Annotated Reference Outline for the Toxicological Review of Hexahydro-1 3 5-trinitro-1 3 5-triazine (rdx)


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ANNOTATED REFERENCE OUTLINE
FOR THE TOXICOLOGICAL REVIEW
OF
HEXAHYDRO-l,3,5-TRINITRO-l,3,5-
TRIAZINE (RDX)
(CAS No. 121-82-4)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
November 23, 2010
NOTICE
This document is an [author: insert Agency Review, Interagency Review or External Review]
draft. This information is distributed solely for the purpose of pre-dissemination peer 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.
U.S. Environmental Protection Agency
Washington, DC

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REVIEWS
ATSDR (Agency for Toxic Substances and Disease Registry). (1995) Public Health Service, U.S. Department of
Health and Human Services. Toxicological profile for RDX. Available from ATSDR, Atlanta, GA, and National
Technical Information Service, Springfield, VA; and .
McLellan, WL; Harley, WR; Brown, ME. (1992) Hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). In: Roberts WC,
Hartley WR, eds. Drinking Water Health Advisory: Munitions. United States Environmental Protection Agency.
Boca Raton, FL: Lewis, pp. 133-180.
Small, MJ; Rosenblatt, DH. (1974) Technical Report 7404 Munitions Production Products of Potential Concern as
Waterborne Pollutants - Phase II. US Army Medical Bioengineering Research and Development Laboratory.
Aberdeen Proving Ground, MD.
U.S. EPA. (1988) Health advisory for hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). Criteria and Standards
Division, Office of Drinking Water, Washington, DC.
2. CHEMICAL AND PHYSICAL INFORMATION
ACGIH (American Conference of Governmental Industrial Hygienists) (2001). Cyclonite. In Documentation of the
Threshold Limit Values and Biological Exposure Indices (pp. 1-6). Cincinnati, OH: American Conference of
Governmental Industrial Hygienists.
Akhavan, J. (2005) Explosives and propellants. In: Kirk-Othmer Encyclopedia of Chemical Technology. Vol. 10.
New York, NY: John Wiley & Sons, Incorporated; pp. 719-744.
Boileau, J; Fauquignon, C; Hueber, B. (2005) Explosives. In: Ullmann's encyclopedia of industrial chemistry.
Weinheim: Wiley-VCH Verlag GmbH and Company; pp. 1-33.
ChemlD. (2004) RDX. ChemlDplus. National Library of Medicine. Available from:
.
Funk, SB; Roberts, DJ; Crawford, DL; et al. (1993) Initial-phase optimization for bioremediation of munition
compound-contaminated soils. Appl Environ Microbiol 69:2171-2177.
Hawley, GG; Lewis, RJ. (2001) Cyclonite. In: Hawley's condensed chemical dictionary. 14th ed. New York, NY:
John Wiley and Sons, Incorporated; pp. 323.
HSDB (Hazardous Substances Data Bank). (2006) Cyclonite. Hazardous Substances Data Bank, National Library of
Medicine. Available from: .
Lewis, RJ. (2000) Cyclonite. In: Sax's dangerous properties of industrial materials. 10th ed. New York, NY: John
Wiley and Sons, Incorporated; pp. 1050.
Lide, DF. (2005) Cyclonite. In: CRC handbook of chemistry and physics. 86th ed. Boca Raton, FL: CRC Press,
Incorporated; pp. 3-280.
LOGKOW. (2004) 1,3,5-triazine, hexahydro-l,3,5-trinitro-. A databank of evaluated octanol-water partition
coefficients (LogP). Sangster Research Laboratories. Available from:
.
Meyer, R; Kohler, J; Homburg, A. (2002) Cyclonite. In: Explosives. 5th ed. Weinheim, Germany: Wiley-VCH; pp.
68-71.
O'Neil, MJ; Smith, A; Heckelman, PE; et al. (2001) Cyclonite. In: Merck index. 13th ed. Whitehouse Station, NJ:
Merck Research Laboratories; pp. 2767.
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SRI. (2006) Cyclonite. In: Directory of chemical producers. Menlo Park, CA: Access intelligence, LLC; pp. 410.
Yalkowsky, SH; He, Y. (2003) Cyclonite. In: Handbook of aqueous solubility data. Boca Raton, FL: CRC Press; pp.
63.
3. TOXICOKINETICS
Bannon, DI. (2010) Biomarkers of RDX (trinitro hexahydro-l,3,5-trinitro-l ,3,5-triazone) exposure in breath of
swine. Directorate of Toxicology Health Effects Research Program.
[No Author Listed]. (2006) Biomarkers of RDX exposure in breath of swine. Laurel, MD: JohnHopkins University
Applied Physics Laboratory. U.S. Army Center for Health Promotion and Preventive Medicine. Toxicology study
no. 87-XE-059F-06.
Reddy, G; Eisenhut, K; Morrison, SA et al. (1989) Toxicokinetics of 14-C RDX (cyclotrimethylenetrinitramine) in
rats after intratracheal administration. Toxicologist 9:83 (Abstract).
Woody, RC; Kearns, GL; Brewster, MA et al. (1986) The neurotoxicity of cyclotrimethylenetrinitramine (RDX) in a
child: a clinical and pharmacokinetic evaluation. Clin Toxicol 24(4):305-319.
3.1.	ABSORPTION
Crouse, LC; Michie, MW; Major, MA; Leach, GJ; Reddy, G. (2008) Oral bioavailability of
cyclotrimethylenetrinitramine (RDX) from contaminated site soils in rats. Int J Toxicol 27(4):317-322.
Fellows, RJ; Driver, CR; Cataldo, DA; Harvey, SD. (2006) Bioavailability of hexahydro-l,3,5-trinitro-l,3,5-triazine
(RDX) to the prairie vole (Microtus ochrogaster). Environmental toxicology and chemistry 25:1881-1886.
Oxley, J; Smith, J; Kirschenbaum, JL; Shinde, KP; Marimganti, S. (2005) Accumulation of explosives in hair.
Journal of Forensic Sciences 50(4):826-831.
Oxley J; Smith J; Kirschenbaum, LJ; Marimganti, S. (2007) Accumulation of explosives in hair-part II: factors
affecting sorption. Journal of Forensic Sciences 52(6): 1291-1296.
Ozhan, G; Topuz, S; Alpertunga, B. (2003) Determination of cyclonite (RDX) in human plasma by high-
performance liquid chromatography. II Farmaco 58:445-448.
Reddy, G; Allen, NA; Major, MA. (2008) Absorption of [14C]-Cyclotrimethylenetrinitramine (RDX) from soils
through excised human skin. Toxicol Mech Methods 18(7):575-579.
Reifenrath, WG; Kammen, HO; Palmer, WG; Major, MA; Leach, GJ. (2002) Percutaneous absorption of explosives
and related compounds: An empirical model of bioavailability of organic nitro compounds from soil. Toxicol Appl
Pharmacol 182:160-168.
Reifenrath, WG; Kammen, HO; Reddy, G; Major, MA; Leach, GJ. (2008) Interaction of hydration, aging, and
carbon content of soil on the evaporation and skin bioavailability of munition contaminants. J Toxicol Environ
Health A 71(8):486-494.
3.2.	DISTRIBUTION
Guo, L; Xu, H; Chen, Y; et al. (1985) Distribution and metabolism of 3H-RDX in mice. Zhonghua Laodong
Weisheng Zhiyebing Zazhi 3(6):335-339. (Translated)
Schneider, NR; Bradley, SL; Andersen, ME. (1977) Toxicology of cyclotrimethylenetrinitramine: distribution and
metabolism in the rat and the miniature swine. Toxicol Appl Pharmacol 39:531-541.
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Schneider, NR; Bradley, SL; Andersen, ME. (1978) The distribution and metabolism of
cyclotrimethylenetrinitramine (RDX) in the rat after subchronic administration. Toxicol Appl Pharmacol 46:163-
171.
3.3.	METABOLISM
Bhushan, B; Trott, S; Spain, JC; et al. (2003) Biotransformation of hexahydro-1,3,5-triazine (RDX) by rabbit liver
cytochrome P450: insight into the mechanism of RDX biodegradation by Rhodococcus sp. DN22. Am Soc
Microbiol 69:1347-1351.
Cao, CJ etal. (2008) In vitro study of hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) metabolism in human liver.
Toxicology study no. 87-XE-0982-09. Vicksbury, MS: U.S Army Engineer Research and Development Center.
Major, MA; Reddy, G; Berge, MA; Patzer, SS; Li, AC; Gohdes, M. (2007) Metabolite profiling of [14C]hexahydro-
l,3,5-trinitro-l,3,5-triazine (RDX) in Yucatan miniature pigs. JToxicolEnvironHealthA70(14):1191-1202.
Pan, X; Zhang, B; Smith, JN; Francisco, MS; Anderson, TA; Cobb, GP. (2007) N-Nitroso compounds produced in
deer mouse (Peromyscus maniculatus) GI tracts following hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) exposure.
Chemosphere 67(6): 1164-1170.
3.4.	ELIMINATION
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
Krishnan, K; Crouse, LC; Bazar, MA; Majo,r MA; Reddy, G. (2009) Physiologically based pharmacokinetic
modeling of cyclotrimethylenetrinitramine in male rats. J Appl Toxicol 29(7):629-637.
[No Author Listed] (2007) Physiologically based pharmacokinetic (PBPK) modeling of RDX in rats, miniature
swine, and humans. Draft report. U.S. Army Center.
4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
Barsotti, M; Crotti, G. (1949) Epileptic attacks as manifestations of industrial intoxication caused by.
trimethylenetrinitroamine (T4). La Medicina Del Lavoro 40:107-112.
Bell, SC; Gayton-Ely, M; Nida, CM. (2009) Bioassays for bomb-makers: proof of concept. Anal Bioanal Chem
395(2):401-409.
Buck, CR; Wilson, SE. (1976) Occupational health special study no. 32-049-75/76: Adverse health effects of
selected explosives (TNT, RDX). January-November, 1975. U.S. Army Environmental Hygiene Agency, Aberdeen
Proving Ground, MD.
Davies, JO; Roberts, DM; Hittarage, A; Buckley, NA. (2007) Oral C-4 plastic explosive in humans - a case series.
Clin Toxicol 45(5):454-457.
Goldberg, DJ; Green, ST; Nathwani, D; et al. (1992) RDX intoxication causing seizures and a widespread petechial
rash mimicking meningococcaemia. J Royal Soc Med 85:181.
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Harrell-Bruder, B; Hutchins, KL. (1995) Seizures caused by ingestion of composition C-4. Ann Emerg Med 26:746-
748.
Hathaway, JA; Buck, CR. (1977) Absence of health hazards associated with RDX manufacture and use. J Occup
Med 19(4):269-272.
Hett, DA; Fitchner, K. (2002) A plastic explosive by mouth. J R Soc Med 95(5):251-252.
Hollander, AI; Colbach, EM. (1969) Composition C-4 induced seizures: a report of five cases. Mil Med 134(13):
1529-1530.
Kaplan, AS; Berghout, CF; Peczenik, A. (1965) Human intoxication from RDX. Arch Environ Health 10:877-883.
Kasuske, L; Schofer, JM; Hasegawa, K. (2009) Two marines with generalized seizure activity. J Emerg Nurs
35(6):542-543.
Ketel, WB; Hughes, JR. (1972) Toxic encephalopathy with seizures secondary to ingestion of composition C-4: a
clinical and electroencephalographic study. Neurology 22:871-876.
Knepshield, JH; Stone, WJ. (1972) Toxic effects following ingestion of C-4 plastic explosive. In: Keup W, ed. Drug
abuse: Current concepts and research. New York: Charles C. Thomas; pp. 296-300.
Kucukardali, Y; Acar, HV; Ozkan, S; et al. (2003) Accidental oral poisoning caused by RDX (cyclonite): a report of
5 cases. J Intensive Care Med 18(l):42-46.
Ma, B; Li, H. (1992) Neurobehavioral effects of hexogen. Gongye Weisheng Yu Zhiyebing 19(l):20-23.
(Translated)
Merrill SL. (1968) Ingestion of an explosive material, composition C-4. USARV Medical Bulletin 8:5-10.
Ryu, H; Han, JK; Jung, JW; Bae, B; Nam, K. (2007) Human health risk assessment of explosives and heavy metals
at a military gunnery range. Environ Geochem Health 29(4):259-269.
Stone, WJ; Paletta, TL; Heiman, EM; et al. (1969) Toxic effects following ingestion of C-4 plastic explosive. Arch
Intern Med 124:726-730.
Sundermann, FW. (1944) Hazards to the health of individuals working with RDX. ATI Collection, Fort Belvoir, VA.
Testud, F; Glanclaude, J-M; Imperatori, J; et al. (1996a) Acute hexogen poisoning after occupational exposure:
Report of two cases. Arch Mai Prof 57(5):342-346.
Testud, F; Glanclaude, J-M; Descotes, J. (1996b) Acute hexogen poisoning after occupational exposure. J Toxicol:
Clin Toxicol 34(1): 109-111.
West, RR; Stafford, DA. (1997) Occupational exposures and haematological abnormalities among ordinance factory
workers: a case control study. Leuk Res 21(7):675-680.
4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN
ANIMALS—ORAL AND INHALATION
Brown, D. (1975) The acute and chronic biochemical and behavioral effects of cyclotrimethylenetrinitramine.
Maryland University, Baltimore School of Pharmacy, Baltimore, MD.
Crouse, LCB; Michie, MW; Major, MA; Johnson, MS; Lee, RB; Paulus, HI. (2006) Subchronic oral toxicity of
RDX in rats. Aberdeen Proving Ground, MD. US Army Center for Health Promotion and Preventive Medicine.
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Furedi-Machacek, EM; Levine, BS; Lish, PM. (1984) Determination of the chronic mammalian toxicological effects
of RDX. Acute dermal toxicity test of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in rabbits. Prepared by IIT
Research Institute, Chicago, IL, for U.S. Army Medical Research and Development Command, Frederick, MD
Hart, ER. (1974) Subacute toxicity of RDX and TNT in dogs. Litton Bionetics Incorporated, Kensington, MD.
Hart, ER. (1976) Two-year chronic toxicity study in rats. Litton Bionetics Incorporated, Kensington MD.
Levine, BS; Furedi, EM; Gordon, DC; et al. (1981a) Thirteen week oral (diet) toxicity study of trinitrotoluene
(TNT), hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) and TNT/RDX mixtures in the Fischer 344 rat. Prepared by
IIT Research Institute, Chicago, IL, for U.S. Army Medical Research and Development Command, Frederick, MD.
Levine, BS; Furedi, EM; Gordon, DC; etal. (1981b) Thirteen week toxicity study of hexahydro-1,3.5-trinitro-1.3.5-
triazine (RDX) in Fischer 344 rats. Toxicol Letters 8:241-245.
Levine, BS; Furedi, EM; Gordon, DE; et al. (1990) Toxic interactions of the munitions compounds TNT and RDX in
F344 rats. Fundam Appl Toxicol 15:373-380.
Levine BS; Furedi EM; Rac VS; et al. (1983) Determination of chronic mammalian toxicological effects of RDX:
(Twenty-four month chronic toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the
Fischer 344 rat). Volume 1. Prepared by ITT Research Institute, Chicago, IL.
Lish, PM; Levine, BS; Furedi, EM et al. (1984) Determination of chronic mammalian toxicological effects of RDX:
(Twenty-four month chronic toxicity/carcinogenicity study of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the
B6C3F1 hybrid mouse). Phase 6. Volume 1. Prepared by ITT Research Institute, Chicago, IL.
Parker GA; Reddy G; Major MA. (2006) Reevaluation of a twenty-four-month chronic toxicity/carcinogenicity study
of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the B6C3F1 hybrid mouse. International Journal of Toxicology
25:373-378.
Von Oettingen, WF; Donahue, DD; Yagoda, H; et al. (1949) Toxicity and potential dangers of
cyclotrimethylenetrinitramine (RDX). J Ind Hyg Toxicol 3 l(l):21-31.
Wong, LCK; Cholakis, JM; Hong, CB; et al. (1982) Acute and subchronic oral toxicologic studies of hexahydro-
l,3,5-trinitro-l,3,5-triazine (RDX) in rats and mice (Abstract). Toxicologist 2:34.
4.3.	REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Angerhofer, RA; Davis, G; Balazewski, L (1986) Teratological assessment of trinitro-RDX in rats. U.S. Army
Environmental Hygiene Agency, Aberdeen Proving Ground, MD.
Hess-Ruth A et al. (2007) RDX pilot for developmental. Aberdeen Proving Ground, MD: U.S. Army Environmental
Center. Toxicology study no. 85-XC-064Y-07.
Minor, JL; Short, RD; Van Goethem, DL et al. (1982) Mutagenic and reproductive studies of hexahydro-1,3,5-
trinitro-1,3,5-triazine (RDX) in rats and rabbits. Toxicologist 2:34-35.
4.4.	OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES
Berry, AP; Arbuckle, JBR; Nicol J. (1983) Cyclonite poisoning in a dog. Vet Record 113(19):449.
Bruchim Y; Saragusty J; Weisman A; Sternheim D. (2005) Cyclonite (RDX) intoxication in a police working dog.
VetRec. 157(12):354-356.
Burdette, LJ; Cook, LL; Dyer, RS. (1988) Convulsant properties of cyclotrimethylenetrinitramine (RDX):
spontaneous, audiogenic, and amygdaloid kindled seizure activity. Toxicol Appl Pharmacol 92:436-444.
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Cholakis, JM; Wong, LCK; VanGoethem, DL; et al. (1980) Mammalian toxicological evaluation of RDX. Prepared
by Midwest Research Institute, Kansas City, MO, for U.S. Army Medical Research and Development Command,
Frederick, MD.
Dilley, JV; Tyson, CA; Newell, GW. (1978) Mammalian toxicological evaluation of TNT wastewaters. Volume II:
Acute and subacute mammalian toxicity of TNT and the LAP mixture. Prepared by SRI International, Menlo Park,
CA, for U.S. Army Medical Research and Development Command, Washington, DC.
Dilley, JV; et al. (1982) Short-term oral toxicity of 2,4,6-trinitrotoluene and hexahydro-l,3,5-trinitrol,3,5-triazine
mixture in mice, rats, and dogs. J Toxicol Environ Health 9:587-610.
Ferguson, JW; Mccain, WC. (1999) Fourteen-day feeding study of hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX) in
the white-footed mouse, Peromyscus leucopus, 2 June-23 July 1997. Toxicological study no. 6955-31-97-05-02.
Cincinnati, OH: U.S. Environmental Protection Agency.
French, JE; Bradley, SL; Schneider, NR et al. (1976) Cyclotrimethylenetrinitramine (RDX)-induced ultrastructural
changes in rat liver and kidney. Toxicol Appl Pharmacol 37:122.
MacPhail, RC; Walker, QD; Cook, LC. (1985) Neurotoxicology of cyclotrimethylenetrinitramine (RDX). U.S. Army
Medical Research and Development Command, Frederick, MD.
Martin, DP; Hart, ER. (1974) Subacute toxicity of RDX and TNT in monkeys. Prepared by Litton Bionetics, Inc.,
Kensington, MD, for Office of Naval Research, Arlington, VA.
McNamara, BP; Averill, HP; Owens, EJ et al. (1974) The toxicology of cyclotrimethylenetrinitramine (RDX) and
cyclotetramethylenetetranitramine (HMX) solutions in dimethylsulfoxide (DMSO), cyclohexanone, and acetone.
Edgewood Arsenal Technical Report, Department of the Army.
Meyer, SA; Marchand, AJ; Hight, JL; et al. (2005) Up-and-down procedure (UDP) determinations of acute oral
toxicity of nitroso degradation products of hexahydro-1,3,5-trinitro 1,3,5-triazine (RDX). J Appl Toxicol 25:427-434.
Sklyanskaya, RM; Pozhariskii, FI. (1944) On the question of hexogen toxicity. Farmakologiia i toksikologiia
7(3):43-47.
Smith, JN; Liu, J; Espino, MA; Cobb, GP (2007) Age dependent acute oral toxicity of hexahydro-1,3,5-trinitro-
1,3,5-triazine (RDX) and two anaerobic N-nitroso metabolites in deer mice (Peromyscus maniculatus).
Chemosphere 67:2267-2273.
Stork, CM; Kos, S; Langden, B et al. (2000) Acute canine C-4 explosive ingestion resulting in prolonged status
epilepticus. NACCT Abstracts 526-527.
4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF
ACTION
Bannon, DI; Dillman, JF; Hable, MA; Phillips, CS; Perkins, EJ. (2009) Global gene expression in rat brain and liver
after oral exposure to the explosive hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX). ChemRes Toxicol. 22(4):620-
625.
Bannon, DI; Johnson, M; Williams, L et al. (2009) RDX and miRNA expression in B6C3Flmice. Environ Health
Perspect 117(3):A98; author reply A98-99.
Ehrich, M; Wu, X; Werre, SR; Major, MA; McCain, WC; Reddy, G (2009) Calcium signaling in neuronal cells
exposed to the munitions compound Cyclotrimethylenetrinitramine (RDX). Int J Toxicol 28(5):425-435.
Major, M. (2005) Evaluation of cytotoxic potential of RDX in primary rat and human neuronal cultures.
Edgewater, MD: Aberdeen Proving Ground.
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Meyer, SA. (2006) Role of myelofibrosis in hematotoxicity of munitions RDX environmental degradation product
MNX. Prepared for U.S. Army Medical Research and Materiel Command. Fort Detrick MD.
Meyer, SA. (2007) Role of myelofibrosis in hematotoxicity of munitions RDX environmental degradation product
MNX. Prepared for U.S. Army Medical Research and Materiel Command. Fort Detrick MD.
Meyer, SA. (2008) Role of myelofibrosis in hematotoxicity of munitions RDX environmental degradation product
MNX. Prepared for U.S. Army Medical Research and Materiel Command. Fort Detrick MD.
Meyer, SA. (2009) Role of myelofibrosis in hematotoxicity of munitions RDX environmental degradation product
MNX. Prepared for U.S. Army Medical Research and Materiel Command. Fort Detrick MD.
Perkins, EJ; Bao, W; Guan, X; Ang, CY; Wolfinger, RD; Chu, TM; Meyer, SA; Inouye, LS. (2006) Comparison of
transcriptional responses in liver tissue and primary hepatocyte cell cultures after exposure to hexahy dro-1,3,5-
trinitro-l,3,5-triazine. BMC Bioinformatics 7 (Suppl. 4), 22.
Way, M; McCain, W. (2007) Protective effects of the calcium channel blocker, Verapamil, in rats exposed to RDX.
U.S. Army Center for Health Promotion and Preventive Medicine. Toxicology study no. 85-XC-08RU-08.
Williams, LR; Johnstone, A; Bannon, DI; Shafer, TJ. (2010) RDX binds to the convulsant site of the GABAA
receptor and increases spontaneous firing rates of cortical neurons in vitro. Presented at Society of Toxicology 49th
Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010. Online.
http://cfpub.epa.gov/si/si_public_record_Report.cfm?dirEntryID=216690.
Williams, L; Bannon, DI. (2009) Mechanism of RDX-induced seizures in rats. Army Environmental Center IMAE-
CD UAEC, Hoadley Road APG, MD 21010-5401.
Zhang, B; Pan, X. (2009) RDX induces aberrant expression of microRNAs in mouse brain and liver. Environmental
Health Perspectives 117(2):231-240.
4.5.1. Genotoxicity and Mutagenicity
Arfsten, DP; Davenport, R; Schaeffer, DJ. (1994) Reversion of bioluminescent bacteria (Mutatox™) to their
luminescent state upon exposure to organic compounds, munitions, and metal salts. Biomed Environ Sci 7:144-149.
Berthe-Corti, L; et al. (1998). Cytotoxicity and mutagenicity of a 2,4,6-trinitrotoluene (TNT) and hexogen
contaminated soil in S. typhimurium and mammalian cells. Chemosphere 37(2):209-18.
George, SE; Huggins-Clark, G; Brook, LR. (2001) Use of a Salmonella microsuspension bioassay to detect the
mutagenicity of munitions compounds at low concentrations. Mutat Res 490:45-56.
Lachance, B; Robidoux, PY; Hawari, J; et al. (1999) Cytotoxic and genotoxic effects of energetic compounds on
bacterial and mammalian cells in vitro. Mutat Res 444:25-39.
Min, D; Quiong, W; Bin, L; Ruizhang, C. (1995) The mutagenicity of several chemicals by vicia-micronucleus
(Vicia-MCN) assay. 26th Annual meeting of the Environmental Mutagen Society, March 12-16, 1995; St. Louis, MI.
Environ Mol Mutagen 25(Suppl 25): 10.
Neuwoehner, J; Schofer, A; Erlenkaemper, B; Steinbach, K; Hund-Rinke, TK; Eisentraeger, A. (2007) Toxicological
characterization of 2,4,6-trinitrotoluene, its transformation products, and two nitramine explosives. Environ Toxicol
Chem 26(6): 1090-1099.
Pan, X; San Francisco, MJ; Lee, C; et al. (2007) Examination of the mutagenicity of RDX and its N-nitroso
metabolites using the Salmonella reverse mutation assay. Mutat Res 629(l):64-69.
Reddy, G; Erexson, GL; Cifone, MA; Major, MA; Leach GJ. (2005) Genotoxicity assessment of hexahy dro-1,3,5-
trinitro-l,3,5-triazine (RDX). Int J Toxicol 24(6):427-434.
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Simmon, VF; Spanggord, RJ; Eckford, SL; et al. (1977). Mutagenicity of some munitions wastewater chemicals and
chlorine test kit reagents. Prepared by SRI International, Menlo Park, CA.
Tan, EI; Ho, CH; Griest, WH; et al. (1992) Mutagenicity of trinitrotoluene and its metabolites formed during
composting. J Toxicol Environ Health 36:165-175.
Whong, WZ; Speciner, ND; Edwards, GS. (1980) Mutagenicity activity of tetryl, a nitroaromatic explosive, in three
microbial test systems. Toxicol Lett 5:11-17.
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4.6.	SYNTHESIS OF MAJOR NONCANCER EFFECTS
4.6.1.	Oral
4.6.2.	Inhalation
4.6.3.	Mode of Action Information
4.7.	EVALUATION OF CARCINOGENICITY
4.7.1.	Summary of Overall Weight-of-Evidence
4.7.2.	Synthesis of Human, Animal, and Other Supporting Evidence
4.7.3.	Mode of Action Information
4.8.	SUSCEPTIBLE POPULATIONS AND LIFE STAGES
A-9
DRAFT - DO NOT CITE OR QUOTE

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