolute and 

relative weights in males at 

≥6.1 mg/kg/day and in 

females at ≥31.7 mg/kg/day, 

fatty generation at 

≥6.1/8.0 mg/kg/day, bile 

duct proliferation and 

cholangiofibrosis at 

138.0/168.4 mg/kg/day, and 

granulomas in females at 

≥31.7 mg/kg/day

Renal 138.0

Endocr 138.0

Neuro 138.0

Repro 138.0

Other noncancer 

(blood glucose)

6.1 25.5 Decreased blood glucose 

levels at ≥25.5/

31.7 mg/kg/day

Aida et al. 1992

Note: BDCM was microencapsulated and added to the diet.

32 Rat

(SpragueDawley)

25 F

GDs 6–21

(W)

0, 2.2, 18.4, 

45.0, 82.0 

CS, BW, 

MX, DX

Develop 45 82 Minor ossification delays

Christian et al. 2001a
BROMODICHLOROMETHANE 37

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

33 Rat

(SpragueDawley)

30 F

GDs 6–21

(W)

0, 4.1–12.6, 

11.6–40.2, 

29.5–109 

CS, BW, 

RX, MX, 

DX, HP

Repro 51.7 No alterations in 

reproductive function in a 

2-generation study

Develop 94.5 14% decrease in pup’s body 

weight on PND 22, which 

was likely due to taste 

aversion.

Christian et al. 2001b 

34 Rat

(SpragueDawley)

10 M

28 days

(W) 

0, 0.52, 5.2, 

45 

CS, HE, 

BC,HP

Bd wt 45

Hemato 45

Hepatic 45

Renal 45

Chu et al. 1982

35 Rat

(F344)

6 M

26 weeks

(W) 

0, 5, 49 IX Immuno 5 49 Decreased response to Con 

A in splenic lymphocytes

French et al. 1999

36 Rat

(Eker)

8 M, 8 F

4 or 

10 months

(W)

M: 0, 3.5 

35.0 

F: 0, 6.5, 

48.0 

CS, OW, 

HP

Bd wt 35.0

Gastro 35.0

Hepatic 3.5 35.0 Increases in the incidence of 

centrilobular swelling and 

clear cell foci

Hooth et al. 2002
BROMODICHLOROMETHANE 38

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

37 Rat

(F344)

6 M

5 days/week

4 weeks

(GO) or 

(GW) 

0, 100 OW, HP Renal 100

Lipsky et al. 1993

38 Rat

(F344)

5 M

5 days/week

4 weeks

(GO) 

0, 50, 100 BW, UR, 

BC, OW, 

HP

Bd wt 100

Renal 100 Decreases in urine pH and 

increases in formic acid 

excretion; minimal to slight 

cytoplasmic vacuolation in 

cortical tubules of 2/5 rats 

exposed to 100 mg/kg

Lock et al. 2004

39 Rat

(Eker)

8 M, 8 F

10 months

(W) 

0, 6.5, 48.0 CS, OW, 

HP

Gastro 6.5 Increase in aberrant crypt 

foci in colon

Other noncancer 

(urinary bladder)

48.0

McDorman et al. 2003

40 Rat

(Fisher 

344)

12 M, 

12 F

6 months

(W) 

M: 0, 9.1, 

27.3, 72.9 

F: 0, 9.0, 

26.9, 71.7 

NX, HP Neuro 71.7 No biologically relevant 

alterations in FOB tests or 

histopathological 

examination of the brain, 

spinal cord, hindlimb nerves, 

or optic nerve

Moser et al. 2007
BROMODICHLOROMETHANE 39

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

41 Rat

(F344/N)

10 M, 

10 F

5 days/week

13 weeks

(GO) 

0, 19, 38, 

75, 150, 

300 

CS, BW, HP Death 300 5/10 males and 

2/10 females died

Bd wt 75 150 300 Decreases in body weight 

gain (30 and 12% less than 

controls) at 150 mg/kg, 

decrease in body weight 

gain of 32% in females at 

300 mg/kg, no weight gain in 

males at 300 mg/kg

Resp 300

Cardio 300

Gastro 300

Hepatic 150 F 300 F Centrilobular degeneration, 

mild bile duct hyperplasia, 

and enlarged hepatocytes 

(females only)

Renal 150 300 Degeneration of the 

proximal tubular epithelial 

cells

Endocr 300

Immuno 150 300 Lymphoid atrophy of the 

thymus, spleen, and lymph 

nodes in males; this may 

have been secondary to the 

marked decrease in body 

weight gain

Repro 150 300 Mild to moderate atrophy of 

the seminal vesicles and/or 

prostate at 300 mg/kg

NTP 1987
BROMODICHLOROMETHANE 40

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

42 Rat

(F344/N)

10 M

22 days

(W) 

0, 6, 12, 20, 

38, 71 

CS, WI, 

BW, OW, 

HE, BC, HP

Bd wt 20 38 12 and 17% decrease in 

body weight gain at 38 and 

71 mg/kg/day; this is likely 

secondary to the decrease 

in water consumption

Resp 71

Cardio 71

Gastro 71

Hemato 71

Hepatic 71

Renal 71

Endocr 71

Immuno 71

Neuro 71

Repro 71

NTP 2006

43 Mouse

(ICR)

16 M

30 days

(GW) 

0, 100 NX Neuro 100 No alterations in 

performance on a passive 

avoidance learning test

Balster and Borzelleca 1982

44 Mouse

(ICR)

6–13 M

60 days

(GW) 

0, 100, 400 NX Neuro 100 Alterations in operant 

behavior 

Balster and Borzelleca 1982
BROMODICHLOROMETHANE 41

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

45 Mouse

(ICR)

6–8 M

90 days

(GW) 

0, 1.2 11.6 NX Neuro 11.6 No dose-related alterations 

on two tests of motor 

performance or a test of 

exploratory behavior

Balster and Borzelleca 1982

46 Mouse

(C57BL/6)

6 F

16 days

(GW) 

0, 50, 125, 

250 

IX Immuno 250 No alterations in the 

response to T-lymphocyte or 

B-lymphocyte stimulants

French et al. 1999

47 Mouse

(B6C3F1)

6 M

5 days/week

4 weeks

(GO) 

0, 25, 50 BW, UR, 

BC, OW, 

HP

Bd wt 50

Renal 50

Lock et al. 2004

48 Mouse

(B6C3F1)

10 M, 

10 F

5 days/week

13 weeks

(GO) 

M: 0, 6.25, 

12.5, 25, 

50, 100 

F: 0, 25, 

50, 100, 

200, 400 

CS, BW, HP Bd wt 100 M

400 F

Resp 100 M

400 F

Cardio 100 M

400 F

Gastro 100 M

400 F

Hepatic 100 M

100 F 200 F

Enlarged centrilobular 

hepatocytes and 

microgranulomas 

Renal 50 M 

400 F

100 M Focal necrosis of the 

proximal renal tubular 

epithelium 

Endocr 100 M

400 F
BROMODICHLOROMETHANE 42

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Immuno 100 M

400 F

Neuro 100 M

400 F

Repro 100 M

400 F

NTP 1987

49 Mouse

(B6C3F1)

10 M

22 days

(W) 

0, 6, 10, 16, 

29, 51 

CS, WI, 

BW, OW, 

HE, BC, HP

Bd wt 51

Resp 51

Cardio 51

Gastro 51

Hemato 51

Hepatic 51

Renal 51

Endocr 51

Immuno 51

Neuro 51

Repro 51

NTP 2006

50 Rabbit

(New 

Zealand 

white)

25 F

GDs 6–29

(W)

0, 1.4, 13.4, 

35.6, 55.3 

CS, BW, 

MX, DX

Develop 55.3

Christian et al. 2001a 
BROMODICHLOROMETHANE 43

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

CHRONIC EXPOSURE

51 Rat

(Wistar)

40 M, 

40 F

2 years

(F) 

M: 0, 6.1, 

25.5, 138.0 

F: 0, 8.0, 

31.7, 168.4 

CS, WI, 

BW, OW, 

HE, BC, HP

Bd wt 25.5 138.0 Decreased body weight gain 

in males (23–25%) and 

females (31–39%)

Resp 138.0

Cardio 138.0

Gastro 138.0

Hemato 138.0

Hepatic 6.1c Increases in absolute and 

relative weights at 

≥6.1/8.0 mg/kg/day after 

12 months of exposure and 

at ≥31.7 mg/kg/day after 

18 months of exposure; fatty 

generation at 

≥6.1 mg/kg/day in males 

and at ≥31.7 mg/kg/day in 

females, bile duct 

proliferation at 31.7 (females 

only) and 138.0/

168.4 mg/kg/day only after 

12 months of exposure; 

cholangiofibrosis at 

138.0/168.4 mg/kg/day; and 

granulomas in females at 

31.7 and 168.4 mg/kg/day 

after 12, 18, or 24 months of 

exposure and in males at 

≥6.1 mg/kg/day only after 

24 months of exposure

BMDL10 of 0.78 mg/kg/day
BROMODICHLOROMETHANE 44

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Renal 138.0

Endocr 138.0

Neuro 138.0

Repro 138.0

Other noncancer 

(blood glucose)

31.7 168.4 Increase blood glucose 

levels in males only

Cancer No increases in tumor 

incidence

Aida et al. 1992

Note: BDCM was microencapsulated and added to the diet.

52 Rat

(F344)

78 M

104 weeks

(W) 

0, 3.9, 20.6, 

36.3 

CS, BW, FI, 

BC, OW, 

HP

Bd wt 36.3

Resp 36.3

Cardio 36.3

Gastro 36.3

Hepatic 36.3

Renal 20.6 36.3 Renal tubular cell 

hyperplasia

Endocr 36.3

Cancer No increases in the 

incidence of tubular cell 

adenoma or carcinoma

George et al. 2002

53 Rat

(F344)

7 M

52 weeks

(W) 

0, 22, 39 RX, HP Repro 22 39 Decreases in sperm velocity 

from the cauda epididymidis; 

no changes in sperm motility

Klinefelter et al. 1995
BROMODICHLOROMETHANE 45

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

54 Rat

(F344/N)

50 M, 

50 F

5 days/week

2 years

(GO) 

0, 50, 100 CS, WI, 

BW, OW, 

HP

Bd wt 50 100 Decreases in body weight 

gain; terminal weights 

12 and 21% lower in males 

and females 

Resp 100

Cardio 100

Gastro 100

Hepatic 50 Fatty metamorphosis; 

increases in clear cell 

change at ≥50 mg/kg, 

eosinophilic cytoplasmic 

change, and focal cell 

change in females at 

100 mg/kg

Renal 50 100 Tubular epithelial cell 

cytomegaly in males at 

≥50 mg/kg; increased 

incidence in nephrosis in 

females at 100 mg/kg

Endocr 100

Immuno 100

Repro 100

Cancer 50 Adenocarcinomas in the 

large intestine in males at 

50 mg/kg and males and 

females at 100 mg/kg; renal 

tubular cell adenocarcinoma 

at 100 mg/kg

NTP 1987
BROMODICHLOROMETHANE 46

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

55 Rat

(F344/N)

50 M

2 years

(W)

0, 6, 12, 25 CS, WI, 

BW, OW, 

HP

Bd wt 25

Resp 25

Cardio 25

Gastro 25

Hepatic 25

Renal 25

Endocr 25

Immuno 25

Repro 25

Cancer No increases in malignant 

tumors

NTP 2006

56 Rat

(Wistar)

58 M, 

58 F

Lifetime

(W)

M: 0, 90 

F: 0, 190 

BW, HP Bd wt 90 M

190 F

Decreased body weight 

(approximately 30%) in 

males and females

Hepatic 90M 190 F Increased incidence of 

hepatic adenofibrosis 

Cancer 190 F Increased incidence of 

hepatic neoplastic nodules 

in females only; no 

additional description of the 

tumors was provided

Tumasonis et al. 1985
BROMODICHLOROMETHANE 47

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

57 Mouse

(B6C3F1)

78 M

104 weeks

(W) 

0, 8.1, 27.2, 

43.3 

CS, BW, FI, 

BC, OW, 

HP

Bd wt 43.3

Gastro 43.3

Hepatic 43.3

Renal 43.3

Endocr 43.3

Cancer No increases in the 

incidence of hepatocellular 

adenomas or carcinomas

George et al. 2002

58 Mouse

(B6C3F1)

50 M, 

50 F

5 days/week

2 years

(GO) 

M: 0, 25 50 

F: 0, 75, 

150

CS, BW, HP Death 75 F Decreased survival in 

females administered 75 or 

150 mg/kg; the incidences of 

non-accidental deaths were 

24/50, 37/50, and 35/50 in 

the 0, 75, and 150 mg/kg 

groups

Bd wt 50 M

75 F 150 F

25% lower body weights 

than controls in females

Resp 50 M

150 F

Cardio 50 M

150 F

Gastro 50 M

150 F

Hepatic 25 M

150 F

50M Hepatic fatty metamorphosis 
BROMODICHLOROMETHANE 48

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral

Figure 

keya

Species 

(strain)

No./group

Exposure 

parameters

Doses

(mg/kg/day)

Parameters 

monitored Endpoint

NOAEL 

(mg/kg/day)

Less 

serious 

LOAEL 

(mg/kg/day)

Serious 

LOAEL 

(mg/kg/day) Effect

Renal 150 F 25 M Renal cytomegaly 

Endocr 25 M 50 M

75 F

Thyroid follicular cell 

hyperplasia 

Immuno 50 M

150 F

Repro 50 M

150 F

Cancer 50 M

75 F

Renal tubular adenomas or 

adenocarcinomas in males 

at 50 mg/kg, hepatocellular 

adenomas or adenoma or 

carcinomas in females at 

≥75 mg/kg

NTP 1987 

59 Mouse

(B6C3F1)

50 F

2 years

(W) 

0, 9, 18, 36 CS, WI, 

BW, OW, 

HP

Bd wt 36

Resp 36

Cardio 36

Gastro 36

Hepatic 36

Renal 36

Endocr 36

Immuno 36
BROMODICHLOROMETHANE 

2. HEALTH EFFECTS

Table 2-3. Levels of Significant Exposure to Bromodichloromethane – Oral 

Less 

Species serious Serious 

Figure (strain) Exposure Doses Parameters NOAEL LOAEL LOAEL 

keya No./group parameters (mg/kg/day) monitored Endpoint (mg/kg/day) (mg/kg/day) (mg/kg/day) Effec

 Repro 36

 Cancer No s

neop

NTP 2006 

aThe number corresponds to entries in Figure 2-3.bUsed to derive an acute-duration oral minimal risk level (MRL) of 0.07 mg/kg/day based on the BMDL05 of 7.15 mg/kg/day and an unce

extrapolation from animals to humans and 10 for human variability). 

cUsed to derive a chronic-duration oral MRL of 0.008 mg/kg/day based on the BMDL10 of 0.78 mg/kg/day and an uncertainty factor of 10

from animals to humans and 10 for human variability). 

ALT = alanine aminotransferase; AST = aspartate aminotransferase; BC = biochemistry; BDCM = bromodichloromethane; BI = biochemwt = body weight; Cardio = cardiovascular; CS = clinical signs; Develop = developmental; DX = developmental toxicity; ED50 = dose resu

Endocr = endocrine; (F) = exposure in feed; F = female(s); FI = food intake; FX = fetal toxicity; G = gavage, neat; Gastro = gastrointestin

GO = gavage in oil vehicle; GW = gavage in water vehicle; HE = hematology; Hemato = hematological; HP = histopathology; Immuno = LD50 = lethal dose, 50% kill; LE = lethality; LOAEL = lowest-observed-adverse-effect level; M = male(s); MRL = Minimal Risk Level; Mus

MX = maternal toxicity; Neuro = neurological; NOAEL = no observed-adverse-effect level; NR = not reported; NS = not specified; NX = nfunction; OW = organ weight; PND = postnatal day; Repro = reproductive; Resp = respiratory; UR = urinalysis; W = water
BROMODICHLOROMETHANE 50

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMODICHLOROMETHANE 51

2. HEALTH EFFECTS

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

Acute (≤14 days)
BROMODICHLOROMETHANE 52

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMODICHLOROMETHANE 53

2. HEALTH EFFECTS

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

Intermediate (15-364 days)
BROMODICHLOROMETHANE 

2. HEALTH EFFECTS

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

Chronic (≥365 days)
BROMODICHLOROMETHANE 55

2. HEALTH EFFECTS

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

Chronic (≥365 days)
BROMODICHLOROMETHANE 56

2. HEALTH EFFECTS

2.2 DEATH

Deaths have been reported in laboratory animals following acute or intermediate inhalation exposure and 

acute, intermediate, and chronic oral exposure. Increases in mortality were observed in two strains of 

mice exposed to 30 ppm bromodichloromethane vapor for 1 week (Torti et al. 2001). Deaths were also 

observed at 30 ppm in a similar 3-week study, but only in one of the two mouse strains tested (Torti et al. 

2001). 

Oral LD50 values of 916 and 969 mg/kg were calculated in male and female rats (Chu et al. 1980). Deaths 

were also noted in rats receiving a single dose of 600 mg/kg (NTP 1987), but not in rats dosed for 14 days 

with 600 mg/kg/day (NTP 1987). However, another study reported 33% mortality in rats administered 

300 mg/kg/day for 5 days (Thornton-Manning et al. 1994). The differences between the two studies may 

be due to the gavage vehicle used, oil in the NTP study versus an aqueous solution in the ThorntonManning study. In contrast to the lack of sex differences observed in rats, male mice appear to be more 

sensitive to the lethal effect of bromodichloromethane than female mice. LD50 values of 450 and 

900 mg/kg were calculated in males and female mice, respectively (Bowman et al. 1978). NTP (1987) 

reported 100% mortality in male mice administered 600 mg/kg once or 150 mg/kg/day for 14 days; in 

females, 40% mortality occurred at 600 mg/kg and no deaths occurred at 150 or 300 mg/kg/day in the 

repeated exposure study. 

Most intermediate- and chronic-duration studies did not test lethal doses. NTP (1987) reported increases 

in mortality in male and female rats administered 300 mg/kg for 13 weeks. No deaths were observed in 

studies testing lower doses in rats or mice (Aida et al. 1989, 1992; Chu et al. 1982; Hooth et al. 2002; 

Lock et al. 2004; McDorman et al. 2003; NTP 2006) or in female mice administered 400 mg/kg (NTP 

1987). No deaths were noted in rats administered ≤190 mg/kg/day for chronic durations (Aida et al. 

1992; George et al. 2002; NTP 1987, 2006; Tumasonis et al. 1985). In mice, decreases in survival were 

observed in female mice administered 75 or 150 mg/kg for 2 years (NTP 1987); no deaths were observed 

in mice chronically exposed to lower doses (George et al. 2002; NTP 2006).

2.3 BODY WEIGHT

No human studies have evaluated the effect of bromodichloromethane exposure on body weights. In 

general, alterations in body weight do not appear to be a sensitive indicator of bromodichloromethane 

toxicity in laboratory animals. In C57BL/6 mice, inhalation exposure to ≥30 ppm for 1 week resulted in 

decreases in body weight gain (Torti et al. 2001); increases in mortality were also observed at these 
BROMODICHLOROMETHANE 57

2. HEALTH EFFECTS

concentrations. No alterations in body weight gain were observed when the mice were exposed for 

3 weeks or in another mouse strain exposed for 1 or 3 weeks (Torti et al. 2001). 

Several acute-duration oral studies have reported decreases in body weight gain in rats administered doses 

≥300 mg/kg (Chu et al. 1982; Lilly et al. 1996, 1997; NTP 1987; Thornton-Manning et al. 1994); other rat 

studies utilizing doses ≤400 mg/kg, did not find body weight alterations (Keegan et al. 1998; Lilly et al. 

1994). Two mouse studies evaluated body weight, one found a significant decrease at 250 mg/kg 

(Munson et al. 1982), and the other reported no effect at 148 mg/kg (Condie et al. 1983). Several studies 

have reported decreases in maternal weight gain following acute-duration oral exposure to ≥25 mg/kg 

(Bielmeier et al. 2001; Narotsky et al. 1997; Ruddick et al. 1983).

In intermediate-duration oral studies, 12–30% decreases in body weight gain were observed in rats 

administered 138–180 mg/kg bromodichloromethane (Aida et al. 1989, 1992; NTP 1987). A 12–17% 

decrease was also observed in rats exposed to 38 mg/kg/day bromodichloromethane in drinking water; 

however, significant decreases in water consumption were also observed at this dose level and the 

decrease in body weight is likely to be secondary to the decreased water intake (NTP 2006). No 

alterations in body weight were observed in rats administered 35 or 45 mg/kg (Chu et al. 1982; Lock et al. 

2004) or in mice administered 50–400 mg/kg (Lock et al. 2004; NTP 1987, 2006). Decreases in body 

weight were also observed in rats and mice following chronic-duration exposure to ≥90 mg/kg/day (Aida 

et al. 1992; NTP 1987; Tumasonis et al. 1985), but not at lower doses (George et al. 2002; NTP 2006).

2.4 RESPIRATORY

The respiratory tract has not been examined in the available inhalation exposure studies in mice (Torti et 

al. 2001). No respiratory effects have been reported in animal oral exposure studies (Aida et al. 1989, 

1992; George et al. 2002; NTP 1987, 2006; Ruddick et al. 1983).

2.5 CARDIOVASCULAR

No human studies have evaluated the cardiotoxicity of bromodichloromethane. No histological 

alterations were observed in the hearts of rats and mice orally administered bromodichloromethane at 

doses as high as 200 mg/kg/day (Ruddick et al. 1983), 400 mg/kg/day (Aida et al. 1989, 1992; NTP 1987, 

2006), or 138 mg/kg/day (Aida et al. 1992; George et al. 2002; NTP 1987, 2006) for acute-, intermediate-, 

or chronic-durations, respectively.
BROMODICHLOROMETHANE 58

2. HEALTH EFFECTS

2.6 GASTROINTESTINAL

No human studies have evaluated the gastrointestinal toxicity of bromodichloromethane. No nonneoplastic alterations have been observed in the gastrointestinal tract in most acute- (Ruddick et al. 1983), 

intermediate- (Aida et al. 1989, 1992; Hooth et al. 2002; NTP 1987, 2006), or chronic-duration (Aida et 

al. 1992; George et al. 2002; NTP 1987, 2006) oral studies in rats and mice. The NOAEL values for each 

duration category are 200, 400, and 138 mg/kg/day, respectively. McDorman et al. (2003) found an 

increase in the number of Eker rats having aberrant crypt foci in the colon following a 10-month exposure 

to 6.5 or 48.0 mg/kg/day in bromodichloromethane in drinking water. However, there were no significant 

increases in the total number of aberrant crypt foci, mean per colon, total number of crypts with aberrant 

foci, or distribution of aberrant foci in the different regions of the colon. The investigators considered 

aberrant crypt foci to be a preneoplastic lesion.

2.7 HEMATOLOGICAL

No studies examining hematological indices in humans were identified. Erythrocyte counts and 

hematocrit were significantly reduced in male rats 14 days after administration of a single dose of 

≥390 mg/kg, and hemoglobin was significantly reduced in males and females at ≥546 mg/kg (Chu et al. 

1982). No other acute (Munson et al. 1982; Ruddick et al. 1983), intermediate (Aida et al. 1989, 1992; 

Chu et al. 1982; NTP 2006), or chronic (Aida et al. 1992) oral studies reported erythrocyte or hemoglobin 

alterations, although the doses tested were lower than those in the Chu et al. (1982) acute study. The only 

other hematological alteration observed was a decrease in fibrinogen levels in female mice administered 

125 mg/kg/day and male and female mice administered 250 mg/kg/day for 14 days (Munson et al. 1982). 

2.8 MUSCULOSKELETAL

No studies evaluated the potential of bromodichloromethane to induce musculoskeletal alterations in 

humans. No histological alterations were observed in skeletal muscle of pregnant rats administered 

200 mg/kg/day bromodichloromethane on GDs 6–15 (Ruddick et al. 1983). No longer-term studies 

examining musculoskeletal endpoints were identified.
BROMODICHLOROMETHANE 59

2. HEALTH EFFECTS

2.9 HEPATIC

Information on the hepatoxicity of bromodichloromethane in humans is limited to a study which utilized 

NHANES data and did not find an association between bromodichloromethane blood levels and aspartate 

aminotransferase levels (Burch et al. 2015); this study is described in greater detail in Table 2-1. Animal 

studies provide strong evidence of the hepatotoxicity of bromodichloromethane. Based on a systematic 

review of the human and animal data, it is concluded that the liver is a presumed target of bromodichloromethane in humans (see Appendix C for additional information). The available animal data for 

bromodichloromethane and animal studies for two related compounds (bromoform and dibromochloromethane) (ATSDR 2005) provide evidence that oral exposure to bromodichloromethane results in an 

accumulation of fat in the liver as evidenced by increases in liver weight, centrilobular swelling, 

vacuolization, and fatty degeneration. Bromodichloromethane also appears to damage the bile duct. The 

animal studies also demonstrate vehicle-specific differences in hepatotoxicity, with greater toxicity 

associated with oil vehicles than aqueous vehicles.

A single dose of bromodichloromethane administered via gavage resulted in liver damage at doses as low 

as 74 mg/kg (Condie et al. 1983). At this dose, centrilobular pallor was observed in mice. At 

≥81.9 mg/kg, marked increases in alanine aminotransferase, aspartate aminotransferase, and sorbitol 

dehydrogenase were observed in rats and mice (Condie et al. 1983; Keegan et al. 1998; Lilly et al. 1994, 

1996). At 400 mg/kg, mild centrilobular vacuolar degeneration and minimal centrilobular hepatocellular 

necrosis were observed in rats (Lilly et al. 1994, 1996). The toxicity of bromodichloromethane was 

greater when it was administered in a corn oil vehicle than when administered in an aqueous vehicle 

(Lilly et al. 1994). The magnitude of the increases in alanine aminotransferase and aspartate 

aminotransferase was greater for the corn oil vehicle, particularly 48 hours after administration when the 

enzyme levels were at least twice as high in the corn oil vehicle group compared to the aqueous vehicle 

group. Similarly, the incidences of hepatocellular necrosis 48 hours post-administration were 5/6 in the 

oil vehicle group and 2/6 in the aqueous vehicle group. Bromodichloromethane was more toxic following 

repeated acute exposure (5–14 days), with increases in alanine aminotransferase and aspartate 

aminotransferase observed at ≥250 mg/kg/day (Munson et al. 1982; Thornton-Manning et al. 1994) and 

centrilobular hepatocellular vacuolar degeneration at ≥150 mg/kg/day (Thornton-Manning et al. 1994).

Intermediate-duration studies have reported hepatic effects ranging from increases in liver weight to fatty 

degeneration. There is a considerable amount of overlap between the NOAEL and LOAEL values for 

hepatotoxicity between studies, which may be due to differences in study durations and/or administration 
BROMODICHLOROMETHANE 60

2. HEALTH EFFECTS

route. Administration of bromodichloromethane via gavage with an oil vehicle resulted in vacuolization 

in rats exposed to ≥60 mg/kg/day for 1 month (Aida et al. 1989) and centrilobular degeneration in rats 

exposed to 300 mg/kg for 3 months (NTP 1987); the NOAELs for these studies were 20 and 150 mg/kg, 

respectively. Microencapsulating bromodichloromethane dissolved in oil and adding it to the diet 

resulted in hepatocellular vacuolization, swelling, and necrosis in rats exposed to 180 mg/kg/day for 

1 month (Aida et al. 1989) and fatty degeneration in male rats exposed to ≥6.1 mg/kg/day for 6 months 

(LOAEL in females was 31.7 mg/kg/day) (Aida et al. 1992). Two studies administering bromodichloromethane in drinking water did not find increases in liver lesions at the highest doses tested, 45 mg/kg/day 

for 28 days (Chu et al. 1982) and 71 mg/kg/day for 22 days (NTP 2006). However, a third study 

identified a LOAEL of 35 mg/kg/day for centrilobular swelling in rats exposed to 35 mg/kg/day for 4 or 

10 months (Hooth et al. 2002). The Aida et al. (1989) studies allow for a direct comparison between 

exposure routes since the gavage and dietary studies utilized the same rat strain (Wistar), dose levels, and 

exposure duration (1 month). The gavage study identified a lower LOAEL (60 mg/kg/day) for 

vacuolization than the dietary study (180 mg/kg/day). Enlarged hepatocytes with vacuolization were also 

observed in female mice administered via gavage ≥200 mg/kg bromodichloromethane in corn oil (NTP 

1987); no liver effects were observed in a 13-week drinking water study in which mice were exposed to 

doses as high as 51 mg/kg/day (NTP 2006).

Eight studies have evaluated the chronic toxicity of bromodichloromethane in rats and mice (Aida et al. 

1992; George et al. 2002; NTP 1987, 2006; Tumasonis et al. 1985). With the exception of the lifetime 

drinking water exposure study conducted by Tumasonis et al. (1985), the other studies involved a 2-year 

exposure to bromodichloromethane administered via gavage with a corn oil vehicle (NTP 1987), in 

drinking water (George et al. 2002; NTP 2006), or in the diet (Aida et al. 1992). The Aida et al. (1992) 

study identified the lowest LOAEL for hepatic effects; at ≥6.1 mg/kg/day, fatty degeneration was 

observed in the liver of male rats exposed for 12, 18, or 24 months; the LOAEL in the female rats was 

31.7 mg/kg/day after 12 and 18 months and 8.0 mg/kg/day after 24 months of exposure. Fatty 

metamorphosis was observed in rats administered ≥50 mg/kg (lowest dose tested) for 2 years (NTP 1987). 

In drinking water studies, no histological alterations were observed in the liver of rats exposed to 

56.3 mg/kg/day (George et al. 2002). NTP (2006) noted that minimal to mild liver inflammation of 

questionable significance was observed at 12 and 25 mg/kg/day; the biological relevance of the lesion 

was questioned since the lesion morphology is consistent with spontaneous inflammation observed in 

aging rats, which is considered to be due to bacterial showering from the intestinal tract. Tumasonis et al. 

(1985) reported an increase in the incidence of hepatic adenofibrosis in female rats exposed to 

190 mg/kg/day. In a mouse gavage study, an increase in fatty metamorphosis was observed in males at 
BROMODICHLOROMETHANE 61

2. HEALTH EFFECTS

50 mg/kg/day, but no lesions were observed in females at 150 mg/kg (NTP 1987). A drinking water 

study by George et al. (2002) did not find liver effects at the highest dose tested (43.3 mg/kg/day). 

In addition to the hepatocellular effects noted in rats and mice, intermediate- and chronic-duration 

exposure has resulted in damage to the bile duct. Bile duct proliferation and cholangiofibrosis was 

observed in rats exposed to 138.0 (males)/168.4 (females) mg/kg/day for 6, 12, 18, and 24 months (Aida 

et al. 1992) and mild bile duct hyperplasia was observed in rats administered 300 mg/kg for 13 weeks 

(NTP 1987).

There are limited data on the mechanisms of bromodichloromethane hepatotoxicity. The available data 

suggest that its toxicity is due to the production of reactive intermediates. As reported by ThorntonManning et al. (1994), pretreatment of rats with the cytochrome P450 inhibitor, 1-aminobenzotriazole, 

significantly reduced the hepatic toxicity of bromodichloromethane and pre-treatment with acetone, a 

CYP2E1 inducer, greatly increased its toxicity. Additionally, pretreatment with the glutathione synthesis 

inhibitor butathione sulfoxime (BSO) increased bromodichloromethane’s toxicity (Gao et al. 1996). 

Similarly, adding glutathione to hepatic microsomes under anaerobic conditions decreased binding of 

[14C]bromodichloromethane to lipids (Gao et al. 1996). These data demonstrate a protective role of 

glutathione that is consistent with metabolism of bromodichloromethane to one or more reactive species.

2.10 RENAL

No studies have evaluated the renal toxicity of bromodichloromethane in humans. However, based on the 

available animal studies, the kidney is a suspected target in humans (see Appendix C for more 

information on the systematic review of these data). 

In inhalation studies, renal tubular degeneration was observed in mice exposed to ≥10 ppm bromodichloromethane for 1 or 3 weeks (Torti et al. 2001); the NOAELs identified in these studies were 1 and 

3 ppm, respectively. Increased incidence of nephrosis was also observed at 10 ppm in a 13-week study 

(Torti et al. 2001); the NOAEL was 3 ppm. 

In single-dose oral studies, mild to marked renal tubule degeneration and minimal-to-moderate renal 

tubule necrosis were observed in rats following administration via gavage with corn oil or aqueous 

vehicles at 200 mg/kg (Lilly et al. 1996) and/or 400 mg/kg (Lilly et al. 1994). Increases in serum urea 

nitrogen, urinary glucose, and urinary protein levels were observed at 400 mg/kg/day (Lilly et al. 1994), 
BROMODICHLOROMETHANE 62

2. HEALTH EFFECTS

and decreases in urinary pH and osmolarity were observed at ≥200 mg/kg (Lilly et al. 1994). Similarly, 

renal tubule degeneration and tubular regeneration were observed in rats administered ≥150 mg/kg/day 

for 5 days (Thornton-Manning et al. 1994), and tubular necrosis and increases in serum creatinine and 

urea nitrogen were observed at 300 mg/kg/day. The acute studies provide some suggestive evidence of 

species differences in that no renal effects have been observed in mice administered bromodichloromethane for 5 days at doses as high as 150 mg/kg/day (Thornton-Manning et al. 1994). Another study 

found intratubular mineralization and epithelial hyperplasia at 148 mg/kg/day in mice exposed for 14 days 

(Condie et al. 1983), but did not report tubular degeneration or regeneration.

Similar renal effects have been reported in rats and mice in intermediate- and chronic-duration studies. 

Degeneration of proximal tubular epithelial cells were observed in rats administered 300 mg/kg for 

13 weeks (NTP 1987) and nephrosis was observed in rats (females only) administered 100 mg/kg for 

2 years (NTP 1987). Another rat study reported renal tubular cell hyperplasia in rats exposed to 

36.3 mg/kg/day for 2 years (George et al. 2002). Other intermediate and chronic studies did not find 

histological alterations in the kidneys at doses as high as 180 mg/kg/day (Aida et al. 1989, 1992; Chu et 

al. 1982; Lipsky et al. 1993; Lock et al. 2004; NTP 2006). As noted in NTP (2006), differences in the 

route of administrations (gavage versus feed versus water) and stability of the bromodichloromethane in 

water and feed may have accounted for the overlap between the NOAEL and LOAEL values. In mice, 

proximal tubular focal necrosis was observed in males administered 100 mg/kg for 13 weeks (NTP 1987), 

but no effects were observed in females at doses as high as 400 mg/kg. An increase in the incidence of 

renal tubular epithelial cell cytomegaly was also observed in mice at 25 mg/kg for 2 years (NTP 1987). 

No renal effects were observed in mice administered via gavage 50 mg/kg/day for 4 weeks (Lock et al. 

2004) or exposed to 36 mg/kg/day in drinking water for 2 years (NTP 2006).

2.11 DERMAL

No human or animal studies have evaluated the dermal toxicity of bromodichloromethane.

2.12 OCULAR

No human studies examined potential ocular effects following inhalation, oral, or direct contact exposure 

to bromodichloromethane. Mild eye irritation was noted in mice exposed to ≥30 ppm bromodichloromethane vapors for 1 week (Torti et al. 2001); the investigators did not report incidence data. Eye 

irritation was not noted in a 3-week study conducted by this group.
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2.13 ENDOCRINE

In general, endocrine tissues do not seem to be a target of bromodichloromethane toxicity; see 

Section 2.16 for a discussion of alterations in reproductive hormone levels. Human studies evaluating 

endocrine endpoints following exposure to bromodichloromethane were not identified. No histological 

alterations were observed in rats following exposure to ≤200 mg/kg/day on GDs 6–15 (Ruddick et al. 

1983), intermediate-duration exposure of rats to ≤300 mg/kg/day (Aida et al. 1989, 1992; NTP 1987, 

2006) or mice to ≤400 mg/kg/day (NTP 1987, 2006), or chronic-duration exposure of rats to 

≤138 mg/kg/day (Aida et al. 1992; NTP 1987, 2006). Thyroid follicular cell hyperplasia was observed in 

male mice administered via gavage 50 mg/kg or in females administered ≥75 mg/kg (NTP 1987); no 

endocrine effects were observed in mice exposed to ≤36 mg/kg/day in drinking water (NTP 2006).

2.14 IMMUNOLOGICAL

Immunotoxicity is a suspected health effect for humans based on a systematic review of several studies 

examining immunological endpoints in laboratory animals orally exposed to bromodichloromethane (see 

Appendix C for more information). Epidemiological data are limited to a study examining immune 

markers following a 40-minute swim in a chlorinated pool (Vlaanderen et al. 2017). Decreases in C-X-C 

motif chemokine 10, C-C motif chemokine 22, C-reactive protein, and vascular endothelial growth factor 

and increases in interleukin-1rA were associated with exhaled breath bromodichloromethane levels.

Acute exposures have resulted in decreased responses to humoral and cell-mediated immune stimulants in 

rats administered ≥75 mg/kg/day for 5 days (French et al. 1999) or mice administered 250 mg/kg/day for 

14 days (Munson et al. 1982). Following a 26-week exposure to 49 mg/kg/day, an impaired response to 

the mitogen concanavalin A was observed in splenic lymphocytes, but there was no altered response in 

the lymph node lymphocytes or responses by either type of lymphocyte to other mitogens or to 

Salmonella tymphimurium (French et al. 1999). 

The available data provide some suggestive evidence that rats may be more sensitive to the immunotoxic 

effects of bromodichloromethane than mice. No alterations in immune function were observed in mice 

exposed to 62 mg/kg/day in drinking water for 14 days (French et al. 1999) or administered 

125 mg/kg/day via gavage with an aqueous vehicle for 14 days (Munson et al. 1982) or 250 mg/kg/day 

for 16 days (French et al. 1999). These NOAELs are higher than LOAEL values in rats. Although 
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bromodichloromethane results in impaired immune function, no histological alterations were observed in 

lymphoid tissues following acute (Ruddick et al. 1983), intermediate (NTP 1987, 2006), or chronic (NTP 

1987, 2006) exposure; the lymphoid atrophy observed at 300 mg/kg in the NTP (1987) intermediateduration rat study was likely secondary to a decrease in body weight rather than a direct effect on the 

lymphoid tissue.

2.15 NEUROLOGICAL

No studies were located regarding neurological effects in humans exposed to bromodichloromethane. 

Balster and Borzelleca (1982) performed a series of tests in mice ≥24 hours after the last of a series of 

doses of bromodichloromethane. Exposure to doses of 1.2–11.6 mg/kg/day for 14–90 days had no effect 

on tests of coordination, strength, endurance, or exploratory activity, and 90-day exposure to 

100 mg/kg/day did not affect passive avoidance learning. Exposure to 100 or 400 mg/kg/day for 60 days 

did result in an acute effect on operant behavior learning, but this change tended to diminish over the 

exposure period, suggesting that there was no progressive effect and that partial tolerance developed. 

One other study evaluating neurological function did not find alterations in performance on functional 

observational battery tests in rats exposed to 71.7 mg/kg/day for 6 months (Moser et al. 2007). No 

histological alterations in the brain and/or peripheral nerves were observed in rats or mice exposed to 

bromodichloromethane for acute (Ruddick et al. 1983), intermediate (Aida et al. 1992; Moser et al. 2007; 

NTP 1987, 2006), or chronic (Aida et al. 1992; NTP 1987, 2006) durations.

2.16 REPRODUCTIVE

In a systematic review of the available reproductive toxicity data for bromodichloromethane, it was 

determined that hazard identification for reproductive toxicity potential could not be classified due to the 

inconsistent results found in epidemiology and laboratory animal studies (see Appendix C for more 

information). A small number of human (Table 2-1) and laboratory animal (Table 2-2) studies evaluated 

the reproductive toxicity of bromodichloromethane; the studies examined potential effects on sperm 

parameters, menstrual cycle, fertility, hormone levels, and reproductive organ pathology. Three 

epidemiological studies examined reproductive endpoints associated with environmental exposure to 

bromodichloromethane. Interpretation of the study results is limited by the lack of confirming studies and 

potentially confounding exposure to other compounds, particularly other disinfection byproducts. Zeng et 

al. (2013) did not find a significant association between blood bromodichloromethane levels and sperm 
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concentration, sperm count, or sperm motility in men. Associations between exposure to bromodichloromethane in drinking water and decreasing overall menstrual cycle length and follicular phase length 

specifically, as measured by urine estrogen and progesterone metabolite levels, were found in women 

participating in a reproductive health study (Windham et al. 2003). In a large prospective cohort study, a 

decreased time to pregnancy was associated with an estimate of the amount of bromodichloromethane 

ingested from tap water (MacLehose et al. 2008); however, no associations were found for other 

bromodichloromethane dose metrics. A fourth study examined possible interactions between CYP2E1, 

GSTZ1, and GSTT1 polymorphisms and bromodichloromethane levels in drinking water on sperm 

motility, sperm count, and sperm concentration (Yang et al. 2016). The only observed association was 

found in men with blood bromodichloromethane levels ≥1.70 μg/mL and a CYP2E1 rs2031920 CC 

polymorphism.

Most studies evaluating the histopathology of the testes and uterus did not find alterations (Aida et al. 

1992; NTP 1987, 2006; Ruddick et al. 1983). One study did find mild to moderate atrophy of the seminal 

vesicles and/or prostate in rats administered a lethal dose of 300 mg/kg for 13 weeks (NTP 1987). A 

2-generation reproduction study in rats did not find any alterations in reproductive parameters at the 

highest dose tested (51.7 mg/kg/day) (Christian et al. 2001b). No alterations in the percentage of motile 

or progressively motile sperm were observed in rats exposed to doses of 39 mg/kg/day for 52 weeks 

(Klinefelter et al. 1995); however, the study did find significant decreases in sperm velocity at 

39 mg/kg/day. A study in rats found a diminished responsiveness to luteinizing hormone when 75 mg/kg 

bromodichloromethane was administered on GDs 8–10 (Bielmeier et al. 2001, 2004, 2007). 

2.17 DEVELOPMENTAL

The available human and animal studies provide evidence that developmental toxicity is a presumed 

health effect of bromodichloromethane in humans (see Appendix C for information on the systematic 

review). 

A number of epidemiology studies have examined the association between exposure to trihalomethanes, 

bromodichloromethane among them, and developmental effects in humans (Table 2-1). Specific 

endpoints examined have included birth weight and length, small for gestational age (SGA), various birth 

defects, gestational age, preterm delivery, spontaneous abortion, stillbirth, and incidence of hypospadias. 

Overall, these studies provide limited evidence for an association between bromodichloromethane and 

developmental effects, possibly due to the main limitation of non-differential misclassification of 
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individual exposure. In addition, the various studies have used different approaches to assess exposure, 

including blood levels of bromodichloromethane, bromodichloromethane in water supplied to the places 

of residence, and total dose (measured concentration of bromodichloromethane in water plus estimates of 

water ingestion combined with inhalation and dermal exposure through showering and bathing, and other 

activities). There is considerable uncertainty due to self-recollection of water use and due to spatial and 

seasonal variation of disinfection byproducts within a distribution system.

Mixed results have been reported in studies examining the potential effect of bromodichloromethane 

exposure and birth weight. Birth weight was not significantly associated with bromodichloromethane 

levels in blood during late pregnancy (median 2.5 ng/L) in a case-control study of pregnant women in 

China (Cao et. al. 2016), with daily doses ≤0.34 μg bromodichloromethane/day during the entire 

pregnancy or individual trimesters in a nested-case-control study of pregnant women in Lithuania 

(Danileviciute et al. 2012), or with bromodichloromethane levels in water (Hoffman et al. 2008). In a 

retrospective cohort study of 196,000 live births in Massachusetts between 1995 and 1998, exposure to 

water containing ≥5 μg bromodichloromethane/L during the third trimester of pregnancy was associated 

with a reduction in birth weight of 12 g (Wright et al. 2004). A more recent study of the same population, 

that included evaluation of 672,120 live births, confirmed the earlier observations and reported that 

exposure to a mean concentration of 6.1 μg bromodichloromethane/L in water during the third trimester 

was associated with reductions in birth weight of 49–63 g in unadjusted models; the association remained 

significant in adjusted models, but the magnitude of the reductions in birth weight were considerably 

lower (Rivera-Núñez and Wright 2013).

Evaluations of small for gestational age (SGA) have also provided seemingly inconsistent results. SGA 

was not associated with exposure to bromodichloromethane assessed by measuring its concentration in 

blood (Cao et al. 2016), assessed as total intake via multi-route exposure (Danileviciute et al. 2012), or by 

average water concentration (Hoffman et al. 2008). In contrast, SGA was associated with third trimester 

bromodichloromethane water supply levels of ≥19 μg/L in a retrospective cohort study of 341,982 live 

births in Australia (Summerhayes et al. 2012). In general, larger associations were seen in nonsmokers 

than in smokers, which the investigators attributed to the relatively large smoking effect on SGA possibly 

masking the effects of subtle risk factors such as trihalomethane exposure on SGA. An association 

between SGA and ≥5 μg bromodichloromethane/L in water during the third trimester was reported in the 

earlier study of women in Massachusetts (Wright et al. 2004); bromodichloromethane was also associated 

with longer gestational age (0.5–0.6 days) in this study. The most recent study of this population did not 

find an association after adjustments for confounding variables (Rivera-Núñez and Wright 2013); 
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gestational age was not evaluated. In the two studies of women in Massachusetts, preterm delivery was 

not associated with bromodichloromethane levels in the water supply (Rivera-Núñez and Wright 2013; 

Wright et al. 2004).

Four studies evaluated associations between exposure to bromodichloromethane and risk of congenital 

anomalies. Mean bromodichloromethane levels in water during pregnancy were associated with an

increase in risk of neural tube defects in a prospective cohort study of residents of Nova Scotia, Canada 

(Dodds and King 2001); no associations were found for cardiovascular defects or cleft defects. A study 

of women from Massachusetts did not find associations between bromodichloromethane water levels and 

the risk of cardiovascular defects (Wright et al. 2017). In a study of women from Lithuania, internal 

bromodichloromethane dose during the first month of pregnancy was associated with an increased risk of 

heart anomalies in comparisons of the third tertile (0.051–0.436 μg/day) versus the first tertile (0.000–

0.013 μg/day) (Grazuleviciene et al. 2013); no associations were found for musculoskeletal or urogenital 

anomalies. An intake of ≥6 μg bromodichloromethane/day (combined estimates of water consumption, 

dishwashing, showering, and swimming during the first trimester) was associated with an increased risk 

of hypospadias in male offspring in a small case-control study in England (Iszatt et al. 2011); notably, the 

concentration of bromodichloromethane in water was not associated with hypospadias. However, 

elevated risk of hypospadias was associated with consumption of cold tap water at home, total water, 

bottled water, and total fluid (the concentrations of bromodichloromethane in water was not provided, but 

mean total trihalomethanes ranged from 15 to 51 μg/L).

As with other effects, mixed results have been found in studies examining the possible association 

between bromodichloromethane and the risk of stillbirth or spontaneous abortions. In a prospective 

cohort study of Canadian women, exposure to exposure to ≥20 μg bromodichloromethane/L in the water 

during pregnancy almost doubled the risk of stillbirth (King et al. 2000). Analysis of risk in a continuous 

representation showed a 29% increase in risk with each 10 μg bromodichloromethane/L. Risk of 

unexplained stillbirth was not associated with bromodichloromethane, but risk of stillbirth caused by 

asphyxia was increased 32% per 10 μg/L bromodichloromethane. In contrast, a study of women living in 

Massachusetts did not find an association between bromodichloromethane levels in municipal water and 

all causes of stillbirths, but did find an association with unexplained stillbirths (Rivera-Núñez et al. 

(2018). A large prospective study of pregnant women in California found a doubling of the risk of 

spontaneous abortion among women with high personal exposure to bromodichloromethane in the tap 

water (Waller et al. 1998); the risk was further increased after adjustment for high exposure to other 

trihalomethanes.
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A study of 3-day-old infants found an inverse association between maternal blood bromodichloromethane 

levels and neonatal neurological assessment test scores (Chen et al. 2019); no other epidemiological 

studies evaluated potential neurodevelopmental effects.

Several studies provide information regarding the developmental effects of bromodichloromethane in 

laboratory animals following oral exposure. With the exception of one study in rabbits, all have been 

conducted in rats. The results of these studies indicate that: (1) F344 rats are considerably more 

susceptible than Sprague-Dawley rats, particularly for the endpoint of full-litter resorptions; (2) mode of 

administration of bromodichloromethane, gavage vs. drinking water, and the vehicle influence the 

toxicity; (3) bromodichloromethane is not teratogenic; and (4) effects occur in animals at exposure levels 

significantly higher than what humans normally encounter through residential or environmental exposures 

to bromodichloromethane.

The lowest LOAEL for developmental effects in animals was 50 mg/kg/day for full-litter resorptions in 

F344 rats dosed by gavage on GDs 6–15; no significant resorptions occurred at 25 mg/kg/day (Narotsky 

et al. 1997). A significantly higher resorption rate was reported when doses of 75 mg/kg/day were 

administered in an oil vehicle (83%) than when given in an aqueous vehicle (8%). The difference may 

have been due, at least in part, to a slower measured elimination rate of bromodichloromethane when 

administered in the oil vehicle compared to the aqueous vehicle. Comparative evaluation of F344 rats 

and Sprague-Dawley rats showed that full-litter resorptions occurred in the former at a rate of 62% (8/13) 

following dosing with 75 mg/kg/day, whereas the rate was 0% in the latter strain dosed with 

≤100 mg/kg/day (Bielmeier et al. 2001). The investigators noted that it was not clear whether the 

difference in sensitivity was due to strain differences in reproductive physiology or toxicokinetics. 

Studies in F344 rats indicate that the early gestation window as the most sensitive time period for 

bromodichloromethane-induced full-litter resorptions. Bielmeier et al. (2001) observed 75 and 50% fulllitter resorption rates when rats were administered 75 mg/kg/day doses on GDs 6–10 and 6–15, 

respectively, while administration on GDs 11–15 resulted in 0% full-litter resorptions. It should be noted 

that in these studies, doses of bromodichloromethane that induced full-litter resorptions (≤100 mg/kg/day) 

also significantly reduced maternal body weight gain during gestation; however, there was no significant 

effect on pup viability or neonatal body weight in pregnancies with live litters sacrificed on postnatal day 

(PND) 6 (Bielmeier et al. 2004). 
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Additional studies that examined a wide range of developmental endpoints in Sprague-Dawley rats and 

New Zealand white rabbits exposed during gestation to ≤200 mg/kg/day did not report full-litter 

resorptions (Christian et al. 2001a, 2001b; Ruddick et al. 1983). 

Studies in rats reported minor delays in ossification of the forelimbs and hindlimbs following maternal 

doses of 82 mg/kg/day in drinking water on GDs 6–21 (Christian et al. 2001a) and of the sternebrae of 

fetuses from dams dosed with 200 mg/kg/day by gavage on GDs 6–15 (Ruddick et al. 1983). The 

respective NOAELs were 45 and 100 mg/kg/day. However, no developmental abnormalities were 

reported in fetuses from rabbits following maternal doses of ≤55.3 mg/kg/day in the drinking water on 

GDs 6–29 (Christian et al. 2001a). Other endpoints evaluated in these studies included number of corpora 

lutea, implantation sites, live and dead fetuses and early and late resorptions, fetal body weight, sex ratios, 

and external and soft tissue abnormalities; none were significantly affected by exposure to 

bromodichloromethane. 

Bromodichloromethane was also tested in a 2-generation reproductive toxicity study in rats (Christian et 

al. 2001b). The most significant effect was a 14% reduction in body weight in pups from the F1 

generation on PND 21; the maternal dose estimated by the investigators during lactation days 1–15 was 

94.2 mg/kg/day. The decrease in pup body weight began when the pups started drinking water containing 

bromodichloromethane and there was a 20% decrease in water intake in this group which was attributed 

to taste aversion. Thus, the decrease in body weight was considered to be secondary to taste aversion and 

was not considered toxicologically relevant. Relative spleen weight was also significantly reduced in F1 

pups on PND 21 (10–28%). Small but significant delays in preputial separation in F1 males and in 

vaginal patency in F1 females were reported. However, the differences lost significance when the effects 

were analyzed using body weight at weaning as covariate. Histological evaluation of unspecified tissues 

of weanling F1 or F2 pups did not show treatment-related alterations. 

Support for the developmental toxicity of bromodichloromethane come from several in vitro studies. In 

vitro studies by Chen et al. (2003, 2004) provide some support for the association between bromodichloromethane exposure and increases in spontaneous abortion risks. These studies found bromodichloromethane-induced decreases in the secretion of chorionic gonadotrophin in cultured human placental 

trophoblasts. It is noted that trophoblasts are the sole source of chorionic gonadotrophin in humans and 

play a major role in maintenance of the conceptus. In porcine embryos, exposure to bromodichloromethane resulted in decreases in blastocyst rate and alterations in hormonal response (Pagé-Larivière et 

al. 2016). The study also found gene alterations that are consistent with cardiac anomalies.
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2.18 OTHER NONCANCER

The available studies in laboratory animals provide suggestive evidence that oral exposure to bromodichloromethane may result in a decrease in blood glucose levels. Decreases in blood glucose levels were 

observed in rats exposed to bromodichloromethane in the diet for 1, 6, or 18 months (Aida et al. 1989, 

1992). However, these data are inconsistent and there is overlap between the NOAEL and LOAEL 

values. Following 6 months of exposure, the LOAEL was 25.5 (males)/31.7 (females) mg/kg/day and the 

NOAEL was 6.1/8.0 mg/kg/day; however, after 18 months, only females were affected and the NOAEL 

and LOAEL values were 31.7 and 168.4 mg/kg/day. This study (Aida et al. 1992) also reported 

significant increases in blood glucose levels in males exposed to 6.1 or 25.5 mg/kg/day, but not 

138.0 mg/kg/day, for 12 months. Acute, single administration studies did not find significant alterations 

in blood glucose levels (Chu et al. 1982; Lilly et al. 1994, 1996).

No histological alterations were observed in the urinary bladder of rats exposed to 48.0 mg/kg/day 

bromodichloromethane for 10 months (McDorman et al. 2003).

2.19 CANCER

Information on the carcinogenicity of bromodichloromethane is limited to oral exposure studies in 

humans and animals. Numerous epidemiological studies indicate that there may be an association 

between ingestion of chlorinated drinking water (which typically contains bromodichloromethane) and 

increased risk of cancer in humans (e.g., Cantor et al. 1998; Gottlieb et al. 1981; Kanarek and Young 

1982; Marienfeld et al. 1986), but such studies cannot provide information on whether any effects 

observed are due to bromodichloromethane or to one or more of the hundreds of other byproducts that are 

also present in chlorinated water. Three studies (Bove et al. 2007; Jones et al. 2019; Min and Min 2016)

evaluated risk by individual trihalomethane. No associations were found between bromodichloromethane 

levels in public water supplies and rectal cancer risk (Bove et al. 2007) or between whole blood bromodichloromethane levels and total cancer deaths (Min and Min 2016). The third study (Jones et al. 2019) 

found an association between bromodichloromethane levels in municipal water and an increased risk of 

rectal cancer, but no association with colon cancer.

Several chronic oral studies in laboratory animals have examined the carcinogenic potential of bromodichloromethane. Gavage exposure studies have found significant increases in the incidence of neoplastic 
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lesions in rats and mice. Administration of bromodichloromethane in corn oil for 2 years resulted in 

increases in the incidence of adenocarcinomas in the large intestine of male rats administered 50 mg/kg 

and male and female rats administered 100 mg/kg (NTP 1987). Increases in the incidences of renal 

tubular cell adenocarcinomas and/or combined incidence of adenoma and adenocarcinomas were 

observed in male and female rats at 100 mg/kg (NTP 1987) and in male mice administered 50 mg/kg 

(NTP 1987). In female mice, increases in the incidences of hepatocellular adenomas and/or carcinomas 

were observed at 75 and 150 mg/kg (NTP 1987). Tumasonis et al. (1985) also reported a significant 

increase in hepatic neoplastic nodules (no additional information was provided) in female rats exposed to 

190 mg/kg/day bromodichloromethane in drinking water over a lifetime. Increases in the incidence of 

skin squamous cell papilloma and/or carcinoma were observed in male rats administered 50 mg/kg, but 

not at 100 mg/kg or in females at either dose (NTP 1987). Drinking water studies testing lower doses 

(≤36.3 mg/kg/day in rats and ≤43.3 mg/kg/day in mice) did not find dose-related increases in neoplastic 

lesions (George et al. 2002; NTP 2006); one study (George et al. 2002) found a significant increase in 

hepatocellular adenomas and carcinomas in male rats exposed to 3.9 mg/kg/day, but not in groups 

exposed to 20.6 or 36.3 mg/kg/day. Another study did not find significant increases in neoplastic lesions 

in male and female rats exposed to doses as high as 138.0 or 168.4 mg/kg/day, respectively, bromodichloromethane microencapsulated and added to the diet (Aida et al. 1992).

NTP (2006) explored possible differences in organ dosimetry between drinking water or dietary 

administration and gavage administration using physiologically based pharmacokinetic (PBPK) modeling 

to predict neoplasm incidences in the kidney and large intestine in rats exposed to bromodichloromethane 

in drinking water. Given the water concentrations used, the model predicted kidney cancer rates of <1%, 

which is consistent with the empirical incidence of 0/50 in the NTP (2006) drinking water study, 

suggesting that the difference between the 1987 and 2006 studies was due to organ dosimetry. However, 

predicted incidences of large intestine neoplasms (3.5–10% depending on the dose metric used) were 

higher than the observed incidences (2% at 12 mg/kg/day and 0% at 6 and 25 mg/kg/day). NTP (2006) 

noted that the difference in large intestine tumors between the studies may have also been due to 

differences in fiber content of the diet used in each study (higher fiber content in the 2006 study compared 

to the 1987 study).

NTP, EPA, and IARC have classified bromodichloromethane as reasonably anticipated to be a human 

carcinogen (NTP 2016), a probable human carcinogen (Group B2) (IRIS 2002), or possibly carcinogenic 

to humans (Group 2B) (IARC 2016), respectively. The cancer classifications are based on inadequate 

data in humans and sufficient evidence in animal studies.
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2.20 GENOTOXICITY

This section is divided into two subsections. The first subsection discusses the results of in vitro and 

in vivo studies evaluating the genotoxicity of bromodichloromethane. The second subsection presents the 

results of in vivo studies evaluating epigenetic DNA alterations.

Genotoxicity. Bromodichloromethane has displayed mixed results for genotoxic activity in a variety of in 

vivo and in vitro tests with organisms ranging from bacteria to humans. As summarized in Table 2-4, 

bromodichloromethane produced mixed results in gene mutation studies using Salmonella typhimurium 

(Mortelmans et al. 1986; NTP 1987; Simmon et al. 1977; Sofuni et al. 1996; Varma et al. 1988; Zeiger 

1990). Negative results were reported with and without metabolic activation in three studies (Mortelmans 

et al. 1986; NTP 1987; Zeiger 1990). Varma et al. (1988) reported positive results with metabolic 

activation in two strains and with or without activation in another two strains; Simmon et al. (1977) also 

reported an increase in gene mutations when tested with metabolic activation, but only when the assay 

was performed under a desiccator. Inconclusive results were reported by Sofuni et al. (1996), as only one 

study out of three produced an increased mutation frequency in the presence of activation only. A weakly 

positive result was reported in Saccharomyces cerevisiae in the absence of metabolic activation only 

(Nestmann and Lee 1985). Positive results for gene mutations were also found in mouse lymphoma cells 

with metabolic activation (McGregor et al. 1988; NTP 1987).

Table 2-4. Genotoxicity of Bromodichloromethane In Vitro

Results

Species (test system) Endpoint

Activation

With Without Reference

Salmonella typhimurium (TA98, 

TA100, TA1535, TA1537)

Gene mutation – – NTP 1987

S. typhimurium (strains not 

reported)

Gene mutation (+)a – Sofuni et al. 1996

S. typhimurium (TA1535, 

TA1537)

Gene mutation + + Varma et al. 1988

S. typhimurium (TA98, TA100) Gene mutation + – Varma et al. 1988

S. typhimurium (strains not 

reported)

Gene mutation – – Zeiger 1990

S. typhimurium (TA100) Gene mutation No data +b Simmon et al. 1977

S. typhimurium (TA97, TA98, 

TA100, TA1535, TA1537)

Gene mutation No data - Mortelmans et al. 

1986
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Table 2-4. Genotoxicity of Bromodichloromethane In Vitro

Results

Species (test system) Endpoint

Activation

With Without Reference

Saccharomyces cerevisiae

(XVI85-14C reversion; D7 gene 

conversion)

Gene mutation – (+) Nestmann and Lee 

1985

Mouse lymphoma Gene mutation + – NTP 1987

Mouse lymphoma Gene mutation + – McGregor et al. 

1988

Human hepatoma (HepG2) cells DNA damage (OTM) No data + Zhang et al. 2012

Human lymphoblastic leukemia 

cells (CCRF-CEM)

DNA damage (single 

strand breaks)

No data + Geter et al. 2004

Rat primary hepatocytes DNA damage (single 

strand breaks)

No data – Geter et al. 2004

Human primary kidney cells DNA damage (single 

strand breaks)

No data + Robbiano et al. 

2004

Rat primary kidney cells DNA damage (single 

strand breaks)

No data + Robbiano et al. 

2004

Human primary kidney cells Micronucleus test No data + Robbiano et al. 

2004

Rat primary kidney cells Micronucleus test No data + Robbiano et al. 

2004

CHL cells Chromosomal 

aberrations

+ – Ishidate et al.1988

CHL cells Chromosomal 

aberrations

+ (+) Matsuoka et al. 

1996

CHO cells Chromosomal 

aberrations, sister 

chromatid exchange

– – NTP 1987

CHO cells Chromosomal 

aberrations, sister 

chromatid exchange

– – Anderson et al. 

1990

Rat erythroblastic leukemia cells Sister chromatid 

exchanges

– + Fujie et al. 1993

Human lymphocytes Sister chromatid 

exchange

NA – Morimoto and 

Koizumi 1983; 

Tucker et al. 1993

aResults were only positive in assays conducted by one of three laboratories.

bResults were positive when assay was conducted in a desiccator; results were negative when tested in standard 

assay.

+ = positive results; (+) = weakly positive results; – = negative results; BDCM = bromodichloromethane; 

CHO = Chinese hamster ovary; CHL = Chinese hamster lung; NA: not applicable; OTM = olive tail moment
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DNA damage was observed in human cell lines (Geter et al. 2004; Zhang et al. 2012), rat hepatocytes 

(Geter et al. 2004), and human and rat kidney cells (Robbiano et al. 2004), all tested without metabolic 

activation. A toxicogenomic genotoxicity assay using S. cerevisiae provided evidence of DNA damage 

(Lan et al. 2018). Inconsistent results have been found in clastogenicity assays. Increases in micronuclei 

formation were observed in human and rat kidney cells (Robbiano et al. 2004). Four studies found 

negative results for chromosomal aberrations and/or sister chromatid exchanges (Anderson et al. 1990; 

Morimoto and Koizumi 1983; NTP 1987; Tucker et al. 1993). However, other studies have found 

positive results for chromosomal aberrations (Ishidate et al. 1988; Matsuoka et al. 1996) or sister 

chromatid exchanges (Fujie et al. 1993).

The in vivo genotoxicity of bromodichloromethane has been evaluated in humans, rats, and mice 

(Table 2-5). In a human study, a 1 μg/m3 increase in bromodichloromethane levels in expired air was 

associated with an increase in frequency of micronucleated peripheral blood lymphocytes; however, 

bromodichloromethane only accounted for 10% of the increase in micronuclei formation (Kogevinas et al. 

2010). No significant associations were found for micronuclei formation in exfoliated urothelial cells 

(assessed 2 weeks postexposure), DNA damage in peripheral blood lymphocytes, or reverse mutations in 

a urine mutagenicity assay (Kogevinas et al. 2010). 

Table 2-5. Genotoxicity of Bromodichloromethane In Vivo

Species (exposure route) Endpoint Results Reference

Human (urine samples evaluated 

in Salmonella assay)

Reverse mutations (Ames 

assay)

– Kogevinas et al. 2010

Human (peripheral blood 

lymphocytes; whole-body 

exposure in indoor pool)

DNA damage (comet assay) – Kogevinas et al. 2010

Rat (single gavage dose of 0.3 or 

0.6 mM/kg in deionized water or 

0.25% emulphor; 0.6–2.4 g/L in 

drinking water for 2 or 5 weeks)

DNA damage (single strand 

breaks)

– Geter et al. 2004

Rat (single gavage dose of 

1.5 mmol/kg in 4% emulphor)

DNA damage (single strand 

breaks)

– Potter et al. 1996

Rat (single gavage dose of 

458 mg/kg)

DNA damage in kidney cells 

(single strand breaks)

+ Robbiano et al. 2004

Rat (single gavage dose of 

135 or 450 mg/kg in 

methylcellulose)

Unscheduled DNA 

synthesis in liver cells

– Stocker et al. 1997

Human (peripheral blood 

lymphocytes; whole-body 

exposure in indoor pool)

Micronucleus test + Kogevinas et al. 2010
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Table 2-5. Genotoxicity of Bromodichloromethane In Vivo

Species (exposure route) Endpoint Results Reference

Human (exfoliated urothelial 

cells; whole-body exposure in 

indoor pool)

Micronucleus test – Kogevinas et al. 2010

Rat (single gavage dose of 

458 mg/kg)

Micronucleus test in kidney 

cells

+ Robbiano et al. 2004

Mouse (inhalation exposure to 1–

150 ppm 6 hour/day for 7 days or 

0.5–30 ppm 6 hours/day, 

7 days/week for 3 weeks) 

Micronucleus test in bone 

marrow and peripheral 

blood

(+) Torti et al. 2002

Rat (bone marrow; 

intraperitoneal)

Chromosomal aberrations + Fujie et al. 1990

Rat (bone marrow; gavage in 

water)

Chromosomal aberrations (+) Fujie et al. 1990

Mouse (50 or 100 mg/kg/day via 

gavage in corn oil for 4 days)

Sister chromatid exchange 

in bone marrow cells 

+ Morimoto and Koizumi 1983; 

Tucker et al. 1993

– = negative result; + = positive result; (+) = weakly positive results

Inconsistent results have been found in studies examining the potential of bromodichloromethane to cause 

DNA damage. Although Robbiano et al. (2004) found a significant increase in single strand breaks in 

kidney cells of rats administered a single dose of bromodichloromethane; studies by Geter et al. (2004) 

and Potter et al. (1996) did not find increases in kidney, liver, or duodenum epithelial cells of rats 

following single dose or repeated oral exposure. No increases in unscheduled DNA activity were 

observed in the livers of rats administered a single gavage dose of bromodichloromethane (Stocker et al. 

1997). In general, positive results have been observed in several studies evaluating bromodichloromethane-induced clastogenic alterations. A weak induction of micronuclei was observed in mature red 

blood cells of mice exposed to 15 ppm bromodichloromethane vapor for 13 weeks (Torti et al. 2002). A 

significant increase in micronuclei in bone marrow cells was also observed in mice exposed to 100 ppm 

for 1 week, but the increase was not statistically significant at the next highest concentration (150 ppm); 

no significant increases in bone marrow nuclei were observed following a 3-week exposure to ≤15 ppm 

(Torti et al. 2002). Significant increases in micronuclei formation were also observed in kidney cells of 

rats administered via gavage 458 mg/kg bromodichloromethane (Robbiano et al. 2004). A dose-related 

increase in the frequency of chromosomal aberrations was observed in bone marrow cells of rats 

administered bromodichloromethane via intraperitoneal injection (Fujie et al. 1990); a weakly positive 

result was also reported in this study for rats receiving bromodichloromethane via gavage for 5 days. 

Increases in the frequency of sister chromatic exchanges were observed in mice administered bromodichloromethane for 4 days (Morimoto and Koizumi 1983). Although there are inconsistencies in the 
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findings, overall the available data provide suggestive evidence that bromodichloromethane has the 

potential to damage DNA and chromosomes. 

Epigenetic DNA Alterations. Two studies evaluated the potential of bromodichloromethane to induce 

epigenetic DNA alterations. A study of pregnant women found no associations between maternal blood 

bromodichloromethane levels (measured in late pregnancy) and DNA methylation in Alu and long 

interspersed nucleotide element-1 repetitive elements in cord blood after adjustments for prenatal body 

mass index (BMI), infant sex, passive smoking, and marital status (Yang et al. 2017). A second study 

(Tao et al. 2005) found significant reductions in DNA methylation in renal cells of mice administered 

bromodichloromethane via gavage in corn oil or in drinking water and rats administered bromodichloromethane via gavage (Tao et al. 2005). The decreases in DNA methylation were dose-related.
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BIOMARKERS, CHEMICAL INTERACTIONS

3.1 TOXICOKINETICS 

No studies were located regarding bromodichloromethane toxicokinetics in humans, but there are limited 

data from studies in animals. These data are summarized below.

• Bromodichloromethane is rapidly absorbed through the gastrointestinal tract and skin and is 

presumed to be rapidly absorbed through the respiratory tract.

• Absorbed bromodichloromethane is distributed throughout the body with the highest 

concentrations found in the fat, liver, lungs, and kidneys. 

• The predominant pathway for bromodichloromethane metabolism is cytochrome P450 oxidation. 

Bromodichloromethane can also be metabolized via reduction to a dichloromethyl radical or 

glutathione conjugation catalyzed by glutathione transferase.

• Bromodichloromethane is rapidly excreted; the half-life following a single oral dose was 1.5–

2.5 hours in rats and mice. The major route of excretion is expiration of the parent compound or 

carbon dioxide in exhaled air; smaller amounts of bromodichloromethane are excreted in the 

urine and feces.

3.1.1 Absorption 

There are limited data on the bromodichloromethane absorption following inhalation exposure. Based on 

its physical-chemical properties and by analogy to another trihalomethane (chloroform) (ATSDR 1997), it 

is assumed that bromodichloromethane will be well absorbed.

Direct evidence of oral and dermal absorption of bromodichloromethane in humans comes from studies 

measuring blood levels of bromodichloromethane following ingestion or dermal exposure to 

bromodichloromethane (Leavens et al. 2007) or following ingestion, bathing, or showering with tap water 

containing trihalomethanes, including bromodichloromethane (Backer et al. 2000; Lynberg et al. 2001). 

Following oral exposure, bromodichloromethane is rapidly absorbed with peak blood levels of 

13C-bromodichloromethane occurring 11 minutes after exposure (Leavens et al. 2007). Following a 

1-hour dermal exposure, peak blood levels were observed at the end of the exposure, also suggesting that 

it is rapidly absorbed through the skin (Leavens et al. 2007).
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Animal studies support the findings in humans that bromodichloromethane is rapidly absorbed following 

oral exposure (Aida et al. 1989; da Silva et al. 1999, 2000; Lilly et al. 1998; Mink et al. 1986; NTP 2006; 

Smith et al. 1985). In rats, peak blood levels were found 5–15 minutes (NTP 2006) or approximately 

30 minutes (da Silva et al. 1999, 2000) after gavage administration. In contrast, a monkey study reported 

peak blood levels 4 hours after a gavage dose (Smith et al. 1985). Although studies have not quantified 

percent absorption, Mink et al. (1986) reported 62.7 and 92.7% recovery of radiolabeled bromodichloromethane in expired air, urine, and internal organs of rats and mice, respectively. Several animal studies 

found vehicle-specific differences in absorption rates. Mathews et al. (1990) found that 87–94% of 

radioactivity was excreted within 24 hours of single administration of 1–100 mg/kg bromodichloromethane. Lilly et al. (1998) and NTP (2006) found a more rapid initial uptake of bromodichloromethane 

dissolved in an aqueous solution than when it was dissolved in corn oil. Bromodichloromethane in olive 

oil administered via gavage was more rapidly absorbed than when the bromodichloromethane was 

dissolved in olive oil, microencapsulated, and added to the diet (Aida et al. 1989). 

3.1.2 Distribution 

Absorbed bromodichloromethane is distributed throughout the body. Six hours after a single intravenous 

administration of 10 mg/kg [14C]-bromodichloromethane in rats, the highest percentage of radioactivity is 

found in the fat, followed by muscle, liver, skin, blood, small intestine, and kidneys (Smith et al. 1985). 

In contrast, the highest percentage of radioactivity in rats after a single gavage dose is found in the 

stomach, followed by the liver, fat, muscle, small intestine, blood, skin, and kidney (Smith et al. 1985). 

Only a small amount of radioactivity was measured 24 hours after rats received a single gavage dose of 1, 

10, or 100 mg/kg [14C]-bromodichloromethane. When tissue levels of radioactivity are compared based 

on tissue to blood ratios (see Table 3-1), the highest levels were found in the liver, kidney, stomach, small 

intestine, and large intestine (Mathews et al. 1990). Single administration studies found differences in the 

liver:blood ratios with the highest ratios present in rats administered 1 mg/kg as compared to 100 mg/kg. 

No evidence of bioaccumulation of radioactivity was observed in rats administered 10 or 100 mg/kg/day 

for 10 days. Mathews et al. (1990) examined the kidney and small intestines to examine the relative 

distribution between different regions. In the kidneys, 6–8 times higher levels of radioactivity were 

detected in the cortex, as compared to the medulla. No significant differences in radioactivity levels were 

found between the duodenum, jejunum, and ileum. Although no studies were located regarding 

distribution following inhalation or dermal exposure, it is expected to be similar to that of oral exposure 

based on the similarity of the distribution following intravenous and oral exposure (Smith et al. 1985).
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Table 3-1. Tissue to Blood Ratios of Radioactivity 24-Hours After Gavage 

Administration of [14C]-Bromodichloromethane to Male Ratsa

Single administration 10-Day administration

1 mg/kg 10 mg/kg 100 mg/kg 10 mg/kg/day 100 mg/kg/day

Adipose 0.83 0.42 0.68 1.01 1.99

Large intestine 3.33 2.30 2.89 1.74 3.03

Small intestine 3.71 2.91 2.45 1.91 3.18

Kidney 4.93 5.98 8.2 6.51 13.64

Liver 44.46 20.05 11.41 14.30 14.72

Muscle 2.38 1.99 1.56 0.59 1.14

Skin 1.28 0.94 0.90 1.23 2.21

Stomach 4.21 3.31 8.33 2.01 2.99

aData from Mathews et al. (1990).

Batterman et al. (2002), Kenyon et al. (2016), and Lilly et al. (1997) determined partition coefficients for 

bromodichloromethane. In humans, blood:air, blood:urine, and milk:blood partition coefficients of 26.6, 

4.13, and 1.26 were calculated (Batterman et al. 2002); Kenyon et al. (2016) estimated blood:air partition 

coefficients of 17.33 and 14.61 for male and female, respectively. A blood:air partition coefficient of 

31.4 was calculated for rats (Lilly et al. 1997).

3.1.3 Metabolism 

Three pathways have been identified for the metabolism of bromodichloromethane: (1) cytochrome P450 

oxidation to phosgene (Allis and Zhao 2002; Allis et al. 2002; NTP 2006; Lilly et al. 1997; Mathews et al. 

1990; Zhao and Allis 2002); (2) reduction to dichloromethyl radical (Lilly et al. 1997; Tomasi et al. 

1985); and (3) glutathione conjugation (NTP 2006; Ross and Pegram 2003). 

The predominant pathway is oxidation catalyzed by cytochrome P450. In vivo studies have identified 

four cytochrome P450 isozymes that are responsible for metabolizing bromodichloromethane in rats: 

CYP2E1, CYP2B1/2, CYP1A2, and CYP3A1 (Allis and Zhao 2002). Four isozymes are involved in 

humans: CYP2E1, CYP1A2, CYP2A6, and CYP3A4 (Allis and Zhao 2002). In vitro studies by these 

investigators showed that 90 and 60% of bromodichloromethane is metabolized by CYP2E1 in rats and 

humans, respectively; in humans, CYP3A4 accounts for most of the rest of the cytochrome metabolism. 

Oxidation of bromodichloromethane via CYP2E1 results in the formation of phosgene, which hydrolyzes 

to produce carbon dioxide (Allis and Zhao 2002; Lilly et al. 1997; Mathews et al. 1990). PBPK modeling 
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estimates that following oral exposure to bromodichloromethane approximately 97% of the metabolism 

occurs in the liver; approximately 90% of total metabolism occurs on the first pass through the liver (NTP 

2006). Cytochrome P450 oxidation accounts for 99% of the bromodichloromethane metabolism in the 

liver and 84–88% of the metabolism in the kidney and colon. Cytochrome P450 oxidation in the liver is 

also the primary metabolism pathway following inhalation exposure to bromodichloromethane (Allis et 

al. 2001). Several studies have shown that as the bromodichloromethane exposure level increases, the 

percentage of metabolism due to CYP2E1 decreases (Allis and Zhao 2002; Zhao and Allis 2002). 

Although the metabolism of bromodichloromethane via glutathione conjugation catalyzed by glutathione 

transferase (GST) is quantitatively minor, the reactive metabolites formed may be toxicologically 

significant (Ross and Pegram 2003). In humans and rodents, the primary glutathione transferase isoform 

involved in bromodichloromethane metabolism is glutathione transferase theta 1-1 (GST T1-1) (Leavens 

et al. 2007; Ross and Pegram 2003). The GST T1-1 reactive metabolites are unstable, react with 

biomolecules near the site of generation, and have not been detected in circulation (Leavens et al. 2007). 

The reactive glutathione conjugates may result in the formation of DNA adducts (Ross and Pegram 2003). 

Using PBPK modeling, NTP (2006) analyzed the relative contribution of cytochrome P450 and GST 

metabolism in the liver, kidney, and colon in rats following oral exposure to bromodichloromethane. The 

ratios of cytochrome P450/GST were 95, 6.9, and 6.0 in the liver, kidney, and colon following 

administration of 50 mg/kg. Following administration of 100 mg/kg, the ratios were 77, 7.1, and 5.3, 

respectively. The dose-related changes are likely due to first pass cytochrome P450 saturation in the liver 

and the higher levels of bromodichloromethane in the blood and availability to other tissues.

3.1.4 Excretion 

The major route of excretion of bromodichloromethane in rats, mice, and monkeys is exhaled alveolar air, 

either as parent bromodichloromethane, or as volatile metabolites such as carbon dioxide (Mathews et al. 

1990; Mink et al. 1986; Smith et al. 1985). Small amounts are excreted in the urine and feces. Twentyfour hours after a single exposure to 1, 10, or 100 mg/kg [14C]-bromodichloromethane, 71–82% of the 

radiolabel was expired as carbon dioxide, 3–5% as carbon monoxide, and 3–6% as expired volatiles 

(Mathews et al. 1990). Urinary and fecal excretion accounted for 4 and 0.7–3%, respectively, of the 

excreted radiolabel (Mathews et al. 1990). Similar excretion patterns were observed in another study of 

rats (Mink et al. 1986), a study in mice (Mink et al. 1986), and a study in monkeys (Smith et al. 1985). 
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No route-specific differences in excretion patterns were observed in monkeys administered bromodichloromethane via gavage or intravenous injection (Smith et al. 1985).

The half-lives of bromodichloromethane in rats and mice following a single oral administration 

(100 mg/kg and 150, respectively) were estimated to be 1.5 and 2.5 hours, respectively (Mink et al. 1986), 

and the half-life in monkeys was 4–8 hours (Smith et al. 1985). This indicates that bromodichloromethane is effectively excreted and that tissue accumulation of bromodichloromethane is unlikely.

In a repeated-dose gavage study in rats (Mathews et al. 1990), the daily excretion of radiolabel 

(approximately 75%) did not change over the course of the 10-day administration of 10 mg/kg/day. 

However, administration of 100 mg/kg/day resulted in expiration of 30% of the radiolabel as carbon 

dioxide during the 8 hours after administration on day 1. On days 2–10, 60% of the label was expired as 

carbon dioxide. 

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. 

Single species PBPK models have been developed for bromodichloromethane; however, a PBPK model 

that could be used to extrapolate from laboratory animals to humans for risk assessment has not been 

identified for this chemical. Kenyon et al. (2016) developed a human PBPK model that allows for the 

assessment of the contribution of multiple exposure routes (inhalation, oral, and dermal) to overall 

internal dose metrics for bromodichloromethane. The model predicts that dermal exposure and inhalation 

exposure during bathing will substantially contribute to the overall internal dose of bromodichloromethane. Lilly and associates developed a PBPK model in rats that allows predictions of tissue 

distribution and metabolism following inhalation (Lilly et al. 1997) or gavage administration with an oil 

or aqueous vehicle (Lilly et al. 1998). The model consists of five compartments (liver, kidney, fat, slowly 
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perfused tissues, and rapidly perfused tissues) and assumes that 95% of bromodichloromethane 

metabolism occurs in the liver and the remaining 5% occurs in the kidney. 

3.1.6 Animal-to-Human Extrapolations 

No studies were identified that provide evidence to suggest differences in the toxicity or toxicokinetics of 

bromodichloromethane between humans and animals. There are limited human toxicology studies that do 

not allow for a comparison to rat and mouse toxicity studies. Some species differences have been noted 

between rats and mice, although the targets of toxicity appear to be similar. The available data suggest 

that the toxicity of bromodichloromethane is mediated by its reactive metabolites which are most likely 

formed by cytochrome P450 isoforms, particularly CYP2E1 (Allis and Zhao 2002; Lilly et al. 1997, 

1998). CYP2E1 in rats is closely related to human CYP2E1 (Allis and Zhao 2002). Other P450 isoforms 

may also play an important role in bromodichloromethane metabolism at low concentrations; these 

isoforms differ in humans and rats (Allis and Zhao 2002; Zhao and Allis 2002); however, the contribution 

of other isoforms to the overall bromodichloromethane metabolism is not known. 

3.2 CHILDREN AND OTHER POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans. Potential effects on offspring resulting from exposures of parental 

germ cells are considered, as well as any indirect effects on the fetus and neonate resulting from maternal 

exposure during gestation and lactation. Children may be more or less susceptible than adults to health 

effects from exposure to hazardous substances and the relationship may change with developmental age. 

This section also discusses unusually susceptible populations. A susceptible population may exhibit 

different or enhanced responses to certain chemicals than most persons exposed to the same level of these 

chemicals in the environment. Factors involved with increased susceptibility may include genetic 

makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). 

These parameters can reduce detoxification or excretion or compromise organ function. 

Populations at greater exposure risk to unusually high exposure levels to bromodichloromethane are 

discussed in Section 5.7, Populations with Potentially High Exposures.
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There are limited data on the toxicity of bromodichloromethane in children and the toxicity of 

bromodichloromethane is assumed to be similar to adults. As discussed in Section 2.16, gestational 

exposure to bromodichloromethane has resulted in full-litter resorption and delays in skeletal ossification 

in rats (Bielmeier et al. 2001; Christian et al. 2001a; Narotsky et al. 1997; Ruddick et al. 1983) and 

decreases in birth weight (Wright et al. 2004; Rivera-Núñez and Wright 2013) and increases in stillbirths 

or spontaneous abortions (King et al. 2000; Waller et al. 1998) in humans. No human or animal studies 

assessed the risks associated with childhood exposures. Animal data provide strong evidence that the 

liver is one of the critical targets of toxicity for bromodichloromethane (see Section 2.9 for details); 

mechanistic data suggest that a reactive metabolite is the causative agent. In rats (and humans), 

bromodichloromethane is primarily metabolized in the liver by the cytochrome P450 isoform CYP2E1 

(Allis and Zhao 2002). As discussed in EPA (2005b), CYP2E1 levels rapidly increase during the first 

24 hours after birth and the levels in children aged 1–10 years are similar to adults. A study evaluating 

human hepatic CYP2E1 expression during development found that CYP2E1 levels increased with age 

(Johnsrud et al. 2003). At 0–30 days of age, the median levels were approximately half that of infants 

31–90 days of age and approximately 4 times lower than at age 91 days to 18 years. The lower levels of 

CYP2E1 may result in increased susceptibility of very young infants. Using the Kenyon et al. (2016) 

PBPK model, Kenyon et al. (2019) demonstrated that extrahepatic levels of bromodichloromethane were 

higher in neonates and infants, as compared to adults.

Persons with existing renal or hepatic disease might also be more susceptible, since these organs are 

adversely affected by exposure to bromodichloromethane. The elderly may represent an unusually 

susceptible population because they may have age-related deficiencies of liver and kidney function. They 

may also be frequently exposed to metabolism-influencing medications.

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 
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exposure to bromodichloromethane are discussed in Section 3.3.1. The National Report on Human 

Exposure to Environmental Chemicals provides an ongoing assessment of the exposure of a generalizable 

sample of the U.S. population to environmental chemicals using biomonitoring (see http://www.cdc.gov/

exposurereport/). If available, biomonitoring data for bromodichloromethane 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 bromodichloromethane 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

Human studies have identified blood, alveolar air, and urine levels of bromodichloromethane as 

biomarkers of exposure. Since bromodichloromethane is rapidly excreted, these biomarkers assess recent 

exposure. A number of human studies have found associations between exposure to 

bromodichloromethane in tap water (Backer et al. 2000; Lynberg et al. 2001; Nuckols et al. 2005; 

Riederer et al. 2014; Rivera-Núñez et al. 2012) and blood bromodichloromethane levels. In 2015–2016, 

the geometric median blood bromodichloromethane level in the United States was below the detection 

limit of 6.00 pg/mL (CDC 2019); see Section 5.6 for a more detailed presentation of the NHANES 

biomonitoring data. Lynberg et al. (2001) reported that blood bromodichloromethane levels were 

approximately 1,000-fold lower than the bromodichloromethane level in a resident’s tap water. Exposure 

to bromodichloromethane in tap water can occur via multiple routes of exposure from several daily 

activities including consumption of tap water, showering, and bathing. A study comparing the relative 
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contribution of different activities found the highest levels of blood bromodichloromethane in subjects 

showering for 10 minutes, as compared to those bathing for 10 minutes or drinking 1 L of water in 

10 minutes (Backer et al. 2000). A more detailed analysis of water use activity and bromodichloromethane blood levels found increases in blood levels associated with showering, bathing, and hand dish 

washing, but not with consumption of hot or cold beverages, clothes washing, or hand washing (Nuckols 

et al. 2005). Bromodichloromethane levels increased approximately 7–16-, 8.2–12-, or 3-fold after 

showering, bathing, or hand dish washing, respectively. Using NHANES 1999–2006 data, Riederer et al. 

(2014) examined predictors of blood bromodichloromethane levels. Water concentration was one of the 

major predictors of blood levels. Other factors that were negatively associated with blood bromodichloromethane levels included diabetes and eating cruciferous vegetables. Backer et al. (2000) examined 

the possible association of polymorphisms and bromodichloromethane blood levels. A significant 

association was found for the CYP2D6 *4/*4 enzyme variant (decreased metabolizing activity).

Studies of pool workers and swimmers report increases in bromodichloromethane levels in alveolar air 

(Aggazzotti et al. 1998; Caro and Gallego 2007, 2008; Lindstrom et al. 1997; Pleil and Linstrom 1997). 

Alveolar air bromodichloromethane levels increased rapidly during the entire 1–2 hours exposure period 

(Caro and Gallego 2008). Alveolar air levels rapidly declined and returned to pre-exposure levels within 

1 hour post-exposure (Aggazzotti et al. 1998; Caro and Gallego 2008). One study estimated a half-life of 

26 minutes (Caro and Gallego 2008). Pleil and Lindstrom (1997) estimated a half-time of 0.45–

0.63 minutes in blood based on alveolar elimination in swimmers exposed for 2 hours.

Studies in pool workers and swimmers have also established urinary bromodichloromethane as a 

biomarker of exposure (Caro and Gallego 2007, 2008). Urinary bromodichloromethane levels increased 

1.8 times in workers at an indoor pool for 2 hours and 2.5 times in workers near the pool for 4 hours 

(Caro and Gallego 2007). Much higher increases in urinary bromodichloromethane were found in 

swimmers; a 3–4-fold increase in levels were observed following a 1-hour swim, suggesting that 

increased ventilation rate and dermal exposure increased the amount of bromodichloromethane absorbed. 

A half-time for bromodichloromethane in urine was estimated to be 45 minutes (Caro and Gallego 2008).

3.3.2 Biomarkers of Effect

There are no specific biomarkers to characterize the effects caused by bromodichloromethane. The 

available evidence suggests that the hepatotoxicity of bromodichloromethane is likely due to oxidative 

damage from reactive intermediates. Measurement of biomarkers of oxidative stress such as glutathione 
BROMODICHLOROMETHANE 86

3. TOXICOKINETICS, SUSCEPTIBLE POPULATIONS, BIOMARKERS, CHEMICAL INTERACTIONS

and oxidative response agents such as NrF2 could be indicative of liver toxicity. However, measurement 

of these agents would not be specific to bromodichloromethane.

3.4 INTERACTIONS WITH OTHER CHEMICALS

Hewitt et al. (1983) reported that pretreatment of rats with an oral dose of acetone increased the hepatic 

and renal toxicity of an oral dose of bromodichloromethane given 18 hours later, as evidenced by 

increased relative liver weight, increased serum alanine aminotransferase and aspartate aminotransferase 

activities, increases in relative kidney weight, and increases in blood urea nitrogen levels, as compared to 

rats pretreated with water.

Several studies have examined toxicokinetic interactions between bromodichloromethane and other 

trihalomethanes and chloroacetic acids. The blood area under the curve (AUC) obtained in rats receiving 

a single gavage dose of 0.25 mmol/kg bromodichloromethane was significantly lower than the AUC 

when bromodichloromethane was administered with three other trihalomethanes (chloroform, 

dibromochloromethane, and bromoform, 0.25 mmol/kg of each compound); the AUC was 8.15 times 

higher when administered with other trihalomethanes (da Silva et al. 1999). The investigators suggested 

that this may be due to metabolic interactions between the compounds. Similar results were found when 

binary mixtures of trihalomethanes were tested (da Silva et al. 2000). Co-administration via intravenous 

injection of bromodichloromethane with trichloroacetic acid or monochloroacetic acid also resulted in 

higher blood bromodichloromethane levels (St. Pierre et al. 2003). In vitro studies demonstrated that the 

increases in bromodichloromethane blood levels were due to metabolic inhibition by other 

trihalomethanes or trichloroacetic acid (St. Pierre et al. 2005). 
BROMODICHLOROMETHANE 87

CHAPTER 4. CHEMICAL AND PHYSICAL INFORMATION

4.1 CHEMICAL IDENTITY

Bromodichloromethane is a trihalomethane with one bromide atom and two chloride atoms. It is a

colorless liquid with relatively high vapor pressure and high water solubility. It was previously used as a 

halogenated fire retardant. Bromodichloromethane is a disinfection byproduct formed during the 

chlorination of waters. 

Table 4-1 lists common synonyms, trade names, and other pertinent identification information for bromodichloromethane.

Table 4-1. Chemical Identity of Bromodichloromethane

Characteristic Information Reference

Chemical name Bromodichloromethane HSDB 2012

Synonym(s) and registered 

trade name(s)

Dichlorobromomethane; BDCM; 

monobromodichloromethane; 

methane, bromodichloro-; 

Halon 1021

HSDB 2012; NIOSH 2015

Chemical formula CHBrCl2 HSDB 2012

Chemical structure Haynes 2014

CAS Registry Number 75-27-4 HSDB 2012

CAS = Chemical Abstracts Service 

4.2 PHYSICAL AND CHEMICAL PROPERTIES

Table 4-2 lists important physical and chemical properties of bromodichloromethane.

Cl C

Br

Cl

H
BROMODICHLOROMETHANE 88

4. CHEMICAL AND PHYSICAL INFORMATION

Table 4-2. Physical and Chemical Properties of Bromodichloromethane

Property Information Reference

Molecular weight 163.829 Haynes 2014

Color Colorless O’Neil 2013

Physical state Liquid O’Neil 2013

Melting point -56.0°C Haynes 2014

Boiling point 90°C Haynes 2014

Density: Haynes 2014

at 20°C/4°C 1.980

Odor No data

Odor threshold:

Water No data

Air No data

Taste threshold No data

Solubility:

Water 3,030 mg/L at 30°C Yalkowsky et al. 2010

Organic solvent(s) Very soluble in ethanol, acetone, and 

benzene; slightly soluble in carbon 

tetrachloride 

Haynes 2014

Partition coefficients:

Log Kow 2.00 HSDB 2012

Log Koc 1.8 Mabey et al. 1982

Vapor pressure 

at 20°C 50 mm Hg HSDB 2012

Henry's law constant 2.12x10-3 at 25°C EPA 1987

Autoignition temperature No data 

Flashpoint No data

Flammability limits No data

Conversion factors 1 ppm=6.70 mg/m3

1 mg/m3=0.15 ppm

Verschueren 1977

Explosive limits No data
BROMODICHLOROMETHANE 89

CHAPTER 5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Bromodichloromethane has been identified in at least 238 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 bromodichloromethane has been evaluated is not known. The number of sites in 

each state is shown in Figure 5-1. Of these sites, 233 are located within the United States, 2 are located in 

the Virgin Islands, and 3 are located in Puerto Rico (not shown).

Figure 5-1. Number of NPL Sites with Bromodichloromethane Contamination

• The most likely route of exposure for the general public to bromodichloromethane is through 

ingestion, inhalation, and dermal contact of chlorinated drinking water. 

• A median bromodichloromethane intake of 2.8–4.2 μg/day from drinking water has been 

estimated; inhalation and dermal exposure would add to this daily intake.
BROMODICHLOROMETHANE 90

5. POTENTIAL FOR HUMAN EXPOSURE

• Bromodichloromethane is formed as a byproduct of water disinfection methods using 

chlorination. This is the primary source of bromodichloromethane in the environment. 

• Its principal use is as a chemical intermediate for organic synthesis and as a chemical reagent.

• Volatilization is an important fate process. Bromodichloromethane evaporates from sources and 

enters the environment as a gas, which is slowly broken down in air. Residual

bromodichloromethane may be broken down slowly by bacteria. 

• In the atmosphere, bromodichloromethane is thought to undergo slow degradation through 

oxidative pathways, with a half-life of about 2–3 months.

5.2 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

5.2.1 Production

The principal anthropogenic source of bromodichloromethane is its unintentional formation as a 

byproduct during the chlorination of water containing organic materials and bromide. It has been 

reported as the second most frequently detected trihalomethane, following chloroform, in drinking water 

(Bellar et al. 1974; EPA 2003; Krasner et al. 1989). Bromodichloromethane is formed when chlorinebased chemical disinfectants react with organic matter and bromide present in the system. The reaction is 

dependent on water quality and the treatment process used for disinfection. Factors such as organic 

matter concentration, bromide and chlorine concentration, temperature, pH, and contact time affect the 

production of byproducts during disinfection (WHO 2000). 

Synthesis of bromodichloromethane can be achieved by treating a mixture of chloroform and bromoform 

with triethylbenzylammonium chloride and sodium hydroxide (IARC 1991). Bromodichloromethane is 

produced commercially by the reaction of dichloromethane with aluminum bromide. 

No information is available in the TRI database on facilities that manufacture or process bromodichloromethane because this chemical is not required to be reported under Section 313 of the Emergency 

Planning and Community Right-to-Know Act (Title III of the Superfund Amendments and 

Reauthorization Act of 1986) (EPA 2005a).

5.2.2 Import/Export

No data on imports or exports of bromodichloromethane were located. Little, if any, of either is expected.
BROMODICHLOROMETHANE 91

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Use

In the past, bromodichloromethane has been used as a solvent for fats, waxes, and resins, as a flame 

retardant, as a heavy liquid for mineral and salt separations, and as a fire extinguisher fluid ingredient 

(USGS 2006a). At present, the principal use of bromodichloromethane is as a chemical intermediate for 

organic synthesis and as a chemical laboratory reagent, particularly as a standard in the analysis of 

drinking water (IARC 1991; O’Neil 2013; Sittig 1985; Verschueren 1983). Bromodichloromethane is not 

listed as an ingredient in fire extinguishers or solvents as of April 2017, but it is listed as a possible 

colorant constituent in dyes and pigments as well as a polar organic compound in fragrances of consumer 

products; it may be used in pesticides or fracking practices, and it is a component of several water 

standard kits (Dionisio et al. 2015; EPA 2014a).

5.2.4 Disposal

Bromodichloromethane is categorized as a hazardous waste constituent (40 CFR 261 App. VIII) and, 

therefore, must be disposed of in accordance with Resource Conservation and Recovery Act (RCRA) 

regulations. Acceptable disposal methods include incineration using liquid injection, rotary kiln, or 

fluidized bed techniques. At the present time, land disposal of bromodichloromethane is also permitted, 

although trihalomethanes are being evaluated for land disposal prohibition.

Bromodichloromethane has been detected in the raw and treated waste water of numerous industries 

(EPA 1983), but no quantitative data on amounts of bromodichloromethane disposed of to the 

environment were located. 

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 2005a). 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 
BROMODICHLOROMETHANE 92

5. POTENTIAL FOR HUMAN EXPOSURE

facilities that combust coal and/or oil for the purpose of generating electricity for distribution in 

commerce), 4953 (limited to facilities regulated under RCRA Subtitle C, 42 U.S.C. section 6921 et seq.), 

5169, 5171, and 7389 (limited S.C. section 6921 et seq.), 5169, 5171, and 7389 (limited to facilities 

primarily engaged in solvents recovery services on a contract or fee basis); and if their facility produces, 

imports, or processes ≥25,000 pounds of any TRI chemical or otherwise uses >10,000 pounds of a TRI 

chemical in a calendar year (EPA 2005a).

5.3.1 Air

There is no information on releases of bromodichloromethane to the atmosphere from manufacturing and 

processing facilities because these releases are not required to be reported (EPA 2005a).

No studies were located regarding industrial release of bromodichloromethane into air. Because of the 

low volume of bromodichloromethane currently in use, it is expected that releases from industrial 

activities are probably small.

Class et al. (1986) observed trace levels of bromodichloromethane, 0.7–6.7 ng/m3 (<l ppt), and other 

bromomethanes in seawater and in the air above the ocean at several locations in the Atlantic between 

1982 and 1985. The presence of bromodichloromethane was attributed to biosynthesis and release of 

bromodichloromethane by macroalgae (Class et al. 1986; Gschwend et al. 1985).

In 1978 through 1986, releases of bromodichloromethane from indoor and outdoor swimming pools were 

measured from the surface of the pool up to 2 m above the pool surface; air concentrations of 

bromodichloromethane ranged between 0.2 and 210 μg/m3 (IARC 1991). 

5.3.2 Water

There is no information on releases of bromodichloromethane to water from manufacturing and 

processing facilities because these releases are not required to be reported (EPA 2005a).

The principal source of bromodichloromethane in the environment is from chlorination of water. EPA 

(1980) estimated that >800 kkg (1 kkg=1 metric ton) are produced annually in this way. It is presumed 

that essentially all of this is ultimately released into the environment, mainly through volatilization. This 
BROMODICHLOROMETHANE 93

5. POTENTIAL FOR HUMAN EXPOSURE

may occur either indoors (e.g., while showering, washing, cooking, etc.) or outdoors after discharge of the 

water to the surface.

Bromodichloromethane has been detected in waste water from a number of industrial discharges and 

municipal wastewater treatment facilities, usually at concentrations between 1 and 100 μg/L (Dunovant et 

al. 1986; Perry et al. 1979; Staples et al. 1985). These levels of bromodichloromethane are similar to 

those found in many chlorinated drinking water supplies, and probably most discharges of this sort do not 

represent a major source of bromodichloromethane release to the environment.

Releases of water containing bromodichloromethane that may enter groundwater include water use 

techniques such as the recharge of chlorinated waters for lawn and garden irrigation in commercial and 

residential areas, leaking swimming pools and water lines, leaking chlorinated water distribution and 

sewer pipes, and unintentional backflow of chlorinate water to supply wells (USGS 2003, 2006a).

5.3.3 Soil

There is no information on releases of bromodichloromethane to soil from manufacturing and processing 

facilities because these releases are not required to be reported (EPA 2005a).

Water use techniques such as the recharge of chlorinated public waters for lawn and garden irrigation in 

commercial and residential areas may contribute to bromodichloromethane in the soil environment 

(USGS 2006a). 

Monitoring efforts during the summer and fall of 2008 at the Love Canal in Niagara Falls, New York 

identified bromodichloromethane as a contaminant in the soil/sediment/water samples (Hauser and 

Bromberg 1982). 

Hoekstra et al. (1998) detected bromodichloromethane at concentrations ranging from 0.03 to 0.31 ng/L 

(0.0003–0.0031 μg/L) in soil-air samples taken from soil layers, at depths of 10–160 m below the surface, 

in a Douglas fir forest near Apeldoorn in the Netherlands. Bromodichloromethane was not detected in the 

ambient air samples taken 5–10 cm above the soil surface. Concentrations of bromodichloromethane in 

the soil layers were higher in the deeper layers reaching a maximum at a depth of 120 cm. 
BROMODICHLOROMETHANE 94

5. POTENTIAL FOR HUMAN EXPOSURE

5.4 ENVIRONMENTAL FATE

5.4.1 Transport and Partitioning

Air. Because of the relatively high vapor pressure of bromodichloromethane (50 mm Hg at 20°C), the 

principal transport process in the environment is volatilization (Class et al. 1986; Gschwend et al. 1985). 

Over 99% of all bromodichloromethane in the environment is estimated to exist in air (EPA 1980).

Bromodichloromethane may be removed from air by washout in rainfall (Class et al. 1986), but the 

average rate of this transport process has not been estimated. It is expected that bromodichloromethane 

removed from air in this way is likely returned to air through volatilization.

Water. Volatilization from surface waters depends on factors such as turbulence and temperature. A 

measured Henry’s Law constant for bromodichloromethane of 2.12x10-3 at 25°C indicates that 

volatilization from water is an important fate process. The volatilization half-life from rivers and streams 

has been estimated to range from 33 minutes to 12 days, with a typical half-life of 35 hours (Kaczmar et 

al. 1984). Volatilization rates from surface soils have not been studied in detail, but Wilson et al. (1981) 

found that about 50% of bromodichloromethane applied to a soil column in the laboratory escaped by 

volatilization. A fate study in a waste water treatment wetland near Phoenix, Arizona, receiving 

chlorinated municipal wastewaters, resulted in 83% removal of bromodichloromethane. Volatilization 

was indicated as the primary removal process, with an atmospheric flux of 2.47 g/day/ha (Keefe et al. 

2004).

Bromodichloromethane is moderately soluble in water (3,030 mg/L). Significant transport of bromodichloromethane can occur in water, especially in groundwater where volatilization is restricted. This 

transport pathway may be important at waste sites or other locations where bromodichloromethane spills 

lead to groundwater contamination.

Sediment and Soil. An estimated log Koc value of 1.8 (Mabey et al. 1982) indicates that 

bromodichloromethane is expected to possess high mobility in soil surfaces and has the potential to leach 

into groundwater. Bromodichloromethane applied to the surface of a sandy soil (92% sand, 5.9% silt, 

2.1% clay, <0.1% organic carbon) in a packed column experiment quickly percolated to the bottom of the 

column (140 cm) when eluted with water (Wilson et al. 1981). Roughly 48% of the initially applied 

amount was collected in column effluent and about 54% was shown to volatilize from the column. 
BROMODICHLOROMETHANE 95

5. POTENTIAL FOR HUMAN EXPOSURE

Other Media. The moderate solubility and low log Kow indicate that bioaccumulation of 

bromodichloromethane by fish or other aquatic species is likely to be minor, but no estimate of a 

bioaccumulation factor in aquatic species was located.

5.4.2 Transformation and Degradation

Air. Pathways responsible for bromodichloromethane degradation in the atmosphere are not well 

studied, but likely involve oxidative reaction with hydroxyl radicals or singlet oxygen (EPA 1980; Mabey 

et al. 1982). Bromodichloromethane does not contain chromophores that will absorb light at wavelengths 

>290 nm, and therefore, direct photochemical decomposition is not likely to be significant (EPA 1980). 

The typical atmospheric lifetime of bromodichloromethane has been estimated to be 2–3 months (EPA 

1980). This relatively persistent tropospheric half-life of bromodichloromethane suggests that a small 

percentage of the bromodichloromethane present in air will eventually diffuse into the stratosphere where 

it will be destroyed by photolysis. In addition, long-range global transport is possible.

Water. Hydrolysis of bromodichloromethane in aqueous media is very slow, with an estimated rate 

constant at neutral pH of 5.76x10-8 hour-1 (Mabey et al. 1982). This corresponds to a half-life of 

>1,000 years.

Biodegradation in aqueous media may be significant in some cases. For example, Tabak et al. (1981) 

reported 35% loss of the test substance in a static test after 7 days of incubation in a medium inoculated 

with sewage at 25°C. Repeated culturing lead to increased losses, up to 59% after 28 days, indicating 

gradual adaptation of the degradative microbes. Tabak et al. (1981) also examined the volatilization of 

bromodichloromethane after 10 days at 25°C. The study resulted in 8% loss of test substance due to 

volatilization, indicating that biodegradation is the prominent degradation process for bromodichloromethane (Tabak et al. 1981).

Under anaerobic aquatic conditions where volatilization cannot occur, biodegradation may be the 

predominant mechanism for degradation of bromodichloromethane. In a continuous-flow biofilm reactor 

with a settled sewage inoculum and three zones (aerobic, denitrifying, and sulfate-reducing regions) 

bromodichloromethane achieved >99% transformation, coinciding with the onset of the sulfate-reducing 

zone in the column; concentrations were approximately 46 and <0.1 μg/L in the influent and effluent, 

respectively, after 120 days (Cobb and Bouwer 1991). Bouwer et al. (1981) and Bouwer and McCarty 
BROMODICHLOROMETHANE 96

5. POTENTIAL FOR HUMAN EXPOSURE

(1983a) studied the degradation of bromodichloromethane under aerobic and anaerobic conditions in both 

static and continuous flow systems inoculated with mixed methanogenic bacterial cultures from sewage. 

Degradation was found to be very limited under aerobic conditions, but essentially complete within 

2 days under anaerobic conditions. Minimal to no degradation was observed by Bouwer et al. (1981) 

under aerobic conditions after a 6-week study using mixed methanogenic bacterial cultures in sterile and 

seeded conditions. Under anaerobic conditions, rapid degradation (>99% after 2 days) was observed by 

Bouwer and McCarty (1983a). Slow degradation under anaerobic conditions (50–70% in 16 weeks) 

occurred in sterile media, indicating that a chemical mechanism (hypothesized to be reductive 

dehalogenation) was operative in addition to the rapid microbial degradation. Microbial degradation was 

also observed under anaerobic conditions in media inoculated with denitrifying bacteria (Bouwer and 

McCarty 1983b). 

Sediment and Soil. Biodegradation of bromodichloromethane in soil has not been studied, but 

studies in aqueous media indicate that biodegradation might occur under anaerobic conditions (Bouwer et 

al. 1981; Bouwer and McCarty 1983a, 1983b; Tabak et al. 1981). This suggests that, in regions of soil 

where volatilization is restricted, biodegradation could be a major removal process.

5.5 LEVELS IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to bromodichloromethane depends, in part, on the 

reliability of supporting analytical data from environmental samples and biological specimens. 

Concentrations of bromodichloromethane 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 bromodichloromethane 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 5-1 shows the lowest limit of detections that are achieved by analytical analysis in environmental 

media. Bromodichloromethane has been detected in indoor and outdoor air, water sources, and in soil; an 

overview summary of the range of concentrations detected in environmental media is presented in 

Table 5-2.
BROMODICHLOROMETHANE 97

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-1. Lowest Limit of Detection Based on Standardsa

Media Detection Limit Reference

Air 0.019 ppbv EPA 1999

Drinking water 0.003 μg/L EPA 1990

Surface water and groundwater 0.049 μg/L USGS 1998

Soil 0.02 μg/L EPA 2014d, 2002, 1996a, 1996b, 1996c

Sediment 0.02 μg/L EPA 2014d, 2002, 1996a, 1996b, 1996c

Whole blood 0.29 ng/L; 0.36 ng/L Bonin et al. 2005

aDetection limits based on using appropriate preparation and analytics. These limits may not be possible in all 

situations.

Table 5-2. Summary of Environmental Levels of Bromodichloromethane

Media Low High For more information

Outdoor air (ppbv) 0.00076 0.180 Table 5-6

Indoor air (ppbv) 0.01 0.49 Table 5-7

Surface water (ppb) 0.3 1.1 Table 5-9

Ground water (ppb) 0.02 23 Table 5-10

Drinking water (ppb) Range of mean levels 1.0–20.3 Table 5-11

Food (ppb) Trace 37 Tables 5-13 and 5-14

Soil No monitoring data were located

Detections of bromodichloromethane in air, water, and soil at NPL sites are summarized in Table 5-3.

Table 5-3. Bromodichloromethane Levels in Water, Soil, and Air of National 

Priorities List (NPL) Sites

Medium Mediana

Geometric 

meana

Geometric 

standard 

deviationa

Number of 

concentrations NPL sites

Water (ppb) 6 8.01 7,560 100 64

Soil (ppb) 9.35 7.26 2,190 6 6

Air (ppbv) 0.10 0.13 228 3 3

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.
BROMODICHLOROMETHANE 98

5. POTENTIAL FOR HUMAN EXPOSURE

5.5.1 Air

Data from the EPA Air Quality System (AQS) database were used to calculate the annual mean percentile 

distributions of bromodichloromethane from multiple monitoring locations across the nation for the years 

2010–2018 (EPA 2019). The results of these data are summarized in Table 5-4. The AQS database is 

EPA's source of criteria air pollutant and hazardous air pollutant (HAP) monitoring data. Monitoring data 

for other years may be obtained directly from the EPA AQS website.

Table 5-4. Percentile Distribution of Annual Mean Bromodichloromethane 

Concentrations (ppbv) Measured in Ambient Air at Locations 

Across the United States

Year

Number of U.S. 

locations 25th 50th 75th 95th Maximum

2010 151 0.0089 0.010 0.033 0.10 0.47

2011 127 0.0079 0.012 0.029 0.099 0.47

2012 124 0.0072 0.010 0.050 0.075 0.23

2013 117 0.0095 0.0097 0.050 0.052 0.24

2014 116 0.0090 0.012 0.050 0.067 0.12

2015 52 0.0090 0.0090 0.050 0.11 0.23

2016 101 0.0000 0.0000 0.000328 0.0023 0.35

2017 87 0.0000 0.0000 0.0000 0.0020 0.12

2018 83 0.0000 0.0000 0.0005 0.0019 0.033

Source: EPA 2019

The 2012 and 2013 National Monitoring Program sponsored by the EPA compiled 24-hour air sample 

data from 64 and 66 monitoring sites, respectively, located in 26 states across the United States (EPA 

2015a, 2014b). Samples from 34 sites were assessed for volatile organic compounds, including 

bromodichloromethane, in 2013 and samples from 30 sites were obtained for 2012. The percent of 

detections at each site ranged from about 0 to 15%, with the exception of the site in Northbrook, Illinois 

at which bromodichloromethane was detected in 93% of the 61 samples at that site in 2013 and 100% of 

the samples in 2012 (EPA 2015b, 2014c). The results of these data are summarized in Table 5-5.
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5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-5. Statistical Summary of Bromodichloromethane Concentrations from 

the 2012 and 2013 National Monitoring Program

Non 

detectsa

Measured 

detectsa

Measured 

detects 

<MDL

Minimum 

(ppbv)b

Maximum 

(ppbv)

Arithmetic 

mean 

(ppbv)

Median 

(ppbv)

25th

(ppbv)

75th

(ppb)

Standard 

deviation 

(ppbv)

2013

1,728 155 113 0.005 8.36 0.009 0 0 0 0.205 

2012

1,350 116 NR 0.006 4.10 0.010 0 0 0 0.152 

aOut of 1,883 valid samples in 2013 and 1,466 valid samples in 2012.

bExcludes zeros for non-detects.

MDL = method detection limit

Source: EPA 2014b, 2015a

Ambient air monitoring data for bromodichloromethane, including data for concentrations detected during 

water-related activities, are compiled in Tables 5-6, 5-7, and 5-8.

Table 5-6. Outdoor Air Monitoring Data for Bromodichloromethane

Location(s)

Geographic 

type Date(s) Range

Mean

concentration Notes Reference

Texas, 

North 

Carolina, 

Arkansas

Suburban, 

urban, source 

dominated

Not 

specified 

(1983 or 

earlier)

0.00076–

0.180 ppbv

0.0011 ppbv Not detected in 

two of the rural, 

remote sites 

monitored in 

Arkansas

Brodzinsky and 

Singh 1983

California Urban, 

industrial

1982/1983 0.01–0.10 ppbv Detected above 

0.01 ppbv in 35% 

of the samples

Shikiya et al. 

1984

Atlantic 

Ocean

Open ocean 1982/1984/

1985

0.001–0.007 

ppbv 

Air samples at 

several locations; 

attributed to 

releases from 

macroalgae

Class et al. 

1986

Texas, 

Louisiana, 

North 

Carolina, 

Arkansas

Suburban, 

urban, source 

dominated

Not 

specified 

(2005 or 

earlier)

0.74 μg/m3

(0.11 ppbv)

Outdoor air EPA 2005b

Germany Surface air 

above 

swimming 

pools

1995–1999 0.03–

2.0 μg/m3

(0.0045–

0.3 ppbv)

0.1–0.4 μg/m3 

(0.02–

0.06 ppbv) 

Measured 20 or 

150 cm above 

the water surface 

of outdoor pools

WHO 2006
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Table 5-6. Outdoor Air Monitoring Data for Bromodichloromethane

Location(s)

Geographic 

type Date(s) Range

Mean

concentration Notes Reference

United 

States

Surface air 

above 

swimming 

pools

1986 <0.1 μg/m3

(<0.02 ppbv)

Not reported Measured 200 

cm above the 

water surface 

outdoor pools 

WHO 2006

Table 5-7. Indoor Air Monitoring Data for Bromodichloromethane

Location(s)

Geographic 

type Date(s)

Mean

concentration Notes Reference

New Jersey Suburban Not specified 

(1999 or 

earlier)

0.38–0.75 μg/m3 

(0.056–

0.11 ppbv)

Indoor air of 

48 households

EPA 2005b

Southwestern 

United States

Urban living 

space air

August 1997 0.01–0.49 ppbv Indoor air concentrations 

from 24-hour integrated 

samples 0.2–0.9 μg/m3

(0.03–0.13 ppbv); air 

exchange rates in the 

home influenced 

concentrations

Kerger et al. 

2005

Italy Surface air 

above 

indoor 

swimming 

pools

1993–1998 17.4–20 μg/m3

(2.61–3 ppbv)

Measured 20 cm above 

water surface of indoor 

pool

WHO 2006

Germany Surface air 

above 

swimming 

pools

1995–1999 4.1–9.2 μg/m3 

(0.62–1.38 ppbv)

Measured 20 or 150 cm 

above the water surface 

of indoor pools

WHO 2006

United States Surface air 

above 

swimming 

pools

1986 Range of <0.1–

10 μg/m3 (0.02–2 

ppbv)

Measured 200 cm above 

the water surface of 

indoor pools 

WHO 2006
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Table 5-8. Water-Related Activities and Indoor Air Monitoring Data for 

Bromodichloromethane 

Activity Range

Showeringa,b

Prior: 0.3–20.9 μg/m3 (0.04–3.12 ppbv)

During: 33.1–141.5 μg/m3 (4.94–21.1 ppbv)

After: 14.8–96 μg/m3 (2.21–14.3 ppbv)

Bathinga,c

Prior: 0.4–2.1 μg/m3 (0.06–0.31 ppbv)

During: 7.0–65.1 μg/m3 (1.0–9.71 ppbv)

After: 5.9–29.0 μg/m3 (0.88–4.33 ppbv)

aThe average concentration of bromodichloromethane in the household water samples was reported as 42.0 μg/L. 

bDurations of showers were 6.8–20 minutes; ventilated and non-ventilated scenarios were assessed. cDurations of bath were 6.8–20 minutes.

Source: Kerger et al. 2000

5.5.2 Water

Bromodichloromethane occurs in water primarily as a byproduct of the chlorination process used for 

disinfection, but it also can be found in surface waters from biosynthesis by macroalgae. 

The concentration of bromodichloromethane in chlorinated water depends on reaction conditions during 

the chlorination process. Important parameters include temperature, pH, bromide ion concentration in the 

source water, fulvic and humic substance concentration in the water, and chlorination treatment practices 

(EPA 1985). The amount of bromodichloromethane tends to increase as a function of increasing organic 

content and bromide ion in the source water (Arguello et al. 1979; Bellar et al. 1974). 

Concentrations of bromodichloromethane in swimming pool waters are affected by several factors 

including the frequency and number of swimmers in the pool, the chlorine dose used for disinfection, the 

bromide content, and the source water used (Kim et al. 2002).

Water monitoring data for bromodichloromethane are compiled in Tables 5-9, 5-10, 5-11, and 5-12.
BROMODICHLOROMETHANE 102

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-9. Surface Water Monitoring Data for Bromodichloromethane

Location(s) Geographic type Date(s) Range

Mean

concentration Notes Reference

California, Utah, 

Florida

Monitoring sites January–

December 2012

Not 

detected–

140 μg/L

Mean: 

11.07 μg/L; 

median: 0.0 μg/L

EPA STORET data: Routine 

monitoring samples from: 

California Department of Water 

Resources; Hopland Band of Pomo 

Indians Tribal EPA; Dade 

Environmental Resource 

Management (Florida); Utah 

Department of Environmental Quality; 

water depths 0–1 m

WQP 2017

California, Utah, 

Florida 

Monitoring sites January–

December 2013

Not 

detected–

25.0 μg/L

Mean: 0.74 μg/L; 

median: 0.0 μg/L

EPA STORET data: Routine 

monitoring samples from: 

California Department of Water 

Resources; Hopland Band of Pomo 

Indians Tribal EPA; Dade 

Environmental Resource 

Management (Florida); Utah 

Department of Environmental Quality; 

water depths 0–1 m

WQP 2017

California; Utah, 

Florida 

Monitoring sites January–

December 2014

Not 

detected–

51.90 μg/L

Mean: 1.93 μg/L; 

median: 1.2 μg/L

EPA STORET data: Routine 

monitoring samples from: 

California Department of Water 

Resources; Hopland Band of Pomo 

Indians Tribal EPA; Dade 

Environmental Resource 

Management (Florida); Utah 

Department of Environmental Quality; 

water depths 0–12 m

WQP 2017
BROMODICHLOROMETHANE 103

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-9. Surface Water Monitoring Data for Bromodichloromethane

Location(s) Geographic type Date(s) Range

Mean

concentration Notes Reference

California; 

Minnesota

Monitoring sites January–October 

2015

Not 

detected–

13.00 μg/L

Mean: 1.99 μg/L; 

median: 0.0 μg/L

EPA STORET data: Routine 

monitoring samples from: 

California Department of Water 

Resources; Minnesota Pollution 

Control Agency-Ambient Surface 

Water; water depths 0–1 m

WQP 2017

Atlantic Ocean Open ocean; African 

coast, West Africa, 

Porto Santo, Sao 

Miguel, Bermuda 

Islands, Tenerife

1982/1984/1985 0.0001–

0.001 μg/L 

(seawater); 

0.0004 μg/L 

(rain) 

Not reported Surface water concentrations 

attributed to releases from 

macroalgae

Class et al. 

1986

Gila River

Phoenix, Arizona

River surface water 1997–1998 Not detected Not reported Rostad et 

al. 2000

The Rhine, Meuse, 

northern delta 

area, and 

Westerscheld

Surface water 1992–1997 <100 μg/L Not reported Miermans et 

al. 2000
BROMODICHLOROMETHANE 104

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-10. Groundwater Monitoring Data for Bromodichloromethane

Location(s) Type Date(s) Range

Mean

concentration Notes Reference

Salt Lake 

Valley, Utah

Well 1999 0.02–

0.51 μg/L 

Not reported Detected in 17 of 30 wells sampled; attributed to the 

recharge of chlorinated public supply waters used to 

irrigate lawns and gardens in residential areas

USGS 2003

United States Shallow 

groundwater

1996 and 2002 Trace: 

≤0.2 μg/L

Not reported Detected in 14% of samples; ≥0.2 in 1.7% of the 

samples

Squillace et 

al. 2004

United States Domestic wells 1986–2001 0.2–7.0 μg/L Not reported Detected in 124 of 2,400 wells sampled USGS 

2006b

United States Public wells 1986–2001 0.2–21 μg/L Not reported Detected in 46 of 1,095 wells sampled USGS 

2006b

United States Untreated 

Ground and 

source water

1985–2002 0.02–

23 μg/L

Not reported Detected in 1–3% of the aquifers samples; 0.1–1.7% 

shallow groundwaters; more frequently detected in 

groundwater samples collected from urban areas as 

compared to agricultural areas

USGS 

2006b

United States Untreated 

Ground; public 

and domestic 

wells

1997–2007 0.08–

0.09 μg/L 

(median 

values)

Not reported 10% (66 out of 631) of the public well samples; 1.7% 

(33 out of 1,861) of the domestic well samples; 

detected at a higher frequency in wells surrounded 

by urban areas compared with undeveloped, mixed, 

and agricultural surroundings

Carter et al. 

2012

United States Public wells 1993–2007 Not reported Detected in 11% of the samples (932 wells) USGS 

2010b

United States Principal aquifers 1991–2010 >0.2 μg/L Not reported 0.93% frequency of detection of 

bromodichloromethane in 40 aquifers in the United 

States used for drinking water; 1.67% frequency of 

detection of bromodichloromethane in 22 aquifers 

beneath urban areas

USGS 2015

Taiwan Groundwater Not specified 

(2000 or prior)

Not reported Detected in less than 5% of 214 sample taken at 

30 industrial sites

Kuo 2000

Tampa Bay, 

Florida

Groundwater in 

an aquifer

October 2002–

January 2003; 

August–

September 2004

0.040 μg/L Not reported Detected 3 times in 30 source-water samples 

collected from 30 community water system wells 

during the first phase, concentration not reported; 

1 time in 11 source-water samples collected during 

the second phase

USGS 2007
BROMODICHLOROMETHANE 105

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-11. Drinking Water Monitoring Data for Bromodichloromethane

Location(s) Type Date(s) Range

Mean

concentration Notes Reference

United States Finished water August 

1973–

February 

1974

1.1–

20.8 μg/L

Not reported Sampling sites not reported Bellar et al. 1974

Tampa Bay, Florida Finished water August–

September 

of 2004

0.053–

7.48 μg/L

Not reported Detected in 10 of 10 finished water 

samples

USGS 2007

United States Drinking water 2000–2004 1.0, 15.0, and 

20.3 μg/L

Three locations were sampled weekly; it 

was found that all trihalomethanes were 

removed after heating the drinking water; 

faucet filters completely removed 

trihalomethanes and pitcher filters 

removed on average 40% of the 

trihalomethanes.

Savitz et al. 2006

India Finished water March 

2009–June 

2009

0.03–315 μg/L 

(median 

12.40 μg/L)

Samples collected from water treatment 

plant endpoints at 11 locations

Basu et al. 2011

United States Drinking/finished 

water

1991–2003 1.62 μg/L Detected in 3 out of 34 tap water samples FDA 2006

Italy Italian tap water Not specified 

(2005 or 

prior)

0.249 μg/L Not reported Not detected in Italian mineral water, 

contaminated mineral water, Italian 

superficial snow, or Antarctic superficial 

snow

Zoccolillo et al. 

2005

Korea Tap water 2009 Maximum 

10.7 μg/L

6.1 μg/L (median 

6.3 μg/L)

Detected in 100% of 770 tap water 

samples from six municipal water 

treatment plants using chlorination 

disinfection methods; highest 

concentrations were observed in the 

summer samples

Lee et al. 2013
BROMODICHLOROMETHANE 106

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-11. Drinking Water Monitoring Data for Bromodichloromethane

Location(s) Type Date(s) Range

Mean

concentration Notes Reference

United States Drinking water 1988–1989 Seasonal 

medians 

4.1–10 μg/L

Not reported 35 water utilities; 25 across the United 

States and 10 in California

Krasner et al. 

1989

Canada Drinking water 1976–1977 2.9 μg/L Not reported Reported concentration in winter samples 

from water supplies serving 38% of the 

population in 70 communities

WHO 2000

United States, 

Florida, 

Washington, 

Pennsylvania, 

Ohio, Michigan 

Drinking water 1974–1986 Not 

detected–

73 μg/L

1–20 μg/L Coleman et al. 

1975; EPA 1979; 

Furlong and D'itri 

1986; Symons et 

al. 1975
BROMODICHLOROMETHANE 107

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-12. Swimming Pool Water Monitoring Data for Bromodichloromethane

Location(s) Type Date(s) Range

Mean

concentration Notes Reference

Miami, Florida Saltwater and 

freshwater 

swimming 

pools

Not specified 

(1980 or 

prior)

13–34 μg/L Beech et al. 

1980

Poland, Italy, United 

States, Germany, 

Hungary, and the 

United Kingdom

Swimming 

pools

1981–2002 <0.1–150 μg/L 1.3–22.6 μg/L WHO 2006

Not reported Laboratory 

study of pool 

water

7.9 μg/L Not reported Concentration in 

groundwater 

control 4.4 μg/L

Kim et al. 

2002

Portugal Indoor 

swimming 

pools

April–

November 

2011

1–21.5 μg/L Not reported Detected in 99% of 

the pool water 

samples

Silva et al. 

2012

Not reported Swimming 

pools

February–

August 2008

Specific concentrations of bromodichloromethane were not reported, it was noted 

that its occurrence was sporadic compared 

with the other disinfection byproducts that 

appeared regularly in the samples

Not reported Water was 

sampled 20–30 cm 

below pool surface

Weaver et 

al. 2009
BROMODICHLOROMETHANE 108

5. POTENTIAL FOR HUMAN EXPOSURE

5.5.3 Sediment and Soil

Little information was located regarding concentrations of bromodichloromethane in ambient soils. 

Because of its volatility, it is likely that bromodichloromethane would be present only at low levels in 

most soils. 

Bromodichloromethane was detected in <1% of 705 soil samples taken from 30 industrial sites 

investigated in Taiwan. Sites included chemical and petrochemical industrial districts, technology 

industrial parks, general industrial districts, metal processing areas, oil refinery plants, pesticide

manufacturing facilities, and landfills. Samples were collected via purge-and-trap techniques using EPA 

method 5035 (Kuo 2000). 

5.5.4 Other Media

Bromodichloromethane is not a common contaminant of food, occurring only in trace quantities in some 

samples (trace quantities are concentrations above the method detection limit but below the method 

quantification limit). 

A market basket study conducted by the U.S. Food and Drug Administration (FDA) in 1991–2003 

evaluated over 400 food products (FDA 2006). Bromodichloromethane was detected in about 10% of the 

foods, mostly at trace levels. Data are provided in Table 5-13.

Table 5-13. Bromodichloromethane Detections in Food from the U.S. Food and 

Drug Administration (FDA) 1991–2003 Market Basket Survey

Food Number of detections Number of samples

Mean concentration 

(ppb)

Processed American cheese 1 44 0.07

Boiled beef/pork frankfurters 4 44 0.39

Beef/pork bolognas 2 44 0.43

Salami lunch meats 1 44 0.09

Popcorn popped in oil 1 40 0.13

Raw/frozen strawberry samples 1 43 0.07

Regular carbonated colas 4 44 0.43

Diet carbonated colas 4 44 0.36

Plain milk chocolate candy bars 1 44 0.09
BROMODICHLOROMETHANE 109

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-13. Bromodichloromethane Detections in Food from the U.S. Food and 

Drug Administration (FDA) 1991–2003 Market Basket Survey

Food Number of detections Number of samples

Mean concentration 

(ppb)

Light vanilla ice creams 3 44 0.16

Salted margarines 3 44 0.30

Salted butters 1 44 0.14

Baby food beef and gravy 1 44 0.07

Swiss cheeses 3 44 0.36

Cream cheese 1 44 0.09

Fast food chicken nuggets 3 44 0.23

Graham crackers 1 44 0.07

Fast food french fries 1 44 0.07

Fast food tacos with beef and 

cheese

1 44 0.09

Take out pizzas 1 44 0.11

Vanilla ice creams 5 44 0.34

Fruit sherbets 3 44 0.32

Fruit popsicles 6 44 0.50

Sour creams 4 44 0.30

Carbonated fruit drinks 3 44 0.43

Fast food chicken legs 1 4 0.75

Pan cooked catfish 1 4 0.75

Salted and roasted sunflower 

seeds

1 4 1.0

Bottled cranberry juice cocktails 1 4 1.75

Orange juices 1 4 0.75

Prepared potato salads 1 4 1.0

Prepared coleslaws 1 4 0.75

Fried eggs with added fat 1 40 0.33

Canned pork and bean 

samples

1 44 0.25

Creamy peanut butter 1 44 0.23

Homemade cornbread 1 44 0.30

Raw orange 1 44 0.32

Canned pineapple 1 44 0.32

Bottled apple juice 1 44 0.75

Fresh/frozen, boiled collards 1 44 0.32

Tomatoes 1 44 0.25

Green peppers 1 44 0.32

Fast food quarter-pound 

hamburgers on a bun

1 44 0.84
BROMODICHLOROMETHANE 110

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-13. Bromodichloromethane Detections in Food from the U.S. Food and 

Drug Administration (FDA) 1991–2003 Market Basket Survey

Food Number of detections Number of samples

Mean concentration 

(ppb)

Creamy low calorie salad 

dressing

1 4 2.5

Source: FDA 2006

A 5-year study of 70 foods was conducted from 1996 to 2000 using purge-and-trap methods (FlemingJones and Smith 2003). Forty-one of the foods had at least one detection of a volatile organic compound 

over 100 ppb. Bromodichloromethane was detected in 10 of these 41 foods at concentrations ranging 

from 3 to 5 ppb, with the expectation of the highest concentration found in 1 sample of cooked hamburger 

at 37 ppb. Data are provided in Table 5-14. 

Table 5-14. Bromodichloromethane in Food

Food Number of detections Concentration ppb

American cheese 1 3

Fruit-flavored sherbet 1 3

Popsicle 1 3

Fast food french fries 1 3

Fast food chicken nuggets 1 3

Carbonated cola 2 3

Sour cream 1 4

Beef frankfurters 2 4–5

Popcorn popped in oil 1 5

Cooked hamburger 1 37

Source: Fleming-Jones and Smith 2003

Hiatt and Pia (2004) screened 35 milk samples from eight grocery stores in Las Vegas, Nevada in January 

and February 2002. Concentrations of bromodichloromethane were 0.02–0.30 μg/L in whole milk, 0.03–

0.37 μg/L in 2% milk, and 0.04–0.14 μg/L in 1% milk. 

A market basket study of 39 food items detected bromodichloromethane in one dairy composite at 

1.2 ppb and in butter at 7 ppb (Entz et al. 1982). A study of bromodichloromethane in food processing 

water and processed foods revealed no detectable levels except in ice cream at one processing plant (0.6–

2.3 ppt) (Uhler and Diachenko 1987). Soft drinks have been found to contain bromodichloromethane 
BROMODICHLOROMETHANE 111

5. POTENTIAL FOR HUMAN EXPOSURE

(Abdel-Rahman 1982; Entz et al. 1982), but usually at concentrations (0.1–6 μg/L) below those found in 

municipal water supplies. Cooking foods in water containing bromodichloromethane is unlikely to lead 

to contamination, since bromodichloromethane would rapidly volatilize (Kool et al. 1981).

Bromodichloromethane is biosynthesized by marine macroalgae, and has been measured in these 

organisms at 7–22 ng/g dry weight (Gschwend and MacFarlane 1985). Whether bromodichloromethane 

enters and accumulates in the food chain from this source appears to be unlikely, but has not been studied.

Bromodichloromethane has been detected in the milk of rats at a concentration of 0.38 μg/g after 

exposure to 112 mg/kg-day, but was not detected in placentas, amniotic fluid, or fetal tissue collected on 

GD 21, nor plasma collected from postpartum day 29 weanling pups, after similar exposures (EPA 

2005b). Bromodichloromethane was detected in one fetus and in the placentas of rabbits exposed to 

76 mg/kg/day, but it was not detected in placentas of rabbits exposed to approximately 32 mg/kg/day, nor 

in amniotic fluid or the remaining fetuses from rabbits exposed to doses of approximately 76 mg/kg/day 

(EPA 2005b).

5.6 GENERAL POPULATION EXPOSURE

The general population can be exposed to bromodichloromethane via ingestion and dermal contact of 

water containing this chemical and also by inhalation of bromodichloromethane that has volatilized into 

air. Exposure may occur when people are involved in water-related actives such as showering, bathing, 

swimming pool activities, and washing dishes in water containing bromodichloromethane. Occupational 

exposure may occur via inhalation and dermal contact for individuals who work at swimming pools (e.g., 

lifeguards).

No studies were located examining the exposures of children to bromodichloromethane. Exposure will 

likely occur through inhalation, dermal contact, and, ingestion of water containing bromodichloromethane. Exposures would be expected to vary depending on the amount of water consumed, the length 

of time a child spends doing water-related activities, and the quality of the water the child is exposed to. 

The average exposures to bromodichloromethane for the general human population from surface water 

and groundwater systems have been estimated at 20 and 8.1 μg/person/day, respectively (EPA 2005b). 

The estimated exposure of the general human population to bromodichloromethane from ingesting 

drinking water containing bromodichloromethane, assuming a median bromodichloromethane 
BROMODICHLOROMETHANE 112

5. POTENTIAL FOR HUMAN EXPOSURE

concentration of 1.4–2.1 μg/L (ppb) and a water intake for an adult of 2 L/day, would be 2.8–4.2 μg/day 

(EPA 2005b). Exposure can also occur by inhalation of bromodichloromethane volatilized from 

chlorinated water (e.g., while showering, cooking, or swimming), and by dermal contact with such water. 

In 67% of breath samples, collected from 11 subjects in Texas and North Carolina, bromodichloromethane concentrations ranged from 0.12 to 4.36 μg/m3 (EPA 2005b). Based on a chemical structure 

analogy to chloroform, an estimated dermal exposure to bromodichloromethane in a child swimming 

2 hours/day in a saline pool would typically be 0.003 mg/day, with a maximum of 0.04 mg/day (Beech et 

al. 1980). Higher exposure levels might occur through ingestion of water contaminated with bromodichloromethane near a waste site, but available data suggest that this is not a common occurrence.

The updated Fourth National Report on Human Exposure to Environmental Chemicals (CDC 2019) 

includes results from the assessment of bromodichloromethane levels in the National Health and Nutrition 

Examination Survey (NHANES) for blood samples from the U.S. general population surveyed during the 

years 2001–2016. As shown in Table 5-15, geometric mean bromodichloromethane levels were 2.21, 

1.50, 1.41, 1.52, 1.61, and 1.34 pg/mL for the survey years 2001–2002, 2003–2004, 2005–2006, 2007–

2008, 2009–2010, and 2011–2012 respectively; in 2013–2014 and 2015–2016, geometric mean levels 

could not be calculated because the proportion of results below the limit of detection was too high to 

provide a valid result. The analytical method used for the analysis was gas chromatography with highresolution mass spectrometry (Bonin et al. 2005). The limits of detection (LODs) for survey years 2001–

2002, 2003–2004, 2005–2006 2007–2008, 2009–2010, 2011–2012, 2013–2014, and 2015–2016 are 

0.233, 0.62, 0.62, 0.62, 0.62, 0.62, 6.00, and 6.00 pg/mL, respectively.

After activities such as bathing, showering, or swimming in chlorinated water, median blood levels of 

bromodichloromethane increased over baseline levels, and then returned to baseline during the next 1–

2 hours following the end of the activity (Ashley et al. 2005; Lourencetti et al. 2010; Silva et al. 2013). 

Ashley et al. (2005) and Gordon et al. (2006) investigated human exposure to bromodichloromethane via 

dermal, ingestion, and inhalation pathways. Activities included drinking a hot and cold beverage, 

showering/bathing in hot water, drinking 0.5 L of tap water, washing and drying a load of laundry, 

washing hands, running a dishwasher, and opening and removing dishes from a dishwasher, washing 

clothes with chlorine bleach, washing dishes by hand, and staying in a room adjoining an operating 

shower. These activities led to approximately a 3–4-fold increase in bromodichloromethane levels in the 

blood of the seven subjects following showering, bathing, or hand washing. Dermal exposure was cited 
BROMODICHLOROMETHANE 113

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-15. Blood Bromodichloromethane Levels in the NHANES U.S. Population

Survey 

years

Geometric mean 

(95% CI) (pg/mL)

Selected percentiles (95% confidence intervaI) (pg/mL) Sample 

50th 75th 90th 95th size

Total 2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

2.21 (1.65–2.97)

1.50 (1.20–1.86)

1.41 (1.09–1.83)

1.52 (1.24–1.86)

1.61 (1.23–2.10)

1.34 (1.07–1.67)

*

*

2.30 (1.56–3.21)

1.40 (1.10–1.90)

1.30 (0.880–1.80) 

1.42 (1.05–1.90)

1.44 (0.911–2.33)

1.18 (0.817–1.66)

<LOD

<LOD

4.63 (3.24–6.20)

3.40 (2.60–4.20)

3.00 (2.10–4.40)

3.13 (2.50–4.20)

3.84 (2.64–5.33)

2.94 (2.07–3.92)

<LOD

<LOD

8.45 (5.86–12.0)

6.20 (5.30–7.00)

6.30 (4.30–9.70) 

6.42 (4.70–8.30)

7.89 (6.36–9.58)

5.89 (4.32–8.29)

7.00 (<LOD–8.00)

9.00 (6.00–13.0)

12.0 (7.68–19.2)

9.50 (7.00–12.0)

10.0 (6.80–14.0)

9.59 (7.05–14.6)

12.0 (9.65–14.5)

8.95 (6.35-13.5)

10.0 (8.00–11.0)

13.0 (9.00–21.0)

785

1,322

3,139

2,982

3,275

2,700

3,160

3,077

Age group

12–19 years 2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

1.23 (0.954–1.58) 

1.49 (1.19–1.86)

1.42 (0.912–2.34)

*

*

*

1.00 (0.620–1.60)

1.26 (0.910–1.88)

3.84 (2.65–5.82)

0.956 (<LOD–1.21)

<LOD

<LOD

2.80 (1.70–4.10)

3.10 (2.42–4.05)

8.41 (5.45–12.7)

2.03 (1.51–3.00)

<LOD

<LOD

5.50 (4.10–7.20)

6.20 (4.13–8.52)

8.41 (5.45–12.7)

4.19 (3.06–6.62)

<LOD

6.00 (<LOD–10.0)

8.20 (6.20–12.0)

9.02 (6.20–15.0)

13.0 (8.78–18.0)

9.06 (6.49–13.7)

9.00 (6.00–10.0)

9.00 (<LOD–15.0)

932

482

558

507

594

543

20–59 years 2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012a

2013–2014a

2015–2016a

2.21 (1.65–2.97) 

1.50 (1.20–1.86) 

1.45 (1.11–1.89) 

1.60 (1.28–2.01)

1.67 (1.24–2.26)

1.38 (1.09–1.075)

*

*

2.30 (1.56–3.21)

1.40 (1.10–1.90)

1.30 (0.900–1.90)

1.56 (1.13–2.04)

1.53 (0.893–2.56)

1.22 (0.862–1.82)

<LOD

<LOD

4.63 (3.24–6.20)

3.40 (2.60–4.20)

3.10 (2.10–4.60)

3.33 (2.61–4.43)

4.07 (2.66–5.85)

2.91 (2.08–3.88)

<LOD

<LOD

8.45 (5.86–12.0)

6.20 (5.30–7.00)

6.40 (4.30–10.0) 

6.90 (4.94–9.29)

8.47 (6.66–10.2)

6.00 (4.35–8.62)

7.00 (<LOD–9.00)

9.00 (6.00–14.0)

12.0 (7.68–19.2)

9.50 (7.00–12.0)

11.0 (6.90–14.0)

11.0 (7.39–15.6)

13.0 (10.1–16.2)

9.06 (6.49–13.7)

10.0 (8.00–12.0)

15.0 (10.0–19.0)

785

1,322

1,537

1,607

1,797

2,196

2,566

2,534

≥60 years 2005–2006

2007–2008

2009–2010

1.43 (0.996–2.05) 

1.28 (1.07–1.53)

1.41 (1.13–1.78)

1.40 (0.850–2.00)

1.20 (0.870–1.59)

1.33 (0.851–1.86)

3.20 (1.60–5.90)

2.60 (1.90–3.41)

3.25 (2.39–4.25)

6.50 (3.20–15.0)

4.88 (3.67–6.50)

6.07 (5.07–7.59)

9.70 (5.00–18.0)

7.39 (5.70–8.80)

8.42 (6.95–11.6)

670

893

920
BROMODICHLOROMETHANE 114

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-15. Blood Bromodichloromethane Levels in the NHANES U.S. Population

Survey 

years

Geometric mean 

(95% CI) (pg/mL)

Selected percentiles (95% confidence intervaI) (pg/mL) Sample 

50th 75th 90th 95th size

Sex

Males 2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

2.19 (1.60–3.00) 

1.48 (1.18–1.85) 

1.39 (1.07–1.80) 

1.52 (1.24–1.87)

1.48 (1.18–1.85)

1.33 (1.06–1.67)

*

*

2.31 (1.63–3.21)

1.40 (0.940–2.00)

1.20 (0.830–1.70)

1.50 (1.03–1.95)

1.41 (0.861–2.23)

1.17 (0.756–1.69)

<LOD

<LOD

4.64 (3.21–6.08)

3.40 (2.60–4.30)

3.00 (2.00–4.30)

3.23 (2.59–4.20)

3.79 (2.46–5.62)

2.91 (2.08–3.88)

<LOD

<LOD

7.96 (5.74–15.3)

6.60 (5.40–7.20)

6.50 (4.30–10.0)

6.72 (4.80–9.02)

8.32 (6.36–10.6)

5.92 (4.48–8.29)

7.00 (<LOD–9.00)

9.00 (6.00–14.0)

13.0 (6.93–20.5)

11.0 (7.20–14.0)

11.0 (6.80–16.0)

11.0 (7.31–15.9)

13.0 (10.1–17.2)

9.17 (6.65–13.3)

10.0 (8.00–12.0)

14.0 (9.00–21.0)

382

650

1,489

1,487

1,616

1,363

1,523

1,523

Females 2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

2.24 (1.66–3.01) 

1.51 (1.21–1.90) 

1.44 (1.10–1.88) 

1.51 (1.22–1.87)

1.62 (1.24–2.16)

1.35 (1.06–1.67)

*

*

2.28 (1.49–3.24)

1.50 (1.10–1.90)

1.30 (0.900–1.90)

1.40 (1.01–1.92)

1.53 (0.946–2.46)

1.22 (0.828–1.70)

<LOD

<LOD

4.63 (3.09–7.01)

3.30 (2.50–4.20)

3.10 (2.10–4.60)

3.03(2.42–4.10)

3.92 (2.79–5.19)

2.94 (1.96–4.06)

<LOD

<LOD

8.62 (5.26–12.9)

6.10 (4.69–7.30)

6.20 (4.20–9.40)

6.20 (4.60–7.82)

7.67 (6.22–9.28)

5.87 (4.05–8.63)

6.00 (<LOD–8.00)

8.00 (<LOD–13.0)

11.1 (7.68–25.0)

7.80 (6.40–12.0)

9.40 (6.30–13.0)

8.31 (6.80–12.9)

11.2 (8.99–13.9)

8.63 (5.87–13.3)

9.00 (7.00–11.0)

13.0 (7.00–21.0)

403

672

1,650

1,495

1,659

1,337

1,637

1,554

Race/ethnicity

Mexican 

Americans

2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

3.28 (2.29–4.68) 

1.65 (1.15–2.38) 

1.95 (1.19–3.18) 

1.61 (1.27–2.03)

2.19 (1.37–3.49)

1.53 (1.16–2.04)

*

*

3.32 (2.19–4.70)

1.60 (0.820–2.80)

1.90 (1.00–3.70)

1.57 (1.08-2.20)

2.18 (1.10–4.16)

1.19 (0.761–2.16)

<LOD

<LOD

6.81 (3.71–10.4)

3.50 (2.60–4.90)

4.40 (2.10–9.10)

3.44 (2.42–4.50)

5.50 (3.20–8.98)

3.44 (2.41–5.20)

<LOD

<LOD

10.8 (8.24–14.7)

7.30 (4.50–10.0)

9.10 (4.80–17.0)

5.93 (4.70-8.15)

11.3 (6.59–19.5)

9.06 (5.21–15.4)

<LOD

9.00 (7.00–12.0)

14.7 (11.1–20.5)

10.0 (7.30–11.0)

14.0 (7.50–22.0)

8.90 (6.80-13.2)

16.2 (11.2–22.5)

15.9 (6.55–40.0)

10.0 (<LOD–14.0)

13.0(9.00–17.0)

227

244

771

574

667

298

500

552

Non-Hispanic

blacks

2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

2.32 (1.82–2.94) 

1.56 (1.15–2.13) 

1.74 (1.27–2.37) 

1.72 (1.42–2.08)

1.97 (1.50–2.58)

1.84 (1.09–3.12)

*

*

2.50 (1.56–3.55)

1.70 (1.10–2.20)

1.70 (1.00–2.70)

1.70 (1.30–2.21)

1.99 (1.41–2.53)

1.72 (0.734–3.80)

<LOD

<LOD

4.57 (3.60–5.56)

2.90 (2.15–3.80)

3.80 (2.70–4.80)

3.29 (2.80–4.01)

3.76 (2.55–5.82)

4.48 (2.11–8.95)

<LOD

<LOD

8.69 (5.63–9.49)

5.10 (3.80–6.60)

6.40 (4.50–8.90)

5.78 (4.70–7.30)

7.70 (5.35–10.2)

9.60 (5.03–15.2)

7.00 (<LOD–10.0)

7.00 (<LOD–13.0)

10.0 (5.89–13.5)

6.60 (4.90–13.0)

8.70 (6.60–11.0)

7.49 (6.03–9.70)

10.5 (8.52–13.4)

13.0 (8.47–22.3)

9.00 (8.00–11.0)

11.0 (6.00–18.0)

130

290

817

593

579

712

603

639
BROMODICHLOROMETHANE 115

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-15. Blood Bromodichloromethane Levels in the NHANES U.S. Population

Survey 

years

Geometric mean 

(95% CI) (pg/mL)

Selected percentiles (95% confidence intervaI) (pg/mL) Sample 

50th 75th 90th 95th size

Non-Hispanic 

whites

2001–2002

2003–2004

2005–2006

2007–2008

2009–2010

2011–2012

2013–2014

2015–2016

2.02 (1.42–2.87) 

1.42 (1.11–1.81) 

1.29 (0.989–1.67) 

1.45 (1.11–1.87)

1.46 (1.06–2.02)

1.18 (0.909–1.53)

*

*

2.16 (1.36–3.09)

1.30 (0.850–1.90)

1.10 (0.710–1.70)

1.32 (0.917–1.90)

1.25 (06.73–2.30)

1.03 (<LOD–1.51)

<LOD

<LOD

4.34 (2.92–6.01)

3.30 (2.30–4.40)

2.70 (1.80–4.10)

3.03 (2.23–4.30)

3.59 (2.22–5.37)

2.55 (1.65–3.42)

<LOD

<LOD

7.33 (4.72–15.3)

6.20 (5.20–7.20)

5.80 (4.00–8.60)

6.50 (4.20–9.29)

7.28 (5.51–9.28)

4.83 (3.26–6.95)

7.00 (<LOD–10.0)

9.00 (<LOD–15.0)

11.1 (6.01–26.1)

9.80 (6.70–13.0)

9.40 (6.20–14.0)

9.59 (6.30–15.3)

10.9 (8.50–14.3)

7.54 (4.79–12.6)

9.00 (8.00–11.0)

14.0 (8.00–21.0)

365

684

1,318

1,347

1,470

933

1,288

999

All Hispanics 2011–2012

2013–2014

2015–2016

1.70 (1.39–2.08)

*

*

1.52 (1.11–2.16)

<LOD

<LOD

3.66 (2.86–4.69)

<LOD

<LOD

8.08 (5.98–9.67)

7.00 (<LOD–10.0)

9.00 (7.00–12.0)

12.9 (7.51–22.1)

11.0 (8.00–14.0)

13.0 (9.00–17.0)

587

798

964

Asians 2011–2012

2013–2014

2015–2016

1.49 (1.20–1.84)

*

*

1.43 (0.998–1.96)

<LOD

<LOD

3.04 (2.39–4.11)

<LOD

<LOD

5.23 (4.63–6.51)

9.00 (<LOD–12.0)

9.00 (6.00–13.0)

7.44 (5.99–9.64)

12.0 (9.00–15.0)

14.0 (12.00–15.0)

388

361

349

aValues for participants 20+ years of age.

*= geometric mean not calculated because the proportion of results below the limit of detection (0.62 in 2011–2012 and 6.00 pg/mL in 2013–2014 and 2015 and 

2016) was too high to provide a valid result; LOD = limit of detection; NHANES = National Health and Nutrition Examination Survey

Source: CDC 2019; https://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Volume1_Jan2019-508.pdf
BROMODICHLOROMETHANE 116

5. POTENTIAL FOR HUMAN EXPOSURE

as the primary route of exposure during bathing, while inhalation played a stronger role during showering 

(Gordon et al. 2006). 

Tables 5-16, 5-17, and 5-18 contain available human blood, breath, and urine concentrations of 

bromodichloromethane resulting from exposure to this substance via water-related activities.

5.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

The environmental medium most likely to be contaminated with bromodichloromethane is chlorinated 

water, so any person with above-average contact with such water could have above-average exposures. 

This includes individuals who drink very large quantities of water. It may also include persons with 

swimming pools or saunas, where exposure could occur by inhalation (especially if the pool or sauna is 

indoors) or by dermal contact. Since bromodichloromethane levels depend on the organic content of the 

source water before chlorination, persons whose water source is high in organics are likely to have 

finished water with higher-than-average bromodichloromethane levels.

People working in chemical plants or laboratories where bromodichloromethane is made or used would 

also have potentially high exposures to the chemical, most likely by inhalation exposure. Persons living 

near waste sites may have potentially high exposure to bromodichloromethane, but this can only be 

evaluated on a case-by-case basis.

People working at and using chlorinated swimming pools (especially indoor pools), such as lifeguards, 

pool and/or water venue operators, and regular or professional/athletic swimmers, may be exposed to 

bromodichloromethane more often than the general population (Fantuzzi et al. 2001; Lindstrom et al. 

1997). 
BROMODICHLOROMETHANE 117

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-16. Exposure and Blood Concentrations

Population and exposure 

scenario

Study

date

Average media 

concentration 

Average blood 

concentration 

before activity

Average blood 

concentration 

during activity 

Average blood 

concentration 

after activity Reference

100 subjects, ages 18–45; 

10-minute controlled showera

2004 70.9–74.3 μg/m3 

(shower air);

19.9 μg/L (shower 

water)

0.00225 μg/L 

(2.25 ng/L)

0.0648 μg/L 

(64.8 ng/L)

(10 minutes after 

shower)

0.0326 μg/L 

(32.6 ng/L)

(30 minutes after 

shower)

Silva et al. 

2013

7 subjects, ages 21–30; hot water 

shower 

Not 

reported

8.0–46.4 μg/L (tap 

water)

Not reported 25.5–95.2 ng/L 

(5 minutes after 

shower)

Not reported Ashley et al. 

2005

7 subjects, ages 21–30; hot water 

bath 

Not 

reported

6.3–33.0 μg/L (tap 

water)

Not reported 26.0–64.7 ng/L 

(5 minutes after bath)

Not reported Ashley et al. 

2005

150 women; showering/bathing, 

bathing children, postshower/

bathroom time, washing dishes by 

hand, and swimming in summer

Not 

reported

1.3–12.2 μg/L (water) 1.1–4.7 ng/Lb RiveraNúñez et al. 

2012

150 women; showering/bathing, 

bathing children, postshower/

bathroom time, washing dishes by 

hand, and swimming in winter

Not 

reported

6.0–7.3 μg/L (water) 2.1–5.6 ng/Lb RiveraNúñez et al. 

2012

150 women; ingestion of water; 

showering/bathing, bathing 

children, postshower/bathroom 

time, washing dishes by hand, 

and swimming

Not 

reported

6.3–8.5 μg/L (yearly 

average water)

2.0–3.3 ng/L RiveraNúñez et al. 

2012

150 women; non-ingestion of 

water; showering/bathing, bathing 

children, postshower/bathroom 

time, washing dishes by hand, 

and swimming

Not 

reported

6.3–8.5 μg/L (yearly 

average water)

2.3–2.6 ng/L RiveraNúñez et al. 

2012

31 adult subjects; drinking tap 

water

Not 

reported

5.52 μg/L 2.6 pg/mL 3.8 pg/mL 

(10 minutes after 

drink)

2.8 pg/mL 

(60 minutes after 

drink)

Backer et al. 

2000
BROMODICHLOROMETHANE 118

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-16. Exposure and Blood Concentrations

Population and exposure 

scenario

Study

date

Average media 

concentration 

Average blood 

concentration 

before activity

Average blood 

concentration 

during activity 

Average blood 

concentration 

after activity Reference

31 adult subjects; bathing Not 

reported

6.22 μg/L 2.3 pg/mL 17.0 pg/mL 

(10 minutes after 

bath)

9.9 pg/mL 

(30 minutes after 

bath)

Backer et al. 

2000

31 adult subjects; showering Not 

reported

6.27 μg/L 3.3 pg/mL 19.4 pg/mL 

(10 minutes after 

shower)

10.3 pg/mL 

(30 minutes after 

shower)

Backer et al. 

2000

50 females; showering 1999 12.2–13.5 ppb (μg/L)

(median house water 

concentrations)

6.2–6.8 ppb (μg/L)

Not reported 38–43 ppb (μg/L) Lynberg et 

al. 2001

a40°C shower temperature and a water flow rate between 5.6 and 6.7 L/minute; average concentration of bromodichloromethane in shower water. bAverage concentration throughout specified season.
BROMODICHLOROMETHANE 119

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-17. Exposure and Breath (Alveolar Air) Concentrations

Population and exposure 

scenario

Average media 

concentration 

Average breath

concentration 

before activity

Average breath 

concentration 

during activity

Average breath 

concentration 

after activity Reference

9 subjects ages 22–37; 10-minute 

controlled shower

1.9 μg/L (shower 

water)

1.1 μg/m3 (shower air)

0.1 μg/m3 1.3 μg/m3 Lourencetti et al. 

2010

11 subjects; 40-minute swim indoor 

pool

1.9 μg/L (pool water)

1.1 μg/m3 (pool air)

0.1 μg/m3 1.8 μg/m3 Lourencetti et al. 

2010

Swimmers exposed under training 

conditions for 2 hours using indoor 

pool

2.68 μg/m3 (pool air) Not reported; 

<2.68 μg/m3

3–3.2 μg/m3 

(1 hour into activity); 

4.5–5.5 μg/m3 

(2 hours into activity)

2 μg/m3 (outside for 

10 minutes); 

<1 μg/m3 (outside 

for 55 minutes)

Lindstrom et al. 

1997

32 subjects working at public indoor 

pools

2–5.3 μg/L (pool 

water);

8.7, 3.5, and 

2.9 μg/m3 (poolside, 

reception area, and 

engine room)

0.3–9.5 μg/m3

(average 

concentrations during 

work day)

Fantuzzi et al. 2001
BROMODICHLOROMETHANE 120

5. POTENTIAL FOR HUMAN EXPOSURE

Table 5-18. Exposure and Urine Concentrations

Population and exposure 

scenario

Average media 

concentration 

Average urine

concentration 

before activity

Average urine 

concentration at end 

of exposure

Average urine

concentration 

postexposure Reference

14 male and female indoor 

swimming pool workers ages 23–

50; 2–4-hour work shifts

2.2 μg/L 

(2,200 ng/L) 

(pool water)

18–23 ng/L (mean 

20 ng/L)

23.9 ng/L (2 hour shift)

26.9 ng/L (4 hour shift)

Caro and Gallego 

2007

1 indoor swimming pool worker; 

2-hour work shift

2.2 μg/L 

(2,200 ng/L) 

(pool water)

20 ng/L 40 ng/L 20 ng/L (120 minutes after 

exposure)

Caro and Gallego 

2007

10 swimmers using indoor pool 

ages 23–50; 2 times/week 1 hour 

swimming

2.2 μg/L 

(2,200 ng/L) 

(pool water)

21.0 ng/L 70.4 ng/L (at the end 

of 1 hour)

Caro and Gallego 

2007

1 swimmer using indoor pool; 

2 times/week 1 hour swimming

2.2 μg/L 

(2,200 ng/L) 

(pool water)

20 ng/L 80 ng/L (at the end of 

1 hour)

20 ng/L (180 minutes after 

exposure)

Caro and Gallego 

2007
BROMODICHLOROMETHANE 121

CHAPTER 6. ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of bromodichloromethane 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 bromodichloromethane.

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/ocular exposure of humans and 

animals to bromodichloromethane 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 bromodichloromethane. The number of human and animal studies examining each endpoint is indicated regardless of 

whether an effect was found and the quality of the study or studies. 

As illustrated in Figure 6-1, most of the data on the toxicity of bromodichloromethane come from oral 

studies in laboratory animals. The most commonly examined endpoints were body weight, liver, and 

kidneys. A small number of studies involving exposure to bromodichloromethane in tap water primarily 

examined developmental toxicity endpoints. The laboratory animal toxicity database consists of a small 

number of inhalation studies examining a couple of potential endpoints and no dermal exposure 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 
BROMODICHLOROMETHANE 122

6. ADEQUACY OF THE DATABASE

Figure 6-1. Summary of Existing Health Effects Studies on 

Bromodichloromethane By Route and Endpoint* 

Potential body weight, liver, and kidney effects were the most studied endpoints 

The majority of the studies examined oral exposure in animals (versus humans) 

*Includes studies discussed in Chapter 2; a total of 84 studies (including those 

finding no effect) have examined toxicity; most studies examined multiple 

endpoints.
BROMODICHLOROMETHANE 123

6. ADEQUACY OF THE DATABASE

health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific 

information missing from the scientific literature.

Acute-Duration MRLs. The available acute inhalation database was not considered adequate for 

derivation of an MRL. Several limitations were identified, including the lack of examination of the 

respiratory tract, lack of reporting incidence data for the liver and kidney lesions, and lack of 

developmental toxicity studies, particularly since developmental toxicity is a sensitive endpoint following 

oral exposure. Additional inhalation toxicity studies are needed; these studies should include examination 

of suspected sensitive targets including the respiratory tract, kidney, and liver. Developmental toxicity 

studies are also needed to determine whether this is a more sensitive endpoint than liver or kidney 

toxicity.

Intermediate-Duration MRLs. The available intermediate inhalation database was not considered 

adequate for derivation of an MRL. The lowest LOAEL identified in the 3-week study conducted by 

Torti et al. (2001) was for renal toxicity. As with acute inhalation exposure, a number of limitations were 

identified in the database, including the lack of incidence data for the kidney lesions, lack of examination 

of the respiratory tract, lack of developmental toxicity data, and relatively short duration of the only 

intermediate-duration study. Additional studies involving at least 13 weeks of exposure and examination 

of a wide array of tissues and systems are needed to derive an inhalation MRL. 

The database for intermediate-duration oral exposure was considered inadequate for derivation of an 

MRL. Although the existing database includes a number of adequate studies examining relevant 

endpoints, an MRL based on the lowest LOAEL (6.1 mg/kg/day) was lower than the MRL derived for 

chronic-duration oral exposure. Additional studies testing lower doses and with a larger number of 

animals per group would provide valuable information for deriving an intermediate-duration oral MRL. 

Chronic-Duration MRLs. The lack of chronic-duration inhalation studies precluded derivation of a 

chronic MRL. Chronic toxicity studies examining a wide range of endpoints are needed to identify the 

most sensitive target and establish concentration-response relationships.

Health Effects. Toxicokinetic studies (Backer et al. 2000; Kenyon et al. 2016; Nuckols et al. 2005) 

provide evidence that inhalation and dermal exposure to bromodichloromethane are significant 

contributors to the blood bromodichloromethane levels. However, Torti et al. (2001) is the only available 

inhalation study in laboratory animals and no dermal exposure studies were identified. Inhalation and 
BROMODICHLOROMETHANE 124

6. ADEQUACY OF THE DATABASE

dermal exposure studies examining a wide range of potential endpoints are needed to identify whether the 

critical targets of toxicity for these routes differ from oral exposure targets and establish dose-response 

relationships. Oral toxicity studies in laboratory animals have administered bromodichloromethane via 

drinking water, gavage in oil, and feed. In humans, exposure via drinking water would be prominent oral 

exposure route. Studies are needed to investigate possible differences between various oral exposure 

subroutes; these data could provide insight into the applicability of dietary and gavage administration 

studies for assessing potential human toxicity of bromodichloromethane.

Hepatic. Oral exposure studies in laboratory animals have found considerable overlap in NOAEL 

and LOAEL values across studies, which are likely due to differences in oral route of exposure 

(i.e., gavage, drinking water, feed) and the vehicle used (Aida et al. 1989, 1992; Chu et al. 1982; 

Hooth et al. 2002; NTP 2006). Additional studies are needed to evaluate the relevance of each of 

these routes to humans exposed to bromodichloromethane in tap water.

Renal. Available oral exposure studies in laboratory animals suggest a higher toxicity associated 

with gavage administration than drinking water or feed exposure (Aida et al. 1989, 1992; Chu et al. 

1982; Lipsky et al. 1993; Lock et al. 2004; NTP 1987, 2006). Additional studies are needed to 

explain these differences and evaluate whether the results of gavage studies are applicable to humans.

Reproductive. Human and animal studies provide suggestive evidence that the reproductive 

system of males and females are sensitive targets of bromodichloromethane toxicity (Bielmeier et al. 

2001, 2004, 2007; Windham et al. 2003). However, the findings of many of the studies have not been 

confirmed and it is not known if the alterations would result in impaired reproductive function. 

Additional studies in animals examining reproductive endpoints in males and females would provide 

data useful for determining whether reproductive toxicity is an endpoint of concern for the general 

population.

Developmental. Studies in F344 rats (Bielmeier et al. 2001; Narotosky et al. 1997) have found 

increases in full-litter resorptions; however, this was not found when Sprague-Dawley rats were 

similarly exposed to the same or higher doses (Bielmeier et al. 2001) and was not observed in another 

developmental toxicity study (Christian et al. 2001a) or a 2-generation study (Christian et al. 2001b). 

Although this endpoint was used as the basis of the acute-duration oral MRL, additional research is 

needed to explain the strain difference and assess whether it is a relevant endpoint in humans. 
BROMODICHLOROMETHANE 125

6. ADEQUACY OF THE DATABASE

Epidemiology and Human Dosimetry Studies. A small number of epidemiology studies have 

evaluated the toxicity of bromodichloromethane in populations exposed to the compound in tap water 

using either bromodichloromethane levels in blood or tap water as exposure metrics (Bove et al. 2007; 

Burch et al. 2015; Cao et al. 2016; Danileviciute et al. 2012; Dodd and King 2001; Grazuleviciene et al. 

2013; Hoffman et al. 2008; Iszatt et al. 2011; King et al. 2000; MacLehose et al. 2008; Rivera-Núñez and 

Wright 2013; Summerhayes et al. 2012; Waller et al. 1998; Wright et al. 2004; Zeng et al. 2013). A 

common limitation of these studies is the lack of control for the presence of other trihalomethanes and 

disinfection byproducts, many of which have similar toxic endpoints as bromodichloromethane. 

Additionally, epidemiology studies controlling confounding exposures and examining endpoints that have 

been shown to occur at low doses in laboratory animals (hepatic, renal, immunological, reproductive, and 

developmental) would be useful. In vitro studies (Chen et al. 2003, 2004) suggest an effect on 

trophoblasts; in vivo studies in nonhuman primates would provide additional information for the 

interpretation of the human studies finding increases in spontaneous abortions.

Biomarkers of Exposure and Effect. Levels of bromodichloromethane in alveolar air, urine, and 

blood have been used as biomarkers of exposure. Although increases in these levels are associated with 

exposure, additional research is needed to extrapolate biomarker levels to external exposure doses.

Absorption, Distribution, Metabolism, and Excretion. There are limited data on the toxicokinetic 

properties of bromodichloromethane following inhalation or dermal exposure; since these routes are 

major contributors to blood levels in populations using tap water containing bromodichloromethane, 

additional toxicokinetic data would be useful. Studies would also be useful evaluating potential 

metabolic saturation; these data would be useful for assessing the applicability of high-dose studies in 

laboratory animals to low-dose human exposure scenarios. A PBPK model that would allow 

extrapolation from animals to humans would decrease the uncertainties in MRL derivations.

Comparative Toxicokinetics. There are limited data available that allow for a comparison of the 

toxicokinetic properties across species. Since metabolites are responsible for the toxicity of 

bromodichloromethane, studies comparing metabolism in different animal species and humans could 

provide valuable information in extrapolating animal toxicity data to humans.

Children’s Susceptibility. No studies have evaluated the toxicity of bromodichloromethane in 

children or young animals. Bromodichloromethane is primarily metabolized by CYP2E1, which is fully 

developed in children; it is not known if there would be toxicodynamic differences between children and 
BROMODICHLOROMETHANE 126

6. ADEQUACY OF THE DATABASE

adults that might influence susceptibility. Studies in young animals and/or children would be useful to 

address these concerns.

Physical and Chemical Properties. Further studies on these parameters do not appear to be 

essential.

Production, Import/Export, Use, Release, and Disposal. Data on current uses and disposal 

practices would be valuable in determining whether industrial activities pose an important source of 

human exposure to bromodichloromethane.

Environmental Fate. Studies to obtain reliable quantitative rate values for the key fate processes of 

bromodichloromethane would be valuable. Of particular importance would be studies on the 

volatilization of bromodichloromethane from chlorinated drinking water, and on the atmospheric 

reactions of bromodichloromethane. Studies of chemical and biological transformation and degradation 

rates in soil and water under conditions comparable to those around waste sites would also be helpful.

Bioavailability from Environmental Media. Based on the physical properties of bromodichloromethane, it is not expected that bioavailability would vary widely between water, soil, food, and other 

media. Investigative studies on the relative bioavailability of bromodichloromethane in different 

environmental media would add to the understanding of this chemical’s behavior.

Food Chain Bioaccumulation. Studies on bromodichloromethane uptake and retention by fish, 

plants, and other food sources would be helpful.

Exposure Levels in Environmental Media. Studies of bromodichloromethane levels in air 

(especially indoor air) in the vicinity of open bodies of chlorinated water, including water treatment 

plants, would be helpful. In view of the ready volatilization of bromodichloromethane from water, 

airborne levels in such locations might be significant.

Exposure Levels in Humans. Additional data on bromodichloromethane levels in air to estimate 

inhalation exposure in ambient air or the workplace would be beneficial. It would be helpful to know 

how rapidly bromodichloromethane would volatilize from a glass of water, a bathtub full of water, and a 

swimming pool, and what concentration would then be in the breathing zone of occupants of the house.
BROMODICHLOROMETHANE 127

6. ADEQUACY OF THE DATABASE

Exposures of Children. Based on the concentrations of bromodichloromethane measured in water 

used for drinking and bathing, studies are needed to assess the inhalation, dermal, ocular, and oral 

exposures of children during water-related activities. Data on inhalation and dermal doses would 

especially be useful for in and around both indoor and outdoor swimming pools.

Analytical Methods. Since bromodichloromethane may be toxic to humans, very low levels in water, 

air, or other media may be of concern, so improvements in detection sensitivity would be valuable,

especially in environmental media such as water and air.

6.3 ONGOING STUDIES

No ongoing studies were identified for bromodichloromethane.
BROMODICHLOROMETHANE 128

CHAPTER 7. REGULATIONS AND GUIDELINES

Pertinent international and national regulations, advisories, and guidelines regarding 

bromodichloromethane in air, water, and other media are summarized in Table 7-1. This table is not an 

exhaustive list, and current regulations should be verified by the appropriate regulatory agency.

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

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

may be of concern at hazardous waste sites. See Section 1.3 and Appendix A for detailed information on 

the MRLs for bromodichloromethane.

Table 7-1. Regulations and Guidelines Applicable to Bromodichloromethane

Agency Description Information Reference

Air

EPA RfC Not evaluated IRIS 2002

Subchronic p-RfC 0.02 mg/m3 a EPA 2009a

WHO Air quality guidelines Not listed WHO 2010

Water & Food

EPA Drinking water standards and health 

advisories 

EPA 2018a

1-Day health advisory (10-kg child) 1 mg/L

10-Day health advisory (10-kg child) 0.6 mg/L

DWEL 0.1 mg/L

Lifetime health advisory No data

10-4 Cancer risk 0.1 mg/L

National primary drinking water regulations EPA 2009b

MCL - Total trihalomethanes 0.080 mg/L

MCLG - Bromodichloromethane 0 mg/L

RfD 0.02 mg/kg/dayb IRIS 2002

Subchronic p-RfD 0.008 mg/kg/dayc EPA 2009a

WHO Drinking water quality guidelines WHO 2017

Guideline value 0.06 mg/L (60 μg/L)

TDI 21.4 μg/kg body weight

FDA Substances Added to Food Not listedd FDA 2019

Allowable level for disinfection byproducts in 

bottled water – Total trihalomethanes

0.080 mg/L FDA 2017

Cancer

HHS Carcinogenicity classification Reasonably anticipated to 

be a human carcinogen

NTP 2016

EPA Carcinogenicity classification B2e IRIS 2002
BROMODICHLOROMETHANE 129

7. REGULATIONS AND GUIDELINES

Table 7-1. Regulations and Guidelines Applicable to Bromodichloromethane

Agency Description Information Reference

IARC Carcinogenicity classification Group 2Bf IARC 1999

Occupational

OSHA PEL (8-hour TWA) for general industry No data OSHA 2018a

PEL (8-hour TWA) for shipyards and 

construction

No data OSHA 2018b

PEL (8-hour TWA) for construction No data OSHA 2018c

NIOSH REL (up to 10-hour TWA) No data NIOSH 2018

Emergency Criteria

EPA AEGLs-air No data EPA 2018b

DOE PACs-air DOE 2018a

PAC-1g 1.3 mg/m3

PAC-2g 14 mg/m3

PAC-3g 85 mg/m3

aThe subchronic p-RfC is based on a NOAEL of 20 mg/m3 for kidney degeneration in mice. bThe RfD is based on a LOAEL of 17.9 mg/kg/day for renal cytomegaly in a chronic mouse gavage bioassay.

cThe subchronic p-RfD is based on pregnancy loss in gavage-treated rats. dThe 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." eB2: probable human carcinogen. f

Group 2B: possibly carcinogenic to humans.

gDefinitions of PAC terminology are available from U.S. Department of Energy (DOE 2018b).

AEGL = acute exposure guideline levels; DOE = Department of Energy; DWEL = drinking water equivalent level; 

EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency; FDA = Food and 

Drug Administration; FEMA = Flavor Extract Manufacturer's Association; GRAS = generally recognized as safe;

HHS = Department of Health and Human Services; IARC = International Agency for Research on Cancer; 

IRIS = Integrated Risk Information System; JECFA = Joint FAO/WHO Expert Committee on Food Additives; 

LOAEL = lowest-observed-adverse-effect level; MCL = maximum contaminant level; MCLG = maximum contaminant 

level goal; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; 

OSHA = Occupational Safety and Health Administration; PAC = protective action criteria; PEL = permissible 

exposure limit; PPRTV = provisional peer-reviewed toxicity value; p-RfC = provisional inhalation reference 

concentration; p-RfD = provisional oral reference dose; REL = recommended exposure limit; RfC = inhalation 

reference concentration; RfD = oral reference dose; TDI = tolerable daily intake; TLV = threshold limit value; 

TWA = time-weighted average; WHO = World Health Organization
BROMODICHLOROMETHANE 130

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BROMODICHLOROMETHANE 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.
BROMODICHLOROMETHANE 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.
BROMODICHLOROMETHANE A-3

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Bromodichloromethane 

75-27-4

March 2020

Final

Inhalation

Acute

MRL Summary: There are insufficient data for derivation of an acute-duration inhalation MRL. 

Rationale for Not Deriving an MRL: The acute-duration inhalation database was not considered suitable 

for derivation of an MRL due to several data gaps: lack of examination of the respiratory tract, lack of 

incidence data in the only available inhalation study, and lack of developmental toxicity studies. 

There are limited data on the acute inhalation toxicity of bromodichloromethane. Torti et al. (2001) 

reported hepatic, renal, body weight, and ocular effects in two strains of mice exposed to bromodichloromethane vapor 6 hours/day, 7 days/week for 1 week. The kidney was the most sensitive target, with 

tubular degeneration and nephrosis observed at ≥10 ppm; the NOAEL was 1 ppm. At 30 ppm, 

hepatocellular centrilobular degeneration and decreases in body weight gain were observed. Increases in 

mortality were observed at ≥30 ppm; the cause of death was not reported, but the investigators noted that 

animals exposed to 100 and 150 ppm were lethargic with labored breathing. There are several 

methodological and reporting deficiencies in the Torti et al. (2001) study that limit its usefulness for 

deriving an MRL. One limitation is the lack of examination of the respiratory tract, which could be a 

sensitive target of toxicity. Mild eye irritation was noted at 30 ppm, so it is possible that bromodichloromethane also resulted in respiratory tract irritation. Another limitation is the lack of reporting of 

incidence data for the liver and kidney lesions; only a description of the lesions was provided. Thus, there 

is some uncertainty in identifying NOAEL and LOAEL values for the study. 

Acute-duration oral studies have found developmental toxicity to be a more sensitive target of toxicity 

than the kidney or liver. For example, increases in the incidence of full-litter resorptions were observed 

in rats administered ≥50 mg/kg/day during gestation (Narotsky et al. 1997); the lowest LOAEL for kidney 

effects in rats was 150 mg/kg/day with a NOAEL of 75 mg/kg/day (Thornton-Manning et al. 1994) and 

the lowest LOAEL for liver effects was 74 mg/kg/day with a NOAEL of 37 mg/kg/day (Condie et al. 

1983). Although the causative agent (bromodichloromethane or a metabolite) of the litter resorptions is 

not known, there are no data to suggest that developmental effects will not be a sensitive endpoint 

following inhalation exposure. 

Agency Contacts (Chemical Managers): Susan Ingber 
BROMODICHLOROMETHANE A-4

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Bromodichloromethane 

75-27-4

March 2020

Final

Inhalation

Intermediate

MRL Summary: There are insufficient data for derivation of an intermediate-duration inhalation MRL.

Rationale for Not Deriving an MRL: The intermediate-duration inhalation database was not considered 

suitable for derivation of an MRL due to several data gaps: lack of incidence data for histological 

alterations, lack of examination of the respiratory tract, and relatively short duration of the only available 

intermediate-duration study (Torti et al. 2001), as well as the lack of developmental toxicity studies. 

The intermediate-duration inhalation database for bromodichloromethane is limited to several mouse 

studies conducted by Torti et al. (2001). In two strains of mice, renal tubular degeneration was observed 

following exposure to 10 or 30 ppm 6 hours/day, 7 days/week for 3 weeks; the NOAEL was 3 ppm. No 

hepatic, body weight, or urinary bladder effects were observed in these studies at the highest 

concentration of 30 ppm. Minimal centrilobular hepatocellular degeneration was observed at 10 and 

30 ppm in p53 heterogenous mouse strains (Torti et al. 2001). The kidney and liver lesions observed in 

the mice were described; however, no incidence data were provided Torti et al. (2001). Thus, there is 

some uncertainty in identifying NOAEL and LOAEL values for the study. Torti et al. (2001) also 

exposed the heterogenous mouse strains to ≤15 ppm bromodichloromethane for 13 weeks. The 

investigators noted minimal cortical scarring and tubular karyocytomegaly in the kidneys, but did not 

provide any additional information that would allow for identification of a LOAEL; no other effects were 

noted. This study in transgenic mice was not considered a suitable basis for an MRL. The Torti et al. 

(2001) studies did not include an examination of the respiratory tract; results from the acute-duration 

inhalation study by these investigators provide suggestive evidence (labored breathing at lethal 

concentrations and eye irritation at 30 ppm) that bromodichloromethane exposure may affect the 

respiratory tract. Intermediate and chronic oral studies (NTP 1987) also provide suggestive evidence that 

the renal toxicity of bromodichloromethane increases with exposure duration. Thus, a 3-week study may 

not be suitable for establishing an MRL for continuous exposure for up to 1 year. 

Liver, kidney, immunological, neurological, and developmental effects have been observed in 

intermediate-duration oral studies (Aida et al. 1989, 1992; Balster and Borzelleca 1982; Christian et al. 

2001a; French et al. 1999; NTP 1987). The available data suggest that the liver may be the most sensitive 

effect for oral exposure; however, based on the Torti et al. (2001) inhalation study, the kidney may be 

more sensitive than the liver following inhalation exposure. The LOAELs for kidney (71 mg/kg/day), 

immunological (49 mg/kg/day), and developmental (82 mg/kg/day) effects identified in intermediateduration oral studies are similar. However, immunological and developmental toxicity have not been 

assessed in inhalation studies. Given these data gaps, there is considerable uncertainty in establishing an 

intermediate-duration inhalation MRL for bromodichloromethane at this time.

Agency Contacts (Chemical Managers): Susan Ingber 
BROMODICHLOROMETHANE A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Bromodichloromethane 

75-27-4

March 2020

Final

Inhalation

Chronic

MRL Summary: There are insufficient data for derivation of a chronic-duration inhalation MRL.

Rationale for Not Deriving an MRL: No chronic-duration inhalation studies were identified. 

Agency Contacts (Chemical Managers): Susan Ingber 
BROMODICHLOROMETHANE A-6

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:

Bromodichloromethane 

75-27-4

March 2020

Final

Oral

Acute

0.07 mg/kg/day

Full-litter resorption

Narotsky et al. 1997

BMDL05 of 7.15 mg/kg/day

100

15

Rat

MRL Summary: An acute-duration oral MRL of 0.07 mg/kg/day was derived for bromodichloromethane 

based on an increased incidence of full-litter resorptions in rats administered bromodichloromethane via 

gavage on GDs 6–15 (Narotsky et al. 1997). The MRL is based on a BMDL05 of 7.15 mg/kg/day and a 

total uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human 

variability). 

Selection of the Critical Effect: A number of studies have evaluated the toxicity of bromodichloromethane following acute, oral exposure; these studies examine a wide range of potential endpoints 

including liver and kidney effects (Condie et al. 1983; Keegan et al. 1998; Lilly et al. 1994, 1996; 

Munson et al. 1982; Ruddick et al. 1983; Thornton-Manning et al. 1994), immunotoxicity (French et al. 

1999), reproductive toxicity (Bielmeier et al. 2001), and developmental toxicity (Bielmeier et al. 2001, 

2004; Narotsky et al. 1997; Ruddick et al. 1983). The LOAELs for these studies range from 50 to 

400 mg/kg/day; a summary of select LOAELs is presented in Table A-1 (studies identifying LOAELs for 

body weight effects were not included since this is not considered a primary effect of bromodichloromethane). 

The available data suggest that developmental toxicity, particularly full-litter resorption, is the most 

sensitive endpoint following acute-duration oral exposure. In multiple studies conducted by Bielmeier et 

al. (2001) and Narotsky et al. (1997), full-litter resorptions have been observed at 50 mg/kg/day (8–17%

resorptions) and ≥75 mg/kg/day (17–100% resorptions). Similar LOAELs (≥74–75 mg/kg/day) were 

identified for liver and immunological effects. The liver effects consisted of centrilobular pallor, vacuolar

degeneration and necrosis, and increases in liver enzymes (Condie et al. 1983; Keegan et al. 1998; Lilly et 

al. 1994, 1996; Munson et al. 1982; Thornton-Manning et al. 1994). Two studies demonstrated impaired

immune responses in rats and mice administered ≥75 mg/kg/day (French et al. 1999; Munson et al. 1982). 

The kidney appears to be slightly less sensitive than other targets, with LOAEL values ranging from 

148 to 400 mg/kg/day. The effects included tubular degeneration, hyperplasia, and necrosis, and 

increases in blood urea nitrogen levels (Condie et al. 1983; Lilly et al. 1994, 1996; Munson et al. 1982; 

Thornton-Manning et al. 1994). 
BROMODICHLOROMETHANE A-7

APPENDIX A

Table A-1. Summary of Relevant LOAEL Values Following Acute Oral Exposure to Bromodichloromethane

Species

Duration/

route

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Developmental effects

F344 rat GDs 6–15

(GW)

25 50 17% full-litter resorption Narotsky et al. 1997

F344 rat GDs 6–15

(GO)

25 50 8% full-litter resorption Narotsky et al. 1997

F344 rat GDs 6–10

(GW)

– 75a 62% full-litter resorption Bielmeier et al. 2001

F344 rat GDs 8–9, or 

GD 0

(GW)

– 75a 64% full-litter resorption Bielmeier et al. 2001

F344 rat GDs 6–10 or 

GDs 6–15

(GW)

– 75a 75 or 50% full-litter resorption Bielmeier et al. 2001

F344 rat GDs 6–10

(GW)

– 75a 80% full-litter resorption Bielmeier et al. 2004

SpragueDawley ratGDs 6–10

(GW)

100 0% full-litter resorption Bielmeier et al. 2001

SpragueDawley ratGDs 6–15

(GO)

100 200 Delayed ossification of sternebrae Ruddick et al. 1983

Kidney effects

CD-1 mouse 14 days

(GO)

74 148 Intratubular mineralization, epithelial hyperplasia, and 

cytomegaly

Condie et al. 1983

Fischer 344 rat 5 days

(GW)

75 150 Tubular vacuolar degeneration Thornton-Manning et 

al. 1994

Fischer 344 rat Once

(GW)

200 Proximal tubule necrosis Lilly et al. 1996

CD-1 mouse 14 days

(GW)

125 250 Increased blood urea nitrogen levels Munson et al. 1982

Fischer 344 rat Once

(GW) or (GO)

200 400 Renal tubule degeneration and necrosis Lilly et al. 1994
BROMODICHLOROMETHANE A-8

APPENDIX A

Table A-1. Summary of Relevant LOAEL Values Following Acute Oral Exposure to Bromodichloromethane

Species

Duration/

route

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Liver effects

CD-1 mouse 14 days

(GO)

37 74 Centrilobular pallor Condie et al. 1983

Fischer 344 rat 5 days

(GW)

75 150 Hepatocellular vacuolar degeneration Thornton-Manning et 

al. 1994

Fisher 344 rat Once

(G)

163.8 245.7 Increases in alanine aminotransferase, aspartate 

aminotransferase, and sorbitol dehydrogenase

Keegan et al. 1998

CD-1 mouse 14 days

(GW)

125 250 Aspartate aminotransferase and alanine 

aminotransferase levels

Munson et al. 1982

Fischer 344 rat Once

(GW) or (GO)

200 400 Vacuolar degeneration and necrosis Lilly et al. 1994

Fischer 344 rat Once

(GW)

200 400 Centrilobular necrosis and vacuolar degeneration Lilly et al. 1996

Immunological effects

F344 rat 5 days

(GW)

– 75 Impaired response to T-lymphocyte stimulants French et al. 1999

CD-1 mouse 14 days

(GW)

125 250 Altered response to sheep red blood cells Munson et al. 1982

aConsidered a serious LOAEL.

G = gavage; GD = gestation day; GO = gavage in oil vehicle; GW = gavage in water vehicle; LOAEL = lowest observed adverse effect level; 

NOAEL = no-observed-adverse-effect level
BROMODICHLOROMETHANE A-9

APPENDIX A

The lowest LOAEL for an acute-duration study was 50 mg/kg/day for full-litter resorptions in rats 

(Narotsky et al. 1997) and this was selected as the critical effect for the MRL. Although the Narotsky et 

al. (1997) and Bielmeier et al. (2001) studies have consistently shown an increase in pregnancy loss in 

F344 rats administered bromodichloromethane via gavage on GDs 6–10, other studies have not found this 

effect in Sprague-Dawley rats or in rabbits. No pregnancy losses were observed in Sprague-Dawley rats 

administered gavage doses as high as 100 mg/kg/day on GDs 6–10 (Bielmeier et al. 2001) or 

200 mg/kg/day on GDs 6–15 (Ruddick et al. 1983), exposed via drinking water to 82.0 mg/kg/day on 

GDs 6–21 (Christian et al. 2001a), or exposed in drinking water to 29.5–109 mg/kg/day in a 2-generation 

study (Christian et al. 2001b). Additionally, no pregnancy losses were observed in New Zealand white 

rabbits exposed to doses as high as 55.3 mg/kg/day on GDs 6–29 (Christian et al. 2001a). Support for the 

applicability of the pregnancy loss effect for derivation of an MRL comes from human studies that found 

significant associations between bromodichloromethane in tap water and an increased risk of spontaneous 

abortion (Waller et al. 1998) or stillbirths (King et al. 2000); it is noted that these studies involved 

exposure to multiple disinfection byproducts, including other trihalomethanes.

Selection of the Principal Study: As summarized in Table A-1, Bielmeier et al. (2001) and Narotsky et 

al. (1997) conducted several studies evaluating full-litter resorptions in rats. Together, the studies 

demonstrate a dose-response relationship between bromodichloromethane exposure and full-litter 

resorption. The incidence of full-litter resorptions in selected studies conducted by these investigators are 

presented in Table A-2. Since the Narotsky et al. (1997) studies tested lower concentrations and 

identified a NOAEL, it was selected as the principal study for the MRL.

Table A-2. Incidence of Full-Litter Resorptions in F344 Rats Administered 

Bromodichloromethane via Gavage

Dose (mg/kg/day)

0 25 50 75 100

Narotsky et al. 1997 (GW) 0/14 (0%) 0/12 (0%) 2/12 (17%) 3/14 (21%)

Narotsky et al. 1997 (GO) 0/12 (0%) 0/14 (0%) 1/13 (8%) 10/12 (83%)

Bielmeier et al. 2001 (GDs 6–15) 0% 50%

Bielmeier et al. 2001 (GDs 9) 0% 64% 100%

G = gavage; GD = gestation day; GO = gavage in oil vehicle; GW = gavage in water vehicle

Summary of the Principal Study:

Narotsky MG, Pegram RA, Kavlock RJ. 1997. Effect of dosing vehicle on the developmental toxicity of 

bromodichloromethane and carbon tetrachloride in rats. Fundam Appl Toxicol 40:30-36.

Groups of pregnant F344 rats (12–14/group) were administered 0, 25, 50, or 75 mg /kg/day bromodichloromethane by gavage in corn oil or an aqueous vehicle on GDs 6–15. Endpoints monitored included 

maternal weight and clinical signs. Pups were examined and weighed individually on PNDs 1 and 6. 

Dams were killed on PND 6, and the number of uterine implantations were recorded. The uteri of rats 

that did not deliver were stained to detect cases of full-litter resorptions. 

Clinical signs seen only in the corn oil vehicle rats included hunched back (75 mg/kg/day) and 

chromodacryorrhea/lacrimation (≥50 mg/kg/day). Piloerection occurred at 75 mg/kg/day with both 

vehicles and at 50 mg/kg/day with the aqueous vehicle. Body weight gain on GDs 6–8 was reduced about 

83% in rats dosed with 25 mg/kg/day in aqueous vehicle and about 61% with the oil vehicle (statistically 
BROMODICHLOROMETHANE A-10

APPENDIX A

significant only in aqueous vehicle group). Rats in the higher dose groups lost weight (both vehicles). 

Body weight gains were not reported at other time periods. Full-litter resorptions occurred in 50 and 

75 mg/kg/day groups for both vehicles, but were not observed in controls or 25 mg/kg/day groups. The 

incidences of full-litter resorption are presented in Table A-2. In surviving litters, there was no significant 

effect on gestation length, postnatal viability, or pup weight on PND 1 or 6. In a toxicokinetic study also 

conducted, bromodichloromethane levels in the blood declined faster in aqueous vehicle groups than in 

corn oil vehicle groups; the blood half-times were 2.7 and 3.6 hours, respectively. 

Selection of the Point of Departure: The BMDL05 of 7.15 mg/kg/day for full-litter resorption was 

selected as the basis of the MRL. 

Benchmark dose (BMD) modeling was conducted to identify a point of departure using the incidence data 

for full-litter resorptions in rats administered bromodichloromethane in an aqueous vehicle. The oil 

vehicle data were not modeled since administration in an aqueous vehicle is most likely to mimic human 

exposure to bromodichloromethane in water. The data were fit to all available dichotomous models in 

EPA’s Benchmark Dose Software (BMDS, version 3.1.1) using the extra risk option. Adequate model fit 

was judged by three criteria: goodness-of-fit statistics (p-value >0.1), visual inspection of the doseresponse curve, and scaled residual at the data point (except the control) closest to the predefined 

benchmark response (BMR). Among all of the models providing adequate fit to the data, the lowest 

BMDL (95% lower confidence limit on the benchmark concentration) was selected as the point of 

departure when the difference between the BMDLs estimated from these models was >3-fold; otherwise, 

the BMDL from the model with the lowest Akaike’s Information Criterion (AIC) was chosen. Since the 

endpoint was developmental toxicity, a BMR of 5% was used. The model predictions for the gavage in 

aqueous solution are presented in Table A-3 and the fit of the selected model is presented in Figure A-1. 

A BMDL05 value of 7.15 mg/kg/day was calculated using the incidence data for rats administered 

bromodichloromethane via gavage in aqueous solution. Although the BMDL05 of 7.15 mg/kg/day was 

lower than the empirical NOAEL of 25 mg/kg/day identified in the study, it was selected as the point of 

departure because it provides a better indicator of the dose-response relationship than the NOAEL, which 

is a single data point. 
BROMODICHLOROMETHANE A-11

APPENDIX A

Table A-3. Model Predictions for Full-Litter Resorptions in Rats Orally 

Administered Bromodichloromethane in an Aqueous Vehicle 

(Narotsky et al. 1997)

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMD05

(mg/kg/day)

BMDL05

(mg/kg/day)

Dose 

below 

BMD

Dose 

above 

BMD

Overall 

largest

Gammac 2 0.77 0.68 -0.48 0.67 0.67 32.30 36.34 10.61

Logistic 2 1.49 0.47 -0.57 0.98 0.98 31.10 41.00 25.03

LogLogisticd 2 0.77 0.68 -0.52 0.66 0.66 30.34 35.59 9.60

LogProbitd 1 5.70 0.02 -1.22 -1.13 1.50 38.92 ND ND

Multistage (1-degree)e 2 1.06 0.59 0.00 -0.93 -0.93 31.22 18.28 9.48

Multistage (2-degree)e 3 0.75 0.86 -0.60 0.60 0.60 28.43 32.80 10.43

Multistage (3-degree)e 2 0.77 0.68 -0.59 0.61 0.61 32.43 33.22 10.43

Probit 2 1.27 0.53 -0.53 0.90 0.90 30.81 39.58 23.38

Dichotomous Hillf 1 0.00 0.99 -0.00 0.00 0.00 31.36 43.66 7.15

Weibullc 2 0.82 0.67 -0.54 0.68 0.68 30.40 35.31 10.47

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMD; also the largest residual at any dose.

cPower restricted to ≥1.

dSlope restricted to ≥1.

eBetas restricted to ≥0.

f

Selected model. BMDLs for models providing adequate fit were sufficiently close (differed by <3-fold), so the model 

with the lowest AIC was selected (Dichotomous Hill).

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMDL = 95% lower confidence limit on the BMD (subscripts denote 

benchmark response: i.e., 050 = exposure concentration associated with 5% extra risk); DF = degrees of freedom; 

ND = not determined, goodness-of-fit p-value <0.1
BROMODICHLOROMETHANE A-12

APPENDIX A

Figure A-1. Fit of Dichotomous Hill Model to Data on Incidence of FullLitter Resorption in Rats Administered Bromodichloromethane in 

Aqueous Vehicle 

Adjustment for Intermittent Exposure: Not applicable.

Uncertainty Factor: The BMDL05 is divided by a total uncertainty factor of 100 

• 10 for extrapolation from animals to humans

• 10 for human variability

MRL = BMDL05 ÷ UFs

 7.15 mg/kg/day ÷ (10 x 10) = 0.07 mg/kg/day 

Other Additional Studies or Pertinent Information: EPA (2005b) estimated that the average exposure 

of the general population to bromodichloromethane is 20 μg/person/day (0.0003 mg/kg/day assuming a 

reference body weight of 70 kg) from surface water systems and 8.1 μg/person/day (0.0001 mg/kg/day) 

from groundwater systems. These average intakes are approximately 1,000-fold lower than the MRL. 

Agency Contacts (Chemical Managers): Susan Ingber 

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

-5 5 15 25 35 45 55 65 75 Response

Dose (mg/kg/day)

Estimated Probability Response at BMD Data BMD BMDL
BROMODICHLOROMETHANE A-13

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical Name: 

CAS Numbers:

Date:

Profile Status:

Route:

Duration:

Bromodichloromethane 

75-27-4

March 2020

Final

Oral

Intermediate

MRL Summary: The available intermediate oral data were not considered adequate for derivation of an 

intermediate-duration oral MRL. However, the chronic MRL of 0.008 mg/kg/day was considered 

protective for intermediate-duration exposure. 

Rationale for Not Deriving an MRL: Intermediate-duration studies have evaluated a wide range of 

possible targets of bromodichloromethane toxicity. Studies conducted by Aida et al. (1989, 1992) and 

NTP (1987, 2006) have included histopathological examination of most major tissues; the Aida et al. 

(1989, 1992) studies also included examination of hematological and serum clinical chemistry 

parameters. In addition, other studies have evaluated potential targets in the immune system (French et 

al. 1999), neurological system (Balster and Borzelleca 1982; Moser et al. 2007), reproductive system 

(Christian et al. 2001b), and developmental toxicity (Christian et al. 2001a, 2001b). These studies have 

identified LOAEL values for liver, kidney, immune, neurobehavioral, and developmental effects; the 

LOAELs for these effects are summarized in Table A-4. Based on these LOAELs, the liver appears to be 

the most sensitive target of toxicity. The observed effects include alterations in serum enzymes (alanine 

aminotransferase and aspartate aminotransferase), hepatocellular vacuolization, swelling, fatty 

degeneration, and necrosis in rats (Aida et al. 1989, 1992; Hooth et al. 2002; NTP 1987) and mice (NTP 

1987) administered bromodichloromethane via gavage, drinking water, or feed for 1–6 months. The 

lowest LOAEL was 6.1 mg/kg/day in rats exposed for 6 months (Aida et al. 1992). 

The lowest LOAEL for other effects range from 49 mg/kg/day for immunological effects to 

100 mg/kg/day for neurobehavioral effects. The data supporting these other endpoints are not as strong as 

for liver effects, and there are some inconsistencies in the results depending on the endpoint examined. 

The immunological effect observed at 49 mg/kg/day is a decreased response by splenic lymphocytes to 

concanavalin A in rats exposed to bromodichloromethane in drinking water for 26 weeks (French et al. 

1999). The study did not find an altered response to another T-cell mitogen (phytohemagglutinin-p) or a 

significant response to Salmonella stimulation to B-lymphocytes. Acute exposure studies at higher doses 

(≥75 mg/kg/day) have found more consistent responses to T-lymphocyte mitogens (French et al. 1999) 

and sheep red blood cells (Munson et al. 1982). The renal effects observed in 13-week gavage studies 

(NTP 1987) included proximal tubule epithelial cell degeneration in rats at 214 mg/kg/day and proximal 

tubular necrosis in mice at ≥71 mg/kg/day. Other intermediate-duration studies in rats have not reported 

renal effects; however, the doses tested were lower than the NTP (1987) study (Aida et al. 1989, 1992; 

Chu et al. 1982; Lipsky et al. 1993; Lock et al. 2004; NTP 2006). The results of acute (Lilly et al. 1994, 

1996; Thornton-Mannin et al. 1994) and chronic (George et al. 2002; NTP 1987) studies support the 

identification of the kidney as a sensitive target of toxicity. Christian et al. (2001a) reported minor delays 

in skeletal ossification in the offspring of rats exposed to 82 mg/kg/day in drinking water on GDs 6–21. 

This was not found in a 2-generation study utilizing similar dose levels (Christian et al. 2001b). The last 

effect that has been observed following intermediate exposure is impaired learning in an operant behavior 

test in mice receiving gavage administration of 100 mg/kg/day for 60 days (Balster and Borzelleca 1982). 

Balster and Borzelleca (1982) conducted several neurobehavioral studies and found negative results in the 

passive avoidance learning test at 100 mg/kg/day (30-day exposure) and in tests of motor performance 

and exploratory behavior at 11.6 mg/kg/day (90-day exposure). Moser et al. (2007) also found no 

alterations in performance on functional battery tests in rats exposed to 71.7 mg/kg/day for 6 months. 
BROMODICHLOROMETHANE A-14

APPENDIX A

Table A-4. Summary of Relevant LOAEL Values Following Intermediate-Duration Oral to Bromodichloromethane

Species

Duration

(route)

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Liver effects

Wistar rats 6 months (F) – 6.1 Hepatocellular fatty degeneration (males only) Aida et al. 1992

Eker rats 4 or 

10 months

(W)

3.5 35 Centrilobular swelling Hooth et al. 2002

Wistar rats 1 month

(GO)

20 60 Hepatocellular vacuolization Aida et al. 1989

Wistar rats 1 month

(F)

60 180 Hepatocellular vacuolization, swelling, and necrosis Aida et al. 1989

B6C3F1 mice 13 weeks

(GO)

71a 142a Enlarged centrilobular hepatocytes and vacuolization 

(females only)

NTP 1987

F344 rats 13 weeks

(GO)

107a 214a Centrilobular degeneration, mild bile duct hyperplasia NTP 1987

Immunological effects

F344 rats 26 weeks

(GW)

5 49 Decreased response to mitogen in splenic lymphocytes French et al. 1999

Kidney effects

B6C3F1 mice 13 weeks

(GO)

36a 71a Proximal tubular epithelial cell focal necrosis (males 

only)

NTP 1987

F344 rats 13 weeks

(GO)

107a 214a Proximal tubular epithelial cell degeneration NTP 1987

Developmental effects

SpragueDawley ratsGDs 6–21

(W)

45 82 Minor delays in ossification Christian et al. 2001a
BROMODICHLOROMETHANE A-15

APPENDIX A

Table A-4. Summary of Relevant LOAEL Values Following Intermediate-Duration Oral to Bromodichloromethane

Species

Duration

(route)

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Neurobehavioral effects

ICR mice 60 days (GW) 100 Alterations in operant behavior Balster and 

Borzelleca 1982

aAdjusted for intermittent exposure (5 days/7 days).

F = feed; GD = gestation day; GO = gavage in oil; GW = gavage in water; LOAEL = lowest observed adverse effect level; NOAEL = no observed-adverse-effect 

level; W = water
BROMODICHLOROMETHANE A-16

APPENDIX A

Based on the available data, the liver appears to be the most sensitive target of bromodichloromethane 

intermediate-duration toxicity.

Nine studies have investigated the potential of bromodichloromethane to induce liver effects in laboratory 

animals (Aida et al. 1989, 1992; Chu et al. 1982; Hooth et al. 2002; NTP 1987, 2006); the results of these 

studies are summarized in Table A-5. Comparisons of NOAEL/LOAEL values across studies show a 

considerable amount of overlap, which likely results from differences in exposure routes and vehicles that 

could influence absorption, metabolism, and delivery of the compound to target organs; strain differences 

and exposure duration may have also influenced the results. A 1-month study by Aida et al. (1989) 

allows for a comparison of the effect levels between gavage with oil vehicle and feed exposure. The 

NOAEL and LOAEL values were 20 and 60 mg/kg/day, respectively, for hepatocellular vacuolization in 

rats administered bromodichloromethane via gavage in olive oil. In contrast, the NOAEL and LOAEL 

values for feed administration were 60 and 180 mg/kg/day for hepatocellular vacuolization, swelling, and 

necrosis. These results suggest that gavage administration is a more toxic exposure route than feed. In a 

PBPK modeling study conducted by NTP (2006), the plasma AUCs were lower for drinking water 

exposure than gavage in oil exposure. The study also found that a higher percentage of 

bromodichloromethane was metabolized by cytochrome P450 than by glutathione transferase. 

A comparison between the results of the Aida et al. (1989) gavage study and the NTP (1987) 3-month 

gavage studies suggest that Wistar rats may be more sensitive than F344 rats based on the NOAEL of 

197 mg/kg/day for F344 rats, which is higher than the LOAEL of 60 mg/kg/day in Wistar rats; a 

toxicokinetic basis for this difference has not been established. Studies conducted by Aida and associates 

also demonstrate an increasing toxicity with exposure duration. After 6 months of exposure to 

bromodichloromethane in the feed, hepatocellular degeneration was observed at 6.1 mg/kg/day; in 

contrast, the NOAEL for the 1-month feed study was 60 mg/kg/day.

Although gavage administration may be a more toxic route of exposure, continuous exposure laboratory 

animal studies (administration in feed or drinking water) are likely more representative of general 

population exposure to bromodichloromethane in tap water. Of the drinking water and feed studies, Aida 

et al. (1992) identified the lowest LOAEL of 6.1 mg/kg/day. Derivation of an intermediate-duration oral 

MRL based on the Aida et al. (1992) study was considered using the NOAEL/LOAEL approach; the fatty 

degeneration incidence data were not suitable for BMD modeling because the maximal response (100%) 

was observed at all non-control dose levels in the males. Using the LOAEL as the point of departure for 

the MRL and an uncertainty factor of 1,000 (10 for extrapolation from a LOAEL, 10 for extrapolation 

from animal studies, and 10 for human variability) would result in an MRL of 0.006 mg/kg/day. This 

MRL is lower than the chronic-duration MRL also based on hepatic fatty degeneration in rats exposed to 

bromodichloromethane for 2 years (Aida et al. 1992). The intermediate and chronic studies identified the 

same LOAEL values; however, there was greater confidence in the chronic MRL because a larger number 

of animals were examined at 24 months (13–19/exposure group compared to 5/exposure group in the 

6-month study) and the chronic data allowed for use of BMD modeling.
BROMODICHLOROMETHANE A-17

APPENDIX A

Table A-5. Summary of Hepatic Effects Following Intermediate-Duration Oral to 

Bromodichloromethane

Species Duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Feed administration

Wistar rats 6 months – 6.1 Hepatocellular fatty 

degeneration (males only)

Aida et al. 1992

Wistar rats 1 month 60 180 Hepatocellular vacuolization, 

swelling, and necrosis

Aida et al. 1989

Gavage (oil vehicle) administration

Wistar rats 1 month 20 60 Hepatocellular vacuolization Aida et al. 1989

B6C3F1 

mice

13 weeks 71a 142a Enlarged centrilobular 

hepatocytes and 

vacuolization (females only)

NTP 1987

F344 rats 13 weeks 107a 214a Centrilobular degeneration, 

mild bile duct hyperplasia

NTP 1987

Drinking water administration

Eker rats 4 or 

10 months

3.5 35 Centrilobular swelling Hooth et al. 2002

F344/N rats 22 days 71 – NTP 2006

B6C3F1 

mice

22 days 51 – NTP 2006

SpragueDawley rats28 days 45 – Chu et al. 1982

aAdjusted for intermittent exposure (5 days/7 days).

LOAEL = lowest observed adverse effect level; NOAEL = no observed-adverse-effect level

Agency Contacts (Chemical Managers): Susan Ingber
BROMODICHLOROMETHANE A-18

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:

Bromodichloromethane 

75-27-4

March 2020

Final

Oral

Chronic

0.008 mg/kg/day

Hepatocellular fatty degeneration

Aida et al. 1992

BMDL10 of 0.78 mg/kg/day

100

51

Rat

MRL Summary: A chronic-duration oral MRL of 0.008 mg/kg/day was derived for bromodichloromethane based on an increased incidence of hepatocellular fatty degeneration in male rats exposed to 

bromodichloromethane in the diet for 24 months (Aida et al. 1992). The MRL is based on a BMDL10 of 

0.78 mg/kg/day and a total uncertainty factor of 100 (10 for extrapolation from animals to humans and 

10 for human variability).

Selection of the Critical Effect: A number of studies have evaluated the possible association between 

exposure to bromodichloromethane and adverse health effects in humans; in particular, these studies 

evaluate potential hepatic, developmental, and reproductive endpoints. No significant associations 

between blood bromodichloromethane levels and aspartate aminotransferase levels were found in a study 

utilizing the NHANES database (Burch et al. 2015). Nine studies have examined whether bromodichloromethane in drinking water was associated with alterations in birth weight, congenital anomalies, or 

stillbirths. One study found a significant association for stillbirths (King et al. 2000). Mixed results were 

found for birth weight, birth length, or small for gestational age (SGA) (Cao et al. 2016; Danileviciute et 

al. 2012; Rivera-Núñez and Wright 2013; Summerhayes et al. 2012; Wright et al. 2004) and for the 

malformations, in particular neural tube defects, heart anomalies, and hypospadias (Dodds and King 

2001; Grazuleviciene et al. 2013; Iszatt et al. 2011) with some studies finding significant associations. Of 

the three studies examining possible associations between bromodichloromethane and reproductive 

parameters, significant associations between bromodichloromethane in water and a shorter time to 

pregnancy (MacLehose et al. 2008) and a decreased menstrual cycle length (Windham et al. 2003) were 

found; no association was found between blood bromodichloromethane levels and sperm parameters 

(Zeng et al. 2013). Although some studies have found significant associations, the studies do not 

establish causality and bromodichloromethane levels in drinking water only accounted for a small portion 

of the risk of these effects.

Nine studies have evaluated the chronic toxicity of bromodichloromethane in rats and mice (Aida et al. 

1992; George et al. 2002; Klinefelter et al. 1995; NTP 1987, 2006; Tumasonis et al. 1985). These studies 

have identified three sensitive targets of non-neoplastic toxicity: liver, kidney, and sperm; the LOAELs 

for these effects are presented in Table A-6. In the liver, the accumulation of fat resulted in hepatocellular 

degeneration in rats exposed to ≥ 6.1 mg/kg/day in the diet for 1–2 years (Aida et al. 1992) and fatty 

metamorphosis in rats and mice administered via gavage ≥36 mg/kg/day for 2 years (NTP 1987). A 

fourth study reported hepatic adenofibrosis in rats following a lifetime exposure to 190 mg/kg/day in 

drinking water (Tumasonis et al. 1985). Renal and sperm effects have also been observed at dose levels 

of 36–39 mg/kg/day (George et al. 2002; Klinefelter et al. 1995; NTP 1987). Although the results of the 
BROMODICHLOROMETHANE A-19

APPENDIX A

Table A-6. Summary of Relevant LOAEL Values Following Chronic-Duration Oral to Bromodichloromethane

Species Duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Liver effects

Wistar rats 1–2 years – 6.1 Hepatocellular fatty degeneration and granulomas 

(males only) 

Aida et al. 1992

F344 rats 2 years – 36a Fatty metamorphosis NTP 1987

B6C3F1 mice 2 years 18a 36a Fatty metamorphosis (males only) NTP 1987

Wistar rats Lifetime – 190 Hepatic adenofibrosis (females only) Tumasonis et al. 

1985

Kidney effects

F344 rats 2 years 20 36.3 Renal tubular cell hyperplasia George et al. 2002

F344 rats 2 years 36a Tubular epithelial cell cytomegaly (males only) NTP 1987

B6C3F1 mice 18a 36a Tubular epithelial cell cytomegaly (males only) NTP 1987

Reproductive effects

F344 rats 1 year 22 39 Decreased sperm velocity Klinefelter et al. 1995

aAdjusted for intermittent exposure (5 days/7 days).

LOAEL = lowest observed adverse effect level; NOAEL = no observed-adverse-effect level
BROMODICHLOROMETHANE A-20

APPENDIX A

NTP (1987) rat and mice studies suggest that the liver and kidneys are equally sensitive to bromodichloromethane toxicity, the Aida et al. (1992) studies did not find kidney effects at doses as high as 

138.0 mg/kg/day in males and 168.4 mg/kg/day in females. Bolus administration versus continuous 

exposure may have accounted for the differences between the studies. PBPK modeling conducted by 

NTP (2006) found an approximately 10-fold difference in maximal bromodichloromethane blood levels 

following administration of 50 mg/kg via gavage and 33 mg/kg via drinking water; likewise, the 24-hour 

AUC was 1.5 times higher following gavage. Given these possible differences, gavage administration 

may not be a relevant route of exposure for estimating an MRL for humans since the general population is 

primarily exposed to bromodichloromethane in tap water. Among the drinking water and feed studies, 

the lowest LOAEL was 6.1 mg/kg/day for liver effects; thus, fatty degeneration of the liver was selected 

as the critical effect for the chronic-duration oral MRL.

Selection of the Principal Study: The hepatotoxicity of bromodichloromethane has been investigated in 

eight studies of rats or mice administered the compound via gavage (NTP 1987), feed (Aida et al. 1992), 

or drinking water (George et al. 2002; NTP 2006; Tumasonis et al. 1985); the results of these studies are 

presented in Table A-7. Four studies have identified LOAEL values in rats or mice for damage associated 

with fat accumulation (Aida et al. 1992; NTP 1987) or for adenofibrosis (Tumasonis et al. 1985). The 

lowest LOAEL was 6.1 mg/kg/day identified by Aida et al. (1992); this study was selected as the 

principal study for the MRL.

Table A-7. Summary of Hepatic Effects Following Chronic-Duration Oral to 

Bromodichloromethane

Species Duration

NOAEL

(mg/kg/day)

LOAEL

(mg/kg/day) Effect Reference

Feed administration

Wistar rats 1–2 years – 6.1 Fatty degeneration Aida et al. 1992

Gavage (oil vehicle) administration

F344 rats – 36a Fatty metamorphosis NTP 1987

B6C3F1 mice 2 years 18a 36a Fatty metamorphosis NTP 1987

Drinking water administration

Wistar rats Lifetime – 190 Hepatic adenofibrosis Tumasonis et al. 

1985

B6C3F1 mice 2 years 43.3 George et al. 

2002

F344 rats 2 years 36.3 George et al. 

2002

B6C3F1 mice 2 years 36 – NTP 2006

F344/N rats 2 years 25 – NTP 2006

aAdjusted for intermittent exposure (5 days/7 days).

LOAEL = lowest observed adverse effect level; NOAEL = no observed-adverse-effect level

Summary of the Principal Study:

Aida Y, Yasuhara K, Takada K, et al. 1992. Chronic toxicity of microencapsulated 

bromodichloromethane administered in the diet to Wistar rats. J Toxicol Sci 17:51-68.
BROMODICHLOROMETHANE A-21

APPENDIX A

Groups of 40 male and 40 female Wistar rats were exposed to 0.014, 0.055, or 0.22% bromodichloromethane microencapsulated in the diet for up to 2 years; a control group of 70 male and 70 female rats 

was exposed to placebo granules added to the diet at the same concentration as the high-dose group. The 

investigators estimated the doses to be 6.1, 25.5, and 138.0 mg/kg/day for males and 8.0, 31.7, and 

168.4 mg/kg/day for females. The following parameters were used to assess toxicity: daily observations, 

body weights (measured weekly for 6 months, biweekly during months 6–12, and monthly for the last 

year of the study), food intake (measured at the same frequency as body weight), hematology indices 

(erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, 

mean corpuscular hemoglobin concentration, and platelet and leukocyte counts), clinical chemistry 

indices (urea nitrogen, creatinine, glucose, triglycerides, cholinesterase, alanine aminotransferase, 

aspartate aminotransferase, gamma-glutamyl transpeptidase), liver and kidney weights, histopathological 

examination of major tissues and organs, and staining of liver sections for the detection of mucous 

substances in the bile ducts. Histopathological examination was also conducted in animals sacrificed 

after 12 (9/sex for controls and 5/sex/bromodichloromethane group) and 18 (9/sex for controls and 

5/sex/bromodichloromethane group) months of exposure.

No dose-related alterations in mortality were observed. Mild piloerection and emaciation were observed 

in the 138.0/168.4 mg/kg/day group; the symptoms were first observed after 1 month of exposure and 

persisted throughout the study. No significant alterations in food intake were observed. Significant 

decreases in body weights were observed in the 138.0/168.4 mg/kg/day group after 12 and 18 months of 

exposure; males weighed 25 and 23% less than controls and females weighed 31 and 39% of controls. 

Increases in absolute and relative liver weights were observed in all exposed groups at 12 months and in 

the two highest groups after 18 months of exposure. Increases in relative kidney weights were observed 

in the 138.0/168.4 mg/kg/day group. No hematological alterations were observed. The following 

significant alterations in clinical chemistry parameters were observed after 12 months of exposure: 

increases in blood glucose levels in males only at 6.1 and 25.5 mg/kg/day; increased creatinine in females 

only at 168.4 mg/kg/day; increased gamma glutamyl transpeptidase at 138.0/168.4 mg/kg/day; decreased 

triglycerides in males at 6.1, 25.5, and 138.0 mg/kg/day and females at 168.4 mg/kg/day; decreased 

aspartate aminotransferase in males at 25.5 and 138.0 mg/kg/day and females at 168.4 mg/kg/day; 

decreased alanine aminotransferase at 8.0 (females only) and 138.0/168.4 mg/kg/day; and decreased 

cholinesterase in females at 31.7 and 168.4 mg/kg/day. After 18 months of exposure, the following 

alterations were observed: decreased blood glucose in females only at 168.4 mg/kg/day; decreased 

triglycerides at 25.5/31.7 and 138.0/168.4 mg/kg/day; decreased cholinesterase in males at 

138.0 mg/kg/day and in females at 8.0, 31.7, and 168.4 mg/kg/day; slightly increased alanine 

aminotransferase in females 168.4 mg/kg/day; increased gamma-glutamyl transpeptidase at 

31.7 mg/kg/days (females only) and 138.0/168.4 mg/kg/day; and increased blood urea nitrogen in females 

at 168.4 mg/kg/day. After 12 months of exposure, the following effects were observed in the liver: fatty 

degeneration in males at ≥6.1 mg/kg/day and in females at ≥31.7 mg/kg/day; bile duct proliferation in 

males at 138.0 mg/kg/day and in females at ≥31.7 mg/kg/day; cholangiofibrosis at 

138.0/168.4 mg/kg/day; and granulomas in females at ≥31.7 mg/kg/day. After 18 months of exposure, 

the liver effects included: fatty degeneration in males at ≥6.1 mg/kg/day and in females at 

≥31.7 mg/kg/day; cholangiofibrosis at 138.0/168.4 mg/kg/day; and granulomas at 31.7 (females only) and 

138.9/168.4 mg/kg/day. After 24 months of exposure, liver effects included: fatty degeneration at 

≥6.1 mg/kg/day; granulomas in males at ≥6.1 mg/kg/day and in females ≥31.7 mg/kg/day; and 

cholangiofibrosis at 138.0/168.4 mg/kg/day. The incidences of these lesions are presented in Table A-8. 

No other exposure-related increases in non-neoplastic lesions were observed. No increases in neoplastic 

lesions were observed; however, cholangiocarcinomas were observed in 3/40 females in the 

168.4 mg/kg/day group, compared to 0/70 controls.
BROMODICHLOROMETHANE A-22

APPENDIX A

Table A-8. Incidences of Liver Lesions in Male and Female Rats Exposed to Bromodichloromethane in the Diet 

for 12, 18, or 24 Months (Aida et al. 1992)

12 months 18 months 24 months

Doses (mg/kg/day) Doses (mg/kg/day) Doses (mg/kg/day)

Males 0 6.1 25.5 138.0 0 6.1 25.5 138.0 0 6.1 25.5 138.0

Fatty degeneration 0/9 5/5 5/5 5/5 1/9 3/5 5/5 5/5 0/24 5/14 12/13 19/19

Granuloma 0/9 0/5 0/5 1/5 0/9 0/5 2/5 4/5 0/24 4/14 9/13 19/19

Bile duct proliferation 1/9 1/5 0/5 5/5 9/9 5/5 5/5 5/5 24/24 13/14 13/13 19/19

Cholangiofibrosis 0/9 0/5 0/5 5/5 0/9 0/5 0/5 3/5 0/24 0/14 0/13 4/19

Females 0 8.0 31.7 168.4 0 8.0 31.7 168.4 0 8.0 31.7 168.4

Fatty degeneration 0/9 0/5 5/5 4/5 0/9 1/5 5/5 5/5 2/32 8/19 18/18 18/18

Granuloma 0/9 0/5 5/5 5/5 0/9 0/5 5/5 5/5 0/32 0/19 17/18 18/18

Bile duct proliferation 0/9 0/5 3/5 5/5 6/9 2/5 4/5 5/5 28/32 16/19 17/18 18/18

Cholangiofibrosis 0/9 0/5 0/5 5/5 0/9 0/5 0/5 4/5 0/32 0/19 0/18 12/18
BROMODICHLOROMETHANE A-23

Selection of the Point of Departure: The BMDL10 of 1.57 mg/kg/day for hepatocellular fatty 

degeneration in male rats was selected as the POD.

The Aida et al. (1992) study identifies a LOAEL of 6.1 mg/kg/day for fatty degeneration in male rats 

exposed to bromodichloromethane for 12, 18, or 24 months; a significant increase in the incidence of 

granulomas was also observed in males exposed to ≤6.1 mg/kg/day for 24 months. The lowest LOAELs 

in female rats were 31.7 mg/kg/day for fatty degeneration following exposure for 12 or 18 months and 

8.0 mg/kg/day for fatty degeneration following exposure for 24 months. BMD modeling was conducted 

to identify a point of departure using the incidence data for fatty degeneration at 24 months; the 24-month 

data were selected over the 12- and 18-month data due to the large number of animals examined (13–

19/sex at 25 months versus 5/sex at 12 and 18 months). The data were fit to some of the available 

dichotomous models in EPA’s BMDS (version 3.1.1) using the extra risk option. Adequate model fit was 

judged by three criteria: goodness-of-fit statistics (p-value >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 BMDL was selected as the point of departure 

when the difference between the BMDLs estimated from these models was >3-fold; otherwise, the 

BMDL from the model with the lowest AIC was chosen. A BMR of 10% over the control incidence was 

used. The model predictions for males and females are presented in Table A-9 and the fit of the selected 

models are presented in Figures A-2 and A-3. The lowest BMDL10 values in the male and female rats 

were 0.78 for the first-degree Multistage model and 2.57 mg/kg/day for the Probit model; the BMDL10 for 

the males was selected as the point of departure for the MRL since it was lower than the female BMDL10.

Intermittent Exposure: Not applicable.

The BMDL10 is divided by a total uncertainty factor of 100

• 10 for extrapolation from animals to humans

• 10 for human variability

MRL = BMDL10 ÷ UFs

0.78 mg/kg/day ÷ (10 x 10) = 0.008 mg/kg/day

Other Additional Studies or Pertinent Information: EPA (2005b) estimated that the average exposure of 

the general population to bromodichloromethane is 20 μg/person/day (0.0003 mg/kg/day assuming a 

reference body weight of 70 kg) from surface water systems and 8.1 μg/person/day (0.0001 mg/kg/day) 

from groundwater systems. These average intakes are approximately 25-fold lower than the MRL.

Agency Contacts (Chemical Managers): Susan Ingber
BROMODICHLOROMETHANE A-24

APPENDIX A

Table A-9. Model Predictions for Hepatocellular Fatty Degeneration in 

Rats Exposed to Bromodichloromethane in the Diet for 24 Months 

(Aida et al. 1992)

Model DF χ2

χ2

Goodnessof-fit 

p-valuea

Scaled residualsb

AIC

BMD10

(mg/kg/day)

BMDL10

(mg/kg/day)

Dose 

below 

BMD

Dose 

above 

BMD

Overall 

largest

Male Rats

Gammac 2 0.00 1.00 -0.00 0.00 0.00 29.30 2.08 0.80

Logistic 3 5.63 0.13 -1.88 0.96 -1.88 36.20 4.77 3.25

LogLogisticd 2 0.04 0.98 -0.00 0.02 0.19 29.38 2.97 0.94

LogProbitd 1 0.00 0.95 -0.00 0.01 0.06 31.31 2.95 0.86

Multistage (1-degree)e,f 2 0.31 0.86 -0.00 -0.42 -0.42 29.63 1.21 0.78

Multistage (2-degree)e 2 0.00 1.00 -0.00 -0.00 0.00 29.30 1.60 0.80

Multistage (3-degree)e 1 0.00 1.00 -0.00 -0.00 0.00 31.30 1.60 0.80

Dichotomous Hill 0 0.04 NA -0.00 0.02 0.19 33.38 ND-1 ND-1

Probit 2 3.59 0.17 -1.17 1.39 1.39 33.90 4.37 2.87

Female Rats

Gammac 2 1.09 0.58 0.05 -0.44 0.94 46.76 ND-2 ND-2

Logistic 3 6.31 0.09 -1.76 0.71 1.76 52.31 ND-3 ND-3

LogLogisticd 2 0.01 1.00 0.00 -0.00 0.08 44.84 6.03 2.84

LogProbitd 1 0.00 1.00 0.00 0.00 0.00 46.83 6.56 2.67

Multistage (1-degree)e 2 2.14 0.34 0.14 -1.03 1.03 47.95 ND-1 ND-1

Multistage (2-degree)e 2 0.09 1.00 0.01 -0.03 0.09 44.84 3.72 1.10

Multistage (3-degree)e 1 0.00 1.00 0.00 -0.00 -0.00 46.83 4.32 1.01

Dichotomous Hill 1 0.00 0.94 0.00 -0.00 0.08 46.84 6.02 2.84

Probitf 3 1.38 0.71 -0.84 0.63 -0.84 44.59 3.60 2.57

Weibullc 2 1.44 0.49 0.07 -0.61 1.03 47.27 ND-2 ND-2

aValues <0.1 fail to meet conventional goodness-of-fit criteria. bScaled residuals at doses immediately below and above the BMD; also the largest residual at any dose.

cPower restricted to ≥1.

dSlope restricted to ≥1.

eBetas restricted to ≥0.

f

Selected model. BMDLs for models providing adequate fit were not sufficiently close (differed by >3-fold). 

Therefore, the model with lowest BMDL (1st degree multistage) was selected.

AIC = Akaike Information Criterion; BMD = maximum likelihood estimate of the exposure concentration associated 

with the selected benchmark response; BMDL10 = 95% lower confidence limit on the BMD for a benchmark response 

of 10% extra risk; DF = degrees of freedom; ND-1 = not determined, BMDL was 10 times lower than the lowest nonzero dose; ND-2 = not determined, lower limit includes zero; ND-3 = not determined, goodness-of-fit p-value <0.1
BROMODICHLOROMETHANE A-25

APPENDIX A

Figure A-2. Fit of 1st Degree Multistage Model for Hepatocellular

Fatty Degeneration in Male Rats Exposed to

Bromodichloromethane (mg/kg/day)

Figure A-3. Fit of Probit Model for Hepatocellular Fatty Degeneration in Female

Rats Exposed to Bromodichloromethane (mg/kg/day)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 20 40 60 80 100 120

Response

Dose

Estimated Probability Response at BMD Linear Extrapolation Data BMD BMDL

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 20 40 60 80 100 120 140 160

Response

Dose

Estimated Probability Response at BMD Data BMD BMDL
BROMODICHLOROMETHANE B-1

APPENDIX B. LITERATURE SEARCH FRAMEWORK FOR 

BROMODICHLOROMETHANE

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 bromodichloromethane. 

B.1 LITERATURE SEARCH AND SCREEN 

A literature search and screen was conducted to identify studies examining health effects, toxicokinetics, 

mechanisms of action, susceptible populations, biomarkers, chemical interactions, physical and chemical 

properties, production, use, environmental fate, environmental releases, and environmental and biological 

monitoring data for bromodichloromethane. 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 bromodichloromethane have undergone peer review by at least three 

ATSDR-selected experts who have been screened for conflict of interest. The inclusion criteria used to 

identify relevant studies examining the health effects of bromodichloromethane 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
BROMODICHLOROMETHANE B-2

APPENDIX B

Table B-1. Inclusion Criteria for the Literature Search and Screen

Developmental effects

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 

bromodichloromethane 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 bromodichloromethane. 

The query strings used for the literature search are presented in Table B-2. 
BROMODICHLOROMETHANE B-3

APPENDIX B

The search was augmented by searching the Toxic Substances Control Act Test Submissions (TSCATS), 

NTP website, and National Institute of Health Research Portfolio Online Reporting Tools Expenditures 

and Results (NIH RePORTER) databases using the queries presented in Table B-3. Additional databases 

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 

bromodichloromethane 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 (75-27-4[rn] OR "bromodichloromethane"[nm] OR "BDCM"[tw] OR "Bromodichloromethane"[tw] OR "Bromodichlormethane"[tw] OR "Bromodichloromethane"[tw] OR 

"Dichlorobromomethane"[tw] OR "Dichloromonobromomethane"[tw] OR "Methane, 

bromodichloro-"[tw] OR "Monobromodichloromethane"[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 (75-27-4[rn] OR "BDCM" OR "Bromo-dichloromethane" OR "Bromodichlormethane" OR 

"Bromodichloromethane" OR "Dichlorobromomethane" OR "Dichloromonobromomethane" 

OR "Methane, bromodichloro-" OR "Monobromodichloromethane") 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 10:31:35 ON 03 MAY 2019

L41 3645 SEA FILE=TOXCENTER 75-27-4 

L42 3548 SEA FILE=TOXCENTER L41 NOT PATENT/DT 

L43 3483 SEA FILE=TOXCENTER L42 NOT TSCATS/FS 

L44 446 SEA FILE=TOXCENTER L43 AND ED>=20150101 

 ACT TOXQUERY/Q

 ---------

L45 QUE (CHRONIC OR IMMUNOTOX? OR NEUROTOX? OR TOXICOKIN? OR 

 BIOMARKER? OR NEUROLOG?) 

L46 QUE (PHARMACOKIN? OR SUBCHRONIC OR PBPK OR 

EPIDEMIOLOGY/ST,CT,

 IT) 

L47 QUE (ACUTE OR SUBACUTE OR LD50# OR LD(W)50 OR LC50# OR 

 LC(W)50) 

L48 QUE (TOXICITY OR ADVERSE OR POISONING)/ST,CT,IT 

L49 QUE (INHAL? OR PULMON? OR NASAL? OR LUNG? OR RESPIR?) 

L50 QUE ((OCCUPATION? OR WORKPLACE? OR WORKER?) AND EXPOS?) 
BROMODICHLOROMETHANE B-4

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

L51 QUE (ORAL OR ORALLY OR INGEST? OR GAVAGE? OR DIET OR DIETS 

OR 

 DIETARY OR DRINKING(W)WATER?) 

L52 QUE (MAXIMUM AND CONCENTRATION? AND (ALLOWABLE OR 

PERMISSIBLE))

L53 QUE (ABORT? OR ABNORMALIT? OR EMBRYO? OR CLEFT? OR FETUS?) 

L54 QUE (FOETUS? OR FETAL? OR FOETAL? OR FERTIL? OR MALFORM? 

OR 

 OVUM?) 

L55 QUE (OVA OR OVARY OR PLACENTA? OR PREGNAN? OR PRENATAL?) 

L56 QUE (PERINATAL? OR POSTNATAL? OR REPRODUC? OR STERIL? OR 

 TERATOGEN?) 

L57 QUE (SPERM OR SPERMAC? OR SPERMAG? OR SPERMATI? OR 

SPERMAS? OR 

 SPERMATOB? OR SPERMATOC? OR SPERMATOG?) 

L58 QUE (SPERMATOI? OR SPERMATOL? OR SPERMATOR? OR 

SPERMATOX? OR 

 SPERMATOZ? OR SPERMATU? OR SPERMI? OR SPERMO?) 

L59 QUE (NEONAT? OR NEWBORN? OR DEVELOPMENT OR 

DEVELOPMENTAL?) 

L60 QUE (ENDOCRIN? AND DISRUPT?) 

L61 QUE (ZYGOTE? OR CHILD OR CHILDREN OR ADOLESCEN? OR 

INFANT?) 

L62 QUE (WEAN? OR OFFSPRING OR AGE(W)FACTOR?) 

L63 QUE (DERMAL? OR DERMIS OR SKIN OR EPIDERM? OR CUTANEOUS?) 

L64 QUE (CARCINOG? OR COCARCINOG? OR CANCER? OR PRECANCER? 

OR 

 NEOPLAS?) 

L65 QUE (TUMOR? OR TUMOUR? OR ONCOGEN? OR LYMPHOMA? OR 

CARCINOM?) 

L66 QUE (GENETOX? OR GENOTOX? OR MUTAGEN? OR 

GENETIC(W)TOXIC?) 

L67 QUE (NEPHROTOX? OR HEPATOTOX?) 

L68 QUE (ENDOCRIN? OR ESTROGEN? OR ANDROGEN? OR HORMON?) 

L69 QUE (OCCUPATION? OR WORKER? OR WORKPLACE? OR EPIDEM?) 

L70 QUE L45 OR L46 OR L47 OR L48 OR L49 OR L50 OR L51 OR L52 OR 

 L53 OR L54 OR L55 OR L56 OR L57 OR L58 OR L59 OR L60 OR L61 OR 

 L62 OR L63 OR L64 OR L65 OR L66 OR L67 OR L68 OR L69 

L71 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?) 

L72 QUE (MARMOSET? OR FERRET? OR GERBIL? OR RODENT? OR 

LAGOMORPHA 

 OR BABOON? OR CANINE OR CAT OR CATS OR FELINE OR MURINE) 

L73 QUE L70 OR L71 OR L72 

L74 QUE (HUMAN OR HUMANS OR HOMINIDAE OR MAMMALS OR MAMMAL? 

OR 
BROMODICHLOROMETHANE B-5

APPENDIX B

Table B-2. Database Query Strings 

Database

search date Query string

 PRIMATES OR PRIMATE?) 

L75 QUE L73 OR L74 

 ---------

L76 267 SEA FILE=TOXCENTER L44 AND L75 

L77 20 SEA FILE=TOXCENTER L76 AND MEDLINE/FS 

L78 240 DUP REM L76 (27 DUPLICATES REMOVED)

 ANSWERS '1-240' FROM FILE TOXCENTER

 D SCAN L78

L2 0 SEA FILE=TOXCENTER 59665-18-8 OR 57049-13-5

Table B-3. Strategies to Augment the Literature Search

Source Query and number screened when available

TSCATS via 

Chemview

05/2019 Data submitted to EPA; Compounds searched: 75-27-4

NTP

05/2019 "75-27-4" "Bromodichloromethane" "Dichlorobromomethane" 

"Monobromodichloromethane"

"BDCM" "Bromo-dichloromethane" "Methane, bromodichloro-"

"Dichloromonobromomethane" "Bromodichlormethane"

Regulations.gov

05/2019 "75-27-4" "Bromodichloromethane" "Dichlorobromomethane" 

"Monobromodichloromethane"

NIH RePORTER

05/2019 Text Search: "BDCM" OR "Bromo-dichloromethane" OR "Bromodichlormethane" OR 

"Bromodichloromethane" OR "Dichlorobromomethane" OR 

"Dichloromonobromomethane" OR "Methane, bromodichloro-" OR 

"Monobromodichloromethane" (Advanced), Search in: Projects Admin IC: All, Fiscal 

Year: Active Projects

Other Identified throughout the assessment process

The 2019 results were: 

• Number of records identified from PubMed, TOXLINE, and TOXCENTER (after duplicate 

removal): 209

• Number of records identified from other strategies: 28

• Total number of records to undergo literature screening: 237

B.1.2 Literature Screening 

A two-step process was used to screen the literature search to identify relevant studies on 

bromodichloromethane: 
BROMODICHLOROMETHANE B-6

APPENDIX B

• 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: 235

• Number of studies considered relevant and moved to the next step: 50

Full Text Screen. The second step in the literature screening process was a full text review of individual 

studies considered relevant in the title and abstract screen step. Each study was reviewed to determine 

whether it was relevant for inclusion in the toxicological profile. 

• Number of studies undergoing full text review: 50

• Number of studies cited in the pre-public draft of the toxicological profile: 211

• Total number of studies cited in the profile: 241

A summary of the results of the literature search and screening is presented in Figure B-1.
BROMODICHLOROMETHANE B-7

APPENDIX B

Figure B-1. May 2019 Literature Search Results and Screen for 

Bromodichloromethane
BROMODICHLOROMETHANE C-1

APPENDIX C. FRAMEWORK FOR ATSDR’S SYSTEMATIC REVIEW OF 

HEALTH EFFECTS DATA FOR BROMODICHLOROMETHANE

To increase the transparency of ATSDR’s process of identifying, evaluating, synthesizing, and 

interpreting the scientific evidence on the health effects associated with exposure to 

bromodichloromethane, ATSDR utilized a slight modification of NTP’s Office of Health Assessment and 

Translation (OHAT) systematic review methodology (NTP 2013, 2015; Rooney et al. 2014). ATSDR’s 

framework is an eight-step process for systematic review with the goal of identifying the potential health 

hazards of exposure to bromodichloromethane:

• Step 1. Problem Formulation

• Step 2. Literature Search and Screen for Health Effects Studies

• Step 3. Extract Data from Health Effects Studies

• Step 4. Identify Potential Health Effect Outcomes of Concern

• Step 5. Assess the Risk of Bias for Individual Studies

• Step 6. Rate the Confidence in the Body of Evidence for Each Relevant Outcome

• Step 7. Translate Confidence Rating into Level of Evidence of Health Effects

• Step 8. Integrate Evidence to Develop Hazard Identification Conclusions

C.1 PROBLEM FORMULATION

The objective of the toxicological profile and this systematic review was to identify the potential health 

hazards associated with inhalation, oral, or dermal/ocular exposure to bromodichloromethane. The 

inclusion criteria used to identify relevant studies examining the health effects of bromodichloromethane

are presented in Table C-1. 

Data from human and laboratory animal studies were considered relevant for addressing this objective. 

Human studies were divided into two broad categories: observational epidemiology studies and 

controlled exposure studies. The observational epidemiology studies were further divided: cohort studies 

(retrospective and prospective studies), population studies (with individual data or aggregate data), and 

case-control studies.

Table C-1. Inclusion Criteria for Identifying Health Effects Studies

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
BROMODICHLOROMETHANE C-2

APPENDIX C

Table C-1. Inclusion Criteria for Identifying Health Effects Studies

Cardiovascular effects

Gastrointestinal effects

Hematological effects

Musculoskeletal effects

Hepatic effects

Renal effects

Dermal effects

Ocular effects

Endocrine effects

Immunological effects

Neurological effects

Reproductive effects

Developmental effects

Other noncancer effects

Cancer

C.2 LITERATURE SEARCH AND SCREEN FOR HEALTH EFFECTS STUDIES

A literature search and screen was conducted to identify studies examining the health effects of 

bromodichloromethane. The literature search framework for the toxicological profile is discussed in 

detail in Appendix B.

C.2.1 Literature Search

As noted in Appendix B, the current literature search was intended to update the draft toxicological 

profile for bromodichloromethane released for public comment in 2018. See Appendix B for the 

databases searched and the search strategy. 

A total of 209 records relevant to all sections of the toxicological profile were identified (after 

duplicate removal). 

C.2.2 Literature Screening

As described in Appendix B, a two-step process was used to screen the literature search to identify 

relevant studies examining the health effects of bromodichloromethane.

Title and Abstract Screen. In the Title and Abstract Screen step, 236 records were reviewed; 

12 documents were considered to meet the health effects inclusion criteria in Table C-1 and were moved 

to the next step in the process. 

Full Text Screen. In the second step in the literature screening process for the systematic review, a full 

text review of the 12 health effects documents identified in the update literature was performed. From 

those 12 documents, 8 studies were included in the qualitative review. Additionally, 77 studies cited in 

the LSE tables for the existing profile were included in the full study screen bringing the total number of 

studies for the qualitative review to 85. 
BROMODICHLOROMETHANE C-3

APPENDIX C

C.3 EXTRACT DATA FROM HEALTH EFFECTS STUDIES

Relevant data extracted from the individual studies selected for inclusion in the systematic review were 

collected in customized data forms. A summary of the type of data extracted from each study is presented 

in Table C-2. For references that included more than one experiment or species, data extraction records 

were created for each experiment or species. 

Table C-2. Data Extracted From Individual Studies

Citation

Chemical form

Route of exposure (e.g., inhalation, oral, dermal)

Specific route (e.g., gavage in oil, drinking water)

Species

Strain

Exposure duration category (e.g., acute, intermediate, chronic)

Exposure duration

Frequency of exposure (e.g., 6 hours/day, 5 days/week)

Exposure length

Number of animals or subjects per sex per group 

Dose/exposure levels

Parameters monitored

Description of the study design and method

Summary of calculations used to estimate doses (if applicable)

Summary of the study results

Reviewer’s comments on the study

Outcome summary (one entry for each examined outcome)

No-observed-adverse-effect level (NOAEL) value

Lowest-observed-adverse-effect level (LOAEL) value

Effect observed at the LOAEL value

A summary of the extracted data for each study is presented in the Supplemental Document for 

Bromodichloromethane and overviews of the results of the inhalation and oral exposure studies (no 

dermal exposure studies were identified) are presented in Sections 2.2–2.18 of the profile and in the 

Levels Significant Exposures tables in Section 2.1 of the profile (Tables 2-2 and 2-3, respectively).

C.4 IDENTIFY POTENTIAL HEALTH EFFECT OUTCOMES OF CONCERN 

Overviews of the potential health effect outcomes for bromodichloromethane identified in human and 

animal studies are presented in Tables C-3 and C-4, respectively. The available human studies examined 

a limited number of endpoints (hepatic, immunological, reproductive, and developmental effects) and 

reported immunological, reproductive, and developmental effects. Animal studies examined a number of 

endpoints following inhalation or oral exposure. These studies examined most endpoints and reported 

body weight, gastrointestinal, hematological, hepatic, renal, ocular, endocrine, immunological, 

reproductive, developmental, and other noncancer (alterations in blood glucose) effects. Hepatic, renal, 

immunological, reproductive, and developmental effects were considered sensitive outcomes (i.e., effects 

were observed at low concentrations or doses). Studies examining these potential outcomes were carried 

through to Steps 4–8 of the systematic review. Eighty-five studies (published in 54 documents) 

examining these potential outcomes were carried through to Steps 4–8 of the systematic review. 
BROMODICHLOROMETHANE C-4 

APPENDIX C

Table C-3. Overview of the Health Outcomes for Bromodichloromethane Evaluated In Human Studies Body weight Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Dermal Ocular Endocrine Immunological Neurological Reproductive Developmental Other Noncancer

Caner

Inhalation studies

Cohort

Case control

Population

Case series

Oral studies

Cohort 2 9 1

2 8 1

Case control 4 1

2 1

Population 1 1 1 1

0 1 0 0

Case series

Dermal studies

Cohort

Case control

Population

Case series

Number of studies examining endpoint 0 1 2 3 4 5-9 ≥10

Number of studies reporting outcome 0 1 2 3 4 5-9 ≥10
BROMODICHLOROMETHANE C-5 

APPENDIX C

Table C-4. Overview of the Health Outcomes for Bromodichloromethane Evaluated in Experimental Animal 

Studies

Body weightRespiratoryCardiovascularGastrointestinalHematologicalMusculoskeletalHepaticRenalDermalOcularEndocrineImmunologicala Neurologicala Reproductivea DevelopmentalOther NoncancerCaner

Inhalation studies

Acute-duration 2 2 2 2 2

2 2 2 2 0

Intermediate-duration 3 2 2 3

0 0 2 0

Chronic-duration

Oral studies

Acute-duration 16 1 1 1 3 1 9 8 1 3 3 4 7 5

12 0 0 0 2 0 7 6 0 2 2 3 7 1

Intermediate-duration 11 7 7 9 6 9 11 7 2 8 6 3 2

5 0 0 1 0 6 2 0 1 1 2 1 1

Chronic-duration 8 7 7 7 1 8 7 7 1 6 1 8

4 0 0 0 0 4 3 1 0 1 1 3

Dermal studies

Acute-duration

Intermediate-duration

Chronic-duration

Number of studies examining endpoint 0 1 2 3 4 5-9 ≥10

Number of studies reporting outcome 0 1 2 3 4 5-9 ≥10

aNumber of studies examining endpoint includes study evaluating histopathology, but not evaluating function.
BROMODICHLOROMETHANE C-6

APPENDIX C

C.5 ASSESS THE RISK OF BIAS FOR INDIVIDUAL STUDIES

C.5.1 Risk of Bias Assessment

The risk of bias of individual studies was assessed using OHAT’s Risk of Bias Tool (NTP 2015). The 

risk of bias questions for observational epidemiology studies, human-controlled exposure studies, and 

animal experimental studies are presented in Tables C-5, C-6, and C-7, respectively. Each risk of bias 

question was answered on a four-point scale:

• Definitely low risk of bias (++)

• Probably low risk of bias (+)

• Probably high risk of bias (-)

• Definitely high risk of bias (– –)

In general, “definitely low risk of bias” or “definitely high risk of bias” was used if the question could be 

answered with information explicitly stated in the study report. If the response to the question could be 

inferred, then “probably low risk of bias” or “probably high risk of bias” response was typically used. 

Table C-5. Risk of Bias Questionnaire for Observational Epidemiology Studies

Selection bias

Were the comparison groups appropriate?

Confounding bias

Did the study design or analysis account for important confounding and modifying variables?

Attrition/exclusion bias

Were outcome data complete without attrition or exclusion from analysis?

Detection bias

Is there confidence in the exposure characterization?

Is there confidence in outcome assessment?

Selective reporting bias

Were all measured outcomes reported?

Table C-6. Risk of Bias Questionnaire for Human-Controlled Exposure Studies

Selection bias

Was administered dose or exposure level adequately randomized?

Was the allocation to study groups adequately concealed?

Performance bias

Were the research personnel and human subjects blinded to the study group during the study?

Attrition/exclusion bias

Were outcome data complete without attrition or exclusion from analysis?

Detection bias

Is there confidence in the exposure characterization?

Is there confidence in outcome assessment?

Selective reporting bias

Were all measured outcomes reported?
BROMODICHLOROMETHANE C-7

APPENDIX C

Table C-7. Risk of Bias Questionnaire for Experimental Animal Studies

Selection bias

Was administered dose or exposure level adequately randomized?

Was the allocation to study groups adequately concealed?

Performance bias

Were experimental conditions identical across study groups?

Were the research personnel blinded to the study group during the study?

Attrition/exclusion bias

Were outcome data complete without attrition or exclusion from analysis?

Detection bias

Is there confidence in the exposure characterization?

Is there confidence in outcome assessment?

Selective reporting bias

Were all measured outcomes reported? 

After the risk of bias questionnaires were completed for the health effects studies, the studies were 

assigned to one of three risk of bias tiers based on the responses to the key questions listed below and the 

responses to the remaining questions. 

• Is there confidence in the exposure characterization? (only relevant for observational studies)

• Is there confidence in the outcome assessment? 

• Does the study design or analysis account for important confounding and modifying variables? 

(only relevant for observational studies)

First Tier. Studies placed in the first tier received ratings of “definitely low” or “probably low” risk of 

bias on the key questions AND received a rating of “definitely low” or “probably low” risk of bias on the 

responses to at least 50% of the other applicable questions.

Second Tier. A study was placed in the second tier if it did not meet the criteria for the first or third tiers.

Third Tier. Studies placed in the third tier received ratings of “definitely high” or “probably high” risk of 

bias for the key questions AND received a rating of “definitely high” or “probably high” risk of bias on 

the response to at least 50% of the other applicable questions.

The results of the risk of bias assessment for the different types of bromodichloromethane health effects 

studies (observational epidemiology and animal experimental studies) are presented in Tables C-8 and

C-9, respectively.
BROMODICHLOROMETHANE C-8

APPENDIX C

Table C-8. Summary of Risk of Bias Assessment for Bromodichloromethane—Observational Epidemiology 

Studies

Reference

Risk of bias criteria and ratings

Selection 

bias

Confounding 

bias

Attrition / 

exclusion bias Detection bias

Selective 

reporting bias

Comparison groups appropriate?Study design or analysis account for important confounding and modifying variables?*Outcome data complete without attrition or exclusion from Risk of bias tier

analysis?

Confidence in exposure characterization?*Confidence in outcome assessment?*All measured outcomes reported?

Outcome: Hepatic Effects

Cross-sectional studies

Burch et al. 2015 ++ - + + + + Third

Outcome: Immunological Effects

Cohort studies

Vlaanderen et al. 2017 ++ - + + + + Third

Outcome: Reproductive Effects

Cohort studies

MacLehose et al. 2008 ++ - + - + + Third 

Windham et al. 2003 ++ - + - + + Third 

Cross-sectional studies

Zeng et al. 2013 ++ - + + + + Third 

Outcome: Developmental Effects

Cohort studies

Cao et al. 2016 ++ - + + + + Third

Chen et al. 2019 ++ - + + + + Third

Dodds and King 2001 ++ - + - + + Third 

Grazuleviciene et al. 2013 ++ - + - + + Third

King et al. 2000 ++ - + - + + Third

Rivera-Núñez and Wright 

2013

++ - + - + + Third

Summerhayes et al. 2012 ++ - + - + + Third

Waller et al. 1998 ++ - + - + + Third
BROMODICHLOROMETHANE C-9

APPENDIX C

Table C-8. Summary of Risk of Bias Assessment for Bromodichloromethane—Observational Epidemiology 

Studies

Reference

Risk of bias criteria and ratings

Selection 

bias

Confounding 

bias

Attrition / 

exclusion bias Detection bias

Selective 

reporting bias

Comparison groups appropriate?Study design or analysis account for important confounding and modifying variables?*Outcome data complete without attrition or exclusion from Risk of bias tier

analysis?

Confidence in exposure characterization?*Confidence in outcome assessment?*All measured outcomes reported?

Wright et al. 2004 ++ - + - + + Third

Case-control Studies

Danileviciute et al. 2012 ++ - + - + + Third

Iszatt et al. 2011 ++ - + - + + Third

Rivera-Núñez et al. 2018 ++ - + - + + Third

Wright et al. 2017 ++ - + - + + Third

++ = definitely low risk of bias; + = probably low risk of bias; – = probably high risk of bias; – – = definitely high risk of bias; na = not applicable

*Key question used to assign risk of bias tier
BROMODICHLOROMETHANE C-10

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

Outcome: Hepatic Effects

Inhalation acute exposure

Torti et al. 2001 (C57BL/6 mouse) ++ + ++ + + + + + First

Torti et al. 2001 (FVN mouse) ++ + ++ + + + + + First

Inhalation intermediate exposure

Torti et al. 2001 (C57BL/6 mouse) ++ + ++ + + + + + First

Torti et al. 2001 (FVN mouse ++ + ++ + + + + + First

Oral acute exposure

Condie et al. 1983 (mouse) - + + + + - + + First

Keegan et al. 1998 (rat) - + + + + + + + First

Lilly et al. 1994 (rat, GW) + + + + + + + + First

Lilly et al. 1994 (rat, GO) + + + + + + + + First

Lilly et al. 1996 (rat) + + + + + + + + First

Munson et al. 1982 (mouse) - + + + + + + + First

Ruddick et al. 1983 (rat) + + + + + + + + First

Thornton-Manning et al. 1994 (rat) + + + + + + + + First

Thornton-Manning et al. 1994 

(mouse) + + + + + + + + First

Oral intermediate exposure

Aida et al. 1989 (rat, F) - + + + + + + + First

Aida et al. 1989 (rat, W) - + + + + + + + First

Aida et al. 1992 (rat) + + + + + + + + First

Chu et al. 1982 (rat) - + + + + - + + First

Hooth et al. 2002 (rat) + + + + + + + + First
BROMODICHLOROMETHANE C-11

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

NTP 1987 (rat) ++ + + + + ++ + + First

NTP 1987 (mouse) ++ + + + + ++ + + First

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Oral chronic exposure

Aida et al. 1992 (rat) + + + + + + + + First

George et al. 2002 (rat) + + + + + + + + First

George et al. 2002 (mouse) + + + + + + + + First

NTP 1987 (rat) ++ + + + + ++ + ++ First

NTP 1987 (mouse) ++ + + + + ++ + ++ First

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Tumasonis et al. 1985 (rat) - + + + + + + + First

Outcome: Renal Effects

Inhalation acute exposure

Torti et al. 2001 (C57BL/6 mouse) ++ + ++ + + + + + First

Torti et al. 2001 (FVN mouse) ++ + ++ + + + + + First

Inhalation intermediate exposure

Torti et al. 2001 (C57BL/6 mouse) ++ + ++ + + + + + First

Torti et al. 2001 (FVN mouse) ++ + ++ + + + + + First

Oral acute exposure

Condie et al. 1983 (mouse) - + + + + - + + First

Lilly et al. 1994 (rat, GW) + + + + + + + + First
BROMODICHLOROMETHANE C-12

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

Lilly et al. 1994 (rat, GO) + + + + + + + + First

Lilly et al. 1996 (rat) + + + + + + + + First

Munson et al. 1982 (mouse) - + + + + + + + First

Ruddick et al. 1983 (rat) + + + + + + + + First

Thornton-Manning et al. 1994 (rat) + + + + + + + + First

Thornton-Manning et al. 1994 

(mouse) + + + + + + + + First

Oral intermediate exposure

Aida et al. 1989 (rat, F) - + + + + + + + First

Aida et al. 1989 (rat, W) - + + + + + + + First

Aida et al. 1992 (rat) + + + + + + + + First

Chu et al. 1982 (rat) - + + + + - + + First

Lipsky et al. 1993 (rat) - + + + + - + + First

Lock et al. 2004 (rat) - + + + + + + + First

Lock et al. 2004 (mouse) - + + + + + + + First

NTP 1987 (rat) ++ + + + + ++ + ++ First

NTP 1987 (mouse) ++ + + + + ++ + ++ First

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Oral chronic exposure

Aida et al. 1992 (rat) + + + + + + + + First

George et al. 2002 (rat) + + + + + + + + First

George et al. 2002 (mouse) + + + + + + + + First

NTP 1987 (rat) ++ + + + + ++ + ++ First
BROMODICHLOROMETHANE C-13

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

NTP 1987 (mouse) ++ + + + + ++ + ++ First

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Outcome: Immunological Effects

Oral acute exposure

French et al. 1999 (rat, 5 days) - + + + + + + + First

French et al. 1999 (rat, 14 days) - + + + + + + + First

Munson et al. 1982 - + + + + + + + First

Oral intermediate exposure

French et al. 1999 (mouse, 16 

days; GW) - + + + + + + + First

French et al. 1999 (rat, 26 weeks; 

W) - + + + + + + + First

Outcome: Reproductive Effects

Oral acute exposure

Bielmeier et al. 2001 (rat, GDs 8–9) - + + + + + + ++ First

Bielmeier et al. 2004 (rat) - + + + + + + ++ First

Bielmeier et al. 2007 (rat) - + + + + + + ++ First

Ruddick et al. 1983 (rat) + + + + + + + + First

Oral intermediate exposure

Aida et al. 1992 (rat) + + + + + + + + First

Christian et al. 2001b ++ + + + + + + + First

NTP 1987 (rat) ++ + + + + ++ + ++ First

NTP 1987 (mouse) ++ + + + + ++ + ++ First
BROMODICHLOROMETHANE C-14

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Oral chronic exposure

Aida et al. 1992 (rat) + + + + + + + + First

Klinefelter et al. 1995 (rat) - + + + + + + + First

NTP 1987 (rat) ++ + + + + ++ + ++ First

NTP 1987 (mouse) ++ + + + + ++ + ++ First

NTP 2006 (rat) ++ + + + + ++ + ++ First

NTP 2006 (mouse) ++ + + + + ++ + ++ First

Outcome: Developmental Effects

Oral Acute Exposure

Bielmeier et al. 2001 (rat, GDs 6–

10) - + + + + + + ++ First

Bielmeier et al. 2001 (SpragueDawley rat, GDs 6–10) - + + + + + + ++ First

Bielmeier et al. 2001 (rat, GDs 8–9) - + + + + + + ++ First

Bielmeier et al. 2001 (rat, GDs 6–10 

or 6–15) - + + + + + + ++ First

Bielmeier et al. 2004 (rat) - + + + + + + ++ First

Narotsky et al. 1997 (rat) ++ + + + + + + ++ First

Ruddick et al. 1983 (rat) + + + + + + + + First
BROMODICHLOROMETHANE C-15

APPENDIX C

Table C-9. Summary of Risk of Bias Assessment for Bromodichloromethane—Experimental Animal Studies

Reference

Risk of bias criteria and ratings

Selection bias Performance bias

Attrition/ 

exclusion bias Detection bias

Selective 

reporting 

bias

Administered dose or exposure level adequately randomized?Allocation to study groups adequately concealed?Experimental conditions identical across study groups?Research personnel blinded to the study group during the study?Outcome data complete without attrition or exclusion from analysis?Confidence in exposure characterization?Confidence in outcome assessment?*All measured outcomes reported?Risk of bias tier

Oral intermediate exposure

Christian et al. 2001a (rat) ++ + + + + + + + First

Christian et al. 2001a (rabbit) ++ + + + + + + + First

Christian et al. 2001b (rat) ++ + + + + + + + First

++ = definitely low risk of bias; + = probably low risk of bias; – = probably high risk of bias; – – = definitely high risk of bias; na = not applicable

*Key question used to assign risk of bias tier
BROMODICHLOROMETHANE C-16

APPENDIX C

C.6 RATE THE CONFIDENCE IN THE BODY OF EVIDENCE FOR EACH RELEVANT 

OUTCOME

Confidences in the bodies of human and animal evidence were evaluated independently for each potential 

outcome. ATSDR did not evaluate the confidence in the body of evidence for carcinogenicity; rather, the 

Agency defaulted to the cancer weight-of-evidence assessment of other agencies including DHHS, EPA, 

and IARC. The confidence in the body of evidence for an association or no association between exposure 

to bromodichloromethane and a particular outcome was based on the strengths and weaknesses of 

individual studies. Four descriptors were used to describe the confidence in the body of evidence for 

effects or when no effect was found:

• High confidence: the true effect is highly likely to be reflected in the apparent relationship

• Moderate confidence: the true effect may be reflected in the apparent relationship

• Low confidence: the true effect may be different from the apparent relationship

• Very low confidence: the true effect is highly likely to be different from the apparent 

relationship

Confidence in the body of evidence for a particular outcome was rated for each type of study: casecontrol, case series, cohort, population, human-controlled exposure, and experimental animal. In the 

absence of data to the contrary, data for a particular outcome were collapsed across animal species, routes 

of exposure, and exposure durations. If species (or strain), route, or exposure duration differences were 

noted, then the data were treated as separate outcomes.

C.6.1 Initial Confidence Rating

In ATSDR’s modification to the OHAT approach, the body of evidence for an association (or no 

association) between exposure to bromodichloromethane and a particular outcome was given an initial 

confidence rating based on the key features of the individual studies examining that outcome. The 

presence of these key features of study design was determined for individual studies using four “yes or 

no” questions, which were customized for epidemiology, human controlled exposure, or experimental 

animal study designs. Separate questionnaires were completed for each outcome assessed in a study. The 

key features for observational epidemiology (cohort, population, and case-control) studies, human 

controlled exposure, and experimental animal studies are presented in Tables C-10, C-11, and C-12, 

respectively. The initial confidence in the study was determined based on the number of key features 

present in the study design: 

• High Initial Confidence: Studies in which the responses to the four questions were “yes”. 

• Moderate Initial Confidence: Studies in which the responses to only three of the questions 

were “yes”. 

• Low Initial Confidence: Studies in which the responses to only two of the questions were “yes”. 

• Very Low Initial Confidence: Studies in which the response to one or none of the questions 

was “yes”. 
BROMODICHLOROMETHANE C-17

APPENDIX C

Table C-10. Key Features of Study Design for Observational Epidemiology 

Studies

Exposure was experimentally controlled 

Exposure occurred prior to the outcome

Outcome was assessed on individual level rather than at the population level

A comparison group was used

Table C-11. Key Features of Study Design for Human-Controlled Exposure 

Studies

A comparison group was used or the subjects served as their own control

A sufficient number of subjects were tested

Appropriate methods were used to measure outcomes (i.e., clinically-confirmed outcome versus selfreported)

Appropriate statistical analyses were performed and reported or the data were reported in such a way to 

allow independent statistical analysis

Table C-12. Key Features of Study Design for Experimental Animal Studies

A concurrent control group was used

A sufficient number of animals per group were tested

Appropriate parameters were used to assess a potential adverse effect

Appropriate statistical analyses were performed and reported or the data were reported in such a way to 

allow independent statistical analysis

The presence or absence of the key features and the initial confidence levels for studies examining 

hepatic, renal, immunological, reproductive, and developmental effects observed in the observational 

epidemiology and animal experimental studies are presented in Tables C-13 and C-14, respectively.

Table C-13. Presence of Key Features of Study Design for 

Bromodichloromethane—Observational Epidemiology Studies

Key features 

Reference

Controlled exposureExposure prior to outcomeOutcomes assessed on an individual level Comparison group

Initial study 

confidence

Outcome: Hepatic effects

Cross-sectional studies

Burch et al. 2015 No No Yes Yes Low

Outcome: Immunological effects

Cohort studies

Vlaanderen et al. 2017 No Yes Yes Yes Moderate
BROMODICHLOROMETHANE C-18

APPENDIX C

Table C-13. Presence of Key Features of Study Design for 

Bromodichloromethane—Observational Epidemiology Studies

Key features 

Reference

Controlled exposureExposure prior to outcomeOutcomes assessed on an individual level Comparison group

Initial study 

confidence

Outcome: Reproductive effects

Cohort studies

MacLehose et al. 2008 No No Yes Yes Low

Windham et al. 2003 No No Yes Yes Low

Cross-sectional studies

Zeng et al. 2013 No No Yes Yes Low

Outcome: Developmental effects

Cohort studies

Cao et al. 2016 No No Yes Yes Low

Chen et al. 2019 No No Yes Yes Low

Dodds and King 2001 No No Yes Yes Low

Grazuleviciene et al. 2013 No No Yes Yes Low

King et al. 2000 No No Yes Yes Low

Rivera-Núñez and Wright 2013 No No Yes Yes Low

Summerhayes et al. 2012 No No Yes Yes Low

Waller et al. 1998 No No Yes Yes Low

Wright et al. 2004 No No Yes Yes Low

Case-control studies

Danileviciute et al. 2012 No No Yes Yes Low

Iszatt et al. 2011 No No Yes Yes Low

Rivera-Núñez et al. 2018 No No Yes Yes Low

Wright et al. 2017 No No Yes Yes Low
BROMODICHLOROMETHANE C-19

APPENDIX C

Table C-14. Presence of Key Features of Study Design for 

Bromodichloromethane—Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

Outcome: Hepatic Effects

Inhalation acute exposure

Torti et al. 2001 (C57BL/6 mouse) Yes No Yes Yes Moderate

Torti et al. 2001 (FVN mouse) Yes No Yes Yes Moderate

Inhalation intermediate exposure

Torti et al. 2001 (C57BL/6 mouse) Yes No Yes Yes Moderate

Torti et al. 2001 (FVN mouse) Yes No Yes Yes Moderate

Oral acute exposure

Condie et al. 1983 (mouse) Yes No Yes Yes Moderate

Keegan et al. 1998 (rat) Yes No No Yes Low

Lilly et al. 1994 (rat, GW) Yes No Yes Yes Moderate

Lilly et al. 1994 (rat, GO) Yes No Yes Yes Moderate

Lilly et al. 1996 (rat) Yes No Yes Yes Moderate

Munson et al. 1982 (mouse) Yes No No Yes Low

Ruddick et al. 1983 (rat) Yes No Yes Yes Moderate

Thornton-Manning et al. 1994 (rat) Yes No Yes Yes Moderate

Thornton-Manning et al. 1994 (mouse) Yes No Yes Yes Moderate

Oral intermediate exposure

Aida et al. 1989 (rat, F) Yes No Yes Yes Moderate

Aida et al. 1989 (rat, W) Yes No Yes Yes Moderate

Aida et al. 1992 (rat) Yes Yes Yes Yes High

Chu et al. 1982 (rat) Yes No Yes Yes Moderate

Hooth et al. 2002 (rat) Yes No Yes Yes Moderate

NTP 1987 (rat) Yes Yes Yes Yes High

NTP 1987 (mouse) Yes Yes Yes Yes High

NTP 2006 (rat) Yes No Yes Yes Moderate

NTP 2006 (mouse) Yes No Yes Yes Moderate

Oral chronic exposure

Aida et al. 1992 (rat) Yes Yes Yes Yes High

George et al. 2002 (rat) Yes No Yes Yes Moderate

George et al. 2002 (mouse) Yes No Yes Yes Moderate

NTP 1987 (rat) Yes Yes Yes Yes High

NTP 1987 (mouse) Yes Yes Yes Yes High

NTP 2006 (rat) Yes No Yes Yes Moderate

NTP 2006 (mouse) Yes No Yes Yes Moderate
BROMODICHLOROMETHANE C-20

APPENDIX C

Table C-14. Presence of Key Features of Study Design for 

Bromodichloromethane—Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

Tumasonis et al. 1985 (rat) Yes Yes Yes Yes High

Outcome: Renal Effects

Inhalation acute exposure

Torti et al. 2001 (C57BL/6 mouse) Yes No Yes Yes Moderate

Torti et al. 2001 (FVN mouse) Yes No Yes Yes Moderate

Inhalation intermediate exposure

Torti et al. 2001 (C57BL/6 mouse) Yes No Yes Yes Moderate

Torti et al. 2001 (FVN mouse) Yes No Yes Yes Moderate

Oral acute exposure

Condie et al. 1983 (mouse) Yes No Yes Yes Moderate

Lilly et al. 1994 (rat, GW) Yes No Yes Yes Moderate

Lilly et al. 1994 (rat, GO) Yes No Yes Yes Moderate

Lilly et al. 1996 (rat) Yes No Yes Yes Moderate

Munson et al. 1982 (mouse) Yes No No Yes Low

Ruddick et al. 1983 (rat) Yes No Yes Yes Moderate

Thornton-Manning et al. 1994 (rat) Yes No Yes Yes Moderate

Thornton-Manning et al. 1994 (mouse) Yes No Yes Yes Moderate

Oral intermediate exposure

Aida et al. 1989 (rat, F) Yes No Yes Yes Moderate

Aida et al. 1989 (rat, W) Yes No Yes Yes Moderate

Aida et al. 1992 (rat) Yes Yes Yes Yes High

Chu et al. 1982 (rat) Yes No Yes Yes Moderate

Lipsky et al. 1993 (rat) Yes No Yes Yes Moderate

Lock et al. 2004 (rat) Yes No Yes Yes Moderate

Lock et al. 2004 (mouse) Yes No Yes Yes Moderate

NTP 1987 (rat) Yes Yes Yes Yes High

NTP 1987 (mouse) Yes Yes Yes Yes High

NTP 2006 (rat) Yes No Yes Yes Moderate

NTP 2006 (mouse) Yes No Yes Yes Moderate

Oral chronic exposure

Aida et al. 1992 (rat) Yes Yes Yes Yes High

George et al. 2002 (rat) Yes No Yes Yes Moderate

George et al. 2002 (mouse) Yes No Yes Yes Moderate

NTP 1987 (rat) Yes Yes Yes Yes High

NTP 1987 (mouse) Yes Yes Yes Yes High
BROMODICHLOROMETHANE C-21

APPENDIX C

Table C-14. Presence of Key Features of Study Design for 

Bromodichloromethane—Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

NTP 2006 (rat) Yes No Yes Yes Moderate

NTP 2006 (mouse) Yes No Yes Yes Moderate

Outcome: Immunological Effects

Oral acute exposure

French et al. 1999 (rat, 5 days) Yes No Yes Yes Moderate

French et al. 1999 (rat, 14 days) Yes No Yes Yes Moderate

Munson et al. 1982 (mouse) Yes No No Yes Low

Oral intermediate exposure

French et al. 1999 (mouse, 16 days; 

GW) Yes No Yes Yes Moderate

French et al. 1999 (rat, 26 weeks, W) Yes No Yes Yes Moderate

Outcome: Reproductive Effects

Oral acute exposure

Bielmeier et al. 2001 (rat, GDs 8–9) Yes Yes No Yes Moderate

Bielmeier et al. 2004 (rat) Yes Yes No Yes Moderate

Bielmeier et al. 2007 (rat) Yes No No Yes Low

Ruddick et al. 1983 (rat) Yes Yes No Yes Moderate

Oral intermediate exposure

Aida et al. 1992 (rat) Yes Yes No Yes Moderate

Christian et al. 2001b Yes Yes Yes Yes High

NTP 1987 (rat) Yes Yes No Yes Moderate

NTP 1987 (mouse) Yes Yes No Yes Moderate

NTP 2006 (rat) Yes Yes No Yes Moderate

NTP 2006 (mouse) Yes Yes No Yes Moderate

Oral chronic exposure

Aida et al. 1992 (rat) Yes Yes No Yes Moderate

Klinefelter et al. 1995 (rat) Yes Yes Yes Yes High

NTP 1987 (rat) Yes Yes No Yes Moderate

NTP 1987 (mouse) Yes Yes No Yes Moderate

NTP 2006 (rat) Yes Yes No Yes Moderate

NTP 2006 (mouse) Yes Yes No Yes Moderate
BROMODICHLOROMETHANE C-22

APPENDIX C

Table C-14. Presence of Key Features of Study Design for 

Bromodichloromethane—Experimental Animal Studies

Key feature

Reference

Concurrent control groupSufficient number of animals per groupAppropriate parameters to assess potential effectAdequate data for statistical analysis

Initial study 

confidence

Outcome: Developmental Effects

Oral Acute Exposure

Bielmeier et al. 2001 (rat, GDs 6–10) Yes Yes No Yes Moderate

Bielmeier et al. 2001 (Sprague-Dawley 

rat, GDs 6–10) Yes Yes No Yes Moderate

Bielmeier et al. 2001 (rat, GDs 8–9) Yes Yes No Yes Moderate

Bielmeier et al. 2001 (rat, GDs 6–10 or 

6–15) Yes Yes No Yes Moderate

Bielmeier et al. 2004 (rat) Yes Yes No Yes Moderate

Narotsky et al. 1997 (rat) Yes Yes No Yes Moderate

Ruddick et al. 1983 (rat) Yes Yes Yes No Moderate

Oral intermediate exposure

Christian et al. 2001a (rat) Yes Yes Yes Yes High

Christian et al. 2001a (rabbit) Yes Yes Yes Yes High

Christian et al. 2001b (rat) Yes Yes No Yes Moderate

A summary of the initial confidence ratings for each outcome is presented in Table C-15. If individual 

studies for a particular outcome and study type had different study quality ratings, then the highest 

confidence rating for the group of studies was used to determine the initial confidence rating for the body 

of evidence; any exceptions were noted in Table C-15.

Table C-15. Initial Confidence Rating for Bromodichloromethane Health Effects 

Studies

Initial study 

confidence

Initial confidence 

rating

Outcome: Hepatic Effects

Inhalation acute exposure

Animal studies

Torti et al. 2001 (C57BL/6 mouse) Moderate Moderate Torti et al. 2001 (FVN mouse) Moderate

Inhalation intermediate exposure

Animal studies

Torti et al. 2001 (C57BL/6 mouse) Moderate Moderate Torti et al. 2001 (FVN mouse) Moderate
BROMODICHLOROMETHANE C-23

APPENDIX C

Table C-15. Initial Confidence Rating for Bromodichloromethane Health Effects 

Studies

Initial study 

confidence

Initial confidence 

rating

Oral acute exposure

Animal studies

Condie et al. 1983 (mouse) Moderate

Moderate

Keegan et al. 1998 (rat) Low

Lilly et al. 1994 (rat, GW) Moderate

Lilly et al. 1994 (rat, GO) Moderate

Lilly et al. 1996 (rat) Moderate

Munson et al. 1982 (mouse) Low

Ruddick et al. 1983 (rat) Moderate

Thornton-Manning et al. 1994 (rat) Moderate

Thornton-Manning et al. 1994 (mouse) Moderate

Oral intermediate exposure

Animal studies

Aida et al. 1989 (rat, F) Moderate

High

Aida et al. 1989 (rat, W) Moderate

Aida et al. 1992 (rat) High

Chu et al. 1982 (rat) Moderate

Hooth et al. 2002 (rat) Moderate

NTP 1987 (rat) High

NTP 1987 (mouse) High

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate

Oral chronic exposure

Human studies

Burch et al. 2015 Low Low

Animal studies

Aida et al. 1992 (rat) High

High

George et al. 2002 (rat) Moderate

George et al. 2002 (mouse) Moderate

NTP 1987 (rat) High

NTP 1987 (mouse) High

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate

Tumasonis et al. 1985 (rat) High

Outcome: Renal Effects

Inhalation acute exposure

Animal studies

Torti et al. 2001 (C57BL/6 mouse) Moderate Moderate Torti et al. 2001 (FVN mouse) Moderate
BROMODICHLOROMETHANE C-24

APPENDIX C

Table C-15. Initial Confidence Rating for Bromodichloromethane Health Effects 

Studies

Initial study 

confidence

Initial confidence 

rating

Inhalation intermediate exposure

Animal studies

Torti et al. 2001 (C57BL/6 mouse) Moderate Moderate Torti et al. 2001 (FVN mouse) Moderate

Oral acute exposure

Animal studies

Condie et al. 1983 (mouse) Moderate

Moderate

Lilly et al. 1994 (rat, GW) Moderate

Lilly et al. 1994 (rat, GO) Moderate

Lilly et al. 1996 (rat) Moderate

Munson et al. 1982 (mouse) Low

Ruddick et al. 1983 (rat) Moderate

Thornton-Manning et al. 1994 (rat) Moderate

Thornton-Manning et al. 1994 (mouse) Moderate

Oral intermediate exposure

Animal studies

Aida et al. 1989 (rat, F) Moderate

High

Aida et al. 1989 (rat, W) Moderate

Aida et al. 1992 (rat) High

Chu et al. 1982 (rat) Moderate

Lipsky et al. 1993 (rat) Moderate

Lock et al. 2004 (rat) Moderate

Lock et al. 2004 (mouse) Moderate

NTP 1987 (rat) High

NTP 1987 (mouse) High

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate

Oral chronic exposure

Animal studies

Aida et al. 1992 (rat) High

High

George et al. 2002 (rat) Moderate

George et al. 2002 (mouse) Moderate

NTP 1987 (rat) High

NTP 1987 (mouse) High

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate
BROMODICHLOROMETHANE C-25

APPENDIX C

Table C-15. Initial Confidence Rating for Bromodichloromethane Health Effects 

Studies

Initial study 

confidence

Initial confidence 

rating

Outcome: Immunological Effects

Oral acute exposure

Animal studies

French et al. 1999 (rat, 5 days) Moderate

French et al. 1999 (rat, 14 days) Moderate Moderate

Munson et al. 1982 (mouse) Low

Oral intermediate exposure

Animal studies

French et al. 1999 (mouse, 16 days; GW) Moderate Moderate French et al. 1999 (rat, 26 weeks; W) Moderate

Acute dermal exposure

Human studies

Vlaanderen et al. 2017 Moderate Moderate

Outcome: Reproductive Effects

Oral acute exposure

Animal studies

Bielmeier et al. 2001 (rat, GDs 8–9) Moderate

Moderate Bielmeier et al. 2004 (rat) Moderate

Bielmeier et al. 2007 (rat) Low

Ruddick et al. 1983 (rat) Moderate

Oral intermediate exposure

Animal studies

Aida et al. 1992 (rat) Moderate

High

Christian et al. 2001b High

NTP 1987 (rat) Moderate

NTP 1987 (mouse) Moderate

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate

Oral chronic exposure

Human studies

MacLehose et al. 2008 Low

Windham et al. 2003 Low Low

Zeng et al. 2013 Low
BROMODICHLOROMETHANE C-26

APPENDIX C

Table C-15. Initial Confidence Rating for Bromodichloromethane Health Effects 

Studies

Initial study 

confidence

Initial confidence 

rating

Animal studies

Aida et al. 1992 (rat) Moderate

High

Klinefelter et al. 1995 (rat) High

NTP 1987 (rat) Moderate

NTP 1987 (mouse) Moderate

NTP 2006 (rat) Moderate

NTP 2006 (mouse) Moderate

Outcome: Developmental Effects

Oral acute exposure

Animal studies

Bielmeier et al. 2001 (F344 rat, GDs 6–10) Moderate

Moderate

Bielmeier et al. 2001 (Sprague-Dawley rat, GDs 6–

10)

Moderate

Bielmeier et al. 2001 (rat, GDs 8–9) Moderate

Bielmeier et al. 2001 (rat, GDs 6–10 or 6–15) Moderate

Bielmeier et al. 2004 (rat) Moderate

Narotsky et al. 1997 (rat) Moderate

Ruddick et al. 1983 (rat) Moderate

Oral intermediate exposure

Animal studies

Christian et al. 2001a (rat) High

Christian et al. 2001b (rat) Moderate High

Christian et al. 2001a (rabbit) High

Oral chronic exposure

Human studies

Cao et al. 2016 Low

Low

Chen et al. 2019 Low

Danileviciute et al. 2012 Low

Dodds and King 2001 Low

Grazuleviciene et al. 2013 Low

Iszatt et al. 2011 Low

King et al. 2000 Low

Rivera-Núñez et al. 2018 Low

Rivera-Núñez and Wright 2013 Low

Summerhayes et al. 2012 Low

Waller et al. 1998 Low

Wright et al. 2004 Low

Wright et al. 2017 Low
BROMODICHLOROMETHANE C-27

APPENDIX C

C.6.2 Adjustment of the Confidence Rating

The initial confidence rating was then downgraded or upgraded depending on whether there were 

substantial issues that would decrease or increase confidence in the body of evidence. The nine properties 

of the body of evidence that were considered are listed below. The summaries of the assessment of the 

confidence in the body of evidence for hepatic, renal, immunological, reproductive, and developmental

effects are presented in Table C-16. If the confidence ratings for a particular outcome were based on 

more than one type of human study, then the highest confidence rating was used for subsequent analyses. 

An overview of the confidence in the body of evidence for all health effects associated with 

bromodichloromethane exposure is presented in Table C-17.

Five properties of the body of evidence were considered to determine whether the confidence rating 

should be downgraded: 

• Risk of bias. Evaluation of whether there is substantial risk of bias across most of the studies 

examining the outcome. This evaluation used the risk of bias tier groupings for individual studies 

examining a particular outcome (Tables C-8 and C-9). Below are the criteria used to determine 

whether the initial confidence in the body of evidence for each outcome should be downgraded 

for risk of bias:

o No downgrade if most studies are in the risk of bias first tier

o Downgrade one confidence level if most studies are in the risk of bias second tier

o Downgrade two confidence levels if most studies are in the risk of bias third tier

• Unexplained inconsistency. Evaluation of whether there is inconsistency or large variability in 

the magnitude or direction of estimates of effect across studies that cannot be explained. Below 

are the criteria used to determine whether the initial confidence in the body of evidence for each 

outcome should be downgraded for unexplained inconsistency:

o No downgrade if there is little inconsistency across studies or if only one study evaluated 

the outcome

o Downgrade one confidence level if there is variability across studies in the magnitude or 

direction of the effect

o Downgrade two confidence levels if there is substantial variability across studies in the 

magnitude or direct of the effect

• Indirectness. Evaluation of four factors that can affect the applicability, generalizability, and 

relevance of the studies: 

o Relevance of the animal model to human health—unless otherwise indicated, studies in 

rats, mice, and other mammalian species are considered relevant to humans 

o Directness of the endpoints to the primary health outcome—examples of secondary 

outcomes or nonspecific outcomes include organ weight in the absence of histopathology 

or clinical chemistry findings in the absence of target tissue effects

o Nature of the exposure in human studies and route of administration in animal studies—

inhalation, oral, and dermal exposure routes are considered relevant unless there are 

compelling data to the contrary 

o Duration of treatment in animal studies and length of time between exposure and 

outcome assessment in animal and prospective human studies—this should be considered 

on an outcome-specific basis
BROMODICHLOROMETHANE C-28

APPENDIX C

Below are the criteria used to determine whether the initial confidence in the body of evidence for 

each outcome should be downgraded for indirectness:

o No downgrade if none of the factors are considered indirect 

o Downgrade one confidence level if one of the factors is considered indirect 

o Downgrade two confidence levels if two or more of the factors are considered indirect

• Imprecision. Evaluation of the narrowness of the effect size estimates and whether the studies 

have adequate statistical power. Data are considered imprecise when the ratio of the upper to 

lower 95% CIs for most studies is ≥10 for tests of ratio measures (e.g., odds ratios) and ≥100 for 

absolute measures (e.g., percent control response). Adequate statistical power is determined if 

the study can detect a potentially biologically meaningful difference between groups (20% 

change from control response for categorical data or risk ratio of 1.5 for continuous data). Below 

are the criteria used to determine whether the initial confidence in the body of evidence for each 

outcome should be downgraded for imprecision:

o No downgrade if there are no serious imprecisions 

o Downgrade one confidence level for serious imprecisions 

o Downgrade two confidence levels for very serious imprecisions 

• Publication bias. Evaluation of the concern that studies with statistically significant results are 

more likely to be published than studies without statistically significant results. 

o Downgrade one level of confidence for cases where there is serious concern with 

publication bias
BROMODICHLOROMETHANE C-29

APPENDIX C

Table C-16. Adjustments to the Initial Confidence in the Body of Evidence 

Initial confidence

Adjustments to the initial 

confidence rating Final confidence

Outcome: Hepatic Effects

Human studies Low -2 risk of bias Very Low

Animal studies High +1 large magnitude of effect High

Outcome: Renal Effects

Animal studies High -1 inconsistency Moderate

Outcome: Immunological Effects

Human studies Moderate -2 risk of bias, -1 imprecision Very Low

Animal studies Moderate None Moderate

Outcome: Reproductive Effects

Human studies Low -2 risk of bias Very Low

Animal studies High -1 inconsistency. -1 imprecision Low

Outcome: Developmental Effects

Human studies Low -2 risk of bias Very Low

Animal studies High +1 large magnitude of effect High
BROMODICHLOROMETHANE C-30

APPENDIX C

Table C-17. Confidence in the Body of Evidence for Bromodichloromethane

Outcome Confidence in body of evidence

Human studies Animal studies

Hepatic effects Very Low High

Renal effects No data Moderate

Immunological effects Very Low Moderate

Reproductive effects Very Low Low

Developmental effects Very Low High

Four properties of the body of evidence were considered to determine whether the confidence rating 

should be upgraded: 

• Large magnitude of effect. Evaluation of whether the magnitude of effect is sufficiently large 

so that it is unlikely to have occurred as a result of bias from potential confounding factors. 

o Upgrade one confidence level if there is evidence of a large magnitude of effect in a few 

studies, provided that the studies have an overall low risk of bias and there is no serious 

unexplained inconsistency among the studies of similar dose or exposure levels; 

confidence can also be upgraded if there is one study examining the outcome, provided 

that the study has an overall low risk of bias

• Dose response. Evaluation of the dose-response relationships measured within a study and 

across studies. Below are the criteria used to determine whether the initial confidence in the body 

of evidence for each outcome should be upgraded:

o Upgrade one confidence level for evidence of a monotonic dose-response gradient

o Upgrade one confidence level for evidence of a non-monotonic dose-response gradient 

where there is prior knowledge that supports a non-monotonic dose-response and a nonmonotonic dose-response gradient is observed across studies

• Plausible confounding or other residual biases. This factor primarily applies to human studies 

and is an evaluation of unmeasured determinants of an outcome such as residual bias towards the 

null (e.g., “healthy worker” effect) or residual bias suggesting a spurious effect (e.g., recall bias). 

Below is the criterion used to determine whether the initial confidence in the body of evidence for 

each outcome should be upgraded:

o Upgrade one confidence level for evidence that residual confounding or bias would 

underestimate an apparent association or treatment effect (i.e., bias toward the null) or 

suggest a spurious effect when results suggest no effect

• Consistency in the body of evidence. Evaluation of consistency across animal models and 

species, consistency across independent studies of different human populations and exposure 

scenarios, and consistency across human study types. Below is the criterion used to determine 

whether the initial confidence in the body of evidence for each outcome should be upgraded:

o Upgrade one confidence level if there is a high degree of consistency in the database
BROMODICHLOROMETHANE C-31

APPENDIX C

C.7 TRANSLATE CONFIDENCE RATING INTO LEVEL OF EVIDENCE OF HEALTH 

EFFECTS

In the seventh step of the systematic review of the health effects data for bromodichloromethane, the 

confidence in the body of evidence for specific outcomes was translated to a level of evidence rating. The 

level of evidence rating reflected the confidence in the body of evidence and the direction of the effect 

(i.e., toxicity or no toxicity); route-specific differences were noted. The level of evidence for health 

effects was rated on a five-point scale: 

• High level of evidence: High confidence in the body of evidence for an association between 

exposure to the substance and the health outcome

• Moderate level of evidence: Moderate confidence in the body of evidence for an association 

between exposure to the substance and the health outcome

• Low level of evidence: Low confidence in the body of evidence for an association between 

exposure to the substance and the health outcome

• Evidence of no health effect: High confidence in the body of evidence that exposure to the 

substance is not associated with the health outcome

• Inadequate evidence: Low or moderate confidence in the body of evidence that exposure to the 

substance is not associated with the health outcome OR very low confidence in the body of 

evidence for an association between exposure to the substance and the health outcome

A summary of the level of evidence of health effects for bromodichloromethane is presented in

Table C-18.

Table C-18. Level of Evidence of Health Effects for Bromodichloromethane

Outcome

Confidence in body 

of evidence

Direction of health 

effect

Level of evidence for 

health effect

Human studies

Hepatic effects Very Low Health effect Inadequate

Renal effects No data No data

Immunological effects Very Low Health effect Inadequate

Reproductive effects Very Low Health effect Inadequate

Developmental effect Very Low Health effect Inadequate

Animal studies

Hepatic effects High Health effect High

Renal effects Moderate Health effect Moderate

Immunological effects Moderate Health effect Moderate

Reproductive effects Low Health effect Low

Developmental effect High Health effect High
BROMODICHLOROMETHANE C-32

APPENDIX C

C.8 INTEGRATE EVIDENCE TO DEVELOP HAZARD IDENTIFICATION CONCLUSIONS

The final step involved the integration of the evidence streams for the human studies and animal studies 

to allow for a determination of hazard identification conclusions. For health effects, there were four 

hazard identification conclusion categories:

• Known to be a hazard to humans

• Presumed to be a hazard to humans 

• Suspected to be a hazard to humans 

• Not classifiable as to the hazard to humans 

The initial hazard identification was based on the highest level of evidence in the human studies and the 

level of evidence in the animal studies; if there were no data for one evidence stream (human or animal), 

then the hazard identification was based on the one data stream (equivalent to treating the missing 

evidence stream as having low level of evidence). The hazard identification scheme is presented in 

Figure C-1 and described below:

• Known: A health effect in this category would have:

o High level of evidence for health effects in human studies AND a high, moderate, or low 

level of evidence in animal studies.

• Presumed: A health effect in this category would have:

o Moderate level of evidence in human studies AND high or moderate level of evidence in 

animal studies OR

o Low level of evidence in human studies AND high level of evidence in animal studies

• Suspected: A health effect in this category would have:

o Moderate level of evidence in human studies AND low level of evidence in animal 

studies OR

o Low level of evidence in human studies AND moderate level of evidence in animal 

studies

• Not classifiable: A health effect in this category would have:

o Low level of evidence in human studies AND low level of evidence in animal studies

Other relevant data such as mechanistic or mode-of-action data were considered to raise or lower the level 

of the hazard identification conclusion by providing information that supported or opposed biological 

plausibility. 

Two hazard identification conclusion categories were used when the data indicated that there may be no 

health effect in humans:

• Not identified to be a hazard in humans

• Inadequate to determine hazard to humans

If the human level of evidence conclusion of no health effect was supported by the animal evidence of no 

health effect, then the hazard identification conclusion category of “not identified” was used. If the 

human or animal level of evidence was considered inadequate, then a hazard identification conclusion 

category of “inadequate” was used. As with the hazard identification for health effects, the impact of 

other relevant data was also considered for no health effect data. 
BROMODICHLOROMETHANE C-33

APPENDIX C

Figure C-1. Hazard Identification Scheme

The hazard identification conclusions for bromodichloromethane are listed below and summarized in 

Table C-19. 

Presumed Health Effects

• Hepatic effects 

o Inadequate evidence from a cross-sectional study (Burch et al. 2015) examining the 

association between serum bromodichloromethane levels and alanine aminotransferase 

levels. 

o High level of evidence in mice following acute inhalation exposure (Torti et al. 2001) and 

in rats and mice following acute (Condie et al. 1983; Keegan et al. 1998; Lilly et al. 1994, 

1996; Munson et al. 1982; Thornton-Manning et al. 1994), intermediate (Aida et al. 1992; 

Hooth et al. 2002; NTP 1987), and chronic (Aida et al. 1992; NTP 1987) oral exposure.

• Developmental effects

o Although a number of epidemiology studies found associations between exposure to 

bromodichloromethane and developmental effects, the human data were considered 

inadequate for evaluating the potential hazard due to the low initial confidence in these 

studies and the high risk of bias.

o High level of evidence from acute (Bielmeier et al. 2001, 2004; Narotsky et al. 1997) and 

intermediate (Christian et al. 2001a) oral exposure in rats. The most sensitive 
BROMODICHLOROMETHANE C-34

APPENDIX C

developmental endpoint was full-litter resorption in F344 rats, but not in Sprague-Dawley 

rats (Bielmeier et al. 2001, 2004; Narotsky et al. 1997).

Suspected Health Effects

• Renal effects 

o No human data are available on the potential renal toxicity of bromodichloromethane. 

o Moderate evidence of renal toxicity in mice following acute or intermediate inhalation 

exposure and in rats and mice following acute (Condie et al. 1983; Lilly et al. 1994, 

1996; Munson et al. 1982; Thornton-Manning et al. (1994), intermediate (NTP 1987), 

and chronic (George et al. 2002; NTP 1987) oral exposure.

• Immunological effects

o Very low evidence in an epidemiological study that evaluated immune markers in 

subjects swimming in chlorinated water for 40 minutes (Vlaanderen et al. 2017). No data 

are available on whether inhalation, oral, or dermal exposure to bromodichloromethane 

impairs immune function. 

o Moderate evidence in animal studies based on two studies that found altered responses to 

immune stimulants after acute gavage administration (French et al. 1999; Munson et al. 

1982) or intermediate oral exposure in rats (French et al. 1999). 

Not Classifiable Effects

• Reproductive effects

o Inadequate evidence in cohort and cross-sectional studies that examined sperm 

parameters (Zeng et al. 2013), menstrual cycle (Windham et al. 2003), and time to 

pregnancy (MacLehose et al. 2008).

o Low evidence in animal studies (Aida et al. 1992; Bielmeier et al. 2001, 2004, 2007; 

Christian et al. 2001b; Klinefelter et al. 1995; NTP 1987, 2006; Ruddick et al. 1983). 

Studies evaluating the histopathology of the reproductive system have not found 

alterations at nonlethal doses (Aida et al. 1992; NTP 1987, 2006). Bielmeier et al. (2001, 

2004, 2007) reported significant alterations in reproductive hormone levels in pregnant 

rats, and Klinefelter et al. (1995) reported decreases in sperm velocity, but no changes in 

sperm motility. No alterations in reproductive function were observed in a 2-generation 

study in rats (Christian et al. 2001b). The lack of consistency across studies and the 

indirectness of the observed effects decreased the initial confidence in these studies. 

Table C-19. Hazard Identification Conclusions for Bromodichloromethane

Outcome Hazard identification 

Hepatic effects Presumed health effect 

Renal effects Suspected health effect 

Immunological effects Suspected health effect

Reproductive effects Not classifiable

Developmental effects Presumed health effect
BROMODICHLOROMETHANE D-1

APPENDIX D. 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 
BROMODICHLOROMETHANE D-2

APPENDIX D

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 D-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 
BROMODICHLOROMETHANE D-3

APPENDIX D

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 D-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.
BROMODICHLOROMETHANE D-4

APPENDIX D

(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.
BROMODICHLOROMETHANE

D-5

APPENDIX D
BROMODICHLOROMETHANE

D-6

APPENDIX D
BROMODICHLOROMETHANE E-1

APPENDIX E. 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).
BROMODICHLOROMETHANE E-2

APPENDIX E

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/.
BROMODICHLOROMETHANE F-1

APPENDIX F. 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.
BROMODICHLOROMETHANE F-2

APPENDIX F

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.
BROMODICHLOROMETHANE F-3

APPENDIX F

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.
BROMODICHLOROMETHANE F-4

APPENDIX F

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. 
BROMODICHLOROMETHANE F-5

APPENDIX F

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.
BROMODICHLOROMETHANE F-6

APPENDIX F

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.
BROMODICHLOROMETHANE G-1

APPENDIX G. 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
BROMODICHLOROMETHANE G-2

APPENDIX G

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
BROMODICHLOROMETHANE G-3

APPENDIX G

NIOSH National Institute for Occupational Safety and Health

NLM National Library of Medicine

nm nanometer

nmol nanomole

NOAEL no-observed-adverse-effect level

NPL National Priorities List

NR not reported

NRC National Research Council

NS not specified

NTP National Toxicology Program

OR odds ratio

OSHA Occupational Safety and Health Administration

PAC Protective Action Criteria

PAH polycyclic aromatic hydrocarbon

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PEHSU Pediatric Environmental Health Specialty Unit

PEL permissible exposure limit

PEL-C permissible exposure limit-ceiling value

pg picogram

PND postnatal day

POD point of departure

ppb parts per billion

ppbv parts per billion by volume

ppm parts per million

ppt parts per trillion

REL recommended exposure level/limit

REL-C recommended exposure level-ceiling value

RfC reference concentration

RfD reference dose

RNA ribonucleic acid

SARA Superfund Amendments and Reauthorization Act

SCE sister chromatid exchange

SD standard deviation

SE standard error

SGOT serum glutamic oxaloacetic transaminase (same as aspartate aminotransferase or AST)

SGPT serum glutamic pyruvic transaminase (same as alanine aminotransferase or ALT)

SIC standard industrial classification

SMR standardized mortality ratio

sRBC sheep red blood cell

STEL short term exposure limit

TLV threshold limit value

TLV-C threshold limit value-ceiling value

TRI Toxics Release Inventory

TSCA Toxic Substances Control Act

TWA time-weighted average

UF uncertainty factor

U.S. United States

USDA United States Department of Agriculture

USGS United States Geological Survey

USNRC U.S. Nuclear Regulatory Commission
BROMODICHLOROMETHANE

G-4

APPENDIX G

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