Department of Defense Comments on the Draft Toxicological Review of Urea, June 2010

Dcpiirtmcnl of Defense C omments 011 the
Draft Toxicological Rexiew of I resi, June 2010
( ommcnls suhni 1 lied b\ ( hcmical
Material Risk Management Directorate
Organization Department of Defense
Dale Submitted 2 J111 \ 2<) |n
*( ommciil categories. Science or methods (S). 1 Editorial. grammar spel 11 ny. clan Ileal urns needed (1.). or Oilier (()) Also please indicate il' Major 1 e al'lecls I he
outcome, conclusions or implementation ol' the assessment
Comment
No.
Section
Pn «e £
Paragraph
(enter
"(llohiil" if
report
section-
wide)
Comment
Suggested Action, Revision
iincl References (if necessary)
C 'alcgorv
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 to
examine the potential toxicity of urea's
metabolites, ammonia and carbon monoxide for
example.
The document should clearly state the
rationale for determining whether to evaluate
metabolites and degradation products in the
Toxicological Review, and which ones are
appropriate for analysis.
S
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 not provide
inconsistent information.
E
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 exogenous ly administered urea. " It is not clear
why EPA is discounting the stated "majority of
the literature " that addresses endogenous urea.
The Toxicological Review should clearly state
the decision criteria regarding the use of data
on endogenous and exogenous forms of the
chemical and its evaluation of the chemical's
potential toxicity.
S
4
3.3.
Metabolism
3.5. Physiolo-
Page 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 considered
metabolism please explain where EPA believes
these transformations would be considered in
the toxicokinetics (TK) of a chemical.
S
Page 1 of 4

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Dcpiirtmcnl of Defense C omments 011 the
Draft Toxicologic^! Rexiew of I resi, June 2010
( ommenls suhni 1 lied b\ ( hemical
Material Risk Management Directorate
Organization Department of Defense
Dale Submitted 2 J111 \ 2<) |n
*( ommenl categories. Science or methods (S). 1 Editorial. grammar spel 11 ny. clan Ileal urns needed (1.). or Oilier (()) Also please indicate il' Major 1 e al'lecls I he
outcome, conclusions or implementation ol' the assessment
Comment
No.
Section
Pn «e £
I'siriigmph
(enter
"(llohiil" if
report
section-
wide)
Comment
Suggested Action, Revision
iiiul References (if necessary)
C iitegorv

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 Carcino-
genicity
5.2.1 Choice
of Principa
Study ad
Critical Effect
- with
Rationale and
Justification
Pages 25, 2nd
Para
Page 75, 1st
Para
Page 80, 1st
Para
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 certainly
contribute to the transparency of the documents
in future reviews.
0
6
3.5 Physiolo-
gically Based
Toxicokinetic
Models
Page 20,
1st Para
We believe the "F" in the second line needs a
subscript, probably "oa "
Please correct as warranted.
E
Page 2 of 4

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Dcpiirtmcnl of Defense C omments 011 the
Draft Toxicologic^! Rexiew of I resi, June 2010
( ommenls suhni 1 lied li\ ( hemical
Material Risk Management Directorate
Organization Department of Defense
Dale Submitted 2 J111 \ 2<) |n
*( ommenl categories. Science or methods (S). 1 Editorial. grammar spel 11 ny. clan Ileal urns needed (1.). or Oilier (()) Also please indicate il' Major 1 e al'lecls I he
outcome, conclusions or implementation ol' the assessment
Comment
No.
Section
Pn «e £
I'siriigmph
(enter
"(llohiil" if
report
section-
wide)
Comment
Suggested Action, Revision
iiiul References (if necessary)
C iitegorv
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 (FEVi) 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 at
least one analysis in another recent IRIS
document.
The quality control procedures for producing
IRIS documents should ensure biomarkers and
test results are given similar interpretations for
every chemical analyzed within the same time
frame. When substantial differences in
interpretation are made due to changes in
understanding of the results, these should be
noted.
0
8
4.2.1.2
Chronic
Studies
Page 34, 1st
Para
In this paragraph, it is stated that "Among Urea-
exposed male rats, there was a significant
occurrence in tumor incidence (21/50, 27/48,
25/48, and 35/50) at the high dose for interstitial
adenomas 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 procedures for producing
IRIS documents should ensure that animal
bioassay results are given similar
interpretations for every chemical assessment
within the same time frame. When substantial
differences in interpretation are made due to
changes in understanding of the results, these
should be noted.
0
Page 3 of 4

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Dcpiirtmcnl of Defense C omments 011 the
Drsil'l Toxicologic.il Rexiew of I resi, June 2010
( ommcnls suhni 1 lied b\ ( hcmical
Material Risk Management Directorate
Organization Department of Defense
Dale Submitted 2 J111 \ 2<) |n
*( ommciil categories. Science or methods (S). 1 Editorial. grammar spel 11 ny. clan Ileal urns needed (1.). or Oilier (()) Also please indicate il' Major 1 e al'lecls I he
outcome, conclusions or implementation ol' the assessment
Comment
No.
Section
Pn «e £
I'siriigmph
(enter
"(llohiil" if
report
section-
wide)
Comment
Suggested Action, Revision
iiiul References (if necessary)
C iitegorv

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 etal (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 have
been resolved by contacting the NCI.
As part of its review process, EPA should
consider resolving issues concerning studies
from other Federal agencies.
O
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 being an
endogenous product of protein catabolism and
that organisms have homeostatic mechanisms
by which physiologic concentrations of urea
are regulated and that the dose of urea required
for toxicity would need to be sufficient to upset
these physiologic mechanisms.
S
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