Page 1 of 4 

Department of Defense Comments on the 

Draft Toxicological Review of Urea, June 2010 

Comments submitted by: Chemical Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 2 July 2010 

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph 

(enter 

“Global” if 

report 

sectionwide) 

Comment Suggested Action, R

and References (if n

1 2. Chemical 

And Physical Information 

Page 4: 1st Para 

We have noticed some recent IRIS Toxicological Reviews have based the toxicity of a chemical on its metabolites, here we note that EPA chose not toexamine the potential toxicity of urea’s metabolites, ammonia and carbon monoxide for example. 

 The document should clearly rationale for determining whemetabolites and degradation pToxicological Review, and whappropriate for analysis. 

2 2. Chemical 

and Physical 

Information 

Page 5, 2nd

Para 

Inhalation and dermal routes being the most probable occupational routes of exposure is inconsistent with first sentence of Section 3.1, which states that the primary route of exposure is oral. 

Clarify statements so they do inconsistent information. 

3 3. 

Toxicokinetics

Page 7: 2nd Para 

Unlike previous IRIS reviews of endogenously occurring chemicals where all data on the chemical was reviewed, EPA states for this chemical that “This section will only present results from studies of exogenously administered urea.” It is not clear why EPA is discounting the stated “majority of 

the literature” that addresses endogenous urea.

The Toxicological Review shthe decision criteria regarding on endogenous and exogenouchemical and its evaluation of potential toxicity. 

4 3.3. 

Metabolism 3.5. PhysioloPage 12, 1st Para This section initially states that “there is little evidence that endogenous urea is metabolized”, but it does demonstrate that urea is readily hydrolyzed in the g.i. tract. The statement seems to be also in contradiction with the PBPK model in figure 3.2 (page 19), where (according to the If bacterial hydrolysis is not c

metabolism please explain whthese transformations would bthe toxicokinetics (TK) of a c
Page 2 of 4 

Department of Defense Comments on the 

Draft Toxicological Review of Urea, June 2010 

Comments submitted by: Chemical Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 2 July 2010 

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph 

(enter 

“Global” if 

report 

sectionwide) 

Comment Suggested Action, R

and References (if n

gically Based Toxicokinetic Models 

Page 19 discussion in the text) Pool A is the urea of hepatic 

origin (hence inside the body) and the elimination from this pool includes that of bacterial hydrolysis. 

Does this mean that EPA does not consider chemical changes in the g.i. tract “metabolism”? 

5 4.1.2.1 Cohort 

Studies 4.7 Evaluation of Carcinogenicity 5.2.1 Choice of Principa Study ad Critical Effect – with Rationale and Justification 

Pages 25, 2nd

Para Page 75, 1stPara Page 80, 1stPara 

We are pleased that EPA recognizes the limited significance of statistically significant increases in 

biomarkers when these are within “normal physiologic range”. 

This continued practice will ccontribute to the transparency in future reviews. 

6 3.5 Physiologically Based 

Toxicokinetic Models 

Page 20, 1st Para 

We believe the “F” in the second line needs a subscript, probably “oa”

Please correct as warranted. 
Page 3 of 4 

Department of Defense Comments on the 

Draft Toxicological Review of Urea, June 2010 

Comments submitted by: Chemical Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 2 July 2010 

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph 

(enter 

“Global” if 

report 

sectionwide) 

Comment Suggested Action, R

and References (if n

7 4.1.2.1 Cohort 

Studies 

Page 26, 1st Para 

This analysis appears to discount statistically significant changes in peak expiratory flow rate 

per minute (PEFR/min) in the absence of significant changes in forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) that are said to be the “screening 

markers for obstructive or restrictive pulmonary effects.” While we do not object to this conclusion, we believe it is not consistent with atleast one analysis in another recent IRIS document.

The quality control procedureIRIS documents should ensurtest results are given similar inevery chemical analyzed withframe. When substantial diffeinterpretation are made due to understanding of the results, tnoted. 

8 4.2.1.2 

Chronic Studies 

Page 34, 1st

Para 

In this paragraph, it is stated that “Among Ureaexposed male rats, there was a significant 

occurrence 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 the 

change in the incidence of malignant lymphoma occurrence did not show a dose response these results were considered by the authors to be of questionable biological significance.” We agree that the absence of a dose-response effect for lymphomas suggests that these are of limited significance. However, it is interesting to note that in other IRIS assessments the finding of a significant trend and a statistically significant 

The quality control procedureIRIS documents should ensurbioassay results are given siminterpretations for every chemwithin the same time frame. Wdifferences in interpretation achanges in understanding of tshould be noted. 
Page 4 of 4 

Department of Defense Comments on the 

Draft Toxicological Review of Urea, June 2010 

Comments submitted by: Chemical Material Risk Management Directorate 

 Organization: Department of Defense Date Submitted: 2 July 2010 

*Comment categories: Science or methods (S); Editorial, grammar/spelling, clarifications needed (E); or Other (O). Also please inoutcome, conclusions or implementation of the assessment. 

Comment 

No. Section 

Page & 

Paragraph 

(enter 

“Global” if 

report 

sectionwide) 

Comment Suggested Action, R

and References (if n

difference between control and the highest dose (the response of which did not change in the reanalysis) have been used previously as both demonstrations of carcinogenicity and for a linear extrapolation to low doses. 

9 4.2.1.2 

Chronic Studies 

Page 34, 1st

Para 

The text states: “(There is a discrepancy in Fleischman et al (1980) between the table providing the data and the narrative”. Given that 

the dissimilar results were from a National Cancer Institute (NCI) study, perhaps the issue could havebeen resolved by contacting the NCI.

As part of its review process, consider resolving issues concfrom other Federal agencies. 

10 4.6.1 Oral 

Exposure 

70 The information of this section would be enhanced 

and put in perspective if it included information on 

urea being an endogenous product of protein catabolism. This additional information would inform the reader that organisms have homeostatic mechanism by which physiologic concentrations of urea are regulated and that humans excrete 20-30 grams per day via the urine.

Include information on urea bendogenous product of protein that organisms have homeostaby which physiologic concentare regulated and that the dose for toxicity would need to be these physiologic mechanism