EPA 635/R-04/067

www.epa.gov/iris

TOXICOLOGICAL REVIEW

 

OF

1,2-DIBROMOETHANE

(CAS No. 106-93-4)

In Support of Summary Information on the

Integrated Risk Information System (IRIS)

June 2004

U.S. Environmental Protection Agency

Washington, DC
ii

DISCLAIMER

This document has been reviewed in accordance with U.S. Environmental Protection

Agency policy and approved for publication. Mention of trade names or commercial products

does not constitute endorsement or recommendation for use.
iii

CONTENTS —TOXICOLOGICAL REVIEW for 1,2-DIBROMOETHANE

 (CAS No. 106-93-4)

LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

LIST OF FIGURES ........................................................... vii

FOREWORD ............................................................... .viii

AUTHORS, CONTRIBUTORS, AND REVIEWERS ................................ ix

1. INTRODUCTION ..........................................................1

2. CHEMICAL AND PHYSICAL PROPERTIES RELEVANT TO ASSESSMENT ........3

3. TOXICOKINETICS RELEVANT TO ASSESSMENTS ............................5

3.1. ABSORPTION .....................................................5

3.2. METABOLISM .....................................................5

3.3. DISTRIBUTION ................................................... 10

3.4. EXCRETION ...................................................... 11

3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS .... 11

4. HAZARD IDENTIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.1. STUDIES IN HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.1.1. LETHALITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.1.2. REPRODUCTIVE TOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

4.1.3. CANCER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 

ANIMALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.2.1. CARCINOGENICITY BIOASSAYS AND CHRONIC ORAL 

STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

4.2.2. CARCINOGENICITY BIOASSAY AND CHRONIC INHALATION

STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

4.2.3. SUBCHRONIC INHALATION STUDIES ....................... 28

4.2.4. OTHER STUDIES .......................................... 32

4.3. REPRODUCTIVE AND DEVELOPMENTAL STUDIES IN ANIMALS - ORAL

AND INHALATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

4.3.1. INHALATION STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

4.3.2 ORAL STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

4.4. OTHER STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

4.4.1. REPRODUCTIVE/DEVELOPMENTAL . . . . . . . . . . . . . . . . . . . . . . . . 43

4.4.2. DEVELOPMENTAL NEUROTOXICITY . . . . . . . . . . . . . . . . . . . . . . . 45

4.4.3. GENOTOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

4.4.4. ACUTE TOXICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND

MODE OF ACTION – ORAL AND INHALATION . . . . . . . . . . . . . . . . . . . . 50
iv

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER

CHARACTERIZATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4.6.1. HUMAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4.6.2. ANIMAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

4.6.3. MODE OF ACTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

4.6.4. WEIGHT-OF-EVIDENCE CHARACTERIZATION . . . . . . . . . . . . . . . 56

4.7. SUSCEPTIBLE POPULATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

4.7.1. POSSIBLE CHILDHOOD SUSCEPTIBILITY . . . . . . . . . . . . . . . . . . . . 58

4.7.2. POSSIBLE GENDER DIFFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . 58

5. DOSE-RESPONSE ASSESSMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

5.1. ORAL REFERENCE DOSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

5.1.1. METHODS OF ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

5.1.2. RfD DERIVATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

5.2. INHALATION REFERENCE CONCENTRATION (RfC) . . . . . . . . . . . . . . . . . . 63

5.2.1. METHODS OF ANALYSIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.2.2. RfC DERIVATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

5.3. CANCER ASSESSMENT ............................................ 68

5.3.1. ORAL CARCINOGENICITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

5.3.2. INHALATION CARCINOGENICITY . . . . . . . . . . . . . . . . . . . . . . . . . . 81

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE

RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

6.1. HUMAN HAZARD POTENTIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

6.2. DOSE RESPONSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

7. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

APPENDIX A. External Peer Review–Summary of Comments and Disposition . . . . . . . . . . A-1

APPENDIX B. BMDS Analyses of Noncancer Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . B-1

APPENDIX C. Dose-Response Analyses of Cancer Endpoints . . . . . . . . . . . . . . . . . . . . . . . . C-1

C.1. Analyses in support of slope factor for oral exposure . . . . . . . . . . . . . . . . . . . . . . C-1

C.2. Analyses in support of inhalation unit risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-34
v

LIST OF TABLES

Table 2-1. Chemical and physical properties of 1,2-dibromoethane .......................4

Table 4-1. Incidence of tumors in Osborne-Mendel rats in 1,2-dibromoethane oral gavage

bioassay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Table 4-2. Incidence of tumors in B6C3F1 mice in 1,2-dibromoethane oral gavage bioassay . . 25

Table 4-3. Nasal cavity tumor types in rats following chronic inhalation of 

1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Table 4-4. Lung tumor types in mice following chronic inhalation of 

1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Table 4-5. Enhancement of 1,2-dibromoethane-induced tumor with disulfiram coadministration

in rats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Table 4-6. Lung tumor incidence in A/J mice following exposure to 1,2-dibromoethane via

several routes of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

Table 5-1. Oral subchronic and chronic studies in laboratory animals . . . . . . . . . . . . . . . . . . . 61

Table 5-2 Application of uncertainty factors (UFs) for RfD calculation . . . . . . . . . . . . . . . . . 62

Table 5-3. Inhalation subchronic and chronic studies in laboratory animalse . . . . . . . . . . . . . . 64

Table 5-4. Reproductive and developmental inhalation studies in laboratory animals . . . . . . . 65

Table 5-5. HEC estimates from BMDLs derived from NTP (1982); Table B-2, Appendix B . . 67

Table 5-6. Observed and adjusted tumor incidences (and percentages) in rats and mice exposed 

by oral gavage to 1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Table 5-7. Human equivalent exposures and adjustment factors for extrapolating from less-thanchronic exposure to lifetime exposure for the exposure periods in the NCI gavage study of 1,2-

dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Table 5-8. Estimation of benchmark doses (BMD), lower 95% confidence limits (BMDL),

estimated model parameter q and standard error (se), and goodness-of-fit p-value; using Poly-3

adjusted tumor incidence rates (Table 5-1), for animals exposed orally to 1,2-dibromoethane . 80

Table 5-9. Observed and adjusted tumor incidence rates in rats and mice exposed to 1,2-
vi

dibromoethane by inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Table 5-10: Summary of regional gas dose ratios for estimating human equivalent exposures

corresponding to respiratory tumors observed in NTP inhalation bioassay . . . . . . . . . . . . . . . . 89

Table 5-11. Estimates of benchmark concentration (BMC) associated with an extra risk of 10%,

lower 95% confidence limits (BMCL), estimated model parameter (and standard error), and

goodness-of-fit p-value; using Poly-3 incidence rates listed in Table B-3 (Appendix B), for

animals exposed by inhalation to 1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

Table 5-12. Estimation of benchmark concentration (BMC) associated with an extra risk of

10%, lower 95% confidence limits (BMCL), estimated model parameter (and standard error),

and goodness-of-fit p-value, using multistage-Weibull time-to-tumor modeling for animals

exposed by inhalation to 1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Table 5-13. Estimation of benchmark concentration (BMC) associated with an extra risk of

10%, lower 95% confidence limits (BMCL), estimated model parameter (and standard error),

and goodness-of-fit p-value; using multistage-Weibull time-to-tumor modeling, for animals

exposed by inhalation to 1,2-dibromoethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
vii

LIST OF FIGURES

Figure 3-1. Metabolism of dibromoethane by the oxidative route . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3-2. Metabolism of dibromoethane by the conjugative route . . . . . . . . . . . . . . . . . . . . . . 9

Figure 5-1. Log-probit model of nasal inflammation in female mice . . . . . . . . . . . . . . . . . . . . . 68

Figure C-1. Kaplan-Meier hazard curves for the incidence of forestomach squamous cell

carcinomas in male rats in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-7

Figure C-2. Cumulative incidence curves for hemangiosarcomas in male rats in the oral gavage

study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-10

Figure C-3. Cumulative incidence curves for thyroid follicular cell adenomas or carcinomas in

male rats in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-13

Figure C-4. Kaplan-Meier hazard curves for the incidence of forestomach squamous cell

carcinomas in female rats in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-16

Figure C-5. Cumulative incidence curves for hemangiosarcomas in female rats in the oral

gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-17

Figure C-6. Cumulative incidence curves for hepatocellular carcinomas and neoplastic nodules

in female rats in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-20

Figure C-7. Cumulative incidence curves for adrenocortical carcinomas and neoplastic nodules

in female rats in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-23

Figure C-8. Kaplan-Meier hazard curves for the incidence of forestomach squamous cell

carcinomas in male mice in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-26

Figure C-9: Cumulative incidence curves for lung adenomas in male mice in the oral gavage

study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-27

Figure C-10. Kaplan-Meier hazard curves for the incidence of forestomach squamous cell

carcinomas in female mice in the oral gavage study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-30

Figure C-11. Cumulative incidence curves for lung adenomas in female mice in the oral gavage

study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-31
viii

FOREWORD

The purpose of this Toxicological Review is to provide scientific support and rationale

for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to 1,2-

dibromoethane. It is not intended to be a comprehensive treatise on the chemical or

toxicological nature of 1,2-dibromoethane.

In Section 6, Major Conclusions in the Characterization of Hazard and Dose Response,

EPA has characterized its overall confidence in the quantitative and qualitative aspects of hazard

and dose response by addressing knowledge gaps, uncertainties, quality of data, and scientific

controversies. The discussion is intended to convey the limitations of the assessment and to aid

and guide the risk assessor in the ensuing steps of the risk assessment process. 

For other general information about this assessment or other questions relating to IRIS,

the reader is referred to EPA’s IRIS Hotline at 202-566-1676.
ix

 AUTHORS, CONTRIBUTORS, AND REVIEWERS

CHEMICAL MANAGER AND AUTHORS

Jeff Gift (chemical manager)

National Center for Environmental Assessment

U.S. Environmental Protection Agency 

Research Triangle Park, NC

Mark Greenberg (chemical manager)

National Center for Environmental Assessment

U.S. Environmental Protection Agency 

Research Triangle Park, NC.

Karen Hogan

National Center for Environmental Assessment

U.S. Environmental Protection Agency

Washington, DC

Audrey Cummings, Ph.D

National Center for Environmental Assessment

U.S. Environmental Protection Agency

Research Triangle Park, NC

John J. Liccione, Ph.D

Sciences International, Inc.

Alexandria, VA

Joseph A. Spinnato III, Ph.D

Sciences International, Inc.

Alexandria, VA

David Gaylor, Ph.D

Sciences International, Inc.

Alexandria, VA

REVIEWERS

This document and the accompanying IRIS Summary have been peer reviewed by EPA

scientists and independent scientists external to EPA. Comments from all peer reviewers were

evaluated carefully and considered by the Agency during the finalization of this assessment.

During the finalization process, the IRIS Program Director achieved common understanding of

the assessment among the Office of Research and Development; Office of Air and Radiation;
x

Office of Prevention, Pesticides, and Toxic Substances; Office of Solid Waste and Emergency

Response; Office of Water; Office of Policy, Economics, and Innovation; Office of Children’s

Health Protection; Office of Environmental Information, and EPA’s regional offices.

INTERNAL EPA REVIEWERS 

Esther Rinde, Ph.D.

Office of Prevention, Pesticides and Toxic Substances

U.S. Environmental Protection Agency

Washington, DC

Sanjivani Diwan, Ph.D.

Office of Research and Development

U.S. Environmental Protection Agency

Washington, DC

EXTERNAL PEER REVIEWERS

Michael J. DiBartolomeis, Ph.D., D.A.B.T.

California Environmental Protection Agency

Office of Environmental Health Hazard Assessment

Oakland, CA

Lynne T. Haber, Ph.D.

Toxicology Excellence for Risk Assessment

Cincinnati, OH

Cynthia Van Landingham, M.S.

Environ International Corporation

Ruston, LA

Summaries of the external peer reviewers’ comments and the disposition of their

recommendations are in Appendix A.
1

1. INTRODUCTION

This document presents background information and justification for the Integrated Risk

Information System (IRIS) Summary of the hazard and dose-response assessment of 1,2-

dibromoethane. IRIS Summaries may include an oral reference dose (RfD), inhalation reference

concentration (RfC) and a carcinogenicity assessment.

The RfD and RfC provide quantitative information for noncancer dose-response

assessments. The toxicity values are based on the assumption that thresholds exist for certain

toxic effects such as cellular necrosis but may not exist for other toxic effects such as some

carcinogenic responses. In general, the RfD is an estimate (with uncertainty spanning perhaps an

order of magnitude) of a daily exposure to the human population (including sensitive subgroups)

that is likely to be without an appreciable risk of deleterious noncancer effects during a lifetime. 

It is expressed in units of mg/kg-day. The inhalation RfC is analogous to the oral RfD, but

provides a continuous inhalation exposure estimate. The inhalation RfC considers toxic effects

for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory

system (extrarespiratory or systemic effects). It is generally expressed in units of mg/m3

.

The carcinogenicity assessment provides information on the carcinogenic hazard potential

of the substance in question and quantitative estimates of risk from oral and inhalation exposure. 

The information includes a weight-of-evidence judgment of the likelihood that the agent is a

human carcinogen and the conditions under which the carcinogenic effects may be expressed. 

Quantitative risk estimates are presented in three ways to better facilitate their use: (1) generally,

the slope factor is the result of application of a low-dose extrapolation procedure and is presented

as the risk per mg/kg-day of oral exposure; (2) the unit risk is the quantitative estimate in terms of

either risk per μg/L drinking water or risk per μg/m3

 air breathed; and (3) the 95% lower bound

and central estimate on the estimated concentration of the chemical substance in drinking water or

air that presents cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000.

Development of these hazard identification and dose-response assessments for 1,2-

dibromoethane has followed the general guidelines for risk assessment as set forth by the National

Research Council (1983). EPA guidelines that were used in the development of this assessment

may include the following: Guidelines for the Health Risk Assessment of Chemical Mixtures (U.S.
2

EPA, 1986a), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Guidelines for

Developmental Toxicity Risk Assessment (U.S. EPA, 1991), Guidelines for Reproductive Toxicity

Risk Assessment (U.S. EPA, 1996b), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA,

1998a), Draft Revised Guidelines for Carcinogen Assessment (U.S. EPA, 1999),

Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S.

EPA, 1988), (proposed) Interim Policy for Particle Size and Limit Concentration Issues in

Inhalation Toxicity (U.S. EPA, 1994a), Methods for Derivation of Inhalation Reference

Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994b), Use of the

Benchmark Dose Approach in Health Risk Assessment (U.S. EPA, 1995), Science Policy Council

Handbook: Peer Review (U.S. EPA, 1998b, 2000a), Science Policy Council Handbook: Risk

Characterization (U.S. EPA, 2000b), Benchmark Dose Technical Guidance Document (U.S.

EPA, 2000c), Supplementary Guidance for Conducting Health Risk Assessment of Chemical

Mixtures (U.S. EPA, 2000d), and A Review of the Reference Dose and Reference Concentration

Processes (U.S. EPA, 2002).

The literature search strategy employed for this compound was based on the CASRN and

at least one common name. Any pertinent scientific information submitted by the public to the

IRIS Submission Desk was also considered in the development of this document. The relevant

literature was reviewed through May 2003.
3

2. CHEMICAL AND PHYSICAL PROPERTIES RELEVANT TO ASSESSMENT

1,2-Dibromoethane, also known as ethylene dibromide, is a colorless, heavy liquid that

has a mildly sweet, chloroform-like odor (HSDB, 1999). It is sparingly soluble in water and

miscible with most organic solvents. It is soluble in alcohol, ether, acetate, and benzene. The

physical properties of 1,2-dibromoethane are listed in Table 2-1.

Prior to the phaseout of leaded gasoline in the United States, 1,2-dibromoethane was

primarily used as an anti-knock compound. Sources of 1,2-dibromoethane included emissions

and exhaust from vehicles using leaded gasoline. Its use as a fumigant for citrus, grain, and soil

was discontinued in 1984 (U.S. Environmental Protection Agency [EPA], 2000e). It is currently

used as a solvent for resins, gums, and waxes; as a chemical intermediate in the synthesis of dyes

and pharmaceuticals; and as a precursor in the synthesis of vinyl chloride. Also, 1,2-

dibromoethane appears to be formed naturally by microalgae growth and has been detected in

ocean waters and air. 

1,2-Dibromoethane exhibits low-to-moderate soil adsorption, with experimental Koc

values ranging from 14 to 160, indicating that 1,2-dibromoethane will leach quickly into

groundwater. 1,2-Dibromoethane volatilizes readily from surface soil as predicted by its

relatively high vapor pressure (11.2 mm Hg at 25°C). 1,2-Dibromoethane is very stable towards

hydrolysis (half-life, T1/2 = 13.2 years at pH 7 and 20°C) and is more likely to undergo aerobic

biodegradation in the soil rather than abiotic degradation. After 8 weeks under anaerobic

conditions in the presence of denitrifying bacteria, no biodegradation was observed compared

with 97% degradation to ethylene under aerobic conditions.

In aquatic environments, the primary removal process for 1,2-dibromoethane is

evaporation: the volatilization half-life from a typical lake or river is 1–5 days. Biodegradation of

1,2-dibromoethane in groundwater can be slow (with half-lives in months), and biotic hydrolysis

only readily occurs in the presence of a natural catalyst such as hydrogen sulfide. The presence

of hydrogen sulfide increases the rate of hydrolysis from several years to approximately 2

months. 

In the ambient atmosphere, 1,2-dibromoethane exists as a vapor, and, although it
4

undergoes degradation in a reaction with photochemically produced hydroxyl radicals, it is likely

to be persistent. Direct photolysis is not likely to occur.

Table 2-1. Chemical and physical properties of 1,2-dibromoethane

Property Value Reference

Molecular weight 187.88 HSDB, 1999

Density at 25°C 2.172 g/mL

Melting point 9.8°C

Boiling point 131-132°C

Vapor pressure at 25°C 11.2 mm Hg

Henry’s Law constant 8.2 × 10-4 atm-m3

/mol

Water solubility at 25°C 4150 mg/L

Koc 66

1 ppm = 7.68 mg/m3 at 25°C and 760 mm Hg.
5

3. TOXICOKINETICS RELEVANT TO ASSESSMENTS

3.1. ABSORPTION

 1,2-Dibromoethane absorption via the gastrointestinal tract was described by Hissink et

al. (2000) using data from Roth et al. (1993). Hissink et al. (2000) found that orally exposed rats

appeared to absorb 1,2-dibromoethane via two first-order processes presumed to be from the

stomach to the intestines and from the intestines to the liver. For the purposes of their models

(see section 3.5), Hissink et al. (2000) estimated rat absorption parameters from in vivo oral and

intravenous (i.v.) exposures and assumed human absorption was not different from that of rats. 

For rats dosed orally (gavage) with 50 and 150 mg 1,2-dibromoethane/kg, absorption was

reported to be fast, with blood concentrations nearing estimated Cmax levels within 30 minutes. 

Oral exposure to 1 gram of 1,2-dibromoethane resulted in serum 1,2-dibromoethane

concentrations of approximately 1 ppm (0.1% of the dose based on blood volume) in one minipig

15 minutes after compound administration (Kirby et al., 1980). Very rapid 1,2-dibromoethane

metabolism was considered as causing relatively low serum 1,2-dibromoethane concentrations. 

Inhalation studies (National Toxicology Program [NTP], 1982; Stinson et al., 1981; Nitschke et

al., 1981; Reznik et al., 1980; Short et al., 1978; Smith and Goldman, 1983) show that 1,2-

dibromoethane is absorbed via the inhalation route of exposure and distributed systemically. 

Stott and McKenna (1984) showed that 1,2-dibromoethane is about 50% absorbed when

presented to either the upper or lower respiratory tract of Fisher 344 rats at a flow rate equivalent

to the animals’ respiratory minute volume (53 mL/min). Following dermal exposure to 1 mL

1,2-dibromoethane in guinea pigs, 1,2-dibromoethane blood levels increased rapidly to 2.1 :g/mL

after 1 hour and decreased slightly to 1.8 :g/mL after 6 hours (Jakobson et al., 1982). 

3.2. METABOLISM

1,2-Dibromoethane is metabolized by two major pathways, cytochrome-P450-

monooxygenase and glutathione (GSH) conjugation via glutathione-S-transferase (GST). These

pathways are depicted in Figures 3-1 and 3-2. Oxidative metabolism by cytochrome-P450 leads

to the formation of the reactive metabolite 2-bromoacetaldehyde (Hill et al., 1978) via

dehydrohalogenation of a gem-halohydrin. This route has been demonstrated to account for 80%
6

of the metabolism of 1,2-dibromoethane in the rat (van Bladeren et al., 1981). 2-

Bromoacetaldehyde can then be converted to s-(2-hydroxyethyl) glutathione (HEG) and Scarboxymethylglutathione (CMG) through several different pathways involving either direct

interaction with GSH or oxidative metabolism to 2-bromoethanol and 2-bromoacetic acid

followed by conjugation with GSH (Jean and Reed, 1992). However, only the former pathway

involving direct interaction of 2-bromoacetaldehyde with GSH is believed to be catalyzed by

GSTs (Jean and Reed, 1992). Under hypoxic conditions, free radical intermediates have been

generated in microsomal and hepatocyte assays (Tomasi et al., 1983). 

1,2-Dibromoethane can also conjugate directly with GSH by a GST-mediated reaction to

form S-(2-bromoethyl)GSH (Jean and Reed, 1992), a half-mustard that can spontaneously

rearrange to an episulfonium ion, thiiranium, and is further hydrolyzed to S-($-

hydroxyethyl)GSH; or it can bind to DNA (Hodgson and Levi, 1994; Jean and Reed, 1992;

Peterson et al., 1988). S-(2-bromoethyl)GSH can also undergo further GSH conjugation to form

S,S-1,2-ethanediyl-bis-GSH (Jean and Reed, 1992). Formation of these GSH-containing

metabolites correlated with a 71% depletion of intracellular GSH. In vitro studies have shown

that approximately 60% of the episulfonium ion is trapped as S,S-ethanediyl-bis-GSH with the

remainder reacting with water to form S-hydroxyethylGSH (Cmarik et al., 1990). The

episulfonium ion is believed to be responsible for the genotoxicity of 1,2-dibromoethane. The

major adduct derived from the episulfonium pathway is S-[2-N7-guanyl)ethyl]GSH (Koga et al.,

1986). However, N2

- and O6-guanyl adducts may also contribute (Cmarik et al., 1992; Kim and

Guengerich, 1997; Kim and Guengerich, 1998). These may explain the predominance of GC:AT

transitions in Escherichia coli (Foster et al., 1988) and Drosophila melanogaster (Ballering et al.,

1994).

The half-mustard (Ozawa and Guengerich, 1983) and 2-bromoacetaldehyde (Guengerich

and Persmark, 1994) can react with DNA to generate miscoding adducts, although the rate of

reaction of 2-bromoacetaldehyde with DNA has been shown to be rather slow (Guengerich et al.,

1981). The in vitro rate of hydrolysis of S-(2-bromoethyl)GSH is 1.6/min-1 with a T1/2 of 0.44

min (Wheeler et al., 2001).

In vivo metabolic studies have identified a number of urinary metabolites following 1,2-

dibromoethane exposure. Nachtomi et al. (1966) identified S-(hydroxyethyl)mercapturic acid as

a major urinary metabolite and S-($-hydroxyethyl)cysteine as a minor metabolite following oral
7

administration of 100 mg/kg 1,2-dibromoethane in albino rats. S-(hydroxyethyl)mercapturic acid,

thiodiacetic acid, and thiodiacetic acid sulfoxide have been identified as major urinary

metabolites following oral administration of 1,2-dibromoethane in Wistar rats (Wormhoudt et al.

1998). Thiodiacetic acid formation is dependent on cytochrome-P450 oxidation for formation

and not GSH conjugation (Wormhoudt et al., 1997). S-[2-(N7

-guanyl)ethyl]-N-acetylcysteine,

which is derived from the nucleic acid adduct S-[2-(N7-guanyl)ethyl]GSH, has also been

identified as a urinary metabolite in rats following intraperitoneal injection (Kim and Guengerich,

1989). 

Van Bladeren et al. (1981) reported that the oxidative route compared to the conjugative

route occurred in a ratio of about 4:1 in rats. This would mean that 1,2-dibromoethane is

preferentially metabolized to 2-bromoacetaldehyde and then conjugated with GSH. The

cytochrome-P450 isozyme responsible for the oxidation of 1,2-dibromoethane to 2-

bromoacetaldehyde appears to be CYP2E1. Wormhoudt et al. (1996a) found that microsomes

from Wistar rats pretreated with pyrazole, an inducer of CYP2E1, had a turnover (Vmax/Km ) of

1,2-dibromoethane to 2-bromoacetaldehyde 74 times greater than microsomes from rats

pretreated with $-naphthoflavone, an inducer of CYP2A1. Similarly, heterologously expressed

CYP2E1 had a catalytic efficiency in terms of Vmax/Km 100 times greater than CYP2B6 and 600

times greater than CYP2A6 (Wormhoudt et al., 1996b). The same study found that

heterologously expressed CYP1A1, CYP1A2, CYP2C8, CYP2C9, CYP2C18, CYP3A4, and

CYP3A5 had no ability to metabolize 1,2-dibromoethane to 2-bromoacetaldehyde. Microsomes

from 21 different human livers were able to catalyze the oxidation of 1,2-dibromoethane to 2-

bromoacetaldehyde with activities that ranged from 22.2 to1027.6 pmol/min-mg of protein 

(Wormhoudt et al., 1996b). This oxidation was significantly inhibited by specific CYP2E1

inhibitors, disulfiram and diethyldithiocarbamate. 

The results of several experiments suggest that of the several mammalian GSH

transferases that can catalyze conjugation with GSH (Cmarik et al., 1990), theta-class GSH

transferase (GSTT) may be most important for conjugation of 1,2-dibromoethane. Investigation

of human erythrocyte cytosol from 12 people not exposed to 1,2-dibromoethane revealed that two

of the cytosols did not catalyze GSH conjugation with 1,2-dibromoethane (Ploemen et al., 1995). 

Every cytosol had similar activity toward the classic GSH substrate, 1-chloro-2,4-dinitrobenzene. 

However, the two cytosol enzymes incapable of catalyzing 1,2-dibromoethane-GSH conjugation

were also incapable of catalyzing GSH conjugation with 1,2-epoxy-3-(p-nitrophenoxy)-propane
8

(EPNP). EPNP is a highly selective substrate for GSTT, and this suggests that GSTT is specific

for GSH conjugation of 1,2-dibromoethane in human erythrocyte cytosol. Human GSTT is

polymorphic in humans (Pemble et al., 1994; Warholm et al., 1995; Nelson et al., 1995;

Kempkes et al., 1996). If the carcinogenicity of 1,2-dibromoethane is attributable only to a

conjugate formed only by GSTT, people with a null genotype leading to no activity for this

enzyme may not be as susceptible to cancer from 1,2-dibromoethane (see discussion in section

4.7).

In vitro experiments found Salmonella typhimurium expressing human GST-2 had greater

genotoxicity following 1,2-dibromoethane exposure than strains that did not express this enzyme

(Thier et al., 1996). Simula et al. (1993) reported that GST-" expression increased the

mutagenicity of 1,2-dibromoethane in an S. typhimurium assay but GST-B did not. The authors

did not investigate the role of GST-2. 

Figure 3-1. Metabolism of dibromoethane by the oxidative route.
9

Figure 3-2. Metabolism of dibromoethane by the conjugative route.
10

3.3 DISTRIBUTION

Following oral administration of 15 mg/kg 14C-1,2-dibromoethane in rats, retention of the

compound 24 hours after administration was limited to 3% of administered label in organs with

the majority of the dose retained in the kidney, liver, and spleen (Plotnick et al., 1979). Fortyeight hours after exposure, 1.1% of administered label was present in the liver. Disulfiram, a

compound known to enhance the toxicity of 1,2-dibromoethane in animals, significantly

increased the tissue concentration of 14C-1,2-dibromoethane in liver, kidneys, spleen, testes, and

brain of male Sprague-Dawley rats that consumed a diet containing 0.05% disulfiram for 12 days

prior to oral intubation with 15 mg/kg 14C-1,2-dibromoethane (Plotnick et al., 1979). Also, label

associated with liver nuclei was significantly increased in disulfiram-treated rats. As would be

expected, urinary elimination of 14C-1,2-dibromoethane was decreased significantly with

increased tissue binding. 

One hundred sixty-eight hours after i.v. (10 and 50 mg/kg) or oral (50 and 150 mg/kg)

administration of 14C-1,2-dibromoethane, <1% of administered label was found in the liver, lungs,

and kidneys and 0.3% was present in erythrocytes (Wormhoudt et al., 1998). Short et al. (1979),

who monitored total radioactivity in whole organs (kidney, stomach, liver, and testes) and tissue

fractions 4 hours after oral administration of 10 and 100 mg/kg 14C-1,2-dibromoethane, found that

label was greater in the kidney, liver, and stomach than in testes. A portion of the label in these

tissues was covalently bound to DNA, RNA, and protein. 

In mice, irreversibly bound metabolites of 14C-1,2-dibromoethane (2.6 mg/kg) were

reported to be highest in the nasal mucosa, followed by the liver, lung, and kidney, 3 hours after

intraperitoneal (i.p.) injection (Brittebo et al., 1989). Similarly, Hill et al. (1978) reported

significant macromolecular binding to epithelial tissues of the respiratory tract, liver, kidney, and

small intestine of rats following i.p. injection of 0.8 mg/kg 14C-1,2-dibromoethane. In one male

cynomolgous monkey administered 4 :mol/kg 14C-1,2-dibromoethane intraperitoneally, the liver

and kidney proximal tubules had the highest amount of administered radioactivity per mg of

tissue, but very little binding was observed in the lung and other organs of the respiratory tract

(Brandt et al., 1987). When tissues from a female monkey were incubated with 20 :M 14C-1,2-

dibromoethane, the distribution of bound metabolites in the kidney was identical to that observed

in vivo. The authors also described a distinct zone of binding in the adrenal zona reticularis, both

in vitro and in vivo. Significant levels of radiolabeled metabolites irreversibly bound to the
11

adrenal cortex, nasal cavity, lung, and other tissues of rats (Sprague-Dawley and Fischer) and

C57BL mice were also observed by Kowalski et al. (1985) after i.v. and i.p. injection of 14C-1,2-

dibromoethane. For results in fetal tissues, see section 4.7.1.

3.4. EXCRETION

1,2-Dibromoethane is eliminated mainly in the urine. In vivo metabolic studies have

identified a number of urinary metabolites, including S-(hydroxyethyl)mercapturic acid and S-($-

hydroxyethyl)cysteine following oral administration of 100 mg/kg 1,2-dibromoethane in albino

rats (Nachtomi et al., 1966) ). S-(hydroxyethyl)mercapturic acid, thiodiacetic acid, and

thiodiacetic acid sulfoxide have been identified as major urinary metabolites following oral

administration of 1,2-dibromoethane in Wistar rats (Wormhoudt et al., 1998). S-[2-(N7

-

guanyl)ethyl]-N-acetylcysteine, which is derived from the nucleic acid adduct S-[2-(N7-

guanyl)ethyl]GSH, has also been identified as a urinary metabolite in rats following

intraperitoneal injection (Kim and Guengerich, 1989). 

Following oral administration of 15 mg/kg 14C-1,2-dibromoethane in rats, 72% of the dose

was excreted in the urine and 1.65% in the feces (Plotnick et al., 1979). Forty-eight hours later,

73% of the dose had been accounted for in the urine and 3% in the feces. Similar results were

reported by Wormhoudt et al. (1998), who found that following i.v. (10 and 50 mg/kg) or oral (50

and 150 mg/kg) administration of 14C-1,2-dibromoethane, 75 - 82% of the radioactivity was

excreted in the urine within 48 hours, 3.2 - 4% was eliminated in the feces within 48 hours, and

0.53 - 7.2% was eliminated in the expired air within 2 hours. The only major difference between

the two routes of administration was that a much higher percentage of the dose was eliminated in

the expired air following i.v. administration. 

3.5. PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELS

Hissink et al. (2000) have developed a PBPK model for 1,2-dibromoethane for rats and

humans that is largely based on in vitro data published by Ploemen et al. (1997). Due primarily to

the higher relative ventilation rate, cardiac output, and metabolic rate of rats, the Hissink et al.

(2000) model predicts that blood concentrations of 1,2-dibromoethane and the metabolites of both
12

pathways (P450 oxidative and GST conjugation) described above would be higher in rats than in

humans. Their model predicts that this would be the case for average humans and for humans

with extremely high contributions from one or the other pathway (i.e., high GST/P450 or

P450/GST contribution ratios). Assuming that a GSH conjugate is the toxicant and that total

GSH conjugate level correlates to the specific toxic episulfonium ion would suggest that humans

may be less sensitive than rats to the genotoxic and carcinogenic effects of 1,2-dibromoethane. 

The model has not been fully validated, however, and makes several assumptions that affect the

conclusions, including the following: (1) there is no P450 activity in human kidneys but

significant P450 activity in rat kidneys; (2) there is considerably lower GSH activity in human

skeletal muscle, lung, and stomach compared with rat; and (3) that steady state levels were

reached in blood after an 8-hour exposure. The model only simulated an 8-hour exposure, and

longer simulation runs are needed to evaluate steady-state levels and subsequent differences in

GSH conjugate levels. The model also does not include terms for GSH synthesis and

degradation rates (also needed for chronic exposures), factors that can greatly affect GSH

conjugate levels. It also does not attempt to distinguish (or correlate) the episulfonium conjugate

from all other GSH conjugates or the P450 metabolite conjugates from the parent compound GSH

conjugates. Given these limitations, it would not be appropriate to use the Hissink et al. (2000)

model at this time for quantitative (route-to-route or animal-to-human) extrapolations. However,

the Hissink et al. (2000) report and model provide useful information regarding the mode of

action of 1,2-dibromoethane, particularly with respect to the cancer effects of 1,2-dibromoethane.
13

4. HAZARD IDENTIFICATION

4.1. STUDIES IN HUMANS

4.1.1. Lethality

Olmstead (1960) described a case report of a 43-year old woman who ingested capsules

containing 1,2-dibromoethane. Symptoms included abdominal pain, nausea, vomiting, diarrhea,

darkening of the urine, tachypnea, and marked agitation; she died 54 hours after ingesting of the

capsules. Histological examination revealed massive central lobular necrosis of the liver with

focal proximal tubular epithelial damage in the kidney. Olmstead (1960) commented that these

changes were similar to those observed in various experimental animals following oral

administration of 1,2-dibromoethane.

Six cases of suicidal poisoning via ingestion of 1,2-dibromoethane were reported by

Saraswat et al. (1986). Two of the six individuals died. In one of these individuals, postmortem

examination revealed massive liver necrosis; ulceration of the oral cavity; congestion and erosion

of the stomach; congestion of the lungs, spleen, brain, and kidneys; pulmonary edema; and cloudy

swelling of the kidney with occasional tubular necrosis. The other individual showed

centrilobular necrosis of the liver and congestion of the lungs and stomach. Clinical signs

observed in those who survived ingestion of 1,2-dibromoethane included nausea, vomiting, and

burning of the throat.

 1,2-Dibromoethane was lethal to two workers following acute exposure to 1,2-

dibromoethane in a tank (Letz et al., 1984). One worker exhibited metabolic acidosis, central

nervous system depression, and liver damage. The other worker displayed metabolic acidosis and

hepatic and renal failure. Elevated serum bromide concentrations were detected in both cases

prior to death. 
14

4.1.2. Reproductive Toxicity

Semen quality has been studied in papaya workers with long-term exposure to 1,2-

dibromoethane used in the fumigation of papaya (Ratcliffe et al., 1987). Workers at six papaya

fumigation plants located near Hilo, Hawaii, were assessed for potential 1,2-dibromoethanerelated reproductive toxicity. 

Exposure of the papaya workers to 1,2-dibromoethane was characterized in detail by

Clapp (1986). The workers were exposed to 1,2-dibromoethane for an average of 5 years.

Samples were reported to be collected on at least two separate days to give an estimate of

exposure during the workweek. Three to four packers/sorters and one to two forklift operators

were sampled per plant for an 8-hour work shift; in three of the plants, air samples were taken

both in 1982 and 1983. In these three plants, there is a considerable amount of variation between

the 1982 and 1983 mean air sample concentrations measured for the same plant. Full-shift

exposures of 16 to 175 ppb (0.1 to 1.4 mg/m3

) among the six plants investigated were reported

with a geometric mean of 88 ppb (0.68 mg/m3) and peak exposures as high as 262 ppb (2.0

mg/m3). Significant plant-to-plant variation was reported: full-shift exposures for papaya

packers/sorters ranged from 36 to 148 ppb (0.3 - 1.1 mg/m3) and those for forklift operators

ranged from 16 to 175 ppb (0.1 - 1.4 mg/m3

). A sugar processing plant adjacent to one of the

fumigation plants served as a control group for exposed workers. 

Semen was collected and delivered for analysis within 1 hour of collection (Ratcliffe et

al., 1987). The following potentially confounding variables were considered: tobacco smoking

(current, ex-smokers, and nonsmokers), marijuana use (times per week), alcohol consumption

(drinks per week), caffeine consumption (cups of coffee and/or tea per day), history of urogenital

disorders, prescription medication taken in the past year, history of fever in the past three months,

abstinence time, subject age, sample age, and racial background. The only significant difference

between control and exposed workers was marijuana use, which was higher in exposed workers

(41.3%) than in controls (20.9%). 

Ratcliffe et al. (1987) reported summary air exposure data, but there was moderate dermal

exposure that could not be quantified (Schrader et al., 1988). Semen of exposed workers

exhibited significantly decreased average sperm count per ejaculate and percentage of viable and

motile sperm. There were statistical increases in certain types of morphological abnormalities
15

(tapered heads, absent heads, and abnormal tails) in exposed workers. There was also a

significant increase in percentage of subjects with sperm counts fewer than 20 million in exposed

workers (21.7% compared to 4.7% in controls). The highly variable inhalation exposures and the

confounding dermal exposures preclude the use of this population for the development of an RfC. 

A comparison of 1,2-dibromoethane-exposed cohorts of forestry workers in Colorado

(short-term exposure) and papaya workers from the Ratcliffe et al. (1987) study (long-term

exposure) was performed by Schrader et al. (1988). Ten 1,2-dibromoethane-exposed and six

unexposed forestry workers were identified for the study. Schrader et al. (1988) reported that 8-

hour air samples were collected for three days during the six-week fumigation season and several

short-term (15-minute and 1-hour) samples were also taken. Short-term exposure concentrations

ranged from non-detectable levels to 2165 ppb (16.6 mg/m3

) for workers filling truck tanks with

1,2-dibromoethane, 57 to 525 ppb (0.4 to 4.0 mg/m3) for workers spraying log piles, and 8 to 184

ppb (0.1 to 1.4 mg/m3) for workers pouring an 1,2-dibromoethane emulsion on log piles. The

results of the 8-hour samples were not reported, but a time-weighted average exposure of 60 ppb

(0.5 mg/m3

) was reported. It should be noted that dermal exposure was recognized as a major

potential route of exposure. Schrader et al. (1988) stated that dermal exposure in forestry workers

was excessive, and the papaya workers described in Ratcliffe et al. (1987) were subject to

moderate dermal exposure. Attempts to quantify the dermal route of exposure were unsuccessful. 

Exposed and control worker ejaculates were collected 1–2 weeks before exposure and during the

last week of exposure.

When postexposure semen samples of forestry workers were compared to those collected

pre-exposure, sperm velocity was significantly decreased in all 10 exposed workers compared to

controls, and nine exposed workers had significantly decreased semen volume compared to

controls. Sperm viability, sperm concentration, semen pH, sperm morphology, and sperm

morphometry of exposed workers were not significantly different from controls. Sperm motility

was a measured parameter, but there was no explicit indication of the percent of motile sperm in

the report. It is assumed that there was no effect of 1,2-dibromoethane on motility.

These results contrast with those of papaya workers described in Ratcliffe et al. (1987). 

Schrader et al. (1988) suggest that the differences in toxic responses between the two studies were

due to the duration of exposure. Markers of mature sperm function, such as sperm velocity, might

be expected to be altered during short-term exposure, but morphogenic effects, as seen in
16

Ratcliffe et al. (1987), would not be observed unless exposure occurred for at least the duration of

one spermatogenic cycle (74 days). Therefore, Schrader et al. (1988) conclude that the two

studies complement each other when the duration of exposure (6 weeks vs. 5 years) is considered.

Wong et al. (1979) conducted a retrospective evaluation of reproductive performance of

male workers in four chemical plants that produced 1,2-dibromoethane during the 1958-1977

time period. This was done by comparing actual numbers of live births delivered by their wives

compared to the expected numbers of live births derived from national fertility tables published

by the National Center for Health Statistics. In addition to 1,2-dibromoethane, one plant

produced dibromochloropropane (a known male reproductive toxicant), another produced “other

brominated compounds,” workers in another plant were also probably exposed to ethylene

dichloride (EDC), and the remaining plant was limited to 1,2-dibromoethane production. 1,2-

Dibromoethane was monitored through industrial hygiene studies, except at one plant in which

1,2-dibromoethane levels were not determined. Observed and expected births were adjusted for

maternal age, parity, race, and calendar year for all 1,2-dibromoethane-exposed workers at all

four plants. Workers were classified as being exposed to either < 0.5 ppm (< 3.8 mg/m3

) or 

0.5–5.0 ppm (3.8 - 38 mg/m3). There was no difference between observed and expected births in

wives of workers for three of the plants. There was, however, a significant difference (< 0.05)

pertaining to the plant producing 1,2-dibromoethane and also using EDC: the 1,2-dibromoethane

levels at this plant ranged from 0.1 to 4 ppm (0.8 to 30 mg/m3). Considering the limited

exposure data and co-exposure to other chemicals, no conclusions can be drawn concerning the

potential antifertility effect of 1,2-dibromoethane from this study. 

Sperm counts have been assessed in agricultural workers with known exposure to 1,2-

dibromoethane (Takahashi et al., 1981). Volunteers were asked to complete a medical history

questionnaire related to possible factors that could affect spermatogenesis. Agricultural workers

and unexposed controls were asked to provide semen samples. Sperm count, morphology, and

motility were determined 0.5–1 hour after collection. Co-exposure to dibromochloropropane

(DBCP) also occurred in agricultural workers, but levels of DBCP and 1,2-dibromoethane

exposure could not be precisely determined. The only observed adverse effect in the workers was

significantly lower sperm counts compared to controls. Conclusions about the effect of 1,2-

dibromoethane on male fertility cannot be determined from this study because of a lack of

exposure data and co-exposure to DBCP, a well-documented gonadotoxin. 
17

Fertility history was evaluated for male workers employed in a 1,2-dibromoethane

production facility (Turner and Barry, 1979) by examining family size. A total of 82 married

workers employed at the time of the study (1977) was identified, 41 of whom were determined to

have very low or no exposure to 1,2-dibromoethane, while the remaining 41 had some exposure

to 1,2-dibromoethane. Of those thought to have some exposure, 13 were regular process workers,

17 were process operators with variable exposure, and 11 were maintenance workers with

sporadic potential exposure. In addition, 75 process workers were identified from company

records of all married employees who had left employment by the time of the survey. 

Presumably, this earlier employed group would have had higher exposure to 1,2-dibromoethane

than in the first set identified, but no information was mentioned concerning exposure categories. 

No exposure measurements or frequency information was available for any of the workers,

however. A comparison group of 80 men was selected for this historical group from the patients

of a local general practitioner, excluding any ever employed at the facility. For all groups of men,

the investigators compared average number of children per family on joining the company with

the average number of children at the time of the survey and concluded that there were no

statistical differences among any of the groups. Among those employed at the time of the survey,

average family sizes were slightly higher among those thought to be exposed to 1,2-

dibromoethane (2.18 to 2.85 children per family) than for those thought not to be exposed (1.95). 

Ages of the men were similar, and average number of years employed when the children were

born varied from 1.5 to 4.5 among those with exposure and was 5 years for those without

exposure. For the historical group and its control, family sizes were very similar at 1.97 and 1.98

children/family, respectively; however, no information was provided regarding comparability of

ages of the men or of the amount of time over which the fertility rates were evaluated. Due to

several limitations of the study design– lack of exposure data, small sample size (especially

within exposure categories), and apparent lack of control regarding whether any of the families

were trying to have more children– this study is inconclusive regarding the effect of 1,2-

dibromoethane on male fertility.

4.1.3. Cancer

Mortality of workers occupationally exposed to 1,2-dibromoethane has been investigated in

several studies (Ott et al., 1980; Sweeney et al., 1986). Ott et al. (1980) investigated the cause of

death of 161 workers occupationally exposed to 1,2-dibromoethane in two production facilities,
18

one in operation from 1942 to 1969 and the other from the mid-1920s to 1976. The study

primarily focused on cancer mortality and respiratory disease. Quantitative data from which to

calculate an 8-hour time-weighted average (TWA) were not available for the first facility. 

However, area sampling data from 1950, 1952, and 1971 - 72 and personal air monitoring in 1975

allowed for estimation of 1,2-dibromoethane exposure in the second facility. Area samples from

1950 ranged from 1 - 10.6 ppm (7.7 - 81.4 mg/m3

), 19 - 31 ppm (146 - 238 mg/m3) in 1952, 0 -

110 ppm (0 - 845 mg/m3) from 1971 - 1972, and 1.8 - 96 ppm (14 - 737 mg/m3) in 1975. An

estimated TWA of 3.5 ppm (26.9 mg/m3) was calculated for 1971 - 1972 and 5 ppm (38.4 mg/m3)

for 1975.

 

In the first facility, two deaths from malignant neoplasms were observed compared to 3.6

expected. No other organic bromide compounds were manufactured at this facility and exposure

was primarily limited to 1,2-dibromoethane, bromine, ethylene, sulfur dioxide, and chlorine. In

the second facility, 5 deaths were attributed to malignant neoplasms compared to 2.2 expected. 

However, this facility manufactured other organic bromide chemicals, such as vinyl bromide,

trimethylene chlorobromide, propylene chlorobromide, ethyl bromoacetate, isobutyl bromide, and

acetylene tetrabromide, to which workers were potentially exposed. In addition to organic

bromide chemicals, workers in the second plant were also indirectly exposed to allyl chloride,

benzene, bromochloromethane, carbon tetrachloride, chloroform, ethyl bromide, hydrogen

bromide, methylene chloride, methylene dibromide, tert-bromobutyl phenol, and tert-butyl

phenol. 

The neoplasms were not tissue-specific as can be seen from the following incidence: three

lung, two stomach, one prostate, one reticulum-cell sarcoma, one pancreas, and one unknown. In

addition, two of the lung neoplasms were associated with workers who had prior history of

working with arsenicals which can also cause this type of cancer. The authors did not count these

two workers as contributors to the total neoplasm population from this facility because of their

prior arsenical exposure. Also, the two workers who succumbed to stomach cancer were father

and son and were reported to have a family history of cancer. Smoking history for neoplasmrelated deaths was available for one of nine workers. The study is inconclusive in regards to 1,2-

dibromoethane as a potential human carcinogen because of co-exposure to other potential

carcinogens. 

Sweeney et al. (1986) studied the cause-specific mortality of 156 male workers in a
19

chemical plant that manufactured tetraethyl lead. The study was undertaken to investigate an

apparent cluster of three cases of multiple myeloma and four cases of brain cancer. In this

historical prospective study, employees who worked at least 1 day between 1952 and 1977 were

eligible for the study. Other chemicals used in the tetraethyl lead manufacturing processes were

ethylene dibromide, ethylene dichloride, chloroethane, ethylene, inorganic lead, and dyes. 

Environmental exposure data were available for some chemicals, but the work history records

were not sufficiently detailed to construct exposure indices. Consequently, the exposure levels of

the various chemicals and particular combinations of chemicals could not be determined.

The standardized mortality ratios (SMRs) for carcinomas at several sites were slightly

elevated: colon and rectum (5 observed vs. 3.7 expected); trachea, bronchus, and lung (14

observed vs. 12.5 expected); and brain (4 observed vs 1.88 expected). No SMRs were

statistically significantly elevated, however. The investigators reported that there was low power

for detecting excess risk of mortality from multiple myeloma (27% at a 5% significance level),

brain cancer (31%), or other rare cancers. Concerning the apparent clusters, it was determined

that there had been some misclassification of original diagnoses, as one brain cancer was actually

a metastatic carcinoma of the lung. One of the three multiple myeloma cases died subsequent to

the end date of the study, however, and was not included in the analysis. It is not clear why the

study period ended in 1977, given that the study’s purpose was to investigate these specific cases.

Mortality in the Sweeney et al. (1986) study from all causes was lower than that predicted

based on the death rates of United States males (156 observed vs. 211 expected). This is common

in occupational studies and is frequently characterized as the “healthy worker effect.” Ideally, the

most appropriate comparison group would have been a group of workers exposed to similar levels

of the same chemicals except ethylene dibromide. Overall, the study is inconclusive, given the

small study size and co-exposure to other chemicals. However, it does not rule out an association

of increased cancer incidence with exposure to 1,2-dibromoethane.

Turner and Barry (1979) evaluated mortality due to cancer and other causes in two 1,2-

dibromoethane production facilities operated by the same company. One facility (Factory A)

operated from 1940 to 1970, while the second (Factory B) started operating in 1952 and was still

in operation at the time of the study (1977). Records for men who had been employed at least 4

years during the operation of the facility, with potential exposure to 1,2-dibromoethane, were

examined. No exposure measurements or frequency information was available for any of the
20

workers, however. From Factory A, 117 men were identified with potential exposure to 1,2-

dibromoethane for at least 4 years, 34 of whom had died at the time of the study. From Factory

B, 274 men were identified with potential exposure to 1,2-dibromoethane for at least 4 years, 26

of whom had died by the time of the study. Death rate per 1000 man-years was calculated within

broad age-at-death categories (25-44, 45-64, 65-74, and 75 years and over) due to the small

number of subjects and compared with analogous death rates in the local population in 1961 and

1970 to help consider possible differences associated with date of death. Death rates for all

causes and for cancer only were similar or lower in the exposed groups than in the local

population for all age groups, except in the 75 years and over group (Factory A only; there were

none in this age group in the Factory B set). In the oldest age group, the death rate among

exposed workers was 149.9 per 1000 man-years for all causes, while the analogous death rate for

the local population was 136.5 in 1961 and 135.8 in 1970. For cancer, the death rate was 21.3,

while the analogous rate in the local population was 16.2 in 1961 and 17.0 in 1970; however,

there was only one cancer case in the exposed group. Given the extremely small study size, lack

of exposure information, and insufficient allowance for cancer latency, especially for Factory B,

this study is inconclusive regarding the effect of 1,2-dibromoethane on carcinogenicity.

4.2. PRECHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN 

ANIMALS

4.2.1. Carcinogenicity Bioassays and Chronic Oral Studies

The National Cancer Institute (NCI) (1978) examined the potential carcinogenicity of 1,2-

dibromoethane in rats and mice. Male and female Osborne-Mendel rats and B6C3F1 mice

(50/sex/species/exposure group; n = 20 in untreated control group and n = 20 in vehicle control

group) were administered 1,2-dibromoethane in corn oil by gastric intubation for 5 days/week

until sacrificed. 

Rats: The initial doses utilized for male and female rats were 40 and 80 mg/kg-day. 

However, high treatment-related mortality (18/50 males and 20/50 females) caused a

discontinuation in the intubation of the high-dose group after treatment in week 16. Intubation of

this group was suspended for 13 weeks and then restarted at week 30. At this time the surviving
21

rats received the low-dose regimen. All surviving male and female rats in both dosage groups

were sacrificed at weeks 49 and 61, respectively. Time-weighted average low- and high-doses

were 38 and 41 mg/kg-day for male rats, and 37 and 39 mg/kg-day for female rats.

The treated and vehicle control rats were placed on test simultaneously at the age of 8

weeks with intubation of vehicle controls suspended after 49 weeks, followed by a 14-day

observation period. All male and female vehicle controls were sacrificed in week 63 at the age of

71 weeks. Gavage of female vehicle controls was suspended after 61 weeks and was followed by

a 2-week observation period. Untreated controls (5 weeks of age) were placed on test 15 weeks

after the start of the treated rats and vehicle controls. Thus, all untreated (without vehicle)

controls were on test for 107 weeks. 

 Treatment-related effects included squamous cell carcinoma of the forestomach in rats of

both sexes, judged by the investigators to be a possible cause of the high mortality. There was a

positive association (p < 0.001) in both groups between increasing dosage and accelerated

mortality. Because 40% of high-dose females died in week 15 either during intubation or shortly

thereafter, it was suggested that acute toxic reactions were the likely cause of those deaths. 

However, squamous cell carcinomas (in all low-dose females surviving beyond week 15) were

also considered by the investigators to be associated with mortality in this group. There was no

mention in the report if gavage error contributed to the incidence of early mortality. 

 There were statistically significant increases in tumor incidence for both male and female

rats, both at the point of contact (forestomach) and systemically. Crude incidences of

forestomach tumors were 90% in low-dose males and 80% in low-dose females, but 66% and

58% in high dose animals. Lower incidence in the high-dose group may have been due to the

higher rate of early deaths. Metastases of the forestomach tumors to multiple organs were

common. There was an elevated incidence of hepatocellular carcinoma in high-dose female rats

only. Hemangiosarcoma, particularly of the spleen, was observed in male and female animals. 

Males also had a small incidence of hemangiosarcoma in other organs: liver, kidney, pancreas,

and abdominal cavity. The incidence of hemangiosarcomas was statistically significant for lowdose animals only. The incidence of these selected neoplastic lesions in the rat is summarized in

Table 4-1.

 Non-neoplastic lesions in the high-dose animals of both sexes included hyperkeratosis and
22

acanthosis of the forestomach (12/50 males and 18/50 females). The incidence of hyperkeratosis

and acanthosis was lower in low-dose animals with only 4/50 females (compared with 1/20

untreated controls) and no males presenting this adverse effect. Peliosis (mottled-blue liver)

hepatitis was observed in 0/40 controls, 10/50 low-dose, and 9/50 high-dose males and in 0/40

controls, 1/47 low-dose, and 5/48 high-dose females. Inflammation of the liver was also present

in 1/40 controls, 4/50 low-dose, and 5/50 high-dose males and in 0/40 controls, 4/47 low-dose,

and 2/48 high-dose females. Degeneration of the adrenal cortex was noted in 0/40 controls and

13/48 and 9/47 low- and high-dose males. The incidence of adrenocortical degeneration was

slightly lower in females (1/40 controls, 3/44 low-dose, and 8/45 high-dose animals). 

Testicular atrophy was observed in 11/20 untreated controls, 0/20 vehicle controls, and

14/49 and 18/50 low- and high-dose males, respectively. Because the untreated controls were on

test for a far longer period (107 weeks) than the treated or vehicle controls, the vehicle controls

are the appropriate reference group. It was stated that necropsy was performed on each animal

regardless of whether it died, was sacrificed while moribund, or was at the end of the study. Thus,

the incidence data for testicular atrophy for only those male rats that survived until the end of

study (35 weeks) were likely higher than the data given for the original 50 rats (18 of which died

early). The results suggest that the low dose (38 mg/kg-day) was a lowest-observed adverse-effect

level (LOAEL), indicating that 1,2-dibromoethane induced early development of testicular

lesions.

Mice: Male and female mice were initially treated with low and high doses of 60 and 120

mg/kg/day, respectively. At week 11, low- and high-dose concentrations were increased to 100

and 200 mg/kg-day, respectively. Treatment with increased doses continued for 2 weeks and then

returned to initial concentrations at week 13. The high-dose treatments were further decreased to

60 mg/kg/day in week 40. At week 54, compound treatment was ceased in both low- and highdose groups. All surviving male mice and high-dose female mice were sacrificed by week 78,

while low-dose females were sacrificed at week 90. Time-weighted average low- and high-doses

were 62 and 107 mg/kg/day, respectively, for mice of both sexes. 

Mortality was high in all treated groups (p < 0.001). Only 20/50 low- and 10/50 highdose males survived for at least 58 weeks. Due to excessive mortality, males were sacrificed at

week 78. Of the males that survived to at least week 26, 44/46 low-dose and 29/40 high-dose

males exhibited squamous-cell carcinoma of the forestomach. In females, 28/50 low-dose and
23

8/50 high-dose animals survived at least 70 weeks. Low- and high-dose females were terminated

at weeks 90 and 78, respectively. As in males, early development of squamous-cell carcinoma of

the forestomach was observed, with the first occurrence in the low-dose group at week 40 and the

first occurrence in the high-dose group at week 34. Of the high-dose females that survived to at

least week 34, 28/35 exhibited squamous-cell carcinoma of the forestomach.

Squamous-cell carcinoma of the forestomach was the primary tumor observed in both

sexes. Similar to rats, this neoplasm metastasized throughout the abdominal cavity and lung. In

addition, lung adenomas were observed in all mouse exposure groups of both sexes and were

considered compound-related. There was a significant positive association between dosage and

incidence for both sexes. Although there was little evidence of lung carcinomas (one in the lowdose females), the adenomas nevertheless are considered evidence of a carcinogenic response and

are relevant for human risk assessment. The incidence of these selected neoplastic lesions in the

mouse is summarized in Table 4-2.

Non-neoplastic lesions were observed primarily in the forestomach of treated mice. 

Acanthosis was observed in 0/40 controls, 1/50 low-dose, and 5/49 high-dose males and in 0/40

controls and 9/50 high-dose females. Hyperkeratosis of the forestomach was also observed in

13/49 high-dose males and in 0/40 controls, 1/49 low-dose, and 12/50 high-dose females. 

Testicular atrophy was also observed in 10/47 high-dose male mice (none in 39 control animals or

in 45 low-dose animals). Thus, 1,2-dibromoethane appears to have caused early development of

testicular atrophy as it had in male rats.

The carcinogenicity of 1,2-dibromoethane and its potential metabolites was the focus of a

study by Van Duuren et al. (1985). Groups of 30 male and 30 female B6C3F1 mice were

administered bromoacetaldehyde, bromoethanol, or 1,2-dibromoethane in drinking water at a

concentration of 4 mM for each compound for 15–18 months. Untreated control groups,

consisting of 50 mice of each sex, were given distilled drinking water. Based on measured

drinking water consumption, the authors estimated that 1,2-dibromoethane-treated male mice

received 116 mg/kg/day, and 1,2-dibromoethane-treated female mice received 103 mg/kg/day on

average.

Van Duuren et al. reported that 1,2-dibromoethane-treated animals had significant

mortality and weight loss that were not observed in the other treatment groups. Survival in males
24

was approximately 25% at week 65 when the group was terminated, while survival in females

dropped to this level by about week 74. 1,2-Dibromoethane-induced squamous carcinoma of the

forestomach was observed in 26 of 28 male mice necropsied and in 22 of 29 female mice. In

addition, five forestomach papillomas were observed in these 29 females. Males also exhibited

eight squamous carcinomas of the glandular stomach. As in the NCI study, there were metastases

of the squamous carcinomas to other organs. Bromoethanol induced leukemia (2/29 in both

males and females compared with 2/50 for female controls and none in males) and had a high

incidence (10/29 males and 9/29 females compared with 1/50 in each of the control groups) of

forestomach papillomas. The incidence of tumor-bearing mice treated with bromoacetaldehyde

was lower than untreated controls. The authors concluded that it was unlikely that

bromoacetaldehyde or bromoethanol were the activated carcinogenic intermediates of 1,2-

dibromoethane.

Table 4-1. Incidence of tumors in Osborne-Mendel rats in 1,2-

dibromoethane oral gavage bioassay

Organ/tissue

Tumor

Control

0 mg/kg-day

Vehicle control

0 mg/kg-day 38 mg/kg-day 41 mg/kg-day

incid. % incid. % incid. % incid. %

Males

Stomach

Forestomach papilloma or

tumor 0/20 0 0/20 0 45/50 90 33/50 66

Circulatory system

Hemangiosarcoma 0/20 0 0/20 0 11/50 22 4/50 8

Thyroid gland

Follicular cell adenoma or

carcinoma 1/20 5 0/20 0 5/50 10 8/49 16

Females

Forestomach

Tumors 0/20 0 0/20 0 40/50 80 29/50 58

Liver

Hepatocellular carcinoma 0/20 0 0/20 0 1/47 2 5/48 10

Circulatory system

Hemangiosarcoma 0/20 0 0/20 0 1/49 2 3/48 6

Adrenals

Adrenocortical carcinoma 0/20 0 0/20 0 0/44 0 4/45 9
25

Source: NCI, 1978.

Table 4-2. Incidence of tumors in B6C3F1 mice in 1,2-dibromoethane oral

gavage bioassay

Organ/tissue

Tumor

Control

0 mg/kg-day

Vehicle control

0 mg/kg-day 62 mg/kg-day 107 mg/kg-day

incid. % incid. % incid. % incid. %

Males 

Forestomach

Squamous cell papilloma or

carcinoma 0/20 0 0/20 0 45/50 90 31/49 63 

Lung

Adenoma 0/20 0 0/20 0 4/45 8 10/47 21

Females

Forestomach

Papillomas or tumors 0/20 0 0/20 0 47/48 92 28/50 56

Lung

Adenoma 0/20 0 0/20 0 10/48 20 5/50 10

Source: NCI, 1978.

4.2.2. Carcinogenicity Bioassay and Chronic Inhalation Studies

The National Toxicology Program (NTP, 1982) performed an inhalation carcinogenicity

bioassay in rats and mice. Male and female Fischer 344 rats and B6C3F1 mice (n = 50 per sex,

species, and exposure group) were exposed to 0, 10, or 40 ppm (0, 77, or 307 mg/m3

) 1,2-

dibromoethane for 6 hr/day, 5 days/week. The study was designed to assess potential adverse

effects of 1,2-dibromoethane following 103 weeks of exposure. However, high mortality in both

species prompted early termination in some of the exposure groups.

Rats: High-exposure male rats exhibited high mortality (90%) resulting in termination of

that exposure group at week 88. Similarly, high-exposure female rats exhibited high mortality

(84%) and were terminated at week 91. Mortality in control and low-exposure rats of both sexes

were comparable.

Mean body weights of high-exposure rats of either sex were decreased compared to
26

controls throughout the study. However, body weight data were reported graphically in the text,

and determination of the week that the decrease in body weight became significant ($10% of

controls) is difficult to determine. Nasal cavity tumors were the primary neoplastic lesion

observed in rats. The total numbers of animals with primary nasal cavity tumors were

significantly increased (p < 0.001) in 1,2-dibromoethane-exposed male rats (0/50 control, 39/50

low-exposure, and 41/50 high-exposure) and female rats (1/50 control, 34/49 low-exposure, and

43/50 high-exposure). These summary statistics were presented in Tables 5 and 6 of the NTP

report. Table 4-3 is a summary of the incidences of nasal cavity tumor types, including those

from animals that died on study.

Other neoplastic lesions were also observed. Hemangiosarcoma of the spleen was

observed in 1 low-exposure and 15 high-exposure male rats, and this tumor type was also

observed in 5 high-exposure females. Male rats had a dose-dependent increase in mesothelioma

of the tunica vaginalis (1/50 control, 13/50 low-exposure, and 26/50 high-exposure). Female rats

had a statistically significant increase in mammary fibroadenomas in both exposure groups (4/50

control, 29/49 low-exposure, and 24/50 high-exposure). In addition, 4/50 high-exposure females

were observed to have adenocarcinoma of the mammary glands compared to 1/50 for controls. 

Lung carcinoma (4/50) and adenoma (1/50) were also reported in high-exposure females.

Several non-neoplastic lesions were considered related to treatment. A dose-dependent

increase in hepatic necrosis was observed in 2/50 control, 6/50 low-exposure, and 19/50 highexposure males and 2/50 control, 3/49 low-exposure, and 13/48 high-exposure females. Toxic

nephropathy was observed in 4/50 low-exposure and 28/50 high-exposure males and 8/50 highexposure females. This lesion was not observed in any of the controls. Dose-dependent testicular

degeneration (1/50 control, 10/50 low-exposure, and 18/49 high-exposure) and atrophy (1/50

control, 2/50 low-exposure, and 5/49 high-exposure) was observed in male rats, and spermatic

granulomas were observed in high-exposure males (2/49). Female rats were observed to have a

dose-dependent degeneration of the adrenal cortex (4/50 control, 7/49 low-exposure, and 13/47

high-exposure). Adrenocortical degeneration was only observed in one male from each exposure

group. Retinal atrophy was also observed in 1/50 low-exposure male, 10/50 low-exposure

females, and 5/50 high-exposure females.

Mice: As mentioned previously, high mortality prompted early termination of some of the

mouse exposure groups. Low-exposure female mice displayed moderate mortality (62%) with
27

controls displaying 20% mortality. Exposures were not terminated until the end of the

experiment (104-106 weeks). High-exposure female mice exhibited excessive mortality (86%)

with treatment terminated at week 90. Mortality was high in exposure and control groups of male

mice, and all male mice were sacrificed at 78 weeks. The principal cause of mortality in male

mice was ascending, suppurative urinary tract infection, progressing to necrotic and ulcerative

lesions around the urethral opening; chronic or suppurative cystitis; and ascending, suppurative

pyelonephritis. These effects in the male mice were not related to exposure. 

Mean body weights of high-exposure mice were decreased compared to controls

throughout the study. However, body weight data were reported graphically in the text, and

determination of the week that decrease in body weight became significant ($10% of controls) is

difficult to determine. As in rats, the principal neoplastic lesions observed were manifest in the

respiratory tract. However, tumors were primarily found in the lung of mice and not the nasal

cavities. The total numbers of animals with lung tumors were significantly increased (p < 0.001)

in high-exposure male mice (0/41 control, 3/48 low-exposure, and 25/46 high-exposure) and

female mice (4/49 control, 11/49 low-exposure, and 42/50 high-exposure) (p < 0.045 and <

0.001, respectively). These summary statistics were presented in Tables 8 and 9 of the NTP

report. Table 4-4 is a summary of the incidence of lung tumor types, including those from animals

that died on study. 

In addition to the above-mentioned lung neoplasms, high-exposure females had an

increased incidence of carcinoma (6/50), adenoma (2/50), and adenomatous polyp (3/50) of the

nasal cavity. Hemangiosarcomas were observed in 2 high-exposure males, 11 low-exposure

females, and 23 high-exposure females, and hemangiomas occurred in 2 high-exposure males, 1

low-exposure female, and 4 high-exposure females. These lesions were primarily observed in the

retroperitoneal cavity in areas adjacent to the adrenal glands, kidneys, ovaries, and uteri of female

mice. Occasionally the hemangiosarcoma and hemangioma invaded the adjacent organ. 

Fibrosarcoma was observed in 2 high-exposure males, 5 low-exposure females, and 15 highexposure females, with the majority of fibrosarcomas located in subcutaneous tissues. Malignant

mammary tumors (adenocarcinoma, adenocarcinoma with squamous metaplasia, or

adenosquamous carcinoma) were reported in 2/50 controls, 18/50 low-exposure, and 10/50 highexposure females.

Non-neoplastic lesions were generally not observed in male mice probably due to the high
28

mortality. The majority of non-neoplastic lesions observed in female mice were located in the

respiratory tract. Dose-dependent epithelial hyperplasia of the lung alveoli, bronchioles, and

bronchi was observed. Hyperplasia was also observed in the nasal cavities of high-exposure

females (13/50). Suppurative inflammation of the nasal cavity was also observed in low-exposure

(4/50) and high-exposure (20/50) females. In addition, adenomatous hyperplasia of the lung was

reported in high-exposure females (37/50). In other tissues of female mice, dose-dependent

hematopoiesis in the spleen was observed (0/50 control, 8/49 low-exposure, and 16/49 highexposure), and a low, dose-dependent incidence of hepatic necrosis was also reported (0/50

control, 2/50 low-exposure, and 5/50 high-exposure). 

Proliferative lesions in the nasal epithelium have been reported in mice following longterm inhalation exposure to 1,2-dibromoethane (Stinson et al., 1981). Groups of 50 male and 50

female B6C3F1 mice were exposed to 10 or 40 ppm (77 or 307 mg/m3

) 1,2-dibromoethane 6

hours/day, 5 days/week for 103 (10 ppm) or 90 (40 ppm) weeks. At 10 ppm (77 mg/m3), 1 male

and 3 female mice developed focal epithelial hyperplasia, which increased in incidence to 10

male and 11 female mice at 40 ppm (307 mg/m3

) exposure. Benign neoplasms were observed in

the 40 ppm (307 mg/m3) exposure groups of male and female mice and identified as squamous

papilloma (three in males and seven in females) and adenomas (two females); the latter were also

observed to have squamous papilloma. Benign neoplasms first appeared in male mice at 59

weeks and in female mice at 79 weeks. Carcinomas were present in seven female mice exposed

to 40 ppm (307 mg/m3) 1,2-dibromoethane. The first carcinoma appeared at 45 weeks, and

carcinomas were identified as squamous carcinoma (n = 2), adenocarcinoma (n = 2), and mixed

carcinoma (n = 3). Sarcomas were observed in one 10 ppm (77 mg/m3

) female (characterized as

poorly differentiated) and two 40 ppm (307 mg/m3

) females (hemangiosarcoma). Mortality was

not reported, and no other toxicological parameters were monitored.

4.2.3. Subchronic Inhalation Studies

Preliminary to chronic bioassays, the NTP (1982) conducted subchronic inhalation studies

in rats and mice. Male and female Fischer 344 rats (n = 4 to 6 per sex and exposure group) and

B6C3F1 mice (n = 10 per sex and exposure group) were exposed to 0, 3, 15, or 75 ppm (0, 23,

115, or 576 mg/m3

) 1,2-dibromoethane, 6 hours/day, 5 days/week for 13 weeks. No deaths were

reported for rats at any exposure group. High-exposure female rats had depressed weight gain,

and male rats exhibited a dose-dependent depression of weight gain for all exposures. In rats of
29

both sexes exposed to 75 ppm (576 mg/m3) 1,2-dibromoethane, swelling and/or vacuolation of

adrenal cortical cells and decreases in thyroid follicular size were observed. In mice, 4/10 males

in the 3 ppm (23 mg/m3) exposure group and 1 female in the 75 ppm (576 mg/m3) exposure group

died prior to the termination of the study. A dose-dependent decrease in body weight was

observed for both sexes. Eye irritation was observed in both sexes in the 75 ppm (576 mg/m3

)

exposure group at weeks 12 and 13. In the high-exposure mice, 3 males and 9 females exhibited

megalocytic cells in the lining of the bronchioles. Based on the frank effects observed at 75 ppm

(576 mg/m3), 10 and 40 ppm (77and 307 mg/m3) exposures to 1,2-dibromoethane were chosen for

chronic toxicity and cancer studies described above.

 

Nitschke et al. (1981) described the results of a study designed principally to evaluate the

role of 1,2-dibromoethane in inducing nasal lesions. Male and female F344 rats were exposed by

inhalation to 1,2-dibromoethane at 0, 3, 10, or 40 ppm (0, 23, 77, or 307 mg/m3) for 6 hours/day,

5 days/week for 13 weeks. Forty male and 20 female rats were used per exposure group, and

serial sacrifices of 10 males per exposure group were conducted at 1, 6, and 13 weeks; 10 females

per exposure group were sacrificed at 13 weeks. The remaining male and female animals were

sacrificed 88–89 days postexposure. No treatment-related effects were observed in the urinalysis

of male rats. However, the female rats in the 40 ppm (307 mg/m3) exposure group exhibited a

slight decrease in specific gravity of the urine compared to controls; this parameter returned to

normal in the postexposure period. No hematological effects of toxicological significance were

observed in any of the exposure groups.
30

Table 4-3. Nasal cavity tumor types in rats following chronic inhalation of 

1,2-dibromoethane

Tumor type Control

male

10 ppm

male

40 ppm

male

Control

female 

10 ppm

female

40 ppm

female

Adenomatous polyp 0/50 18/50 5/50 0/50 5/50 5/50

Adenoma 0/50 11/50 0/50 0/50 11/50 3/50

Adenocarcinoma 0/50 20/50 28/50 0/50 20/50 29/50

Carcinoma 0/50 0/50 21/50 0/50 0/50 25/50

Squamous cell

carcinoma 0/50 3/50 3/50 1/50 1/50 5/50

Source: NTP, 1982.

Table 4-4. Lung tumor types in mice following chronic inhalation of 

1,2-dibromoethane

Tumor type Control

male

10 ppm

male

40 ppm

male

Control

female 

10 ppm

female

40 ppm

female

Carcinoma-bronchus 0/41 0/48 0/46 0/49 1/49 4/50

Adenoma-bronchus 0/41 0/48 2/46 0/49 0/49 5/50

Adenomatous polypbronchus 0/41 0/48 3/46 0/49 0/49 1/50

Adenomatous polypbronchiole 0/41 0/48 2/46 0/49 1/49 2/50

Alveolar/bronchiolar

adenoma 0/41 0/48 11/46 3/49 7/49 13/50

Alveolar/bronchiolar

carcinoma 0/41 3/48 19/46 1/49 5/49 37/50

Source: NTP, 1982.

Males exposed to 40 ppm (307 mg/m3) showed significantly decreased body weights

throughout most of the 13-week exposure period, which returned to control levels during the

recovery period. No significant differences in body weight were observed for any other exposure

groups. Relative liver and kidney weights were significantly elevated in the 40 ppm (307 mg/m3

)

males at 6 and 13 weeks. Females in the 40 ppm (307 mg/m3

) exposure group had elevated liver

weights only. Organ weights returned to control levels during the recovery period. The principal

histopathological finding was scattered-to-diffuse nasal epithelial hyperplasia with focal necrosis
31

at all sacrifice periods for animals exposed to 40 ppm (307 mg/m3). This increased in severity at

week 6 and progressed to diffuse or focal nonkeratinizing squamous metaplasia of the respiratory

epithelium by week 13. Males in the 10 ppm exposure group exhibited single or multiple nasal

epithelial hyperplasia foci at all three sacrifice intervals; this effect was also present in 10 ppm

females at 13 weeks. The respiratory epithelial effects in the 10 and 40 ppm (77 and 307 mg/m3

)

groups had completely resolved, except for one animal, during the recovery period. No testicular,

kidney, liver, or lung effects were observed. Thyroid and adrenals, a target of 1,2-dibromoethane

in the NTP (1982) subchronic study, were not examined by histopathology. The study authors

identified 3 ppm (23 mg/m3) as the no-observed adverse effect level (NOAEL) from these results.

Reznik et al. (1980) also examined the respiratory system in both the rat and mouse

exposed subchronically to 1,2-dibromoethane. Male and female F344 rats (5

animals/sex/exposure group) and B6C3F1 mice (10 animals/sex/exposure group) were exposed by

inhalation to 0, 3, 15, or 75 ppm (0, 23, 115, or 576 mg/m3) 1,2-dibromoethane for 6 hr/day, 5

days/week, for 13 weeks. Apparently, there was no mortality as none was reported.

Histomorphological changes were observed in the nasal cavity of both species exposed to 75 ppm

(576 mg/m3

) 1,2-dibromoethane with a much lower incidence in rats at 15 ppm (115 mg/m3). The

concentration-dependent changes included cytomegaly, focal hyperplasia, squamous metaplasia,

and loss of cilia. Rats and mice exposed to 75 ppm (576 mg/m3) showed severe necrosis and

atrophy of the olfactory epithelium. No lesions were noted in any other tissue (e.g., liver, kidney,

and testis). NOAELs identified in this study were 3 ppm (23 mg/m3

) in rats and 15 ppm (115

mg/m3

) in mice. LOAELs were 15 ppm (115 mg/m3) in rats and 75 ppm (576 mg/m3) in mice.

Rowe et al. (1952) reported the results of a study that examined the toxicity of 1,2-

dibromoethane (99% pure) to rats, rabbits, guinea pigs, and monkeys following inhalation

exposure. Chamber concentrations were within 10% of desired concentrations. Examination of

tissues (lung, heart, liver, kidney, spleen, testis, pancreas, and adrenal gland) was performed with

light microscopy. The strains of the animals were not specified. Rats were exposed to 50 ppm

(384 mg/m3) 1,2-dibromoethane for 7 hours/day, 5 days/week, for 91 days. High mortality (50%)

in male rats was attributed to pneumonia and infections of the upper respiratory tract. Male rats

also exhibited statistically significant increases in relative lung, kidney, and liver weights and

decreased testicular weight. In females, 4/20 animals died before study termination, and relative

liver and kidney weights were increased while spleen weight was decreased. Histological

examination did not reveal any significant changes except patches of pneumonic consolidation in
32

male rats. Guinea pigs were exposed in the same manner as rats, except that exposure was

terminated after 80 days. Body weight gain was depressed in both sexes, but mortality was not

different than in controls. Microscopic examination of tissues revealed a slight central fatty

degeneration of the liver and slight internal congestion and edema of the kidney tubular

epithelium. No other changes were observed. There were no apparent effects of toxicological

significance in rabbits exposed to 50 ppm (384 mg/m3

) 1,2-dibromoethane for 7 hr/day, 5

days/week, for 84 days. There were slight, but not significant, increases in liver and kidney

weights. 

Monkeys exposed to 50 ppm (384 mg/m3

) 1,2-dibromoethane for 7 hr/day, 5 days/week, for

70 days exhibited fatty degeneration of the liver and increased relative kidney weight. Animals

were also described as appearing ill, nervous, and unkempt throughout the experimental period. 

In addition, the same species were exposed to 25 ppm (192 mg/m3

) 1,2-dibromoethane 7 hr/day, 5

days/week, for 213, 205, 214, and 200 days for rats, guinea pigs, rabbits, and monkeys,

respectively. No adverse effects were noted in any species except for high mortality in male rats

(50%) and male and female guinea pigs (50 and 25%, respectively). 

The investigators stated that rabbits and monkeys and probably rats and guinea pigs can

tolerate daily repeated 7-hour exposures to 25 ppm (192 mg/m3) 1,2-dibromoethane without

adverse effects. However, this statement should be regarded with extreme caution due to the

limitations of this study. Evidence from the previously mentioned subchronic studies (Nitschke et

al., 1981; Reznik et al., 1980) suggests that the nasal cavity in rats is the major target organ

following inhalation exposure to 1,2-dibromoethane. This tissue was not examined by Rowe et

al. (1952). In addition, the study is limited because of the number of guinea pigs (7 per sex in 50

ppm exposure group, 8 per sex in 25 ppm exposure group), rabbits (3 male and 1 female for both

exposure groups), and monkeys (1 per sex for both exposure groups) used in this study. The use

of a larger number of animals might have detected significant adverse effects. Also, the study

provided limited details of methods used. 

4.2.4. Other Studies

Male Fischer 344 rats (eight animals per dose group) were given 40 or 80 mg/kg 1,2-

dibromoethane in corn oil by gavage 5 days per week for 2 weeks (Ghanayem et al., 1986). Fifty
33

percent of high-dose rats exhibited an increased incidence of forestomach cellular proliferation

compared to none in the low-dose group, vehicle controls, and two negative control groups. 

Hyperkeratosis was also significantly increased in high-dose animals. The study authors

concluded that induced forestomach cellular proliferation provides a “favorable environment” for

neoplastic development in the forestomach. 

The potential influence of disulfiram on the metabolism and carcinogenicity of 1,2-

dibromoethane has been studied (Wong et al., 1982). During the oxidative metabolism of 1,2-

dibromoethane, 2-bromoacetaldehyde is formed, which then undergoes further oxidative

metabolism or conjugation with GSH. Disulfiram inhibits aldehyde dehydrogenase and may alter

the metabolism of 1,2-dibromoethane by preventing further metabolism of 2-bromoacetaldehyde. 

The study authors hypothesized that because disulfiram is used to treat alcoholics, alcoholics

might be at a greater risk to 1,2-dibromoethane toxicity due to modified metabolism. To test this

hypothesis, four groups of 48 male and 48 female Sprague-Dawley rats received either control air,

control air and 0.05% disulfiram in the diet, 20 ppm (154 mg/m3

) 1,2-dibromoethane and control

diet, or 20 ppm (154 mg/m3

) 1,2-dibromoethane and 0.05% disulfiram in the diet for 18 months. 

1,2-Dibromoethane air concentrations were maintained for 7 hr/day, 5 days/week.

Rats in the control air/0.05% disulfiram group showed decreased body weight gain

throughout the experimental period. They also had consistently lower body weight gains than rats

exposed to 1,2-dibromoethane alone. Rats in the 20 ppm (154 mg/m3) 1,2-dibromoethane/0.05%

disulfiram group displayed lower body weight gains compared to all other exposure groups

throughout the experiment. Weight gain reduction appeared to be correlated with decreased food

consumption except in animals exposed to 1,2-dibromoethane alone. Excessive mortality was

observed in animals receiving 1,2-dibromoethane/control diet and 1,2-dibromoethane/disulfiram

compared to controls and disulfiram-diet rats. 1,2-Dibromoethane/control rats had normal

hematological parameters, but 1,2-dibromoethane/disulfiram animals showed decreased

hematocrit, hemoglobin, and red blood cell (RBC) counts. Control air/disulfiram animals had an

increased incidence of hemosiderosis in the spleen, while females displayed an increase in

mammary tumors. 

Tumor incidence is listed in Table 4-5. Rats exposed to 1,2-dibromoethane alone had an

increased incidence of splenic hemangiosarcoma and adrenal tumors with males exhibiting an

increase in subcutaneous mesenchymal tumors and females having a high incidence of mammary
34

tumors. 1,2-Dibromoethane/disulfiram rats exhibited an increase in liver, kidney, and thyroid

tumors compared to rats receiving 1,2-dibromoethane or disulfiram alone. Hemangiosarcoma

was present in the liver, spleen, and mesentery, and males had an increase in lung tumors and

testicular atrophy when compared to animals receiving 1,2-dibromoethane alone. From this

study, it appears that disulfiram increases the toxicity and carcinogenicity of 1,2-dibromoethane.

Table 4-5. Enhancement of 1,2-dibromoethane-induced tumor with disulfiram 

coadministration in rats 

 

Control/

control diet

Control/

disulfiram diet

1,2-

Dibromoethane/

control diet

1,2-

Dibromoethane/

disulfiram diet

Tumor type Malea Femalea Malea Femalea Maleb Femalea Malea Femalec

Liver 0 0 1 0 2 3 36 32

Kidney 0 0 0 0 33 1 17 7

Adrenal 2 1 1 0 11 6 6 8

Subcutaneous 3 0 1 0 11 1 4 4

Thyroid 4 5 1 1 3 1 18 18

Lung 0 0 0 0 3 0 9 2

Hemangiosarcoma

Spleen 0 0 0 0 6 0 30 19

Mesentery 1 8 4 18 5 9 15 11

a

 Groups consisted of 48 rats at the initiation of the study; all were examined histopathologically. b

 Group consisted of 48 rats at theinitiation of the study, but two rats were not examined due to autolysis. c

 Group consisted of 48 rats at the initiation of the study, but three rats were not examined due to autolysis.

Source: Wong et al. (1982).

1,2-Dibromoethane has been evaluated in the A/J mouse lung tumor bioassay by several

routes of exposure (Stoner et al, 1986; Adkins et al, 1986). Stoner et al. (1986) exposed groups of

approximately 16 male and 16 female A/J mice to 1,2-dibromoethane either by gavage at 840

mg/kg or intraperitoneally at 168, 420, or 840 mg/kg. Control groups received a comparable

injection of vehicle, trycaprylin-2 for the gavage study and tricaprylin-1 for the intraperitoneal

study. Injections were administered 3 times per week for a total of 24 injections. The mice were

observed until 24 weeks after the first administration, then sacrificed and examined for lung
35

tumors. The results are summarized in Table 4-6. Both male and female mice showed increased

tumor incidence at 840 mg/kg, both by oral and intraperitoneal administration, of at least twice

the corresponding control response. The response in the high-dose female mice by the

intraperitoneal route, at 14/16 (88%), was markedly higher than that in the high-dose male mice

(44%). The authors concluded that 1,2-dibromoethane was active in only the females at only the

highest dose when given intraperitoneally and inactive in both sexes when given orally. Note that

these studies have limited power to detect increases in tumor incidence, relative to chronic

studies; that is, if each treatment group had started with 50 mice, all of the high-dose responses,

except in the male mice treated intraperitoneally, would have been statistically significantly

increased relative to vehicle control. While this outcome is driven in part by the lower than

average response in the vehicle control mice, at about 14 - 20% compared with about 30% across

all of the untreated and vehicle controls, this experiment does not clearly rule out the possibility

that oral administration of 1,2-dibromoethane is associated with induction of lung adenomas in

A/J mice.

In a second set of studies, Adkins et al. (1986) exposed groups of 30 and 60 female A/J

mice by inhalation to 0, 20 or 50 ppm 1,2-dibromoethane for 6 hr/day, 5 days/week, for 6 months

(24 weeks) and then sacrificed and examined for lung tumors. In the first study, which started

with 30 mice per group, 51% of the control animals and 100% of all surviving dibromoethaneexposed animals developed lung adenomas. A dose-related increase in pulmonary adenoma

formation was observed in the second study with 60 mice per group: 26%, 68%, and 100% of

the surviving control, low-dose, and high-dose mice, respectively, developed lung adenomas. 

The authors concluded that the two studies together indicated a concentration-related increase in

the frequency and incidence of adenoma formation, significant and reproducible at 50 ppm. 

These data are also summarized in Table 4-6.

These studies demonstrate qualitative evidence of lung tumor induction by several routes of

exposure. Because only results from animals who survived the 24-week experimental period are

considered in the A/J mouse lung tumor assay, it is possible that tumor incidences are

underreported and would therefore be inadequate for a quantitative dose-response assessment. 

The evidence does not clarify whether lung tumors are solely the result of portal of entry effects

in the case of inhalation exposure to dibromoethane but does demonstrate that lung tumors can

result from systemic exposure to dibromoethane.
36

Table 4-6. Lung tumor incidence in A/J mice following exposure to 1,2-

dibromoethane via several routes of exposure

Sex Exposure level

Number of

mice placed

on test

Number of

mice

surviving at

24 weeks

Number (%) of surviving

mice with lung tumors

Oral exposurea

Male 840 mg/kg, 3 times/week 16 16 7 (44)

 0 mg/kg, 3 times/week 16 15 -c (20)

Female 840 mg/kg, 3 times/week 16 16 5 (31)

0 mg/kg, 3 times/week 16 14 - (14)

Intraperitoneal exposurea

Male 840 mg/kg, 3 times/week 16 16 7 (44)

420 mg/kg, 3 times/week 16 15 3 (20)

168 mg/kg, 3 times/week 15 14 2 (14)

0 mg/kg, 3 times/week 16 15 - (30)

Female 840 mg/kg, 3 times/week 16 16 14 (88)

420 mg/kg, 3 times/week 16 16 9 (56)

168 mg/kg, 3 times/week 17 17 4 (24)

0 mg/kg, 3 times/week 16 15 - (30)

Inhalationb

Female 50 ppm, 6h/d, 5d/wk 30 11 - (100)

20 ppm, 6h/d, 5d/wk 30 11 - (100)

0 ppm, 6h/d, 5d/wk 30 30 - (51)

Female 50 ppm, 6h/d, 5d/wk 60 57 - (100)

20 ppm, 6h/d, 5d/wk 60 57 - (68)

0 ppm, 6h/d, 5d/wk 60 58 - (26)

a

 Source: Stoner et al. (1986).

b

 Source: Adkins et al. (1986).

c

 Only the percentage was reported. 
37

4.3. REPRODUCTIVE AND DEVELOPMENTAL STUDIES IN ANIMALS - ORAL AND

INHALATION 

4.3.1. Inhalation Studies

The potential effects of 1,2-dibromoethane on reproduction in male and female rats have

been reported (Short et al., 1979). Male Charles River CD rats (9-10/group) were exposed wholebody to 0, 19, 39, and 89 ppm (0, 146, 300, and 684 mg/m3

) 1,2-dibromoethane for 7 hours/day,

5 days/week, for 10 weeks, and females (20/group) were exposed to 0, 20, 39, and 80 ppm (0,

154, 300, and 614 mg/m3

) 1,2-dibromoethane for 7 hours/day, 7 days/week, for 3 weeks. Males

in the 89 ppm (684 mg/m3

) exposure group and females in the 80 ppm (614 mg/m3) exposure

group gained less weight, consumed less food, and had higher mortality rates (21% males, 20%

females) than controls. In the 89 ppm (684 mg/m3

) group, testicular weight and testosterone

concentrations were significantly reduced, and none of the males in this group were able to

impregnate non-exposed females after the 10-week exposure period, compared to a 90%

impregnation rate for the other exposed males. Also, atrophy of the testis, epididymis, prostate,

and seminal vesicle was observed in the 89 ppm (684 mg/m3

) group. No treatment-related

reproductive effects were observed in males exposed to 19 or 39 ppm (146 or 300 mg/m3

) 1,2-

dibromoethane. The litters from these males were normal with respect to total implants, viable

implants, and resorptions. The fact that measures of the quality and count of sperm were not

taken is considered a significant study limitation, however, given the effects observed in other

studies of human and bull sperm following 1,2-dibromoethane exposure.

After females were exposed for 3 weeks, they were mated with non-exposed males and

vaginal smears were taken. Vaginal smears were normal in the 20 and 39 ppm (154 and 300

mg/m3

) exposure groups, but the 80 ppm (614 mg/m3) group was in constant diestrus and did not

begin a normal cycle until 3 or 4 days postexposure. This resulted in fewer females in this group

mating during a 10-day mating period with non-exposed males. For all 1,2-dibromoethane

exposure groups, all mated females were pregnant when sacrificed at mid-gestation and had

normal uterine contents for total implants, viable implants, and resorptions. Hormone levels

were not measured. In the high exposure group, there was an incidence of 6/20 animals with mild

vacuolated degeneration of the epithelium of the uterus (3/20 in controls) and 3/20 incidence of

ovarian cysts (0/20 in controls). The study authors concluded that, although adverse reproductive
38

effects were observed in both sexes, these effects only occurred at concentrations that were

associated with significant morbidity and mortality.

The effects of 1,2-dibromoethane administered by inhalation to rats and mice during

gestation were also reported by Short et al.(1978). Pregnant Charles River CD rats (15-17/group)

and CD-1 mice (18-22/group) were exposed whole-body at concentrations of 0, 20, 38, and 80

ppm (0, 154, 292, and 614 mg/m3

) for 23 hr/day. Exposure began on day 6 of gestation and lasted

for 10 days. High mortality was observed in rats exposed to 80 ppm (614 mg/m3) 1,2-

dibromoethane, and weight loss was apparent in the 38 and 80 ppm (292 and 614 mg/m3)

exposure groups. Feed consumption was decreased in all exposure groups and failed to recover in

the high-exposure group after exposure. Total number of implants was decreased, and the

number of resorptions increased in the rat high-exposure group. However, there was no

examination of the uterus at necropsy to definitively determine the number of implantation sites. 

Inasmuch as there was no effect of exposure in the Short et al. (1979) intermittent-exposure study,

the effects seen here are likely due to the continuous exposure. Decreased fetal weight was noted

in the 38 ppm (292 mg/m3) exposure group. No viable fetuses were observed in the highexposure group. None of the external or soft tissue anomalies (occluded nasal passage,

hydronephrosis, solidified kidney cortex, distended urinary bladder, inferior vena cava

hemorrhage, and blunt snout) noted in rat fetuses were dose-dependent.

Mice exhibited high mortality in the 38 ppm (292 mg/m3) group and complete mortality in

the 80 ppm (614 mg/m3

) group. Weight gain was reduced in mice that were exposed to 20 and 38

ppm (154 and 292 mg/m3

) 1,2-dibromoethane but returned to normal in all but one animal in the

38 ppm (292 mg/m3

) group. From this study, it appears that pregnant mice may be more

sensitive to 1,2-dibromoethane than pregnant rats. Also, the CD-1 may be more sensitive than the

B6C3F1 as mortality was not seen (Reznik et al., 1980) in the latter strain after 13 weeks of

exposure to levels higher than 38 ppm (292 mg/m3

). The 20 ppm (154 mg/m3) mice had an

increase in late resorptions and decreased fetal weight compared to controls, and mice exposed to

38 ppm (292 mg/m3

) 1,2-dibromoethane had a decrease in viable fetuses, increased resorptions,

and reduced fetal body weights. Although the observed fetotoxic and teratogenic effects

occurred at exposures that also caused maternal toxicity, it can be difficult to distinguish direct

effects of 1,2-dibromoethane on the fetus from secondary effects resulting from maternal toxicity.

Smith and Goldman (1983) examined potential behavioral effects in offspring of rats
39

exposed to 1,2-dibromoethane. Pregnant female Long-Evans hooded rats (12/group) were

exposed to 0, 0.43, 6.67, or 66.67 ppm (0, 3, 51, or 512 mg/m3

) 1,2-dibromoethane by inhalation

for 4 hr/day, 3 days/week from day 3 to 20 of gestation. Defecation during exposure was directly

related to the concentration of 1,2-dibromoethane (p < 0.001). Mid- and high-exposure animals

defecated significantly more (p < 0.01 and p < 0.05, respectively) than controls. There was also

an inverse relationship between exposure and weight gain that was statistically significant. There

was no significant difference in the number of delivering females or litter size, but low- and midexposure pups weighed significantly more than controls while high-exposure pups weighed

significantly less than controls. These weight effects in pups were not observed by day 66 postgestation. 

In newborn animals, rotorod performance on days 30 and 63 post-gestation was

significantly (p < 0.005) increased in the mid- and high-exposure groups (6 and 6 per group). The

toxicological significance of an increase in rotorod performance is not clear since there was a

differential effect at certain rod speeds as well as a sex times speed interaction. The terminal

performances of the mid- and high-exposure offspring in T-maze discrimination were also

significantly (p < 0.001) different, with the high-dose group performing better than control. No

other behavioral parameters in offspring were influenced by exposure. Measures of maternal

behavior (nest rating and pup retrieval) were not influenced by exposure to 1,2-dibromoethane. 

The authors concluded that 1,2-dibromoethane produced long-term and possibly permanent

alterations in the behavior of exposed offspring. The increased defecation and decreased weight

gain (p < 0.05) in dams suggest maternal stress could have influenced behavior in the offspring,

but the number of neonates tested was too small to make a definitive conclusion. 

4.3.2. Oral Studies

Several studies have examined the potential reproductive toxicity of 1,2-dibromoethane in

bulls after oral treatment. Amir and Ben-David (1973) examined the effects of 1,2-

dibromoethane on bull spermatozoa. Three bulls (15 - 20 months) were administered (by gelatin

capsules) 10 doses of 1,2-dibromoethane (4 mg/kg) on alternate days. Semen was collected 2 - 3

times per week before, during, and for 2 - 3 months after treatment. During the third week after

the start of treatment, sperm abnormalities became evident. 1,2-Dibromoethane-induced effects

in the sperm included coiled tails, acrosomic effects, acrosome loss, decreased motility,
40

degeneration, and disintegration. From the beginning of the fourth week and until day 40 after

the first treatment, approximately 90 - 100% of the sperm were observed to be abnormal.

Gradually, sperm abnormalities decreased, and, approximately 60 days after the first treatment

(one month post-treatment), the percent of sperm abnormalities had returned to control levels. 

Amir and Volcani (1967) provided further evidence of the effect of 1,2-dibromoethane on

sperm by examining bull testes histologically. Three bull calves (4 days old) were orally treated

with 2 mg/kg 1,2-dibromoethane for 17.5 - 22.5 months. Semen was collected with the aid of an

artificial vagina for 4 - 6 six months prior to castration of one testis of each bull. Histological

examination of the castrated testis revealed a depopulation in the majority of seminiferous

tubules, the lumens of which were either empty or filled with cell debris. The caput and corpus

epididymis were empty of spermatozoa and connective-tissue cells were thickened around the

ductus. A high pseudostratified epithelium was also observed in both the caput and corpus. 1,2-

Dibromoethane administration was discontinued after castration, and recovery of semen

properties was monitored. In two bulls, recovery of semen properties was complete within 3 - 4

months. However, the third animal had decreased sperm density and motility for several more

months although no sperm morphological abnormalities were observed. Seven months after

castration, the bulls were slaughtered and the remaining testis was examined histologically. 

Seminiferous tubules of two of the bulls were normal, but in the third animal the majority of the

seminiferous tubules remained inactive, showing hyalinization and hyperplasia of the interstitial

tissue. The caput and corpus epididymis were normal in the two bulls but were still abnormal in

the third animal. 

The effects of 1,2-dibromoethane on sperm production in bulls have also been studied

(Amir and Volcani, 1965). Four bull calves (4 days old) were fed 1,2-dibromoethane for 14–16

months. During the first 3 months of the calves’ life, 2 mg/kg-day of 1,2-dibromoethane was fed

to calves in milk. 1,2-Dibromoethane was then administered in feed (2 mg/kg-day) for an

additional 9 months. After the first year of life, the method of administration was again altered by

administering 4 mg/kg of 1,2-dibromoethane to calves in gelatin capsules on alternate days. 1,2-

Dibromoethane treatment did not appear to affect the growth or health of the animals compared to

controls. The libido of the treated bulls was similar to that of untreated animals. However,

effects on the sperm were observed when semen was collected at termination of 1,2-

dibromoethane administration. These consisted of abnormalities (tailless, coiled tails, pyriform

heads), low sperm density, and poor sperm motility. Recovery after discontinuation of the
41

treatment varied from 10 days to approximately 3 months in different animals.

Amir (1973) provided evidence that 1,2-dibromoethane affected the shape of the

spermatozoa during maturation in the epididymis and during spermogenesis. In this experiment,

two bulls (15 - 20 months old) were orally administered 4 mg/kg 1,2-dibromoethane on alternate

days for 12 and 21 days (7 and 10 doses, respectively). Smears of testicular spermatozoa,

different parts of the epididymis, and the ductus deferens were analyzed for morphological

abnormalities. In the animal that received seven doses of 1,2-dibromoethane, approximately 50%

of spermatozoa from the testis and 10% of the spermatozoa from the first two segments of the

caput epididymis had misshapen heads. Various segments of the epididymis also contained

sperm with tail and acrosomal defects. In the animals that received 10 doses, almost the entire

spermatozoa population of both the testis and caput epididymis had misshapen heads. The

number of spermatozoa in the corpus and caput epididymides with tail and acrosomal defects also

increased. 

 

Amir and Lavon (1976) examined the protein changes in the epididymal and ejaculated

spermatozoa of young (15 - 18 months) and old (4.5 - 5.5 years) bulls following 1,2-

dibromoethane treatment. Bulls were administered 10 doses of 4 mg/kg 1,2-dibromoethane orally

on alternate days. Treatment with 1,2-dibromoethane did not significantly change total nitrogen,

amino acid, or lipoprotein content of epididymal and ejaculated spermatozoa. However, the

amino acid composition of spermatozoan proteins did reveal an increase in the percent isoleucine

and tyrosine of the caput epididymis, arginine, and glycine in the cauda epididymis, and proline in

ejaculate. Ejaculate lipoproteins had an increase in percent half-cystine and tyrosine and a

decrease in percent threonine, serine, glutamic acid, and isoleucine. 

 In addition to reporting on abnormal sperm, Amir et al. (1977) reported a reduction in

DNA and protein content of sperm in three bulls treated with 10 oral doses of 4 mg/kg 1,2-

dibromoethane on alternate days. Semen was collected twice weekly during treatment and for 5

weeks posttreatment and analyzed for morphological changes and DNA and protein content. 

DNA and protein content decreased during the first 13 days postexposure but returned to normal

by days 20 and 27 postexposure for DNA and protein, respectively. A statistically significant

decrease in DNA content was observed in the corpus and cauda epididymis. Protein content was

only significantly reduced in the cauda epididymides. The study authors hypothesized that 1,2-

dibromoethane-induced sperm abnormalities might have been due to an alkylating effect of the
42

chemical on the normal amino acid sequence of the sperm proteins during the replacement of the

somatic histones by sperm histones in late spermiogenesis. 

Amir (1975) studied individual differences in the response of bulls to 1,2-dibromoethane

treatment. Thirteen young (15 - 24 months) and two adult (4.5 - 5 years) bulls received 10 oral

doses (by gelatin capsules) of 4 mg/kg 1,2-dibromoethane on alternate days. In untreated

animals, only 2 - 4% of spermatozoa had misshapen heads. However, in treated young animals, a

“large proportion” of spermatozoa had misshapen heads at 1 day postexposure. The area of the

genital tract with the greatest percentage of abnormal sperm varied among individual animals, but

generally, the ductus efferentes had the highest proportion (50 - 90%). In young bulls, the

maximum percentage (80 - 100%) of spermatozoa with misshapen heads that appeared in the

ejaculate varied from 2 to 10 days after end of treatment. Reasons for this variation may be

differences in the sperm transit time through the epididymis as well as the variation in the release

time of the affected spermatozoa from the testis. The study author states that the effects of 1,2-

dibromoethane treatment was more acute in adult bulls. Sperm concentration was only slightly

decreased in young bulls but was significantly decreased in adults. Also, the percentage of sperm

with misshapen heads returned to control levels (~ 5%) by week 5 postexposure in young bulls;

but, in adults, the percentage of abnormal spermatozoa at week 5 postexposure was

approximately 45% and remained elevated at 16 weeks postexposure (25%). 

In all of these studies on bulls, the experimental design employed sample sizes that were

too small to indicate statistically significant increases in effects observed. However, the power of

all of these studies has been examined and found to be low for a number of reasons (Dobbins,

1987). Despite statistical problems with these studies, they provide a substantial qualitative

evidence that bull sperm is sensitive to 1,2-dibromoethane exposure.
43

4.4. OTHER STUDIES

4.4.1. Reproductive/Developmental

The effects of 1,2-dibromoethane on semen quality and fertility in the rabbit have been

evaluated (Williams et al., 1991). Male New Zealand white rabbits (8–10 per group) were given

1,2-dibromoethane in corn oil at 0, 15, 30, or 45 mg/kg-day for 5 days by subcutaneous

administration. Weekly semen samples were collected for 6 weeks pre-exposure, during

exposure, and for 12 weeks postexposure. Semen samples were analyzed for sperm

concentration, number, morphology, viability, motion parameters, pH, osmolality, volume,

fructose, citrate, carnitine, protein, and acid phosphatase. Male fertility was assessed at 4 and 12

weeks by artificial insemination of three females/male with 1 million motile sperm.

Significant mortality (30%) was observed in the 45 mg/kg dose group. Food consumption

was decreased in dosed animals. There was no change in group mean body weight for any dose

group compared to controls. Liver function enzymes (SDH and ALT) were significantly elevated

in three surviving animals from the 45 mg/kg dose group. In the 45 mg/kg dose group,

curvilinear velocity, straight-line velocity, percent motility, and amplitude of lateral head

displacement were the only sperm characteristics statistically decreased by 1,2-dibromoethane

exposure. Motility was also decreased in the 30 mg/kg dose group. The low- and mid-dose

groups had significant decreases in ejaculate volume, and there was a dose-dependent decrease in

pH. Male fertility, fetal structural development, litter size, and mean fetal weight were not

affected by 1,2-dibromoethane exposure. There was no discussion about fetal survival. The

toxicological implications of this study are limited considering the route of administration. 

The binding of 1,2-dibromoethane to fetal epithelial tissue in mice has been reported

(Kowalski et al., 1985, 1986). Pregnant C57BL mice in different stages of gestation (days 13–17)

were injected i.v. with 14C-1,2-dibromoethane (1.2–1.6 mg/kg) and then sacrificed. In addition,

three fetuses were injected in utero on days 17 or 18 of gestation to circumvent the effect of

maternal disposition on the fate of 1,2-dibromoethane in fetal tissues. Autoradiography and

computer-assisted image analysis were utilized to investigate the binding of 1,2-dibromoethane to

fetal epithelial tissue. Metabolites were not identified. At day 13 of gestation, radioactivity was

uniformly distributed in fetuses. Average radioactivity amounted to 6 and 55% of maternal blood

and liver levels, respectively, and was completely extracted by organic solvents. The fetuses
44

from dams treated on days 16 or 17 of gestation had a high concentration of radioactivity in the

epithelia of the oral cavity, esophagus, forestomach, nasal mucosa, trachea, bronchi, and liver and

in the thymus, lens, and choroid plexus. The radioactivity of the last three tissues was completely

extractable by organic solvents, but the epithelial- and liver-associated radioactivity was only

partially extractable. The distribution of radioactivity in fetuses treated in utero was similar to

that of fetuses from dams treated on days 16 and 17. In vitro studies with excised fetal tissues

were performed to assess possible fetal epithelial metabolism of 1,2-dibromoethane. The results

indicated that fetal epithelia can produce 1,2-dibromoethane metabolites that bind to tissue. 

Abnormal sperm have been observed in rams following subcutaneous treatment with 1,2-

dibromoethane (Eljack and Hrudka, 1979). Rams were administered 1,2-dibromoethane (7.8–

13.5 mg/kg-day) subcutaneously for 12 days. Sperm motility began to decline during week 5

after start of compound administration and declined maximally between weeks 9 and 10. 

Acrosomal and nuclear abnormalities were also observed. The acrosomal abnormalities began to

appear in week 5 and were characterized by enlarged and misshapen apical segments. Nuclear

abnormalities appeared later and were characterized by a misshapen nuclei and the formation of

nuclear cristae.

The spermicidal effect of 1,2-dibromoethane in bulls and rams was reviewed by Amir

(1991). Differences in the pathology of spermatozoic effects between the two species was

discussed. While in the bulls, the abnormal spermatozoa issued from the affected spermatids

were also collected in the ejaculates; this was not the case with treated rams. In the rams, the

abnormal spermatids seem to be phagocytised in the epididymis before their arrival in the

ejaculate. In addition, whereas the alkylating effect of 1,2-dibromoethane occurred also in the

upper parts of the epididymis of the bulls, causing tail and acrosome defects to the spermatozoa,

in the rams such an effect seems to occur all along the epididymal duct. These differences

between bulls and rams in the sites of the genital tract where the chemical takes effect, and in the

mechanism of this effect, are an indication of probable differences in the physiology of the

reproductive tract between these species.

A model to assess potential developmental toxicity of dihaloalkanes in humans has been

described (Mitra et al., 1992). Glutathione S-transferase isozymes from human fetal liver were

purified and used to investigate the potential embryotoxicity of 1,2-dibromoethane in rat embryos

in culture. Five isozymes were detected in the human fetal liver. All enzymes were capable of
45

metabolizing 1,2-dibromoethane. 1,2-Dibromoethane activation by one of the isozymes,

designated P-3, resulted in toxicity to cultured rat embryos. 1,2-Dibromoethane metabolism by

GST caused significant decreases in crown-rump length, yolk sac diameter, somite number, and

composite score for different morphological features. Central nervous and olfactory structures

were most severely affected. Yolk sack circulation and allantois were also affected. The

conclusion drawn was that 1,2-dibromoethane is a suspected developmental toxicant in humans.

In a study by Brown-Woodman et al. (1998), three solvents--chloroform,

dichloromethane, and dibromoethane--were examined for embryotoxic/teratogenic potential using

rat embryo culture. The results showed that each of the solvents had a concentration-dependent

embryotoxic effect on the developing rat embryo in vitro. The effect and no-effect concentrations

(expressed in μmol/mL culture medium), respectively, for each of the halogenated hydrocarbons

tested were dibromoethane--0.33, < 0.18; chloroform--2.06, 1.05; dichloromethane--6.54, 3.46.

Histological studies were performed after exposure of rat embryos to an embryotoxic level of

each of the halogenated hydrocarbons studied for increasing time periods up to the standard 40-

hour culture. Marked cell death in the neuroepithelium of the developing neural tube was a

prominent feature in all embryos exposed to an embryotoxic level of these solvents for periods of

16 hours or longer.

Bishop et al. (1997) examined alterations in the reproductive patterns of female mice

exposed to 1,2-dibromoethane. Female mice were given a single i.p. injection of 100 or 150

mg/kg 1,2-dibromoethane and allowed to mate with untreated males for the duration of the female

reproductive life span. 1,2-Dibromoethane treatment had no effect on total pups born, number of

litters per female, or first and second litter size.

4.4.2. Developmental Neurotoxicity

Fanini et al. (1984) studied the effects of paternal exposure of rats to 1,2-dibromoethane

on behavior in developing offspring. Male Fischer 344 rats were treated i.p. with a daily dose of

1.25, 2.5, 5.0, or 10 mg/kg 1,2-dibromoethane for 5 successive days and then mated with

untreated females at 4 or 9 weeks after treatment. A comprehensive behavioral assessment of

motor reflexes and motor coordination was conducted up to 21 days of age. 
46

Paternal 1,2-dibromoethane exposure did not alter the development of surface righting

ability in 3 - 6-day-old neonates or the ability of 10- and 15-day-old neonates to demonstrate

negative geotaxis. The acquisition of cliff avoidance in the F1 progeny bred at week 4 was

suppressed in progeny of 5 mg/kg males on days 4 and 5, but cliff avoidance was not significantly

different than controls after day 5. Cliff avoidance was not significantly different than in control

F1 progeny bred at week 9. 

Swimming direction in week 4 progeny was significantly different (swimming in circles

rather than straight) than controls on days 6 and 8, but this was not observed on days 10 or 12. 

No effect on swimming direction was observed in week 9 progeny. However, the ability of week

9 progeny to raise their heads higher with age when forced to swim was slower compared to

controls. Week 4 progeny did not exhibit this trait. Rats typically swim with hindlimbs while

keeping the forelimbs stationary, but significantly fewer animals swam in this manner on day 16

in week 4 progeny compared to controls. Open-field ambulation was significantly repressed in

weeks 4 and 9 F1 progeny on days 14 and 21. While the results are suggestive of developmental

neurotoxicity, none of these effects exhibited a linear dose-response relationship. The study

authors state that this is typical of behavioral teratology studies. The authors also hypothesize

that the premeiotic stages of spermatogenesis are sensitive to the genotoxic effects of 1,2-

dibromoethane. 

Hsu et al. (1985) examined the activities of various neurotransmitter enzymes in the

developing brain of F1 progeny of 1,2-dibromoethane-treated males. Male Fisher 344 rats were

treated intraperitoneally with 5 daily doses of 1 mg/kg-day 1,2-dibromoethane. The activities of

choline acetyltransferase, acetylcholinesterase, and glutamic acid decarboxylase were examined

in various brain regions of the F1 progeny from 7 to 90 days of age. Selected brain regions

included the cerebellum, corpus striatum, frontal cortex, hippocampus, and hypothalamus. 

Choline acetyltransferase was significantly decreased in the hypothalamus of 7-day-old

rats but was significantly increased in the cerebellum, corpus striatum, hippocampus, and

hypothalamus of 21-day-old rats. Acetylcholinesterase was significantly increased in the corpus

striatum and hippocampus of 7-day-old rats, decreased in the cerebellum, corpus striatum, and

hippocampus of 14-day-old rats, and increased in the hypothalamus and hippocampus of 21-dayold rats. However, acetylcholinesterase was decreased in the cerebellum of 21-day-old rats. 

Glutamic acid decarboxylase was increased in the corpus striatum of 21-day-old rats, but
47

decreased in the frontal cortex of 21- and 90-day-old rats. Although this study did not examine

behavior, the study authors considered that these alterations might have been associated with

behavioral abnormalities observed in developing offspring by Fanini et al. (1984). 

4.4.3. Genotoxicity

The evidence for 1,2-dibromoethane’s potential genotoxicity is strong. 1,2-

Dibromoethane is a direct-acting mutagen in bacteria. 1,2-Dibromoethane was positive for S.

typhimurium revertant strains TA1535, TA100, and TA98 (Barber et al., 1981). Metabolic

activation was not necessary for the mutagenic effects. 1,2-Dibromoethane induced point

mutations in S. typhimurium strains TA1535 and TA100, S. coelicolor, and A. nidulans (Carere

and Morpurgo, 1981). Wheeler et al. (2001) has shown that expression of a variety of GSTs

within S. typhimurium 1535 caused a dose-dependent increase in the number of revertants upon

incubation with 1,2-dibromoethane. The half-mustard, S-(2-bromoethyl)GSH, resulted in a

significant increase in the number of revertants with S. typhimurium (without expressed GSTs)

with the response dependent on whether the leaving group was Br-, Cl-, or Fl-. The first Brleaving group of 1,2-dibromoethane appeared to be associated with the highest reversion rate

fastest decomposition rate for the half-mustard. It was hypothesized that the stability of the halfmustard likely plays an important role in its ability to enter cells and cause mutations.

1,2-Dibromoethane has also been shown to induce reproducible positive responses in

chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells (Ivett et

al., 1989; Tan and Hsie, 1981; Brimer et al., 1982; Ballering et al., 1998; Graves et al., 1996). 

1,2-Dibromoethane enhanced the production of micronuclei in tetrads of microsporogenesis of

Tradescantia (Ma et al., 1978). 

1,2-Dibromoethane has been demonstrated to cause hepatic DNA damage in rats

following oral administration (Kitchin and Brown, 1986, 1987). 1,2-Dibromoethane also induced

DNA damage in the stomach, kidney, liver, lung, and bladder in mice when administered

intraperitoneally (Sasaki et al., 1998). The 1,2-dibromoethane-induced DNA damage could not

be attributed to toxic cell death. DiRenzo et al. (1982) demonstrated that 1,2-dibromoethane can

bind covalently to calf thymus DNA in vitro. Following i.p. administration, label was shown to

bind DNA in the liver, kidney, stomach, and lung of rats and mice (Arfellini et al., 1984); binding
48

was highest in the liver and kidney. S-[2-(N7-guanyl)ethyl]glutathione has been identified as the

major DNA adduct in rats following treatment with 1,2-dibromoethane (Kim et al., 1990; Koga et

al., 1986).

1,2-Dibromoethane was negative when tested for dominant lethal and electrophoreticallydetectable specific-locus mutations in germ cells of male DBA/2J mice following i.p. injection of

100 mg/kg 1,2-dibromoethane (Barnett et al., 1992). 1,2-Dibromoethane was also negative when

tested for micronucleated reticulocyte induction in mice (Asita et al., 1992). A slight but

significant increase in sister chromatid exchange was noted in mice administered 1,2-

dibromoethane by the i.p. route; however, the increase was not dose-related (Krishna et al., 1985). 

Kale and Baum (1979) reported sex-linked recessive lethal mutations in spermatozoa of D.

melanogaster. In a later study, Kale and Baum (1983) provided evidence that D. melanogaster

embryonic spermatogonia are particularly sensitive to 1,2-dibromoethane exposure.

Dusek et al. (2003) used chick embryo in ovo to investigate the effects of 1,2-

dibromoethane on hematopoiesis at a developmental stage where the primitive erythroid cells

divide and differentiate in circulation. Early after 1,2-dibromoethane treatment on embryonic day

3, annexin V/propidium iodide labelling showed acute cell death of erythroid elements, which

was subsequently compensated for by the release of immature cells into the circulation. At the

same time, the comet assay indicated increased DNA damage in 1,2-dibromoethane-exposed

blood cells when compared with controls. After embryonic day 5, there was no indication for

ongoing prominent cell death in the 1,2-dibromoethane-treated group. However, the DNA

damage assessed by the comet assay persisted until embryonic day 10 in the peripheral blood

cells and for even longer in cells from thymus and bursa. The kinetics of DNA fragmentation in

both erythroid and lymphoid cells implied genotoxic damage by 1,2-dibromoethane to the stem

cells of the definitive elements and transmission of this damage through the successive cell generations.

Bjorge et al. (1996) paper tested testicular cells, prepared from human organ transplant

donors and from Wistar rats, for DNA damage caused by 15 known reproductive toxicants. Four

chemicals induced significant levels of single-stranded DNA breaks in testicular cells from both

species: styrene oxide (> or = 100 microM, rat and human), 1,2-dibromoethane (> or = 100

microM, rat; 1000 microM human), thiram (> or = 30 microM, rat; > or = 100 microM, human),

and chlordecone (300 microM, rat; > or = 300 microM, human).
49

1,2-Dibromoethane was positive when tested for gene mutations in two human

lymphoblastoid cell lines, AHH-1 and TK6 (Crespi et al., 1985). For the AHH-1 line, gene

mutations were measured at the hypoxanthine guanine phosphoribosyl transferase locus, while,

for the TK6 line, gene mutations were measured at the thymidine kinase locus. 1,2-

Dibromoethane-induced sister chromatid exchanges were detected in human peripheral

lymphocyte cultures (Tucker et al., 1984). 1,2-Dibromoethane induced both dose- and timedependent increases in micronuclei in both mononucleated and binucleated human peripheral

lymphocytes (Channarayappa et al., 1992). 

1,2-Dibromoethane exposed papaya workers (n = 60) described by the Ratcliffe et al.

study (1987) were assessed for genotoxic damage by monitoring sister chromatid exchanges and

chromosomal aberrations (Steenland et al., 1986). As previously described (section 4.1.2.),

workers from a nearby sugar plant served as controls (n = 42). Exposure to 1,2-dibromoethane

was not associated with sister chromatid exchanges. There was a statistically significant increase

in chromosomal exchanges, but this was the least frequent chromosomal aberration observed in

this study. The study authors considered it possible that this finding was due to chance, given that

multiple comparisons were made and that no significance was found when combining both types

of chromosomal aberrations (exchanges and deletions). Therefore, the study authors concluded

that exposure to low concentrations of 1,2-dibromoethane was not associated with chromosomal

aberrations or sister chromatid exchanges. 

Steenland et al. (1985) performed a cytogenetic examination of forestry workers and

controls described in the Schrader et al. (1988) study (section 4.1.2.). Sister chromatid exchanges

and chromosomal aberrations were assessed in peripheral lymphocytes. There was no significant

increase in either sister chromatid exchanges or chromosomal aberrations in 1,2-dibromoethaneexposed forestry workers. 

4.4.4. Acute Toxicity

Rowe et al. (1952) performed a comprehensive acute oral and inhalation toxicity study in

the rat, mouse, guinea pig, chicks, and rabbits. The acute oral LD50 s (mg/kg) were 146 (male

rats), 117 (female rats), 420 (female mice), 55 (female rabbits), 79 (male and female chicks), and

110 (male and female guinea pigs). For the acute inhalation study, rats were exposed to
50

100–10,000 ppm 1,2-dibromoethane for up to 16 hours while guinea pigs were exposed to 200 or

400 ppm for up to 7 hours. The 9-hour LC50 for rats was approximately 200 ppm. All guinea

pigs exposed to 200 or 400 ppm for 2–7 hours died.

Centrilobular necrosis and sinusoidal dilations in the liver were observed in adult male

albino rats treated with 110 mg/kg 1,2-dibromoethane by oral intubation (Broda et al., 1976). The

centrilobular necrotic changes were reported by the authors to be similar to those caused by

carbon tetrachloride. 

Storer and Conolly (1983) conducted a comparative genotoxicity and acute hepatoxicity

study of 1,2-dibromoethane in mice. Non-necrogenic doses of 1,2-dibromoethane (0.25 or 0.5

mmol/kg) were administered to male B6C3F1 mice by i.p. injection. DNA damage was then

assessed by an alkaline DNA unwinding assay, which assessed single strand breaks or alkalilabile sites in hepatic DNA. The high dose caused a significant decrease in percent doublestranded DNA recovered. Liver and kidney damage were assessed following single i.p. injections

of 0, 0.5, 0.75, 1.0, or 1.5 mmol/kg 1,2-dibromoethane. 1,2-Dibromoethane was observed to be

hepatotoxic as measured by a dose-dependent increase in liver weight, serum IDH, and serum

AAT. Renal toxicity was also observed as a dose-dependent increase in kidney weight and BUN. 

Four of five animals died following i.p injection of 1.5 mmol/kg 1,2-dibromoethane. 

4.5. SYNTHESIS AND EVALUATION OF MAJOR NONCANCER EFFECTS AND

MODE OF ACTION%ORAL AND INHALATION 

The epidemiological studies pertaining to subchronic and chronic effects focused

primarily on reproductive and cytogenetic endpoints. The human data suggest that 1,2-

dibromoethane is a male reproductive toxin. Decreased sperm count, ejaculate volume, and

motility, and abnormal sperm morphology, have been reported in workers following long-term

inhalation exposure to 1,2-dibromoethane (Ratcliffe et al., 1987). Workers exposed to 1,2-

dibromoethane for 6 weeks displayed decreased sperm velocity and volume (Schrader et al.,

1988). Also, male workers in a plant manufacturing 1,2-dibromoethane exhibited a significant

decrease in fertility (Wong, 1979). However, these studies have at least one limitation (e.g.,

inadequate exposure data, potential exposure to other reproductive toxins, moderate-to-extensive

dermal exposure potential, or other confounding factors) that renders any interpretation,
51

particularly a quantitative assessment, of the evidence regarding the potential of inhaled 1,2-

dibromoethane to induce reproductive effects in humans inconclusive.

The evidence that inhaled 1,2-dibromoethane is associated with reproductive and

developmental effects in laboratory animals is incontrovertible. Reproductive and developmental

effects have been reported in rats and mice following inhalation exposure (Short et al., 1978,

1979). Effects in male rats included decreased testicular weight, decreased serum testosterone

levels, testicular atrophy, and impairment of reproductive performance. Testicular atrophy has

also been observed in male mice. Reported developmental effects in rats and mice consisted of

decreased fetal body weight, increased resorptions, decreased fetal survival, and/or skeletal

anomalies; however, these reproductive and developmental effects occurred at doses associated

with significant toxicity and/or mortality in parental/maternal animals. There are also indications

that there may be species and strain differences in response among pregnant animals. Oral

administration of 1,2-dibromoethane also has been shown to adversely affect male reproductive

endpoints. When 1,2-dibromoethane was administered orally to bulls at doses that did not affect

the growth or health of the animals, it was shown to adversely affect various sperm parameters. 

Adverse effects included altered sperm morphology, decreased motility, and depleted sperm from

seminiferous tubules. In addition, the spermicidal effect of 1,2-dibromoethane occurs during

spermatogenesis, indicating that the effect is not direct. Overall, the data indicate that 1,2-

dibromoethane is a male reproductive toxin in animals. 

Cytogenetic studies in humans are quite limited. Steenland et al. (1985, 1986) found no

evidence of genotoxicity following inhalation exposure to 1,2-dibromoethane. However,

concentrations to which workers were exposed were quite low and may have been below levels

that would induce DNA damage in humans. Genetic mutations have been observed in human

peripheral lymphocyte cultures (Channarayappa et al., 1992; Tucker et al., 1984), and DNA

damage has been noted in rats and mice (Arfellini et al., 1984; Kitchin and Brown, 1986, 1987).

Animal studies have demonstrated noncancer effects in rats and mice after subchronicand chronic-duration inhalation or oral exposure to 1,2-dibromoethane. Early mortality,

depression of body weight gain, and nonneoplastic lesions of the respiratory system, liver, kidney,

testis, eye, and adrenal cortex in rats and mice were reported in a chronic inhalation study (NTP,

1982). Proliferative lesions of the nasal epithelium in mice have also been reported after chronic

inhalation exposure to 1,2-dibromoethane (Stinson et al., 1981). It appears the respiratory
52

system, particularly the nasal epithelium, is the target tissue following inhalation exposure in both

species. Excessive mortality, weight gain depression, testicular atrophy, forestomach lesions, and

liver and adrenocortical degeneration were reported in rats after long-term oral exposure to 1,2-

dibromoethane (NCI, 1978). In mice, long-term oral exposure to 1,2-dibromoethane was

associated with body weight depression, high mortality, and testicular atrophy. The systemic

effects associated with long-term oral exposure are generally consistent with those resulting from

inhalation dosing. The results of the NCI study (1978) suggest that the forestomach is the target

organ following oral exposure in rats and mice. 

The results of a subchronic inhalation study in rats and mice revealed weight gain

depression, swelling of adrenocortical cells, decreases in thyroid follicle size, and formation of

megalocytic cells of the lining of bronchioles in rats and mice (NTP, 1982). In addition, Nitschke

et al. (1981) reported elevated relative liver and kidney weights, focal epithelial hyperplasia of the

nares, and diffuse respiratory hyperplasia. Similar respiratory effects were reported by Reznik et

al. (1980), and Rowe et al. (1952) reported adverse liver and kidney effects in rats, guinea pigs,

and monkeys. The subchronic toxicity data are in general consistent with reported chronic

effects. 

Some of the effects of 1,2-dibromoethane, particularly effects in the liver and nasal tract,

are clearly related to its cytotoxicity. The mechanism of 1,2-dibromoethane-mediated

cytotoxicity has been studied in isolated rat hepatocytes (Khan et al., 1993). It was demonstrated

that microsomal cytochrome P-450-dependent oxidative metabolism of 1,2-dibromoethane

produces the metabolite 2-bromoacetaldehyde. The results suggest that the cytotoxic mechanisms

for 1,2-dibromoethane may possibly be attributed to lipid peroxidation and/or protein binding

induced by 2-bromoacetaldehyde. In addition, the study authors considered that the conjugation

of 1,2-dibromoethane with GSH may also contribute to cytotoxicity. Botti et al. (1982, 1986,

1989a, 1989b) and Masini et al. (1986) provided evidence that 1,2-dibromoethane-induced

depletion of hepatic mitochondrial GSH correlated with hepatotoxicity and perturbations in

mitochondrial Ca2+ homeostasis. 

The results of in vitro and in vivo experiments suggest that the renal toxicity of 1,2-

dibromoethane may be due to its biotransformation by GSH conjugation followed by further

conversion in the kidney to highly reactive metabolites (Novotna et al., 1994). Repeated

administration of 1,2-dibromoethane to rats has been shown to enhance the content of GSH in the

liver and kidney (Mann and Darby, 1985). It has been suggested that lipid peroxidation may play

a role in the 1,2-dibromoethane-induced pathogenesis of liver cell necrosis (Albano et al., 1984).
53

4.6. WEIGHT-OF-EVIDENCE EVALUATION AND CANCER CHARACTERIZATION

%SYNTHESIS OF HUMAN, ANIMAL, AND OTHER SUPPORTING EVIDENCE,

CONCLUSIONS ABOUT HUMAN CARCINOGENICITY, AND LIKELY MODE OF

ACTION

4.6.1. Human

In a cancer study of 161 workers at two 1,2-dibromoethane manufacturing plants, Ott et

al. (1980) reported that total cancer deaths of workers exposed to 1,2-dibromoethane did not

exceed those expected based on national rates. There was an increase in deaths due to malignant

neoplasms at one plant while the population at the second plant actually had fewer deaths due to

malignant neoplasms than expected. Similarly, Sweeney et al. (1986) studied the cause-specific

mortality of 156 male workers in a chemical plant that manufactured tetraethyl lead. The findings

of both studies are inconclusive due to the small sample size, lack of control group, poorly

characterized exposure assessment, and exposure to other potential or known carcinogens.

Therefore, human data are inconclusive regarding the potential carcinogenicity of 1,2-

dibromoethane to humans.

4.6.2. Animal

The results of animal oral and inhalation bioassays have demonstrated that 1,2-

dibromoethane is a carcinogen in rats and mice of both sexes at multiple sites. Long-term oral

administration of 1,2-dibromoethane was associated with forestomach carcinomas,

hemangiosarcomas, and lung adenomas or carcinomas in rats and mice as well as hepatocellular

and adrenocortical carcinomas (female rats) and thyroid follicular cell adenomas (male rats)

(NCI, 1978; Van Duuren et al., 1985). The majority of the cancers associated with oral dosing

were forestomach carcinomas. The relevance of forestomach effects to humans has been

questioned, particularly for nongenotoxic chemicals whose mode of action is believed to involve

irritation and cell proliferation from long-term exposure (Poet et al., 2003). It is true that the

forestomach is not present in humans and contains features, such as minimal vascularization and

stratified squamous cells, that result in a longer residence time of food-borne agents than is

received by comparable human organs such as the oesophagus and the glandular stomach (Grice,
54

1988; Poet et al., 2003). In this case, however, effects in this organ are believed to be of potential

relevance to humans because 1,2-dibromoethane and other genotoxic chemicals do not appear to

require precursor events (e.g., irritation) associated with long residence time to induce these kinds

of tumors. 1,2-Dibromoethane does not appear to cause significant irritation in the forestomach

and was reported to induce forestomach tumors after just 168 days of exposure (NCI, 1978). 

Long-term inhalation exposure of rats and mice to 1,2-dibromoethane resulted in nasal

cavity carcinomas and adenocarcinomas, alveolar/bronchiolar carcinomas, splenic

hemangiosarcomas, mammary gland adenocarcinomas, subcutaneous fibrosarcomas, and tunica

vaginalis mesotheliomas in rats and mice (NTP, 1982; Stinson et al., 1981; Wong et al., 1982). 

The majority of the cancers were in the lungs of mice and in the nasal cavities of rats. The NTP

(1982) inhalation study was well designed, using an adequate number of animals of both sexes,

but was limited because of excessive mortality in the high-dose groups of both species, moderate

mortality in low-dose female mice, and excessive mortality in male mice not related to 1,2-

dibromoethane exposure. The Wong et al. (1982) study, which reported that disulfiram enhanced

the toxicity and carcinogenicity of 1,2-dibromoethane, is limited because there was only one

exposure dose. 

1,2-Dibromoethane has been reported to be a direct acting mutagen in S. typhimurium

assays (Barber et al., 1981). 1,2-Dibromoethane has also been shown to induce point mutations

in S. typhimurium strains TA 1535 and TA 100, S. coelicolor, and A. nidulans (Carere and

Morpungo, 1981). 1,2-Dibromoethane-induced chromosomal aberrations and sister chromatid

exchanges have been demonstrated in Chinese hamster ovary cells (Ballering et al., 1998; Brimer

et al., 1982; Graves et al., 1996; Ivett et al., 1989; Tan and Hsie, 1981;). 1,2-Dibromoethane has

also been shown to bind to DNA in vivo and in vitro (Arfellini et al., 1984; Kim et al., 1990; Koga

et al., 1986), and DNA damage has been reported in rats and mice following oral and i.p.

administration (Kitchin and Brown, 1986, 1987; Sasaki et al., 1998). In D. melanogaster, 1,2-

dibromoethane induced sex-linked recessive lethal mutations in spermatozoa and mutations in

embryonic spermatogonia (Kale and Baum, 1979, 1983). 1,2-Dibromoethane has also been

shown to produce mutations in human cells lines AHH-1 and TK-6 (Crespi et al., 1985), and

sister-chromatid exchanges and increases in micronuclei have been demonstrated in human

peripheral lymphocyte cultures (Channarayappa et al., 1992; Tucker et al., 1984). The above

studies indicate that 1,2-dibromoethane is genotoxic in a variety of test systems. 
55

4.6.3. Mode of Action

The genotoxicity of 1,2-dibromoethane is thought to be related to its conjugation with

GSH as catalyzed by glutathione S-transferase (Cmarik et al., 1990; Inskeep and Guengerich,

1984; Sundheimer et al., 1982; Van Bladeren et al., 1980, 1982). The conjugation results in the

formation of an episulfonium ion that can react with DNA (Peterson et al., 1988). As mentioned

previously, the major DNA adduct formed is S-[2-(N7

-guanyl)ethyl]glutathione. Findings from a

forward mutation assay utilizing the bacteriophage M13 lacZ gene and mutation spectra have

established the importance of this adduct in 1,2-dibromoethane-mediated mutagenicity (Cmarik et

al., 1992). 

The results of a study designed to examine the ability of purified rat and human

glutathione S-transferases to conjugate 1,2-dibromoethane with glutathione revealed that the

metabolism of 1,2-dibromoethane by glutathione-S-transferase and the genotoxic effects of 1,2-

dibromoethane are similar for rats and humans (Cmarik et al., 1990). Additional evidence that

1,2-dibromoethane is genotoxic via modification at ring nitrogens in DNA, primarily at the N7-

guanine site, was obtained from the mutation spectra of 1,2-dibromoethane in excision repairproficient and repair-deficient strains of D. melanogaster (Ballering et al., 1994).

Working et al. (1986) also provided some evidence that the conjugation of 1,2-

dibromoethane with GSH and its subsequent metabolism may be involved in its genotoxic

properties. The ability of 1,2-dibromoethane to cause DNA damage was associated with

unscheduled DNA synthesis (UDS) in rat hepatocytes and spermatocytes exposed both in vitro

and in vivo. Inhibition of cytochrome P-450-mediated oxidation in vitro did not affect 1,2-

dibromoethane-induced UDS in either cell type; however, depletion of cellular GSH inhibited the

induction of UDS in both cell types. Inhibition of hepatic mixed-function oxidases in vivo was

associated with positive UDS response to 1,2-dibromoethane in spermatocytes, but there was no

effect on 1,2-dibromoethane-induced UDS in hepatocytes. 

1,2-Dibromoethane has been demonstrated to act as an initiator of cell transformation in

the two-stage BALB/c3T3 cell transformation test (Colacci et al., 1995, 1996). The cell

transformation test is regarded as a model system for carcinogenesis in vivo. Utilizing (-

glutamyl-transpeptidase-positive foci as an early histochemical marker for hepatocarcinogenesis,

1,2-dibromoethane has been shown to possess promoter activity in the rat liver (Milks et al.,

1982). 1,2-Dibromoethane has been demonstrated to induce a mitogenic response in the rat liver
56

(Ledda-Columbano et al., 1987a; Nachtomi and Farber, 1978; Nachtomi and Sarma, 1977). A

single oral administration of 1,2-dibromoethane to male rats was reported to induce cell

proliferation in the kidney, as monitored by increased thymidine incorporation into DNA and by

mitotic index (Ledda-Columbano et al., 1987b). It has been suggested that minor perturbations in

Ca2+ levels might play a role in triggering cell proliferation, while a more severe interference with

the homeostatic control of Ca2+ may lead to cell death (Ledda-Columbano et al., 1987b;

Nachtomi and Farber, 1978). 

4.6.4. Weight-of-Evidence Characterization

Under the Draft Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), 1,2-

dibromoethane is considered “likely to be carcinogenic to humans” based on strong evidence of

carcinogenicity in animals and inconclusive evidence of carcinogenicity in an exposed human

population. This weight-of-evidence carcinogenicity characterization replaces the previous

classification of "B2; probable human carcinogen," entered on IRIS on September 7, 1988. The

new classification and slope factor estimates are based on a review of newer data and a reanalysis

of the data used in the earlier assessment. Based on the consistent findings of several studies

reporting increased incidences of a variety of tumors in rats and mice of both sexes by different

routes of administration at both the site of application and at distant sites, it can be concluded that

there is strong evidence of the carcinogenicity of 1,2-dibromoethane in animals. The available

evidence further supports a conclusion that 1,2-dibromoethane is a genotoxic carcinogen based on

evidence from a variety of in vitro and in vivo test systems. 

4.7. SUSCEPTIBLE POPULATIONS

As has been described, GSTs are believed to play an important role in the mode of action

for 1,2-dibromoethane carcinogenicity. Human GSTs comprise several subfamilies of

isoenzymes: principally GSTM, GSTP, and GSTT. A polymorphism in the GSH conjugation of

1,2-dibromoethane by GSTT was demonstrated in the cytosol derived from human erythrocytes

(Guengerich et al., 1995; Ploemen et al., 1995). Erythrocyte cytosols from 2 out of 12 subjects

were unable to catalyze the conjugation of 1,2-dibromoethane with GSH due to a mutation of

GSTT. The relevance of this genetic polymorphism to interindividual differences in response to

1,2-dibromoethane and in response to other carcinogens is not clear. However, deletions in
57

subunit 1 of the GSTT gene (GSTT1) are known to produce null genotypes that lead to absence of

activity of these enzymes (Seow et al., 2002). Further, the expression of the rat theta class

glutathione-S-transferase 5-5 (which is structurally similar to the human theta class GSTT) in S.

typhimurium TA1535 increased the mutagenicity of 1,2-dibromoethane (Thier et al., 1996). 

Moreover, the mutagenicity of 1,2-dibromoethane was enhanced (compared to controls) in S.

typhimurium TA1535 cells expressing the human theta ortholog GSTT1-1 (the homodimer of

GSTT1) (Thier et al., 1996). GSTT1-1 polymorphism is apparently responsible for the bimodal

distribution of sensitivity to sister chromatid exchange induction observed after in vitro exposure

to butadiene diepoxide and other chemicals (Thier et al., 1996). While this polymorphism may

reduce human susceptibility to 1,2-dibromoethane induced cancers, it should be noted that GST

polymorphisms resulting in null or low activity of this genotype are generally thought to increase

overall cancer risk (Seow et al., 2002).

DeLeve (1997) addressed the issue of whether variations in endogenous GSH in human

cells could modify the genotoxicity of 1,2-dibromoethane. The incidence of sister chromatid

exchanges in normal fibroblasts and in fibroblasts obtained from two human individuals with

greatly reduced intracellular GSH levels due to hereditary generalized GSH synthetase

deficiency, an inborn error of GSH metabolism, was studied. The induction of sister chromatid

exchanges was significantly lower in the fibroblasts with GSH synthetase deficiency compared to

control cells. DeLeve (1997) concluded that low endogenous GSH levels may protect against

1,2-dibromoethane-induced genotoxicity in human fibroblasts. In addition, DeLeve (1997) noted

that little is known about the range of normal intracellular GSH in the population.

As mentioned previously, 2-bromoacetaldehyde is formed during the oxidative

metabolism of 1,2-dibromoethane and undergoes further metabolism or conjugation with GSH

(Wong et al., 1982). There may be considerable interhuman variability in their ability to catalyze

the oxidation of 1,2-dibromoethane to 2-bromoacetaldehyde. Microsomes from 21 different

human livers were able to catalyze the oxidation of 1,2-dibromoethane to 2-bromoacetaldehyde

with activities that ranged from 22.2 to1027.6 pmol/min-mg of protein (Wormhoudt et al.,

1996b). It has also been suggested that since disulfiram is used to treat alcoholics, these

individuals may be at a greater risk to 1,2-dibromoethane toxicity (Wong et al., 1982). 

Disulfiram inhibits aldehyde dehydrogenase and may alter the metabolism of 1,2-dibromoethane

by preventing the further metabolism of 2-bromoacetaldehyde. Disulfiram has been reported to

enhance the carcinogenicity of 1,2-dibromoethane (Elliott and Ashby, 1980). 
1 Ambient Air Pollution: Respiratory Hazards to Children statement by the American Academy of

Pediatrics, online at http://www.aap.org/policy/04408.html - also the topic of the journal Pediatrics, Volume 92, No.

3, 1993 (which could not be retrieved prior to submitting these comments).

58

4.7.1. Possible Childhood Susceptibility

There are no human studies indicating that children are more susceptible to the toxic

effects of 1,2-dibromoethane. However, there is evidence in mice that fetal epithelia can bind

14C-1,2-dibromoethane nonvolatile metabolites after i.v. injection to pregnant animals in different

stages of gestation (Kowalski et al., 1986). High-level binding was observed in the oral

epithelium, nasal mucosa, and forestomach. These results suggest that fetuses are likely to be

exposed to 1,2-dibromoethane from maternal circulation. The embryotoxic potential of 1,2-

dibromoethane to humans has been suggested by the results of an in vitro study with cultured rat

embryos in which it was shown that bioactivation of 1,2-dibromoethane by GST induced

manifestations of embryotoxicity (Mitra et al., 1992). 

It has been concluded that children’s respiratory vulnerability is in part due to the fact that

they have narrower airways than those of adults, and thus irritation that would produce only a

slight response in an adult can result in potentially significant obstruction in the airways of a

young child.1 As such, the nasal inflamation effects of 1,2-dibromoethane may have a more

significant health impact for infants and small children.

4.7.2 Possible Gender Differences

There are no human or animal data that suggest that gender differences in toxicity or

carcinogenicity might occur as a result of exposure to 1,2-dibromoethane. 
2

NCI also studied mice, but high mortality in both dose groups of male and female mice precludes the use

of these bioassays for derivation of an RfD.

3

Mortality adjusted incidence used for the BMD analysis of this data was 4/42 and 9/25 in the low and high

dose groups, respectively. (See Table B-1 and output files in Appendix B.) 

59

5. DOSE-RESPONSE ASSESSMENTS

5.1. ORAL REFERENCE DOSE

An RfD can be derived based upon results of a rat chronic oral exposure study reported by

NCI (1978).2

 In this study 50 Osborne-Mendel rats/sex/group were administered 1,2-

dibromoethane in corn oil, by gastric intubation. The initial doses utilized for male and female

rats were 40 and 80 mg/kg-day. High treatment-related mortality (18/50 males and 20/50

females) caused a discontinuation in the intubation of the high-dose group after treatment in week

16. Intubation of this group was suspended for 13 weeks and then restarted at week 30. At this

time the surviving rats received the low-dose regimen. All surviving male and female rats in both

dosage groups were sacrificed at weeks 49 and 61, respectively. The authors calculated timeweighted average low- and high-doses of 38 and 41 mg/kg-day for male rats, and 37 and 39

mg/kg-day for female rats.

Peliosis was chosen as one of three co-critical endpoints for use in RfD derivation. 

Among male rats, liver peliosis was observed in 0/40 control, 10/50 low-dose, and 9/50 high-dose

groups.3 Among female rats, peliosis was observed in 0/40 control, 4/47 low-dose, and 2/48 highdose groups. Peliosis is marked by engorgement of the liver with blood due to blockage of the

lumen of the sinus or destruction of the epithelial wall of the sinusoid. Peliosis is not considered

to be a precursor to liver cancer. Although hepatocellular carcinomas were detected in 5/48

female rats, the increase was not statistically significant. No increases in hepatocellular tumors

were detected in males. Squamous cell tumors found in the liver were the result of metastases

from forestomach tumors.

Another co-critical endpoint in this study is the induction of testicular atrophy. The

incidence of atrophy was 0/20 in vehicle controls, 14/49 in the low-dose group, and 18/50 in the
4

Mortality adjusted rates used for the BMD analysis of this data were 14/43 and 18/36 in the low and high

dose groups, respectively. (See Table B-1 and output files in Appendix B.)

5

The allometric adjustment refers to the scaling of doses between species according to body mass raised to

the 3/4 power which the Agency has endorsed for carcinogens. The presumption of this adjustment is that equal

doses in these units (i.e., mg/kg3/4/day) when administered daily over a lifetime, will result in equal risk across

mammalian species (USEPA, 2002a). The bulls were assumed to weigh 1000 kg (Amir, 1975). After allometric

adjustment, the doses given to the NCI (1978) male rats were less than 2 times, and therefore similar to, the doses

given to the Amir and Volcani (1965; 1967) bulls (11 vs 21 mg/kg3/4/day).

6

Mortality adjusted rates used for the BMD analysis of this data were 13/48 and 9/26 in the low and high

dose groups, respectively. (See Table B-1 and output files in Appendix B.)

60

high dose group.4 Testicular atrophy was also noted in 11/20 untreated control rats sacrificed at

107 weeks. Testicular atrophy in the latter group are likely to be age related, since they were not

seen in 61 week controls and because the duration was much longer than for exposed rats. The 61

week vehicle controls are therefore considered to be the appropriate control group 

Although tumors of the tunica vaginalis, the serous covering of the testes, were reported in

the NCI (1978) study, testicular atrophy is not considered a precursor to this effect. The tunica

albuginea, a dense, fibrous membrane, lies between the testis and the tunica vaginalis. Thus, the

tunica vaginalis is neither in direct contact with the testes nor is it composed of structurally or

functionally related tissue. The reported testicular effects can, therefore, be considered a

noncarcinogenic endpoint separated from nearby tunica vaginalis tumors. 

Testicular effects were also reported in bulls administered oral doses of 2-4 mg/kg 1,2-

dibromoethane (Amir and Ben-David, 1973; Amir and Volcani, 1965, 1967). Although doses

were lower, these studies were not selected for RfD development because of the small numbers of

animals and the use of one exposure level and because they are ruminants with a significantly

different physiology. Moreover, an allometric adjustment would result in a dose quite similar to

those used in the NCI (1978) study.5 These bull studies, however, provide supporting evidence

for testicular effects of low-dose 1,2-dibromoethane. 

A third co-critical endpoint, was adrenal cortical degeneration (0/40 controls, 13/48 lowdose, and 9/47 high-dose) in the male Osborne-Mendel rats of the NCI (1978) study.6

 A similar

effect was observed in the female rats of this study (1/40 controls, 3/44 low-dose, and 8/45 highdose animals) and female F344 rats of the NTP (1982) chronic inhalation study. NCI (1978)

reported an increased incidence of adrenal tumors in female Osborne-Mendel rats following oral

exposure, and Wong et al. (1982) identified an increased incidence of adrenal tumors in both male
61

and female Sprague-Dawley rats following inhalation exposure. However, adrenal tumors were

not observed in male Osborne-Mendel rats of the NCI (1978) oral study and were not observed in

the F344 rats of either sex in the NTP (1982) inhalation study. Thus, a clear association between

this degenerative effect and adrenal tumors cannot be established, and use of this endpoint in

support of a noncancer RfD is deemed appropriate.

Table 5-1. Oral subchronic and chronic studies in laboratory animals

Reference Species (strain) Sex

 Animals/

dose 

Exposure

Regimen

 NOAEL

(mg/kg-day)

LOAEL

(mg/kg-day)

NCI, 1978 Rat M 50 49 weeks,

5d/wk

-- 38a

(Osborne-Mendel) F 50 61 weeks,

5d/wk

-- 37a

Amir and

Volcani,

1967

Bull

(Calves)

M 3 17.5-22.5b

Months

-- 2c

Amir and

Volcani,

1965

Bull

(Calves)

M 4 14-16b

Months

-- 2c

a Critical effects were peliosis and adrenal cortical degeneration in males and females and testicular atrophy in males. b

 Animals were dosed orally via milk (1-3 mo), feed (4-9 mo) and via gelatin capsules (> 1 yr).

c

 Critical effects were adverse alterations in various sperm parameters and testicular histology.

5.1.1. Methods of Analysis

RfDs can be derived by either development of a benchmark dose or through determination

of a NOAEL or a LOAEL. TWA doses for male and female rats of the NCI (1978) study were

very similar, but a higher incidence and severity of effects were observed in male rats at the low

dose. Adjustment of the lower TWA low dose for intermittent exposure of 5 days/week (38

mg/kg-day × 5/7) results in a LOAEL of 27 mg/kg-day. A benchmark dose analysis was

performed for all three of the co-critical endpoints (Appendix B, Table B-1). This analysis was

done using both the initial, unadjusted doses of 40 and 80 mg/kg-day and TWA doses reported by

the authors. Because the peliosis and adrenal cortical degeneration effects occurred at a much

greater incidence towards the end of the study, the BMD assessments that used TWA doses may

be more appropriate for these endpoints. However, because the incidence of testicular atrophy

was similar at the beginning, middle, and end of the study (6/20 at 9-24 wks; 4/10 at 25-39 wks;

4/9 at 40-44 wks and 4/11 at 45-49 wks) the dose rate may be more critical to the occurrence of

this effect. However, there is not enough data to make a definitive determination in this regard. 
62

Depending on whether unadjusted or TWA doses were used, BMDL10 estimates for these three

endpoints ranged from approximately 7-10 mg/kg-day. Because of high mortality and unusual

dosing in the high dose group, there is a great deal of uncertainty associated with these BMD

results, and they are only provided here in support of the NOAEL/LOAEL approach. Adjustment

of the lower TWA low dose for intermittent exposure of 5 days/week (38 mg/kg-day × 5/7)

results in a LOAEL of 27 mg/kg-day. 

Table 5-2 Application of uncertainty factors (UFs) for RfD calculation

POD and UF Factors NOAEL/

LOAEL

Point of Departure (POD)-based on testicular, liver, and adrenal 

effects in male rats and adjusted for intermittent exposure.

LOAEL = 27 

 (mg/kg-day)

UFH = Variation from average humans to sensitive humans 10

UFA = Uncertainty in extrapolating from rodents to humans 10

UFS = Uncertainty in extrapolating from subchronic to chronic effect

levels

1

UFL = Uncertainty in extrapolating from LOAELs to NOAELs

(NOAEL/LOAEL approach)

10

UFD = Uncertainty in database 10

UF(Total) 10,000a

RfD (mg/kg-day) 9E-3

a

The UF(Total) is reduced from 10,000 to recommended maximum uncertainty factor of 3000 for the purposes of

calculating the final RfD due to recognized overlap in UFs (U.S.EPA, 2002a, page 4-41; U.S.EPA, 1994; Dourson

and Stara, 1983).

5.1.2. RfD Derivation

The adjusted daily dose of 27 mg/kg can be considered a LOAEL for peliosis (20%

response), testicular atrophy (29% response), and adrenal cortical degeneration (27% response). 

Because testicular atrophy occurs with high incidence in aged untreated rats, the lack of testicular

atrophy in the vehicle control group at 61 weeks suggests that 1,2-dibromoethane hastens the

onset of testicular atrophy. Uncertainty factors of 10 for interspecies variability, 10 for

intraspecies variability in sensitivity, and 10 for adjustment from a LOAEL to a NOAEL were

assigned, as there was no information available that suggested other values were appropriate. 

A 10-fold uncertainty factor accounting for the extent and quality of the database was
7

The NTP (1982) study of male mice was not considered as relevant for derivation of an RfC because of

high mortality in control and exposed groups due to complications from urinary tract infections that were not

exposure related.

63

deemed necessary due primarily to the poor quality of the principal study, the lack of high quality

developmental and reproductive studies by the oral route of exposure, and limited studies in bulls

that suggest adverse effects on sperm at low doses. High mortality in the principal study (NCI,

1978) causes considerable uncertainty with respect to the exposures that the animals received and

with respect to the responses that might have been observed had the animals survived to term. 

The lack of a multigeneration study is also of concern in light of the genotoxicity of 1,2-

dibromoethane, because any genetic damage to the germ cells of the F1 generation would not be

detected until the F2 generation. Developmental toxicity studies covering major organogenesis

(but not studies covering the entire period of gestation) are available in two species via the

inhalation route, and inhalation systemic toxicity studies that evaluated the respiratory tract are

available in two species. There is also some limited evidence for neurobehavioral

developmental effects caused by 1,2-dibromoethane as well as endocrine disruption (based on

effects on other endocrine organs as well as changes in hormone levels). 

A subchronic to chronic uncertainty factor was not considered necessary because all

animals of the low dose group were continuously exposed for approximately one year. This

results in a overall uncertainty factor, UF(Total), of 10,000. In general, the individual uncertainty

factors that comprise the UF(Total) are expected to be conservative with respect to the behavior of

the average chemical (Dourson and Stara, 1983). For this reason, the Agency has recommended

the application of a maximum uncertainty factor of 3000 for the purposes of calculating RfDs and

RfCs (U.S.EPA, 2002a, pages 4-41; U.S.EPA, 1994b). Application of a total uncertainty factor of

3,000 to the LOAEL of 27 mg/kg-day yields an RfD of 9 E-3 mg/kg-day. 

5.2. INHALATION REFERENCE CONCENTRATION (RfC)

An RfC can be derived based upon the NTP (1982) bioassay of 1,2-dibromoethane. In

this study the noncarcinogenic effects observed are hepatic necrosis (male and female rats),

testicular degeneration (male rats), retinal atrophy (female rats), adrenal cortical degeneration

(female rats), splenic hematopoiesis (female mice), and inflammation of the nasal cavity (female

mice).7

 The critical liver endpoint differs somewhat from that which was used to develop the oral
64

RfD (peliosis). They are, however, both measures of liver toxicity and are likely to be closely

related. Because liver cancer induction was not statistically significantly increased in either sex

following inhalation exposure to 1,2-dibromoethane and because necrosis is not considered a

necessary precursor to induction of liver cancer, necrosis is considered to be a suitable endpoint

for quantifying the noncancer effects of 1,2-dibromoethane.

Table 5-3. Inhalation subchronic and chronic studies in laboratory animalsa

Reference Species (strain) Sex

No./

dose

group

Exposure

duration

NOAEL

(mg/m3

)

LOAEL

(mg/m3)

NTP, 1982 Rat (F344) M 50 103 weeks -- 76.8

F 50 103 weeks -- 76.8

NTP, 1982 Mouse (B6C3F1) M

F

48

50

78 weeks b

106 weeks

–

--

76.8

76.8

Stinson et al., 1981 Mouse (B6C3F1) M

F

50

50

103 weeks

103 weeks

–

--

76.8

76.8

Nitschke et al., 1981 c Rat (F344) M

F

10

10

13 weeks d

13 weeks e

23

23

76.8

76.8

Reznik et al.,

1980c

Rat (F344) M

F

5

5

13 weeks d

13 weeks e

23

23

115

115

Reznik et al.,

1980c

Mouse (B6C3F1) M

F

10

10

13 weeks d

13 weeks e

115

115

576

576 ____________________________________________________________________________________________________________________________________________________________

a

 Results of Rowe et al. (1952) not included because of the many limitations of that investigation. b

Mortality was high in exposure and control groups of male mice.

c

 Study was designed principally to evaluate the role of 1,2-dibromoethane in promoting nasal lesions. d

 Forty males per exposure group; serial sacrifices of 10 males per exposure group were conducted at 1, 6, and 13

weeks; remaining animals were sacrificed 88–89 days postexposure.

e

 Twenty females per exposure group; 10 females per exposure group were sacrificed at 13 weeks; remaining animals

were sacrificed 88–89 days postexposure.
65

Table 5-4. Reproductive and developmental inhalation studies in laboratory

animals

Reference Species (strain) Sex

#/Dose

group

Exposure

Duration

NOAEL

(mg/m3)

LOAEL

(mg/m3)

Short et al., 1978 Rat (Charles River

CD)

M&F 15-17 10 days a 154 292 b

Short et al., 1978 Mouse (CD-1) M&F 18-22 10 days a -- 154 b

Short et al.,

1979

Rat (Charles River

CD)

M

F

9-10

20

10 weeks c

3 weeks c

300

300

684 d

614 d

Smith and Goldman,

1983

Rat (Long-Evans) F 12 Days 3 to 20 of

gestation e

3.3 51 f

a

 For 23 hr/day beginning on day 6 of gestation.

b

 Developmental effects plus some maternal toxicity.

c

 For 7 hr/day, 5 days/week.

d

 Reproductive effects plus significant morbidity and mortality.

e

 For 4 hr/day, 3 days/week.

f

 Based on behavioral effects in offspring.

5.2.1. Methods of Analysis

Because the NTP study demonstrated adequate spacing of exposure levels with increasing

response levels with increasing exposure levels, the inhalation toxicity of 1,2-dibromoethane was

evaluated using benchmark dose (BMD) analysis. A summary of the dose-response data and

results and the actual EPA BMDS model runs are provided in Table B-2 of Appendix B. The

benchmark doses were estimated for both 10% and 5% extra risk. An extra risk of 10% has

generally been the default benchmark response (BMR) level for quantal data because it is at or

near the limit of sensitivity in most bioassays. The Agency’s benchmark dose technical guidance

(U.S.EPA, 2000c) does indicate that a lower BMR can be used if a study has “greater than usual

sensitivity.” However, this study cannot be said to have greater than usual sensitivity because it

involved only two dose groups and high mortality in all dose groups. In addition, responses in the

low dose group were in the range of or greater than 10% for virtually all endpoints under

consideration. BMD estimates for lower response levels are more dependent on model choice

(i.e., the range of BMD and BMDL estimates are more variant across models). Therefore, the

BMDL for an extra risk of 10% is used for the RfC derivation. 

5.2.2. RfC Derivation
66

To derive an RfC, the BMDL10 values presented in Table B-2 of Appendix B were

adjusted to equivalent continuous exposures, converted to human equivalent concentrations

(HECs), and then divided by uncertainty factors. The lowest of the resulting values was

determined to be the RfC. 

Human equivalent exposures were estimated following the EPA RfC methodology

(U.S.EPA, 1994b). 1,2-Dibromoethane is relatively insoluble in water and demonstrates systemic

toxicity, although there was some respiratory tract toxicity that may or may not be considered

portal of entry effects. Therefore, 1,2-dibromoethane is considered a Category 2 gas. For

Category 2 gases, HEC values are calculated using methods for category 1 gases for portal-ofentry effects and category 3 methods for systemic effects (U.S.EPA, 1994b). Thus, in Table 5-5,

the EPA RfC method for Category 3 gases was used to derive BMDL10 (HEC)s for the liver,

testicular, retinal, adrenal, and splenic effects, and the method for Category 1 gases was used to

derive BMDL10(HEC) for nasal effects. The NTP (1982) data for nasal inflammation in female

mice resulted in the lowest BMDL10(HEC) of 2.8 mg/m3. Figure 5-1 is a plot showing the

selected, BMDS log-probit model results for this endpoint. The model runs that resulted in the

BMDL10 estimates for nasal inflammation and other effects are summarized in Appendix B, Table

B-2. 

An uncertainty factor of 3 was applied for interspecies pharmacodynamics as a

consequence of considering human equivalent dosimetry above and due to the lack of data

suggesting a more or less divergent response in humans. An uncertainty factor of 10 for

intraspecies variability in sensitivity results was applied, as well as a default value due to the lack

of data indicating a different degree of variability in humans.

An uncertainty factor for less than lifetime exposure is considered to be unnecessary

because the principal study was carried out for at least 88 weeks. A database uncertainty factor of

10 is applied. High mortality in the principal study (NTP, 1982) causes considerable uncertainty

with respect to the exposures that the animals received and with respect to the responses that

might have been observed had the animals survived to term. A one-generation inhalation

reproductive toxicity study is available but no multigeneration study. The lack of the

multigeneration study is of particular concern in light of the genotoxicity of 1,2-dibromoethane, 

Table 5-5. HEC estimates from BMDLs derived from NTP (1982); Table B-2,

Appendix B
67

Male Rats Female Rats Female Mice

Hepatic

necrosis

(mg/m3)

a

Testicular

degeneration

(mg/m3

)

Hepatic

necrosis

(mg/m3)

Adrenal

cortical

degeneration

(mg/m3

)

Retinal

atrophy

(mg/m3)

Splenic

hematopoiesis

(mg/m3

)

Nasal

inflammation

(mg/m3

)

NOAEL NAb NA NA NA NA NA NA

LOAEL 76.8 76.8 76.8 76.8 76.8 76.8 76.8

BMDS modelc Probit LogLogistic LogProbit LogLogistic LogLog LogLogistic LogProbit

BMD10 131.774 53.2579 172.374 124.823 125.806 59.554 102.192

BMDL10 105.343 35.0725 122.02 66.495 105.41 40.2456 80.1088

BMDL10 (ADJ)d 18.8 6.3 21.8 12.0 18.8 7.2 14.3

BMDL10 (HEC)e 18.8 6.3 21.8 12.0 18.8 7.2 2.8

a

Assuming a temperature of 25°C, a barometric pressure of 760 mm Hg, and a molecular weight for 1,2-

dibromoethane of 187.88, 1 ppm ' 7.68 mg/m3

 (187.88/24.45). b

NA=not applicable.

c

In accordance with EPA draft guidance (U.S.EPA, 2000d), the selected models were chosen on the basis of goodness

of fit criteria (AIC and chi-square residual values) and visual inspection.

d

Adjustment to continuous exposure involved multiplying the BMDL by 5 d/7 d × 6 hr/24 hr.

e

HEC values were calculated in accordance with U.S. EPA (1994b) RfC methods. For extrarespiratory effects, a

default adjustment factor of 1.0 was used for adjusting from ADJ to HEC values because 1,2-dibromoethane blood:air

partition coefficients are not known for the experimental species and humans. For the respiratory effect (nasal

inflammation), the HEC was calculated for an effect in the extrathoracic (ET) region. Minute volumemouse = 0.041

L/min, minute volumehuman = 13.8 L/min, surface area(ET)mouse = 3 cm3

, surface area(ET)human = 200 cm2. Regional gas

dose ratio(ET) = [minute volumemouse/surface area(ET)mouse]/[minute volumehuman/surface area(ET)human] = 0.198.

BMDL(HEC) = BMDL(ADJ) × regional gas dose ratio(ET) = 14.3 mg/m3

 × 0.198 = 2.8 mg/m3.

because any genetic damage to the germ cells of the F1 generation would not be detected until the

F2 generation. Furthermore, the absence of an evaluation of sperm in reproductive toxicity study

is of concern in light of the effects observed in humans and bulls. Developmental toxicity studies

covering major organogenesis (but not studies covering the entire period of gestation) are

available in two species via the inhalation route, and inhalation systemic toxicity studies that

evaluated the respiratory tract are also available in two species. There is also some limited

evidence for neurobehavioral developmental effects caused by 1,2-dibromoethane as well as

endocrine disruption (based on effects on other endocrine organs as well as changes in hormone

levels). 

The composite uncertainty factor is 300 (10 for UFH, 3 for UFA, and 10 for UFD). 

Application of this composite factor to the BMDL10(HEC) of 2.8 mg/m3

 yields an RfC of 9 E-3

mg/m3

. 
68

0

0.1

0.2

0.3

0.4

0.5

0.6

0 50 100 150 200 250 300

Fraction Affected

dose

Probit Model with 0.95 Confidence Level

15:29 09/03 2003

BMDL BMD

 

Probit

Figure 5-1: Log-Probit Model of Nasal Inflammation in Female Mice (NTP (1982)

5.3 CANCER ASSESSMENT

There are no definitive reports of cancer in humans associated with exposure to 1,2-

dibromoethane; the available epidemiological studies have numerous limitations (section 4.1.3.)

and are inconclusive. Chronic bioassays in rats and mice by both oral and inhalation routes

provide evidence of tumors in multiple organ systems and also at direct points of contact (e.g.,

nasal cavity and lung tumors following inhalation and forestomach tumors following ingestion).

NCI (1978) provided evidence for the induction of forestomach squamous cell carcinoma
69

and hemangiosarcoma in male and female rats, thyroid follicular cell adenomas in male rats, and

hepatocellular carcinomas and adrenocortical carcinomas in female rats following gavage

administration of 1,2-dibromoethane. In addition, there were increases in forestomach tumors and

lung adenomas in mice of both sexes. The effects in rats and mice are supported by carcinogenic

findings (forestomach tumors) in a drinking water study in mice (Van Duuren et al., 1985),

conducted at a single dose comparable to the high dose in the NCI mouse study. NTP (1982)

provided evidence of 1,2-dibromoethane-induced nasal cavity tumor and other benign and

malignant tumors in male and female Fischer 344 rats and in female B6C3F1 mice in a 2-year

inhalation cancer bioassay. Further, screening level evidence from A/J mouse lung tumor assays

supports tumor induction by the oral, inhalation, dermal, and intraperitoneal routes of exposure

(Adkins et al., 1986; Stoner et al., 1986; Van Duuren et al., 1979). In addition, 1,2-dibromoethane

has been reported to be a direct acting mutagen in S. typhimurium assays and has also been shown

to induce point mutations in S. typhimurium. 1,2-Dibromoethane has also been demonstrated to

induce chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells

and bind to DNA in vivo and in vitro.

This weight-of-evidence carcinogenicity characterization and quantitative estimate of

carcinogenicity from oral exposure replace the previous classification of "B2; probable human

carcinogen," and oral slope factor of 85 mg/kg/day entered on IRIS on September 7, 1988. The

new classification and slope factor estimate are based on a review of newer data and a reanalysis

of the data used in the earlier assessment. This is based on the consistent findings of several

studies reporting increased incidences of a variety of tumors in rats and mice of both sexes by

different routes of administration at both the site of application and at distant sites. It can be

concluded that there is strong evidence of the carcinogenicity of 1,2-dibromoethane in animals. 

The available evidence further supports a conclusion that 1,2-dibromoethane is a genotoxic

carcinogen based on evidence from a variety of in vitro and in vivo test systems. Under the Draft

Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), 1,2-dibromoethane is considered

“likely to be carcinogenic to humans” based on strong evidence of carcinogenicity in animals and

inconclusive evidence of carcinogenicity in an exposed human population. 

 

There is some indication that a glutathione-dependent metabolite may be implicated in 1,2-

dibromoethane’s carcinogenic activity (as reported by Hissink et al., 2000), but the available

evidence does not make any quantitative estimates possible. The carcinogenicity of 1,2-

dibromoethane is evaluated according to the linear approach as described in U.S. EPA (1999),

because 1,2-dibromoethane has demonstrated genotoxicity and not enough in addition is known
70

about the mode of action to support a nonlinear low-dose extrapolation (see section 4.6.3.).

5.3.1. Oral Carcinogenicity

5.3.1.1. Choice of Oral Study/Data with Rationale and Justification

The study by NCI (1978) was used for development of an oral slope factor. Although the

drinking water study by Van Duuren et al. (1985) used an adequate number of animals and

examined proper endpoints, the study is limited for development of an oral slope factor because

only one dose level was examined. The NCI (1978) study used an adequate number of test

animals and two dose levels plus untreated and vehicle control groups, and examined appropriate

toxicological endpoints.

5.3.1.2. Oral Dose-Response Data

In the NCI (1978) study, male and female Osborne-Mendel rats and B6C3F1 mice were

administered 1,2-dibromoethane by gavage 5 days/week. High mortality in both species in all

exposure groups necessitated reduced dosage levels, reduced frequency of dosing (see section

4.2.1.), and early termination of the studies. Time-weighted average low- and high-doses were 38

and 41 mg/kg/day for male rats, 37 and 39 mg/kg/day for female rats, and 62 and 107 mg/kg/day

for mice of both sexes. Male and female rats were sacrificed at weeks 49 and 61, respectively. All

surviving male mice and high-dose female mice were sacrificed at week 78, while low-dose

females were sacrificed at week 90.

Tumor incidences were elevated with increasing exposure level at several sites: 

forestomach squamous cell carcinoma, hemangiosarcoma, thyroid follicular cell adenomas in male

and female rats, hepatocellular carcinomas in female rats, and forestomach squamous cell

carcinoma and lung adenoma in both sexes of mice. Benign and malignant tumors were combined

for sites where an eventual progression from the benign to the malignant form was plausible (for

example, lung alveolar/bronchiolar adenomas or carcinomas, and forestomach squamous cell

papillomas or carcinomas). These data are summarized in Table 5-6.

Because there was high mortality in both species that resulted in early termination of the

study, statistical procedures that can reflect the influence of intercurrent mortality on site-specific
71

tumor incidence rates were used to evaluate the tumor incidence levels. The individual animal

data were not included in the bioassay report and were requested from NTP/NCI for this purpose

(see Appendix C for a listing of the tumor incidence data by time of death). Subsequent to the

completion of the NCI study of 1,2-dibromoethane, the NTP has adopted the Poly-3 procedure

(Bailer and Portier, 1988) for adjusting tumor incidence rates for intercurrent mortality. The

procedure is based on the observation that the cumulative incidence of tumors tends to increase

with time raised to the second through the fourth powers for a large proportion of cases. In the

Poly-3 procedure, for a study of T weeks duration, an animal that is removed from the study after t

weeks (t < T) without a specified type of tumor of interest is given a weight of (t/T)3

. An animal

that survives until the terminal sacrifice at T weeks is assigned a weight of (T/T)3

 = 1. An animal

that develops the specific type of tumor of interest obviously lived long enough to develop the

tumor and is also assigned a weight of 1. The Poly-3 tumor incidence, adjusted for intercurrent

mortality up to time T, is the number of animals in a dose group with the specified type of tumor

divided by the sum of the weights (the effective number of animals at risk). The tumor incidences

adjusted using this procedure are also provided in Table 5-6 with the results of applying the

Cochran-Armitage test for trend to the adjusted incidences.

Note that the low-dose female rats and both sexes of mice all had adjusted incidences of

100% for forestomach tumors, while the low-dose male rats had an adjusted incidence of 95%. 

Considering only the administered dose rate and adjusted tumor incidence at the low dose, female

rats were slightly more sensitive than male rats to 1,2-dibromoethane exposure. In addition,

forestomach tumors appeared the earliest in the female rat study, at week 12 in both dose groups,

contrasted with week 15 in the high-dose male rats and week 31 in the low-dose male rats.

5.3.1.3. Oral Dose Adjustments and Extrapolation Methods

In preparation for carrying out dose-response analyses of the tumor data, adjustments to the

administered doses for approximating human equivalent, continuous exposure levels were

considered. Following EPA default procedures, the time-weighted daily average doses were

converted to human equivalent doses on the basis of (body weight)3/4 (U.S.EPA, 1992). This

adjustment is summarized in Table 5-7.

The dose levels as reported by NCI had been averaged over the period of observation in

terms of weeks, with time-weighted average low and high doses of 38 and 41 mg/kg/day for male

rats, and 37 and 39 mg/kg/day for female rats. Although some of the survival-adjusted incidence
72

of lesions and tumors in the high-dose rats were no higher than in the low dose groups, there is

some evidence that there was a dose rate effect - that is, that the rate at which the 1,2-

dibromoethane was administered was more directly related to the effects seen than was the timeweighted average. The tumor incidence by time curves shown in Figures C-1 through C-11

(Appendix C) illustrates that, for many of the significant tumor sites, the incidence in the highdose group started earlier than in the corresponding low-dose group. One exception might be the

forestomach tumors in female rats (Figure C-4, Appendix C), for whom the incidence in the two

groups was very similar. However, since the incidence in the low-dose female rats was effectively

100% after adjusting for competing causes of mortality, the observation that the high dose female

rats did not reach 100% much sooner does not really inform a characterization of a dose rate

effect. In addition, the mice in the van Duuren et al. study (1985) received a daily oral exposure

that was slightly higher than the high dose in the NCI mouse study. Their response was slightly

less than the NCI mice, most likely attributable to drinking water administration rather than the

oral gavage in the NCI study - another example of dose rate differences. Most notably,18 high

dose male rats died in week 15, three of which had forestomach tumors, while in the low-dose

group the first forestomach tumor was not observed until week 31. For this reason dose averaging

over the period of the study may not be the most representative measure of exposure.

Another adjustment typically made to extrapolate to continuous daily exposure, that is

lowering each dose by multiplying by (5 days)/(7 days)=0.71, was not incorporated prior to doseresponse modeling, also in recognition of the possible dose rate effect. However, the assumption

that a cumulative amount of exposure delivered over different time periods producing a similar

effect may be more likely to hold at very low exposures. Since this is a linear adjustment, it can be

incorporated after dose-response modeling as an alternative characterization to compare results. 

Because the studies all ended before the usual 104 weeks, an adjustment to extrapolate to

lifetime human exposure was considered. EPA typically adjusts each dose level by a factor related

to the Poly-3 adjustment. That is, each dose is adjusted by multiplying by (T/104)3

, where T is the

time of final sacrifice in a given dose group. When all groups have been terminated at the same

time, this adjustment is linear, and can be applied before or after modeling is completed. The rat

studies were terminated at approximately 50% of their intended length, which results in lowering

the male and female doses by factors of 10 and 5, respectively. It was decided to consider the

adjustment as an alternative characterization after the modeling is complete. Although the female

mouse groups were terminated at different times, at 90 (low-dose) and 78 (high-dose) weeks, it

was decided to apply a composite lifetime equivalent adjustment after modeling, to parallel the
73

risk estimates derived from the rat study. Calculation of the lifetime exposure adjustments is

summarized in Table 5-7.

The results of the oral bioassays were characterized by fitting dose-response models to the

tumor results showing significant elevations with increasing exposure. Because there was high

mortality in both species that also resulted in early termination of each study, models which can

reflect the influence of intercurrent mortality on site-specific tumor incidence rates were

considered. EPA has generally used two approaches. Modest effects on survival can be addressed

by omitting the animals in each treatment group who died before the first occurrence of the tumors

being analyzed. In these bioassays, however, effects on survival were not modest. Consequently,

for the quantal model analyses, intercurrent mortality was addressed using the Poly-3 adjusted data

discussed in section 5.3.1.2. The poly-3 adjustment is an approximate adjustment that may not

characterize the extremes of tumor incidence (Bailer and Portier, 1988), however. When tumors

appear earlier with increasing exposure levels, the multistage-Weibull model is the preferred

model because it incorporates the time at which death-with-tumor occurred (e.g., U.S.EPA: 1988b

- 1,2-dibromoethane; 2001 - bromate; 2002b - 1,3-butadiene). However, the multistage-Weibull

model cannot accommodate variable dosing schedules as in this study. Consequently, the more

approximate approach using the Poly-3 adjusted data was the most suitable dose-response method

for these data.

Dose-response analyses were conducted from the individual animal data for sites

demonstrating an increased cancer incidence summarized in Table 5-6. Etiologically different

tumor types were not combined across sites prior to modeling because the numbers of animals at

risk differed by tumor site, depending on the patterns of intercurrent mortality.

EPA generally uses the multistage model with quantal cancer data, to estimate a 95% upper

confidence limit (UCL) on cancer risk (extra risk) for humans. The multistage model has the form

P(d) = 1 - exp[-(q0 + q1d + q2d2

 + ... + qkdk)],

where P(d) represents the lifetime risk (probability) of cancer at dose (i.e., human equivalent

exposure concentration in this case) d, and parameters qi $ 0, for i = 0, 1, ..., k. The model

parameters and 95% UCL were calculated using the multistage model in the EPA BMDS software. 

Extra risk over the background tumor rate is defined as [P(d) - P(0)]/[1 - P(0)]. Point estimates of

the dose coefficients (qis), and consequently the extra risk function, at any dose d are calculated by
74

maximizing the likelihood function with respect to the tumor incidence data. The incremental

lifetime unit cancer risk for humans (q1*) is defined as the 95% UCL on the parameter q1, which is

the linear dose coefficient. This 95% UCL represents a plausible upper bound on the true risk. 

5.3.1.4. Oral Slope Factor

The results of applying quantal models to the Poly-3 adjusted tumor incidence data are

provided in Table 5-8. The data for forestomach tumors for female rats and both sets of mice

could not be adequately fit by the available models. For the remaining tumor data, a point of

departure (PoD) near the lower end of the observed data was selected for linear extrapolation to

low doses, consistent with the Draft Guidelines for Carcinogen Risk Assessment (U.S.EPA, 1999). 

An oral slope factor for each of these tumor sites was calculated by dividing the BMR level by the

corresponding BMDL for these points of departure. A slope factor for each data set not fit by a

model (e.g., forestomach tumors) was approximated by dividing the response at the low dose –

100% in each case – by the low dose.

Under the assumption that dose rate is the most important dose metric, estimated human

equivalent oral slope factors ranged from 0.013 to 0.12 (mg/kg/day)-1, for less than lifetime

exposure. The highest slope factor corresponded to forestomach tumors in male rats. Adjustment

for lifetime exposure, using the default adjustments listed in Table 5-7, leads to a range of 0.065 to

1.0 (mg/kg/day)-1 for oral slope factors, as presented in the last column of Table 5-8.

The approximate slope factors for the other forestomach tumor (female rats; male and

female mice) sets were at least as high, which is notable because these were central tendency

estimates. No useful upper bound estimate was possible with the response already at 100%. 

These estimates and the estimate from the male rats are only useful if it can be assumed that

carcinogenicity associated with 1,2-dibromoethane follows a linear relationship throughout the

range of doses below 93%-100% response.

There is some concern that the forestomach tumors may result primarily as a portal of entry

effect and may not have a dose-response pattern that extends linearly from the observed responses. 

The hemangiosarcomas and other tumors demonstrate absorption of 1,2-dibromoethane, although

it is not clear whether absorption was impacted by adverse effects in the forestomach. In addition,

there is considerable uncertainty in extrapolating from the period of the experiment, 49 weeks for

the male rats, to full lifetime exposure. Given the multiplicity of tumor sites, however, basing the
75

slope factor on one tumor site underestimates oral carcinogenic potential of 1,2-dibromoethane, all

else being equal.

In order to gain some understanding of the total risk from multiple tumor sites in male and

female rats, it was assumed that the more significant tumor types observed were mechanistically

independent - that is, that the occurrence of hemangiosarcomas, say, was not dependent upon

whether there were forestomach tumors. Accordingly, a statistically appropriate upper bound risk

was estimated using the following steps: (1) the central tendency, or maximum likelihood

estimates (MLE) of unit potency were summed across forestomach tumors, hemangiosarcomas,

and thyroid follicular cell adenomas for male rats and across hemangiosarcomas, hepatocellular

carcinomas, adrenocortical carcinomas in female rats; (2) an estimate of the 95% upper bound on

the summed unit risk was calculated by assuming a normal distribution for the individual risk

estimates, and deriving the variance of the risk estimate for each tumor site from its 95% upper

confidence limit (UCL) according to the formula 

95% UCL = MLE + 1.645 A s.d.,

where 1.645 is the t-statistic corresponding to a one-sided 95% confidence interval and >120

degrees of freedom, and the standard deviation (s.d.) is the square root of the variance of the MLE. 

The variances were summed across tumor sites to obtain the variance of the sum of the MLE. The

95% UCL on the sum of the individual MLEs was calculated from the variance of the sum using

the same formula. 

Summing the cancer risks in this manner, after the dose-response for each tumor site has

been evaluated, is superior to EPA’s previous practice of carrying out one dose-response analysis

of tumor-bearing animals. The primary reason is that the biological relevance of the multistage

model is maximized by allowing different multistage models to be fit to qualitatively different

tumor types that might not be expected to develop through exactly the same modes of action. 

Time courses in the tumor types evaluated here did vary, for example. In this case, however, these

summed estimates are approximate because the risk estimates could not be taken from analogous

segments of the respective dose-response curves. For example, the risk for the male forestomach

tumors comes from the portion of the dose-response near 90% response, while the risks for the

other two sites are from a much lower portion (<20%) of their respective dose-response curves.

The resulting 95% UCL on the slope factor for the summed risk of forestomach tumors,
76

hemangiosarcomas, and thyroid follicular cell adenomas for male rats was 0.13 (mg/kg/day)-1. The

slope factor for forestomach tumors was nearly an order of magnitude higher than for the other two

tumor sites, and the variability in the slope factor based on forestomach tumors alone was the

greatest of the three sites, so the other sites end up having very little effect on the upper bound of

the summed risks. Since risk values are rounded to one significant figure, the summed cancer

slope factor is equivalent to that for forestomach tumors alone.

For comparison, the sum of the three significant tumor sites for females rats, excluding the

forestomach tumors, has a 95% UCL of 0.044 (mg/kg/day)-1. If the summed risk estimate is

combined with the approximate slope factor estimated for female rat forestomach tumors of 0.1

(mg/kg/day)-1, this results in an estimate of 0.14 (mg/kg/day)-1. Although this risk estimate is

higher than that obtained from the male rats, the contribution of risk from the forestomach tumors

for female rats is relatively uncertain–there was no dose-response information between 0% and

100% response levels (and the modeling approach could not provide a confidence interval). The

lowest response level for the males was still relatively high, close to 90%, but a confidence limit

was estimable. The slope factor should be based on the sum of the male rat tumors slope factors

rather than the sum of the female rat slope factors.

At low doses, it is not known whether or not there would be a dose rate effect. Without

information to the contrary, the estimated cancer slope factor should be adjusted to daily exposure

by multiplying by (7 days)/(5 days). The recommended oral slope factor for approximately half a

lifetime of exposure is 0.13 (mg/kg/day)-1 × 7/5 = 0.18 (mg/kg/day)-1.

For application to lifetime exposures, the default lifetime exposure adjustment factor for male rats

of 0.1, described in Table 5-7, leads to a slope factor of 1.8 (mg/kg/day)-1. This slope factor should

not be used with exposures greater than approximately 0.5 mg/kg/day (i.e, the human equivalent

lifetime exposure level corresponding to 90% risk of forestomach tumors), since the observed

dose-response would not be expected to continue linearly above this estimated lifetime-equivalent

exposure level.

An oral slope factor of 85 (mg/kg/day)-1 was listed previously on IRIS (U.S. EPA, 1988b). 

The earlier assessment used the multistage-Weibull model, which has a form similar to the

multistage model (Equation 5-1):

P(d,t) = 1 - exp[-(q0 + q1d + q2d2

 + ... + qkdk)*(t - t0)

z

], (5-2)
77

with the addition of the time t that a tumor was observed, raised to the z power. The model fit to

the NCI (1978) data fit z = 7.6 to the time that tumors were observed, which contrasts with the

power of 3 used in the current analysis, through the Poly-3 adjustment for deaths occurring before

the end of the study, and through the lifetime exposure adjustment for extrapolating from the end

of the study to full lifetime. These modeling differences resulted in a less extreme extrapolation to

lifetime exposure from the truncated bioassay that was available. Several quantitative

considerations and assumptions were also updated in the reanalysis, including the use of (body

weight)3/4 scaling rather than surface area scaling, (body weight)2/3, to estimate human equivalent

doses; estimation of risk close to the range of the observed data rather than extrapolated to the

exposure expected to be associated with 1 × 10-6 extra risk; and extrapolation to a human lifetime

of 70 rather than 76.2 years.
78

Table 5-6. Observed and adjusted tumor incidences (and percentages) in

rats and mice exposed by oral gavage to 1,2-dibromoethane

Tumor site

Incidence

adjustment

Dose groupsa

Tumor incidenceb

Trend

test

p-valuec

Male rats 0 mg/kg/day Low dose High dose

Forestomach papillomas

or tumors

None (observed)

Poly-3

0/20

0/13

0%

0%

45/50

45/50

90.0%

90.0%

33/50

33/34

66.0%

97.1% <0.001

Hemangiosarcoma None (observed)

Poly-3

0/20

0/13

0%

0%

11/50

11/42

22.0%

26.2%

4/50

4/23

8.0%

17.4% 0.12d

Thyroid follicular cell

adenoma or carcinoma 

None (observed)

Poly-3

0/20

0/13

0%

0%

5/50

5/39

10.0%

12.8%

8/50

8/23

16.0%

36.4% 0.001

Female Rats

Forestomach papillomas

or tumors

None (observed)

Poly-3

0/20

0/19

0%

0%

40/50

40/40

80%

100%

29/50

29/29

58%

100% <0.001

Hemangiosarcoma None (observed)

Poly-3

0/20

0/19

0%

0%

0/50

0/20

0%

0%

3/50

3/17

6.0%

17.6% 0.026

Hepatocellular carcinoma

or neoplastic nodule 

None (observed)

Poly-3

0/20

0/19

0%

0%

1/50

1/20

2.0%

5.0%

6/50

6/18

12.0%

33.3% 0.006

Adrenocortical

carcinoma

None (observed)

Poly-3

0/20

0/19

0%

0%

1/50

1/21

2.0%

4.8%

4/50

4/17

8.0%

23.5% <0.001

Male mice

Forestomach papillomas

or tumors

Observed

Poly-3

0/20

0/18

0%

0%

45/50

45/45

90%

100%

31/50

31/32

64.0%

96.9% <0.001

Alveolar/bronchiolar

adenoma

Observed

Poly-3

0/20

0/18

0%

0%

4/50

4/20

8%

20%

10/50

10/18

20.0%

55.6% <0.001

Female mice

Forestomach papillomas

or tumors

Observed

Poly-3

0/20

0/18

0%

0%

47/48

47/47

97.9%

100%

28/50

28/31

56.0%

93.3% <0.001

Alveolar/bronchiolar

adenoma

Observed

Poly-3

0/20

0/18

0%

0%

10/48

10/30

20.0%

33.3%

5/50

5/18

10.0%

27.8% 0.027

a

 The NCI bioassay doses were administered 5 days/week. The doses reported by NCI (1978) reflect averaging over

the total number of weeks of the study, but not over 7 days/week.

b

 Numbers of animals at risk for observed incidences do not always agree with those given in Table 4-1 because the

individual animal data tables containing the times of observation did not include notations of tissues missing due to

autolysis, etc.

c

 Cochran-Armitage test for trend, using the Poly-3 adjusted incidence data.

d

 Trend test for male rat hemangiosarcomas was not statistically significant (the dose-response was not monotonically

increasing), the low-dose response (26%) was statistically significantly elevated relative to control (Fisher’s exact test,

p = 0.04). 

Source: NCI, 1978.
79

Table 5-7. Human equivalent exposures and adjustment factors for

extrapolating from less-than-chronic exposure to lifetime exposure for the

exposure periods in the NCI gavage study of 1,2-dibromoethane (NCI,

1978) 

Sex, species

Bioassay doses

(mg/kg/day)

Body

weighta

(kg)

Human

equivalent

exposuresb

(mg/kg/day)

Time of

terminal

sacrifice

(weeks)

Lifetime

exposure

adjustment

factorc

Male rats Low Weeks 1-49d 40

0.45

11

High Weeks 1-16 49 0.10

17-28

29-49d

80

0

40

22

Female rats Low Weeks 1-61d 40

0.30

10

High Weeks 1-16 61 0.20

17-28

29-61d

80

0

40

20

Male mice Low Weeks 1-10

11-12

13-53

60

100

60

0.030

8.

6

78 0.42 High Weeks 1-10

11-12

13-39

40-53

120

200

120

60

17

Female mice Low Weeks 1-10

11-12

13-53

60

100

60

0.025

8.

2

90 0.64

High Weeks 1-10

11-12

13-39

40-53

120

200

120

60

16 78 0.42

a

 Body weights are lifetime averages, rounded to the nearest 0.05 kg (rats) or 0.005 kg (mice). b

 The doses initially administered by NCI (1978) were adjusted for human equivalence by multiplying by [animal

body weight (kg)/70 kg]0.25. c

 Lifetime exposure adjustment factor = (t/104)3, where t is the time of final sacrifice in a particular dose group. d

 Male rats were purposely not dosed during weeks 42 and 46, female rats not during weeks 42, 47, 52, and 56.
80

Table 5-8. Estimation of benchmark doses (BMD), lower 95% confidence

limits (BMDL), and oral slope factors; using Poly-3 adjusted tumor

incidence rates (see Table 5-1), for animals exposed orally to 1,2-

dibromoethane (NCI, 1978)

Sex,

species Tumor type

Point of departure

Partial

lifetime

exposure

oral slope

factora

(mg/kg/day)-1

Lifetimeadjusted oral

slope factorb

(mg/kg/day)-1

Benchmark

response

BMD,

mg/kg/day

BMDL,

mg/kg/day

Male

rats

Forestomach 90% 11.9 9.1 0.10 1.0

Hemangiosarcoma 20% 12.8 8.6 0.023 0.23

Thyroid follicular

cell adenoma

12.5% 10.8 5.7 0.022 0.22

Female

rats

Forestomachc 100% 10 - (0.1) (0.50)

Hemangiosarcoma 10% 18 7.9 0.013 0.065

Hepatocellular

carcinoma

15% 11 6.5 0.023 0.12

Adrenocortical

carcinoma

10% 10 5.4 0.018 0.090

Male

mice

Forestomachc 100% 8.6 - 0.12 0.29

Lung adenoma 30% 9.3 6.1 0.049 0.12

Female

mice

Forestomachc 100% 8.2 - 0.12 0.23

Lung adenoma 25% 8.6 5.8 0.043 0.082

a

 Slope factors were estimated by dividing the BMR (expressed as a proportion) by the BMDL. The slope factors

should not be used with exposures higher than the corresponding BMDL, because the dose-response relationships tend

to be nonlinear above the point of departure. They also only describe risk for exposure lasting the specified percentage

of a lifetime.

b

 Slope factors were adjusted for lifetime exposure equivalence using the sex- and species-specific adjustments from

Table 5-7, under the assumption that tumor incidence over time increases with the third power of time.

c

 Because there were no data available between 0% and 100% responses, curve fitting with meaningful confidence

bounds is not possible. An approximate slope factor is derived by dividing the proportion responding at the lowest

dose by that dose, expressed as the human equivalent dose, given in the BMD column.
81

5.3.2. Inhalation Carcinogenicity

5.3.2.1. Choice of Inhalation Study/Data with Rationale and Justification

Three studies were identified that reported 1,2-dibromoethane-induced tumors following

inhalation. Stinson et al. (1981) reported benign neoplasms and carcinomas of the nasal cavity in

male and female B6C3F1 mice. Although the study was well designed and an adequate number of

test animals were used, this study is limited for the development of an inhalation slope factor

because only the nasal cavities of the animals were examined. NTP (1982) demonstrated that the

nasal cavity is not necessarily the most sensitive site of tumor formation in mice. Therefore the

Stinson et al. (1981) study was not used because similarly sensitive sites (lung, circulatory system)

were not examined. The study by Wong et al. (1982) is also not suitable for the development of an

inhalation slope factor because only one dose group was examined. The NTP (1982) study was

well-conducted, used an adequate number of test animals and dose levels, and examined

appropriate toxicological endpoints. Therefore, the study by NTP (1982) was used for

development of an inhalation unit risk.

5.3.2.2. Inhalation Dose-Response Data

In the NTP (1982) study, groups of 50 F344 rats and B6C3F1 mice of each sex were

exposed by inhalation to concentrations of 10 or 40 ppm 1,2-dibromoethane, 6 hours per day for 5

days per week. Untreated controls consisted of 50 rats and 50 mice of each sex exposed in

chambers to ambient air. Terminal sacrifices were conducted at 106 weeks in control animals and

at 104 weeks in low-dose animals. Survival in low-dose and control rats was similar for both

sexes. Terminal sacrifices were conducted at 79 weeks in the male mice, 89 weeks in the highdose male rats and 91 weeks in the high-dose female rats and mice. Although the treated male

mice demonstrated histopathology similar to that seen in the female mice, high mortality in all

groups that was not related to treatment and that started by week 10 of the study made these data

unsuitable for quantitative assessment.

Because there was increased mortality in both species that resulted in early termination of

the study, statistical procedures that can reflect the influence of intercurrent mortality on sitespecific tumor incidence rates were used to evaluate the tumor incidence levels. The Poly-3

procedure, described in section 5.3.3., was used for these data. Tumor incidences were statistically

significantly elevated with increasing exposure level at several sites: nasal cavity and circulatory
82

system (hemangiosarcoma) in all three data sets; mesothelioma in male rats; mammary

fibroadenoma or adenocarcinoma in female rats; alveolar/bronchiolar adenoma or carcinoma in

female rats and mice; and adenomas or carcinomas of the bronchus, subcutaneous fibrosarcomas,

or mammary adenocarcinomas in female mice. These data are summarized in Table 5-9. The

individual times of tumor observations for each tumor type analyzed are listed in Appendix C2.

5.3.2.3. Inhalation Dose Adjustments and Extrapolation Methods

In order to extrapolate to low environmental exposure, the results of the inhalation bioassay

were characterized by fitting dose-response models to the tumor results showing significant

elevations with increasing exposure. Differences in survival and time course of tumor observation

among dose groups were addressed using both quantal dose-response models (with Poly-3

adjusted data) and the multistage-Weibull model. 

Human equivalent exposures were estimated following the EPA RfC methodology

(U.S.EPA, 1994b). 1,2-Dibromoethane is relatively insoluble in water and demonstrates systemic

toxicity although there was some respiratory tract toxicity which may or may not be considered

portal of entry effects. Therefore, 1,2-dibromoethane is considered a Category 2 gas. Following

the RfC Methodology, the respiratory tract effects were assessed alternatively as portal of entry

effects or systemic effects while the rest of the effects were assessed as systemic effects.

For systemic effects, conversion to human equivalent concentrations involves comparison

of the blood:air partition coefficients for humans, mice, and rats (U.S.EPA, 1994b). Gargas et al.

(1989) reported a blood:air partition coefficient for rats of 119 for 1,2-dibromoethane. For their

pharmacokinetic model, Hissink et al. (2000) assumed that the value for humans would be the

same as for rats (see section 3). Without further information, the same assumption is made for this

assessment. Therefore, no adjustment for interspecies pharmacokinetics is assumed to be

necessary to estimate human equivalent concentrations for systemic effects. The equivalent

average continuous concentrations for systemic effects are respectively, (10 ppm) × (30 hrs per

wk)/(24 hrs per day × 7 days per wk) = 1.8 ppm and (40 × 30)/(24 × 7) = 7.1 ppm. 

For portal of entry effects, the human equivalent concentration is derived by multiplying

the duration-adjusted concentrations by an interspecies dosimetric adjustment for gas:respiratory

effects in affected regions of the lung. For example, for effects seen in male rats in the extrathoracic region, the adjustment uses the following calculation (U.S. EPA, 1994b):
83

RGDR(ET) = (MVa/Sa)/(MVh/Sh), (Equation 5-3)

where

RGDR(ET) = regional gas dose ratio for the nasal cavity (extra-thoracic area of the

respiratory system)

MVa = animal minute volume ( male rat: 0.21 L/min)

MVh = human minute volume (13.8 L/min)

Sa = surface area of the extra-thoracic region of the animal respiratory

system (rat: 15.0 cm2)

Sh = surface area of the extra-thoracic region of the human respiratory

system (200 cm2

)

Using these default values, the RGDR(ET)rat, male = (0.21/15)/(13.8/200) = 0.20. The resulting

adjustments for rats and female mice are summarized in Table 5-10. In addition, female rats and

mice were also observed to have tumors in other regions of the respiratory tract. The

corresponding RGDRs are also summarized in Table 5-10.

Because the high-dose groups in all three studies were terminated slightly earlier than the

remaining groups, an adjustment to extrapolate to lifetime human exposure was applied to these

exposure levels prior to quantal dose-response modeling. Unlike the oral studies (see section

5.3.1.3.), the early termination was only approximately 10% of the intended length and only

affected one group in each set. The high-dose male rat exposure level was multiplied by (t/104)3 =

(89/104)3

 = 0.63, and the female rat and mouse exposure levels were multiplied by (91/104)3 =

0.67. 

In addition to a quantal analysis (as described in section 5.3.1.3), the characteristics of the

dose-response relationships for different tumor sites were assessed through time-to-tumor analyses

in order to adjust for competing mortality from cancer at other sites and differing time courses of

tumor incidence with increasing dose. The general model used for the time-to-tumor (or time-toresponse) analyses was the multistage-Weibull model, which has the form

P(d,t) = 1 - exp[-(q0 + q1d + q2d2

 + ... + qkdk)*(t - t0)

z

]

where P(d,t) represents the probability of a tumor (or other response) by age t (in bioassay weeks)

for dose d (i.e., human equivalent exposure), and parameters z$1, t0$0, and qi$0 for i = 0, 1, ..., k,
84

where k = the number of dose groups - 1. The parameter t0 represents the time between when a

potentially fatal tumor becomes observable and when it causes death (see below). The analyses

were conducted using the computer software TOX_RISK version 5.2 (Crump, 2000), which is

based on Weibull models drawn from Krewski et al. (1983). Parameters are estimated using the

method of maximum likelihood. Note that it was not necessary to adjust the administered dose for

lifetime exposure prior to modeling, because the software program characterizes the tumor

incidence over time from which it provides an extrapolation to lifetime exposure.

Tumor types were categorized by tumor context as either fatal or incidental tumors, in

order to adjust appropriately for competing risks. Incidental tumors are those tumors thought not

to have caused the death of an animal, while fatal tumors are thought to have resulted in animal

death. For the rats, nasal cavity tumors were treated as fatal tumors unless observed at the terminal

sacrifice in which case they were considered incidental. Furthermore, these tumors were

considered rapidly fatal, and t0 was set equal to 0 as there were insufficient data to reliably

estimate t0 in any event. Tumors at all other sites were treated as incidental for the rats. These

determinations are consistent with the determination made by EPA for 1,3-butadiene (U.S. EPA,

2002b). The work of Portier et al. (1986) in analyzing tumor types in NTP historical controls

lends support to these tumor context assumptions. For the mice, there were more tumor types

observed than for the rats, and it was not clear which tumor type may have been most uniformly

the cause of death. It was not possible to carry out an animal by animal determination of cause of

death. Consequently, all of the significant female mouse tumors were considered incidental. 

Specific n-stage Weibull models were selected for the individual tumor types for each sex

based on the values of the log-likelihoods according to the strategy used by EPA (U.S.EPA,

2002b). If twice the difference in log-likelihoods was less than a chi-square with degrees of

freedom equal to the difference in the number of stages included in the models being compared,

the models were considered comparable and the most parsimonious model (i.e., the lowest-stage

model) was selected.

5.3.2.4. Inhalation Unit Risk

The results of applying quantal models to the Poly-3 adjusted tumor incidence data are

provided in Table 5-11. In several cases, the multistage model could not provide an adequate fit (p

> 0.1). The log-logistic model was applied in these cases. The model output is provided in

Appendix C2. Consistent with the Draft Guidelines for Carcinogen Risk Assessment (U.S.EPA,
85

1999), a point of departure near the lower end of the observed data was selected for linear

extrapolation to low doses. An inhalation unit risk for each tumor site was calculated by dividing

the BMR level by the corresponding BMCL. Estimated unit risks ranged from 0.039 (ppm)-1 to

4.8 (ppm)-1. The highest slope factor for each species/sex combination resulting from quantal

dose-response modeling corresponded to nasal cavity tumors.

The results of applying the multistage-Weibull data to the time-to-tumor data are

summarized in Table 5-12, and the model output and dose-response curves are provided in

Appendix C2. The maximum likelihood estimates of the BMDs and 95% lower bounds (BMDLs)

for 10% extra risk for each tumor are provided, consistent with the BMDS technical guidance

(U.S.EPA, 2000d). Currently, the TOX_RISK software does not provide estimates corresponding

to risks higher than 10%, so the unit risks were based on the BMDL10s. The highest slope factor

for each species/sex combination resulting from time-to-tumor modeling corresponded to nasal

cavity tumors. However, approximate points of departure can be estimated from the central

tendency risk estimate at the lower end of the observed data range for each tumor site and are

provided in Table 5-13. These are provided only for comparison, since an estimate of the upper

bound on risk is not available; these approximate risks follow the same patterns as the other unit

risks, with the nasal cavity tumors showing the highest risk.

Unit risks calculated using the time-to-tumor approach were similar to those calculated

using the quantal approach, within a factor of 3. Goodness of fit varied between the two

approaches, with fits from one model not uniformly better than the other. The highest unit risks

within each sex and species corresponded to nasal cavity tumors in all cases, with nasal cavity

tumors an order of magnitude higher in male and female rats than in female mice. Because there

did not appear to be substantial model dependence in the results, the highest unit risks were used to

develop the overall unit risk. The quantal dose-response curves for these two data sets are

provided in Appendix C2, Model Outputs C-9 and C-15. An inhalation unit risk for exposure to

1,2-dibromoethane is calculated by dividing the response rate of 0.87 (87%) by the BMCL87 for

nasal cavity tumors in male rats, or 0.87/ 0.18 ppm = 4.8 (ppm)-1. At 25o

C and standard pressure

(760 mm Hg), 1 ppm × (molecular wt )/24.5 mg/m3

. The molecular weight of 1,2-dibromoethane

is 188. Thus, one ppm is equivalent to 188/24.5 = 7.7 mg/m3

 of 1,2-dibromoethane. Hence, the

inhalation unit risk can be expressed as 4.8 (ppm)-1/7.7 [(mg/m3

)/ppm] . 0.6 (mg/m3)

-1.

This unit risk should not be used with exposures greater than 0.18 ppm, or 0.023 mg/m3

. Above

this level, the dose-response is not linear, and the modeled dose-response pattern should be used to
86

estimate risk.

This inhalation unit risk is approximately 3-fold higher than the inhalation unit risk of 0.22

(mg/m3

)

-1 listed previously on IRIS (U.S. EPA, 1988b). The use of the RfC methodology to

characterize human equivalent exposures in the nasal region contributes a 5-fold increase over the

previous unit risk, all else being equal. The changes in cancer risk assessment since that time

account for the remaining difference, primarily extrapolating linearly from a point within the

observed data rather than from a modeled estimate of 1 × 10-6 risk.

There are several areas of uncertainty. First, there is uncertainty associated with

extrapolating to low doses from relatively high responses in the rats, greater than 70% in the low

dose groups. These studies did continue for close to the full lifetime, however, unlike the oral

study. Second, there is some uncertainty involving the appropriate dose metric for some of the

respiratory tumors. For the results from both modeling approaches, the unit risks for the

respiratory sites are also expressed in terms of systemic toxicity rather than portal of entry effects,

that is, as if the observed toxicity occurred after absorption and systemic distribution of the

carcinogenic moiety. In the case of the alveolar/bronchiolar adenomas in female rats and mice,

there is some indication from the oral study that these tumors can occur after ingestion of 1,2-

dibromoethane, at least in the female mice. Following the RfC methodology, if systemic toxicity

were solely responsible for these tumors, then the unit risks for these sites should be about 2- to 3-

fold higher than if the tumors were due solely to portal of entry effects. There is no evidence that

the nasal cavity tumors would result from systemic toxicity.

Last, reliance on single tumor sites probably somewhat underestimates the carcinogenic

potential of 1,2-dibromoethane by the inhalation route. Using the same analysis that was applied

to the oral slope factors to consider total risk from multiple tumor sites (see section 5.3.1.4), the

combined risk of the significant tumors for male and female rats and for female mice was

considered. As with those analyses, these sums are approximate (see section 5.3.1.4 for details).

For the rats, the risks of nasal cavity tumors were clearly much larger than for the other sites, so it

is not surprising that the final outcome only increases to 5.0 (ppm)-1, which when converted to

units of mg/m3

 still rounds to 0.6 (mg/m3)

-1.

For the female rats, the sum of the five significant sites increases the unit risk for nasal

cavity tumors more than for the males, with a sum of 3.9 (ppm)-1 compared with 3.5 (ppm)-1 for

nasal cavity tumors alone. For the female mice, however, four of the six sites were very similar,
87

with respiratory (lung/bronchial or alveolar/bronchiolar) adenomas or carcinomas somewhat

lower. The resulting 95% UCL on the slope factor for all six sites was 0.86 (ppm)-1, almost three

times higher than the risk for nasal cavity tumors alone, but roughly a factor of six lower than the

unit risk based on male rat nasal cavity tumors.
88

Table 5-9. Observed and adjusted tumor incidence rates in rats and mice

exposed to 1,2-dibromoethane by inhalation

Tumor site

Incidence

adjustment

Administered concentration Trend test 

p-valued

0 ppm 10 ppm 40 ppm

Male rats

Nasal cavity tumorsa None (observed)

Poly-3

1/50

1/46

2.0%

2.2%

39/50

39/45

78.0%

86.6%

41/50 

41/43

82.0%

95.3% <0.001

Hemangiosarcoma None (observed)

Poly-3

0/50

0/46

0%

 0%

1/50

1/43

2.0%

2.2%

15/50 

15/28

30.0%

53.6% <0.001

Mesothelioma, tunica

vaginalis

None (observed)

Poly-3

1/50

1/46

2.0%

2.1%

8/50

8/43

16.3%

18.6%

25/50 

25/35

50.0%

71.4% <0.001

Female Rats

Nasal cavity tumorsb None (observed)

Poly-3

1/50

1/47

2.0%

2.1%

34/49

34/46

70.8%

73.9%

43/50

43/46

86.0%

93.5% <0.001

Hemangiosarcoma None (observed)

Poly-3

0/50

0/47

0%

 0%

 0/49

0/42

0%

 0%

5/50

5/26

10.0%

19.2% <0.001

Mammary

 fibroadenoma

None (observed)

Poly-3

4/50

4/47

8.0%

8.5%

29/49

29/46

59.2%

63.0%

24/50

24/34

48.0%

70.6% <0.001

Mammary

adenocarcinoma

None (observed)

Poly-3

1/50

1/47

2.0%

2.1%

0/49

0/42

0%

 0%

4/50

4/26

8.0%

15.4% 0.023

Alveolar/bronchiolar

adenoma/carcinoma

None (observed)

Poly-3

0/50

0/47

0%

 0%

0/49

0/42

0%

 0%

5/50

5/25

10.0%

20.0% <0.001

Female Mice

Nasal cavity tumorsc None (observed)

Poly-3

0/50

0/46

0%

 0%

0/50

0/38

0%

 0%

8/50

8/27

16.0%

29.6% <0.001

Hemangiosarcoma None (observed)

Poly-3

0/50

0/46

0%

0%

12/50

12/40

24.0%

30.0%

25/50

25/35

50.0%

71.4% <0.001

Alveolar/bronchiolar

adenoma/carcinoma

None (observed)

Poly-3

4/50

4/46

8.0%

8.7%

11/50

11/40

22.0%

27.5%

41/50

41/44

82.0%

93.2% <0.001

 Lung/bronchial

adenoma/carcinoma

None (observed)

Poly-3

0/50

0/46

0%

 0%

1/50

1/38

2.0%

2.6%

8/50

8/26

16.0%

30.8% <0.001

Fibrosarcoma None (observed)

Poly-3

0/50

0/46

0%

 0%

5/50

5/39

10.0%

12.8%

11/50

11/27

22.0%

40.7% <0.001

Mammary

adenocarcinoma

None (observed)

Poly-3

2/50

2/46

4.0%

 4.3%

14/50

14/40

28.0%

35.0%

9/50

9/27

18.0%

33.3% 0.001

a

 Adenoma, carcinoma, adenocarcinoma, adenomatous polyp, papillary adenoma, squamous cell carcinoma, or

squamous cell papilloma.

b

 Adenoma, carcinoma, adenocarcinoma, adenomatous polyp, papillary adenoma, papillary polyp, or squamous cell

carcinoma.

c

 Adenoma or carcinoma. d Cochran-Armitage test for trend, using the Poly-3 adjusted incidence data.

Source: NTP 1982.
89

Table 5-10: Summary of regional gas dose ratios for estimating human

equivalent exposures corresponding to respiratory tumors observed in

NTP (1982) inhalation bioassay 

Sex,

species

Body

weight,

kg

Minute

volumea,

L/min

Affected respiratory

regions

 Surface

areab

Regional

gas dose

ratioc

Human equivalent

continuousd

concentrations

Lowdose,

 ppm

Highdose,

ppm

Male

rats

0.30 0.21 Extra-thoracic (nasal cavity) 15.0 cm2 0.20 0.36 1.42

Female

rats

0.20 0.15 Extra-thoracic (nasal cavity)

Pulmonary

15.0 cm2

0.34 m2

0.14

1.73

0.25

3.1

0.99

12.3

Female

mice

0.035 0.041 Extra-thoracic (nasal cavity)

Tracheobronchial

Pulmonary

3.0 cm2

3.5 cm2

0.05 m2

0.20

2.7

3.2

0.36

4.86

5.8

1.42

19.2

22.7

a

 Minute volumes were estimated using the allometric equations provided in the RfC methodology document (U.S.

EPA, 1994b):

MVmouse: ln(MV) = 0.326 + 1.05 ln(BW)

MVrat: ln(MV) = -0.578 + 0.821 ln(BW)

b

 Surface areas provided in the RfC methodology document (U.S. EPA, 1994b). In addition, the corresponding surface

areas for humans:

Extra-thoracic (nasal cavity): 200 cm2

Tracheobronchial: 3,200 cm2

Pulmonary: 54 m2

c

 RGDR = (MVa/Sa)/(MVh/Sh), where 

RGDR = regional gas dose ratio for a specific area of the respiratory system

Mva = animal minute volume

Mvh = human minute volume (13.8 L/min)

Sa= surface area of the specified region of the animal respiratory system

Sh= surface area of the specified region of the human respiratory system

d

 Administered concentrations were low dose, 10 ppm, and high dose, 40 ppm. A continuous exposure adjustment was

included by multiplying by (5 days/7 days) × (6 hours/24 hours) = 0.178. Human equivalent

continuous concentrations were estimated by multiplying equivalent continuous exposures (not shown) by the regional

gas dose ratio. 
90

Table 5-11. Estimates of benchmark concentration (BMC), lower 95%

confidence limits (BMCL), and unit risks; using Poly-3 incidence ratesa,

for animals exposed by inhalation to 1,2-dibromoethane (NTP, 1982)

Sex,

species Tumor type

Point of departure Unit risk (ppm)-1

BMR

BMC,

ppm

BMCL,

ppm

Regional

respiratory

dosimetryc

Systemic

dosimetryd

Male

rats

Nasal tumors 87% 0.38 0.18 4.8 0.96

Hemangiosarcoma 10% 1.9 1.5 NR 0.067

Mesothelioma 20% 1.9 1.3 NR 0.15

Female

rats

Nasal tumors 70% 0.26 0.20 3.5 0.49

Alveolar/bronchiolar

adenoma/carcinoma

10% 6.6 3.4 0.029 0.051

Hemangiosarcoma 10% 3.9 2.0 NR 0.050

Mammary

fibroadenomab

55% 1.9 1.2 NR 0.46 

Mammary

adenocarcinoma

10% 5.7 2.6 NR 0.039

Female

mice

Nasal tumors 25% 0.96 0.73 0.34 0.068

Lung/bronchial

adenoma/carcinoma

10% 5.4 3.3 0.03 0.082

Alveolar/bronchiolar

adenoma/carcinoma

30% 6.0 4.8 0.062 0.20

Hemangiosarcoma 35% 1.8 1.4 NR 0.25

Fibrosarcoma 15% 1.7 1.1 NR 0.14

Mammary

adenocarcinomab

25% 2.1 1.3 NR 0.19

a

 Tumor incidence data (Poly-3 incidence rates in Table 5-9) were fit using the general form of the multistage

model: P(d) = 1 - exp(-q0 - q1d - ... -q6d6

), except where p-values are footnoted (see footnote b). b

 In cases where the multistage model did not provide an adequate fit (p<0.1), the log-logistic model was used:

P(d) = q0 + (1- q0 )/[1+exp(-a-b*ln(d)]. c

 Reported modeling results reflect RGDR dosimetry adjustments as summarized in Table 5-10. NR indicates that

regional respiratory dosimetry was not relevant for particular tumor sites. d

 Reported unit risks reflect use of human equivalent lifetime concentrations. For respiratory tract endpoints, unit

risks corresponding to systemic toxicity rather than portal of entry effects were estimated by multiplying the

RGDR-based unit risks by the corresponding RGDR adjustments.
91

Table 5-12. Estimates of benchmark concentration (BMC) associated with

an extra risk of 10%, lower 95% confidence limits (BMCL), and unit

risks; using multistage-Weibull time-to-tumor modelinga

, for animals

exposed by inhalation to 1,2-dibromoethane (NTP, 1982)

Sex, species Tumor type

Point of departure Unit riskc

 (ppm)-1

 BMC10,

 ppm

 BMCL10,

 ppm 

Regional

respiratory

dosimetryb

Systemic

dosimetryc

Male rats Nasal tumors 0.065 0.053 1.9 0.38

Hemangiosarcoma 3.1 2.3 NR 0.040

Mesothelioma 0.92 0.69 NR 0.14

Female rats Nasal tumors 0.057 0.046 2.2 0.31

Alveolar/ bronchial

adenoma/ carcinoma

1.7 0.64 0.16 0.27

Hemangiosarcoma 7.5 3.8 NR 0.026

Mammary fibroadenoma 0.042 0.030 NR 3.3

Mammary

adenocarcinoma

1.7 0.71 

 

NR 0.14

Female mice Nasal tumors 0.86 0.84 0.12 0.024

Alveolar/ bronchiolar

adenoma/

carcinoma

3.7 2.2 0.045 0.14

 Lung/bronchial

adenoma/ carcinoma

9.3 4.4 0.022 0.059

Hemangiosarcoma 0.69 0.052 NR 0.19

Fibrosarcoma 1.9 1.1 NR 0.090

Mammary

adenocarcinoma

2.2 1.2 

 NR 0.083

a

 Individual tumor incidence data (Appendix C-2) were fit using the multistage-Weibull model: 

 P(d) = 1 - exp[(-q0 - q1d - ... -q6d6

)tz]. b

 Reported modeling results reflect RGDR dosimetry adjustments as summarized in Table 5-10. NR indicates

that regional respiratory dosimetry was not relevant for particular tumor sites. c

 Reported unit risks reflect use of human equivalent lifetime concentrations.
92

Table 5-13. Approximate unit risks, using central tendency dose-response

estimates from multistage-Weibull time-to-tumor modeling, for animals

exposed by inhalation to 1,2-dibromoethane (NTP, 1982)

Sex, species Tumor type

Point of departure Central tendency 

unit risk,

 (ppm)-1 BMRa Low doseb

, ppm

Male Rats Nasal tumors 0.92 0.36 2.6

Hemangiosarcoma 0.03 1.8 0.017

Mesothelioma 0.21 1.8 0.12

Female rats Nasal tumors 0.82 0.36 2.3

Alveolar/ bronchiolar 

adenoma/ carcinoma

0.033 3.1 0.011

Hemangiosarcoma 0.026 1.8 0.014

Mammary fibroadenoma 0.73 1.8 0.41

Mammary adenocarcinoma 0.048 1.8 0.027

Female mice Nasal tumors 0.043 0.36 0.12

Alveolar/ bronchiolar 

adenoma/ carcinoma

0.084 5.8 0.014

 Lung/bronchial 

adenoma/ carcinoma

0.049 4.9 0.010

Hemangiosarcoma 0.31 1.8 0.17

Fibrosarcoma 0.088 1.8 0.049

Mammary adenocarcinoma 0.16 1.8 0.089

a

 Central tendency BMR estimated using time-to-tumor models referenced in Table 5-12. b

 Low dose (100 ppm) adjusted by site for sex- and species-specific RGDR dosimetry, as summarized in Table 5-

10.
93

6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF 

HAZARD AND DOSE RESPONSE

6.1. HUMAN HAZARD POTENTIAL

1,2-Dibromoethane is a colorless liquid that has a chloroform-like odor and evaporates

easily. It has limited solubility in water but is miscible and soluble in many organic solvents. 1,2-

Dibromoethane was used primarily as an anti-knock compound in leaded gasoline and also has

been used as a fumigant for grain, fruits, and soil. Today, it is more likely to be used as a solvent

in resins, gums, and waxes, and as a intermediate in dye and pharmaceutical manufacturing. Past

exposure from 1,2-dibromoethane was primarily from emissions and exhaust from vehicles using

leaded gasoline and from its use as a fumigant. However, with restrictions on the use of leaded

gasoline and limited fumigation practices, exposure to 1,2-dibromoethane has decreased.

It appears from both human and animal studies that 1,2-dibromoethane is rapidly absorbed

by the oral, inhalation, and dermal routes. Animal studies indicate that 1,2-dibromoethane is

metabolized by two pathways: oxidation by P450-monooxygenases and GSH conjugation

mediated by glutathione-S-transferase. 1,2-Dibromoethane is eliminated mainly in the urine as

mercapturic acid derivatives. However, a small amount of 1,2-dibromoethane is eliminated in the

expired air and feces.

No subchronic- or chronic-duration human studies were located concerning ingestion of

1,2-dibromoethane. Noncancer effects reported in experimental animals orally exposed to 1,2-

dibromoethane include weight gain depression, high mortality, hyperkeratosis and acanthosis of

the forestomach, liver and adrenal cortex degeneration, and testicular atrophy (NCI, 1978). In

mice, weight gain depression, high mortality, and testicular atrophy have been reported (NCI,

1978). All non-neoplastic changes reported following oral exposure to 1,2-dibromoethane have

occurred at doses that also produced cancer. In bulls, oral administration of 1,2-dibromoethane

produced adverse alterations in various sperm parameters and testicular histology (Amir and

Volcani, 1965, 1967). Although doses were lower, these studies were not selected for RfD

development because of the small numbers of animals and use of one exposure level and because

bulls are ruminants with a significantly different physiology. Moreover, an allometric adjustment
8

After allometric adjustment, the doses given to the NCI (1978) male rats were less than 2 times, and

therefore similar to, the doses given to the Amir and Volcani (1965, 1967) bulls (11 vs 21 mg/kg3/4/day). 

94

would result in a dose quite similar to those used in the NCI (1978) study.8 These bull studies,

however, provide supporting evidence for testicular effects of low-dose 1,2-dibromoethane.

In humans, inhalation exposure to 1,2-dibromoethane in the workplace has been reported to

cause adverse reproductive and fertility effects (Ratcliffe et al., 1987; Schrader et al., 1988; Wong

et al., 1979). Specifically, decreases in average sperm count, percentage of viable sperm, and

percentage of motile sperm have been documented following long-term exposure. Morphological

abnormalities in sperm, such as tapered heads, absent heads, and abnormal tails, have also been

reported following chronic exposure. Short-term exposures have been associated with sperm

abnormalities in workers exposed to 1,2-dibromoethane. After six weeks of exposure to 1,2-

dibromoethane, sperm velocity and semen volume were reported to decrease. Decreased

reproductive performance of occupationally exposed workers was assessed by the number of live

births to exposed workers’ wives. Poor exposure data and moderate-to-extensive exposure by the

dermal route limit the value of these findings for risk assessment purposes. Reproductive studies

in laboratory animals (Short et al., 1978) provide useful quantitative information for risk

assessment purposes but suffer from a lack of sperm quality and count measures.

In chronic animal studies, weight gain depression, high mortality, hepatic necrosis,

nephropathy, testicular atrophy, and degeneration of the adrenal cortex have only been reported in

rats and mice at exposures that also cause cancer. The results of subchronic inhalation studies

revealed weight gain depression, swelling of adrenocortical cells, decreases in thyroid follicle size,

and formation of megalocytic cells of the lining of bronchioles in rats and mice (NTP, 1982;

Nitschke et al., 1981; Reznik et al., 1980). In rats, relative liver and kidney weights, focal

epithelial hyperplasia of the nares, and diffuse respiratory hyperplasia have also been reported. 

Cancers have not been reported following subchronic-duration inhalation exposure to 1,2-

dibromoethane. 

There are no reports of cancer in humans associated with exposure to 1,2-dibromoethane. 

However, the human studies have serious limitations, such as poor exposure assessment and coexposure to other potential carcinogens. Oral exposure to 1,2-dibromoethane induces cancer of the

forestomach in rats and mice (NCI, 1978). The relevance of forestomach effects to humans has

been questioned, particularly for nongenotoxic chemicals whose mode of action is believed to

involve irritation and cell proliferation from long-term exposure ( Poet et al., 2003). While the
95

forestomach contains features, such as minimal vascularization and stratified squamous cells,

which result in a longer residence time of food-borne agents than is received by the oesophageal

tissue or the glandular stomach (Grice, 1988; Poet et al., 2003), effects in this organ are believed to

be relevant to 1,2-dibromoethane and other genotoxic chemicals that do not appear to require

precursor events (e.g., irritation) associated with long residence time to induce tumors. 

Hemangiosarcoma in male rats, hepatocellular carcinoma in female rats, and lung cancer in mice

were also reported following oral exposure to 1,2-dibromoethane (NCI, 1978). Chronic-duration

inhalation exposure produces tumors of the nasal cavity in rats and lung tumors in mice (NTP,

1982). Hemangiosarcoma, mesothelioma of the tunica vaginalis, mammary carcinoma, lung

adenoma, and fibrosarcoma have also been reported following long-term exposure to 1,2-

dibromoethane (NTP, 1982). 

There is also no evidence from human studies that 1,2-dibromoethane is genotoxic. 

Steenland et al. (1985, 1986) performed a cytogenetic examination on exposed workers to

investigate induction of sister chromatid exchanges and chromosomal aberrations in peripheral

lymphocytes and found no significant increase in either parameter. However, exposure

concentrations were low and may not have been capable of inducing chromosomal damage. In

contrast to human studies, there is strong evidence from in vitro and in vivo animal studies that

1,2-dibromoethane is genotoxic. 1,2-Dibromoethane is a direct-acting mutagen in bacteria. 1,2-

Dibromoethane was positive for S. typhimurium revertant strains TA1535, TA100, and TA98

(Barber et al., 1981) and induced point mutations in S. typhimurium strains TA1535 and TA100, S.

coelicolor, and A. nidulans (Carere and Morpurgo, 1981). 1,2-Dibromoethane has been shown to

induce chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells

(Ivett et al., 1989; Tan and Hsie, 1981; Brimer et al., 1982; Ballering et al., 1998; Graves et al.,

1996). 1,2-Dibromoethane has also been reported to induce gene mutations in two human

lymphoblastoid cell lines, AHH-1 and TK6 (Crespi et al., 1985), and sister chromatid exchanges

in human peripheral lymphocyte cultures (Tucker et al., 1984). In vivo, 1,2-dibromoethane

induced DNA damage in rats following oral administration (Kitchin and Brown, 1986, 1987;

Sasaki et al., 1998). Intraperitoneal administration of radiolabeled 1,2-dibromoethane has been

shown to bind DNA in the liver, kidney, stomach, and lung of rats and mice (Arfellini et al., 1984),

and S-[2-(N7

-guanyl)ethyl]glutathione has been identified as the major DNA adduct formed in rats

following treatment with 1,2-dibromoethane (Kim et al., 1990; Koga et al., 1986).

The genotoxicity of 1,2-dibromoethane is thought to be related to its conjugation with GSH

as catalyzed by glutathione-S-transferase, which results in the formation of an episulfonium ion

that can react with DNA to form S-[2-(N7

-guanyl)ethyl]glutathione DNA. 1,2-Dibromoethane has
96

been reported to cause DNA damage and UDS in rat hepatocytes and spermatocytes exposed both

in vitro and in vivo, and inhibition of cytochrome P-450-mediated oxidation in either cell type did

not inhibit UDS. However, depletion of cellular GSH inhibited the induction of UDS in both cell

types, which suggests that GSH conjugation and not P450 oxidation is responsible for the

genotoxic effects of 1,2-dibromoethane. Inhibition of hepatic mixed-function oxidases in vivo was

associated with positive UDS response to 1,2-dibromoethane in spermatocytes, but there was no

effect on 1,2-dibromoethane-induced UDS in hepatocytes.

1,2-Dibromoethane-induced cytotoxicity may be dependent on its metabolism by

cytochrome P450 and/or conjugation with GSH. Microsomal cytochrome P-450-dependent

oxidative metabolism of 1,2-dibromoethane produces the metabolite 2-bromoacetaldehyde. This

metabolite has been reported to cause lipid peroxidation and protein binding. Glutathione

conjugation may also contribute to cytotoxicity. Depletion of hepatic mitochondrial GSH by 1,2-

dibromoethane has been correlated with hepatotoxicity and perturbations in mitochondrial Ca2+

homeostasis. The results of in vitro and in vivo experiments suggest that the renal toxicity of 1,2-

dibromoethane may be due to its biotransformation by GSH conjugation followed by further

conversion in the kidney to highly reactive metabolites. It has been suggested that lipid

peroxidation may play a role in the 1,2-dibromoethane-induced pathogenesis of liver cell necrosis. 

The available evidence further supports a conclusion that 1,2-dibromoethane is a genotoxic

carcinogen. Under the Draft Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), 1,2-

dibromoethane is classified as “likely to be carcinogenic to humans” via both the oral and

inhalation routes of exposure based on strong evidence of carcinogenicity in animals and

inconclusive evidence of carcinogenicity in an exposed human population. Under the Guidelines

for Carcinogen Risk Assessment (U.S. EPA, 1986a), 1,2-dibromoethane would be classified as

Group B2 –Probable Human Carcinogen.

In conclusion, while the potential for human exposure to 1,2-dibromoethane is limited,

studies suggest that even low levels of 1,2-dibromoethane exposure can pose considerable health

risks. 1,2-Dibromoethane is rapidly absorbed by all potential routes of human exposure and is a

likely human carcinogen and reproductive toxicant. There is also some limited evidence for

neurobehavioral developmental effects caused by 1,2-dibromoethane as well as endocrine

disruption (based on effects on other endocrine organs as well as changes in hormone levels). As

is discussed in Chapter 5, the database associated with 1,2-dibromoethane’s potential to cause

effects on the developing fetus and newborn is limited. Additional research in this area could

increase the certainty of this assessment.
97

6.2. DOSE RESPONSE

An RfD of 9E-3 mg/kg-day was derived. It is based on liver, testicular, and adrenal effects

observed in male rats following chronic oral exposure. The RfD is supported by a benchmark dose

analysis of these effects and is based on a LOAEL of 27 mg/kg-day and application of an

uncertainty factor of 3000, which was reduced from an overall uncertainty factor of 10,000 (10 for

interspecies, 10 for intraspecies, 10 for LOAEL to NOAEL extrapolation, 10 for database

deficiency) in recognition of the lack of independence of the individual factors and that the

multiplication of four or five values of 10 is likely to yield unrealistically conservative RfCs

(Dourson and Stara, 1983; U.S. EPA, 1994, 2002). 

An RfC of 9E-3 mg/m3

 was derived based on induction of liver pathology in both male and

female rats using benchmark dose methodology in a lifetime inhalation bioassay (NTP, 1982). 

The RfC was calculated by application of uncertainty factors 3 for interspecies, 10 for intraspecies,

and 10 for database uncertainty to the BMDL(HEC) of 2.8 mg/m3

.

A cancer oral slope factor of 2 (mg/kg-day)-1 was calculated from the carcinogenicity

bioassay in male rats (NCI, 1978) using benchmark dose methodology. An inhalation cancer slope

factor estimate of 0.6 (mg/m3)

-1 was calculated from an inhalation carcinogenicity bioassay in male

rats (NTP 1982).

Confidence in the study utilized to derive the RfD and oral cancer slope factor is low to

medium. Although the critical study was of chronic duration and involved a large number of

animals, high mortality, close dose spacing, and the absence of a NOAEL made this study difficult

to assess. Confidence in the oral database is also considered to be medium. Although oral data on

reproductive/developmental effects are very limited, some indication of doses that might cause

these effects can be obtained from gavage studies in bulls and inhalation studies in rats and mice. 

The overall confidence in these oral benchmarks is considered to be low to medium. 

Confidence in the study used to derive the RfC and inhalation cancer slope factor is

medium. The NTP (1982) inhalation study was well designed, using an adequate number of

animals of both sexes, but was limited because of excessive mortality in the high-dose groups of

both species, moderate mortality in low-dose female mice, and excessive mortality in male mice

not related to 1,2-dibromoethane exposure. Confidence in the inhalation database is medium. 
98

There are systemic inhalation toxicity studies in two species, one-generation (but no

multigeneration) reproductive study, and developmental toxicity studies in two species that did not

cover the full period of gestation. Although animal studies have shown that

reproductive/developmental effects in females are likely to occur only at doses inducing maternal

toxicity, the possibility remains that sperm quality may be adversely affected at lower doses. The

overall confidence in these inhalation benchmarks is medium.
99

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APPENDIX A. External Peer Review–Summary of Comments and Disposition 

The Toxicological Review that supports the IRIS file for 1,2-dibromoethane has 

undergone both internal peer review performed by scientists within EPA or other federal 

agencies and a more formal external peer review performed by scientists chosen by EPA’s 

contractor in accordance with U.S. EPA (1994c). Comments made by the internal reviewers 

were addressed prior to submitting the documents for external peer review and are not part of 

this appendix. Public comments also were read and carefully considered. The three external 

peer reviewers were tasked with providing written answers to general questions on the overall 

assessment and on chemical-specific questions in areas of scientific controversy or uncertainty. 

A summary of comments made by the external reviewers and EPA’s response to these comments 

follows. 

General Charge Question 1. Are you aware of any other data/studies that are relevant (i.e., 

useful for the hazard identification or dose-response assessment) for the assessment of the 

adverse health effects, both cancer and noncancer, of this chemical? 

Comment: Reviewers identified specific studies (see below) addressing carcinogenicity that 

they felt had not been adequately considered in the assessment. 

A/J mice studies and other secondary oncogenicity studies: Stoner et al. (1986), Adkins et al 

(1986), and Van Duuren et al. (1979) studies should be considered. 

Response: We agree that the studies identified [Stoner et al. (1986), Adkins et al (1986), Van 

Duuren et al. (1979)] are relevant. They have been summarized and considered in the weight of 

evidence. 

Chronic bioassay: While the Van Duuren (1985) study was described in the assessment, one 

reviewer felt it had not been adequately considered in the dose-response assessment. 

Response: We agree with the comment, and have more thoroughly characterized the consistency 

of this drinking water study with the oral gavage study. In the case of the mouse oral gavage 

study, the change in dosing regimen did not result in two similar dose levels, however, as with 

the rats. Drinking water is a more realistic exposure medium, though, so, although this study 

used much higher dose levels and reported less complete tumor incidence data (no times of 

observation and no information concerning which animals had multiple tumors), it should be 

considered more thoroughly. 

Epidemiology studies: Sweeney et al. (1986) and Turner and Barry (1979) should be 

considered. 

Response: EPA agrees that Sweeney et al. (1986) should be included in the document and it is 

included in Section 4 with a qualitative discussion of the limitations of the study and its use in 

the quantitative assessment of the carcinogenicity of this chemical. There are several limitations 

A-1
to this study. Levels of 1,2-dibromoethane were not reported, except that they were below 

OSHA standards (20 ppm) and NIOSH recommended standards. 1,2-Dibromoethane was 

apparently added to tetraethyl lead to reduce the deposition of inorganic lead on engine parts and 

was used continuously because of the chemical plant’s start-up, so workers were exposed from 

the beginning of the study period, however. Another limitation of the study was lack of a more 

comparable control group, unexposed workers. This study neither establishes nor dismisses an 

association between occupational 1,2-dibromoethane exposure and carcinogenicity. 

Turner and Barry (1979) came to the attention of one reviewer as a secondary citation. As 

indicated by the same reviewer, this study had major limitations, including lack of information 

concerning duration and magnitude of exposure, number of workers studied, and length of time 

elapsing since first exposure, which make the study inconclusive and of little or no value to this 

assessment. However, its contributions and limitations have been summarized. 

PBPK studies: Hissink et al. (2000) and Ploemen et al. (1997) should be considered. 

Response: EPA agrees and the studies identified [Hissink et al. (2000) and Ploemen et al. 

(1997)] have been summarized and considered in the document for their relevance in 

characterizing human relevance and potential use for route-to-route extrapolation and for the 

estimation of human equivalent concentrations from laboratory animal studies. Given the 

limitations of these studies, however (see Section 3.5), it would not be appropriate to use the 

Hissink et al. (2000) model at this time for quantitative (route-to-route or animal-to-human) 

extrapolations. However, the Hissink et al. (2000) report and model provide useful information 

regarding the mode of action of 1,2-dibromoethane, particularly with respect to the cancer 

effects of 1,2-dibromoethane. 

Comment: One reviewer suggested that EPA should consider requiring additional studies of 

(presumably pesticide) registrants to characterize the dose-response for developmental 

neurotoxicity (adverse behavioral effects) and the endocrine disruptive potential of 1,2-

dibromoethane. 

Response: Additional studies in these areas may help to improve the certainty of the RfC and 

RfD. The extent to which additional studies in these areas would benefit the 1,2-dibromoethane 

risk assessment is addressed in Section 6 of the EDB IRIS toxicological review document. 

General Charge Question 2. For the RfD and RfC, has the most appropriate critical effect been 

chosen (i.e., that adverse effect appearing first in a dose-response continuum)? For the cancer 

assessment, are the tumors observed biologically significant? relevant to human health? Points 

relevant to this determination include whether or not the choice follows from the dose-response 

assessment, whether the effect is considered adverse, and if the effect (including tumors observed 

in the cancer assessment) and the species in which it is observed is a valid model for humans. 

Comment: With respect to the RfD, one reviewer questioned whether all co-critical effects were 

identified and discussed. Another reviewer did not feel that the Agency had adequately justified 

A-2
not using a benchmark dose approach on the oral data. 

Response: A discussion of co-critical endpoints, including liver, testicular, and adrenal cortical 

effects has been added to Section 5.1. A benchmark dose analysis of these data was performed 

and is discussed in Section 5.1.1. Details are included in Appendix B (Table B-1 and associate 

output files) of the toxicological review. The RfD estimates that result from the BMD (5E-3 

mg/kg/day) and NOAEL/LOAEL (9E-3 mg/kg/day) assessment approaches are very similar. 

Because of high mortality and unusual dosing in the high dose group, there is a great deal of 

uncertainty associated with these BMD results and they are only provided in support of the 

NOAEL/LOAEL approach. 

Comment: With respect to the RfC, one reviewer suggested that all co-critical effects be 

considered and analyzed via the benchmark dose approach. 

Response: A benchmark dose analysis of all co-critical endpoints, including liver, testicular, 

adrenal cortical, splenic, and nasal effects, has been added to Section 5.2. The details of this 

analysis are provided in Appendix B of the toxicological review. 

Comment: One reviewer pointed out that 1,2-dibromoethane is most likely a Category 2 gas, 

and the portal of entry effects should be reevaluated accordingly. 

Response: 1,2-Dibromoethane is relatively insoluble in water and demonstrates systemic 

toxicity, although there was some respiratory tract toxicity that may or may not be considered 

portal of entry effects. EPA agrees that dosimetry for 1,2-dibromoethane’s effects at points of 

contact should take into account EPA’s RfC Methodology (U.S.EPA, 1994b) for Category 2 

gases. Following the RfC Methodology, the respiratory tract effects were assessed alternatively 

as portal of entry effects or systemic effects while the rest of the effects were assessed as 

systemic effects. This approach has been incorporated into the assessment (e.g., Table 5-4 of the 

toxicological review and Table 1 of the summary document and associate descriptive text), and 

the new human equivalent concentration (HEC) estimates have resulted in the critical effect for 

the RfC changing from liver necrosis to nasal inflammation. 

Comment: Two reviewers requested a better rationale for the use of forestomach tumors in the 

cancer risk assessment. 

Response: The Agency believes that forestomach tumors caused by genotoxic carcinogens such 

as 1,2-dibromoethane are more applicable to humans than forestomach tumors caused by 

nongenotoxic mechanisms that require cellular damage, turnover, and a long residence time of 

the chemical in the forestomach. Additional rationale/explanation of the use of forestomach 

tumors for the 1,2-dibromoethane assessment and their applicability to humans has been added 

to Sections 4.6, 6, and other sections of the toxicological review. 

General Charge Question 3. Have the noncancer and cancer assessments been based on the 

most appropriate studies? These studies should present the critical effect/cancer (tumors or 

A-3
appropriate precursor) in the clearest dose-response relationship. If not, what other study (or 

studies) should be chosen and why? 

Comment: All reviewers felt that the appropriate studies were chosen. 

General Charge Question 4. In the IRIS Summary document, studies included in the RfD and 

RfC under the heading "Supporting/Additional Studies" are meant to lend scientific justification 

for the designation of critical effect by including any relevant pathogenesis in humans, any 

applicable mechanistic information, any evidence corroborative of the critical effect, or to 

establish the comprehensiveness of the database with respect to various endpoints (such as 

reproductive/developmental toxicity studies). Should other studies be included under the 

"Supporting/Additional" category? Should some studies be removed? 

Comment: One reviewer felt that the summary document was too short and needed more detail 

to support the choice of study, species, sex, and critical effect for both the RfC and RfD. 

Response: Additional detail and supporting documentation has been added to the summary 

document. 

General Charge Question 5. For the noncancer assessments, are there other data that should 

be considered in developing the uncertainty factors or the modifying factor? Do the data 

support the use of different values than those proposed? 

Comment: For the RfD, the reviewers agreed with the uncertainty factors that were applied, but 

one reviewer disagreed with the rational for the 3-fold database uncertainty factor. This 

reviewer pointed out that the lack of oral reproductive and developmental studies should be 

stressed as a primary basis for this UF. 

Response: The Agency agrees that the rationale for the RfD database UF should include the lack 

of oral reproductive and developmental toxicity studies, and it has been revised in both Chapter 5 

of the toxicological review and Section I.A.3. of the IRIS summary document to take into 

account the reviewer’s comments. In fact, the RfD database UF has been increased to 10 to 

account for this uncertainty and the problems with the critical study associated with the high 

mortality and odd dosing regimen of the high-dose group. 

Comment: For the RfC, two reviewers questioned the lack of a database UF and one reviewer 

questioned the rationale used for the application of an effect level extrapolation factor (ELF, 

comparable to a LOAEL to NOAEL UF) to the BMDL10 point of departure. 

Response: In the external review draft of this assessment, the Agency did not apply a database 

UF, but did apply an ELF. After considering the reviewer comments, the Agency agrees that a 

database uncertainty factor is warranted due to the lack of any multigenerational reproductive 

toxicity studies given the genotoxicity of this compound and the spermatotoxicity concerns. 

Given that the merits and approach for the application of an ELF are still under discussion within 

A-4
the Agency and the point of departure in this case is the lower bound 95% confidence limit on 

the dose that causes a 10% increase in a minimal effect, the Agency has determined that the 

application of an ELF is not warranted in this case. The overall UF remains 300 but is now 

based on 10 for UFH, 3 for UFA, and 10 for UFD. 

General Charge Question 6. Do the confidence statements and weight-of-evidence statements 

present a clear rationale and accurately reflect the utility of the studies chosen, the relevancy of 

the effects (cancer and noncancer) to humans, and the comprehensiveness of the database? Do 

these statements make sufficiently apparent all the underlying assumptions and limitations of 

these assessments? If not, what needs to be added? 

Comment: Two reviewers felt that the confidence statements should be improved for both the 

RfD and RfC and that lower confidence should be placed on the RfD. One reviewer felt that the 

confidence discussions should be included in Section 6 of the toxicological review. 

Response: The Agency generally agreed with the reviewer comments, and the confidence 

statements have been revised and expanded accordingly. 

Specific Charge Question 1. Regarding the RfD and RfC 

(a) Is the Agency justified in not making use of the bull studies of sperm effects to 

quantify noncancer risk? 

Comment: All reviewers agreed that the bull studies should not be used to quantify human risk, 

citing the small sample size and differences in physiology (including absorption and metabolism) 

between bulls and humans. One reviewer felt that the latter reason was more valid than the 

former because of the consistent adverse response observed in these studies. 

Response: The text in Sections 4.3.2 and 6 has been modified to emphasize the physiological 

differences between bulls and humans as the primary reason these studies were not used as the 

basis for the RfD. 

(b) Is liver necrosis an appropriate noncancer endpoint for derivation of an RfC? 

Comment: All reviewers felt that liver necrosis was an appropriate endpoint, but one reviewer 

suggested that the nasal inflammation endpoint in mice was also appropriate and might result in 

a lower value if the RfC were derived using the method described in EPA (1994b) for calculating 

HEC values for category 1 gases. 

Response: The current EPA practice is to perform “endpoint specific” HEC calculations. In 

other words, HEC values are calculated using EPA (1994b) methods for category 1 gases for 

portal-of-entry effects and category 3 methods for systemic effects. The HEC for nasal 

inflammation effects was originally calculated using the method described for category 3 gases. 

When the HEC was recalculated using the method for category 1 gases, the resultant HEC value 

A-5
was lower than the liver necrosis HEC value and was thereby used to derive the revised RfC of 

9E-3 mg/m3

. 

Specific Charge Question 2. Regarding the cancer assessment 

(a) Were the adjustments made to account for early tumor formation and mortality 

adequate and clear? 

Comment: Two reviewers noted that the cancer dose-response modeling was carried out using a 

nonstandard EPA method. 

Response: An interim approach that approximated the multistage-Weibull model has been 

deleted. The cancer dose-response modeling was carried out using the multistage-Weibull model 

for time-to-tumor. These results are presented in parallel with the results from the survivaladjusted tumor incidences. Upon further consideration, the multistage-Weibull model appears 

not to be suitable for use with the oral data because of the unusual dosing schedule that was 

used; the multistage-Weibull model currently available can only handle a single level of 

exposure per group when dose rate is an issue. The multistage-Weibull is still superior to the 

multistage model when survival has been differentially impacted, leading to competing causes of 

death confounding the response patterns, and when tumors occur earlier with increasing 

exposure, as was stated in the document. A more transparent explanation supporting the use of 

the multistage-Weibull model has been added. The output from the multistage model for all 

cancer dose-response analyses has also been added. 

(b) Was it appropriate to attempt a low dose extrapolation from the high tumor incidence 

estimates obtained after the lifetime extrapolation approach? 

Comment: All reviewers agreed that low-dose extrapolation was appropriate and that the linear 

approach should be used. 

(c) Was the use of forestomach tumors adequately justified given the absence of this 

organ in humans? 

Comment: Two reviewers agreed that the use of forestomach tumors was appropriate. One 

reviewer indicated that use of forestomach tumors was questionable because the NCI study was a 

gavage study and the tumors could have been by [long-term contact and] irritation that would not 

be relevant to humans. 

Response: The rationale for using the forestomach tumors has been enhanced in the text of the 

toxicological review in Sections 4.6, 5, and 6. Because EDB is genotoxic, the occurrence of 

these tumors may not depend on irritation and cell damage caused by long retention times in the 

forestomach compartment of rodents (an argument that has been made for lack of relevancy to 

humans). Thus, it is felt that these tumors must be considered. Some expert consultation had led 

to the conclusion that the forestomach tumors should be treated as incidental since it was not 

A-6
clear that death had been caused by the tumor and not some other more acute lesion. After more 

review, it appears that the forestomach tumors should be treated as the most likely cause of death 

for all animals who had them in the oral study, except those whose tumors were only detected at 

the terminal sacrifice. The other tumor types in the oral study have now been taken to be 

incidental, although in the few early deaths where there were no forestomach tumors some of 

these may have been the cause of death. 

The discussion of forestomach tumors in the weight-of-evidence section (Section 4.6) has been 

expanded to include the following discussion: 

The relevance of forestomach effects to humans has been questioned, particularly 

for nongenotoxic chemicals whose mode of action is believed to involve irritation 

and cell proliferation from long-term exposure (Poet et al., 2003). It is true that 

the forestomach is not present in humans and contains features, such as minimal 

vascularization and stratified squamous cells, that result in a longer residence time 

of food-borne agents than is received by comparable human organs such as the 

oesophagus and the glandular stomach (Grice, 1988; Poet et al., 2003). In this 

case, however, effects in this organ are believed to be of potential relevance to 

humans because 1,2-dibromoethane and other genotoxic chemicals do not appear 

to require precursor events (e.g., irritation) associated with long residence time to 

induce these kinds of tumors. 1,2-Dibromoethane does not appear to cause 

significant irritation in the forestomach and was reported to induce forestomach 

tumors after just 168 days of exposure (NCI, 1978). 

Other 

Comment: In several areas of the noncancer and cancer portions of the assessment, reviewers 

noted instances of tables being mislabeled or missing. They suggested adding tables or adding 

information to existing tables in order to summarize study information (study characteristics, 

results, statistical significance). Inconsistent interpretation of observed effects was also noted. 

Numerous instances were identified where additional study information would be useful. 

Response: Inconsistencies in the document have been corrected, and the requested information 

has been added to the text and in additional tables. 

A-7
APPENDIX B. BMDS Analyses of Noncancer Endpoints 

Table B-1. BMDS analysis of NCI (1978) in support of RFD 

Model 

Peliosis in male rats 

(see pp. B-2 to B-4)a 

Testicular atrophy in male 

rats 

(see pp. B-5 to B-8)a 

Adrenal cortical 

degeneration in male rat 

(see pp. B-9 to B-11)a 

No dose 

adjustment 

TWA dose 

adjustment 

No dose 

adjustment 

TWA dose 

adjustment 

No dose 

adjustment 

TWA dose 

adjustment 

Multistage Power 

BMD10 

BMDL10 

AIC 

p-value 

1 

17.0924 

11.9529 

80.9598 

0.9119 

6 

32.3459 

9.12312 

80.7837 

0.9964 

1 

11.5101 

8.68059 

106.298 

0.9389 

7 

31.3928 

6.77996 

106.182 

0.9958 

1 

15.9817 

11.4453 

92.4547 

0.6547 

3 

26.1145 

8.46243 

91.6386 

0.9878 

Weibull BMD10 

BMDL10 

AIC 

p-value 

17.0924 

11.9529 

80.9598 

0.9119 

32.8565 

9.12815 

82.7764 

1.0000 

11.5101 

8.68059 

106.298 

0.9389 

31.8256 

6.78526 

108.173 

0.9999 

15.9817 

11.4453 

92.4547 

0.6547 

28.6819 

8.47521 

93.614 

1.0000 

Gamma BMD10 

BMDL10 

AIC 

p-value 

17.0924 

11.9529 

80.9598 

0.9119 

32.6612 

9.1141 

80.7968 

0.9898 

11.5101 

8.68059 

106.298 

0.9389 

30.2683 

6.65175 

106.403 

0.8918 

15.9817 

11.4453 

92.4547 

0.6547 

29.5879 

8.47521 

93.614 

1.0000 

Logistic BMD10 

BMDL10 

AIC 

p-value 

34.7812 

26.6526 

86.6093 

0.1038 

32.8668 

21.2288 

82.7831 

0.9521 

26.2594 

20.6013 

113.248 

0.0614 

31.9776 

18.675 

108.175 

0.9754 

33.2869 

25.5276 

98.8978 

0.0540 

30.205 

20.0266 

93.6949 

0.8137 

LogLogist BMD10 

BMDL10 

AIC 

p-value 

14.89 

9.59883 

80.8128 

0.9820 

33.2451 

7.65899 

82.7764 

1.0000 

9.88164 

6.19692 

108.173 

1.0000 

32.5999 

5.29211 

108.173 

1.0000 

13.6897 

9.05438 

92.0322 

0.8114 

29.3368 

6.96311 

93.614 

1.0000 

Probit BMD10 

BMDL10 

AIC 

p-value 

32.6319 

25.0429 

86.1626 

0.1193 

33.1771 

19.6937 

82.7764 

0.9989 

24.7944 

19.5476 

112.678 

0.0727 

32.4969 

17.0531 

108.173 

0.9999 

31.1452 

23.9958 

98.4693 

0.0604 

29.4539 

18.6165 

93.6245 

0.9338 

LogProbit BMD10 

BMDL10 

AIC 

p-value 

26.0742 

19.937 

81.8126 

0.5923 

33.6301 

15.3227 

82.7764 

1.0000 

19.5799 

15.4431 

106.87 

0.7020 

33.0559 

12.0592 

108.173 

1.0000 

24.5429 

19.063 

93.8791 

0.3186 

29.9603 

14.5032 

93.614 

1.0000 

First occurrence 

of effect (weeks)b 

Low dose - 39 

High dose - 36 

Low dose - 38 

High dose - 15 

Low dose - 41 

High dose - 35 

BMDL10 (mg/m3

) 9.59883 9.12312 8.68059 6.77996 9.05438 8.46243 a The output file for the selected model (usually that which resulted in the lowest AIC) is included in this Appendix.

b An attempt was made account for early mortality. In general, rats that died before the first occurrence of the effect 

(see Appendix C) were excluded from the analysis of that effect. However, 13 rats that died at 15 weeks without 

testicular atrophy were excluded from the analysis even though this effect was observed in 5 rats at that time. 

B-1
Output B-1. Peliosis in male rats 

Multistage Model with 0.95 Confidence Level 

0.5

BMDL BMD

Multistage 

Fraction Affected 0.4

0.3

0.2

0.1

0

0 5 10 15 20 25 30 35 40 45 

dose 

14:26 02/12 2004 

==================================================================== 

Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $

Input Data File: F:\BMDS\DATA\EDB\MALERATORAL\PMULT.(d)

Gnuplot Plotting File: F:\BMDS\DATA\EDB\MALERATORAL\PMULT.plt

Thu Feb 12 09:44:29 2004 

==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2-beta3*dose^3-beta4*dose^4-beta5*dose^5-beta6*dose^6)] 

The parameter betas are restricted to be positive 

Dependent variable = Peliosis

Independent variable = Dose 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 7

Total number of specified parameters = 0

Degree of polynomial = 6

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

B-2 
 Beta(1) = 0 

Beta(2) = 0 

Beta(3) = 0 

Beta(4) = 0 

Beta(5) = 0 

Beta(6) = 0 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(1) -Beta(2) -Beta(3)

-Beta(4) -Beta(5) have been estimated at a boundary point, or have been specified by the

user, and do not appear in the correlation matrix ) 

Beta(6) 

Beta(6) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0 NA 

Beta(2) 0 NA 

Beta(3) 0 NA 

Beta(4) 0 NA 

Beta(5) 0 NA 

Beta(6) 9.19938e-011 3.90849e-011 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-39.3882 

Deviance Test DF P-value 

Fitted model -39.3918 0.00729548 2 0.9964 

Reduced model -45.6631 12.5499 2 0.001883 

AIC: 80.7837 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 20 0.000 

i: 2 

38.0000 0.2419 10.161 10 42 -0.021 

i: 3 

41.0000 0.3540 8.850 9 25 0.026 

Chi-square = 0.01 DF = 2 P-value = 0.9964 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 32.3459 

BMDL = 9.12312 

B-3
Output B-2. Testicular atrophy in male rats 

Multistage Model with 0.95 Confidence Level 

0.7

0.6

BMDL BMD

Multistage 

Fraction Affected 0.5

0.4

0.3

0.2

0.1

0

0 5 10 15 20 25 30 35 40 45 

dose 

17:05 02/12 2004 

==================================================================== 

Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $

Input Data File: F:\BMDS\DATA\EDB\MALERATORAL\TDMULT.(d)

Gnuplot Plotting File: F:\BMDS\DATA\EDB\MALERATORAL\TDMULT.plt

Thu Feb 12 09:32:35 2004 

==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2-beta3*dose^3-beta4*dose^4-beta5*dose^5-beta6*dose^6-beta7*dose^7)] 

The parameter betas are restricted to be positive 

Dependent variable = TD

Independent variable = Dose 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 8

Total number of specified parameters = 0

Degree of polynomial = 7

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-4 
 Default Initial Parameter Values 

Background = 2.04281e-014

Beta(1) = 0 

Beta(2) = 0 

Beta(3) = 0 

Beta(4) = 0 

Beta(5) = 0 

Beta(6) = 0 

Beta(7) = 0 

**** WARNING: Completion code = -4. Optimum not found. Trying new starting pont  

** ** WARNING 0: Completion code = -4 trying new start  

** ** WARNING 1: Completion code = -4 trying new start  

** ** WARNING 2: Completion code = -4 trying new start  

** ** WARNING 3: Completion code = -4 trying new start  

** ** WARNING 4: Completion code = -4 trying new start  

** ** WARNING 5: Completion code = -4 trying new start  

** ** WARNING 6: Completion code = -4 trying new start  

** ** WARNING 7: Completion code = -4 trying new start  

** ** WARNING 8: Completion code = -4 trying new start  

** ** WARNING 9: Completion code = -4 trying new start  

Asymptotic Correlation Matrix of Parameter Estimates 

( ** * The model parameter(s) -Background -Beta(1) -Beta(2) -Beta(3)

-Beta(4) -Beta(5) -Beta(6)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(7) 

Beta(7) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0 NA 

Beta(2) 0 NA 

Beta(3) 0 NA 

Beta(4) 0 NA 

Beta(5) 0 NA 

Beta(6) 0 NA 

Beta(7) 3.50648e-012 9.6754e-013 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-52.0865 

Deviance Test DF P-value 

Fitted model -52.0908 0.00849527 2 0.9958 

Reduced model -62.2989 20.4248 2 <.0001 

AIC: 106.182 

B-5
 Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 

i: 2 

38.0000 0.3305 14.211 

i: 3 

41.0000 0.4949 17.815 

Chi-square = 0.01 DF = 2 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 31.3928 

BMDL = 6.77996 

0 20 0.000 

14 43 -0.022 

18 36 0.021 

P-value = 0.9958 

B-6
Output B-3. Adrenal cortical degeneration in male rats 

Multistage Model with 0.95 Confidence Level 

0.5

BMDL BMD

Multistage 

Fraction Affected 0.4

0.3

0.2

0.1

0

0 5 10 15 20 25 30 35 40 45 

dose 

17:18 02/12 2004 

==================================================================== 

Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $

Input Data File: F:\BMDS\DATA\EDB\MALERATORAL\TDMULT.(d)

Gnuplot Plotting File: F:\BMDS\DATA\EDB\MALERATORAL\TDMULT.plt

Thu Feb 12 09:08:13 2004 

==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

Observation # < parameter # for Multistage model.

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2-beta3*dose^3)] 

The parameter betas are restricted to be positive 

Dependent variable = ACD

Independent variable = Dose 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 4

Total number of specified parameters = 0

Degree of polynomial = 3

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-7 
 Default Initial Parameter Values 

Background = 0 

Beta(1) = 0 

Beta(2) = 0 

Beta(3) = 6.04978e-006 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(1) -Beta(2)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(3) 

Beta(3) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0 NA 

Beta(2) 0 NA 

Beta(3) 5.91603e-006 2.31258e-006 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-44.807 

Deviance Test DF P-value 

Fitted model -44.8193 0.0246029 2 0.9878 

Reduced model -51.1468 12.6797 2 0.001765 

AIC: 91.6386 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 20 0.000 

i: 2 

38.0000 0.2772 13.306 13 48 -0.032 

i: 3 

41.0000 0.3348 8.706 9 26 0.051 

Chi-square = 0.02 DF = 2 P-value = 0.9878 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 26.1145 

BMDL = 8.46243 

B-8
Table B-2. BMDS analysis of NTP (1982) study in support of RfC 

development 

Model 

Male rats 

(see pp. B-2 to B-9)

a 

Female rats 

(see pp. B-10 to B-17)

a 

Female mice 

(see pp. B-18 to B-25)

a 

Hepatic 

necrosis 

(mg/m3) 

Testicular 

degeneration 

(mg/m3) 

Hepatic 

necrosis 

(mg/m3) 

Adrenal 

cortical 

degeneration 

(mg/m3) 

Retinal 

atrophy 

(mg/m3) 

Splenic 

hematopoiesis 

(mg/m3) 

Nasal 

inflammation 

(mg/m3) 

Multistage Degree 

AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

2 

125.893 

Undefined 

91.71/46.99 

53.26/25.93 

1 

130.016 

0.1750 

64.98/31.64 

46.00/22.4 

1 

100.267 

0.3801 

127.3/46.99 

80.38/25.93 

1 

127.524 

0.8796 

133.7/65.07 

76.83/37.40 

1 

105.441 

0.0026 

Ind 

Ind 

2 

109.213 

0.3972 

69.61/33.89 

50.53/24.60 

1 

97.8497 

0.7308 

69.07/33.63 

50.11/24.40 

Weibull AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

Gamma AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

Logistic AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

LogLogist AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

Probit AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

LogProbit AIC 

p-value 

BMD10/BMD05 

BMDL10/BMDL05 

First occurrence of 

effect (weeks)

b 

BMDL10/BMDL05 

125.893 

Undefined 

90.75/48.97 

53.26/25.93 

130.016 

0.1750 

64.98/31.64 

46.00/22.4 

101.438 

Undefined 

180.9/48.97 

86.16/25.93 

127.524 

0.8796 

133.7/65.07 

76.83/37.40 

105.441 

0.0026 

Ind 

Ind 

109.213 

0.3972 

69.61/33.89 

50.53/24.60 

99.1781 

1.0000 

92.05/53.15 

52.20/25.41 

125.893 

Undefined 

90.51/49.38 

53.26/25.93 

130.016 

0.1750 

64.98/31.64 

46.00/22.4 

101.438 

Undefined 

176.8/49.38 

86.16/25.93 

127.524 

0.8796 

133.7/65.07 

76.83/37.40 

107.847 

Undefined 

Ind 

Ind 

109.213 

0.3972 

69.61/33.89 

50.53/24.60 

99.1781 

1.0000 

91.60/53.87 

52.20/25.41 

124.454 

0.4584 

142.0/85.93 

114.0/66.07 

134.001 

0.0228 

Ind 

Ind 

99.4539 

0.9009 

187.7/85.93 

148.8/66.07 

127.741 

0.6239 

180.2/102.8 

130.6/73.98 

105.579 

0.0029 

Ind 

Ind 

117.737 

0.0136 

Ind 

Ind 

102.199 

0.1525 

161.5/109.5 

129.6/80.51 

125.893 

Undefined 

89.86/50.56 

44.74/21.19 

129.198 

0.3300 

53.26/25.23 

35.07/16.61 

101.438 

Undefined 

177.4/50.56 

80.26/21.19 

127.506 

0.9452 

124.8/59.13 

66.50/31.50 

105.41 

0.0025 

Ind 

Ind 

108.411 

0.6274 

59.55/28.21 

40.25/19.06 

99.1781 

1.0000 

90.94/54.76 

46.31/21.94 

124.302 

0.5248 

131.8/77.79 

105.3/60.04 

133.606 

0.0266 

Ind 

Ind 

99.4839 

0.8311 

177.4/77.79 

138.2/60.04 

127.703 

0.6527 

173.3/96.77 

122.9/68.47 

105.565 

0.0028 

Ind 

Ind 

117.25 

0.0156 

Ind 

Ind 

101.717 

0.1871 

148.2/98.3 

118.8/72.45 

124.557 

0.4091 

120.4/83.76 

87.37/60.75 

134.738 

0.0102 

Ind 

Ind 

99.4453 

0.9336 

172.4/83.76 

122.0/60.75 

128.174 

0.4103 

196.3/136.5 

126.9/88.22 

107.847 

Undefined 

Ind 

Ind 

117.94 

0.0034 

Ind 

Ind 

97.7045 

0.7543 

102.2/71.06 

80.11/55.71 

Low dose - 7 

High dose - 53 

Low dose - 7 

High dose - 50 

Low dose - 13 

High dose - 67 

Low dose - 13 

High dose - 63 

Low dose - 52 

High dose - 63 

105.3/60.04 35.07/16.61 122.0/60.75 66.50/31.50 NA 40.25/19.06 80.11/55.71 

a TheBMD/BMDL data in this table are rounded to four significant figures. The output file for the selected model 

(based on AIC and visual fit) is included in this Appendix. Benchmark doses were estimated for both 10% and 5% 

extra risk. An extra risk of 10% has generally been the default benchmark response (BMR) level for quantal data 

unless a study has “greater than usual sensitivity” (U.S. EPA, 2000). Ind = Indeterminate because p-value < 0.1. 

b

An adjustment to account for early mortality was considered but not applied. Few deaths occurred prior to the first 

occurrence of these effects in rats (see Appendix C). While first occurrence data were not available for female mice, 

mortality did not begin to increase in either exposure group until week 60, and there is no reason to believe that an 

irritant effect such as nasal inflammation would have a delayed onset beyond this time point. 

B-9
Output B-4. Hepatic necrosis in male rats of NTP (1982) 

Probit Model with 0.95 Confidence Level 

0.5

0.4

BMDL BMD 

Probit 

Fraction Affected 

0.3

0.2

0.1

0

0 50 100 150 200 250 300 

dose 

13:04 02/16 2004 

==================================================================== 

Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $

Input Data File: C:\BMDS\DATA\MTBE\CHUNFEMALES\UNSAVED1.(d)

Gnuplot Plotting File: C:\BMDS\DATA\MTBE\CHUNFEMALES\UNSAVED1.plt

Mon Feb 16 13:05:37 2004 

==================================================================== 

Hepatic Necrosis in Male Rats of NTP (1982)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = CumNorm(Intercept+Slope*Dose),

where CumNorm(.) is the cumulative normal distribution function

Dependent variable = COLUMN3

Independent variable = COLUMN1

Slope parameter is not restricted

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-10 
 Default Initial (and Specified) Parameter Values

background = 0 Specified

intercept = -1.6355 

slope = 0.0044451 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

intercept slope 

intercept 1 -0.81 

slope -0.81 1 

Parameter Estimates 

Variable Estimate Std. Err. 

intercept -1.61217 0.219178 

slope 0.00430755 0.000976355 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood) Deviance Test DF 

-59.9467 

P-value 

Fitted model -60.1512 0.409113 1 0.5224 

Reduced model -70.709 21.5247 2 <.0001 

AIC: 124.302 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0535 2.673 2 50 -0.4232 

77.0000 0.1002 5.009 6 50 0.4666 

307.0000 0.3860 19.300 19 50 -0.08718 

Chi-square = 0.40 DF = 1 P-value = 0.5248 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 131.774 

BMDL = 105.343 

B-11
Output B-5. Testicular degeneration in male rats of NTP (1982) 

Log-Logistic Model with 0.95 Confidence Level 

Fraction Affected 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

BMDL BMD 

Log-Logistic 

0 50 100 150 200 250 300 

dose 

17:49 08/05 2003 

=========================================================== 

Logistic Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:20 $

Input Data File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\MR_TD_LOGLOGISTIC.(d)

Gnuplot Plotting File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\MR_TD_LOGLOGISTIC.plt 

Thu Jul 31 08:55:46 2003 

=========================================================== 

Testicular Degeneration in Male Rats of NTP (1982)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = M_TD

Independent variable = Dose

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-12 
 User has chosen the log transformed model 

Default Initial Parameter Values 

background = 0.02 

intercept = -6.08038 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

background intercept 

background 1 -0.39 

intercept -0.39 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.023983 0.0231825 

intercept -6.17237 0.272892 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-62.141 

Deviance Test DF P-value 

Fitted model -62.5988 0.915693 1 0.3386 

Reduced model -73.4374 22.5929 2 <.0001 

AIC: 129.198 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0240 1.199 1 50 -0.1841 

77.0000 0.1591 7.954 10 50 0.7913 

307.0000 0.4050 19.847 18 49 -0.5376 

Chi-square = 0.95 DF = 1 P-value = 0.3300 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 53.2579 

BMDL = 35.0725 

B-13
Output B-6. Hepatic necrosis in female rats of NTP (1982) 

Probit Model with 0.95 Confidence Level 

0.45

0.4

0.35

BMDL BMD 

Probit 

Fraction Affected 

0.3

0.25

0.2

0.15

0.1

0.05

0

0 50 100 150 200 250 300 

dose 

18:00 08/05 2003 

=========================================================== 

Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $

Input Data File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FR_HN_LOGPROBIT.(d)

Gnuplot Plotting File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FR_HN_LOGPROBIT.plt 

Thu Jul 31 10:39:58 2003 

=========================================================== 

Heoatic Necrosis in Female Rats of NTP (1982)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = Background

+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

where CumNorm(.) is the cumulative normal distribution function

Dependent variable = F_HN

Independent variable = Dose

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-14 
 User has chosen the log transformed model 

Default Initial (and Specified) Parameter Values

background = 0.04 

intercept = -6.39367 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

background intercept 

background 1 -0.41 

intercept -0.41 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.0413485 0.0231704 

intercept -6.43122 0.228121 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-47.7192 

Deviance Test DF P-value 

Fitted model -47.7226 0.0069185 1 0.9337 

Reduced model -54.6511 13.8638 2 0.0009761 

AIC: 99.4453 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0413 2.067 2 50 -0.04789 

77.0000 0.0590 2.892 3 49 0.06572 

307.0000 0.2720 13.056 13 48 -0.01819 

Chi-square = 0.01 DF = 1 P-value = 0.9336 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 172.374 

BMDL = 122.02 

B-15
Output B-7. Adrenal cortical degeneration in female rats of NTP (1982) 

Log-Logistic Model with 0.95 Confidence Level 

0.45 

0.4 

0.35 

0.3 

0.25 

0.2 

0.15 

0.1 

0.05 

0 BMDL BMD 

Log-Logistic 

0 50 100 150 200 250 300 

dose 

15:34 08/06 2003 

=========================================================== 

Logistic Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:20 $

Input Data File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FR_ACD_LOGLOGISTIC.(d)

Gnuplot Plotting File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FR_ACD_LOGLOGISTIC.plt 

Thu Jul 31 10:58:48 2003 

======================================================== 

Adrenal Cortical Degeneration in Female Rats of NTP (1982)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = F_ACD

Independent variable = Dose

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

User has chosen the log transformed model Fraction Affected 

B-16
 Default Initial Parameter Values 

background = 0.08 

intercept = -6.99302 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

background intercept 

background 1 -0.56 

intercept -0.56 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.0811145 0.0352056 

intercept -7.02412 0.460426 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-61.7505 

Deviance Test DF P-value 

Fitted model -61.7529 0.00471493 1 0.9453 

Reduced model -65.2427 6.9844 2 0.03043 

AIC: 127.506 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0811 4.056 4 50 -0.02887 

77.0000 0.1401 6.863 7 49 0.05649 

307.0000 0.2783 13.082 13 47 -0.02653 

Chi-square = 0.00 DF = 1 P-value = 0.9452 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 124.823 

BMDL = 66.495 

B-17
Output B-8. Splenic hematopoiesis in female mice of NTP (1982) 

Log-Logistic Model with 0.95 Confidence Level 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

Fraction Affected 

BMDL BMD 

Log-Logistic 

0 50 100 150 200 250 300 

dose 

15:56 08/06 2003 

=========================================================== 

Logistic Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:20 $

Input Data File: C:\BMDS\DATA\1,2-dibromoethane\FM_SH_LOGLOGIST.(d)

Gnuplot Plotting File: C:\BMDS\DATA\1,2-dibromoethane\FM_SH_LOGLOGIST.plt

Wed Jul 02 11:11:32 2003 

=========================================================== 

Splenic Hematopoiesis in Female Mice of NTP (1982)

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = Splenic_Hem

Independent variable = Dose

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

User has chosen the log transformed model

B-18 
 Default Initial Parameter Values 

background = 0 

intercept = -6.2138 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -background -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

intercept 

intercept 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0 NA 

intercept -6.28411 0.244499 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-52.7602 

Deviance Test DF P-value 

Fitted model -53.2053 0.890189 2 0.6408 

Reduced model -65.5992 25.678 2 <.0001 

AIC: 108.411 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0000 0.000 0 50 0 

77.0000 0.1256 6.155 8 49 0.7952 

307.0000 0.3642 17.845 16 49 -0.5477 

Chi-square = 0.93 DF = 2 P-value = 0.6274 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 59.554 

BMDL = 40.2456 

B-19
Output B-9. Nasal inflammation in female mice of NTP (1982) Fraction Affected 

0 

0.1 

0.2 

0.3 

0.4 

0.5 

0.6 

0 50 100 150 200 250 300 

dose 

Probit Model with 0.95 Confidence Level 

15:29 09/03 2003 

BMDL BMD 

Probit 

==================================================================== 

Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $

Input Data File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FM_NI_LOGPROBIT.(d)

Gnuplot Plotting File: F:\BMDS\DATA\1,2-dibromoethane\INHALATION\1,2-

dibromoethane\FM_NI_LOGPROBIT.plt 

Fri Aug 29 14:46:40 2003

==================================================================== 

Nasal Inflammation in Female Mice, LogProbit

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = Background

+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), 

where CumNorm(.) is the cumulative normal distribution function

Dependent variable = N_Inflammation

Independent variable = Dose

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

B-20 
 User has chosen the log transformed model 

Default Initial (and Specified) Parameter Values

background = 0 

intercept = -5.86426 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -background -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

intercept 

intercept 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0 NA 

intercept -5.9084 0.149992 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-47.5891 

Deviance Test DF P-value 

Fitted model -47.8522 0.526361 2 0.7686 

Reduced model -65.9505 36.7229 2 <.0001 

AIC: 97.7045 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0000 0.000 0 50 0 

77.0000 0.0588 2.942 4 50 0.6359 

307.0000 0.4280 21.398 20 50 -0.3997 

Chi-square = 0.56 DF = 2 P-value = 0.7543 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 102.192 

BMDL = 80.1088 

B-21
APPENDIX C. Dose-Response Analyses of Cancer Endpoints 

C-1. Analyses in support of slope factor for oral exposure 

Table C-1. Number of animals with and without specified tumor types at 

time of death, male rats orally exposed to 1,2-dibromoethane 

Forestomach tumors Hemangiosarcomas 

Death with Death without Death with Death without 

Thyroid follicular cell 

adenoma/carcinoma 

Death with Death without 

tumor tumor 

0 1 

0 1 

0 9 

0 9 

0 1 

0 1 

0 2 

0 1 

0 1 

0 1 

0 1 

0 2 

0 1 

0 1 

0 1 

0 6 

1 2 

0 0 

0 2 

0 2 

0 5 

4 15 

0 1 

1 17 

0 1 

0 1 

0 1 

0 1 

0 1 

1 0 

0 1 

0 2 

0 2 

1 0 

0 4 

0 1 

1 2 

1 1 

0 1 

3 6

0 1 

1 0 

0 1 

8 0 

Week of 

Group death tumor tumor 

Control 28 

29 0 1 

49 0 9 

63 0 9 

Low-dose 31 

32 1 0 

34 2 0 

35 1 0 

36 1 0 

37 1 0 

38 1 0 

39 2 0 

40 1 0 

41 1 0 

42 1 0 

43 5 1 

44 3 0 

45 0 0 

46 2 0 

47 2 0 

48 5 0 

49 15 4 

High-dose 9 

15 3 15 

24 1 0 

26 0 1 

30 1 0 

31 1 0 

34 1 0 

35 1 0 

36 1 0 

38 2 0 

39 2 0 

40 1 0 

41 4 0 

42 1 0 

44 3 0 

45 2 0 

47 1 0 

49 

Source: NCI, 1978. 

tumor tumor 

0 1 

0 1 

0 9 

0 9 

1 0 

0 1 

2 0 

0 1 

0 1 

0 1 

1 0 

0 2 

0 1 

0 1 

0 1 

0 6 

0 3 

0 0 

0 2 

0 2 

1 4 

6 13 

0 1 

0 18 

0 1 

1 0 

0 1 

0 1 

0 1 

0 1 

0 1 

0 2 

0 2 

0 1 

0 4 

1 0 

0 3 

1 1 

0 1 

1 7

C-1
Table C-2. Number of animals with and without specified tumor types 

at time of death, female rats orally exposed to 1,2-dibromoethane 

Group Week 

Forestomach tumors Hemangioarcoma 

Hepatocellular 

carcinomas 

Adrenocortical 

carcinomas 

Death 

with 

tumor 

Death 

without 

tumor 

Death 

with 

tumor 

Death 

without 

tumor 

Death 

with 

tumor 

Death 

without 

tumor 

Death 

with 

tumor 

Death 

without 

tumor 

Control 49 0 1 0 1 0 1 0 1

63 0 19 0 19 0 19 0 19 

Low-dose 1 0 5 0 5 0 5 0 5 

1 0 2 0 2 0 2 0 2 

3 0 1 0 1 0 1 0 1 

4 0 1 0 1 0 1 0 1 

5 0 1 0 1 0 1 0 1 

11 0 1 0 1 0 1 0 1 

12 1 1 0 2 0 2 0 2 

24 1 0 0 1 0 1 0 1 

25 1 0 0 1 0 1 0 1 

28 1 0 0 1 0 1 0 1 

34 1 0 0 1 0 1 0 1 

35 1 0 0 1 0 1 0 1 

38 2 0 0 2 0 2 0 2 

39 1 0 0 1 0 1 0 1 

42 1 0 0 1 0 1 0 1 

43 1 0 0 1 0 1 0 1 

44 1 0 0 1 0 1 0 1 

45 2 0 0 2 0 2 0 2 

46 4 0 0 4 0 4 0 4 

48 2 0 0 2 0 2 0 2 

49 4 0 0 4 0 4 0 4 

50 2 0 0 2 0 2 0 2 

51 1 0 0 1 0 1 0 1 

52 2 0 0 2 0 2 0 2 

53 1 0 0 1 0 1 0 1 

54 2 0 0 2 0 2 0 2 

56 2 0 0 2 0 2 0 2 

57 2 0 0 2 0 2 0 2 

59 1 0 0 1 0 1 0 1 

60 1 0 0 1 0 1 0 1 

61 2 0 0 2 1 1 1 1 

High-dose 

12 1 0 0 1 0 1 0 1 

14 0 1 0 1 0 1 0 1 

15 2 18 0 20 0 20 0 20 

33 1 0 0 1 1 0 0 1 

39 1 0 0 1 0 1 0 1 

40 1 0 0 1 0 1 0 1 

41 1 0 0 1 0 1 1 0 

42 2 0 1 1 0 2 0 2 

45 2 0 0 2 0 2 0 2 

47 1 0 0 1 0 1 0 1 

48 1 0 0 1 0 1 0 1 

50 1 0 0 1 0 1 0 1 

51 1 0 0 1 1 0 1 0 

53 4 0 0 4 1 3 0 4 

54 1 0 0 1 0 1 0 1 

55 1 0 0 1 0 1 0 1 

56 3 0 1 2 1 2 1 2 

58 3 0 0 3 0 3 0 3 

59 1 0 1 0 0 1 1 0 

61 1 0 0 1 1 0 0 1 

Source: NCI, 1978. 

C-2 
Table C-3. Number of animals with and without 

specified tumor types at time of death, male mice 

orally exposed to 1,2-dibromoethane 

Group Week 

Control 11

36

59

Low-dose 12

19

21

24

26

29

33

36

40

42

43

45

46

48

49

50

52

53

54

56

58

59

60

64

65

66

68

69

72

73

74

78

Forestomach tumors Lung adenomas 

Death with 

tumor 

Death without 

tumor 

Death with 

tumor 

Death without 

tumor 

0 1 0 1 

0 1 0 1 

0 18 0 18 

0 1 0 1 

0 1 0 1 

0 1 0 1 

1 0 0 1 

0 1 0 1 

1 0 0 1 

1 0 0 1 

2 0 0 2 

1 0 0 1 

2 0 0 2 

2 1 0 3 

2 0 0 2 

2 0 0 2 

1 0 0 1 

1 0 0 1 

2 0 0 2 

3 0 0 3 

2 0 0 2 

1 0 0 1 

1 0 0 1 

2 0 1 1 

1 0 0 1 

1 0 0 1 

3 0 0 3 

1 0 0 1 

2 0 1 1 

1 0 1 0 

2 0 0 2 

3 0 0 3 

1 0 0 1 

1 0 1 0 

2 0 0 2 

C-3
Table C-3. Number of animals with and without 

specified tumor types at time of death, male mice 

orally exposed to 1,2-dibromoethane (continued) 

Group Week 

High-dose 12

13

14

21

26

27

32

34

38

39

41

42

43

44

45

46

47

48

49

52

53

54

55

57

59

60

61

65

66

68

74

77

Forestomach tumors Lung adenomas 

Death with 

tumor 

Death without 

tumor 

Death with 

tumor 

Death without 

tumor 

0 4 0 4 

0 4 0 4 

0 1 0 1 

0 1 0 1 

1 2 1 2 

0 1 0 1 

1 0 0 1 

0 1 0 1 

0 1 0 1 

0 2 0 2 

1 0 1 0 

0 1 0 1 

1 0 1 0 

2 0 0 2 

2 0 1 1 

1 0 0 1 

1 0 0 1 

2 0 0 2 

2 0 0 2 

3 0 2 1 

2 0 0 2 

1 0 0 1 

1 0 0 1 

1 0 0 1 

2 1 1 2 

1 0 1 0 

1 0 0 1 

1 0 0 1 

1 0 1 0 

1 0 0 1 

1 0 0 1 

1 0 1 0 

Source: NCI, 1978. 

C-4
Table C-4. Number of animals with and without specified 

tumor types at time of death, female mice orally exposed to 

1,2-dibromoethane 

Group Week 

Control 15

51

59

60

Low-dose 18

40

43

50

52

54

55

57

58

59

61

63

65

66

67

68

69

70

73

75

76

77

78

79

82

83

85

86

90

Forestomach tumors Lung adenomas 

Death with 

tumor 

Death without 

tumor 

Death with 

tumor 

Death without 

tumor 

0 1 0 1 

0 1 0 1 

0 9 0 9 

0 9 0 9 

0 1 0 1 

2 0 0 2 

1 0 0 1 

1 0 1 0 

1 0 0 1 

1 0 0 1 

2 0 0 2 

0 0 0 0 

1 0 1 0 

1 0 0 1 

1 0 0 1 

1 0 0 1 

2 0 0 2 

2 0 0 2 

1 0 0 1 

1 0 0 1 

1 0 0 1 

2 0 1 1 

2 0 0 2 

3 0 0 3 

3 0 0 3 

2 0 2 0 

1 0 1 0 

1 0 0 1 

2 0 1 1 

1 0 0 1 

2 0 0 2 

2 0 0 2 

7 0 3 4 

C-5
Table C-4. Number of animals with and without specified 

tumor types at time of death, female mice orally exposed to 

1,2-dibromoethane 

Group Week 

High-dose 12

13

27

28

34

37

39

40

41

42

43

44

49

50

51

52

53

54

55

57

58

61

62

65

66

67

69

70

71

73

76

78

Forestomach tumors Lung adenomas 

Death with 

tumor 

Death without 

tumor 

Death with 

tumor 

Death without 

tumor 

0 9 0 9 

0 4 0 4 

0 1 0 1 

0 1 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

0 1 0 1 

0 1 0 1 

1 0 0 1 

1 1 0 2 

0 1 1 0 

1 0 1 0 

1 0 0 1 

1 0 1 0 

2 1 0 3 

0 1 0 1 

2 0 0 2 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

1 0 0 1 

2 0 0 2 

2 1 2 1 

Source: NCI, 1978. 

C-6
Figure C-1. Kaplan-Meier hazard curves for the incidence of forestomach 

squamous cell carcinomas in male rats in the oral gavage study (NCI, 1978). 

C-7
Output C-1. Multistage analysis of forestomach tumors in male rats, 1,2-dibromoethane 

oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = fs_tumors

Independent variable = hec_feb04 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.164564 

Beta(1) = 0.160289 

Beta(2) = 0 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(2)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.193784 0.0322577 

Beta(2) 0 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-20.7657 

Deviance Test DF P-value 

Fitted model -21.0724 0.613548 2 0.7358 

Reduced model -47.9793 54.4274 2 <.0001 

AIC: 44.1449 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 13 0.000 

i: 2 

11.0000 0.8814 44.068 45 50 0.178 

i: 3 

22.0000 0.9859 33.521 33 34 -1.105 

C-8
 Chi-square = 0.74 DF = 2 P-value = 0.6899 

Benchmark Dose Computation 

Specified effect = Specified effect = 0.9 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.5437 

BMD = 11.8822 

BMDL = 0.418668 

BMDL = 9.14972 

0.1 

C-9
Figure C-2. Cumulative incidence curves for hemangiosarcomas in male rats 

in the oral gavage study (NCI, 1978.). 

C-10
Output C-2. Multistage analysis of hemangiosarcomas in male rats, 1,2-dibromoethane 

oral gavage exposure 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = hemang

Independent variable = hec_feb04 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.0670325 

Beta(1) = 0.00868433 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0174672 0.00979878 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-34.7785 

Deviance Test DF P-value 

Fitted model -37.0119 4.4667 2 0.1072 

Reduced model -38.185 6.81305 2 0.03316 

AIC: 76.0237 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 13 0.000 

i: 2 

11.0000 0.1748 7.342 11 42 0.604 

i: 3 

22.0000 0.3191 7.338 4 23 -0.668 

C-11
 Chi-square = 4.44 DF = 2 

Benchmark Dose Computation 

P-value = 0.1087 

Specified effect = 0.2 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 12.775 

BMDL = 8.58053 

Specified effect = 

Risk Type = 

Confidence level = 

BMD = 

BMDL = 

0.1 

Extra risk 

0.95 

6.0319 

4.05142 
Figure C-3. Cumulative incidence curves for thyroid follicular cell adenomas 

or carcinomas in male rats in the oral gavage study (NCI, 1978). 

C-13
Output C-3. Multistage analysis of thyroid follicular cell adenomas in male rats, 1,2-

dibromoethane oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = tfca

Independent variable = hec_feb04 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0194293 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0159794 0.00900218 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-29.7955 

Deviance Test DF P-value 

Fitted model -30.1036 0.616179 2 0.7348 

Reduced model -34.5849 9.57879 2 0.008317 

AIC: 62.2073 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 13 0.000 

i: 2 

11.0000 0.1612 6.286 5 39 -0.244 

C-14
i: 3 

22.0000 0.2964 6.817 8 23 0.247 

Chi-square = 0.61 DF = 2 P-value = 0.7388 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.125 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 6.59354 BMD = 10.8101 

BMDL = 4.30664 BMDL = 5.72909 

C-15
Figure C-4. Kaplan-Meier hazard curves for the incidence of forestomach 

squamous cell carcinomas in female rats in the oral gavage study (NCI, 1978). 

C-16
Figure C-5. Cumulative incidence curves for hemangiosarcomas in female 

rats in the oral gavage study (NCI, 1978). 

C-17
Output C-4. Multistage analysis of hemangiosarcomas in female rats, 1,2-dibromoethane 

oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = hemang

Independent variable = mg_kg_day 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0097078 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.00588915 0.0102062 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-7.92199 

Deviance Test DF P-value 

Fitted model -9.41847 2.99296 2 0.2239 

Reduced model -11.6984 7.5528 2 0.02291 

AIC: 20.8369 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 19 0.000 

i: 2 

10.0000 0.0572 1.144 0 20 -1.061 

i: 3 

C-18
 20.0000 0.1111 1.889 3 17 0.662 

Chi-square = 1.95 DF = 2 P-value = 0.3775 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 17.8906 

BMDL = 7.87117 

C-19
Figure C-6. Cumulative incidence curves for hepatocellular carcinomas and 

neoplastic nodules in female rats in the oral gavage study (NCI, 1978). 

C-20
Output C-5. Multistage analysis of hepatocellular carcinomas in female rats, 1,2-

dibromoethane oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = hepcarc

Independent variable = mg_kg_day 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0202733 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0142265 0.0112183 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-15.4276 

Deviance Test DF P-value 

Fitted model -16.5126 2.1701 2 0.3379 

Reduced model -21.2314 11.6077 2 0.003016 

AIC: 35.0252 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 19 0.000 

i: 2 

10.0000 0.1326 2.652 1 20 -0.718 

C-21
i: 3 

20.0000 0.2476 4.457 6 18 0.460 

Chi-square = 1.90 DF = 2 P-value = 0.3875 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.15 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 7.40594 BMD = 11.4237 

BMDL = 4.20627 BMDL = 6.48818 

C-22
Figure C-7. Cumulative incidence curves for adrenocortical carcinomas and 

neoplastic nodules in female rats in the oral gavage study (NCI, 1978). 

C-23
Output C-6. Multistage analysis of adrenocortical carcinomas in female rats, 1,2-

dibromoethane oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = adren

Independent variable = mg_kg_day 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0134132 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0101304 0.0111373 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-13.2454 

Deviance Test DF P-value 

Fitted model -13.6828 0.874853 2 0.6457 

Reduced model -16.8494 7.20797 2 0.02722 

AIC: 29.3657 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

C-24
 0.0000 0.0000 0.000 0 19 0.000 

i: 2 

10.0000 0.0963 1.927 1 20 -0.532 

i: 3 

20.0000 0.1834 3.118 4 17 0.346 

Chi-square = 0.80 DF = 2 P-value = 0.6706 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 10.4005 

BMDL = 5.39277 

C-25
Figure C-8. Kaplan-Meier hazard curves for the incidence of forestomach 

squamous cell carcinomas in male mice in the oral gavage study (NCI, 1978). 

C-26
Figure C-9: Cumulative incidence curves for lung adenomas in male mice in 

the oral gavage study (NCI, 1978). 

C-27
Output C-7: Multistage analysis of alveolar/bronchiolar adenomas in male mice, 1,2-

dibromoethane oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = lung_ad

Independent variable = dose_feb04 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0476155 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0382824 0.0159921 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-22.3734 

Deviance Test DF P-value 

Fitted model -22.9321 1.11758 2 0.5719 

Reduced model -31.4908 18.2348 2 0.0001097 

AIC: 47.8643 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 18 0.000 

i: 2 

8.6000 0.2805 5.610 4 20 -0.399 

i: 3 

17.0000 0.4784 8.611 10 18 0.309 

C-28
 Chi-square = 1.07 DF = 2 P-value = 0.5850 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.3 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 2.75219 BMD = 9.31695 

BMDL = 1.81432 BMDL = 6.14197 

C-29
Figure C-10. Kaplan-Meier hazard curves for the incidence of forestomach 

squamous cell carcinomas in female mice in the oral gavage study (NCI, 

1978). 

C-30
Figure C-11. Cumulative incidence curves for lung adenomas in female mice 

in the oral gavage study (NCI, 1978). 

C-31
Output C-8. Multistage analysis of alveolar/bronchiolar adenomas in female mice, 1,2-

dibromoethane oral gavage exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = lung_ad

Independent variable = dose_feb04 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.0746256 

Beta(1) = 0.0205875 

Beta(2) = 0 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(2)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0335146 0.0159519 

Beta(2) 0 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-29.7306 

Deviance Test DF P-value 

Fitted model -31.1232 2.78529 2 0.2484 

Reduced model -35.3734 11.2855 2 0.003543 

AIC: 64.2465 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 18 0.000 

i: 2 

8.2000 0.2403 7.209 10 30 0.510 

C-32
i: 3 

16.0000 0.4151 7.471 5 18 -0.565 

Chi-square = 2.82 DF = 2 P-value = 0.2442 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.25 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 3.14372 BMD = 8.58379 

BMDL = 2.10812 BMDL = 5.75613 

C-33
C-2. Analyses in support of inhalation unit risk 

Table C-5. Number of animals with and without specified tumor types at 

time of death, male rats exposed by inhalation to 1,2-dibromoethane 

Group Week 

Control 77 

88 

89 

90 

93 

97 

99 

102 

103 

104 

106 

Low-dose 7 

38 

56 

85 

86 

93 

95 

96 

97 

98 

99 

102 

104 

High-dose 43 

50 

53 

56 

62 

63 

64 

67 

68 

69 

70 

71 

74 

76 

77 

78 

80 

81 

82 

83 

84 

85 

86 

87 

88 

89 

All nasal tumors 

Death with Death without 

tumor tumor tumor 

0 1 0 

0 1 0 

0 1 0 

0 1 0 

0 2 0 

0 1 0 

0 1 0 

0 1 0 

0 3 0 

1 18 0 

0 19 0 

0 1 0 

0 1 0 

0 1 0 

0 1 0 

0 1 0 

0 1 0 

0 1 0 

1 1 1 

1 0 0 

1 0 0 

1 0 0 

3 0 0 

32 3 0 

1 0 0 

0 1 1 

0 1 0 

1 0 0 

0 1 0 

0 1 1 

2 0 0 

1 1 0 

2 0 0 

0 1 0 

2 2 1 

0 1 1 

1 0 0 

2 0 1 

1 0 1 

1 0 0 

5 0 2 

2 0 0 

3 0 0 

1 0 0 

3 0 0 

2 0 1 

2 0 0 

2 0 2 

1 0 1 

5 1 3 

Hemangiosarcomas 

Death with Death without Death with 

tumor 

1 

1 

1 

1 

2 

1 

1 

1 

3 

19 

19 

1 

1 

1 

1 

1 

1 

1 

1 

1 

1 

1 

3 

35 

1 

0 

1 

1 

1 

0 

2 

2 

2 

1 

3 

0 

1 

1 

0 

1 

3 

2 

3 

1 

3 

1 

2 

0 

0 

3 

Mesothelioma 

Death 

tumor tumor 

0 1 

0 1 

0 1 

0 1 

0 2 

0 1 

0 1 

0 1 

0 3 

1 18 

0 19 

0 1 

0 1 

0 1 

0 1 

0 1 

0 1 

0 1 

1 1 

0 1 

0 1 

0 1 

0 3 

7 28 

0 1 

1 0 

1 0 

1 0 

0 1 

1 0 

1 1 

1 1 

1 1 

0 1 

3 1 

0 1 

0 1 

1 1 

1 0 

0 1 

0 5 

1 1 

1 2 

0 1 

1 2 

0 2 

1 1 

2 0 

1 0 

6 0 

Source: NTP, 1982. 

C-34
Table C-6. Number of animals with and without specified tumor types at 

time of death, female rats exposed by inhalation to 1,2-dibromoethane 

Group Week 

Control 59

88

93

97

98

101

103

104

106

Low-dose 8

13

52

79

82

98

99

104

High-dose 54

55

60

63

67

69

71

72

73

76

78

79

80

82

83

84

85

86

87

88

89

90

91

Nasal tumor Fibroadenoma Mammary adenocarcinoma 

Death with 

tumors 

Death without 

tumors 

Death with 

tumors 

Death without 

tumors 

Death with 

tumors 

Death without 

tumors 

0 

0 

0 

1 

0 

0 

0 

0 21 3 18 0 21 

0 21 1 20 1 20 

0 

0 

1 

0 

0 

3 

1 

29 9 21 17 0 38 

0 

0 

1 

2 

0 

1 

1 

1 

2 

1 

1 

1 

1 

1 

2 

3 

1 

3 

2 

1 

5 

2 

11 0 10 

1 0 1 0 1 

1 0 1 0 1 

1 0 1 0 1 

0 0 1 0 1 

1 0 1 0 1 

2 0 2 0 2 

1 0 1 0 1 

1 0 1 0 1 

1 0 1 0 1 

0 1 0 0 1 

1 0 1 0 1 

1 1 0 0 1 

2 5 0 0 5 

0 1 0 0 1 

1 0 1 0 1 

1 0 1 0 1 

0 0 1 0 1 

0 1 1 0 2 

1 0 1 1 0 

1 0 2 0 2 

0 0 1 0 1 

1 1 1 0 2 

0 0 2 1 1 

0 0 1 0 1 

0 0 1 0 1 

0 0 1 0 1 

0 0 1 0 1 

0 1 0 0 1 

0 2 0 0 2 

0 1 2 1 2 

0 0 1 0 1 

0 1 2 0 3 

0 2 0 0 2 

0 1 0 0 1 

1 5 1 0 6 

0 1 1 0 2 

8 3 1 

C-35
Table C-6. Number of animals with and without 

specified tumor types at time of death, female rats 

exposed by inhalation to 1,2-dibromoethane 

(continued) 

Group Week 

Hemangiosarcoma 

Alveolar/bronchiolar 

adenoma/carcinoma

Death with 

tumor 

Death without 

tumor 

Death with 

tumor 

Death without 

tumor 

Control 0 1 0 1

Low-dose 

High-dose 

59 

0 

0 

88 0 1 

93 0 1 

97 0 1 

98 0 1 

101 0 2 

103 0 1 

104 0 21 

106 0 21 

8 1 

13 0 1 

52 0 1 

79 0 1 

82 0 1 

98 0 5 

99 0 1 

104 0 38 

54 1 

55 0 1 

60 0 1 

63 0 2 

67 0 1 

69 0 2 

71 0 1 

72 0 2 

73 1 1 

76 0 1 

78 0 1 

79 0 1 

80 0 1 

82 0 1 

83 0 2 

84 0 3 

85 0 1 

86 0 3 

87 1 0 

88 1 1 

89 0 6 

90 0 2 

91 2 

0 1 

0 1 

0 1 

0 1 

0 2 

0 1 

0 21 

0 21 

0 1 

0 1 

0 1 

0 1 

0 1 

0 5 

0 1 

0 38 

0 1 

0 1 

0 1 

0 2 

0 1 

0 2 

0 1 

0 2 

0 2 

0 1 

0 1 

0 1 

0 1 

0 1 

0 2 

0 3 

1 0 

0 3 

1 1 

0 1 

1 5 

0 2 

9 2 9

Source: NTP, 1982. 

C-36
Table C-7. Number of animals with and without specified tumor types at 

time of death, female mice exposed by inhalation to 1,2-dibromoethane 

Group Week 

Control 24 

85 

86 

94 

95 

96 

98 

100 

101 

104 

106 

Low-dose 4 

54 

56 

62 

66 

73 

82 

84 

90 

91 

94 

95 

96 

97 

98 

100 

101 

102 

104 

High-dose 19 

45 

50 

63 

65 

66 

68 

70 

71 

73 

74 

75 

77 

78 

79 

81 

82 

83 

84 

85 

86 

87 

89 

90 

91 

Hemangiosarcoma 

Death with Death without Death with Death without 

tumor tumor tumor tumor 

0 1 0 1 

Alveolar/bronchiolar 

adenoma/carcinoma 

Death with Death without 

tumor tumor 

0 1 

Nasal tumors 

0 19 0 19 1 18 

0 1 0 1 0 1 

0 1 0 1 

0 1 0 1 

0 1 0 1 

0 1 0 1 

0 1 0 1 

0 1 0 1 

0 1 1 0 

1 0 0 1 

1 2 0 3 

1 0 0 1 

1 2 1 2 

1 2 3 0 

0 2 1 1 

0 3 0 3 

2 0 0 2 

1 2 1 2 

1 1 0 2 

4 15 

0 1 

0 1 0 1 

0 1 1 0 

1 2 2 1 

0 1 1 0 

1 0 0 1 

1 0 1 0 

1 1 2 0 

0 2 1 1 

0 1 1 0 

0 1 1 0 

0 1 1 0 

1 1 1 1 

0 1 1 0 

3 1 4 0 

1 1 2 0 

2 1 2 1 

2 0 2 0 

0 1 1 0 

3 0 3 0 

1 2 3 0 

1 0 0 1 

2 1 2 1 

1 0 1 0 

0 8 4 4 8 0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 

0 

0 

1 

0 

0 

0 

0 

1 

0 

1 

0 

0 

1 

2 

0 

0 

0 

0 

1 

0 

0 

0 

1 

1 

1 

1 

1 

1 

1 

1 

22 

1 

1 

1 

1 

1 

1 

1 

1 

3 

1 

3 

3 

2 

3 

2 

3 

2 

0 

1 

3 

0 

1 

1 

2 

2 

0 

1 

0 

2 

1 

3 

0 

3 

2 

1 

3 

2 

1 

3 

1 

0 

0 

0 

0 

0 

0 

0 

0 

0 

1 0 1 

1 0 1 

1 0 1 

1 0 1 

1 0 1 

1 0 1 

1 0 1 

1 0 1 

22 3 19 

0 19 3 16 

0 1 0 1 

C-37
Table C-7. Number of animals with and without specified tumor types at time of death, 

female mice exposed by inhalation to 1,2-dibromoethane (continued) 

Lung/bronchial 

adenoma/carcinoma Fibrosarcoma Mammary adenocarcinoma 

Death with Death without Death with Death without Death with Death without 

Group Week 

0 1 0 1 0 1 

tumor tumor tumor tumor tumor tumor 

0 19 0 19 0 19 

0 1 0 1 1 0 

Control 24 

85 0 1 0 1 0 1 

86 0 1 0 1 0 1 

94 0 1 0 1 0 1 

95 0 1 0 1 0 1 

96 0 1 0 1 0 1 

98 0 1 0 1 0 1 

100 0 1 0 1 0 1 

101 0 1 0 1 1 0 

104 0 22 0 22 1 21 

106 

Low-dose 4 

0 19 1 18 5 14 

0 1 0 1 0 1 

1 7 0 8 0 8 

54 0 1 1 0 0 1 

56 0 1 0 1 0 1 

62 0 1 0 1 0 1 

66 0 1 0 1 0 1 

73 0 1 0 1 0 1 

82 0 1 0 1 0 1 

84 0 1 1 0 0 1 

90 0 1 0 1 0 1 

91 0 3 0 3 1 2 

94 0 1 0 1 0 1 

95 0 3 0 3 1 2 

96 0 3 0 3 0 3 

97 1 1 0 2 0 2 

98 0 3 2 1 2 1 

100 0 2 0 2 0 2 

101 0 3 0 3 2 1 

102 0 2 0 2 2 0 

104 

High-dose 19 

45 0 1 0 1 0 1 

50 0 1 1 0 1 0 

63 0 3 0 3 1 2 

65 0 1 0 1 0 1 

66 0 1 0 1 0 1 

68 0 1 0 1 0 1 

70 0 2 0 2 1 1 

71 1 1 0 2 0 2 

73 0 1 0 1 0 1 

74 1 0 0 1 0 1 

75 0 1 0 1 1 0 

77 1 1 1 1 0 2 

78 0 1 0 1 0 1 

79 1 3 1 3 2 2 

81 0 2 1 1 1 1 

82 0 3 1 2 0 3 

83 0 2 0 2 0 2 

84 1 0 0 1 0 1 

85 1 2 1 2 2 1 

86 0 3 1 2 0 3 

87 0 1 0 1 0 1 

89 1 2 3 0 0 3 

90 0 1 1 0 0 1 

91 

Source: NTP, 1982. 

C-38 
Output C-9. Multistage analysis of nasal cavity tumors in male rats, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = nasal_tum

Independent variable = rgdr_ppm

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

User has chosen the log transformed model

Default Initial Parameter Values 

background = 0.0217391 

intercept = 3.14555 

slope = 1.27162 

Asymptotic Correlation Matrix of Parameter Estimates 

background intercept slope 

background 1 -0.028 0.0028 

intercept -0.028 1 0.89 

slope 0.0028 0.89 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.0217391 0.0215013 

intercept 3.14555 0.820541 

slope 1.27162 0.93693 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood) Deviance Test DF 

-30.5769 

P-value 

Fitted model -30.5769 0 0 NA 

Reduced model -89.9347 118.716 2 <.0001 

AIC: 67.1538 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0217 1.000 1 46 0 

0.3600 0.8667 39.000 39 45 0 

0.8900 0.9535 41.000 41 43 0 

Chi-square = 0.00 DF = 0 P-value = NA 

Benchmark Dose Computation 

C-39
Specified effect = 0.1 Specified effect = 0.87 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.0149722 BMD = 0.375782 

BMDL = 0.0030344 BMDL = 0.182764 

C-40
Output C-10. Multistage-Weibull analysis of nasal cavity tumors in male rats, 1,2-

dibromoethane inhalation exposure 

C-41
Generating Model Fit Table ---

TITLE: Nasal cavity tumors, male rats 

Model: One Stage Weib Dataset: C:\Program

Files\TOX_RISK\edb_inh\mr_Nasal_f.ttd 

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -1.785287e+002 

Parameter Estimates : 

Q 0 = 1.347227E-022

Q 1 = 4.773207E-020

Z = 1.000000E+001 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 1 0 

0.36 50 7 32 

1.42 50 36 5 

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 7.1965E-001 Upper Bound(q1*) = 8.8228E-001 

Induction Time (T0) Set by User to 0 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 5.0690E-004 6.2145E-004 Not Reqstd

1.0000E-005 70.00 5.0690E-003 6.2145E-003 Not Reqstd

0.0001 70.00 5.0692E-002 6.2148E-002 Not Reqstd

0.0010 70.00 5.0715E-001 6.2176E-001 Not Reqstd

0.01 70.00 5.0945E+000 6.2458E+000 Not Reqstd

0.10 70.00 5.3407E+001 6.5476E+001 Not Reqstd 

C-42
Output C-11. Multistage analysis of hemangiosarcomas in male rats, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = hemang

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0 

Beta(2) = 1.01882 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(1)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(2) 

Beta(2) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0 NA 

Beta(2) 0.75631 0.293177 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-24.0861 

Deviance Test DF P-value 

Fitted model -26.2309 4.28957 2 0.1171 

Reduced model -46.6858 45.1993 2 <.0001 

AIC: 54.4618 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 46 0.000 

C-43
i: 2 

0.3600 0.0934 4.015 1 43 -0.828 

i: 3 

0.8900 0.4507 12.619 15 28 0.343 

Chi-square = 3.31 DF = 2 P-value = 0.1906 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 0.373241 

BMDL = 0.291394 

C-44
Output C-12. Multistage-Weibull analysis of hemangiosarcomas in male rats, 1,2-

dibromoethane inhalation exposure 

Generating Model Fit Table ---

TITLE: hemangiosarcomas, male rats 

Model: Two Stage Weib

Files\TOX_RISK\edb_inh\mr_hemang_i.ttd 

Dataset: C:\Program 

Functional form: 1 - EXP[( -Q0 - Q1 * D - Q2 * D^2) * (T - T0)^Z]

Maximum Log-Likelihood = -3.508137e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 0.000000E+000

Q 2 = 6.309854E-004

Z = 1.293779E+000 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 0 

0.36 50 0 1 

1.42 50 0 15 

Generating Extrapolated Doses Table ---

TITLE: hemangiosarcomas, male rats 

Dataset: C:\Program Files\TOX_RISK\edb_inh\mr_hemang_i.ttd

Exposure Pattern

Model: Two Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.3189E-004 Upper Bound(q1*) = 7.0002E-002 

C-45
 Induction Time (T0) Set by User to 0 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 6.3887E-003 1.9286E+000 Not Reqstd

1.0000E-005 70.00 6.3884E-002 6.0988E+000 Not Reqstd

0.0001 70.00 6.3857E-001 1.9287E+001 Not Reqstd

0.0010 70.00 6.3583E+000 6.1003E+001 Not Reqstd

0.01 70.00 6.1072E+001 1.9335E+002 Not Reqstd

0.10 70.00 4.6604E+002 6.2601E+002 Not Reqstd 

C-46
Output C-13. Multistage analysis of mesotheliomas in male rats, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = meso

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.0134084 

Beta(1) = 0 

Beta(2) = 1.56244 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Beta(1)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Background Beta(2) 

Background 1 -0.49 

Beta(2) -0.49 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0.0208905 0.11861 

Beta(1) 0 NA 

Beta(2) 1.52272 0.433051 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-46.416 

Deviance Test DF P-value 

Fitted model -46.4358 0.0395632 1 0.8423 

Reduced model -72.8358 52.8395 2 <.0001 

AIC: 96.8716 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

C-47
i: 1 

0.0000 0.0209 0.961 1 46 0.041 

i: 2 

0.3600 0.1962 8.438 8 43 -0.065 

i: 3 

0.8900 0.7069 24.742 25 35 0.036 

Chi-square = 0.04 DF = 1 P-value = 0.8431 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.2 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.263045 BMD = 0.382809 

BMDL = 0.138834 BMDL = 0.263662 

C-48
Output C-14. Multistage-Weibull analysis of mesotheliomas in male rats, 1,2-

dibromoethane inhalation exposure 

Generating Model Fit Table ---

TITLE: mesotheliomas, male rats 

Model: One Stage Weib Dataset: C:\Program Files\TOX_RISK\edb_inh\mr_meso.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -6.157661e+001 

Parameter Estimates : 

Q 0 = 1.735778E-004

Q 1 = 5.786966E-003

Z = 1.000000E+000 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 1 

0.36 50 0 8 

1.42 50 0 25 

Generating Extrapolated Doses Table ---

TITLE: mesotheliomas, male rats 

Dataset: C:\Program Files\TOX_RISK\edb_inh\mr_meso.ttd

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.5763E-001 Upper Bound(q1*) = 3.4365E-001 

Induction Time (T0) Set by User to 0 

C-49
 Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 1.3014E-003 1.7360E-003 Not Reqstd

1.0000E-005 70.00 1.3014E-002 1.7360E-002 Not Reqstd

0.0001 70.00 1.3015E-001 1.7360E-001 Not Reqstd

0.0010 70.00 1.3021E+000 1.7368E+000 Not Reqstd

0.01 70.00 1.3080E+001 1.7447E+001 Not Reqstd

0.10 70.00 1.3712E+002 1.8290E+002 Not Reqstd 

C-50
Output C-15. Multistage analysis of nasal cavity tumors in female rats, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = all_nasal

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.132247 

Beta(1) = 4.03267 

Beta(2) = 0 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Beta(2)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Background Beta(1) 

Background 1 -0.48 

Beta(1) -0.48 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0.0220652 0.143887 

Beta(1) 4.70131 0.855238 

Beta(2) 0 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-42.3319 

Deviance Test DF P-value 

Fitted model -42.7387 0.813627 1 0.3671 

Reduced model -95.3053 105.947 2 <.0001 

AIC: 89.4774 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

C-51
i: 1 

0.0000 0.0221 1.037 1 47 -0.037 

i: 2 

0.2500 0.6981 32.112 34 46 0.195 

i: 3 

0.6600 0.9561 43.979 43 46 -0.507 

Chi-square = 0.87 DF = 1 P-value = 0.3523 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.7 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.0224109 BMD = 0.256093 

BMDL = 0.0177547 BMDL = 0.202887 

C-52
Output C-16. Multistage-Weibull analysis of nasal cavity tumors in female rats, 1,2-

dibromoethane inhalation exposure 

C-53
Generating Model Fit Table ---

TITLE: Nasal cavity tumors - all, female rats

Model: One Stage Weib Dataset: C:\Program

Files\TOX_RISK\edb_inh\fr_Nasal_f.ttd 

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -1.673437e+002 

Parameter Estimates : 

Q 0 = 1.275305E-022

Q 1 = 4.632330E-020

Z = 1.000000E+001 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 1 0 

0.25 50 5 29 

0.99 49 32 11 

Generating Extrapolated Doses Table ---

TITLE: Nasal cavity tumors - all, female rats 

Dataset: C:\Program Files\TOX_RISK\edb_inh\fr_Nasal_f.ttd

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 8.2967E-001 Upper Bound(q1*) = 1.0275E+000 

Induction Time (T0) Set by User to 0 

Do 

se 

Es 

ti 

ma 

te 

s 

(p

pb

) 

95 

.0 

0 

% 

C-54
 95.00 % 

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 4.3525E-004 5.3904E-004 Not Reqstd

1.0000E-005 70.00 4.3525E-003 5.3904E-003 Not Reqstd

0.0001 70.00 4.3527E-002 5.3906E-002 Not Reqstd

0.0010 70.00 4.3546E-001 5.3931E-001 Not Reqstd

0.01 70.00 4.3744E+000 5.4175E+000 Not Reqstd

0.10 70.00 4.5858E+001 5.6793E+001 Not Reqstd 

C-55
Output C-17. Multistage analysis of alveolar/bronchiolar adenomas, carcinomas in female 

rats, 1,2-dibromoethane inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = alv_br

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.358396 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.197519 0.252845 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-12.5101 

Deviance Test DF P-value 

Fitted model -15.1907 5.36137 2 0.06852 

Reduced model -20.5225 16.0249 2 0.0003313 

AIC: 32.3815 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 47 0.000 

i: 2 

0.2500 0.0482 2.024 0 42 -1.051 

C-56
i: 3 

0.6600 0.1222 3.056 5 25 0.725 

Chi-square = 3.54 DF = 2 P-value = 0.1707 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 0.533421 

BMDL = 0.276777 

C-57
Output C-18. Multistage-Weibull analysis of alveolar/bronchiolar adenomas, carcinomas in 

female rats, 1,2-dibromoethane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fr_Alv_br.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -1.706675e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 1.213408E-007

Z = 2.453743E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) 

tumors tumors 

0 50 0 0 

3.10 50 0 0 

12.30 50 0 5 

Exposure Pattern

of animals with fatal with incidental 

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.7040E-002 Upper Bound(q1*) = 7.3685E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 6.0694E-003 1.6540E-002 Not Reqstd

1.0000E-005 70.00 6.0694E-002 1.6540E-001 Not Reqstd

0.0001 70.00 6.0697E-001 1.6540E+000 Not Reqstd

0.0010 70.00 6.0724E+000 1.6548E+001 Not Reqstd

0.01 70.00 6.0999E+001 1.6623E+002 Not Reqstd

0.10 70.00 6.3947E+002 1.7426E+003 Not Reqstd 

C-58
Output C-19. Multistage analysis of hemangiosarcomas in female rats, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = hemang

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.343027 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.192493 0.249396 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-12.7283 

Deviance Test DF P-value 

Fitted model -15.3194 5.18217 2 0.07494 

Reduced model -20.5672 15.6776 2 0.0003941 

AIC: 32.6389 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 47 0.000 

i: 2 

C-59
 0.2500 0.0470 1.973 0 42 -1.049 

i: 3 

0.6600 0.1193 3.102 5 26 0.695 

Chi-square = 3.39 DF = 2 P-value = 0.1837 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 0.547347 

BMDL = 0.284013 

C-60
Output C-20. Multistage-Weibull analysis of hemangiosarcomas in female rats, 1,2-

dibromoethane inhalation exposure 

Generating Model Fit Table ---

TITLE: Circ. system: hemangiomas, female rats

Model: One Stage Weib

Files\TOX_RISK\edb_inh\fr_Hemang_i.ttd 

Dataset: C:\Program 

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -1.736830e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 1.388308E-004

Z = 1.000000E+000 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 0 

1.80 50 0 0 

7.10 50 0 5 

Generating Extrapolated Doses Table ---

TITLE: Circ. system: hemangiomas, female rats 

Dataset: C:\Program Files\TOX_RISK\edb_inh\fr_Hemang_i.ttd

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 6.2570E-003 Upper Bound(q1*) = 1.2277E-002 

C-61
 Induction Time (T0) Set by User to 0 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 3.6427E-002 7.1476E-002 Not Reqstd

1.0000E-005 70.00 3.6428E-001 7.1476E-001 Not Reqstd

0.0001 70.00 3.6429E+000 7.1479E+000 Not Reqstd

0.0010 70.00 3.6446E+001 7.1512E+001 Not Reqstd

0.01 70.00 3.6611E+002 7.1836E+002 Not Reqstd

0.10 70.00 3.8380E+003 7.5307E+003 Not Reqstd 

C-62
Output C-21. Multistage analysis of mammary fibroadenomas in female rats, 1,2-

dibromoethane inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = fibro_inc

Independent variable = ppm

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

User has chosen the log transformed model

Default Initial Parameter Values 

background = 0.0851064 

intercept = -0.381425 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

background intercept 

background 1 -0.3 

intercept -0.3 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.0874464 0.0417909 

intercept -0.445308 0.268769 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-64.5786 

Deviance Test DF P-value 

Fitted model -65.3126 1.46797 1 0.2257 

Reduced model -87.3632 45.5692 2 <.0001 

AIC: 134.625 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0874 4.110 4 47 -0.05679 

1.8000 0.5762 26.504 29 46 0.7447 

C-63
 4.8000 0.7761 26.386 24 34 -0.9816 

Chi-square = 1.52 DF = 1 P-value = 0.2174 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.55 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.173441 BMD = 1.90785 

BMDL = 0.111687 BMDL = 1.22856 

C-64
Output C-22. Multistage-Weibull analysis of mammary fibroadenomas in female rats, 1,2-

dibromoethane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fr_Mamm_fib.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -7.896265e+001 

Parameter Estimates : 

Q 0 = 6.239703E-014

Q 1 = 3.012200E-013

Z = 6.030535E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 4 

1.80 50 0 29 

7.10 50 0 24 

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 1.1295E+000 Upper Bound(q1*) = 1.5809E+000 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 2.8289E-004 3.9597E-004 Not Reqstd

1.0000E-005 70.00 2.8290E-003 3.9597E-003 Not Reqstd

0.0001 70.00 2.8291E-002 3.9599E-002 Not Reqstd

0.0010 70.00 2.8304E-001 3.9616E-001 Not Reqstd

0.01 70.00 2.8432E+000 3.9796E+000 Not Reqstd 

C-65
 0.10 70.00 2.9806E+001 4.1719E+001 Not Reqstd

Output C-23. Multistage analysis of mammary adenocarcinomas in female rats, 1,2-

dibromoethane inhalation exposure 

==================================================================== 

Multistage Model. $Revision: 2.1 $ $Date: 2000/08/21 03:38:21 $

Input Data File: F:\KHOGAN02\_BMDS\EDB_INH_FR.(d)

Gnuplot Plotting File: F:\KHOGAN02\_BMDS\EDB_INH_FR.plt

Mon Feb 16 14:11:39 2004 

==================================================================== 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = m_aden

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.238933 

Asymptotic Correlation Matrix of Parameter Estimates 

Background Beta(1) 

Background 1 -0.59 

Beta(1) -0.59 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0.0136816 0.116137 

Beta(1) 0.131115 0.303951 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood) Deviance Test DF 

-16.0018 

P-value 

Fitted model -18.4844 4.96513 1 0.02586 

Reduced model -20.5672 9.13067 2 0.01041 

AIC: 40.9688 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0137 0.643 1 47 0.563 

C-66
i: 2 

0.2500 0.0455 1.910 0 42 -1.048 

i: 3 

0.6600 0.0954 2.482 4 26 0.676 

Chi-square = 3.23 DF = 1 P-value = 0.0723 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 0.803575 

BMDL = 0.357022 

C-67
Output C-24. Multistage-Weibull analysis of mammary adenocarcinomas in female rats, 

1,2-dibromoethane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fr_Mamm_ad.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -2.060090e+001 

Parameter Estimates : 

Q 0 = 1.146848E-004

Q 1 = 9.364217E-005

Z = 1.000000E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 1 

1.80 50 0 0 

7.10 50 0 4 

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.7175E-002 Upper Bound(q1*) = 6.6137E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 6.7621E-003 1.6457E-002 Not Reqstd

1.0000E-005 70.00 6.7622E-002 1.6458E-001 Not Reqstd

0.0001 70.00 6.7625E-001 1.6458E+000 Not Reqstd

0.0010 70.00 6.7655E+000 1.6466E+001 Not Reqstd

0.01 70.00 6.7962E+001 1.6540E+002 Not Reqstd

0.10 70.00 7.1246E+002 1.7340E+003 Not Reqstd 

C-68
Output C-25. Multistage analysis of nasal cavity tumors in female mice, 1,2-dibromoethane

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = all_nasal

Independent variable = rgdr_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0 

Beta(2) = 0.412082 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background -Beta(1)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(2) 

Beta(2) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0 NA 

Beta(2) 0.313575 0.224054 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-16.4077 

Deviance Test DF P-value 

Fitted model -18.1251 3.4347 2 0.1795 

Reduced model -28.7452 24.675 2 <.0001 

AIC: 38.2501 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 46 0.000 

C-69
C-70

i: 2

 0.3600 0.0398 1.513 0 38 -1.041

i: 3

 0.9500 0.2465 6.655 8 27 0.268

 Chi-square = 1.94 DF = 2 P-value = 0.3797

 Benchmark Dose Computation

Specified effect = 0.1

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.579653

 BMDL = 0.431521

Specified effect = 0.25

Risk Type = Extra risk 

Confidence level = 0.95

 BMD = 0.957824

 BMDL = 0.733903
Output C-26. Multistage-Weibull analysis of nasal cavity tumors in female mice, 1,2-

dibromoethane inhalation exposure 

Generating Model Fit Table ---

TITLE: Female mice nasal cavity tumors

Model: One Stage Weib Dataset: C:\Program

Files\TOX_RISK\edb_inh\fm_nasal.ttd 

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -2.495443e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 1.177299E-003

Z = 1.000000E+000 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 0 

0.36 50 0 0 

1.42 50 0 8 

Generating Extrapolated Doses Table ---

TITLE: Female mice nasal cavity tumors 

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_nasal.ttd

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 5.4729E-002 Upper Bound(q1*) = 8.0545E-002 

C-71
 Induction Time (T0) Set by User to 0 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 5.5495E-003 8.1673E-003 Not Reqstd

1.0000E-005 70.00 5.5496E-002 8.1674E-002 Not Reqstd

0.0001 70.00 5.5498E-001 8.1677E-001 Not Reqstd

0.0010 70.00 5.5523E+000 8.1714E+000 Not Reqstd

0.01 70.00 5.5775E+001 8.2084E+001 Not Reqstd

0.10 70.00 8.3863E+002 8.6051E+002 Not Reqstd 

C-72
Output C-27. Multistage analysis of lung/bronchial adenomas, carcinomas in female mice, 

1,2-dibromoethane inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = lungbr

Independent variable = tb_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.0299027 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0194024 0.0142568 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-20.6726 

Deviance Test DF P-value 

Fitted model -22.4636 3.58204 2 0.1668 

Reduced model -31.1506 20.9561 2 <.0001 

AIC: 46.9272 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 46 0.000 

i: 2 

C-73
 4.8600 0.0900 3.419 1 38 -0.778 

i: 3 

12.9000 0.2214 5.757 8 26 0.500 

Chi-square = 3.00 DF = 2 P-value = 0.2227 

Benchmark Dose Computation 

Specified effect = 0.1 

Risk Type = Extra risk 

Confidence level = 0.95 

BMD = 5.43029 

BMDL = 3.28056 

C-74
Output C-28. Multistage-Weibull analysis of lung/bronchial adenomas, carcinomas in 

female mice, 1,2-dibromoethane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_trbr.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -2.704645e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 9.896876E-005

Z = 1.000000E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) 

tumors tumors 

0 49 0 0 

4.86 50 0 1 

19.20 50 0 8 

of animals with fatal with incidental 

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 5.0781E-003 Upper Bound(q1*) = 1.0765E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 4.1524E-002 8.8023E-002 Not Reqstd

1.0000E-005 70.00 4.1524E-001 8.8024E-001 Not Reqstd

0.0001 70.00 4.1526E+000 8.8028E+000 Not Reqstd

0.0010 70.00 4.1545E+001 8.8067E+001 Not Reqstd 

C-75
 0.01 70.00 4.1733E+002 8.8466E+002 Not Reqstd

0.10 70.00 4.3750E+003 9.2742E+003 Not Reqstd 

C-76
Output C-29. Multistage analysis of alveolar/bronchiolar adenomas, carcinomas in female 

mice, 1,2-dibromoethane inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1-beta2*dose^2)] 

The parameter betas are restricted to be positive 

Dependent variable = alv_br

Independent variable = pulm_ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 3

Total number of specified parameters = 0

Degree of polynomial = 2

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0.02142 

Beta(1) = 0 

Beta(2) = 0.0114798 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Beta(1)

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Background Beta(2) 

Background 1 -0.39 

Beta(2) -0.39 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0.0763105 0.115724 

Beta(1) 0 NA 

Beta(2) 0.0100582 0.00220996 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-48.069 

Deviance Test DF P-value 

Fitted model -48.6198 1.10154 1 0.2939 

Reduced model -88.859 81.5799 2 <.0001 

AIC: 101.24 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

C-77
 -----------------------------------------------------------------------

i: 1 

0.0000 0.0763 3.510 4 46 0.151 

i: 2 

5.7600 0.3384 13.536 11 40 -0.283 

i: 3 

15.2000 0.9096 40.021 41 44 0.270 

Chi-square = 1.06 DF = 1 P-value = 0.3040 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.3 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 3.23653 BMD = 5.95493 

BMDL = 2.04555 BMDL = 4.84281 

C-78
Output C-30. Multistage-Weibull analysis of alveolar/bronchiolar adenomas, carcinomas in 

female mice, 1,2-dibromoethane inhalation exposure 

Model: Two Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_alvbr.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D - Q2 * D^2) * (T - T0)^Z]

Maximum Log-Likelihood = -5.951707e+001 

Parameter Estimates : 

Q 0 = 1.853318E-006

Q 1 = 0.000000E+000

Q 2 = 1.448222E-007

Z = 2.314668E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) 

tumors tumors 

0 49 0 4 

5.80 50 0 11 

22.70 50 0 41 

of animals with fatal with incidental 

Exposure Pattern

Model: Two Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 3.9741E-005 Upper Bound(q1*) = 1.6248E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 2.7511E-002 1.1247E+001 Not Reqstd

1.0000E-005 70.00 2.7510E-001 3.5567E+001 Not Reqstd

0.0001 70.00 2.7502E+000 1.1248E+002 Not Reqstd

0.0010 70.00 2.7419E+001 3.5576E+002 Not Reqstd 

C-79
 0.01 70.00 2.6643E+002 1.1276E+003 Not Reqstd

0.10 70.00 2.1863E+003 3.6508E+003 Not Reqstd 

C-80
Output C-31. Multistage analysis of hemangiosarcomas in female mice, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = hemang

Independent variable = ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.26484 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.235085 0.0535051 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-45.374 

Deviance Test DF P-value 

Fitted model -45.6745 0.600956 2 0.7405 

Reduced model -74.4981 58.2481 2 <.0001 

AIC: 93.349 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 46 0.000 

i: 2 

1.8000 0.3450 13.801 12 40 -0.199 

i: 3 

4.8000 0.6765 23.676 25 35 0.173 

C-81
 Chi-square = 0.59 DF = 2 P-value = 0.7454 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.35 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.44818 BMD = 1.83245 

BMDL = 0.342107 BMDL = 1.39876 

C-82
Output C-32. Multistage-Weibull analysis of hemangiosarcomas in female mice, 1,2-

dibromoethane inhalation exposure 

Generating Model Fit Table ---

TITLE: Female mice hemangiosarcomas 

Model: One Stage Weib

Files\TOX_RISK\edb_inh\fm_hemang_inc.ttd 

Dataset: C:\Program 

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -5.867227e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 7.001441E-007

Z = 2.709143E+000 

T0 = 0.000000E+000 Set by User 

Avg. Doses -------------------- Number --------------------

(ppm) of animals with fatal with incidental 

tumors tumors 

0 50 0 0 

1.80 50 0 12 

7.10 50 0 25 

Generating Extrapolated Doses Table ---

TITLE: Female mice hemangiosarcomas 

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_hemang_inc.ttd

Exposure Pattern

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg/day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 6.8278E-002 Upper Bound(q1*) = 8.9891E-002 

C-83
 Induction Time (T0) Set by User to 0 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 4.9725E-003 6.5466E-003 Not Reqstd

1.0000E-005 70.00 4.9726E-002 6.5466E-002 Not Reqstd

0.0001 70.00 4.9728E-001 6.5469E-001 Not Reqstd

0.0010 70.00 4.9750E+000 6.5498E+000 Not Reqstd

0.01 70.00 4.9976E+001 6.5795E+001 Not Reqstd

0.10 70.00 5.2391E+002 6.8975E+002 Not Reqstd 

C-84
Output C-33. Multistage analysis of fibrosarcomas in female mice, 1,2-dibromoethane 

inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background + (1-background)*[1-EXP(

-beta1*dose^1)] 

The parameter betas are restricted to be positive 

Dependent variable = fibro_inc

Independent variable = ppm 

Total number of observations = 3

Total number of records with missing values = 0

Total number of parameters in model = 2

Total number of specified parameters = 0

Degree of polynomial = 1

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

Default Initial Parameter Values 

Background = 0 

Beta(1) = 0.111017 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -Background

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

Beta(1) 

Beta(1) 1 

Parameter Estimates 

Variable Estimate Std. Err. 

Background 0 NA 

Beta(1) 0.0959514 0.0438874 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-33.1848 

Deviance Test DF P-value 

Fitted model -33.4118 0.454099 2 0.7969 

Reduced model -45.933 25.4965 2 <.0001 

AIC: 68.8237 

Goodness of Fit 

Dose Est._Prob. Expected Observed Size Chi^2 Res. 

-----------------------------------------------------------------------

i: 1 

0.0000 0.0000 0.000 0 46 0.000 

i: 2 

C-85
 1.8000 0.1586 6.186 5 39 -0.228 

i: 3 

4.8000 0.3691 9.965 11 27 0.165 

Chi-square = 0.44 DF = 2 P-value = 0.8022 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.15 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 1.09806 BMD = 1.69376 

BMDL = 0.745016 BMDL = 1.14919 

C-86
Output C-34. Multistage-Weibull analysis of fibrosarcomas in female mice, 1,2-

dibromoethane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_fibsarc.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -4.280865e+001 

Parameter Estimates : 

Q 0 = 0.000000E+000

Q 1 = 4.944679E-004

Z = 1.000000E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) 

tumors tumors 

0 50 0 0 

1.80 50 0 5 

7.10 50 0 11 

Exposure Pattern

of animals with fatal with incidental 

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.5367E-002 Upper Bound(q1*) = 4.3105E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 1.0370E-002 1.7621E-002 Not Reqstd

1.0000E-005 70.00 1.0370E-001 1.7621E-001 Not Reqstd

0.0001 70.00 1.0370E+000 1.7622E+000 Not Reqstd

0.0010 70.00 1.0375E+001 1.7630E+001 Not Reqstd

0.01 70.00 1.0422E+002 1.7709E+002 Not Reqstd

0.10 70.00 1.0926E+003 1.8565E+003 Not Reqstd 

C-87
Output C-35. Multistage-Weibull analysis of mammary adenocarcinomas in female mice, 

1,2-dibromothane inhalation exposure 

BMDS MODEL RUN 

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 

The form of the probability function is: 

P[response] = background+(1-background)/[1+EXP(-intercept-slope*Log(dose))]

Dependent variable = m_aden

Independent variable = ppm

Slope parameter is restricted as slope >= 1

Total number of observations = 3

Total number of records with missing values = 0

Maximum number of iterations = 250

Relative Function Convergence has been set to: 1e-008

Parameter Convergence has been set to: 1e-008

User has chosen the log transformed model

Default Initial Parameter Values 

background = 0.0434783 

intercept = -1.65098 

slope = 1 

Asymptotic Correlation Matrix of Parameter Estimates 

( *** The model parameter(s) -slope

have been estimated at a boundary point, or have been specified by the user,

and do not appear in the correlation matrix ) 

background intercept 

background 1 -0.44 

intercept -0.44 1 

Parameter Estimates 

Variable Estimate Std. Err. 

background 0.051207 0.0351732 

intercept -1.86383 0.33506 

slope 1 NA 

NA - Indicates that this parameter has hit a bound

implied by some inequality constraint and thus

has no standard error. 

Analysis of Deviance Table 

Model 

Full model 

Log(likelihood)

-51.3106 

Deviance Test DF P-value 

Fitted model -53.0044 3.38748 1 0.06569 

Reduced model -59.7173 16.8133 2 0.0002234 

AIC: 110.009 

Goodness of Fit 

Scaled 

Dose Est._Prob. Expected Observed Size Residual 

------------------------------------------------------------------------

0.0000 0.0512 2.356 2 46 -0.2378 

1.8000 0.2583 10.330 14 40 1.326 

4.8000 0.4561 12.314 9 27 -1.281 

C-88
 Chi-square = 3.45 DF = 1 P-value = 0.0631 

Benchmark Dose Computation 

Specified effect = 0.1 Specified effect = 0.25 

Risk Type = Extra risk Risk Type = Extra risk 

Confidence level = 0.95 Confidence level = 0.95 

BMD = 0.716491 BMD = 2.14947 

BMDL = 0.433751 BMDL = 1.30125 

C-89
Output C-36. Multistage-Weibull analysis of mammary adenocarcinomas in female mice, 

1,2-dibromothane inhalation exposure 

Model: One Stage Weib

Dataset: C:\Program Files\TOX_RISK\edb_inh\fm_mam_ad.ttd

Functional form: 1 - EXP[( -Q0 - Q1 * D ) * (T - T0)^Z]

Maximum Log-Likelihood = -6.928667e+001 

Parameter Estimates : 

Q 0 = 1.069724E-003

Q 1 = 3.577742E-004

Z = 1.000000E+000 

T0 = 0.000000E+000 

Avg. Doses -------------------- Number --------------------

(ppm) 

tumors tumors 

0 50 0 2 

1.80 50 0 14 

7.10 50 0 9 

Exposure Pattern

of animals with fatal with incidental 

Model: One Stage Weib Age Begins: 0 Age Ends: 70

Target Species: Human Weeks/Year: 52 Days/Week: 7

Route: Air Hours/Day : 24

Animal to human conversion method: PPM IN AIR 

Unit Potency [ per mg/kg-day ] (computed for Risk of 1.0E-6)

Lower Bound = Not Reqstd MLE = 2.1170E-002 Upper Bound(q1*) = 3.8976E-002 

Dose Estimates (ppb) 

95.00 % 95.00 %

Incid Extra Risk Time Lower Bound MLE Upper Bound

1.0000E-006 70.00 1.1468E-002 2.1114E-002 Not Reqstd

1.0000E-005 70.00 1.1468E-001 2.1114E-001 Not Reqstd

0.0001 70.00 1.1469E+000 2.1115E+000 Not Reqstd

0.0010 70.00 1.1474E+001 2.1125E+001 Not Reqstd

0.01 70.00 1.1526E+002 2.1221E+002 Not Reqstd

0.10 70.00 1.2083E+003 2.2246E+003 Not Reqstd 

C-90