### 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 **p reliminary**  **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 Re search 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— DO NOT CITE OR QUOTE **DISCLAIMER**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 constitut e endorsement o r 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.


### iii DRAFT

— DO NOT CITE OR QUOTE 

# 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.


### iv DRAFT

— DO NOT CITE OR QUOTE 

# 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 da tabase 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 genotoxic ity

................................................................ 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
F i gure 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.



### v DRAFT

— DO NOT CITE OR QUOTE 

### 1

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 

# PREFACE

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

and p reliminary e xposure

- response arrays for h exahydro

- 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 co m ment 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

- r e sponse relationships. The draft literature search strategy, preliminary evidence tables, and p r eliminary exposure

response arrays are responsive to the National Research Council (NRC) 2011 report Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formalde h y de

. 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 systemat ic r e view of the scientific literature. In addition, NRC recommendations for standardized presentation of key study data are addressed in the preliminary

evidence tables and preliminary e xpo sure

- response arrays.
EPA welcomes all comments on the draft li t er ature search strategy , preliminary evidence
tables, and preliminary e xpo sure

- response arrays, such as remarks on the following:

• t he clarity and transparency of the materials;

• t he approach for identifying pertinent studies;

• t he s election of studies for data extraction to preliminary evidence tables and exposure

response arrays ;

• a n y methodological considerations that could affect the interpretation of or confidence

i n study results ; a nd

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

ev aluation of human health hazard or dose

- r e sponse relationships. The preliminary evidence tables and exposure

- r es ponse arrays should be regarded solely as representing the data on each endpoint that have been identified as a result of the d r aft literature search strategy. They do not reflect any conclusions as to hazard identification or dose

- r es ponse assessment. After obtaining public input and conducting additional study evaluation and data integration, EPA will revise these materials to s upport 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. 

### 1-1 DRAFT

— DO NOT CITE OR QUOTE 

# 1. DRAFT LITERATURE SEARCH STRATEGY

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

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

summarized gr a phically in Figure 1 -1 . The literature search for RDX was conducted in five online scientific databases in February 2013. Fo r four of these databases (Pubmed, Toxline, Toxcenter, and TSCATS) the detailed search strategy is provided in Table 1 -2 . Giv e n the military applicatio ns of RDX, the Defense Technical Information Center (DTIC) database was searched. B ec ause of

limitations in the classification and distribution of materials in D TIC , a separate search strategy was applied, which is described in Tab l e 1 -3 . The computerize d database searches were augmented by review of online regulatory sources as well as “forward” and “backward” Web of Science searches of 2 recent reviews (T ab l e 1 -4 ). A special strategy was app l ied to searches of the DTIC online database. A total of 858 citations were identified, including 504 where the full

- te x t 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 8 58 citations, 8 citations with

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

Those 8 cit ations with unlimited distribution ( t hat were not duplicated in other databases) were uploaded to the Health and Environmental Research Online (HERO) website 1 

### ( http://hero.epa.gov ).

The 10 limited

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

focus on whether t hey provided additional primary health effects data ) to d e termine whether EPA should seek authorization for public distribution and upload to HERO. A review of the abstract or

f ul l

- te xt of the documents associated with the citation resulted in the followi ng 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 n o t to provide additional primary health effects data because they either described a study plan for, or reported data from

, ex p eriments that were subsequently published ( Wil l iams et al., 2011 ; Hathaway and Buck, 1977 ) and had already been identified by the literature search strategy;

• 1 citation was i dentified 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

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

### 1-2 DRAFT

— DO NOT CITE OR QUOTE • 1 citation was identified as relevant and provided animal inhalation data, but was not 

### 1

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 brought forward fo r 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 hav e 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 tha t i t was unlikely the report would provide primary

health effect s dat a t hat warranted further review.

The rationale s for exclusion of the other 841 ref er ences that were not selected for further

consideration are summarized in Table 1 -5.

Af ter electronically eliminating duplicates from the citations retrieved through these

d atabases, 90 6 citations were identified. A dditional ly, 18 citations were obtained using additional search strategies described in Table 1 -4

. T h e resulting 924 citatio ns were screened u sing the title,
abstract, and in limited instances, fu l l text for pertinence to examining the health effects of RDX exposure. A total of 652 ref er ences were identified as not being pertinent and were excluded f rom further consideration ( see F i g ure 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

- r es p onse arrays ( see Section 1.2.1). A tota l of 2 10 references were considered pertinent, but not as primary sources of health effects data (e.g., adsorption/distribution/metabolism/excretion [ ADME ] stu d ies), and were kept as additional resources for development of the Toxicological Review (see Sec tio n 1.2.2 ). If a reference did not provide enough material to evaluate pertinence (e.g., no abstract), it wa s r e served for further possible review; 15 su ch 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 T o x ico logical R eview. As illustrated in Figure 1

- 1, s tudies were identified and “tagged” in HERO based on information provided in the title and/or abstract; in some case s th i s information was supplemented by further review of the full text of the corresponding document. Based on this review, stu d ies

we re distributed in different g r oups that reflect the primary content of the citation. It should be

noted that stu d ies we re not given multiple tags, and the inclusion of a citation in a given category (or tag) does not preclude its use in o n e or more other categor ies . For example, Woody et al. (1986 ) is a case report that describes accidental ingestion of RDX by a child. In Fi gure 1

- 1 it is included in the human studies category of primary health effects data. T his case report also provides pharmacokinetic data and could be a pertinent source of i nformation on the toxicokinetics

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

toxicokinetic s . 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. 

### 1-3 DRAFT

— DO NOT CITE OR QUOTE s trategy of only using one tag per reference is utilized to allow the public and stakeholders to more 

### 1

2

3

4 easily distin guish 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. 

### 1-4 DRAFT

— DO NOT CITE OR QUOTE **Table 1-1** 

**. Overview of d**  **atabase s**  **earch s**  **trategy for RDX**  

### 1

2 Database Keywords

Pubmed
Toxline

TSCATS1
WOS
Toxcenter
DTIC Chemical CASRN : 121

- 82 -4 Syn onyms : Cyclonite OR RDX OR Cyclotrimethylenetrinit ramine OR "cyc lotrimethylene trinitramine" OR "Hexahydro

- 1, 3,5

- trinitro

- 1,3,5

- triazine" OR "Hexahydr o- 1,3,5

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

- trinitro

- 1,3,5

- triazine" OR "1,3,5

- Triaz a- 1,3,5

- trinitrocyclohexane" OR "1,3,5

- Trini tro

- 1,3,5

- triazacyclohexane" OR "1,3,5

- Trini trohexahydro

- 1,3,5

- triazine" OR "1,3,5

- T rinitrohexahydro -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" O R Cyclotrimethylenenitramine OR Trimethylenetrinitramine OR "Trimethylene
trinitramine" OR Trimethyleentrinitramine OR "Trinitr ocyclotrimethylene
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.**  

### 1

2

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

### 1-5 DRAFT

— DO NOT CITE OR QUOTE

### Preliminary Materials for the IRIS Toxicological Review of RDX

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

### 1-6 DRAFT

— DO NOT CITE OR QUOTE **Table 1-2** 

**. Summary of**  **detailed s**  **earch s**  **trategies for RDX (Pubmed, Toxline,**  

### 1 **Toxcenter, TSCATS)** 

### 2

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]
O R "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

- trinitro

1,3,5

- 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])) 112

PubMed

Date limit:
1950's

4/2012 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

- tr initro

- 1,3,5

- triazina"[tw] OR "Hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazin"[tw] OR "Perhydro

- 1,3,5

- trinitro

1,3,5

- 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

- trinitro

1,3,5

- triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[t w] OR Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw] OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR 33 7

### 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 "PB XW 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])) O R "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 Cyclotrimethylenetrini tramine[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

- trinitro

1,3,5

- triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw]
OR Trinitrotr imethylenetriamine[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 (Cycl onite[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

- trinitro

1,3,5

- triazine"[tw] OR Cyclotrimethylenenitramine[tw] OR Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR Trimethyleentrinitramine[tw] OR "Trinitrocyclotrime thylene 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 (t o[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

- trinitro

1,3,5

- triazine"+"1,3,5

- Triaza

- 1,3,5

- trinitrocyc lohexane"+"1,3,5

- Trinitro

1,3,5

- 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

- trinitro

1,3,5

- triazina"+"Hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazin"+"Perhydro

- 1,3,5

- trinitro

- 1,3,5

- triazine"+"Cyclotrimethylenenitramine"+"Trimethylenetrinitramine"+"Tri methylene
trinitramine"+"Trim ethyleentrinitramine"+"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

- s

triazine" OR Hexogen OR "1,3,5

- trinitro

- 1,3,5

- tri azine" 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

- t riazina" 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 bi omarker? 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? O R 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 fer til? 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 end ocrin? 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 lim ited 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

- s

triazine" OR Hexogen OR "1,3,5

- trinitro

- 1,3,5

- tri azine" 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

- t riazina" 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 pharm acokin? 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 ov a 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

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

### 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 androge n? 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 lagom orpha 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 overla p with Toxline
Merged
Reference
Set 1 Including additional strategies and DTIC (after duplicate removal) 92 4



### 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 "Hexahydro

1,3,5

- trinitro -s- triazine" OR Hexogen OR Cyclotrime thylenenitramine 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 O R 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
anima ls OR Invertebrates OR venomous animals OR wildlife OR biodegradation)) and ("121

- 82

- 4" OR Cyclonite OR RDX OR 304 (7 s elected 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 -stri azine" 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

age nts 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 **Table 1**  **-4**

**. Processes used to augment the search of core databases for RDX**  

### 1

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 -t rinitro

- 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
refe rences 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 Assessm ents 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 Li st 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 I NCHEM ( 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 

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

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 ( h ttp://hero.epa.gov/ RDX ).

**1.2.1. P**  **rimary Source s**  **of Health Effects Data**

Data from citations in **b old**  are displayed in tabular or graphical form in Section 2. See

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

exposure

- r esponse 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. B arsotti, M., & Crotti, G. (1949). [Attacchi epileptici come manifestazione di intossicazion e professionale da trimetilen

- t rinitroamina (T4)]. La Medicina del Lavoro, 40 (4), 107

- 112.

3. D avies, J. O. J., Roberts, D. M., Hittarage, A., & Buckley, N. A. (2007). Oral C

- 4 plastic explosive
in humans - A ca se series. Clinical Toxicology, 45 (5), 454

- 457. doi: 10.1080/15563650601118044

4. G oldberg, 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. J ournal of the Royal Society of M edicine, 85 (3), 181.
5. H arrell

- Bruder, B., & Hutchins, K. L. (1995). Seizures caused by ingestion of composition C

4. A nnals of Emergency Medicine, 26 (6), 746

- 748.

**6. H**  **athaway, J. A., & Buck, C. R. (1977). Absence of health hazards associated with RDX**
**manufac t**  **ure and use.** Journal of Occupational and Environmental Medicine, 19 **(4),**

**269**

**- 2**  **72.**

7. H ett, 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. H ollander, A., & Colbach, E. (1969). Composition C

- 4 induced seizures: A report of five cases. Military Medicine, 134 ( 13), 1529

- 1530.

9. K aplan, A. S., Berghout, C. F., & Peczenik, A. (1965). Human intoxication from RDX. Archives of Environmental Health, 10

, 877

- 883.

10. K asuske, L., S chofer, J. M., & Hasegawa, K. (2009). Two marines with generalized seizure activity. Jo urnal of Emergency Nursing, 35 (6), 542

- 543. doi: 10.1016/j.jen.2008.05.001

11. K etel, W. B., & Hughes, J. R. (1972). Toxic encephalopathy with seizures secondary to ingestio n of composition C

- 4. A clinical and electroencephalographic study. Neurology,

22 (8), 871

- 8 76.

12. K nepshield, J. H., & Stone, W. J. (Eds.). (1972). Toxic effects following ingestion of C

- 4 plastic explosive . Sp ringfield, IL: Charles C. Thomas.

13. K üçükardali, 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. M**  **a, 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 Z

hiyebin / Industrial health and occupational diseases, 19 **(1), 20**

**- 23.**  

### 1
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
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. St one, 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. T estud, 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. T estud, 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. T estud, F., Glanclaude, J. M., & Descotes, J. (1996). Acute hexogen poisoning after occupational exposure. Journal of Toxicology - C linical Toxicology, 34 (1), 109

- 111. doi: 10.3109/15563659609020244

**20. W**  **est, R. R., & Stafford, D. A. (1997). Occupational exposures and haematological**
**abnormal i**  **ties among ordnance factory workers: A case control study.** Leukemia Research, 21 **( 7), 675** 

**- 680.** 

21. W oody, 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**

**- R**  **DX in rats. Aberdeen Proving Ground: U.S. Army Environmental Hygiene**  **Agency.**

2. B rown, D. (1975). The acute and chronic biochemical and behavioral effects of cyclotrimethylenetrinitramine. B altimore, MD: Maryland Univer si ty Baltimore School of Pharmacy.

3. B urdette, 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. C**  **holakis, J., Wong, L., Van Goethem, D., Minor, J., & Short, R. (1980). Mammalian toxicological evaluation of RDX (pp. 1** 

**- 1**  **58). Kansas City, MO: Midwest Research**

**Institute.**
**5. C**  **rouse, L. C. B., Michie, M. W., Major, M., Johnson, M. S., Lee, R. B., & Paulus, H. I. (2006). Sub**  **c hronic oral toxicity of RDX in rats. Aberdeen Proving Ground, MD: U.S.**  **Army Center for Health Promotion and Preventive Medicine.**

6. D illey, 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. F uredi

- 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

-

### 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- 17 DRAFT

— DO NOT CITE OR QUOTE t riazine (RDX) in rabbits. Chicago, IL: IIT Research Institute. 

### 1
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
42
43 **8. Hart, E. (1974). Subacute toxicity of RDX and TNT in dogs. Final report. Kensington,**  **MD: Litton Bionetics, Inc.**

**9. H**  **art, E. (1976). Two**

**- year chronic toxicity study in rats. Kensington, MD: Litton**  **Bionetics, Inc.**

10. H askell, L. (1942). Initial submission: Toxicity of RDX (cyclotrimethylenetrinitramine) with cover letter dated 101592. Wilmington, DE: DuPont Chemical Company.

11. J aligama, S., Kale, V. M., Wilbanks, M. S., Perkins, E. J., & Meyer, S. A. (2013). Delayed myelosuppression with acute exposure to hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (RDX) and environmental degradation product hexahydro -1- n itroso

- 3,5

- dinitro

- 1,3,5

- triazine (MNX)

in rats. Toxicology and Applied Pharmacology, 266 (3), 443

- 4 51. doi: 10.1016/j.taap.2012.11.022

**12. L**  **evine, B., Furedi, E., Gordon, D., Burns, J., & Lish, P. (1981). Thirteen week oral (diet) toxicity study of trinitrotoluene (TNT), hexahydro** 

**- 1**  **, 3, 5**

**- trinitro** 

**- 1, 3, 5** 

**- triazine**  **(RDX) and TNT/RDX mixtures in the Fischer 344 rat. Final report. Chicago, IL: IIT** 
**Research Institute.**

**13. L**  **evine, B., Furedi, E., Sagartz, J., Rac, V., & Lish, P. (1984). Determination of the chronic mammalian toxicological effects of RDX: Twenty** 

**- f**  **our month chronic toxicity/carcinogenicity**  **s tudy of hexahydro** 

**- 1,3,5** 

**- trinitro** 

**- 1,3,5** 

**- triazine (RDX) in the**  **B6C3F1 hybrid mouse. Phase VI final report. Volume 3. Chicago, IL: IIT Research**

**Institute.**

**14. L**  **evine, B. S., Furedi, E. M., Gordon, D. E., Barkley, J. J., & Lish, P. M. (1990). Toxic**

**interactions o**  **f the munitions compounds TNT and RDX in F344 rats.** Fundamental and Applied Toxicology, 15 **(2 ), 373** 

**- 380. doi: 10.1016/0272** 

**- 0590(90)90062**  **-o 15.**  **L evine, B. S., Furedi, E. M., Gordon, D. E., Burns, J. M., & Lish, P. M. (1981). Thirteen**  **week toxicity study of hexa hy**  **dro**

**- 1,3,5** 

**- trinitro** 

**- 1,3,5** 

**- triazine (RDX) in Fischer 344** 

**rats.** T oxicology Letters, 8 **(4**

**- 5), 241** 

**- 245. doi: 10.1016/0378** 

**- 4274(81)90108**  **-9**

**16. L**  **evine, B. S., Lish, P. M., Furedi, E. M., Rac, V. S., & Sagartz, J. M. (1983). Determination**
**of the chronic mammalian toxi cological effects of RDX (twenty** 

**- four month chronic**  **toxicity/carcinogenicity study of hexahydro**

**- 1,**  **3,5**

**- trinitro** 

**- 1,3,5** 

**- triazine [RDX] in the**  **Fischer 344 rat Phase V: Final report. Chicago, IL: IIT Research Institute.**

**17. L**  **ish, P. M., Levine, B. S., Furedi**

**- Macha**  **cek, E. M., Sagartz, E. M., & Rac, V. S. (1984). Determination of the chronic mammalian toxicological effects of RDX: twenty** 

**- f**  **our month chronic toxicity/carcinogenicity study of hexahydro** 

**- 1,**  **3,5**

**- trinitro** 

**- 1,3,5** 

**- triazine (RDX) in the B6C3F1 hybrid mouse (pp.**  **367). Fort Detrick, Frederick, MD: US Army Research and Development Command.** 

**18. M**  **acPhail, R., Walker, Q., & Cook, L. (1985). Neurotoxicology of cyclotrimethylenetrinitramine (RDX). Final report. Research Triangle Park, NC: U.S.**  **Environmental Protection Agency, Health Effects Research Laboratory,**  **Neurotoxicology Division.**

**19. M**  **artin, D., & Hart, E. (1974). Subacute toxicity of RDX and TNT in monkeys (pp. 1**

**- 216). Kensington, MD: Litton Bionetics, Inc.** 

20. M cNamara, B. P., Averill, H. P., Owens, E. J., Callahan, J. F., Fairchild, D. G., Cinchta, H. P.,

### 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- 18 DRAFT

— DO NOT CITE OR QUOTE B iskup, D. K. (1974). The toxicology of cyclotrimethylenetrinitramine (RDX) and 

### 1
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
42 cyclotetramethylenetetranitramine (HMX) solutions in dimethylsulfoxide (DMSO), cyclohexanone, and acetone. Aberdeen Proving Ground, MD: Edgewoo d Arsenal.

**21. Parker, G. (2001). Attachment 1: Pathology Working Group**  **- Chairperson's report:**  **Reevaluation: Twenty**

**- f**  **our month chronic toxicity/carcinogenicity study of hexahydro** 

**- 1**  **,3,5**

**- trinitro** 

**- 1,3.5** 

**- triazine (RDX) in the B6C3F1 hybrid mouse. Research**  **Triangle P**  **ark, NC: National Institute of Environmental Health Sciences.**

**22. Pa**  **rker, G. A., Reddy, G., & Major, M. A. (2006). Reevaluation of a twenty**

**- four** 

**- month**  **chronic toxicity/carcinogenicity study of hexahydro**

**- 1**  **,3,5**

**- trinitro** 

**- 1,3,5** 

**- triazine**  **(RDX) in the B6C3F1 hybri d m**  **ouse.** International Journal of Toxicology, 25 **(5), 373**

**- 378. doi: 10.1080/10915810600846245** 

23. St ork, C., Kos, S., Langden, B., & Cantor, R. (2000). Acute canine C

- 4 explosive ingestion resulting in prolonged status epilepticus

. **24. T**  **hompson, C. A. (1983). Twenty** 

**- four month chronic toxicity/carcinogenicity study of**  **hexahydro**

**- 1**  **,3,5**

**- trinitro** 

**- 1,3,5** 

**- triazine (RDX) in the Fischer 344 rat. Twenty** 

**- four**  **month interim report. Necropsy observations. Chicago, IL: IIT Research Institute.**
**25. V**  **on Oettingen, W., Donahue, D., Yagoda, H., Monaco, A., & Harris, M. (1949). Toxicity**  **and potential dangers of cyclotrimethylenetrinitramine (RDX).** Journal of Industrial Hygiene and Toxicology, 31 **(1 ), 21** 

**- 31.** 

26. W illiams, L., & Bannon, D. (2009). Mechanism of RDX

- induced seizures in rats. A berdeen Proving Ground, MD: U.S. Army Center for Health Promotion and Preventive Medicine, Directorate of Toxicology, Health Effects Research Program.

**1.2.2. No**  **t Primary Source of Health Effects Data , but Kept**  **a s Additional Resources** 
Regulatory Documents (8 citations)

1. . Guidance for characterizing explosives contaminated soils: Sampling and selecting on

- site analytical methods. (1996). Idaho Falls; Department of Energy, Washington, DC.: Technical Information Center Oak Ridge Tennessee.

2. AC GIH . (2001). Documentation of the Threshold Limit Values and Biological Exposure Indices

- C yclonite (2nd ed.). Cincinnati, OH.

3. An onymous. (1997). Protect Your Family. Reduce Contamination at Home (Vol. U, pp. 97

- 125): Anonymous.

4. AT SDR . (1995). Toxicological P rofile for RDX. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
5. AT SDR . (2012). Toxicological Profile for RDX (Update) (Vol. GRA and I). Research Triangle Park, NC.; Agency for Toxic Substances and Disease Registry, Atlanta, GA: U.S. Depar t ment of Health and Human Services, Public Health Service.

6. M cLellan, W. L., Hartley, W. R., & Brower, M. E. (1988). Health advisory for hexahydro

- 1,3,5

- trinitro

- 1 ,3,5

- triazine (RDX). Washington, DC: U.S. Environmental Protection Agency; Office of Drinking Water; Criteria and Standards Division.

7. NI OSH . (1995). Occupational safety and health guidelines for chemical hazards. Supplement

IV

- O HG. Cincinnati, Ohio: U.S. Department of Health and Human Services.

8. W ollin, K. M., & Dieter, H. H. (2005). [New drinking w ater reference values for monocyclic

### 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- 19 DRAFT

— DO NOT CITE OR QUOTE n itro compounds]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 48 (11), 

### 1
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
42 1289

- 1295. doi: 10.1007/s00103

- 005

- 1157 -8

Reviews (13 citations)

1. Dacre, J. C. (1994). Hazard evaluation of Army compounds in the environment. [Review]. Drug Metabolism Reviews, 26 ( 4), 649

- 662. doi: 10.3109/03602539408998320

2. D avis, R. A. (Ed.). (1993). Aliphatic nitro nitrate and nitrite compounds (Vol. IIA): John Wiley and Sons, Inc.

3. E lamin, B. K., Callegari, E., Gramantieri, L., Sabbioni, S., & Negrini, M. (2011). MicroRNA response to environmental mutagens in liver. [Review]. Mutation Research, 717 (1- 2 ), 67

- 76. doi: 10.1016/j.mrfmmm.2011.03.015

4. H oek, B. (2004). Military explosives and health: Organic energetic compound syndrome? [Rev iew]. Medicine, Conflict and Survival, 20 (4), 326

- 333. doi: 10.1080/1362369042000285955
5. I nouye, L., Lachance, B., & Gong, P. (2009). Genotoxicity of explosives. pp. 177

- 209.

6. J uhasz, A. L., & Naidu, R. (2007). Explosives: fate, dynamics, and ecological impact in terrestrial and marine environments. [Review]. Reviews of Environmental Contamination and Toxicology, 191

, 163

- 215.

7. L ima, D. R., Bezerra, M. L., Neves, E. B., & Moreira, F. R. (2011). Impact of ammunition and military explosives on human health and the environment. [Review]. Reviews on Environmental Health, 26 ( 2), 101

- 110.

8. M cLellan, W. L., Harley, W. R., & Brower, M. E. (Eds.). (1992). Hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine (RDX) . B o ca Raton, FL: Lewis Publishers.

9. M eyer, R., Homburg, A., & Köhler, J. (2002). Explosives - Cyclonite . Weinheim: Wiley

- VCH.

10. M urnyak, G., Vandenberg, J., Yaroschak, P. J., Williams, L., Prabhakaran, K., & Hinz, J. (2011). Emerging contaminants: Presentations at the 2009 Toxicology and Risk Assessment Conference. [Review]. Toxicology and Applied Pharmacology, 254 ( 2), 167

- 169. doi: 10.1016/j.taap.2010.10.021

11. N ikolic, S., Medic

- Saric, M., Rendic, S., & Trinajstic, N. (1994). Toxic effects and a structure

-- propert y study of organic explosives, propellants, and related compounds. [Review]. Drug Metabolism Reviews, 26 ( 4), 717

- 738. doi: 10.3109/03602539408998324

12. Sch neider, N. R. (1979). Bibliography on toxicology of cyclotrimethylenetrinitramine (RDX). Veterinary and Human Toxicology, 21 (6 ), 449

- 450.

13. Su llivan, J. B., Jr. (Ed.). (1992). Cryogenics, oxidizers, reducing agents, and explosives (Vol. Clinical Principles of Environmental Health): Williams & Wilkins.

Ecosystem Effects (38 citations)

1. . Evaluation of the metabolic fate of munitions material (TNT & RDX) in plant systems and initial assessment of material interaction with plant genetic material. Validation of the metabolic fate of munitions materials (TNT, RDX) in mature crops. (1995). Richland, WA; Departme n t 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;

De p artment of Energy, Washington, DC: Technical Information Center Oak Ridge Tennessee.

### 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- 20 DRAFT

— DO NOT CITE OR QUOTE 3

. . Evaluation of the Toxicological Effects of Explosives on Higher Plants, and the Effects on 

### 1
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
42
43 Soil After Demining with Reconstructed Military Tanks. (1997). Kjeller : Forei gn Technology

- Studsvik Energiteknik AB.

4. . Ecological Soil Characterization of the Delta Creek and Washington Impact Areas, Fort Greely, Alaska. (2001). Fort Collins. Center for Environmental Management of Military
Lands
5. . SE RDP CU

- 1129 Biological Assessmen t for Characterizing Contamination Risk at the

Genetic

- , I ndividual

- , and Population

- Level. (2004). Vicksburg, MS. Engineer Research and Development Center

6. . T oxicity of Nitro

- Heterocyclic and Nitroaromatic Energetic Materials to Terrestrial Plants

in a Na t ural Sandy Loam Soil. (2005). Aberdeen Proving Ground, MD.

7. An derson, J. A., Cañas, J. E., Long, M. K., Zak, J. C., & Cox, S. B. (2010). Bacterial community dynamics in high and low bioavailability soils following laboratory exposure to a range of hexahydr o- 1 ,3,5

- trinitro

- 1,3,5

- triazine concentrations. Environmental Toxicology and Chemistry, 29 ( 1), 38

- 44. doi: 10.1002/etc.9

8. Ar my, U. S. (1993). Toxicity of Nitroguanidine, Nitroglycerin, Hexahydro

- 1,3,5

- Trinitro

1,3,5

- T riazine (RDX), and 2,4,6

- Trinitrotoluene (TNT) to Selected Freshwater Aquatic Organisms: U.S. Army.

9. Ar my, 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.

10. Ar my, U. S. (1995). Evaluation of the metabolic fate of munitions material (TNT & RDX) 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.

11. Ar my, U. S. (1995). Evaluation of the Metabolic Fate of Munitions Material (TNT RDX) in Plant Systems and Initial Assessment of Material Interaction with Plant Genetic Material: U.S. Army.

12. B aker, L. M., Larsen, C. T., Sriranganathan, N., Jones, D. E., Johnson, M. S., & Gogal, R. M. (2004). Effects of energetic compounds on the Northern Bobwhite quail and biotransformation applications of the intestinal flora. Bulletin of Environmental Contamination and Toxicology, 72 (1 ), 1

- 6. doi: 10.1007/s00128

- 003

- 0233 -8

13. B rentner, L. B., Mukherji, S. T., Walsh, S. A., & Schnoor, J. L. (2010). Localization of hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (RDX) and 2,4,6

- trinitrotoluene (TNT) in poplar and switchgrass plants using phosphor imager autoradiography. Environmental Pollution,
158 (2), 470

- 4 75. doi: 10.1016/j.envpol.2009.08.022

14. D rzyzga, O., Gorontzy, T., Schmidt, A., & Blotevogel, K. H. (1995). Toxicity of explosives and related compounds to the luminescent bacterium Vibrio fischeri NRRL -B- 1 1177. Archives of
Environmental Contamination and T ox icology, 28 (2). doi: 10.1007/bf00217621
15. E kman, D. R., Wolfe, N. L., & Dean, J. F. (2005). Gene expression changes in Arabidopsis thaliana seedling roots exposed to the munition hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine. Environmental Science and Technology

, 39 (16), 6313

- 6320.

16. F ellows, R. J., Driver, C. R., Cataldo, D. A., & Harvey, S. D. (2006). Bioavailability of hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (RDX) to the prairie vole (Microtus ochrogaster). Environmental Toxicology and Chemistry, 25 ( 7), 1881

- 18 86. doi: 10.1897/05

- 446r1.1

### 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- 21 DRAFT

— DO NOT CITE OR QUOTE 1 7. Garcia

- Reyero, N., Escalon, B. L., Loh, P. R., Laird, J. G., Kennedy, A. J., Berger, B., & Perkins, E. 

### 1
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
42
43 J. (2012). Assessment of chemical mixtures and groundwater effects on Daphnia magna transcriptomics. Environmental Science and Technology, 46 (1), 42

- 50. doi: 10.1021/es201245b

18. Gogal, O. M., Jr., Johnson, M. S., Larsen, C. T., Prater, M. R., Duncan, R. B., Ward, D. L., Holladay, S. D. (2003). Dietary oral exposure to l,3,5

- t rinitro

- 1,3,5

- triazine in the northern bobwhite (Colin u s virginianus). Environmental Toxicology and Chemistry, 22 (2), 381

- 387. doi: 10.1002/etc.5620220220

19. G ong, P., Hawari, J., Thiboutot, S., Ampleman, G., & Sunahara, G. I. (2001). Ecotoxicological effects of hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine on soil microbial activities. Environmental Toxicology and Chemistry, 20 ( 5), 947

- 951.

20. G ust, K. A., Pirooznia, M., Quinn, M. J., Johnson, M. S., Escalon, L., Indest, K. J., Perkins, E. J. (2009). Neurotoxicogenomic Investigations to Assess Mechanisms of Action of th e Munitions Constituents RDX and 2,6

- D NT in Northern Bobwhite (Colinus virginianus). Toxicological Sciences, 110 ( 1), 168

- 180. doi: 10.1093/toxsci/kfp091

21. J antschi, L., & Bolboaca, S. D. (2008). A structural modelling study on marine sediments toxicity. M ari ne Drugs, 6 (2), 372

- 388. doi: 10.3390/md20080017

22. J ohnson, M. S., Quinn, M. J., Bazar, M. A., Gust, K. A., Escalon, B. L., & Perkins, E. J. (2007). Subacute toxicity of oral 2,6

- d initrotoluene and 1,3,5

- trinitro

- 1,3,5

- triazine (RDX) exposure
to the northern b obwhite (Colinus virginianus). Environmental Toxicology and Chemistry,

26 (7), 1481

- 14 87. doi: 10.1897/06

- 525.1

23. J ohnson, M. S., & Salice, C. J. Toxicity of energetic compounds to wildlife species.

24. J uck, D., Driscoll, B. T., Charles, T. C., & Greer, C. W. (2003). Effect of experimental contamination with the explosive hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine on soil bacterial

communities. F EMS Microbiology Ecology, 43 (2), 255

- 262. doi: 10.1111/j.1574

- 6941.2003.tb01065.x
25. L arson, S. L., Jones, R. P., Escalon, L., & Parker, D. (1999). Classification of explosives transformation products in plant tissue. Environmental Toxicology and Chemistry, 18 (6 ),

1270

- 1 276. doi: 10.1002/etc.5620180629

26. M cFarland, C. A., Quinn, M. J., Jr., Bazar, M. A., Talent, L. G., & Johnson, M. S. (2009). Toxic effects of oral hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine in the western fence lizard (Sceloporus occidentalis). Environmental Toxicology and Chemistry, 28 ( 5), 1043

- 1050. doi: 10.1897/08

- 4 19.1

27. Q uinn, M. J., Bazar, M. A., McFarland, C. A., Perkins, E. J., Gust, K. A., & Johnson, M. S. (2009). Sublethal effects of subacute exposure to RDX (1,3,5

- t rinitro

- 1,3,5

- triazine) in the northern bobwhite (Colinus virginianus). Environmental Toxicology and Chemistry, 28 ( 6), 1266

- 1270. doi: 10.1897/0 8- 4 18.1

28. Q uinn, M. J., Hanna, T. L., Shiflett, A. A., McFarland, C. A., Cook, M. E., Johnson, M. S., Perkins, E. J. (2013). Interspecific effects of 4A

- DNT (4

- amino

- 2,6

- dinitrotoluene) and RDX (1,3,5

- trinitro

- 1 ,3,5

- triazine) in Japanese quail, Northern bobw hite, and Zebra finch. Ecotoxicology,

22 (2), 231

- 2 39. doi: 10.1007/s10646

- 012

- 1019 -8

29. Sm ith, J. N., Espino, M. A., Liu, J., Romero, N. A., Cox, S. B., & Cobb, G. P. (2009). Multigenerational effects in deer mice (Peromyscus maniculatus) exposed to hexahydro

-

### 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- 22 DRAFT

— DO NOT CITE OR QUOTE 1 ,3,5

- trinitroso

- 1,3,5

- triazine (TNX). Chemosphere, 75 (7), 910

- 914. doi: 

### 1
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
42
43 10.1016/j.chemosphere.2009.01.010

30. Smith, J. N., Liu, J., Espino, M. A., & Cobb, G. P. (2007). Age dependent acute oral toxicity of hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (RDX) and t wo anaerobic N

- nitroso metabolites in deer mice (Peromyscus maniculatus). Chemosphere, 67 ( 11), 2267

- 2273. doi: 10.1016/j.chemosphere.2006.12.005

31. Sm ith, J. N., Pan, X., Gentles, A., Smith, E. E., Cox, S. B., & Cobb, G. P. (2006). Reproductive
effects of hex a hydro

- 1,3,5

- trinitroso

- 1,3,5

- triazine in deer mice (Peromyscus maniculatus) during a controlled exposure study. Environmental Toxicology and Chemistry, 25 ( 2), 446

- 451. doi: 10.1897/05

- 2 77r.1

32. Su nahara, G. I., Dodard, S., Sarrazin, M., Paquet, L., Ampleman, G., Thiboutot, S., Renoux, A. Y. (1998). Development of a soil extraction procedure for ecotoxicity characterization of energetic compounds. Ecotoxicology and Environmental Safety, 39 ( 3), 185

- 194. doi: 10.1006/eesa.1997.1624

33. Su nahara, G. I., Dodard, S., Sarrazin, M., Paquet, L., Hawari, J., Greer, C. W., Renoux, A. Y. (1999). Ecotoxicological characterization of energetic substances using a soil extraction procedure. E cotoxicology and Environmental Safety, 43 (2), 138

- 148. doi: 10.1006/eesa.1999.1763

34. S unaha ra, G. I., Lachance, B., Hawari, J., Greer, C. W., Guiot, S., Thiboutot, S., Renoux, A. (1997). Ec otoxicity Tests t o Assess Bioremediation o f Soils Containing Energetic Substances (Vol. Niagara Falls, pp. 20

- 2 2): Sunahara, GI; Lachance, B; Hawari, J; Greer , CW; Guiot, S; Thiboutot, S; Ampleman, G; Renoux, A.
35. T anaka, S., Brentner, L. B., Merchie, K. M., Schnoor, J. L., Yoon, J. M., & Van Aken, B. (2007). Analysis of gene expression in poplar trees (Populus deltoides x nigra, DN34) exposed to the toxic explos i ve hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine (RDX). International Journal of Phytoremediation, 9 ( 1), 15

- 30. doi: 10.1080/15226510601139375

36. W arner, C. M., Gust, K. A., Stanley, J. K., Habib, T., Wilbanks, M. S., Garcia

- Reyero, N., & Perkins, E. J. (2012). A systems toxicology approach to elucidate the mechanisms involved in RDX species

- s pecific sensitivity. Environmental Science and Technology, 46 (14), 7790

- 7798. doi: 10.1021/es300495c

37. W illiams, L. R., Wong, K., Stewart, A., Suciu, C., Gaikwad, S., Wu, N., Ka lueff, A. V. (2012). Behavioral and physiological effects of RDX on adult zebrafish. Comparative Biochemistry and Physiology - P art C: Toxicology and Pharmacology, 155 (1), 33

- 38. doi: 10.1016/j.cbpc.2011.02.010

38. W infield, L. E., Rodgers, J. H., & D'Surney, S. J. (2004). The responses of selected terrestrial plants to short (<12 days) and long term (2, 4 and 6 weeks) hexahydro

- 1 ,3,5

- trinitro

1,3,5

- t riazine (RDX) exposure. Part I: Growth and developmental effects. Ecotoxicology,

13 (4), 335

- 3 47.

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. Z hang, 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. 

### 1- 23 DRAFT

— DO NOT CITE OR QUOTE E nvironmental Health Perspectives, 117 (3), A98

- A99. doi: 10.1289/ehp.0800276R 

### 1

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
42 Risk Assessments (11 citations)

1. . Development of a Multimedia Exposure Assessment Model for Evaluating Ecological Risk
of Ex posure to Military

- Related Compounds (MRCs) at Military Sites. (1998). Vicksburg, MS.

2. B attelle. (1998). Life

- Cycle Inventory

- Based Comparison of an RDX

- Based and a TNAZ

Based GBU

- 2 4 Munition. Columbus, OH.

3. D aniels, J. I., & Knezovich, J. P. (1994). Human health risks from TNT, RDX, and HMX in environmental media and consideration of the US Regulatory Environment. CA; Department of Energy, Washington, DC: U.S. Department of Energy, Lawrence Livermore National Laboratory.

4. E tnier, E. L. (1989). Water quality criteria for hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine (RDX). [Review]. R egulatory Toxicology and Pharmacology, 9 (2), 147

- 157. doi: 10.1016/0273

- 2300(89)90032 -9
5. E tnier, E. L., & Hartley, W. R. (1990). Comparison of water quality criterion and lifetime
healt h advisory for hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine (RDX). [Review]. Regulatory Toxicology and Pharmacology, 11 ( 2), 118

- 122. doi: 10.1016/0273

- 2300(90)90015 -4

6. J ames, R. C., Roberts, S. M., & Roberts, S. M. (1994). Evaluation of the Adequacy of the
Thres h old Limit Value for Cyclonite. Applied Occupational and Environmental Hygiene, 9 (7),
485

- 4 92. doi: 10.1080/1047322x.1994.10388358

7. Mar iussen, E. (1997). Evaluation of the health risk and the environmental effects of explosives after demining with reconstru ct ed military tanks. Kjeller: Foreign Technology

Studsvik Energiteknik AB(TFSEAB).

8. M cKone, T. E., & Layton, D. W. (1986). Screening the potential risks of toxic substances using a multimedia compartment model: estimation of human exposure. Regulatory Toxic o logy and Pharmacology, 6 ( 4), 359

- 380.

9. R yu, H., Han, J. K., Jung, J. W., Bae, B., & Nam, K. (2007). Human health risk assessment of explosives and heavy metals at a military gunnery range. Environmental Geochemistry and Health, 29 ( 4), 259

- 269. doi: 10.100 7/s10653

- 007

- 9101 -5

10. Sw eeney, L. M., Gut, C. P., Gargas, M. L., Reddy, G., Williams, L. R., & Johnson, M. S. (2012). Assessing the non

- c ancer risk for RDX (hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine) using physiologically based pharmacokinetic (PBPK) modeling. [R eview]. Regulatory Toxicology and Pharmacology, 62 ( 1), 107

- 114. doi: 10.1016/j.yrtph.2011.12.007

11. Sw eeney, L. M., Okolica, M. R., Gut, C. P., Jr., & Gargas, M. L. (2012). Cancer mode of action, weight of evidence, and proposed cancer reference value for hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (RDX). Regulatory Toxicology and Pharmacology, 64 ( 2), 205

- 224. doi: 10.1016/j.yrtph.2012.07.005

Exposure Levels (96 citations)

1. . Evaluation of the environmental fate and behavior of munitions material (TNT, RDX) in s oil and plant systems: Environmental fate and behavior of RDX. Final report. (1990). Richland, WA; Department of Energy, Washington, DC: Technical Information Center Oak Ridge

Tennessee.

2. . Su perfund Record of Decision (EPA Region 4): Milan Army Ammunition Plant, TN. (First

### 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- 24 DRAFT

— DO NOT CITE OR QUOTE R emedial Action), September 1992. (1992) (pp. 74). 

### 1
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
42
43 3. . Environmental behavior and chemical fate of energetic compounds (TNT, RDX, tetryl) in soil and plant systems. (1993). Richland, WA; Department of Energy, Washington, DC:
Technical Infor m ation Center Oak Ridge Tennessee.

4.

. Validation of the metabolic fate of munitions materials (TNT, RDX) in mature crops and evaluation of plant DNA adducts and DNA mutation frequency as biomarkers. (1994). Richland, WA; Department of Energy, Washington, DC : Technical Information Center Oak Ridge Tennessee.
5.

. New Lower Estimate for Soils Contaminated with Secondary Explosives and the Associated Implications. (1997). Arlington, VA

. 6.

. Environmental Behavior and Fate of Explosives in Groundwater from the Milan Army Ammunition Plant in Aquatic and Wetland Plants. Fate of TNT and RDX. (1998). Vicksburg,
MS. Environmental Lab.

7.

. Miljoefarliga Aemnen i Dumpad Ammunition (Compounds in Dumped and Unexploded Ordnance, Possible Environmental Hazards). (1998). Umea (Swed e n). Avedelningen foer NBC Skydd.: Foreign Technology

- St udsvik Energiteknik AB.

8. . Sit e Characterization for Explosives Contamination at a Military Firing Range Impact Area. (1998). Hanover, NH.

9.

. Conceptual Model and Process Descriptor Formulations for Fat e and Transport of UXO. (1999). Vicksburg, MS.

10.

. Adsorption and Transformation of Explosives in Low

- Carbon Aquifer Soils. (2000). Vicksburg, MS. Environmental Lab.

11.

. Evaluating the Use of Snow

- Covered Ranges to Estimate the Explosives Residues that
Result F rom Detonation of Army Munitions. (2000). Hanover, NH. Cold Regions Research and Engineering Lab.

12.

. Adsorption and Transformation of RDX in Low

- Carbon Aquifer Soils. (2001). Washington,

DC.

13. . C haracterization of Explosives Contamination at Military Firing Ranges. (2001). Hanover,

NH.

14. . Sa mpling for Explosives Residues at Fort Greely, Alaska. Reconnaissance Visit July 2000. (2001). Hanover, NH. Cold Regions Research and Engineering Lab.
15.

. Environmental Fate and Transport Process Descriptors for Explosives. (2002). Vicksburg,
MS. Environmental Lab.

16.

. Range Characterization Studies at Donnelly Training Area, Alaska: 2001 and 2002. (2004). Hanover, NH. Cold Regions Research and Engineering Lab.

17.

. Sampling Strategies Near a Low

- Order Detonation and a Target at a n Artillery Impact Area. (2004). Hanover, NH. Cold Regions Research and Engineering Lab.

18.

. Elution of Energetic Compounds from Propellant and Composition B Residues. (2005). Hanover, NH. Cold Regions Research and Engineering Lab.

19. . E nergetic Residues From Live

- Fire Detonations of 120

- mm Mortar Rounds. (2005). Hanover, NH. Cold Regions Research and Engineering Lab.

20. . I dentity and Distribution of Residues of Energetic Compounds at Military Live

- Fire Training Ranges. (2005). Vicksburg, MS. Engineer Research an d Development Center.

### 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- 25 DRAFT

— DO NOT CITE OR QUOTE 2 1. . Residues from Live Fire Detonations of 155

- mm Howitzer Rounds. (2005). Hanover, NH. 

### 1
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
42
43 Cold Regions Research and Engineering Lab.

22. . Molecular Structure Determines Chemical Reactivities and, Thus, Transformation Pathways. (2006). Vicksb u rg, MS. Environmental Lab.

23. . P hotochemical Degradation of Composition B and Its Components. (2007). Vicksburg, MS.
Environmental Lab.

24.

. Fate of Nitroaromatic (TNT) and Nitramine (RDX and HMX) Explosives in Fractured and Weathered Soils. (2008). Vicksburg, MS . Engineer Research and Development Center.
25. . H and Grenade Residuals (Environmental Security Technology Certification Program). (2009). Vicksburg, MS. Environmental Lab.

26. A bdul

- Karim, N., Morgan, R., Binions, R., Temple, T., & Harrison, K. (2012). The Sp atial Distribution of Postblast RDX Residue: Forensic Implications. Journal of Forensic Sciences

. doi: 10.1111/1556

- 4 029.12045

27. Ar my, U. S. (1992). Slow Release of PCB, TNT, and RDX From Soils and Sediments: U.S. Army.

28. Ar my, U. S. (1993). Relationship between the Leachability Characteristics of Unique Energetic Compounds and Soil Properties: U.S. Army.

29. Ar my, U. S. (1993). Transport and Fate of Nitroaromatic and Nitramine Explosives in Soils from Open Burning/Open Detonation Operations: Milan Army Ammuni t ion Plant (MAAP): U.S. Army.

30. Ar my, U. S. (1994). Sorption

- Desorption and Transport of TNT and RDX in Soils: U.S. Army.

31. Ar my, U. S. (1995). Uptake of explosives from contaminated soil by existing vegetation at the Iowa Army Ammunition Plant: U.S. Army.

32. Ar m y, U. S. (1996). Recent Developments in Formulating Model Descriptors for Subsurface Transformation and Sorption of TNT, RDX, and HMX (Vol. 829, pp. 219

- 2 29): U.S. Army.

33. Ar my, U. S. (1997). Plant Uptake of Explosives from Contaminated Soil and Irrigation W ater at the Former Nebraska Ordnance Plant, Mead, Nebraska: U.S. Army.

34. Ar my, U. S. (1997). Review of Fate and Transport Processes of Explosives: U.S. Army.
35. Ar my, U. S. (1998). Transformation of RDX and HMX Under Controlled Eh/pH Conditions: U.S. Army.

36. AT SD R . (1992). Health Assessment for Nebraska Army Ordnance Plant (Former), Mead, Saunders County, Nebraska, Region 7. CERCLIS No. NE6211890011. Atlanta, GA.: Department H.E.W. Office of Toxic Substance and Disease.

37. AT SDR . (1993). Health Assessment for Milan A rmy Ammunition Plant, Milan, Carroll and Gibson Counties, Tennessee, Region 4. CERCLIS No. TN0210020582. September 30, 1993. Atlanta, GA.: Department H.E.W. Office of Toxic Substance and Disease.

38. AT SDR . (1999). Public Health Assessment for Iowa Army Ammunition Plant, Middletown, Des Moines County, Iowa, Region 7. CERCLIS No. IA7213820445. Atlanta, GA. Div. of Health Assessment and Consultation: Department H.E.W. Office of Toxic Substance and Disease.

39. B est, E. P., Sprecher, S. L., Larson, S. L., Fredrickson, H. L., & Bader, D. F. (1999). Environmental behavior of explosives in groundwater from the Milan Army Ammunition Plant in aquatic and wetland plant treatments. Removal, mass balances and fate in groundwater of TNT and RDX. Chemosphere, 38 ( 14), 3383

- 3396.

40. B est, E. P., Sprecher, S. L., Larson, S. L., Fredrickson, H. L., & Bader, D. F. (1999).

### 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- 26 DRAFT

— DO NOT CITE OR QUOTE E nvironmental behavior of explosives in groundwater from the Milan Army Ammunition 

### 1
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
42
43 Plant in aquatic and wetland plant treatments. Uptake and fate of TNT and RDX in pla nts. Chemosphere, 39 (12), 2057

- 2072.

41. Bhadra, R., Wayment, D. G., Williams, R. K., Barman, S. N., Stone, M. B., Hughes, J. B., & Shanks, J. V. (2001). Studies on plant

- m ediated fate of the explosives RDX and HMX. Chemosphere, 44 ( 5), 1259

- 1264.

42. B ordeleau, G., Martel, R., Lévesque, R., Ampleman, G., Thiboutot, S., & Marois, A. (2012). Overestimation of nitrate and nitrite concentrations in water samples due to the presence of nitroglycerin or hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine. Journal of Chr omatography A, 1252

, 130

- 1 35. doi: 10.1016/j.chroma.2012.06.082

43. C arroll, J. W., Guinivan, T. L., Tuggle, R. M., Williams, K. E., & Lillian, D. L. (1979). Assessment of hazardous air pollutants from disposal of munitions in a prototype fluidized bed

incinera tor. American Industrial Hygiene Association Journal, 40 (2), 147

- 158. doi: 10.1080/15298667991429444

44. C enter, U. S. A. E. (1998). Pyrolysis/Gas Chromatography/Mass Spectrometry of Energetic Materials. Aberdeen Proving Ground, MD.
45. C rowson, A., & Cawthorne, R. (2012). Quality assurance testing of an explosives trace analysis laboratory

-- further improvements to include peroxide explosives. Science and Justice, 52 ( 4), 217

- 225. doi: 10.1016/j.scijus.2012.07.001

46. C rowson, A., Doyle, S. P., Todd, C. C., Watson, S., & Zolnhofer, N. (2007). Quality assurance testing of an explosives trace analysis laboratory

-- further improvements. Journal of Forensic Sciences, 52 ( 4), 830

- 837. doi: 10.1111/j.1556

- 4029.2007.00464.x

47. C ullum, H. E., McGavigan, C., Uttley, C. Z., Stroud, M. A., & Warren, D. C. (2004). A second survey of high explosives traces in public places. Journal of Forensic Sciences, 49 ( 4), 684

- 690.

48. D ontsova, K. M., Yost, S. L., Simunek, J., Pennington, J. C., & Williford, C. W. (2006). Dissolution and transport of TN T , RDX, and composition B in saturated soil columns. Journal of Environmental Quality, 35 ( 6), 2043

- 2054. doi: 10.2134/jeq2006.0007

49. D ouglas, T. A., Walsh, M. E., Weiss, J. C., McGrath, C. J., & Trainor, T. P. (2012). Desorption and
Transformation of Nitroar o matic (TNT) and Nitramine (RDX and HMX) Explosive Residues
on Detonated Pure Mineral Phases. Water, Air, and Soil Pollution, 223 ( 5), 2189

- 2200. doi: 10.1007/s11270

- 0 11

- 1015 -2
50. E fer, J., Wennrich, L., Lewin, U., Blasberg, L., & Engewald, W. (1996). The Infl uence o f t he

Matrix o n t h e Analysis o f Explosives a nd t heir Metabolites i n Ground Water Around a Former Ammunition Plant (Vol. 87), p p . Weinheim): Efer, J; Wennrich, L; Lewin, U; Blasberg, L; Engewald, W.
51. F uller, M. E., Schaefer, C. E., Andaya, C., Lazouskaya, V., Fallis, S., Wang, C., & Jin, Y. (2012).
Dissolution kinetics of sub

- m illimeter Composition B detonation residues: role of particle size and particle wetting. Chemosphere, 88 ( 5), 591

- 597. doi: 10.1016/j.chemosphere.2012.03.038
52. H arvey, S. D., Fellows, R. J., Cataldo, D. A., & Bean, R. M. (1991). Fate of the explosive hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine (rdx) in soil and bioaccumulation in bush bean hydroponic plants. Environmental Toxicology and Chemistry, 10 ( 7), 845

- 855. doi:

### 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- 27 DRAFT

— DO NOT CITE OR QUOTE 1 0.1002/etc.5620100701 

### 1
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
42
43 53. Hess

- Ruth, A., Crouse, L., & Roszell, L. (2007). RDX pilot development neurotoxicity test in rats. Aberdeen Proving Ground: U.S. Army Center for Health Promotion and Preventive
Medicine.
54. H ildenbrand, M., & Luckner, L. (1995). Laborative Untersuchungen zur Beschreibung des Migrationsverhaltens sprengstofftypischer Verbindungen in Porengrundwasserleitern. A cta Hydrochimica et Hydrobiologica, 23 ( 3), 111

- 120. doi: 10.1002/aheh.19950230304
55. H ildenbrand, M., & Neumann, V. (1995). REV

- reactor and soil column st udies of sorption and migration of explosives in Elsnig sandy aquifers (Vol. 39, pp. 131

- 1 35): Hildenbrand, M;
Neumann, V.
56. H offsommer, J. C., & Rosen, J. M. (1973). Hydrolysis of explosives in sea water. Bulletin of
Environmental Contamination and Toxicolo g

y, 10 (2), 78

- 79.
57. H ou, Y. (1991). A preliminary study on ultraviolet photodegradation of RDX (cyclonite, cyclotrimethylene trinitramine) (Vol. BEIJING, pp. 90

- 9 3): Hou, Y.
58. K unz, R. R., Gregory, K. E., Aernecke, M. J., Clark, M. L., Ostrinskaya, A., & Fountain, A. W. (2012). Fate dynamics of environmentally exposed explosive traces. Journal of Physical Chemistry A, 116 ( 14), 3611

- 3624. doi: 10.1021/jp211260t
59. K won, M. J., O'Loughlin, E. J., Antonopoulos, D. A., & Finneran, K. T. (2011). Geochemical and
microb i ological processes contributing to the transformation of hexahydro

- 1,3,5

- trinitro

1,3,5

- t riazine (RDX) in contaminated aquifer material. Chemosphere, 84 (9), 1223

- 1230. doi: 10.1016/j.chemosphere.2011.05.027

60. L arson, S. L. (1997). Fate of explosive contamin ants in plants. Annals of the New York Academy of Sciences, 829

, 195

- 201.

61. L ever, J. H., Taylor, S., Perovich, L., Bjella, K., & Packer, B. (2005). Dissolution of composition
B detonation residuals. Environmental Science and Technology, 39 ( 22), 8803

- 8811.

62. L ynch, J. C., Brannon, J. M., & Delfino, J. J. (2002). Dissolution rates of three high explosive compounds: TNT, RDX, and HMX. Chemosphere, 47 ( 7), 725

- 734.

63. M cDiarmid, M. A., & Weaver, V. (1993). Fouling one's own nest revisited. [Review]. American Journa l of Industrial Medicine, 24 (1), 1

- 9.

64. Mc Kone, T. E., & Maddalena, R. L. (2007). Plant uptake of organic pollutants from soil: bioconcentration estimates based on models and experiments. [Review]. Environmental Toxicology and Chemistry, 26 ( 12), 2494

- 2504. doi: 10.1897/06

- 269.1
65. M ontgomery, M. T., Coffin, R. B., Boyd, T. J., & Osburn, C. L. (2013). Incorporation and mineralization of TNT and other anthropogenic organics by natural microbial assemblages from a small, tropical estuary. Environmental Pollution, 174 , 257

- 2 64. doi: 10.1016/j.envpol.2012.11.036

66. N avy, U. S. (1996). Solid

- State Photodecomposition of Energetic Nitramines (RDX and HMX): U.S. Navy.

67. O h, S. Y., & Chiu, P. C. (2009). Graphite - and soot

- mediated reduction of 2,4

- dinitrotoluene and hexahydro

- 1 ,3,5

- trinitro

- 1,3,5

- triazine. Environmental Science and Technology, 43 (18),

6983

- 6 988.

68. O xley, J. C., Smith, J. L., Resende, E., Pearce, E., & Chamberlain, T. (2003). Trends in explosive

contamination. Jo urnal of Forensic Sciences, 48 (2), 334

- 342.

### 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- 28 DRAFT

— DO NOT CITE OR QUOTE 6 9. Ozhan, G., Topuz, S., & Alpertunga, B. (2003). Determination of cyclonite (RDX) in human 

### 1
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
42
43 plasma by high

- performance liquid chromatography. Farmaco, 58 (6), 445

- 448. doi: 10.1016/s0014

- 827x(03)00069 -7

70. Preiss, A., Levsen, K., Humpfer, E., & Spraul, M. (1996). Application of high

- field proton nuclear magnetic resonance ((1)H

- N MR) spectroscopy for the analysis of explosives and related compounds in groundwater samples - a comparison with the high

- performance liquid chromatography (HPLC) method. Analytical and Bi o analytical Chemistry, 356 (7), 445

- 451. doi: 10.1007/s0021663560445

71. Ra ymondi, R. (1992). Explosive Washout Lagoons Soils Operable Unit Supplemental Investigation Technical and Environmental Management Support of Installation Restoration Technology Developm e nt Program, Umatilla Depot Activity, Hermiston. Oregon. Phase 2 (Vol. GRA and I). United States (USA): Raymondi, R.

72. R ocheleau, S., Lachance, B., Kuperman, R. G., Hawari, J., Thiboutot, S., Ampleman, G., & Sunahara, G. I. (2008). Toxicity and uptake of cyclic nitramine explosives in ryegrass Lolium

perenne. E nvironmental Pollution, 156 (1), 199

- 206. doi: 10.1016/j.envpol.2007.12.012

73. Sch neider, U., & Koenig, W. (1988). Contaminations b y Chemical Armament Factories Risk
Potential o f Soil a nd Groundwater Contam inations b y Closed Down Chemical Armament Industry Plants i n We st a nd East Germany (Vol. K, p p. Dordrecht): Schneider, U; Koenig, W.

74. Se lim, H. M., Xue, S. K., & Iskandar, I. K. (1995). Transport o f 2,4,6

- Trinitrotoluene a nd Hexahydro

- 1 ,3,5

- Trinitro

- 1,3,5 -T riazine i n Soils

. Soil Science, 160 (5), 328

- 339. doi: 10.1097/00010694

- 1 99511000

- 00002
75. Se rna, C. J., Bartz, P. R., Donahoe, S. B., & Arbogast, M. (1990). Remedial Investigation Report for Lake City Army Ammunition Plant. Volume 1 (Vol. GRA and I): Serna, C J ; Bartz, PR; Donahoe, SB; Arbogast, M.

76. Sim ini, M., & Checkai, R. T. (1995). Yield a nd Biomass o f Crop Plants Irrigated w ith T NT a nd

R D X Contaminated Water (Vol. Pittsburgh, pp. 12

- 16): Simini, M; Checkai, RT.

77. Sim ini, M., & Checkai, R. T. (1996). Uptake of R DX a nd T NT i n Crop Plants Irrigated w ith Contaminated Water (Vol. North Central Division , p p. 27

- 31): Simini, M; Checkai, RT.

78. Sin gh, J., Comfort, S. D., Hundal, L. S., & Shea, P. J. (1998). Long

- term RDX sorption and fate in
soil. Jo urnal of Environmenta l Quality, 27 (3), 572

- 577.

79. Sp anggord, R. J., Gibson, B. W., Keck, R. G., & Newell, G. W. (1978). Mammalian toxicological evaluation of TNT wastewaters. Vol. I, Chemistry studies. Fort Detrick, Frederick, MD: U.S. Army Medical Research and Development Comm an d.

80. T aylor, S., Lever, J. H., Fadden, J., Perron, N., & Packer, B. (2009). Simulated rainfall

- driven dissolution of TNT, Tritonal, Comp B and Octol particles. Chemosphere, 75 ( 8), 1074

- 1081. doi: 10.1016/j.chemosphere.2009.01.031

81. T hompson, P. L., Ramer, L. A., & Schnoor, J. L. (1999). Hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine translocation in poplar trees. Environmental Toxicology and Chemistry, 18 ( 2), 279

- 284. doi: 10.1002/etc.5620180226

82. U .S, EP A (1991). Superfund Record of Decision (EPA Region 10): Bangor N aval Submarine Base, Site F (Operable Unit 2), Bangor, WA. (First Remedial Action), September 1991. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

### 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- 29 DRAFT

— DO NOT CITE OR QUOTE 8 3. U.S, EPA (1991). Superfund Record of Decision (EPA Reg ion 10): Bangor Ordnance Disposal 

### 1
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
42
43 (USN Submarine Base), Bangor, WA. (First Remedial Action), December 1991. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

84. U.S, EPA (1992). Superfund record of decision (EPA region 5): Savanna Army Depot, Savanna, IL. (First remedial action), March 1992. Washington, DC.
85. U .S, EPA (1992). Superfund Record of Decision (EPA Region 10): Umatilla Army Depot (Lagoons), Soils Operable Unit 2, Hermiston, OR. (First Remedial Action ) , September 1992. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

86. U .S, EPA (1995). Superfund Record of Decision (EPA Region 7): Cornhusker Army Ammunition Plant, Operable Unit 1, Hall County, Grand Isla nd, NE., September 29, 1994. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

87. U .S, EPA (1998). Superfund Record of Decision (EPA Region 6): Louisiana Army Ammunition Plant, Soil Source Operable Unit, Doy line, LA., March 4, 1997. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

88. U .S, EPA (1999). Superfund Record of Decision (EPA Region 3): Naval Weapons Station

Yorktown, Operable Units 6 and 7, Yorktown, V A., March 23, 1998. Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.

89. U SGS . (2003). Diffusion and Drive

- Point Sampling to Detect Ordnance

- Related Compounds in Shallow Ground Water Beneath Snake Pond, Ca pe Cod, Massachusetts, 2001

- 0 2. Northborough, MA. Water Resources Div: US Geological Survey.

90. W alsh, M. E., Taylor, S., Hewitt, A. D., Walsh, M. R., Ramsey, C. A., & Collins, C. M. (2010). Field observations of the persistence of Comp B explosives residues in a salt marsh impact area. Chemosphere, 78 ( 4), 467

- 473. doi: 10.1016/j.chemosphere.2009.10.021

91. W ang, C., Fuller, M. E., Schaefer, C., Caplan, J. L., & Jin, Y. (2012). Dissolution of explosive compounds TNT, RDX, and HMX under continuous flow conditions. Journal of Hazardous Materials, 217

- 218 , 187

- 193. doi: 10.1016/j.jhazmat.2012.03.012

92. W ang, 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. X ue, 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

- 3 27.

94. Y oon, 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: 10.1080/1522651050050 7128
95. Y ue, 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

- 9 3.

96. Z heng, 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. 

### 1- 30 DRAFT

— DO NOT CITE OR QUOTE HMX in streambed sediments: Implications for riverbank filtration. Chemosphere, 76 (9), 

### 1
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
42 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

- t rinitrotoluene (TNT) and hexogen contaminated soil in S. typhimurium and

m ammalian cells. Chemosphere, 37 ( 2 ), 209

- 218. doi: 10.1016/s0045

- 6535(98)00039 -3

2. D illey, J., Tyson, C., Spanggord, R., Sasmore, D., Newell, G., & Dacre, J. (1982). Short

- t erm oral toxicity of a 2, 4, 6

- t r inltrotoluene and hexahydro

- 1, 3, 5

- trinitro

- 1, 3, 5

- triazine mixture in mice, rats, and dogs. Journ al of Toxicology and Environmental Health, Part A: Current Issues,

9 ( 4), 587

- 6 10. doi: 10.1080/15287398209530189

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

no ntraditional assays in an integrated environme n t al assessment of contaminated ground

water. E nvironmental Toxicology and Chemistry, 16 (9), 1816

- 1 820. 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. B hushan, B., Trott, S., Spain, J. C., Halasz, A., Paquet, L., & Hawari, J. (2003).

B iotransformation of hexahydro

- 1

, 3,5

- trinitro

- 1,3,5

- triazine (RDX) by a rabbit live r 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

- 13 51 .2003

3. C rouse, L. C. B., Michie, M. W., Major, M. A., Leach, G. J., & Reddy, G. (2008). Oral
b ioavailability of cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats. International Journal of Toxicology, 27 ( 4 ), 317

- 322. doi: 10.1080/10915810802366885

4. G uo, L., Xu, H., Chen, Y., & Chang, Y. (1985). Distribution and metabolism of tritium

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

- 339.
5. K rishnan, K., Crouse, L. C. B., Bazar, M. A., Major, M. A., & Reddy, G. (2009). Physiologically
b ased pharmacokinetic modeling of cyclo t rimethylenetrinitramine in male rats. Journal of Applied Toxicology, 29 ( 7 ), 629

- 637. doi: 10.1002/jat.1455

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

p rofiling of [14C]hexahydro

- 1

, 3,5

- trinitro

- 1,3,5 -t riazine (RDX) in Yucatan miniature pigs. Journal of Toxicology and Environmental Health, Part A: Current Issues, 70 ( 1 4), 1191

- 1202. doi: 10.1080/15287390701252717

7. M intzer, E., Kizerian, A., Grant, K., Hoppe, E. W., & Campbell, J. A. (2007). Saliva as a mat r ix for the detection of RDX, and TNT and its major metabolites as biomarkers for exposure by Gas Chromatography/Mass Spectrometry. NW

- 0 0 7.

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

m etabolism, and excret i o n of 14C

- RDX following oral administration to minipigs. Madison,
WI: Covance Laboratories Inc.

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

### 1- 31 DRAFT

— DO NOT CITE OR QUOTE (RDX) in B6C3F1 mice (Mus musculus). Environmental Toxicology and Chemistry . doi: 

### 1
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
42
43 10.1002/etc.2188

10. P an, X., Zhang, B., Smith, J. N., San Francisco, M., Anderson, T. A., & Cobb, G. P. (2007). N

Nitroso compounds produced in dee r 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. R eddy, G., Allen, N. A., & Major, M. A. (2008). Absorption of 14C

cy clotrimet h y lenetrinitramine (RDX) from soils through excised human skin. Toxicology Mechanisms and Methods, 18 ( 7 ), 575

- 579. doi: 10.1080/15376510701703466

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

P ercutaneous absorption of explosives and related compounds: An empirical model of bioavailability of organic nitro compounds from soil. Toxicology and Applied Pharmacology,

182 (2), 160

- 1 6 8. doi: 10.1006/taap.2002.9436

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

- 4 94. doi: 10.1080/15287390801906956

14. Sch neider, N., Bradley, S., & Andersen, M. (1976). Metabolism of [1 4C]cyclotrimethylenetrinitramine (RDX) in the rat. Toxicology and Applied Pharmacology,

37 (1), 137. doi: 10.1016/s0041

- 0 0 8x(76)80011 -7
15. Sch neider, N., Bradley, S., & Andersen, M. (1977). Toxicology of

cy clotrimethylenetrinitramine (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. Sch neider, N., Bradley, S., & Andersen, M. (1978). The distribution and metabolism of

cy clotrimethylenetrinitramine (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. C otruvo, J. A., Sim mon, 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

- 1 4 0. doi: 10.1111/j.1749

- 6632.1977.tb19259.x

3. G eorge, S. E., Huggins

- C lark, 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. L achance, 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. Ne u woehner, J., Schofer, A., Erlenkaemper, B., Steinbach, K., Hund

- R inke, K., & Eisentraeger, A. (2007). Toxicological characterization of 2,4,6

- tr i nitrotoluene, 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. 

### 1- 32 DRAFT

— DO NOT CITE OR QUOTE products, and two nitramine explosives. Environmental Toxicology and Chemistr y, 26 (6), 

### 1
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
42
43 1090

- 1099. doi: 10.1897/06

- 471r.1

6. P an, 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

- n i troso metabolites using the Salmonella reverse mutation assay. Mutatio n Re s earch: Genetic Toxicology and Environmental Mutagenesis, 629 ( 1 ), 64

- 69. doi: 10.1016/j.mrgentox.2007.01.006

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

as sessment of hexahydro

- 1

, 3,5

- trinitro

- 1,3,5

- triazi ne (RDX). International Journal of Toxicology, 24 ( 6 ), 427

- 434. doi: 10.1080/10915810500366922

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

m etabolites formed during composting. Journal of Toxicology and Environ me n tal Health, Part A: Current Issues, 36 ( 3 ), 165

- 175. doi: 10.1080/15287399209531632

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

n itroaromatic explosive, in three microbial test systems. Toxicology Letters, 5 ( 1 ) , 11

- 17. doi: 10.1016/0378

- 4 2 74(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

-
t rinitro

- 1 ,3,5

- t riazine (RDX). Chemical Research in Toxicology, 22 (4), 620

- 625. doi: 10.1021/tx800444k

2. B annon, 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

- 39 3.

3. C orcelli, 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, 1 75 (1

- 3), 1096

- 1100. doi: 10.1016/j.jhazmat.2009.10.054

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

s ignaling in neuronal cells exposed to the munitions compound cyclotrimethylenetrinitramine (RDX). Internation al Journal of Toxicology, 28 ( 5 ), 425

- 435. doi: 10.1177/1091581809340331
5. F ord

- G reen, J., Isayev, O., Gorb, L., Perkins, E. J., & Leszczynski, J. (2012). Evaluation of natural and nitramine binding energies to 3

- D m odels of the S1S2 domains in the N

- methyl

D :
- as partate receptor. Journal of Molecular Modeling, 18 ( 4), 1273

- 1284. doi: 10.1007/s00894

- 0 1 1

- 1152 -y 6. F orgacs, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A., & Zacharewski, T. R. ( 2012). BLTK1 Murine Leydig Cells: A Novel Steroidogenic Mo d el for Evaluating the Effects of Reproductive and Developmental Toxicants. Toxicological Sciences, 127 ( 2 ), 391

- 402. doi: 10.1093/toxsci/kfs121

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

as integrated d is cr ete multiple organ co

- cultures (IdMOC) and as individual primary cultures. Columbia, MD: In Vitro ADMET Laboratories.

8. M eyer, S. A. (2006). Role of myelofibrosis in hematotoxicity of munition RDX environmental
d egradation product MNX. 2006 Update. Monro e , L A: 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 9. Meyer, S. A. (2007). Role of myelofibrosis in hematotoxicity of munitions RDX 

### 1
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 environmental degradation product MNX. 2007 Update. Monroe, LA: University of Louisiana

at Monroe.

10. P erkins, 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. d oi: 10.1186/1471

- 2 105 -7- s4

- s22

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

V erapamil in rats exposed to RDX. Aberdeen Proving Ground, MD: U.S. Army Center for
Health Promotion and Preventive Medicine.

12. W illiams, 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

- c o nvulsant site and blocks GABA(A) receptor

- m e diated currents in the amygdala: a mechanism for RDX

- induced

seizur es. E nvironmental Health Perspectives, 119 (3), 357

- 363. doi: 10.1289/ehp.1002588

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

a nd liver. Environmental Health Perspectives, 117 ( 2 ), 231

- 240. doi: 10.1289/ehp.11841

**1.2.3. K**  **ept 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 ( 1 2), 354

- 356.

2. C roft, P. E. (1983). Cyclonite poisoning in a dog. [Letter]. Veterinary Record, 113 ( 20), 477. doi: 10.1136/vr.113.20.477 -a 3. J acobs, A. (1991). Haematological study at Ordnance Factory [Unpublished report]. Cardiff,

U K: University of Wales College of Medicin e.
4. K ale, V. M. (2007). Mechanistic studies on hepatotoxicity of chloroacetanilide herbicides and
h ematotoxicity of munitions compound RDX and environmental degradation product MNX. (Doctoral Dissertation), University of Louisiana at Monroe, Monroe, LA. Ret r i eved from http://proquest.umi.com/pqdlink?did=1445039451&Fmt=7&clientI d=79356&RQT=309&VName=PQD
5. L ittlewood, J. D., Watkins, S. B., & Watney, G. C. (1983). Cyclonite poisoning in a dog. [Letter].

V

eterinary Record, 113 ( 2 1), 503. doi: 10.1136/vr.113.21. 503 -a 6. M iller, K. C. (1973). Toxicity and Adverse Effects of RDX: an Annotated Bibliography: Miller,

K C.

7. M indi, Q. W., Li, B., & Chen, R. (1995). The Mutagenicity o f Several Chemicals b y Vicia
Micronucleus Vicia -M CN A s say (Vol. ST, pp. 12

- 16): Mindi, QW; Li , B; Chen, R.

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

F

armakologiya i Toksikologiya, 7 ( 3 ), 43

- 47.

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

A rbeitsschutz, 1

, 5 1

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

- 

### 1
2
3
4

5

6

7
8
9
10
11
12
13

14 72.

2. Z hang, 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 Chimiqu es Expro Inc." (1983) (Vol. Government of Quebec): Gouvernement du QuÃ¢ebec.

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

113 (19), 449.

3. D e Cramer, K. G., & Short, R. P. (1992). Plastic explosive poisoning i n dogs. Journal of the

S outh African Veterinary Medical Association, 63 ( 1 ), 30

- 31.

4. Wa ng, Y ., Y an, C., Xia, B., & Tang, H. (2001). Study on health standard of octogen in air of workplaces. G o ngye Weisheng yu Zhiyebin / Industrial health and occupational diseases,

27 (3), 134

- 1 3 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. 

### 2-1 DRAFT

— DO NOT CITE OR QUOTE 

### 1

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 

# 2. PRELIMINARY EVIDENCE TABLES AND
EXPOSURE

- RESPONSE ARRAYS

**2.1. Data Extraction:**  **Preparation of Preliminary Evidence Table**  **s and**  **Exposure**

**- Response Array**  **s**

The 47 references identified as primary sources of health effects data were considered for data extraction to evidence tables and exposure

- res p onse arrays. References were first collated with respect to exposure route, exposure duration, and type of endpoint, t o i d entify those most pertinent for evaluating the human health effects from chronic oral or in halation exposure to RDX

. As a result, data from 27 stu d ies with one or more of the following characteristics were not

extracted into evidence tables or exposur e- res p onse arrays:

• The study involved human case reports, d er mal exposure or intravenous /intraperitoneal

exposure;

• The study only involved acute or sh o r t

- term exposures (less than 30 days), and it was not conducted in the context of immune, developmental, neurological or r eproductive toxicity;

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

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

nor w ere RDX

- r el ated effects observe d for those endpoints in any of the other available references

.

Data from the 20 r em ai ning references were summarized in preliminary evidence tables. No studies were excluded based on study quality considerations, so as to allow for public input on

method ological considerations that could affect the interpretation of

, o r confidence in

, each study’s
results. In some instances, ref er ences are grouped together as “related” references because they

represent pilot (e.g., range

- f in ding), unpublished (e.g., technical report s, some with multiple

volumes ), and/or p ub lished (e.g., journal article) versions of the same study. The tables for noncarcinogenic effects appear fi r st and are arranged in the order from the health effect with the

most data to the heal t h 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

, tab l es present data on ge n otoxic effects of RDX and its metabolites

. Within each endpoint, the studies are presented beginning with chronic studies followed by tho s e with subchronic exposures

. The

information in the preliminary ev id ence tables is displayed graphically in preliminary exposure

response arrays. In these arrays, a sig n ificant effect (indicated by a filled datapoint) is based on statistical significance, wit h the exceptio n 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 For these two endpoints, it was determined that the severity of the endpoints (seizures a nd death) 

### 1

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 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 statistical ly significan t 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 expos ed to RDX (30 in G roup A [26 male s ; 4 female s ]; 30 in
G roup B [24 male s ; 6 female s ])

, compared to
32 workers with similar age

, education level

, and length of employment from same plant with no exposure to RDX (27 male s ; 5 female s).

Exposure measure s : 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 measure s : Five neurobehavioral
function tests and five additional memory
subtests.

Analysis: V ariance (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 **Ta ble**  **2-2**

**. Evidence**  **pertaining to neurological effects in animals following**  

### 1 2 **oral exposure to RDX**

Reference and Study Design Results

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

Mice, B6C3F 1 , 85/sex/group; interim sacrifices (10/sex/group) at 6 a nd 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

2 4 mo One male mouse in the 35 mg/kg

- d dose group and one female

mouse in the 175/100 mg/kg -d a group convulsed near the end of the
stud y.

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 e videnced 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

2 4 mo Tremors, convulsions

, and hyper

- responsiveness to stimuli were noted at 40 mg/kg -d a ; no incidence data were reported.

Cholakis et al. (1980 )

Mice, B6C3F 1 , 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 female s a ; no incidence data were reported.

Cholakis et al. (1980 )

Rats, F3 44, 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

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

### 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 8 a 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 c ontrol

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

- d

Diet

13 wks Hyper

- reactivity to approach was o bserved in groups receiving
≥100 mg/kg

- d a ; 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 groups a ; 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 10 a

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

### 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

- 6 DRAFT

— DO NOT CITE OR QUOTE Reference and Study Design Results

Von Oettingen et al. (1949 )

Dogs, breed not specified

, 5 females /gr oup (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 reflexes a ; 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 acousti c startle

- response wer e reported

.

Cholakis et al. (1980 )

Rats, F344, 24

– 25 females/group

0, 0.2, 2.0, or 20 mg/kg

Gavage

GD s 6

– 19 Convulsions and hyperactivity in 18/25 dams at 20 mg/kg a ; one female at 2.0 mg/kg

- d exhibited convulsions.

Angerhofer et a l. (1986 ) ( range

- finding study )
Rats, Sprague

- Dawley, 6 pregnant females/group

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

- d
Gavage

GD s 6

– 15 Convulsions preceding death were observed at ≥ 40 mg/kg

- d a ; 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

GD s 6

– 15 Convulsions and hyperactivity a 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.

### 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. 

### 2-7 DRAFT

— DO NOT CITE OR QUOTE **Figure 2-1**  **. Exposure**

**- response array of**  **neurological effects following oral exposure to**  **RD X**  

### 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. 

### 2-8 DRAFT

— DO NOT CITE OR QUOTE 

## 2.3. **Mortality Evidence Table and Array** 1

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, B6C3F 1 , 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

2 4 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

2 4 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, B6C3F 1 , 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

### 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

- 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

9 0 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

c ontrol

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 1/20 f 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 1/3 g 0/3

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

Martin and Hart (1974 )
Monkeys, Cynomolgus o r 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 1/3 h

### 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 )

Rabbit s, 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

Cholaki s 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 7/24 i

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, o r 20 mg/kg -d
Gavage

GD s 6– 15 Doses 0 2 6 20
Mortality (incidence)

F 0/39 1/40 1/40 16/51

*Statistically significant ( p < 0.05) based on analysis by 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- 11 DRAFT

— DO NOT CITE OR QUOTE a Interim sacrifices (10 animals/sex/dose) were performed at 27 and 53 weeks ( Levine et al., 1983 ) or 26 and 

### 1 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

T

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

### 2- 12 DRAFT

— DO NOT CITE OR QUOTE **Figure 2-2**  **. Exposure**

**- response array of mortality following oral exposure to RDX**  

### 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- 13 DRAFT

— DO NOT CITE OR QUOTE 

## 2.4. **Reproductive and Developmental Effects Evidence Tables and** 1

2

3 4 

## Array

**Table 2-4** 

**. Evidence**  **pertaining to reproductive and developmental effects in**  **animals following oral e x**  **posure 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 w hite

, 11

– 12/group

0, 0.2, 2.0, or 20 mg/kg -d
Gavage

GD s 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 w hite

, 11

– 12/group

0, 0.2, 2.0, or 20 mg/kg -d
Gavage

GD s 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

GD s 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

GD s 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 w hite

, 11

– 12/group

0, 0.2, 2.0, or 20 mg/kg -d
Gavage

GD s 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

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

### 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

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

### 2- 16 DRAFT

— DO NOT CITE OR QUOTE **Figure 2-3** 

**. Exposure** 

**- response array of**  **reproductive and developmental effects following oral exposure to RDX.** 

### 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- 17 DRAFT

— DO NOT CITE OR QUOTE **Ta ble**  **2-5**

**. Evidence**  **pertaining t o**  **male reproductive effects in animals**  

### 1 2 **following oral exposure to RDX**

Reference and Study Design Results

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

Mice, B6C3F 1 , 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

2 4 mo Doses 0 1.5 7.0 35 175/ 100

Test icular degeneration (incidence)
0/63 2/60 2/62 6/59 3/27 a

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 te stes (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

2 4 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 s acrifice

### 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- 18 DRAFT

— DO NOT CITE OR QUOTE Reference and Study Design Results

Cholakis et al. (1980 )

Mice, B6C3F 1 , 10

– 12/sex/group

Exp eriment 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%

Exp eriment 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 male s 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/kg

d
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

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

### 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 c ontrol

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 w eight ( percent change compared to control )

0% 1% 1%

- 2% – –
Relative testes wei ght ( 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, a long 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 **Figure 2-4** 

**. Exposure** 

**- response array of male reproductive**  **effects following oral**  **exposure to RDX** 

**.** 

### 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- 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/m 3 (mean 0.28 mg/m 3 ).

Effect measur es: 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, B6C3F 1 , 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 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

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

### 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

2 4 mo Note: Percent change in liver weights of male and female mice w as 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/grou p) at 6 and

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

Diet

2 4 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, B6C3F 1 , 10

– 12/sex/group

Exp eriment 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

Exp eriment 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/kg

d

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, B6C3F 1 , 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

2 4 mo Histopathological lesions in liver other than adenomas and carcinomas were not significantly different compared to controls.

Hart (1976 )
Rats, Sprague

- Da wley, 100/sex/group

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

Diet
2 yrs Histopathological examination per formed 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, B6C3F 1 , 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; mil d (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 c ontrol

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

d

Diet

13 wks Histopathological examination of liver did not reveal any signif icant 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, B6C3F 1 , 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

2 4 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

2 4 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 c ontrol

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

d

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/m 3 (mean 0.28 mg/m 3 ).

Effect measures: Renal function tests (blood)

Analysis: Types of statistical tests werenot reported (assumed to be t

- tests for comparison of means and χ 2 tests for Test Referent (n = 237) RDX exposed

Undetected

(n = 22) 3 >0.01 mg/m (n = 45)

B lood 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, B6C3F 1 , 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

2 4 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

2 4 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, B6C3F 1 , 10

– 12/sex/group

Exp eriment 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%

Exp eriment 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

Cholaki s 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/kg

d

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 c ontrol

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

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

### 2- 32 DRAFT

— DO NOT CITE OR QUOTE Reference and Study Design Results

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

Mice, B6C3F 1 , 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

2 4 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

2 4 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 )

Mi ce, B6C3F 1 , 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 male s 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

Cholaki s 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 compar ed 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 c ontrol

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 diff erences 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 ( i ncidence)

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

**Figure 2-6** 

**. Exposure** 

**- response array of**  **renal effects following oral exposure to RDX.**  

### 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- 35 DRAFT

— DO NOT CITE OR QUOTE 

## 2.7. **Carcinogenicity Evidence Tables** 1

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, B6C3F 1 , 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

2 4 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 3/31 a

Hepatocellular carcinomas (incidence)

M 13/63 20/60 16/62 18/59 6/27

F 0/65 4/62 3/64 6/64 3/31 a
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 2/31 a
Hepatocellular carcinomas (incidence)

F 0/67 1/62 3/63 2/64 2/31 a
Hepatocellular adenoma or carcinoma combined (incidence)

F 1/67 b 4/62 5/63 b 10/64 4/31 a

Hart (1976 )
Rats, Sprague

- Dawley, 100/sex/group

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

Diet
2 yrs Hepa tocellular 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
sacrif ices (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):

N ot 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

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

### 2- 36 DRAFT

— DO NOT CITE OR QUOTE **Table 2-**  **11**

**. Lung tumors observed in chronic animal bioassays following oral**  

### 1 2

3 **exposure to RDX**

Reference and Study Design Results

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

Mice, B6C3F 1 , 85/sex/group;

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

0, 1.5, 7.0, 35, or 175/100 mg/kg

- d (high do se reduced to 100 mg/kg

- d in
wk 11 due to excessive mortality)

Diet

2 4 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 3/31 a
Alveolar/bronchiolar carcinomas (incidence)

M 3/63 6/60 3/62 7/59 5/27 a

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 7/31 a

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):

N one 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

2 4 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 

## 2.8. **Other Systemic Effects Evidence Tables** 1

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 assigne d to two groups: <LOD or ≥0.01 mg/m 3 (mean

0.28 mg/m 3 ).

Effect measures: Hematology tests.

Analysis: Types of statistical tests were not reported (assumed to be t

- tests for comparison of means and χ 2 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/m 3 (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/m 3

Hemoglobin (<14) 15/237 3/22 4/45

### 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- 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, B6C3F 1 , 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

2 4 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 sacrif ices (10/sex/grou p) at 6 and

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

Diet

2 4 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/kg

d
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).

Marti n 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, B6C3F 1 , 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 m ortality)

Diet

2 4 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 (1 976 )
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 f ibrosis ( percent incidence; n umber not reported)

M 20%

– – 5%

F 5%

– – 1%
Endocardial disease ( percent incidence; n umber 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 sacrif ices (10/se x/group) at 6 and

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

Diet

2 4 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, B6C3F 1 , 10

– 12/sex/group

Exp eriment 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%

Exp eriment 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

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

### 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/kg

d
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 c ontrol

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

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

### 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, B6C3F 1 , 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

2 4 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 sacrif ices (10/sex/group) at 6 and

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

Diet

2 4 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% 103 c % 184 c % 15%

F 0% 7% 12% 354 c % 251 c %
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, B6C3F 1 , 10

– 12/sex/group

Exp eriment 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%

Exp eriment 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/kg

d
Gavage

90 d No effects were observed on thy mus 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 s pl een w eight (

percent change compared to control )

M 0%

- 3%

- 6% 3% 1% 5%

F 0% 1% 8% 23*% 17*% 24*%
Relative spleen w eight ( percent change compared to control )

M 0% 3% 4% 7%

- 1% 2%

F 0% 1% 0% 6%

- 1%

- 2%
Absolute thymus w eight ( percent change compared to control )

M 0%

- 1% 3%

- 10%

- 12%

- 25%

F 0%

- 7% 12% 19% 32% 19%
Relative thymus w eight (

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

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

### 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 c ontrol

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 w eight ( 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

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

### 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, B6C3F 1 , 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

2 4 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 sacrif ices (10/sex/group) at 6 and

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

Diet

2 4 mo No GI effects were observed as clinical signs or on gross pathology or histopathology
examination.

Crous e et al. (2006 )

Rats, F344, 10/sex/group

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

d
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 con vulsions.

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

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

### 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, B6C3F 1 , 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
do se reduced to
100 mg/kg

- d in wk 11 due to excessive mortality)

Diet

2 4 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 % 250 c % 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 sacrif ices 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

2 4 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, B6C3F 1 , 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

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

### 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/kg

d
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 c ontrol

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

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

### 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

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

### 2- 51 DRAFT

— DO NOT CITE OR QUOTE 

## 2.9. **Genotoxic Effects** 1

2 **Table 2-**  **14**

**. Summary of in vitro studies of**  **RDX genotoxicity**

Endpoint Test system Dose/
concentration a Results b

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

m utation Vibrio fischeri 0.004 μg/tube ± + Mutatox assay with metabolic activation (S9) Arfsten et al. (1994 )

Reverse
mutation ( u mu 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

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

### 2- 52 DRAFT

— DO NOT CITE OR QUOTE E ndpo i nt T e st sy st e m D o s e/

con ce n t r a t i on a Res u l t s b

C o mme n t s Ref er en c e W i th o u t

a c ti v a ti o n Wit h

a c ti v a ti o n

I nduc t i o n o f

t he sf iA g en e ( SO S

c h r om ot e s t ) E sc h e r ic h ia

. c o li P Q 37 20. 6 μ g / m L

− − N o o bs e r v e d e ffe c t c o nc e nt r a t i o n; t e s t e d a t hi g he s t c o nc e nt r a t i o n w he r e t he i ndu c t i o n r a t e

wa s b e l o w 1

. 5 f o r th e f i r s t ti m e a n d th e g r o wth
f a c t or w a s b e l ow 0. 5 N eu w o eh n er et

a l . ( 200 7 )

R ev er s e

mu t at i o n S

. t y phi m ur i um , TA 98, TA 10 0 24. 8 μ g / m L

− − N o o bs e r v e d e ffe c t c o nc e nt r a t i o n; m e t a bo l i c

a c ti v a ti o n wi th S 9 N eu w o eh n er et

a l . ( 200 7 )

R ev er s e

mu t at i o n S

. t y phi m ur i um TA 98, TA 1 00 2. 6 μ g / m L

− − N o o bs e r v e d e ffe c t c o nc e nt r a t i o n; m e t a bo l i c

a c ti v a ti o n wi th S 9 La c h a n c e et a l

. ( 1999 )

R ev er s e

mu t at i o n S

. t y phi m ur i um TA 1535, TA 15 36

, TA 153 7, TA 15 38 TA 10 0, TA 98 30. 8 μ g / m L

- - M e t a b o lic a c t iv a t io n w it h S 9 C o tr u v o e t a l

. ( 1977 )

G e no t o x i c i t y s t udi e s i n no nm am m al i an e uk ar y o t i c o r gani s m s

R e c o m b in a t io n i nduc t i o n S

. c e r e v isia e D3 23 μ g / m L

− − S t udy a ut ho r s c o nc l ude d t ha t t hi s

m ic ro o rg a n is m d id n o t a p p e a r t o b e u s e f u l f o r d e t e c t in g m u t a g e n ic it y in s e v e ra l c o m p o u n d s
t es t ed Si mmo n e t a l

. ( 1977 )

R e c o m b in a t io n i nduc t i o n S

. c e r e v isia e D3 30. 8 μ g / m L

- - M e t a b o lic a c t iv a t io n w it h S 9 C o tr u v o e t a l

. ( 1977 )

G e n o t o x ic it y st u d ie s in m a m m a lia n c e ll s

F o rw a rd

mu t at i o n C h in e s e h a m s t e r lu n g f ib ro b la s t s V79 c e l l s 40 μ g / m L

− − M in im a l c y to to x i c i ty o b s e r v e d a t 40 μg / m L ( lim it o f s o lu b il it y ) La c h a n c e e t a l

. ( 1999 )

Mu ta ti o n L 5178 Y m o u s e l y m p h om a c e l l s 500 μg / m L
− − N o o r l o w c y to to x i c i ty s e e n a t th e s e

c o n c e n tr a ti o n s ; h o we v e r , p r e c i p i ta te wa s
ob s e r v e d > 250 μg / m L Red d y et a l

. ( 2005 )

U ns c he dul e d

D N A s y nt he s i s ; D N A r e pa i r WI

- 3 8 c e lls

, hum a n di pl o i d
f ib r o b la s t s 4, 0 00 μ g / m L

- - P re c ip it a t e s w e re o b s e rv e d a t c o n c e n t ra t io n s o f

R D X ≥ 40 μ g / m L D ille y e t a l

. ( 1979 )

a Lowest effective dose for positive results; highest dose tested for negative results. 

### 1 2 b + = positive; ± = equivocal or weakly positive; − = negative

### 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- 53 DRAFT

— DO NOT CITE OR QUOTE **Ta ble**  **2- 15** 

**. Summary of in vivo**  **studies of RDX**  **genotoxicity** 

### 1

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 t o be negative
for the induction of lethal
mutations Males in the hig h- dose group experienced lower food consumption and weight gain compared with all other

groups Ch olakis et al. (1980 )

### 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- 54 DRAFT

— DO NOT CITE OR QUOTE **Ta ble**  **2- 16** 

**. Summary of in vitro and in vivo**  **studies of RDX metabolite genotoxicity**  

### 1

Endpoint Test system Dose/
concentration a Results b

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 NR c – – Mononitroso metabolite, MNX; metabolic
activation with S9 Snodgrass (1984 )

Genotoxicity studies in mammalian cells

— in vitro

Forward
mutation Mouse lymphoma thymidine
kinase NR c + + Mononitroso metabolite, MNX; metabolic
activation with S9 Snodgrass (1984 )

Chromosomal
aberrations Chinese hamster ovary cells NR c

– + Mononitroso metabolite, MNX; metabolic
activation with S9 Snodgrass (1984 )

Unscheduled DNA synthesis; DNA repair Primary rat hepatocytes NR c + 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 NR c – 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