EPA/635/R-13/140

Preliminary Materials

www.epa.gov/iris

Preliminary Materials for the Integrated Risk Information System (IRIS) 

Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

[CASRN 121-82-4] 

July 2013

NOTICE

This document is comprised of preliminary materials, consisting of a literature search strategy, 

evidence tables, and exposure-response arrays. This information is distributed solely for the 

purpose of pre-dissemination review under applicable information quality guidelines. It has not 

been formally disseminated by EPA. It does not represent and should not be construed to represent 

any Agency determination or policy. It is being circulated for review of its technical accuracy and 

science policy implications.

National Center for Environmental Assessment

Office of Research and Development

U.S. Environmental Protection Agency

Washington, DC
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

ii DRAFT—DO NOT CITE OR QUOTE

DISCLAIMER

This document is comprised of preliminary materials for review purposes only. This 

information is distributed solely for the purpose of pre-dissemination review under applicable 

information quality guidelines. It has not been formally disseminated by EPA. It does not represent 

and should not be construed to represent any Agency determination or policy. Mention of trade 

names or commercial products does not constitute endorsement or recommendation for use.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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CONTENTS

PREFACE....................................................................................................................................................... v

1. DRAFT LITERATURE SEARCH STRATEGY............................................................................................. 1-1

1.1. Literature Search and Screening Strategy for RDX...................................................................... 1-1

1.2. List of References Based on Search Strategy for RDX ............................................................... 1-15

1.2.1. Primary Sources of Health Effects Data ......................................................................... 1-15

1.2.2. Not Primary Source of Health Effects Data, but Kept as Additional Resources.............. 1-18

1.2.3. Kept for Possible Further Review................................................................................... 1-33

2. PRELIMINARY EVIDENCE TABLES AND EXPOSURE-RESPONSE ARRAYS.............................................. 2-1

2.1.Data Extraction: Preparation of Preliminary Evidence Tables and Exposure-Response 

Arrays.......................................................................................................................................... 2-1

2.2.Neurological Effects Evidence Tables and Array ......................................................................... 2-3

2.3.Mortality Evidence Table and Array............................................................................................ 2-8

2.4.Reproductive and Developmental Effects Evidence Tables and Array ...................................... 2-13

2.5. Liver Effects Evidence Tables and Array.................................................................................... 2-21

2.6.Kidney Effects Evidence Tables and Array................................................................................. 2-29

2.7.Carcinogenicity Evidence Tables............................................................................................... 2-35

2.8.Other Systemic Effects Evidence Tables.................................................................................... 2-37

2.9.Genotoxic Effects...................................................................................................................... 2-51
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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TABLES

Table 1-1. Overview of database search strategy for RDX ...................................................................... 1-4

Table 1-2. Summary of detailed search strategies for RDX (Pubmed, Toxline, Toxcenter, TSCATS)........ 1-6

Table 1-3. Summary of detailed search strategies for RDX (DTIC) ........................................................ 1-10

Table 1-4. Processes used to augment the search of core databases for RDX...................................... 1-12

Table 1-5. Summary disposition of DTIC database citations................................................................. 1-13

Table 2-1. Evidence pertaining to neurological effects in humans following exposure to RDX............... 2-3

Table 2-2. Evidence pertaining to neurological effects in animals following oral exposure to RDX ........ 2-4

Table 2-3. Evidence pertaining to mortality following oral exposure to RDX.......................................... 2-8

Table 2-4. Evidence pertaining to reproductive and developmental effects in animals following 

oral exposure to RDX.................................................................................................... 2-13

Table 2-5. Evidence pertaining to male reproductive effects in animals following oral exposure 

to RDX .......................................................................................................................... 2-17

Table 2-6. Evidence pertaining to liver effects of RDX in humans......................................................... 2-21

Table 2-8. Evidence pertaining to renal effects of RDX in humans........................................................ 2-29

Table 2-9. Evidence pertaining to renal effects in animals following oral exposure to RDX ................. 2-29

Table 2-10. Liver tumors observed in chronic animal bioassays following oral exposure to RDX ......... 2-35

Table 2-11. Lung tumors observed in chronic animal bioassays following oral exposure to RDX ......... 2-36

Table 2-12. Evidence pertaining to other systemic effects (hematological) of RDX in humans ............ 2-37

Table 2-13. Evidence pertaining to other systemic effects in animals following oral exposure to 

RDX............................................................................................................................... 2-38

Table 2-14. Summary of in vitro studies of RDX genotoxicity ............................................................... 2-51

Table 2-15. Summary of in vivo studies of RDX genotoxicity ................................................................ 2-53

Table 2-16. Summary of in vitro and in vivo studies of RDX metabolite genotoxicity........................... 2-54

FIGURES

Figure 1-1. Literature search approach for RDX...................................................................................... 1-5

Figure 2-1. Exposure-response array of neurological effects following oral exposure to RDX................ 2-7

Figure 2-2. Exposure-response array of mortality following oral exposure to RDX............................... 2-12

Figure 2-3. Exposure-response array of reproductive and developmental effects following oral 

exposure to RDX........................................................................................................... 2-16

Figure 2-4. Exposure-response array of male reproductive effects following oral exposure to 

RDX............................................................................................................................... 2-20

Figure 2-5. Exposure-response array of liver effects following oral exposure to RDX........................... 2-28

Figure 2-6. Exposure-response array of renal effects following oral exposure to RDX. ........................ 2-34
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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PREFACE

This document presents the draft literature search strategy, preliminary evidence tables, 

and preliminary exposure-response arrays for hexahydro-1,3,5-trinitro-1,3,5-triazine (henceforth 

referred to as RDX) prepared under the auspices of EPA’s Integrated Risk Information System 

(IRIS) Program. This material is being released for public viewing and comment prior to a public 

meeting, providing an opportunity for the IRIS Program to engage in early discussions with 

stakeholders and the public on data that may be used to identify adverse health effects and 

characterize exposure-response relationships. 

The draft literature search strategy, preliminary evidence tables, and preliminary exposureresponse arrays are responsive to the National Research Council (NRC) 2011 report Review of the 

Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde. The literature search 

strategy, which describes the processes for identifying scientific literature, screening studies for 

consideration, and selecting studies for inclusion in evidence tables, is responsive to NRC 

recommendations regarding systematic review of the scientific literature. In addition, NRC 

recommendations for standardized presentation of key study data are addressed in the preliminary 

evidence tables and preliminary exposure-response arrays. 

EPA welcomes all comments on the draft literature search strategy, preliminary evidence 

tables, and preliminary exposure-response arrays, such as remarks on the following:

• the clarity and transparency of the materials; 

• the approach for identifying pertinent studies;

• the selection of studies for data extraction to preliminary evidence tables and exposureresponse arrays; 

• any methodological considerations that could affect the interpretation of or confidence 

in study results; and

• any additional studies published or nearing publication that may provide data for the 

evaluation of human health hazard or dose-response relationships.

The preliminary evidence tables and exposure-response arrays should be regarded solely as 

representing the data on each endpoint that have been identified as a result of the draft literature 

search strategy. They do not reflect any conclusions as to hazard identification or dose-response 

assessment. After obtaining public input and conducting additional study evaluation and data 

integration, EPA will revise these materials to support the hazard identification and dose-response 

assessment in a draft Toxicological Review.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1. DRAFT LITERATURE SEARCH STRATEGY

1 1.1. Literature Search and Screening Strategy for RDX

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The overall literature search approach is shown in Table 1-1 and the results are 

summarized graphically in Figure 1-1. The literature search for RDX was conducted in five online 

scientific databases in February 2013. For four of these databases (Pubmed, Toxline, Toxcenter, 

and TSCATS) the detailed search strategy is provided in Table 1-2. Given the military applications 

of RDX, the Defense Technical Information Center (DTIC) database was searched. Because of 

limitations in the classification and distribution of materials in DTIC, a separate search strategy was 

applied, which is described in Table 1-3. The computerized database searches were augmented by 

review of online regulatory sources as well as “forward” and “backward” Web of Science searches of 

2 recent reviews (Table 1-4). 

A special strategy was applied to searches of the DTIC online database. A total of 858 

citations were identified, including 504 where the full-text document had unlimited distribution, 

304 classified as “distribution limited to U.S. Government agencies only,” and 50 classified as 

“distribution limited to Department of Defense only.” Of the 858 citations, 8 citations with 

unlimited distribution and 10 citations with limited distribution were selected for further review. 

Those 8 citations with unlimited distribution (that were not duplicated in other databases) were 

uploaded to the Health and Environmental Research Online (HERO) website1 (http://hero.epa.gov). 

The 10 limited-distribution citations were evaluated for relevance to the assessment (i.e., with a

focus on whether they provided additional primary health effects data) to determine whether EPA 

should seek authorization for public distribution and upload to HERO. A review of the abstract or 

full-text of the documents associated with the citation resulted in the following determinations:

• 4 of the 10 citations could be excluded from further consideration because the reports 

were not specific to RDX, or addressed environmental properties (e.g., leaching);

• 3 of the citations were determined not to provide additional primary health effects data 

because they either described a study plan for, or reported data from, experiments that 

were subsequently published (Williams et al., 2011; Hathaway and Buck, 1977) and had 

already been identified by the literature search strategy;

• 1 citation was identified as actually having unlimited distribution (duplicate record in 

DTIC database), and was added to the HERO database (Lish et al., 1984); 

 

1 HERO is a database of scientific studies and other references used to develop EPA’s risk assessments aimed at 

understanding the health and environmental effects of pollutants and chemicals. It is developed and managed in EPA’s 

Office of Research and Development (ORD) by the National Center for Environmental Assessment (NCEA). The database 

includes more than 300,000 scientific articles from the peer-reviewed literature. New studies are added continuously to 

HERO. 
Preliminary Materials for the IRIS Toxicological Review of RDX

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1 • 1 citation was identified as relevant and provided animal inhalation data, but was not 

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brought forward for further review because of study quality considerations. These 

study quality considerations included lack of a control group, small numbers of animals, 

incomplete information on dosage or exposure levels, and inadequate reporting; 

• 1 citation did not have an abstract or full text available outside of the Department of 

Defense. Based on the title, this report appeared to deal specifically with the 

manufacture and chemical/explosive properties of RDX. Given the available 

information, it was determined that it was unlikely the report would provide primary 

health effects data that warranted further review. 

The rationales for exclusion of the other 841 references that were not selected for further 

consideration are summarized in Table 1-5. 

 After electronically eliminating duplicates from the citations retrieved through these 

databases, 906 citations were identified. Additionally, 18 citations were obtained using additional 

search strategies described in Table 1-4. The resulting 924 citations were screened using the title, 

abstract, and in limited instances, full text for pertinence to examining the health effects of RDX 

exposure. A total of 652 references were identified as not being pertinent and were excluded from 

further consideration (see Figure 1-1 for the exclusion categories). A total of 47 references were 

identified as potential primary sources of health effects data and were considered for data 

extraction to evidence tables and exposure-response arrays (see Section 1.2.1). A total of 210

references were considered pertinent, but not as primary sources of health effects data (e.g., 

adsorption/distribution/metabolism/excretion [ADME] studies), and were kept as additional 

resources for development of the Toxicological Review (see Section 1.2.2). If a reference did not 

provide enough material to evaluate pertinence (e.g., no abstract), it was reserved for further 

possible review; 15 such studies were identified for RDX (see Section 1.2.3). EPA welcomes 

comments on studies identified for possible further review that may inform their utility to the 

development of the Toxicological Review. 

As illustrated in Figure 1-1, studies were identified and “tagged” in HERO based on 

information provided in the title and/or abstract; in some cases this information was supplemented 

by further review of the full text of the corresponding document. Based on this review, studies 

were distributed in different groups that reflect the primary content of the citation. It should be 

noted that studies were not given multiple tags, and the inclusion of a citation in a given category

(or tag) does not preclude its use in one or more other categories. For example, Woody et al. 

(1986) is a case report that describes accidental ingestion of RDX by a child. In Figure 1-1 it is 

included in the human studies category of primary health effects data. This case report also 

provides pharmacokinetic data and could be a pertinent source of information on the toxicokinetics

of RDX. In this instance, however, Woody et al. (1986) is not assigned a second tag for

toxicokinetics. For the purposes of this preliminary description of the literature search process, the 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 strategy of only using one tag per reference is utilized to allow the public and stakeholders to more 

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easily distinguish between citations that would be excluded from further review and those that may 

be utilized in the development of the assessment. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 Table 1-1. Overview of database search strategy for RDX

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Database Keywords

Pubmed

Toxline

TSCATS1

WOS

Toxcenter

DTIC

Chemical CASRN: 121-82-4 

Synonyms: Cyclonite OR RDX OR Cyclotrimethylenetrinitramine OR 

"cyclotrimethylene trinitramine" OR "Hexahydro-1,3,5-trinitro-1,3,5-triazine"

OR "Hexahydro-1,3,5-trinitro-s-triazine" OR Hexogen OR "1,3,5-trinitro-1,3,5-

triazine" OR "1,3,5-Triaza-1,3,5-trinitrocyclohexane" OR "1,3,5-Trinitro-1,3,5-

triazacyclohexane" OR "1,3,5-Trinitrohexahydro-1,3,5-triazine" OR "1,3,5-

Trinitrohexahydro-s-triazine" OR "1,3,5-Trinitroperhydro-1,3,5-triazine" OR 

"Esaidro-1,3,5-trinitro-1,3,5-triazina" OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazin" OR "Perhydro-1,3,5-trinitro-1,3,5-triazine" OR 

Cyclotrimethylenenitramine OR Trimethylenetrinitramine OR "Trimethylene 

trinitramine" OR Trimethyleentrinitramine OR "Trinitrocyclotrimethylene 

triamine" OR Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR 

Geksogen OR Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af) 

108" OR "PBXW 108(E)" OR "Pbx(AF) 108"

Synonym and CASRN search for all databases; Toxcenter, Pubmed, and WOS

limited using toxicity-related keywords

Toxicity-related terms (see Table 1-2 for specific keywords) 

Toxicity (including duration, effects to children and occupational exposure); 

development; reproduction; teratogenicity; exposure routes; 

pharmacokinetics; toxicokinetics; metabolism; body fluids; endocrinology; 

carcinogenicity; genotoxicity; antagonists; inhibitors

ChemID Searched by CASRN 

TSCATS 2 & 8e submissions
Preliminary Materials for the IRIS Toxicological Review of RDX

Figure 1-1. Literature search approach for RDX.

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This document is a draft for review purposes only and does not constitute Agency policy.

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Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 Table 1-2. Summary of detailed search strategies for RDX (Pubmed, Toxline, 

2 Toxcenter, TSCATS)

Database Set # Terms Hits

PubMed

Date limit:

1/1/2012 – 

2/2013

1A1 (Cyclonite[tw] OR RDX[tw] OR Cyclotrimethylenetrinitramine[tw] OR 

"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazine"[tw] OR "Hexahydro-1,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw] 

OR "1,3,5-trinitro-1,3,5-triazine"[tw] OR "1,3,5-Triaza-1,3,5-

trinitrocyclohexane"[tw] OR "1,3,5-Trinitro-1,3,5-triazacyclohexane"[tw] 

OR "1,3,5-Trinitrohexahydro-1,3,5-triazine"[tw] OR "1,3,5-

Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-

triazine"[tw] OR "Esaidro-1,3,5-trinitro-1,3,5-triazina"[tw] OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazin"[tw] OR "Perhydro-1,3,5-trinitro1,3,5-triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR 

Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR 

Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] 

OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 

Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR 

"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF) 

108"[tw]) AND (("2012/01/01"[Date - MeSH] : "3000"[Date - MeSH]) OR 

("2012/01/01"[Date - Entrez] : "3000"[Date - Entrez]) OR 

("2012/01/01"[Date - Create] : "3000"[Date - Create]))

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PubMed

Date limit:

1950's4/2012

1A2 ((((121-82-4) OR (Cyclonite[tw] OR Cyclotrimethylenetrinitramine[tw] OR 

"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazine"[tw] OR "Hexahydro-1,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw] 

OR "1,3,5-trinitro-1,3,5-triazine"[tw] OR "1,3,5-Triaza-1,3,5-

trinitrocyclohexane"[tw] OR "1,3,5-Trinitro-1,3,5-triazacyclohexane"[tw] 

OR "1,3,5-Trinitrohexahydro-1,3,5-triazine"[tw] OR "1,3,5-

Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-

triazine"[tw] OR "Esaidro-1,3,5-trinitro-1,3,5-triazina"[tw] OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazin"[tw] OR "Perhydro-1,3,5-trinitro1,3,5-triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR 

Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR 

Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] 

OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 

Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR 

"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF) 

108"[tw]) OR (rdx[tw])) NOT medline[sb]) OR (((121-82-4) OR 

(Cyclonite[tw] OR Cyclotrimethylenetrinitramine[tw] OR 

"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazine"[tw] OR "Hexahydro-1,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw] 

OR "1,3,5-trinitro-1,3,5-triazine"[tw] OR "1,3,5-Triaza-1,3,5-

trinitrocyclohexane"[tw] OR "1,3,5-Trinitro-1,3,5-triazacyclohexane"[tw] 

OR "1,3,5-Trinitrohexahydro-1,3,5-triazine"[tw] OR "1,3,5-

Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-

triazine"[tw] OR "Esaidro-1,3,5-trinitro-1,3,5-triazina"[tw] OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazin"[tw] OR "Perhydro-1,3,5-trinitro1,3,5-triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR 

Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR 

Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] 

OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 

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Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-7 DRAFT—DO NOT CITE OR QUOTE

Database Set # Terms Hits

Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR 

"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF) 

108"[tw]) OR (rdx[tw])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR 

(me[sh] AND (humans[mh] OR animals[mh])) OR ci[sh] OR bl[sh] OR cf[sh] 

OR ur[sh] OR ((pharmacokinetics[mh] OR metabolism[mh]) AND 

(humans[mh] OR mammals[mh])) OR "dose-response relationship, 

drug"[mh] OR risk[mh] OR "toxicity tests"[mh] OR noxae[mh] OR 

cancer[sb] OR "endocrine system"[mh] OR "endocrine disruptors"[mh] OR 

"Hormones, Hormone Substitutes, and Hormone Antagonists"[mh] OR 

triazines/ai OR ("Inhalation Exposure"[Mesh] OR "Maternal 

Exposure"[Mesh] OR "Maximum Allowable Concentration"[Mesh] OR 

"Occupational Exposure"[Mesh] OR "Paternal Exposure"[Mesh] OR 

"Environmental Exposure"[Mesh:noexp])))) NOT (((((121-82-4) OR 

(Cyclonite[tw] OR Cyclotrimethylenetrinitramine[tw] OR 

"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazine"[tw] OR "Hexahydro-1,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw] 

OR "1,3,5-trinitro-1,3,5-triazine"[tw] OR "1,3,5-Triaza-1,3,5-

trinitrocyclohexane"[tw] OR "1,3,5-Trinitro-1,3,5-triazacyclohexane"[tw] 

OR "1,3,5-Trinitrohexahydro-1,3,5-triazine"[tw] OR "1,3,5-

Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-

triazine"[tw] OR "Esaidro-1,3,5-trinitro-1,3,5-triazina"[tw] OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazin"[tw] OR "Perhydro-1,3,5-trinitro1,3,5-triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR 

Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR 

Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] 

OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 

Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR 

"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF) 

108"[tw]) OR (rdx[tw])) NOT medline[sb]) OR (((121-82-4) OR 

(Cyclonite[tw] OR Cyclotrimethylenetrinitramine[tw] OR 

"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-1,3,5-trinitro-1,3,5-

triazine"[tw] OR "Hexahydro-1,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw] 

OR "1,3,5-trinitro-1,3,5-triazine"[tw] OR "1,3,5-Triaza-1,3,5-

trinitrocyclohexane"[tw] OR "1,3,5-Trinitro-1,3,5-triazacyclohexane"[tw] 

OR "1,3,5-Trinitrohexahydro-1,3,5-triazine"[tw] OR "1,3,5-

Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-

triazine"[tw] OR "Esaidro-1,3,5-trinitro-1,3,5-triazina"[tw] OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazin"[tw] OR "Perhydro-1,3,5-trinitro1,3,5-triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR 

Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR 

Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] 

OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 

Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR 

"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF) 

108"[tw]) OR (rdx[tw])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR 

(me[sh] AND (humans[mh] OR animals[mh])) OR ci[sh] OR bl[sh] OR cf[sh] 

OR ur[sh] OR ((pharmacokinetics[mh] OR metabolism[mh]) AND 

(humans[mh] OR mammals[mh])) OR "dose-response relationship, 

drug"[mh] OR risk[mh] OR "toxicity tests"[mh] OR noxae[mh] OR 

cancer[sb] OR "endocrine system"[mh] OR "endocrine disruptors"[mh] OR 

"Hormones, Hormone Substitutes, and Hormone Antagonists"[mh] OR 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-8 DRAFT—DO NOT CITE OR QUOTE

Database Set # Terms Hits

triazines/ai OR ("Inhalation Exposure"[Mesh] OR "Maternal 

Exposure"[Mesh] OR "Maximum Allowable Concentration"[Mesh] OR 

"Occupational Exposure"[Mesh] OR "Paternal Exposure"[Mesh] OR 

"Environmental Exposure"[Mesh:noexp])))) AND (invertebrates OR 

aquatic organisms OR fish OR fishes OR amphibians OR earthworm*))

Toxline

Date limit 

2011-2013

1B1 @OR+("Cyclonite"+"RDX"+"Cyclotrimethylenetrinitramine"+"cyclotrimeth

ylene trinitramine"+"Hexahydro-1,3,5-trinitro-1,3,5-

triazine"+"Hexahydro-1,3,5-trinitro-s-triazine"+"Hexogen"+"1,3,5-trinitro1,3,5-triazine"+"1,3,5-Triaza-1,3,5-trinitrocyclohexane"+"1,3,5-Trinitro1,3,5-triazacyclohexane"+"1,3,5-Trinitrohexahydro-1,3,5-triazine"+"1,3,5-

Trinitrohexahydro-s-triazine"+@term+@rn+121-82-

4)+@AND+@range+yr+2011+2013+@NOT+@org+pubmed+pubdart+crisp

+tscats

5

1B2 @OR+("1,3,5-Trinitroperhydro-1,3,5-triazine"+"Esaidro-1,3,5-trinitro1,3,5-triazina"+"Hexahydro-1,3,5-trinitro-1,3,5-triazin"+"Perhydro-1,3,5-

trinitro-1,3,5-

triazine"+"Cyclotrimethylenenitramine"+"Trimethylenetrinitramine"+"Tri

methylene 

trinitramine"+"Trimethyleentrinitramine"+"Trinitrocyclotrimethylene 

triamine"+"Trinitrotrimethylenetriamine"+"CX 

84A"+"Cyklonit"+"Geksogen"+"Heksogen"+"Hexogeen"+"Hexolite"+"KHP 

281")+@AND+@range+yr+2011+2013+@NOT+@org+pubmed+pubdart+c

risp+tscats

0

Toxline

Date limit:

1907 –

4/2012

1B3 casrn or synonyms

-removed invertebrates, aquatic organisms, amphibians, earthworms

507

TSCATS 1C1 @term+@rn+121-82-4+@AND+@org+tscats 4

Toxcenter 

Date limit:

1/1/2012 –

2/2013

1D1 ((121-82-4 NOT (patent/dt OR tscats/fs)) OR (Cyclonite OR RDX OR 

Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazine" OR "Hexahydro-1,3,5-trinitro-striazine" OR Hexogen OR "1,3,5-trinitro-1,3,5-triazine" OR "1,3,5-Triaza1,3,5-trinitrocyclohexane" OR "1,3,5-Trinitro-1,3,5-triazacyclohexane" OR 

"1,3,5-Trinitrohexahydro-1,3,5-triazine" OR "1,3,5-Trinitrohexahydro-striazine" OR "1,3,5-Trinitroperhydro-1,3,5-triazine" OR "Esaidro-1,3,5-

trinitro-1,3,5-triazina" OR "Hexahydro-1,3,5-trinitro-1,3,5-triazin" OR 

"Perhydro-1,3,5-trinitro-1,3,5-triazine" OR Cyclotrimethylenenitramine 

OR Trimethylenetrinitramine OR "Trimethylene trinitramine" OR 

Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR

Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR Geksogen OR 

Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af) 108" OR 

"PBXW 108(E)" OR "Pbx(AF) 108") AND (py>2012 OR ed>20120101) AND 

(chronic OR immunotox? OR neurotox? OR toxicokin? OR biomarker? OR 

neurolog? OR pharmacokin? OR subchronic OR pbpk OR 

epidemiology/st,ct, it) OR acute OR subacute OR ld50# OR lc50# OR 

(toxicity OR adverse OR poisoning)/st,ct,it OR inhal? OR pulmon? OR 

nasal? OR lung? OR respir? OR occupation? OR workplace? OR worker? 

OR oral OR orally OR ingest? OR gavage? OR diet OR diets OR dietary OR 

26
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-9 DRAFT—DO NOT CITE OR QUOTE

Database Set # Terms Hits

drinking(w)water OR (maximum and concentration? and (allowable OR 

permissible)) OR (abort? OR abnormalit? OR embryo? OR cleft? OR fetus? 

OR foetus? OR fetal? OR foetal? OR fertil? OR malform? OR ovum OR ova 

OR ovary OR placenta? OR pregnan? OR prenatal OR perinatal? OR 

postnatal? OR reproduc? OR steril? OR teratogen? OR sperm OR 

spermac? OR spermag? OR spermati? OR spermas? OR spermatob? OR 

spermatoc? OR spermatog? OR spermatoi? OR spermatol? OR 

spermator? OR spermatox? OR spermatoz? OR spermatu? OR spermi? OR 

spermo? OR neonat? OR newborn OR development OR developmental? 

OR zygote? OR child OR children OR adolescen? OR infant OR wean? OR 

offspring OR age(w)factor? OR dermal? OR dermis OR skin OR epiderm? 

OR cutaneous? OR carcinog? OR cocarcinog? OR cancer? OR precancer? 

OR neoplas? OR tumor? OR tumour? OR oncogen? OR lymphoma? OR 

carcinom? OR genetox? OR genotox? OR mutagen? OR genetic(w)toxic? 

OR nephrotox? OR hepatotox? OR endocrin? OR estrogen? OR androgen? 

OR hormon? OR rat OR rats OR mouse OR mice OR muridae OR dog OR 

dogs OR rabbit? OR hamster? OR pig OR pigs OR swine OR porcine OR 

goat OR goats OR sheep OR monkey? OR macaque? OR marmoset? OR 

primate? OR mammal? OR ferret? OR gerbil? OR rodent? OR lagomorpha 

OR baboon? OR bovine OR canine OR cat OR cats OR feline OR pigeon? 

OR occupation? OR worker? OR epidem?) AND (biosis/fs AND py>1999 

AND (caplus/fs AND 4-?/cc)

Duplicates were removed; Biosis subfile results were date limited to avoid 

extensive overlap with Toxline

Toxcenter

Date limit:

1907 –

4/2012

1D2 ((121-82-4 NOT (patent/dt OR tscats/fs)) OR (Cyclonite OR RDX OR 

Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazine" OR "Hexahydro-1,3,5-trinitro-striazine" OR Hexogen OR "1,3,5-trinitro-1,3,5-triazine" OR "1,3,5-Triaza1,3,5-trinitrocyclohexane" OR "1,3,5-Trinitro-1,3,5-triazacyclohexane" OR 

"1,3,5-Trinitrohexahydro-1,3,5-triazine" OR "1,3,5-Trinitrohexahydro-striazine" OR "1,3,5-Trinitroperhydro-1,3,5-triazine" OR "Esaidro-1,3,5-

trinitro-1,3,5-triazina" OR "Hexahydro-1,3,5-trinitro-1,3,5-triazin" OR 

"Perhydro-1,3,5-trinitro-1,3,5-triazine" OR Cyclotrimethylenenitramine 

OR Trimethylenetrinitramine OR "Trimethylene trinitramine" OR 

Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR

Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR Geksogen OR 

Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af) 108" OR 

"PBXW 108(E)" OR "Pbx(AF) 108")AND (chronic OR immunotox? OR 

neurotox? OR toxicokin? OR biomarker? OR neurolog? OR pharmacokin? 

OR subchronic OR pbpk OR epidemiology/st,ct, it) OR acute OR subacute 

OR ld50# OR lc50# OR (toxicity OR adverse OR poisoning)/st,ct,it OR 

inhal? OR pulmon? OR nasal? OR lung? OR respir? OR occupation? OR 

workplace? OR worker? OR oral OR orally OR ingest? OR gavage? OR diet 

OR diets OR dietary OR drinking(w)water OR (maximum and 

concentration? and (allowable OR permissible)) OR (abort? OR 

abnormalit? OR embryo? OR cleft? OR fetus? OR foetus? OR fetal? OR 

foetal? OR fertil? OR malform? OR ovum OR ova OR ovary OR placenta? 

OR pregnan? OR prenatal OR perinatal? OR postnatal? OR reproduc? OR 

steril? OR teratogen? OR sperm OR spermac? OR spermag? OR spermati? 

OR spermas? OR spermatob? OR spermatoc? OR spermatog? OR 

spermatoi? OR spermatol? OR spermator? OR spermatox? OR spermatoz? 

337
Preliminary Materials for the IRIS Toxicological Review of RDX

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1-10 DRAFT—DO NOT CITE OR QUOTE

Database Set # Terms Hits

OR spermatu? OR spermi? OR spermo? OR neonat? OR newborn OR 

development OR developmental? OR zygote? OR child OR children OR 

adolescen? OR infant OR wean? OR offspring OR age(w)factor? OR 

dermal? OR dermis OR skin OR epiderm? OR cutaneous? OR carcinog? OR 

cocarcinog? OR cancer? OR precancer? OR neoplas? OR tumor? OR 

tumour? OR oncogen? OR lymphoma? OR carcinom? OR genetox? OR 

genotox? OR mutagen? OR genetic(w)toxic? OR nephrotox? OR 

hepatotox? OR endocrin? OR estrogen? OR androgen? OR hormon? OR 

rat OR rats OR mouse OR mice OR muridae OR dog OR dogs OR rabbit? 

OR hamster? OR pig OR pigs OR swine OR porcine OR goat OR goats OR 

sheep OR monkey? OR macaque? OR marmoset? OR primate? OR 

mammal? OR ferret? OR gerbil? OR rodent? OR lagomorpha OR baboon? 

OR bovine OR canine OR cat OR cats OR feline OR pigeon? OR 

occupation? OR worker? OR epidem?) AND (biosis/fs AND py>1999 AND 

(caplus/fs AND 4-?/cc)

Duplicates were removed; Biosis subfile results were date limited to avoid 

extensive overlap with Toxline

Merged 

Reference 

Set

1 Including additional strategies and DTIC (after duplicate removal) 924 

Table 1-3. Summary of detailed search strategies for RDX (DTIC)

1 

2 

Database Set # Terms Hits

DTIC

Search 

date: 

2/11/2013

2A1 key:((toxicity OR phramacokinetics OR toxicology OR pharmacology OR 

poisoning OR toxic hazards OR radiation hazards OR radiation effects OR 

toxic diseases OR toxic agents OR lethal agents OR antidotes OR death OR 

"signs and symptoms" OR cancer OR carinogens OR physiology OR 

biochemistry OR body weight OR anatomy OR body fluids OR metabolism 

OR immunology OR mutagens OR teratogenic compounds OR mutations 

OR antimetabolites) NOT (aquatic animals OR Invertebrates OR venomous

animals OR wildlife OR biodegradation)) and ("121-82-4" OR Cyclonite OR 

RDX OR Cyclotrimethylenetrinitramine OR "cyclotrimethylene 

trinitramine" OR "Hexahydro-1,3,5-trinitro-1,3,5-triazine" OR "Hexahydro1,3,5-trinitro-s-triazine" OR Hexogen OR Cyclotrimethylenenitramine OR 

Trimethylenetrinitramine OR "Trimethylene trinitramine" OR 

Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR 

Trinitrotrimethylenetriamine OR Hexolite ) and distco:(A) | Report Date: 

All dates

504

(8 selected and 

added to HERO)

2A2 Searched for: distco:(govt) and key:((toxicity OR phramacokinetics OR 

toxicology OR pharmacology OR poisoning OR toxic hazards OR radiation 

hazards OR radiation effects OR toxic diseases OR toxic agents OR lethal 

agents OR antidotes OR death OR "signs and symptoms" OR cancer OR 

carinogens OR physiology OR biochemistry OR body weight OR anatomy 

OR body fluids OR metabolism OR immunology OR mutagens OR 

teratogenic compounds OR mutations OR antimetabolites) NOT (aquatic 

animals OR Invertebrates OR venomous animals OR wildlife OR 

biodegradation)) and ("121-82-4" OR Cyclonite OR RDX OR 

304

(7 selected for 

further 

consideration)
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-11 DRAFT—DO NOT CITE OR QUOTE

Database Set # Terms Hits

Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazine" OR "Hexahydro-1,3,5-trinitro-striazine" OR Hexogen OR Cyclotrimethylenenitramine OR 

Trimethylenetrinitramine OR "Trimethylene trinitramine" OR 

Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR 

Trinitrotrimethylenetriamine OR Hexolite ) | Report Date: All dates

2A3 Searched for: distco:(dod) and key:((toxicity OR phramacokinetics OR 

toxicology OR pharmacology OR poisoning OR toxic hazards OR radiation 

hazards OR radiation effects OR toxic diseases OR toxic agents OR lethal 

agents OR antidotes OR death OR "signs and symptoms" OR cancer OR 

carinogens OR physiology OR biochemistry OR body weight OR anatomy 

OR body fluids OR metabolism OR immunology OR mutagens OR 

teratogenic compounds OR mutations OR antimetabolites) NOT (aquatic 

animals OR Invertebrates OR venomous animals OR wildlife OR 

biodegradation)) and ("121-82-4" OR Cyclonite OR RDX OR 

Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR 

"Hexahydro-1,3,5-trinitro-1,3,5-triazine" OR "Hexahydro-1,3,5-trinitro-striazine" OR Hexogen OR Cyclotrimethylenenitramine OR 

Trimethylenetrinitramine OR "Trimethylene trinitramine" OR 

Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR 

Trinitrotrimethylenetriamine OR Hexolite ) | Report Date: All dates

50

(3 selected for 

further 

consideration)

Merged 2 858

(8 added to HERO; 

see text)

1 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-12 DRAFT—DO NOT CITE OR QUOTE

1 Table 1-4. Processes used to augment the search of core databases for RDX

System Used Selected Key Reference(s) or Sources Date

Additional References 

Identified

Web of 

Science, 

forward search

Sweeney, LM; Gut, CP, Jr.; Gargas, ML; Reddy, G; Williams, 

LR; Johnson, MS. (2012). Assessing the non-cancer risk for 

RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) using 

physiologically based pharmacokinetic (PBPK) modeling. 62: 

107-114.

1 search result

3/2013 0 citations added

Sweeney, LM; Okolica, MR; Gut, CP, Jr; Gargas, ML. (2012). 

Cancer mode of action, weight of evidence, and proposed 

cancer reference value for hexahydro-1,3,5-trinitro-1,3,5-

triazine (RDX). Regul Toxicol Pharmacol 64: 205-224

0 search results

3/2013 0 citations added

Web of 

Science, 

backward 

search

Sweeney, LM; Gut, CP, Jr.; Gargas, ML; Reddy, G; Williams, 

LR; Johnson, MS. (2012). Assessing the non-cancer risk for 

RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) using 

physiologically based pharmacokinetic (PBPK) modeling. 62: 

107-114.

35 cited papers

3/2013 0 citations added

Sweeney, LM; Okolica, MR; Gut, CP, Jr; Gargas, ML. (2012). 

Cancer mode of action, weight of evidence, and proposed 

cancer reference value for hexahydro-1,3,5-trinitro-1,3,5-

triazine (RDX). Regul Toxicol Pharmacol 64: 205-224

69 cited papers

3/2013 3 citations added

Background 

Check 

Combination of CASRN and synonyms searched on the 

following websites:

ATSDR http://www.atsdr.cdc.gov/substances/index.asp

(Note: the reference list for the ATSDR toxicological profile 

for RDX was compared to the search results and relevant 

references were added)

CalEPA (Office of Environmental Health Hazard Assessment) 

(http://www.oehha.ca.gov/risk.html) 

eChemPortal

(http://www.echemportal.org/echemportal/participant/page

.action?pageID=9) 

EPA Acute Exposure Guideline Levels 

(http://www.epa.gov/oppt/aegl/pubs/chemlist.htm) 

EPA – IRISTrack/New Assessments and Reviews

(http://cfpub.epa.gov/ncea/iristrac/) to find dates

(http://www.epa.gov/ncea/iris/index.html) to find data

EPA NSCEP 

(http://www.epa.gov/ncepihom/) 

EPA Science Inventory

(http://cfpub.epa.gov/si/) 

Federal Docket 

www.regulations.gov

Health Canada First Priority List Assessments

4/11/2012 15 citations added
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-13 DRAFT—DO NOT CITE OR QUOTE

(http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psl1-

lsp1/index-eng.php) 

Health Canada Second Priority List Assessments

(http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psl2-

lsp2/index-eng.php) 

IARC 

(http://monographs.iarc.fr/htdig/search.html) 

IPCS INCHEM 

(http://www.inchem.org/) 

NAS 

via NAP (http://www.nap.edu/) 

NCI

(http://www.cancer.gov) 

NCTR 

(http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofS

cientificandMedicalPrograms/NCTR/default.htm) 

National Institute for Environmental Health Sciences (NIEHS)

http://www.niehs.nih.gov/

NIOSHTIC 2 

(http://www2a.cdc.gov/nioshtic-2/) 

NTP - RoC, status, results, and management reports 

(http://ntpsearch.niehs.nih.gov/query.html) 

WHO assessments – CICADS, EHC

(http://www.who.int/ipcs/assessment/en/) 

1 

2 

3 Table 1-5. Summary disposition of DTIC database citations

Criteria Percent of Citations 

Exclusion - Not chemical-specific ~50%

Exclusion - Bioremediation or biodegradation 5%

Exclusion - Chemical/physical properties of explosive properties <5%

Exclusion - Physical or chemical treatment <5%

Exclusion - Miscellaneous, including:

• Superfund RODs for which the abstract did not specify whether RDX was 

a contaminant of concern

• Meeting minutes and conference proceedings for which only general 

categories of topics were included in the DTIC record

• DTIC records containing only a title containing inadequate information 

with which to classify the citation

~35% 

Exclusion Total 98% (841 total)

Additional Resource – Regulatory documents <5%

Additional Resource – Reviews <5%

Additional Resource – Ecosystem effects <5%

Additional Resource – Risk assessments <5%

Additional Resource – Exposure levels <5%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-14 DRAFT—DO NOT CITE OR QUOTE

Additional Resource – Measurement methods <5%

Additional Resource – Mixture only <5%

Additional Resource – Toxicokinetics <5%

Possible Further Review – No abstract <5%

Possible Further Review – inadequate reporting in abstract <5%

Inclusion Total ~2% (17 total)

TOTAL NUMBER OF DTICS CITATIONS (including 10 limited distribution for further 

review)

858

1 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-15 DRAFT—DO NOT CITE OR QUOTE

1 1.2. List of References Based on Search Strategy for RDX 

2 

3 

4 

5 

6 

7 

8 

9 

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

Citations for excluded references are not listed here, but can be found on the Health and 

Environmental Research Online (HERO) Web site (http://hero.epa.gov/RDX). 

1.2.1. Primary Sources of Health Effects Data

Data from citations in bold are displayed in tabular or graphical form in Section 2. See 

Section 2.1 for a description of the process of selecting these studies for evidence tables and 

exposure-response arrays. 

Human Health Effects (21 citations)

1. ATSDR. (1996). Symptom and disease prevalence with biomarkers health study Cornhusker 

Army Ammunition Plant Hall County, Nebraska. Atlanta, GA. Div. of Health Studies. 

2. Barsotti, M., & Crotti, G. (1949). [Attacchi epileptici come manifestazione di intossicazione 

professionale da trimetilen-trinitroamina (T4)]. La Medicina del Lavoro, 40(4), 107-112. 

3. Davies, J. O. J., Roberts, D. M., Hittarage, A., & Buckley, N. A. (2007). Oral C-4 plastic explosive 

in humans - A case series. Clinical Toxicology, 45(5), 454-457. doi: 

10.1080/15563650601118044

4. Goldberg, D. J., Green, S. T., Nathwani, D., McMenamin, J., Hamlet, N., & Kennedy, D. H. 

(1992). RDX intoxication causing seizures and a widespread petechial rash mimicking 

meningococcaemia. Journal of the Royal Society of Medicine, 85(3), 181. 

5. Harrell-Bruder, B., & Hutchins, K. L. (1995). Seizures caused by ingestion of composition C4. Annals of Emergency Medicine, 26(6), 746-748. 

6. Hathaway, J. A., & Buck, C. R. (1977). Absence of health hazards associated with RDX 

manufacture and use. Journal of Occupational and Environmental Medicine, 19(4), 

269-272. 

7. Hett, D., & Fichtner, K. (2002). A plastic explosive by mouth. Journal of the Royal Society of 

Medicine, 95(5), 251-252. doi: 10.1258/jrsm.95.5.251

8. Hollander, A., & Colbach, E. (1969). Composition C-4 induced seizures: A report of five cases. 

Military Medicine, 134(13), 1529-1530. 

9. Kaplan, A. S., Berghout, C. F., & Peczenik, A. (1965). Human intoxication from RDX. Archives 

of Environmental Health, 10, 877-883. 

10. Kasuske, L., Schofer, J. M., & Hasegawa, K. (2009). Two marines with generalized seizure 

activity. Journal of Emergency Nursing, 35(6), 542-543. doi: 10.1016/j.jen.2008.05.001

11. Ketel, W. B., & Hughes, J. R. (1972). Toxic encephalopathy with seizures secondary to 

ingestion of composition C-4. A clinical and electroencephalographic study. Neurology, 

22(8), 871-876. 

12. Knepshield, J. H., & Stone, W. J. (Eds.). (1972). Toxic effects following ingestion of C-4 plastic 

explosive. Springfield, IL: Charles C. Thomas.

13. Küçükardali, Y., Acar, H. V., Özkan, S., Nalbant, S., Yazgan, Y., Atasoyu, E. M., Danaci, M. 

(2003). Accidental oral poisoning caused by RDX (cyclonite): A report of 5 cases. Journal of 

Intensive Care Medicine, 18(1), 42-46. doi: 10.1177/0885066602239123

14. Ma, B., & Li, H. (1992). Neurobehavioral effects of hexogen. Gongye Weisheng yu 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-16 DRAFT—DO NOT CITE OR QUOTE

1 Zhiyebin / Industrial health and occupational diseases, 19(1), 20-23. 

2 

3 

4 

5 

6 

7 

8 

9 

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

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31

32

33

34

35

36

37

38

39

40

41

42

43

15. Merrill, S. L. (1968). Ingestion of an explosive material, composition C-4: A report of two 

cases. U.S. Army Vietnam Medical Bulletin, 8, 5-11. 

16. Stone, W., Paletta, T., Heiman, E., Bruce, J. I., & Knepshield, J. H. (1969). Toxic effects 

following ingestion of C-4 plastic explosive. Archives of Internal Medicine, 124(6), 726-730. 

17. Testud, F., Glancaude, J. M., Imperatori, J., Le Meur, B., & Descotes, J. (1996). Acute poisoning 

from occupational exposure to hexogen, a novel nitrate explosive. Medicina y Seguridad del 

Trabajo(171), 119-127. 

18. Testud, F., Glanclaude, J., Imperatori, J., Le Meur, B., & Descotes, J. (1996). [Acute hexogen 

poisoning after occupational exposure, report of 2 cases]. Archives des Maladies 

Professionnelles de Medecine du Travail et de Securite Sociale, 57(5), 342-346. 

19. Testud, F., Glanclaude, J. M., & Descotes, J. (1996). Acute hexogen poisoning after 

occupational exposure. Journal of Toxicology - Clinical Toxicology, 34(1), 109-111. doi: 

10.3109/15563659609020244

20. West, R. R., & Stafford, D. A. (1997). Occupational exposures and haematological 

abnormalities among ordnance factory workers: A case control study. Leukemia 

Research, 21(7), 675-680. 

21. Woody, R. C., Kearns, G. L., Brewster, M. A., Turley, C. P., Sharp, G. B., & Lake, R. S. (1986). The 

neurotoxicity of cyclotrimethylenetrinitramine (RDX) in a child: A clinical and 

pharmacokinetic evaluation. Clinical Toxicology, 24(4), 305-319. doi: 

10.3109/15563658608992595

Animal Health Effects (26 citations)

1. Angerhofer, R., Davis, G., & Balezewski, L. (1986). Teratological assessment of 

Trinitro-RDX in rats. Aberdeen Proving Ground: U.S. Army Environmental Hygiene 

Agency.

2. Brown, D. (1975). The acute and chronic biochemical and behavioral effects of 

cyclotrimethylenetrinitramine. Baltimore, MD: Maryland University Baltimore School of 

Pharmacy.

3. Burdette, L., Cook, L., & Dyer, R. (1988). Convulsant properties of 

cyclotrimethylenetrinitramine (RDX): Spontaneous, audiogenic, and amygdaloid kindled 

seizure activity. Toxicology and Applied Pharmacology, 92(3), 436-444. doi: 10.1016/0041-

008x(88)90183-4 

4. Cholakis, J., Wong, L., Van Goethem, D., Minor, J., & Short, R. (1980). Mammalian 

toxicological evaluation of RDX (pp. 1-158). Kansas City, MO: Midwest Research 

Institute.

5. Crouse, L. C. B., Michie, M. W., Major, M., Johnson, M. S., Lee, R. B., & Paulus, H. I. 

(2006). Subchronic oral toxicity of RDX in rats. Aberdeen Proving Ground, MD: U.S. 

Army Center for Health Promotion and Preventive Medicine.

6. Dilley, J. V., Tyson, C. A., & Newell, G. W. (1979). Mammalian toxicological evaluation of TNT 

wastewaters. Volume II: Acute and subacute mammalian toxicity of TNT and the LAP 

mixture. Menlo Park, CA: SRI International.

7. Furedi-Machacek, M., Levine, B., & Lish, P. (1984). Determination of the chronic mammalian 

toxicological effects of RDX. Acute dermal toxicity test of hexehydro-1,3,5-trinitro-1,3,5-
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1 triazine (RDX) in rabbits. Chicago, IL: IIT Research Institute.

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B6C3F1 hybrid mouse. Phase VI final report. Volume 3. Chicago, IL: IIT Research 

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15. Levine, B. S., Furedi, E. M., Gordon, D. E., Burns, J. M., & Lish, P. M. (1981). Thirteen 

week toxicity study of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in Fischer 344 

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16. Levine, B. S., Lish, P. M., Furedi, E. M., Rac, V. S., & Sagartz, J. M. (1983). Determination 

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Fischer 344 rat Phase V: Final report. Chicago, IL: IIT Research Institute.

17. Lish, P. M., Levine, B. S., Furedi-Machacek, E. M., Sagartz, E. M., & Rac, V. S. (1984). 

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Preliminary Materials for the IRIS Toxicological Review of RDX

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triazine (RDX). Boca Raton, FL: Lewis Publishers.

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metabolic fate of munitions materials (TNT, RDX) in mature crops. (1995). Richland, WA; 

Department of Energy, Washington, DC: Technical Information Center Oak Ridge Tennessee.

2. . Evaluation of the metabolic fate of munitions material (TNT & RDX) in plant systems. 

Initial assessment of plant DNA mutation spectra as a biomarker. (1995). Richland, WA; 

Department of Energy, Washington, DC: Technical Information Center Oak Ridge Tennessee.
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1 3. . Evaluation of the Toxicological Effects of Explosives on Higher Plants, and the Effects on 

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5. . SERDP CU-1129 Biological Assessment for Characterizing Contamination Risk at the 

Genetic-, Individual-, and Population-Level. (2004). Vicksburg, MS. Engineer Research and 

Development Center

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8. Army, U. S. (1993). Toxicity of Nitroguanidine, Nitroglycerin, Hexahydro-1,3,5-Trinitro1,3,5-Triazine (RDX), and 2,4,6-Trinitrotoluene (TNT) to Selected Freshwater Aquatic 

Organisms: U.S. Army.

9. Army, U. S. (1995). Evaluation of Metabolic Fate of Munitions Material (TNT and RDX) in 

Plant Systems and Initial Assessment of DNA Mutation Spectra as a Biomarker: U.S. Army.

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in plant systems and initial assessment of material interaction with plant genetic material 

(DNA). Initial assessment of plant DNA adducts as biomarkers: U.S. Army.

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Editorials (2 citations)

1. Bannon, D. I., Johnson, M., Williams, L., Adams, V., Perkins, E., Gust, K., & Gong, P. (2009). 

RDX and miRNA expression in B6C3F1 Mice. [Letter]. Environmental Health Perspectives, 

117(3), A98. doi: 10.1289/ehp.0800276

2. Zhang, B., & Pan, X. (2009). RDX and miRNA expression: Zhang and Pan respond. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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Materials, 217-218, 187-193. doi: 10.1016/j.jhazmat.2012.03.012

92. Wang, C., Fuller, M. E., Schaefer, C. E., Fu, D., & Jin, Y. (2012). Modeling the dissolution of 

various types of mixed energetic residues under different flow conditions. Journal of 

Hazardous Materials, 235-236, 138-143. doi: 10.1016/j.jhazmat.2012.07.035

93. Xue, S. K., Iskandar, I. K., & Selim, H. M. (1995). Adsorption-desorption of 2, 4, 6-

trinitrotoluene and hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine in soils. Soil Science, 160(5), 

317-327. 

94. Yoon, J. M., Van Aken, B., & Schnoor, J. L. (2006). Leaching of contaminated leaves following 

uptake and phytoremediation of RDX, HMX, and TNT by poplar. International Journal of 

Phytoremediation, 8(1), 81-94. doi: 10.1080/15226510500507128

95. Yue, H., Wan, H., Chai, W. l., Wu, H. m., Kao, X. b., & Wang, Y. l. (2011). Investigation on 

occupational hazard factors in small and middle test workplaces of explosive industry. 

Chinese Journal of Public Health Engineering / Zhongguo wei sheng gong cheng xue, 10(2), 

91-93. 

96. Zheng, W., Lichwa, J., D'Alessio, M., & Ray, C. (2009). Fate and transport of TNT, RDX, and 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 HMX in streambed sediments: Implications for riverbank filtration. Chemosphere, 76(9), 

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1167-1177. doi: 10.1016/j.chemosphere.2009.06.043

Mixtures Only (3 citations)

1. Berthe-Corti, L., Jacobi, H., Kleihauer, S., & Witte, I. (1998). Cytotoxicity and mutagenicity of 

a 2,4,6-trinitrotoluene (TNT) and hexogen contaminated soil in S. typhimurium and 

mammalian cells. Chemosphere, 37(2), 209-218. doi: 10.1016/s0045-6535(98)00039-3 

2. Dilley, J., Tyson, C., Spanggord, R., Sasmore, D., Newell, G., & Dacre, J. (1982). Short-term oral 

toxicity of a 2, 4, 6-trinltrotoluene and hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine mixture in 

mice, rats, and dogs. Journal of Toxicology and Environmental Health, Part A: Current Issues, 

9(4), 587-610. doi: 10.1080/15287398209530189

3. Twerdok, L. E., Burton, D. T., Gardner, H. S., Shedd, T. R., & Wolfe, M. J. (1997). The use of 

nontraditional assays in an integrated environmental assessment of contaminated ground 

water. Environmental Toxicology and Chemistry, 16(9), 1816-1820. doi: 

10.1002/etc.5620160908

Toxicokinetics (16 citations)

1. Bell, S. C., Gayton-Ely, M., & Nida, C. M. (2009). Bioassays for bomb-makers: Proof of concept. 

Analytical and Bioanalytical Chemistry, 395(2), 401-409. doi: 10.1007/s00216-009-2851-4 

2. Bhushan, B., Trott, S., Spain, J. C., Halasz, A., Paquet, L., & Hawari, J. (2003). 

Biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) by a rabbit liver 

cytochrome P450: Insight into the mechanism of RDX biodegradation by Rhodococcus sp. 

strain DN22. Applied and Environmental Microbiology, 69(3), 1347-1351. doi: 

10.1128/aem.69.3.1347-1351.2003

3. Crouse, L. C. B., Michie, M. W., Major, M. A., Leach, G. J., & Reddy, G. (2008). Oral 

bioavailability of cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats. 

International Journal of Toxicology, 27(4), 317-322. doi: 10.1080/10915810802366885

4. Guo, L., Xu, H., Chen, Y., & Chang, Y. (1985). Distribution and metabolism of tritium-labeled 

hexogen in white mice. Zhonghua Laodong Weisheng Zhiyebing Zazhi, 3(6), 335-339. 

5. Krishnan, K., Crouse, L. C. B., Bazar, M. A., Major, M. A., & Reddy, G. (2009). Physiologically 

based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats. Journal of 

Applied Toxicology, 29(7), 629-637. doi: 10.1002/jat.1455

6. Major, M. A., Reddy, G., Berge, M. A., Patzer, S. S., Li, A. C., & Gohdes, M. (2007). Metabolite 

profiling of [14C]hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in Yucatan miniature pigs. 

Journal of Toxicology and Environmental Health, Part A: Current Issues, 70(14), 1191-1202. 

doi: 10.1080/15287390701252717

7. Mintzer, E., Kizerian, A., Grant, K., Hoppe, E. W., & Campbell, J. A. (2007). Saliva as a matrix 

for the detection of RDX, and TNT and its major metabolites as biomarkers for exposure by 

Gas Chromatography/Mass Spectrometry. NW-007. 

8. Musick, T. J., Berge, M. A., Patzer, S. S., & Tilch, K. R. (2010). Absorption, distribution, 

metabolism, and excretion of 14C-RDX following oral administration to minipigs. Madison, 

WI: Covance Laboratories Inc.

9. Pan, X., Ochoa, K. M., San Francisco, M. J., Cox, S., Dixon, K., Anderson, T., & Cobb, G. (2013). 

Absorption, distribution, and biotransformation of hexahydro-1,3,5-trinitro-1,3,5-triazine 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 (RDX) in B6C3F1 mice (Mus musculus). Environmental Toxicology and Chemistry. doi: 

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10. Pan, X., Zhang, B., Smith, J. N., San Francisco, M., Anderson, T. A., & Cobb, G. P. (2007). NNitroso compounds produced in deer mouse (Peromyscus maniculatus) GI tracts following 

hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) exposure. Chemosphere, 67(6), 1164-1170. 

doi: 10.1016/j.chemosphere.2006.10.077

11. Reddy, G., Allen, N. A., & Major, M. A. (2008). Absorption of 14Ccyclotrimethylenetrinitramine (RDX) from soils through excised human skin. Toxicology 

Mechanisms and Methods, 18(7), 575-579. doi: 10.1080/15376510701703466

12. Reifenrath, W. G., Kammen, H. O., Palmer, W. G., Major, M. M., & Leach, G. J. (2002). 

Percutaneous absorption of explosives and related compounds: An empirical model of 

bioavailability of organic nitro compounds from soil. Toxicology and Applied Pharmacology, 

182(2), 160-168. doi: 10.1006/taap.2002.9436

13. Reifenrath, W. G., Kammen, H. O., Reddy, G., Major, M. A., & Leach, G. J. (2008). Interaction of 

hydration, aging, and carbon content of soil on the evaporation and skin bioavailability of 

munition contaminants. Journal of Toxicology and Environmental Health, Part A: Current 

Issues, 71(8), 486-494. doi: 10.1080/15287390801906956

14. Schneider, N., Bradley, S., & Andersen, M. (1976). Metabolism of 

[14C]cyclotrimethylenetrinitramine (RDX) in the rat. Toxicology and Applied Pharmacology, 

37(1), 137. doi: 10.1016/s0041-008x(76)80011-7 

15. Schneider, N., Bradley, S., & Andersen, M. (1977). Toxicology of 

cyclotrimethylenetrinitramine (RDX): Distribution and metabolism in the rat and the 

miniature swine. Toxicology and Applied Pharmacology, 39(3), 531-541. doi: 10.1016/0041-

008x(77)90144-2 

16. Schneider, N., Bradley, S., & Andersen, M. (1978). The distribution and metabolism of 

cyclotrimethylenetrinitramine (RDX) in the rat after subchronic administration. Toxicology 

and Applied Pharmacology, 46(1), 163-171. doi: 10.1016/0041-008x(78)90147-3 

Genotoxicity (9 citations)

1. Arfsten, D., Davenport, R., & Schaeffer, D. (1994). Reversion of bioluminescent bacteria 

(Mutatox TM) to their luminescent state upon exposure to organic compounds, munitions, 

and metal salts. Biomedical and Environmental Sciences, 7(2), 144-149. 

2. Cotruvo, J. A., Simmon, V. F., & Spanggord, R. J. (1977). Investigation of mutagenic effects of 

products of ozonation reactions in water. Annals of the New York Academy of Sciences, 298(1

Aquatic Pollu), 124-140. doi: 10.1111/j.1749-6632.1977.tb19259.x

3. George, S. E., Huggins-Clark, G., & Brooks, L. R. (2001). Use of a Salmonella microsuspension 

bioassay to detect the mutagenicity of munitions compounds at low concentrations. 

Mutation Research, 490(1), 45-56. doi: 10.1016/s1383-5718(00)00150-9 

4. Lachance, B., Robidoux, P. Y., Hawari, J., Ampleman, G., Thiboutot, S., & Sunahara, G. I. 

(1999). Cytotoxic and genotoxic effects of energetic compounds on bacterial and 

mammalian cells in vitro. Mutation Research, 444(1), 25-39. doi: 10.1016/s1383-

5718(99)00073-x 

5. Neuwoehner, J., Schofer, A., Erlenkaemper, B., Steinbach, K., Hund-Rinke, K., & Eisentraeger, 

A. (2007). Toxicological characterization of 2,4,6-trinitrotoluene, its transformation 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

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1 products, and two nitramine explosives. Environmental Toxicology and Chemistry, 26(6), 

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1090-1099. doi: 10.1897/06-471r.1

6. Pan, X., San Francisco, M. J., Lee, C., Ochoa, K. M., Xu, X., Liu, J., Cobb, G. P. (2007). 

Examination of the mutagenicity of RDX and its N-nitroso metabolites using the Salmonella 

reverse mutation assay. Mutation Research: Genetic Toxicology and Environmental 

Mutagenesis, 629(1), 64-69. doi: 10.1016/j.mrgentox.2007.01.006

7. Reddy, G., Erexson, G. L., Cifone, M. A., Major, M. A., & Leach, G. J. (2005). Genotoxicity 

assessment of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). International Journal of 

Toxicology, 24(6), 427-434. doi: 10.1080/10915810500366922

8. Tan, E., Ho, C., Griest, W., & Tyndall, R. (1992). Mutagenicity of trinitrotoluene and its 

metabolites formed during composting. Journal of Toxicology and Environmental Health, 

Part A: Current Issues, 36(3), 165-175. doi: 10.1080/15287399209531632

9. Whong, W. Z., Speciner, N. D., & Edwards, G. S. (1980). Mutagenic activity of tetryl, a 

nitroaromatic explosive, in three microbial test systems. Toxicology Letters, 5(1), 11-17. doi: 

10.1016/0378-4274(80)90142-3 

Mechanistic Data (13 citations)

1. Bannon, D. I., Dillman, J. F., Hable, M. A., Phillips, C. S., & Perkins, E. J. (2009). Global gene 

expression in rat brain and liver after oral exposure to the explosive hexahydro-1,3,5-

trinitro-1,3,5-triazine (RDX). Chemical Research in Toxicology, 22(4), 620-625. doi: 

10.1021/tx800444k

2. Bannon, D. I., Dillman, J. F., Perkins, E. J., Bao, W., Wolfinger, R. D., Chu, T., & Phillips, C. S. 

(2006). Acute RDX exposure and gene expression in the rat brain. [Abstract]. Toxicologist, 

90(S1), 392-393.

3. Corcelli, A., Lobasso, S., Lopalco, P., Dibattista, M., Araneda, R., Peterlin, Z., & Firestein, S. 

(2010). Detection of explosives by olfactory sensory neurons. Journal of Hazardous 

Materials, 175(1-3), 1096-1100. doi: 10.1016/j.jhazmat.2009.10.054

4. Ehrich, M., Wu, X., Werre, S. R., Major, M. A., McCain, W. C., & Reddy, G. (2009). Calcium 

signaling in neuronal cells exposed to the munitions compound 

cyclotrimethylenetrinitramine (RDX). International Journal of Toxicology, 28(5), 425-435. 

doi: 10.1177/1091581809340331

5. Ford-Green, J., Isayev, O., Gorb, L., Perkins, E. J., & Leszczynski, J. (2012). Evaluation of 

natural and nitramine binding energies to 3-D models of the S1S2 domains in the N-methylD: -aspartate receptor. Journal of Molecular Modeling, 18(4), 1273-1284. doi: 

10.1007/s00894-011-1152-y 

6. Forgacs, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A., & Zacharewski, T. R. 

(2012). BLTK1 Murine Leydig Cells: A Novel Steroidogenic Model for Evaluating the Effects 

of Reproductive and Developmental Toxicants. Toxicological Sciences, 127(2), 391-402. doi: 

10.1093/toxsci/kfs121

7. Li, A. P. (2010). Evaluation of the cytotoxic potential of RDX in primary human cell cultures 

as integrated discrete multiple organ co-cultures (IdMOC) and as individual primary 

cultures. Columbia, MD: In Vitro ADMET Laboratories.

8. Meyer, S. A. (2006). Role of myelofibrosis in hematotoxicity of munition RDX environmental 

degradation product MNX. 2006 Update. Monroe, LA: University of Louisiana at Monroe.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-33 DRAFT—DO NOT CITE OR QUOTE

1 9. Meyer, S. A. (2007). Role of myelofibrosis in hematotoxicity of munitions RDX 

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environmental degradation product MNX. 2007 Update. Monroe, LA: University of Louisiana 

at Monroe.

10. Perkins, E. J., Bao, W., Guan, X., Ang, C. Y., Wolfinger, R. D., Chu, T. M., Inouye, L. S. (2006). 

Comparison of transcriptional responses in liver tissue and primary hepatocyte cell cultures 

after exposure to hexahydro-1, 3, 5-trinitro-1, 3, 5-triazine. B M C Bioinformatics, 7(Suppl 4), 

S22. doi: 10.1186/1471-2105-7-s4-s22

11. Way, M. R., & McCain, W. C. (2007). Protective effects of the calcium channel blocker, 

Verapamil in rats exposed to RDX. Aberdeen Proving Ground, MD: U.S. Army Center for 

Health Promotion and Preventive Medicine.

12. Williams, L. R., Aroniadou-Anderjaska, V., Qashu, F., Finne, H., Pidoplichko, V., Bannon, D. I., 

& Braga, M. F. (2011). RDX binds to the GABA(A) receptor-convulsant site and blocks 

GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced 

seizures. Environmental Health Perspectives, 119(3), 357-363. doi: 10.1289/ehp.1002588

13. Zhang, B., & Pan, X. (2009). RDX induces aberrant expression of microRNAs in mouse brain 

and liver. Environmental Health Perspectives, 117(2), 231-240. doi: 10.1289/ehp.11841

1.2.3. Kept for Possible Further Review

No abstract (9 citations)

1. Bruchim, Y., Saragusty, J., Weisman, A., & Sternheim, D. (2005). Cyclonite (RDX) intoxication 

in a police working dog. Veterinary Record, 157(12), 354-356. 

2. Croft, P. E. (1983). Cyclonite poisoning in a dog. [Letter]. Veterinary Record, 113(20), 477. 

doi: 10.1136/vr.113.20.477-a 

3. Jacobs, A. (1991). Haematological study at Ordnance Factory [Unpublished report]. Cardiff, 

UK: University of Wales College of Medicine.

4. Kale, V. M. (2007). Mechanistic studies on hepatotoxicity of chloroacetanilide herbicides and 

hematotoxicity of munitions compound RDX and environmental degradation product MNX.

(Doctoral Dissertation), University of Louisiana at Monroe, Monroe, LA. Retrieved from 

http://proquest.umi.com/pqdlink?did=1445039451&Fmt=7&clientI 

d=79356&RQT=309&VName=PQD 

5. Littlewood, J. D., Watkins, S. B., & Watney, G. C. (1983). Cyclonite poisoning in a dog. [Letter]. 

Veterinary Record, 113(21), 503. doi: 10.1136/vr.113.21.503-a 

6. Miller, K. C. (1973). Toxicity and Adverse Effects of RDX: an Annotated Bibliography: Miller, 

KC.

7. Mindi, Q. W., Li, B., & Chen, R. (1995). The Mutagenicity of Several Chemicals by Vicia 

Micronucleus Vicia-MCN Assay (Vol. ST, pp. 12-16): Mindi, QW; Li, B; Chen, R.

8. Sklyanskaya, R. M., & Pozhariskii, F. I. (1944). On the question of hexogen toxicity. 

Farmakologiya i Toksikologiya, 7(3), 43-47. 

9. Vogel, W. (1951). Hexogen poisoning in human beings. Zentralblatt fuer Arbeitsmedizin und 

Arbeitsschutz, 1, 51-54. 

Foreign language (2 citations) 

1. Dong, Y., Li, J., Xiang, S., Yang, S., Bao, Z., Fan, H., Li, Z. (1997). [Application of serum bile acid 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a draft for review purposes only and does not constitute Agency policy.

1-34 DRAFT—DO NOT CITE OR QUOTE

1 chromatography to the diagnoses of liver diseases]. Hua Xi Yi Ke Da Xue Xue Bao, 28(1), 69-

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72. 

2. Zhang, M. D. (1982). Food poisoning caused by hexogen: A report of 8 cases. Zhonghua 

Yufang Yixue Zazhi, 16(4), 229-231. 

Inadequate reporting in abstract (4 citations)

1. . Final report on occupational health and safety at the plants of "Les Produits Chimiques 

Expro Inc." (1983) (Vol. Government of Quebec): Gouvernement du QuÃ¢ebec.

2. Berry, A., Arbuckle, J., & Nicol, J. (1983). Cyclonite poisoning in a dog. Veterinary Record, 

113(19), 449. 

3. De Cramer, K. G., & Short, R. P. (1992). Plastic explosive poisoning in dogs. Journal of the 

South African Veterinary Medical Association, 63(1), 30-31. 

4. Wang, Y., Yan, C., Xia, B., & Tang, H. (2001). Study on health standard of octogen in air of 

workplaces. Gongye Weisheng yu Zhiyebin / Industrial health and occupational diseases, 

27(3), 134-136. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-1 DRAFT—DO NOT CITE OR QUOTE

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2. PRELIMINARY EVIDENCE TABLES AND 

EXPOSURE-RESPONSE ARRAYS

2.1. Data Extraction: Preparation of Preliminary Evidence Tables and 

Exposure-Response Arrays 

The 47 references identified as primary sources of health effects data were considered for 

data extraction to evidence tables and exposure-response arrays. References were first collated 

with respect to exposure route, exposure duration, and type of endpoint, to identify those most 

pertinent for evaluating the human health effects from chronic oral or inhalation exposure to RDX. 

As a result, data from 27 studies with one or more of the following characteristics were not 

extracted into evidence tables or exposure-response arrays:

• The study involved human case reports, dermal exposure or intravenous/intraperitoneal

exposure;

• The study only involved acute or short-term exposures (less than 30 days), and it was not 

conducted in the context of immune, developmental, neurological or reproductive toxicity;

• The data in the study only included endpoints related to possible mechanisms of toxicity; 

• No effects were associated with exposure to RDX for the endpoints evaluated in the study, 

nor were RDX-related effects observed for those endpoints in any of the other available 

references. 

Data from the 20 remaining references were summarized in preliminary evidence tables. 

No studies were excluded based on study quality considerations, so as to allow for public input on 

methodological considerations that could affect the interpretation of, or confidence in, each study’s 

results. In some instances, references are grouped together as “related” references because they 

represent pilot (e.g., range-finding), unpublished (e.g., technical reports, some with multiple 

volumes), and/or published (e.g., journal article) versions of the same study. The tables for 

noncarcinogenic effects appear first and are arranged in the order from the health effect with the 

most data to the health effect with the least data. The tables for carcinogenic effects follow, along 

with other systemic effects, which are those with little data to determine hazard. Finally, tables 

present data on genotoxic effects of RDX and its metabolites. Within each endpoint, the studies are 

presented beginning with chronic studies followed by those with subchronic exposures. The 

information in the preliminary evidence tables is displayed graphically in preliminary exposureresponse arrays. In these arrays, a significant effect (indicated by a filled datapoint) is based on 

statistical significance, with the exception of the arrays for mortality and neurological endpoints. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-2 DRAFT—DO NOT CITE OR QUOTE

1 For these two endpoints, it was determined that the severity of the endpoints (seizures and death) 

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warranted identification based on biological significance. A study with a low number of animals per 

dose group may preclude identifying a change from the control as statistically significant when the 

incidence is low; however, given the severity of the effect, the observed effect was identified as 

biologically significant. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-3 DRAFT—DO NOT CITE OR QUOTE

2.2. Neurological Effects Evidence Tables and Array

Table 2-1. Evidence pertaining to neurological effects in humans following 

exposure to RDX

1 

2 

3 

4 

Reference and Study Design Results

Ma and Li (1992) (China)

Cross-sectional study, 60 workers exposed to 

RDX (30 in Group A [26 males; 4 females]; 30 in

Group B [24 males; 6 females]), compared to 

32 workers with similar age, education level, 

and length of employment from same plant 

with no exposure to RDX (27 males; 5 females). 

Exposure measures: Details of exposure 

measurement were not provided; exposed 

workers were divided into two groups based on 

RDX concentration in the air:

3 Concentration (mg/m )

Group A 0.407 (± 0.332)

Group B 0.672 (± 0.556)

a Effect measures : Five neurobehavioral

function tests and five additional memory 

subtests. 

Analysis: Variance (F-test); unadjusted linear 

regression, multiple regression, and correlation 

analysis. 

Neurobehavioral function tests, scaled scores (mean, standard 

deviation):

Test Group A Group B Control

Memory retention*

Simple reaction time

Choice reaction time

Block design*

Letter cancellation 

96.9 (9.6)

539 (183)

775 (161)

16.0 (4.3)

1449 (331)

91.1 (10.3)

578 (280)

770 (193)

13.5(6.7)

1484 (443)

111.3 (9.3)

493 (199)

763 (180)

18.0 (5.4)

1487 (343)

*p < 0.01 (overall F-test); no statistically significant differences 

between Group A and Group B. 

Lower score indicates worse performance.

Memory retention subtests, scaled scores (mean, standard 

deviation):

Subtest Group A Group B Control

Directional memory*

Associative learning* 

Image free recall* 

Recognition of nonsense 

pictures*

Associative recall of 

portrait characteristics* 

17.2 (4.9)

20.0 (4.3)

20.9 (4.1)

23.2 (4.9)

20.3 (4.4)

18.1 (5.7)

18.5 (4.6)

20.4 (3.3)

21.6 (4.3)

18.5 (4.3)

23.5 (3.6)

24.9 (5.1)

24.1 (3.8)

26.3 (3.6)

26.3 (3.3)

*p < 0.01 (overall F-test); no statistically significant differences 

between Group A and Group B. 

Lower score indicates worse performance.

Total behavioral score negatively correlated with exposure index 

(high exposure correlated with poor performance).

a

Symptom data were not included in evidence table because of incomplete reporting. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-4 DRAFT—DO NOT CITE OR QUOTE

1 Table 2-2. Evidence pertaining to neurological effects in animals following 

2 oral exposure to RDX

Reference and Study Design Results

Lish et al. (1984); Levine et al. (1984) 

Mice, B6C3F1, 85/sex/group; interim 

sacrifices (10/sex/group) at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high 

dose reduced to 100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

One male mouse in the 35 mg/kg-d dose group and one female

mouse in the 175/100 mg/kg-da group convulsed near the end of the 

study.

Hart (1976) 

Rats, Sprague-Dawley, 100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

No neurological effects, as evidenced by clinical signs or changes in 

appearance or behavior, were reported.

Levine et al. (1983); Thompson (1983) 

Rats, F344, 75/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Tremors, convulsions, and hyper-responsiveness to stimuli were 

noted at 40 mg/kg-da; no incidence data were reported.

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group

0, 40, 60, or 80 mg/kg-d for 2 wks followed 

by 0, 320, 160, or 80 mg/kg-d (TWA doses of 

0, 79.6, 147.8, or 256.7 mg/kg-d for males 

and 0, 82.4, 136.3, or 276.4 mg/kg-d for 

females)b

Diet

13 wks

Hyperactivity and/or nervousness observed in 50% of the high-dose 

males; no signs observed in females

a

; no incidence data were 

reported.

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

No neurological effects, as evidenced by clinical signs or changes in 

appearance or behavior, were reported. 
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-5 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Cholakis et al. (1980)

Rats, CD, two-generation study; 

F0: 22/sex/group; F1: 26/sex/group; 

F2: 10/sex/group 

F0 and F1 parental animals: 0, 5, 16, or 

50 mg/kg-d

Diet

13 wks

No neurological effects were reported.

Crouse et al. (2006)

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d

Gavage

90 d

Doses 0 4 8a 10 12 15

Convulsions (incidence)

M 0/10 0/10 1/10 3/10 8/10 7/10

F 0/10 0/10 2/10 3/10 5/10 5/10

Tremors (incidence)

M 0/10 0/10 0/10 0/10 2/10 3/10

F 0/10 0/10 0/10 0/10 0/10 1/10

Levine et al. (1990); Levine et al. (1981a); 

Levine et al. (1981b)

Rats, F344, 10/sex/group; 30/sex for control

0, 10, 30, 100, 300, or 600 mg/kg-d

Diet

13 wks

Hyper-reactivity to approach was observed in groups receiving 

≥100 mg/kg-da

; no incidence data were reported.

Tremors and convulsions were observed prior to death in some 

animals receiving 600 mg/kg-d; no incidence data were reported.

Von Oettingen et al. (1949)

Rats, sex/strain not specified, 20/group

0, 15, 25, or 50 mg/kg-d

Diet

3 mo

Hyperirritability and convulsions were observed in the 25 and 

50 mg/kg-d groupsa; no incidence data were reported.

Hart (1974)

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d

Diet

90 d

No neurological effects, as evidenced by clinical signs or changes in 

appearance or behavior, were reported.

Martin and Hart (1974)

Monkeys, Cynomolgus or Rhesus, 

3/sex/group

0, 0.1, 1, or 10 mg/kg-d

Gavage

90 d

Doses 0 0.1 1 10a

CNS effects characterized as trembling, shaking, jerking, or 

convulsions (incidence)

M 0/3 0/3 0/3 2/3

F 0/3 0/3 0/3 2/3
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2-6 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Von Oettingen et al. (1949)

Dogs, breed not specified, 5 females/group 

(control); 7 females/group (exposed)

0 or 50 mg/kg-d

Diet

6 d/wk for 6 wks

Treated dogs exhibited convulsions, excitability, ataxia, and 

hyperactive reflexesa; no incidence data were reported.

MacPhail et al. (1985)

Rats, Sprague-Dawley derived CD, 8–

10 males or females/group 

0, 1, 3, or 10 mg/kg-d

Gavage

30 d

No changes in motor activity, flavor aversion, scheduled-controlled 

response, or acoustic startle-response were reported.

Cholakis et al. (1980)

Rats, F344, 24–25 females/group

0, 0.2, 2.0, or 20 mg/kg

Gavage

GDs 6–19

Convulsions and hyperactivity in 18/25 dams at 20 mg/kga; one 

female at 2.0 mg/kg-d exhibited convulsions.

Angerhofer et al. (1986) (range-finding 

study)

Rats, Sprague-Dawley, 6 pregnant 

females/group

0, 10, 20, 40, 80, or 120 mg/kg-d

Gavage

GDs 6–15

Convulsions preceding death were observed at ≥40 mg/kg-da; no 

incidence data were reported.

Angerhofer et al. (1986)

Rats, Sprague-Dawley, 39–51 mated 

females/group

0, 2, 6, or 20 mg/kg-d

Gavage

GDs 6–15

Convulsions and hyperactivitya were observed at 20 mg/kg-d; no 

incidence data were reported.

a

Mortality was reported in some RDX-treated groups in this study; see mortality evidence tables for additional 

details.

b

Doses were calculated by the study authors.
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2-7 DRAFT—DO NOT CITE OR QUOTE

1 Figure 2-1. Exposure-response array of neurological effects following oral exposure to RDX
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-8 DRAFT—DO NOT CITE OR QUOTE

1 2.3. Mortality Evidence Table and Array

2 Table 2-3. Evidence pertaining to mortality following oral exposure to RDX

Reference and Study Design Results

Lish et al. (1984); Levine et al. (1984) 

Mice, B6C3F1, 85/sex/group; interim 

sacrifices (10/sex/group) at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high 

dose reduced to 100 mg/kg-d in wk 11 

due to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Mortality (incidence)a

M 20/65 23/65 25/65 29/65 41/65

F 16/65 21/65 14/65 21/65 42/65

After the high dose was reduced to 100 mg/kg-d, survival was similar to 

controls.

Hart (1976) 

Rats, Sprague-Dawley, 100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Mortality (incidence)b

M 34/94 30/95 25/86 33/92

F 20/83 32/95 29/100 33/96

Levine et al. (1983); Thompson (1983) 

Rats, F344, 75/sex/group; interim 

sacrifices (10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Mortality (incidence)a

M 17/55 19/55 30/55* 26/55 51/55*

F 12/55 10/55 13/55 14/55 27/55*

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group

0, 40, 60, or 80 mg/kg-d for 2 wks 

followed by 0, 320, 160, or 80 mg/kg-d 

(TWA doses of 0, 79.6, 147.8, or 

256.7 mg/kg-d for males and 0, 82.4, 

136.3, or 276.4 mg/kg-d for females)c

Diet

13 wks

Doses 0 80 160 320

Mortality (incidence)

M 0/10 0/10 0/10 4/10*

F 0/11 0/12 0/10 2/12

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Mortality (incidence)

M 0/10 0/10 0/10 0/10 0/10 0/10

F 1/10 0/10 0/10 0/10 0/10 0/10
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2-9 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Cholakis et al. (1980)

Rats, CD, two-generation study; F0: 

22/sex/group; F1: 26/sex/group; F2: 

10/sex/group 

F0 and F1 parental animals: 0, 5, 16, or 

50 mg/kg-d

Diet

13 wks

Doses 0 5 16 50

Mortality in F0 adults (incidence)d

M 0/22 0/22 0/22 2/22

F 0/22 0/22 0/22 6/22

M&F 0/44 0/44 0/44 8/44*

Crouse et al. (2006)

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d

Gavage

90 d

Doses 0 4 8 10 12 15

Mortality (incidence)

M 0/10 0/10 1/10 3/10 2/10 3/10

F 0/10 0/10 1/10 2/10 5/10 4/10

Levine et al. (1990); Levine et al. (1981a); 

Levine et al. (1981b)

Rats, F344, 10/sex/group; 30/sex for 

control

0, 10, 30, 100, 300, or 600 mg/kg-d

Diet

13 wks

Doses 0 10 30 100 300 600

Mortality (incidence)e

M 0/30 0/10 0/10 8/10 10/10 10/10

F 0/30 1/10 0/10 5/10 10/10 10/10

Von Oettingen et al. (1949)

Rats, sex/strain not specified, 20/group

0, 15, 25, or 50 mg/kg-d

Diet

3 mo

Doses 0 15 25 50

Mortality (incidence)

0/20 1/20f 8/20 8/20

Hart (1974)

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d

Diet

90 d

Doses 0 0.1 1 10

Mortality (incidence)

M 0/3 0/3 1/3g 0/3

F 0/3 0/3 0/3 0/3

Martin and Hart (1974)

Monkeys, Cynomolgus or Rhesus,

3/sex/group

0, 0.1, 1, or 10 mg/kg-d

Gavage

90 d

Doses 0 0.1 1 10

Mortality (incidence)

M 0/3 0/3 0/3 0/3

F 0/3 0/3 0/3 1/3h
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-10 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Von Oettingen et al. (1949) 

Dogs, breed not specified, 

5 females/group (control); 

7 females/group (exposed)

0 or 50 mg/kg-d 

Diet

6 d/wk for 6 wks

Doses 0 50

Mortality (incidence)

F 0/5 1/7

MacPhail et al. (1985) 

Rats, Sprague-Dawley derived CD, 8–

10 males or females/group 

0, 1, 3, or 10 mg/kg-d

Gavage

30 d

No mortality was reported (incidence data were not provided).

Cholakis et al. (1980) 

Rabbits, New Zealand white, 11–

12 pregnant females/group

0, 0.2, 2.0, or 20 mg/kg-d 

Diet

GDs 7–29

Doses 0 0.2 2.0 20

Mortality (incidence)

F 0/11 0/11 0/11 0/12

Cholakis et al. (1980) 

Rats, F344, 24–25 females/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 6–19

Doses 0 0.2 2.0 20

Mortality (incidence)

F 0/24 0/24 0/23 7/24i

Angerhofer et al. (1986) (range-finding 

study)

Rats, Sprague-Dawley, 6 pregnant 

females/group

0, 10, 20, 40, 80, or 120 mg/kg-d 

Gavage

GDs 6–15

Doses 0 10 20 40 80 120

Mortality (incidence)

F 0/6 0/6 0/6 6/6 6/6 6/6

Angerhofer et al. (1986) 

Rats, Sprague-Dawley, 39–51 mated 

females/group

0, 2, 6, or 20 mg/kg-d 

Gavage

GDs 6–15

Doses 0 2 6 20

Mortality (incidence)

F 0/39 1/40 1/40 16/51

1 *Statistically significant (p < 0.05) based on analysis by study authors.
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-11 DRAFT—DO NOT CITE OR QUOTE

a 1 Interim sacrifices (10 animals/sex/dose) were performed at 27 and 53 weeks (Levine et al., 1983) or 26 and 

2 

3 

4 

5 

6 

7 

8 

9 

10

11

12

13

53 weeks (Lish et al., 1984); these animals were not included in the mortality incidences.

b

A malfunctioning heating system resulted in the premature deaths of 59 animals across groups; these animals 

were omitted from mortality results. c

Doses were calculated by the study authors.

d

Data for male and female rats were combined for statistical analysis.

e

Animals receiving 300 mg/kg-day died by week 3 of the study; animals receiving 600 mg/kg-day died by week 1 of 

the study. 

f

The study authors noted that the single death at 15 mg/kg-day was probably not treatment-related and noted 

that a large encapsulated cyst had replaced a lobe of the lung.

g

The study authors stated that the animal died from bacteremia derived from a lesion unrelated to RDX treatment.

h

The affected animal exhibited severe neurological effects following RDX administration and was euthanized.

i

Includes one rat that was accidentally killed.
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-12 DRAFT—DO NOT CITE OR QUOTE

1 Figure 2-2. Exposure-response array of mortality following oral exposure to RDX
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-13 DRAFT—DO NOT CITE OR QUOTE

1 2.4. Reproductive and Developmental Effects Evidence Tables and 

2 

3 

4 

Array

Table 2-4. Evidence pertaining to reproductive and developmental effects in 

animals following oral exposure to RDX 

Reference and Study Design Results

Offspring survival

Cholakis et al. (1980) 

Rats, CD, two-generation study;

F0: 22/sex/group; F1: 26 sex/group; 

F2: 10 sex/group 

F0 and F1 parental animals: 0, 5, 16, or 

50 mg/kg-d 

Diet

13 wks

Doses 0 5 16 50

Stillborn pups (incidence)

F1 8/207 6/296 4/259 16/92*

F2 6/288 6/290 2/250 24/46*

Offspring survival at birth (percent of fetuses)

F1 96% 98% 98% 83*%

F2 98% 98% 99% 48*%

F0 maternal deaths occurred at 50 mg/kg-d. Only six F1 females in this 

group survived to serve as parental animals; none of the six died during 

subsequent treatment.

Cholakis et al. (1980) 

Rabbits, New Zealand white, 11–

12/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 7–29

Doses 0 0.2 2 20

Early resorptions (mean percent per dam)

6% 5% 4% 1%

Late resorptions (mean percent per dam)

8% 5% 3% 3%

Complete litter resorptions (number of litters)

0 0 0 2 

Viable fetuses (mean percent per dam):

85% 82% 77% 94%

Cholakis et al. (1980) 

Rats, F344, 24–25 females/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 6–19

Doses 0 0.2 2.0 20

Early resorptions (mean percent per dam) 

6.0% 2.5% 4.8% 15.3% 

Late resorptions (mean percent per dam)

0.5% 0.5% 0.3% 1.6%

Complete litter resorptions (number of litters)

0 0 0 2

Viable fetuses (mean percent per dam)

93.2% 97.6% 94.9% 81.4%

Significant maternal mortality (7/24 dams) occurred at 20 mg/kg-d.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-14 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Angerhofer et al. (1986) 

Rats, Sprague-Dawley, 39–51 mated 

females/group (25–29 pregnant 

dams/group)

0, 2, 6, or 20 mg/kg-d 

Gavage

GDs 6–15

Doses 0 2 6 20

Resorptions (percent of total implantations)

4.8% 6.1% 5.9% 6.4%

Early resorptions (percent of total implantations)

4.8% 6.1% 5.9% 6.2%

Late resorptions (percent of total implantations)

0% 0% 0% 0.27%

Live fetuses (mean percent per litter)

100% 100% 100% 100%

Significant maternal mortality (16/51) occurred at 20 mg/kg-d.

Offspring growth

Cholakis et al. (1980) 

Rabbits, New Zealand white, 11–

12/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 7–29

Doses 0 0.2 2.0 20

Fetal body weight (percent change compared to control)

0% 19% 24% 15%

Cholakis et al. (1980)

Rats, F344, 24–25 females/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 6–19

Doses 0 0.2 2.0 20

Fetal body weight (percent change compared to control)

0% 2% 3% -7%

Significant maternal mortality (7/24 dams) occurred at 20 mg/kg-d.

Angerhofer et al. (1986)

Rats, Sprague-Dawley, 39–51 mated 

females/group (25–29 pregnant 

dams/group)

0, 2, 6, or 20 mg/kg-d 

Gavage

GDs 6–15

Doses 0 2 6 20

Fetal body weight (percent change compared to control)

0% -4% -2% 9%a

Fetal body length (percent change compared to control)

0% -1% -1% -5%a

Significant maternal mortality (16/51) occurred at 20 mg/kg-d. 

Morphological development

Cholakis et al. (1980) 

Rabbits, New Zealand white, 11–

12/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 7–29

Doses 0 0.2 2.0 20

Spina bifida (incidence)

Fetuses 0/88 0/99 0/94 3/110

Litters 0/11 0/11 0/11 2/12

Misshapen eye bulges (incidence)

Fetuses 0/88 0/99 0/94 3/110

Litters 0/11 0/11 0/11 1/12

Cleft palate (incidence)

Fetuses 0/39 1/46 2/44 2/52

Litters 0/11 1/11 1/11 1/12
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-15 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Enlarged front fontanel (incidence)

Fetuses 0/49 5/53 2/50 8/58

Litters 0/11 2/11 2/11 2/12

Cholakis et al. (1980) 

Rats, F344, 24–25 females/group

0, 0.2, 2.0, or 20 mg/kg-d 

Gavage

GDs 6–19

No gross or soft-tissue anomalies were seen in any exposure group. No 

treatment-related increase in the incidence of litters with skeletal

anomalies was observed. 

Significant maternal mortality (7/24 dams) occurred at 20 mg/kg-d.

Angerhofer et al. (1986) 

Rats, Sprague-Dawley, 39–51 mated 

females/group (25–29 pregnant 

dams/group)

0, 2, 6, or 20 mg/kg-d 

Gavage

GDs 6–15

No treatment-related increase in the incidence of anomalies was 

observed.

Doses 0 2 6 20

Total malformations (percent of fetuses with malformations)

1% 1% 0% 2%

Significant maternal mortality (16/51) occurred at 20 mg/kg-d.

*Statistically significant (p < 0.05) based on analysis by study authors. a

Statistically significant dose-related trend (p ≤ 0.05) by Jonckheere-Terpstra test, performed for this assessment. 

Average fetal weights or lengths for each litter comprised the sample data for this test.
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-16 DRAFT—DO NOT CITE OR QUOTE

1 Figure 2-3. Exposure-response array of reproductive and developmental effects following oral exposure to RDX.
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-17 DRAFT—DO NOT CITE OR QUOTE

1 Table 2-5. Evidence pertaining to male reproductive effects in animals

2 following oral exposure to RDX

Reference and Study 

Design Results

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim 

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Testicular degeneration (incidence)

0/63 2/60 2/62 6/59 3/27a

Absolute testes weight; wk 105 (percent change compared to control)

0% -6% 0% -2% -6%

Relative testes weight; wk 105 (percent change compared to control)

0% -4% 2% -2% -2%

Prostate was examined microscopically in control and 175/100 mg/kg-d groups; no 

effects were observed.

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/dose

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Absolute testes (with epididymis) weight; wk 104 

0% -2% 2% 5% 

Relative testes (with epididymis) weight; wk 104 

0% -1% 7% 9%

Testes were examined microscopically in control and 10 mg/kg-d groups; no 

degeneration or other treatment-related effects were observed. Prostate was not 

examined microscopically.

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Testes, germ cell degeneration; 12 mo

b (incidence)

SS 0/10 0/10 0/10 0/10 4/10*

SDMS – – 1/3 – 4/19

Testes, germ cell degeneration; 24 mo (incidence)

SS 0/38 0/36 0/25 0/29 0/4

SDMS 0/16 0/19 0/27 0/26 0/27

Prostate, suppurative prostatitis; 24 mo (incidence)

SS 0/38 1/36 2/25* 4/29* 0/4

SDMS 2/16 3/19 7/27* 8/26 19/27*

Testes weights were not measured at termination due to testicular masses in nearly 

all males.

SDMS = spontaneous death or moribund sacrifice; SS = scheduled sacrifice
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-18 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Cholakis et al. (1980) 

Mice, B6C3F1, 10–

12/sex/group

Experiment 1: 0, 10, 14, 20, 

28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute testes weight (percent change compared to control)

0% – – – -4% -4%

Relative testes weight (percent change compared to control)

0% – – – 2% -1%

Experiment 2: 0, 40, 60, or 

80 mg/kg-d for 2 wks 

followed by 0, 320, 160, or 

80 mg/kg-d (TWA doses of 

0, 79.6, 147.8, or 

256.7 mg/kg-d for males 

and 0, 82.4, 136.3, or 

276.4 mg/kg-d for 

females)a

Diet

13 wks

Doses 0 80 160 320

Absolute testes weight (percent change compared to control)

0% 4% -4% -8%

Relative testes weight (percent change compared to control)

0% 1% -4% -9%

Testes were examined microscopically in control and 320 mg/kg-d groups; no effects 

were observed.

Cholakis et al. (1980) 

Rats, F344, 10/sex/dose

0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute testes weight (percent change compared to control)

0% – – – -2% 0%

Relative testes weight (percent change compared to control)

0% – – – 2% 9%

Testes were examined microscopically in control and 40 mg/kg-d groups; no effects 

were observed. Prostate was not weighed or examined microscopically.

Cholakis et al. (1980) 

Rats, CD, two-generation 

study; F0: 22/sex/group; 

F1: 26/sex/group; F2: 

10/sex/group 

F0 and F1 parental 

animals: 0, 5, 16, or 

50 mg/kg-d 

Diet

13 wks

In F2 offspring of 0, 5, and 16 mg/kg-d groups. No high-dose F2 animals available.

Doses 0 5 16 50

Absolute testes weight (percent change compared to control)

0% 3% -31% –

Testes were examined microscopically in all F2 groups; no effects observed.

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

Doses 0 4 8 10 12 15

Absolute testes weight (percent change compared to control)

0% -3% -5% -4% -4% -8%

Relative testes weight (percent change compared to control)

0% 4% 5% 0% -6% -10*%

Prostate, mild subacute inflammation (incidence)

0/10 – – – – 1/8
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-19 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Levine et al. (1990); Levine 

et al. (1981a); Levine et al. 

(1981b) 

Rats, F344, 10/sex/group; 

30/sex for control

0, 10, 30, 100, 300, or 

600 mg/kg-d 

Diet

13 wks

Doses 0 10 30 100 300 600

Testes, germ cell degeneration (incidence)

0/10 0/10 0/10 0/10 1/9 1/10

Absolute testes weight (percent change compared to control)

0% 1% 1% -2% – – 

Relative testes weight (percent change compared to control)

0% 4% 5% 19*% – –

Prostate was examined microscopically in control, 30, and 100 mg/kg-d groups; no 

effects were observed.

Hart (1974) 

Dogs, Beagle, 3/sex/dose

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Doses 0 0.1 1 10

Absolute testes (with epididymis) weight (percent change compared to control)

0% – – 51%

Testes and prostate were not examined microscopically.

*Statistically significant (p < 0.05) based on analysis by study authors. a

Although the study authors did not observe a statistically significant increase in the incidence of testicular 

degeneration, they determined that the incidences at the 35 and 175/100 mg/kg-day dose groups were 

“notable” when compared to concurrent (0%) and historical (1.5%) incidences.

b

Testicular atrophy was observed at 12 months, along with a statistically reduced mean testes weight (compared 

with controls). By 24 months, all male rats (including controls) had testicular masses; testes weights were not 

recorded, and an increased incidence of testicular degeneration was not observed. 

1 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-20 DRAFT—DO NOT CITE OR QUOTE

1 Figure 2-4. Exposure-response array of male reproductive effects following oral exposure to RDX.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-21 DRAFT—DO NOT CITE OR QUOTE

2.5. Liver Effects Evidence Tables and Array

Table 2-6. Evidence pertaining to liver effects of RDX in humans 

1 

2 

3 

4 

5 

Reference and Study Design Results

Hathaway and Buck (1977) (United Liver function tests in men; mean (standard deviation not reported)

States)

Cross-sectional study, 2,022 workers, 

1,491 participated (74% response rate). 

Analysis group: limited to whites; 

69 exposed to RDX alone and 24 exposed 

to RDX and HMX; 338 not exposed to 

RDX, HMX, or TNT.

Exposure measures: Exposure 

determination based on job title and 

industrial hygiene evaluation. Exposed 

subjects assigned to two groups: less 

than the limit of detection (LOD) or 

≥0.01 mg/m3 (mean 0.28 mg/m3

).

Effect measures: Liver function tests.

Test

Referent

(n = 237)

RDX exposed

3 Undetected >0.01 mg/m

(n = 22) (n = 45)

LDH

Alkaline 

phosphatase

ALA (SGOT)

AST (SGPT)

Bilirubin

173

82

22

21

0.5

191

78

25

26

0.4

174

80

21

18

0.4

No differences were statistically significant. Similar results in women.

Liver function tests in men: prevalence of abnormal values

Test 

(abnormal range) Referent

RDX exposed

3 Undetected >0.01 mg/m

LDH (>250) 2/237 1/22 0/45

Analysis: Types of statistical tests were Alkaline 34/237 1/22 6/45 not reported (assumed to be t-tests for 

χ

2 comparison of means and tests for phosphatase

(>1.5) comparison of proportions). AST (SGOT) (>35) 20/237 4/22 2/45

ALT (SGPT) (>35) 15/237 2/22 0/45

Bilirubin (>1.0) 5/237 1/22 1/45

No differences were statistically significant. Similar results in women.

Table 2-7. Evidence pertaining to liver effects in animals following oral exposure to 

RDX

Reference and Study Design Results

Liver weight

Lish et al. (1984); Levine et al. 

(1984) 

Mice, B6C3F1, 85/sex/group; 

interim sacrifices (10/sex/group) 

at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kgd (high dose reduced to 

Doses 0 1.5 7.0 35 175/100

Absolute liver weight at 104 wks (percent change compared to control)

M 0% 28*% 11% 12% 35*%

F 0% 7% 7% 15% 18*%

Relative liver weight at 104 wks (percent change compared to control)

M 0% 32*% 12% 14% 46*%

F 0% 6% 8% 18% 45*%
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-22 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

100 mg/kg-d in wk 11 due to 

excessive mortality)

Diet

24 mo

Note: Percent change in liver weights of male and female mice was reduced in 

all dose groups when mice with liver tumors were removed from the analysis.

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Absolute liver weight (percent change compared to control)

M 0% -6% -6% -6%

F 0% 7% -11% 1%

Relative liver weight (percent change compared to control)

M 0% -5% -2% -3% 

F 0% 17% -2% 13%

Levine et al. (1983); Thompson 

(1983) 

Rats, F344, 75/sex/group; interim 

sacrifices (10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Absolute liver weight at 105 wks (percent change compared to control)

M 0% 3% -7% 1% -8%

F 0% 1% -4% 3% 0%

Relative liver weight at 105 wks (percent change compared to control)

M 0% 1% 0% 2% 11%

F 0% 1% -2% 6% 18*%

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group

Experiment 1: 0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute liver weight (percent change compared to control)

M 0% – – – -6% -5%

F 0% – – – -4% -1%

Relative liver weight (percent change compared to control)

M 0% – – – -4% -4%

F 0% – – – -6% 1%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-23 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Experiment 2: 0, 40, 60, or 

80 mg/kg-d for 2 wks followed by 

0, 320, 160, or 80 mg/kg-d (TWA 

doses of 0, 79.6, 147.8, or 

256.7 mg/kg-d for males and 0, 

82.4, 136.3, or 276.4 mg/kg-d for

females)a

Diet

13 wks

Doses 0 80 160 320

Absolute liver weight (percent change compared to control)

M 0% 2% 12% 26*%

F 0% 4% 9% 29*%

Relative liver weight (percent change compared to control)

M 0% 0% 9% 25*%

F 0% 4% 4% 22*% 

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute liver weight (percent change compared to control)

M 0% – – – -2% -5%

F 0% – – – 6% 4%

Relative liver weight (percent change compared to control)

M 0% – – – 2% 3%

F 0% – – – 10% 11%

Cholakis et al. (1980) 

Rats, CD, two-generation study; 

F0: 22/sex/group; 

F1: 26/sex/group; 

F2: 10/sex/group 

F0 and F1 parental animals: 0, 5, 

16, or 50 mg/kg-d 

Diet

13 wks

Doses 0 5 16 50

Absolute liver weight (percent change compared to control)

M 0% 7% -16% – 

F 0% 0% -14% – 

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d 

Gavage

90 d

Doses 0 4 8 10 12 15

Absolute liver weight (percent change compared to control)

M 0% -6% -9% 0% 7% 5%

F 0% 1% 7% 18*% 15% 28*%

Relative liver weight (percent change compared to control)

M 0% 0% -1% 2% 5% 2%

F 0% 1% -2% 2% -3% 2%

Levine et al. (1990); Levine et al. 

(1981a); Levine et al. (1981b) 

Rats, F344, 3–4 wks old; 

10/sex/group; 30/sex/group for 

controls

0, 10, 30, 100, 300, or 600 mg/kgd 

Diet

13 wks

Data were not reported for rats in the 300 or 600 mg/kg-d dose groups 

because all of the rats died before the 13-wk necropsy.

Doses 0 10 30 100 300 600

Absolute liver weight (percent change compared to control)

M 0% 5% -1% -2% – –

F 0% 2% 4% 16*% – – 

Relative liver weight (percent change compared to control)

M 0% 8% 6% 1% – –

F 0% 3% 5% 19*% – – 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-24 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Doses 0 0.1 1 10

Absolute liver weight (percent change compared to control)

M 0% – – 53%

F 0% – – 3%

Martin and Hart (1974) 

Monkeys, Cynomolgus or Rhesus, 

3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Doses 0 0.1 1 10

Absolute liver weight (percent change compared to control)

M+F 0% 2% 6% 16%

Histopathological lesions

Lish et al. (1984); Levine et al. 

(1984) 

Mice, B6C3F1, 85/sex/group; 

interim sacrifices (10/sex/group) 

at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kgd (high dose reduced to 

100 mg/kg-d in wk 11 due to 

excessive mortality)

Diet

24 mo

Histopathological lesions in liver other than adenomas and carcinomas were 

not significantly different compared to controls.

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Histopathological examination performed only for controls and 10 mg/kg-d 

rats; no significant differences compared to controls were reported. 

Levine et al. (1983); Thompson 

(1983) 

Rats, F344, 3–4 wks old; 

75/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Microgranulomas (incidence)

M 0/38 0/36 0/25 0/29 0/4

F 10/43 19/45 12/42 17/41 4/28
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-25 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group 

0, 80, 60, or 40 mg/kg-d for 2 wks 

followed by 0, 80, 160, or 

320 mg/kg-d (TWA doses of 0, 

79.6, 147.8, or 256.7 mg/kg-d for 

males and 0, 82.4, 136.3, or 

276.4 mg/kg-d for females)a

Diet

13 wks

Doses 0 80 160 320

Liver microgranulomas; mild (incidence)

M 2/10 – – 1/9

F 2/11 – – 7/11*

Increased karyomegaly of hepatocytes

M 0/10 – – 5/9*

F – – – – 

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Liver granulomas; mild (incidence)

M 0/10 – – – – 1/10

F – – – – – –

Liver portal inflammation

M 2/10 – – – – 3/10

F 1/10 – – – – 7/10

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d 

Gavage

90 d

Histopathology examination of the 15 mg/kg-d group showed one male rat 

with mild liver congestion and one female rat with a moderate-sized focus of 

basophilic cytoplasmic alteration; neither finding was attributed to treatment 

with RDX.

Levine et al. (1990); Levine et al. 

(1981a); Levine et al. (1981b) 

Rats, F344, 10/sex/group; 30/sex

for control

0, 10, 30, 100, 300, or 600 mg/kgd 

Diet

13 wks

Histopathological examination of liver did not reveal any significant differences 

compared to controls. 

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Histopathological examination performed only for controls and 10 mg/kg-d 

dogs; no significant differences compared to controls were reported.

Martin and Hart (1974) 

Monkeys, Cynomolgus or Rhesus, 

3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

An increase in the amount of iron-positive material in liver cord cytoplasm was 

reported in monkeys treated with 10 mg/kg-d RDX; however, the study authors 

considered the toxicological significance to be uncertain.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-26 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Serum chemistry

Lish et al. (1984); Levine et al. 

(1984) 

Mice, B6C3F1, 85/sex/group; 

interim sacrifices (10/sex/group) 

at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kgd (high dose reduced to 

100 mg/kg-d in wk 11 due to 

excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Serum cholesterol at 105 wks (percent change compared to control)

M 0% 11% -11% 5% 39%

F 0% 5% 15% 25% 38%

Serum triglycerides at 105 wks (percent change compared to control)

M 0% 21% -20% 10% -25%

F 0% 34% 28% 41% 28%

Levine et al. (1983); Thompson 

(1983) 

Rats, F344, 75/sex/group; interim 

sacrifices (10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Serum cholesterol at 104 wks (percent change compared to control)

M 0% 15% 38% 19% -6%

F 0% 6% 3% -7% -9%

Serum triglycerides at 104 wks (percent change compared to control)

M 0% 14% -15% -12% -52%

F 0% 18% 5% -42% -51*%

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d 

Gavage

90 d

Doses 0 4 8 10 12 15

Serum cholesterol (percent change compared to control)

M 0% -3% -10*% -16*% -18*% -11*%

F 0% -1% -8% -4% -4% -1%

Serum triglycerides (percent change compared to control)

M 0% 1% 1% -7% -2% -19%

F 0% -16% -21% 7% -37% 18%

Levine et al. (1990); Levine et al. 

(1981a); Levine et al. (1981b) 

Rats, F344, 10/sex/group; 30/sex

for control

0, 10, 30, 100, 300, or 600 mg/kgd 

Diet

13 wks

Data were not reported for 300 and 600 mg/kg-d dose groups because all of 

the animals died before the 13-wk blood sampling.

Doses 0 10 30 100 300 600

Serum triglyceride levels (percent change compared to control)

M 0% -14% -34% -62*% – – 

F 0% -12% -29% -50*% – – 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-27 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Martin and Hart (1974) 

Monkeys, Cynomolgus or Rhesus, 

3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Serum biochemistry analysis revealed scattered deviations, but they appear to 

have no toxicological significance.

Doses 0 0.1 1 10

Serum cholesterol (percent change compared to control)

M 0% -17% -2% -7%

F 0% 7% 7% 7%

*Statistically significant (p < 0.05) based on analysis by study authors. a

Doses were calculated by the study authors.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-28 DRAFT—DO NOT CITE OR QUOTE

Figure 2-5. Exposure-response array of liver effects following oral exposure to RDX.

1 

2 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-29 DRAFT—DO NOT CITE OR QUOTE

2.6. Kidney Effects Evidence Tables and Array

Table 2-8. Evidence pertaining to renal effects of RDX in humans

1 

2 

3 

4 

5 

Reference and Study Design Results

Hathaway and Buck (1977) Renal function tests in men: mean (standard deviation not reported)

Cross-sectional study, 2,022 workers, 

1,491 participated (74% response rate). 

Analysis group: limited to whites; 

69 workers exposed to RDX alone and 

24 workers exposed to RDX and HMX, 

compared to 338 workers not exposed to 

RDX, HMX, or TNT.

Exposure measures: Exposure 

determination based on job title and 

industrial hygiene evaluation; exposed 

subjects assigned to two groups: 

undetected (<LOD) or ≥0.01 mg/m3 (mean 

0.28 mg/m3).

Effect measures: Renal function tests 

(blood)

Analysis: Types of statistical tests 

werenot reported (assumed to be t-tests 

for comparison of means and χ2 tests for 

Test

Referent

(n = 237)

RDX exposed

Undetected

(n = 22)

3 >0.01 mg/m

(n = 45)

Blood urea 

nitrogen

15.5 15.6 16.4

Total protein 7.2 7.2 7.3

No differences were statistically significant. Similar results in women.

comparison of proportions). 

Table 2-9. Evidence pertaining to renal effects in animals following oral 

exposure to RDX

Reference and Study Design Results

Kidney weights

Lish et al. (1984); Levine et al. (1984) 

Mice, B6C3F1, 85/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high dose 

reduced to 100 mg/kg-d in wk 11 due to 

excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Absolute kidney weight at 104 wks (percent change compared to 

control)

M 0% -1% 4% 9*% 19*%

F 0% 3% 1% 1% -2%

Relative kidney weight at 104 wks (percent change compared to 

control)

M 0% 3% 6% 11*% 27*%

F 0% 1% 1% 2% 19*%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-30 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Hart (1976) 

Rats, Sprague-Dawley, 100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Absolute kidney weight (percent change compared to control)

M 0% -3% -7% 2%

F 0% 14% -4% 8%

Relative kidney weight (percent change compared to control)

M 0% -1% -4% 4%

F 0% 22% 3% 18% 

Levine et al. (1983); Thompson (1983) 

Rats, F344, 75/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Absolute kidney weight at 105 wks (percent change compared to 

control)

M 0% 2% -7% 1% 0%

F 0% 3% 3% 2% 2%

Relative kidney weight at 105 wks (percent change compared to 

control)

M 0% 1% 0% 2% 20*%

F 0% 3% 6% 5% 21*%

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group

Experiment 1: 0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute kidney weight (percent change compared to control)

M 0% – – – 18% 2%

F 0% – – – -8% -5%

Relative kidney weight (percent change compared to control)

M 0% – – – 29% 0%

F 0% – – – -8% -3%

Experiment 2: 0, 40, 60, or 80 mg/kg-d for 

2 wks followed by 0, 320, 160, or 80 mg/kg-d 

(TWA doses of 0, 79.6, 147.8, or 256.7 mg/kg-d 

for males and 0, 82.4, 136.3, or 276.4 mg/kg-d 

for females)a 

Diet

13 wks

Doses 0 80 160 320

Absolute kidney weight (percent change compared to control)

M 0% 8% 11% 13%

F 0% -5% -3% 0%

Relative kidney weight (percent change compared to control)

M 0% 5% 9% 10%

F 0% -5% -4% -5%

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute kidney weight (percent change compared to control)

M 0% – – – -2% -5%

F 0% – – – 1% 0%

Relative kidney weight (percent change compared to control)

M 0% – – – 1% 5%

F 0% – – – 6% 6%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-31 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Cholakis et al. (1980) 

Rats, CD, two-generation study; 

F0: 22/sex/group; F1: 26/sex/group; 

F2: 10/sex/group 

F0 and F1 parental animals: 0, 5, 16, 50 mg/kgd 

Diet

13 wks

Doses 0 5 16 50

Absolute kidney weight (percent change compared to control)

M 0% 6% -12% – 

F 0% -4% -21*% – 

Crouse et al. (2006)

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d 

Gavage

90 d

Doses 0 4 8 10 12 15

Absolute kidney weight (percent change compared to control)

M 0% -3% -4% -1% 3% 5%

F 0% 2% 5% 13*% 10% 15*%

Relative kidney weight (percent change compared to control)

M 0% 3% 6% 2% 1% 3%

F 0% 1% -3% -1% -6% -7*%

Levine et al. (1990); Levine et al. (1981a); 

Levine et al. (1981b) 

Rats, F344, 10/sex/group; 30/sex for control

0, 10, 30, 100, 300, or 600 mg/kg-d 

Diet

13 wks

Data were not reported for rats in the 300 or 600 mg/kg-d groups 

because all of the rats died before the 13-wk necropsy. 

Doses 0 10 30 100 300 600

Absolute kidney weight (percent change compared to control)

M 0% 1% 1% -9% – –

F 0% 1% 3% -1% – –

Relative kidney weight (percent change compared to control)

M 0% 5% 7% 10% – –

F 0% 3% 5% 2% – –

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Numerical values given only for control and 10 mg/kg-d groups.

Doses 0 0.1 1 10

Absolute kidney weight (percent change compared to control)

M 0% – – 38%

F 0% – – -18%

Martin and Hart (1974)

Monkeys, Cynomolgus or Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Doses 0 0.1 1 10

Absolute kidney weight (percent change compared to control)

M+F 0% -2% -3% 4%

Histopathological lesions
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-32 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Lish et al. (1984); Levine et al. (1984) 

Mice, B6C3F1, 85/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high dose 

reduced to 100 mg/kg-d in wk 11 due to 

excessive mortality)

Diet

24 mo

The incidence of cytoplasmic vacuolization of renal tubules was 

greater for RDX-treated males than the control group males after 

6 mo of treatment. However, at 12 and 24 mo of treatment, this 

lesion was observed as frequently in control animals as animals

treated with RDX. 

Hart (1976) 

Rats, Sprague-Dawley, 100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Histopathological examination of kidney did not reveal any 

significant differences compared to controls; lesions observed 

were not attributed to RDX treatment; incidence data were 

reported only for control and 10 mg/kg-d groups.

Levine et al. (1983); Thompson (1983) 

Rats, F344, 75/sex/group; interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Data were analyzed separately for animals sacrificed on schedule 

(SS) and those that died spontaneously or were sacrificed 

moribund (SDMS); incidence data were not reported for females.

Doses 0 0.3 1.5 8.0 40

Medullary papillary necrosis; 24 mo (incidence)

M (SS): 0/38 0/36 0/25 0/29 0/4

F (SDMS): 0/17 1/19 0/27 0/26 18/27*

Suppurative pyelitis; 24 mo (incidence)

M (SS): 0/38 0/36 0/25 0/29 0/4

F (SDMS): 0/17 1/19 0/27 1/26 5/27*

Uremic mineralization; 24 mo (incidence)

M (SS): 1/38 0/36 0/25 0/29 0/4

F (SDMS): 0/17 1/19 2/27 0/26 13/27

Cholakis et al. (1980) 

Mice, B6C3F1, 10–12/sex/group 

0, 80, 60, 40 mg/kg-d for 2 wks followed by 0, 

80, 160, or 320 mg/kg-d (TWA doses of 0, 79.6, 

147.8, or 256.7 mg/kg-d for males and 0, 82.4, 

136.3, or 276.4 mg/kg-d for females)a

Diet

13 wks

Incidence data reported only for controls and the 320 mg/kg-d 

group.

Doses 0 80 160 320

Tubular nephrosis (incidence)

M 0/10 – – 4/9*

F 0/11 – – 1/11

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 40 mg/kg-d 

Diet

13 wks

Histopathological examination of kidney did not reveal any 

significant differences compared to controls; incidence data were 

reported only for control and 40 mg/kg-d groups. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-33 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Cholakis et al. (1980)

Rats, CD, two-generation study; F0: 

22/sex/group; F1: 26/sex/group; F2: 

10/sex/group 

F0 and F1 parental animals: 0, 5, 16, or 

50 mg/kg-d 

Diet

13 wks

Data were reported only for F2 generation controls and 5 and 

16 mg/kg-d groups.

Doses 0 5 16 50

Cortical cysts (incidence)

M 4/10 4/10 8/10 –

F 3/10 4/10 8/10 – 

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kg-d 

Gavage

90 d

Histopathological examination of kidney did not reveal any 

significant differences compared to controls; incidence data were 

reported only for control and 15 mg/kg-d groups. 

Levine et al. (1990); Levine et al. (1981a); 

Levine et al. (1981b) 

Rats, F344, 10/sex/group; 30/sex for control

0, 10, 30, 100, 300, or 600 mg/kg-d 

Diet

13 wks

Histopathological examination of kidney did not reveal any 

significant differences compared to controls.

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Histopathological examination of kidney did not reveal any 

significant differences compared to controls; incidences were 

reported only for control and 10 mg/kg-d groups.

Martin and Hart (1974) 

Monkeys, Cynomolgus or Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Doses 0 0.1 1 10

Medulla; mineralization, minimal to mild (incidence)

M+F 0/6 1/6 0/6 4/6

*Statistically significant (p < 0.05) based on analysis by study authors. a

Doses were calculated by the study authors.

1 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-34 DRAFT—DO NOT CITE OR QUOTE

 1 

2 Figure 2-6. Exposure-response array of renal effects following oral exposure to RDX.
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-35 DRAFT—DO NOT CITE OR QUOTE

1 2.7. Carcinogenicity Evidence Tables

2 

3 

4 

Table 2-10. Liver tumors observed in chronic animal bioassays following oral 

exposure to RDX 

Reference and Study Design Results

Lish et al. (1984); Levine et al. (1984)

Mice, B6C3F1, 85/sex/group; interim 

sacrifices (10/sex/group) at 6 and 

12 mo

0, 1.5, 7.0, 35, or 175/100 mg/kg-d 

(high dose reduced to 100 mg/kg-d 

in wk 11 due to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Hepatocellular adenomas (incidence)

M 8/63 6/60 1/62* 7/59 7/27

F 1/65 1/62 6/64 6/64 3/31a

Hepatocellular carcinomas (incidence)

M 13/63 20/60 16/62 18/59 6/27

F 0/65 4/62 3/64 6/64 3/31a

Hepatocellular adenoma or carcinoma combined (incidence)

M 21/63 26/60 17/62 25/59 13/27

F 1/65 5/62 9/64* 12/64* 6/31*a

Pathology workgroup reanalysis of liver lesion slides from female mice 

(Parker et al., 2006; Parker, 2001)

b

Doses 0 1.5 7.0 35 175

Hepatocellular adenomas (incidence)

F 1/67 3/62 2/63 8/64 2/31a

Hepatocellular carcinomas (incidence)

F 0/67 1/62 3/63 2/64 2/31a

Hepatocellular adenoma or carcinoma combined (incidence)

F 1/67b 4/62 5/63b 10/64 4/31a

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Hepatocellular adenomas (incidence)

None reported by the study authors.

Doses 0 1.0 3.1 10

Hepatocellular carcinomas (incidence)

M 1/82 – – 1/77

F 1/72 – – 1/81

Levine et al. (1983); Thompson 

(1983) 

Rats, F344, 75/sex/group; interim 

sacrifices (10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Hepatocellular adenomas (incidence):

None reported by the study authors

Doses 0 0.3 1.5 8.0 40

Hepatocellular carcinomas (incidence)

M 1/55 0/55 0/52 2/55 2/31

F 0/53 1/55 0/54 0/55 0/48

Hepatocellular adenoma or carcinoma combined (incidence):

Not determined. 

*Statistically significant difference compared to the control group (p < 0.05), identified by the authors. a

Statistically significant trend (p < 0.05) was identified using Cochran-Armitage trend tests performed by EPA.

b

It is not clear why the numbers of animals at risk in the control group (n = 67) and 7 mg/kg-day dose group 

(n = 63) differed from the numbers reported in the original study (n = 65 and 64, respectively).
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-36 DRAFT—DO NOT CITE OR QUOTE

1 Table 2-11. Lung tumors observed in chronic animal bioassays following oral 

2 

3 

exposure to RDX 

Reference and Study Design Results

Lish et al. (1984); Levine et al. 

(1984) 

Mice, B6C3F1, 85/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high dose 

reduced to 100 mg/kg-d in 

wk 11 due to excessive 

mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Alveolar/bronchiolar adenomas (incidence)

M 6/63 5/60 5/62 7/59 1/27

F 4/65 2/62 5/64 9/64 3/31a

Alveolar/bronchiolar carcinomas (incidence)

M 3/63 6/60 3/62 7/59 5/27a

F 3/65 1/62 3/64 3/64 4/31

Alveolar/bronchiolar adenoma or carcinoma combined (incidence)

M 9/63 11/60 8/62 14/59 6/27

F 7/65 3/62 8/64 12/64 7/31a

Hart (1976)

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Alveolar/bronchiolar adenoma (incidence)

M 2/83 – – 1/77

F 0/73 – – 0/82

Alveolar/bronchiolar carcinoma (incidence): 

None reported by study authors. 

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 12 mo

0, 0.3, 1.5, 8.0, or 40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Alveolar/bronchiolar adenomas (incidence)

M 1/55 0/15 1/17 0/16 1/31

F 3/53 0/7 0/8 1/10 0/48

Alveolar/bronchiolar carcinomas (incidence) 

M – – – – – 

F 0/53 0/7 1/8 0/10 0/48

Alveolar/bronchiolar adenoma or carcinoma combined (incidence)

M – – – – – 

F 3/53 0/7 1/8 1/10 0/48

a

Statistically significant trend (p < 0.05) was identified using Cochran-Armitage trend test performed by EPA. 
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-37 DRAFT—DO NOT CITE OR QUOTE

1 2.8. Other Systemic Effects Evidence Tables

2 

3 

Table 2-12. Evidence pertaining to other systemic effects (hematological) of 

RDX in humans

Reference and Study Design Results

Hematological Effects

West and Stafford (1997) (United Kingdom)

Case-control study, 32 cases with abnormal and 

322 controls with normal hematology test drawn 

from 1991 study of 404 workers at ammunitions 

plant; participation rate 97% of cases, 93% of 

controls. Analysis limited to men (29 cases, 

282 controls).

Exposure measures: Exposure determination 

based on employee interviews and job title 

analysis; data included frequency (hours/day, 

days/year), duration (years), and intensity (low 

[1–10 ppm], moderate [10–100 ppm], and high 

[100–1,000 ppm], based on ventilation 

considerations).

Effect measures: Hematology tests; blood 

disorder defined as neutropenia (2.0 x 109/l), low 

platelet count (<150 x 109/l), or macrocytosis 

(mean corpuscular volume = 99 fl or >6% 

macrocytes).

Analysis: Unadjusted odds ratio.

Odds ratio (95% CI) [number of exposed cases] of blood disorder 

and RDX

Low intensity, 50 hr-duration 1.7 (0.7,4.2) [22]

Medium intensity, 50-hr duration 1.6 (not reported) [5]

High intensity, 50-hr duration 1.2 (0.3, 5.3) [2]

Hathaway and Buck (1977) (United States)

Cross-sectional study, 2,022 workers, 

1,491 participated (74% response rate). Analysis 

limited to whites; 69 exposed to RDX alone and 

24 exposed to RDX and HMX; 338 not exposed to 

RDX, HMX, or TNT.

Exposure measures: Exposure determination 

based on job title and industrial hygiene 

evaluation. Exposed subjects assigned to two 

groups: <LOD or ≥0.01 mg/m3 (mean 

0.28 mg/m3).

Effect measures: Hematology tests. 

Analysis: Types of statistical tests were not 

reported (assumed to be t-tests for comparison of 

means and χ2 tests for comparison of 

proportions). 

Hematology tests in men; mean (standard deviation not reported)

Test

Referent

(n = 237)

RDX exposed

Undetected

(n = 22)

>0.01 mg/m3

(n = 45)

Hemoglobin 15.2 14.7 15.2

Hematocrit 42 45.6 47

Reticulocyte 

count 

0.7 0.9 0.7

No differences were statistically significant. Similar results in 

women.

Hematology tests in men: prevalence of abnormal values

Test

(abnormal 

range) Referent

RDX exposed

Undetected >0.01 mg/m3

Hemoglobin 

(<14)

15/237 3/22 4/45
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-38 DRAFT—DO NOT CITE OR QUOTE

Reference and Study Design Results

Hematocrit 

(<40)

Reticulocyte 

count (>1.5)

1/237 1/22 1/45

18/237 3/22 2/45

No differences were statistically significant. Similar results in 

women.

Table 2-13. Evidence pertaining to other systemic effects in animals following 

oral exposure to RDX

1

2

3

Reference and 

Design

Study Results

Ocular effects

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim 

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Cataracts; 103 wks (incidence)a

M 

F 

2/47

2/50

2/41

1/37

0/41

6/52

2/37

0/46

2/16

1/26

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Cataracts; 103 wks (incidence)

M 

F 

8/40

14/44

6/39

4/48

6/31

11/44

8/35

8/43

2/6

22/30*

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

No ocular effects were observed (gross examination of eye was performed in all 

animals, and microscopic examination in control and 40 mg/kg-d animals).
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-39 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

No ocular effects were observed (opthalmic examinations were performed in all 

animals within 1 wk of sacrifice, and microscopic examination of the eye was 

performed in control and 15 mg/kg-d animals).

Martin and Hart (1974) 

Monkeys, Cynomolgous or 

Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d 

No ocular effects were observed (opthalmoscopic examination was performed at the 

end of exposure). 

Cardiovascular effects

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim 

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

Absolute heart weight; 104 wks (percent change compared to control)

M 0% 4% 4% 5% 7%

F 0% 1% 5% 2% -5%

Relative heart-to-body weight; 104 wks (percent change compared to control)

M 0% 7% 5% 5% 13*%

F 0% 0% 6% 4% 17*%

Body weight was significantly lower at termination in males and females exposed to 

175/100 mg/kg-d (-5 and -19%, respectively). 

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

Myocardial fibrosis (percent incidence; number not reported)

M 20% – – 5%

F 5% – – 1%

Endocardial disease (percent incidence; number not reported)

M 1% – – 3%

F 0% – – 0%

Absolute heart weight; 104 wks (percent change compared to control)

M 0% -6% -2% -5%

F 0% 13% 3% 15%

Relative heart-to-body weight; 104 wks (percent change compared to control)

M 0% -2% 4% 1%

F 0% 23% 13% 27%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-40 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

Doses 0 0.3 1.5 8.0 40

Absolute heart weight; 104 wks (percent change compared to control)

M 0% 3% -2% -2% 1%

F 0% -1% 0% -4% -3%

Relative heart-to-body weight; 104 wks (percent change compared to control)

M 0% 2% 6% 0% 22%

F 0% -2% 3% -1% 15%

Cholakis et al. (1980)

Mice, B6C3F1, 10–

12/sex/group

Experiment 1: 0, 10, 14, 20, 

28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute heart weight (percent change compared to control)

M 0% – – – 7% 7%

F 0% – – – 0% 0%

Relative heart weight (percent change compared to control)

M 0% – – – 6% 0%

F 0% – – – -4% 0%

Experiment 2: 0, 40, 60, or 

80 mg/kg-d for 2 wks 

followed by 0, 320, 160, or 

80 mg/kg-d (TWA doses of 

0, 79.6, 147.8, or 

256.7 mg/kg-d for males 

and 0, 82.4, 136.3, or 

276.4 mg/kg-d for 

females)b

Diet

13 wks

Doses 0 80 160 320

Focal myocardial degeneration (incidence):

M** 0/10 – – 5/10*

F*** 0/11 – – 2/11

Absolute heart weight (percent change compared to control)

M 0% 0% 0% 8%

F 0% 0% 0% 8%

Relative heart-to-body weight (percent change compared to control)

M 0% 0% -2% 6%

F 0% 0% -2% 2%

**Includes one affected and three unaffected animals that died prematurely.

***Includes one unaffected animal that died prematurely.

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Focal myocardial degeneration (incidence)

M 3/10 – – – – 1/10

F 2/10 – – – – 6/10

Absolute heart weight (percent change compared to control)

M 0% – – – 0% -8*%

F 0% – – – -6% -11*%

Relative heart-to-body weight (percent change compared to control)

M 0% – – – 3% 0%

F 0% – – – -3% -8%

Relative heart-to-brain weight (percent change compared to control)
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-41 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

M 0% – – – -4% -10*%

F 0% – – – -5% -11*%

Cholakis et al. (1980) 

Rats, CD, two-generation 

study; F0: 22/sex/group; 

F1: 26/sex/group; F2: 

10/sex/group 

F0 and F1 parental 

animals: 0, 5, 16, or 

50 mg/kg-d 

Diet

13 wks

No cardiac effects were observed (microscopic examination of heart was performed in 

randomly selected F2 animals). 

Heart weight data were reported only for F2 generation controls, 5 and 16 mg/kg-d 

groups.

Doses 0 5 16 50

Absolute heart weight (percent change compared to control)

F2 M 0% 3.2% -6.5% –

F2 F 0% 15% -3.7% – 

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

Doses 0 4 8 10 12 15

Cardiomyopathy (incidence)

M 2/10 – – – – 3/8

F 0/10 – – – – 1/6

Absolute heart weight (percent change compared to control)

M 0% -2% -7% -1% 1% 11%

F 0% -2% 0% 8% 7% 6%

Relative heart-to-body weight (percent change compared to control)

M 0% 4% 2% 1% -1% 8%

F 0% -2% -7% -6% -9% -16*%

Levine et al. (1990); Levine 

et al. (1981a); Levine et al. 

(1981b) 

Rats, F344, 10/sex/group; 

30/sex for control

0, 10, 30, 100, 300, or 

600 mg/kg-d 

Diet

13 wks

All animals in the 300 and 600 mg/kg-d groups died prior to study termination.

Doses 0 10 30 100 300 600

Chronic focal myocarditis (incidence)

M 8/30 8/10 6/10 1/10 1/10 0/10

F 8/30 3/10 1/10 1/10 1/10 1/9

Absolute heart weight (percent change compared to control)

M 0% -2% -10% -15% – – 

F 0% -3% 0% -5% – – 

Relative heart-to-body weight (percent change compared to control)

M 0% 2% -4% 3% – –

F 0% -2% 0% -3% – –

Von Oettingen et al. 

(1949) 

Rats (sex/strain not 

specified); 20/group

0, 15, 25, or 50 mg/kg-d 

Diet

3 mo

The study authors reported that there were no cardiac effects (microscopic 

examination of the heart was performed in all rats; data were not shown).
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-42 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Doses 0 0.1 1 10

Focal hyalinization of the heart (incidence)

M 0/3 – – 0/3

F 0/3 – – 1/3

Absolute heart weight (percent change compared to control)

M 0% – – 31%

F 0% – – 5.7%

Martin and Hart (1974) 

Monkeys, Cynomolgous or 

Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d 

Doses 0 0.1 1 10

Myocarditis (incidence in control and 10 mg/kg-d groups)

M 1/3 – – 1/3

F 0/3 – – 0/3

Absolute heart weight (percent change compared to control)

M 0% 7% -1% 5%

F 0% 10% 12% -12%

Immune effects

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim 

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

No immune effects were observed with routine hematology, clinical chemistry, or

histopathology evaluations.

Doses 0 1.5 7.0 35 175/100

WBC count; 105 wks (percent change compared to control)

M 0% -13% -8% -16% -30%

F 0% 12% 39*% 28% 0%

Absolute spleen weight; 105 wks (percent change compared to control)

M 0% 24% 31% -10% -28%

F 0% 4% 15% -17% 16%

Relative spleen weight; 105 wks (percent change compared to control)

M 0% 26% 32% -11% -21%

F 0% 4% 15% -17% 44%

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

WBC count; 104 wks (percent change compared to control)

M 0% -13% -22*% -34*%

F 0% 5% -32*% -12%

Absolute spleen weight; 104 wks (percent change compared to control) 

M 0% -11% -16% -4%

F 0% 58% 8% 37%

Relative spleen weight; 104wks (percent change compared to control)

M 0% -11% -14% 1%

F 0% 77% 19% 55%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-43 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

No immune effects were observed with routine hematology, clinical chemistry and 

histopathology evaluations.

Doses 0 0.3 1.5 8.0 40

WBC count; 105 wks (percent change compared to control)

M 0% -11% 103c % 184c % 15%

F 0% 7% 12% 354c % 251c%

Absolute spleen weight; 105 wks (percent change compared to control)

M 0% 5% -10% -32% -49%

F 0% -28% -44% -35% 17%

Relative spleen weight; 105 wks (percent change compared to control)

M 0% 9% 4% -29% -38%

F 0% -34% -45% -36% 9%

Cholakis et al. (1980) 

Mice, B6C3F1, 10–

12/sex/group

Experiment 1: 0, 10, 14, 20, 

28, or 40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

Absolute spleen weight (percent change compared to control)

M 0% – – – 18% 13%

F 0% – – – -2% -8%

Relative spleen weight (percent change compared to control)

M 0% – – – 24% 14%

F 0% – – – -3% -5%

Experiment 2: 0, 40, 60, 

80 mg/kg-d for 2 wks 

followed by 0, 320, 160, or 

80 mg/kg-d (TWA doses of 

0, 79.6, 147.8, or 

256.7 mg/kg-d for males 

and 0, 82.4, 136.3, or 276.4 

mg/kg-d for females)b

Diet

13 wks

Doses 0 80 160 320

WBC count (percent change compared to control)

M 0% -27% -12% 30%

F 0% -17% 3% -3%

Absolute spleen weight (percent change compared to control)

M 0% 17% 0% -17%

F 0% -22% 0% 0%

Relative spleen weight (percent change compared to control)

M 0% 25% 5% 0%

F 0% -12% 0% -3%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-44 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

WBC count (percent change compared to control)

M 0% – – – -12% 7%

F 0% – – – 17% 30%

Absolute spleen weight (percent change compared to control)

M 0% – – – 2% -4%

F 0% – – – -10% -12*%

Relative spleen weight (percent change compared to control)

M 0% – – – 5% 5%

F 0% – – – -8% -8%

Cholakis et al. (1980) 

Rats, CD, two-generation 

study; F0: 22/sex/group; 

F1: 26/sex/group; 

F2: 10/sex/group 

F0 and F1 parental 

animals: 0, 5, 16, or 

50 mg/kg-d 

Diet

13 wks

No immune effects were observed upon routine histopathology evaluation.

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

No effects were observed on thymus or spleen histology, red and white blood cell 

populations, or lymphocyte populations.

Doses 0 4 8 10 12 15

WBC count (percent change compared to control)

M 0% -5% -12% -7% 1% -3%

F 0% 22% 45% 12% 52% 29%

Absolute spleen weight (percent change compared to control)

M 0% -3% -6% 3% 1% 5%

F 0% 1% 8% 23*% 17*% 24*%

Relative spleen weight (percent change compared to control)

M 0% 3% 4% 7% -1% 2%

F 0% 1% 0% 6% -1% -2%

Absolute thymus weight (percent change compared to control)

M 0% -1% 3% -10% -12% -25%

F 0% -7% 12% 19% 32% 19%

Relative thymus weight (percent change compared to control)

M 0% -1% 3% -10% -12% -25%

F 0% -7% 4% 4% 12% -6%
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-45 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Levine et al. (1990); Levine 

et al. (1981a); Levine et al. 

(1981b) 

Rats, F344, 10/sex/group; 

30/sex for control

0, 10, 30, 100, 300, or 

600 mg/kg-d 

Diet

13 wks

Data were not reported for rats in the 300 or 600 mg/kg dose groups because all of the 

rats died before the 13-wk necropsy.

Doses 0 10 30 100 300 600

WBC count (percent change compared to control)

M 0% 4% 7% 15% – –

F 0% 23*% 24*% 62*% – –

Absolute spleen weight (percent change compared to control)

M 0% -11% -16% -34% – –

F 0% 2% 12% 0% – – 

Relative spleen weight (percent change compared to control)

M 0% -9% -12% -21% – –

F 0% 2% 12% 3% – –

Von Oettingen et al. 

(1949) 

Rats, sex/strain not 

specified, 20/group

0, 15, 25, or 50 mg/kg-d 

Diet

3 mo

Doses 0 15 25 50

WBC count (percent change compared to control)

M 0% -30% 7% -6%

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Doses 0 0.1 1 10

WBC count (percent change compared to control)

M 0% 5% 2% -19%

F 0% -2% 24% 6%

Absolute spleen weight (percent change compared to control)

M 0% – – 123%

F 0% – – -11%

Martin and Hart (1974) 

Monkeys, Cynomolgous or 

Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d 

Doses 0 0.1 1 10

WBC count (percent change compared to control)

M 0% -32% 0% -3%

F 0% -38% -1% -41%
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-46 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Gastrointestinal (GI) effects

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim 

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

No GI effects were observed as clinical signs or on gross pathology or histopathology 

examination.

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

No GI effects were observed as clinical signs or on gross pathology or histopathology 

examination.

Crouse et al. (2006)

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

No GI effects were observed on gross pathology or histopathology examination. 

Increased salivation and blood stains around the mouth were noted (affected doses 

and incidences were not reported); it is not clear whether these effects occurred in 

animals also experiencing convulsions.

Von Oettingen et al. 

(1949) 

Rats (sex/strain not 

specified); 20/group

0, 15, 25, or 50 mg/kg-d 

Diet

3 mo

Congestion of the GI tract was observed in 50 and 100 mg/kg-d rats that also exhibited 

mortality (40%) and severe neurotoxicity. 
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-47 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

Martin and Hart (1974) 

Monkeys (Cynomolgus or 

Rhesus); 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Vomiting was observed more frequently in the 1 and 10 mg/kg-d groups compared to 

the control or 0.1 mg/kg-d groups, although some episodes occurred during the 

intubation procedure.

Hart (1974) 

Dogs, Beagle, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

Some nausea and vomiting were reported (incidences and affected dose groups were 

not reported).

Hematological effects

Lish et al. (1984); Levine et 

al. (1984) 

Mice, B6C3F1, 

85/sex/group; interim

sacrifices (10/sex/group) at 

6 and 12 mo

0, 1.5, 7.0, 35, or 

175/100 mg/kg-d (high 

dose reduced to 

100 mg/kg-d in wk 11 due 

to excessive mortality)

Diet

24 mo

Doses 0 1.5 7.0 35 175/100

RBC count; 105 wks (percent change compared to control)

M 0% -4% 3% -3% 14%

F 0% 4% -7% 5% 3%

Hemoglobin; 105 wks (percent change compared to control)

M 0% -6% 3% -5% 9%

F 0% 2% -7% 3% 1%

Hematocrit; 105 wks (percent change compared to control)

M 0% -4% 3% -4% 9%

F 0% 3% -6% 3% 1%

Platelets; 105 wks (percent change compared to control)

M 0% 33% 9% 21% 27%

F 0% -14% -7% 1% 5%

Hart (1976) 

Rats, Sprague-Dawley, 

100/sex/group

0, 1.0, 3.1, or 10 mg/kg-d 

Diet

2 yrs

Doses 0 1.0 3.1 10

RBC count; 104 wks (percent change compared to control)

M 0% 3% 7% -2%

F 0% -14% 7% 2%

Reticulocyte count; 104 wks (percent change compared to control)

M 0% 250c% 500*c% 850*c%

F 0% 180*c% -40% 20%

Hemoglobin; 104 wks (percent change compared to control)

M 0% 3% 4% 0%

F 0% -1% 1% -2%

Levine et al. (1983); 

Thompson (1983) 

Rats, F344, 75/sex/group; 

interim sacrifices 

Doses 0 0.3 1.5 8.0 40

Hemoglobin levels; 105 wks (percent change compared to control)

M 0% 6% 6% 3% -13%

F 0% -5% 1% -9% -14%
Preliminary Materials for the IRIS Toxicological Review of RDX

This document is a preliminary draft for review purposes only and does not constitute Agency policy.

2-48 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

(10/sex/group) at 6 and 

12 mo

0, 0.3, 1.5, 8.0, or 

40 mg/kg-d 

Diet

24 mo

RBC count; 105 wks (percent change compared to control)

M 0% 5% 2% -1% -9%

F 0% -2% 2% -9% -13%

Platelet count; 105 wks (percent change compared to control)

M 0% 6% -4% -10% -7%

F 0% 14% -4% 5% 22%

Hematocrit; 105 wks (percent change compared to control)

M 0% 5% 5% 2% -7%

F 0% -5% 0% -8% -12%

Cholakis et al. (1980) 

Mice, B6C3F1, 10–

12/sex/group 

0, 80, 60, or 40 mg/kg-d for 

2 wks followed by 0, 80, 

160, or 320 mg/kg-d (TWA 

doses of 0, 79.6, 147.8, or 

256.7 mg/kg-d for males 

and 0, 82.4, 136.3, or 

276.4 mg/kg-d for 

females)b

Diet

13 wks

Doses 0 80 160 320

RBC count (percent change compared to control)

M 0% -5% -12*% -2%

F 0% -10% -1% 1%

Reticulocytes (percent change compared to control)

M 0% -36% -13% 15%

F 0% 21% 25% -19%

Hematocrit (percent change compared to control)

M 0% -1% -6% 0%

F 0% -8% 2% 1%

Hemoglobin (percent change compared to control)

M 0% -2% -7*% -3%

F 0% -5% 4% 1%

Platelets (percent change compared to control)

M 0% 33% 28% 22%

F 0% 3% 9% 39%

Cholakis et al. (1980) 

Rats, F344, 10/sex/group

0, 10, 14, 20, 28, or 

40 mg/kg-d 

Diet

13 wks

Doses 0 10 14 20 28 40

RBC count (percent change compared to control)

M 0% – – – 3% -1%

F 0% – – – -1% -7%

Hemoglobin (percent change compared to control)

M 0% – – – 2% -1%

F 0% – – – -1% -1%

Platelet (percent change compared to control)

M 0% – – – 11% 16*%

F 0% – – – -23% -13%

Reticulocytes (percent change compared to control)

M 0% – – – 26% 76*%

F 0% – – – -2% 17%

Hematocrit (percent change compared to control)
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-49 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

M 0% – – – 3% 0%

F 0% – – – 0% -2%

Crouse et al. (2006) 

Rats, F344, 10/sex/group

0, 4, 8, 10, 12, or 15 mg/kgd 

Gavage

90 d

Doses 0 4 8 10 12 15

RBC count (percent change compared to control)

M 0% 1% -7% -2% -4% -5%

F 0% 3% 3% -1% 2% -2%

Hemoglobin (percent change compared to control)

M 0% -1% -5% 0% -1% -6%

F 0% 2% 4% -1 4% -4%

Platelet count (percent change compared to control)

M 0% 21% 11% 13% -8% 34%

F 0% 6% 40% 47% 34% -36%

Hematocrit (percent change compared to control)

M 0% 2% -5% 0% -1% -4%

F 0% 3% 4% 0% 4% -2%

Levine et al. (1990); Levine 

et al. (1981a); Levine et al. 

(1981b) 

Rats, F344, 10/sex/group; 

30/sex for control

0, 10, 30, 100, 300, or 

600 mg/kg-d 

Diet

13 wks

Data were not reported for rats in the 300 or 600 mg/kg dose groups because all of the 

rats died before the 13-wk necropsy.

Doses 0 10 30 100 300 600

Hematocrit (percent change compared to control)

M 0% -2% -1% -5% – – 

F 0% 0% -4% -7% – –

Hemoglobin (percent change compared to control)

M 0% -3% -1% -6% – –

F 0% 0% -4% -8*% – –

RBC count (percent change compared to control)

M 0% -2% -2% -5% – –

F 0% -1% -4% -5% – – 

Reticulocytes (percent change compared to control)

M 0% -4% 10% 28% – –

F 0% 9% 73% 71% – – 

Von Oettingen et al. 

(1949) 

Rats, sex/strain not 

specified, 20/group

0, 15, 25, or 50 mg/kg-d 

Diet

3 mo

Doses 0 15 25 50

RBC count (percent change compared to control)

M+F 0% -23% -12% -14%

Hemoglobin (percent change compared to control)

M+F 0% -25% -7% -11%

Hart (1974) 

Dogs, Beagle, 3/sex/group

Doses 0 0.1 1 10

RBC count (percent change compared to control)

M 0% -3% 3% 2%
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-50 DRAFT—DO NOT CITE OR QUOTE

Reference and Study 

Design Results

0, 0.1, 1, or 10 mg/kg-d 

Diet

90 d

F 0% 13% 7% 11%

Reticulocyte count (percent change compared to control)

M 0% -66% 0% -50%

F 0% -17% -50% 0%

Hematocrit (percent change compared to control)

M 0% -4% 2% 0%

F 0% 6% 1% 7%

Hemoglobin (percent change compared to control)

M 0% 5% -2% 0%

F 0% 8% -2% 8%

Martin and Hart (1974) 

Monkeys, Cynomolgous or 

Rhesus, 3/sex/group

0, 0.1, 1, or 10 mg/kg-d 

Gavage

90 d

Histopathological examination revealed increased numbers of degenerate or necrotic 

megakaryocytes in all bone marrow sections.

Doses 0 0.1 1 10

RBC count (percent change compared to control)

M 0% -3% 2% -3%

F 0% 0% -1% 2%

Reticulocyte count (percent change compared to control)

M 0% -33% -50% -50%

F 0% -18% -36% 45%

Hematocrit (percent change compared to control)

M 0% -7% -4% -1%

F 0% 10% 7% 3%

Hemoglobin (percent change compared to control)

M 0% -10% -8% -6%

F 0% 6% 6% 3%

*Statistically significantly different compared to the control, as determined by study authors (p < 0.05). a

Incidence counts exclude individuals from which blood was obtained via the orbital sinus.

b

Doses were calculated by the study authors.

c

Standard deviations accompanying the mean response in a given dose group were high, suggesting uncertainty in 

the accuracy of the reported percent change compared to control. 

1 
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-51 DRAFT—DO NOT CITE OR QUOTE

1 2.9. Genotoxic Effects

2 Table 2-14. Summary of in vitro studies of RDX genotoxicity 

Endpoint Test system

Dose/

concentrationa

Resultsb

Comments Reference

Without 

activation

With 

activation

Genotoxicity studies in prokaryotic organisms

Reverse

mutation

Salmonella. typhimurium TA1535, 

TA1537, TA1538, TA98, TA100

1,000 μg/plate − − Metabolic activation with S9 Cholakis et al. 

(1980) 

Reverse 

mutation

S. typhimurium TA1535, TA1537, 

TA1538 TA100, TA98

14 μg/plate − − Effect of disinfection treatments on 

mutagenicity tested: RDX was not mutagenic in 

any strain before or after disinfection 

treatment with chlorine or ozone 

Simmon et al. 

(1977) 

Reverse

mutation 

S. typhimurium TA98, TA100 250 μg/plate − − Study authors noted that results were 

consistent with literature

George et al. 

(2001)

Reverse 

mutation

S. typhimurium TA98, TA100 1 mg/plate − − Metabolic activation with S9 Tan et al. 

(1992)

Reverse

mutation

S. typhimurium TA98, TA100 1,090 μg/plate − − High S9 activation (9%) used Pan et al. 

(2007)

Reverse

mutation

S. typhimurium TA97a 32.7 μg/plate − ± High S9 activation (9%) used; study authors 

concluded that RDX “required intensive

metabolic activation” to exhibit mutagenicity in 

this strain

Pan et al. 

(2007) 

Reverse 

mutation

Vibrio fischeri 0.004 μg/tube ± + Mutatox assay with metabolic activation (S9) Arfsten et al. 

(1994) 

Reverse 

mutation (umu

test)

Salmonella choleraesius subsp. 

chol. (prior Salmonella 

typhimurium) TA1535/pSK1002; 

20.6 μg/mL − − No observed effect concentration; tested at 

highest concentration where the induction rate 

was below 1.5 for the first time and the growth 

factor was below 0.5

Neuwoehner et 

al. (2007) 

Reverse 

mutation

(NM2009 test)

S. choleraesius subsp. chol. 

NM2009, 

TA1535/pSK1002/pNM12

20.6 μg/mL − − No observed effect concentration; tested at 

highest concentration where the induction rate 

was below 1.5 for the first time and the growth 

factor was below 0.5

Neuwoehner et 

al. (2007) 
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-52 DRAFT—DO NOT CITE OR QUOTE

Endpoint Test system

Dose/

concentrationa

Results

b

Comments Reference

Without 

activation

With

activation

Induction of

the sfiA gene 

(SOS 

chromotest)

Escherichia. coli PQ37 20.6 μg/mL − − No observed effect concentration; tested at

highest concentration where the induction rate

was below 1.5 for the first time and the growth

factor was below 0.5

Neuwoehner et

al. (2007)

Reverse 

mutation

S. typhimurium, TA98, TA100 24.8 μg/mL − − No observed effect concentration; metabolic

activation with S9

Neuwoehner et

al. (2007)

Reverse 

mutation

S. typhimurium TA98, TA100 2.6 μg/mL − − No observed effect concentration; metabolic

activation with S9

Lachance et al.

(1999)

Reverse 

mutation

S. typhimurium TA1535, TA1536,

TA1537, TA1538 TA100, TA98

30.8 μg/mL - - Metabolic activation with S9 Cotruvo et al.

(1977)

Genotoxicity studies in nonmammalian eukaryotic organisms

Recombination

induction

S. cerevisiae D3 23 μg/mL − − Study authors concluded that this

microorganism did not appear to be useful for 

detecting mutagenicity in several compounds

tested

Simmon et al.

(1977)

Recombination

induction

S. cerevisiae D3 30.8 μg/mL - - Metabolic activation with S9 Cotruvo et al.

(1977)

Genotoxicity studies in mammalian cells

Forward

mutation

Chinese hamster lung fibroblasts

V79 cells

40 μg/mL − − Minimal cytotoxicity observed at 40 μg/mL

(limit of solubility)

Lachance et al. 

(1999)

Mutation L5178Y mouse lymphoma cells 500 μg/mL − − No or low cytotoxicity seen at these

concentrations; however, precipitate was

observed >250 μg/mL

Reddy et al.

(2005)

Unscheduled

DNA synthesis;

DNA repair

WI-38 cells, human diploid

fibroblasts

4,000 μg/mL - - Precipitates were observed at concentrations of

RDX ≥40 μg/mL

Dilley et al.

(1979)

a 1 Lowest effective dose for positive results; highest dose tested for negative results.

2 b

+ = positive; ± = equivocal or weakly positive; − = negative
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-53 DRAFT—DO NOT CITE OR QUOTE

1 Table 2-15. Summary of in vivo studies of RDX genotoxicity

2 

3 

Endpoint Test system

Dose/

concentration Results Comments Reference

In vivo genotoxicity studies in mammalian systems

Micronucleus 

formation

CD-1 mouse bone marrow Single dose of 62.5, 

125, or 250 mg/kg

No significant decrease in 

PCE:NCE ratios; no 

induction of 

micronucleated PCE at any 

dose

250 mg/kg was maximum 

tolerated dose determined in 

dose range-finding study

Reddy et al. (2005) 

Dominant lethal 

mutations

Male CD rats dosed and mated with 

untreated female rats

0, 5, 16, or 

50 mg/kg-day for 

15 wk

No statistically or 

biologically significant 

effects on fertility; 

determined to be negative 

for the induction of lethal 

mutations

Males in the high-dose group 

experienced lower food 

consumption and weight gain 

compared with all other 

groups

Cholakis et al. 

(1980) 
Preliminary Materials for the IRIS Toxicological Review of RDX

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2-54 DRAFT—DO NOT CITE OR QUOTE

1 Table 2-16. Summary of in vitro and in vivo studies of RDX metabolite genotoxicity

Endpoint Test system

Dose/

concentrationa

Resultsb

Comments Reference

Without 

activation

With 

activation

Genotoxicity studies in prokaryotic organisms

Reverse

mutation

Salmonella typhimurium TA97a, 

TA102

22 μg/plate – + Mono and trinitroso metabolites (MNX and 

TNX); high S9 activation (9%) used

Pan et al. (2007) 

Reverse

mutation

S. typhimurium TA1535, TA1537, 

TA1538, TA98, TA100

500 ug/plate + + Positive only for TNX; MNX and DNX were 

negative

George et al. (2001) 

Reverse 

mutation

S. typhimurium TA1535, TA1537, 

TA1538, TA98, TA100

NRc – – Mononitroso metabolite, MNX; metabolic 

activation with S9

Snodgrass (1984) 

Genotoxicity studies in mammalian cells—in vitro

Forward 

mutation

Mouse lymphoma thymidine 

kinase 

NRc + + Mononitroso metabolite, MNX; metabolic 

activation with S9

Snodgrass (1984)

Chromosomal 

aberrations

Chinese hamster ovary cells NRc – + Mononitroso metabolite, MNX; metabolic 

activation with S9

Snodgrass (1984)

Unscheduled 

DNA synthesis; 

DNA repair

Primary rat hepatocytes NRc + Mononitroso metabolite, MNX; additional 

metabolic activation not required with S9

Snodgrass (1984)

In vivo genotoxicity studies in mammalian systems

Dominant lethal 

mutations

Male mice dosed and mated with 

untreated female mice

NRc – Mononitroso metabolite, MNX; additional 

metabolic activation not required with S9

Snodgrass (1984) 

2 

3 

4 

5 

a

Lowest effective dose for positive results; highest dose tested for negative results. b

+ = positive; ± = equivocal or weakly positive; − = negative c

NR = not reported