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Draft Charge to the Science Advisory Board for the

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

March 2016

Introduction

The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of a draft 

Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) developed in support of the 

Agency’s online database, the Integrated Risk Information System (IRIS). IRIS is prepared and 

maintained by EPA’s National Center for Environmental Assessment (NCEA) within the Office of 

Research and Development (ORD). 

IRIS is a human health assessment program that evaluates scientific information on effects that may 

result from exposure to specific chemicals in the environment. Through IRIS, EPA provides high 

quality science-based human health assessments to support the Agency’s regulatory activities and 

decisions to protect public health. IRIS assessments contain information for chemicals that can be 

used to support hazard identification and dose-response assessment, two of the four steps in the 

human health risk assessment process. When supported by available data, IRIS provides health 

effects information and toxicity values for health effects (including cancer and effects other than 

cancer) resulting from chronic exposure. IRIS toxicity values may be combined with exposure 

information to characterize public health risks of chemicals; this risk characterization information 

can then be used to support risk management decisions. 

An existing assessment for RDX includes a reference dose (RfD) posted on the IRIS database in 

1988 and oral slope factor (OSF) and a cancer descriptor posted in 1990. The IRIS Program is 

conducting a reassessment of RDX. The draft Toxicological Review of RDX is based on a 

comprehensive review of the available scientific literature on the noncancer and cancer health 

effects in humans and experimental animals exposed to RDX. Additionally, appendices for chemical 

and physical properties, toxicokinetic information, summaries of toxicity studies, and other 

supporting materials are provided as Supplemental Information (see Appendices A to D) to the draft 

Toxicological Review. 

The draft assessment was developed according to guidelines and technical reports published by 

EPA (see Preamble), and contains both qualitative and quantitative characterizations of the human 

health hazards for RDX, including a cancer descriptor of the chemical’s human carcinogenic 

potential, a noncancer toxicity value for chronic oral exposure (RfD), and a cancer risk estimate for 

oral exposure. 
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Charge questions on the draft Toxicological Review of RDX

1. Literature search/study selection and evaluation. The section on Literature Search Strategy 

| Study Selection and Evaluation describes the process for identifying and selecting pertinent 

studies. Please comment on whether the literature search strategy, study selection 

considerations, and study evaluation considerations are appropriate and clearly described. 

Please identify additional peer-reviewed studies that the assessment should consider. 

2. Toxicokinetic modeling. In Appendix C, Section C.1.5, the draft assessment presents a 

summary, evaluation, and further development of published PBPK models for RDX in rats, mice, 

and humans (Sweeney et al., 2012a, b). 

2a. Are the conclusions reached based on EPA’s evaluation of the models scientifically 

supported? Do the revised PBPK models adequately represent RDX toxicokinetics? Are the 

model assumptions and parameters clearly presented and scientifically supported? Are the 

uncertainties in the model appropriately considered and discussed? 

2b. The average concentration of RDX in arterial blood (expressed as area under the curve) was 

selected over peak concentration as the dose metric for interspecies extrapolation for oral 

points of departure (PODs) derived from rat data. Is the choice of dose metric for each 

hazard sufficiently explained and appropriate? The mouse PBPK model was not used to 

derive PODs for noncancer or cancer endpoints because of uncertainties in the model and 

because of uncertainties associated with selection of a dose metric for cancer endpoints. Is 

this decision scientifically supported?

2c. In Section 2.1.3 of the draft assessment, an uncertainty factor of 10 for human variation is 

applied in the derivation of the RfD. Does the toxicokinetic modeling support the use of a 

different factor instead? 

3. Hazard identification and dose–response assessment. In Chapter 1, the draft assessment 

evaluates the available human, animal, and mechanistic studies to identify health outcomes that 

may result from exposure to RDX. In Chapter 2, the draft assessment develops organ/systemspecific reference values for the health outcomes identified in Chapter 1, then selects overall 

reference values for each route of exposure. The draft assessment uses EPA’s guidance 

documents (see http://www.epa.gov/iris/basic-information-about-integrated-riskinformation-system#guidance) to reach the following conclusions.

[Note: As suggested by the Chemical Assessment Advisory Committee panel that reviewed the 

draft IRIS assessment of benzo[a]pyrene, the charge questions in this section are organized by 

health outcome, with a question on each hazard identification followed by questions on the 

corresponding organ/system-specific toxicity values. This suggestion, however, entails some 

redundancy, as some questions apply equally to multiple health outcomes.] 

3a. Nervous system effects. 

(i) Nervous system hazard (Sections 1.2.1, 1.3.1). The draft assessment concludes that 

nervous system toxicity is a human hazard of RDX exposure. Please comment on 

whether the available human, animal, and mechanistic studies support this 

conclusion. Please comment on whether the selection of convulsions as the endpoint 

to represent this hazard is scientifically supported and clearly described.
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(ii) Nervous system-specific toxicity values (Section 2.1.1). Please comment on

whether the selection of studies reporting nervous system effects is scientifically

supported and clearly described. Considering the difference in toxicokinetics between 

gavage and dietary administration (described in Appendix C, Section C.1, and in the 

context of specific hazards in the toxicological review), is it appropriate to consider 

the Crouse et al. (2006) study, which used gavage administration? Please comment on 

whether the characterization of convulsions as a severe endpoint, and the potential 

relationship to mortality, is appropriately described.

(iii) Points of departure for nervous system endpoints (Section 2.1.2). Please comment 

on whether the calculation of PODs for these studies is scientifically supported and 

clearly described. Does the severity of convulsions warrant the use of a benchmark 

response level of 1% extra risk? Is calculation of the lower bound on the benchmark 

dose (BMDL) for convulsions appropriate and consistent with the EPA’s Benchmark 

Dose Guidance?

(iv) Uncertainty factors for nervous system endpoints (Section 2.1.3). Please comment 

on whether the application of uncertainty factors to these PODs is scientifically 

supported and clearly described. The subchronic and database uncertainty factors 

incorporate multiple considerations; please comment specifically on the scientific 

rationale for the application of a subchronic uncertainty factor of 1 and a database 

uncertainty factor of 3.1

(v) Nervous system-specific reference dose (Section 2.1.4). Please comment on 

whether the organ/system-specific reference dose derived for nervous system effects 

is scientifically supported and clearly characterized. 

3b. Kidney and other urogenital system effects. 

(i) Kidney and other urogenital system hazard (Sections 1.2.2, 1.3.1). The draft 

assessment concludes that kidney and other urogenital system toxicity is a potential 

human hazard of RDX exposure. Please comment on whether the available human, 

animal, and mechanistic studies support this conclusion. Please comment on whether 

the selection of suppurative prostatitis as the endpoint to represent this hazard is 

scientifically supported and clearly described.

(ii) Kidney and other urogenital system-specific toxicity values (Section 2.1.1). Please 

comment on whether the selection of the Levine et al. (1983) study that describes 

kidney and other urogenital system effects is scientifically supported and clearly 

described.

(iii) Points of departure for kidney and other urogenital system endpoints (Section 

2.1.2). Please comment on whether the calculation of a POD for this study is 

scientifically supported and clearly described. 

 1 Note that the database uncertainty factor applies to each of the hazards identified in the toxicological 

review. 
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(iv) Uncertainty factors for kidney and other urogenital system endpoints (Section 

2.1.3). Please comment on whether the application of uncertainty factors to the POD is 

scientifically supported and clearly described. 

(v) Kidney and other urogenital system-specific reference dose (Section 2.1.4). 

Please comment on whether the organ/system-specific reference dose derived for 

kidney and other urogenital system effects is scientifically supported and clearly 

characterized. 

3c. Developmental and reproductive system effects. 

(i) Developmental and reproductive system hazard (Sections 1.2.3, 1.3.1). The draft 

assessment concludes that there is suggestive evidence of male reproductive effects 

associated with RDX exposure, based on evidence of testicular degeneration in male 

mice. The draft assessment did not draw any conclusions as to whether

developmental effects are a human hazard of RDX exposure. Please comment on 

whether the available human, animal, and mechanistic studies support these

conclusions. 

(ii) Reproductive system-specific toxicity values (Section 2.1.1). Please comment on 

whether the selection of the Lish et al. (1984) study that describes male reproductive 

system effects is scientifically supported and clearly described. 

(iii) Points of departure for reproductive system endpoints (Section 2.1.2). Please 

comment on whether the calculation of a POD for this study is scientifically supported

and clearly described. 

(iv) Uncertainty factors for reproductive system endpoints (Section 2.1.3). Please 

comment on whether the application of uncertainty factors to the POD is scientifically 

supported and clearly described. 

(v) Reproductive system-specific reference dose (Section 2.1.4). Please comment on 

whether the organ/system-specific reference dose derived for reproductive system 

effects is scientifically supported and clearly characterized. 

3d. Other noncancer hazards (Sections 1.2.4, 1.2.6, 1.3.1). The draft assessment did not draw 

any conclusions as to whether liver, ocular, musculoskeletal, cardiovascular, immune, or 

gastrointestinal effects are human hazards of RDX exposure. Please comment on whether 

the available human, animal, and mechanistic studies support this conclusion. 

3e. Cancer. 

(i) Cancer hazard (Sections 1.2.5, 1.3.2). There are plausible scientific arguments for 

more than one hazard descriptor as discussed in Section 1.3.2. The draft assessment 

concludes that there is suggestive evidence of carcinogenic potential for RDX, and that 

this descriptor applies to all routes of human exposure. Please comment on whether 

the available human, animal, and mechanistic studies support this conclusion. 

(ii) Cancer-specific toxicity values (Section 2.3.1). As noted in EPA’s 2005 Guidelines for 

Carcinogen Risk Assessment, “When there is suggestive evidence, the Agency generally 
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would not attempt a dose-response assessment, as the nature of the data generally 

would not support one; however, when the evidence includes a well-conducted study, 

quantitative analyses may be useful for some purposes, for example, providing a sense 

of the magnitude and uncertainty of potential risks, ranking potential hazards, or 

setting research priorities.” Does the draft assessment adequately explain the 

rationale for quantitative analysis, considering the uncertainty in the data and the 

suggestive nature of the weight of evidence, and is the selection of the Lish et al. 

(1984) study for this purpose scientifically supported and clearly described? 

(iii) Points of departure for cancer endpoints (Section 2.3.2, 2.3.3). Please comment on 

whether the calculation of PODs and oral slope factors is scientifically supported and 

clearly described. 

4. Dose-response analysis. In Chapter 2, the draft assessment uses the available human, animal, 

and mechanistic studies to derive candidate toxicity values for each hazard that is credibly 

associated with RDX exposure in Chapter 1, identify an organ/system-specific RfD, then selects 

an overall toxicity value for each route of exposure. The draft assessment uses EPA’s guidance 

documents (see http://www.epa.gov/iris/basic-information-about-integrated-riskinformation-system#guidance) in the following analyses.

4a. Oral reference dose for effects other than cancer (Sections 2.1.5–2.1.8). The draft 

assessment presents an overall oral reference dose of 3 × 10-3 mg/kg-day, based on nervous 

system effects as described in the Crouse et al. (2006) study. Please comment on whether 

this selection is scientifically supported and clearly described, including consideration of 

mortality as described in Section 2.1.6, and consideration of the organ/system-specific 

reference dose derived from the toxicity study by Cholakis et al. (1980) that is lower (by 

approximately fivefold) as described in Section 2.1.4.

4b. Inhalation reference concentration for effects other than cancer (Section 2.2). The 

draft assessment does not derive an inhalation reference concentration as the available 

studies were insufficient to characterize inhalation hazard and conduct dose-response 

analysis, and no toxicokinetic studies of RDX were available to support development of a

PBPK inhalation model. If you believe that the available data might support an inhalation 

reference concentration, please describe how one might be derived. 

4c. Oral slope factor for cancer (Section 2.3.3–2.3.4). The draft assessment presents an 

overall oral slope factor of 0.038 per mg/kg-day based the combination of liver and lung 

tumors in female mice. Please comment on whether this derivation is scientifically 

supported and clearly described.

4d. Inhalation unit risk for cancer (Section 2.4). The draft assessment does not derive an 

inhalation unit risk because inhalation carcinogenicity data were not available, nor were 

toxicokinetic studies of inhalation of RDX available to support development of an inhalation 

PBPK model. If you believe that the available data might support an inhalation unit risk, 

please describe how one might be derived. 

5. Executive summary. Does the executive summary clearly and appropriately present the major 

conclusions of the assessment?