Department of Defense Comments on 

1,2,4- and 1,3,5-Trimethylbenzene Interagency Science Consultation Toxicological Review a

Comments submitted by: Chemical Material Risk Management Program Organization: Department of Defense Date Submitted: 2/9/2012 *Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please indica

conclusions or implementation of the assessment. 

Comment No. 

Section Pages Comment Suggested Action, Revisio

(if necessary) 

1 General 

DoD believes that the EPA draft trimethylbenzenes (TMB) Toxicological Review represents a significant positive change in format and readability. 

N/A 

2 Preamble 2 7 

EPA 2009 is not included in the list of references. 

Add the reference to the list 

3 Preamble, 3.3 8 - 9 

Although this section explains the preferred types of exposures, the section does not contain definitions or examples. These definitions in the IRIS glossary are subject to change without notice. DoD would like to see contemporaneous definitions of "acute", "subchronic" and "chronic" exposures for both commonly used laboratory animals and people; these could be presented in a table. 

Please supply definitions anacute, subchronic, and chropeople and for all of the spethe quantitative analysis of t

4 Preamble, 4.2 9 

In evaluating the quality of an epidemiological study, EPA does not include the need to demonstrate a reasonable dose-response 

EPA should discuss its critedose-response observations studies. DoD notes in partic
relationship. As dose-response relationships 

are fundamental to all, high quality toxicological studies, this requirement, and whether the data must show a positive trend, a statistically significant increase, a biologically significant change, and/or other criteria should be presented in this section. 

reliance on statistics rather tinformative information, as wof a discussion about dose-

5 Preamble, 4.3 10 

In the third paragraph, EPA should state that it will clearly identify that its interpretation of the 

data differ from the scientists who conducted the study, as well as discussing why its conclusions differ. DoD would prefer if EPA would also commit to trying to contact at least one of the authors to determine their reaction to EPA's interpretation, and to allow those authors to comment on EPA's interpretation of the data, as they may have additional information about the study that was not published. 

Disagreeing with the concluscientists who designed and experiment should only be dclear and undisputed reasonEPA consider discussing its reinterpretation of the data wbefore relying on a different estimating toxicity of a chem

6 Preamble 5.2 11 

DoD disagrees with EPA's statement that "causality is not at issue in controlled experiments". Unless a well designed experiment has been replicated exactly (often not the case for the critical experiment on which EPA bases its RfDs, RfC, and cancer potency 

values) statistically significant results can be false positives. At p = 0.05, there is a 1 in 20 probability of a false positive, even in a well controlled experiment. 

EPA should delete this clauone independent reference its assertion. 

7 Preamble 5.3 12 EPA's use of the term "genetic toxicity" is not We highly recommend that 
defined and is neither clear nor transparent, 

especially in a section on mode of action (MOA). EPA's 2005 cancer guidelines and guidance do not use this term, but rather refer to a "mutagenic mode of action". Frequently, genetic toxicity includes effects that are not considered mutations, the term used in the rest of the document. DoD has previously mentioned EPA's tendency to use the terms "genotoxic" and "mutagenic" loosely, and as these terms have significant implications within EPA's guidelines and guidance, we would like to see more precision in their use. 

toxicity" and "mutagenicity" words), as they have significwithin EPA's guidelines and glossary does not include a "genetic toxi8city" or "genotoalways agree with definitionEPA's web sites and can be notice or review. 

8 Preamble 5.4 12 

The text does not mention a critical clause of the 2005 cancer guidelines: That the WOE for a chemical's MOA can vary by route of exposure or by level of exposure, etc. This section would be interpreted by many individuals as asserting that only one WOE is possible per chemical per endpoint. 

EPA should include importaWOE section to clearly and what is in its guidelines. Thexplicitly state that there can WOE for carcinogenicity, e.gcan vary by route of exposuexposure, etc. 

9 Preamble, 7.3 14 

EPA states that the choice of point of departure 

(POD) is based on statistical and biological factors and cites the draft BMD guidance (U.S. EPA 2000b) and EPA's 2005 guidelines for carcinogen risk assessment. The text goes on to state that for dichotomous responses, a 10% response will be used for "minimally adverse effects" and "5% or lower for more severe effects." Neither of the cited references have statements that agree with EPA's assertion. 

This language should be remcurrent Preamble and insteathe BMD guidance documenrecommendations can be prformally evaluated by the scregulatory community. EPA the citations of EPA2000a v
Both documents indicate that the benchmark 

response (BMR) that determines the POD should be near the low end of the range of data and that a 10% BMR should also be estimated for facilitating comparisons across chemicals. These concepts are also applied to the suggested methods for calculating the POD from continuous data. We know of no such severityrelated guidance regarding the POD for nonlinear extrapolations in either of these documents. The definition of "minmally adverse" or "more severe" is a key aspect of the POD, but there is no available guidance as to how different effects should be categorized. Furthermore, the BMD guidance is listed in the references as U.S. EPA 2000a, rather than 2000b. 

10 

Preamble 7.3 and 7.4 

14 

These sections, that cover standard procedures used, contain several statements that are not consistent with EPA's 2005 cancer guidelines. If IRIS is proposing that these statements are standard practice within its toxicological review, it should both state that these are deviations and should provide a rationale for its deviation from guidelines. We believe that the cancer guidelines are applicable to the entire agency. 

1. None of the cited EPA guidelines or 

guidance suggests use of a "standard value" for a point of departure for extrapolation, much less "(10% response 

This section should be caref

ensure consistency with EPreferences cited.

1. Please delete any r

standard response POD for extrapolatioand cancer guidelinstandard values for comparisons among that case the best elower confidence varecommended for u

2. The use of the lowe
for animal data, 1% for epidemiologic 

data, depending on the observed response rates)."    These values are recommended as frequently used based on historical observations of results and the power of the standard studies.  They are also recommended to be estimated and reported for the purposes of comparing potencies across chemicals.   The phrase that is in EPA's guidance is "near the low end of the observable range is used" which will differ by experimental design.

2. The statement that "For dichotomous 

responses, the point of departure is the 95% lower bound on the dose associated with a small increase of a biologically significant effect." requires addition of the qualifier "generally" or "usually" to be consistent with the cited sources.  In particular, the BMD draft indicates that the maximum likelihood estimate should be used for some purposes.

3. EPA's guidelines discuss use of a 

biologially based model to extrapolate to lower doses. They do not advocate "Below the range where confidence bounds on the predictions are reasonably precise, extrapolation may continue using a linear model."

qualified, as it is in t

3. According to EPA's 

use of a biologically obviates extrapolatinonlinear. The statbe deleted or clearly deviating from EPA provide a rationale f

4. The concept of a "li

"other activity" as a determining whethelinear or nonlinear sinconsistent with EPOtherwise, the text explain that IRIS is guidance and providdeviation. 

5. The suggestion that 

a criteria for type of either be deleted or that IRIS is deviatinguidance and providdeviation. 

6. IRIS documents sho

"genetic toxicity" anhow they differ (if IRthey do), and how threlate to EPA's mutaaction. 
4. EPA's 2005 cancer guidelines 

differentiate low dose extrapolation procedures for MOAs that are linear at low doses, MOAs that are nonlinear (including nonlinear, no threshold) at low doses, and chemicals for which the MOA cannot be determined.  They do not provide for a linear extrapolation "the doseresponse curve is expected to have a linear component

below the point of departure. [emphasis added]" .  As many highly nonliear function have a "linear component" or can be fit to curves that have a linear component, this statement directly contradicts both the text and the intent of EPA's cancer guidelines.  (DoD notes that the concept  of a linear component is discussed with regard to chemicals with multiple MOAs, but does not make that a condition that requires a linear extrapolation.)

5. EPA's assertion that "Agents or their 

metabolites for which human exposures or body burdens are near doses associated with key events leading to an effect." is not included in the cited guidelines.  IRIS has often asserted that IRIS documents do not consider exposure levels.  If this is accurate, such a 
consideration is not relevant to this 

document.  If IRIS documents do consider exposure levels, this introduction should discuss those aspects of EPA's cancer guidelines that do refer to exposure, e.g., different WOEs for different levels of exposure.

6. The statement that "the agent does not 

demonstrate mutagenic or other activity consistent with linearity at lower doses." is not part of the criteria in EPA's cancer guidelines for using a non-linear extrapolation. The guidelines state that chemicals with a mutagenic MOA, not just mutagenic activity, are expected to have a linear extrapolation. This statement asserts a much lower criterion for imposing a linear extrapolation. Nor do the guidelines reference "other activity consistent with linearity" as a measure. The guideline only discuss such concepts within the context of the MOA, not individual key events of the MOA. 

11 Preamble 7.5 15 

Statement #3 is incorrect. The cited EPA guidance document recommends use of the age-dependent adjustment factors ONLY for 

chemicals that have been demonstrated to have a mutagenic MOA that do not have chemicalspecific data on early-life exposure, not 

EPA should correct this mis
"suspected carcinogens" as stated here. 

12 Preamble 7.6 15 

EPA states that "if the point of departure is based on toxicokinetic modeling, dosimetry modeling or allometric scaling", UFA = 10^0.5 is applied to account for "the remaining uncertainty involving toxicodynamic differences." The U.S. EPA (2011b) guidance states (p 21) that "processes pertinent to the consideration of this UF are recognized to include both toxicokinetics and toxicodynamics." While IRIS has instituted a "common practice" of asserting such a division after PBPK modeling, it should either provide a written citation for this practice, and indicate whether it has been externally peer reviewed, or explicitly state that this is an IRIS-developed policy that has or has not been externally peer reviewed. If such a guidance document is prior to 2011, it should also provide a rationale for not following the more recent guidance. 

EPA should revise the text tU.S. EPA (2011b) guidance

13 

Preface, Executive Summary, Literature Search 

20, 23, 26, 29 The table numbering goes Table 1, Table II, Table 3, Table IV. 

EPA should pick a format (Anumerals) and implement it would prefer if this and othewere corrected prior to interthey increase the difficulty owithin the document and unstructure of the document. 

14 

Preface, Programmatic Interest 

21 

It is stated related isomers, 1,2,3-trimethylbenzene is not included in the review. This is one of the components of mixture of 

Suggest adding a brief explaincluding 1,2,3-trimethylbentoxicological review. 
three isomers. 

15 

Executive Summary 

21 

We noted that the previous TMB PPRTVs not referenced nor discussed as “Other” Assessments. 

Please provide a brief discuPPRTV values. This is espegiven the differing conclusioif finalized, the toxicity valuereplace the PPRTV values. are available to the public aaddressed in the IRIS asses

16 

Executive Summary 

22 

The first heading suggests a summary of effects following inhalation exposure to 1,2,4-TMB only, however discusses data, or lack thereof, for both isomers. 

EPA needs to clearly match to the isomer discussion wit“1,3,5-TMB” to the first head

17 

Executive Summary 

22 

The statement “No human studies were found for 1,3,5-TMB” is not accurate, as 1,3,5-TMB exposure was part of the occupational cohort for Norseth et al (1991), (Appendix A.2 pg 48), and is a known constituent of the solvent mixtures 

from Battig et al (1958). Additionally, Jarnberg et al (1996), Kostrewski et al (1995, 1997), and Jones (2006) studied human volunteers exposed to 1,3,5-TMB and CNS-type effects were evaluated. 

Clarify the statement if the iwas that no human studies toxicological information weTMB. Although, it is not cleTMB studies are any less infor 1,2,4-TMB. Particularly, should be added to the assediscussed in the respective 

18 

Executive summary 

22 

It is not true that no human studies were found for 1,3,5-TMB. While Kostrzewski et al. (1995) primarily reports toxicokinetic data, it is noted in this paper that no effects were observed upon 

follow up. 

EPA should revise the text. 

19 Executive 22 It is not clear why EPA has chosen to assess Please provide some rationa
Summary only 1,2,4- and 1,3,5-TMB, not 1,2,3-TMB. TMB is not also assessed. 

20 

Executive summary/global 22,23 The text is inconsistent regarding the use of superscripts, or in-line use (e.g., 10-2 mg/m3). Superscripts should be con

21 

Executive Summary 

23 

The UF for database insufficiencies should be 

reduced to 1. Two reasons are given for the deficiency. The first reason is the lack of a chronic study. However, EPA has already used a UF of 10 to account for this deficiency. Therefore, including it here is double counting the deficiency. The second reason is the lack of a twogeneration study. As the one-generation study showed NO effects at doses that were below those that caused maternal toxicity and as the effects observed were relatively minor and related to maternal toxicity, i.e., both had less weight gain that are known to be associated, most toxicologist would find the conducting of a two-generational study redundant, and wasteful of resources (including many animals), as no effects would be expected. Reduction to 1 would be consistent with procedures outlined in EPA's RfD/RfC guidance. 

EPA should reduce the UFD 

22 

Executive Summary 

23 

DoD does not understand why the confidence in the critical study is "medium" as all of the characteristics of the study (as reported) appear to be according to guidelines. Similarly, given our comments on reducing the UF on the 

EPA should definitely changthe critical study to "high" or for considering it "medium". DoD on reducing the uncertRfC, EPA should reconside
database to 1, we believe the confidence in the 

database for the RfC should also be "high". 

evaluation of the database. 

23 

Executive summary 

23, 24, 26 

UFH and UFS are unnecessarily large. We will amplify our comments below (p 71). It is not appropriate to cite the lack of a chronic study as justification for UFD (p 23 and 24) because this gap is captured in UFS. 

Conduct a sensitivity analysmodel predictions for the kemetric to better inform the sreduce the value of UFS, anjustification for, or value of, 

24 

Executive Summary 

24 

DoD does not agree that the combined UFs would be 10,000. First, the previous comments about double-counting the lack of a chronic study and the inappropriateness of requiring a two-generational study when the onegenerational study showed minor effects in maternal toxicity are also appropriate here. That would reduce the combined UF to 3,000. The data presented in Appendix B demonstrate that the UF of 10 for a NOAEL to a LOAEL is unnecessary as well. The data for this isomer fit the benchmark dose as well as that of the other isomer. Therefore, a BMDL would be used as the point of departure, and the composite UFs would be the same as the previous, either 1,000 or 3,000 depending on whether EPA agrees with DoD with regard to the completeness of the database. 

As the data for both isomers equivalent quality, we recomthe RfC for 1,3,5-TMB from inferring it from 1,2,4-TMB. 
25 

Executive summary 

25 A period is missing near the end of the first 

paragraph. 

Revise "same research instread "...same research instit

26 

Executive Summary - Section 1.1 - Appendix A.2 

There is significant discrepancy between the studies listed in the Executive Summary, those discussed in the endpoint-specific Hazard ID sections, and those summarized in Appendix A.2. DoD cannot find the Appendix Study Summary information for Battig et al (1956)/MOE (2006) (listed as studies of human exposures to 1,2,4-TMB). EPA is missing Battig et al (1958), which was used in the previous PPRTV so must exist in the translated form somewhere. Billionnet et al. (2011) is summarized in Appendix A.2., but not listed in the Executive Summary or Section 1.1. Lammers et al (2007) is summarized in the Appendix under the “summary of animal studies” only; the human summary and study information should be broken into a separate study summary and be located in the human study section. 

Please correct these referensure the document is prope

27 1.1 

DoD appreciates EPA’ effort to synthesize the 

toxicological data and provide an integrated summary of information, HOWEVER, EPA needs to still provide some of the basic information for each study and should immediately direct the reader to the Appendix for detailed study summaries. For example, dosePlease add a few more deta

hazard identification synthesspecific Appendix section thstudy. 
ranges could be replaced with specific 

dose/concentrations administered, and sex/species information could be given where appropriate. It would be helpful to reference the Appendix study summary (explicitly with page number) the first time a study is mentioned. 

28 1.1.1 25 

Given that a lack of a suitable oral study (for either compound) is a significant database limitation, it is not clear why EPA did not have the Koch Industries (1995) study, the basis for the 2009 1,3,5-TMB PPRTV “Appendix Oral screening value”, peer-reviewed. 

EPA should obtain a peer-reIndustries (1995) oral 1,3,5-the resulting chronic RfD of (derived in the 1,3,5-TMB Pcompared to and discussed extrapolated and isomer-ad0.006 mg/kg-day. 

29 1.1 32 

While EPA does a good job at the integrated discussion of endpoints and the respective potential MOAs, the discussion on neurotoxic effects, in particular, does not highlight that all of the available information is circumstantial; a full functional observation battery is missing and the toxicological significance of most of the animal data is questionable with significant uncertainties and limitations within the respective studies (only one species, one sex, same laboratory, etc). 

EPA needs to make sure thpresented in an unbiased mneurotoxicity data is weak wuncertainties and limitations study. 

30 1.1.1 33 

In various places throughout the text, EPA mentions that the decrease in pain sensitivity measured in Korsak and Rydzynski 1996 did not persist two weeks after exposures were terminated. And in fact, the table shown in 

DoD does not feel that the ulimitations in Korsak and Ryappropriately discussed. Reneurobehavioral effects is nconsidered in EPA’s interpre
Appendix A.2-5 (pg 54) clearly shows the loss of 

effect (only the high-dose was tested for persistence). Yet, this possible “reversibility” of the effect is not adequately discussed and may, in fact, make this study/endpoint not suitable for chronic toxicity value derivation. Derivation of the RfD/C based on a shorter-term exposure requires the consideration of reversibility in the interpretation of the data. Korsak and Rydzynski 

1996 was dismissed as a potential principal study in the 1,2,4-TMB 2007 PPRTV due to “unclear toxicological significance” and “concentration-responses are difficult to interpret.” 

Further, given the apparent and other limitations of the sthat EPA reconsider Korsak for RfC/D derivation. 

31 1.1.1 34 

EPA makes inconsistent statements regarding the relative severity of the two TMB isomers (cf. pages 24, 58). 

The text should be revised t

32 1.1.1 35 

Further explanation is needed regarding how the open field test results suggest latency. Presumably the authors mean that after 25 days, complete clearance of 1,2,4-TMB is expected, but this rationale and the authors' rationale for why they did open field testing at that time should be explained. 

EPA should more clearly stathis statement, rather than eto infer this significant commassessing toxicity. 

33 1.1.1 36 

The first couple of sentences on this page are potentially confusing and neither clear nor transparent. 

Reword the first part of the s"...exposure to 1,2,4-TMB o

to more clearly indicate the exposure to "mixtures contaLikewise, clearly indicate tha
term spatial memory studies 

exposure (in contrast to the exposure studies noted in th

34 1.1.2 and 1.1.4 48, 54 

The concentrations used in the study should be listed individually (as in Tables 1-1, 1-2, and 1-4) rather than as a range (as in Tables 1-3 and 1-5); the absence of this information limits the utility and clarity of the summary tables. Such clarity is necessary to review other statements in the document. 

Revise Tables 1-3 and 1-5 bnominal concentration, to bestudy and match the format this section. 

35 1.1.3 51 

In the second sentence of this section, the document switches from a summary of the lack of human data to discussing animal data without identifiying the species. 

At first use, note that the stuwith rats. We also suggest animal data be discussed in paragraphs (or separate secof data warrant). 

36 1.1.4 54-55 

On page 55, paragraph one, last line, it is described NOAEL and LOAEL determined from these acute exposure studies are provide in Table 1-5, but in the table only LOAELs are described. 

Please clarify and correct. 

37 1.1.4 56 

In the first paragraph, line 3, the years (2000, 1997) are provided, but no authors’ names are cited. 

Please clarify and add autho

38 1.1.5 56 

Borriston Laboratories (1984) study administered 1,2,4-TMB to Fischer-344 rats by gavage for 4 weeks and examined nephrotoxicity. Although a minor contribution, this study seems to be missing from EPA’s 

Please add a mention/refereLabs (1984) 
assessment. 

39 1.2.2 64 

It would be helpful if this table included the neurological endpoints; it would also make it more consistent with Table 1-6. 

Add neurological endpoints 

40 1.3 66 

Only one report (Maltoni et al 1997) is provided as weight of evidence for carcinogenicity. No discussion is provided to support the WOE concerning the mutagenic mode of action. 

Suggest adding the negative key mutagenicity assays in negative gentoxicity data frofor micronucleus formation imarrow cell to show a stronof mutagenic potential. 

41 2.1.1 68 

EPA has chosen, in this assessment, to conduct the benchmark dose analysis using external dose as the input, rather than an internal dose, as was used in the recent TCE and methanol assessments. The previous approach, of using internal dose as the input, has a greater toxicological relevance, and should be used in all assessments. We note that the weekly average venous blood concentrations do not 

have a linear relationship with dose/concentration (e.g., POD ADJ = 

0.187 mg/L at 174.1 mg/m3 vs. 0.867 at 492 mg/m3, for Korsak et al., 2000), so the order of the two steps (BMD analysis and internal POD estimation) could have an impact on the candidate RfC. 

EPA should redo the analysmodeling first, BMD analysis endpoints. At a minimum, Eanalysis for the key endpoinimpact of this change from tthe TCE and methanol asseshould update the draft BMD this consideration. 

42 2.1.1 69 

The rationale for choosing the weekly average venous blood concentration, rather than the seemingly more toxicologically relevant metric of 

We suggest that EPA changinternal dose metric, or provrationale (preferably with ref
weekly average concentration in the richly 

perfused tissues should be explained. The impact of this choice should be determined via PBPK modeling. 

currently selected dose met

43 2.1.2, 2.1.6, 2.2.2 69, 78, 85 

None of the HECs/HEDs can be verified because the model code has not been made available to the reviewers. (This reviewer could not find it on the HERO website, as reported in Appendix A.) 

All necessary supporting infmodel code, should be avaiat all stages of the review, inand external reviews. Withosuch data, it is not possible adequate scientific review. 

44 2.1.2 71 

EPA has conducted the interspecies extrapolation prior to the application of uncertainty factors, despite demonstrated nonlinear relationships between external and internal concentration in rats (page 68) and humans (page 85). 

EPA should apply the uncerinternal point of departure (dmodeling), then use the humderive the RfC. At a minimuapply this alternative approaresults so that the impact of clearly identified (and discusuncertainties). Moreover, as this appears to practice, EPA should providrationale for the procedure, clarity, so that reviewers can being consistent in its procechemicals. When such incoobserved in the absence of for reference, it is not possibprovide chemical-specific cocross-chemical inconsistenc

45 2.1.2 71 EPA has underutilized the PBPK model with EPA should conduct a sens
respect to the insights that can be gained 

regarding uncertainty factors. A sensitivity analysis of a relevant human internal dose metric (e.g., blood or RPT AUC) at the HED/HEC would help identify parameters that have an impact on EPA's selection among the dose metrics that could, especially in this case where significant nonlinearities are obvious, significantly affect the estimated RfC. It is possible that human variability in, for example, "expression of enzymes involved in 1,2,4-TMB metabolism" may have minimal impact on dosimetry in other tissues, and support the use of a lower value for UFH. 

human PBPK model to aid ia scientifically robust value using the default value. As review panels have repeatesensitivity analyses of PBPK recommends that such an apart of the standard practice PBPK models, and be perfoexternal peer review. As the analysis are expected to sigthe reviewers' opinions of eidose metric or appropriate uuncertainty factors, and EPA provide an opportunity for pcomment after the external suggests that all such analyprovided to the external peepublic stakeholders. 

46 2.1.2 71 

When assigning the UFD the strengths and limitations of the database need to be more clearly discussed. EPA should integrate the available information and discuss the overall strengths and weakness of the database. 

DoD recommends EPA use approach when discussing tweaknesses of the total datadata may provide insight as additional information may bmight consider (1) developinthat shows presence and abon type of study, route, duralife stage and general endpo(2) using a qualitative and intotal database to inform decunderlying uncertainty. We move away from making ge
about the available databas

informed decision about crit

47 2.1.2 71 

As noted above (comment on Preamble section 7.6, page 15), UFA = 3 is understood to encompass both toxicodynamics and residual toxicokinetic uncertainty after dosimetric/allometric adjustment, per U.S. EPA (2011b). 

EPA should revise the text treflect the UFA rationale de(2011b). 

48 2.1.2 71 and 73 

EPA does not appear to have considered the possibility of using any value other than 10 for UFS. Considering the modest differences in magnitude of effect between acute, short-term (4 week) and subchronic studies, UFS ~4 (Hasegawa et al., 2010) or lower should be considered. Reference: Hasegawa et al. (2010). A proposal of new uncertainty factor application to derive tolerable daily intake. Regul. Toxicol. Pharmacol. 58:237-42. 

EPA should reduce UFS frovalue or explain why they ha

49 2.1.2 and 2.1.6 72, 80 

EPA says there is no information on the transfer of 1,2,4-TMB or 1,3,5-TMB across the placenta. As noted by Saillenfait et al. (2005), fetal blood TMB levels were 55-98% of maternal TMB levels in a rat study (Ungvary et al., 1983) and TMB was identified in cord blood of term infants (Dowty and Laseter, 1976). We have some concern regarding the review of the literature. 

EPA needs to revise their stthe lack of data on TMBs' abplacenta and reference thes

50 2.1.5 74 EPA does not discuss uncertainties due to the EPA should conduct the ana
order in which they have conducted various 

steps in the RfC process (rat internal dosimetry calculations, BMD analysis, uncertainty factor application, interspecies and route-to-route extrapolation), or note the change from the process previously used for TCE and methanol. 

provide quantitative informathese choices, document thToxicological Review, and dappropriate. EPA should alreferences, if available, so tdetermine whether these desuggested by others or are been generated within the IRhave not been externally pe

51 2.1.5 74 

This section states that no information is available to identify a biologically significant decrease in maternal weight gain, and thus uses a BMR based on a change equivalent to 1 SD of the control mean. 

EPA should apply the well-ethat a 10% decrease in (absweight is an adverse effect, the analysis based on weigh

52 2.1.5 74 

There is no reference to support the assertion that a 5% decrease in fetal body weight is a biologically significant response because 

developing organisms "may" be more sensitive to such changes. 

EPA should provide referenassertion, or redo their analdecrease in body weight apanimals. 

53 2.1.5 75 

EPA notes that no PBPK model exists for 1,3,5-TMB. 

EPA should explain why thePBPK model for 1,3,5-TMB, existence of the 1,2,4-TMB kinetic data sets should havsubstantial head start in devmodel. For other chemicalsto either significantly modify 

PBPK models. EPA should for not taking such action in provide decision criteria for 
existing models. Without su

possible for reviewers and sdetermine if EPA is being coevaluation and allocation of 

54 2.1.5 76 

EPA did not carry forward the decreased pain sensitivity NOAEL identified by Wiaderna et al. (2002) for POD, HEC, and candidate RfC calculation. 

EPA should carry forward thsensitivity finding for 1,3,5-Tanimals reported by Wiaderadditional comparative inforproposed 1,3,5-TMB RfC. 

55 3 92 

DoD suggests that EPA provide documents (preferably available on web sites) rather than the text of web site (EPA, 2011a, "IRIS Process 

Retrieved August 24, 2011") Text of web sites change as do URLs. A document with a title and a reference number can still be retrieved.

Please make the cited text a unlikely to change over time

56 Appendix A 

A-7 and elsewhere 

There are numerous typographical errors throughout Section A.1 with respect to referencing tables and figures, mostly within the text, but including citations in Table A.1-7. For example, Page 7, Figure C-1 should be Figure A-1. Table A.2-1 should be Table A.1-1. Moreover, all of the appendices are individually listed in the Table of Contents as starting on page 94 when they do not. It is difficult to perform a review when references are incorrect. We believe that the software used to create these documents allows insertion of 

EPA should thoroughly chectables and figures througho
codes so that the Table of Contents (and also 

references) is automatically constructed and can be quickly updated. 

57 Appendix A A-9 

No units are provided for alveolar ventilation in Table A.1-2, limiting the utility of this summary table. 

Add units (liters/min?) for alvTable A.1-2. 

58 Appendix A A-9 to A-10 Text is duplicated from page A-7. EPA should delete one copy 

desired, cite the section whe

59 Appendix A A-13 Text needs to be reworded. 

Change "A lung compartmedescribe for gas exchange" compartment is used to des

60 Appendix A A-16 

EPA states that revised model code and modeling results are available on EPA's HERO database. We did not find any such information there. 

As noted above (comment onecessary supporting informmodel code, should be madreviewers at all stages of the interagency and external rev

61 AppendixA A-24 

"Minimize" is used where "maximize" was meant (see page A-25 for increase in LLF). Change "minimize" to "maxi

62 Appendix A A-26 

All of the figure and table references within Table A.1-7 are incorrect. Unlike other locations, the errors will not be corrected by changing all "A.2" references to "A.1". For example, the venous blood data of Swiercz et al. (2003), the key toxicokinetic data set, were depicted in Figure A.1-9, not Figure A.2-8. 

Correct the figure and table 

63 Appendix A A-32 There appears to be a typographical error for the model predicted venous blood concentration at Verify that the model value s

rather than 74.21 mg/L, and 
75 ppm. entry. 

As with other comments, we about errors in reporting datNeither DoD nor most of the have the resources to perfocheck of all the data providedocument. While we have perrors we have observed, wthere are likely others that wencourage EPA to institute Qthat ensure that all data that document are accurate prioof its document. 

64 Appendix A A-37 

While sensitivity analysis of PBPK models for test species are very useful to verify parameter identifiability, as documented here, further sensitivity analyses of the human model would also be very useful to inform the selection of UFH and to identify potentially pharmacokinetically sensitive subpopulations. 

EPA should conduct a senshuman steady state blood oconcentrations of 1,2,4-TMB HED or RfC and RfD. 

65 Appendix B B-6 

EPA asserts that "a 5% decrease in body weight was determined as biologically significant for prenatal rats", but provides no references for this assertion. 

As previously noted (commeEPA should provide referenor redo their analysis using body weight applied to adult suggests that EPA should fotoxicological practices, or prto why such practices are nochemical. 

66 Appendix B B-8 and following While EPA notes that scaled residuals may be EPA should add information 
tables used to assess model fit (page B-7), they do not 

provide that information in their tables. Thus, external reviewers are not able to independently determine if such criteria have been appropriately considered by EPA in its selection of the model from which the POD is determined. 

residuals both for clarity and independent review of its ac

67 Appendix B B-8 and following figures BMDS figure outputs do not provide units. Units should be provided in the legends. Legends of all BMDS figure

units for the dose/concentra

68 Appendix B B-12 Table B-7 footnote “a” contains an error: the p- value cannot = 0.0.02286. EPA should correct footnote 69 General 

We have noted several typographical errors in our review, but also want to note that there are incomplete sentences, missing verbs and other minor editorial issues that require correction 

Suggest having a tech editodocument in addition to a Q
Department of Defense Comments on 

Trimethylbenzenes IASC draft charge 

Comments submitted by: Chemical Material Risk Management Program Organization: Department of Defense Date Submitted: 2/9/2012 *Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please indica

conclusions or implementation of the assessment. 

Comment No. 

Section Pages Comment Suggested Action, Revisio

(if necessary) 

1 (A) 1. 1 

DoD would like to add "accurate" to the evaluation of the overall assessment of the document on which the reviewers are asked to opine. 

Please add "accurate" to the logical, clear and concise" in Please also add "accuratelyaccurately] presented and s

2 General 

DoD greatly appreciates the introductory material that EPA has supplied in this new format for IRIS document. We provided many comments on this section, including some instances where our reading of EPA's guidelines and guidance appears to differ from that presented in the text. DoD assumes that this text will be in each forthcoming IRIS document. While we commend EPA for its efforts, we suggest that EPA have this section separately reviewed by an external review panel whose members have 

EPA should clearly identify tmaterial as new for the IRIS should note that issues have interagency reviewers and amembers if they have carefumaterial, if they have providmaterial, and if they feel thethe available resources (e.gAlternatively, if EPA agrees charge to the peer reviewerthat the introductory materiaassigned review, that it will b
expertise in EPA's guidelines and guidance 

and/or regulatory risk assessment procedures. Ideally, this should be completed before the text, and any chemical-specific decisions made based on the text on which issues have been raised, is released for public comment and external peer review. As DoD understands that the external review panel for trimethylbenzes will be select for expertise for a chemical-specific review, DoD suggest that, if EPA disagrees with the idea of reviewing the introductory material separately, the experts of the panel be asked their opinions of this issue. 

public comment and externabefore it is included in any fiand that it should only be of their review if this document that depend on the statemehave been raised.