Page 1 of 4Department of Defense Comments on theDraftToxicological Review of Urea, June 2010Comments submitted by: ChemicalMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 2 July 2010*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsectionwide)CommentSuggested Action, Revisionand References (if necessary)Category*12. ChemicalAnd PhysicalInformationPage 4:1stParaWe have noticed some recent IRIS ToxicologicalReviews have based the toxicity of a chemical onits metabolites, here we note that EPA chose not toexamine the potential toxicity of urea’smetabolites, ammonia and carbon monoxide forexample.The document should clearly state therationale for determining whether to evaluatemetabolites and degradation products in theToxicological Review, and which ones areappropriate for analysis.S22. Chemicaland PhysicalInformationPage 5, 2ndParaInhalation and dermal routes being the mostprobable occupational routes of exposure isinconsistent with first sentence of Section 3.1,which states that the primary route of exposure isoral.Clarify statements so they do not provideinconsistent information.E33.ToxicokineticsPage 7: 2ndParaUnlike previous IRIS reviews of endogenouslyoccurring chemicals where all data on the chemicalwas reviewed, EPA states for this chemical that“This section will only present results from studiesof exogenously administered urea.”It is not clearwhy EPA is discounting the stated“majority ofthe literature”that addresses endogenous urea.The Toxicological Review should clearly statethe decision criteria regarding the use of dataon endogenous and exogenous forms of thechemical and its evaluation of the chemical’spotential toxicity.S4 3.3.Metabolism3.5. PhysioloPage 12, 1stParaThis section initially states that“there is littleevidence that endogenous urea is metabolized”,but it does demonstrate that urea is readilyhydrolyzed in the g.i. tract. The statement seemsto be also in contradiction with the PBPK model infigure 3.2 (page 19), where (according to theIf bacterial hydrolysis is not consideredmetabolism please explain where EPA believesthese transformations would be considered inthe toxicokinetics (TK) of a chemical.SPage 2 of 4Department of Defense Comments on theDraftToxicological Review of Urea, June 2010Comments submitted by: ChemicalMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 2 July 2010*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsectionwide)CommentSuggested Action, Revisionand References (if necessary)Category*gically BasedToxicokineticModelsPage 19 discussion in the text) Pool A is the ureaof hepaticorigin (hence inside the body) and the eliminationfrom this pool includes that of bacterial hydrolysis.Does this mean that EPA does not considerchemical changes in the g.i. tract “metabolism”?5 4.1.2.1 CohortStudies4.7 Evaluationof Carcinogenicity5.2.1 Choiceof PrincipaStudy adCritical Effect– withRationale andJustificationPages 25, 2ndParaPage 75, 1stParaPage 80, 1stParaWe are pleased that EPA recognizes the limitedsignificance of statistically significant increasesinbiomarkers when these are within“normalphysiologic range”.This continued practice will certainlycontribute to the transparency of the documentsin future reviews.O63.5 Physiologically BasedToxicokineticModelsPage 20,1stParaWe believe the“F”in the second line needs asubscript, probably“oa”Please correct as warranted. EPage 3 of 4Department of Defense Comments on theDraftToxicological Review of Urea, June 2010Comments submitted by: ChemicalMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 2 July 2010*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsectionwide)CommentSuggested Action, Revisionand References (if necessary)Category*74.1.2.1 CohortStudiesPage 26,1stParaThis analysis appears to discount statisticallysignificant changes inpeak expiratory flow rateper minute (PEFR/min) in the absence ofsignificant changes in forced vital capacity(FVC) and forced expiratory volume in onesecond (FEV1) that are said to be the“screeningmarkers for obstructive or restrictive pulmonaryeffects.”While we do not object to thisconclusion, we believe it is not consistent with atleast one analysis in another recent IRISdocument.The quality control procedures for producingIRIS documents should ensure biomarkers andtest results are given similar interpretations forevery chemical analyzed within the same timeframe. When substantial differences ininterpretation are made due to changes inunderstanding of the results, these should benoted.O84.2.1.2ChronicStudiesPage 34, 1stParaIn this paragraph, it is stated that “Among Ureaexposed male rats, there was a significantoccurrence in tumor incidence (21/50, 27/48,25/48, and 35/50) at the high dose for interstitialadenomas in the testes(p=0.004)”....“Since thechange in the incidence of malignant lymphomaoccurrence did not show a dose response theseresults were considered by the authors to be ofquestionable biological significance.”We agreethat the absence of a dose-response effect forlymphomas suggests that these are of limitedsignificance. However, it is interesting to note thatin other IRIS assessments the finding of asignificant trend and a statistically significantThe quality control procedures for producingIRIS documents should ensure that animalbioassay results are given similarinterpretations for every chemical assessmentwithin the same time frame. When substantialdifferences in interpretation are made due tochanges in understanding of the results, theseshould be noted.OPage 4 of 4Department of Defense Comments on theDraftToxicological Review of Urea, June 2010Comments submitted by: ChemicalMaterial Risk Management DirectorateOrganization: Department of DefenseDate Submitted: 2 July 2010*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E);or Other (O). Also please indicate if Major i.e. affects theoutcome, conclusions or implementation of the assessment.CommentNo.SectionPage &Paragraph(enter“Global” ifreportsectionwide)CommentSuggested Action, Revisionand References (if necessary)Category*difference between control and the highest dose(the response of which did not change in thereanalysis) have been used previously as bothdemonstrations of carcinogenicity and for a linearextrapolation to low doses.9 4.2.1.2ChronicStudiesPage 34, 1stParaThe text states:“(There is a discrepancy inFleischman et al (1980) between the tableproviding the data and the narrative”.Given thatthe dissimilar results were from a National CancerInstitute (NCI) study, perhaps the issue could havebeen resolved by contacting the NCI.As part of its review process, EPA shouldconsider resolving issues concerning studiesfrom other Federal agencies.O104.6.1 OralExposure70The information of this section would be enhancedand put in perspective if it included information onurea being an endogenous product of proteincatabolism. This additional information wouldinform the reader that organisms have homeostaticmechanism by which physiologic concentrationsof urea are regulated and that humans excrete 20-30 grams per day via the urine.Include information on urea being anendogenous product of protein catabolism andthat organisms have homeostatic mechanismsby which physiologic concentrations of ureaare regulated and that the dose of urea requiredfor toxicity would need to be sufficient to upsetthese physiologic mechanisms.S