EPA's Response to Interagency Comments on the Final Interagency Science Discussion Draft
of the IRIS Toxicological Review of
Hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX)
August 2018
Purpose: The Integrated Risk Information System (IRIS) assessment development process of May
2009 includes two steps (Step 3 and 6b) where the Executive Office of the President and other
federal agencies can comment on draft assessments. Comments on the Final Interagency Science
Discussion draft of the IRIS Toxicological Review of Hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX)
were provided by the Department of Defense (DOD), none of which DoD considered to be major
scientific comments. The following are EPA's responses to interagency comments. All interagency
comments were taken into consideration in revising the draft assessment prior to posting on the
IRIS database.
For a complete description of the IRIS process, including Interagency Science Discussion, visit the
IRIS website at www.epa.gov/iris.
Interagency Science Discussion Comments and Responses:
Topic #1: Qualifiers regarding the relative potency of RDX and bicuculline - DoD observed
that text comparing RDX to bicuculline, added in response to the SAB recommendation to include
more material in support of subclinical effects of RDX and the potential for developmental
neurotoxicity, may be somewhat misleading. DoD pointed to evidence that RDX is a significantly
weaker inhibitor of GABAa than bicuculline and therefore potentially significantly less likely to
cause developmental neurotoxicity.
EPA Response: EPA agrees that the evidence is consistent with bicuculline as a more
potent GABAa inhibitor than RDX. Section 1.3.3 (Susceptible Populations and Life Stages for
Cancer and Noncancer Outcomes) was revised to note differences in potencies of RDX and
bicuculline as GABAa inhibitors.
Topic #2: Calculation of point of departure (POD) values when expressed as a human
equivalent dose (HED) - DoD offered the comment that the PODhed values based on peak RDX
concentration in arterial blood (Cmax) as the dose metric and data from the Crouse etal. (2006) and
Cholakis etal. (1980) studies were incorrectly calculated. Specifically, they noted in Table 2-2 that
a factor of 0.540 should have been applied to the lower bound on the benchmark dose (BMDLos) of
2.66 mg/kg-day from Crouse etal. (2006) to obtain a PODhed of 1.4 mg/kg-day (rather than

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1.7 mg/kg-day). Similarly, the PODhed derived from the Cholakis etal. fl9801 study using Cmax as
the dose metric should have been 0.34 mg/kg-day rather than 0.41 mg/kg-day.
EPA Response: The calculations in the final Agency Review/Interagency Science Discussion
draft were in fact correct, but EPA agrees that the assessment was not sufficiently clear
about which factors to apply when calculating the POD using either area under the curve
(AUC) or Cmax as the dose metric. Table 2-2 [Summary of derivation of point of departures
(PODs) following oral exposure to hexahydro-l,3,5-trinitro-l,3,5-triazine (RDX)] and the
PBPK appendix (Section C.1.5, "Rat to Human Extrapolations" and "Mouse to Human
Extrapolations") were revised to clarify which factors to apply in calculating PODhed values
with the different dose metrics.
Topic #3: Clarification regarding the use of organ/system-specific values - DoD commented
that the SAB recommendation to develop or cite documentation for the use of organ-specific
reference values for individual chemicals was not entirely addressed. DoD observed that it was not
clear when organ-specific reference values would be used, but presumed from the revisions made
that these values would be reserved for estimating organ-specific hazard as dictated by
circumstances described in Risk Assessment Guidance for Superfund Part A (U.S. EPA. 1989).
EPA Response: EPA revised Section 2.1.4 of the Toxicological Review to clarify that the use
of organ/system-specific values could be useful not only for assessments performed using
EPA's Risk Assessment Guidance for Superfund (U.S. EPA. 1989). but more generally for EPA
program and regional offices to identify other potential health hazards above the reference
dose and to inform decisions involving multiple-chemical exposures based on a common
target organ.
References
Cholakis. TM: Wong. LCK: Van Goethem. PL: Minor. 1: Short. R: Sprinz. H: Ellis. HV. III. (1980).
Mammalian toxicological evaluation of RDX. (DAMD17-78-C-8027). Kansas City, MO:
Midwest Research Institute, http://www.dtic.mil/dtic/tr/fulltext/u2 /a09 2 5 31 .p df
Crouse. LCB: Michie. MW: Major. M: Tohnson. MS: Lee. RB: Paulus. HI. (2006). Subchronic oral
toxicity of RDX in rats. (Toxicology Study No. 85-XC-5131-03). Aberdeen Proving Ground,
MD: U.S. Army Center for Health Promotion and Preventive Medicine.
http: //www, dtic.mil/dtic/tr/fulltext/u2/1050903.pdf
U.S. EPA (U.S. Environmental Protection Agency). (1989). Risk assessment guidance for superfund
[EPA Report], (EPA/540/1-89/002). Washington, DC.

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