r/EPA
EPA/635/R-13/140
Preliminary Materials
www.epa.gov/iris
Preliminary Materials for the Integrated Risk Information System (IRIS)
Toxicological Review of Hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX)
[CASRN 121-82-4]
July 2013
NOTICE
This document is comprised of preliminary materials, consisting of a literature search strategy,
evidence tables, and exposure-response arrays. This information is distributed solely for the
purpose of pre-dissemination review under applicable information quality guidelines. It has not
been formally disseminated by EPA. It does not represent and should not be construed to represent
any Agency determination or policy. It is being circulated for review of its technical accuracy and
science policy implications.
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Preliminary Materials for the IRIS Toxicological Review ofRDX
DISCLAIMER
This document is comprised of preliminary materials for review purposes only. This
information is distributed solely for the purpose of pre-dissemination review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does not represent
and should not be construed to represent any Agency determination or policy. Mention of trade
names or commercial products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
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.GenotoxicEffects 2-51
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
TABLES
Table 1-1. Overview of database search strategy for RDX 1-4
Table 1-2. Summary of detailed search strategies for RDX (Pubmed, Toxline, Toxcenter, TSCATS) 1-6
Table 1-3. Summary of detailed search strategies for RDX (DTIC) 1-10
Table 1-4. Processes used to augment the search of core databases for RDX 1-12
Table 1-5. Summary disposition of DTIC database citations 1-13
Table 2-1. Evidence pertaining to neurological effects in humans following exposure to RDX 2-3
Table 2-2. Evidence pertaining to neurological effects in animals following oral exposure to RDX 2-4
Table 2-3. Evidence pertaining to mortality following oral exposure to RDX 2-8
Table 2-4. Evidence pertaining to reproductive and developmental effects in animals following
oral exposure to RDX 2-13
Table 2-5. Evidence pertaining to male reproductive effects in animals following oral exposure
to RDX 2-17
Table 2-6. Evidence pertaining to liver effects of RDX in humans 2-21
Table 2-8. Evidence pertaining to renal effects of RDX in humans 2-29
Table 2-9. Evidence pertaining to renal effects in animals following oral exposure to RDX 2-29
Table 2-10. Liver tumors observed in chronic animal bioassays following oral exposure to RDX 2-35
Table 2-11. Lung tumors observed in chronic animal bioassays following oral exposure to RDX 2-36
Table 2-12. Evidence pertaining to other systemic effects (hematological) of RDX in humans 2-37
Table 2-13. Evidence pertaining to other systemic effects in animals following oral exposure to
RDX 2-38
Table 2-14. Summary of in vitro studies of RDX genotoxicity 2-51
Table 2-15. Summary of in vivo studies of RDX genotoxicity 2-53
Table 2-16. Summary of in vitro and in vivo studies of RDX metabolite genotoxicity 2-54
FIGURES
Figure 1-1. Literature search approach for RDX 1-5
Figure 2-1. Exposure-response array of neurological effects following oral exposure to RDX 2-7
Figure 2-2. Exposure-response array of mortality following oral exposure to RDX 2-12
Figure 2-3. Exposure-response array of reproductive and developmental effects following oral
exposure to RDX 2-16
Figure 2-4. Exposure-response array of male reproductive effects following oral exposure to
RDX 2-20
Figure 2-5. Exposure-response array of liver effects following oral exposure to RDX 2-28
Figure 2-6. Exposure-response array of renal effects following oral exposure to RDX 2-34
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2 PREFACE
3 This document presents the draft literature search strategy, preliminary evidence tables,
4 and preliminary exposure-response arrays for hexahydro-l,3,5-trinitro-l,3,5-triazine (henceforth
5 referred to as RDX) prepared under the auspices of EPA's Integrated Risk Information System
6 (IRIS) Program. This material is being released for public viewing and comment prior to a public
7 meeting, providing an opportunity for the IRIS Program to engage in early discussions with
8 stakeholders and the public on data that may be used to identify adverse health effects and
9 characterize exposure-response relationships.
10 The draft literature search strategy, preliminary evidence tables, and preliminary exposure-
11 response arrays are responsive to the National Research Council (NRC) 2011 report Review of the
12 Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde. The literature search
13 strategy, which describes the processes for identifying scientific literature, screening studies for
14 consideration, and selecting studies for inclusion in evidence tables, is responsive to NRC
15 recommendations regarding systematic review of the scientific literature. In addition, NRC
16 recommendations for standardized presentation of key study data are addressed in the preliminary
17 evidence tables and preliminary exposure-response arrays.
18 EPA welcomes all comments on the draft literature search strategy, preliminary evidence
19 tables, and preliminary exposure-response arrays, such as remarks on the following:
20 • the clarity and transparency of the materials;
21 • the approach for identifying pertinent studies;
22 • the selection of studies for data extraction to preliminary evidence tables and exposure-
23 response arrays;
24 • any methodological considerations that could affect the interpretation of or confidence
25 in study results; and
26 • any additional studies published or nearing publication that may provide data for the
27 evaluation of human health hazard or dose-response relationships.
28 The preliminary evidence tables and exposure-response arrays should be regarded solely as
29 representing the data on each endpoint that have been identified as a result of the draft literature
30 search strategy. They do not reflect any conclusions as to hazard identification or dose-response
31 assessment. After obtaining public input and conducting additional study evaluation and data
32 integration, EPA will revise these materials to support the hazard identification and dose-response
33 assessment in a draft Toxicological Review.
34
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1. DRAFT LITERATURE SEARCH STRATEGY
1 1.1. Literature Search and Screening Strategy for RDX
2 The overall literature search approach is shown in Table 1-1 and the results are
3 summarized graphically in Figure 1-1. The literature search for RDX was conducted in five online
4 scientific databases in February 2013. For four of these databases (Pubmed, Toxline, Toxcenter,
5 and TSCATS) the detailed search strategy is provided in Table 1-2. Given the military applications
6 of RDX, the Defense Technical Information Center (DTIC) database was searched. Because of
7 limitations in the classification and distribution of materials in DTIC, a separate search strategy was
8 applied, which is described in Table 1-3. The computerized database searches were augmented by
9 review of online regulatory sources as well as "forward" and "backward" Web of Science searches of
10 2 recent reviews (Table 1-4).
11 A special strategy was applied to searches of the DTIC online database. A total of 858
12 citations were identified, including 504 where the full-text document had unlimited distribution,
13 304 classified as "distribution limited to U.S. Government agencies only," and 50 classified as
14 "distribution limited to Department of Defense only." Of the 858 citations, 8 citations with
15 unlimited distribution and 10 citations with limited distribution were selected for further review.
16 Those 8 citations with unlimited distribution (that were not duplicated in other databases) were
17 uploaded to the Health and Environmental Research Online (HERO) website1 (http://hero.epa.gov).
18 The 10 limited-distribution citations were evaluated for relevance to the assessment (i.e., with a
19 focus on whether they provided additional primary health effects data) to determine whether EPA
20 should seek authorization for public distribution and upload to HERO. A review of the abstract or
21 full-text of the documents associated with the citation resulted in the following determinations:
22 • 4 of the 10 citations could be excluded from further consideration because the reports
23 were not specific to RDX, or addressed environmental properties (e.g., leaching);
24 • 3 of the citations were determined not to provide additional primary health effects data
25 because they either described a study plan for, or reported data from, experiments that
26 were subsequently published (Williams etal.. 2011: Hathaway and Buck. 1977) and had
27 already been identified by the literature search strategy;
28 • 1 citation was identified as actually having unlimited distribution (duplicate record in
29 DTIC database), and was added to the HERO database (Lish etal.. 1984):
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.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 • 1 citation was identified as relevant and provided animal inhalation data, but was not
2 brought forward for further review because of study quality considerations. These
3 study quality considerations included lack of a control group, small numbers of animals,
4 incomplete information on dosage or exposure levels, and inadequate reporting;
5 • 1 citation did not have an abstract or full text available outside of the Department of
6 Defense. Based on the title, this report appeared to deal specifically with the
7 manufacture and chemical/explosive properties of RDX. Given the available
8 information, it was determined that it was unlikely the report would provide primary
9 health effects data that warranted further review.
10
11 The rationales for exclusion of the other 841 references that were not selected for further
12 consideration are summarized in Table 1-5.
13 After electronically eliminating duplicates from the citations retrieved through these
14 databases, 906 citations were identified. Additionally, 18 citations were obtained using additional
15 search strategies described in Table 1-4. The resulting 924 citations were screened using the title,
16 abstract, and in limited instances, full text for pertinence to examining the health effects of RDX
17 exposure. A total of 652 references were identified as not being pertinent and were excluded from
18 further consideration (see Figure 1-1 for the exclusion categories). A total of 47 references were
19 identified as potential primary sources of health effects data and were considered for data
20 extraction to evidence tables and exposure-response arrays (see Section 1.2.1). A total of 210
21 references were considered pertinent, but not as primary sources of health effects data (e.g.,
22 adsorption/distribution/metabolism/excretion [ADME] studies), and were kept as additional
23 resources for development of the Toxicological Review (see Section 1.2.2). If a reference did not
24 provide enough material to evaluate pertinence (e.g., no abstract), it was reserved for further
25 possible review; 15 such studies were identified for RDX (see Section 1.2.3). EPA welcomes
26 comments on studies identified for possible further review that may inform their utility to the
27 development of the Toxicological Review.
28 As illustrated in Figure 1-1, studies were identified and "tagged" in HERO based on
29 information provided in the title and/or abstract; in some cases this information was supplemented
30 by further review of the full text of the corresponding document Based on this review, studies
31 were distributed in different groups that reflect the primary content of the citation. It should be
32 noted that studies were not given multiple tags, and the inclusion of a citation in a given category
33 (or tag) does not preclude its use in one or more other categories. For example, Woody et al.
34 (1986) is a case report that describes accidental ingestion of RDX by a child. In Figure 1-1 it is
35 included in the human studies category of primary health effects data. This case report also
36 provides pharmacokinetic data and could be a pertinent source of information on the toxicokinetics
37 of RDX. In this instance, however, Woody etal. (1986) is not assigned a second tag for
38 toxicokinetics. For the purposes of this preliminary description of the literature search process, the
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 strategy of only using one tag per reference is utilized to allow the public and stakeholders to more
2 easily distinguish between citations that would be excluded from further review and those that may
3 be utilized in the development of the assessment
4
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Table 1-1. Overview of database search strategy for RDX
Database
Pubmed
Toxline
TSCATS1
WOS
Toxcenter
DTIC
ChemID
TSCATS 2 & 8e submissions
Keywords
Chemical CASRN: 121-82-4
Synonyms: Cyclonite OR RDX OR Cyclotrimethylenetrinitramine OR
"cyclotrimethylene trinitramine" OR "Hexahydro-l,3,5-trinitro-l,3,5-triazine"
OR "Hexahydro-l,3,5-trinitro-s-triazine" OR Hexogen OR "1,3,5-trinitro- 1,3,5-
triazine" OR "l,3,5-Triaza-l,3,5-trinitrocyclohexane" OR "1,3,5-Trinitro- 1,3,5-
triazacyclohexane" OR "l,3,5-Trinitrohexahydro-l,3,5-triazine" OR "1,3,5-
Trinitrohexahydro-s-triazine" OR "l,3,5-Trinitroperhydro-l,3,5-triazine" OR
"Esaidro- 1,3,5-trinitro- 1,3,5-triazina" OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazin" OR "Perhydro-l,3,5-trinitro-l,3,5-triazine" OR
Cyclotrimethylenenitramine ORTrimethylenetrinitramine OR "Trimethylene
trinitramine" ORTrimethyleentrinitramine OR "Trinitrocyclotrimethylene
triamine" OR Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR
Geksogen OR Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af)
108" OR "PBXW 108(E)" OR "Pbx(AF) 108"
Synonym and CASRN search for all databases; Toxcenter, Pubmed, and WOS
limited using toxicity-related keywords
Toxicity-related terms (see Table 1-2 for specific keywords)
Toxicity (including duration, effects to children and occupational exposure);
development; reproduction; teratogenicity; exposure routes;
pharmacokinetics; toxicokinetics; metabolism; body fluids; endocrinology;
carcinogenicity; genotoxicity; antagonists; inhibitors
Searched by CASRN
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Database Searches
(see Tables 1-2 and 1-3 for keywords and limits)
Pubmed Toxcenter
n=449 n=29
Toxline (incl. TSCATS)
n=418
TSCATS 2
n=2
DTIC
n=8
(After duplicates removed electronically)
n=906
Additional Search Strategies
(see Table 1-4 for methods and results)
n=18
Combined Oataset
n=924
1
2
Manual Screening For Pertinence
(Title/Abstract/Full Text)
Excluded/Not Pertinent (652)
19 Abstract only
125 Not chemical specific
13 Use in sample prep or assay
146 Bioremediation or biodegradation
96 Chemical/physical properties or
explosive properties
57 Chemical or physical treatment
179 Measurement methods
17 Miscellaneous
Kept for Possible Further Review (15)
9 No abstract
2 Foreign language
4 Inadequate reporting in abstract
Not Primary Source of Health Effects
Data, but Kept as Additional Resource
(210)
8 Regulatory documents
13 Reviews
38 Ecosystem effects
2 Editorials
11 Risk assessments
96 Exposure levels
3 Mixtures only
16 Toxicokinetics
10 Genotoxicity
13 Mechanistic data
Primary Sources of Health Effects
Data (47)
21 Human health effects studies
4 Occupational
17 Case Reports
26 Animal toxicology studies
Figure 1-1. Literature search approach for RDX.
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2
Table 1-2. Summary of detailed search strategies for RDX (Pubmed, Toxline,
Toxcenter, TSCATS)
Database
Set#
Terms
Hits
PubMed
Date limit:
1/1/2012 -
2/2013
1A1
(Cyclonite[tw] OR RDX[tw] OR Cyclotrimethylenetrinitramine[tw] OR
"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazine"[tw] OR"Hexahydro-l,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw]
OR "l,3,5-trinitro-l,3,5-triazine"[tw] OR "l,3,5-Triaza-l,3,5-
trinitrocyclohexane"[tw] OR "l,3,5-Trinitro-l,3,5-triazacyclohexane"[tw]
OR "l,3,5-Trinitrohexahydro-l,3,5-triazine"[tw] OR "1,3,5-
Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-
triazine"[tw] OR "Esaidro-l,3,5-trinitro-l,3,5-triazina"[tw] OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazin"[tw] OR"Perhydro-l,3,5-trinitro-
l,3,5-triazine"[tw] ORCyclotrimethylenenitramine[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] ORCyclotrimethylenetrinitramine[tw] OR
"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazine"[tw] OR"Hexahydro-l,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw]
OR "l,3,5-trinitro-l,3,5-triazine"[tw] OR "l,3,5-Triaza-l,3,5-
trinitrocyclohexane"[tw] OR "l,3,5-Trinitro-l,3,5-triazacyclohexane"[tw]
OR "l,3,5-Trinitrohexahydro-l,3,5-triazine"[tw] OR "1,3,5-
Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-
triazine"[tw] OR "Esaidro-l,3,5-trinitro-l,3,5-triazina"[tw] OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazin"[tw] OR"Perhydro-l,3,5-trinitro-
l,3,5-triazine"[tw] ORCyclotrimethylenenitramine[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] ORCyclotrimethylenetrinitramine[tw] OR
"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazine"[tw] OR"Hexahydro-l,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw]
OR "l,3,5-trinitro-l,3,5-triazine"[tw] OR "l,3,5-Triaza-l,3,5-
trinitrocyclohexane"[tw] OR "l,3,5-Trinitro-l,3,5-triazacyclohexane"[tw]
OR "l,3,5-Trinitrohexahydro-l,3,5-triazine"[tw] OR "1,3,5-
Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-
triazine"[tw] OR "Esaidro-l,3,5-trinitro-l,3,5-triazina"[tw] OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazin"[tw] OR"Perhydro-l,3,5-trinitro-
l,3,5-triazine"[tw] ORCyclotrimethylenenitramine[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
337
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Database
Set#
Terms
Hits
Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR
"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF)
108"[tw]) OR (rdx[tw])) AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR
(me[sh] AND (humans[mh] OR animals[mh])) OR ci[sh] OR bl[sh] OR cf[sh]
OR ur[sh] OR ((pharmacokinetics[mh] OR metabolism[mh]) AND
(humans[mh] OR mammals[mh])) OR "dose-response relationship,
drug"[mh] OR risk[mh] OR "toxicity tests"[mh] OR noxae[mh] OR
cancer[sb] OR "endocrine system"[mh] OR "endocrine disruptors"[mh] OR
"Hormones, Hormone Substitutes, and Hormone Antagonists"[mh] OR
triazines/ai OR ("Inhalation Exposure"[Mesh] OR "Maternal
Exposure"[Mesh] OR "Maximum Allowable Concentration"[Mesh] OR
"Occupational Exposure"[Mesh] OR "Paternal Exposure"[Mesh] OR
"Environmental Exposure"[Mesh:noexp])))) NOT (((((121-82-4) OR
(Cyclonite[tw] ORCyclotrimethylenetrinitramine[tw] OR
"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazine"[tw] OR"Hexahydro-l,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw]
OR "l,3,5-trinitro-l,3,5-triazine"[tw] OR "l,3,5-Triaza-l,3,5-
trinitrocyclohexane"[tw] OR "l,3,5-Trinitro-l,3,5-triazacyclohexane"[tw]
OR "l,3,5-Trinitrohexahydro-l,3,5-triazine"[tw] OR "1,3,5-
Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-
triazine"[tw] OR "Esaidro-l,3,5-trinitro-l,3,5-triazina"[tw] OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazin"[tw] OR"Perhydro-l,3,5-trinitro-
l,3,5-triazine"[tw] ORCyclotrimethylenenitramine[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] ORCyclotrimethylenetrinitramine[tw] OR
"cyclotrimethylene trinitramine"[tw] OR "Hexahydro-l,3,5-trinitro-l,3,5-
triazine"[tw] OR"Hexahydro-l,3,5-trinitro-s-triazine"[tw] OR Hexogen[tw]
OR "l,3,5-trinitro-l,3,5-triazine"[tw] OR "l,3,5-Triaza-l,3,5-
trinitrocyclohexane"[tw] OR "l,3,5-Trinitro-l,3,5-triazacyclohexane"[tw]
OR "l,3,5-Trinitrohexahydro-l,3,5-triazine"[tw] OR "1,3,5-
Trinitrohexahydro-s-triazine"[tw] OR "1,3,5-Trinitroperhydro-1,3,5-
triazine"[tw] OR "Esaidro-l,3,5-trinitro-l,3,5-triazina"[tw] OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazin"[tw] OR"Perhydro-l,3,5-trinitro-
l,3,5-triazine"[tw] ORCyclotrimethylenenitramine[tw] OR
Trimethylenetrinitramine[tw] OR "Trimethylene trinitramine"[tw] OR
Trimethyleentrinitramine[tw] OR "Trinitrocyclotrimethylene triamine"[tw]
OR Trinitrotrimethylenetriamine[tw] OR "CX 84A"[tw] OR Cyklonit[tw] OR
Geksogen[tw] OR Heksogen[tw] OR Hexogeen[tw] OR Hexolite[tw] OR
"KHP 281"[tw] OR "PBX (af) 108"[tw] OR "PBXW 108(E)"[tw] OR "Pbx(AF)
108"[tw]) OR (rdx[tw]» AND (to[sh] OR po[sh] OR ae[sh] OR pk[sh] OR
(me[sh] AND (humans[mh] OR animals[mh])) OR ci[sh] OR bl[sh] OR cf[sh]
OR ur[sh] OR «pharmacokinetics[mh] OR metabolism[mh]) AND
(humans[mh] OR mammals[mh])) OR "dose-response relationship,
drug"[mh] OR risk[mh] OR "toxicity tests"[mh] OR noxae[mh] OR
cancer[sb] OR "endocrine system"[mh] OR "endocrine disruptors"[mh] OR
"Hormones, Hormone Substitutes, and Hormone Antagonists"[mh] OR
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
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-l,3,5-trinitro-1,3,5-
triazine"+"Hexahydro-l,3,5-trinitro-s-triazine"+"Hexogen"+"l,3,5-trinitro-
l,3,5-triazine"+"l,3,5-Triaza-l,3,5-trinitrocyclohexane"+"l,3,5-Trinitro-
1,3,5-triazacyclohexane"+" 1,3,5-Trinitrohexahydro-l,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
1B2
@OR+("l,3,5-Trinitroperhydro-l,3,5-triazine"+"Esaidro-l,3,5-trinitro-
l,3,5-triazina"+"Hexahydro-l,3,5-trinitro-l,3,5-triazin"+"Perhydro-1,3,5-
trinitro-1,3,5-
triazine"+"Cyclotrimethylenenitramine"+"Trimethylenetrinitramine"+"Tri
methylene
trinitramine"+"Trimethyleentrinitramine"+"Trinitrocyclotrimethylene
triamine"+"Trinitrotrimethylenetriamine"+"CX
84A"+"Cyklonit"+"Geksogen"+"Heksogen"+"Hexogeen"+"Hexolite"+"KHP
281")+@AND+@range+yr+2011+2013+@NOT+@org+pubmed+pubdart+c
risp+tscats
Toxline
Date limit:
1907-
4/2012
IBS
casrn or synonyms
-removed invertebrates, aquatic organisms, amphibians, earthworms
507
TSCATS
1C1
@term+@rn+121-82-4+@AND+@org+tscats
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-l,3,5-trinitro-l,3,5-triazine" OR "Hexahydro-l,3,5-trinitro-s-
triazine" OR Hexogen OR "l,3,5-trinitro-l,3,5-triazine" OR "1,3,5-Triaza-
1,3,5-trinitrocyclohexane" OR "l,3,5-Trinitro-l,3,5-triazacyclohexane" OR
"l,3,5-Trinitrohexahydro-l,3,5-triazine" OR "1,3,5-Trinitrohexahydro-s-
triazine" OR "l,3,5-Trinitroperhydro-l,3,5-triazine" OR "Esaidro-1,3,5-
trinitro-l,3,5-triazina" OR "Hexahydro-l,3,5-trinitro-l,3,5-triazin" OR
"Perhydro-l,3,5-trinitro-l,3,5-triazine" ORCyclotrimethylenenitramine
OR Trimethylenetrinitramine OR "Trimethylene trinitramine" OR
Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR
Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR Geksogen OR
Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af) 108" OR
"PBXW 108(E)" OR "Pbx(AF) 108") AND (py>2012 OR ed>20120101) AND
(chronic OR immunotox? OR neurotox? OR toxicokin? OR biomarker? OR
neurolog? OR pharmacokin? OR subchronic OR pbpk OR
epidemiology/st,ct, it) OR acute OR subacute OR Id50# OR Ic50# OR
(toxicity OR adverse OR poisoning)/st,ct,it OR inhal? OR pulmon? OR
nasal? OR lung? OR respir? OR occupation? OR workplace? OR worker?
OR oral OR orally OR ingest? OR gavage? OR diet OR diets OR dietary OR
26
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Database
Set#
Terms
Hits
drinking(w)water OR (maximum and concentration? and (allowable OR
permissible)) OR (abort? OR abnormalit? OR embryo? OR cleft? OR fetus?
OR foetus? OR fetal? OR foetal? OR fertil? OR malform? OR ovum OR ova
OR ovary OR placenta? OR pregnan? OR prenatal OR perinatal? OR
postnatal? OR reproduc? OR steril? OR teratogen? OR sperm OR
spermac? OR spermag? OR spermati? OR spermas? OR spermatob? OR
spermatoc? OR spermatog? OR spermatoi? OR spermatol? OR
spermator? OR spermatox? OR spermatoz? OR spermatu? OR spermi? OR
spermo? OR neonat? OR newborn OR development OR developmental?
OR zygote? OR child OR children OR adolescen? OR infant OR wean? OR
offspring OR age(w)factor? OR dermal? OR dermis OR skin OR epiderm?
OR cutaneous? OR carcinog? OR cocarcinog? OR cancer? OR precancer?
OR neoplas? OR tumor? OR tumour? OR oncogen? OR lymphoma? OR
carcinom? OR genetox? OR genotox? OR mutagen? OR genetic(w)toxic?
OR nephrotox? OR hepatotox? OR endocrin? OR estrogen? OR androgen?
OR hormon? OR rat OR rats OR mouse OR mice OR muridae OR dog OR
dogs OR rabbit? OR hamster? OR pig OR pigs OR swine OR porcine OR
goat OR goats OR sheep OR monkey? OR macaque? OR marmoset? OR
primate? OR mammal? OR ferret? OR gerbil? OR rodent? OR lagomorpha
OR baboon? OR bovine OR canine OR cat OR cats OR feline OR pigeon?
OR occupation? OR worker? OR epidem?) AND (biosis/fs AND py>1999
AND (caplus/fs AND 4-?/cc)
Duplicates were removed; Biosis subfile results were date limited to avoid
extensive overlap with Toxline
Toxcenter
Date limit:
1907-
4/2012
1D2
((121-82-4 NOT (patent/dt OR tscats/fs)) OR (Cyclonite OR RDX OR
Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazine" OR "Hexahydro-l,3,5-trinitro-s-
triazine" OR Hexogen OR "l,3,5-trinitro-l,3,5-triazine" OR "1,3,5-Triaza-
1,3,5-trinitrocyclohexane" OR "l,3,5-Trinitro-l,3,5-triazacyclohexane" OR
"l,3,5-Trinitrohexahydro-l,3,5-triazine" OR "1,3,5-Trinitrohexahydro-s-
triazine" OR "l,3,5-Trinitroperhydro-l,3,5-triazine" OR "Esaidro-1,3,5-
trinitro-l,3,5-triazina" OR "Hexahydro-l,3,5-trinitro-l,3,5-triazin" OR
"Perhydro-l,3,5-trinitro-l,3,5-triazine" ORCyclotrimethylenenitramine
OR Trimethylenetrinitramine OR "Trimethylene trinitramine" OR
Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR
Trinitrotrimethylenetriamine OR "CX 84A" OR Cyklonit OR Geksogen OR
Heksogen OR Hexogeen OR Hexolite OR "KHP 281" OR "PBX (af) 108" OR
"PBXW 108(E)" OR "Pbx(AF) 108")AND (chronic OR immunotox? OR
neurotox? OR toxicokin? OR biomarker? OR neurolog? OR pharmacokin?
OR subchronic OR pbpk OR epidemiology/st,ct, it) OR acute OR subacute
OR Id50# OR Ic50# OR (toxicity OR adverse OR poisoning)/st,ct,it OR
inhal? OR pulmon? OR nasal? OR lung? OR respir? OR occupation? OR
workplace? OR worker? OR oral OR orally OR ingest? OR gavage? OR diet
OR diets OR dietary OR drinking(w)water OR (maximum and
concentration? and (allowable OR permissible)) OR (abort? OR
abnormalit? OR embryo? OR cleft? OR fetus? OR foetus? OR fetal? OR
foetal? OR fertil? OR malform? OR ovum OR ova OR ovary OR placenta?
OR pregnan? OR prenatal OR perinatal? OR postnatal? OR reproduc? OR
steril? OR teratogen? OR sperm OR spermac? OR spermag? OR spermati?
OR spermas? OR spermatob? OR spermatoc? OR spermatog? OR
spermatoi? OR spermatol? OR spermator? OR spermatox? OR spermatoz?
337
This document is a draft for review purposes only and does not constitute Agency policy,
1-9 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Database
Merged
Reference
Set
Set#
1
Terms
OR spermatu? OR spermi? OR spermo? OR neonat? OR newborn OR
development OR developmental? OR zygote? OR child OR children OR
adolescen? OR infant OR wean? OR offspring OR age(w)factor? OR
dermal? OR dermis OR skin OR epiderm? OR cutaneous? OR carcinog? OR
cocarcinog? OR cancer? OR precancer? OR neoplas? OR tumor? OR
tumour? OR oncogen? OR lymphoma? OR carcinom? OR genetox? OR
genotox? OR mutagen? OR genetic(w)toxic? OR nephrotox? OR
hepatotox? OR endocrin? OR estrogen? OR androgen? OR hormon? OR
rat OR rats OR mouse OR mice OR muridae OR dog OR dogs OR rabbit?
OR hamster? OR pig OR pigs OR swine OR porcine OR goat OR goats OR
sheep OR monkey? OR macaque? OR marmoset? OR primate? OR
mammal? OR ferret? OR gerbil? OR rodent? OR lagomorpha OR baboon?
OR bovine OR canine OR cat OR cats OR feline OR pigeon? OR
occupation? OR worker? OR epidem?) AND (biosis/fs AND py>1999 AND
(caplus/fsAND4-?/cc)
Duplicates were removed; Biosis subfile results were date limited to avoid
extensive overlap with Toxline
Including additional strategies and DTIC (after duplicate removal)
Hits
924
1
2
Table 1-3. Summary of detailed search strategies for RDX (DTIC)
Database
DTIC
Search
date:
2/11/2013
Set#
2A1
2A2
Terms
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-l,3,5-trinitro-l,3,5-triazine" OR "Hexahydro-
1,3,5-trinitro-s-triazine" OR Hexogen OR Cyclotrimethylenenitramine OR
Trimethylenetrinitramine OR "Trimethylene trinitramine" OR
Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR
Trinitrotrimethylenetriamine OR Hexolite ) and distco:(A) | Report Date:
All dates
Searched for: distco:(govt) and key:((toxicity OR phramacokinetics OR
toxicology OR pharmacology OR poisoning OR toxic hazards OR radiation
hazards OR radiation effects OR toxic diseases OR toxic agents OR lethal
agents OR antidotes OR death OR "signs and symptoms" OR cancer OR
carinogens OR physiology OR biochemistry OR body weight OR anatomy
OR body fluids OR metabolism OR immunology OR mutagens OR
teratogenic compounds OR mutations OR antimetabolites) NOT (aquatic
animals OR Invertebrates OR venomous animals OR wildlife OR
biodegradation)) and ("121-82-4" OR Cyclonite OR RDX OR
Hits
504
(8 selected and
added to HERO)
304
(7 selected for
further
consideration)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Database
Set#
Terms
Hits
Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazine" OR "Hexahydro-l,3,5-trinitro-s-
triazine" OR Hexogen OR Cyclotrimethylenenitramine OR
Trimethylenetrinitramine OR "Trimethylene trinitramine" OR
Trimethyleentrinitramine OR "Trinitrocyclotrimethylene triamine" OR
Trinitrotrimethylenetriamine OR Hexolite ) | Report Date: All dates
2A3
Searched for: distco:(dod) and key:((toxicity OR phramacokinetics OR
toxicology OR pharmacology OR poisoning OR toxic hazards OR radiation
hazards OR radiation effects OR toxic diseases OR toxic agents OR lethal
agents OR antidotes OR death OR "signs and symptoms" OR cancer OR
carinogens OR physiology OR biochemistry OR body weight OR anatomy
OR body fluids OR metabolism OR immunology OR mutagens OR
teratogenic compounds OR mutations OR antimetabolites) NOT (aquatic
animals OR Invertebrates OR venomous animals OR wildlife OR
biodegradation)) and ("121-82-4" OR Cyclonite OR RDX OR
Cyclotrimethylenetrinitramine OR "cyclotrimethylene trinitramine" OR
"Hexahydro-l,3,5-trinitro-l,3,5-triazine" OR "Hexahydro-l,3,5-trinitro-s-
triazine" 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
858
(8 added to HERO;
see text)
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Table 1-4. Processes used to augment the search of core databases for RDX
System Used
Selected Key Reference(s) or Sources
Date
Additional References
Identified
Web of
Science,
forward search
Sweeney, LM; Gut, CP, Jr.; Gargas, ML; Reddy, G; Williams,
LR; Johnson, MS. (2012). Assessing the non-cancer risk for
RDX (hexahydro-l,3,5-trinitro-l,3,5-triazine) using
physiologically based pharmacokinetic (PBPK) modeling. 62:
107-114.
1 search result
Sweeney, LM; Okolica, MR; Gut, CP, Jr; Gargas, ML. (2012).
Cancer mode of action, weight of evidence, and proposed
cancer reference value for hexahydro-l,3,5-trinitro-1,3,5-
triazine (RDX). Regul Toxicol Pharmacol 64: 205-224
0 search results
3/2013
0 citations added
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-l,3,5-trinitro-l,3,5-triazine) using
physiologically based pharmacokinetic (PBPK) modeling. 62:
107-114.
35 cited papers
Sweeney, LM; Okolica, MR; Gut, CP, Jr; Gargas, ML. (2012).
Cancer mode of action, weight of evidence, and proposed
cancer reference value for hexahydro-l,3,5-trinitro-1,3,5-
triazine (RDX). Regul Toxicol Pharmacol 64: 205-224
69 cited papers
3/2013
0 citations added
3/2013
3 citations added
Background
Check
Combination of CASRN and synonyms searched on the
following websites:
ATSDR http://www.atsdr.cdc.gov/substances/index.asp
(Note: the reference list for the ATSDR toxicological profile
for RDX was compared to the search results and relevant
references were added)
CalEPA (Office of Environmental Health Hazard Assessment)
(http://www.oehha.ca.gov/risk.html)
eChemPortal
(http://www.echemportal.org/echemportal/participant/page
4/11/2012
15 citations added
.action?pagelD=9)
EPA Acute Exposure Guideline Levels
(http://www.epa.gov/oppt/aegl/pubs/chemlist.htm)
EPA- IRISTrack/New Assessments and Reviews
(http://cfpub.epa.gov/ncea/iristrac/) to find dates
(http://www.epa.gov/ncea/iris/index.html) to find data
EPANSCEP
(http://www.epa.gov/ncepihom/)
EPA Science Inventory
(http://cfpub.epa.gov/si/)
Federal Docket
www.regulations.gov
Health Canada First Priority List Assessments
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2
(http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psll-
Ispl/index-eng.php)
Health Canada Second Priority List Assessments
(http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psl2-
Isp2/index-eng.php)
IARC
(http://monographs.iarc.fr/htdig/search.html)
IPCSINCHEM
(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/
NIOSHTIC2
(http://www2a.cdc.gov/nioshtic-2/)
NTP - RoC, status, results, and management reports
(http://ntpsearch.niehs.nih.gov/querv.html)
WHO assessments - CICADS, EHC
(http://www.who.int/ipcs/assessment/en/)
Table 1-5. Summary disposition of DTIC database citations
Criteria
Exclusion - Not chemical-specific
Exclusion - Bioremediation or biodegradation
Exclusion - Chemical/physical properties of explosive properties
Exclusion - Physical or chemical treatment
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
Exclusion Total
Percent of Citations
~50%
5%
<5%
<5%
~35%
98% (841 total)
Additional Resource - Regulatory documents
Additional Resource - Reviews
Additional Resource - Ecosystem effects
Additional Resource - Risk assessments
Additional Resource - Exposure levels
<5%
<5%
<5%
<5%
<5%
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Additional Resource - Measurement methods
Additional Resource - Mixture only
Additional Resource -Toxicokinetics
Possible Further Review- No abstract
Possible Further Review- inadequate reporting in abstract
Inclusion Total
<5%
<5%
<5%
<5%
<5%
~2% (17 total)
TOTAL NUMBER OF DTICS CITATIONS (including 10 limited distribution for further
review)
858
This document is a draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 1.2. List of References Based on Search Strategy for RDX
2 Citations for excluded references are not listed here, but can be found on the Health and
3 Environmental Research Online (HERO) Web site (http://hero.epa.gov/RDX).
4 1.2.1. Primary Sources of Health Effects Data
5 Data from citations in bold are displayed in tabular or graphical form in Section 2. See
6 Section 2.1 for a description of the process of selecting these studies for evidence tables and
7 exposure-response arrays.
8
9 Human Health Effects (21 citations)
10 1. ATSDR. (1996). Symptom and disease prevalence with biomarkers health study Cornhusker
11 Army Ammunition Plant Hall County, Nebraska. Atlanta, GA. Div. of Health Studies.
12 2. Barsotti, M., & Crotti, G. (1949). [Attacchi epileptici come manifestazione di intossicazione
13 professionale da trimetilen-trinitroamina (T4)]. La Medicina delLavoro, 40(4), 107-112.
14 3. Davies, J. 0.}., Roberts, D. M., Hittarage, A, & Buckley, N. A. (2007). Oral C-4 plastic explosive
15 in humans - A case series. Clinical Toxicology, 45(5), 454-457. doi:
16 10.1080/15563650601118044
17 4. Goldberg, D. J., Green, S. T., Nathwani, D., McMenamin, J., Hamlet, N., & Kennedy, D. H.
18 (1992). RDX intoxication causing seizures and a widespread petechial rash mimicking
19 meningococcaemia./ourna/ of the Royal Society of Medicine, 85(3), 181.
20 5. Harrell-Bruder, B., & Hutchins, K. L. (1995). Seizures caused by ingestion of composition C-
21 4. Annals of Emergency Medicine, 26(6), 746-748.
22 6. Hathaway, J. A., & Buck, C. R. (1977). Absence of health hazards associated with RDX
23 manufacture and use. Journal of Occupational and Environmental Medicine, 19(4),
24 269-272.
25 7. Hett, D., & Fichtner, K. (2002). A plastic explosive by mouth. Journal of the Royal Society of
26 Medicine, 95(5), 251-252. doi: 10.1258/jrsm.95.5.251
27 8. Hollander, A, &Colbach, E. (1969). Composition C-4 induced seizures: A report of five cases.
28 Military Medicine, ^34(13), 1529-1530.
29 9. Kaplan, A. S., Berghout, C. F., & Peczenik, A. (1965). Human intoxication from RDX. Archives
30 of Environmental Health, 10, 877-883.
31 10. Kasuske, L., Schofer, J. M., & Hasegawa, K. (2009). Two marines with generalized seizure
32 activity. Journal of Emergency Nursing, 35(6), 542-543. doi: 10.1016/j.jen.2008.05.001
33 11. Ketel, W. B., & Hughes, J. R. (1972). Toxic encephalopathy with seizures secondary to
34 ingestion of composition C-4. A clinical and electroencephalographic study. Neurology,
35 22(8), 871-876.
36 12. Knepshield, J. H., & Stone, W. J. (Eds.). (1972). Toxic effects following ingestion of C-4 plastic
37 explosive. Springfield, IL: Charles C. Thomas.
38 13. Kiiciikardali, Y., Acar, H. V., Ozkan, S., Nalbant, S., Yazgan, Y., Atasoyu, E. M., Danaci, M.
39 (2003). Accidental oral poisoning caused by RDX (cyclonite): A report of 5 cases. Journal of
40 Intensive Care Medicine, 18(1}, 42-46. doi: 10.1177/0885066602239123
41 14. Ma, B., & Li, H. (1992). Neurobehavioral effects of hexogen. Gongye Weishengyu
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 Zhiyebin /Industrial health and occupational diseases, 19(1), 20-23.
2 15. Merrill, S. L. (1968). Ingestion of an explosive material, composition C-4: A reportof two
3 cases. U.S. Army Vietnam Medical Bulletin, 8, 5-11.
4 16. Stone, W., Paletta, T., Heiman, E., Bruce, J. I., & Knepshield, J. H. (1969). Toxic effects
5 following ingestion of C-4 plastic explosive. Archives of Internal Medicine, 124(6], 726-730.
6 17. Testud, F., Glancaude, J. M., Imperatori, J., Le Meur, B., & Descotes, J. (1996). Acute poisoning
7 from occupational exposure to hexogen, a novel nitrate explosive. Medicinay Seguridad del
8 Trabajo(l7l], 119-127.
9 18. Testud, F., Glanclaude, J., Imperatori, J., Le Meur, B., & Descotes, J. (1996). [Acute hexogen
10 poisoning after occupational exposure, report of 2 cases]. Archives des Maladies
11 Professionnelles de Medecine du Travail et de Securite Sociale, 57(5), 342-346.
12 19. Testud, F., Glanclaude, J. M., & Descotes, J. (1996). Acute hexogen poisoning after
13 occupational exposure. Journal of Toxicology - Clinical Toxicology, 34(1), 109-111. doi:
14 10.3109/15563659609020244
15 20. West, R. R., & Stafford, D. A. (1997). Occupational exposures and haematological
16 abnormalities among ordnance factory workers: A case control study. Leukemia
17 Research, 21(7), 675-680.
18 21. Woody, R. C., Kearns, G. L., Brewster, M. A., Turley, C. P., Sharp, G. B., & Lake, R. S. (1986). The
19 neurotoxicity of cyclotrimethylenetrinitramine (RDX) in a child: A clinical and
20 pharmacokinetic evaluation. Clinical Toxicology, 24(4), 305-319. doi:
21 10.3109/15563658608992595
22 Animal Health Effects (26 citations)
23 1. Angerhofer, R., Davis, G., & Balezewski, L. (1986). Teratological assessment of
24 Trinitro-RDX in rats. Aberdeen Proving Ground: U.S. Army Environmental Hygiene
25 Agency.
26 2. Brown, D. (1975). The acute and chronic biochemical and behavioral effects of
27 cyclotrimethylenetrinitramine. Baltimore, MD: Maryland University Baltimore School of
28 Pharmacy.
29 3. Burdette, L., Cook, L., & Dyer, R. (1988). Convulsant properties of
30 cyclotrimethylenetrinitramine (RDX): Spontaneous, audiogenic, and amygdaloid kindled
31 seizure activity. Toxicology and Applied Pharmacology, 92(3), 436-444. doi: 10.1016/0041-
32 008x(88)90183-4
33 4. Cholakis, J., Wong, L., Van Goethem, D., Minor, J., & Short, R. (1980). Mammalian
34 toxicological evaluation of RDX (pp. 1-158). Kansas City, MO: Midwest Research
35 Institute.
36 5. Crouse, L. C. B., Michie, M. W., Major, M., Johnson, M. S., Lee, R. B., & Paulus, H. I.
37 (2006). Subchronic oral toxicity of RDX in rats. Aberdeen Proving Ground, MD: U.S.
38 Army Center for Health Promotion and Preventive Medicine.
39 6. Dilley, J. V., Tyson, C. A., & Newell, G. W. (1979). Mammalian toxicological evaluation of TNT
40 wastewaters. Volume II: Acute and subacute mammalian toxicity of TNT and the LAP
41 mixture. Menlo Park, CA: SRI International.
42 7. Furedi-Machacek, M., Levine, B., & Lish, P. (1984). Determination of the chronic mammalian
43 toxicological effects of RDX. Acute dermal toxicity test of hexehydro-l,3,5-trinitro-l,3,5-
This document is a draft for review purposes only and does not constitute Agency policy.
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1 triazine (RDX) in rabbits. Chicago, IL: IIT Research Institute.
2 8. Hart, E. (1974). Subacute toxicity of RDX and TNT in dogs. Final report. Kensington,
3 MD: Litton Bionetics, Inc.
4 9. Hart, E. (1976). Two-year chronic toxicity study in rats. Kensington, MD: Litton
5 Bionetics, Inc.
6 10. Haskell, L. (1942). Initial submission: Toxicity of RDX (cyclotrimethylenetrinitramine) with
7 cover letter dated 101592. Wilmington, DE: DuPont Chemical Company.
8 11. Jaligama, S., Kale, V. M, Wilbanks, M. S., Perkins, E.}., & Meyer, S. A. (2013). Delayed
9 myelosuppression with acute exposure to hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) and
10 environmental degradation product hexahydro-l-nitroso-3,5-dinitro-1,3,5-triazine (MNX)
11 in rats. Toxicology and Applied Pharmacology, 266(3), 443-451. doi:
12 10.1016/j.taap.2012.11.022
13 12. Levine, B., Furedi, E., Gordon, D., Burns, ]., & Lish, P. (1981). Thirteen week oral (diet)
14 toxicity study of trinitrotoluene (TNT), hexahydro-1, 3, 5-trinitro-l, 3, 5-triazine
15 (RDX) and TNT/RDX mixtures in the Fischer 344 rat. Final report. Chicago, IL: IIT
16 Research Institute.
17 13. Levine, B., Furedi, E., Sagartz, ]., Rac, V., & Lish, P. (1984). Determination of the
18 chronic mammalian toxicological effects of RDX: Twenty-four month chronic
19 toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-l,3,5-triazine (RDX) in the
20 B6C3F1 hybrid mouse. Phase VI final report. Volume 3. Chicago, IL: IIT Research
21 Institute.
22 14. Levine, B. S., Furedi, E. M., Gordon, D. E., Barkley, J. ]., & Lish, P. M. (1990). Toxic
23 interactions of the munitions compounds TNT and RDX in F344 rats. Fundamental
24 and Applied Toxicology, 15(2), 373-380. doi: 10.1016/0272-0590(90)90062-0
25 15. Levine, B. S., Furedi, E. M., Gordon, D. E., Burns, J. M., & Lish, P. M. (1981). Thirteen
26 week toxicity study of hexahydro-1,3,5-trinitro-l,3,5-triazine (RDX) in Fischer 344
27 rats. Toxicology Letters, 8(4-5), 241-245. doi: 10.1016/0378-4274(81)90108-9
28 16. Levine, B. S., Lish, P. M., Furedi, E. M., Rac, V. S., & Sagartz, J. M. (1983). Determination
29 of the chronic mammalian toxicological effects of RDX (twenty-four month chronic
30 toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-l,3,5-triazine [RDX] in the
31 Fischer 344 rat Phase V: Final report. Chicago, IL: IIT Research Institute.
32 17. Lish, P. M., Levine, B. S., Furedi-Machacek, E. M., Sagartz, E. M., & Rac, V. S. (1984).
33 Determination of the chronic mammalian toxicological effects of RDX: twenty-four
34 month chronic toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-l,3,5-
35 triazine (RDX) in the B6C3F1 hybrid mouse (pp. 367). Fort Detrick, Frederick, MD: US
36 Army Research and Development Command.
37 18. MacPhail, R., Walker, Q., & Cook, L. (1985). Neurotoxicology of
38 cyclotrimethylenetrinitramine (RDX). Final report. Research Triangle Park, NC: U.S.
39 Environmental Protection Agency, Health Effects Research Laboratory,
40 Neurotoxicology Division.
41 19. Martin, D., & Hart, E. (1974). Subacute toxicity of RDX and TNT in monkeys (pp. 1-
42 216). Kensington, MD: Litton Bionetics, Inc.
43 20. McNamara, B. P., Averill, H. P., Owens, E. J., Callahan, J. F., Fairchild, D. G., Cinchta, H. P.,
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1 Biskup, D. K. (1974). The toxicology of cyclotrimethylenetrinitramine (RDX) and
2 cyclotetramethylenetetranitramine (HMX) solutions in dimethylsulfoxide (DMSO),
3 cyclohexanone, and acetone. Aberdeen Proving Ground, MD: Edgewood Arsenal.
4 21. Parker, G. (2001). Attachment 1: Pathology Working Group- Chairperson's report:
5 Reevaluation: Twenty-four month chronic toxicity/carcinogenicity study of
6 hexahydro-l,3,5-trinitro-l,3.5-triazine (RDX) in the B6C3F1 hybrid mouse. Research
7 Triangle Park, NC: National Institute of Environmental Health Sciences.
8 22. Parker, G. A., Reddy, G., & Major, M. A. (2006). Reevaluation of a twenty-four-month
9 chronic toxicity/carcinogenicity study of hexahydro-l,3,5-trinitro-l,3,5-triazine
10 (RDX) in the B6C3F1 hybrid mouse. International Journal of Toxicology, 25(5), 373-
11 378. doi: 10.1080/10915810600846245
12 23. Stork, C., Kos, S., Langden, B., & Cantor, R. (2000). Acute canine C-4 explosive ingestion
13 resulting in prolonged status epilepticus.
14 24. Thompson, C. A. (1983). Twenty-four month chronic toxicity/carcinogenicity study of
15 hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) in the Fischer 344 rat. Twenty-four
16 month interim report. Necropsy observations. Chicago, IL: IIT Research Institute.
17 25. Von Oettingen, W., Donahue, D., Yagoda, H., Monaco, A., & Harris, M. (1949). Toxicity
18 and potential dangers of cyclotrimethylenetrinitramine (RDX). Journal of Industrial
19 Hygiene and Toxicology, 31 (1), 21-31.
20 26. Williams, L, & Bannon, D. (2009). Mechanism of RDX-induced seizures in rats. Aberdeen
21 Proving Ground, MD: U.S. Army Center for Health Promotion and Preventive Medicine,
22 Directorate of Toxicology, Health Effects Research Program.
23 1.2.2. Not Primary Source of Health Effects Data, but Kept as Additional Resources
24 Regulatory Documents (8 citations)
25 1. . Guidance for characterizing explosives contaminated soils: Sampling and selecting on-site
26 analytical methods. (1996). Idaho Falls; Department of Energy, Washington, DC.: Technical
27 Information Center Oak Ridge Tennessee.
28 2. ACGIH. (2001). Documentation of the Threshold Limit Values and Biological Exposure Indices
29 - Cyclonite (2nd ed.). Cincinnati, OH.
30 3. Anonymous. (1997). Protect Your Family. Reduce Contamination at Home (Vol. U, pp. 97-
31 125): Anonymous.
32 4. ATSDR. (1995). Toxicological Profile for RDX. Atlanta, GA: U.S. Department of Health and
33 Human Services, Public Health Service.
34 5. ATSDR. (2012). Toxicological Profile for RDX (Update) (Vol. GRA and I). Research Triangle
35 Park, NC.; Agency for Toxic Substances and Disease Registry, Atlanta, GA: U.S. Department of
36 Health and Human Services, Public Health Service.
37 6. McLellan, W. L., Hartley, W. R, & Brower, M. E. (1988). Health advisory for hexahydro-1,3,5-
38 trinitro-1,3,5-triazine (RDX). Washington, DC: U.S. Environmental Protection Agency; Office
39 of Drinking Water; Criteria and Standards Division.
40 7. NIOSH. (1995). Occupational safety and health guidelines for chemical hazards. Supplement
41 IV-OHG. Cincinnati, Ohio: U.S. Department of Health and Human Services.
42 8. Wollin, K. M., & Dieter, H. H. (2005). [New drinking water reference values for monocyclic
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1 nitro compounds]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 48(11),
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8 3. Elamin, B. K., Callegari, E., Gramantieri, L, Sabbioni, S., & Negrini, M. (2011). MicroRNA
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10 doi: 10.1016/j.mrfmmm.2011.03.015
11 4. Hoek, B. (2004). Military explosives and health: Organic energetic compound syndrome?
12 [Review]. Medicine, Conflict and Survival, 20(4), 326-333. doi:
13 10.1080/1362369042000285955
14 5. Inouye, L., Lachance, B., & Gong, P. (2009). Genotoxicity of explosives, pp. 177-209.
15 6. Juhasz, A. L., & Naidu, R. (2007). Explosives: fate, dynamics, and ecological impact in
16 terrestrial and marine environments. [Review]. Reviews of Environmental Contamination
17 and Toxicology, 191,163-215.
18 7. Lima, D. R, Bezerra, M. L., Neves, E. B., & Moreira, F. R. (2011). Impact of ammunition and
19 military explosives on human health and the environment [Review]. Reviews on
20 Environmental Health, 26(2), 101-110.
21 8. McLellan, W. L., Harley, W. R, & Brower, M. E. (Eds.). (1992). Hexahydro-l,3,5-trinitro-1,3,5-
22 triazine (RDX). Boca Raton, FL: Lewis Publishers.
23 9. Meyer, R, Homburg, A, & Kohler, J. (2002). Explosives - Cyclonite. Weinheim: Wiley-VCH.
24 10. Murnyak, G., Vandenberg, J., Yaroschak, P. J., Williams, L., Prabhakaran, K., & Hinz, J. (2011).
25 Emerging contaminants: Presentations at the 2009 Toxicology and Risk Assessment
26 Conference. [Review]. Toxicology and Applied Pharmacology, 254(2), 167-169. doi:
27 10.1016/j.taap.2010.10.021
28 11. Nikolic, S., Medic-Saric, M., Rendic, S., & Trinajstic, N. (1994). Toxic effects and a structure-
29 property study of organic explosives, propellants, and related compounds. [Review]. Drug
30 Metabolism Reviews, 26(4), 717-738. doi: 10.3109/03602539408998324
31 12. Schneider, N. R. (1979). Bibliography on toxicology of cyclotrimethylenetrinitramine (RDX).
32 Veterinary and Human Toxicology, 21 (6), 449-450.
33 13. Sullivan, J. B., Jr. (Ed.). (1992). Cryogenics, oxidizers, reducing agents, and explosives (Vol.
34 Clinical Principles of Environmental Health): Williams & Wilkins.
35 Ecosystem Effects (38 citations]
36 1. . Evaluation of the metabolic fate of munitions material (TNT & RDX) in plant systems and
37 initial assessment of material interaction with plant genetic material. Validation of the
38 metabolic fate of munitions materials (TNT, RDX) in mature crops. (1995). Richland, WA;
39 Department of Energy, Washington, DC: Technical Information Center Oak Ridge Tennessee.
40 2. . Evaluation of the metabolic fate of munitions material (TNT & RDX) in plant systems.
41 Initial assessment of plant DNA mutation spectra as a biomarker. (1995). Richland, WA;
42 Department of Energy, Washington, DC: Technical Information Center Oak Ridge Tennessee.
This document is a draft for review purposes only and does not constitute Agency policy.
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1 3. . Evaluation of the Toxicological Effects of Explosives on Higher Plants, and the Effects on
2 Soil After Demining with Reconstructed Military Tanks. (1997). Kjeller: Foreign
3 Technology-Studsvik Energiteknik AB.
4 4. . Ecological Soil Characterization of the Delta Creek and Washington Impact Areas, Fort
5 Greely, Alaska. (2001). Fort Collins. Center for Environmental Management of Military
6 Lands
7 5. . SERDP CU-1129 Biological Assessment for Characterizing Contamination Risk at the
8 Genetic-, Individual-, and Population-Level. (2004). Vicksburg, MS. Engineer Research and
9 Development Center
10 6. . Toxicity of Nitro-Heterocyclic and Nitroaromatic Energetic Materials to Terrestrial Plants
11 in a Natural Sandy Loam Soil. (2005). Aberdeen Proving Ground, MD.
12 7. Anderson, J. A., Canas, J. E., Long, M. K., Zak, J. C., & Cox, S. B. (2010). Bacterial community
13 dynamics in high and low bioavailability soils following laboratory exposure to a range of
14 hexahydro-l,3,5-trinitro-l,3,5-triazine concentrations. Environmental Toxicology and
15 Chemistry, 29(1), 38-44. doi: 10.1002/etc.9
16 8. Army, U. S. (1993). Toxicity of Nitroguanidine, Nitroglycerin, Hexahydro-l,3,5-Trinitro-
17 1,3,5-Triazine (RDX), and 2,4,6-Trinitrotoluene (TNT) to Selected Freshwater Aquatic
18 Organisms: U.S. Army.
19 9. Army, U. S. (1995). Evaluation of Metabolic Fate of Munitions Material (TNT and RDX) in
20 Plant Systems and Initial Assessment of DNA Mutation Spectra as a Biomarker: U.S. Army.
21 10. Army, U. S. (1995). Evaluation of the metabolic fate of munitions material (TNT & RDX)
22 in plant systems and initial assessment of material interaction with plant genetic material
23 (DNA). Initial assessment of plant DNA adducts as biomarkers: U.S. Army.
24 11. Army, U. S. (1995). Evaluation of the Metabolic Fate of Munitions Material (TNT RDX) in
25 Plant Systems and Initial Assessment of Material Interaction with Plant Genetic Material:
26 U.S. Army.
27 12. Baker, L. M., Larsen, C. T., Sriranganathan, N., Jones, D. E., Johnson, M. S., & Gogal, R. M.
28 (2004). Effects of energetic compounds on the Northern Bobwhite quail and
29 biotransformation applications of the intestinal flora. Bulletin of Environmental
30 Contamination and Toxicology, 72(1), 1-6. doi: 10.1007/s00128-003-0233-8
31 13. Brentner, L. B., Mukherji, S. T., Walsh, S. A., & Schnoor, J. L. (2010). Localization of
32 hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) and 2,4,6-trinitrotoluene (TNT) in poplar and
33 switchgrass plants using phosphor imager autoradiography. Environmental Pollution,
34 158(2), 470-475. doi: 10.1016/j.envpol.2009.08.022
35 14. Drzyzga, 0., Gorontzy, T., Schmidt, A., & Blotevogel, K. H. (1995). Toxicity of explosives and
36 related compounds to the luminescent bacterium Vibrio fischeri NRRL-B-11177. Archives of
37 Environmental Contamination and Toxicology, 28(2). doi: 10.1007/bf00217621
38 15. Ekman, D. R, Wolfe, N. L., & Dean, J. F. (2005). Gene expression changes in Arabidopsis
39 thaliana seedling roots exposed to the munition hexahydro-l,3,5-trinitro-l,3,5-triazine.
40 Environmental Science and Technology, 39(16), 6313-6320.
41 16. Fellows, R. J., Driver, C. R., Cataldo, D. A., & Harvey, S. D. (2006). Bioavailability of
42 hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) to the prairie vole (Microtus ochrogaster).
43 Environmental Toxicology and Chemistry, 25(7), 1881-1886. doi: 10.1897/05-446rl.l
This document is a draft for review purposes only and does not constitute Agency policy.
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1 17. Garcia-Reyero, N., Escalon, B. L, Loh, P. R, Laird, J. G., Kennedy, A. J., Berger, B., & Perkins, E.
2 J. (2012). Assessment of chemical mixtures and groundwater effects on Daphnia magna
3 transcriptomics. Environmental Science and Technology, 46(1), 42-50. doi:
4 10.1021/es201245b
5 18. Gogal, 0. M., Jr., Johnson, M. S., Larsen, C. T., Prater, M. R, Duncan, R. B., Ward, D. L., Holladay,
6 S. D. (2003). Dietary oral exposure to l,3,5-trinitro-l,3,5-triazine in the northern bobwhite
7 (Colinus virginianus). Environmental Toxicology and Chemistry, 22(2), 381-387. doi:
8 10.1002/etc.5620220220
9 19. Gong, P., Hawari, J., Thiboutot, S., Ampleman, G., & Sunahara, G. I. (2001). Ecotoxicological
10 effects of hexahydro-l,3,5-trinitro-l,3,5-triazine on soil microbial activities. Environmental
11 Toxicology and Chemistry, 20(5), 947-951.
12 20. Gust, K. A, Pirooznia, M., Quinn, M. J., Johnson, M. S., Escalon, L., Indest, K. J., Perkins, E. J.
13 (2009). Neurotoxicogenomic Investigations to Assess Mechanisms of Action of the
14 Munitions Constituents RDX and 2,6-DNT in Northern Bobwhite (Colinus virginianus).
15 Toxicological Sciences, 110(1], 168-180. doi: 10.1093/toxsci/kfp091
16 21. Jantschi, L., & Bolboaca, S. D. (2008). A structural modelling study on marine sediments
17 toxicity. Marine Drugs, 6(2), 372-388. doi: 10.3390/md20080017
18 22. Johnson, M. S., Quinn, M. J., Bazar, M. A., Gust, K. A, Escalon, B. L., & Perkins, E. J. (2007).
19 Subacute toxicity of oral 2,6-dinitrotoluene and l,3,5-trinitro-l,3,5-triazine (RDX) exposure
20 to the northern bobwhite (Colinus virginianus). Environmental Toxicology and Chemistry,
21 26(7), 1481-1487. doi: 10.1897/06-525.1
22 23. Johnson, M. S., & Salice, C. J. Toxicity of energetic compounds to wildlife species.
23 24. Juck, D., Driscoll, B. T., Charles, T. C., & Greer, C. W. (2003). Effect of experimental
24 contamination with the explosive hexahydro-l,3,5-trinitro-l,3,5-triazine on soil bacterial
25 communities. FEMS Microbiology Ecology, 43(2), 255-262. doi: 10.1111/J.1574-
26 6941.2003.tb01065.x
27 25. Larson, S. L., Jones, R. P., Escalon, L., & Parker, D. (1999). Classification of explosives
28 transformation products in plant tissue. Environmental Toxicology and Chemistry, 18(6],
29 1270-1276. doi: 10.1002/etc.5620180629
30 26. McFarland, C. A, Quinn, M. J., Jr., Bazar, M. A., Talent, L. G., & Johnson, M. S. (2009). Toxic
31 effects of oral hexahydro-l,3,5-trinitro-l,3,5-triazine in the western fence lizard
32 (Sceloporus occidentalis). Environmental Toxicology and Chemistry, 28(5), 1043-1050. doi:
33 10.1897/08-419.1
34 27. Quinn, M. J., Bazar, M. A, McFarland, C. A, Perkins, E. J., Gust, K. A, & Johnson, M. S. (2009).
35 Sublethal effects of subacute exposure to RDX (l,3,5-trinitro-l,3,5-triazine) in the northern
36 bobwhite (Colinus virginianus). Environmental Toxicology and Chemistry, 28(6), 1266-1270.
37 doi: 10.1897/08-418.1
38 28. Quinn, M. J., Hanna, T. L., Shiflett, A. A., McFarland, C. A, Cook, M. E., Johnson, M. S., Perkins,
39 E. J. (2013). Interspecific effects of 4A-DNT (4-amino-2,6-dinitrotoluene) and RDX (1,3,5-
40 trinitro-1,3,5-triazine) in Japanese quail, Northern bobwhite, and Zebra finch. Ecotoxicology,
41 22(2), 231-239. doi: 10.1007/sl0646-012-1019-8
42 29. Smith, J. N., Espino, M. A., Liu, J., Romero, N. A., Cox, S. B., & Cobb, G. P. (2009).
43 Multigenerational effects in deer mice (Peromyscus maniculatus) exposed to hexahydro-
This document is a draft for review purposes only and does not constitute Agency policy.
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1 l,3,5-trinitroso-l,3,5-triazine (TNX). Chemosphere, 75(7], 910-914. doi:
2 10.1016/j.chemosphere.2009.01.010
3 30. Smith, J. N., Liu,}., Espino, M. A, & Cobb, G. P. (2007). Age dependent acute oral toxicity of
4 hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) and two anaerobic N-nitroso metabolites in
5 deer mice (Peromyscus maniculatus). Chemosphere, 67(11), 2267-2273. doi:
6 10.1016/j.chemosphere.2006.12.005
7 31. Smith, J. N., Pan, X., Gentles, A, Smith, E. E., Cox, S. B., & Cobb, G. P. (2006). Reproductive
8 effects of hexahydro-l,3,5-trinitroso-l,3,5-triazine in deer mice (Peromyscus maniculatus)
9 during a controlled exposure study. Environmental Toxicology and Chemistry, 25(2), 446-
10 451. doi: 10.1897/05-277r.l
11 32. Sunahara, G. I., Dodard, S., Sarrazin, M., Paquet, L, Ampleman, G., Thiboutot, S., Renoux, A. Y.
12 (1998). Development of a soil extraction procedure for ecotoxicity characterization of
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14 10.1006/eesa.l997.1624
15 33. Sunahara, G. I., Dodard, S., Sarrazin, M., Paquet, L., Hawari, J., Greer, C. W., Renoux, A. Y.
16 (1999). Ecotoxicological characterization of energetic substances using a soil extraction
17 procedure. Ecotoxicology and Environmental Safety, 43(2], 138-148. doi:
18 10.1006/eesa.l999.1763
19 34. Sunahara, G. I., Lachance, B., Hawari, J., Greer, C. W., Guiot, S., Thiboutot, S., Renoux, A.
20 (1997). Ecotoxicity Tests to Assess Bioremediation of Soils Containing Energetic Substances
21 (Vol. Niagara Falls, pp. 20-22): Sunahara, GI; Lachance, B; Hawari, J; Greer, CW; Guiot, S;
22 Thiboutot, S; Ampleman, G; Renoux, A.
23 35. Tanaka, S., Brentner, L. B., Merchie, K. M., Schnoor, J. L., Yoon, J. M., & Van Aken, B. (2007).
24 Analysis of gene expression in poplar trees (Populus deltoides x nigra, DN34) exposed to
25 the toxic explosive hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). International Journal of
26 Phytoremediation, 9(1), 15-30. doi: 10.1080/15226510601139375
27 36. Warner, C. M., Gust, K. A, Stanley, J. K., Habib, T., Wilbanks, M. S., Garcia-Reyero, N., &
28 Perkins, E. J. (2012). A systems toxicology approach to elucidate the mechanisms involved
29 in RDX species-specific sensitivity. Environmental Science and Technology, 46(14), 7790-
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31 37. Williams, L. R, Wong, K., Stewart, A, Suciu, C., Gaikwad, S., Wu, N., Kalueff, A. V. (2012).
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35 38. Winfield, L. E., Rodgers, J. H., & D'Surney, S. J. (2004). The responses of selected terrestrial
36 plants to short (<12 days) and long term (2, 4 and 6 weeks) hexahydro-1,3,5-trinitro-
37 1,3,5-triazine (RDX) exposure. Part I: Growth and developmental effects. Ecotoxicology,
38 13(4], 335-347.
39 Editorials (2 citations)
40 1. Bannon, D. I., Johnson, M., Williams, L., Adams, V., Perkins, E., Gust, K., & Gong, P. (2009).
41 RDX and miRNA expression in B6C3F1 Mice. [Letter]. Environmental Health Perspectives,
42 117(3], A98. doi: 10.1289/ehp.0800276
43 2. Zhang, B., & Pan, X. (2009). RDX and miRNA expression: Zhang and Pan respond.
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1 Environmental Health Perspectives, 117(3], A98-A99. doi: 10.1289/ehp.0800276R
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15 health advisory for hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). [Review]. Regulatory
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18 Threshold Limit Value for Cyclonite. Applied Occupational and Environmental Hygiene, 9(7),
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26 9. Ryu, H., Han, J. K., Jung, J. W., Bae, B., & Nam, K. (2007). Human health risk assessment of
27 explosives and heavy metals at a military gunnery range. Environmental Geochemistry and
28 Health, 29(4), 259-269. doi: 10.1007/sl0653-007-9101-5
29 10. Sweeney, L. M., Gut, C. P., Gargas, M. L., Reddy, G., Williams, L. R, & Johnson, M. S. (2012).
30 Assessing the non-cancer risk for RDX (hexahydro-l,3,5-trinitro-l,3,5-triazine) using
31 physiologically based pharmacokinetic (PBPK) modeling. [Review]. Regulatory Toxicology
32 and Pharmacology, 62(1), 107-114. doi: 10.1016/j.yrtph.2011.12.007
33 11. Sweeney, L. M., Okolica, M. R, Gut, C. P., Jr., & Gargas, M. L. (2012). Cancer mode of action,
34 weight of evidence, and proposed cancer reference value for hexahydro-l,3,5-trinitro-l,3,5-
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36 10.1016/j.yrtph.2012.07.005
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42 2. . Superfund Record of Decision (EPA Region 4): Milan Army Ammunition Plant, TN. (First
This document is a draft for review purposes only and does not constitute Agency policy.
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2 3. . Environmental behavior and chemical fate of energetic compounds (TNT, RDX, tetryl) in
3 soil and plant systems. (1993). Richland, WA; Department of Energy, Washington, DC:
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11 6. . Environmental Behavior and Fate of Explosives in Groundwater from the Milan Army
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24 Result From Detonation of Army Munitions. (2000). Hanover, NH. Cold Regions Research
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26 12. . Adsorption and Transformation of RDX in Low-Carbon Aquifer Soils. (2001). Washington,
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28 13. . Characterization of Explosives Contamination at Military Firing Ranges. (2001). Hanover,
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30 14. . Sampling for Explosives Residues at Fort Greely, Alaska. Reconnaissance Visit July 2000.
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33 MS. Environmental Lab.
34 16. . Range Characterization Studies at Donnelly Training Area, Alaska: 2001 and 2002. (2004).
35 Hanover, NH. Cold Regions Research and Engineering Lab.
36 17. . Sampling Strategies Near a Low-Order Detonation and a Target at an Artillery Impact Area.
37 (2004). Hanover, NH. Cold Regions Research and Engineering Lab.
38 18. . Elution of Energetic Compounds from Propellant and Composition B Residues. (2005).
39 Hanover, NH. Cold Regions Research and Engineering Lab.
40 19. . Energetic Residues From Live-Fire Detonations of 120-mm Mortar Rounds. (2005).
41 Hanover, NH. Cold Regions Research and Engineering Lab.
42 20. . Identity and Distribution of Residues of Energetic Compounds at Military Live-Fire
43 Training Ranges. (2005). Vicksburg, MS. Engineer Research and Development Center.
This document is a draft for review purposes only and does not constitute Agency policy.
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1 21. . Residues from Live Fire Detonations of 155-mm Howitzer Rounds. (2005). Hanover, NH.
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3 22. . Molecular Structure Determines Chemical Reactivities and, Thus, Transformation
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7 24. . Fate of Nitroaromatic (TNT) and Nitramine (RDX and HMX) Explosives in Fractured and
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20 30. Army, U. S. (1994). Sorption-Desorption and Transport of TNT and RDX in Soils: U.S. Army.
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39 39. Best, E. P., Sprecher, S. L, Larson, S. L, Fredrickson, H. L, & Bader, D. F. (1999).
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43 40. Best, E. P., Sprecher, S. L., Larson, S. L., Fredrickson, H. L., & Bader, D. F. (1999).
This document is a draft for review purposes only and does not constitute Agency policy.
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1 Environmental behavior of explosives in groundwater from the Milan Army Ammunition
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23 47. Cullum, H. E., McGavigan, C., Uttley, C. Z., Stroud, M. A., & Warren, D. C. (2004). A second
24 survey of high explosives traces in public places. Journal of Forensic Sciences, 49(4), 684-
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26 48. Dontsova, K. M., Yost, S. L., Simunek, J., Pennington, J. C., & Williford, C. W. (2006).
27 Dissolution and transport of TNT, RDX, and composition B in saturated soil columns. Journal
28 of Environmental Quality, 35(6), 2043-2054. doi: 10.2134/jeq2006.0007
29 49. Douglas, T. A., Walsh, M. E., Weiss, J. C., McGrath, C. J., & Trainor, T. P. (2012). Desorption and
30 Transformation of Nitroaromatic (TNT) and Nitramine (RDX and HMX) Explosive Residues
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32 10.1007/S11270-011-1015-2
33 50. Efer, J., Wennrich, L., Lewin, U., Blasberg, L., & Engewald, W. (1996). The Influence of the
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36 L; Engewald, W.
37 51. Fuller, M. E., Schaefer, C. E., Andaya, C., Lazouskaya, V., Fallis, S., Wang, C., & Jin, Y. (2012).
38 Dissolution kinetics of sub-millimeter Composition B detonation residues: role of particle
39 size and particle wetting. Chemosphere, 88(5), 591-597. doi:
40 10.1016/j.chemosphere.2012.03.038
41 52. Harvey, S. D., Fellows, R. J., Cataldo, D. A, & Bean, R. M. (1991). Fate of the explosive
42 hexahydro-l,3,5-trinitro-l,3,5-triazine (rdx) in soil and bioaccumulation in bush bean
43 hydroponic plants. Environmental Toxicology and Chemistry, 10(7], 845-855. doi:
This document is a draft for review purposes only and does not constitute Agency policy.
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1 10.1002/etc.5620100701
2 53. Hess-Ruth, A, Grouse, L, & Roszell, L. (2007). RDX pilot development neurotoxicity test in
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5 54. Hildenbrand, M., & Luckner, L. (1995). Laborative Untersuchungen zur Beschreibung des
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14 cyclotrimethylene trinitramine) (Vol. BEIJING, pp. 90-93): Hou, Y.
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19 microbiological processes contributing to the transformation of hexahydro-l,3,5-trinitro-
20 1,3,5-triazine (RDX) in contaminated aquifer material. Chemosphere, 84(9), 1223-1230. doi:
21 10.1016/j.chemosphere.2011.05.027
22 60. Larson, S. L. (1997). Fate of explosive contaminants in plants. Annals of the New York
23 Academy of Sciences, 829,195-201.
24 61. Lever, J. H., Taylor, S., Perovich, L., Bjella, K., & Packer, B. (2005). Dissolution of composition
25 B detonation residuals. Environmental Science and Technology, 39(22], 8803-8811.
26 62. Lynch, J. C., Brannon, J. M., & Delfino, J. J. (2002). Dissolution rates of three high explosive
27 compounds: TNT, RDX, and HMX. Chemosphere, 47(7], 725-734.
28 63. McDiarmid, M. A, & Weaver, V. (1993). Fouling one's own nest revisited. [Review]. American
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30 64. McKone, T. E., & Maddalena, R. L. (2007). Plant uptake of organic pollutants from soil:
31 bioconcentration estimates based on models and experiments. [Review]. Environmental
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33 65. Montgomery, M. T., Coffin, R. B., Boyd, T. J., & Osburn, C. L. (2013). Incorporation and
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37 66. Navy, U. S. (1996). Solid-State Photodecomposition of Energetic Nitramines (RDX and HMX):
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39 67. Oh, S. Y, & Chiu, P. C. (2009). Graphite- and soot-mediated reduction of 2,4-dinitrotoluene
40 and hexahydro-l,3,5-trinitro-l,3,5-triazine. Environmental Science and Technology, 43(18),
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42 68. Oxley, J. C., Smith, J. L., Resende, E., Pearce, E., & Chamberlain, T. (2003). Trends in explosive
43 contamination. Journal of Forensic Sciences, 48(2], 334-342.
This document is a draft for review purposes only and does not constitute Agency policy.
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1 69. Ozhan, G., Topuz, S., & Alpertunga, B. (2003). Determination of cyclonite (RDX) in human
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4 70. Preiss, A, Levsen, K., Humpfer, E., & Spraul, M. (1996). Application of high-field proton
5 nuclear magnetic resonance ((l)H-NMR) spectroscopy for the analysis of explosives and
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9 71. Raymondi, R. (1992). Explosive Washout Lagoons Soils Operable Unit Supplemental
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11 Technology Development Program, Umatilla Depot Activity, Hermiston. Oregon. Phase 2
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13 72. Rocheleau, S., Lachance, B., Kuperman, R. G., Hawari,}., Thiboutot, S., Ampleman, G., &
14 Sunahara, G. I. (2008). Toxicity and uptake of cyclic nitramine explosives in ryegrass Lolium
15 perenne. Environmental Pollution, ^56(1), 199-206. doi: 10.1016/j.envpol.2007.12.012
16 73. Schneider, U., & Koenig, W. (1988). Contaminations by Chemical Armament Factories Risk
17 Potential of Soil and Groundwater Contaminations by Closed Down Chemical Armament
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19 74. Selim, H. M., Xue, S. K., & Iskandar, I. K. (1995). Transport of 2,4,6-Trinitrotoluene and
20 Hexahydro-l,3,5-Trinitro-l,3,5-Triazine in Soils. Soil Science, 160(5], 328-339. doi:
21 10.1097/00010694-199511000-00002
22 75. Serna, C. J., Bartz, P. R, Donahoe, S. B., & Arbogast, M. (1990). Remedial Investigation Report
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24 Donahoe, SB; Arbogast, M.
25 76. Simini, M., & Checkai, R. T. (1995). Yield and Biomass of Crop Plants Irrigated with TNT and
26 RDX Contaminated Water (Vol. Pittsburgh, pp. 12-16): Simini, M; Checkai, RT.
27 77. Simini, M., & Checkai, R. T. (1996). Uptake of RDX and TNT in Crop Plants Irrigated with
28 Contaminated Water (Vol. North Central Division, pp. 27-31): Simini, M; Checkai, RT.
29 78. Singh, J., Comfort, S. D., Hundal, L. S., & Shea, P. J. (1998). Long-term RDX sorption and fate in
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31 79. Spanggord, R. J., Gibson, B. W., Keck, R. G., & Newell, G. W. (1978). Mammalian toxicological
32 evaluation of TNT wastewaters. Vol. I, Chemistry studies. Fort Detrick, Frederick, MD: U.S.
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34 80. Taylor, S., Lever, J. H., Fadden, J., Perron, N., & Packer, B. (2009). Simulated rainfall-driven
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37 81. Thompson, P. L., Ramer, L. A, & Schnoor, J. L. (1999). Hexahydro-l,3,5-trinitro-l,3,5-triazine
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40 82. U.S, EPA (1991). Superfund Record of Decision (EPA Region 10): Bangor Naval Submarine
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42 Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and
43 Remedial Response.
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1 83. U.S, EPA (1991). Superfund Record of Decision (EPA Region 10): Bangor Ordnance Disposal
2 (USN Submarine Base), Bangor, WA. (First Remedial Action), December 1991. Washington,
3 DC. Office of Emergency and Remedial Response: Office of Emergency and Remedial
4 Response.
5 84. U.S, EPA (1992). Superfund record of decision (EPA region 5): Savanna Army Depot,
6 Savanna, IL. (First remedial action), March 1992. Washington, DC.
7 85. U.S, EPA (1992). Superfund Record of Decision (EPA Region 10): Umatilla Army Depot
8 (Lagoons), Soils Operable Unit 2, Hermiston, OR. (First Remedial Action), September 1992.
9 Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and
10 Remedial Response.
11 86. U.S, EPA (1995). Superfund Record of Decision (EPA Region 7): Cornhusker Army
12 Ammunition Plant, Operable Unit 1, Hall County, Grand Island, NE., September 29,1994.
13 Washington, DC. Office of Emergency and Remedial Response: Office of Emergency and
14 Remedial Response.
15 87. U.S, EPA (1998). Superfund Record of Decision (EPARegion 6): Louisiana Army
16 Ammunition Plant, Soil Source Operable Unit, Doyline, LA, March 4,1997. Washington, DC.
17 Office of Emergency and Remedial Response: Office of Emergency and Remedial Response.
18 88. U.S, EPA (1999). Superfund Record of Decision (EPA Region 3): Naval Weapons Station-
19 Yorktown, Operable Units 6 and 7, Yorktown, VA, March 23,1998. Washington, DC. Office of
20 Emergency and Remedial Response: Office of Emergency and Remedial Response.
21 89. USGS. (2003). Diffusion and Drive-Point Sampling to Detect Ordnance-Related Compounds
22 in Shallow Ground Water Beneath Snake Pond, Cape Cod, Massachusetts, 2001-02.
23 Northborough, MA. Water Resources Div: US Geological Survey.
24 90. Walsh, M. E., Taylor, S., Hewitt, A. D., Walsh, M. R, Ramsey, C. A., & Collins, C. M. (2010). Field
25 observations of the persistence of Comp B explosives residues in a salt marsh impact area.
26 Chemosphere, 78(4), 467-473. doi: 10.1016/j.chemosphere.2009.10.021
27 91. Wang, C., Fuller, M. E., Schaefer, C., Caplan, J. L, & Jin, Y. (2012). Dissolution of explosive
28 compounds TNT, RDX, and HMX under continuous flow conditions. Journal of Hazardous
29 Materials, 217-218,187-193. doi: 10.1016/j.jhazmat.2012.03.012
30 92. Wang, C., Fuller, M. E., Schaefer, C. E., Fu, D., & Jin, Y. (2012). Modeling the dissolution of
31 various types of mixed energetic residues under different flow conditions. Journal of
32 Hazardous Materials, 235-236,138-143. doi: 10.1016/j.jhazmat2012.07.035
33 93. Xue, S. K., Iskandar, I. K., & Selim, H. M. (1995). Adsorption-desorption of 2, 4, 6-
34 trinitrotoluene and hexahydro-1, 3, 5-trinitro-l, 3, 5-triazine in soils. Soil Science, 160(5],
35 317-327.
36 94. Yoon, J. M., Van Aken, B., & Schnoor, J. L. (2006). Leaching of contaminated leaves following
37 uptake and phytoremediation of RDX, HMX, and TNT by poplar. International Journal of
38 Phytoremediation, 8(1), 81-94. doi: 10.1080/15226510500507128
39 95. Yue, H., Wan, H., Chai, W. 1., Wu, H. m., Kao, X. b., & Wang, Y. 1. (2011). Investigation on
40 occupational hazard factors in small and middle test workplaces of explosive industry.
41 Chinese Journal of Public Health Engineering / Zhongguo wei sheng gong cheng xue, 10(2],
42 91-93.
43 96. Zheng, W., Lichwa, J., D'Alessio, M., & Ray, C. (2009). Fate and transport of TNT, RDX, and
This document is a draft for review purposes only and does not constitute Agency policy.
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1 HMX in streambed sediments: Implications for riverbank filtration. Chemosphere, 76(9),
2 1167-1177. doi: 10.1016/j.chemosphere.2009.06.043
3 Mixtures Only (3 citations)
4 1. Berthe-Corti, L, Jacobi, H., Kleihauer, S., & Witte, I. (1998). Cytotoxicity and mutagenicity of
5 a 2,4,6-trinitrotoluene (TNT) and hexogen contaminated soil in S. typhimurium and
6 mammalian cells. Chemosphere, 37(2], 209-218. doi: 10.1016/s0045-6535(98)00039-3
7 2. Dilley,}., Tyson, C., Spanggord, R., Sasmore, D., Newell, G., & Dacre, J. (1982). Short-term oral
8 toxicity of a 2, 4, 6-trinltrotoluene and hexahydro-1, 3, 5-trinitro-l, 3, 5-triazine mixture in
9 mice, rats, and dogs. Journal of Toxicology and Environmental Health, Part A: Current Issues,
10 9(4), 587-610. doi: 10.1080/15287398209530189
11 3. Twerdok, L. E., Burton, D. T., Gardner, H. S., Shedd, T. R, & Wolfe, M. J. (1997). The use of
12 nontraditional assays in an integrated environmental assessment of contaminated ground
13 water. Environmental Toxicology and Chemistry, 16(9], 1816-1820. doi:
14 10.1002/etc.5620160908
15 Toxicokinetics (16 citations)
16 1. Bell, S. C., Gayton-Ely, M., & Nida, C. M. (2009). Bioassays for bomb-makers: Proof of concept.
17 Analytical and Bioanalytical Chemistry, 395(2], 401-409. doi: 10.1007/s00216-009-2851-4
18 2. Bhushan, B., Trott, S., Spain, J. C., Halasz, A, Paquet, L., & Hawari, J. (2003).
19 Biotransformation of hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) by a rabbit liver
20 cytochrome P450: Insight into the mechanism of RDX biodegradation by Rhodococcus sp.
21 strain DN22. Applied and Environmental Microbiology, 69(3), 1347-1351. doi:
22 10.1128/aem.69.3.1347-1351.2003
23 3. Grouse, L. C. B., Michie, M. W., Major, M. A, Leach, G. J., & Reddy, G. (2008). Oral
24 bioavailability of cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats.
25 International Journal ofToxicology, 2 7(4), 317-322. doi: 10.1080/10915810802366885
26 4. Guo, L., Xu, H., Chen, Y., & Chang, Y. (1985). Distribution and metabolism of tritium-labeled
27 hexogen in white mice. Zhonghua Laodong Weisheng Zhiyebing Zazhi, 3(6], 335-339.
28 5. Krishnan, K., Grouse, L. C. B., Bazar, M. A, Major, M. A, & Reddy, G. (2009). Physiologically
29 based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats. Journal of
30 Applied Toxicology, 29(7], 629-637. doi: 10.1002/jat.l455
31 6. Major, M. A, Reddy, G., Berge, M. A, Patzer, S. S., Li, A. C., & Gohdes, M. (2007). Metabolite
32 profiling of [14C]hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) in Yucatan miniature pigs.
33 Journal of Toxicology and Environmental Health, Part A: Current Issues, 70(14), 1191-1202.
34 doi: 10.1080/15287390701252717
35 7. Mintzer, E., Kizerian, A, Grant, K., Hoppe, E. W., & Campbell, J. A. (2007). Saliva as a matrix
36 for the detection of RDX, and TNT and its major metabolites as biomarkers for exposure by
37 Gas Chromatography/Mass Spectrometry. NW-007.
38 8. Musick, T. J., Berge, M. A, Patzer, S. S., & Tilch, K. R. (2010). Absorption, distribution,
39 metabolism, and excretion of 14C-RDX following oral administration to minipigs. Madison,
40 WI: Covance Laboratories Inc.
41 9. Pan, X., Ochoa, K. M., San Francisco, M. J., Cox, S., Dixon, K., Anderson, T., & Cobb, G. (2013).
42 Absorption, distribution, and biotransformation of hexahydro-l,3,5-trinitro-l,3,5-triazine
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 (RDX) in B6C3F1 mice (Mus musculus). Environmental Toxicology and Chemistry, doi:
2 10.1002/etc.2188
3 10. Pan, X., Zhang, B., Smith, J. N., San Francisco, M., Anderson, T. A, & Cobb, G. P. (2007). N-
4 Nitroso compounds produced in deer mouse (Peromyscus maniculatus) GI tracts following
5 hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) exposure. Chemosphere, 67(6), 1164-1170.
6 doi: 10.1016/j.chemosphere.2006.10.077
7 11. Reddy, G., Allen, N. A, & Major, M. A. (2008). Absorption of 14C-
8 cyclotrimethylenetrinitramine (RDX) from soils through excised human skin. Toxicology
9 Mechanisms and Methods, 18(7], 575-579. doi: 10.1080/15376510701703466
10 12. Reifenrath, W. G., Kammen, H. 0., Palmer, W. G., Major, M. M., & Leach, G. J. (2002).
11 Percutaneous absorption of explosives and related compounds: An empirical model of
12 bioavailability of organic nitro compounds from soil. Toxicology and Applied Pharmacology,
13 182(2], 160-168. doi: 10.1006/taap.2002.9436
14 13. Reifenrath, W. G., Kammen, H. 0., Reddy, G., Major, M. A., & Leach, G. J. (2008). Interaction of
15 hydration, aging, and carbon content of soil on the evaporation and skin bioavailability of
16 munition contaminants. Journal of Toxicology and Environmental Health, Part A: Current
17 Issues, 71(8], 486-494. doi: 10.1080/15287390801906956
18 14. Schneider, N., Bradley, S., & Andersen, M. (1976). Metabolism of
19 [14C]cyclotrimethylenetrinitramine (RDX) in the rat. Toxicology and Applied Pharmacology,
20 37(1), 137. doi: 10.1016/s0041-008x(76)80011-7
21 15. Schneider, N., Bradley, S., & Andersen, M. (1977). Toxicology of
22 cyclotrimethylenetrinitramine (RDX): Distribution and metabolism in the rat and the
23 miniature swine. Toxicology and Applied Pharmacology, 39(3), 531-541. doi: 10.1016/0041-
24 008x(77)90144-2
25 16. Schneider, N., Bradley, S., & Andersen, M. (1978). The distribution and metabolism of
26 cyclotrimethylenetrinitramine (RDX) in the rat after subchronic administration. Toxicology
27 and Applied Pharmacology, 46(1), 163-171. doi: 10.1016/0041-008x(78)90147-3
28 Genotoxicity (9 citations)
29 1. Arfsten, D., Davenport, R, & Schaeffer, D. (1994). Reversion of bioluminescent bacteria
30 (Mutatox TM) to their luminescent state upon exposure to organic compounds, munitions,
31 and metal salts. Biomedical and Environmental Sciences, 7(2), 144-149.
32 2. Cotruvo, J. A, Simmon, V. F., & Spanggord, R. J. (1977). Investigation of mutagenic effects of
33 products of ozonation reactions in water. Annals of the New York Academy of Sciences, 298(1
34 Aquatic Pollu), 124-140. doi: 10.1111/j.l749-6632.1977.tbl9259.x
35 3. George, S. E., Huggins-Clark, G., & Brooks, L. R. (2001). Use of a Salmonella microsuspension
36 bioassay to detect the mutagenicity of munitions compounds at low concentrations.
37 Mutation Research, 490(1), 45-56. doi: 10.1016/sl383-5718(00)00150-9
38 4. Lachance, B., Robidoux, P. Y., Hawari, J., Ampleman, G., Thiboutot, S., & Sunahara, G. I.
39 (1999). Cytotoxic and genotoxic effects of energetic compounds on bacterial and
40 mammalian cells in vitro. Mutation Research, 444(1), 25-39. doi: 10.1016/sl383-
41 5718(99)00073-x
42 5. Neuwoehner, J., Schofer, A., Erlenkaemper, B., Steinbach, K., Hund-Rinke, K., & Eisentraeger,
43 A. (2007). Toxicological characterization of 2,4,6-trinitrotoluene, its transformation
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 products, and two nitramine explosives. Environmental Toxicology and Chemistry, 26(6),
2 1090-1099. doi: 10.1897/06-471r.l
3 6. Pan, X., San Francisco, M. J., Lee, C., Ochoa, K. M., Xu, X., Liu, J., Cobb, G. P. (2007).
4 Examination of the mutagenicity of RDX and its N-nitroso metabolites using the Salmonella
5 reverse mutation assay. Mutation Research: Genetic Toxicology and Environmental
6 Mutagenesis, 629(1), 64-69. doi: 10.1016/j.mrgentox.2007.01.006
7 7. Reddy, G., Erexson, G. L, Cifone, M. A, Major, M. A, & Leach, G. J. (2005). Genotoxicity
8 assessment of hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). International Journal of
9 Toxicology, 24(6), 427-434. doi: 10.1080/10915810500366922
10 8. Tan, E., Ho, C., Griest, W., & Tyndall, R. (1992). Mutagenicity of trinitrotoluene and its
11 metabolites formed during composting. Journal of Toxicology and Environmental Health,
12 Part A: Current Issues, 36(3), 165-175. doi: 10.1080/15287399209531632
13 9. Whong, W. Z., Speciner, N. D., & Edwards, G. S. (1980). Mutagenic activity of tetryl, a
14 nitroaromatic explosive, in three microbial test systems. Toxicology Letters, 5(1), 11-17. doi:
15 10.1016/0378-4274(80)90142-3
16 Mechanistic Data (13 citations)
17 1. Bannon, D. I., Dillman, J. F., Hable, M. A, Phillips, C. S., & Perkins, E. J. (2009). Global gene
18 expression in rat brain and liver after oral exposure to the explosive hexahydro-1,3,5-
19 trinitro-1,3,5-triazine (RDX). Chemical Research in Toxicology, 22(4), 620-625. doi:
20 10.1021/tx800444k
21 2. Bannon, D. I., Dillman, J. F., Perkins, E. J., Bao, W., Wolfinger, R. D., Chu, T., & Phillips, C. S.
22 (2006). Acute RDX exposure and gene expression in the rat brain. [Abstract]. Toxicologist,
23 90(S1), 392-393.
24 3. Corcelli, A., Lobasso, S., Lopalco, P., Dibattista, M., Araneda, R., Peterlin, Z., & Firestein, S.
25 (2010). Detection of explosives by olfactory sensory neurons. Journal of Hazardous
26 Materials,^ 75(1-3), 1096-1100. doi: 10.1016/j.jhazmat.2009.10.054
27 4. Ehrich, M., Wu, X., Werre, S. R., Major, M. A, McCain, W. C., & Reddy, G. (2009). Calcium
28 signaling in neuronal cells exposed to the munitions compound
29 cyclotrimethylenetrinitramine (RDX). International Journal of Toxicology, 28(5), 425-435.
30 doi: 10.1177/1091581809340331
31 5. Ford-Green, J., Isayev, 0., Gorb, L., Perkins, E. J., & Leszczynski, J. (2012). Evaluation of
32 natural and nitramine binding energies to 3-D models of the S1S2 domains in the N-methyl-
33 D: -aspartate receptor. Journal of Molecular Modeling, 18(4-], 1273-1284. doi:
34 10.1007/s00894-011-1152-y
35 6. Forgacs, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A, & Zacharewski, T. R.
36 (2012). BLTK1 Murine Leydig Cells: A Novel Steroidogenic Model for Evaluating the Effects
37 of Reproductive and Developmental Toxicants. Toxicological Sciences, 127(2], 391-402. doi:
38 10.1093/toxsci/kfsl21
39 7. Li, A. P. (2010). Evaluation of the cytotoxic potential of RDX in primary human cell cultures
40 as integrated discrete multiple organ co-cultures (IdMOC) and as individual primary
41 cultures. Columbia, MD: In Vitro ADMET Laboratories.
42 8. Meyer, S. A. (2006). Role of myelofibrosis in hematotoxicity of munition RDX environmental
43 degradation product MNX. 2006 Update. Monroe, LA: University of Louisiana at Monroe.
This document is a draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 9. Meyer, S. A. (2007). Role of myelofibrosis in hematotoxicity of munitions RDX
2 environmental degradation product MNX. 2007 Update. Monroe, LA: University of Louisiana
3 at Monroe.
4 10. Perkins, E.}., Bao, W., Guan, X., Ang, C. Y., Wolfinger, R. D., Chu, T. M., Inouye, L. S. (2006).
5 Comparison of transcriptional responses in liver tissue and primary hepatocyte cell cultures
6 after exposure to hexahydro-1, 3, 5-trinitro-l, 3, 5-triazine. B M CBioinformatics, 7(Suppl 4),
7 S22. doi: 10.1186/1471-2105-7-s4-s22
8 11. Way, M. R, & McCain, W. C. (2007). Protective effects of the calcium channel blocker,
9 Verapamil in rats exposed to RDX. Aberdeen Proving Ground, MD: U.S. Army Center for
10 Health Promotion and Preventive Medicine.
11 12. Williams, L. R, Aroniadou-Anderjaska, V., Qashu, F., Finne, H., Pidoplichko, V., Bannon, D. I.,
12 & Braga, M. F. (2011). RDX binds to the GABA(A) receptor-convulsant site and blocks
13 GABA(A) receptor-mediated currents in the amygdala: a mechanism for RDX-induced
14 seizures. Environmental Health Perspectives, 119(3], 357-363. doi: 10.1289/ehp.l002588
15 13. Zhang, B., &Pan, X. (2009). RDX induces aberrant expression of microRNAs in mouse brain
16 and liver. Environmental Health Perspectives, 117(2), 231-240. doi: 10.1289/ehp.ll841
17 1.2.3. Kept for Possible Further Review
18 No abstract (9 citations)
19 1. Bruchim, Y., Saragusty,}., Weisman, A, & Sternheim, D. (2005). Cyclonite (RDX) intoxication
20 in a police working dog. Veterinary Record, 157(12), 354-356.
21 2. Croft, P. E. (1983). Cyclonite poisoning in a dog. [Letter]. Veterinary Record, 113(20], 477.
22 doi: 10.1136/vr.ll3.20.477-a
23 3. Jacobs, A. (1991). Haematological study at Ordnance Factory [Unpublished report]. Cardiff,
24 UK: University of Wales College of Medicine.
25 4. Kale, V. M. (2007). Mechanistic studies on hepatotoxicity of chloroacetanilide herbicides and
26 hematotoxicity of munitions compound RDX and environmental degradation product MNX.
27 (Doctoral Dissertation), University of Louisiana at Monroe, Monroe, LA. Retrieved from
28 http://proquest.umi.com/pqdlink?did=1445039451&Fmt=7&clientI
29 d=79356&RQT=309&VName=PQD
30 5. Littlewood, J. D., Watkins, S. B., & Watney, G. C. (1983). Cyclonite poisoning in a dog. [Letter].
31 Veterinary Record, 113(21], 503. doi: 10.1136/vr.ll3.21.503-a
32 6. Miller, K. C. (1973). Toxicity and Adverse Effects of RDX: an Annotated Bibliography: Miller,
33 KC.
34 7. Mindi, Q. W., Li, B., & Chen, R. (1995). The Mutagenicity of Several Chemicals by Vicia
35 Micronucleus Vicia-MCN Assay (Vol. ST, pp. 12-16): Mindi, QW; Li, B; Chen, R.
36 8. Sklyanskaya, R. M., & Pozhariskii, F. I. (1944). On the question of hexogen toxicity.
37 Farmakologiya i Toksikologiya, 7(3), 43-47.
38 9. Vogel, W. (1951). Hexogen poisoning in human beings. Zentralblattfuer Arbeitsmedizin und
39 Arbeitsschutz, 1, 51-54.
40 Foreign language (2 citations)
41 1. Dong, Y., Li, J., Xiang, S., Yang, S., Bao, Z., Fan, H., Li, Z. (1997). [Application of serum bile acid
This document is a draft for review purposes only and does not constitute Agency policy.
1-33 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 chromatography to the diagnoses of liver diseases]. Hua Xi Yi Ke Da Xue Xue Bao, 28(1), 69-
2 72.
3 2. Zhang, M. D. (1982). Food poisoning caused by hexogen: A report of 8 cases. Zhonghua
4 Yufang Yixue Zazhi, 16(4], 229-231.
5 Inadequate reporting in abstract (4 citations)
6 1. . Final report on occupational health and safety at the plants of "Les Produits Chimiques
7 Expro Inc." (1983) (Vol. Government of Quebec): Gouvernement du QuAtebec.
8 2. Berry, A, Arbuckle,}., & Nicol, J. (1983). Cyclonite poisoning in a dog. Veterinary Record,
9 113(1914-4-9.
10 3. De Cramer, K. G., & Short, R. P. (1992). Plastic explosive poisoning in dogs. Journal of the
11 South African Veterinary Medical Association, 63(1), 30-31.
12 4. Wang, Y., Yan, C., Xia, B., &Tang, H. (2001). Study on health standard of octogen in air of
13 workplaces. Gongye Weishengyu Zhiyebin / Industrial health and occupational diseases,
14 27(3), 134-136.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2. PRELIMINARY EVIDENCE TABLES AND
EXPOSURE-RESPONSE ARRAYS
2 2.1. Data Extraction: Preparation of Preliminary Evidence Tables and
3 Exposure-Response Arrays
4 The 47 references identified as primary sources of health effects data were considered for
5 data extraction to evidence tables and exposure-response arrays. References were first collated
6 with respect to exposure route, exposure duration, and type of endpoint, to identify those most
7 pertinent for evaluating the human health effects from chronic oral or inhalation exposure to RDX.
8 As a result, data from 27 studies with one or more of the following characteristics were not
9 extracted into evidence tables or exposure-response arrays:
10 • The study involved human case reports, dermal exposure or intravenous/intraperitoneal
11 exposure;
12 • The study only involved acute or short-term exposures (less than 30 days), and it was not
13 conducted in the context of immune, developmental, neurological or reproductive toxicity;
14 • The data in the study only included endpoints related to possible mechanisms of toxicity;
15 • No effects were associated with exposure to RDX for the endpoints evaluated in the study,
16 nor were RDX-related effects observed for those endpoints in any of the other available
17 references.
18 Data from the 20 remaining references were summarized in preliminary evidence tables.
19 No studies were excluded based on study quality considerations, so as to allow for public input on
20 methodological considerations that could affect the interpretation of, or confidence in, each study's
21 results. In some instances, references are grouped together as "related" references because they
22 represent pilot (e.g., range-finding), unpublished (e.g., technical reports, some with multiple
23 volumes), and/or published (e.g., journal article) versions of the same study. The tables for
24 noncarcinogenic effects appear first and are arranged in the order from the health effect with the
25 most data to the health effect with the least data. The tables for carcinogenic effects follow, along
26 with other systemic effects, which are those with little data to determine hazard. Finally, tables
27 present data on genotoxic effects of RDX and its metabolites. Within each endpoint, the studies are
28 presented beginning with chronic studies followed by those with subchronic exposures. The
29 information in the preliminary evidence tables is displayed graphically in preliminary exposure-
30 response arrays. In these arrays, a significant effect (indicated by a filled datapoint) is based on
31 statistical significance, with the exception of the arrays for mortality and neurological endpoints.
This document is a preliminary draft for review purposes only and does not constitute Agency policy.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 For these two endpoints, it was determined that the severity of the endpoints (seizures and death)
2 warranted identification based on biological significance. A study with a low number of animals per
3 dose group may preclude identifying a change from the control as statistically significant when the
4 incidence is low; however, given the severity of the effect, the observed effect was identified as
5 biologically significant
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
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.2. Neurological Effects Evidence Tables and Array
2
3
Table 2-1. Evidence pertaining to neurological effects in humans following
exposure to RDX
Reference and Study Design
Ma and Li (1992) (China)
Cross-sectional study, 60 workers exposed to
RDX (30 in Group A [26 males; 4 females]; 30 in
Group B [24 males; 6 females]), compared to
32 workers with similar age, education level,
and length of employment from same plant
with no exposure to RDX (27 males; 5 females).
Exposure measures: Details of exposure
measurement were not provided; exposed
workers were divided into two groups based on
RDX concentration in the air:
Concentration (mg/m3)
Group A 0.407 (± 0.332)
Group B 0.672 (±0.556)
Effect measures3: Five neurobehavioral
function tests and five additional memory
subtests.
Analysis: Variance (F-test); unadjusted linear
regression, multiple regression, and correlation
analysis.
Results
Neurobehavioral function tests, scaled scores (mean, standard
deviation):
Test
Memory retention*
Simple reaction time
Choice reaction time
Block design*
Letter cancellation
Group A Group B Control
96.9(9.6) 91.1(10.3) 111.3(9.3)
539 (183) 578 (280) 493 (199)
775(161) 770(193) 763(180)
16.0(4.3) 13.5(6.7) 18.0(5.4)
1449 (331) 1484 (443) 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
Directional memory*
Associative learning*
Image free recall*
Recognition of nonsense
pictures*
Associative recall of
portrait characteristics*
Group A Group B Control
17.2(4.9) 18.1(5.7) 23.5(3.6)
20.0(4.3) 18.5(4.6) 24.9(5.1)
20.9(4.1) 20.4(3.3) 24.1(3.8)
23.2(4.9) 21.6(4.3) 26.3(3.6)
20.3 (4.4) 18.5 (4.3) 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).
aSymptom data were not included in evidence table because of incomplete reporting.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2
Table 2-2. Evidence pertaining to neurological effects in animals following
oral exposure to RDX
Reference and Study Design
Results
Lishetal.(1984): Levineetal. (1984)
Mice, BSCSFi, 85/sex/group; interim
sacrifices (10/sex/group) at 6 and 12 mo
0,1.5, 7.0, 35, or 175/100 mg/kg-d (high
dose reduced to 100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
One male mouse in the 35 mg/kg-d dose group and one female
mouse in the 175/100 mg/kg-da group convulsed near the end of the
study.
Hart (1976)
Rats, Sprague-Dawley, 100/sex/group
0,1.0, 3.1, or 10 mg/kg-d
Diet
2 yrs
No neurological effects, as evidenced by clinical signs or changes in
appearance or behavior, were reported.
Levineetal. (1983): Thompson (1983)
Rats, F344, 75/sex/group; interim sacrifices
(10/sex/group) at 6 and 12 mo
0,0.3,1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Tremors, convulsions, and hyper-responsiveness to stimuli were
noted at 40 mg/kg-da; no incidence data were reported.
Cholakisetal.U980)
Mice, B6C3Fi, 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 females3; no incidence data were
reported.
Cholakisetal.U980)
Rats, F344,10/sex/group
0,10,14, 20, 28, or 40 mg/kg-d
Diet
13 wks
No neurological effects, as evidenced by clinical signs or changes in
appearance or behavior, were reported.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal.(1980)
Rats, CD, two-generation study;
FO: 22/sex/group; Fl: 26/sex/group;
F2: 10/sex/group
FO and Fl parental animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al. (1981a);
Levineetal.(1981b)
Rats, F344, 10/sex/group; 30/sex for control
0, 10, 30, 100, 300, or 600 mg/kg-d
Diet
13wks
Von Oettingen et al. (1949)
Rats, sex/strain not specified, 20/group
0,15, 25, or 50 mg/kg-d
Diet
3 mo
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus,
3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
No neurological effects were reported.
Doses 0 4 8a 10 12
15
Convulsions (incidence)
M 0/10 0/10 1/10 3/10 8/10
F 0/10 0/10 2/10 3/10 5/10
7/10
5/10
Tremors (incidence)
M 0/10 0/10 0/10 0/10 2/10
F 0/10 0/10 0/10 0/10 0/10
3/10
1/10
Hyper-reactivity to approach was observed in groups receiving
>100 mg/kg-da; no incidence data were reported.
Tremors and convulsions were observed prior to death in some
animals receiving 600 mg/kg-d; no incidence data were reported.
Hyperirritability and convulsions were observed in the 25
50 mg/kg-d groups3; no incidence data were reported.
and
No neurological effects, as evidenced by clinical signs or changes in
appearance or behavior, were reported.
Doses 0 0.1 1
10a
CWS effects characterized as trembling, shaking, jerking, or
convulsions (incidence)
M 0/3 0/3 0/3
F 0/3 0/3 0/3
2/3
2/3
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Results
Von Oettingen et al. (1949)
Dogs, breed not specified, 5 females/group
(control); 7 females/group (exposed)
0 or 50 mg/kg-d
Diet
6 d/wk for 6 wks
Treated dogs exhibited convulsions, excitability, ataxia, and
hyperactive reflexes3; no incidence data were reported.
MacPhailetal. (1985)
Rats, Sprague-Dawley derived CD, 8-
10 males or females/group
0,1, 3, or 10 mg/kg-d
Gavage
30 d
No changes in motor activity, flavor aversion, scheduled-controlled
response, or acoustic startle-response were reported.
Cholakisetal.(1980)
Rats, F344, 24-25 females/group
0,0.2, 2.0, or 20 mg/kg
Gavage
CDs 6-19
Convulsions and hyperactivity in 18/25 dams at 20 mg/kga; one
female at 2.0 mg/kg-d exhibited convulsions.
Angerhofer et al. (1986) (range-finding
study)
Rats, Sprague-Dawley, 6 pregnant
females/group
0,10, 20,40, 80, or 120 mg/kg-d
Gavage
CDs 6-15
Convulsions preceding death were observed at >40 mg/kg-da; no
incidence data were reported.
Angerhofer et al. (1986)
Rats, Sprague-Dawley, 39-51 mated
females/group
0, 2, 6, or 20 mg/kg-d
Gavage
CDs 6-15
Convulsions and hyperactivity3 were observed at 20 mg/kg-d; no
incidence data were reported.
aMortality was reported in some RDX-treated groups in this study; see mortality evidence tables for additional
details.
bDoses were calculated by the study authors.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-6 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
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Figure 2-1. Exposure-response array of neurological effects following oral exposure to 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
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.3. Mortality Evidence Table and Array
2 Table 2-3. Evidence pertaining to mortality following oral exposure to RDX
Reference and Study Design
Lish et al. (1984); Levine et al. (1984)
Mice, B6C3Fi, 85/sex/group; interim
sacrifices (10/sex/group) at 6 and 12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high
dose reduced to 100 mg/kg-d in wk 11
due to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley, 100/sex/group
0,1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Levine et al. (1983): Thompson (1983)
Rats, F344, 75/sex/group; interim
sacrifices (10/sex/group) at 6 and 12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, BSCSFi, 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)0
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or 40 mg/kg-d
Diet
13 wks
Results
Doses
0 1.5 7.0 35 175/100
Mortality (incidence)0
M
F
20/65 23/65 25/65 29/65 41/65
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.
Doses
0 1.0 3.1 10
Mortality (incidence/1
M
F
Doses
34/94 30/95 25/86 33/92
20/83 32/95 29/100 33/96
0 0.3 1.5 8.0 40
Mortality (incidence)0
M
F
Doses
17/55 19/55 30/55* 26/55 51/55*
12/55 10/55 13/55 14/55 27/55*
0 80 160 320
Mortality (incidence)
M
F
Doses
0/10 0/10 0/10 4/10*
0/11 0/12 0/10 2/12
0 10 14 20 28 40
Mortality (incidence)
M
F
0/10 0/10 0/10 0/10 0/10 0/10
1/10 0/10 0/10 0/10 0/10 0/10
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-8 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal.(1980)
Rats, CD, two-generation study; FO:
22/sex/group; Fl: 26/sex/group; F2:
10/sex/group
FO and Fl parental animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Grouse et al. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al. (1981a);
Levineetal.(1981b)
Rats, F344, 10/sex/group; 30/sex for
control
0, 10, 30, 100, 300, or 600 mg/kg-d
Diet
13wks
Von Oettingen et al. (1949)
Rats, sex/strain not specified, 20/group
0,15, 25, or 50 mg/kg-d
Diet
3 mo
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus,
3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
Doses 0
5 16 50
Mortality in FO adults (incidence)1*
M 0/22
F 0/22
M&F 0/44
Doses 0 4
0/22 0/22 2/22
0/22 0/22 6/22
0/44 0/44 8/44*
8 10 12 15
Mortality (incidence)
M 0/10 0/10
F 0/10 0/10
Doses 0 10
1/10 3/10 2/10 3/10
1/10 2/10 5/10 4/10
30 100 300 600
Mortality (incidence^
M 0/30 0/10
F 0/30 1/10
Doses 0
0/10 8/10 10/10 10/10
0/10 5/10 10/10 10/10
15 25 50
Mortality (incidence)
0/20
Doses 0
l/20f 8/20 8/20
0.1 1 10
Mortality (incidence)
M 0/3
F 0/3
Doses 0
0/3 l/3g 0/3
0/3 0/3 0/3
0.1 1 10
Mortality (incidence)
M 0/3
F 0/3
0/3 0/3 0/3
0/3 0/3 l/3h
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-9 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
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
MacPhailetal. (1985)
Rats, Sprague-Dawley derived CD, 8-
10 males or females/group
0, 1, 3, or 10 mg/kg-d
Gavage
30 d
Cholakisetal.(1980)
Rabbits, New Zealand white, 11-
12 pregnant females/group
0, 0.2, 2.0, or 20 mg/kg-d
Diet
CDs 7-29
Cholakisetal.(1980)
Rats, F344, 24-25 females/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 6-19
Aneerhofer et al. (1986) (ranee-finding
study)
Rats, Sprague-Dawley, 6 pregnant
females/group
0, 10, 20, 40, 80, or 120 mg/kg-d
Gavage
CDs 6-15
Angerhoferetal. (1986)
Rats, Sprague-Dawley, 39-51 mated
females/group
0, 2, 6, or 20 mg/kg-d
Gavage
CDs 6-15
Results
Doses
0 50
Mortality (incidence)
F
0/5 1/7
No mortality was reported (incidence data were not provided).
Doses
0 0.2 2.0 20
Mortality (incidence)
F
Doses
0/11 0/11 0/11 0/12
0 0.2 2.0 20
Mortality (incidence)
F
Doses
0/24 0/24 0/23 7/241
0 10 20 40 80 120
Mortality (incidence)
F
Doses
0/6 0/6 0/6 6/6 6/6 6/6
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.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-10 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 Interim sacrifices (10 animals/sex/dose) were performed at 27 and 53 weeks (Levine et al., 1983) or 26 and
2 53 weeks (Lish et al., 1984); these animals were not included in the mortality incidences.
3 A malfunctioning heating system resulted in the premature deaths of 59 animals across groups; these animals
4 were omitted from mortality results.
5 cDoses were calculated by the study authors.
6 Data for male and female rats were combined for statistical analysis.
7 eAnimals receiving 300 mg/kg-day died by week 3 of the study; animals receiving 600 mg/kg-day died by week lof
8 the study.
9 fThe study authors noted that the single death at 15 mg/kg-day was probably not treatment-related and noted
10 that a large encapsulated cyst had replaced a lobe of the lung.
11 gThe study authors stated that the animal died from bacteremia derived from a lesion unrelated to RDX treatment.
12 hThe affected animal exhibited severe neurological effects following RDX administration and was euthanized.
13 'includes one rat that was accidentally killed.
This document is a preliminary draft for review purposes only and does not constitute Agency policy.
2-11 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
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Gestational (dams)
' changes identified as statisically significant based on analysis by study authors
1 during the first 11 weeks of the study, mortality was observed at a dose of 175 mg/kg-day, the dose was lowered to 100 mg/kg-day for the
remainder of the study. See the mortality evidence table.
Figure 2-2. Exposure-response array of mortality following oral exposure to RDX
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-12 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.4. Reproductive and Developmental Effects Evidence Tables and
2 Array
3 Table 2-4. Evidence pertaining to reproductive and developmental effects in
4 animals following oral exposure to RDX
Reference and Study Design
Results
Offspring survival
Cholakisetal.(1980)
Rats, CD, two-generation study;
FO: 22/sex/group; Fl: 26 sex/group;
F2: 10 sex/group
FO and Fl parental animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Cholakisetal.(1980)
Rabbits, New Zealand white, 11-
12/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 7-29
Cholakisetal.(1980)
Rats, F344, 24-25 females/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 6-19
Doses
0 5
16
50
Stillborn pups (incidence)
Fl
F2
8/207 6/296
6/288 6/290
4/259
2/250
16/92*
24/46*
Offspring survival at birth (percent of fetuses)
Fl
F2
96% 98%
98% 98%
98%
99%
83*%
48*%
FO maternal deaths occurred at 50 mg/kg-d. Only six Fl females in this
group survived to serve as parental animals; none of the six died during
subsequent treatment.
Doses
0 0.2
2
20
E arly 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):
Doses
85% 82%
0 0.2
77%
2.0
94%
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%
Significant maternal mortality (7/24 dams) occurred at 20 m
81.4%
g/kg-d.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-13 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
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
CDs 6-15
Results
Doses 026
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%
Significant maternal mortality (16/51) occurred at 20 mg
100%
/kg-d.
Offspring growth
Cholakisetal.(1980)
Rabbits, New Zealand white, 11-
12/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 7-29
Cholakisetal. (1980)
Rats, F344, 24-25 females/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 6-19
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
CDs 6-15
Doses 0 0.2 2.0
20
Fetal body weight (percent change compared to control)
0% 19% 24%
Doses 0 0.2 2.0
15%
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.
Doses 026
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%
Significant maternal mortality (16/51) occurred at 20 mg
-5%a
/kg-d.
Morphological development
Cholakisetal. (1980)
Rabbits, New Zealand white, 11-
12/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 7-29
Doses 0 0.2 2.0
20
Spina bifida (incidence)
Fetuses 0/88 0/99 0/94
Litters 0/11 0/11 0/11
3/110
2/12
Misshapen eye bulges (incidence)
Fetuses 0/88 0/99 0/94
Litters 0/11 0/11 0/11
3/110
1/12
Cleft palate (incidence)
Fetuses 0/39 1/46 2/44
Litters 0/11 1/11 1/11
2/52
1/12
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-14 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal.(1980)
Rats, F344, 24-25 females/group
0, 0.2, 2.0, or 20 mg/kg-d
Gavage
CDs 6-19
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
CDs 6-15
Results
Enlarged front fontanel (incidence)
Fetuses 0/49 5/53 2/50
Litters 0/11 2/11 2/11
8/58
2/12
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.
No treatment-related increase in the incidence of anomalies was
observed.
Doses 026
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.
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.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-15 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
100
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ro
73
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1 Statisticallv signficant dose-related trend (p •• = 0.05) by Jonckheere-Terpstra test performed for this assessment
Figure 2-3. Exposure-response array of reproductive and developmental effects following oral exposure to 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
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1
2
Table 2-5. Evidence pertaining to male reproductive effects in animals
following oral exposure to RDX
Reference and Study
Design
Lish et al. (1984); Levine et
al. (1984)
Mice, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/dose
0,1.0, 3.1, or 10 mg/kg-d
Diet
2 yrs
Levine etal. (1983):
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
Results
Doses 0 1.5 7.0 35
175/100
Testicular degeneration (incidence)
0/63 2/60 2/62 6/59
3/27a
Absolute testes weight; wk 105 (percent change compared to control)
0% -6% 0% -2%
-6%
Relative testes weight; wk 105 (percent change compared to control)
0% -4% 2% -2%
-2%
Prostate was examined microscopically in control and 175/100 mg/kg-d groups; no
effects were observed.
Doses 0 1.0 3.1
10
Absolute testes (with epididymis) weight; wk 104
0% -2% 2%
5%
Relative testes (with epididymis) weight; wk 104
0% -1% 7%
9%
Testes were examined microscopically in control and 10 mg/kg-d groups; no
degeneration or other treatment-related effects were observed. Prostate was not
examined microscopically.
Doses 0 0.3 1.5 8.0
40
Testes, germ cell degeneration; 12 mob (incidence)
SS 0/10 0/10 0/10 0/10
SDMS - - 1/3 -
4/10*
4/19
Testes, germ cell degeneration; 24 mo (incidence)
SS 0/38 0/36 0/25 0/29
SDMS 0/16 0/19 0/27 0/26
0/4
0/27
Prostate, suppurative prostatitis; 24 mo (incidence)
SS 0/38 1/36 2/25* 4/29*
SDMS 2/16 3/19 7/27* 8/26
Testes weights were not measured at termination due to testicular masses
all males.
SDMS = spontaneous death or moribund sacrifice; SS = scheduled sacrifice
0/4
19/27*
in nearly
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-17 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Cholakisetal.(1980)
Mice, B6C3Fi, 10-
12/sex/group
Experiment 1: 0, 10, 14, 20,
28, or 40 mg/kg-d
Diet
13 wks
Experiment 2: 0, 40, 60, or
80 mg/kg-d for 2 wks
followed by 0, 320, 160, or
80 mg/kg-d (TWA doses of
0, 79.6, 147.8, or
256.7 mg/kg-d for males
andO, 82.4, 136.3, or
276.4 mg/kg-d for
females)3
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/dose
0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13 wks
Cholakisetal.(1980)
Rats, CD, two-generation
study; FO: 22/sex/group;
Fl: 26/sex/group; F2:
10/sex/group
FO and Fl parental
animals: 0, 5, 16, or
50 mg/kg-d
Diet
13 wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-
d
Gavage
90 d
Results
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%
Doses 0 80 160
-1%
320
Absolute testes weight (percent change compared to control)
0% 4% -4%
-8%
Relative testes weight (percent change compared to control)
0% 1% -4%
Testes were examined microscopically in control and 320 mg/kg-d groups;
were observed.
Doses 0 10 14 20 28
-9%
no effects
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.
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.
Doses 0 4 8 10 12
15
Absolute testes weight (percent change compared to control)
OP/o -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
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-18 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Levine et al. (1990): Levine
et al. (1981a): Levine et al.
(1981b)
Rats, F344, 10/sex/group;
30/sexfor control
0, 10, 30, 100, 300, or
600 mg/kg-d
Diet
13wks
Hart (1974)
Dogs, Beagle, 3/sex/dose
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Results
Doses 0 10 30 100
300 600
Testes, germ cell degeneration (incidence)
0/10 0/10 0/10 0/10
1/9 1/10
Absolute testes weight (percent change compared to control)
0% 1% 1% -2%
Relative testes weight (percent change compared to control)
0% 4% 5% 19*%
Prostate was examined microscopically in control, 30, and 100 mj
effects were observed.
Doses 0 0.1 1
;/kg-d groups; no
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.
aAlthough 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.
bTesticular atrophy was observed at 12 months, along with a statistically reduced mean testes weight (compared
with controls). By 24 months, all male rats (including controls) had testicular masses; testes weights were not
recorded, and an increased incidence of testicular degeneration was not observed.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-19 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1000 q
• signifcantly changed O not significantly changed
(
(
o
o
o
Lishetal., 1984 (mouse)
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t; .s « i ^ ^
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.5. Liver Effects Evidence Tables and Array
2 Table 2-6. Evidence pertaining to liver effects of RDX in humans
Reference and Study Design
Hathaway and Buck (1977) (United
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, H MX, or TNT.
Exposure measures: Exposure
determination based on job title and
industrial hygiene evaluation. Exposed
subjects assigned to two groups: less
than the limit of detection (LOD) or
>0.01 mg/m3 (mean 0.28 mg/m3).
Effect measures: Liver function tests.
Analysis: Types of statistical tests were
not reported (assumed to be t-tests for
comparison of means and x2 tests for
comparison of proportions).
Results
Liver function tests in men; mean (standard deviation not reported)
Test
LDH
Alkaline
phosphatase
ALA (SCOT)
AST (SGPT)
Bilirubin
RDX exposed
Referent Undetected >0.01 mg/m3
(n = 237) (n = 22) (n = 45)
173 191 174
82 78 80
22 25 21
21 26 18
0.5 0.4 0.4
No differences were statistically significant. Similar results in women.
Liver function tests in men: prevalence of abnormal values
Test
(abnormal range)
LDH (>250)
Alkaline
phosphatase
(>1.5)
AST (SCOT) (>35)
ALT(SGPT)(>35)
Bilirubin (>1.0)
RDX exposed
Referent Undetected >0.01 mg/m3
2/237 1/22 0/45
34/237 1/22 6/45
20/237 4/22 2/45
15/237 2/22 0/45
5/237 1/22 1/45
No differences were statistically significant. Similar results in women.
4
5
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!, 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
F
0% 28*%
0% 7%
11%
7%
12% 35*%
15% 18*%
Relative liver weight at 104 wks (percent change compared to control)
M
F
0% 32*%
0% 6%
12%
8%
14% 46*%
18% 45*%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-21 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
100 mg/kg-d in wk 11 due to
excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0,1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Levine et al. (1983); Thompson
(1983)
Rats, F344, 75/sex/group; interim
sacrifices (10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, BSCSFi, 10-12/sex/group
Experiment 1: 0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13 wks
Results
Note: Percent change in liver weights of male and female mice was reduced in
all dose groups when mice with liver tumors were removed from the analysis.
Doses
0 1.0 3.1 10
Absolute liver weight (percent change compared to control)
M
F
0% -6% -6% -6%
0% 7% -11% 1%
Relative liver weight (percent change compared to control)
M
F
Doses
0% -5% -2% -3%
0% 17% -2% 13%
0 0.3 1.5 8.0 40
Absolute liver weight at 105 wks (percent change compared to control)
M
F
0% 3% -7% 1% -8%
0% 1% -4% 3% 0%
Relative liver weight at 105 wks (percent change compared to control)
M
F
Doses
0% 1% 0% 2% 11%
0% 1% -2% 6% 18*%
0 10 14 20 28 40
Absolute liver weight (percent change compared to control)
M
F
0% - -6% -5%
0% - -4% -1%
Relative liver weight (percent change compared to control)
M
F
0% - -4% -4%
0% - -6% 1%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-22 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Experiment 2: 0, 40, 60, or
80 mg/kg-d for 2 wks followed by
0, 320, 160, or 80 mg/kg-d (TWA
doses of 0, 79.6, 147.8, or
256.7 mg/kg-d for males and 0,
82.4, 136.3, or 276.4 mg/kg-d for
females)3
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or 40 mg/kg-d
Diet
13 wks
Cholakisetal.(1980)
Rats, CD, two-generation study;
FO: 22/sex/group;
Fl: 26/sex/group;
F2: 10/sex/group
FO and Fl parental animals: 0, 5,
16, or 50 mg/kg-d
Diet
13 wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al.
(1981a): Levine et al. U981b)
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
Results
Doses
0 80 160
320
Absolute liver weight (percent change compared to control)
M
F
0% 2% 12%
0% 4% 9%
26*%
29*%
Relative liver weight (percent change compared to control)
M
F
Doses
0% 0% 9%
0% 4% 4%
0 10 14 20
25*%
22*%
28 40
Absolute liver weight (percent change compared to control)
M
F
0% -
0% -
-2% -5%
6% 4%
Relative liver weight (percent change compared to control)
M
F
Doses
0% -
0% -
0 5 16
2% 3%
10% 11%
50
Absolute liver weight (percent change compared to control)
M
F
Doses
0% 7% -16%
0% 0% -14%
0 4 8 10
12 15
Absolute liver weight (percent change compared to control)
M
F
0% -6% -9% 0%
0% 1% 7% 18*%
7% 5%
15% 28*%
Relative liver weight (percent change compared to control)
M
F
0% 0% -1% 2%
0% 1% -2% 2%
Data were not reported for rats in the 300 or 600 mg/kg-d dose
because all of the rats died before the 13-wk necropsy.
Doses
0 10 30 100
5% 2%
-3% 2%
groups
300 600
Absolute liver weight (percent change compared to control)
M
F
0% 5% -1% -2%
0% 2% 4% 16*%
Relative liver weight (percent change compared to control)
M
F
0% 8% 6% 1%
0% 3% 5% 19*%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-23 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus,
3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Results
Doses
0 0.1 1 10
Absolute liver weight (percent change compared to control)
M
F
Doses
0% - - 53%
0% - - 3%
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, BSCSFi, 85/sex/group;
interim sacrifices (10/sex/group)
at 6 and 12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-
d (high dose reduced to
100 mg/kg-d in wk 11 due to
excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0,1.0, 3.1, or 10 mg/kg-d
Diet
2 yrs
Levine et al. (1983): Thorrmson
(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
Histopathological lesions in liver other than adenomas and carcinomas were
not significantly different compared to controls.
Histopathological examination performed only for controls and 10 mg/kg-d
rats; no significant differences compared to controls were reported.
Doses
0 0.3 1.5 8.0 40
Microgranulomas (incidence)
M
F
0/38 0/36 0/25 0/29 0/4
10/43 19/45 12/42 17/41 4/28
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-24 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal.(1980)
Mice, BSCSFi, 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)3
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or 40 mg/kg-d
Diet
13 wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al.
U981a): Levine et al. U981b)
Rats, F344, 10/sex/group; 30/sex
for control
0, 10, 30, 100, 300, or 600 mg/kg-
d
Diet
13 wks
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus,
3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
Doses 0 80
160 320
Liver microgranulomas; mild (incidence)
M 2/10
F 2/11
1/9
7/11*
Increased karyomegaly ofhepatocytes
M 0/10
F - -
Doses 0 10 14 20
5/9*
28 40
Liver granulomas; mild (incidence)
M 0/10 -
F _
1/10
Liver portal inflammation
M 2/10 -
F 1/10 -
3/10
7/10
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.
Histopathological examination of liver did not reveal any significant differences
compared to controls.
Histopathological examination performed only for controls and 10 mg/kg-d
dogs; no significant differences compared to controls were reported.
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.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-25 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Results
Serum chemistry
Lish et al. (1984); Levine et al.
(1984)
Mice, BSCSFi, 85/sex/group;
interim sacrifices (10/sex/group)
at6 and 12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-
d (high dose reduced to
100 mg/kg-d in wk 11 due to
excessive mortality)
Diet
24 mo
Levine et al. (1983); Thompson
(1983)
Rats, F344, 75/sex/group; interim
sacrifices (10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al.
(1981a): Levine et al. (1981b)
Rats, F344, 10/sex/group; 30/sex
for control
0, 10, 30, 100, 300, or 600 mg/kg-
d
Diet
13wks
Doses
0 1.5 7.0 35 175/100
Serum cholesterol at 105 wks (percent change compared to control)
M
F
0% 11% -11% 5% 39%
0% 5% 15% 25% 38%
Serum triglycerides at 105 wks (percent change compared to control)
M
F
Doses
0% 21% -20% 10% -25%
0% 34% 28% 41% 28%
0 0.3 1.5 8.0 40
Serum cholesterol at 104 wks (percent change compared to control)
M
F
0% 15% 38% 19% -6%
0% 6% 3% -7% -9%
Serum triglycerides at 104 wks (percent change compared to control)
M
F
Doses
0% 14% -15% -12% -52%
0% 18% 5% -42% -51*%
04 8 10 12 15
Serum cholesterol (percent change compared to control)
M
F
0% -3% -10*% -16*% -18*% -11*%
0% -1% -8% -4% -4% -1%
Serum triglycerides (percent change compared to control)
M
F
0% 1% 1% -7% -2% -19%
0% -16% -21% 7% -37% 18%
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
F
0% -14% -34% -62*%
0% -12% -29% -50*%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-26 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus,
3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Results
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
F
0%
0%
-17%
7%
-2%
7%
-7%
7%
*Statistically significant (p < 0.05) based on analysis by study authors.
aDoses were calculated by the study authors.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-27 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1000 q
1
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These studies were excluded from array because only absolute liver weight was reported: Cholakis, 1980 (2-gen rat): Hart 1974; M artin and Hart 1974
M - Mortality observed at this dose and above
Figure 2-5. Exposure-response array of liver effects following oral exposure to 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
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.6. Kidney Effects Evidence Tables and Array
2 Table 2-8. Evidence pertaining to renal effects of RDX in humans
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 (0.01 mg/m3 (mean
0.28 mg/m3).
Effect measures: Renal function tests
(blood)
Analysis: Types of statistical tests
werenot reported (assumed to be t-tests
for comparison of means and x2 tests for
comparison of proportions).
Test
Blood urea
nitrogen
Total protein
Referent
(n = 237)
15.5
7.2
RDX exposed
Undetected
(n = 22)
15.6
7.2
>0.01 mg/m
(n = 45)
16.4
7.3
No differences were statistically significant. Similar results in women.
4
5
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!, 85/sex/group; interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high dose
reduced to 100 mg/kg-d in wk 11 due to
excessive mortality)
Diet
24 mo
Doses
0
1.5 7.0
35
175/100
Absolute kidney weight at 104 wks (percent change compared to
control)
M
F
0%
0%
-1% 4%
3% 1%
9*%
1%
19*%
-2%
Relative kidney weight at 104 wks (percent change compared to
control)
M
F
0%
0%
3% 6%
1% 1%
11*%
2%
27*%
19*%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-29 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Hart (1976)
Rats, Sprague-Dawley, 100/sex/group
0, 1.0, 3.1, orlOmg/kg-d
Diet
2yrs
Levine et al. (1983); Thompson (1983)
Rats, F344, 75/sex/group; interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, B6C3Fi, 10-12/sex/group
Experiment 1: 0, 10, 14, 20, 28, or 40 mg/kg-d
Diet
13wks
Experiment 2: 0, 40, 60, or 80 mg/kg-d for
2 wks followed by 0, 320, 160, or 80 mg/kg-d
(TWA doses of 0, 79.6, 147.8, or 256.7 mg/kg-d
for males and 0, 82.4, 136.3, or 276.4 mg/kg-d
for females)3
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, 40 mg/kg-d
Diet
13 wks
Results
Doses
0 1.0 3.1 10
Absolute kidney weight (percent change compared to control)
M
F
0% -3% -7% 2%
0% 14% -4% 8%
Relative kidney weight (percent change compared to control)
M
F
Doses
0% -1% -4% 4%
0% 22% 3% 18%
0 0.3 1.5 8.0 40
Absolute kidney weight at 105 wks (percent change compared to
control)
M
F
0% 2% -7% 1% 0%
0% 3% 3% 2% 2%
Relative kidney weight at 105 wks (percent change compared to
control)
M
F
Doses
0% 1% 0% 2% 20*%
0% 3% 6% 5% 21*%
0 10 14 20 28 40
Absolute kidney weight (percent change compared to control)
M
F
0% - 18% 2%
0% - -8% -5%
Relative kidney weight (percent change compared to control)
M
F
Doses
0% - 29% 0%
0% - -8% -3%
0 80 160 320
Absolute kidney weight (percent change compared to control)
M
F
0% 8% 11% 13%
0% -5% -3% 0%
Relative kidney weight (percent change compared to control)
M
F
Doses
0% 5% 9% 10%
0% -5% -4% -5%
0 10 14 20 28 40
Absolute kidney weight (percent change compared to control)
M
F
0% - -2% -5%
0% - 1% 0%
Relative kidney weight (percent change compared to control)
M
F
0% - 1% 5%
0% - - - 6% 6%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-30 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal.(1980)
Rats, CD, two-generation study;
FO: 22/sex/group; Fl: 26/sex/group;
F2: 10/sex/group
FO and Fl parental animals: 0, 5, 16, 50 mg/kg-
d
Diet
13wks
Grouse et al. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990): Levine et al. (1981a):
Levineetal.(1981b)
Rats, F344, 10/sex/group; 30/sex for control
0, 10, 30, 100, 300, or 600 mg/kg-d
Diet
13wks
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
Doses
0 5 16 50
Absolute kidney weight (percent change compared to control)
M
F
Doses
0% 6% -12%
0% -4% -21*%
04 8 10 12 15
Absolute kidney weight (percent change compared to control)
M
F
0% -3% -4% -1% 3% 5%
0% 2% 5% 13*% 10% 15*%
Relative kidney weight (percent change compared to control)
M
F
0% 3% 6% 2% 1% 3%
0% 1% -3% -1% -6% -7*%
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
F
0% 1% 1% -9%
0% 1% 3% -1%
Relative kidney weight (percent change compared to control)
M
F
0% 5% 7% 10%
0% 3% 5% 2%
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
F
Doses
0% - - 38%
0% - - -18%
0 0.1 1 10
Absolute kidney weight (percent change compared to control)
M+F
0% -2% -3% 4%
Histopathological lesions
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-31 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Lish et al. (1984); Levine et al. (1984)
Mice, BSCSFi, 85/sex/group; interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-d (high dose
reduced to 100 mg/kg-d in wk 11 due to
excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley, 100/sex/group
0,1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Levine et al. (1983); Thompson (1983)
Rats, F344, 75/sex/group; interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, B6C3Fi, 10-12/sex/group
0, 80, 60, 40 mg/kg-d for 2 wks followed by 0,
80, 160, or 320 mg/kg-d (TWA doses of 0, 79.6,
147.8, or 256.7 mg/kg-d for males and 0, 82.4,
136.3, or 276.4 mg/kg-d for females)3
Diet
13 wks
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or 40 mg/kg-d
Diet
13 wks
Results
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.
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.
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):
F(SDMS):
0/38 0/36 0/25 0/29 0/4
0/17 1/19 0/27 0/26 18/27*
Suppurative pyelitis; 24 mo (incidence)
M (SS):
F(SDMS):
0/38 0/36 0/25 0/29 0/4
0/17 1/19 0/27 1/26 5/27*
Uremic mineralization; 24 mo (incidence)
M (SS):
F(SDMS):
1/38 0/36 0/25 0/29 0/4
0/17 1/19 2/27 0/26 13/27
Incidence data reported only for controls and the 320 mg/kg-d
group.
Doses
0 80 160 320
Tubular nephrosis (incidence)
M
F
0/10 - - 4/9*
0/11 - - 1/11
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.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-32 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Cholakisetal. (1980)
Rats CD two-generation study FO1
22/sex/group; Fl: 26/sex/group; F2:
10/sex/group
FO and Fl parental animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-d
Gavage
90 d
Levine et al. (1990); Levine et al. (1981a):
Levineetal.(1981b)
Rats, F344, 10/sex/group; 30/sex for control
0, 10, 30, 100, 300, or 600 mg/kg-d
Diet
13wks
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgus or Rhesus, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
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
Histopathological examination of kidney did not reveal any
significant differences compared to controls; incidence data were
reported only for control and 15 mg/kg-d groups.
Histopathological examination of kidney did not reveal any
significant differences compared to controls.
Histopathological examination of kidney did not reveal any
significant differences compared to controls; incidences were
reported only for control and 10 mg/kg-d groups.
Doses 0 0.1 1 10
Medulla; mineralization, minimal to mild (incidence)
M+F 0/6 1/6 0/6 4/6
*Statistically significant (p < 0.05) based on analysis by study authors.
aDoses were calculated by the study authors.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-33 DRAFT—DO NOT CITE OR QUOTE
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1000
100 --
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ish et ah, 1984 (mo
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Thefollov/ing studies \vere excluded from array because absolute kidney weight was reported: Cholakis, 19SO (2-genrat); Hart, 1974; Martin and Hart, 1974
M - Mortality observed at this dose and above
Figure 2-6. Exposure-response array of renal effects following oral exposure to 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
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Preliminary Materials for the IRIS Toxicological Review ofRDX
2
3
1 2.7. Carcinogenicity Evidence Tables
Table 2-10. Liver tumors observed in chronic animal bioassays following oral
exposure to RDX
Reference and Study Design
Lish et al. (1984); Levine et al. (1984)
Mice, BSCSFi, 85/sex/group; interim
sacrifices (10/sex/group) at 6 and
12 mo
0, 1.5, 7.0, 35, or 175/100 mg/kg-d
(high dose reduced to 100 mg/kg-d
in wk 11 due to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0, 1.0, 3.1, or 10 mg/kg-d
Diet
2 yrs
Levine et al. (1983): Thompson
(1983)
Rats, F344, 75/sex/group; interim
sacrifices (10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Results
Doses
0 1.5
7.0 35
175/100
Hepatocellular adenomas (incidence)
M
F
8/63 6/60
1/65 1/62
1/62* 7/59
6/64 6/64
7/27
3/31a
Hepatocellular carcinomas (incidence)
M
F
13/63 20/60
0/65 4/62
Hepatocellular adenoma or carcinoma
M
F
21/63 26/60
1/65 5/62
16/62 18/59
3/64 6/64
combined (incidence)
17/62 25/59
9/64* 12/64*
Pathology workgroup reanalysis of liver lesion slides from female
(Parker et al., 2006; Parker, 2001)b
Doses
0 1.5
7.0 35
6/27
3/31a
13/27
6/31*a
mice
175
Hepatocellular adenomas (incidence)
F
1/67 3/62
2/63 8/64
2/31a
Hepatocellular carcinomas (incidence)
F
0/67 1/62
Hepatocellular adenoma or carcinoma
F
l/67b 4/62
3/63 2/64
combined (incidence)
5/63b 10/64
2/31a
4/31a
Hepatocellular adenomas (incidence)
None reported by the study authors.
Doses 0
1.0 3.1
10
Hepatocellular carcinomas (incidence)
M 1/82
F 1/72
1/77
1/81
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
F 0/53 1/55
Hepatocellular adenoma or carcinoma
Not determined.
0/52 2/55
0/54 0/55
combined (incidence):
2/31
0/48
*Statistically significant difference compared to the control group (p < 0.05), identified by the authors.
Statistically significant trend (p< 0.05) was identified using Cochran-Armitage trend tests performed by EPA.
blt 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).
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-35 DRAFT—DO NOT CITE OR QUOTE
-------
1
2
Preliminary Materials for the IRIS Toxicological Review ofRDX
Table 2-11. Lung tumors observed in chronic animal bioassays following oral
exposure to RDX
Reference and Study Design
Lish et al. (1984); Levine et al.
(1984)
Mice, BSCSFi, 85/sex/group;
interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high dose
reduced to 100 mg/kg-d in
wk 11 due to excessive
mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0, 1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Levine etal. (1983):
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and 12 mo
0, 0.3, 1.5, 8.0, or 40 mg/kg-d
Diet
24 mo
Results
Doses
0 1.5
7.0
35
175/100
Alveolar/bronchiolar adenomas (incidence)
M
F
6/63 5/60
4/65 2/62
5/62
5/64
7/59
9/64
1/27
3/3 la
Alveolar/bronchiolar carcinomas (incidence)
M
F
3/63 6/60
3/65 1/62
3/62
3/64
7/59
3/64
5/27a
4/31
Alveolar/bronchiolar adenoma or carcinoma combined (incidence)
M
F
Doses
9/63 11/60
7/65 3/62
0 1.0
8/62
8/64
14/59
12/64
3.1
6/27
7/3 la
10
Alveolar/bronchiolar adenoma (incidence)
M
F
2/83
0/73
—
1/77
0/82
Alveolar/bronchiolar carcinoma (incidence):
None reported by study authors.
Doses
0 0.3
1.5
8.0
40
Alveolar/bronchiolar adenomas (incidence)
M
F
1/55 0/15
3/53 0/7
1/17
0/8
0/16
1/10
1/31
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
Statistically significant trend (p < 0.05) was identified using Cochran-Armitage trend test performed by EPA.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.8. Other Systemic Effects Evidence Tables
2
3
Table 2-12. Evidence pertaining to other systemic effects (hematological) of
RDX in humans
Reference and Study Design
Results
Hematological Effects
West and Stafford (1997) (United Kingdom)
Case-control study, 32 cases with abnormal and
322 controls with normal hematology test drawn
from 1991 study of 404 workers at ammunitions
plant; participation rate 97% of cases, 93% of
controls. Analysis limited to men (29 cases,
282 controls).
Exposure measures: Exposure determination
based on employee interviews and job title
analysis; data included frequency (hours/day,
days/year), duration (years), and intensity (low
[1-10 ppm], moderate [10-100 ppm], and high
[100-1,000 ppm], based on ventilation
considerations).
Effect measures: Hematology tests; blood
disorder defined as neutropenia (2.0 x 109/1), low
platelet count (<150 x 109/1), or macrocytosis
(mean corpuscular volume = 99 fl or >6%
macrocytes).
Analysis: Unadjusted odds ratio.
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, H MX, or TNT.
Exposure measures: Exposure determination
based on job title and industrial hygiene
evaluation. Exposed subjects assigned to two
groups: 0.01 mg/m3 (mean
0.28 mg/m3).
Effect measures: Hematology tests.
Analysis: Types of statistical tests were not
reported (assumed to be t-tests for comparison of
means and x2 tests for comparison of
proportions).
Odds ratio (95% Cl) [number of exposed cases] of blood disorder
and RDX
Low intensity, 50 hr-duration
Medium intensity, 50-hr duration
High intensity, 50-hr duration
1.7 (0.7,4.2) [22]
1.6 (not reported) [5]
1.2(0.3,5.3)[2]
Hematology tests in men; mean (standard deviation not reported)
Referent
Test (n = 237)
RDX exposed
Undetected >0.01 mg/m3
(n = 22) (n = 45)
Hemoglobin 15.2 14.7 15.2
Hematocrit 42 45.6 47
Reticulocyte 0.7 0.9 0.7
count
No differences were statistically significant. Similar results in
women.
Hematology tests in men: prevalence of abnormal values
Test
(abnormal
range) Referent
RDX exposed
Undetected >0.01 mg/m3
Hemoglobin 15/237 3/22 4/45
(<14)
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study Design
Results
Hematocrit
(<40)
Reticulocyte
count (>1.5)
1/237
18/237
1/22
3/22
1/45
2/45
No differences were statistically significant. Similar results in
women.
2
3
Table 2-13. Evidence pertaining to other systemic effects in animals following
oral exposure to RDX
Reference and Study
Design
Results
Ocular effects
Lish et al. (1984); Levine et
al. (1984)
Mice, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
Levine etal. (1983);
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
Cholakis etal. (1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13wks
Doses
0 1.5 7.0 35 175/100
Cataracts; 103 wks (incidence)0
M
F
Doses
2/47 2/41 0/41 2/37 2/16
2/50 1/37 6/52 0/46 1/26
0 0.3 1.5 8.0 40
Cataracts; 103 wks (incidence)
M
F
8/40 6/39 6/31 8/35 2/6
14/44 4/48 11/44 8/43 22/30*
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).
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-
d
Gavage
90 d
Martin and Hart (1974)
Monkeys, Cynomolgous or
Rhesus, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Results
No ocular effects were observed (opthalmic examinations were performed in all
animals within Iwk of sacrifice, and microscopic examination of the eye was
performed in control and 15 mg/kg-d animals).
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, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0, 1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Doses
0 1.5 7.0 35
175/100
Absolute heart weight; 104 wks (percent change compared to control)
M
F
0% 4% 4% 5%
0% 1% 5% 2%
7%
-5%
Relative heart-to-body weight; 104 wks (percent change compared to control)
M
F
0% 7% 5% 5%
0% 0% 6% 4%
Body weight was significantly lower at termination in males and females
175/100 mg/kg-d (-5 and -19%, respectively).
Doses
0 1.0 3.1
13*%
17*%
exposed to
10
Myocardialfibrosis (percent incidence; number not reported)
M
F
20%
5%
5%
1%
Endocardial disease (percent incidence; number not reported)
M
F
1%
0%
3%
0%
Absolute heart weight; 104 wks (percent change compared to control)
M
F
0% -6% -2%
0% 13% 3%
-5%
15%
Relative heart-to-body weight; 104 wks (percent change compared to control)
M
F
0% -2% 4%
0% 23% 13%
1%
27%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-39 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Levineetal.(1983):
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
Cholakisetal. (1980)
Mice, B6C3Fi, 10-
12/sex/group
Experiment 1: 0, 10, 14, 20,
28, or 40 mg/kg-d
Diet
13wks
Experiment 2: 0, 40, 60, or
80 mg/kg-d for 2 wks
followed by 0, 320, 160, or
80 mg/kg-d (TWA doses of
0, 79.6, 147.8, or
256.7 mg/kg-d for males
and 0, 82.4, 136.3, or
276.4 mg/kg-d for
females)b
Diet
13 wks
Cholakisetal. (1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13 wks
Results
Doses
0 0.3 1.5 8.0
40
Absolute heart weight; 104 wks (percent change compared to control)
M
F
0% 3% -2% -2%
0% -1% 0% -4%
1%
-3%
Relative heart-to-body weight; 104 wks (percent change compared to control)
M
F
Doses
0% 2% 6% 0%
0% -2% 3% -1%
0 10 14 20 28
22%
15%
40
Absolute heart weight (percent change compared to control)
M
F
0% - 7%
0% - 0%
7%
0%
Relative heart weight (percent change compared to control)
M
F
Doses
0% - 6%
0% - -4%
0%
0%
0 80 160 320
Focal myocardial degeneration (incidence):
M**
F***
0/10
0/11
5/10*
2/11
Absolute heart weight (percent change compared to control)
M
F
0% 0% 0%
0% 0% 0%
8%
8%
Relative heart-to-body weight (percent change compared to control)
M
F
0% 0% -2%
0% 0% -2%
6%
2%
**lncludes one affected and three unaffected animals that died prematurely.
***lncludes one unaffected animal that died prematurely.
Doses
0 10 14 20 28
40
Focal myocardial degeneration (incidence)
M
F
3/10 -
2/10 -
1/10
6/10
Absolute heart weight (percent change compared to control)
M
F
0% - 0%
0% - -6%
-8*%
-11*%
Relative heart-to-body weight (percent change compared to control)
M
F
0% - 3%
0% - -3%
0%
-8%
Relative heart-to-brain weight (percent change compared to control)
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-40 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Cholakisetal.(1980)
Rats, CD, two-generation
study; FO: 22/sex/group;
Fl: 26/sex/group; F2:
10/sex/group
FO and Fl parental
animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-
d
Gavage
90 d
Levine et al. (1990); Levine
et al. (1981a); Levine et al.
(1981b)
Rats, F344, 10/sex/group;
30/sex for control
Om 3n inn 3nn nr
600 mg/kg-d
Diet
13wks
Von Oettingen et al.
(1949)
Rats (sex/strain not
specified); 20/group
0, 15, 25, or 50 mg/kg-d
Diet
3 mo
Results
M 0% - -4% -10*%
F 0% - -5% -11*%
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)
F2M
F2F
Doses
0% 3.2% -6.5%
0% 15% -3.7%
0 4 8 10 12 15
Cardiomyopathy (incidence)
M
F
2/10 3/8
0/10 1/6
Absolute heart weight (percent change compared to control)
M
F
0% -2% -7% -1% 1% 11%
0% -2% 0% 8% 7% 6%
Relative heart-to-body weight (percent change compared to control)
M
F
0% 4% 2% 1% -1% 8%
0% -2% -7% -6% -9% -16*%
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
F
8/30 8/10 6/10 1/10 1/10 0/10
8/30 3/10 1/10 1/10 1/10 1/9
Absolute heart weight (percent change compared to control)
M
F
0% -2% -10% -15%
0% -3% 0% -5%
Relative heart-to-body weight (percent change compared to control)
M
F
0% 2% -4% 3%
0% -2% 0% -3%
The study authors reported that there were no cardiac effects (microscopic
examination of the heart was performed in all rats; data were not shown).
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-41 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgous or
Rhesus, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Results
Doses
0 0.1 1
10
Focal hyalinization of the heart (incidence)
M
F
0/3
0/3
0/3
1/3
Absolute heart weight (percent change compared to control)
M
F
Doses
0%
0%
0 0.1 1
31%
5.7%
10
Myocarditis (incidence in control and 10 mg/kg-d groups)
M
F
1/3
0/3
1/3
0/3
Absolute heart weight (percent change compared to control)
M
F
0% 7% -1%
0% 10% 12%
5%
-12%
Immune effects
Lish et al. (1984): Levine et
al. (1984)
Mice, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/s ex/group
0, 1.0, 3.1, or 10 mg/kg-d
Diet
2 yrs
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
F
0% -13% -8% -16%
0% 12% 39*% 28%
-30%
0%
Absolute spleen weight; 105 wks (percent change compared to control)
M
F
0% 24% 31% -10%
0% 4% 15% -17%
-28%
16%
Relative spleen weight; 105 wks (percent change compared to control)
M
F
Doses
0% 26% 32% -11%
0% 4% 15% -17%
0 1.0 3.1
-21%
44%
10
WBC count; 104 wks (percent change compared to control)
M
F
0% -13% -22*%
0% 5% -32*%
-34*%
-12%
Absolute spleen weight; 104 wks (percent change compared to control)
M
F
0% -11% -16%
0% 58% 8%
-4%
37%
Relative spleen weight; 104wks (percent change compared to control)
M
F
0% -11% -14%
0% 77% 19%
1%
55%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-42 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Levineetal.(1983):
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, B6C3Fi, 10-
12/sex/group
Experiment 1: 0, 10, 14, 20,
28, or 40 mg/kg-d
Diet
13wks
Experiment 2: 0, 40, 60,
80 mg/kg-d for 2 wks
followed by 0, 320, 160, or
80 mg/kg-d (TWA doses of
0, 79.6, 147.8, or
256.7 mg/kg-d for males
andO, 82.4, 136.3, or 276.4
mg/kg-d for females)
Diet
13 wks
Results
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
F
0% -11% 103C% 184C%
0% 7% 12% 354C%
15%
251C%
Absolute spleen weight; 105 wks (percent change compared to control)
M
F
0% 5% -10% -32%
0% -28% -44% -35%
-49%
17%
Relative spleen weight; 105 wks (percent change compared to control)
M
F
Doses
0% 9% 4% -29%
0% -34% -45% -36%
0 10 14 20 28
-38%
9%
40
Absolute spleen weight (percent change compared to control)
M
F
0% - 18%
0% - -2%
13%
-8%
Relative spleen weight (percent change compared to control)
M
F
Doses
0% - 24%
0% - -3%
0 80 160
14%
-5%
320
WBC count (percent change compared to control)
M
F
0% -27% -12%
0% -17% 3%
30%
-3%
Absolute spleen weight (percent change compared to control)
M
F
0% 17% 0%
0% -22% 0%
-17%
0%
Relative spleen weight (percent change compared to control)
M
F
0% 25% 5%
0% -12% 0%
0%
-3%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-43 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13wks
Cholakisetal.(1980)
Rats, CD, two-generation
study; FO: 22/sex/group;
Fl: 26/sex/group;
F2: 10/sex/group
FO and Fl parental
animals: 0, 5, 16, or
50 mg/kg-d
Diet
13wks
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-
d
Gavage
90 d
Results
Doses
0 10 14 20
28
40
WBC count (percent change compared to control)
M
F
0% -
0% -
-12%
17%
7%
30%
Absolute spleen weight (percent change compared to control)
M
F
0% -
0% -
2%
-10%
-4%
-12*%
Relative spleen weight (percent change compared to control)
M
F
0% -
0% -
No immune effects were observed upon routine histopathology
5%
-8%
evaluation.
No effects were observed on thymus or spleen histology, red and white blood
populations, or lymphocyte populations.
Doses
0 4 8 10
12
5%
-8%
cell
15
WBC count (percent change compared to control)
M
F
0% -5% -12% -7%
0% 22% 45% 12%
1%
52%
-3%
29%
Absolute spleen weight (percent change compared to control)
M
F
0% -3% -6% 3%
0% 1% 8% 23*%
1%
17*%
5%
24*%
Relative spleen weight (percent change compared to control)
M
F
0% 3% 4% 7%
0% 1% 0% 6%
-1%
-1%
2%
-2%
Absolute thymus weight (percent change compared to control)
M
F
0% -1% 3% -10%
0% -7% 12% 19%
-12%
32%
-25%
19%
Relative thymus weight (percent change compared to control)
M
F
0% -1% 3% -10%
0% -7% 4% 4%
-12%
12%
-25%
-6%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-44 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Levine et al. (1990); Levine
etal. (1981a); Levine etal.
(1981b)
Rats, F344, 10/sex/group;
30/sexfor control
0, 10, 30, 100, 300, or
600 mg/kg-d
Diet
13wks
Von Oettingen et al.
(1949)
Rats, sex/strain not
specified, 20/group
0, 15, 25, or 50 mg/kg-d
Diet
3 mo
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgous or
Rhesus, 3/sex/group
0,0.1, 1, or 10 mg/kg-d
Gavage
90 d
Results
Data were not reported for rats in the 300 or 600 mg/kg dose
rats died before the 13-wk necropsy.
Doses
0 10 30 100
groups because all of the
300 600
WBC count (percent change compared to control)
M
F
0% 4% 7% 15%
0% 23*% 24*% 62*%
Absolute spleen weight (percent change compared to control)
M
F
0% -11% -16% -34%
0% 2% 12% 0%
Relative spleen weight (percent change compared to control)
M
F
Doses
0% -9% -12% -21%
0% 2% 12% 3%
0 15 25
50
WBC count (percent change compared to control)
M
Doses
0% -30% 7%
0 0.1 1
-6%
10
WBC count (percent change compared to control)
M
F
0% 5% 2%
0% -2% 24%
-19%
6%
Absolute spleen weight (percent change compared to control)
M
F
Doses
0%
0%
0 0.1 1
123%
-11%
10
WBC count (percent change compared to control)
M
F
0% -32% 0%
0% -38% -1%
-3%
-41%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-45 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Results
Gastrointestinal (Gl) effects
Lish et al. (1984): Levine et
al. (1984)
Mice, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
No Gl effects were observed as clinical signs or on gross pathology or histopathology
examination.
Levine et al. (1983):
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
No Gl effects were observed as clinical signs or on gross pathology or histopathology
examination.
Grouse et al. (2006)
Rats, F344,10/sex/group
0, 4, 8,10,12, or 15 mg/kg-
d
Gavage
90 d
No Gl effects were observed on gross pathology or histopathology examination.
Increased salivation and blood stains around the mouth were noted (affected doses
and incidences were not reported); it is not clear whether these effects occurred in
animals also experiencing convulsions.
Von Oettingen et al.
(1949)
Rats (sex/strain not
specified); 20/group
0,15, 25, or 50 mg/kg-d
Diet
3 mo
Congestion of the Gl tract was observed in 50 and 100 mg/kg-d rats that also exhibited
mortality (40%) and severe neurotoxicity.
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-46 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Martin and Hart (1974)
Monkeys (Cynomolgus or
Rhesus); 3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Hart (1974)
Dogs, Beagle, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Diet
90 d
Results
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.
Some nausea and vomiting were reported (incidences and affected
not reported).
dose groups were
Hematological effects
Lish et al. (1984); Levine et
al. (1984)
Mice, B6C3Fi,
85/sex/group; interim
sacrifices (10/sex/group) at
6 and 12 mo
0, 1.5, 7.0, 35, or
175/100 mg/kg-d (high
dose reduced to
100 mg/kg-d in wk 11 due
to excessive mortality)
Diet
24 mo
Hart (1976)
Rats, Sprague-Dawley,
100/sex/group
0, 1.0, 3.1, or 10 mg/kg-d
Diet
2yrs
Levine etal. (1983);
Thompson (1983)
Rats, F344, 75/sex/group;
interim sacrifices
Doses 0 1.5 7.0 35
175/100
RBC count; 105 wks (percent change compared to control)
M 0% -4% 3% -3%
F 0% 4% -7% 5%
14%
3%
Hemoglobin; 105 wks (percent change compared to control)
M 0% -6% 3% -5%
F 0% 2% -7% 3%
9%
1%
Hematocrit; 105 wks (percent change compared to control)
M 0% -4% 3% -4%
F 0% 3% -6% 3%
9%
1%
Platelets; 105 wks (percent change compared to control)
M 0% 33% 9% 21%
F 0% -14% -7% 1%
Doses 0 1.0 3.1
27%
5%
10
RBC count; 104 wks (percent change compared to control)
M 0% 3% 7%
F 0% -14% 7%
-2%
2%
Reticulocyte count; 104 wks (percent change compared to control)
M 0% 250C% 500*c%
F 0% 180*c% -40%
850*c%
20%
Hemoglobin; 104 wks (percent change compared to control)
M 0% 3% 4%
F 0% -1% 1%
Doses 0 0.3 1.5 8.0
0%
-2%
40
Hemoglobin levels; 105 wks (percent change compared to control)
M 0% 6% 6% 3%
F 0% -5% 1% -9%
-13%
-14%
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-47 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
(10/sex/group) at 6 and
12 mo
0, 0.3, 1.5, 8.0, or
40 mg/kg-d
Diet
24 mo
Cholakisetal.(1980)
Mice, B6C3Fi, 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
Cholakisetal.(1980)
Rats, F344, 10/sex/group
0, 10, 14, 20, 28, or
40 mg/kg-d
Diet
13 wks
Results
RBC count; 105 wks (percent change compared to control)
M
F
0% 5% 2% -1%
0% -2% 2% -9%
-9%
-13%
Platelet count; 105 wks (percent change compared to control)
M
F
0% 6% -4% -10%
0% 14% -4% 5%
-7%
22%
Hematocrit; 105 wks (percent change compared to control)
M
F
Doses
0% 5% 5% 2%
0% -5% 0% -8%
0 80 160
-7%
-12%
320
RBC count (percent change compared to control)
M
F
0% -5% -12*%
0% -10% -1%
-2%
1%
Reticulocytes (percent change compared to control)
M
F
0% -36% -13%
0% 21% 25%
15%
-19%
Hematocrit (percent change compared to control)
M
F
0% -1% -6%
0% -8% 2%
0%
1%
Hemoglobin (percent change compared to control)
M
F
0% -2% -7*%
0% -5% 4%
-3%
1%
Platelets (percent change compared to control)
M
F
Doses
0% 33% 28%
0% 3% 9%
0 10 14 20 28
22%
39%
40
RBC count (percent change compared to control)
M
F
0% - 3%
0% - -1%
-1%
-7%
Hemoglobin (percent change compared to control)
M
F
0% - 2%
0% - -1%
-1%
-1%
Platelet (percent change compared to control)
M
F
0% - 11%
0% - -23%
16*%
-13%
Reticulocytes (percent change compared to control)
M
F
0% - 26%
0% - -2%
76*%
17%
Hematocrit (percent change compared to control)
This document is a preliminary draft for review purposes only and does not constitute Agency policy,
2-48 DRAFT—DO NOT CITE OR QUOTE
-------
Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
Grouse etal. (2006)
Rats, F344, 10/sex/group
0, 4, 8, 10, 12, or 15 mg/kg-
d
Gavage
90 d
Levine et al. (1990): Levine
et al. (1981a): Levine et al.
(1981b)
Rats, F344, 10/sex/group;
30/sex for control
0, 10, 30, 100, 300, or
600 mg/kg-d
Diet
13wks
Von Oettingen etal.
(1949)
Rats, sex/strain not
specified, 20/group
0, 15, 25, or 50 mg/kg-d
Diet
3 mo
Hart (1974)
Dogs, Beagle, 3/sex/group
Results
M
F
Doses
0%
0%
048
—
10
3% 0%
0% -2%
12 15
RBC count (percent change compared to control)
M
F
0% 1% -7%
0% 3% 3%
-2%
-1%
-4% -5%
2% -2%
Hemoglobin (percent change compared to control)
M
F
0% -1% -5%
0% 2% 4%
0%
-1
-1% -6%
4% -4%
Platelet count (percent change compared to control)
M
F
0% 21% 11%
0% 6% 40%
13%
47%
-8% 34%
34% -36%
Hematocrit (percent change compared to control)
M
F
0% 2% -5%
0% 3% 4%
Data were not reported for rats in the 300 or 600 mg
rats died before the 13-wk necropsy.
Doses
0 10 30
0%
0%
/kg dose j
100
-1% -4%
4% -2%
groups because all of the
300 600
Hematocrit (percent change compared to control)
M
F
0% -2% -1%
0% 0% -4%
-5%
-7%
— —
Hemoglobin (percent change compared to control)
M
F
0% -3% -1%
0% 0% -4%
-6%
-8*%
— —
RBC count (percent change compared to control)
M
F
0% -2% -2%
0% -1% -4%
-5%
-5%
— —
Reticulocytes (percent change compared to control)
M
F
Doses
0% -4% 10%
0% 9% 73%
0 15
28%
71%
25
— —
50
RBC count (percent change compared to control)
M+F
0% -23%
-12%
-14%
Hemoglobin (percent change compared to control)
M+F
Doses
0% -25%
0 0.1
-7%
1
-11%
10
RBC count (percent change compared to control)
M
0% -3%
3%
2%
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Reference and Study
Design
0,0.1, 1, or lOmg/kg-d
Diet
90 d
Martin and Hart (1974)
Monkeys, Cynomolgous or
Rhesus, 3/sex/group
0,0.1, 1, or lOmg/kg-d
Gavage
90 d
Results
F
0% 13% 7%
11%
Reticulocyte count (percent change compared to control)
M
F
0% -66% 0%
0% -17% -50%
-50%
0%
Hematocrit (percent change compared to control)
M
F
0% -4% 2%
0% 6% 1%
0%
7%
Hemoglobin (percent change compared to control)
M
F
0% 5% -2%
0% 8% -2%
Histopathological examination revealed increased numbers of degenerate
megakaryocytes in all bone marrow sections.
Doses
0 0.1 1
0%
8%
or necrotic
10
RBC count (percent change compared to control)
M
F
0% -3% 2%
0% 0% -1%
-3%
2%
Reticulocyte count (percent change compared to control)
M
F
0% -33% -50%
0% -18% -36%
-50%
45%
Hematocrit (percent change compared to control)
M
F
0% -7% -4%
0% 10% 7%
-1%
3%
Hemoglobin (percent change compared to control)
M
F
0% -10% -8%
0% 6% 6%
-6%
3%
*Statistically significantly different compared to the control, as determined by study authors (p < 0.05).
Incidence counts exclude individuals from which blood was obtained via the orbital sinus.
Doses were calculated by the study authors.
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.
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Preliminary Materials for the IRIS Toxicological Review ofRDX
1 2.9. Genotoxic Effects
Table 2-14. Summary of in vitro studies of RDX genotoxicity
Endpoint
Test system
Dose/
concentration3
Results'1
Without
activation
With
activation
Comments
Reference
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation
Reverse
mutation (umu
test)
Reverse
mutation
(NM2009test)
Salmonella, typhimurium TA1535,
TA1537, TA1538, TA98, TA100
S. typhimurium TA1535, TA1537,
TA1538 TA100, TA98
S. typhimurium TA98, TA100
S. typhimurium TA98, TA100
S. typhimurium TA98, TA100
S. typhimurium TA97a
Vibrio fischeri
Salmonella choleraesius subsp.
chol. (prior Salmonella
typhimurium) TA1535/pSK1002;
S. choleraesius subsp. chol.
NM2009,
TA1535/pSK1002/pNM12
1,000 |jg/plate
14 u.g/plate
250 |jg/plate
1 mg/plate
1,090 |jg/plate
32.7 ug/plate
0.004 |Jg/tube
20.6 |Jg/mL
20.6 |Jg/mL
-
-
-
-
±
-
-
-
-
±
+
Metabolic activation with S9
Effect of disinfection treatments on
mutagenicity tested: RDX was not mutagenic in
any strain before or after disinfection
treatment with chlorine or ozone
Study authors noted that results were
consistent with literature
Metabolic activation with S9
High S9 activation (9%) used
High S9 activation (9%) used; study authors
concluded that RDX "required intensive
metabolic activation" to exhibit mutagenicity in
this strain
Mutatox assay with metabolic activation (S9)
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
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
Cholakisetal.
(1980)
Simmon et al.
H977)
George et al.
(2001)
Tanetal.
(1992)
Pan et al.
(2007)
Pan et al.
(2007)
Arfsten et al.
(1994)
Neuwoehneret
al. (2007)
Neuwoehneret
al. (2007)
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Endpoint
Induction of
the sfiA gene
(SOS
chromotest)
Reverse
mutation
Reverse
mutation
Reverse
mutation
Test system
Escherichia. coli PQ37
S. typhimurium, TA98, TA100
S. typhimurium TA98, TA100
S. typhimurium TA1535, TA1536,
TA1537, TA1538 TA100, TA98
Dose/
concentration3
20.6 |Jg/mL
24.8|jg/mL
2.6u.g/mL
30.8|jg/mL
Results'1
Without
activation
-
-
-
With
activation
-
-
-
Comments
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
No observed effect concentration; metabolic
activation with S9
No observed effect concentration; metabolic
activation with S9
Metabolic activation with S9
Reference
Neuwoehner et
al. (2007)
Neuwoehner et
al. (2007)
Lachance et al.
(1999)
Cotruvo etal.
(1977)
Genotoxicity studies in nonmammalian eukaryotic organisms
Recombination
induction
Recombination
induction
S. cerevisiae D3
S. cerevisiae D3
23 u.g/mL
30.8|jg/mL
-
-
Study authors concluded that this
microorganism did not appear to be useful for
detecting mutagenicity in several compounds
tested
Metabolic activation with S9
Simmon etal.
(1977)
Cotruvo etal.
(1977)
Genotoxicity studies in mammalian cells
Forward
mutation
Mutation
Unscheduled
DNA synthesis;
DNA repair
Chinese hamster lung fibroblasts
V79 cells
L5178Y mouse lymphoma cells
WI-38 cells, human diploid
fibroblasts
40 u.g/mL
500 |Jg/mL
4,000 |Jg/mL
-
-
Minimal cytotoxicity observed at 40 u.g/mL
(limit of solubility)
No or low cytotoxicity seen at these
concentrations; however, precipitate was
observed >250 u.g/mL
Precipitates were observed at concentrations of
RDX>40u.g/mL
Lachance et al.
(1999)
Reddvetal.
(2005)
Dillevetal.
(1979)
1 aLowest effective dose for positive results; highest dose tested for negative results.
2 b+ = positive; ± = equivocal or weakly positive; - = negative
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Table 2-15. Summary of in vivo studies of RDX genotoxicity
Endpoint
Test system
Dose/
concentration
Results
Comments
Reference
In vivo genotoxicity studies in mammalian systems
Micronucleus
formation
Dominant lethal
mutations
CD-I mouse bone marrow
Male CD rats dosed and mated with
untreated female rats
Single dose of 62.5,
125, or250mg/kg
0, 5, 16, or
50 mg/kg-day for
15 wk
No significant decrease in
PCE:NCE ratios; no
induction of
micronucleated PCE at any
dose
No statistically or
biologically significant
effects on fertility;
determined to be negative
for the induction of lethal
mutations
250 mg/kg was maximum
tolerated dose determined in
dose range-finding study
Males in the high-dose group
experienced lower food
consumption and weight gain
compared with all other
groups
Reddvetal. (2005)
Cholakisetal.
(1980)
2
3
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Preliminary Materials for the IRIS Toxicological Review ofRDX
Table 2-16. Summary of in vitro and in vivo studies of RDX metabolite genotoxicity
Endpoint
Test system
Dose/
concentration3
Results'1
Without
activation
With
activation
Comments
Reference
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Reverse
mutation
Reverse
mutation
Salmonella typhimurium TA97a,
TA102
S. typhimurium TA1535, TA1537,
TA1538, TA98, TA100
S. typhimurium TA1535, TA1537,
TA1538, TA98, TA100
22 |jg/plate
500 ug/plate
NRC
-
+
-
+
+
-
Mono and trinitroso metabolites (MNX and
TNX); high S9 activation (9%) used
Positive only for TNX; MNX and DNX were
negative
Mononitroso metabolite, MNX; metabolic
activation with S9
Pan etal. (2007)
George etal. (2001)
Snodgrass (1984)
Genotoxicity studies in mammalian cells— in vitro
Forward
mutation
Chromosomal
aberrations
Unscheduled
DNA synthesis;
DNA repair
Mouse lymphoma thymidine
kinase
Chinese hamster ovary cells
Primary rat hepatocytes
NRC
NRC
NRC
+
-
+
+
+
Mononitroso metabolite, MNX; metabolic
activation with S9
Mononitroso metabolite, MNX; metabolic
activation with S9
Mononitroso metabolite, MNX; additional
metabolic activation not required with S9
Snodgrass (1984)
Snodgrass (1984)
Snodgrass (1984)
In vivo genotoxicity studies in mammalian systems
Dominant lethal
mutations
Male mice dosed and mated with
untreated female mice
NRC
Mononitroso metabolite, MNX; additional
metabolic activation not required with S9
Snodgrass (1984)
aLowest effective dose for positive results; highest dose tested for negative results.
+ = positive; ± = equivocal or weakly positive; - = negative
CNR = not reported
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