Department of Defense (DoD) Comments on the Interagency Science Consultation Draft IRIS Assessment of Trimethylbenzenes June 2016
(Date Received: June 28, 2016)
Department of Defense Comments on
Toxicological Review of Trimethylbenzenes Final Draft (Step 6b)
Comments submitted by: OASD(EI&E), ESOH
Directorate, CMRM Program
Organization: Department of Defense
Date Submitted: 6/29/2016
*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please indicate if Major i.e. affects the
outcome, conclusions or implementation of the assessment.
Comment
No.
Section
Pages
Comment
Suggested Action, Revision and References
(if necessary)
"Category
1
2, Preamble
xvi, line 40
The response to the SAB comments on the
Preamble states that the Preamble directs
users to the IRIS' guidance website, we do not
see this in the Preamble. The IRIS website is
mentioned but not in terms of guidance.
Suggest adding specifically noting that links to
guidance used are on the IRIS website and
note the page.
S
2
1, Preamble
xvi, Line 44
Text was deleted from the Preamble that listed
the parties whom EPA requests nominations.
The rationale is not evident and makes us
wonder whether there are changes planned or
have been undertaken to seek nominations for
IRIS assessments. The change also seems to
run counter to the SAB comment that the Scope
section of the Preamble lacks description of
IRIS' purpose and what the assessments are
meant to represent to users.
If changes have been made to the nomination
process it would be useful for us get some
information relative to the new process. To
incorporate the SAB's recommendations,
suggest listing whom nominations are generally
solicited and received from.
S
3
2, Preamble
xvi - xvii
There have been changes made to the text in
this section that make it sound rather insular
and emphasize EPA's needs alone rather than
Please consider revising the statements which
focus on "EPA's needs" and "..questions of
O/M

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EPA in addition to its stakeholders. Though we j interest to the EPA" to better reflect the reality j
understand that EPA may wish to keep their j that IRIS has a multitude of users. j
own needs at the forefront, we would like to 1
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remind EPA that States, the public and other j j
Federal agencies use the outcomes of IRIS j j
assessments regardless of whether there is j j
EPA involvement or oversight of those projects j j
or programs. We believe that broader j j
consideration of the use of IRIS assessments 1
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would better meet the intent of the SAB j j
comments on the Preamble regarding IRIS' j j
purpose and what the assessments mean to j j
users. | j
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2, Preamble
xvii
The text on Systematic Review Protocols states
that they may change during the course of the
assessment. We can understand why additional
search strategies might be added for example,
but are having difficulty imagining situations
where other existing protocols would warrant a
change.
f
Please reconsider this statement and provide j
examples of changes to protocols that might be |
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made during a course of an assessment or 1
S
perhaps provide examples of changes in j
science questions that may require a change to |
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protocols. j
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4, Preamble
xvii - xviii
Much detail regarding evaluation of study
quality was removed from the Preamble in favor
of noting EPA guidance, although without
citations provided for them, and also by stating
that study evaluation criteria will be posted on
the IRIS website. We presume the latter
statement is referring to the Preliminary
Materials that are developed for each chemical.
However, when we looked at the most recent
set of Preliminary Materials, those for Dibutyl
Suggest reconsidering the current text j
regarding study quality and add back in the |
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details that were deleted. We saw the previous |
text to be more transparent. j

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Phthalate dated January 2015 we did see j
evaluation criteria described but no citations to j
EPA Guideline documents so it is confusing j
how the factors that the Preamble states are j
used to judge study quality, are actually used j
together. I

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4, Preamble
xviii
The meaning of "..effects that are more
important or studies that are more informative.."
is not clear.
Consider more precise terms, perhaps an
example substitute for "important" is biologically
significant, we are not sure what is meant by
"informative".
S
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5, Preamble
xix, line 19
"If there is credible evidence of carcinogenicity,
an assessment determines whether the mode-
of-action involves mutagenicity, because this
influences the approach to dose-response
assessment and subsequent application of
adjustment factors for exposures early in life."
This statement isn't precise. All cancers have
mutations, so that if the MOA only has to
"involve" mutagenicity, all cancers would have a
mutagenic MOA, and this classification for
distinguishing carcinogens in EPA's 2005
supplementary guidance would have no utility.
As the Risk Assessment Forum draft document
on mutagenic MOA, and several subsequent
publications support, the mutagenicity must be
caused by the chemical or an immediate
metabolite and must be one of the first key
events in the MOA.
Please correct.
S

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5, Preamble
xviii, line 39
"Each synthesis considers aspects of an
association that may suggest causation:
consistency, exposure-response relationship,
strength of association, temporal relationship,
biological plausibility, coherence, and "natural
experiments" in humans."
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Suggest beginning this sentence with "As
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discussed more completely in the 2005 Cancer | S
Guidelines..." |
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7, Preamble
xix, line 77
Reference values for other than chronic
exposures are not mentioned.
Suggest including acute and subchronic here. J S
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7, Preamble
xx, line 12
"With complex data, an assessment may
develop specialized exposure-response models
if compatible with the scope of the assessment."
It would be useful and save comments and time
later, if EPA committed to an external review of
any novel exposure-response models before
and independently of the external review of the
draft IRIS document. We believe this would also
be consistent with the SAB recommendations
on review of models.
Please indicate that there will be an external
review of any novel exposure-response models
before and independently of the external review
of the draft IRIS document.
s
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7, Preamble and
General
Preamble
; It is not evident why the phrase "Calculation of j
I reference values starts with a point of j
| departure, generally for an early effect that j Recommend distinguishing additional
I precedes overt toxicity." is qualified by early I requirements or procedures that are under
xx, Line 58 j
| effects that precede over toxicity. This is not j discussion to include in future guidance as
j described in the EPA RfD/RfC guidance and j recommended by the SAB.
j seems to run counter to the recommendations j
j by the SAB in their review of the Preamble. |
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S/M
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112 j 9. Preamble
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j "The Preface specifies the scope of an j For clarity and transparency, please add a j
xxi, line 94 J assessment and its relation to prior j sentence that states that the Preface describes j S
I assessments." This statement implies that the ' the process that will be followed for chemicals j
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process described in the Preface to the j that begin the IRIS evaluation j
document to which it is attached was followed j contemporaneous with that version of the j
for that chemical. However, we have been told j Preface. j
that the legacy chemicals did not necessarily j j
follow the process as stated in the Preface. j j
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j 13 I 3, Preamble
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xvii, line 59
"IRIS assessments go beyond standard |
practices of systematic review in including |
pertinent studies." Such an assertion suggest | Suggest deleting this sentence,
that either a reference or examples should be
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included. j
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Preamble
General
The Preamble has been significantly revised. j j
While the SAB CAAC made many suggestions | j
for change in this section, some of which were |
incorporated and some that have not, we don't j I
believe they have been reviewed to determine | ]
1)	whether they have been reviewed for | j
consistency with EPA guidelines and guidance, j I
| We believe the Preamble should be a separate )
2)	to determine whether procedures that are j j
j document that is revised and reviewed S/M
currently not in guidance or policy are | |
independently of any specific chemical's review, j
designated as "under discussion" as such 3) to |
determine whether the Preamble represents | j
what was done for the 1MB analysis and 4) to j |
determine whether the SAB agrees with j j
removal of references from the Preamble | j
though they clearly suggested they should be | |
included. j j
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Executive
xxviii, line 18
Summary
"Dividing the HED [of 3.01] by this composite |
I pipocp rnrrprt I ^
UF of 300 yielded an RfD of 1 x 10-1 mg/kg- j j
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16
Executive
Summary
day" We believe the value should be 1 x 10-2
mg/kg-day.
xxix, line 12
"Dividing the POD for hematological effects
(3.01 mg/kg-day) and neurotoxicity effects (3.5
mg/kg-day) by the composite UF of 100 results
in an RfD of 3 x 10-2 and 4x10-2 mg/kg-day
for decreased monocytes and decreased pain
sensitivity, respectively." While we understand
j the rules of rounding up or rounding down
I numbers, we find it difficult to explain
j scientifically why the same PODs divided by
; 300 result in identical chronic RfDs but divided
by 100 result in subchronic RfDs that differ by
i (1/4 =) 25%.
Suggest an explanation be added for this logical
inconsistency.
17
Appendix A
A-3
j The response the SAB comment states that
j "text was also added to the Preface to describe
j where approaches in the 1MB assessment
j differ from those outline in the Preamble."
! However this was not clearly stated in the
! Preface, it states that approaches were used
! which were available at the time (2012) and a
| problem formulation and protocol development
I began in 2015 with other assessments. It
j seems that the reader is to believe that all other
| aspects of the 1MB assessment are consistent
I with procedures described in the Preamble as it
I is not stated. There is not mention at all of the
| Preamble in the Preface let alone procedures
I described therein.
If there are any other approaches that differ for
TMBs they should be mentioned in the Preface,
or if not it should be so stated in the Preface.

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18
Appendix A
A-11
	|	|
j In the response to GC.4-1 regarding public j
j comments it seems relevant to note the |
I Appendix F is not in the final version of the
j assessment and possibly note the rationale. We
The public comments are not fully addressed
) believe that it would be most transparent and S
here. t
I consistent with the IRIS Process to bring the |
( public comments and responses into the final j
) version of the 1MB assessment as an Appendix j
1
1 and recommend that EPA do so. |
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2.1.2.
2-8, line 15
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Of the study selected, EPA states "no j
information is available regarding the change in j
these responses that would be considered j
biologically significant." Yet in the supplemental j
information for this document (page A-14), it is j Please reconcile these statements. In addition,
stated: "It is EPA's practice that evaluation of j since the assessment states that EPA has a
evidence should first consider biological j "practice" with regard to biological significance,
significance to the extent possible". It appears, we would appreciate a copy or citation of that
therefore, that EPA may not be following its own practice.
"practice". Since the reference for the practice
is not provided, we can't verify how EPA
considers the relative importance of statistical |
significance and biological significance. j
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21
Executive
Summary and
Section 2.2
xxvi - xxix
The subchronic reference values are not as j
easy to quickly find as the chronic values in the j
Executive Summary. This also applies to the I
I The subchronic RfC should be clearly stated
subsections of Section 2.1, but is especially |
I and bolded similar to the chronic RfC.
important for the IRIS Summary which we j
understand will be identical to this Executive j
Summary. |
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Section 2.2 and
Executive
Summary
General
j It is not clear why developmental and maternal
! endpoints are discussed and presented in the
| development of both chronic and subchronic
| reference values. It seems that in comparison
| they would be more relevant for the shorter
I timeframe and less relevant for the chronic
i timeframe.
Suggest explaining the utility of the chronic
developmental reference values versus the
subchronic values.
S/M
23
Section 2.2 and
Executive
Summary
General
The intended use of the developmental and
maternal organ specific reference values are
not clear. Averaging time is an important
consideration for using RfCs and EPA's
guidance for inhalation risk assessment (RAGS
part F) states that "to the extent possible
exposure durations (EDs) evaluated in a site-
specific risk assessment should be consistent
with the ED represented by the toxicity value." If
one had women of child bearing age in a
population it is not clear how the values would
be applied, and though the number is the same
whether one should say they are applying the
chronic or subchronic value.
Suggest providing a citation or some guidance
on the use of the maternal and developmental
organ specific reference values, especially the
reference concentration. It is not clear whether
they would apply throughout gestation, possibly
longer, or whether there is another critical
timeframe that should be considered.
S/M

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