TOXICOLOGICAL PROFILE FOR
 

RDX
 

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

Public Health Service
 

Agency for Toxic Substances and Disease Registry
 

January 2012 
RDX ii 

DISCLAIMER 

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

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

Services. 

 


 

RDX iii 

UPDATE STATEMENT 

A draft for public comment Toxicological Profile for RDX was released in 2010. This present edition 

supersedes any previously released draft or final profile. 

Toxicological profiles are revised and republished as necessary. For information regarding the update 

status of previously released profiles, contact ATSDR at: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Human Health Sciences (proposed)/
 

Environmental Toxicology Branch (proposed) 

1600 Clifton Road NE 

Mailstop F-62 

Atlanta, Georgia 30333
 
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RDX v 

FOREWORD 

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

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

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

and republished as necessary. 

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

information for the hazardous substance described therein. Each peer-reviewed profile identifies and 

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

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

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

The focus of the profiles is on health and toxicologic information. Each toxicological profile begins with 

a public health statement that describes, in nontechnical language, a substance’s relevant toxicological 

properties. Following the public health statement is information concerning levels of significant human 

exposure and, where known, significant health effects. The adequacy of information to determine a 

substance’s health effects is described in a health effects summary. Data needs that are of significance to 

protection of public health are identified by ATSDR and EPA. 

Each profile includes the following: 

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

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

exposure for the substance and the associated acute, subacute, and chronic health effects; 

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

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

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

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

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

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

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

revise these documents in response to public comments and as additional data become available. 

Therefore, we encourage comments that will make the toxicological profile series of the greatest use. 

Christopher J. Portier, Ph.D. 

Assistant Administrator
 

Agency for Toxic Substances and Disease Registry
 
 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 

RDX vi 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS 

Toxicological Profiles are a unique compilation of toxicological information on a given hazardous 

substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation 

of available toxicologic and epidemiologic information on a substance. Health care providers treating 

patients potentially exposed to hazardous substances will find the following information helpful for fast 

answers to often-asked questions. 

Primary Chapters/Sections of Interest 

Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating 

patients about possible exposure to a hazardous substance. It explains a substance’s relevant 

toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of 

the general health effects observed following exposure. 

Chapter 2: Relevance to Public Health: The Relevance to Public Health Section evaluates, interprets, 

and assesses the significance of toxicity data to human health. 

Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type 

of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length 

of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are 

reported in this section. 

NOTE: Not all health effects reported in this section are necessarily observed in the clinical 

setting. Please refer to the Public Health Statement to identify general health effects observed 

following exposure. 

Pediatrics: Four new sections have been added to each Toxicological Profile to address child health 

issues: 

Section 1.6 How Can (Chemical X) Affect Children?
 

Section 1.7 How Can Families Reduce the Risk of Exposure to (Chemical X)?
 

Section 3.7 Children’s Susceptibility
 

Section 6.6 Exposures of Children
 

Other Sections of Interest: 

Section 3.8 Biomarkers of Exposure and Effect 

Section 3.11 Methods for Reducing Toxic Effects 

ATSDR Information Center 

Phone: 1-800-CDC-INFO (800-232-4636) or 1-888-232-6348 (TTY) Fax: (770) 488-4178 

E-mail: cdcinfo@cdc.gov Internet: http://www.atsdr.cdc.gov 

The following additional material can be ordered through the ATSDR Information Center: 

Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an 

exposure history and how to conduct one are described, and an example of a thorough exposure 

history is provided. Other case studies of interest include Reproductive and Developmental 
 

 

 

 

 

 

 

 

RDX vii 

Hazards; Skin Lesions and Environmental Exposures; Cholinesterase-Inhibiting Pesticide 

Toxicity; and numerous chemical-specific case studies. 

Managing Hazardous Materials Incidents is a three-volume set of recommendations for on-scene 

(prehospital) and hospital medical management of patients exposed during a hazardous materials 

incident. Volumes I and II are planning guides to assist first responders and hospital emergency 

department personnel in planning for incidents that involve hazardous materials. Volume III— 

Medical Management Guidelines for Acute Chemical Exposures—is a guide for health care 

professionals treating patients exposed to hazardous materials. 

Fact Sheets (ToxFAQs) provide answers to frequently asked questions about toxic substances. 

Other Agencies and Organizations 

The National Center for Environmental Health (NCEH) focuses on preventing or controlling disease, 

injury, and disability related to the interactions between people and their environment outside the 

workplace. Contact: NCEH, Mailstop F-29, 4770 Buford Highway, NE, Atlanta, 

GA 30341-3724 • Phone: 770-488-7000 • FAX: 770-488-7015. 

The National Institute for Occupational Safety and Health (NIOSH) conducts research on occupational 

diseases and injuries, responds to requests for assistance by investigating problems of health and 

safety in the workplace, recommends standards to the Occupational Safety and Health 

Administration (OSHA) and the Mine Safety and Health Administration (MSHA), and trains 

professionals in occupational safety and health. Contact: NIOSH, 200 Independence Avenue, 

SW, Washington, DC 20201 • Phone: 800-356-4674 or NIOSH Technical Information Branch, 

Robert A. Taft Laboratory, Mailstop C-19, 4676 Columbia Parkway, Cincinnati, OH 45226-1998 

• Phone: 800-35-NIOSH. 

The National Institute of Environmental Health Sciences (NIEHS) is the principal federal agency for 

biomedical research on the effects of chemical, physical, and biologic environmental agents on 

human health and well-being. Contact: NIEHS, PO Box 12233, 104 T.W. Alexander Drive, 

Research Triangle Park, NC 27709 • Phone: 919-541-3212. 

Referrals 

The Association of Occupational and Environmental Clinics (AOEC) has developed a network of clinics 

in the United States to provide expertise in occupational and environmental issues. Contact: 

AOEC, 1010 Vermont Avenue, NW, #513, Washington, DC 20005 • Phone: 202-347-4976 

• FAX: 202-347-4950 • e-mail: AOEC@AOEC.ORG • Web Page: http://www.aoec.org/. 

The American College of Occupational and Environmental Medicine (ACOEM) is an association of 

physicians and other health care providers specializing in the field of occupational and 

environmental medicine. Contact: ACOEM, 25 Northwest Point Boulevard, Suite 700, Elk 

Grove Village, IL 60007-1030 • Phone: 847-818-1800 • FAX: 847-818-9266. 

 


 

	 

	 

RDX viii 

CONTRIBUTORS 

CHEMICAL MANAGER(S)/AUTHOR(S): 

Henry Abadin, M.S.P.H. 

Cassandra Smith, M.S. 

ATSDR, Division of Toxicology and Human Health Sciences (proposed), Atlanta, GA 

Lisa Ingerman, Ph.D., DABT 

Fernando T. Llados, Ph.D.
 

Lynn E. Barber, M.S. 

Daniel Plewak, B.S. 

Gary L. Diamond, Ph.D.
 

SRC, Inc., North Syracuse, NY 

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 

1. Health Effects Review. The Health Effects Review Committee examines the health effects 

chapter of each profile for consistency and accuracy in interpreting health effects and classifying 

end points. 

2.	 Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to 

substance-specific Minimal Risk Levels (MRLs), reviews the health effects database of each 

profile, and makes recommendations for derivation of MRLs. 

3.	 Data Needs Review. The Environmental Toxicology Branch (proposed) reviews data needs 

sections to assure consistency across profiles and adherence to instructions in the Guidance. 

4. Green Border Review. Green Border review assures the consistency with ATSDR policy. 
 

 

 

 

 

 

 

 

RDX	 	 ix 

PEER REVIEW 

A peer review panel was assembled for RDX. The panel consisted of the following members: 

1. Ping Gong, Ph.D., Senior Scientist, SpecPro, Inc., Vicksburg, Mississippi; 

2. Sam Kacew, Ph.D., Associate Director of Toxicology, McLauglin Centre for Population Health 

Risk Assessment, University of Ottawa, Ottawa, Ontario; and 

3. Sharon A. Meyer, Ph.D., Associate Professor, Department of Toxicology, College of Health 

Sciences, University of Louisiana at Monroe, Monroe, Louisiana. 

These experts collectively have knowledge of RDX’s physical and chemical properties, toxicokinetics, 

key health end points, mechanisms of action, human and animal exposure, and quantification of risk to 

humans. All reviewers were selected in conformity with the conditions for peer review specified in 

Section 104(I)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as 

amended. 

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer 

reviewers' comments and determined which comments will be included in the profile. A listing of the 

peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their 

exclusion, exists as part of the administrative record for this compound. 

The citation of the peer review panel should not be understood to imply its approval of the profile's final 

content. The responsibility for the content of this profile lies with the ATSDR. 
RDX x 

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RDX	 xi 

CONTENTS
 

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

UPDATE STATEMENT .............................................................................................................................iii
 

FOREWORD ................................................................................................................................................ v
 

QUICK REFERENCE FOR HEALTH CARE PROVIDERS.....................................................................vi
 

CONTRIBUTORS..................................................................................................................................... viii
 

PEER REVIEW ........................................................................................................................................... ix
 

CONTENTS................................................................................................................................................. xi
 

LIST OF FIGURES .................................................................................................................................... xv
 

LIST OF TABLES.................................................................................................................................... xvii
 

1. PUBLIC HEALTH STATEMENT.......................................................................................................... 1
 

1.1 WHAT IS RDX?........................................................................................................................... 1
 

1.2 WHAT HAPPENS TO RDX WHEN IT ENTERS THE ENVIRONMENT?.............................. 2
 

1.3 HOW MIGHT I BE EXPOSED TO RDX? .................................................................................. 2
 

1.4 HOW CAN RDX ENTER AND LEAVE MY BODY? ............................................................... 3
 

1.5 HOW CAN RDX AFFECT MY HEALTH? ................................................................................ 3
 

1.6 HOW CAN RDX AFFECT CHILDREN? ................................................................................... 4
 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO RDX? ............................... 4
 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN 

EXPOSED TO RDX?................................................................................................................... 5
 
 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH?.................................................................................................. 5
 

1.10 WHERE CAN I GET MORE INFORMATION?......................................................................... 6
 
 

2. RELEVANCE TO PUBLIC HEALTH ................................................................................................... 9
 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO RDX IN THE UNITED 

STATES........................................................................................................................................ 9
 

2.2 SUMMARY OF HEALTH EFFECTS ....................................................................................... 10
 

2.3 MINIMAL RISK LEVELS (MRLs)........................................................................................... 12
 
 

3. HEALTH EFFECTS.............................................................................................................................. 21
 
 

3.1 INTRODUCTION ...................................................................................................................... 21
 

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.................................... 21
 

3.2.1 Inhalation Exposure ............................................................................................................ 22
 

3.2.1.1 Death...............................................................................................................................22
 

3.2.1.2 Systemic Effects.............................................................................................................. 22
 

3.2.1.3 Immunological and Lymphoreticular Effects................................................................. 24
 

3.2.1.4 Neurological Effects ....................................................................................................... 24
 
 

3.2.1.5 Reproductive Effects....................................................................................................... 25
 
 

3.2.1.6 Developmental Effects.................................................................................................... 25
 

3.2.1.7 Cancer............................................................................................................................. 25
 
 

3.2.2 Oral Exposure ..................................................................................................................... 25
 

3.2.2.1 Death...............................................................................................................................25
 

3.2.2.2 Systemic Effects.............................................................................................................. 49
 

3.2.2.3 Immunological and Lymphoreticular Effects ................................................................. 53
 

3.2.2.4 Neurological Effects ....................................................................................................... 53
 
 

3.2.2.5 Reproductive Effects....................................................................................................... 55
 
 
3.2.2.6 Developmental Effects.................................................................................................... 56
 

3.2.2.7 Cancer............................................................................................................................. 57
 

3.2.3 Dermal Exposure................................................................................................................. 58
 

3.2.3.1 Death...............................................................................................................................58
 

3.2.3.2 Systemic Effects.............................................................................................................. 58
 

3.2.3.3 Immunological and Lymphoreticular Effects................................................................. 62
 

3.2.3.4 Neurological Effects ....................................................................................................... 62
 

3.2.3.5 Reproductive Effects....................................................................................................... 62
 
 

3.2.3.6 Developmental Effects.................................................................................................... 62
 

3.2.3.7 Cancer............................................................................................................................. 62
 
 

3.3 GENOTOXICITY....................................................................................................................... 62
 
 

3.4 TOXICOKINETICS ................................................................................................................... 65
 

3.4.1 Absorption........................................................................................................................... 65
 
 

3.4.1.1 Inhalation Exposure ........................................................................................................ 65
 

3.4.1.2 Oral Exposure ................................................................................................................. 65
 

3.4.1.3 Dermal Exposure............................................................................................................. 66
 

3.4.2 Distribution ......................................................................................................................... 67
 

3.4.2.1 Inhalation Exposure ........................................................................................................ 67
 

3.4.2.2 Oral Exposure ................................................................................................................. 67
 

3.4.2.3 Dermal Exposure............................................................................................................. 68
 

3.4.3 Metabolism ......................................................................................................................... 68
 

3.4.4 Elimination and Excretion .................................................................................................. 69
 

3.4.4.1 Inhalation Exposure ........................................................................................................ 69
 

3.4.4.2 Oral Exposure ................................................................................................................. 69
 

3.4.4.3 Dermal Exposure............................................................................................................. 70
 

3.4.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models........... 70
 

3.5 MECHANISMS OF ACTION.................................................................................................... 78
 

3.5.1 Pharmacokinetic Mechanisms............................................................................................. 78
 
 

3.5.2 Mechanisms of Toxicity...................................................................................................... 79
 

3.5.3 Animal-to-Human Extrapolations....................................................................................... 81
 

3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS ........................... 82
 

3.7 CHILDREN’S SUSCEPTIBILITY ............................................................................................ 83
 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT...................................................................... 84
 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to RDX.............................................. 85
 

3.8.2 Biomarkers Used to Characterize Effects Caused by RDX................................................ 86
 

3.9 INTERACTIONS WITH OTHER CHEMICALS...................................................................... 86
 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................................................ 87
 

3.11 METHODS FOR REDUCING TOXIC EFFECTS.................................................................... 87
 

3.11.1 Reducing Peak Absorption Following Exposure ................................................................ 87
 

3.11.2 Reducing Body Burden....................................................................................................... 88
 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects.............................................. 88
 

3.12 ADEQUACY OF THE DATABASE......................................................................................... 88
 

3.12.1 Existing Information on Health Effects of RDX................................................................. 88
 

3.12.2 Identification of Data Needs ............................................................................................... 90
 

3.12.3 Ongoing Studies.................................................................................................................. 97
 

4. CHEMICAL AND PHYSICAL INFORMATION................................................................................ 99
 

4.1 CHEMICAL IDENTITY............................................................................................................ 99
 

4.2 PHYSICAL AND CHEMICAL PROPERTIES .........................................................................99
 

RDX xii 
5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL.......................................................... 103
 

5.1 PRODUCTION......................................................................................................................... 103
 

5.2 IMPORT/EXPORT................................................................................................................... 104
 

5.3 USE........................................................................................................................................... 104
 

5.4 DISPOSAL ...............................................................................................................................104
 

6. POTENTIAL FOR HUMAN EXPOSURE ......................................................................................... 107
 

6.1 OVERVIEW ............................................................................................................................. 107
 

6.2 RELEASES TO THE ENVIRONMENT ................................................................................. 109
 

6.2.1 Air ..................................................................................................................................... 109
 
 

6.2.2 Water................................................................................................................................. 109
 
 

6.2.3 Soil.................................................................................................................................... 110
 
 

6.3 ENVIRONMENTAL FATE..................................................................................................... 110
 
 

6.3.1 Transport and Partitioning ................................................................................................ 110
 

6.3.2 Transformation and Degradation ...................................................................................... 112
 

6.3.2.1 Air ................................................................................................................................. 112
 

6.3.2.2 Water............................................................................................................................. 112
 
 

6.3.2.3 Sediment and Soil ......................................................................................................... 115
 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ................................ 116
 
 

6.4.1 Air ..................................................................................................................................... 116
 
 

6.4.2 Water................................................................................................................................. 116
 
 

6.4.3 Sediment and Soil ............................................................................................................. 118
 

6.4.4 Other Environmental Media.............................................................................................. 119
 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE....................................... 119
 

6.6 EXPOSURES OF CHILDREN ................................................................................................ 120
 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES............................................. 121
 

6.8 ADEQUACY OF THE DATABASE....................................................................................... 121
 
 

6.8.1 Identification of Data Needs ............................................................................................. 122
 
 

6.8.2 Ongoing Studies................................................................................................................ 125
 

7. ANALYTICAL METHODS................................................................................................................ 127
 

7.1 BIOLOGICAL MATERIALS .................................................................................................. 128
 

7.2 ENVIRONMENTAL SAMPLES............................................................................................. 131
 
 

7.3 ADEQUACY OF THE DATABASE....................................................................................... 140
 
 

7.3.1 Identification of Data Needs ............................................................................................. 140
 

7.3.2 Ongoing Studies................................................................................................................ 141
 

8. REGULATIONS, ADVISORIES, AND GUIDELINES..................................................................... 143
 

9. REFERENCES .................................................................................................................................... 147
 

10. GLOSSARY ...................................................................................................................................... 167
 

APPENDICES 

A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS .............................................................A-1
 

B. USER’S GUIDE.................................................................................................................................. B-1
 
 

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS...................................................................... C-1
 

D. INDEX ................................................................................................................................................ D-1
 
 

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RDX xv 

LIST OF FIGURES 

3-1. Levels of Significant Exposure to RDX – Oral .................................................................................. 44 

3-2. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a
 

Hypothetical Chemical Substance...................................................................................................... 72
 

3-3. Existing Information on Health Effects of RDX ................................................................................ 89
 

6-1. Frequency of NPL Sites with RDX Contamination.......................................................................... 108
 
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RDX xvii 

LIST OF TABLES
 

3-1. Levels of Significant Exposure to RDX – Oral .................................................................................. 26 

3-2. Levels of Significant Exposure to RDX – Dermal ............................................................................. 60 

3-3. Genotoxicity of RDX In Vitro ............................................................................................................ 63
 

3-4. Parameter Values for Sweeney et al. (2012) PBPK Model of RDX in Rats and Humans................. 74
 

4-1. Chemical Identity of RDX................................................................................................................ 100
 

4-2. Physical and Chemical Properties of RDX....................................................................................... 101
 

6-1. Ongoing Studies on RDX................................................................................................................. 126
 

7-1. Analytical Methods for Determining RDX in Biological Materials................................................. 129
 

7-2. Analytical Methods for Determining RDX in Environmental Samples........................................... 132
 

7-3. Ongoing Studies on RDX................................................................................................................. 142
 

8-1. Regulations and Guidelines Applicable to RDX.............................................................................. 144
 
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RDX 1 

1. PUBLIC HEALTH STATEMENT 

This public health statement tells you about hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and the effects 

of exposure to it. 

The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the 

nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term 

federal clean-up activities. RDX has been found in at least 31 of the 1,699 current or former NPL sites. 

Although the total number of NPL sites evaluated for this substance is not known, the possibility exists 

that the number of sites at which RDX is found may increase in the future as more sites are evaluated. 

This information is important because these sites may be sources of exposure and exposure to this 

substance may be harmful. 

When a substance is released either from a large area, such as an industrial plant, or from a container, 

such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You 

can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, 

eating, or drinking the substance, or by skin contact. 

If you are exposed to RDX, many factors will determine whether you will be harmed. These factors 

include the dose (how much), the duration (how long), and how you come in contact with it. You must 

also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and 

state of health. 

1.1 WHAT IS RDX? 

Other names for RDX RDX stands for Royal Demolition Explosive, 

also known as cyclonite, hexogen, and 

hexahydro-1,3,5-trinitro-1,3,5-triazine. 

White crystalline solid RDX is an explosive on its own, and can be 

combined with other ingredients to make plastic 

explosives (C-4 contains 91% RDX). Its odor 

and taste are unknown. When heated, acrid 

fumes may be released. 
 

 

 

 

 

 


 


 

RDX 2 

1. PUBLIC HEALTH STATEMENT 

Used in explosives RDX is used as an explosive. It is a synthetic 

product that does not occur naturally in the 

environment. 

1.2 WHAT HAPPENS TO RDX WHEN IT ENTERS THE ENVIRONMENT?
 

Found in water, soil, and air RDX particles can enter air when it is disposed 

of by burning. RDX can enter water from 

disposal of waste water from ammunition 

plants. RDX can enter water or soil from spills 

or leaks from improper disposal at plants or 

hazardous waste sites and at current and 

former military installations. 

Removal from soil, water, and air RDX is slow dissolving in water. It does not 

bind significantly to soils and can leach to 

groundwater from soil. In water and air, RDX 

can break down in hours, but breaks down 

more slowly in soil. It does not build up in fish 

or people. 

1.3 HOW MIGHT I BE EXPOSED TO RDX?
 

Air You may be exposed to RDX by the inhalation, 

oral, or dermal routes, or by any combination of 

these routes. Typically, only people who work 

with RDX can potentially breathe RDX dust or 

get it on their skin. You can be exposed if you 

breathe RDX fumes from explosions or bombing 

ranges of burning RDX. 

Water and soil You may be exposed to RDX by drinking 

contaminated water or by touching 

contaminated soil if you live near facilities that 

produce or use RDX. RDX has been found in 

water and soil near some ammunition plants, 

current or former military installations and 

storage areas. 

Food You may be exposed to RDX by ingesting 

agricultural crops grown in contaminated soils 

irrigated with contaminated water. 
 

 

 

 

 

 

 

 

 

 

 

 


 

RDX 3 

1. PUBLIC HEALTH STATEMENT 

1.4 HOW CAN RDX ENTER AND LEAVE MY BODY? 

Enter the body 

• Inhalation 

• Oral 

• Dermal contact 

RDX can enter your body if you breathe in fumes of burning 

RDX or from the detonation of munitions containing RDX or if 

you breath in the dust from powdered RDX. 

It can also enter the body if you drink water contaminated with 

RDX or accidentally or intentionally ingest explosives 

containing RDX. 

Much less RDX can enter the body through the skin if you 

come in contact with dusts of RDX or with liquids containing 

RDX. 

Leave your body Based on observations made in humans and results from 

studies in animals, most of the RDX appears to be broken 

down rapidly in the body. These products, as well as 

unchanged RDX, are eliminated in the urine and exhaled air in 

a few days. RDX is not expected to accumulate in the body. 

1.5 HOW CAN RDX AFFECT MY HEALTH?
 

Humans If you breathe in dusts of RDX or intentionally or accidentally 

swallow large amounts of RDX, you may develop seizures. 

The seizures are temporary and will stop after the RDX is 

eliminated from your body. 

Some people exposed to large amounts of RDX also have 

alterations in blood pressure and in some components of the 

blood, but these effects may be secondary to the seizures. 

We do not know the effects of long-term, low-level exposure to 

RDX. 

Laboratory animals Animals that had large amounts of RDX placed in the stomach 

with a tube or that ate food mixed with RDX for longer periods 

of time suffered seizures. 

Rats and mice that ate RDX for 3 months or longer had 

decreased body weights and slight liver and kidney damage. 

Cancer There are no studies reported of cancer in people exposed to 

RDX. 

The EPA has determined that RDX is a possible human 

carcinogen based on the presence of liver tumors in mice that 

were exposed to RDX in the food for 1–2 years. 
 

 

 

 

 

 

 

 

 

 


 

RDX 4 

1. PUBLIC HEALTH STATEMENT 

1.6 HOW CAN RDX AFFECT CHILDREN? 

This section discusses potential health effects in humans from exposures during the period from 

conception to maturity at 18 years of age. 

Effects in children There are no studies of children exposed to RDX, but a child 

who accidentally ingested RDX had seizures, which is the 

same effect that occurs in adults exposed to high amounts of 

RDX. 

We do not know whether children are more susceptible to the 

effects of RDX than adults. 

We do not know whether RDX causes birth defects in humans. 

Laboratory animals Exposure of animals to RDX during pregnancy has not caused 

birth defects in newborn animals. However, rats exposed to 

RDX during gestation gave birth to babies with smaller weight 

and length than rats not exposed to RDX. 

In rats exposed to RDX during pregnancy, RDX was able to 

pass through the placenta and reached the fetus. 

Young deer mice (21 days old) were more sensitive than older 

deer mice (50 days old) to the acute toxic effects of RDX. 

Breast milk There are no studies that looked for RDX in human breast milk. 

However, rats exposed to RDX during pregnancy had RDX in 

their milk, suggesting that the same can occur in humans. This 

means that women exposed to RDX who nurse their babies 

could transfer RDX to the babies in the milk. 

1.7 HOW CAN FAMILIES REDUCE THE RISK OF EXPOSURE TO RDX?
 

Consumer products RDX is not found in consumer products. Therefore, families 

are not expected to have contact with RDX through the use of 

consumer products. 

Drinking water Families whose tap or well water may be contaminated with 

RDX may choose to drink or cook with bottled water or to install 

activated carbon water filters. 
 

 

 

 

 

 

 

 

 

 

 

 

 

RDX	 	 5 

1. PUBLIC HEALTH STATEMENT 

1.8 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

RDX? 

Detecting exposure RDX can be measured in blood and urine, but these are not 

routine tests that can be performed in a doctor’s office. 

We do not know whether the presence of RDX in the blood 

indicates that you were exposed briefly a few days before the 

blood was collected or that you are experiencing constant 

exposure. 

Measuring exposure The tests for RDX in blood and urine cannot be used to 

determine how much RDX entered your body. 

The presence of RDX in your blood does not necessarily mean 

that you will suffer adverse health effects. The usual immediate 

health effects are seizures, muscle twitching, or vomiting from 

very high exposures. These would probably occur before you 

had the blood or urine test. 

1.9 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO 

PROTECT HUMAN HEALTH? 

The federal government develops regulations and recommendations to protect public health. Regulations 

can be enforced by law. The EPA, the Occupational Safety and Health Administration (OSHA), and the 

Food and Drug Administration (FDA) are some federal agencies that develop regulations for toxic 

substances. Recommendations provide valuable guidelines to protect public health, but cannot be 

enforced by law. The Agency for Toxic Substances and Disease Registry (ATSDR) and the National 

Institute for Occupational Safety and Health (NIOSH) are two federal organizations that develop 

recommendations for toxic substances. 

Regulations and recommendations can be expressed as “not-to-exceed” levels. These are levels of a toxic 

substance in air, water, soil, or food that do not exceed a critical value. This critical value is usually based 

on levels that affect animals; they are then adjusted to levels that will help protect humans. Sometimes 

these not-to-exceed levels differ among federal organizations because they used different exposure times 

(an 8-hour workday or a 24-hour day), different animal studies, or other factors. 

Recommendations and regulations are also updated periodically as more information becomes available. 

For the most current information, check with the federal agency or organization that provides it. 
 

 

RDX 6 

1. PUBLIC HEALTH STATEMENT 

Some regulations and recommendations for RDX include the following: 

Levels in drinking water set by EPA The EPA has determined that exposure to RDX in 

drinking water at concentrations of 0.1 mg/L for one 

day or 0.1 mg/L for 10 days is not expected to cause 

any adverse effects in a child. 

The EPA has determined that lifetime exposure to 

0.002 mg/L RDX is not expected to cause any 

adverse effects. 

Levels in workplace air set by OSHA OSHA had previously set a legal limit of 1.5 mg/m3

 for 

RDX in March 1989; however, the standard was 

vacated in 1992. 

NIOSH has set a 10-hour time-weighted average 

recommended exposure limit of 1.5 mg/m3 

. 

1.10 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns, please contact your community or state health or 

environmental quality department, or contact ATSDR at the address and phone number below. 

ATSDR can also tell you the location of occupational and environmental health clinics. These clinics 

specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous 

substances. 

Toxicological profiles are also available on-line at www.atsdr.cdc.gov and on CD-ROM. You may 

request a copy of the ATSDR ToxProfilesTM CD-ROM by calling the toll-free information and technical 

assistance number at 1-800-CDCINFO (1-800-232-4636), by e-mail at cdcinfo@cdc.gov, or by writing 

to: 

Agency for Toxic Substances and Disease Registry 

Division of Toxicology and Human Health Sciences (proposed)

 1600 Clifton Road NE 

 Mailstop F-62 

 Atlanta, GA 30333

 Fax: 1-770-488-4178 
 

 

 

 

 

 

 

RDX 7 

1. PUBLIC HEALTH STATEMENT 

Organizations for-profit may request copies of final Toxicological Profiles from the following: 

National Technical Information Service (NTIS) 

5285 Port Royal Road 

Springfield, VA 22161 

Phone: 1-800-553-6847 or 1-703-605-6000 

Web site: http://www.ntis.gov/ 

 

 

RDX 8
 

1. PUBLIC HEALTH STATEMENT 

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RDX 9 

2. RELEVANCE TO PUBLIC HEALTH 

2.1 BACKGROUND AND ENVIRONMENTAL EXPOSURES TO RDX IN THE UNITED 

STATES 

RDX is a military explosive produced by the nitrolysis of hexamine with nitric acid. It is a synthetic 

compound that does not occur naturally in the environment. Effluents and emissions from Army 

ammunition plants and many current and former military installations are responsible for the release of 

RDX into the environment. RDX can enter the air, water, and soil as a consequence of these releases. 

RDX is expected to exist as a particulate in the atmosphere. RDX has low water solubility and is subject 

to photolysis (half-life of 9–13 hours). RDX undergoes biodegradation in water and soil under anaerobic 

conditions to form several biodegradation products. RDX is mobile in soil and can leach into 

groundwater, and can be transported from soils or water to terrestrial and aquatic plants. RDX is not very 

lipid soluble, and therefore, has a low potential for bioaccumulation in aquatic species. 

RDX has been identified in environmental samples, primarily near army munitions depots. Indoor air 

samples collected at ammunition plants were found to contain RDX in concentrations ranging from 

0.032 to 60 mg/m3

. In water, RDX has been identified in a variety of groundwater samples from 

ammunition plants in the United States (<20–13,200 μg/L) and Germany (21–3,800 μg/L). Sediment 

samples from Army depots have been found to contain RDX in concentrations ranging from <0.1 to 

3,574 mg/kg and in composts prepared from contaminated sediments (>2.9–896 mg/kg). Additionally, 

RDX was identified in plant species irrigated with or grown in contaminated water (<20–3,196 μg/L). 

For the general population, including children, exposure to RDX is limited to areas around Army 

ammunition plants where it is manufactured, used in munitions, packed, loaded, or released through the 

demilitarization of antiquated munitions. The most likely route of exposure is ingestion of contaminated 

drinking water or agricultural crops irrigated with contaminated water. Exposure can also occur though 

dermal contact with soil containing RDX or by inhaling contaminated particulate matter produced during 

incineration of RDX-containing waste material. Children playing in contaminated water or soil may also 

be exposed via ingestion. Children can also be exposed if workers inadvertently bring home RDX 

adhered to shoes or clothing. 

Occupational exposure to RDX can occur when workers handle RDX at Army ammunition plants. Under 

these conditions, exposure can occur as a result of release of dust into the workroom air, principally 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 10 

2. RELEVANCE TO PUBLIC HEALTH 

during dumping of dried RDX powder, screening and blending, and clean-up of spilled material. 

Exposure to RDX can also occur through dermal contact during manufacture, handling, and clean-up of 

RDX. RDX was detected at a concentration of 0.052 mg/m3

 (0.47 ppm) in the particulate fraction of only 

one of eight indoor air samples taken from the incorporation area of Holston Army Ammunition Plant in 

Tennessee in 1986. Based on the observed concentration, the potential for exposure to RDX is considered 

to be negligible. 

2.2 SUMMARY OF HEALTH EFFECTS 

There is limited information on the toxicity of RDX in humans; the database consists of studies of 

workers exposed to RDX dust, soldiers using C-4 (a plasticized explosive containing 91% RDX) as a 

cooking fuel, and case reports of individuals ingesting RDX. Most of these studies involve acute 

exposure to RDX and provide limited exposure information. Neurologic dysfunction, primarily seizures 

and convulsions, was the most commonly reported effect. The seizures/convulsions typically occurred 

within several hours of exposure, and in some cases, convulsions were noted for several days after 

exposure. Other neurological symptoms that have been observed in humans include disorientation, 

lethargy, muscle twitching, and marked hyperirritability. 

Studies in laboratory animals support neurological effects as a sensitive end point of RDX. Seizures, 

convulsions, and tremors have been reported in rats, deer mice, dogs, and monkeys orally exposed to 

RDX for acute, intermediate, or chronic durations. As with human exposure, the clonic-tonic convulsions 

and seizures are often observed shortly after exposure; however, a study in monkeys did not report 

seizures in some of the animals until after 34–57 doses of 10 mg/kg/day. In acute-exposure studies, the 

lowest adverse effect level for seizures and convulsions was 17 mg/kg/day, with no seizures at 

12.5 mg/kg/day. In addition to these neurological effects, decreases in motor activity and impaired 

learning were observed in rats following administration of a single gavage dose of 12.5 mg/kg/day; 

however, no alterations in motor activity were observed in rats administered 10 mg/kg/day for 16 or 

30 days. A lower adverse effect level (8 mg/kg/day) was reported in an intermediate-duration study, with 

a no-observed-adverse-effect level (NOAEL) of 4 mg/kg/day. At higher doses (≥40 mg/kg/day), 

hyperactivity, hyperirritability, hyperreactivity, and increased fighting have been observed in rats. 

Although the database is mostly comprised of studies in rats, intermediate-duration studies in monkeys 

and dogs do not suggest species differences in RDX-induced seizures/convulsions. In chronic-duration 

oral studies, seizures and convulsions were observed at 40 mg/kg/day; this dose was also associated with 

88% lethality. No neurological effects were observed in rats chronically exposed to 8 or 10 mg/kg/day. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 11 

2. RELEVANCE TO PUBLIC HEALTH 

The animal data suggest that there may be other targets of RDX toxicity, including the hematological 

system and liver following oral exposure. Small, although significant, decreases in hemoglobin and 

erythrocyte levels were observed following intermediate-duration exposure, but this was not consistently 

found in other intermediate or chronic studies. Several studies found minor changes in serum chemistry 

parameters suggestive of a slight impairment of liver function. These alterations include decreases in 

alanine aminotransferase and in serum triglyceride and/or cholesterol levels and increases in serum 

cholesterol levels. A decrease in blood glucose levels observed in one study of rats may also be related to 

impaired liver function. Hepatomegaly and hepatocellular vacuolization have been reported in rats; 

however, most studies did not report histological alterations in the liver. An intermediate-duration study 

in monkeys reported an increase in vomiting following gavage administration of 10 mg/kg/day RDX; the 

occurrence of vomiting at 0.1 or 1 mg/kg/day was similar to controls. 

There is limited information to suggest that RDX is a reproductive toxicant following oral exposure. An 

increased incidence of spermatic granuloma in the prostate was observed in rats following exposure to 

40 mg/kg/day for 6 months; however, this effect was not observed at longer durations (1 or 2 years) in the 

same study. A nonsignificant increase in testicular degeneration was also observed in this study in rats 

exposed for 6 months to 40 mg/kg/day, but testicular effects were not observed in another study of rats 

exposed to 100 mg/kg/day for 13 weeks. Adverse developmental effects have been observed in rats, 

particularly at maternally toxic doses. Decreases in pup survival and increases in the occurrence of 

stillbirths were observed at 50 mg/kg/day; this dose also resulted in maternal deaths. A decrease in pup 

body weight and an increase in the incidence of renal cysts were observed in F2 pups at 16 mg/kg/day in a 

two-generation study of rats and a decrease in fetal body weight and length were observed in the offspring 

of rats administered 20 mg/kg/day on gestation days 6–15. No adverse developmental (or maternal) 

effects were observed in rabbits. 

The carcinogenic potential of RDX was evaluated in orally exposed rats and mice; no evidence of 

carcinogenicity was observed in two rat studies. In mice, an increase in the combined incidence of 

hepatocellular adenomas and carcinomas was observed in females only. However, a re-evaluation of 

these data using current diagnostic criteria resulted in a reclassification of some hepatocellular adenomas 

as foci of cytoplasmic alterations. As a result of the re-analysis, the combined incidence was significantly 

higher than concurrent controls at 35 mg/kg/day, but not at 100 mg/kg/day and the incidence in the 

35 mg/kg/day group was within the range of historical control data. The investigators suggested that the 

study provided equivocal evidence of carcinogenicity. The International Agency for Research on Cancer 
 

 

 

 

 

 

RDX 12 

2. RELEVANCE TO PUBLIC HEALTH 

(IARC) and the Department of Health and Human Services (DHHS) have not classified the 

carcinogenicity of RDX. EPA classified RDX as a group C carcinogen, possibly carcinogenic to humans; 

however, this evaluation was done prior to the re-evaluation of mouse tumor data. EPA is currently reevaluating RDX. 

2.3 MINIMAL RISK LEVELS (MRLs) 

ATSDR has made estimates of exposure levels posing minimal risk to humans (MRLs) for RDX. An 

MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an 

appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are 

derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive 

health effect(s) for a specific duration within a given route of exposure. MRLs are based on 

noncancerous adverse health effects only and do not consider carcinogenic effects. MRLs can be derived 

for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate 

methodology does not exist to develop MRLs for dermal exposure. 

Although methods have been established to derive levels posing minimal risks to humans (Barnes and 

Dourson 1988; EPA 1990b), uncertainties are associated with these techniques. Furthermore, ATSDR 

acknowledges additional uncertainties inherent in the application of the procedures to derive less than 

lifetime MRLs. As an example, acute inhalation MRLs may not be protective for adverse health effects 

that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity 

reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and 

methods to assess levels of significant human exposure improve, these MRLs will be revised. 

Inhalation MRLs 

ATSDR has not derived inhalation MRLs due to the limited data available on the toxicity of RDX 

following inhalation exposure. Several studies reported convulsions in humans acutely exposed to 

unspecified amounts of RDX (Hollander and Colbach 1969; Kaplan et al. 1965; Testud et al. 1996a). 

Nausea and vomiting have also been reported in humans (Hollander and Colbach 1969; Ketel and Hughes 

1972); however, these individuals may have been exposed to RDX via inhalation and ingestion. Deaths 

due to bronchopneumonia, pneumonia, or pulmonary congestion were observed in rabbits and guinea pigs 

exposed to an unspecified concentration of RDX (Sunderman 1944). The lack of dose-response data for 

the human and animal studies precludes derivation of inhalation MRLs. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 13 

2. RELEVANCE TO PUBLIC HEALTH 

Oral MRLs 

Acute-Duration 

• ATSDR has derived an MRL of 0.2 mg/kg/day for acute-duration oral exposure (14 days or less) 

to RDX. This MRL is based on a NOAEL of 8.5 mg/kg/day and LOAEL of 17 mg/kg/day for 

convulsions/seizures observed in rats administered RDX via gavage 7 days/week for 14 days 

(U.S. Army 2006). A PBPK model was used to predict peak brain concentrations in the rat and to 

estimate human equivalent doses (HEDs). The NOAELHED of 6.45 mg/kg/day was divided by an 

uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustments 

and 10 for human variability). 

The acute toxicity database consists of several human exposure studies reporting convulsions and seizures 

following oral exposure to RDX (Hollander and Colbach 1969; Kasuske et al. 2009; Ketel and Hughes 

1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986). Although some 

studies provide exposure estimates, these values are not considered reliable. Animal studies have also 

identified convulsions and seizures as the most sensitive effect following acute-duration oral exposure 

(Burdette et al. 1988; Meyer et al. 2005; Schneider et al. 1977; U.S. Army 1980b, 1986d, 2006). The 

lowest adverse effect level for convulsions/seizures was 17 mg/kg/day in rats administered RDX via 

gavage for 14 days (U.S. Army 2006); an increase in the incidence of mortality was also observed at this 

dose level (U.S. Army 2006). Several other studies have identified similar lowest-observed-adverseeffect levels (LOAELs); convulsions were observed in rat dams administered via gavage 20 mg/kg/day on 

gestation days 6–15 or 19 (U.S. Army 1980b, 1986d) and seizures were observed in rats administered a 

single gavage dose of 25 mg/kg (Burdette et al. 1988). The dose-response curve for seizures/convulsions 

appears to be fairly steep, with no effects at 8.5 (U.S. Army 2006) or 12.5 (U.S. Army 1985b) mg/kg/day 

and seizures at 17 mg/kg/day (U.S. Army 2006). Additionally, decreases in motor activity and learning 

were observed at a lower dose (12.5 mg/kg/day) in rats receiving a single gavage dose (U.S. Army 

1985b). 

There are limited data on the non-neurological toxicity of RDX following acute-duration exposure. U.S. 

Army (2006) monitored body weight, hematological parameters, clinical chemistry parameters, and organ 

weight in male and female rats administered gavage doses of 2–17 mg/kg/day for 14 days. No 

biologically relevant alterations in these systemic toxicity end points were observed. Decreases in fetal 

weight and length were observed in the offspring of rats administered 20 mg/kg/day on gestation days 6– 

15 (U.S. Army 1986d); however, this exposure was associated with maternal convulsions/seizures and 

death. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 14 

2. RELEVANCE TO PUBLIC HEALTH 

Based on the available data, impaired neurological function was identified as the critical effect for 

derivation of an acute-duration oral MRL. Although the acute database lacks studies adequately assessing 

systemic toxicity, intermediate-duration studies have found no systemic effects at doses lower than those 

affecting the nervous system. The lowest adverse effect level for neurological effects is 12.5 mg/kg/day 

for decreases in motor activity and learning in rats following a single gavage dose (U.S. Army 1985b); 

this study did not identify a NOAEL. In a repeated exposure study by this group (U.S. Army 1985b), no 

significant alterations in motor activity were observed in rats following 15 or 30 days of exposure to 

doses as high as 10 mg/kg/day. At a slightly higher dose (17 mg/kg/day), convulsions and tremors were 

observed in rats administered RDX for 14 days (U.S. Army 2006); no neurological effects were observed 

at 8.5 mg/kg/day. The U.S. Army (2006) study was selected as the principal study because it identified a 

NOAEL and involved repeated exposure, and it is likely that an MRL based on this study would be 

protective for the neurobehavioural effects observed at 12.5 mg/kg/day in the U.S. Army (1985b) study. 

In the U.S. Army (2006) study, groups of 6 male and 6 female Sprague-Dawley rats were administered 

via gavage 0, 2.125, 4.25, 8.5, 17.00, 25.50, 34.00, or 42.5 mg/kg/day as a suspension of RDX/1% 

methylcellulose/0.2% Tween 80 in distilled water 7 days/week for 14 days. Rats were monitored daily 

for toxic signs and morbidity. Body weights and feed consumption were measured on days 0, 1, 3, 7, and 

14. Additional parameters used to assess toxicity included clinical chemistry and hematology values, 

organ weights, and gross necropsies. A significant increase in early deaths was observed at 

≥25.5 mg/kg/day. Tremors and convulsions were observed in rats exposed to ≥17 mg/kg/day. In the 

males exposed to ≥17 mg/kg/day, blood stains around the mouth and nose and low arousal were also 

observed. Increased arousal, blood around the mouth and nose, barbering, and lacrimation were observed 

in females exposed to ≥17 mg/kg/day. No signs of neurological alterations were observed in rats exposed 

to ≤8.5 mg/kg/day. Significant decreases in body weight were observed in male rats exposed to 

≥17 mg/kg/day on days 1 and 7, but there were no significant alterations in male body weight at 

termination. In female rats, significant decreases in body weight gain were observed at ≥34 mg/kg/day on 

day 1 and in the 8.5 mg/kg/day group on day 14; however, the magnitude of the decreased body weight 

was <10% and no significant alterations were observed at higher dose levels. Significant decreases in 

food consumption were also observed during the first 7 days of exposure in males and females exposed to 

≥8.5 mg/kg/day. Significant decreases in absolute liver weights and liver-to-brain weights and increases 

in blood cholesterol levels were observed in females exposed to 8.5 mg/kg/day; these effects were not 

observed at higher dose levels or in males. Due to the lack of dose-response relationships for the 

alterations in liver weight and blood cholesterol levels, these changes observed in the 8.5 mg/kg/day 
 

 

 

 

 

 

 

 

 

 

 

	 

	 

RDX	 15 

2. RELEVANCE TO PUBLIC HEALTH 

female group were not considered biologically relevant. No significant alterations in hematological 

parameters or other clinical chemistry parameters or organ weights were observed. 

The acute-duration oral MRL was derived using the NOAEL/LOAEL approach; the lack of incidence 

data for the neurological effects precluded using a benchmark dose approach. The MRL is based on the 

NOAEL of 8.5 mg/kg/day and a LOAEL of 17 mg/kg/day identified in the U.S. Army (2006) study. The 

available mode of action data suggest that the induction of seizures and/or convulsions is likely associated 

with the binding of RDX to GABA receptors in the brain and the onset of seizures is directly related to 

the levels of RDX in the brain (Gust et al. 2009; Williams et al. 2011). A physiologically based 

pharmacokinetic (PBPK) model (Sweeney et al. 2012) was used to predict peak brain RDX concentration 

and mean brain RDX concentration for each administered dose in the U.S. Army (2006) study. Based on 

a comparison of predicted brain RDX concentrations to the NOAEL and LOAEL values for 

seizures/convulsions observed in intermediate and chronic studies, ATSDR determined that peak brain 

RDX concentration was a more appropriate internal dose metric for derivation of the MRL than mean 

brain RDX concentration. To determine the point of departure for the MRL, the PBPK model was used 

to predict HEDs from peak brain concentration data. Detailed discussions of the PBPK model and 

support for using peak brain concentration as the internal dose metric are presented in Appendix A. The 

PBPK model predicted a peak brain concentration of 6.19 mg/L in rats administered 8.5 mg/kg/day 7 

days/week for 14 days and a HED of 6.455 mg/kg/day. The MRL of 0.2 mg/kg/day was calculated by 

dividing the NOAELHED of 6.45 mg/kg/day for neurological effects (U.S. Army 2006) by an uncertainty 

factor of 30 (3 for extrapolation from animals to humans with dosimetric adjustment and 10 for human 

variability). 

Intermediate-Duration 

•	 ATSDR has derived an MRL of 0.1 mg/kg/day for intermediate-duration oral exposure (15– 

364 days) to RDX. The MRL is based on a 90-day study which identified a NOAEL of 

4 mg/kg/day and LOAEL of 8 mg/kg/day for seizures/convulsions in rats receiving gavage doses 

of RDX 7 days/week (U.S. Army 2006). ATSDR derived the MRL using benchmark dose 

modeling of seizure/convulsion incidence data and PBPK modeling to predict peak brain 

concentrations in the rat and to estimate HEDs. The BMCLHED of 4.13 mg/kg/day was divided by 

an uncertainty factor of 30 (3 for extrapolation from animals to humans with dosimetric 

adjustments and 10 for human variability). 

No human studies have examined the toxicity of RDX following intermediate-duration exposure. Data 

from laboratory animal studies suggest that the nervous system is the most sensitive target of RDX 

toxicity. Convulsions, seizures, and/or tremors have been observed in rats at doses of ≥8 mg/kg/day (U.S. 
 

 

 

 

 

 

 

 

 

 

 

RDX 16 

2. RELEVANCE TO PUBLIC HEALTH 

Army 1983a, 2006; von Oettingen et al. 1949), monkeys at 10 mg/kg/day (U.S. Navy 1974b), and dogs at 

50 mg/kg/day (von Oettingen et al. 1949). In addition, hyperactivity was noted in rats exposed to 

100 mg/kg/day (Levine et al. 1981, 1990). The results of the U.S. Army (2006) study suggest that there is 

a steep dose-response curve for seizure induction. The occurrences of seizures were 0% at 4 mg/kg/day, 

20–30% at 8 mg/kg/day, 45–50% at 10 mg/kg/day, and 80–90% at 12 or 15 mg/kg/day. An increase in 

mortality was often reported at the lowest doses associated with seizures. Less serious adverse health 

effects have been observed at similar or higher dose levels. Several studies have found changes in serum 

chemistry parameters suggestive of impaired liver function, although histological alterations were not 

generally found in the liver. Decreases in serum cholesterol and/or triglycerides were observed at 

≥8 mg/kg/day (U.S. Army 1983a, 2006; Levine et al. 1981) and decreases in serum alanine 

aminotransferase activity levels were observed at 28 mg/kg/day (U.S. Army 1980b). The magnitude of 

these alterations was small and not likely to be biologically significant. Small, although significant, 

decreases in erythrocyte and hemoglobin levels were also observed in rats exposed to 40 mg/kg/day (U.S. 

Army 1983a) and mice exposed to 160 mg/kg/day (U.S. Army 1980b), but this finding has not been 

consistently found in intermediate-duration studies (U.S. Army 1980b, 2006; von Oettingen et al. 1949). 

Emesis was observed in monkeys administered via gavage 10 mg/kg/day for 90 days (U.S. Navy 1974b); 

the incidence in monkeys administered 1 mg/kg/day was not considered to be different from the controls. 

There is limited evidence that RDX is a reproductive toxicant. An increased incidence of spermatic 

granuloma was observed in the prostate of rats exposed to 40 mg/kg/day for 6 months (U.S. Army 

1983a). In a two-generation study in rats, decreases in F2 pup body weight and increases in the incidence 

of renal cysts were observed at 16 mg/kg/day and increases in the number of stillbirths and decreases in 

pup survival were observed in the F1 generation exposed to 50 mg/kg/day (U.S. Army 1980b). 

Impaired neurological function was identified as the critical effect for derivation of an intermediateduration oral MRL. The lowest adverse effect level for this end point is 8 mg/kg/day with a NOAEL of 

4 mg/kg/day (U.S. Army 2006). A slightly higher LOAEL of 10 mg/kg/day was identified in monkeys 

(U.S. Navy 1974b); a NOAEL was not identified in this study. The rat study (U.S. Army 2006) was 

selected as the principal study. In this study, groups of 10 male and 10 female F344 rats were 

administered via gavage 0, 4, 8, 10, 12, or 15 mg/kg/day as a suspension of RDX/1% methylcellulose/ 

0.2% Tween 80 in distilled water 7 days/week for 90 days. Rats were monitored weekly for toxic signs 

and functional observational battery (FOB) observations (home-cage, hand held, and open arena 

observations), and body weights and feed consumption were measured weekly. Additional parameters 

used to assess toxicity included neurobehavioral tests after week 11 (motor activity, grip strength, and 

sensory reactivity to different types of stimuli), ophthalmic examination, urinalysis, clinical chemistry, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

RDX	 17 

2. RELEVANCE TO PUBLIC HEALTH 

hematology, coagulation, organ weights, gross necropsies, and histopathological examination of major 

tissues and organs from rats exposed to 0 or 15 mg/kg/day. Significant increases in mortality rates were 

observed at ≥10 mg/kg/day. Convulsions were observed in most animals dying early. Transient clinical 

signs included changes in arousal, inflammation of eyelash follicles, increased salivation, blood stains 

around mouth and nose, rough haircoat, tremors, and convulsions; the incidence and severity increased 

with dose. The incidences of convulsions were 0/20, 0/20, 3/20, 6/20, 13/20, and 12/20 in rats exposed to 

0, 4, 8, 10, 12, and 15 mg/kg/day, respectively. Although the incidence of convulsions was not 

statistically significant at 8 mg/kg/day, the increased incidence of seizures was considered biologically 

significant and the 8 mg/kg/day dose level was considered a LOAEL. The tremors/convulsions were 

observed within the first week of exposure in the 12 or 15 mg/kg/day groups and persisted throughout the 

study. No significant RDX-related alterations in foot splay, front limb grip strength, or response to 

stimuli were found. Hematological tests showed significant increases in erythrocyte mean cell volume at 

8 (males only), 10, and 12 mg/kg/day and significant decrease in serum cholesterol in males exposed to 

≥8 mg/kg/day. No significant increases in the incidence of histopathological alterations were observed. 

The intermediate-duration oral MRL was derived using benchmark dose modeling and PBPK modeling. 

As discussed for the acute-duration oral MRL, a PBPK model (Sweeney et al. 2012) was used to predict 

peak and mean brain RDX concentrations. Comparisons with empirical seizure data following 

intermediate- or chronic-duration exposure with predicted brain RDX levels provided support for using 

peak brain concentration as the internal dose metric for the MRL derivation. The incidence data for 

convulsions in rats were fit to several dichotomous models using a benchmark response (BMR) of 10% 

and the internal dose metric of peak brain concentration. Detailed discussion of the benchmark dose 

modeling, the PBPK model, and support for the selection of the internal dose metric are presented in 

Appendix A. The log-probit model provided the best fit to the data and was used to estimate a 95% lower 

confidence limit on the benchmark dose (BMDL10) of 3.9624 mg/L. Using PBPK modeling, a HED of 

4.1308 mg/kg/day was predicted from the BMDL10. The MRL of 0.1 mg/kg/day was calculated by 

dividing the BMDLHED of 4.1308 mg/kg/day for neurological effects by an uncertainty factor of 30 (3 for 

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

Chronic-Duration 

•	 ATSDR has derived an MRL of 0.1 mg/kg/day for chronic-duration oral exposure (≥365 days) to 

RDX. This MRL is based on a NOAEL of 8 mg/kg/day and LOAEL of 40 mg/kg/day for 

convulsions/seizures observed in rats exposed to RDX in the diet for 2 years (U.S. Army 1983a). 

A PBPK model was used to predict peak brain concentrations in the rat and to estimate HEDs. 
 

 

 

 

 

 

RDX 18 

2. RELEVANCE TO PUBLIC HEALTH 

The NOAELHED of 4.223 mg/kg/day was divided by an uncertainty factor of 30 (3 for 

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

The chronic oral toxicity of RDX has been evaluated in two rat studies (U.S. Army 1983a; U.S. Navy 

1976) and a mouse study (U.S. Army 1984c). A number of adverse health effects have been observed in 

rats exposed to 40 mg/kg/day including tremors, convulsions, and hyperresponsiveness; decreased 

hematocrit, hemoglobin, and erythrocyte levels; hepatomegaly and decreased serum cholesterol and 

triglycerides; renal papillary necrosis and increased blood urea nitrogen levels; testicular degeneration; 

and cataracts (females only) (U.S. Army 1983a); no adverse effects were observed in rats exposed to 

8 mg/kg/day. The 40 mg/kg/day dose was also associated with an 88% mortality rate. In addition to 

these effects, significant increases in the incidence of suppurative inflammation were observed in the 

prostate of rats exposed to ≥1.5 mg/kg/day (U.S. Army 1983a). U.S. Army (2006) noted that 

inflammation of the prostate gland is a common condition in older rodents and is generally not due to 

toxicity; additionally, the prostate effects in the U.S. Army (1983a) study were predominantly found in 

rats dying early. 

In the U.S. Navy (1976) rat study, no adverse effects were observed at doses as high as 10 mg/kg/day. 

This study did not include a histological examination of the prostate and the animals were monitored 

weekly for overt signs of toxicity. In mice, increases in serum cholesterol levels were observed in 

females exposed to 35 mg/kg/day and increased relative kidney weights and cytoplasmic vacuolization in 

the kidney were observed at 100 mg/kg/day (U.S. Army 1984c). The toxicological significance of the 

increased serum cholesterol level in the absence of other indications of hepatic damage is not known. 

The lowest LOAEL identified in chronic-duration studies is 1.5 mg/kg/day for prostate inflammation; the 

NOAEL for this effect is 0.3 mg/kg/day. However, U.S. Army (1983a) suggested that this effect is likely 

secondary to a bacterial infection in older rats dying early; thus, it was not considered an appropriate basis 

of a chronic-duration MRL. The effects observed in rats (including convulsions/tremors, hematological 

alterations, impaired hepatic function, and renal lesions) exposed to 40 mg/kg/day (NOAEL of 

8 mg/kg/day) were considered as the basis of a chronic-duration MRL. Based on a comparison of the 

effects observed in rats exposed to 40 mg/kg/day and those observed in mice exposed to 35 mg/kg/day, 

rats appear to be more sensitive to the toxicity of RDX than mice; thus, the mouse study was not 

considered for MRL derivation. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 19 

2. RELEVANCE TO PUBLIC HEALTH 

In the U.S. Army (1983a) study, groups of male and female Fischer 344 rats (75/sex/group) were exposed 

to 0, 0.3, 1.5, 8.0, or 40.0 mg/kg/day RDX in the diet for 2 years. The following parameters were used to 

assess toxicity: daily observations, ophthalmic examinations, hematology, clinical chemistry, organ 

weights, and complete histopathology of major tissues and organs of rats in the 0 or 40.0 mg/kg/day groups, 

and histopathological examination of the brain, gonads, heart, liver, kidneys, spleen, and spinal cord of rats 

in the 0.3, 1.5, and 8.0 mg/kg/day groups. Actual RDX doses were within 3% of the intended dose. Deaths 

were observed at 40 mg/kg/day; 88% of males and 41% of females died by week 88. The mean survival 

time for the 40 mg/kg/day males was 14.6 months compared with 22.3 months for the control males. A 

20.6 month survival time was seen for the 40 mg/kg/day females vs. 22.0 months for the control females at 

40 mg/kg/day. A significant decrease in survival time was also observed in the males exposed to 

1.5 mg/kg/day (21.0 months); however, no alterations in survival time was observed in the females exposed 

to 1.5 mg/kg/day (22.2 months) or in the males (22.2 months) or females (22.4 months) exposed to 

8 mg/kg/day. Additionally, there were no significant differences in mortality incidence in the 1.5 or 

8 mg/kg/day groups, as compared to controls. Statistically decreased body weight gain was observed in 

males (20–30%) and females (10–15%) exposed to 40.0 mg/kg/day; statistically significant decreases in 

body weight gain were also observed at 8.0 mg/kg/day, but the body weight was within 10% of controls. 

Tremors and convulsions were observed prior to death at 40 mg/kg/day; the animals were hyperactive to 

approach and had increased fighting. No adverse clinical signs were noted for the lower dose groups. 

Significant decreases in hemoglobin and erythrocyte counts were observed in the 40 mg/kg/day group 

beginning at week 26; the study investigators noted that the anemic state was considered slight and there 

was no evidence of physiologic compensatory responses. Thrombocytosis was observed in rats exposed to 

40 mg/kg/day and elevated platelet counts were observed in 8 mg/kg/day males during weeks 13 and 26. 

Significant decreases in blood glucose, total cholesterol, and triglyceride levels were observed in the 

40 mg/kg/day group starting at week 13. Significant decreases in serum alanine aminotransferase levels 

were observed in males exposed to 8 or 40 mg/kg/day at weeks 26 and 52 and in females at 40 mg/kg/day at 

week 26. Other clinical chemistry alterations included decreases in globulin and albumin levels at weeks 52 

and 78 and increases in serum potassium levels at weeks 26, 52, and 78. A significant increase in the 

incidence of cataracts was observed in females in the 40 mg/kg/day group during weeks 78 and 104. 

Histological alterations observed after 2 years of exposure included suppurative inflammation of the 

prostate in the 1.5, 8, and 40 mg/kg/day groups; renal medullary papillar necrosis, renal pyelitis, and urinary 

bladder luminal distension and cystitis in males exposed to 40 mg/kg/day; splenic extramedullary 

hematopoiesis in female rats exposed to 40 mg/kg/day; and hemosiderin-like pigment in males exposed to 

1.5, 8, or 40 mg/kg/day. In the absence of altered hematological parameters or other effects on the spleen, 

the increased pigment levels observed at 1.5 or 8 mg/kg/day were not considered adverse. 
 

 

 

 

 

RDX 20 

2. RELEVANCE TO PUBLIC HEALTH 

The U.S. Army (1983a) study identified a NOAEL of 8 mg/kg/day and a LOAEL of 40 mg/kg/day for 

tremors and convulsions in rats exposed to RDX in the diet for 2 years. ATSDR derived a chronicduration oral MRL using the NOAEL/LOAEL approach; benchmark dose modeling could not be utilized 

because the investigators did not report incidence data for neurological signs. As discussed for the acuteduration oral MRL, a PBPK model (Sweeney et al. 2012) was used to predict peak and mean brain RDX 

concentrations. Comparisons with empirical seizure data following intermediate- or chronic-duration 

exposure with predicted brain RDX levels provided support for using peak brain concentration as the 

internal dose metric for the MRL derivation. To determine the point of departure for the MRL, the PBPK 

model was also used to predict the HED for a given rat peak brain RDX concentration; detailed 

discussions of the PBPK model and support for selecting peak brain RDX concentration as the internal 

dose metric are presented in Appendix A. The NOAEL from the U.S. Army (1983a) study corresponds to 

peak brain concentrations of 4.051 mg/L and a HED of 4.223 mg/kg/day. The MRL of 0.1 mg/kg/day 

was calculated by dividing the NOAELHED of 4.223 mg/kg/day by an uncertainty factor of 30 (3 for 

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

 

 

 

 

 

 

 

 

 

RDX 21 

3. HEALTH EFFECTS 

3.1 INTRODUCTION 

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

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

descriptions and evaluations of toxicological studies and epidemiological investigations and provides 

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

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

3.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

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

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation, 

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive, 

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure 

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more). 

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

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

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

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

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

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

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

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

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

Agency has established guidelines and policies that are used to classify these end points. ATSDR 

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

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

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

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

 

 

 

 

 

 

 

RDX 22 

3. HEALTH EFFECTS 

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

effects to human health. 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and 

figures may differ depending on the user's perspective. Public health officials and others concerned with 

appropriate actions to take at hazardous waste sites may want information on levels of exposure 

associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no 

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans 

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of RDX are 

indicated in Table 3-1 and Figure 3-1. Because cancer effects could occur at lower exposure levels, 

Figure 3-1 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 

10,000 to 1 in 10,000,000 (10-4 to 10-7), as developed by EPA. 

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

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 

3.2.1 Inhalation Exposure 

3.2.1.1 Death 

No studies were located regarding death in humans after inhalation exposure to RDX. Death attributed to 

impairment of the respiratory system was observed in rabbits and guinea pigs exposed to an unspecified 

concentration of RDX (Sunderman 1944). 

3.2.1.2 Systemic Effects 

Four studies were located regarding systemic effects in humans after inhalation exposure to RDX alone. 

The available studies have reported adverse gastrointestinal, hematological, hepatic, and renal effects in 

workers exposed to C-4 (an explosive composed of 91% RDX) or RDX dusts via inhalation. Since the 

exposure concentration and/or duration were not described for these studies, they are not presented in 

tables or figures. No studies were located regarding respiratory, cardiovascular, musculoskeletal, dermal, 

ocular, or other systemic effects in humans after inhalation exposure to RDX. Case reports are available 

regarding systemic effects in workers exposed to unknown levels of RDX via the inhalation or oral routes 
 

 

 

 

 

 

 

 

 

 

 

RDX 23 

3. HEALTH EFFECTS 

(Ketel and Hughes 1972). These studies are also discussed in Section 3.2.2.2. Only one study is 

available regarding systemic effects in animals after inhalation exposure to RDX (Sunderman 1944). 

This study is limited by insufficient numbers of animals tested, no controls, and no data on exposure 

levels. No studies were located regarding gastrointestinal, hepatic, or dermal effects in animals. 

Respiratory Effects. Three of 6 rabbits died from bronchopneumonia; death of 7 of 18 guinea pigs 

was attributed to pneumonia and pulmonary congestion (Sunderman 1944). 

Cardiovascular Effects. Histopathology revealed the absence of striations in the cardiac muscle of 

guinea pigs exposed to unspecified levels of RDX for 4–67 days (Sunderman 1944). 

Gastrointestinal Effects. Soldiers who were exposed to an unspecified amount of C-4 (91% RDX) 

as a cooking fuel for an unknown duration experienced nausea and vomiting (Hollander and Colbach 

1969; Ketel and Hughes 1972); the soldiers were exposed to RDX via the inhalation and/or oral routes. 

Hematological Effects. Two studies of workers exposed to RDX dusts are available, but neither 

revealed any adverse hematological effects. In one study, workers who were presumably exposed acutely 

to unknown levels of RDX dusts had normal blood counts (Kaplan et al. 1965). In the other study, 

workers exposed to an average of 0.28 mg/m3

 of RDX dusts in the workplace, presumably for a chronic 

period, showed no hematological changes compared to controls (Hathaway and Buck 1977). Transient 

elevation of the white blood count was frequently observed in individuals exposed to C-4 (91% RDX). 

Normal red blood count, leukocytes, and hemoglobin were reported in rats following intermediate 

exposure to RDX. However, in the same study, hemoglobin counts were decreased in guinea pigs 

(Sunderman 1944). 

Hepatic Effects. No liver toxicity was revealed by blood or urine analyses of workers exposed to 

RDX in the air; the duration of exposure was not reported (Hathaway and Buck 1977). 

Renal Effects. Blood and urine analyses of workers exposed to RDX in the air for acute (Kaplan et al. 

1965) or chronic durations (Hathaway and Buck 1977) did not reveal any kidney toxicity. Although no 

renal toxicity was observed after exposure to RDX dust, there were some manifestations of renal damage 

after possible inhalation exposure to C-4 (91% RDX): transient oliguria and proteinuria in two patients 

and acute renal failure in one case (Ketel and Hughes 1972). 
 

 

 

 

 

 

 

RDX 24 

3. HEALTH EFFECTS 

There was no kidney pathology in rats or guinea pigs exposed to RDX, but degeneration of the kidneys 

was found in rabbits exposed to unspecified levels of RDX for an intermediate period (Sunderman 1944). 

This study is limited in that no controls were used, and details of the study were not specified. 

3.2.1.3 Immunological and Lymphoreticular Effects 

Workers at an Army ammunition plant who were exposed to an average of 0.28 mg/m3

 of RDX dusts for 

an unknown period of time showed no significant differences in a test for antinuclear antibodies as 

compared to nonexposed workers. The results of this test provide no evidence of autoimmune disease 

(Hathaway and Buck 1977). No other immunological function tests were performed. 

No studies were located regarding immunological effects in animals after inhalation exposure to RDX. 

3.2.1.4 Neurological Effects 

Convulsions and unconsciousness, accompanied by headache, dizziness, and vomiting, were noted in 

5 out of 26 workers who were exposed to unknown levels of RDX dust in the air (Kaplan et al. 1965). 

Similar findings, such as convulsions, muscle twitching, and confusion, have been reported in five case 

studies of men exposed to C-4 fumes (91% RDX) when it was used as a cooking fuel (Hollander and 

Colbach 1969), and in a worker hand-sieving RDX (Testud et al. 1996a). The workers recovered a few 

days after they were removed from the source of exposure. Testud et al. (1996a) noted that CT scan and 

MRI (performed 1 week after exposure) were normal and electroencephalogram only showed signs of the 

administered anticonvulsant therapy; in the other studies, tests of neurological function were not 

performed. In a study of workers at an RDX facility, no increases in the occurrence of subjective 

symptoms were reported (Ma and Li 1993). Significant differences in performance on tests of memory 

retention and block design were found in workers exposed to 0.407 or 0.672 mg/m3

, as compared to 

controls; however, no differences were found between the two exposed groups. No significant alterations 

in performance on tests of reaction time were noted. 

No studies were located regarding neurological effects in animals after inhalation exposure to RDX. 
 

 

 

 

 

 

 

 

 

 

RDX 25 

3. HEALTH EFFECTS 

No studies were located regarding the following effects in humans or animals after inhalation exposure to 

RDX: 

3.2.1.5 Reproductive Effects 

3.2.1.6 Developmental Effects 

3.2.1.7 Cancer 

3.2.2 Oral Exposure 

3.2.2.1 Death 

No studies were located regarding death in humans after oral exposure to RDX. 

Deaths were reported in animals following acute, intermediate, and chronic exposures to RDX. Three out 

of 12 rats died during induced seizures following acute exposure to 50 mg/kg RDX, which was 

administered by gavage (Burdette et al. 1988). LD50 values for single gavage doses were 71–118 mg/kg 

in rats (U.S. Army 1978b, 1980b), 86–97 mg/kg in mice (U.S. Army 1978b, 1980b), and 136–319 mg/kg 

in deer mice (Smith 2007). Apparent age-related differences in LD50 values were found in deer mice; the 

LD50 values were 136, 319, and 158 mg/kg in 21-, 50-, and 200-day-old mice (Smith et al. 2007). 

Miniature swine died (2/10) following single gavage doses of 100 mg/kg (Schneider et al. 1977). Rat 

dams that were fed 20 mg/kg/day of RDX during gestation had mortality rates of 24% (U.S. Army 1980b, 

1986d). 

In 90-day feeding studies, levels as low as 25 mg/kg/day (von Oettingen et al. 1949) and 100 mg/kg/day, 

produced deaths in rats (Levine et al. 1990), and levels of 320 mg/kg/day produced deaths in mice (U.S. 

Army 1980b). Increased mortality (25%) was observed in rats administered via gavage 10 mg/kg/day 

(U.S. Army 2006); however, no deaths were observed in dogs (U.S. Navy 1974a) or monkeys (U.S. Navy 

1974b) also administered 10 mg/kg/day. In chronic-duration studies, an excessive number of deaths was 

observed in rats exposed to 40 mg/kg/day for 1–2 years compared to controls (U.S. Army 1983a). 

However, an excessive number of deaths was not observed in rats administered 10 mg/kg/day of RDX 

(U.S. Navy 1976). The LD50 values and all reliable LOAEL values for death are recorded in Table 3-1 

and plotted in Figure 3-1. 
10

50

68

50

38

7175

507

20

61

119

510

20

518

25.5

82

100

Table 3-1 Levels of Significant Exposure to RDX - Oral 

a 

Key to 

Figure 

Species 

(Strain) 

Exposure/ 

Duration/ 

Frequency 

(Route) System 

NOAEL 

(mg/kg/day) 

Less Serious 

(mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

ACUTE EXPOSURE Death 

1 Rat 

(Long- Evans) 

once (GW) 50 M (3/12 died during seizures) Burdette et al. 1988 

2 Rat 

(SpragueDawley) 

once (GW) 50 (2/10 died) Schneider et al. 1977 

3 Rat 

(SpragueDawley) 

once (GO) 71 M (LD50 ) 

75 F (9/10 rats died) 

U.S. Army 1978b 

4 Rat 

(Fischer 344) 

Gd 6-19 (GW) 20 F (6/25 died) U.S. Army 1980b 

5 Rat 

(Fischer 344) 

once (G) 119 (LD50) U.S. Army 1980b 

6 Rat 

(SpragueDawley) 

Gd 6-15 (GW) 20 F (31% died) U.S. Army 1986d 

7 Rat 

(SpragueDawley) 

7 d/wk 14 d (GW) 

25.5 (75% mortality) U.S. Army 2006 

8 Rat 

(NS) 

once (GW) 100 (40% mortality) von Oettingen et al. 194
37

8675

60

9759

70

100

509

20

522

17

530

686868

92

357

11

12.5 25

9 

13 

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Mouse once 86 M (LD50) U.S. Army 1978b (Swiss- (GO) Webster) 75 F (5/10 mice died) 

10 Mouse 

(B6C3F1) 

once (G) 97 M (LD50) 

59 F (LD50) 

U.S. Army 1980b 

11 Pig 

(NS) 

Systemic 

12 Rat 

(Fischer 344) 

once (GW) Gd 6-19 (GW) Bd Wt 20 F (12% decrease in maternal body weight) 

100 F (2/10 died) Schneider et al. 1977 

U.S. Army 1980b 

Rat 7 d/wk Hemato 17 U.S. Army 2006 14 d (SpragueDawley) (GW) 

14 Mouse 

(Peromyscus leucopus) 

daily 14 days (F) 

Hepatic 68 F EPA 1999 

Renal 68 F 

Neurological 

15 Human once 

Bd Wt 68 F 

357 M (seizures) Stone et al. 1969 

16 Rat 

(Long- Evans) 

once (GW) 12.5 M 25 M (seizures) Burdette et al. 1988 
512

87

69

50

508

2

20

44

12.5

511

6

20

519

8.5

17

71

100

22 

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

17 Rat 

(SpragueDawley) 

once (GO) 87 F (convulsions in 2/2 rats) Meyer et al. 2005 

18 Rat 

(SpragueDawley) 

once (GW) 50 (convulsions) Schneider et al. 1977 

19 Rat 

(Fischer 344) 

Gd 6-19 (GW) 

2 F 20 F (convulsions and 

hyperactivity in dams) 

U.S. Army 1980b 

20 Rat 

(SpragueDawley) 

once (GW) 12.5 (decreases in motor activity, taste aversion, 

learning, and auditory startle response amplitude) 

U.S. Army 1985b 

21 Rat 

(SpragueDawley) 

Gd 6-15 (GW) 6 F 20 F (convulsions, prostration in dams) U.S. Army 1986d 

Rat 7 d/wk b 8.5 17 (tremors and U.S. Army 2006 14 d (Sprague- convulsions) Dawley) (GW) 

Pig once 100 F (convulsions) Schneider et al. 1977 (NS) (GW) 23 
53

2

9

6

20

26

100

22

100

520

10

79

25

85

50

55

320

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Developmental 

24 Rat 

(Fischer 344) 

Gd 6-19 (GW) 

2 F U.S. Army 1980b 

25 Rat 

(SpragueDawley) 

Gd 6-15 (GW) 6 F 20 F (9% decrease in fetal weight and 5% decrease 

in fetal length) 

U.S. Army 1986d 

INTERMEDIATE EXPOSURE Death 

26 Rat 

(Fischer 344) 

13 wk (F) 100 (65% mortality) Levine et al. 1981 

27 Rat 

(Fischer 344) 

13 wk (F) 100 (13/20 died) Levine et al. 1990 

28 Rat 

(Fischer- 344) 

7 d/wk 90 d (GW) 

10 (25% mortality) U.S. Army 2006 

29 Rat 

(NS) 

90 d (F) 25 (8/20 died) von Oettingen et al. 194

30 Rat 

(NS) 

10 wk (F) 50 (60% mortality) von Oettingen et al. 194

31 Mouse 

(B6C3F1) 

90 d (F) 320 M (4/10 died) U.S. Army 1980b 
39

10101 101

10

10101010

28

100100100

10

10

30

10030 100

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

Systemic 

32 Monkey 90 d 

(Cynomolgus) 7 d/wk 

(GW) 

33 Rat 13 wk 

(Fischer 344) (F) 

System 

Resp Cardio Gastro Hemato Hepatic Renal Endocr Ocular Resp Cardio Gastro Hemato Hepatic Renal Bd Wt 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

10 U.S. Navy 1974b 

10 

1 10 (vomiting in 5/6 animals) 

1 10 (necrotic and degenerate 

megakaryocytes in bone marrow) 

10 10 10 10 

100 Levine et al. 1981 

100 

100 

10 F (increased leukocyte 

counts) 

10 30 (10-14% decrease in 

serum triglycerides) 

100 

30 100 M (17% weight loss) 
23

100100100100

30

100

30 100

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

34 Rat 

(Fischer 344) 

3-13 wk (F) Resp 100 Levine et al. 1990 

Cardio 100 Gastro 100 Hemato 100 Hepatic 30 (decr serum triglyceride 

levels) 

Renal 100 Bd Wt 30 M (13% decrease in body 

weight gain) 

100 M (29% decr body weight 

gain) 
59

4028

40

404040404040404040

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

35 Rat 

(Fischer 344) 

90 d (F) Resp 40 U.S. Army 1980b 

Cardio 28 F 40 F (decreased absolute 

heart weight, myocardial degeneration) 

Gastro 40 Hemato 40 Musc/skel Hepatic Renal 

40 40 40 

Endocr 40 Dermal 40 Ocular 40 Bd Wt 40 
13

4040408

40

408

40

404040408

40

8

40

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

36 Rat 

(Fischer 344) 

6 mo (F) Resp 40 U.S. Army 1983a 

Cardio 40 Gastro 40 Hemato 8 40 (decreased hemoglobin 

and erythrocyte levels) 

Musc/skel Hepatic 

40 

8 40 (decreased serum 

triglyceride and cholesterol levels) 

Renal 40 Endocr 40 Dermal 40 Ocular 40 Bd Wt 8 40 (17% decrease in body 

weight gain) 

Metab 8 40 (decreased blood 

glucose levels) 
521

151515154

8

151515

77

15 25

83

15 50

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a

Key to 

Figure 

Species 

(Strain) 

Frequency 

(Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) Serious (mg/kg/day) 

37 Rat 

(Fischer- 344) 

7 d/wk 90 d (GW) 

Resp Cardio Gastro Hemato Hepatic 

15 15 

15 

15 

4 F 8 M (decreased serum 

cholesterol levels) 

Renal Ocular Bd Wt 

15 15 

15 

38 Rat 

(NS) 

90 d (F) Bd Wt 15 25 (weight loss) 

39 Rat 

(NS) 

10 wk (F) Bd Wt 15 50 (weight loss) 

Reference Chemical Form 

U.S. Army 2006 von Oettingen et al. 194von Oettingen et al. 194
56

320160

320

32080

160

160

320

160 320160

320

320

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) System 

40 Mouse 

(B6C3F1) 

90 d (F) Resp 

Cardio Gastro Hemato Hepatic Renal Endocr Bd Wt 

NOAEL 

(mg/kg/day) 

320 160 M 

320 

80 M 

160 M 160 M 160 M 320 

LOAEL 

Less Serious 

(mg/kg/day) 

Serious 

(mg/kg/day) 

Reference Chemical Form 

320 M (slight myocardial 

degeneration) 

U.S. Army 1980b 

160 M (12% decrease in 

erythrocyte count and 7% decrease in hemoglobin concentration) 

320 M (hepatocellular 

vacuolization) 

320 M (mild tubular nephrosis) 320 F (mild focal subscapular 

fibroplasia in adrenal gland) 
46

100100100100100100100100100

1

10101010101010

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

41 Mouse 

(B6C3F1) 

6 mo (F) Resp 100 U.S. Army 1984c 

Cardio 100 Gastro 100 Hemato 100 Musc/skel 100 Hepatic 100 Renal 100 Endocr 100 Ocular 100 

42 Dog 

(NS) 

90 d (F) Resp 10 U.S. Navy 1974a 

Cardio 10 Hemato 10 Hepatic 10 Renal 10 Endocr 10 Ocular 10 
74

505050505050

50

523

15

400

1

10

25

30

100

21

30

100

46 

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

43 Dog 

(NS) 

6 wk 6 d/wk (C) 

Resp 50 F von Oettingen et al. 194

Cardio 50 F Hemato 50 F Hepatic 50 F Renal 50 F Endocr 50 F 

Immuno/ Lymphoret 

44 Rat 

(Fischer- 344) 

7 d/wk 90 d (GW) 

Bd Wt 

15 

50 F (unspecified weight loss) 

U.S. Army 2006 

Neurological 

45 Monkey 

(Cynomolgus) 

90 d 7 d/wk (GW) 

1 10 (convulsions and 

seizures) 

U.S. Navy 1974b 

Rat 13 wk 30 100 (hyperreactive to Levine et al. 1981 Fischer 344 (F) approach) 

Rat 10 wk 30 100 (hyperreactive to Levine et al. 1990 (Fischer 344) (F) approach) 47 
99

8

40

45

10

524

4

8

78

15

25

84

15

50

54

160

320

75

50

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

a 

Key to 

Figure 

48 49 50 51 52 53 54 

Exposure/ LOAEL 

Duration/ 

Species Frequency NOAEL Less Serious Serious Reference (Route) (Strain) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Rat 25 wk 8 40 (tremor, convulsions, U.S. Army 1983a (Fischer 344) (F) hyperreactive) 

Rat 30 d U.S. Army 1985b 

10 M (Sprague- (GW) 

Dawley) Rat 7 d/wk c4 8 (tremors and U.S. Army 2006 90 d (Fischer- 344) convulsions) (GW) 

Rat (NS) 

90 d (F) 15 25 (convulsions, hyperirritability and 

fighting) 

von Oettingen et al. 194

Rat (NS) 

10 wk (F) 15 50 (hyperirritability and convulsions) von Oettingen et al. 194

Mouse 90 d 160 M 320 M (hyperactivity and/or U.S. Army 1980b (B6C3F1) (F) nervousness) 

Dog 6 wk 50 F (hyperirritability and von Oettingen et al. 194

6 d/wk (NS) convulsions) (C) 
24

100

50

50

515

16 50

14

840

40

514

5

16

50

52

20

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

Reproductive 

55 Rat 

(Fischer 344) 

3-13 wk (F) 100 Levine et al. 1990 

56 Rat 

(Fischer 344) 

2 generation; 13 wk pre-mating, mating, gestation, & lactat. (F) 

50 U.S. Army 1980b 

57 Rat 

(Fischer 344) 

15 wk (F) 16 M 50 M (decreased fertility) U.S. Army 1980b 

58 Rat 

(Fischer 344) 

6 mo (F) 8 M 

40 F 

40 M (spermatic granuloma in 

prostate) 

U.S. Army 1983a 

Developmental 

59 Rat 

(Fischer 344) 

2 generation; 13 wk pre-mating, mating, gestation, & lactat. (F) 

5 16 (decrease in F2 pup body 

weight) 

50 (increase in number of 

stillbirths; decrease in pup survival in F1) 

U.S. Army 1980b 

60 Rabbit 

(NS) 

Gd 7-29 (GW) 20 U.S. Army 1980b 
15

40

19

4040408

40

408

40

8

40

408 408

40

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

CHRONIC EXPOSURE Death 

61 Rat 2 yr 

(Fischer 344) (F) 

Systemic 

62 Rat 1 & 2 yr 

(Fischer 344) (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Endocr Ocular Bd Wt 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

40 M (88% died) U.S. Army 1983a 

40 U.S. Army 1983a 

40 

40 

8 40 (decreases in hematocrit, 

hemoglobin, and erythrocyte levels; splenic extramedullary hematopoiesis) 

40 

8 40 (hepatomegaly, 

decreased serum trigylcerides and cholesterol) 

8 40 (renal papillary necrosis 

with increased BUN) 

40 

8 F 40 F (cataracts) 8 40 M (20-30% decrease in 

body weight gain) 
5

10101010101010

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ LOAEL 

Duration/ 

a 

Key to Species Frequency NOAEL Less Serious Serious Reference 

Figure (Strain) (Route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

63 Rat 

(SpragueDawley) 

2 yr (F) Resp 10 U.S. Navy 1976 

Cardio 10 Gastro 10 Hemato 10 Hepatic Renal 

10 10 

Endocr 10 
47

10035

100

1001001007

35

35

100

100100

17

8

40

18

840

40

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ 

Duration/ 

a Frequency Key to Species (Route) Figure (Strain) 

64 Mouse 1 & 2 yr 

(B6C3F1) (F) 

Neurological 

65 Rat 1 & 2 yr 

(Fischer 344) (F) 

Reproductive 

66 Rat 1 & 2 yr 

(Fischer 344) (F) 

System 

Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Ocular Bd Wt 

LOAEL 

NOAEL Less Serious Serious Reference

(mg/kg/day) (mg/kg/day) (mg/kg/day) Chemical Form 

100 U.S. Army 1984c 

35 100 (increased relative heart 

weight) 

100 100 100 

7 35 F (increased serum 

cholesterol levels) 

35 100 (increased relative kidney 

weights and reversible cytoplasmic vacuolization) 

100 100 

d

8 40 (tremors, convulsions; 

hyperresponsive to stimuli) 

U.S. Army 1983a 

8 M 

40 F 

40 M (testicular degeneration) U.S. Army 1983a 
48

100100

51

35

Table 3-1 Levels of Significant Exposure to RDX - Oral (continued) 

Exposure/ 

Duration/ 

a 

Key to Species Frequency 

Figure (Strain) (Route) System NOAEL (mg/kg/day) Less Serious (mg/kg/day) 

LOAEL 

Serious 

(mg/kg/day) 

Reference Chemical Form 

67 Mouse 

(B6C3F1) 

1 & 2 yr (F) 100 M 

100 F 

U.S. Army 1984c 

Cancer 

68 Mouse 

(B6C3F1) 

1 & 2 yr (F) 35 F (CEL: hepatocellular carcinomas and 

adenomas) 

U.S. Army 1984c 

a The number corresponds to entries in Figure 3-1. b Used to derive an acute-duration oral minimal risk level (MRL) of 0.2 mg/kg/day based on a PBPK model predicted internal dose metric (peak brain RDX concentNOAEL dose; a human equivalent dose (HED) of the NOAEL was also estimated using a PBPK model. The NOAELHED of 6.45 mg/kg/day was divided by an unc30 (3 for extrapolation from animals to human with dosimetric adjustments and 10 for human variability). c Used to derive an intermediate-duration oral MRL of 0.1 mg/kg/day based on a BMDL10 estimated using using a PBPK model predicted internal dose metric (peaconcentration); a human equivalent dose of the BMDL10 was also predicted using a PBPK model. The BMDLHED of 4.1308 mg/kg/day was divided by an uncertafor extrapolation from animals to human with dosimetric adjustment and 10 for human variability). d Used to derive a chronic-duration oral minimal risk level (MRL) of 0.1 mg/kg/day based on a PBPK model predicted internal dose metric (peak brain RDX concentNOAEL dose; a human equivalent dose (HED) of the NOAEL was also estimated using a PBPK model. The NOAELHED of 4.223 mg/kg/day was divided by an un30 (3 for extrapolation from animals to human with dosimetric adjustments and 10 for human variability). Bd Wt = body weight; (C) = capsule; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; (F) = feed; F = Female; (G) = gavage; Gasgastrointestinal; Gd = gestation day; (GO) = gavage in oil; (GW) = gavage in water; Hemato = hematological; Immuno/Lymphoret = immunological/lymphoreticular; dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; min = minute(s); Metab = metabolic; mo = month(s); Musc/skel = musculoskeletal; NOAEno-observed-adverse-effect level; NS = not specified; occup = occupational; Resp = respiratory; wk = week(s); yr = year(s) 
Dea

HeHepRenBodNeuDev

mg/kg/day 

1000 

15 

5r 

100 10m 8r 11p 23p 9m 17r 9m 3r 3r 14m 14m 14m 10m 

1r 2r 18r 

7r 16r 

4r 6r 12r 19r 21r 25r

13r 22r 

16r 20r 

10 

22r 

21r 25r 

19r 24r 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

th 

mato

atic

al 

y W 

rolo 

elo 

logical 

eight 

gical 

pmental 

Figure 3-1 Levels of Significant Exposure to RDX - Oral 

Acute (≤14 days) 

Systemic 

RDX

3. HEALTH EFFECTS

44
Death 

Respiratory Cardiovascular Gastrointestinal Hematological 

mg/kg/day 

1000 

31m 40m 40m 40m 

40m 40m 

100 26r 27r 41m 33r 34r 41m 33r 34r 41m 33r 34r 41m 34r 

40m 

30r 43d 43d 43d 

35r 36r 35r 36r 35r 36r 35r 36r 

35r 29r 

37r 37r 37r 37r 

10 28r 42d 32k 42d 32k 32k 42d 32k 33r 

36r 

1 32k 32k 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 


 


	

Figure 3-1 Levels of Significant Exposure to RDX - Oral (Continued)

Intermediate (15-364 days)
	

Systemic 

RDX

3. HEALTH EFFECTS

45
Musculoskeletal 

Hepatic Renal Endocrine Dermal Ocular 
	


	


 


	

Figure 3-1 Levels of Significant Exposure to RDX - Oral (Continued)

Intermediate (15-364 days)
	

Systemic 

mg/kg/day 

1000 

40m 40m 40m 

40m 40m 40m
	

100
	 41m 41m 41m 33r 34r 41m 41m 

43d 43d 43d 

35r 36r 35r 36r 35r 36r 35r 36r 35r 36r 35r 36r 

33r 34r 

37r 37r 

10 42d 32k 33r 42d 32k 42d 32k 42d 32k 

36r 37r 

37r 

1 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

RDX

3. HEALTH EFFECTS

46
Body Weight 

Metabolic Immuno/Lymphor Neurological Reproductive Developmental 


	


	


	


	


	

Systemic
	

mg/kg/day 

1000 

40m 53m 

53m
	

100
	 33r 34r 46r 47r 55r 

43d 39r 54d 52r 56r 57r 59r 

35r 36r 36r 48r 58r 58r 

33r 34r 46r 47r 

38r 51r 

60h 

57r 59r 37r 38r 39r 44r 51r 52r
	

10
	 45k 49r 

36r 36r 48r 50r 58r 

59r 

50r 

1 45k 

0.1 

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 


 


	

Figure 3-1 Levels of Significant Exposure to RDX - Oral (Continued)

Intermediate (15-364 days)
	 RDX

3. HEALTH EFFECTS

47
Death 

Respiratory Cardiovascular Gastrointestinal Hematological Musculoskeletal Hepatic Renal Endocrine Ocular Body Weight Neurological Reproductive Cancer * 

 

 


	

Figure 3-1 Levels of Significant Exposure to RDX - Oral (Continued)
 

Chronic (≥365 days)
	

Systemic 

mg/kg/day 

1000 

100 64m 64m 64m 64m 64m 64m 64m 64m 67m 67m 

61r 62r 62r 62r 62r 62r 62r 62r 62r 62r 62r 65r 66r 66r 64m 64m 64m 68m 

10 63r 63r 63r 63r 63r 63r 63r 

62r 62r 62r 62r 62r 65r 66r 64m 

1 

*Doses represent the lowest dose tested per study that produced a tumor 0.1 response and do not imply the existence of a threshold for the cancer end

c-Cat 

d-Dog

r-Rat 

p-Pig

q-Cow

 -Humans 

k-Monkey

m-Mouse 

h-Rabbit 

a-Sheep 

f-Ferret 

j-Pigeon

e-Gerbil 

s-Hamster 

g-Guinea Pig 

n-Mink 

o-Other

 Cancer Effect Level-Animals

 LOAEL, More Serious-Animals

LOAEL, Less Serious-Animals

NOAEL - Animals

 Cancer Effect Level-Humans

 LOAEL, More Serious-Humans

LOAEL, Less Serious-Humans

NOAEL - Humans

 LD50/LC50

Minimal Risk Level

 for effects

 other than

 Cancer 

RDX

3. HEALTH EFFECTS

48

ig enic 

p oint. 
 

 

 

 

 

 

 

RDX 49 

3. HEALTH EFFECTS 

3.2.2.2 Systemic Effects 

No studies were located regarding respiratory, musculoskeletal, dermal, or ocular effects in humans after 

acute oral exposure to RDX. No studies were located regarding systemic effects in humans after 

intermediate or chronic oral exposure to RDX. The highest NOAEL values and all reliable LOAEL 

values for systemic effects in each species and duration category are recorded in Table 3-1 and plotted in 

Figure 3-1. 

Respiratory Effects. Adverse respiratory effects were not observed in animals following acute, 

intermediate, or chronic exposure. An acute-duration study in 3 anesthetized dogs showed no significant 

changes in breathing rate when 15 mg/kg RDX was administered by gavage (von Oettingen et al. 1949). 

No histopathology was seen in the lungs, trachea, or bronchi of rats exposed for 3–13 weeks to 

100 mg/kg/day of RDX in the diet (Levine et al. 1990), 40 mg/kg/day RDX in the diet for 90 days (U.S. 

Army 1980b), or 15 mg/kg/day via gavage for 90 days (U.S. Army 2006). Similarly, no histopathological 

alterations were observed in the respiratory system of mice exposed to 100 or 320 mg/kg/day in the diet 

for 3 or 6 months (U.S. Army 1980b, 1984c), dogs exposed to 10 mg/kg/day in the diet for 90 days (U.S. 

Navy 1974a) or 50 mg/kg via capsules 6 days/week for 6 weeks (von Oettingen et al. 1949), or monkeys 

administered 10 mg/kg/day via gavage for 90 days (U.S. Navy 1974b). Chronic-duration studies also 

revealed no histopathology in rats (U.S. Army 1983a; U.S. Navy 1976) or mice (U.S. Army 1984c). 

Cardiovascular Effects. Sinusoidal tachycardia was observed in five men who accidentally ingested 

37–250 mg/kg RDX (Küçükardalĭ et al. 2003). 

Few, if any, changes were observed in cardiovascular parameters measured in animals exposed to RDX. 

An acute-duration study in 3 anesthetized dogs showed no significant changes in heart rate when 

15 mg/kg RDX was administered by gavage (von Oettingen et al. 1949). Intermediate-duration studies 

revealed no histopathology in the heart of rats exposed to 15–100 mg/kg/day of RDX (Levine et al. 1981; 

U.S. Army 2006). Slight myocardial degeneration was observed in rats exposed to 40 mg/kg/day and 

mice exposed to 320 mg/kg/day in the diet for 90 days (U.S. Army 1980b). No pathology was seen in the 

hearts of dogs (U.S. Navy 1974a; von Oettingen et al. 1949) or monkeys (U.S. Navy 1974b) exposed to 

RDX for intermediate periods. Hyaline degeneration of the heart muscles was observed in rats following 

intermediate exposure to 50 mg/kg/day of RDX (Sunderman 1944). Chronic exposure produced no 

cardiac histopathology in rats (U.S. Army 1983a; U.S. Navy 1976), but it increased relative heart weights 

in mice (U.S. Army 1984c). 
 

 

 

 

 

 

 

 

RDX 50 

3. HEALTH EFFECTS 

Gastrointestinal Effects. Humans who accidentally or intentionally consumed unknown levels of 

RDX for an acute period had nausea, vomiting, and abdominal pain (Kasuske et al. 2009; Ketel and 

Hughes 1972; Küçükardalĭ et al. 2003). In three of five cases in which men accidentally ingested 37– 

250 mg/kg, an endoscopic examination conducted 3 days after exposure revealed erosive gastroduodenitis 

(Küçükardalĭ et al. 2003). 

Vomiting was reported in dogs acutely exposed to 100 and 300 mg/kg/day RDX (Sunderman 1944). 

Vomiting was also observed in five of six monkeys administered via gavage 10 mg/kg/day for 90 days, 

compared to one of six in the control group (U.S. Navy 1974b). There were 15 episodes of vomiting 

(excluding vomiting, which occurred during the gavage procedure) in this group compared to 1 episode in 

the control group. In monkeys administered 1 mg/kg/day, two of six animals (three episodes) vomited; 

one other animal in this group vomited only during the gavage procedure. Following intermediate 

exposure of rats to 50 mg/kg/day RDX, mild congestion of the intestines was reported (Sunderman 1944). 

No histopathology was seen in the stomachs or intestines of rats (Levine et al. 1981, 1990; U.S. Army 

1980b, 1983a), mice (U.S. Army 1980b, 1984c), dogs (U.S. Navy 1974a; von Oettingen et al. 1949), or 

monkeys (U.S. Navy 1974b). Chronic exposure also did not produce histopathological alterations in rats 

(U.S. Army 1983a; U.S. Navy 1976) or mice (U.S. Army 1984c). 

Hematological Effects. Humans who accidentally consumed unknown levels of RDX for an acute 

duration generally had normal blood counts (Ketel and Hughes 1972; Woody et al. 1986). Temporary 

decreased hematocrit and leukocytosis were reported in a study of six men who consumed C-4 containing 

RDX (Stone et al. 1969). Similarly, leukocytosis and methemoglobinemia were noted in a report of five 

men accidentally ingesting 37–250 mg/kg RDX (Küçükardalĭ et al. 2003). 

Decreased hemoglobin and erythrocyte levels, increased platelet counts, and splenic extramedullary 

hematopoiesis were observed in male rats exposed to 40 mg/kg/day RDX in the diet for 6 months (U.S. 

Army 1983a). However, oral doses of 15 mg/kg/day (administered via gavage) (U.S. Army 2006) or 

40 mg/kg/day (administered via the diet) (U.S. Army 1980b) for 13 weeks did not result in significant 

hematological effects. Similarly, decreased hemoglobin and erythrocyte levels were observed in mice 

exposed to 160 mg/kg/day for 90 days (U.S. Army 1980b). No significant hematological effects were 

found in mice exposed to 100 mg/kg/day for 6 months (U.S. Army 1984c) and dogs exposed to 

50 mg/kg/day for 6 weeks (von Oettingen et al. 1949). Species differences in hematological responses to 

RDX may relate to differences in their activity of erythrocyte methemoglobin reductase (Rockwood et al. 
 

 

 

 

 

 

 

 

 

 

RDX 51 

3. HEALTH EFFECTS 

2003; Smith and Beutler 1966). Slight, but statistically significant, increases in the number of leukocytes 

were observed in rats exposed to ≥10 mg/kg/day for 13 weeks (Levine et al. 1981). Necrotic and 

degenerative megakaryocytes were observed in the bone marrow of monkeys given 10 mg/kg/day of 

RDX for 90 days (U.S. Navy 1974b). Chronic administration of 40 mg/kg/day of RDX in the diet for 1– 

2 years produced decreased hematocrit, hemoglobin, and erythrocytes in rats; the effects were not 

considered biologically significant and there were no compensatory responses (U.S. Army 1983a). 

Significant increases in platelet levels were also observed at 40 mg/kg/day (U.S. Army 1983a). No 

significant hematological effects were observed in mice chronically exposed to 100 mg/kg/day (U.S. 

Army 1984c). 

Musculoskeletal Effects. No histopathological alterations were observed in muscle or skeletal tissue 

of rats (Levine et al. 1981, 1990; U.S. Army 1980b, 1983a), mice (U.S. Army 1980b, 1984c), or dogs 

(U.S. Navy 1974a) exposed for intermediate periods. Muscles and bones were also normal in rats (U.S. 

Army 1983a; U.S. Navy 1976) and mice (U.S. Army 1984c) exposed for chronic periods. 

Hepatic Effects. Slightly elevated serum aspartate aminotransferase and/or alanine aminotransferase 

(Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969) were observed in humans ingesting unknown 

levels of RDX after using C-4 cooking fuel for an acute duration; other studies reported normal liver 

enzyme levels (Ketel and Hughes 1972). Liver biopsies were normal (Stone et al. 1969). 

Minor adverse hepatic effects have been noted in some animal studies. Slight decreases in alanine 

aminotransferase levels were observed in rats exposed to 40 mg/kg/day for 26 weeks (U.S. Army 1983a). 

Decreases in serum triglyceride levels were noted in rats exposed to ≥10 mg/kg/day RDX for 13 weeks 

(Levine et al. 1981, 1990), decreases in serum cholesterol were observed in male rats administered 

≥8 mg/kg/day for 90 days (U.S. Army 2006), and decreases in serum triglycerides and cholesterol were 

observed in rats exposed to 40 mg/kg/day for 6 months to 2 years (U.S. Army 1983a). Increases in serum 

cholesterol were also observed in female mice exposed to 35 or 100 mg/kg/day for 1–2 years (U.S. Army 

1984c). Increases in liver weight have been observed in rats exposed to 30 or 100 mg/kg/day (Levine et 

al. 1981, 1990) and mice exposed to 100 or 320 mg/kg/day (U.S. Army 1980b, 1984c); hepatomegaly was 

observed in rats exposed to 40 mg/kg/day (U.S. Army 1983a). However, most studies did not find 

histological alterations in the livers of rats (Levine et al. 1981; U.S. Army 1983a), mice (U.S. Army 

1984c), dogs (U.S. Navy 1974a; von Oettingen et al. 1949), white-footed mice (U.S. Army 1999), or 

monkeys (U.S. Navy 1974b). Two studies did find histological effects; hepatocellular vacuolization was 

observed in mice exposed to 320 mg/kg/day for 90 days (U.S. Army 1980b) and fatty degeneration was 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 52 

3. HEALTH EFFECTS 

observed in rats exposed to 50 mg/kg/day for 78 days (Sunderman 1944). Although the alterations in 

serum clinical chemistry parameters may be indicative of minor changes in liver function, the lack of 

histological damage at similar or higher doses suggests that the liver may not be a sensitive target of RDX 

toxicity and the alterations may not be biologically significant. 

Renal Effects. Humans who accidentally consumed unknown levels of RDX for an acute duration 

showed no (Woody et al. 1986) or only slight (Ketel and Hughes 1972; Stone et al. 1969) changes in renal 

function parameters. Proteinuria and glucosuria were observed in men after accidental ingestion of RDX 

(Küçükardalĭ et al. 2003; Merrill 1968). 

Few adverse renal effects were reported in animals. No histopathological alterations were observed in the 

kidneys from white-footed mice following 14-day dietary exposure (U.S. Army 1999) or from rats 

following intermediate exposure periods (Levine et al. 1981, 1990; U.S. Army 1980b, 1983a, 2006). 

Normal kidney parameters were also observed in dogs (U.S. Navy 1974a; von Oettingen et al. 1949) and 

monkeys (U.S. Navy 1974b). In contrast, mild tubular nephrosis was reported in mice given high doses 

(320 mg/kg/day) in the food for 13 weeks, but was not seen at lower doses (160 mg/kg/day) (U.S. Army 

1980b). Following chronic exposure to 40 mg/kg/day of RDX in food, renal papillary necrosis and 

elevated blood urea nitrogen levels were observed in rats (U.S. Army 1983a); these effects were not 

observed at 8 mg/kg/day. Other studies showed normal renal parameters in rats at lower levels 

(10 mg/kg/day) (U.S. Navy 1976). Increased kidney weights, but no other signs of kidney toxicity, were 

observed in mice chronically exposed to 100 mg/kg/day (U.S. Army 1984c). 

Endocrine Effects. No histopathological alterations were observed in the adrenal glands of rats (U.S. 

Army 1980b, 1983a; U.S. Navy 1976), mice (U.S. Army 1984c), dogs (U.S. Navy 1974a), or monkeys 

(U.S. Navy 1974b) exposed for intermediate periods. One study (U.S. Army 1980b) observed mild focal 

subscapular fibroplasia in the adrenal glands of female mice exposed to 320 mg/kg/day RDX for 90 days. 

Dermal Effects. No significant skin lesions were seen in rats (U.S. Army 1980b, 1983a) exposed for 

intermediate periods to RDX in the food. 

Ocular Effects. No significant ophthalmologic alterations were observed in rats administered 

15 mg/kg/day via gavage for 90 days (U.S. Army 2006). Female rats exposed to 40 mg/kg/day of RDX 

in their food for 2 years had cataracts (U.S. Army 1983a), but this was not seen in the male rats in this 
 

 

 

 

 

 

 

 

 

 

 

RDX 53 

3. HEALTH EFFECTS 

study, in male or female rats exposed to 40 mg/kg/day in another study (U.S. Army 1980b), or in mice 

exposed to a higher level (100 mg/kg/day) (U.S. Army 1984c). 

Body Weight Effects. Weight loss or lack of weight gain of >10% was seen in rats fed 25– 

40 mg/kg/day (Levine et al. 1981, 1990; von Oettingen et al. 1949) and dogs fed 50 mg/kg/day (von 

Oettingen et al. 1949) for an intermediate duration, and in rats receiving 40 mg/kg/day RDX (U.S. Army 

1983a) and mice receiving 100 mg/kg/day (U.S. Army 1984c) for a chronic period. 

Metabolic Effects. Hyperglycemia, hypokalemia, and metabolic acidosis with anion gap were 

observed in men accidentally ingesting 37–250 mg/kg RDX (Küçükardalĭ et al. 2003). In rats exposed to 

40 mg/kg/day RDX in the diet for 13–78 weeks, significant decreases in blood glucose levels were 

observed (U.S. Army 1983a). 

3.2.2.3 Immunological and Lymphoreticular Effects 

No studies were located regarding immunological effects in humans after oral exposure to RDX. 

No studies were located regarding immunological effects in animals after acute oral exposure to RDX. 

Studies of intermediate duration (6–13 weeks) failed to reveal any marked pathological alterations in the 

spleen, thymus, and/or lymph nodes in rats (Levine et al. 1990; U.S. Army 1980b), mice (U.S. Army 

1980b), dogs (U.S. Navy 1974a; von Oettingen et al. 1949), or monkeys (U.S. Navy 1974b). No 

significant alterations in spleen and thymus organ weights or cellularity, or in the proportion of cell 

surface markers were observed in rats exposed to 15 mg/kg/day for 90 days (U.S. Army 2006). The 

NOAEL value from the U.S. Army (2006) is recorded in Table 3-1 and plotted in Figure 3-1; NOAEL 

values for studies only examining potential histopathological alterations in lymphoreticular organs were 

not listed. 

3.2.2.4 Neurological Effects 

The available studies have identified the nervous system as a target system in humans following oral 

exposure to RDX. Numerous case reports are available that describe seizures in men (Hollander and 

Colbach 1969; Kasuske et al. 2009; Ketel and Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone 

et al. 1969) and in one child (Woody et al. 1986) after accidental consumption of unknown quantities of 

RDX for acute periods and in men intentionally chewing on C-4 (Goldberg et al. 1992; Harrell-Bruder 

and Hutchins 1995). The RDX was almost always mixed with other components in the form of the 
 

 

 

 

 

 

 

 

RDX 54 

3. HEALTH EFFECTS 

explosive C-4, which is 91% RDX (mixed with polyisobutylene, motor oil, and di-(2-ethylhexyl) 

sebacate). In most of the cases, RDX intakes were not known; Stone et al. (1969) reported doses (357 and 

2,571 mg/kg) for two cases. In a report of five cases (Küçükardalĭ et al. 2003), repetitive tonic-clonic 

convulsions were first observed 4–16 hours after RDX exposure; in one case, convulsions were observed 

for 3 days, although the frequency and duration gradually decreased with time. Most studies reported that 

recovery occurred within a few days or weeks. Accompanying complaints included disorientation, 

nausea, restlessness, muscle twitching, lethargy, and hyperactive deep tendon reflexes. In most cases, no 

other neurological evaluations were performed. Küçükardalĭ et al. (2003) noted abnormalities in 

electroencephalograms (EEG) in three of the five cases. In the case reported by Harrell-Bruder and 

Hutchins (1995), no EEG abnormalities were found. No intermediate- or chronic-duration exposure data 

have been reported for humans. 

Animal studies have also shown that the nervous system is a target system following oral exposure to 

RDX. Seizures were observed in rats receiving a single gavage dose of ≥25 mg/kg (U.S. Army 2006; 

Burdette et al. 1988; Meyer et al. 2005; Schneider et al. 1977), deer mice receiving a gavage dose of 

136 mg/kg (Smith et al. 2007), and miniature swine receiving a single gavage dose of ≥10 mg/kg 

(JHU/U.S. Army 2006; Schneider et al. 1977). Seizures were also observed in 20% of rats administered a 

single dose of 12.5 mg/kg/day; however, the incidence was not significantly different from controls 

(Burdette et al. 1988). Following administration of a single dose of ≥25 mg/kg RDX, seizures and 

convulsions typically occur within 3 hours (U.S. Army 2006; Burdette et al. 1988). Convulsions and 

hyperactivity were also noted in “several” surviving rat dams administered 20 mg/kg/day by gavage during 

gestation days 6–15 (U.S. Army 1986d); incidence data were not provided. Hyperactivity was observed in 

approximately 70% of rat dams administered 20 mg/kg/day RDX via gavage on gestation days 6–19 (U.S. 

Army 1980b). In a 14-day exposure study, tremors and convulsions were observed in rats receiving 

gavage doses of ≥17 mg/kg/day; no marked neurological effects were noted at 8.5 mg/kg/day (U.S. Army 

2006). In neurobehavioral tests, decreases in motor activity, hindlimb splay, taste aversion to saccharine, 

response rate in scheduled-controlled behavior tests, auditory startle amplitude, and increases in startle 

latency were observed in rats receiving a single gavage dose of ≥12.5 mg/kg/day (U.S. Army 1985b). 

Seizures and convulsions have also been observed in rats, monkeys, and dogs exposed to RDX for 

intermediate or chronic durations. Seizures and convulsions were observed in rats administered gavage 

doses ≥8 mg/kg/day for 90 days (U.S. Army 2006), in rats exposed to dietary RDX at doses of 

≥25 mg/kg/day (Sunderman 1944; U.S. Army 1983a; von Oettingen et al. 1949), dogs exposed to 

50 mg/kg/day via a capsule (von Oettingen et al. 1949), and monkeys administered 10 mg/kg/day via 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 55 

3. HEALTH EFFECTS 

gavage (U.S. Navy 1974b). Few studies have reported the time course of the convulsions/seizures. In the 

U.S. Army (2006) study, convulsions/seizures were observed at the beginning of the study in rats 

administered 12 or 15 mg/kg/day and were seen throughout the study; convulsions/seizures were also 

observed at 8 and 10 mg/kg/day, however, the investigators did not note when the convulsions/seizures 

first occurred for these dose levels. In a chronic dietary study, seizures and convulsions were first 

observed after 26 weeks of exposure to 40 mg/kg/day (U.S. Army 1983a). In monkeys, the effects were 

typically observed after 34–57 doses, although effects were also seen in some monkeys after the 2nd or 

12th dose, and did not occur on a regular basis (U.S. Navy 1974b). Other overt neurological signs 

observed following intermediate or chronic exposure include hyperactivity, hyperreactivity, increased 

arousal, and increased fighting in rats exposed to gavage doses of ≥10 mg/kg/day (U.S. Army 2006), in 

rats exposed to ≥25 mg/kg/day in the diet (Levine et al. 1990; U.S. Army et al. 1983a; von Oettingen et 

al. 1949), and dogs administered capsules containing 50 mg/kg/day (von Oettingen et al. 1949). The 

highest NOAELs for overt neurological effects were 4 mg/kg/day in rats receiving gavage doses (U.S. 

Army 2006), 15 mg/kg/day in rats exposed via the diet (von Oettingen et al. 1949), and 1 mg/kg/day in 

monkeys receiving gavage doses (U.S. Navy 1974b). Neurobehavioral performance was assessed in rats 

receiving gavage doses of RDX for 30 or 90 days. No significant alterations were observed in motor 

activity, flavor aversion, scheduled-controlled behavior, or acoustic startle in rats administered 10 

mg/kg/day for 15 or 30 days (U.S. Army 1985b). No RDX-related alterations in foot splay, front limb 

grip strength, or response to stimuli were found in rats administered 15 mg/kg/day for 90 days (U.S. 

Army 2006). No significant histological alterations have been found in the brain (U.S. Army 1983a, 

2006). 

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and 

duration category are recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.2.5 Reproductive Effects 

No studies were located regarding reproductive effects in humans after oral exposure to RDX. 

Toxicity studies lasting 13 weeks showed no pathological changes in the gonads or uteri of rats (Levine et 

al. 1981, 1990; U.S. Army 1980b, 1983a) or mice (U.S. Army 1980b, 1984c) exposed to RDX. No 

functional tests were performed. One study did report spermatic granulomas in the prostates of rats 

exposed to 40 mg/kg/day for 6 months (U.S. Army 1983a); this effect was not observed in rats exposed 

after 1 or 2 years of exposure (U.S. Army 1983a). This study (U.S. Army 1983a) also reported an 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 56 

3. HEALTH EFFECTS 

increase in the incidence of testicular degeneration in rats exposed to 40 mg/kg/day for 6 months (3/10, 

not statistically significant) or 1 year (4/10), but not after 2 years (0/4). 

Histological examinations of rats exposed to ≥1.5 mg/kg/day in the feed for 2 years revealed suppurative 

inflammation in the prostate (U.S. Army 1983a). The prostate effects were predominantly observed in 

rats dying early and may have been secondary to a bacterial infection of the urinary tract. Urinary bladder 

distention and cystitis were observed in rats exposed to 40 mg/kg/day for 1 or 2 years. Testicular 

degeneration was observed in rats exposed to 40 mg/kg/day for 1 year (U.S. Army 1983a); a 

nonstatistically significant increase in testicular degeneration was also observed in mice exposed to 

≥35 mg/kg/day for 1–2 years (U.S. Army 1984c). No significant histological alterations have been 

observed in the ovaries or uterus of rats (U.S. Army 1983a) or mice (U.S. Army 1984c) chronically 

exposed to RDX. 

Two studies examined reproductive function. In a two-generation study, no significant alterations in 

reproduction were observed in the F0 and F1 rats exposed to 16 mg/kg/day in the diet (U.S. Army 1980b). 

At 50 mg/kg/day, nonstatistically significant decreases in fertility were observed in the F0 generation. In 

a dominant lethality assay (U.S. Army 1980b), decreases in fertility were observed in male rats exposed 

to 50 mg/kg/day for 15 weeks prior to mating with unexposed females; however, the investigators noted 

that this effect may have been secondary to the impaired well-being of the males. The highest NOAEL 

values and all reliable LOAEL values for reproductive effects in each species and duration category are 

recorded in Table 3-1 and plotted in Figure 3-1. 

3.2.2.6 Developmental Effects 

No studies were located regarding developmental effects in humans after oral exposure to RDX. 

There are two available developmental studies in rats (exposed for 9 or 13 days during gestation) that are 

inconclusive because of excessive maternal toxicity at the high dose (20 mg/kg/day). In one study, no 

excessive gross, visceral, or skeletal anomalies were found in fetuses when the dams were exposed to 

2 mg/kg/day of RDX (U.S. Army 1980b). High maternal lethality, decreased maternal body weights, and 

adverse maternal neurological effects precluded judgment regarding fetal toxicity at 20 mg/kg/day. The 

other rat study (U.S. Army 1986d) also showed high maternal toxicity (increased mortality and seizures) 

at 20 mg/kg/day. These investigators also reported a significant decrease in fetal weights and lengths at 

≥2 mg/kg/day when data were analyzed on an individual basis rather than a litter basis. However, it 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 57 

3. HEALTH EFFECTS 

appears that there was an overlap in the standard deviations for the fetal body weight and length values; 

when analyzed on a litter basis, decreases in fetal weights and lengths were only significant at the 

20 mg/kg/day dose level. In contrast to rats, rabbits (exposed for 22 days during gestation) showed no 

adverse fetal or maternal effects at 20 mg/kg/day (U.S. Army 1980b). In a two-generation reproduction 

study, an increase in the number of stillbirths, a decrease in the number of pups per litter at birth, and a 

decrease in the number of live litters at weeks 7, 14, and 21 were observed in the F1 offspring of rats 

exposed to 50 mg/kg/day (a dose that also resulted in increased maternal deaths and decreased feed 

consumption) (U.S. Army 1980b). In the F2 generation, a decrease in terminal body weights and an 

increase in renal tubular epithelial-lined cysts were observed at 16 mg/kg/day. Similar cysts were 

observed in F2 pups exposed to 0 or 5 mg/kg/day. The highest NOAEL values and all reliable LOAEL 

values for developmental effects for each species and duration category are recorded in Table 3-1 and 

plotted in Figure 3-1. 

3.2.2.7 Cancer 

No studies were located regarding cancer in humans after oral exposure to RDX. 

RDX was not found to be carcinogenic when fed to F344 rats (U.S. Army 1983a) or Sprague-Dawley rats 

(U.S. Navy 1976) for at least 1 year. Adequate doses, numbers of animals, and survival rates were 

achieved for both of these studies. Only female B6C3F1 mice showed an increased incidence of 

combined hepatocellular adenomas and carcinomas when compared to concurrent or historical controls 

(U.S. Army 1984c). However, a re-evaluation of these data using revised diagnostic criteria resulted in a 

reclassification of several hepatocellular adenomas as foci of cytoplasmic alterations (Parker et al. 2006). 

As noted in the abstract of the Parker et al. (2006) paper, the combined incidence of hepatocellular 

adenomas and carcinomas was significantly increased (no information regarding statistical analysis was 

presented in the paper) in the 35 mg/kg/day group, but not in the 100 mg/kg/day group. The investigators 

noted that the combined incidence of hepatocellular adenomas and carcinomas in the 35 mg/kg/day group 

(10/64, 16%) was within the range of published historical control data (0–21%) and suggested that the 

study provided equivocal evidence of a carcinogenic effect. The 35 mg/kg/day dose is listed as a cancer 

effect level (CEL) in Table 3-1 and Figure 3-1. The lifetime average doses that would result in risk of 

1x10-4, 1x10-5, 1x10-6, and 1x10-7 are 0.9, 0.09, 0.009, and 0.0009 mg/kg/day, respectively, as indicated in 

Figure 3-1. 
 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 58 

3. HEALTH EFFECTS 

3.2.3 Dermal Exposure 

3.2.3.1 Death 

No studies were located regarding death in humans after dermal exposure to RDX. 

Deaths were observed in rabbits receiving repeated dermal applications of 37.5 mg/kg/day RDX in 

cyclohexanone (1/6 deaths) or 27 mg/kg/day RDX in acetone (2/6) deaths; no gross pathological effects 

were seen (U.S. Army 1974). Because of the lack of data presented, it is difficult to determine whether 

RDX alone was responsible for the deaths reported in this study. 

3.2.3.2 Systemic Effects 

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, 

musculoskeletal, hepatic, or renal effects in humans after dermal exposure to RDX. Two older studies of 

dermal and ocular effects were located for humans following dermal exposure to RDX. 

One animal study examined the potential systemic toxicity of RDX following a single dermal application 

(U.S. Army 1974); however, no details were provided regarding the “pathological examination”; thus, 

NOAELs for systemic effects were not presented for this study. The highest NOAEL values and all 

reliable LOAEL values for systemic effects in each species and duration category are recorded in 

Table 3-2. 

Respiratory Effects. No alterations were noted in the respiratory rates of dogs following single or 

multiple dermal exposures to RDX in dimethyl sulfoxide (DMSO) (U.S. Army 1974). 

Cardiovascular Effects. No adverse effects were seen on blood pressure, heart rate, or 

electrocardiograms of dogs dermally exposed to a single application or repeated exposure (5 days/week 

for 4 weeks) of 289 mg/kg RDX in DMSO (U.S. Army 1974). No lesions were seen in the hearts of 

rabbits exposed to 165 mg/kg RDX in DMSO 5 days/week for 4 weeks (U.S. Army 1974). 

Gastrointestinal Effects. Necropsy did not reveal any lesions in the intestines of rabbits exposed to 

165 mg/kg RDX in DMSO 5 days/week for 4 weeks (U.S. Army 1974). 
29

mg/kg/day mg/kg/day

34

mg/kg/day

mg/kg/day

528

mg/kg

mg/kg

36

mg/kg/day

30

mg

mg

Table 3-2 Levels of Significant Exposure to RDX - Dermal 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

ACUTE EXPOSURE 

Systemic 

Gn Pig once or 3 times Dermal 

(NS) Dog once Resp (NS) 

Cardio 

Rabbit once Hemato (NS) 

Dermal 

Neurological 

Dog 3 d Cardio 

(NS) 1x/day 

INTERMEDIATE EXPOSURE 

Systemic 

Gn Pig 3 wk Dermal 

(NS) 3 d/wk 

Ocular 

510 1000 (erythema) U.S. Army 1974 

mg/kg/day mg/kg/day 

289 U.S. Army 1974 

mg/kg/day 

289 

mg/kg/day 

165 

mg/kg 

U.S. Army 1974 

27 (dermatitis) 

mg/kg 

480 U.S. Army 1974 

mg/kg/day 

165 U.S. Army 1974 

mg 

165 

mg 
35

mg/kg/day

mg/kg/daymg/kg/day

32

mg/kg/day

mg/kg/daymg/kg/daymg/kg/daymg/kg/daymg/kg/daymg/kg/day mg/kg/day

Table 3-2 Levels of Significant Exposure to RDX - Dermal (continued) 

Exposure/ LOAEL

Duration/

Species Frequency Reference (Route) (Strain) System NOAEL Less Serious Serious Chemical Form 

(NS) Dog 4 wk 

5 d/wk Resp 289 

mg/kg/day 

U.S. Army 1974 

Cardio 289 

mg/kg/day 

Ocular 289 

mg/kg/day 

(NS) Rabbit 4 wk 

5 d/wk Resp 165 

mg/kg/day 

U.S. Army 1974 

Cardio 165 

mg/kg/day 

Gastro 165 

mg/kg/day 

Musc/skel 165 

mg/kg/day 

Hepatic 165 

mg/kg/day 

Renal 165 

mg/kg/day 

Dermal 37.5 

mg/kg/day 

165 

mg/kg/day 

(dermatitis) 

Cardio = cardiovascular; d = day(s); Gastro = gastrointestinal; Gn Pig = guinea pig; LOAEL = lowest-observed-adverse-effect level; Metab = metabolic; Musc/skel NOAEL = no-observed-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); x = time(s) 
 

 

 

 

 

 

 

RDX 61 

3. HEALTH EFFECTS 

Hematological Effects. Blood samples taken from rabbits after a single exposure to 165 mg/kg RDX 

in DMSO revealed no significant changes in hematological parameters (U.S. Army 1974). 

Musculoskeletal Effects. Necropsy did not reveal pathology in the muscle or bone tissue of rabbits 

exposed to 165 mg/kg RDX in DMSO 5 days/week for 4 weeks (U.S. Army 1974). 

Hepatic Effects. No alterations in serum clinical chemistry parameters were found in rabbits after 

acute or intermediate dermal exposure to RDX. Also, no pathological alterations were noted in the liver 

of rabbits exposed for 4 weeks (U.S. Army 1974). 

Renal Effects. No histological alterations were noted in the kidneys of rabbits exposed to 165 mg/kg 

RDX in DMSO 5 days/week for 4 weeks (U.S. Army 1974). 

Dermal Effects. One volunteer had a patch of skin covered with dry RDX for 2 days. No irritation 

was observed following removal of the gauze coverings (von Oettingen et al. 1949). An accurate dose 

could not be determined because of the lack of information provided in the study. Another study reported 

dermatitis in workers exposed to RDX fumes of unknown levels and for unknown duration (Sunderman 

1944). 

Dermatitis was observed in rabbits exposed once to 27 mg/kg RDX in acetone, 37.5 mg/kg RDX in 

cyclohexanone, or 165 mg/kg RDX in DMSO (U.S. Army 1974); the dermatitis persisted for at least 

30 days and was most pronounced in the rabbits exposed to 165 mg/kg RDX in DMSO. Slight erythema 

was noted in guinea pigs exposed once to 1,000 mg/kg (U.S. Army 1974). Guinea pigs exposed once to 

an unspecified amount of RDX had exudative dermatitis with edema (Sunderman 1944). The lesions 

healed promptly after the guinea pigs were removed from the source of exposure. 

In rabbits repeatedly exposed to 165 mg/kg RDX in DMSO 5 days/week for 4 weeks, dermatitis was 

observed after 14 and 30 days of exposure; no dermal effects were observed at 16.5 mg/kg RDX in 

DMSO or in rabbits administered lower RDX doses in cyclohexanone (37.5 mg/kg/day) or acetone 

(27 mg/kg/day) vehicles (U.S. Army 1974). 
 

 

 

 

 

 

 

 

 

 

RDX 62 

3. HEALTH EFFECTS 

Ocular Effects. There are limited human data regarding the ocular toxicity of RDX. Conjunctivitis 

was reported by workers exposed to RDX fumes (Sunderman 1944); no information was provided 

regarding exposure levels or duration of exposure. 

Cataracts were observed in guinea pigs exposed through cutaneous or intradermal applications of RDX in 

solvents. However, the incidence of cataracts did not appear to be greater than that found after exposure 

to the solvents alone. This suggests that RDX itself did not contribute to cataract formation (U.S. Army 

1974). 

Body Weight Effects. Decreased body weight classified as small and transient (no further details 

were provided) was reported in rabbits after a single dermal application of 2,000 mg/kg of RDX. 

However, by the end of the observation period, most of the surviving animals showed weight gain (U.S. 

Army 1984b). 

No studies were located regarding the following effects in humans or animals after dermal exposure to 

RDX: 

3.2.3.3 Immunological and Lymphoreticular Effects 

3.2.3.4 Neurological Effects 

3.2.3.5 Reproductive Effects 

3.2.3.6 Developmental Effects 

3.2.3.7 Cancer 

3.3 GENOTOXICITY 

No studies were located regarding genotoxicity of RDX in humans following inhalation, oral, or dermal 

exposure to the chemical. One in vitro study was located in which human fibroblasts (WI-38 cells) were 

incubated in the presence of RDX and tritiated thymidine (3H-TdR) to measure unscheduled 

deoxyribonucleic acid (DNA) synthesis (U.S. Army 1978b) (see Table 3-3). RDX was tested in 

concentrations of up to 4,000 μg/mL both with and without metabolic activation. RDX was not found to 

significantly increase the rate of unscheduled DNA synthesis in the cells of any exposure group regardless 

of whether or not metabolic activators were present. Therefore, RDX was not observed to induce DNA 

damage in human fibroblasts under the conditions of the study (U.S. Army 1978b). 
 

 

 

 

 

 

 

 

 

 

 

RDX 63 

3. HEALTH EFFECTS 

Table 3-3. Genotoxicity of RDX In Vitro 

Results 

Species (test system) End point 

With 

activation 

Without 

activation Reference 

Prokaryotic organisms: 

Salmonella typhimurium 

TA98, TA100, TA1535, TA1537, 

TA1538 

Gene mutation B B U.S. Army 1980b 

S. typhimurium 

TA98, TA100, TA1535, TA1537, 

TA1538 

Gene mutation B B U.S. Army 1977b 

S. typhimurium 

TA98, TA100, TA1535, TA1537, 

TA1538 

Gene mutation B B Whong et al. 1980 

S. typhimurium 

TA98, TA100 

Gene mutation B B Lachance et al. 1999 

S. typhimurium 

TA98, TA100 

Gene mutation B B George et al. 2001 

S. typhimurium 

TA98, TA100 

Gene mutation B B Pan et al. 2007 

S. typhimurium 

TA97a 

Gene mutation ± B Pan et al. 2007 

Vibrio fischeri Gene mutation ± ± Arfsten et al. 1994 

Eukaryotic organisms: 

Fungi: 

Saccharomyces cerevisiae Gene mutation B B U.S. Army 1977b 

Mammalian cells: 

Human fibroblasts DNA damage B B U.S. Army 1978b 

Chinese hamster V79 lung cells Gene mutation B B Lachance et al. 1999 

Mouse lymphoma L5178Y cells Gene mutation B B Reddy et al. 2005a 

C = negative result; + = positive result; ± = weak or equivocal result; DNA = deoxyribonucleic acid 
 

 

 

 

 

 

 

 

 

 

RDX 64 

3. HEALTH EFFECTS 

Only two in vivo animal studies were located and both provided negative evidence of mutagenicity. U.S. 

Army (1980b) investigated the effects of oral doses of RDX on dominant lethal mutations in rats. RDX 

was administered to the rats in the diet in doses of 0, 5, 16, or 50 mg/kg/day for 15 weeks. The males in 

each exposure group were then allowed to mate with untreated females for 2 weeks. There were no 

significant effects on the number of corpora lutea, implants, or live or dead embryos (U.S. Army 1980b); 

no dominant lethal mutations were observed. In the other in vivo study, administration of a single gavage 

dose of up to 250 mg RDX/kg to male mice did not significantly increase the incidence of micronuclei in 

bone marrow cells examined 24 hours after dosing (Reddy et al. 2005a). 

The in vitro genotoxicity of RDX has been investigated in several assays (Table 3-3). Most of the results 

of reverse mutation assays with Salmonella typhimurium conducted by several investigators (George et al. 

2001; Lachance et al. 1999; Pan et al. 2007; U.S. Army 1977b, 1980b; Whong et al. 1980), 

Saccharomyces cerevisiae (U.S. Army 1977b), or Vibrio fischeri (Arfsten et al. 1994) have been negative. 

A weakly positive result was found in one S. typhimurium strain (TA97a) (Pan et al. 2007). In 

mammalian cells, forward mutation assays in mouse lymphoma L5178Y cells (Reddy et al. 2005a) and 

hamster V79 lung cells (Lachance et al. 1999) were negative. 

Although the results of in vitro assays have been negative for RDX, some studies of environmental 

biotransformation products of RDX have reported positive results. For example, George et al. (2001) 

reported that hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX) and hexahydro-1,3-dinitroso-5-nitro1,3,5,-triazine, were not mutagenic in S. typhimurium TA98 or TA100 with or without metabolic 

activation, but hexahydro-1,3,5-trinitroso-1,3,5-triazine (TNX) was weakly genotoxic in strain TA100 but 

negative in strain TA98. Studies conducted by Pan et al. (2007) showed that in the presence of metabolic 

activation, both MNX and TNX were mutagenic in S. typhimurium TA97a, weakly mutagenic in strain 

TA102, and not mutagenic in strain TA98; in addition, TNX was weakly mutagenic in strain TA100 in 

the presence of metabolic activation. Pan et al. (2007) also reported that neither MNX nor TNX were 

mutagenic in S. typhimurium TA97a in the absence of metabolic activation. 

Collectively, the available information suggests that RDX is not a mutagenic substance, but some of its 

environmental biotransformation products may be of concern, especially since they have been identified 

as metabolic products in mammals (Major and Reddy 2007). 
 

 

 

 

 

 

 

 

 

 

RDX 65 

3. HEALTH EFFECTS 

3.4 TOXICOKINETICS 

Very little is known regarding the toxicokinetics of RDX in humans, but reports of adverse effects 

following inhalation and oral exposure and measurements of RDX in blood from poisoned individuals 

indicate that RDX is absorbed through the lungs and the gastrointestinal tract. No information is 

available regarding the distribution and metabolism of RDX in humans. A single case study found RDX 

in the cerebrospinal fluid following oral exposure (Woody et al. 1986), suggesting possible distribution to 

the nervous system. RDX was almost completely absorbed in miniature pigs after a single oral dose 

(Major and Reddy 2007). In rats, mixing RDX with soil considerably reduced absorption compared to 

administration of neat RDX (Crouse et al. 2008). No preferential accumulation of RDX in specific tissues 

has been reported in animal studies (Schneider et al. 1977, 1978). Several metabolites were identified in 

the urine from miniature pigs dosed orally with RDX (Major and Reddy 2007). The urine was the main 

route of elimination of 14C-RDX-derived radioactivity (Schneider et al. 1977). 

3.4.1 Absorption 

3.4.1.1 Inhalation Exposure 

Neurological effects have been observed in humans following inhalation exposure, indicating that RDX 

can be absorbed through the lungs (Kaplan et al. 1965; Testud et al. 1996a). The extent of absorption 

through the lungs has not been determined. As described in an abstract, approximately 30% of an 

intratracheal dose was excreted in the urine and feces during a 6-day period (Reddy et al. 1989). 

3.4.1.2 Oral Exposure 

Adverse effects observed in humans following accidental or intentional ingestion of RDX indicate that it 

is absorbed through the gastrointestinal tract (Davies et al. 2007; Hollander and Colbach 1969; HarrellBruder and Hutchins 1995; Kaplan et al. 1965; Kasuske et al. 2009; Ketel and Hughes 1972; Merrill 

1968; Stone et al. 1969). Measurements of RDX in blood provide direct evidence that gastrointestinal 

absorption occurs. A study of a child who ingested an unknown amount of RDX reported an apparent 

peak plasma concentration prior to 24 hours postingestion (Woody et al. 1986). At 24 hours (first time 

measurements were made), the serum concentration of RDX was 10.7 μg/mL and decreased gradually 

thereafter, but it was detectable in serum over a 120-hour period following the estimated time of 

ingestion. Using an estimated volume of distribution of 2.2 L/kg, Woody et al. (1986) estimated an 

ingested dose of 84.8 mg RDX/kg or 1.23 g for the 14.5 kg child. More recently, Küçükardalĭ et al. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 66 

3. HEALTH EFFECTS 

(2003) reported five cases of accidental ingestion of RDX with estimated doses between 37 and 

250 mg/kg (how the doses were estimated was not indicated). Three hours after ingestion, the serum 

concentrations of RDX ranged from 268 to 969 pg/mL. In two of the patients, blood levels 72 hours after 

ingestion were approximately 2-fold those measured 3 hours after ingestion, suggesting very slow 

absorption. 

Administration of a single oral dose of 14C-RDX in 0.5% carboxymethylcellulose in water to miniature 

pigs resulted in relatively low levels of radioactivity (6% of the dose in males and 2% in females) in the 

gastrointestinal contents and feces over a 24-hour period, suggesting nearly complete absorption (Major 

and Reddy 2007). Data shown for a single male pig (two males and two females were used in the study) 

indicate that Peak RDX concentration in plasma in miniature pigs administered single doses of RDX 

occurred 8–12 hours after dosing, indicating that although absorption may have been complete over a 

24-hour period, it occurred at a relatively slow rate (JHU/U.S. Army 2006; Major and Reddy 2007). In 

contrast, a study in rats administered 3 or 18 mg/kg RDX via capsule reported Peak RDX levels in the 

blood 3.5 hours after exposure (Bannon et al. 2009a). 

Crouse et al. (2008) studied the bioavailability of RDX from soil in rats. Rats were administered capsules 

containing neat RDX or RDX mixed with two types of soils. The results showed that administration of 

RDX mixed with soils resulted in peak blood levels of RDX 15–25% lower that when administered neat. 

However, the times to reach peak levels (4–6 hours postdosing) did not appear to differ significantly 

between neat doses of RDX and RDX mixed with soil. 

3.4.1.3 Dermal Exposure 

A study using excised human skin in flow-through diffusion cells showed poor absorption of RDX in this 

type of preparation (Reddy et al. 2008). 14C-RDX was applied in acetone or in two soils differing in their 

carbon content (1.9 vs. 9.5%) to the epidermal surface and receptor fluid was collected for up to 24 hours. 

At this time, the RDX remaining on the skin was washed with soap and water and the radioactivity in the 

washing was counted. Dermal absorption was defined as the amount of radioactivity in the receptor fluid, 

the dermis, and the portion of the epidermis beneath the stratum corneum. A total of 2.5% of the dose 

applied in acetone diffused through the skin into the receptor fluid, whereas 5.7% of the applied dose was 

found in the combined receptor fluid and skin (stratum corneum, epidermis and dermis). Approximately 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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80% of the applied dose was recovered (receptor fluid plus skin plus washings). Application of RDX in 

soil resulted in even less absorption; 2.6% in the low-carbon soil and 1.4% in the high-carbon soil were 

recovered in the receptor fluid and skin in 24 hours. 

A similar study using excised pig skin was conducted earlier by Reifenrath et al. (2002). The results also 

showed relatively poor absorption. Only 4% of the applied dose of RDX in acetone was absorbed over a 

24-hour period. Application of RDX mixed with soil resulted in only 1–2% of the applied dose being 

absorbed. 

3.4.2 Distribution 

3.4.2.1 Inhalation Exposure 

No studies were located in humans or animals regarding distribution following inhalation exposure. 

3.4.2.2 Oral Exposure 

Limited information is available from a study of child who ingested an unknown amount of RDX (Woody 

et al. 1986). RDX was found in the cerebrospinal fluid of the child at a concentration of 8.94 μg/mL 

24 hours after ingestion (only time measured). 

In rats given RDX by gavage, levels in the plasma and brain reached a steady state for 2–24 hours and 

then disappeared 3 days postexposure, but no other tissues were sampled (U.S. Army 1985b). In another 

single exposure study in rats (Bannon et al. 2009a), blood and brain RDX levels paralleled each other 

during the first 48 hours post-exposure; these data suggest that RDX did not accumulate in the brain. 

Miniature swine showed no preferential distribution of RDX to the brain, heart, liver, kidneys, or fat 

24 hours following a single gavage dose of 100 mg RDX/kg (Schneider et al. 1977). Three hours after 

oral administration of RDX to juvenile miniature pigs, the highest levels of RDX were found in the 

hippocampus and cortex compared to the heart, kidney, liver, blood, lung, and muscle (JHU/U.S. Army 

2006). Rats given RDX once by gavage showed the highest levels of RDX in the kidneys, with less in the 

brain and heart, and the least amount in the plasma and liver over a 24-hour observation period (Schneider 

et al. 1977). Tissue/plasma ratios during the first 24 hours varied between 0.15 and 10.46, indicating that 

RDX accumulated to some extent in the tissues examined. In mice administered radiolabelled RDX via 

stomach perfusion, the highest levels of radioactivity were found in the liver, followed by the kidney, 

muscle, lung, spleen, heart, and brain (Guo et al. 1985). Results from longer-term studies showed no 
 

 

 

 

 

 

 

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preferential distribution of RDX in rats given the chemical by gavage or in the drinking water for 90 days 

(Schneider et al. 1978). In a recent study of the effects RDX on gene expression in the brain of rats, 

administration of 3 or 18 mg RDX/kg in a capsule resulted in peak brain and blood concentrations of 

RDX approximately 3.5 hours after dosing, regardless of the dose (Bannon et al. 2009a). No RDX could 

be detected in the brain or blood from low-dose rats 24 hours after dosing or in blood or brain from highdose rats 48 hours after dosing. 

An unpublished study indicates that RDX was found in the brain of rat pups whose mothers were 

administered RDX from gestation day 6 through postnatal day 10 (U.S. Army 2007b). On postnatal days 

0, 3, 5, and 10, dams and pups were tested for RDX in milk and brain, respectively. Significantly higher 

concentrations of RDX were found in the brain from pups sacrificed immediately after birth than in the 

brain of pups sacrificed on postnatal day 10. No explanation was offered for this finding by the 

investigators. It is plausible that the gastrointestinal tract of newborn pups did not absorb RDX, but RDX 

readily crossed the placenta. Alternatively, it could be that newborn pups have the ability to 

metabolize/excrete RDX that is not present in the fetus. In any case, transplacental exposure occurred. 

Since RDX was also found in the dam’s milk, transfer of RDX to the offspring via the milk can also 

occur. 

3.4.2.3 Dermal Exposure 

No studies were located in humans or animals regarding distribution following dermal exposure. 

3.4.3 Metabolism 

There are no studies available regarding RDX metabolism in humans following inhalation, oral, or dermal 

exposure. 

RDX was extensively metabolized in rats (Schneider et al. 1977). Administration of a single gavage dose 

of 50 mg 14C-RDX/kg resulted in <0.6% of the dose in the carcass 4 days after dosing and only 3% was 

excreted unchanged, mostly in the urine. The metabolites were not characterized. 

A study of the metabolism of RDX in miniature pigs showed that RDX is rapidly and extensively 

metabolized by loss of two nitro groups followed by ring cleavage (Major and Reddy 2007). Pigs were 

administered a single gavage dose (43 mg/kg) of 14C-RDX combined with carboxymethylcellulose in 

water and blood and excreta were collected for up to 24 hours. Metabolites were characterized by liquid 
 

 

 

 

 

 

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chromatography/mass spectrometry (LC/MS) in selected samples of urine, plasma, and liver. Analysis of 

urine revealed two major metabolites, 4-nitro-2,4-diazabutanal and 4-nitro-2,4-diazabutanamide. Using a 

more sensitive method of analysis, the investigators also identified MNX in both male and female urine 

and DNX in male urine. Analysis of plasma showed quantifiable amounts of RDX, and trace levels of 

MNX, DNX, and TNX. Analysis of liver extracts showed that most of the radioactivity was in the form 

of water-soluble, high-molecular-weight compounds rather than as RDX or any identifiable metabolites. 

An in vitro study examining RDX metabolism (assessed by measuring loss of RDX) under low oxygen 

conditions determined that 46.6, 40.1, 34.6, 25.5, and 11.6% of the RDX was metabolized in human, rat, 

monkey, pig, and rabbit liver microsomes, respectively, following a 30-minute incubation period (U.S. 

Army 2008). After a 180-minute incubation period, 51.8, 47.2, 35.7, 33.7, and 18.0% of the RDX was 

metabolized, respectively. Under anaerobic conditions with nitrogen replacing oxygen, RDX was 

metabolized by several human recombinant cytochrome P450 isoforms (CYP1A1, CYP2B6, CYP2C8, 

CYP2C18, CYP2E1, CYP3A5); with the exception of CYP1A1, the RDX metabolite, MEDINA, was 

produced. In contrast, under aerobic conditions, no loss of RDX was detected in human liver 

microsomes, S9, hepatocytes, or a number of human recombinant cytochrome 450 isoforms (U.S. Army 

2008). 

RDX was metabolized in vitro by rabbit cytochrome CYP2B4 to 4-nitro-2,4-diazabutanal, nitrite, 

formaldehyde, and ammonia (Bhushan et al. 2003). This reaction was observed in a cell-free, isolated 

enzyme system; therefore, it’s relevance to in vivo metabolism is unknown. 

3.4.4 Elimination and Excretion 

3.4.4.1 Inhalation Exposure 

No relevant information was located from studies in humans. In rats receiving a single intratracheal dose 

of radiolabelled RDX, 23 and 3% of the label was excreted in the urine and feces, respectively, during the 

first 4 days; during the first 6 days, 26 and 5%, respectively, was excreted (Reddy et al. 1989; only 

available as an abstract). 

3.4.4.2 Oral Exposure 

Only one study is available that provides some data on excretion in humans after oral exposure. In a child 

who ingested an unknown amount of RDX, apparent peak concentration in urine occurred at 
 

 

 

 

 

 

 

 

 

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approximately 48 hours after ingestion and in feces 96 hours after ingestion (Woody et al. 1986). RDX 

could still be detected in feces 144 hours following ingestion. 

Rats given a single radiolabeled gavage dose of RDX eliminated 43% of the radioactivity in exhaled air, 

34% in the urine, and 3% in the feces within 4 days; about 10% remained in the carcass (Schneider et al. 

1977). A longer-term study showed similar excretion patterns; during a continuous drinking water study, 

50% was eliminated in the exhaled air, 34% in the urine, and 5% in the feces (Schneider et al. 1978). 

There was no evidence that RDX accumulated in the tissues during longer-term exposure. Following 

administration of radiolabelled RDX to mice via stomach perfusion, 38.18% of the dose was excreted in 

the urine and 26.64% was excreted in the feces on day 1. On days 2–9, 11.20% of the dose was excreted 

in the urine. Ten days after dosing, 75.25% of the dose was excreted in the urine and feces (Guo et al. 

1985). 

Urine was the major route of elimination of 14C-RDX-derived radioactivity in miniature pigs given a 

single dose of the chemical (Major and Reddy 2007). Over a 24-hour period, 16–17% of the administered 

dose was recovered in the urine compared to ≤6% recovered in the gastrointestinal contents and feces. 

3.4.4.3 Dermal Exposure 

No relevant information was located from studies in humans or animals. 

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

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and 

disposition of chemical substances to quantitatively describe the relationships among critical biological 

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry 

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of 

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various 

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based 

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to 

quantitatively describe the relationship between target tissue dose and toxic end points. 

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to 

delineate and characterize the relationships between: (1) the external/exposure concentration and target 

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and 
 

 

 

 

 

 

 

 

 

 

 

 

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3. HEALTH EFFECTS 

Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can 

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from 

route to route, between species, and between subpopulations within a species. The biological basis of 

PBPK models results in more meaningful extrapolations than those generated with the more conventional 

use of uncertainty factors. 

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model 

representation, (2) model parameterization, (3) model simulation, and (4) model validation (Krishnan and 

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of 

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific physicochemical parameters, and species-specific physiological and biological parameters. The 

numerical estimates of these model parameters are incorporated within a set of differential and algebraic 

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations 

provides the predictions of tissue dose. Computers then provide process simulations based on these 

solutions. 

The structure and mathematical expressions used in PBPK models significantly simplify the true 

complexities of biological systems. If the uptake and disposition of the chemical substance(s) are 

adequately described, however, this simplification is desirable because data are often unavailable for 

many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The 

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of 

PBPK models in risk assessment. 

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the 

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). 

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in 

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste 

sites) based on the results of studies where doses were higher or were administered in different species. 

Figure 3-2 shows a conceptualized representation of a PBPK model. 

If PBPK models for RDX exist, the overall results and individual models are discussed in this section in 

terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. 
 

 


 


 


 

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3. HEALTH EFFECTS 

Figure 3-2. Conceptual Representation of a Physiologically Based
 

Pharmacokinetic (PBPK) Model for a Hypothetical
 

Chemical Substance
 

Inhaled chemical Exhaled chemical 

Lungs 

Liver 

Fat 

Slowly 

perfused 

tissues 

Richly 

perfused 

tissues 

Kidney 

Skin 

V 

E 

N 

O 

U 

S 

B 

L 

O 

O 

D 

A 

R 

T 

E 

R 

I 

A 

L 

B 

L 

O 

O 

D 

Vmax 

Km 

Ingestion 

GI 

Tract 

Feces 

Urine

 Chemicals 

contacting skin 

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a 

hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by 

ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Source: adapted from Krishnan and Andersen 1994 
 

 

 

 

 

 

 

 

 

 

RDX 73 

3. HEALTH EFFECTS 

Krishnan Model (Krishnan et al. 2009; U.S. Army 2007a; Sweeney et al. 2012) 

Description of the Model. Krishnan et al. (2009; U.S. Army 2007a) developed a PBPK model for 

simulating kinetics of RDX in rats. The model was subsequently modified and extended to include 

simulations of human kinetics (Sweeney et al. 2012). The structure of the model is essentially identical to 

the generic model depicted in Figure 3-2, with the following tissue compartments: brain, fat, liver, richly 

perfused tissues (RPT), and slowly perfused tissues (SPT). Parameters and parameter values reported in 

Sweeney et al. (2012) are presented in Table 3-4. 

The model simulates absorption of RDX from the gastrointestinal tract as first order transfers to liver 

from stomach (KAS, hour-1) and duodenum (KAD, hour

-1), with first-order transfer from stomach 

contents to duodenum contents (KT, hour-1). Since no other transfers from the gastrointestinal tract are 

simulated (i.e., transfer to lower gastrointestinal-tract or fecal excretion), 100% of the oral dose is 

eventually absorbed at infinite time after an oral dose. Distribution of RDX to tissues is simulated as 

flow-limited transfers in which instantaneous partitioning of RDX between tissue and blood is assumed, 

the tissue-venous blood concentration ratio is given by a tissue-blood partition coefficient, and bloodtissue clearance (L/hour) is assumed to be equivalent to tissue blood flow. Elimination of absorbed RDX 

is assumed to be entirely by metabolism, all of which is attributed to the liver, and is simulated as a first 

order processes (KfC, kg0.33/hour-1). Metabolites of RDX are not simulated in the model. 

Sweeney et al. (2012) derived values for several parameters in the rat model, based on statistical 

optimization of predicted blood concentration kinetics against observations from rat studies not used for 

parameter estimation by Krishnan et al. (2009). A value for a single absorption rate constant in rats was 

estimated by Krishnan et al. (2009) based on model performance (visual inspection of fit to observations) 

in simulating blood RDX kinetics in rats that received a single oral dose of RDX (Schneider et al. 1977). 

Sweeney et al. (2012) derived alternative values for a two-compartment gastrointestinal model (stomach, 

duodenum) by optimization against observed blood RDX kinetics from various rat oral studies (Bannon et 

al. 2009a; Crouse et al. 2008; Krishnan et al. 2009). 

Tissue:blood partition coefficients for RDX were estimated by Krishnan et al. (2009) based on a 

measured n-octanol:water partition coefficient for RDX, and reported water and lipid contents of specific 

tissues. The value for the metabolism rate constant was estimated by evaluating alternative values against 
 

 

 

 

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3. HEALTH EFFECTS 

Table 3-4. Parameter Values for Sweeney et al.(2012) PBPK Model of RDX in Rats 

and Humans 

Value 

Description Rat Human Source 

Body weight (BW, kg) 0.3 

Cardiac output (KQC, L/hour/kg0.74) 15 

70 

14 

Observed 

Brown et al. 1997, as cited in Sweeney 

et al. 2012; Krishnan et al. 2009; 

Timchalk et al. 2002 

Blood flow (KQ) fraction of cardiac output 

Liver (KQL) 0.25 0.175 Brown et al. 1997, as cited in Sweeney 

Brain (KQB) 0.03 

Fat (KQF) 0.09 

0.114 

0.085 

et al. 2012; Krishnan et al. 2009; 

Timchalk et al. 2002 

Slowly perfused tissues (KQS) 0.20 0.2449 

Rapidly perfused tissues (KQR) 0.43 0.3811 1-(KQL+KQB+KQF+KQS) 

Compartment volumes (Vi) fraction of body weight 

Liver (KVL) 0.04 0.026 Brown et al. 1997, as cited in Sweeney 

Brain (KVB) 0.012 

Fat (KVF) 0.07 

0.02 

0.21 

et al. 2012; Krishnan et al. 2009; 

Timchalk et al. 2002 

Rapidly perfused tissues (KVR) 0.04 0.052 

Blood (KVV) 0.06 0.079 

Slowly perfused tissues (KVS) 0.688 0.523 0.91 – (KVL+KVB+KVF+KVR+KVV) 

Tissue:blood partition coefficients 

Liver (PL) 1.2 1.3 Krishnan et al. 2009 (predicted from 

Brain (PB) 1.4 1.6 n-octanol:water partition coefficient) 

Rapidly perfused tissues (PS) 1.4 1.6 

Fat (PF) 5.57 5.57 Optimized—intravenous rat dataa 

Slowly perfused tissues (PR) 0.15 0.15 

Liver metabolism 

Metabolism (KfC, kg0.33/hour) 2.6 11.2 Optimized—intravenous rat dataa 

Optimized—oral human datab 

Gastrointestinal absorption 

Absorption from stomach (KAS, hour -1) 0.033 Optimized—oral human datab 

gavage (rat) 0.83 NA Optimized—oral rat datac 

capsule (rat) 0.12 NA 

coarse (rat) 0.005 

Transfer to duodenum (KT, hour -1) 

NA 

0 Optimized—oral human datab 

gavage (rat) 1.37 NA Optimized—oral rat datac 

capsule (rat) 0 NA 

coarse (rat) 0 

Absorption from duodenum (KAD, hour -1) 

NA 

NA Optimized—oral human datab 

gavage (rat) 0.0258 NA Optimized—oral rat dataa 

capsule (rat) NA NA 

coarse (rat) NA NA 

a

Krishnan et al. 2009. b

Özhan et al. 2003; Woody et al. 1986. c

Bannon et al. 2009a; Crouse et al. 2008; Krishnan et al. 2009; Schneider et al. 1977. 

Source: adapted from Sweeney et al. 2012 
 

 

 

 

 

 

 

 

 

 

 

 

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observed blood RDX kinetics following intravenous dosing of rats with RDX (Schneider et al. 1977). 

Sweeney et al. (2012) re-evaluated the values for the partition coefficients for adipose and slowly 

perfused tissue, and the metabolism rate constant, and simultaneously optimized all three parameters 

against blood RDX kinetics from a rat intravenous study conducted by Krishnan et al. (2009). The 

simultaneous optimization yielded values of 5.57 and 0.15 for the partition coefficients for adipose and 

slowly perfused tissue, respectively, whereas Krishnan et al. (2009) estimated values of 7.55 and 1. The 

optimized value for the metabolism rate constant was 2.6 kg0.3/hour, whereas Krishnan et al. (2009) 

estimated the value to be 2.6 kg/hour. For a 0.4 kg rat (Krishnan et al. 2009), the corresponding values 

for the metabolism rates constants are 3.4 hours-1, based on the Sweeney et al. (2012) estimate, and 

5.5 hours-1, based on the Krishnan et al. (2009) estimate. 

Parameter values for the human model were scaled to body weight (e.g., flows scaled to BW0.74 and 

volumes to BW1

), with the exception of the metabolism and absorption rate constants. Absorption and 

metabolism rate constants for humans were optimized against observations of blood RDX kinetics in 

cases of ingestion exposures in humans (Özhan et al. 2003; Woody et al. 1986). Because doses in the 

human cases were unknown, dose was also optimized for each case. The estimated parameter values 

based on simulation of plasma RDX concentrations in a 3-year old child who ingested an unknown 

amount of RDX (Woody et al. 1986) were: dose 58.9 mg/kg; KAS 0.060/hour; KfC 9.87 kg0.33/hour. 

Corresponding values based on plasma RDX kinetics in adults were: dose 3.5 mg/kg; KAS 0.033/hour; 

KfC 11.2 kg0.33/hour. Sweeney et al. (2012) also estimated the value for the first-order metabolism rate 

constant based on scaling of the rat value against the ratio of in vitro metabolism rates in rats and humans, 

adjusted for microsomal protein (Lipscomb and Poet 2008, as cited in Sweeney et al. 2012; U.S. Army 

2008) as follows: 

where KfC is the first-order metabolism rate constant in human or rat (human or rat, respectively), MRR 

is the in vitro metabolism rate ratio (human:rat), MSP is the microsomal protein yield ratio (human:rat), 

and BWR is the body weight ratio (human:rat). The estimated values for the metabolism rate constant in 

humans was 12.4 kg0.33/hour, which was similar to the value for adults estimated by optimization against 

the Özhan et al. (2003) data. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Validation of the Model. Krishnan et al. (2009) estimated the metabolism rate constant based on 

blood RDX kinetics obtained from an intravenous study in rats (Schneider et al. 1977), and then evaluated 

model performance against data obtained from a different intravenous study conducted in rats (Krishnan 

et al. 2009). The same approach was used to evaluate the gastrointestinal absorption rate constant; data 

from a study in which rats received a single gavage dose of RDX (Krishnan et al. 2009) were used to 

estimate the parameter values, and the resulting model was evaluated against data from a different gavage 

rat study (Schneider et al. 1977). In both evaluations, the studies that were used to evaluate the model 

administered lower doses than the studies used to estimate parameter values. 

As previously described, Sweeney et al. (2012) optimized the absorption and metabolism parameter 

values, and tissue:blood partition coefficients for adipose and SPT in the rat using data from intravenous 

and oral dosing studies reported in Krishnan et al. (2009). The results of optimization of the intravenous 

studies were compared to an independent data set (Schneider et al. 1977) and the results were summarized 

with the following conclusion: “...the agreement between the model and the iv data of Schneier eta l. 

(1977) was very good (not shown).” In the oral dosing studies, rats received a gavage dose of RDX 

dissolved in water. The absorption parameters were re-optimized to simulate blood RDX kinetics in 

studies in which RDX was administered as a granular RDX (coarse) or in a gelatin capsule, or as a 

suspension in water (Bannon et al. 2009a; Crouse et al. 2008; Schneider et al. 1977). One of the studies 

included measurements of brain RDX concentrations (Bannon et al. 2009a). Since these studies were 

used to calibrate the absorption kinetics parameters to account for the different dosing formulations, they 

do not represent a fully independent validation of the rat model for simulating oral dosing. However, 

these evaluations do allow validation of the simulations of distribution and elimination kinetics derived 

from intravenous studies. Blood RDX kinetics obtained for cases of human ingestion of RDX were used 

to estimate values for absorption and metabolism parameters in the human. The human model was not 

evaluated against observations independent of those used to estimate parameter values. 

All of the model calibration and evaluation studies were conducted with data from single-dose studies. 

Although Sweeney et al. (2012) used a statistical procedure (maximum likelihood) to estimate parameter 

values, statistical comparisons of goodness of fit were not reported in Sweeney et al. (2012), and were not 

reported in Krishnan et al. (2009). 

Risk Assessment. The RDX model predicts blood and brain levels of RDX that would occur in 

association with oral doses to RDX. These predictions are potentially useful for predicting internal doses 

of RDX in rats and/or humans (e.g., blood or brain concentrations), and for making extrapolations of 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 77 

3. HEALTH EFFECTS 

these internal dose metrics across species. The model has been used to extrapolate dosages in repeated 

oral dosing studies in rats to equivalent oral dosages in humans in a derivation of human equivalent 

external doses and candidate chronic oral reference doses (Sweeney et al. 2012). Several internal dose 

metrics were explored in the interspecies dosimetry extrapolation. Peak and average brain RDX 

concentrations were used for dosimetry of neurological end points observed in rats in intermediate gavage 

and chronic dietary studies (U.S. Army 1983a, 2006). The time-weighted average RDX concentration in 

richly perfused tissue and steady-state body weight-adjusted rate of metabolism were used for dosimetry 

of prostate inflammation observed in rats in a chronic dietary study (U.S. Army 1984c) and alterations in 

survival time, terminal body weight, and hematocrit and hemoglobin concentrations in rats in a chronic 

dietary study (U.S. Army 1984c). Sweeney et al. (2012) estimated human equivalent external doses 

ranging from 1.6 to 8 mg/kg/day. 

Target Tissues. The RDX model was calibrated to predict blood RDX kinetics following oral 

exposures to RDX, although it also predicts concentrations in brain and other tissues. Sweeney et al. 

(2012) presented simulations of brain RDX concentration in comparison to measurements made in rats 

(Bannon et al. 2009a). The model has been used to predict concentrations of RDX in brain, which has 

been shown to be an important toxicity target tissue for RDX (Sweeney et al. 2012). 

Species Extrapolation. Sweeney et al. (2012) scaled the rat model to humans using a combination 

of allometric scaling and optimization of selected model parameters (absorption and metabolism rate 

constants). The scaled human model has not been evaluated against independent observations not used to 

estimate model parameter values. The model has been used to extrapolate rat dosages to humans based 

on predicted internal dosimetry (Sweeney et al. 2012). 

Interroute Extrapolation. The RDX model as it is currently configured simulates RDX kinetics 

associated with intravenous and oral dosing. Simulation of other potential routes of exposure (e.g., 

inhalation, dermal) would require development of models for the absorption of inhaled RDX, or RDX 

deposited on the skin. 

Strengths and Limitations. Strengths of the model are that it simulates disposition and clearance of 

intravenously injected or ingested RDX in rodents and humans, including predicting levels of RDX in the 

brain, a target tissue for toxicity. However, limitations include: (1) all model calibration and evaluation 

studies were conducted with data from single-dose studies and confidence in simulating RDX kinetics of 

repeated dosing schedules has not been evaluated; (2) the human model was not evaluated against 
 

 

 

 

 

 

 

 

 

 

 

 

 

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3. HEALTH EFFECTS 

observations independent of those used to estimate parameter values; and (3) the validity of predictions of 

brain levels of RDX in humans is based solely on performance of the model in predicting observed blood 

kinetics in humans who ingested unknown doses of RDX (dose was optimized to the blood RDX data). 

3.5 MECHANISMS OF ACTION 

3.5.1 Pharmacokinetic Mechanisms 

Absorption. The mechanism(s) of absorption of RDX is not known. There are no studies that 

calculated rates of absorption that could have provided some indication of a possible mechanism of 

absorption. In rats administered RDX in a capsule, peak blood concentrations were achieved 4–6 hours 

after dosing (Crouse et al. 2008). In a male miniature pig given a single gavage dose of RDX as a 

suspension in 0.5% carboxymethylcellulose in water, peak plasma concentration of RDX occurred at 

approximately 12 hours after dosing, which would suggest a relatively low rate of absorption. Studies 

with excised human and pig skin showed that mixing RDX with soil significantly reduced dermal 

absorption relative to RDX neat (Reddy et al. 2008; Reifenrath et al. 2002). 

Distribution. No specific mechanism of distribution was apparent in the available studies. In rats, the 

distribution of RDX (single doses) seemed unaffected by the route of administration (parenteral vs. oral) 

or by the dose (Schneider et al. 1977). The concentration of RDX-derived radioactivity in most tissues 

was fairly stable between 2 and 24 hours after dosing except in the liver, where it fluctuated widely. High 

concentrations of radioactivity occurred in the liver at 2, 12, and 24 hours after dosing, which led 

Schneider et al. (1978) to suggest that there might be diurnal variations in the hepatic metabolism of 

RDX. In 90-day studies, RDX did not accumulate in any of the tissues examined (Schneider et al. 1978). 

Metabolism. The metabolism of RDX has been studied in some detail in miniature pigs (Major and 

Reddy 2007) and there is some evidence suggesting that a cytochrome orthologue to the rabbit, CYP2B4, 

may be involved (Bhushan et al. 2003). The two major metabolites characterized were 4-nitro-2,4-diazabutanal and 4-nitro-2,4-diazabutanamide. Trace amount of MNX, DNX, and TNX were also detected. 

Some studies have provided some information regarding the role of metabolism in the toxicity of RDX. 

In rats, administration of RDX intravenously resulted in convulsive activity within seconds after the 

injection, which suggested that the convulsions are produced by the parent compound (Schneider et al. 

1977). In a 90-day gavage study in monkeys, convulsive events were associated with higher RDX 

concentrations in plasma (U.S. Navy 1974b), which would also support the idea of the parent compound 

being responsible for the convulsive activity. More recently, Meyer et al. (2005) reported that MNX and 
 

 

 

 

 

 

 

 

 

 

 

 

 

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RDX were equipotent in inducing convulsions and lethality in female Sprague-Dawley rats in single-dose 

gavage studies of 14-day duration; both DNX and TNX were less potent. In a study of age-dependent 

acute toxicity of RDX in deer mice, Smith et al. (2007) reported that, for all three age brackets tested, 

RDX was significantly more potent than MNX and TNX. 

Excretion. The urine and exhaled CO2 were the main routes of excretion of 14C-RDX-derived 

radioactivity in rats following acute- or intermediate-duration exposure to RDX (Schneider et al. 1977, 

1978). In the acute studies, only 3% of the administered radioactivity was recovered in the feces over a 

4-day period (Schneider et al. 1977). The urine was also the main excretory route of radioactivity in 

miniature pigs following a single gavage dose of RDX (Major and Reddy 2007). No information was 

located regarding how the size of the dose might affect the distribution of metabolic products among 

excretory pathways. 

3.5.2 Mechanisms of Toxicity 

The main effect of high doses of RDX in humans and animals is the induction of hyperactivity manifested 

as convulsions or seizures. RDX has also induced other effects; however, because these effects have not 

been well characterized and/or have been seen inconsistently in animal studies, this section will focus 

mainly on the potential mechanisms of neurological effects. In vitro studies in primary human cells, 

including neurons, astrocytes, and microglia cells, have found minimal evidence of cytotoxicity (U.S. 

Army 2010), suggesting that the observed neurological effects of RDX are likely to be reversible effects 

on neurotransmission. Hyperactivity can result from a chemical acting centrally and/or on the peripheral 

nervous system. Chemicals such as organophosphorus pesticides or nerve agents, such as sarin and 

soman, act mainly by inhibiting cholinesterase activity in the brain (McDonough and Shih 1997), but 

limited information is available regarding possible effects of RDX on cholinesterase activity. Based 

purely on the chemical structure of RDX, it seems unlikely that it would possess potent anticholinesterase 

properties. In rats receiving a single intraperitoneal dose of RDX, small, but significant, decreases in 

brain cholinesterase levels were found 1.5, 3, or 6 hours after dosing. By 24 hours after dosing, the 

cholinesterase levels were similar to controls (Maryland University 1975). However, in rats receiving 

2.5 or 6.5 mg/kg/day RDX administered intraperitoneally for 6 or 12 weeks, significant increases in brain 

cholinesterase levels were found. An in vitro study found a 53% decrease in cholinesterase activity in 

brain homogenates incubated with 4.5x10-3 M RDX (Maryland University 1975). In contrast, no 

alterations in frontal lobe or blood acetylcholinesterase activity were observed at the onset of seizures in 

rats administered a single gavage dose of 75 mg/kg RDX (Williams et al. 2011). The Maryland 
 

 

 

 

 

 

 

 

 

 

 

 

 

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University study (1975) also found significant increases in monoamine oxidase activity in rats receiving 

intraperitoneal doses of 2.5 or 6.5 mg/kg/day RDX for 6 or 12 weeks or 0.3 mg/kg/day for 12 weeks. 

However, following a single dose, a small, but not statistically significant, decrease in monoamine 

oxidase activity was observed 0.5, 1.5, 3, 6, or 24 hours after dosing. As with cholinesterase activity, 

RDX induced a dose-related decrease in monoamine oxidase activity in vitro. 

Studies in rats by Burdette et al. (1988) suggested that limbic structures may be a primary target for RDX 

toxicity. The suggestion was based on observations of spontaneous seizure characteristics and an 

accelerated rate of amygdaloid kindling following administration of a subconvulsive dose of RDX. 

Recent studies provide evidence of the involvement of GABA (γ-aminobutyric acid) receptors in RDXinduced neurologic dysfunction. Antagonism of GABAergic neurons within the central nervous system 

leads to generalized nervous system stimulation. Binding of GABA to its receptor opens chlorideselective ion channels leading to influx of chloride into neurons through an electrochemical gradient 

resulting in hyperpolarization of the membrane and inhibition of cell firing. A reduced inhibitory drive 

results in uninhibited activity in effector neurons. Williams et al. (2011) found that RDX binds to the 

picrotoxin convulsant site on GABAA receptors, but did not bind to other neurotransmitter receptors that 

are targets of other known convulsants, including the glutamate family of receptors, nicotinic and 

muscarinic acetylcholine receptors, the glycine receptors, and the batrachotoxin site of the sodium 

channel. This finding is supported by 3-D modeling, which found that RDX does not appear to be a 

ligand for the N-methyl-D-aspartate-glutamate receptor in postsynaptic neurons (Ford-Green et al. 2011). 

In vitro, RDX reduced the frequency and amplitude of spontaneous GABAA receptor-mediated inhibitory 

postsynaptic currents and the amplitude of GABA-evoked postsynaptic currents in the rat basolateral 

amygdala. Williams et al. (2011) also found a significant negative correlation between the levels of RDX 

in the brain and the time to seizure onset in rats administered 75 mg/kg RDX via gavage. These findings 

suggest that the convulsions were due to parent compound rather than a metabolite. Similarly, a study of 

Northern bobwhite quail found 20 times higher brain RDX levels in birds with seizures, compared to 

birds exposed to the same dosage but did not develop seizures (Gust et al. 2009). 

Some support for the hypothesis of an RDX-induced imbalance between inhibitory and excitatory 

systems is provided by a recent study of global gene expression in the brain of rats dosed with either 3 or 

18 mg RDX/kg (Bannon et al. 2009a). Relative to low-dose rats, gene expression in the cerebral cortex of 

high-dose rats was significantly decreased, particularly for processes related to the generation, packaging, 

mobilization, and release of neurotransmitters. Significantly down-regulated was the glutamate signaling 

pathway, which could be a response to excessive excitation resulting from the removal of the inhibition 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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by GABAergic pathways, caused in turn by RDX. In vitro studies using human neuroblastoma cells 

found an RDX-induced transient increase in calcium levels (released from intracellular calcium stores) 

(Ehrich et al. 2009); this increase in calcium may mediate the release of glutamate. Genomic results from 

a study of Northern bobwhite quail found significant alterations in the differential expression of 

transcripts involved the electrophysiology and signal transduction of neurons (Gust et al. 2009). The 

investigators suggested that these alterations may result in an inhibition of neuronal cell repolarization 

postaction potential leading to heightened neuronal excitability and seizures. Zhang and Pan (2009) 

found significant alterations in the number of microRNAs (miRNAs) expressed and expression levels in 

the brains of mice exposed to low levels of RDX in the diet for 28 days. The most affected miRNA was 

MiR-206, which was significantly up-regulated in the brain. The brain-derived neurotrophic factors 

(BDNF) gene is a potential miRNA target. Zhang and Pan (2009) speculated that miR-206 may 

contribute to the neurological effects associated with RDX exposure through its reduction of BDNF gene 

expression. The results of this study should be interpreted cautiously; additional research is needed to 

evaluate the role of altered miRNA expression in RDX toxicity. Bannon et al. (2009b) noted that the 

significance of miRNA as a predictor of toxic insult or disease has not been demonstrated. 

3.5.3 Animal-to-Human Extrapolations 

Virtually all of the information regarding the effects of RDX is derived from cases of acute exposure to 

doses of RDX that induced frank effects. In both humans and animals, high doses of RDX affect 

primarily the nervous system. However, which experimental animal is the best model for human 

exposure is unknown, although the basic mechanism for seizure induction is probably the same in humans 

and animals. Studies in animals have provided enough information to establish approximate blood levels 

of RDX that are associated with convulsive activity (Burdette et al. 1988; Schneider et al. 1977, 1978; 

U.S. Navy 1974b). That information is lacking in humans. Only two of the numerous case reports 

available measured RDX in the blood of the patients, Woody et al. (1986) and Küçükardalĭ et al. (2003). 

Blood levels of RDX reported by Woody et al. (1986) appear to be consistent with what has been 

measured in animal studies administered doses similar to those estimated for the patient in Woody et al. 

(1986). However, blood levels of RDX reported by Küçükardalĭ et al. (2003) were at least 3 orders of 

magnitude lower, even though the doses that the investigators estimated the patients had consumed (37– 

250 mg RDX/kg) were in the range of that estimated by Woody et al. (1986) (84.8 mg RDX/kg). No 

explanation was offered by Küçükardalĭ et al. (2003) for this discrepancy. Although there are limited data 

on the toxicokinetics of RDX in humans, the Krishnan PBPK model (Krishnan et al. 2009; Sweeney et al. 

2012; U.S. Army 2007a) allows for extrapolation of the results of animal studies to humans. 
 

 

 

 

 

 

 

 

 

 

 

 

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3.6 TOXICITIES MEDIATED THROUGH THE NEUROENDOCRINE AXIS 

Recently, attention has focused on the potential hazardous effects of certain chemicals on the endocrine 

system because of the ability of these chemicals to mimic or block endogenous hormones. Chemicals 

with this type of activity are most commonly referred to as endocrine disruptors. However, appropriate 

terminology to describe such effects remains controversial. The terminology endocrine disruptors, 

initially used by Thomas and Colborn (1992), was also used in 1996 when Congress mandated the EPA to 

develop a screening program for “...certain substances [which] may have an effect produced by a 

naturally occurring estrogen, or other such endocrine effect[s]...”. To meet this mandate, EPA convened a 

panel called the Endocrine Disruptors Screening and Testing Advisory Committee (EDSTAC), and in 

1998, the EDSTAC completed its deliberations and made recommendations to EPA concerning endocrine 

disruptors. In 1999, the National Academy of Sciences released a report that referred to these same types 

of chemicals as hormonally active agents. The terminology endocrine modulators has also been used to 

convey the fact that effects caused by such chemicals may not necessarily be adverse. Many scientists 

agree that chemicals with the ability to disrupt or modulate the endocrine system are a potential threat to 

the health of humans, aquatic animals, and wildlife. However, others think that endocrine-active 

chemicals do not pose a significant health risk, particularly in view of the fact that hormone mimics exist 

in the natural environment. Examples of natural hormone mimics are the isoflavinoid phytoestrogens 

(Adlercreutz 1995; Livingston 1978; Mayr et al. 1992). These chemicals are derived from plants and are 

similar in structure and action to endogenous estrogen. Although the public health significance and 

descriptive terminology of substances capable of affecting the endocrine system remains controversial, 

scientists agree that these chemicals may affect the synthesis, secretion, transport, binding, action, or 

elimination of natural hormones in the body responsible for maintaining homeostasis, reproduction, 

development, and/or behavior (EPA 1997). Stated differently, such compounds may cause toxicities that 

are mediated through the neuroendocrine axis. As a result, these chemicals may play a role in altering, 

for example, metabolic, sexual, immune, and neurobehavioral function. Such chemicals are also thought 

to be involved in inducing breast, testicular, and prostate cancers, as well as endometriosis (Berger 1994; 

Giwercman et al. 1993; Hoel et al. 1992). 

There is no evidence suggesting that the reproductive and developmental effects reported in animals 

summarized in Sections 3.2.2.5 and 3.2.2.6, respectively, involve actions of RDX on the neuroendocrine 

axis. No in vitro studies were located regarding endocrine disruption of RDX. 
 

 

 

 

 

 

 

 

 

 

 

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3.7 CHILDREN’S SUSCEPTIBILITY 

This section discusses potential health effects from exposures during the period from conception to 

maturity at 18 years of age in humans, when all biological systems will have fully developed. Potential 

effects on offspring resulting from exposures of parental germ cells are considered, as well as any indirect 

effects on the fetus and neonate resulting from maternal exposure during gestation and lactation. 

Relevant animal and in vitro models are also discussed. 

Children are not small adults. They differ from adults in their exposures and may differ in their 

susceptibility to hazardous chemicals. Children’s unique physiology and behavior can influence the 

extent of their exposure. Exposures of children are discussed in Section 6.6, Exposures of Children. 

Children sometimes differ from adults in their susceptibility to hazardous chemicals, but whether there is 

a difference depends on the chemical (Guzelian et al. 1992; NRC 1993). Children may be more or less 

susceptible than adults to health effects, and the relationship may change with developmental age 

(Guzelian et al. 1992; NRC 1993). Vulnerability often depends on developmental stage. There are 

critical periods of structural and functional development during both prenatal and postnatal life, and a 

particular structure or function will be most sensitive to disruption during its critical period(s). Damage 

may not be evident until a later stage of development. There are often differences in pharmacokinetics 

and metabolism between children and adults. For example, absorption may be different in neonates 

because of the immaturity of their gastrointestinal tract and their larger skin surface area in proportion to 

body weight (Morselli et al. 1980; NRC 1993); the gastrointestinal absorption of lead is greatest in infants 

and young children (Ziegler et al. 1978). Distribution of xenobiotics may be different; for example, 

infants have a larger proportion of their bodies as extracellular water, and their brains and livers are 

proportionately larger (Altman and Dittmer 1974; Fomon 1966; Fomon et al. 1982; Owen and Brozek 

1966; Widdowson and Dickerson 1964). The infant also has an immature blood-brain barrier (Adinolfi 

1985; Johanson 1980) and probably an immature blood-testis barrier (Setchell and Waites 1975). Many 

xenobiotic metabolizing enzymes have distinctive developmental patterns. At various stages of growth 

and development, levels of particular enzymes may be higher or lower than those of adults, and 

sometimes unique enzymes may exist at particular developmental stages (Komori et al. 1990; Leeder and 

Kearns 1997; NRC 1993; Vieira et al. 1996). Whether differences in xenobiotic metabolism make the 

child more or less susceptible also depends on whether the relevant enzymes are involved in activation of 

the parent compound to its toxic form or in detoxification. There may also be differences in excretion, 

particularly in newborns who all have a low glomerular filtration rate and have not developed efficient 
 

 

 

 

 

 

 

 

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tubular secretion and resorption capacities (Altman and Dittmer 1974; NRC 1993; West et al. 1948). 

Children and adults may differ in their capacity to repair damage from chemical insults. Children also 

have a longer remaining lifetime in which to express damage from chemicals; this potential is particularly 

relevant to cancer. 

Certain characteristics of the developing human may increase exposure or susceptibility, whereas others 

may decrease susceptibility to the same chemical. For example, although infants breathe more air per 

kilogram of body weight than adults breathe, this difference might be somewhat counterbalanced by their 

alveoli being less developed, which results in a disproportionately smaller surface area for alveolar 

absorption (NRC 1993). 

There are limited data on the toxicity and toxicokinetic properties of RDX in children. Clonic-tonic 

convulsions were reported in a 3-year-old child ingesting RDX (Woody et al. 1986). As described in the 

case-report, the observed effects are similar to those observed in adults (Goldberg et al. 1992; HarrellBruder and Hutchins 1995; Hollander and Colbach 1969; Kasuske et al. 2009; Ketel and Hughes 1972; 

Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969). The lack of adequate exposure data in most of 

these cases precludes evaluating whether children are more susceptible to RDX toxicity. Age-specific 

differences in LD50 values were found in deer mice; 21-day-old mice were the most sensitive followed by 

200- and 50-day-old animals (Smith et al. 2007). The LD50 in the 50-day-old mice was approximately 

twice as great as the value in 200-day-old mice. It is not known if similar differences would occur for 

other toxic effects. 

As discussed in greater detail in Section 3.2.2.6, developmental effects (decreases in growth and survival) 

have been observed in the offspring of rats orally exposed to RDX (U.S. Army 1980b, 1986d). These 

effects were typically observed at doses associated with RDX-induced seizures in the dams and may not 

have been a direct effect on the fetus/pup. No developmental effects have been observed in rabbits (U.S. 

Army 1980b). 

3.8 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 

1989). 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

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A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction 

between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment 

of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance 

itself, substance-specific metabolites in readily obtainable body fluid(s), or excreta. However, several 

factors can confound the use and interpretation of biomarkers of exposure. The body burden of a 

substance may be the result of exposures from more than one source. The substance being measured may 

be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from 

exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., 

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and 

all of its metabolites may have left the body by the time samples can be taken. It may be difficult to 

identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids 

(e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to RDX are 

discussed in Section 3.8.1. 

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an 

organism that, depending on magnitude, can be recognized as an established or potential health 

impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of 

tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial 

cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung 

capacity. Note that these markers are not often substance specific. They also may not be directly 

adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused 

by RDX are discussed in Section 3.8.2. 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability 

to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or 

other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the 

biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are 

discussed in Section 3.10, Populations That Are Unusually Susceptible. 

3.8.1 Biomarkers Used to Identify or Quantify Exposure to RDX 

RDX was detected in the serum, urine, and feces of a child who consumed unknown levels of RDX in the 

form of C-4 (91% RDX). RDX was measured in the serum for 120 hours and in the feces for 144 hours 

after the presumed time of ingestion (Woody et al. 1986). RDX was also measured in plasma from five 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

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3. HEALTH EFFECTS 

male cases described by Küçükardalǐ et al. (2003). Therefore, the chemical itself is a specific biomarker 

of exposure. Since the metabolism of RDX in humans has not been studied, it is not known whether 

single measurements of RDX in blood or urine could be used only as a biomarker of recent exposure or 

also as a biomarker of low-level prolonged exposure. 

3.8.2 Biomarkers Used to Characterize Effects Caused by RDX 

High oral doses of RDX are known to produce seizures in humans (Davies et al. 2007; Harrell-Bruder and 

Hutchins 1995; Hollander and Colbach 1969; Kaplan et al. 1965; Kasuske et al. 2009; Ketel and Hughes 

1972; Küçükardalǐ et al. 2003; Merrill 1968; Stone et al. 1969; Testud et al. 1996a; Woody et al. 1986) 

and animals (Burdette et al. 1988; Schneider et al. 1977; U.S. Army 1983a; U.S. Navy 1974b; von 

Oettingen et al. 1949), but this effect is not specific to RDX. Thus, there are no known specific 

biomarkers to characterize effects caused by inhalation, oral, or dermal exposure to RDX. 

3.9 INTERACTIONS WITH OTHER CHEMICALS 

Many of the human studies on the accidental inhalation or ingestion of RDX involved composition C-4, 

which was used for demolition by the U.S. Armed Forces during the Vietnam War. Composition C-4 was 

91% RDX, with the other components consisting of polyisobutylene, motor oil, and 2-ethylhexyl 

sebacate. Minimal information is available on the toxicological properties of these components of C-4, 

and it is not known whether they may contribute to the effects seen from exposure to C-4. However, 

since RDX is the primary component of C-4, the assumption has been made that the major effects noted 

from C-4 are due to RDX. In addition, the human and animal reports of ingested RDX usually are not 

limited to pure RDX, but are almost always reports of RDX contaminated with octahydro1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) or other substances. There are no studies regarding the 

interactions of these substances. However, there are several studies in which the oral toxicity of 

trinitrotoluene (TNT) and RDX were investigated. In one study (Levine et al. 1990), TNT and RDX were 

co-administered in the feed of rats for 13 weeks. This co-administration potentiated the decrease in body 

weight gain as compared to RDX alone. TNT antagonized the lethal effects and the hypotriglyceridemia 

induced by RDX. RDX antagonized the hypercholesterolemia, splenomegaly, testicular atrophy, 

hepatocytomegaly, degeneration of the seminiferous tubules, and pigmentation of renal cortices induced 

by TNT. 
 

 

 

 

 

 

 

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3. HEALTH EFFECTS 

3.10 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

A susceptible population will exhibit a different or enhanced response to RDX than will most persons 

exposed to the same level of RDX in the environment. Reasons may include genetic makeup, age, health 

and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters 

result in reduced detoxification or excretion of RDX, or compromised function of organs affected by 

RDX. Populations who are at greater risk due to their unusually high exposure to RDX are discussed in 

Section 6.7, Populations with Potentially High Exposures. 

There are no known populations that would be unusually susceptible to RDX toxicity because of their 

genetic make-up, developmental stage, health status, nutritional status, or chemical exposure history. 

3.11 METHODS FOR REDUCING TOXIC EFFECTS 

This section will describe clinical practice and research concerning methods for reducing toxic effects of 

exposure to RDX. However, because some of the treatments discussed may be experimental and 

unproven, this section should not be used as a guide for treatment of exposures to RDX. When specific 

exposures have occurred, poison control centers and medical toxicologists should be consulted for 

medical advice. 

3.11.1 Reducing Peak Absorption Following Exposure 

A general recommendation for reducing absorption after inhalation exposure to RDX is to move the 

patient to fresh air (HSDB 2009). Emesis is not recommended following oral exposure because of the 

probability of developing seizures (HSDB 2009). Charcoal may be administered to reduce absorption 

following oral exposure. The only information located for reducing absorption following dermal 

exposure specifically of RDX is a study by Twibell et al. (1984) which reported that washing the hands 

immediately after handling RDX can remove approximately 90% of the residue. Information summarized 

by HSDB (2009) suggests removing contaminated clothing and washing the exposed area thoroughly 

with soap and water. In case of eye contact, irrigation of the exposed eyes with copious amounts of room 

temperature water for at least 15 minutes is recommended. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 88 

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3.11.2 Reducing Body Burden 

No information was located on specific methods for reducing the body burden of RDX. However, 

Küçükardalǐ et al. (2003) reported that hemodialysis was unsuccessful in reducing the serum levels of 

RDX in three cases of oral intoxication with the chemical when performed approximately 3 hours after 

ingestion. 

3.11.3 Interfering with the Mechanism of Action for Toxic Effects 

The primary adverse effect of RDX is the induction of convulsive activity and seizures for which standard 

treatments are available. Intravenous administration of a benzodiazepine such as diazepam or lorazepam 

is recommended (HSDB 2009). If seizures recur after diazepam, phenobarbital or propofol should be 

considered (30 mg for adults or 10 mg for children older than 5 years). 

3.12 ADEQUACY OF THE DATABASE 

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of RDX is available. Where adequate information is not 

available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the 

initiation of a program of research designed to determine the health effects (and techniques for developing 

methods to determine such health effects) of RDX. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

3.12.1 Existing Information on Health Effects of RDX 

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 

RDX are summarized in Figure 3-3. The purpose of this figure is to illustrate the existing information 

concerning the health effects of RDX. Each dot in the figure indicates that one or more studies provide 
 

RDX 89 

3. HEALTH EFFECTS 

Figure 3-3. Existing Information on Health Effects of RDX 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Death 

Acute 

Intermediate

Chronic 

Immunologic/Lymphoretic

Neurologic

Reproductive

Developmental

Genotoxic

Cancer 

Systemic 

Inhalation 

Oral 

Dermal 

Human 

Inhalation 

Oral 

Dermal 

Animal 

Existing Studies 
 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 90 

3. HEALTH EFFECTS 

information associated with that particular effect. The dot does not necessarily imply anything about the 

quality of the study or studies, nor should missing information in this figure be interpreted as a “data 

need”. A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data 

Needs Related to Toxicological Profiles (Agency for Toxic Substances and Disease Registry 1989d), is 

substance-specific information necessary to conduct comprehensive public health assessments. 

Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from 

the scientific literature. 

Case studies are available regarding systemic effects in humans following acute exposures to RDX via all 

three routes. One study in the workplace provides information on immunological and neurological effects 

following inhalation exposure for chronic periods (Hathaway and Buck 1977). Neurological effects have 

also been described following acute oral exposures to RDX (Hollander and Colbach 1969; Kasuske et al. 

2009; Ketel and Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 

1986). 

Animal data on inhalation exposure is limited to one study. Oral animal data are available for all 

exposure durations and for all end points. Dermal data on death and systemic effects are available for 

animals exposed to RDX for acute and intermediate exposure periods. 

3.12.2 Identification of Data Needs 

Acute-Duration Exposure. The nervous system is one of the main targets for RDX toxicity in 

humans exposed by the inhalation (Hollander and Colbach 1969; Testud et al. 1996a) or oral (Goldberg et 

al. 1992; Harrell-Bruder and Hutchins 1995; Hollander and Colbach 1969; Kasuske et al. 2009; Ketel and 

Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986) routes, and 

animal studies involving oral exposure support this finding (Burdette et al. 1988; Meyer et al. 2005; 

Schneider et al. 1977; U.S. Army 1985b, 2006). There is a small number of acute-duration animal studies 

and no studies that adequately examined potential systemic effects. Increases in occurrence of 

convulsions, tremors, and/or seizures were consistently observed in the available studies (Burdette et al. 

1988; U.S. Army 1980b, 1985b, 1986d, 2006). In addition, decreases in growth were observed in the 

fetuses of rats exposed to lethal doses of RDX (U.S. Army 1986d). One animal study suggests that the 

skin is a target organ for RDX following dermal exposure (U.S. Army 1974). However, the use of 

solvents confounded the results. No acute inhalation MRLs could be derived because of the lack of 

human and animal studies with accurate exposure estimates. The available acute exposure data for 
 

 

 

 

 

 

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animals was adequate for the derivation of an MRL based on an increased incidence of 

convulsions/seizures/tremors (U.S. Army 2006). Further acute inhalation and oral studies on the 

developmental and neurological effects of RDX would be useful in determining levels that may cause 

harm to humans living near hazardous waste sites; these studies should also evaluate potential systemic 

effects. 

Intermediate-Duration Exposure. No studies examining the toxicity in humans following 

intermediate-duration exposure to RDX were identified. No animal studies were identified examining 

RDX toxicity following inhalation exposure; thus, an intermediate-duration inhalation MRL could not be 

derived. Inhalation studies are needed to identify potential targets of toxicity and establish dose-response 

relationships; these studies would be useful in determining levels that may cause harm to humans who 

live near hazardous waste sites. The nervous system is the target organ for RDX toxicity in animals 

exposed by the oral route for intermediate periods (Levine et al. 1981, 1990; U.S. Army 1983a, 1985b, 

2006; U.S. Navy 1974b; von Oettingen et al. 1949). The most consistently observed effect was 

convulsions, seizures, and tremors. Systemic effects (hematological and serum chemistry alterations), 

reproductive effects (testicular degeneration, possible decrease in male fertility), and developmental 

effects (decreases in growth and decreased viability) have also been observed. However, these effects 

have not been consistently observed across studies. Difference in the exposure route (dietary versus 

gavage) and RDX formulation (finely ground versus coarsely ground) may explain possible differences in 

the results; however, this has not been adequately assessed and additional oral exposure studies are 

needed to evaluate apparent study differences. An intermediate oral MRL based on an increased 

incidence of convulsions in rats was derived (U.S. Army 2006). Studies involving intermediate dermal 

exposure to RDX did not identify a target organ (U.S. Army 1974). 

Chronic-Duration Exposure and Cancer. Only one human study was located for chronicinhalation exposure. This study revealed no adverse health effects following chronic exposures to 

unknown levels of RDX in the air (Hathaway and Buck 1977). No animal studies concerning chronic 

inhalation exposure were located. No chronic inhalation MRLs could be derived because of the lack of 

human and animal studies with accurate exposure estimates. Therefore, further inhalation studies would 

be useful to identify target organs and define the potential for human health risks. 

No human studies concerning chronic oral exposure were located. The most sensitive target organ for 

adverse effects in animals following chronic oral exposure is the nervous system; an increased occurrence 

of convulsions and seizures were observed in rats (U.S. Army 1983a). Mild adverse systemic effects 
 

 

 

 

 

 

 

 

 

 

RDX 92 

3. HEALTH EFFECTS 

have also been observed in rats (U.S. Army 1983a) and mice (U.S. Army 1984c). A second chronicduration study in rats (U.S. Navy 1976) did not find any adverse effects. An increased incidence of 

prostate gland inflammation was observed in rats exposed to RDX for 2 years (U.S. Army 1983a). The 

inflammation was observed at the lowest adverse effect level; it may have been secondary to a bacterial 

infection. Because the second rat study (U.S. Navy 1976) did not examine the prostate, the prostate effect 

could not be confirmed. Additional studies are needed to further evaluate the prostate as a potential target 

of RDX toxicity. These studies should include end points addressing immunotoxicity of chronic exposure 

to RDX. A chronic-duration oral MRL was derived for RDX based on the neurological effects observed 

in the U.S. Army (1983a) study. Only one human study was located for chronic dermal exposure 

(Sunderman 1944). This study reported dermatitis in workers exposed to RDX, but no dose levels were 

reported. No animal studies concerning chronic dermal exposure were located. Additional chronic oral 

and dermal studies would be useful to better define dose levels that may cause a risk to humans. 

No studies are available regarding cancer in humans following any route of exposure. Increased 

incidences of combined hepatocellular adenomas and carcinomas were found in female mice orally 

exposed to RDX (U.S. Army 1984c). A re-evaluation of the histopathology slides from this study 

resulted in a re-classification of several of the tumors as nonneoplastic alterations (Parker et al. 2006). No 

increases in neoplastic lesions were observed in rat oral exposure studies (U.S. Army 1983a; U.S. Navy 

1976). The risk of developing cancer by the inhalation or dermal routes has not been investigated. 

Further inhalation, oral, or dermal carcinogenicity studies would be useful to determine whether RDX 

poses a risk of cancer for humans. 

Genotoxicity. Data from microbial mutagenicity studies using S. typhimurium and S. cerevisiae have 

consistently produced negative results (George et al. 2001; Lachance et al. 1999; Pan et al. 2007; U.S. 

Army 1977b, 1980b; Whong et al. 1980). Therefore, at this time, additional studies with RDX would 

probably not provide any new key information. Studies involving humans and mammalian species are 

few. The three mammalian studies available were negative for DNA damage in human fibroblasts (U.S. 

Army 1978b), dominant lethal mutations in rats (U.S. Army 1980b), and induction of micronuclei in bone 

marrow cells from mice (Reddy et al. 2005a). Additional studies of N-nitroso metabolites of RDX, such 

as MNX and TNX, would be valuable since N-nitroso compounds often yield genotoxicity. Research 

employing toxicogenomics or a combination of genetics, molecular biology, and bioinformatics may be 

able to uncover the molecular targets of RDX. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 93 

3. HEALTH EFFECTS 

Reproductive Toxicity. No data are available on the reproductive toxicity of RDX in humans via 

inhalation, oral, or dermal routes of exposure. No inhalation or dermal studies are available for animals. 

An oral study in mice (U.S. Army 1984c) and one in rats (U.S. Navy 1976) revealed no histopathology in 

the ovaries, testes, or uterus. One oral study (U.S. Army 1983a) did reveal spermatic granulomas in the 

prostate of rats after 6 months of exposure and testicular degeneration in rats exposed for 1 year. This 

study also reported an increased incidence of suppurative inflammation of the prostate in rats exposed for 

2 years; however, the inflammation was primarily observed in rats dying early and there is concern that 

the inflammation may be secondary to a bacterial infection rather than a primary effect of RDX. No 

pharmacokinetic data are available that can be used to determine whether the reproductive system is 

likely to be a target for RDX toxicity. Therefore, further studies to determine whether the prostate is 

indeed the most sensitive organ are important. A two-generation reproductive study in rats (U.S. Army 

1980b) reported nonsignificant decreases in F0 male fertility when the exposed males were mated with 

unexposed females or exposed females; additional studies are needed to confirm this effect. 

Developmental Toxicity. No human studies on developmental effects are available for exposure to 

RDX via inhalation, oral, or dermal routes. No inhalation or dermal studies are available for animals. 

Two acute duration oral studies examined the potential developmental toxicity of RDX. Maternal deaths 

were observed in both studies at the highest dose tested (U.S. Army 1980b, 1986d). No increases in the 

occurrence of fetal malformations were observed (U.S. Army 1980b). One study reported a decrease in 

fetal weight and length at the dose level associated with maternal deaths and neurotoxicity. In a twogeneration study, increases in the occurrence of stillbirths and decreases in pup survival were observed in 

the F1 offspring of dams exposed to lethal doses; a decrease in pup body weights and increase in the 

incidence of renal cysts were observed in the F2 pups (U.S. Army 1980b). The one available oral study in 

rabbits revealed no fetotoxicity (U.S. Army 1980b). No pharmacokinetic data are available that can be 

used to determine whether the developmental system is likely to be a target organ. Further developmental 

studies via the oral route are important to determine whether humans exposed to RDX at or near 

hazardous waste sites are at risk of experiencing adverse developmental effects. 

Immunotoxicity. The only available immunological study in humans reveals no changes in the 

antinuclear antibodies of workers exposed to RDX in the air (Hathaway and Buck 1977). No other 

functional tests were performed. No histopathological alterations were found in the spleen, thymus, or 

lymph nodes of rats (Levine et al. 1990; U.S. Army 1980b, 2006) or mice (U.S. Army 1980b), or in the 

spleens of dogs (U.S. Navy 1974a; von Oettingen et al. 1949) or monkeys (U.S. Navy 1974b), after 

intermediate exposure via the oral route. In addition, no alterations in the proportion of cell surface 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 94 

3. HEALTH EFFECTS 

markers were observed in rats (U.S. Army 2006). A study by Levine et al. (1981) demonstrated mild 

leukocytosis. Further oral studies examining immune function would be useful to determine whether 

RDX adversely affects the immune system. In addition, inhalation and dermal studies would help 

determine whether exposure to RDX at or near hazardous waste sites would affect the human immune 

system. 

Neurotoxicity. The nervous system is a major target organ for RDX toxicity. Seizures have been 

reported in humans exposed for acute periods by inhalation (Kaplan et al. 1965; Testud et al. 1996a), 

ingestion (Goldberg et al. 1992; Harrell-Bruder and Hutchins 1995; Kasuske et al. 2009; Küçükardalĭ et 

al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986), or a combination of the inhalation and oral 

routes (Hollander and Colbach 1969; Ketel and Hughes 1972). Oral studies in animals have supported 

this finding for acute (Burdette et al. 1988; Meyer et al. 2005; Schneider et al. 1977; U.S. Army 1980b, 

1986d, 2006), intermediate (Sunderman 1944; U.S. Army 1983a, 2006; U.S. Navy 1974b; von Oettingen 

et al. 1949), and chronic (U.S. Army 1983a) exposure durations. Neurobehavioral alterations were 

observed in rats receiving a single gavage dose of RDX (U.S. Army 1985b), but not after repeated 

intermediate-duration exposure (U.S. Army 1985b, 2006). The conflicting results may be a reflection of 

when the behavioral tests were conducted, in relation to gavage dosing rather than a duration-related 

difference. Additional neurobehavioral function tests are needed to confirm the results observed in the 

acute study. More sensitive neurological tests in animals via inhalation, oral, or dermal routes would be 

helpful in establishing definite less serious LOAELs. 

Epidemiological and Human Dosimetry Studies. There is one human study that tested blood 

chemistry and hematology in 70 workers exposed to an average of 0.28 mg/m3 of RDX in the air 

(Hathaway and Buck 1977). All of the other human studies are case reports of individuals ingesting RDX 

(Goldberg et al. 1992; Harrell-Bruder and Hutchins 1995; Hollander and Colbach 1969; Ketel and 

Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986) or exposed to 

RDX dust (Kaplan et al. 1965; Testud et al. 1996a). No epidemiology studies are available for exposure 

in drinking water. If populations with appropriate exposures could be identified, it would be useful to 

conduct epidemiologic and human dosimetry studies to establish cause-and-effect relationships and to 

plan future monitoring of individuals living near hazardous waste sites. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 95 

3. HEALTH EFFECTS 

Biomarkers of Exposure and Effect. 

Exposure. Thus far, RDX in urine or blood is the only known biomarker of exposure to RDX. RDX has 

been measured in these media in cases of accidental ingestion of the chemical (Küçükardalǐ et al. 2003; 

Woody et al. 1986). There is no information regarding the metabolism of RDX in humans; therefore, 

monitoring of the blood and/or urine of RDX workers could help identify RDX-derived products that can 

be used as biomarkers in studies of populations living near sites where RDX has been found. 

Effect. There is no known sensitive biomarker for the effects of RDX. The most prominent effects are 

seizures in humans (Davies et al. 2007; Harrell-Bruder and Hutchins 1995; Hollander and Colbach 1969; 

Kaplan et al. 1965; Ketel and Hughes 1972; Küçükardalǐ et al. 2003; Merrill 1968; Stone et al. 1969; 

Testud et al. 1996a; Woody et al. 1986) or animals (Burdette et al. 1988; Schneider et al. 1977; U.S. 

Army 1983a; U.S. Navy 1974b; von Oettingen et al. 1949), but seizures can be evoked by a large number 

of substances and disease states. As mentioned previously, two studies of accidental poisoning with RDX 

measured levels of RDX in blood from the patients. However, additional studies are necessary to 

establish: (1) levels of RDX in blood that are associated with adverse neurological effects and (2) levels 

of exposure that are associated with specific levels of RDX in blood. 

Absorption, Distribution, Metabolism, and Excretion. No studies are available regarding the 

toxicokinetics of RDX in humans. However, pulmonary and gastrointestinal absorption of RDX in 

humans can be inferred from reports of adverse health effects following exposure by these routes 

(Harrell-Bruder and Hutchins 1995; Hollander and Colbach 1969; Kaplan et al. 1965; Ketel and Hughes 

1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Testud et al. 1996a; Woody et al. 1986) 

and from measurements of RDX in blood and urine after exposure in some studies (i.e., Küçükardalĭ et al. 

2003; Woody et al. 1986). Relatively poor dermal absorption of RDX was reported in a study with 

excised human skin (Reddy et al. 2008); similar findings were reported in a study with excised pig skin 

(Reifenrath et al. 2002). No studies were located regarding the metabolism of RDX in humans. Analysis 

of blood and excreta from workers exposed to RDX could provide valuable information regarding the 

metabolism of RDX in humans. No inhalation toxicokinetic data were located in animals. Oral studies in 

rats indicate that mixing RDX with soil considerably reduces its bioavailability (Crouse et al. 2008). A 

recent study in miniature pigs showed that oral administration of RDX in carboxymethylcellulose and 

water results in almost complete absorption (Major and Reddy 2007). Earlier studies in rats provided 

information on some parameters of oral absorption, distribution, and elimination (Schneider et al. 1977, 

1978). These studies did not show any preferential accumulation of RDX in tissues. RDX was found in 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 96 

3. HEALTH EFFECTS 

the brain of rat pups born to dams exposed to RDX during gestation (U.S. Army 2007b). Additional 

studies of the perinatal transfer of RDX in animals are needed, particularly to determine the relative 

contribution of gestational vs. lactational exposure. The metabolism of RDX has been studied in 

miniature pigs and the major metabolites have been characterized (Major and Reddy 2007). Since the 

main target for RDX appears to be the nervous system, additional studies of distribution of RDX and 

metabolites to different brain areas would be valuable. These studies should try to determine possible 

temporal correlations between the presence of RDX and/or metabolites in specific brain areas and the 

manifestation of clinical signs such as convulsive activity and seizures. 

Comparative Toxicokinetics. The only comparative toxicokinetics data available are the results of 

dermal absorption studies in excised human and pig skin, which showed relatively poor absorption in 

both preparations (Reddy et al. 2008; Reifenrath et al. 2002). This suggests that pigs would probably be a 

good animal model for dermal absorption studies. As mentioned previously, analyses of blood and urine 

from subjects exposed to RDX during its manufacture or use or from individuals accidentally or 

intentionally exposed to high amounts of RDX could provide information on the metabolism of RDX in 

humans that can be compared with data collected from animals studies to establish which animal species 

serves as the best model for extrapolating results to humans. A PBPK model was developed that 

simulates disposition of RDX in the rat, swine, and humans (Krishnan et al. 2009; Sweeney et al. 2012; 

U.S. Army 2007a); this model was considered suitable for risk assessment. 

Methods for Reducing Toxic Effects. There are no known mitigation measures specifically for 

RDX-induced toxicity, other than standard anticonvulsant therapy. Since gastrointestinal absorption of 

RDX seems to be quite slow (Küçükardalĭ et al. 2003), studies should focus on developing methods to 

accelerate its removal from the gastrointestinal tract to prevent RDX-induced adverse neurological 

effects. Washing the skin was reported to be effective in removing the chemical from the skin (Twibell et 

al. 1984). No data are available regarding adverse health effects of low-level, long-term exposure of 

humans to RDX; therefore, no specific mitigation studies can be proposed at this time for that exposure 

scenario. 

Children’s Susceptibility. Data needs relating to both prenatal and childhood exposures, and 

developmental effects expressed either prenatally or during childhood, are discussed in detail in the 

Developmental Toxicity subsection above. 
 

 

 

 

 

 

RDX 97 

3. HEALTH EFFECTS 

There are limited data on potential age-related differences in the toxicity and toxicokinetics of RDX. 

Neurological effects, similar to those observed in adults, have been observed in a child accidentally 

ingesting RDX (Woody et al. 1986). However, the lack of dose information precludes determining 

whether children are more susceptible than adults. A study in deer mice found age-related differences in 

lethality (Smith et al. 2007). Additional animal studies are needed to evaluate whether there are potential 

differences in RDX toxicity between adults and children. These studies should include a wide-range of 

ages from birth through old age to assess whether there are differences in susceptibility as the nervous 

system matures. 

Child health data needs relating to exposure are discussed in Section 6.8.1, Identification of Data Needs: 

Exposures of Children. 

3.12.3 Ongoing Studies 

The U.S. Army is concurrently developing a swine PBPK model, which can be extrapolated to humans. 

No ongoing studies pertaining to RDX were identified in the Federal Research in Progress database 

(FEDRIP 2009). 

 

 

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RDX 99 

4. CHEMICAL AND PHYSICAL INFORMATION 

4.1 CHEMICAL IDENTITY 

RDX is a nitramine produced mainly for use in explosives (HSDB 2009). Information regarding the 

chemical identity of RDX is located in Table 4-1. 

4.2 PHYSICAL AND CHEMICAL PROPERTIES 

RDX is a white crystalline solid. Information regarding the physical and chemical properties of RDX is 

located in Table 4-2. Pure RDX is a highly explosive compound that can be initiated by impact, 

temperature, and friction (Akhavan 2004; Boileau et al. 2009; HSDB 2009). RDX is toxic by inhalation 

and dermal routes (Lewis 2007). Acrid fumes of nitrogen oxides may be released when heated to 

decomposition (HSDB 2009; Lewis 2000). 
N N

 

RDX 100 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-1. Chemical Identity of RDX 

Characteristic Information Reference 

Chemical name RDX HSDB 2009 

Synonym(s) Cyclonite; hexogen; cyclotrimethylenetrinitramine; 

hexogen 5W;T4; hexahydro-1,3,5-trinitro1,3,5-triazine; 1,3,5-triaza-1,3,5,-trinitrocyclohexane; 

1,3,5-trinitrohexahydro-1,3,5-triazine; cyclotrimethylenenitramine; hexolite; S-triazine, hexahydro1,3,5-trinitro-; 1,3,5-triazine, hexahydro-1,3,5-trinitro-; 

1,3,5-triazine, perhydro, 1,3,5-trinitro-; trimethylenetrinitramine; sym-trimethylene trinitramine; 1,3,5-trinitrohexahydro-S-triazine; 1,3,5-trinitroperhydro1,3,5-triazine; 1,3,5-trinitro-1,3,5-triazacyclohexane; 

trinitrotrimethylenetriamine 

HSDB 2009 

Registered trade name(s) No data 

Chemical formula C3H6N6O6 HSDB 2009 

Chemical structure NO2 

N 

O’Neil et al. 2006 

O2N NO2 

Identification numbers: 

CAS registry 121-82-4 HSDB 2009 

RTECS XY9450000 RTECS 2009 

EPA hazardous waste No data 

OHM/TADS No data 

DOT/UN/NA/IMDG shipping UN0072; UN0391; UN0483; IMO1.1; DOT Explosive 

1.1D 

HSDB 2009; 

Lewis 2000 

HSDB 2079 HSDB 2009 

NCI No data 

CAS = Chemical Abstracts Service; DOT/UN/NA/IMDG = Department of Transportation/United Nations/North 

America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; 

HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; OHM/TADS = Oil and Hazardous 

Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances 
 

RDX 101 

4. CHEMICAL AND PHYSICAL INFORMATION 

Table 4-2. Physical and Chemical Properties of RDX 

Property Information Reference 

Molecular weight 222.26 Merck 1989 

Color White Akhavan 2004 

Physical state Crystalline solid Akhavan 2004 

Melting point 204–206 °C Boileau et al. 2009; Merck 1989 

Boiling point Decomposes U.S. Army 1991 

Decomposition temperature: 213 °C Akhavan 2004 

Density at 20 °C 1.82 g/mL Merck 1989 

Odor No data 

Odor threshold: 

Water No data 

Air No data 

Solubility: 

Water at 20 °C 38.4–38.9 mg/L; 60 mg/L U.S. Army 1983b, 1991 

Organic solvents Slightly soluble in methanol, ether, ethyl Merck 1989 

acetate, glacial acetic acid 

Partition coefficients: 

Log Kow 0.87 HSDB 2009; PHYSPROP 2009 

Log Koc 1.80a U.S. Army 1987a 

Vapor pressure 

At 20 °C 1x10-9 mm Hg (Torr) U.S. Army 1987a 

At unidentified temperature 0.05 Pa (3.8x10-4 mm Hg) Boileau et al. 2009 

Henry's law constant at 25 °C 2.0x10-11 atm-m3/molb PHYSPROP 2009 

Autoignition temperature No data 

Flashpoint No data 

Flammability limits No data 

Explosive limits Explosion may be prompted by sudden HSDB 2009 

shock, high temperature, or 

combination of both 

a

Calculated value 

b

Estimated value 
RDX 102
 
 

4. CHEMICAL AND PHYSICAL INFORMATION 

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RDX 103 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

5.1 PRODUCTION 

No information is available in the Toxic Release Inventory (TRI) database on facilities that manufacture 

or process RDX because this chemical is not required to be reported under Section 313 of the Emergency 

Planning and Community Right-to-Know Act (Title III of the Superfund Amendments and 

Reauthorization Act of 1986) (EPA 2010). 

RDX is produced by nitrolysis of hexamine with nitric acid (HSDB 2009; Lewis 2007). In the Bachmann 

process, used in the United States, hexamine is reacted with nitric acid, ammonium nitrate, glacial acetic 

acid, and acetic anhydride (Boileau et al. 2009; Budavari and O'Neil 1989; HSDB 2009; U.S. Army 

1978c, 1986e). The crude product is filtered and recrystallized to form RDX (U.S. Army 1986a). The 

Woolrich process, typically used in the United Kingdom and France, does not use acetic anhydride. The 

raw materials consist of hexamine and 98–99% nitric acid; however, this complex exothermic reaction is 

not completely understood (Boileau et al. 2009). 

Another process that has been used to manufacture RDX by the direct nitration of HMX has not yielded a 

percentage of RDX as high as that produced in the Bachmann process (Budavari and O'Neil 1989; U.S. 

Army 1978c). 

Production of RDX peaked in the 1960s when it was ranked third in explosive production by volume in 

the United States (U.S. Army 1986e). The average volume of RDX produced from 1969 to 1971 was 

15 million pounds per month. However, production of RDX decreased to a yearly total of 16 million 

pounds for 1984. 

RDX is not produced commercially in the United States (HSDB 2009). Current production in the United 

States is limited to military use at the Holston Army Ammunition Plant in Kingsport, Tennessee (SRI 

2009). In the past, several Army ammunition plants, such as Louisiana (Shreveport, Louisiana), Lone 

Star (Texarkana, Texas), Iowa (Middletown, Iowa), and Milan (Milan, Tennessee), may have also 

handled and packaged RDX (U.S. Army 1986e). In 1980, RDX was produced at five facilities in the 

United States, including Borden (Fayetteville, North Carolina), Hooker (North Tonawanda, New York), 

Plastics Engineering (Sheboygan, Wisconsin), Tenneco (Fords, New Jersey), and Wright Chemical 
 

 

 

 

 

 

 

 

 

 

 

RDX 104 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

(Riegelwood, North Carolina). U.S. capacity in 1980 was 119 million pounds per year (CMR 1980). In 

2006, 6.9 million pounds were produced at Holston Army Ammunition Plant (EPA 2006c). 

5.2 IMPORT/EXPORT 

No information is available regarding the import or export of RDX. 

5.3 USE 

RDX is a nitramine explosive compound (Turley and Brewster 1987) that can be utilized as a propellant, 

gunpowder, or high explosive depending on the initiation type (Boileau et al. 2009). RDX has both 

military and civilian applications. As a military explosive, RDX can be used alone as a base charge for 

detonators or mixed with another explosive such as TNT to form cyclotols, which produce a bursting 

charge for aerial bombs, mines, and torpedoes (HSDB 2009; Lewis 2000; Sax and Lewis 1989; Stokinger 

1982). As an explosive, RDX is one and a half times more powerful than TNT and is easily initiated with 

mercury fulminate (Lewis 2007). Common military uses of RDX have been as an ingredient in plastic 

bonded explosives or plastic explosives, which have been used as explosive fill in almost all types of 

munition compounds (Gibbs and Popolato 1980; HSDB 2009). The plasticized form of RDX, 

composition C-4, contains 91% RDX, 2.1% polyisobutylene, 1.6% motor oil, and 5.3% 2-ethylhexyl 

sebacate (Turley and Brewster 1987). Combinations of RDX and HMX, another explosive, have been the 

chief ingredients in approximately 75 products (U.S. Army 1978c). 

5.4 DISPOSAL 

Waste water treatment sludges resulting from the manufacture of RDX are classified as hazardous wastes 

and are subject to EPA regulations (EPA 1990a). For more information on regulations that apply to 

RDX, see Chapter 8. 

Propellants and explosives have been disposed of through burning, decomposition, re-use, and recovery 

(Bohn et al. 1997). Byproducts of military explosives such as RDX have also been openly burned in 

many Army ammunition plants in the past. There are indications that, in recent years, as much as 80% of 

waste munitions and propellants have been disposed of by incineration (U.S. Army 1986a). Wastes 

containing RDX have been incinerated by grinding the explosive wastes with a flying knife cutter and 

spraying the ground material with water to form a slurry. The types of incineration used to dispose of 

waste munitions containing RDX include rotary kiln incineration, fluidized bed incineration, and 
 

 

 

 

 

RDX 105 

5. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 

pyrolytic incineration (U.S. Army 1986a). The primary disadvantage of open burning or incineration is 

that explosive contaminants are often released into the air, water, and soils (U.S. Army 1986c). 

Munitions such as RDX have also been disposed of in the past by dumping into deep seawater 

(Hoffsommer and Rosen 1972). 

RDX wastes found in soils and sediments have been degraded in composts using substances such as hay, 

horse feed, sewage sludge, wood shavings or sawdust, animal manure, and fruit and vegetable wastes 

(Greist et al. 1993; Gunderson et al. 1997; U.S. Army 1986b; Williams et al. 1992). In a mechanically 

stirred amended compost, the concentration of RDX in soil was reduced from <800 to 39 mg/kg after 

44 days (Griest et al. 1993). RDX in contaminated soil from a dry explosives washout lagoon decreased 

from 884 to <2.9 mg/kg after 6 months using a 70% organic compost (Gunderson et al. 1997). RDX has 

been removed from munitions waste waters and contaminated groundwater by activated carbon columns 

(Bricka and Sharp 1992; U.S. Army 1987c; Wujcik et al. 1992). No RDX was detected when 

contaminated groundwater containing 487 μg/L of RDX was passed through granular activated carbon 

(GAC) columns at a loading rate of 7.11 gpm/ft, a flow rate of 0.7 gpm, and an empty-bed contact time of 

4.2 minutes (Wujcik et al. 1992). Once carbon columns were saturated with explosive, they were 

traditionally destroyed by open burning. Since this practice is no longer allowed in many areas, other 

disposal alternatives for spent carbons, such as thermal reactivation for reuse, oxidative incineration with 

ash burial, and thermal deactivation with carbon burial, have been investigated (U.S. Army 1987c). In a 

feasibility study, ultraviolet irradiation was found to provide effective treatment of RDX-contaminated 

groundwater (Bricka and Sharp 1992). 

 

 

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RDX 107 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.1 OVERVIEW 

RDX has been identified at 31 out of the 1,699 hazardous waste sites that have been proposed for 

inclusion on the EPA National Priorities List (NPL) (HazDat 2007). However, the number of sites 

evaluated for RDX is not known. The frequency of these sites can be seen in Figure 6-1. 

RDX is a military explosive produced by the nitrolysis of hexamine with nitric acid (Boileau et al. 2009). 

It is a synthetic compound and is not known to exist in nature. Effluents and emissions from ammunition 

plants are responsible for the release of RDX into the environment (Pennington and Brannon 2002; U.S. 

Army 1984a). RDX is expected to exist as a particulate in the atmosphere. When released to water, RDX 

is subject to photolysis (half-life of 9–13 hours). Photoproducts include formaldehyde and nitrosamines 

(U.S. Army 1980a). Alkaline hydrolysis can also occur (Balakrishnan et al. 2003; Heilmann et al. 1996). 

RDX undergoes biodegradation in water and soil under anaerobic conditions (Funk et al. 1993; 

Pennington and Brannon 2002; U.S. Army 1984f). Its biodegradation products include MNX; DNX; 

TNX; hydrazine; 1,1-dimethyl-hydrazine, 1,2-dimethyl-hydrazine; formaldehyde; and methanol 

(McCormick et al. 1981). RDX is mobile in soil, and can leach into groundwater (U.S. Army 1980c), and 

can be transported from soils or water to terrestrial and aquatic plants (Best et al. 1999; Harvey et al. 

1991, 1997; Pennington and Brannon 2002; Simini and Checkai 1996). 

RDX has been identified in environmental samples, primarily near army munition depots (Bishop et al. 

1988; Dacre 1994). Indoor air samples collected at ammunition plants were found to contain RDX in 

concentrations ranging from 0.032 to 60 mg/m3

 (Bishop et al. 1988; U.S. Army 1975). In water, RDX 

has been identified in a variety of groundwater samples from ammunition plants in the United States (<1– 

14,100 μg/L) and Germany (21–3,800 μg/L) (Bart et al. 1997; Best et al. 1999; Godejohann et al. 1998; 

Steuckart et al. 1994; U.S. Army 1988). Sediment samples from Army depots have been found to contain 

RDX in concentrations ranging from <0.1 to 3,574 mg/kg (Simini et al. 1995; Sunahara et al. 1999; U.S. 

Army 1988) and in composts prepared from contaminated sediments (>2.9–896 mg/kg) (Griest et al. 

1995; Gunderson et al. 1997). Additionally, RDX was indentified in plant species irrigated with or grown 

in contaminated water (<20–3,196 μg/L) (Best et al. 1999; Pennington and Brannon 2002). 

For the general population, exposure to RDX is primarily limited to areas around ammunition plants and 

military installations where it is manufactured, converted to munitions, packed, loaded, or released 
RDX 108 

6. POTENTIAL FOR HUMAN EXPOSURE 

Figure 6-1. Frequency of NPL Sites with RDX Contamination 
 

 

 

 

 

 

 

 

 

 

RDX 109 

6. POTENTIAL FOR HUMAN EXPOSURE 

through the demilitarization of antiquated munitions (Hundal et al. 1997; Pennington and Brannon 2002; 

U.S. Army 1980a, 1984a, 1984f). The most likely route of exposure is ingestion of contaminated 

drinking water or agricultural crops irrigated with contaminated water (Harvey et al. 1991, 1997; Simini 

and Checkai 1996). Dermal contact with soil containing RDX or inhalation exposure of contaminated 

particulate matter produced during incineration of RDX-containing waste material are also possible routes 

of exposure. Occupational exposure to RDX can occur when workers handle RDX at Army ammunition 

plants (Hathaway and Buck 1977; Kaplan et al. 1965). According to the National Occupational Exposure 

Survey (NOES) of 1981–1983 conducted by NIOSH, the estimated number of workers potentially 

exposed to RDX in the United States was 488 (NIOSH 1990). 

Since RDX releases are not required to be reported under SARA Section 313, there are no data on RDX 

in the Toxics Release Inventory (TRI 1993). 

6.2 RELEASES TO THE ENVIRONMENT 

6.2.1 Air 

There is no information on releases of RDX to the atmosphere from manufacturing and processing 

facilities because these releases are not required to be reported (EPA 1997). However, all emissions are 

evaluated under Title V of the 1990 federal Clean Air Act Amendments within each state’s Title V 

programs. RDX emissions from the manufacturing process are considered insignificant under the Title V 

air pollution control permits for facilities because they are contained systems. Thus, emission quantities 

are such that dispersion from the facilities is unlikely to be detectable by ambient monitoring. 

RDX can enter the air through the release of contaminated particulate matter formed during the 

incineration of RDX-containing mixtures (U.S. Army 1984a). RDX can also enter the air through 

evaporation from aquatic effluent streams or waste storage lagoons (U.S. Army 1984a). 

6.2.2 Water 

There is no information on releases of RDX to the water from manufacturing and processing facilities 

because these releases are not required to be reported (EPA 1997). Water discharges from RDX 

manufacturing and processing facilities are regulated by the National Pollutant Discharge Elimination 

System (NPDES) permit managed by each state’s NPDES program. The monitoring methodology may 

vary from state to state. 
 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

RDX 110 

6. POTENTIAL FOR HUMAN EXPOSURE 

RDX can be released to water in waste discharge effluents from ammunition production, formulation, 

manufacturing, loading, assembly, and packing, and through the demilitarization and disposal of 

antiquated munitions (Hundal et al. 1997; Pennington and Brannon 2002; U.S. Army 1980a, 1984a, 

1984f). 

6.2.3 Soil 

There is no information on releases of RDX to the soil from manufacturing and processing facilities
 

because these releases are not required to be reported (EPA 1997). Releases to soil are generally confined
 

to manufacturing facilities and points of use such as firing ranges. These sites are monitored by the 

Department of the Army as well as state and federal environmental regulatory authorities under several
 

environmental programs such as CERCLA, RCRA, Emergency Planning and Community Right-to-Know
 

Act (EPCRA). Response activities include monitoring, cleanup, and land use controls as determined 

approporiate.
 

Manufacturing, packing, and use of RDX have often resulted in contamination of soil. RDX can enter
 

soil by leaching from waste lagoons and from improper disposal of contaminated sludge (U.S. Army
 

1984a). RDX can also enter the soil from spills during manufacture, transportation, and storage. 

Releases can also occur from the settling of airborne particulates from manufacturing and demilitarization
 

practices such as incineration onto soil surfaces (Hundal et al. 1997; Pennington and Brannon 2002; U.S. 

Army 1984a).
 

6.3 ENVIRONMENTAL FATE 

6.3.1 Transport and Partitioning 

RDX is expected to exist in the particulate phase in the atmosphere. The solubility of RDX in water is 

low to negligible (Budavari and O'Neil 1989). The following water solubility values have been reported: 

21.8–21.9 mg/L at 10 °C, 38.4–38.9 mg/L at 20 °C, 59.7 mg/L at 25 °C, and 66.7–67 mg/L at 30 °C (U.S. 

Army 1983b; Yalkowsky and He 2003). RDX is slightly soluble in methanol, ether, ethyl acetate, and 

glacial acetic acid (Budavari and O'Neil 1989). The Henry's law constant for RDX is approximately 

2x10-11 atm-m3

/mol (PHYSPROP 2009), indicating that volatilization from water or moist soil surfaces is 

expected to be a slow process. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 111 

6. POTENTIAL FOR HUMAN EXPOSURE 

The soil adsorption coefficients normalized to organic carbon content (Koc) for RDX range from 42 to 

167 (U.S. Army 1980c). These Koc values are indicative of moderate-to-high mobility in soil (Swann et 

al. 1983); therefore, RDX can be expected to leach into groundwater. Experimental data have shown that 

RDX is not readily bound or retained in soil as evidenced by its early breakthrough in column leachates 

(U.S. Army 1985a). A lysimeter study of the migration of RDX in soil showed that RDX was found in 

leachate from the soil columns (U.S. Navy 1982). Based on these Koc values and the experimental data, 

adsorption to sediment and particulate matter in the aquatic environment should not be significant (U.S. 

Army 1980a). Although RDX does not significantly adsorb to sediment, greater adsorption occurs with 

an increase in organic matter or clay content (U.S. Army 1980a). However, the clay content seems to be 

more important than organic matter content in influencing the amount of RDX adsorbed (U.S. Army 

1980a). In a study sponsored by the U.S. Army Medical Research and Development Command 

(USAMRDC), the adsorption rate constant of RDX in soil was found to be low (Kd of <1 mg/g). The 

adsorption constant was linearly correlated with a combination of soil properties, such organic carbon and 

clay content, pH, and cation exchange capacity (U.S. Army 1993a). Adsorption to soil was measured 

using samples from the Louisiana Army Ammunition Plant. RDX was retained on a bentonite/sand 

column with a 90% recovery after 11 pore volumes. Retardation of RDX by fine-silty soils was limited 

(Selim et al. 1995). It appears that sorption of RDX in soils is not solely the result of hydrophobic 

partitioning of RDX to the organic carbon phase of the soils. 

The logarithm of the octanol/water partition coefficient (log Kow) is a useful preliminary indicator of 

potential bioaccumulation of a compound. The log Kow for RDX was estimated to be 0.87 (PHYSPROP 

2009), indicating that RDX is not very lipid soluble and therefore has a low potential for bioaccumulation 

in aquatic species. Experimental bioconcentration factors in edible tissue for bluegill (Lepomis 

macrochirus), channel catfish (Ictalurus punctatus), and fathead minnow (Pimephales promelas) were 

1.9–6.4, 1.2–5.5, and 1.4–5.9, respectively (U.S. Army 1984a). These factors indicate that 

bioaccumulation in aquatic organisms is not an important fate process. 

Data indicate that RDX can be taken up by both terrestrial and aquatic plants (Best et al. 1999; Harvey et 

al. 1991, 1997; Pennington and Brannon 2002; Simini and Checkai 1996; U.S. Army 1990a). Studies of 

bean plants grown in 10 ppm RDX hydroponic solutions and exposed for 1 or 7 days indicated that 

uptake of RDX readily occurred. Following uptake, translocation of the compounds to the aerial tissue 

occurred, resulting in foliar concentrations of 20 and 97 ppm for the 1- and 7-day exposures, respectively. 

Metabolism of RDX to polar metabolites was observed in plants exposed for 7 days (Harvey et al. 1991). 

Additional studies of hydroponic plant-culture systems indicated that RDX (1–10 ppm) was also absorbed 
 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 112 

6. POTENTIAL FOR HUMAN EXPOSURE 

by the roots of blando brome and wheat and that plant absorption was concentration-dependent (U.S. 

Army 1990a). In a simulation of field conditions, uptake of RDX to lettuce leaves, corn stover, and 

alfalfa shoots correlated to levels of RDX (2, 18, and 90 ppb) in the irrigation water (Simini and Checkai 

1996). Submerged aquatic plants, including Elodea, pondweed, and water star-grass, grown using 

sediment and contaminated groundwater containing 1,529 μg/L from the Milan Ammunition Plant in 

Milan, Tennessee had RDX concentrations of 976, 42, and 1,496 μg/L, respectively, after 13 days. The 

emergent plant species, parrot-feather, sweet-flag, reed canary grass, and wool-grass contained RDX at 

3,196, 1,156, 704, and <20 μg/L, respectively (Best et al. 1999). When grown in soil contaminated with 

58 mg/kg RDX, lettuce was found to contain 1,200 mg/kg of RDX, while nutsedge, tomato fruit, corn 

kernels, and corn stover contained RDX at concentrations of 62, 7, 6, and 56 mg/kg, respectively 

(Pennington and Brannon 2002). For plants grown in soils containing 10 ppm RDX over a period of 

60 days, the extent of plant uptake was found to be dependent both on soil type and plant species (Cataldo 

et al. 1993). RDX was transported unchanged from soils to plants and the plant uptake increased as the 

organic matter content of soil decreased. In bush bean plants, RDX was mostly concentrated in leaves 

and seed, with less found in roots, stems, and pods. In the case of wheat and blando brome, RDX mostly 

concentrated in leaves and roots, with very little or none in seeds (Cataldo et al. 1993). After plant 

uptake, RDX in storage tissues of plants (i.e., roots and stems) mostly metabolized to unidentified polar 

metabolites or nonextractable products, while RDX remained mostly unchanged (>50%) in leaves and 

seed tissues (Cataldo et al. 1993). 

6.3.2 Transformation and Degradation 

6.3.2.1 Air 

RDX is expected to exist in the particulate form in the atmosphere, and may be subject to removal from 

air by dry deposition. No data were located on photolysis of RDX in the atmosphere. However, it is 

expected that photolysis of RDX is an important fate process in the atmosphere since RDX absorbs 

ultraviolet wavelengths between 240 and 350 nm (U.S. Army 1986e) and it undergoes rapid photolysis in 

water (U.S. Army 1980a). 

6.3.2.2 Water 

In a hydrolysis study of RDX in seawater (pH 8.1) at 25 °C, 11.6% of initial RDX hydrolyzed in 112 days 

(Hoffsommer and Rosen 1973). Other data found that RDX was stable to hydrolysis in an aqueous 

solution at a pH range normally found in natural waters (U.S. Army 1980a). Therefore, hydrolysis is not 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 113 

6. POTENTIAL FOR HUMAN EXPOSURE 

expected to significantly influence the environmental fate of RDX. Hydrolysis can occur, however, under 

alkaline conditions. RDX underwent alkaline hydrolysis (pH 10) in the presence of water over 17 days. 

The approximate half-life for this reaction was about 7 days and was accompanied by the formation of the 

ring cleavage product 4-nitro-2,4-diazabutanal, as well as NO2

-

, N2O, formaldehyde, and formic acid 

(Balakrishnan et al. 2003). Aqueous alkaline hydrolysis is thought to be a possible method of 

remediating RDX contaminated waste water (Heilmann et al. 1996). 

The primary physical mechanism that degrades RDX in aqueous solutions is photolysis (U.S. Army 

1986e). The range of ultraviolet wavelengths that produce photolytic reactions with RDX is generally 

between 240 and 350 nm (U.S. Army 1986e). RDX in waste water (23.9 mg/L) exposed to ultraviolet 

radiation decomposed with a half-life of 3.7 minutes (Burrows et al. 1984). Photolysis of an aqueous 

solution of RDX in natural sunlight is fairly rapid with an experimental half-life of 9–13 hours. 

Consequently, RDX is not expected to persist for a long period of time in clear, sunlit surface waters 

(U.S. Army 1980a). Formaldehyde and nitrosamines were identified as photoproducts. Nitrosamines 

may be of environmental importance because of their potential mutagenicity/carcinogenicity. Conversion 

to this product, however, occurs only to a limited extent since the product itself is photoreactive (U.S. 

Army 1980a). The rate of photodegradation under different environmental conditions is also dependent 

upon the nature of the water body itself. RDX was shown to degrade very slowly in dark, tea-colored 

lagoon waters at a Louisiana Army Ammunition Plant during a field study at this site (U.S. Army 1983b). 

The half-life for RDX was approximately 2,100 days in winter and 456 days in summer for a lagoon 

50 cm deep (U.S. Army 1983b). The slow rate of degradation was attributed to the rapid attenuation of 

sunlight in the top layers of the water column, thereby preventing photons of radiation from reaching 

RDX, which was reported to be well mixed throughout the water column (U.S. Army 1983b). 

The biodegradation of RDX has been studied under aerobic and anaerobic conditions. RDX did not 

undergo aerobic biodegradation using a variety of inocula and nutrients (Osmon and Klausmeier 1973). 

However, microbial degradation studies were carried out using water and sediment samples collected 

from the Holston River and the waste-water effluents from the Holston Army Ammunition Plant showed 

some degradation (U.S. Army 1980a). Only the addition of river sediments appeared to stimulate the 

aerobic biodegradation of RDX in samples of river water containing either 5.5 or 11.5 ppm of RDX. The 

half-life for the disappearance of RDX in water samples supplemented with sediment was approximately 

7 days. A lag period of 2–3 weeks was observed before a noticeable degradation of RDX occurred. The 

results showed that biodegradation of RDX leads to mineralization of the molecule (U.S. Army 1980a). 

No degradation of RDX was observed during a 90-day aerobic experiment with RDX in the lagoon water 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 114 

6. POTENTIAL FOR HUMAN EXPOSURE 

alone, with added yeast extract, or with 1% of bottom sediment (U.S. Army 1983b). Concentrations of 

RDX remained unchanged when cultures were inoculated with aerobic activated sludge and incubated 

aerobically. No RDX disappeared in uninoculated controls (McCormick et al. 1981). 

Data are available indicating that biodegradation of RDX occurs under anaerobic conditions (U.S. Army 

1984f; Crocker et al. 2006; Funk et al. 1993; Hawari et al. 2000; McCormick et al. 1981; Pennington and 

Brannon 2002; Walker and Kaplan 1992). RDX (50 or 100 μg/mL) disappeared rapidly from nutrient 

broth cultures inoculated with anaerobic sewage sludge and incubated anaerobically. Biodegradation of 

RDX was complete after 4 days (McCormick et al. 1981). The disappearance of RDX was accompanied 

by the appearance of several products identified as the mono-, di-, and trinitroso derivatives of RDX 

formed by sequential reductions of the nitro groups to nitroso groups (Crocker et al. 2006; Hawari et al. 

2000; McCormick et al. 1981; Walker and Kaplan 1992). Anaerobic biodegradation products included 

MNX; DNX; TNX; hydrazine; 1,1-dimethyl-hydrazine; 1,2-dimethyl-hydrazine; formaldehyde; and 

methanol. The nitroso intermediates are known to be hazardous. Both 1,1- and 1,2-dimethylhydrazine, as 

well as hydrazine, are known mutagens and/or carcinogens (McCormick et al. 1981), but may be found 

naturally in the environment (e.g., certain mushrooms). 

After an incubation period of 5 days, 97% of RDX was anaerobically degraded by a mixed population of 

purple photosynthetic bacteria of the genera Chromatium, Rhodospirillum, and Rhodopseudomonas, and 

possibly others (U.S. Navy 1973). Sixty percent of RDX was anaerobically degraded by Chromatium 

alone (U.S. Navy 1973). These photosynthetically active cultures, which do not release oxygen, were 

supplemented with sodium acetate and ammonium chloride. It was hypothesized that RDX was not 

actually metabolized, but rather was being reduced and modified as a result of the active electron transfer 

brought about by the anaerobic photosynthetic activity of the organisms. Data indicate that hydrogen can 

be the sole electron donor in the anaerobic degradation of RDX (Beller 2002). A proposed pathway for 

the degradation of RDX involves reductions leading to destabilization, ring cleavage, and mineralization. 

Degradation intermediates are much more susceptible to degradation under anaerobic conditions than 

under aerobic conditions (Pennington and Brannon 2002). 

RDX (13 ppm) in lagoon waste water at the Louisiana Army Ammunition Plant did not undergo 

anaerobic degradation for approximately 90 days with yeast extract repeatedly added as a nutrient (U.S. 

Army 1983b). The RDX concentration fell to 2.9 ppm at day 90 and to 1.4 ppm at day 92. The authors 

reported that the repeated addition of yeast extract acclimated RDX-utilizing organisms. The RDX­
 

 

 

 

 

 

 

 

 

 

 

RDX 115 

6. POTENTIAL FOR HUMAN EXPOSURE 

acclimated organisms then degraded 9.1 ppm of RDX 93% after 5 days of anaerobic incubation (U.S. 

Army 1983b). 

6.3.2.3 Sediment and Soil 

Three soils containing 0.5–7.2% organic matter were amended with 60 ppm (mg/kg) RDX and incubated 

for 60 days under aerobic conditions (Cataldo et al. 1993). After 60 days, >95% were extractable and 

remained unchanged as parent RDX; only <2% remained nonextractable in the soils. No significant 

transformation products of RDX were observed in the soils. RDX was not biodegraded after 56 days 

following addition to three soil samples (Grant et al. 1995). RDX, present at 30 ppm in soil cultures 

containing added potato starch as an additional carbon source, was not degraded after 24 days (Funk et al. 

1993). These results indicate that RDX may not be easily amenable to aerobic biodegradation in soils. 

Significant biotransformation, however, may occur under certain conditions. The degradation of pink 

water compounds in soil was studied (U.S. Army 1985a). Pink water is a generic term used for colored 

waters that may contain some explosive compounds, including RDX. A simulated pink water containing 

RDX (30 mg/L) was continuously applied to a series of soil columns at different flow rates, with and 

without carbon supplementation. The columns were inoculated with combined samples of microorganisms from activated sludge, anaerobic sludge digest, and garden soil. Concentrations of RDX and 

biotransformation products were monitored on a weekly basis. There appeared to be a significant 

decrease in RDX recovery in the leachate of the column with slow and fast flow with carbon supplement, 

indicating microbial activity. The mononitroso derivative, MNX, and the dinitroso derivatives of RDX 

were identified in the leachate of the column with fast flow (100 mL/day) and carbon supplement (2.0 g/L 

glucose). MNX was also identified in the leachates from the columns with slow flow (40 mL/day) with 

and without carbon supplement (U.S. Army 1985a). Since the nitroso derivatives are intermediates in the 

anaerobic biodegradation of RDX in aqueous systems (Walker and Kaplan 1992), it is likely that the 

observed products resulted from anaerobic biodegradation of RDX. The authors reported that land 

treatment or land farming of pink water should not be considered as a treatment option for pink water. 

Hazardous biotransformation intermediates and unchanged concentrations of some of the pink water 

compounds would contaminate groundwater and soil. RDX, present at 30 ppm in anaerobic soil cultures 

containing added potato starch as an additional carbon source, were totally degraded after 24 days (Funk 

et al. 1993). 
 

 

 

 

 

 

 

 

 

RDX 116 

6. POTENTIAL FOR HUMAN EXPOSURE 

Douglas et al. (2009) added 20 mL of a solution containing 2.3 mg/L RDX to aqueous slurries containing 

pristine soils and soils fractured to simulate the effects of detonation. After 92 days, the measured 

concentration was approximately 1.3–2.2 mg/L in the slurries containing the fractured soils and virtually 

unchanged in the slurries containing the pristine soil. The authors suggested that the observed decrease in 

aqueous concentration in the fractured soil could be caused by enhanced adsorption to fractured soil 

particle surfaces or enhanced transformation in the presence of the fractured soil particles or a 

combination of both. 

6.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

Reliable evaluation of the potential for human exposure to RDX depends in part on the reliability of 

supporting analytical data from environmental samples and biological specimens. Concentrations of 

RDX in unpolluted atmospheres and in pristine surface waters are often so low as to be near the limits of 

current analytical methods. In reviewing data on RDX levels monitored or estimated in the environment, 

it should also be noted that the amount of chemical identified analytically is not necessarily equivalent to 

the amount that is bioavailable. The analytical methods available for monitoring RDX in a variety of 

environmental media are detailed in Chapter 7. 

6.4.1 Air 

No data are available regarding levels of RDX in outdoor air. However, indoor air samples collected at 

Holston Army Ammunition Plant in Kingsport, Tennessee in 1974 contained RDX levels ranging from 

not detected (<0.5 mg/m3

 [4.5 ppm]) to 60 mg/m3 (546 ppm) (U.S. Army 1975). A more recent study 

found that RDX was detected in only one of eight indoor air samples taken from the incorporation area of 

Holston Army Ammunition Plant in 1986; the concentration in this sample was 0.032 mg/m3

 (0.29 ppm) 

in the particulate fraction (Bishop et al. 1988). 

6.4.2 Water 

Seawater samples taken in 1971 from a munitions dumping area 85 miles west of Cape Flattery, 

Washington, and similar samples taken 172 miles south-southeast of Charleston, South Carolina, were 

analyzed for RDX (U.S. Navy 1972). No RDX was found in any of the samples examined (detection 

limit of 5 ppt). RDX was found on-site at the Savanna Army Depot in Illinois in surface water samples at 

a maximum reported concentration of 36.9 ppm (Agency for Toxic Substances and Disease Registry 
 

 

 

 

 

RDX 117 

6. POTENTIAL FOR HUMAN EXPOSURE 

1989c). The Savanna Army Depot is on the NPL. It was an Army munitions plant engaged in munitions 

renovation, loading, demolition, and burning, which was closed in 2000. 

Onsite groundwater sampling at the Milan Army Ammunition Plant near Milan, Tennessee identified 

RDX at concentrations ranging from not detected to 11.24 ppm (detection limit not reported) (Agency for 

Toxic Substances and Disease Registry 1989b). Filtered groundwater samples from the Milan Army 

Ammunition Plant contained RDX at a concentration of 1,443 ppb. Filtration reduced RDX 

concentration in the water samples by 27% (Best et al. 1999). U.S. Army (2011) listed a range of 

detectable concentrations of 50–18,000 ppb in groundwater samples and 80–120 ppb in surface water 

samples taken from Milan Army Ammunition Plant. Groundwater samples from the Umatilla Army 

Depot Activity, a munitions storage and handling depot in Hermiston, Oregon and the Naval Submarine 

Base Bangor in Bangor, Washington contained RDX in concentrations ranging from <20 to 8,160 ppb 

(Bart et al. 1997). 

Groundwater samples from monitoring and extraction wells at the Naval Base Kitsap at Bangor NPL site 

in Kitsap County, Washington, were collected from May 1994 to August 2004. Concentrations of RDX 

in the samples from a 12-acre Bangor Ordnance Disposal site (Site A) ranged from 0.19 to 1,000 ppb in 

perched zone monitoring wells, from 0.19 to 550 ppb in shallow aquifer monitoring wells, and from 0.4 to 

660 μg/L in extraction wells (shallow aquifer). RDX concentrations at the site of a former waste water 

lagoon and overflow ditch (Site F) in groundwater from a shallow aquifer ranged from 0.95 to 3,800 ppb 

(U.S. Navy 2005). 

RDX was identified in environmental samples at Cornhusker Army Ammunition Plant and Louisiana 

Army Ammunition Plant army bases (Dacre 1994). Maximum concentrations of RDX detected in water 

at the Cornhusker Army Ammunition Plant (Nebraska) were 307 and 371 ppb from on- and off-site wells, 

respectively (Agency for Toxic Substances and Disease Registry 1989a). A plume of RDX-contaminated 

groundwater, which stretched 6.5 km, was found near the Cornhusker Army Ammunition Plant. The 

concentrations ranged from 9 to >100 ppb (Spalding and Fulton 1988). A maximum concentration of 

95 ppb in groundwater was reported by U.S. Army (2011) for the Cornhusker Army Ammunition Plant 

The Louisiana Army Ammunition Plant is a shell manufacturing and explosives load, assembly, and pack 

facility (U.S. Army 1988). From 1951 to 1980, waste waters were trucked to and discharged into a series 

of artificial leaching pits, which resulted in contamination of soil, sediments, and groundwater. Levels of 

RDX measured in groundwater at the Louisiana Army Ammunition Plant ranged from 1.3 to 14,100 ppb 

(U.S. Army 1988). U.S. Army (2011) reported a maximum groundwater concentration of 13,200 ppb at 
 

 

 

 

 

RDX 118 

6. POTENTIAL FOR HUMAN EXPOSURE 

this facility. U.S. Army (2011) also reported ranges of groundwater concentrations of 0.0087–86.4 ppb at 

Aberdeen Proving Ground and 3.3–13,000 ppb at Iowa Army Ammunition Plant. The surface water 

concentrations ranged from 0.73 to 7.6 ppb at Aberdeen Proving Ground and 4.4 to 249 ppb at Iowa 

Army Ammunition Plant. 

RDX was identified in a water sample obtained from a military training site in Germany at 21 ppb 

(Godejohann et al. 1998). Two contaminated water samples from the area of a former explosive 

production plant at Elsnig in Saxony, Germany contained RDX at concentrations of 2,380–3,800 and 

310–400 ppb, with the exact concentrations dependent upon the method of detection (Steuckart et al. 

1994). 

6.4.3 Sediment and Soil 

Ocean floor sediment samples taken in 1971 from a munitions dumping area 85 miles west of Cape 

Flattery, Washington, and similar samples taken 172 miles south-southeast of Charleston, South Carolina, 

were analyzed for RDX (U.S. Navy 1972). No RDX was found in any of the sediment samples analyzed. 

RDX was found onsite at the Savanna Army Depot in Illinois in soil samples at a maximum concentration 

of 12.3 ppm (Agency for Toxic Substances and Disease Registry 1989c). RDX was found at the 

Louisiana Army Ammunition Plant in soil and drainage sediments at concentrations ranging from <5 to 

602 mg/kg (U.S. Army 1988). RDX was identified in a composite soil sample at a concentration of 

130.5 mg/kg. The sample was composed of topsoil samples from the site of an explosives factory 

(Sunahara et al. 1999). Soils collected from the Joliet Army Ammunition Plant in Joliet, Illinois 

contained RDX in concentrations ranging from <0.1 to 3,574 mg/kg (Simini et al. 1995). RDX was 

identified in environmental samples at Cornhusker Army Ammunition Plant and Louisiana Army 

Ammunition Plant (Dacre 1994). 

RDX was identified in compost at 884 mg/kg. The compost was prepared using contaminated sediments 

from the Umatilla Army Depot Activity in Hermiston, Oregon (Gunderson et al. 1997). Griest et al. 

(1995) identified RDX in dry compost prepared using soils from Umatilla in concentrations ranging from 

>2.9 to 896 mg/kg. 

U.S. Army (2011) reported range of detectable soil concentrations of 5.45–890 mg/kg at Cornhusker 

Army Ammunition Plant, 0.587–3,300 mg/kg at Milan Army Ammunition Plant, 980 mg/kg at Aberdeen 
 

 

 

 

 

 

 

 

 

 

RDX 119 

6. POTENTIAL FOR HUMAN EXPOSURE 

Proving Ground, and 2.5–75,000 mg/kg at Iowa Army Ammunition Plant; sediment samples from Iowa 

Army Ammunition Plant contained 0.363–14,100 mg/kg RDX. 

6.4.4 Other Environmental Media 

Ocean floor fauna samples (rat tail fish and sea cucumbers) taken in 1971 from munitions dumping areas 

in the Atlantic and Pacific Oceans contained no apparent RDX residues (detection limit of 0.123 μg/kg) 

(U.S. Navy 1972). 

Agricultural crops irrigated with contaminated water have been found to contain RDX. In a laboratory 

study simulating field conditions, uptake of RDX to lettuce leaves, corn stover, and alfalfa shoots 

correlated to levels of RDX in the irrigation water (2, 18, and 90 ppb). RDX did not significantly 

concentrate in tomatoes, bush bean seeds and pods, radish roots, and soybean seeds (Simini and Checkai 

1996). Submerged aquatic plants, including Elodea, pondweed, and water star-grass, grown using 

sediment and contaminated groundwater containing 1,529 μg/L from the Milan Ammunition Plant in 

Milan, Tennessee had RDX concentrations of 976, 42, and 1,496 μg/L, respectively, after 13 days. The 

emergent plant species, parrot-feather, sweet-flag, reed canary grass, and wool-grass contained RDX at 

3,196, 1,156, 704, and <20 μg/L, respectively (Best et al. 1999). When grown in soil contaminated with 

58 mg/kg RDX, lettuce was found to contain 1,200 mg/kg of RDX, while nutsedge, tomato fruit, corn 

kernels, and corn stover contained RDX at concentrations of 62, 7, 6, and 56 mg/kg, respectively 

(Pennington and Brannon 2002). 

6.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

For the general population, exposure to RDX is most likely limited to areas around Army ammunition 

plants where RDX is manufactured, converted to munitions, or released through the demilitarization of 

antiquated munitions (Hundal et al. 1997; Pennington and Brannon 2002; U.S. Army 1980a, 1984a, 

1984f). Two surveys of public places, including taxis, trains, and airplanes, hotels, and private homes, 

rarely detected RDX (Crowson et al. 1996; Cullum et al. 2004). The most likely route of exposure for 

populations living in the vicinity of Army ammunition plants is ingestion of contaminated drinking water 

or agricultural crops that have been irrigated with contaminated water (Harvey et al. 1991, 1997; Simini 

and Checkai 1996). Dermal contact with soil containing RDX and inhalation of contaminated particulate 

matter produced during incineration of RDX-containing waste material are also possible routes of 

exposure. However, since no monitoring data were located regarding levels of RDX in outdoor air, the 

extent of exposure by this route is not known. Dermal contact with contaminated soil is also a possible 
 

 

 

 

 

 

 

 

 

 

 

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6. POTENTIAL FOR HUMAN EXPOSURE 

route of exposure. However, since no absorption data following dermal exposure to RDX were located, 

the extent of exposure by this route is also not known. 

Occupational exposure to RDX can occur when workers handle RDX in explosive plants (Hathaway and 

Buck 1977; Kaplan et al. 1965; Testud et al. 1996b). Inhalation exposure of workers to RDX has 

occurred as a result of release of dust into the workroom air, principally during dumping of dried RDX 

powder, screening and blending, and clean-up of spilled material (Kaplan et al. 1965; Testud et al. 

1996b). Exposure to RDX can also occur through dermal contact during manufacture, handling, and 

clean-up of RDX (Kaplan et al. 1965). RDX was detected at a concentration of 0.052 mg/m3

 (0.47 ppm) 

in the particulate fraction of one indoor air sample taken from the incorporation area of Holston Army 

Ammunition Plants in Tennessee in 1986 (Bishop et al. 1988). Based on the observed concentration, the 

potential for exposure to RDX is considered to be very low. 

According to the NOES (1981–1983), the estimated number of workers potentially exposed to RDX in 

the United States was 488 (NIOSH 1990). 

6.6 EXPOSURES OF CHILDREN 

This section focuses on exposures from conception to maturity at 18 years in humans. Differences from 

adults in susceptibility to hazardous substances are discussed in Section 3.7, Children’s Susceptibility. 

Children are not small adults. A child’s exposure may differ from an adult’s exposure in many ways. 

Children drink more fluids, eat more food, breathe more air per kilogram of body weight, and have a 

larger skin surface in proportion to their body volume. A child’s diet often differs from that of adults. 

The developing human’s source of nutrition changes with age: from placental nourishment to breast milk 

or formula to the diet of older children who eat more of certain types of foods than adults. A child’s 

behavior and lifestyle also influence exposure. Children crawl on the floor, put things in their mouths, 

sometimes eat inappropriate things (such as dirt or paint chips), and spend more time outdoors. Children 

also are closer to the ground, and they do not use the judgment of adults to avoid hazards (NRC 1993). 

Children can be exposed to RDX by inhalation, oral, or dermal contact with the chemical or by any 

combination of these routes. Children residing in areas around Army ammunition plants where RDX is 

manufactured, converted to munitions, or released through the demilitarization of antiquated munitions 

may be exposed to RDX (Hundal et al. 1997; Pennington and Brannon 2002; U.S. Army 1980a, 1984a, 
 

 

 

 

 

 

 

RDX 121 

6. POTENTIAL FOR HUMAN EXPOSURE 

1984f). The primary route of exposure is ingestion of contaminated drinking water. Inhalation exposure 

may result from breathing contaminated particulate matter produced during incineration of 

RDX-containing waste material. Dermal contact with contaminated soil is also a possible route of 

exposure. Children playing in contaminated water or soil may also be exposed via ingestion. 

6.7 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

Exposure of workers can occur via the inhalation, oral, or dermal routes, or by any combination of these 

routes. Workers involved in the production and use of RDX at Army ammunition plants constitute a 

group at risk because of the potential for occupational exposure. Persons living near Army ammunition 

plants or hazardous waste sites may have a higher risk of exposure to RDX resulting from inhalation of 

dusts or fumes, ingestion of contaminated drinking water, or contact with contaminated soil (Hundal et al. 

1997; Pennington and Brannon 2002; Testud et al. 1996b). Military personnel may also be exposed to 

high levels from the use of explosives that contain RDX. Individuals employed in demilitarization of 

nuclear, biological, and chemical weapons as per international treaty agreements may be exposed to high 

levels of RDX, as disassembly of these missiles involves disassembly of RDX-containing bursters and 

detonators. 

6.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of RDX is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to ensure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of RDX. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 122 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.1 Identification of Data Needs 

Physical and Chemical Properties. The physical and chemical properties of RDX are sufficiently 

characterized to permit estimation of its environmental fate (Akhavan 2004; Budavari and O'Neil 1989; 

McKone and Layton 1986; U.S. Army 1986e, 1987a). 

Production, Import/Export, Use, Release, and Disposal. According to the Emergency 

Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required 

to submit substance release and off-site transfer information to the EPA. The TRI, which contains this 

information for 2006, became available in February of 2008. This database is updated yearly and should 

provide a list of industrial production facilities and emissions. 

RDX is not produced commercially in the United States. Production in the United States is limited to 

Holston Army Ammunition Plants in Kingsport, Tennessee (SRI 2009),. Current import/export data for 

RDX are not available. RDX is primarily used as a high explosive (Boileau et al. 2009; HSDB 2009; 

Lewis 2007; Budavari and O'Neil 1989; Turley and Brewster 1987). RDX is primarily found in water, 

groundwater, and soil around Army ammunition plants (Agency for Toxic Substances and Disease 

Registry 1989a, 1989b, 1989c; Bart et al. 1997; Bishop et al. 1988; Dacre 1994; Simini et al. 1995; 

Spalding and Fulton 1988; U.S. Army 1988). Data on the most commonly used disposal methods are 

sufficient (Hoffsommer and Rosen 1972; U.S. Army 1986a, 1986c); however, additional data on the 

amounts of RDX being disposed of and on alternative disposal methods would be useful. RDX wastes 

produced in manufacturing and processing are classified as hazardous wastes and are subject to EPA 

regulations (EPA 1990a). 

Environmental Fate. RDX released to the environment partitions into air, water, and soil (Eisenreich 

et al. 1981; Lyman et al. 1982; U.S. Army 1980a, 1983b, 1987a). RDX is transported in soil, surface 

water, and groundwater (Swann et al. 1983; U.S. Army 1980c, 1983b, 1985a, 1986e, 1987a). 

Volatilization is expected to be a slow transport process (Lyman et al. 1982). RDX is expected to exist as 

a particulate in the atmosphere. No data were located in the literature regarding atmospheric transport of 

RDX. Experimental data are needed regarding photolysis of RDX in the atmosphere. Photolysis is the 

primary mechanism of RDX degradation in water (half-life of 9–13 hours) (U.S. Army 1980a, 1986e). 

Biodegradation of RDX occurs in water and soil, principally under anaerobic conditions (Funk et al. 

1993; McCormick et al. 1981; Osmon and Klausmeier 1973; Pennington and Brannon 2002; U.S. Army 

1984f, 1985a). Biodegradation half-life data for RDX and its breakdown products in water and soil are 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 123 

6. POTENTIAL FOR HUMAN EXPOSURE 

needed. This information will be helpful in better identifying the most important pathways of human 

exposure to RDX. 

Bioavailability from Environmental Media. Absorption data regarding dermal exposure in 

humans are not available. Very limited data indicate that RDX is absorbed following inhalation exposure 

(Kaplan et al. 1965; Testud et al. 1996b). RDX is absorbed through the gastrointestinal system following 

ingestion of the compound (Hollander and Colbach 1969; Ketel and Hughes 1972; Merrill 1968; Stone et 

al. 1969). The oral and dermal routes of exposure may be of concern to humans because of the potential 

for RDX to contaminate drinking water and soil. More information regarding all absorption routes, 

particularly on the absorption of RDX following ingestion of contaminated drinking water and soil or 

plants grown in contaminated environments, is needed to better characterize the bioavailability of RDX. 

Food Chain Bioaccumulation. Based on a low log Kow and low experimental BCF values of 1.2– 

5.9, RDX has a low bioconcentration potential in aquatic organisms (PHYSPROP 2009; U.S. Army 

1984a). No data were located regarding bioconcentration potential in animals. Data are needed regarding 

bioconcentration/biomagnification potential in terrestrial food chains. 

Exposure Levels in Environmental Media. Reliable monitoring data for the levels of RDX in 

contaminated media at hazardous waste sites are needed so that the information obtained on levels of 

RDX in the environment can be used in combination with data on potential pathways of exposure and the 

known body burden of RDX to assess the potential risk of adverse health effects in populations living in 

the vicinity of hazardous waste sites. 

RDX has been detected in surface water, groundwater, and soil at Army ammunition plants and current 

and former military installations (Agency for Toxic Substances and Disease Registry 1989a, 1989b, 

1989c; Bart et al. 1997; Simini et al. 1995; Spalding and Fulton 1988). Data are needed regarding levels 

of RDX in ambient air and occupational air. No data were located regarding human intake estimates for 

each media. Reliable monitoring data are needed for levels of RDX in contaminated media at hazardous 

waste sites. The information on RDX levels in the environment and the resulting body burden of RDX 

can be used to assess the potential risk of adverse health effects in populations living in the vicinity of 

hazardous waste sites. 

Exposure Levels in Humans. RDX has been detected in surface water, groundwater, and soil at 

Army ammunition plants (Agency for Toxic Substances and Disease Registry 1989a, 1989b, 1989c; Bart 
 

 

 

 

 

 

 

 

RDX 124 

6. POTENTIAL FOR HUMAN EXPOSURE 

et al. 1997; Simini et al. 1995; Spalding and Fulton 1988). Data are needed regarding levels of RDX in 

ambient air and occupational air. No data were located regarding human intake estimates for each media. 

Reliable monitoring data are needed for levels of RDX in contaminated media at hazardous waste sites. 

The information on RDX levels in the environment and the resulting body burden of RDX can be used to 

assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste 

sites. 

This information is necessary for assessing the need to conduct health studies on these populations. 

Exposures of Children. RDX has been detected in surface water, groundwater, and soil at Army 

ammunition plants (Agency for Toxic Substances and Disease Registry 1989a, 1989b, 1989c; Bart et al. 

1997; Simini et al. 1995; Spalding and Fulton 1988). Data are needed regarding levels of RDX in 

ambient air. No data were located regarding human intake estimates for each media. Reliable monitoring 

data are needed for levels of RDX in contaminated media at hazardous waste sites as well as potential 

uptake by children through ingestion of drinking water and contaminated crops, and accidental ingestion 

of contaminated soils. Dermal contact is also a concern for children playing in or near contaminated 

areas. The information on RDX levels in the environment and the resulting body burden of RDX can be 

used to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous 

waste sites. 

Child health data needs relating to susceptibility are discussed in Section 3.12.2, Identification of Data 

Needs: Children’s Susceptibility. 

Exposure Registries. No exposure registries for RDX were located. This substance is not currently 

one of the compounds for which a sub-registry has been established in the National Exposure Registry. 

The substance will be considered in the future when chemical selection is made for sub-registries to be 

established. The information that is amassed in the National Exposure Registry facilitates the 

epidemiological research needed to assess adverse health outcomes that may be related to exposure to this 

substance. 
 

 

 

RDX 125 

6. POTENTIAL FOR HUMAN EXPOSURE 

6.8.2 Ongoing Studies 

The Federal Research in Progress (FEDRIP 2009) database provides additional information obtainable 

from a few ongoing studies that may fill in some of the data needs identified in Section 6.8.1. These 

studies are summarized in Table 6-1. 
 

	 

	 

	 

	 

RDX	 126 

6. POTENTIAL FOR HUMAN EXPOSURE 

Table 6-1. Ongoing Studies on RDX 

Investigator Affiliation Research description	 Sponsor 

Chu, K	 Texas Molecular probing and identification of active NSF 

Engineering RDX-utilizing microorganisms 

Experiment 

Station 

Schnoor, JL University of Iowa	 Involvement of an endosymbiotic NSF 

Methylobacterium sp. in the biodegradation of 

explosive RDX and HMX inside poplar tree 

(Populus deltoids x Populus nigra) 

NSF = National Science Foundation 

Source: FEDRIP 2009 
 

 

 

 

 

 

 

 

 

 

 

 

 

 


 

RDX 127 

7. ANALYTICAL METHODS
 

The purpose of this chapter is to describe the analytical methods that are available for detecting, 

measuring, and/or monitoring RDX, its metabolites, and other biomarkers of exposure and effect to RDX. 

The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify 

well-established methods that are used as the standard methods of analysis. Many of the analytical 

methods used for environmental samples are the methods approved by federal agencies and organizations 

such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods 

presented in this chapter are those that are approved by groups such as the Association of Official 

Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, 

analytical methods are included that modify previously used methods to obtain lower detection limits 

and/or to improve accuracy (or trueness) and precision. 

The most common procedures for the analytical separation of RDX in biological and environmental 

materials are high-performance liquid chromatography (HPLC) and gas chromatography (GC). These 

methods have been paired with several types of detectors, including thermal energy analyzer (TEA), 

electrochemical detector (ED), electron capture detector (ECD), and ultraviolet (UV). The TEA is very 

selective for nitroso compounds and when paired with either HPLC or GC, gives excellent selectivity, 

recovery, and precision and high sensitivity (Fine et al. 1984; Lafleur and Morriseau 1980). The limited 

reports of analysis of materials using HPLC and ED indicate detection limits in the low ppb range and 

good reliability (Krull et al. 1984; Lloyd 1983). GC coupled with ECD appears to have good sensitivity 

(low ppb), accuracy, and precision (Bishop et al. 1981, 1988). UV detection has also been used with 

HPLC separation, but few data are available for comparison with other methods (Burrows and 

Brueggemann 1985; Strobel and Tontarski 1983). The data suggest that this method has very good 

accuracy and precision; however, the selectivity may not be as good as that obtained with other detectors. 

Methods based on mass spectrometry (MS) with sensitivity in the sub-ppb range have been described, but 

specific information on their reliability is limited (St. John et al. 1975; Tanner et al. 1983). MS is 

generally accepted to be highly selective. Sample preparation for RDX analytical methods is relatively 

simple, consisting of collection of the sample from air, water, soil, tissue, fluid, residue, or waste followed 

by homogenization if necessary, one or two extraction/clean-up steps, and concentration of the sample. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 128 

7. ANALYTICAL METHODS 

7.1 BIOLOGICAL MATERIALS 

Analytical methods specifically used for the determination of RDX in biological fluids and tissues are 

limited. Methods were located that discussed the analysis of RDX in blood, tissues, urine, and hand 

swabs. The separation methods employed included high-performance liquid chromatography (HPLC) or 

gas chromatography (GC). These were combined with detection by thermal energy analyzer (TEA), 

ultraviolet (UV), electrochemical detector (ED), or electron capture detector (ECD). Both HPLC and 

high-resolution gas chromatography (HRGC) can rapidly separate RDX from other explosives, but HPLC 

has the advantage of being run at ambient temperature, which helps prevent breakdown of the analyte. 

Pertinent data on these methods are presented in Table 7-1. 

Detection of RDX in human and animal plasma as well as human urine and cerebrospinal fluid has been 

accomplished by HPLC/TEA and HPLC/UV (U.S. Army 1981a; Fine et al. 1984; Turley and Brewster 

1987). While both methods provide relatively rapid sample turn-around times, HPLC/TEA is the most 

sensitive and selective of the two, and requires little sample preparation (Fine et al. 1984). The older 

HPLC/UV method (U.S. Army 1981a) had the problem of coelution of a plasma component with the 

RDX peak. This was eradicated by clean-up on a C18 bonded-phase extraction column (Turley and 

Brewster 1987; Woody et al. 1986), but the sensitivity of HPLC/UV was still several orders of magnitude 

less (limit of detection in low ppb) than that of HPLC/TEA (limit of detection in low ppt). Reported 

recoveries ranged from 87.7 to 101% (Turley and Brewster 1987; U.S. Army 1981a; Woody et al. 1986). 

Precision was comparable and ranged from 0.65 to 10% coefficient of variation (CV). 

A method of analyzing feces for RDX was located (Woody et al. 1986). This method used HPLC/UV 

and required extraction of the sample with acetonitrile and sonication. The limit of detection was not 

reported, although based on the data presented, it was assumed to be in the low ppb range. 

One method was located for analysis of tissue samples. The method used HPLC/UV to analyze bovine 

kidney, muscle/fat, and liver samples for RDX, but it could be used to analyze human tissues (U.S. Army 

1981a). Optimal sample preparation methods varied slightly for the different tissues, as did detection 

limits and precision. In general, the detection limit was in the low ppb and recovery was high (in the 

range of 87.7–102.9). Precision ranged from 7 to 16% CV. The primary issue with analysis of tissue 

using this method is the variation in selectivity. Minor differences in sample extraction and 

contamination from unknown sources can create interferences that drastically affect interpretation of 

results and may also adversely affect the sensitivity. 
 

 

 

RDX 129 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining RDX in Biological Materials 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Plasma Extract with methylene 

chloride and pentane; filter; 

HPLC/TEA 100 ng/L No data Fine et al. 

1984 

concentrate 

Plasma Add NaCl/acetic acid solution HPLC/UV 

to sample; extract with 

toluene; add water; evaporate 

organic phase; combine 

aqueous phase with 

acetonitrile-containing internal 

standard; filter 

146 μg/L 87.7 (spike 

levels 0– 

2,000 ng/g; 

SD±19– 

188 ng; 

CV 7–19) 

U.S. Army 

1981a 

Serum and urine Mix sample with internal 

standard; clean up on 

C18-bonded-phase extraction 

column, eluting with 

methanol; concentrate 

HPLC/UV 100 μg/L 90±2.0B101±

1.1 (1– 

10 mg/L in 

serum); 

98±1.6– 

Turley and 

Brewster 

1987 

101±1.3 (1– 

10 mg/L in 

urine) 

Kidney Add NaCl/acetic acid solution HPLC/UV 

to sample; extract with 

toluene; add water; evaporate 

organic phase; combine 

aqueous phase with 

acetonitrile-containing internal 

standard; filter 

95 ng/g 99.5 (spike 

levels 0– 

2,000 ng/g; 

SD±12–58; 

CV 2–11) 

U.S. Army 

1981a 

Muscle/fat Homogenize sample; extract HPLC/UV 

with acetonitrile; concentrate; 

add internal standard and 

purified water; filter 

62 ng/g 102.9 (spike 

levels 0– 

2,000 ng/g; 

SD±2.2–86; 

CV 3.9–14) 

U.S. Army 

1981a 

Liver Homogenize sample; add HPLC/UV 

NaCl/acetic acid solution; 

evaporate; redissolve in 

acetonitrile-containing internal 

standard; filter 

150 ng/g 87.7 (spike 

levels 0– 

1,000 ng/g; 

SD±18–69; 

CV 7–22) 

U.S. Army 

1981a 

Hand swabs Wipe hand with swab soaked HPLC/TEA; 

in acetone; squeeze out HRGC/TEA 

acetone and concentrate 

10 pg/inj No data Fine et al. 

1984 
 

 

 

 

 

 

 

RDX 130 

7. ANALYTICAL METHODS 

Table 7-1. Analytical Methods for Determining RDX in Biological Materials 

Sample matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Hand swabs Wipe hand with swab soaked 

in ether; extract with ether; 

centrifuge to remove debris; 

decant supernatant and 

evaporate; redissolve in 

pentane; clean up on 

Amberlite XAD-7 beads, 

GC/ECD 

TLC 

50 ng/ 

swab 

(1.7 ng/inj) 

20 ng/ 

swab 

47 (at 

200 ng/swab) 

No data 

Douse 1982 

eluting with ethyl acetate; 

evaporate; redissolve in 

pentane and repeat Amberlite 

XAD-7 clean-up 

Hand swabs, 

standards 

Wipe hand with dry swab; 

extract with methanol/ 

potassium phosphate; directly 

inject standards 

HPLC/PMDE 8 pg/inj 

(standards) 

No data Lloyd 1983 

CV = coefficient of variation; ECD = electron capture detection; GC = gas chromatography; HPLC = highperformance liquid chromatography; HRGC = high-resolution gas chromatography; inj = injection; PMDE = pendant 

mercury drop electrode; TEA = thermal energy analyzer; TLC = thin layer chromatography; UV = ultraviolet 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 131 

7. ANALYTICAL METHODS 

The only other methods for biological matrices located were for analysis of hand swabs. These are of 

primary importance in forensics, but they could also be used to determine if dermal exposure of workers 

has occurred. Methods that have been used for the determination of trace amounts of RDX on hands 

include HPLC with TEA or electrochemical detection and HRGC with TEA or ECD (Douse 1982; Fine et 

al. 1984; Lloyd 1983). Thin-layer chromatography has also been tested, but because of the large amounts 

of sample that are required for the analysis, it is useful only as a screening test for high concentration 

samples (Douse 1982). Separation of the sample by HPLC and HRGC are comparable, but reported 

recovery for HRGC is low (Douse 1982). This is likely because of decomposition of the sample, but the 

data are not available to adequately compare the recovery of the two methods. The nature of the detector 

seems to be the most important factor in determining which of the reported methods is most useful for the 

analysis of RDX in hand-swab extracts. ECD appears to be less sensitive (ng amounts) than either 

electrochemical detection using the pendant mercury drop electrode (PMDE) or TEA (pg amounts). In 

addition, in the method reported, clean-up was required to prevent matrix interference (Douse 1982). For 

both the PMDE and TEA methods, clean-up of the sample was not required, and both methods were 

rapid, selective, and of high precision (Fine et al. 1984; Lloyd 1983). 

7.2 ENVIRONMENTAL SAMPLES 

A large variety of methods have been described for the detection of RDX in environmental samples. 

These primarily include HRGC combined with ECD, TEA, mass spectrometry (MS), or flame ionization 

detection (FID); HPLC combined with UV, TEA, MS, photoconductivity (PD), or electrochemical 

detection; automated multiple development high performance thin-layer chromatography (HPTLCAMD); liquid chromatography (LC) with thermospray (TSP) and MS; and several stand-alone MS 

techniques. Other methods have also been proposed, including fluorescent quenching; supercritical fluid 

chromatography (SFC) with UV. Table 7-2 is a summary of several representative methods for 

determining RDX in various environmental media. 

Several methods for determining RDX in air have been investigated. Based on the limited data available, 

the two most common methods are GC/ECD and MS. The data reported are not sufficient to make 

comparisons of sensitivity and reliability between the methods. GC/ECD, however, appears to have good 

sensitivity (low ppb), accuracy, and precision (Bishop et al. 1981, 1988). An alternate method based on 

spectrophotometry also provided similar results for accuracy and precision (±12.4% CV) and had a 

detection limit of the same order of magnitude as that reported using GC/ECD (Eminger and Vejrostova 
 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 


 


 


 


 


 


 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 


 


 


 


 


 


 

	 

	 

	 

	 

RDX	 132 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining RDX in Environmental Samples 

Sample 

Sample Analytical detection Percent 

matrix	 Preparation method method limit recovery Reference 

Air	 Collect sample on 

Tenax-plus-filter tubes; 

desorb with acetonitrile 

Air	 Collect sample on 

Tenax-GC; desorb with 

acetonitrile 

Air	 Collect sample on 

glass-fiber filter; extract 

with ethyl acetate 

Air	 Collect sample in 

sampling tube of glassmicrofibers and silica 

gel; transfer to H2SO4 

solution and react with 

dihydroxynapthalenedisulfonic acid and 

water; dilute with water 

Air	 Incorporate sample into 

bulb containing 

isotopically-labeled 

RDX; extract with 

benzene; transfer to 

capillary tube and 

evaporate 

Air	 Inject sample directly 

into instrument 

Waste water	 Add internal standard 

effluents	 to sample; elute from 

reverse-phase column 

with methanol/water 

Groundwater,	 Dilute sample with 

waste water	 methanol/acetonitrile; 

effluents	 filter; elute from 

reverse-phase column 

with water/acetonitrile/ 

methanol 

HRGC/ECD 17 μg/m3 

HRGC/ECD	 No data 

GC/FID	 0.5 mg/m3 

Spectro- 40 μg/m3 

photometry 

IDMS	 Sub-ppb 

APCI/MS/MS Sub-ppb 

HPLC/UV 0.2 mg/L 

HPLC/UV	 22 μg/L 

No data Bishop et al. 1988
 

93–102; 98±4.4 Bishop et al. 1981
 

average (6–
 

120 μg test level)
 

No data (precision U.S. Army 1975
 

±15%)
 

95.7–97.3	 Eminger and 

Vefrostova 1984 

No data	 St. John et al. 

1975 

No data	 Tanner et al. 1983 

100–102 U.S. Army 1983c 

(measured at 

0.67 mg/L; RSD 

0.36–9.48% 

measured at 

0.27–2.66 ppm) 

101	 Jenkins et al. 

1986; U.S. Army 

1985c 
 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 


 


 


 


 


 


 


 


 

	 
 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 


 


 


 


 


 


 


 


 

	 
 

	 

	 

RDX	 133 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining RDX in Environmental Samples 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Groundwater	 Collect sample on 

Hayesep R solid 

sorbent cartridge; elute 

with acetone; 

concentrate; add 

internal standards; 

dilute with methanol/ 

water 

Surface water, Collect sample on 

well water Porapak resin; rinse 

sorbent with distilled 

water and elute with 

acetone; concentrate; 

add ethanol; 

concentrate; add 

methanol/water 

Water Collect sample on 

XAD-4 resin; elute with 

ethyl acetate; 

concentrate 

Water Liquid/liquid extraction 

using dichloromethane 

Groundwater, Extract sample with 

drinking water isoamyl acetate 

Sea water	 Add internal standard 

to sample; extract with 

benzene; evaporate; 

redissolve in benzene 

Water	 Evaporate sample; 

redissolve in acetone; 

filter; concentrate 

Water	 Inject sample directly 

into instrument 

Groundwater	 Add sample to cyclohexanone/ 

pyrenebutyric acid/ 

cellulose triacetate/ 

isodecyl diphenylphosphate membrane 

in cuvette 

HPLC/UV/ 5B7.5 μg/L 

UV/PD 

HPLC/ED	 ≈1 μg/L 

HRGC/ECD	 <0.1 μg/L 

HPTLC-AMD	 10 ng 

HRGC/ECD	 0.3 μg/L 

GC/ECD	 5 ng/L 

HRGC/ECD	 60 ng/L 

MS (CI)	 40 mg/L 

Fluorescense ≈10 mg/L 

quenching 

104–121	 U.S. Army 1989a 

57–63	 Maskarinec et al. 

1984 

97±5 (spike level Richard and Junk
 

4 μg/L) 1986
 

No data (RSD Steuckart et al.
 

1.6–5.9% for 20– 1994
 

130 ng in solution)
 

56–84 (spike level Hable et al. 1991
 

0.15–3.0 μg/L; 

RSD 9.3–19)
 

70±10 (at 103– Hoffsommer and 

1,400 ng/L) Rosen 1972
 

85	 Haas et al. 1990
 

No data	 Yinon and 

Laschever 1982 

No data	 Jian and Seitz 

1990 
 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

		

		

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

		

		

	 

	 

	 

	 

RDX	 134 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining RDX in Environmental Samples 

Sample 

Sample Analytical detection Percent 

matrix	 Preparation method method limit recovery Reference 

Soil	 Air-dry, grind, and 

sieve sample; extract 

with acetonitrile in 

ultrasonic bath; add 

CaCl2; filter; elute from 

reverse-phase column 

with water/methanol 

Soil	 Adjust sample moisture 

to 20B30%; 

homogenize and sieve; 

extract with acetonitrile 

and sonication; 

centrifuge and filter; 

elute from reversephase column with 

methanol/water 

Soil	 Air-dry sample; extract 

with acetonitrile; filter; 

evaporate; redissolve 

in acetonitrile; elute 

from reverse-phase 

column with 

acetonitrile/water 

Soil	 Homogenize sample; 

extract with acetone; 

filter 

Soil	 Homogenize sample; 

extract with acetone; 

evaporate; react with 

diphenylamine/H2SO4 

Soil	 Grind sample; extract 

with acetone in ultrasonic bath, centrifuge, 

add toluene, and dry; 

remove humic 

substances with 

calcium chloride or 

elution with ethyl 

acetate/petroleum 

ether over biobeads 

Soil	 Extract of soil sample 

and enzyme conjugate 

reagent added to 

immobilized RDX 

antibody; D TECHTM 

RDX test kit required 

HPLC/UV 0.74 μg/g		 84–112 

(multilaboratory 

determination) 

HPLC/UV 0.6 μg/g		 103.7 (spike level 

0.5–200 μg/g; 

CV 0.098) 

HPLC/UV	 0.005 μg/g No data 

HRGC/ECD	 75 ng/g 95 

Spectro- 5 mg/L No data 

photometry 

HPTLC-AMD 10 ng	 No data 

(RSD 1.6–5.9% 

for 20–130 ng in 

solution) 

Immunoassay 5 μg/g	 53–114 (spike 

level 0.53– 

6.82 mg/g; 

SD 0.12–1.21; 

CV 5–46%) 

Bauer et al. 1990; 

Jenkins and Grant 

1987; Jenkins et 

al. 1989; U.S. 

Army 1987b 

(interim AOAC 

method) 

Bongiovanni et al. 

1984 

Lyter 1983 

Haas et al. 1990 

Haas et al. 1990 

Steuckart et al. 

1994 

EPA 1996 
 

 

RDX 135 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining RDX in Environmental Samples 

Sample 

Sample Analytical detection Percent 

matrix Preparation method method limit recovery Reference 

Soil 

Agricultural 

crops (tomato) 

Agricultural 

crops 

(soybean) 

Agricultural 

crops (corn) 

Agricultural 

crops (bush 

bean) 

Agricultural 

crops (radish) 

Agricultural 

crops (alfalfa) 

Agricultural 

crops (lettuce) 

Agricultural 

crops (hot 

pepper) 

Agricultural 

crops (carrot) 

Agricultural 

crops (green 

pepper) 

Soil samples extracted 

with acetone; extract 

passed through ion 

exchange resin; extract 

acidified and mixed 

with zinc dust, color 

developed using a 

NitriVer 3 powder pillow 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Acid hydrolysis; extract 

with diethyl ether 

Colorimetric 

screening 

using spectrophotometry 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

HPLC 

1 μg/g 

5 ng/g 

(laboratory 

-grown); 

17 ng/g 

(fieldgrown) 

50 ng/g 

(laboratory 

-grown) 

51 ng/g 

(laboratory 

-grown, 

stover); 

13 ng/g 

(fieldgrown, 

kernel) 

8 ng/g 

(laboratory 

-grown) 

3.2 ng/g 

(laboratory 

-grown) 

15 ng/g 

(laboratory 

-grown) 

7 ng/g 

(laboratory 

-grown) 

28 ng/g 

(fieldgrown) 

39 ng/g 

(fieldgrown) 

20 ng/g 

(fieldgrown) 

60–140 

90±4 (laboratorygrown; spike level 

5 μg/g dry mass) 

70±3 (spike level 

5 μg/g dry mass) 

75±18 (laboratorygrown; spike level 

5 μg/g dry mass) 

68±11 (spike level 

5 μg/g dry mass) 

103±38 (spike 

level 5 μg/g dry 

mass) 

76±3 (spike level 

5 μg/g dry mass) 

71±9 (spike level 

5 μg/g dry mass) 

No data 

No data 

No data 

EPA 2007 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 

Harvey et al. 1997 
 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

RDX 136 

7. ANALYTICAL METHODS 

Table 7-2. Analytical Methods for Determining RDX in Environmental Samples 

Sample 

matrix Preparation method 

Analytical 

method 

Sample 

detection 

limit 

Percent 

recovery Reference 

Agricultural Acid hydrolysis; extract HPLC 

crops (grapes) with diethyl ether 

18 ng/g 

(fieldgrown) 

No data Harvey et al. 1997 

Explosive 

preparations 

Elute from HPLC 

column with isooctane/ 

ethanol 

HPLC/TEA No data 98–102 Lafleur and 

Morriseau 1980 

Explosives, 

explosion 

debris 

Dissolve sample in 

acetone; dilute in 

methanol 

HPLC/TEA; 

HRGC/TEA 

Low pg No data Fine et al. 1984 

Explosives Extract sample with 

acetone; elute from 

HPLC column with 

HPLC/EC 

(PMDE) 

8 pg/g No data (CV 0.8% Lloyd 1983 

of 1 ng replicates) 

methanol/potassium 

phosphate 

Explosion 

debris 

Extract sample in 

acetone; clean up on 

cyclohexyl column; 

eluting with methylene 

chloride/hexane; clean 

up on cyanopropyl 

column; elute with 

acetonitrile/water 

HPLC/UV No data 99 Strobel and 

Tontarski 1983 

Munitions 

products 

Dissolve sample in 

acetonitrile; add water; 

elute from reverseHPLC/UV No data No data Burrows and 

Brueggemann 

1985 

phase column with 

methanol/water 

Explosives Extract with acetone; HPLC/MS (CI) ≈1 ng 

evaporate; redissolve 

in dichloroethane; elute 

from HPLC column with 

No data Vouros et al. 1977 

dichloroethane/hexane 

Explosives, 

explosive 

residues 

Dissolve in acetone or 

methanol; elute from 

HPLC column with 

HPLC/TSP/ 

MS 

Low pg No data Berberich et al. 

1988 

methanol/ammonium 

acetate 

AMD = automated multiple development; APCI = atmospheric pressure chemical ionization; AOAC = Association of
 

Official Analytical Chemists; CaCl2 = calcium chloride; CI = chemical ionization; CV = coefficient of variation;
 

EC = electrochemical detection; ECD = electron capture detection; ED = electrochemical detection; FID = flame
 

ionization detection; GC = gas chromatography; HPLC = high-performance liquid chromatography; HPTLC = high 

performance thin-layer chromatography; HRGC = high-resolution gas chromatography; H2SO4 = sulfuric acid;
 

IDMS = isotope dilution mass spectrometry; MS = mass spectrometry; PD = photoconductivity detection;
 

PMDE = pendant mercury drop electrode; RSD = relative standard deviation; SD = standard deviation;
 

TEA = thermal energy analyzer; TSP = thermospray; UV = ultraviolet detection
 
 

 

 

 

 

 

 

 

 

 

 

RDX 137 

7. ANALYTICAL METHODS 

1984). MS methods with sensitivity in the sub-ppb range have been described, but specific information 

on their reliability is limited. MS is generally accepted to be highly selective. Of the two MS methods 

described, isotope dilution MS (IDMS) (St. John et al. 1975) and MS/MS with atmospheric pressure 

chemical ionization (APCI) (Tanner et al. 1983), the latter (APCI/MS/MS) is the most rapid and simple to 

perform because the sample of air containing RDX vapors is directly injected into the instrument. The 

high sensitivity and selectivity of MS/MS allow the air sample to be injected without prior treatment or 

concentration. However, the method as presented appears to be primarily useful as a screening technique 

to determine if more rigorous quantitative analysis is required. IDMS requires some sample preparation 

in order to incorporate the known amount of labeled analyte in the sample containing the unknown 

amount of RDX. IDMS has been used to measure the vapor pressure of RDX, which is in the sub-ppb 

range. 

The primary analytical methods for determining RDX in water are HPLC/UV and GC/ECD. These 

methods have been used to determine the chemical in waste-water effluents, groundwater, well water, 

drinking water, and seawater. The critical step in the analysis of RDX by HPLC/UV is separation of the 

sample on a reverse-phase column, which provides good selectivity without risk of thermal breakdown of 

the analyte (Jenkins et al. 1986; U.S. Army 1983c, 1985c). The method is simple, quick, and 

reproducible. Sensitivity is in the low- to mid-ppb range, with good recovery and excellent precision (2– 

7.6% CV). The use of HPLC in combination with photodiode-array detection improves the reliability of 

peak identification (Emmrich et al. 1993). The HPLC-photodiode-array detection method can provide a 

detection limit of 0.09 ppb for RDX in aqueous samples concentrated 1,000-fold by liquid-liquid 

extraction or by solid phase extraction (C-18) (Levsen et al. 1993). The extraction efficiency of RDX 

from water to acetonitrile can be improved by using salting out agents (U.S. Army 1991). The sensitivity 

and selectivity of RDX detection was improved by combining a solid sorbent cartridge to concentrate 

RDX from water and HPLC-tandem ultraviolet and photoconductivity detection (HPLC/UV/PD) (U.S. 

Army 1989a). The system consisted of a UV absorbance detector set to 254 nm and a photoconductivity 

detector equipped with a zinc photoionization source. The serial use of the two detectors effectively 

differentiated RDX from other explosives and from contaminants in the solid sorbent cartridge. In 

addition, the sensitivity was improved by a factor of about 3. To prevent negative baseline drift and 

random spikes in the PD, only highly purified water must be used, and the effluent must be exhaustively 

degassed (U.S. Army 1989a). Automated multiple development high performance thin-layer 

chromatography (HPTLC-AMD) has also been used to analyze water samples. Liquid-liquid extraction 

using dichloromethane was used to prepare the samples. A detection limit of 10 ng was obtained 

(Steuckart et al. 1994). 
 

 

 

 

 

 

 

 

 

 

 

RDX 138 

7. ANALYTICAL METHODS 

For analysis by GC/ECD, water samples may be solvent-extracted (Belkin et al. 1985; Haas et al. 1990; 

Hable et al. 1991; Hoffsommer and Rosen 1972) or collected on a solid sorbent (Richard and Junk 1986). 

Solvent extraction is most commonly used, but solid sorbent collection has the advantages of being faster 

and cheaper than solvent extraction (Richard and Junk 1986). Sensitivity for the GC/ECD methods 

ranges from low to mid ppt, and the recovery and precision are acceptable. Use of the solid sorbent 

improved recovery and precision compared to solvent-extraction methods (Richard and Junk 1986). 

Substitution of ED, using a gold-mercury electrode, improved selectivity compared to ECD detection. 

Sensitivity was not as good, but it remained within an order of magnitude of that found with GC/ECD 

(Maskarinec et al. 1984). Recovery and precision were comparable. A more recent study indicated that 

GC/ECD is not useful in the determination of RDX in water samples, as RDX may undergo thermal 

degradation (Steuckart et al. 1994). 

Other methods that have been used to determine RDX in water are MS, fluorescence quenching, COD, 

and total organic carbon (TOC) (Jian and Seitz 1990; Roth and Murphy 1978; Yinon and Laschever 

1982). COD and TOC (Roth and Murphy 1978) are well-established standard methods for determining 

organic pollution in water, but they are not selective for RDX. MS with chemical ionization (CI) permits 

direct injection of the water sample into the analytical instrument, but the sensitivity is substantially less 

than with the HPLC/UV and GC/ECD methods (Yinon and Laschever 1982). Fluorescence quenching 

also lacks sensitivity, and the method is still under development. However, it does permit in situ 

measurement of samples, and further improvements in the technology may make it a desirable field 

method (Jian and Seitz 1990). Continuous flow immunosensor (CFI) has been found to produce results 

comparable to HPLC in detecting RDX in groundwater samples (Bart et al. 1997). CFI utilizes a small 

column of plastic beads containing immobilized antibodies with the explosive and a fluorescent dyelabeled explosive analog. When the explosive present in the sample displaces the dye-labeled analog in 

the column, the explosive is detected with a detection limit of approximately 20 ppb (Bart et al. 1997). 

The methods that were located for detection of RDX in soil are based primarily on HPLC/UV analysis 

(Bauer et al. 1990; Bongiovanni et al. 1984; Jenkins and Grant 1987; Jenkins et al. 1989; Lyter 1983; U.S. 

Army 1987b). All of the methods involve extraction of the sample with acetonitrile, separation using a 

reverse-phase column, and in most cases, elution with acetonitrile/water. Sensitivity for these methods is 

in the sub- to low-ppm range with good recovery (84–112%) and precision (2.3–24% CV). A variation of 

the method involves the soil sample being extracted with acetonitrile in an ultrasonic bath (Jenkins et al. 

1989; Steuckart et al. 1994). Soil samples can be ground into mortar and extracted with acetone in an 
 

 

 

 

 

 

 

 

 

RDX 139 

7. ANALYTICAL METHODS 

ultrasonic bath maintained at ambient temperature, centrifuged, added to toluene, and dried over 

anhydrous sodium sulfate. Steuckart et al. (1994) removed humic substances with either a calcium 

chloride solution or elution with ethyl acetate/petroleum ether over biobeads. The samples were analyzed 

by HPTLC-AMD with a detection limit of 10 ng (Steuckart et al. 1994). 

Other analytical methods are based on GC/ECD and spectrophotometry (Haas et al. 1990). In both of 

these methods, the samples were extracted with acetone. The detection limit for spectrophotometric 

determination of RDX in soil was in the low-ppm range, while the detection limit for GC/ECD was in the 

mid-ppb range. No information on accuracy and precision were given for the spectrophotometric method; 

however, the accuracy of GC/ECD was comparable to HPLC/UV. 

Methods are available for identification of RDX in agricultural crops. Harvey et al. (1997) utilized HPLC 

to determine RDX concentrations. The samples underwent acid hydrolysis with hydrochloric acid and 

extraction with diethyl ether prior to analysis by HPLC. The detection limits and percent recoveries for a 

variety of crops are listed in Table 7-2 (Harvey et al. 1997). Larson et al. (1999b) used an 18-hour cooled 

sonication extraction technique using acetonitrile to extract RDX from plant tissues that had been exposed 

to contaminated irritation water. The samples were then analyzed with HPLC/UV. 

Several methods have been used to detect and measure RDX in explosive materials and debris from 

explosions. The most common separation procedure is HPLC, but HRGC has also been used. These 

methods have been paired with several types of detectors, including TEA, MS, electrochemical detection, 

and UV. The TEA is very selective for nitroso compounds and when paired with either HPLC or HRGC, 

gives excellent selectivity, recovery, and precision and high sensitivity (Fine et al. 1984; Lafleur and 

Morriseau 1980). GC/MS has been used for confirmation of RDX in samples of explosive materials 

(Burrows and Brueggemann 1985), and HPLC/MS and MS/MS have been investigated as screening 

methods for explosives (McLucky et al. 1985; Vouros et al. 1977). A sophisticated method linking 

HPLC, thermospray (TSP), and MS or MS/MS (with both positive and negative chemical ionization) has 

also been proposed as an extremely sensitive (low pg range) and selective method for detecting RDX in 

explosive residues (Berberich et al. 1988; Verweij et al. 1993). However, there is no evidence that any 

MS-based method is currently used to quantitatively measure RDX in explosives or explosion debris. A 

relatively new method being investigated uses supercritical fluid extraction chromatography (SFC) to 

separate RDX from other analytes and contaminants followed by detection by UV/FID (Griest et al. 

1989). The method is slower but more selective than HPLC/UV. The precision for standard solutions 
 

 

 

 

 

 

 

 

 

 

RDX 140 

7. ANALYTICAL METHODS 

was excellent. However, more work is needed to improve the mobile phase and column packing material 

before samples in complex matrices can be analyzed. 

7.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the 

Administrator of EPA and agencies and programs of the Public Health Service) to assess whether 

adequate information on the health effects of RDX is available. Where adequate information is not 

available, ATSDR, in conjunction with NTP, is required to ensure the initiation of a program of research 

designed to determine the health effects (and techniques for developing methods to determine such health 

effects) of RDX. 

The following categories of possible data needs have been identified by a joint team of scientists from 

ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would 

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean 

that all data needs discussed in this section must be filled. In the future, the identified data needs will be 

evaluated and prioritized, and a substance-specific research agenda will be proposed. 

7.3.1 Identification of Data Needs 

Methods for Determining Biomarkers of Exposure and Effect. 

Exposure. Few methods exist for monitoring exposure to RDX. Methods have been reported for 

detection of the analyte in plasma (Fine et al. 1984; Turley and Brewster 1987; U.S. Army 1981a; Woody 

et al. 1986), urine (Turley and Brewster 1987; Woody et al. 1986), cerebrospinal fluid (Woody et al. 

1986), feces (Woody et al. 1986), and tissues (U.S. Army 1981a), as well as on hands (Douse 1982; Fine 

et al. 1984; Lloyd 1983). The available methods can detect levels in urine and plasma from exposure to 

concentrations below those that would be encountered in most manufacturing situations. In general, these 

methods are reliable and accurate; however, the development of the LC-MS methodology could be useful 

as a definitive method to validate the specificity of the HPLC methods. The data are insufficient to 

permit correlation of RDX levels in the urine or blood with exposure levels. 

Effect. There are no known sensitive biomarkers of effect for RDX. Therefore, no methods 

recommendations can be made for this chemical. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 141 

7. ANALYTICAL METHODS 

Methods for Determining Parent Compounds and Degradation Products in Environmental 

Media. Methods exist to detect and quantify RDX in air (Bishop et al. 1988; Eminger and Vejrostova 

1984; St. John et al. 1975; Tanner et al. 1983; U.S. Army 1974), water (Haas et al. 1990; Hable et al. 

1991; Jian and Seitz 1990; Maskarinec et al. 1984; Richard and Junk 1986; Steuckart et al. 1994; U.S. 

Army 1983c, 1985c, 1989a; Yinon and Laschever 1982), soil (Bongiovanni et al. 1984; Haas et al. 1990; 

Steuckart et al. 1994; U.S. Army 1987b), agricultural crops (Harvey et al. 1997; Larson et al. 1999b), 

explosive materials (Burrows and Brueggemann 1985; Fine et al. 1984; Lafleur and Morriseau 1980; 

Lloyd 1983), and debris from explosions (Fine et al. 1984; Strobel and Tontarski 1983). These methods 

are relatively sensitive and reliable and can be used to detect levels of the compound in the environment 

that cause known adverse health effects. There are some problems involving reduced sensitivity and 

selectivity with all of the commonly used methods. Several proposed improvements in current methods, 

such as combining various analytical methods to increase selectivity, sensitivity, reliability, and/or 

accuracy (Berberich et al. 1988; Krull et al. 1984; U.S. Army 1989a), and investigations of new methods 

(Griest et al. 1989; Jian and Seitz 1990) will be useful in forensics and in monitoring environmental 

contamination from manufacture and disposal of RDX. 

7.3.2 Ongoing Studies 

The information in Table 7-3 was found as a result of a search of the Federal Research in Progress 

database (FEDRIP 2009). 
 

RDX 142 

7. ANALYTICAL METHODS 

Table 7-3. Ongoing Studies on RDX 

Investigator Affiliation Research description Sponsor 

Ram, M Triton Systems, 

Inc. Auburn 

In situ near real-time detection of RDX in soil U.S. Army 

University 

Li, J University of 

Florida 

Enhanced quadrupole resonance technology 

for explosive detection 

NSF 

Indacochea, JE University of 

Illinois at Chicago 

Development of a nanostructured-based 

sensor system for reliable detection of 

improvised explosive devices 

NSF 

Scherer, JJ NovaWave 

Technologies 

Ultrasensitive, real-time explosives sensor NSF 

NSF = National Science Foundation 

Sources: DOD 2009; EPA 2008b; FEDRIP 2009 
 

 

 

 


 

RDX 143 

8. REGULATIONS, ADVISORIES, AND GUIDELINES
 

MRLs are substance specific estimates, which are intended to serve as screening levels, are used by 

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

may be of concern at hazardous waste sites. 

The international and national regulations, advisories, and guidelines regarding RDX in air, water, and 

other media are summarized in Table 8-1. 

ATSDR has derived an acute-duration oral MRL of 0.2 mg/kg/day based on a NOAEL of 8.5 mg/kg/day 

for neurotoxicity in rats administered RDX via gavage 7 days/week for 14 days (U.S. Army 2006b). 

Using a PBPK model, an internal dose metric (peak brain concentration) was simulated and a HED of 

6.4547 mg/kg/day was estimated. An uncertainty factor of 30 (3 for animal to human extrapolation with 

dosimetric adjustment and 10 for human variability) was applied to the NOAELHED. 

ATSDR has derived an intermediate-duration oral MRL of 0.1 mg/kg/day based on a BMDL10 for 

neurological effects in rats administered RDX via gavage 7 days/week for 90 days (U.S. Army 2006b). 

The BMDL10 was estimated using an internal dose metric to simulate peak brain concentration; a HED of 

the BMDL10 was estimated using a PBPK model. The BMDLHED of 4.1308 mg/kg/day was divided by an 

uncertainty factor of 30 (3 for animal to human extrapolation with dosimetric adjustments and 10 for 

human variability). 

ATSDR has derived a chronic-duration oral MRL of 0.1 mg/kg/day based on a NOAEL of 8 mg/kg/day 

for neurotoxicity in rats exposed to dietary RDX for 2 years (U.S. Army 1983a). Using a PBPK model, 

an internal dose metric (peak brain concentration) was simulated and a HED of 4.223 mg/kg/day was 

estimated. An uncertainty factor of 30 (3 for animal to human extrapolation with dosimetric adjustment 

and 10 for human variability) was applied to the NOAELHED. 

EPA (IRIS 2009) has derived an oral reference dose (RfD) of 0.003 mg/kg/day based on a NOAEL 

0.3 mg/kg/day and LOAEL of 1.5 mg/kg/day for inflammation of the prostate in rats exposed to RDX in 

the diet for 2 years (U.S. Army 1983a). An uncertainty factor of 100 (10 for extrapolation from animals 

to humans and 10 to protect against unusually susceptible individuals) was applied to the NOAEL. 
RDX 144 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to RDX 

Agency Description Information Reference 

INTERNATIONAL 

Guidelines: 

IARC Carcinogenicity classification No IARC 2009 

WHO Air quality guidelines No WHO 2000 

Drinking water quality guidelines No WHO 2006 

NATIONAL 

Regulations and 

Guidelines: 

a. Air 

ACGIH TLV (8-hour TWA)a 0.5 mg/m3 ACGIH 2008 

STEL (15-minute TWA) No 

TLV-basis (critical effect) Liver damage 

AIHA ERPG values No AIHA 2008 

EPA AEGL values No EPA 2008a 

Hazardous air pollutant No EPA 2009b 

42 USC 7412 

NIOSH REL (10-hour TWA) 

STEL (15-minute) 

1.5 mg/m3 

3.0 mg/m3 

NIOSH 2005 

IDLH Not determined 

OSHA 

Target organs 

PEL (8-hour TWA) for general industry 

Eyes, skin, and central 

nervous system 

Vacatedb OSHA 1993 

29 CFR 1910.1000, 

Final Rule 

b. Water 

EPA Drinking water standards and health 

advisories 

EPA 2006a 

1-day health advisory for a 10-kg 

child 

0.1 mg/L 

10-day health advisory for a 10-kg 

child 

0.1 mg/L 

DWEL 0.1 mg/L 

Lifetime 

10-4 Cancer risk 

0.002 mg/L 

0.03 mg/L 

National primary drinking water 

standards 

No EPA 2003 

National recommended water quality 

criteria 

No EPA 2006b 

c. Food 

FDA EAFUS Noc FDA 2008 
 

 

 

 

 

 

 

 

 

 

 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

RDX 145 

8. REGULATIONS AND ADVISORIES 

Table 8-1. Regulations and Guidelines Applicable to RDX 

Agency Description Information Reference 

NATIONAL (cont.) 

d. Other 

ACGIH Carcinogenicity classification A4d ACGIH 2008 

EPA Carcinogenicity classification Group Ce IRIS 2009 

RfC No 

RfD 3.0x10-3 mg/kg/day 

Oral slope factor 1.1 mg/kg/day-1 

Superfund, emergency planning, and 

community right-to-know 

Designated CERCLA hazardous No EPA 2009c 

substance 40 CFR 302.4 

Effective date of toxic chemical No EPA 2009d 

release reporting 40 CFR 372.65 

TSCA chemical lists and reporting EPA 2009e 

periods 40 CFR 712.30 

Effective date 09/29/2006 

Reporting date 11/28/2006 

TSCA health and safety data reporting EPA 2009a 

Effective date 09/29/2006 40 CFR 716.120 

Sunset date 11/28/2006 

NTP Carcinogenicity classification No NTP 2005 

a

Skin: refers to the potential significant contribution to the overall exposure by the cutaneous route.
 b

On January 19, 1989, OSHA published its final rule on Air Contaminants, which amended 29 CFR 1910.1000 by
 

lowering 212 of OSHA’s existing PELs for toxic substances and setting PELs for 164 toxic substances that had been 

previously unregulated. A PEL value of 1.5 mg/m3 was adopted for RDX in March 1989. However, on July 7, 1992,
 

the Eleventh Circuit Court of Appeals issued a decision in AFL-CIO vs. OSHA that vacated these revised standards.
 c

The EAFUS list of substances contains ingredients added directly to food that FDA has either approved as food 

additives or listed or affirmed as GRAS.
 d

A4: not classifiable as a human carcinogen.
 e

Group C: possible human carcinogen, based on hepatocellular adenomas and carcinomas in female B6C3F1 mice.
 

ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = acute exposure guideline levels;
 

AIHA = American Industrial Hygiene Association; CERCLA = Comprehensive Environmental Response,
 

Compensation, and Liability Act; CFR = Code of Federal Regulations; DWEL = drinking water equivalent level;
 

EAFUS = Everything Added to Food in the United States; EPA = Environmental Protection Agency;
 

ERPG = emergency response planning guidelines; FDA = Food and Drug Administration; GRAS = Generally
 

Recognized As Safe; IARC = International Agency for Research on Cancer; IDLH = immediately dangerous to life or
 

health; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
 

NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; PEL = permissible 

exposure limit; REL = recommended exposure limit; RfC = inhalation reference concentration; RfD = oral reference
 

dose; STEL = short-term expsoure limit; TLV = threshold limit values; TSCA = Toxic Substances Control Act;
 

TWA = time-weighted average; USC = United States Code; WHO = World Health Organization
 
RDX 146
 
 

8. REGULATIONS AND ADVISORIES 

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RDX 147 

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Altman PL, Dittmer DS. 1974. Biological handbooks: Biology data book. Vol. III. 2nd ed. Bethesda, 

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10. GLOSSARY
 

Absorption—The taking up of liquids by solids, or of gases by solids or liquids. 

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the 

Toxicological Profiles. 

Adsorption—The adhesion in an extremely thin layer of molecules (as of gases, solutes, or liquids) to the 

surfaces of solid bodies or liquids with which they are in contact. 

Adsorption Coefficient (Koc)—The ratio of the amount of a chemical adsorbed per unit weight of 

organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by sediment or soil (i.e., the solid phase) 

divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a 

fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or 

sediment. 

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a 

specified magnitude of changes in a specified adverse response. For example, a BMD10 would be the 

dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 

10%. The BMD is determined by modeling the dose response curve in the region of the dose response 

relationship where biologically observable data are feasible. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological 

or epidemiological data to calculate a BMD. 

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms 

at a specific time or during a discrete time period of exposure divided by the concentration in the 

surrounding water at the same time or during the same period. 

Biomarkers—Broadly defined as indicators signaling events in biologic systems or samples. They have 

been classified as markers of exposure, markers of effect, and markers of susceptibility. 

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces 

significant increases in the incidence of cancer (or tumors) between the exposed population and its 

appropriate control. 

Carcinogen—A chemical capable of inducing cancer. 

Case-Control Study—A type of epidemiological study that examines the relationship between a 

particular outcome (disease or condition) and a variety of potential causative agents (such as toxic 

chemicals). In a case-controlled study, a group of people with a specified and well-defined outcome is 

identified and compared to a similar group of people without outcome. 

Case Report—Describes a single individual with a particular disease or exposure. These may suggest 

some potential topics for scientific research, but are not actual research studies. 
 

 

 

 

 

 

 

 

 

 

RDX 168 

10. GLOSSARY 

Case Series—Describes the experience of a small number of individuals with the same disease or 

exposure. These may suggest potential topics for scientific research, but are not actual research studies. 

Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. 

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological 

Profiles. 

Cohort Study—A type of epidemiological study of a specific group or groups of people who have had a 

common insult (e.g., exposure to an agent suspected of causing disease or a common disease) and are 

followed forward from exposure to outcome. At least one exposed group is compared to one unexposed 

group. 

Cross-sectional Study—A type of epidemiological study of a group or groups of people that examines 

the relationship between exposure and outcome to a chemical or to chemicals at one point in time. 

Data Needs—Substance-specific informational needs that if met would reduce the uncertainties of human 

health assessment. 

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result 

from exposure to a chemical prior to conception (either parent), during prenatal development, or 

postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point 

in the life span of the organism. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a 

toxicant and the incidence of the adverse effects. 

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to 

a chemical; the distinguishing feature between the two terms is the stage of development during which the 

insult occurs. The terms, as used here, include malformations and variations, altered growth, and in utero 

death. 

Environmental Protection Agency (EPA) Health Advisory—An estimate of acceptable drinking water 

levels for a chemical substance based on health effects information. A health advisory is not a legally 

enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. 

Epidemiology—Refers to the investigation of factors that determine the frequency and distribution of 

disease or other health-related conditions within a defined human population during a specified period. 

Genotoxicity—A specific adverse effect on the genome of living cells that, upon the duplication of 

affected cells, can be expressed as a mutagenic, clastogenic, or carcinogenic event because of specific 

alteration of the molecular structure of the genome. 

Half-life—A measure of rate for the time required to eliminate one half of a quantity of a chemical from 

the body or environmental media. 

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a 

contaminant from which one could escape within 30 minutes without any escape-impairing symptoms or 

irreversible health effects. 
 

 

 

 

 

 

 

 

 

 

RDX 169 

10. GLOSSARY 

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from 

exposure to environmental agents such as chemicals. 

Immunological Effects—Functional changes in the immune response. 

Incidence—The ratio of individuals in a population who develop a specified condition to the total 

number of individuals in that population who could have developed that condition in a specified time 

period. 

Intermediate Exposure—Exposure to a chemical for a duration of 15–364 days, as specified in the 

Toxicological Profiles. 

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. 

In Vivo—Occurring within the living organism. 

Lethal Concentration(LO) (LCLO)—The lowest concentration of a chemical in air that has been reported 

to have caused death in humans or animals. 

Lethal Concentration(50) (LC50)—A calculated concentration of a chemical in air to which exposure for 

a specific length of time is expected to cause death in 50% of a defined experimental animal population. 

Lethal Dose(LO) (LDLo)—The lowest dose of a chemical introduced by a route other than inhalation that 

has been reported to have caused death in humans or animals. 

Lethal Dose(50) (LD50)—The dose of a chemical that has been calculated to cause death in 50% of a 

defined experimental animal population. 

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a chemical 

is expected to cause death in 50% of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest exposure level of chemical in a study, 

or group of studies, that produces statistically or biologically significant increases in frequency or severity 

of adverse effects between the exposed population and its appropriate control. 

Lymphoreticular Effects—Represent morphological effects involving lymphatic tissues such as the 

lymph nodes, spleen, and thymus. 

Malformations—Permanent structural changes that may adversely affect survival, development, or 

function. 

Minimal Risk Level (MRL)—An estimate of daily human exposure to a hazardous substance that is 

likely to be without an appreciable risk of adverse noncancer health effects over a specified route and 

duration of exposure. 

Modifying Factor (MF)—A value (greater than zero) that is applied to the derivation of a Minimal Risk 

Level (MRL) to reflect additional concerns about the database that are not covered by the uncertainty 

factors. The default value for a MF is 1. 

Morbidity—State of being diseased; morbidity rate is the incidence or prevalence of disease in a specific 

population. 
 

 

 

 

 

 

 

 

 

 

 

 

RDX 170 

10. GLOSSARY 

Mortality—Death; mortality rate is a measure of the number of deaths in a population during a specified 

interval of time. 

Mutagen—A substance that causes mutations. A mutation is a change in the DNA sequence of a cell’s 

DNA. Mutations can lead to birth defects, miscarriages, or cancer. 

Necropsy—The gross examination of the organs and tissues of a dead body to determine the cause of 

death or pathological conditions. 

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to a 

chemical. 

No-Observed-Adverse-Effect Level (NOAEL)—The dose of a chemical at which there were no 

statistically or biologically significant increases in frequency or severity of adverse effects seen between 

the exposed population and its appropriate control. Effects may be produced at this dose, but they are not 

considered to be adverse. 

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical 

in n-octanol and water, in dilute solution. 

Odds Ratio (OR)—A means of measuring the association between an exposure (such as toxic substances 

and a disease or condition) that represents the best estimate of relative risk (risk as a ratio of the incidence 

among subjects exposed to a particular risk factor divided by the incidence among subjects who were not 

exposed to the risk factor). An OR of >1 is considered to indicate greater risk of disease in the exposed 

group compared to the unexposed group. 

Organophosphate or Organophosphorus Compound—A phosphorus-containing organic compound 

and especially a pesticide that acts by inhibiting cholinesterase. 

Permissible Exposure Limit (PEL)—An Occupational Safety and Health Administration (OSHA) 

allowable exposure level in workplace air averaged over an 8-hour shift of a 40-hour workweek. 

Pesticide—General classification of chemicals specifically developed and produced for use in the control 

of agricultural and public health pests. 

Pharmacokinetics—The dynamic behavior of a material in the body, used to predict the fate 

(disposition) of an exogenous substance in an organism. Utilizing computational techniques, it provides 

the means of studying the absorption, distribution, metabolism, and excretion of chemicals by the body. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent 

chemical or metabolite in an animal system. There are two types of pharmacokinetic models: data-based 

and physiologically-based. A data-based model divides the animal system into a series of compartments, 

which, in general, do not represent real, identifiable anatomic regions of the body, whereas the 

physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically based doseresponse model that quantitatively describes the relationship between target tissue dose and toxic end 

points. These models advance the importance of physiologically based models in that they clearly 

describe the biological effect (response) produced by the system following exposure to an exogenous 

substance. 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX 171 

10. GLOSSARY 

Physiologically Based Pharmacokinetic (PBPK) Model—Comprised of a series of compartments 

representing organs or tissue groups with realistic weights and blood flows. These models require a 

variety of physiological information: tissue volumes, blood flow rates to tissues, cardiac output, alveolar 

ventilation rates, and possibly membrane permeabilities. The models also utilize biochemical 

information, such as air/blood partition coefficients, and metabolic parameters. PBPK models are also 

called biologically based tissue dosimetry models. 

Prevalence—The number of cases of a disease or condition in a population at one point in time. 

Prospective Study—A type of cohort study in which the pertinent observations are made on events 

occurring after the start of the study. A group is followed over time. 

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the 

multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the 

incremental excess cancer risk per unit of exposure (usually μg/L for water, mg/kg/day for food, and 

μg/m3 for air). 

Recommended Exposure Limit (REL)—A National Institute for Occupational Safety and Health 

(NIOSH) time-weighted average (TWA) concentration for up to a 10-hour workday during a 40-hour 

workweek. 

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of 

magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) 

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

The inhalation reference concentration is for continuous inhalation exposures and is appropriately 

expressed in units of mg/m3 or ppm. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the 

daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious 

effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-effect level 

(NOAEL, from animal and human studies) by a consistent application of uncertainty factors that reflect 

various types of data used to estimate RfDs and an additional modifying factor, which is based on a 

professional judgment of the entire database on the chemical. The RfDs are not applicable to 

nonthreshold effects such as cancer. 

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under 

the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA). Reportable 

quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation 

either under CERCLA or under Section 311 of the Clean Water Act. Quantities are measured over a 

24-hour period. 

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result 

from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related 

endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, 

fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of 

this system. 
 

 

 

 

 

 

RDX 172 

10. GLOSSARY 

Retrospective Study—A type of cohort study based on a group of persons known to have been exposed 

at some time in the past. Data are collected from routinely recorded events, up to the time the study is 

undertaken. Retrospective studies are limited to causal factors that can be ascertained from existing 

records and/or examining survivors of the cohort. 

Risk—The possibility or chance that some adverse effect will result from a given exposure to a chemical. 

Risk Factor—An aspect of personal behavior or lifestyle, an environmental exposure, or an inborn or 

inherited characteristic that is associated with an increased occurrence of disease or other health-related 

event or condition. 

Risk Ratio—The ratio of the risk among persons with specific risk factors compared to the risk among 

persons without risk factors. A risk ratio >1 indicates greater risk of disease in the exposed group 

compared to the unexposed group. 

Short-Term Exposure Limit (STEL)—The American Conference of Governmental Industrial 

Hygienists (ACGIH) maximum concentration to which workers can be exposed for up to 15 minutes 

continually. No more than four excursions are allowed per day, and there must be at least 60 minutes 

between exposure periods. The daily Threshold Limit Value-Time Weighted Average (TLV-TWA) may 

not be exceeded. 

Standardized Mortality Ratio (SMR)—A ratio of the observed number of deaths and the expected 

number of deaths in a specific standard population. 

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or 

physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited 

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen—A chemical that causes structural defects that affect the development of an organism. 

Threshold Limit Value (TLV)—An American Conference of Governmental Industrial Hygienists 

(ACGIH) concentration of a substance to which most workers can be exposed without adverse effect. 

The TLV may be expressed as a Time Weighted Average (TWA), as a Short-Term Exposure Limit 

(STEL), or as a ceiling limit (CL). 

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8-hour 

workday or 40-hour workweek. 

Toxic Dose(50) (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation, 

which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. 

Toxicokinetic—The absorption, distribution, and elimination of toxic compounds in the living organism. 
 

 

 

 

RDX 173 

10. GLOSSARY 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or 

Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to 

account for (1) the variation in sensitivity among the members of the human population, (2) the 

uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from 

data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using lowestobserved-adverse-effect level (LOAEL) data rather than no-observed-adverse-effect level (NOAEL) data. 

A default for each individual UF is 10; if complete certainty in data exists, a value of 1 can be used; 

however, a reduced UF of 3 may be used on a case-by-case basis, 3 being the approximate logarithmic 

average of 10 and 1. 

Xenobiotic—Any chemical that is foreign to the biological system. 

 

 

RDX 174
 

10. GLOSSARY 

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RDX A-1 

APPENDIX A. ATSDR MINIMAL RISK LEVELS AND WORKSHEETS 

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 

9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99– 

499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with 

the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most 

commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological 

profiles for each substance included on the priority list of hazardous substances; and assure the initiation 

of a research program to fill identified data needs associated with the substances. 

The toxicological profiles include an examination, summary, and interpretation of available toxicological 

information and epidemiologic evaluations of a hazardous substance. During the development of 

toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to 

identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a 

given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance 

that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration 

of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of 

cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are 

used by ATSDR health assessors to identify contaminants and potential health effects that may be of 

concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or 

action levels. 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor 

approach. They are below levels that might cause adverse health effects in the people most sensitive to 

such chemical-induced effects. MRLs are derived for acute (1–14 days), intermediate (15–364 days), and 

chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, 

MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method 

suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end 

point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the 

liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level 

above the MRL does not mean that adverse health effects will occur. 
RDX A-2 

APPENDIX A 

MRLs are intended only to serve as a screening tool to help public health professionals decide where to 

look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that 

are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of 

the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, 

elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR 

uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health 

principle of prevention. Although human data are preferred, MRLs often must be based on animal studies 

because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes 

that humans are more sensitive to the effects of hazardous substance than animals and that certain persons 

may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold below levels that 

have been shown to be nontoxic in laboratory animals. 

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the 

Division of Toxicology and Human Health Sciences (proposed), expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the 

public. They are subject to change as new information becomes available concomitant with updating the 

toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously 

published levels. For additional information regarding MRLs, please contact the Division of Toxicology 

and Human Health Sciences (proposed), Agency for Toxic Substances and Disease Registry, 1600 Clifton 

Road NE, Mailstop F-62, Atlanta, Georgia 30333. 
 

 

 

 

 

 

 

 

 

 

RDX A-3 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: RDX 

CAS Numbers: 121-82-4 

Date: August 2011 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [X] Acute [ ] Intermediate [ ] Chronic 

Graph Key: 22 

Species: Rat 

Minimal Risk Level: 0.2 [X] mg/kg/day [ ] ppm 

Reference: U.S. Army. 2006. Toxicology study no. 85-XC-5131-03. Subchronic oral toxicity of RDX 

in rats. Aberdeen Proving Ground, MD: U.S. Army Center for Health Promotion and Preventive 

Medicine. 

Experimental design: Groups of six male and six female Sprague-Dawley rats were administered via 

gavage 0, 2.125, 4.25, 8.5, 17.00, 25.50, 34.00, or 42.5 mg/kg/day as a suspension of RDX/1% methylcellulose/0.2% Tween 80 in distilled water 7 days/week for 14 days. Rats were monitored daily for toxic 

signs and morbidity. Body weights and feed consumption were measured on days 0, 1, 3, 7, and 14. 

Additional parameters used to assess toxicity included clinical chemistry (alkaline phosphatase, alanine 

aminotransferase, aspartate aminotransferase, blood urea nitrogen, calcium, sodium, potassium, chlorine, 

cholesterol, creatinine kinase, creatinine, glucose, lactate dehydrogenase, total bilirubin, total protein, 

triglycerides) and hematology (hemoglobin, hematocrit, erythrocytes, mean cell hemoglobin 

concentration, mean cell volume, mean cell hemoglobin, red blood cell distribution width, total and 

differential leukocytes, platelets, and mean platelet volume) values, organ weights (brain, heart, liver, 

kidneys, spleen, adrenals, thymus, epididymides, uterus, testes, ovaries), and gross necropsies. 

Effect noted in study and corresponding doses: A significant increase in early deaths was observed at 

≥25.5 mg/kg/day. Tremors and convulsions were observed in rats exposed to ≥17 mg/kg/day. In the 

males exposed to ≥17 mg/kg/day, blood stains around the mouth and nose and low arousal were also 

observed. Increased arousal, blood around the mouth and nose, barbering, and lacrimation were observed 

in females exposed to ≥17 mg/kg/day. No signs of neurological alterations were observed in rats exposed 

to ≤8.5 mg/kg/day. Significant decreases in body weight were observed in male rats exposed to 

≥17 mg/kg/day on days 1 and 7, but there were no significant alterations in male body weight at 

termination. In female rats, significant decreases in body weight gain were observed at ≥34 mg/kg/day on 

day 1 and in the 8.5 mg/kg/day group on day 14; however, the magnitude of the decreased body weight 

was less than 10% and no significant alterations were observed at higher dose levels. Significant 

decreases in food consumption were also observed during the first 7 days of exposure in males and 

females exposed to ≥8.5 mg/kg/day. Significant decreases in absolute liver weights and liver-to-brain 

weights and increases in blood cholesterol levels were observed in females exposed to 8.5 mg/kg/day; 

these effects were not observed at higher dose levels or in males. Due to the lack of dose-response 

relationships for the alterations in liver weight and blood cholesterol levels, these changes observed in the 

8.5 mg/kg/day female group were not considered biologically relevant. No significant alterations in 

hematological parameters or other clinical chemistry parameters or organ weights were observed. 

Dose and end point used for MRL derivation: The MRL is based on a NOAELHED of 6.45 mg/kg/day for 

tremors and convulsions in a 14-day study. 

[X] NOAEL [ ] LOAEL 
 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 A-4 

APPENDIX A 

PBPK modeling was used to estimate internal dose metrics for brain RDX levels and for estimating 

HEDs. Code for an RDX oral PBPK model was provided by LM Sweeney along with documentation of 

parameter values (Sweeney et al. 2012). The Sweeney et al. (2012) model is based on the rat model 

reported by Krishnan et al. (2009) with modifications made to the gastrointestinal tract parameters, to 

include two compartments (stomach and small intestine). Sweeney et al. (2012) scaled the rat model to 

the human and estimated human gastrointestinal absorption and liver metabolism parameter values based 

on optimization against serum RDX-time profiles from humans accidentally exposed to RDX. Code for 

the Sweeney et al. (2012) model was implemented in acsLX v 3.0.1.6, without modification to the human 

or rat parameter values. Performance of the implementation was verified by comparing output to plots 

shown in Figure 2-4 of Sweeney et al. (2012). 

The model was used for interspecies extrapolation of rat internal dosimetry to humans using the following 

procedure: 

1.	 The rat model was used to simulate external rat dosages used in relevant bioassays and to predict 

the corresponding internal dose metric, peak concentration of RDX in brain (CBpeak) and mean 

concentration of RDX in brain (CBmean). 

2.	 Gavage doses (mg/kg/day) were assumed to be delivered as a single bolus each day, at the 

exposure frequency (days/week) used in the bioassay. 

3.	 Rat model simulations were carried out for 14 days for acute exposures. 

4.	 Rat body weights used in the simulations were the time-weighted average (TWA) body weights 

for each dose group. 

5.	 The human model was used to predict the daily dosage (mg/kg/day) corresponding to the NOAEL 

for peak brain concentration in the rat. 

6.	 A body weight of 70 kg was assumed for humans. 

7.	 Daily doses (mg/kg/day) in humans were assumed to be delivered in 12 consecutive hourly doses, 

separated by 12-hour intervals, 7 days/week. 

8.	 Human model simulations were carried out for 14 days for acute exposures. 

The peak and mean brain concentrations for each dose are presented in Table A-1. 
 

 

 

 

 

 

 

 

 

 


 

RDX A-5 

APPENDIX A 

Table A-1. Estimated Peak and Mean Brain Concentrations in Rats Administered 

RDX Via Gavage 7 Days/Week for 14 Days
 

Dose TWA body Peak brain concentration Mean brain concentration 

(mg/kg/day) weight (kg) (mg/L) (mg/L) 

Males 

0 0.2039 0 0 

2.13 0.2044 1.602 0.6645 

4.25 0.2017 3.198 1.3232 

8.5 0.1915 6.351 2.6018 

17 0.1826 12.619 5.1232 

25.5 0.1886 19.012 7.7666 

34 0.1693a 24.979 9.9956 

42.5 0.1683a 31.198 12.4702 

Females 

0 0.1403 0 0 

2.13 0.1375 1.518 0.5835 

4.25 0.1397 3.042 1.1732 

8.5 0.131 6.033 2.2974 

17 0.1347 12.1211 4.6369 

25.5 0.1374 18.214 7.0007 

34 0.1250a 23.982 9.0492 

42.5 0.1262a 30.016 11.3470 

a

Day 1 body weight used due to high mortality (100% mortality on day 1 in 42.5 mg/kg/day males and females and 

34 mg/kg/day females and 83% mortality on day 1 in 34 mg/kg/day males) 

TWA = time-weighted average 

Source: U.S. Army 2006 

The acute-duration oral MRL was derived using the NOAEL/LOAEL approach; the lack of incidence 

data for the neurological effects precluded using a benchmark dose approach. The U.S. Army (2006) 

study identified a NOAEL of 8.5 mg/kg/day and LOAEL of 17 mg/kg/day for neurological effects. The 

PBPK model was used to predict peak brain RDX concentrations and mean brain RDX concentrations 

associated with these dose levels. In animals dosed with 8.5 mg/kg/day, the model predicted peak brain 

concentrations of 6.351 mg/L in males and 6.033 mg/L in females and mean brain concentrations of 2.602 

and 2.297 mg/L in males and females, respectively. Mechanistic data provide strong support that the 

mode of action for seizures involves binding to GABA receptors and there is a direct relationship between 

RDX levels in the brain and the onset of seizures (Gust et al. 2009; Williams et al. 2011). However, there 

are insufficient data to determine whether peak brain RDX concentration or mean brain RDX 

concentration is the most appropriate internal dose metric. As presented in Table A-2, a comparison of 

the NOAEL and LOAEL values for seizures in rats exposed for intermediate or chronic durations 

suggests that peak brain concentration may be the most appropriate internal dose metric. The mean brain 

concentrations are similar for rats exposed to 8 mg/kg/day for 90 days or 2 years; however, 

seizures/convulsions were observed at this dose level in the 90-day study, but not in the 2-year study. In 

contrast to the mean concentrations, the peak brain concentration in the 90-day study was 34% higher 
 

 

 

 

 


 


 

RDX A-6 

APPENDIX A 

than in the 2-year study; this difference in peak concentrations may explain the apparent difference in 

seizure threshold. Thus, peak brain concentration was selected as the internal dose metric for derivation 

of the acute-duration oral MRL. Since the U.S. Army (2006) study did not identify gender-specific 

differences in RDX sensitivity, the peak brain concentrations were averaged for the male and females 

rats. In the rats administered 8.5 mg/kg/day RDX, the average peak brain RDX concentration was 

predicted to be 6.192 mg/L. This peak brain concentration was used to predict a HED of 

6.455 mg/kg/day using the PBPK model. 

Table A-2. Comparison of NOAEL and LOAEL Values Using Different Dose
 

Metrics Following Intermediate- and Chronic-Duration Exposure to RDX
 

NOAELc 

Intermediate exposurea 

(U.S. Army 2006) 

Chronic exposureb 

(U.S. Army 1983a) 

Administered dose 4 mg/kg/day 8 mg/kg/day 

Peak brain concentration 2.923 mg/L 4.051 mg/L 

Mean brain concentration 

LOAELc 

1.308 mg/L 2.959 mg/L 

Administered dose 8 mg/kg/day 40 mg/kg/day 

Peak brain concentration 6.013 mg/L 18.694 mg/L 

Mean brain concentration 2.615 mg/L 14.403 mg/L 

a

RDX administered via gavage, 7 days/week for 90 days

b

RDX administered via the diet for 2 years c

Average of male and female values 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: Human case reports have 

noted convulsions and seizures in individuals ingesting RDX (Hollander and Colbach 1969; Ketel and 

Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986). Several acute 

toxicity studies have reported convulsions, seizures, or tremors in rats at doses slightly higher than the 

LOAEL of 17 mg/kg/day identified in the U.S. Army (2006) study. These LOAEL values are 

20 mg/kg/day in two gestational exposure studies (U.S. Army 1980b, 1986d) and 25 mg/kg in rats 

administered a single gavage dose (Burdette et al. 1988). In addition, decreases in motor activity and 

learning were observed in rats receiving a single gavage dose of 12.5 mg/kg/day (U.S. Army 1985b). 
 

 

RDX A-7 

APPENDIX A 

Although the potential for systemic effects has not been well investigated following acute exposure, 

intermediate-duration studies (U.S. Army 1980b, 1983a, 2006; U.S. Navy 1974b) provide support that 

neurotoxicity is the most sensitive effect of RDX. 

Agency Contacts (Chemical Managers): Henry Abadin 
 

 

 

 

 

 

RDX A-8 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: RDX 

CAS Numbers: 121-82-4 

Date: August 2011 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [X] Intermediate [ ] Chronic 

Graph Key: 50 

Species: Rat 

Minimal Risk Level: 0.1 [X] mg/kg/day [ ] ppm 

Reference: U.S. Army. 2006. Toxicology study no. 85-XC-5131-03. Subchronic oral toxicity of RDX 

in rats. Aberdeen Proving Ground, MD: U.S. Army Center for Health Promotion and Preventive 

Medicine. 

Experimental design: Groups of 10 male and 10 female F344 rats were administered via gavage 0, 4, 8, 

10, 12, or 15 mg/kg/day as a suspension of RDX/1% methylcellulose/0.2% Tween 80 in distilled water 

7 days/week for 90 days. Rats were monitored weekly for toxic signs and FOB observations (home-cage, 

hand held, and open arena observations); body weights and feed consumption were also measured 

weekly. Additional parameters used to assess toxicity included neurobehavioral tests after week 11 

(motor activity, grip strength, and sensory reactivity to different types of stimuli), ophthalmic 

examination, urinalysis (volume, color, appearance, pH, specific gravity, glucose, bilirubin, urobilinogen, 

ketone, blood, protein, nitrite, leukocytes), clinical chemistry (alkaline phosphatase, alanine 

aminotransferase, aspartate aminotransferase, blood urea nitrogen, calcium, sodium, potassium, chlorine, 

cholesterol, creatinine kinase, creatinine, glucose, lactate dehydrogenase, total bilirubin, total protein, 

triglycerides), hematology (hemoglobin, hematocrit, erythrocytes, mean cell hemoglobin concentration, 

mean cell volume, mean cell hemoglobin, red blood cell distribution width, total and differential 

leukocytes, platelets, and mean platelet volume) values, coagulation (average and activated prothrombin 

time), organ weights (brain, heart, liver, kidneys, spleen, adrenals, thymus, epididymides, uterus, testes, 

ovaries), gross necropsies, and histopathological examination of major tissues and organs from rats 

exposed to 0 or 15 mg/kg/day. In addition, potential immunotoxicity was assessed using the following 

tests: red and white blood cell populations and spleen and thymus relative organ weights, cellularity as a 

proportion of organ weight, and proportion of cell surface markers. 

Effect noted in study and corresponding doses: Increased mortality was observed at ≥8 mg/kg/day; the 

number of preterm deaths were 2/20, 5/20, 8/20, and 7/20 in the 8, 10, 12, and 15 mg/kg/day groups, 

respectively. Convulsions were observed in most animals dying early. Transient clinical signs included 

changes in arousal, blepharosis, increased salivation, blood stains around mouth and nose, rough haircoat, 

tremors, and convulsions; the incidence and severity of these effects increased with dose. Neuromuscular 

effects were observed within the first week of exposure in the higher dose groups and persisted 

throughout the study. Increased arousal was observed in 25, 40, and 100% of rats in the 10, 12, and 

15 mg/kg/day groups; convulsions were observed in 15, 30, 65, and 60% of rats in the 8, 10, 12, and 

15 mg/kg/day groups, respectively; and tremors were observed in 10 and 20% of rats in the 12 and 

15 mg/kg/day groups. Increased urine volume was observed in females exposed to 12 or 15 mg/kg/day; 

the investigators noted that the increased urine volume may be related to the palatability of the suspension 

since higher dose animals were frequently observed drinking immediately after dosing. Significant 

decreases in body weight gain were observed in the male rats; however, body weights were typically 

within 10% of controls. In the females, significant increases in body weight were observed; at 

termination, the females in the 10, 12, and 15 mg/kg/day groups weighed at least 14% more than controls. 
 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 A-9 

APPENDIX A 

Significant alterations in organ weights were observed in male rats; these included increased brain weight 

at 12 and 15 mg/kg/day, decreased relative (to body weight and brain weight) testes weight at 

≥10 mg/kg/day, and decreased relative (to brain weight) epididymis weight at ≥8 mg/kg/day. In the 

females, significant alterations in organ weights included increased spleen, liver, and kidney weights at 

10, 12 (spleen only), or 15 mg/kg/day; relative brain weight at ≥10 mg/kg/day; and increased relative (to 

brain) kidney, liver, and spleen weights at 10 and 15 mg/kg/day. Significant increases in mean cell 

volume were observed at 8 (males only), 10, and 12 mg/kg/day and significant decreases in cholesterol 

levels were observed in males exposed to ≥8 mg/kg/day. No significant increases in the incidence of 

histopathological alterations were observed. A significant increase in abnormal skin appearance (stained 

haircoat) was observed in females exposed to 15 mg/kg/day during week 12. The presence of barbering 

was significantly increased in females exposed to 15 mg/kg/day during weeks 9 and 12. No RDX related 

alterations in immunological parameters were observed. Although the incidence of convulsions was not 

statistically significant at 8 mg/kg/day, this dose level, which likely falls just below the NOAEL/LOAEL 

boundary, was considered a LOAEL due the seriousness of the effect. 

Dose and end point used for MRL derivation: The BMDLHED of 4.1308 mg/kg/day for convulsions was 

used as the point of departure for the MRL. 

[ ] NOAEL [ ] LOAEL [X] BMDL10 

PBPK modeling was used to estimate internal dose metrics for brain RDX levels and for estimating 

HEDs. Code for an RDX oral PBPK model was provided by LM Sweeney along with documentation of 

parameter values (Sweeney et al. 2012). The Sweeney et al. (2012) model is based on the rat model 

reported by Krishnan et al. (2009) with modifications made to the gastrointestinal tract parameters, to 

include two compartments (stomach and small intestine). Sweeney et al. (2012) scaled the rat model to 

the human and estimated human gastrointestinal absorption and liver metabolism parameter values based 

on optimization against serum RDX-time profiles from humans accidentally exposed to RDX. Code for 

the Sweeney et al. (2012) model was implemented in acsLX v 3.0.1.6, without modification to the human 

or rat parameter values. Performance of the implementation was verified by comparing output to plots 

shown in Figure 2-4 of Sweeney et al. (2012). 

The model was used for interspecies extrapolation of rat internal dosimetry to humans using the following 

procedure: 

1.	 The rat model was used to simulate external rat dosages used in relevant bioassays and to predict 

the corresponding internal dose metrics, peak concentration of RDX in brain (CBpeak) and mean 

concentration of RDX in brain (CBmean). 

2.	 Gavage doses (mg/kg/day) were assumed to be delivered as a single bolus each day, at the 

exposure frequency (days/week) used in the bioassay. 

3.	 Rat model simulations were carried out until steady state had been achieved for intermediateduration exposures. 

4.	 Rat body weights used in the simulations were the TWA body weights for each dose group. 

5.	 The human model was used to predict the daily dosage (mg/kg/day) corresponding to the BMDL 

for peak brain concentration in the rat. 

6.	 A body weight of 70 kg was assumed for humans. 
 

 

 

 

 

 

 

 

 

	 

	 

	 

RDX	 A-10 

APPENDIX A 

7.	 Daily doses (mg/kg/day) in humans were assumed to be delivered in 12 consecutive hourly doses, 

separated by 12-hour intervals, 7 days/week. 

8.	 Human model simulations were carried out until steady state had been achieved for intermediateduration exposures. 

The peak and mean brain concentrations for each dose are presented in Table A-3. 

Table A-3. Estimated Peak and Mean Brain Concentrations in Rats Administered 

RDX Via Gavage 7 Days/Week for 90 Days 

Dose TWA body weight Peak brain concentration Mean brain concentration 

(mg/kg/day) (kg) (mg/L) (mg/L) 

Males 

0 0.2558 0 0 

4 0.2435 3.090 1.3947 

8 0.2362 6.154 2.7616 

10 0.2418 7.718 3.4787 

12 0.2446 9.277 4.1903 

15 0.2579 11.683 5.3301 

Females 

0 0.1642 0 0 

4 0.1626 2.923 1.2209 

8 0.1682 5.873 2.4692 

10 0.1714 7.359 3.1057 

12 0.1722 8.837 3.7325 

15 0.1849 11.154 4.7764 

TWA = time-weighted average 

Source: U.S. Army 2006 

The intermediate-duration oral MRL was derived using a benchmark dose modeling approach. Peak 

brain concentration and mean brain concentration were considered potential internal dose metrics for the 

benchmark dose modeling. Mechanistic data provide strong support that the mode of action for seizures 

involves binding to GABA receptors and there is a direct relationship between RDX levels in the brain 

and the onset of seizures (Gust et al. 2009; Williams et al. 2011). However, there are insufficient data to 

determine whether peak brain RDX concentration or mean brain RDX concentration is the most 

appropriate internal dose metric. As presented in Table A-4, the empirical data for seizures/convulsions 

appears to support using peak brain concentration as the internal dose metric. The mean brain 

concentrations are similar for rats exposed to 8 mg/kg/day for 90 days or 2 years; however, 

seizures/convulsions were observed at this dose level in the 90-day study, but not in the 2-year study. In 

contrast to the mean concentrations, the peak brain concentration in the 90-day study was 34% higher 

than in the 2-year study; this difference in peak concentrations may explain the apparent difference in 

seizure threshold. 
 

 

 

 

 


 


 


 


 

RDX A-11 

APPENDIX A 

Table A-4. Comparison of NOAEL and LOAEL Values Using Different Dose
 

Metrics Following Intermediate- and Chronic-Duration Exposure to RDX
 

NOAELc 

Intermediate exposurea 

(U.S. Army 2006) 

Chronic exposureb 

(U.S. Army 1983a) 

Administered dose 4 mg/kg/day 8 mg/kg/day 

Peak brain concentration 2.923 mg/L 4.051 mg/L 

Mean brain concentration 

LOAELc 

1.308 mg/L 2.959 mg/L 

Administered dose 8 mg/kg/day 40 mg/kg/day 

Peak brain concentration 6.013 mg/L 18.694 mg/L 

Mean brain concentration 2.615 mg/L 14.403 mg/L 

a

RDX administered via gavage, 7 days/week for 90 days. b

RDX administered via the diet for 2 years.
 c

Average of male and female values.
 

Data for the incidence of convulsions (summarized in Table A-5) were fit to all available dichotomous 

models in the EPA Benchmark Dose Software (BMDS) (version 2.1.2) using the extra risk option and 

using peak brain RDX concentration as the dose metric. Since the study did not identify gender-specific 

differences in RDX sensitivity, the peak brain concentrations were averaged for the male and female rats 

and these combined values were used for benchmark dose modeling. Adequate model fit was judged by 

three criteria: χ2

 goodness-of-fit p-value (p>0.1), visual inspection of the dose-response curve, and scaled 

residual at the data point (except the control) closest to the predefined BMR. BMDs and lower bounds on 

the BMD (BMDL) associated with a BMR of 10% extra risk were calculated for all models and are 

presented in Table A-6. As assessed by the χ2

 goodness-of-fit statistic, all of the models with the 

exception of the quantal linear and 1-degree polynomial models provided adequate fit to the data. Among 

all of the models providing adequate fit to the data, the BMDL from the model with the lowest Akaike’s 

Information Criteria (AIC) was chosen. The log-probit model provided the best fit to the convulsion 

incidence data and is presented in Figure A-1. The BMDL of 3.9627 mg/L was used to predict a HED of 

4.131 mg/kg/day using the PBPK model. 
 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

RDX A-12 

APPENDIX A 

Table A-5. Incidence of Convulsions in Male and Female Fischer 344 Rats 

Administered RDX 7 Days/Week for 90 Days
 

Dose (mg/kg/day) Peak brain concentration (mg/L) Incidence 

0 0 0/20
 

4 3.005 0/20
 

8 6.013 3/20
 

10 7.539 6/20
 

12 9.057 13/20
 

15 11.419 12/20
 

Source: U.S. Army 2006 

Table A-6. Model Predictions for the Incidence of Convulsions in Rats
 

Administered RDX via Gavage for 90 Days Using Peak Brain
 

Concentration as the Internal Dose Metric
 

Model 

Gammab 

χ2 Goodness of fit 

p-valuea 

0.4648 

AIC 

101.924 

BMD10 

(mg/L) 

5.17803 

BMDL10 

(mg/L) 

3.79207 

Logistic 0.2121 104.808 5.14052 3.99687 

LogLogistic 

LogProbit 

Multistage (1-degree polynomial)c 

Multistage (2-degree polynomialc 

0.4945 

0.5406 

0.3663 

0.0383 

101.781 

101.353 

111.445 

102.99 

5.18956 

5.24819 

3.75703 

NA 

3.8386 

3.9627 

2.82257 

NA 

Probit 0.2696 103.851 5.11305 3.88122 

Weibullb 0.352 103.06 4.87416 3.43247 

Quantal-Linear 0.0383 111.445 NA NA 

a

Values <0.10 fail to meet conventional goodness-of-fit criteria. b

Power restricted to ≥1.
 c

Betas restricted to ≥0.
 

AIC = Akaike’s Information Criterion; BMD = maximum likelihood estimate of the dose associated with the selected 

benchmark response; BMDL = 95% lower confidence limit on the BMD; NA = not applicable, model does not provide 

adequate fit to the data
 

Source: U.S. Army 2006
 
 

 

 

 

 


 


 

RDX A-13 

APPENDIX A 

Figure A-1. Fit of Log Probit Model to Data on the Incidence of Convulsions in 

Rats Administered RDX via Gavage for 90 Days Using Peak Brain RDX
 

Concentration as the Dose Metric
 

LogProbit Model with 0.95 Confidence Level 

Fraction Affected 

0.8

 0.6

 0.4

 0.2

 0 

BMDL BMD 

LogProbit 

0 

21:45 06/09 2011 

2 4 6 

dose 

8 10 12 

Source: U.S. Army 2006 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: No human studies have 

examined the toxicity of RDX following intermediate-duration exposure. Several animal studies have 

reported neurological effects, primarily convulsions, seizures, and/or tremors in rats at doses of 

≥8 mg/kg/day (U.S. Army 1983a, 2006; von Oettingen et al. 1949), monkeys at 10 mg/kg/day (U.S. Navy 

1974b), and dogs at 50 mg/kg/day (von Oettingen et al. 1949). Hyperactivity was noted in rats exposed to 

100 mg/kg/day (Levine et al. 1981, 1990). The results of the U.S. Army (2006) study suggest that there is 

a steep dose-response curve for seizure induction. The occurrences of seizures were 0% at 4 mg/kg/day, 

20–30% at 8 mg/kg/day, 45–50% at 10 mg/kg/day, and 80–90% at 12 or 15 mg/kg/day. 

In addition to these neurological effects, less serious adverse health effects have been observed at similar 

or higher dose levels. Several studies have found changes in serum chemistry parameters suggestive of 
 

 

 

RDX A-14 

APPENDIX A 

impaired liver function, although histological alterations were not generally found in the liver. Decreases 

in serum cholesterol and/or triglycerides were observed at ≥8 mg/kg/day (U.S. Army 1983a, 2006; Levine 

et al. 1981) and decreases in serum alanine aminotransferase levels were observed at 28 mg/kg/day (U.S. 

Army 1980b). The magnitude of these alterations was small and not likely to be biologically significant. 

Minor hematological effects (small decreases in erythrocyte and hemoglobin levels) were observed in rats 

exposed to 40 mg/kg/day (U.S. Army 1983a) and mice exposed to 160 mg/kg/day (U.S. Army 1980b); 

however, other studies have not found significant alterations in hematological parameters (U.S. Army 

1980b, 2006; von Oettingen et al. 1949). Emesis was observed in monkeys administered via gavage 

10 mg/kg/day for 90 days (U.S. Navy 1974b); the incidence in monkeys administered 1 mg/kg/day was 

not considered to be different from the controls. There is limited evidence that RDX is a reproductive 

toxicant. Spermatic granuloma in the prostrate was observed in rats exposed to 40 mg/kg/day for 

6 months (U.S. Army 1983a). Decreases in F2 pup body weight and increases in the incidence of renal 

cysts were observed at 16 mg/kg/day and an increase in the number of stillbirths and decreased pup 

survival were observed in the F1 generation at 50 mg/kg/day was observed in a two-generation study in 

rats (U.S. Army 1980b). 

Agency Contacts (Chemical Managers): Henry Abadin 
 

 

 

 

 

 

 

 

 

 

 

 

 

RDX A-15 

APPENDIX A 

MINIMAL RISK LEVEL (MRL) WORKSHEET 

Chemical Name: RDX 

CAS Numbers: 121-82-4 

Date: August 2011 

Profile Status: Final Post-Public Comment 

Route: [ ] Inhalation [X] Oral 

Duration: [ ] Acute [ ] Intermediate [X] Chronic 

Graph Key: 65 

Species: Rat 

Minimal Risk Level: 0.1 [X] mg/kg/day [ ] ppm 

Reference: U.S. Army. 1983a. Determination of the chronic mammalian toxicological effects of RDX: 

Twenty-four month chronic toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-1,3,5-triazine 

(RDX) in the Fischer 344 rat: Phase V. Vol. 1. Frederick, MD: U.S. Army Medical Research and 

Development Command. ADA160774. (author: Levine BS et al.) 

Experimental design: Groups of male and female Fischer 344 rats (75/sex/group) were exposed to 0, 0.3, 

1.5, 8.0, or 40.0 mg/kg/day RDX in the diet for 2 years. Ten animals/sex/dose were sacrificed during 

weeks 27 and 53. The following parameters were used to assess toxicity: daily observations; ophthalmic 

examinations during weeks 2, 25, 51, 76, and 103; hematology (hematocrit, hemoglogin, mean 

corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, 

erythrocyte count, total and differential leukocyte count, and platelet count) and clinical chemistry 

(glucose, blood urea nitrogen, alanine aminotransferase, bilirubin, creatinine phosphokinase, lactic 

dehydrogenase, alkaline phosphatase, triglycerides, total cholesterol, total protein, albumin, globulin, 

sodium, potassium, chloride, and calcium levels) of blood samples collected during weeks 13, 26, 52, 78, 

and 104; organ weights (adrenal, brain, heart, kidneys, liver, ovaries, spleen, and testes), and complete 

histopathology of major tissues and organs of rats in the 0 or 40.0 mg/kg/day groups, and 

histopathological examination of the brain, gonads, heart, liver, kidneys, spleen, and spinal cord of rats in 

the 0.3, 1.5, and 8.0 mg/kg/day groups. Actual RDX doses were within 3% of the intended dose. 

Effect noted in study and corresponding doses: Deaths were observed at 40 mg/kg/day; 88% of males and 

41% of females died by week 88. The mean survival time for the 40 mg/kg/day males was 14.6 months 

compared with 22.3 months for the control males. A 20.6 month survival time was seen for the 

40 mg/kg/day females vs. 22.0 months for the control females at 40 mg/kg/day. A significant decrease in 

survival time was also observed in the males exposed to 1.5 mg/kg/day (21.0 months); however, no 

alterations in survival time was observed in the females exposed to 1.5 mg/kg/day (22.2 months) or in the 

males (22.2 months) or females (22.4 months) exposed to 8 mg/kg/day. Additionally, there were no 

significant differences in mortality incidence in the 1.5 or 8 mg/kg/day groups, as compared to controls. 

Decreased body weight gain was observed in males (20–30%) and females (10–15%) exposed to 

40.0 mg/kg/day; significant decreases in body weight gain were also observed at 8.0 mg/kg/day, but the 

body weight was within 5% of controls. Slight, but significant, reductions in food intake were observed 

in males at 40.0 mg/kg/day. Tremors and convulsions were observed prior to death at 40 mg/kg/day 

beginning after 26 weeks of exposure. Animals were hyperreactive to approach and had increased 

fighting; hyperreactivity was first observed after 9 weeks of exposure to 40 mg/kg/day. No adverse 

clinical signs were noted for the lower dose groups. Significant decreases in hemoglobin and erythrocyte 

counts were observed in the 40 mg/kg/day group beginning at week 26; the study investigators noted that 

the anemic state was considered slight and there was no evidence of physiologic compensatory responses. 

Thrombocytosis was observed in rats exposed to 40 mg/kg/day and elevated platelet counts were 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 A-16 

APPENDIX A 

observed in 8 mg/kg/day males during weeks 13 and 26. Significant decreases in blood glucose, total 

cholesterol, and triglyceride levels were observed in the 40 mg/kg/day group starting at week 13. 

Significant decreases in serum alanine aminotransferase levels were observed in males exposed to 8 or 40 

mg/kg/day at weeks 26 and 52 and in females at 40 mg/kg/day at week 26. Other clinical chemistry 

alterations included decreases in globulin and albumin levels at weeks 52 and 78 and increases in serum 

potassium levels at weeks 26, 52, and 78. A significant increase in the incidence of cataracts was 

observed in females in the 40 mg/kg/day group during weeks 78 and 104. Splenic extramedullary 

hematopoiesis and spermatic granuloma of the prostate were observed in rats exposed to 40 mg/kg/day 

for 6 months. At 1 year, histological alterations in the urinary bladder (luminal distention and cystitis), 

kidneys (medullary papillary necrosis), and testes (germinal cell degeneration, enlarged seminal vesicles) 

were observed in males exposed to 40 mg/kg/day and in the spleen (enlarged dark-red spleens with 

histological evidence of sinusoidal congestion) of males and females exposed to 40 mg/kg/day. The 

following effects were observed at 2 years: suppurative inflammation of the prostate in the 1.5, 8, and 40 

mg/kg/day groups; renal medullary papillar necrosis, renal pyelitis, and urinary bladder luminal distension 

and cystitis in males exposed to 40 mg/kg/day; splenic extramedullary hematopoiesis in female rats 

exposed to 40 mg/kg/day; and hemosiderin-like pigment in males exposed to 1.5, 8, or 40 mg/kg/day. In 

the absence of altered hematological parameters or other effects on the spleen, the increased pigment 

levels observed at 1.5 or 8 mg/kg/day were not considered adverse. 

Dose and end point used for MRL derivation: The MRL is based on a NOAELHED of 4.223 mg/kg/day 

for tremors and convulsions in a 2-year study. 

[X] NOAEL [ ] LOAEL 

PBPK modeling was used to estimate internal dose metrics for brain RDX levels and for estimating 

HEDs. Code for an RDX oral PBPK model was provided by LM Sweeney along with documentation of 

parameter values (Sweeney et al. 2012). The Sweeney et al. (2012) model is based on the rat model 

reported by Krishnan et al. (2009) with modifications made to the gastrointestinal tract parameters, to 

include two compartments (stomach and small intestine). Sweeney et al. (2012) scaled the rat model to 

the human and estimated human gastrointestinal absorption and liver metabolism parameter values based 

on optimization against serum RDX-time profiles from humans accidentally exposed to RDX. Code for 

the Sweeney et al. (2012) model was implemented in acsLX v 3.0.1.6, without modification to the human 

or rat parameter values. Performance of the implementation was verified by comparing output to plots 

shown in Figure 2-4 of Sweeney et al. (2012). 

The model was used for interspecies extrapolation of rat internal dosimetry to humans using the following 

procedure: 

1.	 The rat model was used to simulate external rat dosages used in relevant bioassays and to predict 

the corresponding internal dose metric, peak concentration of RDX in brain (CBpeak) and mean 

concentration of RDX in brain (CBmean). 

2.	 Dietary doses (mg/kg/day) were assumed to be delivered in 12 consecutive hourly doses, 

separated by 12-hour intervals, at the exposure frequency (days/week) used in the bioassay. 

3.	 Rat model simulations were carried out until steady state had been achieved for chronic-duration 

exposures. 

4.	 Rat body weights used in the simulations were the TWA body weights for each dose group. 
 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 A-17 

APPENDIX A 

5.	 The human model was used to predict the daily dosage (mg/kg/day) corresponding to the NOAEL 

for peak brain concentration in the rat. 

6.	 A body weight of 70 kg was assumed for humans. 

7.	 Daily doses (mg/kg/day) in humans were assumed to be delivered in 12 consecutive hourly doses, 

separated by 12-hour intervals, 7 days/week. 

8.	 Human model simulations were carried out until steady state had been achieved for chronicduration exposures. 

The peak brain concentrations for each dose are presented in Table A-7. 

Table A-7. Estimated Peak and Mean Brain Concentrations in Rats Administered 

RDX Via the Diet for 2 Years 

Dose TWA body weight Peak brain concentration Mean brain concentration 

(mg/kg/day) (kg) (mg/L) (mg/L) 

Males 

0 0.3889 0 0 

0.3 0.3904 0.165	 0.122 

1.5 0.3848 0.823	 0.607 

8 0.373 4.344 3.205 

40 0.3244 20.885 15.304 

Females 

0 0.2302 0 0 

0.3 0.2297 0.142	 0.102 

1.5 0.2278 0.707	 0.511 

8 0.2248 3.763 2.712 

40 0.2218 18.694 13.502 

TWA = time-weighted average 

Source: U.S. Army 1983a 

The U.S. Army (1983a) study identified a NOAEL of 8 mg/kg/day and LOAEL of 40 mg/kg/day for 

tremors and convulsions in rats exposed to RDX in the diet for 2 years. A chronic-duration oral MRL 

was derived using the NOAEL/LOAEL approach; benchmark dose modeling could not be utilized 

because the investigators did not report incidence data for neurological signs. The NOAEL from the U.S. 

Army (1983a) study corresponds to peak brain concentrations of 4.344 and 3.763 mg/L in males and 

females, respectively, and mean brain RDX concentrations of 3.205 and 2.712 mg/L in males and 

females, respectively. Mechanistic data provide strong support that the mode of action for seizures 

involves binding to GABA receptors and there is a direct relationship between RDX levels in the brain 

and the onset of seizures (Gust et al. 2009; Williams et al. 2011). However, there are insufficient data to 

determine whether peak brain RDX concentration or mean brain RDX concentration is the most 

appropriate internal dose metric. As presented in Table A-8, a comparison of the NOAEL and LOAEL 

values for seizures in rats exposed for intermediate or chronic durations suggests that peak brain 
 

 

 

 

 

 

 

 


 


 


 


 

RDX A-18 

APPENDIX A 

concentration may be the most appropriate internal dose metric. The mean brain concentrations are 

similar for rats exposed to 8 mg/kg/day for 90 days or 2 years; however, seizures/convulsions were 

observed at this dose level in the 90-day study, but not in the 2-year study. In contrast to the mean 

concentrations, the peak brain concentration in the 90-day study was 34% higher than in the 2-year study; 

this difference in peak concentrations may explain the apparent difference in seizure threshold. Thus, 

peak brain concentration was selected as the internal dose metric for derivation of the acute-duration oral 

MRL. Since the U.S. Army (1983a) study did not identify gender-specific differences in RDX sensitivity, 

the peak brain concentrations were averaged for the male and females rats. The average peak brain 

concentration of 4.051 mg/L was used to predict a HED of 4.223 mg/kg/day using the PBPK model. 

Table A-8. Comparison of NOAEL and LOAEL Values Using Different Dose
 

Metrics Following Intermediate- and Chronic-Duration Exposure to RDX
 

NOAELc 

Intermediate exposurea 

(U.S. Army 2006) 

Chronic exposureb 

(U.S. Army 1983a) 

Administered dose 4 mg/kg/day 8 mg/kg/day 

Peak brain concentration 2.923 mg/L 4.051 mg/L 

Mean brain concentration 

LOAELc 

1.308 mg/L 2.959 mg/L 

Administered dose 8 mg/kg/day 40 mg/kg/day 

Peak brain concentration 6.013 mg/L 18.694 mg/L 

Mean brain concentration 2.615 mg/L 14.403 mg/L 

a

RDX administered via gavage, 7 days/week for 90 days. b

RDX administered via the diet for 2 years.
 c

Average of male and female values.
 

Uncertainty Factors used in MRL derivation: 

[ ] 10 for use of a LOAEL 

[X] 3 for extrapolation from animals to humans with dosimetric adjustments 

[X] 10 for human variability 

Was a conversion factor used from ppm in food or water to a mg/body weight dose? Not applicable. 

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not 

applicable. 

Was a conversion used from intermittent to continuous exposure? Not applicable. 

Other additional studies or pertinent information that lend support to this MRL: No human studies have 

examined the chronic toxicity of RDX following oral exposure. A number of human case reports have 

noted convulsions and seizures in individuals ingesting RDX (Hollander and Colbach 1969; Ketel and 

Hughes 1972; Küçükardalĭ et al. 2003; Merrill 1968; Stone et al. 1969; Woody et al. 1986). The chronic 

oral toxicity of RDX has been evaluated in two rat studies (U.S. Army 1983a; U.S. Navy 1976) and a 

mouse study (U.S. Army 1984c). A number of adverse health effects have been observed in rats exposed 

to 40 mg/kg/day including tremors, convulsions, and hyperresponsiveness; decreased hematocrit, 
 

 

 

 

 

 

 

RDX A-19 

APPENDIX A 

hemoglobin, and erythrocyte levels; hepatomegaly and decreased serum cholesterol and triglycerides; 

renal papillary necrosis and increased blood urea nitrogen levels; testicular degeneration; and cataracts 

(females only) (U.S. Army 1983a). This dose was also associated with an 88% mortality rate. In addition 

to these effects, significant increases in the incidence of suppurative inflammation were observed in the 

prostate of rats exposed to ≥1.5 mg/kg/day (U.S. Army 1983a). U.S. Army (2006) noted that 

inflammation of the prostate gland is a common condition in older rodents and is generally not due to 

toxicity; additionally, the prostate effects in the U.S. Army (1983a) study were predominantly found in 

rats dying early. 

In the second rat study, no adverse effects were observed at doses as high as 10 mg/kg/day (U.S. Navy 

1976). This study did not include a histological examination of the prostate, and the animals were 

monitored weekly for overt signs of toxicity. In mice, increases in serum cholesterol levels were 

observed in females exposed to 35 mg/kg/day and increased relative kidney weights and cytoplasmic 

vacuolization in the kidney were observed at 100 mg/kg/day. The NOAEL for the hepatic effects was 

7 mg/kg/day. 

Agency Contacts (Chemical Managers): Henry Abadin 
RDX A-20
 
 

APPENDIX A 

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RDX	 	 B-1 

APPENDIX B. USER'S GUIDE 

Chapter 1 

Public Health Statement 

This chapter of the profile is a health effects summary written in nontechnical language. Its intended 

audience is the general public, especially people living in the vicinity of a hazardous waste site or 

chemical release. If the Public Health Statement were removed from the rest of the document, it would 

still communicate to the lay public essential information about the chemical. 

The major headings in the Public Health Statement are useful to find specific topics of concern. The 

topics are written in a question and answer format. The answer to each question includes a sentence that 

will direct the reader to chapters in the profile that will provide more information on the given topic. 

Chapter 2 

Relevance to Public Health 

This chapter provides a health effects summary based on evaluations of existing toxicologic, 

epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weightof-evidence discussions for human health end points by addressing the following questions: 

1. What effects are known to occur in humans? 

2. What effects observed in animals are likely to be of concern to humans? 

3. What exposure conditions are likely to be of concern to humans, especially around hazardous 

waste sites? 

The chapter covers end points in the same order that they appear within the Discussion of Health Effects 

by Route of Exposure section, by route (inhalation, oral, and dermal) and within route by effect. Human 

data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). 

In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also 

considered in this chapter. 

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using 

existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer 

potency or perform cancer risk assessments. Minimal Risk Levels (MRLs) for noncancer end points (if 

derived) and the end points from which they were derived are indicated and discussed. 

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public 

health are identified in the Chapter 3 Data Needs section. 

Interpretation of Minimal Risk Levels 

Where sufficient toxicologic information is available, ATSDR has derived MRLs for inhalation and oral 

routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

RDX B-2 

APPENDIX B 

meant to support regulatory action, but to acquaint health professionals with exposure levels at which 

adverse health effects are not expected to occur in humans. 

MRLs should help physicians and public health officials determine the safety of a community living near 

a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. 

MRLs are based largely on toxicological studies in animals and on reports of human occupational 

exposure. 

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2, 

"Relevance to Public Health," contains basic information known about the substance. Other sections such 

as Chapter 3 Section 3.9, "Interactions with Other Substances,” and Section 3.10, "Populations that are 

Unusually Susceptible" provide important supplemental information. 

MRL users should also understand the MRL derivation methodology. MRLs are derived using a 

modified version of the risk assessment methodology that the Environmental Protection Agency (EPA) 

provides (Barnes and Dourson 1988) to determine reference doses (RfDs) for lifetime exposure. 

To derive an MRL, ATSDR generally selects the most sensitive end point which, in its best judgement, 

represents the most sensitive human health effect for a given exposure route and duration. ATSDR 

cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available 

for all potential systemic, neurological, and developmental effects. If this information and reliable 

quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive 

species (when information from multiple species is available) with the highest no-observed-adverse-effect 

level (NOAEL) that does not exceed any adverse effect levels. When a NOAEL is not available, a 

lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor 

(UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human 

variability to protect sensitive subpopulations (people who are most susceptible to the health effects 

caused by the substance) and for interspecies variability (extrapolation from animals to humans). In 

deriving an MRL, these individual uncertainty factors are multiplied together. The product is then 

divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used 

in developing a substance-specific MRL are provided in the footnotes of the levels of significant exposure 

(LSE) tables. 

Chapter 3 

Health Effects 

Tables and Figures for Levels of Significant Exposure (LSE) 

Tables and figures are used to summarize health effects and illustrate graphically levels of exposure 

associated with those effects. These levels cover health effects observed at increasing dose 

concentrations and durations, differences in response by species, MRLs to humans for noncancer end 

points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 

10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to 

locate data for a specific exposure scenario. The LSE tables and figures should always be used in 

conjunction with the text. All entries in these tables and figures represent studies that provide reliable, 

quantitative estimates of NOAELs, LOAELs, or Cancer Effect Levels (CELs). 

The legends presented below demonstrate the application of these tables and figures. Representative 

examples of LSE Table 3-1 and Figure 3-1 are shown. The numbers in the left column of the legends 

correspond to the numbers in the example table and figure. 
 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 B-3 

APPENDIX B 

LEGEND 

See Sample LSE Table 3-1 (page B-6) 

(1)	 Route of Exposure. One of the first considerations when reviewing the toxicity of a substance 

using these tables and figures should be the relevant and appropriate route of exposure. Typically 

when sufficient data exist, three LSE tables and two LSE figures are presented in the document. 

The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, 

and dermal (LSE Tables 3-1, 3-2, and 3-3, respectively). LSE figures are limited to the inhalation 

(LSE Figure 3-1) and oral (LSE Figure 3-2) routes. Not all substances will have data on each 

route of exposure and will not, therefore, have all five of the tables and figures. 

(2)	 Exposure Period. Three exposure periods—acute (<15 days), intermediate (15–364 days), and 

chronic (365 days or more)—are presented within each relevant route of exposure. In this 

example, an inhalation study of intermediate exposure duration is reported. For quick reference 

to health effects occurring from a known length of exposure, locate the applicable exposure 

period within the LSE table and figure. 

(3)	 Health Effect. The major categories of health effects included in LSE tables and figures are 

death, systemic, immunological, neurological, developmental, reproductive, and cancer. 

NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. 

Systemic effects are further defined in the "System" column of the LSE table (see key number 

18). 

(4)	 Key to Figure. Each key number in the LSE table links study information to one or more data 

points using the same key number in the corresponding LSE figure. In this example, the study 

represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL 

(also see the two "18r" data points in sample Figure 3-1). 

(5)	 Species. The test species, whether animal or human, are identified in this column. Chapter 2, 

"Relevance to Public Health," covers the relevance of animal data to human toxicity and 

Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. 

Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent 

human doses to derive an MRL. 

(6)	 Exposure Frequency/Duration. The duration of the study and the weekly and daily exposure 

regimens are provided in this column. This permits comparison of NOAELs and LOAELs from 

different studies. In this case (key number 18), rats were exposed to “Chemical x” via inhalation 

for 6 hours/day, 5 days/week, for 13 weeks. For a more complete review of the dosing regimen, 

refer to the appropriate sections of the text or the original reference paper (i.e., Nitschke et al. 

1981). 

(7)	 System. This column further defines the systemic effects. These systems include respiratory, 

cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and 

dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered 

in these systems. In the example of key number 18, one systemic effect (respiratory) was 

investigated. 

(8) NOAEL. A NOAEL is the highest exposure level at which no harmful effects were seen in the 

organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system, 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

	 

RDX	 B-4 

APPENDIX B 

which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see 

footnote "b"). 

(9)	 LOAEL. A LOAEL is the lowest dose used in the study that caused a harmful health effect. 

LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help 

readers identify the levels of exposure at which adverse health effects first appear and the 

gradation of effects with increasing dose. A brief description of the specific end point used to 

quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key 

number 18 (hyperplasia) is a Less Serious LOAEL of 10 ppm. MRLs are not derived from 

Serious LOAELs. 

(10)	 Reference. The complete reference citation is given in Chapter 9 of the profile. 

(11)	 CEL. A CEL is the lowest exposure level associated with the onset of carcinogenesis in 

experimental or epidemiologic studies. CELs are always considered serious effects. The LSE 

tables and figures do not contain NOAELs for cancer, but the text may report doses not causing 

measurable cancer increases. 

(12)	 Footnotes. Explanations of abbreviations or reference notes for data in the LSE tables are found 

in the footnotes. Footnote "b" indicates that the NOAEL of 3 ppm in key number 18 was used to 

derive an MRL of 0.005 ppm. 

LEGEND 

See Sample Figure 3-1 (page B-7) 

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the 

reader quickly compare health effects according to exposure concentrations for particular exposure 

periods. 

(13)	 Exposure Period. The same exposure periods appear as in the LSE table. In this example, health 

effects observed within the acute and intermediate exposure periods are illustrated. 

(14)	 Health Effect. These are the categories of health effects for which reliable quantitative data 

exists. The same health effects appear in the LSE table. 

(15)	 Levels of Exposure. Concentrations or doses for each health effect in the LSE tables are 

graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log 

scale "y" axis. Inhalation exposure is reported in mg/m3

 or ppm and oral exposure is reported in 

mg/kg/day. 

(16)	 NOAEL. In this example, the open circle designated 18r identifies a NOAEL critical end point in 

the rat upon which an intermediate inhalation exposure MRL is based. The key number 18 

corresponds to the entry in the LSE table. The dashed descending arrow indicates the 

extrapolation from the exposure level of 3 ppm (see entry 18 in the table) to the MRL of 

0.005 ppm (see footnote "b" in the LSE table). 

(17)	 CEL. Key number 38m is one of three studies for which CELs were derived. The diamond 

symbol refers to a CEL for the test species-mouse. The number 38 corresponds to the entry in the 

LSE table. 
 

 

 

	 

	 

	 

RDX	 B-5 

APPENDIX B 

(18)	 Estimated Upper-Bound Human Cancer Risk Levels. This is the range associated with the upperbound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived 

from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the 

cancer dose response curve at low dose levels (q1*). 

(19)	 Key to LSE Figure. The Key explains the abbreviations and symbols used in the figure. 
1 2 3 4 12 

→

SAMPLE 

Table 3-1. Levels of Significant Exposure to [Chemical x] – Inhalation 

→→

Exposure frequency/ 

Species duration 

Key to figurea INTERMEDIATE EXPOSURE 

↓6 

↓

5 

Systemic 

System ↓7 

NOAEL (ppm) ↓8 

LOAEL (effect) Less serious (ppm) 

↓

9 

Serious (ppm) 

Re

↓

10 

→→

Nit

CHRONIC EXPOSURE 

WoNTNT

(CEL, multiple organs) (CEL, lung tumors, nasal tumors) (CEL, lung tumors, hemangiosarcomas) 

10 (hyperplasia) 

11 ↓20 10 10 

3b 13 wk Resp 

5 d/wk 6 hr/d 18 mo 5 d/wk 7 hr/d 89–104 wk 5 d/wk 6 hr/d 79–103 wk 5 d/wk 6 hr/d 

Rat Rat Rat Mouse 

18 Cancer 38 39 40 a The number corresponds to entries in Figure 3-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5x10-3 ppm; dose adjusted for intermittent expby an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 

RDX B-8
 
 

APPENDIX B 

This page is intentionally blank. 
 

 

RDX C-1 

APPENDIX C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS 

ACGIH American Conference of Governmental Industrial Hygienists 

ACOEM American College of Occupational and Environmental Medicine 

ADI acceptable daily intake 

ADME absorption, distribution, metabolism, and excretion 

AED atomic emission detection 

AFID alkali flame ionization detector 

AFOSH Air Force Office of Safety and Health 

ALT alanine aminotransferase 

AML acute myeloid leukemia 

AOAC Association of Official Analytical Chemists 

AOEC Association of Occupational and Environmental Clinics 

AP alkaline phosphatase 

APHA American Public Health Association 

AST aspartate aminotransferase 

atm atmosphere 

ATSDR Agency for Toxic Substances and Disease Registry 

AWQC Ambient Water Quality Criteria 

BAT best available technology 

BCF bioconcentration factor 

BEI Biological Exposure Index 

BMD/C benchmark dose or benchmark concentration 

BMDX dose that produces a X% change in response rate of an adverse effect 

BMDLX 95% lower confidence limit on the BMDX 

BMDS Benchmark Dose Software 

BMR benchmark response 

BSC Board of Scientific Counselors 

C centigrade 

CAA Clean Air Act 

CAG Cancer Assessment Group of the U.S. Environmental Protection Agency 

CAS Chemical Abstract Services 

CDC Centers for Disease Control and Prevention 

CEL cancer effect level 

CELDS Computer-Environmental Legislative Data System 

CERCLA Comprehensive Environmental Response, Compensation, and Liability Act 

CFR Code of Federal Regulations 

Ci curie 

CI confidence interval 

CL ceiling limit value 

CLP Contract Laboratory Program 

cm centimeter 

CML chronic myeloid leukemia 

CPSC Consumer Products Safety Commission 

CWA Clean Water Act 

DHEW Department of Health, Education, and Welfare 

DHHS Department of Health and Human Services 

DNA deoxyribonucleic acid 

DOD Department of Defense 
 

RDX C-2 

APPENDIX C 

DOE Department of Energy 

DOL Department of Labor 

DOT Department of Transportation 

DOT/UN/ Department of Transportation/United Nations/

 NA/IMDG North America/Intergovernmental Maritime Dangerous Goods Code 

DWEL drinking water exposure level 

ECD electron capture detection 

ECG/EKG electrocardiogram 

EEG electroencephalogram 

EEGL Emergency Exposure Guidance Level 

EPA Environmental Protection Agency 

F Fahrenheit 

F1 first-filial generation 

FAO Food and Agricultural Organization of the United Nations 

FDA Food and Drug Administration 

FEMA Federal Emergency Management Agency 

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act 

FPD flame photometric detection 

fpm feet per minute 

FR Federal Register 

FSH follicle stimulating hormone 

g gram 

GC gas chromatography 

gd gestational day 

GLC gas liquid chromatography 

GPC gel permeation chromatography 

HPLC high-performance liquid chromatography 

HRGC high resolution gas chromatography 

HSDB Hazardous Substance Data Bank 

IARC International Agency for Research on Cancer 

IDLH immediately dangerous to life and health 

ILO International Labor Organization 

IRIS Integrated Risk Information System 

Kd adsorption ratio 

kg kilogram 

kkg metric ton 

Koc organic carbon partition coefficient 

Kow octanol-water partition coefficient 

L liter 

LC liquid chromatography 

LC50 lethal concentration, 50% kill 

LCLo lethal concentration, low 

LD50 lethal dose, 50% kill 

LDLo lethal dose, low 

LDH lactic dehydrogenase 

LH luteinizing hormone 

LOAEL lowest-observed-adverse-effect level 

LSE Levels of Significant Exposure 

LT50 lethal time, 50% kill 

m meter 

MA trans,trans-muconic acid 
 

 

RDX C-3 

APPENDIX C 

MAL maximum allowable level 

mCi millicurie 

MCL maximum contaminant level 

MCLG maximum contaminant level goal 

MF modifying factor 

MFO mixed function oxidase 

mg milligram 

mL milliliter 

mm millimeter 

mmHg millimeters of mercury 

mmol millimole 

mppcf millions of particles per cubic foot 

MRL Minimal Risk Level 

MS mass spectrometry 

NAAQS National Ambient Air Quality Standard 

NAS National Academy of Science 

NATICH National Air Toxics Information Clearinghouse 

NATO North Atlantic Treaty Organization 

NCE normochromatic erythrocytes 

NCEH National Center for Environmental Health 

NCI National Cancer Institute 

ND not detected 

NFPA National Fire Protection Association 

ng nanogram 

NHANES National Health and Nutrition Examination Survey 

NIEHS National Institute of Environmental Health Sciences 

NIOSH National Institute for Occupational Safety and Health 

NIOSHTIC NIOSH's Computerized Information Retrieval System 

NLM National Library of Medicine 

nm nanometer 

nmol nanomole 

NOAEL no-observed-adverse-effect level 

NOES National Occupational Exposure Survey 

NOHS National Occupational Hazard Survey 

NPD nitrogen phosphorus detection 

NPDES National Pollutant Discharge Elimination System 

NPL National Priorities List 

NR not reported 

NRC National Research Council 

NS not specified 

NSPS New Source Performance Standards 

NTIS National Technical Information Service 

NTP National Toxicology Program 

ODW Office of Drinking Water, EPA 

OERR Office of Emergency and Remedial Response, EPA 

OHM/TADS Oil and Hazardous Materials/Technical Assistance Data System 

OPP Office of Pesticide Programs, EPA 

OPPT Office of Pollution Prevention and Toxics, EPA 

OPPTS Office of Prevention, Pesticides and Toxic Substances, EPA 

OR odds ratio 

OSHA Occupational Safety and Health Administration 
 

 

RDX C-4 

APPENDIX C 

OSW Office of Solid Waste, EPA 

OTS Office of Toxic Substances 

OW Office of Water 

OWRS Office of Water Regulations and Standards, EPA 

PAH polycyclic aromatic hydrocarbon 

PBPD physiologically based pharmacodynamic 

PBPK physiologically based pharmacokinetic 

PCE polychromatic erythrocytes 

PEL permissible exposure limit 

pg picogram 

PHS Public Health Service 

PID photo ionization detector 

pmol picomole 

PMR proportionate mortality ratio 

ppb parts per billion 

ppm parts per million 

ppt parts per trillion 

PSNS pretreatment standards for new sources 

RBC red blood cell 

REL recommended exposure level/limit 

RfC reference concentration 

RfD reference dose 

RNA ribonucleic acid 

RQ reportable quantity 

RTECS Registry of Toxic Effects of Chemical Substances 

SARA Superfund Amendments and Reauthorization Act 

SCE sister chromatid exchange 

SGOT serum glutamic oxaloacetic transaminase 

SGPT serum glutamic pyruvic transaminase 

SIC standard industrial classification 

SIM selected ion monitoring 

SMCL secondary maximum contaminant level 

SMR standardized mortality ratio 

SNARL suggested no adverse response level 

SPEGL Short-Term Public Emergency Guidance Level 

STEL short term exposure limit 

STORET Storage and Retrieval 

TD50 toxic dose, 50% specific toxic effect 

TLV threshold limit value 

TOC total organic carbon 

TPQ threshold planning quantity 

TRI Toxics Release Inventory 

TSCA Toxic Substances Control Act 

TWA time-weighted average 

UF uncertainty factor 

U.S. United States 

USDA United States Department of Agriculture 

USGS United States Geological Survey 

VOC volatile organic compound 

WBC white blood cell 

WHO World Health Organization 
 

RDX C-5 

APPENDIX C 

> greater than 

≥ greater than or equal to 

= equal to 

< less than 

≤ less than or equal to 

% percent 

α alpha 

β beta 

γ gamma 

δ delta 

μm micrometer 

μg microgram q1

* cancer slope factor 

– negative 

+ positive 

(+) weakly positive result 

(–) weakly negative result 
RDX C-6
 
 

APPENDIX C 

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RDX D-1 

APPENDIX D. INDEX 

absorbed dose.............................................................................................................................................. 85 

acetylcholine ............................................................................................................................................... 80 

acetylcholinesterase .................................................................................................................................... 79 

adrenal gland............................................................................................................................................... 52 

adsorbed.................................................................................................................................................... 111 

adsorption.......................................................................................................................................... 111, 116
 

aerobic................................................................................................................................. 69, 113, 114, 115
 

alanine aminotransferase........................................................................................................... 11, 16, 19, 51
 

ambient air ........................................................................................................................................ 123, 124
 

anaerobic......................................................................................................... 9, 69, 107, 113, 114, 115, 122
 

aspartate aminotransferase .......................................................................................................................... 51 

bioaccumulation.................................................................................................................................... 9, 111
 

bioavailability ............................................................................................................................... 66, 95, 123
 

bioconcentration factor ............................................................................................................................. 111 

biodegradation....................................................................................................... 9, 107, 113, 114, 115, 126
 

biomarker .................................................................................................................. 84, 85, 86, 94, 127, 140
 

body weight effects............................................................................................................................... 53, 62
 

breast milk............................................................................................................................................. 4, 120
 

cancer.................................................................................................................................... 4, 22, 57, 83, 92
 

carcinogen....................................................................................................................................... 4, 12, 145
 

carcinogenic ........................................................................................................................ 11, 12, 21, 22, 57
 

carcinogenicity.............................................................................................................................. 11, 92, 113
 

carcinomas .............................................................................................................................. 11, 57, 92, 145
 

cardiovascular ................................................................................................................................. 22, 49, 58
 

cardiovascular effects...................................................................................................................... 23, 49, 58
 

cholinesterase.............................................................................................................................................. 79 

clearance ..................................................................................................................................................... 73 

death.................................................................................................................. 13, 19, 21, 22, 23, 25, 58, 90
 

deoxyribonucleic acid (see DNA)......................................................................................................... 62, 63
 

dermal effects.................................................................................................................................. 23, 52, 61
 

developmental effects ........................................................................... 11, 25, 56, 57, 62, 82, 84, 91, 93, 96
 

DNA (see deoxyribonucleic acid)............................................................................................. 62, 63, 85, 92
 

endocrine............................................................................................................................................... 81, 82
 

endocrine effects ......................................................................................................................................... 52 

erythema...................................................................................................................................................... 61 

fetus............................................................................................................................................. 4, 68, 82, 84
 

gastrointestinal effects .................................................................................................................... 23, 50, 58
 

general population......................................................................................................................... 9, 107, 119
 

genotoxic............................................................................................................................................... 21, 64
 

genotoxicity..................................................................................................................................... 62, 64, 92
 

groundwater .............................................. 2, 9, 105, 107, 111, 112, 115, 117, 119, 122, 123, 124, 137, 138
 

half-life............................................................................................................................ 9, 85, 107, 113, 122
 

hematological effects...................................................................................................................... 23, 50, 61
 

hepatic effects ................................................................................................................................. 23, 51, 61
 

hydrolysis.................................................................................................................. 107, 112, 135, 136, 139
 

immune system ........................................................................................................................................... 93 

immunological .................................................................................................................... 21, 24, 53, 88, 93
 

 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 


 

RDX D-2 

APPENDIX D 

immunological effects........................................................................................................................... 24, 53
 

Kow ............................................................................................................................................ 101, 111, 123
 

LD50....................................................................................................................................................... 25, 84
 

lymphoreticular........................................................................................................................................... 53 

metabolic effects ......................................................................................................................................... 53 

micronuclei ........................................................................................................................................... 64, 92
 

milk ......................................................................................................................................................... 4, 68
 

musculoskeletal effects ......................................................................................................................... 51, 61
 

neoplastic .................................................................................................................................................... 92 

neurobehavioral......................................................................................................................... 16, 54, 82, 94
 

neurological effects............................. 10, 14, 15, 17, 24, 53, 54, 55, 56, 62, 79, 81, 88, 90, 91, 94, 96, 143
 

neurotransmitter .......................................................................................................................................... 80 

nuclear....................................................................................................................................................... 121 

ocular effects............................................................................................................................. 49, 52, 58, 62
 

partition coefficients ................................................................................................................. 73, 74, 75, 76
 

pharmacodynamic ....................................................................................................................................... 70 

pharmacokinetic...................................................................................................... 15, 70, 71, 72, 83, 92, 93
 

photolysis...................................................................................................................... 9, 107, 112, 113, 122
 

placenta ................................................................................................................................................... 4, 68
 

rate constant ............................................................................................................................ 73, 75, 77, 111
 

renal effects......................................................................................................................... 22, 23, 52, 58, 61
 

reproductive effects............................................................................................................. 25, 55, 56, 62, 91
 

respiratory effects............................................................................................................................ 23, 49, 58
 

retention ...................................................................................................................................................... 24 

salivation..................................................................................................................................................... 17 

solubility ............................................................................................................................................... 9, 110
 

systemic effects....................................................................................................... 14, 22, 49, 58, 88, 90, 91
 

T3.......................................................................................................................................................... 26, 59
 

T4.............................................................................................................................................................. 100 

toxicokinetic.................................................................................................................. 21, 65, 81, 84, 95, 96
 

tremors ........................................................................................................ 10, 14, 15, 17, 18, 20, 54, 90, 91
 

tumors ..................................................................................................................................................... 4, 92
 

vapor pressure ........................................................................................................................................... 137 

volatilization ............................................................................................................................................. 110