Risk Evaluation for N-Methylpyrrolidone Systematic Review Supplemental File: Data Quality Evaluation of Human Health Hazard Studies


PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
x=,EPA
United States
Environmental Protection Agency
Office of Chemical Safety and
Pollution Prevention
Risk Evaluation for
N-Methylpyrrolidone
Systematic Review Supplemental File:
Data Quality Evaluation of Human Health Hazard Studies -
Animal Studies
CASRN: 872-50-4
October 2019
1

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PEER REVIEW DRAFT - DO NOT CITE OR QUOTE
Table of Contents
1.	Acute and Short-Term Toxicity Studies	4
1.1. Animal toxicity evaluation results of Boenisch et al 2012 for a 19-day
immunotoxicity (inhalation) study on hematological, immune, and respiratory
outcomes	4
1.1.	Animal toxicity evaluation results of E.I. DuPont De Nemours & Co. 1991 for a
4-week inhalation, mortality, and histopathology study on respiratory, endocrine,
hematological, and immune outcomes	8
1.2.	Animal toxicity evaluation results of Gopinathan et al 2013 for a 5-day oral
study on clinical chemistry/biochemical, renal, hematological and immune outcomes
11
1.3.	Animal toxicity evaluation results of Lashmar et al 1989 for an irritation study,
dermal 24-hour study on irritation outcomes	15
1.4.	Animal toxicity evaluation results of Lee et al 1987 for a 4-week inhalation
study on respiratory, hematological, and immune outcomes	19
1.5.	Animal toxicity evaluation results of Malek et al 1997 for a 28-day oral, rats
and mice study on renal, hematology, and histopathology of various organs	21
1.6.	Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group
(1994) for a 4-week dietary study in mice on mortality; nutrition and metabolic/adult
exposure body weight; renal; hepatic; hematological and immune; clinical
chemistry /biochemical; ADME/PBPK and reproductive (male) outcomes	24
1.7.	Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group et
al 1994 for a 28-day diet rat-systemic and repro effects study on clinical
chemistry /biochemical, body weight, hematological, immune, renal, endocrine, and
reproductive outcomes	28
1.8.	Animal toxicity evaluation results of Tatsuno et al 2014 for an immunotoxicity
study on immune outcomes	31
2.	Subchronic Toxicity Studies	34
2.1.	Animal toxicity evaluation results of BASF 1995 for a 90-day diet mouse-liver
toxicity study on hepatic outcomes	34
2.2.	Animal toxicity evaluation results of Malley et al 1999 for a 90-day oral rats
and mice study on neurological/behavior, body weight, hepatic, and renal outcomes .37
2.3.	Animal toxicity evaluation results of Becci et al 1983 for a 13-week diet study
in dogs on body weight, hematological, and immune outcomes	40
3.	Cancer Studies	42
3.1.	Animal toxicity evaluation results of E.I. Dupont De Nemours Co. 1982 for a 2-
year inhalation study in rats on renal and cancer outcomes	42
3.2.	Animal toxicity evaluation results of Malley et al 2001 for an oral cancer rats
and mice study on cancer, hepatic, and renal outcomes	46
3.3.	Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group
1997 for a 2-year cancer bioassay study	48
4.	Reproductive/Developmental Toxicity Studies	51
2

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4.1.	Animal toxicity evaluation results of Becci et al 1982 for a dermal,
developmental study in rats (rf and final-study report in 4214125) on growth (early
life) and development outcomes	51
4.2.	Animal toxicity evaluation results of Ciba-Geigy 1987 for an oral
developmental rat study on growth (early life) and development outcomes	54
4.3.	Animal toxicity evaluation results of E. I. Dupont De Nemours 1979 for a
developmental range-finding: rats study on growth (early life) and development
outcomes	57
4.4.	Animal toxicity evaluation results of Intl Specialty 1979 for dermal
developmental, offspring and maternal effects study on growth (early life) and
development outcomes	60
4.5.	Animal toxicity evaluation results of Exxon Biomedical 1991 for a
multigeneration reproductive toxicity study on rats - reproductive, growth (early life)
and developmental outcomes	63
4.6.	Animal toxicity evaluation results of Exxon 1992 for a developmental toxicity
study in rats on growth (early life) and development outcomes	72
4.7.	Animal toxicity evaluation results of Lee et al 1987 for an inhalation
developmental study on growth (early life) and development outcomes	75
4.8.	Animal toxicity evaluation results of Saillenfait et al 2002 for an oral
developmental rat and maternal effects study on growth (early life), development, and
reproductive outcomes	79
4.9.	Animal toxicity evaluation results of Saillenfait et al 2003 	82
4.10.	Animal toxicity evaluation results of Sitarek et al 2008 for a reproductive-
male study on reproductive outcomes	85
4.11.	Animal toxicity evaluation results of Sitarek et al 2012 for a single generation
reproductive toxicity assessment in rats exposed orally study on hematological and
immune, respiratory, endocrine, hepatic, renal, neurological/behavior, thyroid
outcomes	88
4.12.	Animal toxicity evaluation results of Sitarek et al 2012 for single generation
reproductive toxicity assessment in rats exposed orally study on reproductive
outcomes	92
4.13.	Animal toxicity evaluation results of Solomon et al 1995 for a 2-generation
reproduction/developmental study, inhalation study on reproductive, growth (early
life), and development outcomes	96
3

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1. Acute and Short-Term Toxicity Studies
1.1. Animal toxicity evaluation results of Boenisch et al 2012 for a 19-day
immunotoxicity (inhalation) study on hematological, immune, and
respiratory outcomes
Study reference:
Boenisch, U.,Boehme, A.,Kohajda, T.,Moegel, I.,Schuetze, N.,von Bergen, M.,Simon, J.,Lehmann, I.,Poltc, T.
(2012). Volatile Organic ComDOunds Enhance Allergic Airwav Inflammation in an ExDerimental Mouse
Model PLoS ONE, 7(7), e39817

HERO ID: 2333837

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
See footnote at end of
page.1.
High
1
2
2
Test Substance
2. Test Substance
Source
The source and batch/lot
number of the test
substance was not
reported.
Low
3
1
3

3. Test Substance
Purity
Purity and grade of the
test substance were not
reported.
Low
3
1
3

4. Negative and
Vehicle Controls
The study authors
reported using a
concurrent negative
control group.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study authors did not
report how animals were
allocated to study groups.
Low
3
1
3
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The study authors did not
describe the test
substance preparation or
storage conditions. The
reporting deficiencies are
likely to have a
substantial impact on
results.
Low
3
1
3

8. Consistency of
Exposure
Administration
Critical exposure details,
including the methods
for generating
atmosphere in inhalation
chambers, were not
reported.
Low
3
1
3
1 Metric that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
4

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N-Methylpyrrolidone
Study reference:
Boenisch, U.,Boehme, A.,Kohajda, T.,Moegel, I.,Schuetze, N.,von Bergen, M.,Simon, J.,Lehmann, I.,Poltc, T.
(2012). Volatile Organic ComDOunds Enhance Allergic Airwav Inflammation in an ExDerimental Mouse
Model PLoS ONE, 7(7), e39817
HERO ID: 2333837
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentration
:s
Mean concentrations
were measured (as
reported in supplemental
file SI).
Medium
2
2
4
10. Exposure
Frequency and
Duration
The exposure duration
and frequency were
reported and were
suitable for the study
type (the animals were
exposed in a whole-body
inhalation chamber from
days 0-19 or days 17-19).
High
1
1
1
11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and spacing were
reported and were
relevant for the
assessment.
High
1
1
1
12. Exposure Route
and Method
The exposure route and
method of exposure
(whole body) were
reported; however, there
were reporting
deficiencies in the
chamber (e.g., number of
changes per hour).
Low
3
1
3
Test Organism
13. Test Animal
Characteristics
Ovalbumin-sensitized
and non-sensitized mice
were used. The body
weight, and health status
of mice at the start of the
study were not reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported and were
adequate and the same
for the control and
exposed populations.
High
1
1
1
1 Metric that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
5

HERO ID: 2333837

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
The number per group
was not clearly reported
in the methods (other
than stating that all
animal experiments
involved groups of 4-6
mice/cage). However, the
results appear to have
been based on at least 9
animals per group (e.g.,
see Figures 4, 6A),
although some results
were based on only 4
animals (e.g., Fig 6B,
6C).
Low
3
1
3

16. Outcome
Assessment
Methodology
The outcome assessment
methodology addressed
or reported the intended
outcomes of interest and
was sensitive for the
outcomes of interest.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Details of the outcome
assessment protocol were
reported, and outcomes
were assessed
consistently across study
groups.
High
1
1
1

18. Sampling
Adequacy
Sampling of the
outcomes of interest
were adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding is not required
for objective outcomes.
Not Rated
NA
NA
NA

20. Negative Control
Response
The negative control
responses were reported
and acceptable.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Respiratory rate
measurement was not
reported. This is may
impact results since
NMP is a potential
respiratory irritant.
Low
3
2
6
6

-------
N-Methylpyrrolidone
Study reference:
Boenisch, U.,Boehme, A.,Kohajda, T.,Moegel, I.,Schuetze, N.,von Bergen, M.,Simon, J.,Lehmann, I.,Polte, T.
(2012). Volatile Organic ComDOunds Enhance Allergic Airwav Inflammation in an ExDerimental Mouse
Model PLoS ONE, 7(7), e39817

HERO ID: 2333837





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health Outcomes
Unrelated to
Exposure
Data on attrition and
health outcomes
unrelated to exposure
were not reported for
each study group and this
deficiency may have a
substantial impact on
results.
Low
3
1
3

23. Statistical
Methods
Statistical methods were
reported and were
appropriate for the data
sets.
High
1
1
1
Data Presentation
and Analysis
24. Reporting of
Data
Data for exposure-related
findings were presented
for all outcomes by
exposure group with
quantal or continuous
presentation. Negative
findings were reported
qualitatively and/or
quantitatively.
High
1
2
2


Sum of scores:

29
53
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.8276
Overall Score:
Nearest *:
1.8
Low: >=2.5 and <=j







Overall Quality Level:

Medium

7

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N-Methylpyrrolidone
1.1. Animal toxicity evaluation results of E.I. DuPont De Nemours & Co. 1991 for a
4-week inhalation, mortality, and histopathology study on respiratory,
endocrine, hematological, and immune outcomes
Study reference:
E. I. DuPont De Nemours & Co (1991). Initial submission: four-week inhalation range-finding test on 1-
methyl-2-pyrrolidone (final report) with attachments and cover letter dated 112691,920000398, #88-
920000398

HERO ID: 3563360

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
See footnote at end of
page.1
High
1
2
2
Test Substance
2. Test Substance
Source
Test substance submitted
by identified persons.
Low
3
1
3

3. Test Substance
Purity
Purity was not reported.
Low
3
1
3

4. Negative and
Vehicle Controls
Concurrent controls were
used.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Randomized allocation
of animals was not
reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Methods and equipment
used to generate the
aerosol were reported;
however, storage of the
test material was not
reported.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Nominal and measured
concentrations were
reported, but particle size
and MMAD were not
reported.
Low
3
2
6

10. Exposure
Frequency and
Duration
Duration was reported,
but frequency, in terms
of days/week, was
reported only as 21 six-
hour exposures
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were
reported and justified.
High
1
1
1

12. Exposure Route
and Method
The number of air
changes in the exposure
chamber was not
reported.
Low
3
1
3
8

-------
N-Methylpyrrolidone
Study reference:
E. I. DuPont De Nemours & Co (1991). Initial submission: four-week inhalation range-finding test on 1-
methyl-2-pyrrolidone (final report) with attachments and cover letter dated 112691,920000398, #88-
920000398

HERO ID: 3563360

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The species, strain, sex,
and initial body weight
were reported. The age,
health status, and source
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were not reported.
Low
3
1
3

15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Breathing rates and body
temperature were not
measured to rule out
reflex bradypnea from
irritancy.
Low
3
2
6
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative controls
responded appropriately.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Test animals showed
signs of lethargy and
irregular respiration
which persisted until the
end of each exposure.
Low
3
2
6

22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposures
were reported.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
described in the
appendices and were
appropriate. Analysis of
histopathological results
was not conducted.
Medium
2
1
2

24. Reporting of
Data
Data were reported.
High
1
2
2

Sum of scores:

29
56
9

-------
N-Methylpyrrolidone
Study reference:
E. I. DuPont De Nemours & Co (1991). Initial submission: four-week inhalation range-finding test on 1-
methyl-2-pyrrolidone (final report) with attachments and cover letter dated 112691,920000398, #88-
920000398
HERO ID: 3563360
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.9310
Overall Score:
Nearest *:
1.9
Overall Quality Level:
Medium
10

-------
N-Methylpyrrolidone
1.2. Animal toxicity evaluation results of Gopinathan et al 2013 for a 5-day oral
study on clinical chemistry/biochemical, renal, hematological and immune
outcomes
Study reference:
Gopinathan, S.,O'Neill, E.,Rodriguez, L. A.,Champ, R.,Phillips, M.,Nouraldeen, A. mr,Wendt, M.,Wilson, A.
G. E..Kramer. J. A. (2013). In vivo toxicolosv of exciDients commonlv emDloved in drug discoverv in rats
Journal of Pharmacological and Toxicological Methods, 68(2), 284-295

HERO ID: 3037621

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified.
Medium
2
2
4
Test Substance
2. Test Substance
Source
The source of the test
substance was reported,
but a batch/lot number
was not reported.
Medium
2
1
2
3. Test Substance
Purity
Test substance purity
was not reported, but all
substances tested in the
study were stated to have
been of reagent or
pharmacopeia grade.
Low
3
1
3
Test Design
4. Negative and
Vehicle Controls
The study authors
reported using a
concurrent negative
control group; however,
details were not fully
reported on the negative
control group (whether
the negative control
received the same
preparation as used for
the test substance (e.g.,
vehicle).
Low
3
2
6

5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study reported
methods of allocation of
animals to study groups,
but minor limitations
were observed in that
animals were randomly
stratified by body weight.
Medium
2
1
2
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
Preparation and storage
of the test substance were
not reported.
Low
3
1
3
11

-------
N-Methylpyrrolidone
Study reference:
Gopinathan, S.,O'Neill, E.,Rodriguez, L. A.,Champ, R.,Phillips, M.,Nouraldeen, A. mr,Wendt, M.,Wilson, A.
G. E.,Kramer. J. A. (2013). In vivo toxicolosv of exciDients commonlv emDloved in drug discoverv in rats
Journal of Pharmacological and Toxicological Methods, 68(2), 284-295

HERO ID: 3037621

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Details of the exposure
administration were
reported, and exposures
were administered
consistently across study
groups in a scientifically
sound manner (e.g., dose
volume was acceptable).
High
1
1
1

9. Reporting of
Doses/Concentration
s
Administered doses were
reported without
ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure frequency
and duration were
reported and were
appropriate for the study
type and outcomes of
interest (acute toxicity).
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and dose spacing
was reported and was
acceptable.
High
1
1
1

12. Exposure Route
and Method
The exposure route and
method were reported
and were acceptable.
High
1
1
1

13. Test Animal
Characteristics
The test animal source,
species, strain, and sex
were reported; however,
age, health status, and
starting body weights
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Most husbandry
conditions (e.g.,
temperature, light cycle,
housing) were reported
and were adequate and
similar for all groups;
however, humidity levels
were not reported.
Low
3
1
3

15. Number per
Group
The number of animals
per group (5
males/group) was
reported, appropriate for
the study type and
outcome analysis, and
consistent with studies of
the same or similar type.
High
1
1
1
12

HERO ID: 3037621

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
The outcome assessment
methodology addressed
or reported the intended
outcomes of interest and
was sensitive for the
outcomes of interest
(acute effects).
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Details of the outcome
assessment methodology
were reported, and
outcomes were assessed
consistently across study
groups using the same
protocol for all groups.
High
1
1
1
18. Sampling
Adequacy
Details regarding
sampling for the
outcomes of interest
were reported and the
study used adequate
sampling for the
outcomes of interest.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
The negative control
responses were reported
and acceptable.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
There were no reported
differences among the
study groups that would
influence the outcome.
High
1
2
2
Confounding /
Variable Control
22. Health Outcomes
Unrelated to
Exposure
Data on attrition and
health outcomes
unrelated to exposure
were not reported for
each study group and this
deficiency may have a
substantial impact on
results.
Low
3
1
3
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
clearly described and
were appropriate for the
data sets.
High
1
1
1
13

-------
N-Methylpyrrolidone
Study reference:
Gopinathan, S.,O'Neill, E.,Rodriguez, L. A.,Champ, R.,Phillips, M.,Nouraldeen, A. mr,Wendt, M.,Wilson, A.
G. E.,Kramer. J. A. (2013). In vivo toxicolosv of exciDients commonlv emDloved in drug discoverv in rats
Journal of Pharmacological and Toxicological Methods, 68(2), 284-295
HERO ID: 3037621
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Data for exposure-related
outcomes were reported
for most, but not all,
outcomes by exposure
group. For example,
mottled kidneys were
observed in all treated
groups with a combined
incidence of 8/15 rats
(not observed in the
control group). The
incidence of mottled
kidneys observed by
dose group were not
reported.
Low
3
2
6
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
51
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.7586
Overall Score:
Nearest *:
1.8
Overall Quality Level
Medium
14

-------
N-Methylpyrrolidone
1.3. Animal toxicity evaluation results of Lashmar et al 1989 for an irritation study,
dermal 24-hour study on irritation outcomes
Study reference:
Lashmar. U. T..Hadsraft. J..Thomas. N. (1989). ToDical annlication of Denetration enhancers to the skin of
nude mice: a histopathological study Journal of Pharmacy and Pharmacology, 41(2), 118-122

HERO ID: 3539872

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name; CASRN not
reported.
Medium
2
2
4
Test Substance
2. Test Substance
Source
The source manufacturer
was reported, but
batch/lot numbers were
not; this omission is
unlikely to have a
substantial impact on
results.
Medium
2
1
2

3. Test Substance
Purity
Test substance reported
to be "reagent grade", but
no specific purity was
reported.
Low
3
1
3
Test Design
4. Negative and
Vehicle Controls
A negative control group
(untreated skin) was
used; it is unclear if the
untreated skin area was
subjected to the same
conditions as the exposed
area. A 1% (w/w)
neutralized carbomer gel
was also tested as a
control.
Medium
2
2
4

5. Positive Controls
The use of a positive
control is not indicated
by this study type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
The study did not report
how animals were
allocated to study groups.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Test substance
preparation was briefly
reported. There is a lack
of reporting of the test
substance storage.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
Details of exposure
protocol were limited;
however, this deficiency
is unlikely to have a
substantial impact on the
results.
Medium
2
1
2

9. Reporting of
Doses/Concentration
s
Administered doses are
reported.
High
1
2
2
15

-------
N-Methylpyrrolidone
Study reference:
Lashmar. U. T..Hadsraft. J.,Thomas. N. (1989). ToDical ai)i)lication of Denetration enhancers to the skin of
nude mice: a histopathological study Journal of Pharmacy and Pharmacology, 41(2), 118-122

HERO ID: 3539872

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Exposure duration (24-
hours) was reported and
appropriate for the study.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and the dose
spacing were not
justified by the study
authors; however, the
number of doses and
spacing are adequate to
show results relevant to
the outcome of interest.
Medium
2
1
2

12. Exposure Route
and Method
The exposure route and
method are appropriate
and reported with limited
detail; however, this
deficiency is unlikely to
have a substantial impact
on the results.
Medium
2
1
2
Test Organism
13. Test Animal
Characteristics
The test animal species,
strain, sex, age, and
starting body weight are
reported, but there is no
information on the health
status of the mice
reported. This omission
in reporting is unlikely to
have a substantial impact
on results. It is unclear if
this species (nude
mouse) is an adequate
animal model for the
outcome of interest.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Animal husbandry
conditions were not
sufficiently reported to
determine whether
husbandry was adequate.
Low
3
1
3

15. Number per
Group
The number of animals
per study group was
reported (3) and
appropriate for the study
type.
High
1
1
1
16

-------
N-Methylpyrrolidone
Study reference:
Lashmar. U. T..Hadsraft. J.,Thomas. N. (1989). ToDical annlication of Denetration enhancers to the skin of
nude mice: a histopathological study Journal of Pharmacy and Pharmacology, 41(2), 118-122

HERO ID: 3539872

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
The outcome assessment
methodology was
partially addressed for
the intended outcomes of
interest reported
Medium
2
2
4

17. Consistency of
Outcome
Assessment
The assessment protocol
were reported and
consistent across study
groups and chemicals
tested.
High
1
1
1
Outcome
Assessment
18. Sampling
Adequacy
Details regarding
sampling for the
outcomes of interest
were reported and
adequate.
High
1
1
1

19. Blinding of
Assessors
This metric is not
applicable for initial
histopathology review;
therefore, is not rated for
this study.
Not Rated
NA
NA
NA

20. Negative Control
Response
The untreated control
and 1% gel control
response was adequate.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
PVC and PVCD were
used for occluded dermal
exposure, it is unclear
how this may have
impacted the results.
Medium
2
2
4
Confounding /
Variable Control
22. Health Outcomes
Unrelated to
Exposure
There is no reporting for
attrition and/or health
outcomes unrelated to
exposure, though it is
unlikely to have a
substantial impact on
results.
Medium
2
1
2
Data Presentation
and Analysis
23. Statistical
Methods
No statistical analysis
methods or statistical
results were reported;
however, calculation
methods for irritation
scores were described.
Medium
2
1
2
17

-------
N-Methylpyrrolidone
Study reference:
Lashmar. U. T..Hadsraft. J.,Thomas. N. (1989). ToDical ai)i)lication of Denetration enhancers to the skin of
nude mice: a histopathological study Journal of Pharmacy and Pharmacology, 41(2), 118-122
HERO ID: 3539872
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Not all data was reported
for the outcome. Only
the model relative
irritancy score for the
representative tested
animals. Irritation scores
for individual animals
was not reported for any
exposure group.
Histopathological results
are presented
qualitatively as images of
skin sections.
Medium
2
2
4
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

28
55
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.9643
Overall Score:
Nearest *:
2.0
Overall Quality Level:
Medium
18

-------
N-Methylpyrrolidone
1.4. Animal toxicity evaluation results of Lee et al 1987 for a 4-week inhalation study
on respiratory, hematological, and immune outcomes
Study reference:
Lee. K. P..Chromev. N. C..Culik. R..Barnes. J. R.Schneider. P. W. (1987). Toxicity of N-methvl-2-
pyrrolidone (NMP): teratogenic, subchronic, and two-year inhalation studies Fundamental and Applied
Toxicology, 9(2), 222-235

HERO ID: 3539878

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Structure, nomenclature,
physiochemical
properties provided
High
1
2
2
Test Substance
2. Test Substance
Source
Source not identified
Low
3
1
3

3. Test Substance
Purity
Purity such that effects
due to test substance.
Medium
2
1
2

4. Negative and
Vehicle Controls
Negative controls were
included
High
1
2
2
Test Design
5. Positive Controls
Positive controls not
required
Not Rated
NA
NA
NA

6. Randomized
Allocation
Method of allocation was
not described
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Preparation of test
atmospheres was
described, storage of the
test material was not.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposures were
administered consistently
High
1
1
1

9. Reporting of
Doses/Concentration
s
Aerosol particle size and
MMAD were not
reported.
Low
3
2
6
Exposure
Characterization
10. Exposure
Frequency and
Duration
Duration of exposure did
not extend throughout
organogenesis.
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
Rationale for dose
selection was not
provided
Medium
2
1
2

12. Exposure Route
and Method
Route was appropriate,
but insufficient detail
was provided on the
method (e.g., humidity,
number of air changes
per hour)
Low
3
1
3
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, and sex were
provided; age, and initial
body weight, and health
status were not reported.
Low
3
2
6
19

-------
N-Methylpyrrolidone
Study reference:
Lee. K. P..Chromev. N. C..Culik. R..Barnes. J. R.Schneider. P. W. (1987). Toxicity of N-methvl-2-
pyrrolidone (NMP): teratogenic, subchronic, and two-year inhalation studies Fundamental and Applied
Toxicology, 9(2), 222-235

HERO ID: 3539878

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry was not
adequately reported.
Low
3
1
3

15. Number per
Group
The number of animals
exposed in each group
was adequate
High
1
1
1

16. Outcome
Assessment
Methodology
Breathing rate and body
temperature were not
measured.
Low
3
2
6
Outcome
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
Assessment
18. Sampling
Adequacy
Sampling was adequate
for the outcomes
High
1
1
1

19. Blinding of
Assessors
Subjective outcomes
were not assessed
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative controls
responded appropriately
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Test animals showed
signs of lethargy and
irregular respiration.
Low
3
2
6
22. Health Outcomes
Unrelated to
Exposure
None were reported
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
appropriate when
applied, but all outcomes
were not analyzed.
Medium
2
1
2

24. Reporting of
Data
Data were reported for
outcomes
High
1
2
2

Sum of scores:

29
57
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.9655
Overall Score:
Nearest *:
2.0
Low: >=2.5 and <=j

Overall Quality Level:

Medium

-------
N-Methylpyrrolidone
1.5. Animal toxicity evaluation results of Malek et al 1997 for a 28-day oral, rats and
mice study on renal, hematology, and histopathology of various organs
Study reference:
Malek, D. E.,Malley, L. A.,Slone, T. W.,Elliott, G. S.,Kennedy, G. L.,Mellert, W.,Deckardt, K.,Gembardt,
C..Hildebrand. B..MurDhv. S. R.Bower. D. B..Wright. G. A. (1997). ReDeated dose toxicity studv (28 davs) in
rats and mice with N-methylpyrrolidone (NMP) Drug and Chemical Toxicology, 20(1-2), 63-77

HERO ID: 3539910

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
The source was
identified.
High
1
1
1

3. Test Substance
Purity
The reported purity was
such that effects likely
due to the test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
control animals were
included.
High
1
2
2

5. Positive Controls
Positive controls not
required.
Not Rated
NA
NA
NA
Test Design
6. Randomized
Allocation
Animals were allocated
by computerized
stratified randomization
so no statistically
significant differences
among body weights
were observed.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Limited preparation
details were presented;
however, no information
on NMP analytical
concentration, storage or
stability were reported.
Low
3
1
3

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
of exposure were
reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and spacing were
reported and justified.
High
1
1
1

12. Exposure Route
and Method
The exposure route and
method were appropriate.
High
1
1
1
21

-------
N-Methylpyrrolidone
Study reference:
Malek, D. E.,Malley, L. A.,Slone, T. W.,Elliott, G. S.,Kennedy, G. L.,Mellert, W.,Deckardt, K.,Gembardt,
C..Hildebrand. B.,MurDhv. S. R.Bower. D. B..Wri2ht. G. A. (1997). ReDeated dose toxicity studv (28 days) in
rats and mice with N-methylpyrrolidone (NMP) Drug and Chemical Toxicology, 20(1-2), 63-77

HERO ID: 3539910

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, species,
strain, sex, age, and
initial body weight, and
health status were
reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
except room air changes
were reported.
Medium
2
1
2

15. Number per
Group
The numbers of animals
per group were
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
appropriate.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health effects
unrelated to exposure
were reported.
High
1
1
1
Data Presentation
23. Statistical
Methods
Statistical methods were
reported and appropriate.
High
1
1
1
and Analysis
24. Reporting of
Data
Data were reported.
High
1
2
2

Sum of scores:

28
33
mgn: >-i ana =1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.1786
Overall Score:
Nearest *:
1.2
22

-------
N-Methylpyrrolidone
Study reference:
Malek, D. E.,Malley, L. A.,Slone, T. W.,Elliott, G. S.,Kennedy, G. L.,Mellert, W.,Deckardt, K.,Gembardt,
C..Hildebrand. B.,MurDhv. S. R.Bower. D. B..Wri2ht. G. A. (1997). ReDeated dose toxicity studv (28 days) in
rats and mice with N-methylpyrrolidone (NMP) Drug and Chemical Toxicology, 20(1-2), 63-77
HERO ID: 3539910
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
High
23

-------
N-Methylpyrrolidone
1.6. Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group
(1994) for a 4-week dietary study in mice on mortality; nutrition and
metabolic/adult exposure body weight; renal; hepatic; hematological and
immune; clinical chemistry/biochemical; ADME/PBPK and reproductive (male)
outcomes
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). ReDeated dose toxicity with N-MethvlDvrrolidone in
B6C3F1 mice Administration in the diet for 4 weeks (Range-finding study)

HERO ID: 4214115

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified definitely and
CASRN reported.
High
1
2
2
Test Substance
2. Test Substance
Source
The source of the testing
laboratory (industry
sponsored) test substance
was reported, including
manufacturer and
batch/lot number.
High
1
1
1

3. Test Substance
Purity
The test substance purity
was reported.
High
1
1
1

4. Negative and
Vehicle Controls
Study authors reported
using an appropriate
concurrent negative
control group.
High
1
2
2
Test Design
5. Positive Controls
Not required for study
type
Not Rated
NA
NA
NA
6. Randomized
Allocation
Randomization list was
drawn up by a computer
based on body weight
(laboratory data
processing, Dept of
Toxicology, BASF)
Medium
2
1
2
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The test substance
preparation and storage
conditions were reported
and appropriate for the
test substance.
High
1
1
1
8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported, and exposures
were administered
High
1
1
1

consistently across study
groups.

-------
N-Methylpyrrolidone
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). ReDeated dose toxicity with N-MethvlDvrrolidone in
B6C3F1 mice Administration in the diet for 4 weeks (Range-finding study)

HERO ID: 4214115

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentration
s
The study authors
reported the administered
doses/concentrations,
including the calculated
information from ppm in
diet to mg/kg-day in the
diet for all the exposed
groups without
ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
The exposure frequency
and duration of exposure
were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups (n=4) and
do se/concentration
spacing were justified by
study authors and
considered adequate to
address the purpose of
the study.
High
1
1
1

12. Exposure Route
and Method
The route and method of
exposure were reported
and were suited to the
test substance.
High
1
1
1

13. Test Animal
Characteristics
The test animal species,
strain, sex, health status,
age, and starting body
weight were reported and
the test animal was
obtained from a
commercial source or
laboratory-maintained
colony.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
The study authors
reported all husbandry
conditions and were
adequate and the same
for control and exposed
populations, such that the
only difference was
exposure.
High
1
1
1

15. Number per
Group
The reported number of
animals per study group
was lower than the
typical number used in
studies of the same or
similar type.
Medium
2
1
2
25

HERO ID: 4214115

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

16. Outcome
Assessment
Methodology
The outcome assessment
methodology addressed
or reported the intended
outcome(s) of interest
and was sensitive for the
outcomes(s) of interest.
High
1
2
2

17. Consistency of
Outcome
Assessment
incomplete reporting of
minor details of outcome
assessment protocol
execution, but these
uncertainties or
limitations are unlikely
to have a substantial
impact on results.
Medium
2
1
2
Outcome
Assessment
18. Sampling
Adequacy
Details regarding
sampling for the
outcome(s) of interest
were reported and the
study used adequate
sampling for the
outcome(s) of interest.
High
1
1
1

19. Blinding of
Assessors
The study did not report
whether assessors were
blinded to treatment
group for subjective
outcomes, and this
deficiency is likely to
have a substantial impact
on results.
Low
3
1
3

20. Negative Control
Response
The biological responses
of the negative control
group(s) were adequate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
There were no reported
differences among the
study groups in initial
body weight, food intake,
or respiratory rate that
could influence the
outcome assessment. The
authors did not report
water intake, but it is not
likely to have a
significant impact on
results.
High
1
2
2
26

-------
N-Methylpyrrolidone
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). ReDeated dose toxicity with N-MethvlDvrrolidone in
B6C3F1 mice Administration in the diet for 4 weeks (Range-finding study)
HERO ID: 4214115
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health Outcomes
Unrelated to
Exposure
Details regarding animal
attrition and health
outcomes unrelated to
exposure were reported
for each study group.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
clearly described and
appropriate for
dataset(s).
High
1
1
1
24. Reporting of
Data
Data for exposure-related
findings were presented
for all outcomes by
exposure group.
High
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

30
35
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.1739
Overall Score:
Nearest *:
1.2
Overall Quality Level:
High
27

-------
N-Methylpyrrolidone
1.7. Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group et
al 1994 for a 28-day diet rat-systemic and repro effects study on clinical
chemistry/biochemical, body weight, hematological, immune, renal, endocrine,
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). Subchronic Oral Toxicitv: 28-dav Feeding studv in Rats
with N-Methylpyrrolidone (NMP)

HERO ID: 4214124

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name, synonyms,
CASRN, form, and
structure.
High
1
2
2
Test Substance
2. Test Substance
Source
The source was
identified along with
production date, and tank
number.
High
1
1
1

3. Test Substance
Purity
Purity and composition
are such that effects are
likely due to the test
substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
control animals were
included.
High
1
2
2

5. Positive Controls
Positive control animals
not required.
Not Rated
NA
NA
NA
Test Design
6. Randomized
Allocation
Allocation wad by
computerized stratified
randomization to prevent
no statistically significant
differences among mean
body weights by sex.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Preparation and storage
conditions were
appropriate. Stability,
homogeneity, and
concentration analysis
were conducted and
appropriate.
High
1
1
1
Exposure
Characterization
8. Consistency of
Exposure
Administration
Diets were administered
consistently.
High
1
1
1

9. Reporting of
Doses/Concentration
s
Doses were reported
without ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
Exposure frequency and
duration were reported.
High
1
1
1
28

-------
N-Methylpyrrolidone
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). Subchronic Oral Toxicity: 28-dav Feeding studv in Rats
with N-Methylpyrrolidone (NMP)

HERO ID: 4214124

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and dose spacing
were based on the results
of previous studies.
High
1
1
1

12. Exposure Route
and Method
The route and method
were as specified in TPA
TSCA testing consent
order.
High
1
1
1

13. Test Animal
Characteristics
The source, species,
strain, sex, age, initial
body weight, and health
status were reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported and were
appropriate.
High
1
1
1

15. Number per
Group
The number of animals

per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported.
High
1
2
2

17. Consistency of
Outcome
Assessment
Outcome assessment was
High
1
1
1
Outcome
Assessment
consistent across groups.
18. Sampling
Adequacy
Sampling was adequate
for the outcomes of
interest.
High
1
1
1

19. Blinding of
Assessors
Blinding not required for
the outcomes.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative controls
responded appropriately.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
A palatability study was
conducted prior to the
study which reported that
the dietary levels was
likely to be tolerated by
the rats in a 28-day
study. No other
confounding variables in
test design or procedures
were observed.
High
1
2
2

22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were reported.
High
1
1
1
29

-------
N-Methylpyrrolidone
Study reference:
N-MethvlDvrrolidone Producers GrouD. Inc (1994). Subchronic Oral Toxicity: 28-dav Feeding studv in Rats
with N-Methylpyrrolidone (NMP)
HERO ID: 4214124
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data Presentation
and Analysis
23. Statistical
Methods
Statistical analyses were
described and
appropriate.
High
1
1
1
24. Reporting of
Data
All outcomes were
reported.
High
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
32
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.1034
Overall Score:
Nearest *:
1.1
Overall Quality Level:
High
30

-------
N-Methylpyrrolidone
1.8. Animal toxicity evaluation results of Tatsuno et al 2014 for an immunotoxicity
study on immune outcomes	
Study reference:
Tatsuno. T..Mivazaki. K..Yamashiro. H. (2014). MultiDle solvent. N-methvl-2-Dvrrolidone. acts as a novel
adjuvant for enhancing cutaneous immune responses Bioscience, Biotechnology, and Biochemistry, 78(6), 954-
959

HERO ID: 3540753





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Substance
1. Test Substance
Identity
Test substance identified
by name, but more
information may be in
reference describing
preparation of test tapes.
Medium
2
2
4
2. Test Substance
Source
Source of test substance
not identified.
Low
3
1
3

3. Test Substance
Purity
Purity not reported
Low
3
1
3

4. Negative and
Vehicle Controls
Animals given a placebo
were included.
High
1
2
2
Test Design
5. Positive Controls
Positive controls not
required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Method of randomized
allocation was not
reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Preparation not reported.
Low
3
1
3

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Percentages were
reported.
Medium
2
2
4
10. Exposure
Frequency and
Duration
See footnote at end of
page.1.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were
reported only.
Medium
2
1
2

12. Exposure Route
and Method
See footnote at end of
page.2.
High
1
1
1
1	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
2	Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
31

-------
N-Methylpyrrolidone
Study reference:
Tatsuno. T.,Mivazaki. K.,Yamashiro. H. (2014). MultiDle solvent. N-methvl-2-Dvrrolidone. acts as a novel
adjuvant for enhancing cutaneous immune responses Bioscience, Biotechnology, and Biochemistry, 78(6), 954-
959

HERO ID: 3540753





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, species,
strain, and age were
reported. Health status
and initial body weight
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were not reported.
Low
3
1
3

15. Number per
Group
The number of animals
per group were
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
See footnote at end of
page \
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
See footnote at end of
page \
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding not required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative and placebo
responses were reported
and appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were observed.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were reported.
High
1
1
1
Data Presentation
23. Statistical
Methods
See footnote at end of
page \
High
1
1
1
and Analysis
24. Reporting of
Data
Outcome data were
reported.
High
1
2
2


Sum of scores:

28
46
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.5862
Overall Score:
Nearest *:
1.6
Low: >=2.5 and <=j







Overall Quality Level:

High

32

-------
N-Methylpyrrolidone
33

-------
N-Methylpyrrolidone
2. Subchronic Toxicity Studies	
2.1. Animal toxicity evaluation results of BASF 1995 for a 90-day diet mouse-liver
toxicity study on hepatic outcomes
Study reference:
BASF (1995). N-METHYLPYRROLIDONE - SUBCHRONIC ORAL TOXICITY STUDY IN B6C3F1 MICE
BY ADMINISTRATION IN THE DIET FOR 3 MONTHS, WITH COVER LETTER DATED 11/22/95

HERO ID: 3585204





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and CASRN
High
1
2
2

2. Test Substance
Source
Source not identified but
production container was
listed.
Medium
2
1
2
Test Substance





3. Test Substance
Purity
Purity (99.8%)
determined by gas
chromatography and
such that effects likely
due to the test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were used.
High
1
2
2
Test Design
5. Positive Controls
Positive controls not
required.
Not Rated
NA
NA
NA
6. Randomized
Allocation
Animals allocated by
weight using a
computerized
randomization list.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Preparation and storage
details were provided.
Stability, homogeneity,
and concentration tests
were conducted.
High
1
1
1

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
of exposures were
reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and dose spacing were
reported and justified.
High
1
1
1

12. Exposure Route
and Method
Route and method were
appropriate.
High
1
1
1
34

-------
N-Methylpyrrolidone
Study reference:
BASF (1995). N-METHYLPYRROLIDONE - SUBCHRONIC ORAL TOXICITY STUDY IN B6C3F1 MICE
BY ADMINISTRATION IN THE DIET FOR 3 MONTHS, WITH COVER LETTER DATED 11/22/95

HERO ID: 3585204





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, species,
strain, sex, initial body
weight, and health status
were reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
except air changes were
reported.
Medium
2
1
2

15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
appropriate.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding not required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were observed.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were observed.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical analysis was
conducted and
appropriate.
High
1
1
1
24. Reporting of
Data
Data were presented.
High
1
2
2


Sum of scores:

29
33
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.1364
Overall Score:
Nearest *:
1.1
Low: >=2.5 and <=j







Overall Quality Level:

High

35

-------
N-Methylpyrrolidone
36

-------
N-Methylpyrrolidone
2.2. Animal toxicity evaluation results of Malley et al 1999 for a 90-day oral rats and
mice study on neurological/behavior, body weight, hepatic, and renal outcomes
Study reference:
Malley, L. A.,Kennedy, G. L.,Elliott, G. S.,Slone, T. W.,Mellert, W.,Deckardt, K.,Gembardt, C.,Hildebrand,
B.,Parod, R. J..McCarthv. T. J..Griffiths. J. C. (1999). 90-dav subchronic toxicity studv in rats and mice fed
N-methylpyrrolidone (NMP) including neurotoxicity evaluation in rats Drug and Chemical Toxicology, 22(3),
455-480

HERO ID: 3539912

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
The source was
identified.
Medium
2
1
2

3. Test Substance
Purity
The reported purity was
such that effects likely
due to test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Negative control animals
were included.
High
1
2
2
Test Design
5. Positive Controls
Positive controls not
required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Animals allocated by
computerized stratified
randomization.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Limited preparation
details were reported, but
no storage information
was presented. Stability
of the test substance in
the diet was established.
High
1
1
1

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
Medium
2
1
2
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and spacing were
reported and justified.
High
1
1
1

12. Exposure Route
and Method
The route and method
were reported.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, sex, age, initial
body weight, and health
status were reported.
High
1
2
2
37

-------
N-Methylpyrrolidone
Study reference:
Malley, L. A.,Kennedy, G. L.,Elliott, G. S.,Slone, T. W.,Mellert, W.,Deckardt, K.,Gembardt, C.,Hildebrand,
B.,Parod, R. J.,McCarthv. T. J..Griffiths. J. C. (1999). 90-dav subchronic toxicity studv in rats and mice fed
N-methylpyrrolidone (NMP) including neurotoxicity evaluation in rats Drug and Chemical Toxicology, 22(3),
455-480

HERO ID: 3539912

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All conditions except for
room air changes were
reported.
Medium
2
1
2

15. Number per
Group
the number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported.
High
1
2
2

17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
Outcome
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1
Assessment
19. Blinding of
Assessors
Experimenters
conducting the FOB
evaluations were blind
with respect to the
exposure group of each
animal.
Medium
2
1
2

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were observed.
High
1
1
1
Data Presentation
23. Statistical
Methods
Statistical methods were
appropriate.
High
1
1
1
and Analysis
24. Reporting of
Data
Data were reported.
High
1
2
2

Sum of scores:

30
37
mgn: >-i ana =1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.2174
Overall Score:
Nearest *:
1.2
38

-------
N-Methylpyrrolidone
Study reference:
Malley, L. A.,Kennedy, G. L.,Elliott, G. S.,Slone, T. W.,Mellert, W.,Deckardt, K.,Gembardt, C.,Hildebrand,
B.,Parod, R. J.,McCarthv. T. J.,Griffiths. J. C. (1999). 90-dav subchronic toxicity studv in rats and mice fed
N-methylpyrrolidone (NMP) including neurotoxicity evaluation in rats Drug and Chemical Toxicology, 22(3),
455-480
HERO ID: 3539912
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
High
39

-------
N-Methylpyrrolidone
2.3. Animal toxicity evaluation results of Becci et al 1983 for a 13-week diet study in
dogs on body weight, hematological, and immune outcomes
Study reference:
Becci. P. J.. GeDhart. L. A.. Koschier. F. J.. Johnson. W. D.. Burnette. L. W. (1983). Subchronic feeding studv
in beagle dogs of N-methylpyrrolidone Journal of Applied Toxicology, 3(2), 83-86

HERO ID: 3539728

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
test substance identified
by name and CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
source identified.
Medium
2
1
2

3. Test Substance
Purity
The purity of the test
substance was reported
(99.9%).
High
1
1
1

4. Negative and
Vehicle Controls
Negative control animals
were included.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Allocation method was
not reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Preparation was reported,
but storage and analysis
was not.
Low
3
1
3

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2
Characterization
10. Exposure
Frequency and
Duration
Frequency and duration
were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were
reported, but not
justified.
Medium
2
1
2

12. Exposure Route
and Method
The route and method
were reported.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, and age were
reported. Health status
and initial body weight
were not reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Humidity, housing, and
room air changes were
not reported.
Medium
2
1
2
40

-------
N-Methylpyrrolidone
Study reference:
Becci. P. J.. GeDhart. L. A.. Koschier. F. J.. Johnson. W. D.. Burnette. L. W. (1983). Subchronic feeding studv
in beagle dogs of N-methylpyrrolidone Journal of Applied Toxicology, 3(2), 83-86

HERO ID: 3539728

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

15. Number per
Group
The number of animals
was appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported and appropriate.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were observed.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were observed.
High
1
1
1
Data Presentation
23. Statistical
Methods
Statistical methods were
reported and appropriate
High
1
1
1
and Analysis
24. Reporting of
Data
Data were reported.
High
1
2
2

Sum of scores:

28
38
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.3571
Overall Score:
Nearest *:
1.4
Low: >=z.J ana <=j

Overall Quality Level:

High

-------
N-Methylpyrrolidone
3. Cancer Studies
3.1. Animal toxicity evaluation results of E.I. Dupont De Nemours Co. 1982 for a 2-
year inhalation study in rats on renal and cancer outcomes
Study reference:
E. I. Dupont De Nemours Co, (1982). 2-YEAR INHALATION STUDY WITH N-METHYL-2-
PYRROLIDONE IN RATS (FINAL) WITH COVER LETTER DATED 083090


HERO ID: 4214102





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name.
Medium
2
2
4
Test Substance
2. Test Substance
Source
Sponsor identified as
source of test substance.
Low
3
1
3
3. Test Substance
Purity
Purity such that effects
likely due to the test
substance. Impurities
were identified.
Medium
2
1
2

4. Negative and
Vehicle Controls
Negative controls were
used.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA
6. Randomized
Allocation
Selective allocation was
used so that the mean
body weights were equal
across groups and sex.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Generation of vapors
were reported and
appropriate; storage of
test substance was not
reported.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposure periods were
occasionally shorter than
6 hours or missed
entirely because of
mechanical problems.
Low
3
1
3
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Concentrations were
presented without
ambiguity.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
were reported and
appropriate.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and dose spacing
were appropriate but not
justified.
Medium
2
1
2

12. Exposure Route
and Method
Deficiencies in reporting
of aerosol formation.
High
1
1
1
42

-------
N-Methylpyrrolidone
Study reference:
E. I. Dupont De Nemours Co, (1982). 2-YEAR INHALATION STUDY WITH N-METHYL-2-
PYRROLIDONE IN RATS (FINAL) WITH COVER LETTER DATED 083090


HERO ID: 4214102





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

13. Test Animal
Characteristics
The source, species,
strain, age, health status,
sex, and body weight at
start of test were
reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported.
High
1
1
1

15. Number per
Group
The number of animals





per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Breathing rate was not
reported.
Low
3
2
6

17. Consistency of
Outcome
Outcome assessments
were consistent.
High
1
1
1

Assessment




Outcome
Assessment
18. Sampling
Adequacy
Sampling was adequate
for the endpoints
examined.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
One male control rat was
placed in the female
group. Several rats in the
low-exposure group
escaped and mated.
Several rats escaped and
were never recaptured.
Low
3
2
6
22. Health Outcomes
Unrelated to
Exposure
Three female rats were
impregnated by a male
rat, gave birth, and were
continued in the study.
One low-exposure
female was impregnated,
gave birth, and was
continued on the test.
Low
3
1
3
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
described. It does not
appear that incidence
data were analyzed.
Low
3
1
3
43

-------
N-Methylpyrrolidone
Study reference:
E. I. Dupont De Nemours Co, (1982). 2-YEAR INHALATION STUDY WITH N-METHYL-2-
PYRROLIDONE IN RATS (FINAL) WITH COVER LETTER DATED 083090
HERO ID: 4214102
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Data were presented for
all outcomes.
High
1
2
2
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
52
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.7931
Overall Score:
Nearest *:
1.8
Overall Quality Level:
Medium
44

-------
N-Methylpyrrolidone
45

-------
N-Methylpyrrolidone
3.2. Animal toxicity evaluation results of Malley et al 2001 for an oral cancer rats
and mice study on cancer, hepatic, and renal outcomes
Study reference:
Malley, L. A., Kennedy, G. L., Elliott, G. S., Slone, T. W., Mellert, W., Deckardt, K., Kuttler, K., Hildebrand,
B.. Banton. M. L, Parod. R. J.. Griffiths. J. C. (2001). Chronic toxicity and oncogenicity of N-
methylpyrrolidone (NMP) in rats and mice by dietary administration Drug and Chemical Toxicology, 24(4),
315-338

HERO ID: 3539913

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
Source identified by
name.
Medium
2
1
2
3. Test Substance
Purity
The reported purity was
such that effects are
likely due to the test
substance.
High
1
1
1

4. Negative and
Vehicle Controls
Negative control animals
were included.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
allocation was by
computerized stratified
randomization.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Preparation details were
limited, but stability,
homogeneity, and
concentration analysis
were conducted.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
information were
reported.
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were
reported and justified.
High
1
1
1

12. Exposure Route
and Method
Route and method were
appropriate.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, age, initial body
weight, and health status
were reported.
High
1
2
2
46

-------
N-Methylpyrrolidone
Study reference:
Malley, L. A., Kennedy, G. L., Elliott, G. S., Slone, T. W., Mellert, W., Deckardt, K., Kuttler, K., Hildebrand,
B.. Banton. M. I.. Parod. R. J.. Griffiths. J. C. (2001). Chronic toxicity and oncogenicity of N-
methylpyrrolidone (NMP) in rats and mice by dietary administration Drug and Chemical Toxicology, 24(4),
315-338

HERO ID: 3539913

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All conditions were
reported except for room
air changes.
Medium
2
1
2

15. Number per
Group
The number of animals
was appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
appropriate.
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were
administered
consistently.
High
1
1
1
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposures
were reported.
High
1
1
1
Data Presentation
23. Statistical
Methods
Statistical methods were
reported and appropriate.
High
1
1
1
and Analysis
24. Reporting of
Data
Data were reported.
High
1
2
2

Sum of scores:

29
36
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.2273
Overall Score:
Nearest *:
1.2
Low: >=2.5 and <=j

Overall Quality Level:

High

-------
N-Methylpyrrolidone
3.3. Animal toxicity evaluation results of N-Methylpyrrolidone Producers Group
1997 for a 2-year cancer bioassay study
Study reference:
N-Methylpyrrolidone Producers Group, Inc (1997). FINAL REPORT, ONCOGENICITY STUDY WITH N-
METHYLPYRROLIDONE (NMP) TWO-YEAR FEEDING STUDY IN SPRAGUE DAWLEY RATS, WITH
COVER LETTER DATED 5/22/1998

HERO ID: 4214107





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Identified by structure,
nomenclature, CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
Source and production
date provided
High
1
1
1

3. Test Substance
Purity
Purity such that effects
due to test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were used
High
1
2
2

5. Positive Controls
Positive control animals
were not required
Not Rated
NA
NA
NA
Test Design
6. Randomized
Allocation
Computerized stratified
randomization used to
ensure no body weight
differences among the
groups
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Preparation and storage
were appropriate based
on stability analysis
High
1
1
1

8. Consistency of
Exposure
Administration
Diets administered
consistently across
groups
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Food intake and body
weight were monitored
in order to calculate daily
intakes. Concentrations
were analyzed in the diet
High
1
2
2
10. Exposure
Frequency and
Duration
Diets were provided for
"approximately 24
months" and were
inferred to have been
available ad libitum
Medium
2
1
2

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were based
on previous repeated
dose studies
High
1
1
1

12. Exposure Route
and Method
The route and methods
were suitable for the test
substance
High
1
1
1
Test Organism
13. Test Animal
Characteristics
All characteristics were
reported
High
1
2
2
48

-------
N-Methylpyrrolidone
Study reference:
N-Methylpyrrolidone Producers Group, Inc (1997). FINAL REPORT, ONCOGENICITY STUDY WITH N-
METHYLPYRROLIDONE (NMP) TWO-YEAR FEEDING STUDY IN SPRAGUE DAWLEY RATS, WITH
COVER LETTER DATED 5/22/1998

HERO ID: 4214107





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All conditions were
reported
High
1
1
1

15. Number per
Group
The number of
animals/group was
adequate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcomes methodology
was reported and
sensitive for outcome(s)
of interest
High
1
2
2

17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently
High
1
1
1
Outcome
18. Sampling
Adequacy
Sampling for outcomes
was adequate
High
1
1
1
Assessment
19. Blinding of
Assessors
Blinding was not
reported for peer-review
evaluation of
histopathological
findings, but this is not
expected to impact on the
results.
Medium
2
1
2

20. Negative Control
Response
The negative controls
responded appropriately
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were found.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
appropriate for the
outcomes
High
1
1
1
24. Reporting of
Data
All outcomes were
reported
High
1
2
2


Sum of scores:

30
33
mgn: >-i ana =1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.1000
Overall Score:
Nearest *:
1.1
49

-------
N-Methylpyrrolidone
Study reference:
N-Methylpyrrolidone Producers Group, Inc (1997). FINAL REPORT, ONCOGENICITY STUDY WITH N-
METHYLPYRROLIDONE (NMP) TWO-YEAR FEEDING STUDY IN SPRAGUE DAWLEY RATS, WITH
COVER LETTER DATED 5/22/1998
HERO ID: 4214107
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
High
50

-------
N-Methylpyrrolidone
4. Reproductive/Developmental Toxicity Studies
4.1. Animal toxicity evaluation results of Becci et al 1982 for a dermal,
developmental study in rats (rf and final-study report in 4214125) on growth
(early life) and development outcomes
Study reference:
Becci. P. J..Knickerbocker. M. J..Reasan. E. L..Parent. R. A..Burnette. L. W. (1982). Teratogenicity studv of
N-methylpyrrolidone after dermal application to Sprague-Dawley rats Fundamental and Applied Toxicology,
2(2), 73-76

HERO ID: 3539729

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance was
identified by name.
Medium
2
2
4

2. Test Substance
The sponsor (GAF Corp)
was identified as the
source.
Low

Test Substance
Source
J
J

3. Test Substance
Purity
The purity (99.9%) was
such that effects likely
due to the test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were used in
both studies.
High
1
2
2
Test Design
5. Positive Controls
Concurrent positive
controls were used;
however, a similar
incidence was observed
for incomplete
ossification between
negative and positive
controls.
Low
3
1
3

6. Randomized
Allocation
Method of allocation not
reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Authors note that the
positive control solutions
were prepared fresh
daily, but preparation and
storage of the test
material was not
reported.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
Test material was rubbed
into skin and the test site
remained uncovered. It is
unclear whether doses
Low
3
1
3

were administered
consistently.

9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2
51

-------
N-Methylpyrrolidone
Study reference:
Becci. P. J..Knickerbocker. M. J..Reasan. E. L..Parent. R. A..Burnette. L. W. (1982). Teratogenicity studv of
N-methylpyrrolidone after dermal application to Sprague-Dawley rats Fundamental and Applied Toxicology,
2(2), 73-76

HERO ID: 3539729

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
Frequency and duration
were adequate.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
Exposure groups (n) was
adequate; however, doses
and spacing were not
adequately justified (i.e.,
no effects observed at
500 mg/kg in range
finding study).
Low
3
1
3

12. Exposure Route
and Method
Route and method were
reported.
High
1
1
1

13. Test Animal
Characteristics
The source, species,
strain, and sex were
reported. Age, initial
body weight, and health
status were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Housing, temperature,
and lighting were
reported. Humidity and
air changes were not
reported.
Medium
2
1
2

15. Number per
Group
The number of animals
was appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Treatment through
organogenesis (GD 16 in
rats) is recommended for
teratology assessments.
Medium
2
2
4

17. Consistency of
Outcome
Assessment
Based on examination of
urine, only 1 animal
treated at 75 mg/kg
showed evidence of
Low
3
1
3
Outcome

exposure.

Assessment
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
A similar incidence was
observed for incomplete
ossification between
negative and positive
controls
Low
3
1
3
52

-------
N-Methylpyrrolidone
Study reference:
Becci. P. J..Knickerbocker. M. J..Reasan. E. L..Parent. R. A..Burnette. L. W. (1982). Teratogenicity studv of
N-methylpyrrolidone after dermal application to Sprague-Dawley rats Fundamental and Applied Toxicology,
2(2), 73-76

HERO ID: 3539729





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health effects
unrelated to exposure
were reported.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
described and
appropriate.
High
1
1
1
24. Reporting of
Data
Data were reported for
all outcomes.
High
1
2
2


Sum of scores:

29
53
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.8276
Overall Score:
Nearest *:
1.8
Low: >=2.5 and <=j







Overall Quality Level:

Medium

53

-------
N-Methylpyrrolidone
4.2. Animal toxicity evaluation results of Ciba-Geigy 1987 for an oral developmental
rat study on growth (early life) and development outcomes
Study reference:
Ciba-Geigy, Corp (1987). LETTER FROM CIBA-GEIGY CORPORATION TO USEPA REGARDING
INFORMATION ON THE ENCLOSED REPORTS CONCERNING N-METHYLPYRROLIDONE WITH
ATTACHMENTS

HERO ID: 4214093

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
See footnote at end of
page.1
High
1
2
2
Test Substance
2. Test Substance
Source
The source was not
identified.
Low
3
1
3

3. Test Substance
Purity
The purity was not
reported; stated to be
double distilled.
Low
3
1
3
Test Design
4. Negative and
Vehicle Controls
No information on the
age/weight of negative
(untreated) control
animals was provided.
Medium
2
2
4
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Method of randomization
not reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Information on
storage/stability was not
provided.
Low
3
1
3

8. Consistency of
Exposure
Administration
See footnote at bottom of
page1
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported as
(mm3/kg); however,
specific information
needed to confirm dose
calculations (purity, body
weight) was not
provided.
Low
3
2
6

10. Exposure
Frequency and
Duration
Frequency and duration
were reported; however,
the duration of exposure
was inadequate based on
OECD 422 standards.
Low
3
1
3

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and dose spacing
were inadequate based
on OECD 422 standards.
Low
3
1
3
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic
Review for TSCA Risk Evaluation.
54

-------
N-Methylpyrrolidone
Study reference:
Ciba-Geigy, Corp (1987). LETTER FROM CIBA-GEIGY CORPORATION TO USEPA REGARDING
INFORMATION ON THE ENCLOSED REPORTS CONCERNING N-METHYLPYRROLIDONE WITH
ATTACHMENTS

HERO ID: 4214093





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

12. Exposure Route
and Method
Translated summaries
provided for i.p., oral and
inhalation exposures.
Limited information
provided for generation
of inhalation
concentrations is.
Low
3
1
3

13. Test Animal
Characteristics
The source, species,
strain, and sex were
reported. Age, initial
body weight, and health
status were not reported.
Low
3
2
6
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Housing, feed, water,
temperature, and
humidity were reported.
Lighting and number of
room air changes were
not reported.
Medium
2
1
2

15. Number per
Group
The number of animals
was adequate.
High
1
1
1

16. Outcome
Assessment
Methodology
Description of outcome
assessment methodology
is inadequate.
Low
3
2
6

17. Consistency of
Outcome
Assessment
It is difficult to discern
whether outcomes were
assessed consistently
based on translated text.
Low
3
1
3

18. Sampling
Adequacy
Sampling was adequate.
Medium
2
1
2
Outcome
Assessment
19. Blinding of
Assessors
Blinding not required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were not
appropriate. The total
malformation
rate in untreated controls
(2.6%) exceeded the
spontaneous value
reported in historical
controls (1.7%)
Low
3
1
3
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
55

-------
N-Methylpyrrolidone
Study reference:
Ciba-Geigy, Corp (1987). LETTER FROM CIBA-GEIGY CORPORATION TO USEPA REGARDING
INFORMATION ON THE ENCLOSED REPORTS CONCERNING N-METHYLPYRROLIDONE WITH
ATTACHMENTS
HERO ID: 4214093
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health Outcomes
Unrelated to
Exposure
No information provided
regarding health
outcomes unrelated to
exposure were reported.
Low
3
1
3
Data Presentation
and Analysis
23. Statistical
Methods
Statistical analysis was
not conducted, but data
were available to conduct
analysis.
Low
3
1
3
24. Reporting of
Data
Maternal body weights
were not reported. Litter
data were not presented.
Low
3
2
6
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

29
71
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
2.4423
Overall Score:
Nearest *:
2.4
Overall Quality Level:
Low
56

-------
N-Methylpyrrolidone
4.3. Animal toxicity evaluation results of E. I. Dupont De Nemours 1979 for a
developmental range-finding: rats study on growth (early life) and development
outcomes
Study reference:
E. I. Dupont De Nemours Co., (1979). INITIAL SUBMISSION: TERATOLOGIC DOSE RANGE-FINDING
STUDY W/ N-METHYLPYRROLIDONE IN SPRAGUE DAWLEY RATS WITH COVER LETTER
DATED 09/01/92

HERO ID: 3564297





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and lot number.
Medium
2
2
4
Test Substance
2. Test Substance
Source
The sponsor was
identified as the source
of the test substance.
Low
3
1
3

3. Test Substance
Purity
Test substance purity
was reported
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were included.
High
1
2
2
Test Design
5. Positive Controls
Concurrent positive
controls were used;
however, a similar
incidence of incomplete
ossification was observed
in positive and negative
controls.
Low
3
1
3

6. Randomized
Allocation
A random number
assignment sheet was
used.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Preparation and storage
of test material was not
provided. However, it
was reported that the
positive control agent
was prepared fresh daily.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
Test material was rubbed
into skin and the test site
remained uncovered;
therefore, it is unclear
whether doses were
administered
consistently.
Low
3
1
3

9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Duration and frequency
were inadequate for this
type of study.
Low
3
1
3
57

-------
N-Methylpyrrolidone
Study reference:
E. I. Dupont De Nemours Co., (1979). INITIAL SUBMISSION: TERATOLOGIC DOSE RANGE-FINDING
STUDY W/ N-METHYLPYRROLIDONE IN SPRAGUE DAWLEY RATS WITH COVER LETTER
DATED 09/01/92

HERO ID: 3564297





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
The number of animals
in each group was
adequate; however, dose
selection and spacing
were not
justified/inadequate. No
effects were observed in
animals treated at 500
mg/kg in range finding
study).
Low
3
1
3

12. Exposure Route
and Method
Exposure route and
method were reported.
High
1
1
1
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, initial body
weight, sex, and sexual
state were reported. The
health status and specific
age of the parents was
not reported, but they
were sexually mature.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Housing, feed and water
were reported.
Temperature, humidity,
lighting, and air changes
were not reported.
Medium
2
1
2

15. Number per
Group
The number of animals
was acceptable for a
range-finding study.
High
1
1
1

16. Outcome
Assessment
Methodology
Treatment did not extend
through the entire period
of organogenesis.
Medium
2
2
4
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Based on an examination
of urine, only 1 animal
treated at 75 mg/kg
showed evidence of
exposure.
Low
3
1
3
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required in this study.
Not Rated
NA
NA
NA

20. Negative Control
Response
Similar incidence of
incomplete ossification
observed between
negative and positive
controls.
Low
3
1
3
58

-------
N-Methylpyrrolidone
Study reference:
E. I. Dupont De Nemours Co., (1979). INITIAL SUBMISSION: TERATOLOGIC DOSE RANGE-FINDING
STUDY W/ N-METHYLPYRROLIDONE IN SPRAGUE DAWLEY RATS WITH COVER LETTER
DATED 09/01/92

HERO ID: 3564297





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables in test design
and procedures were
noted.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposures
were reported.
High
1
1
1
Data Presentation
23. Statistical
Methods
Statistical methods were
reported and appropriate.
High
1
1
1
and Analysis
24. Reporting of
Data
Data presentation for all
outcomes was adequate.
High
1
2
2


Sum of scores:

30
54
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.8
Overall Score:
Nearest *:
1.8
Low: >=2.5 and <=j







Overall Quality Level:

Medium

59

-------
N-Methylpyrrolidone
4.4. Animal toxicity evaluation results of Intl Specialty 1979 for dermal
developmental, offspring and maternal effects study on growth (early life) and
development outcomes
Study reference:
Intl Specialty, Prods (1979). INITIAL SUBMISSION: TERATOLOGICAL DOSE RANGE-FINDING
STUDY WITH N-METHYLPYRROLIDONE IN SPRAGUE-DAWLEY RATS (FINAL REPORT) WITH
ATTACHMENTS AND COVER LETTER DATED 022792

HERO ID: 4214125

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Test substance identified
Medium
9
9
A

Identity
by name.

Test Substance
2. Test Substance
Source
Sponsor (GAF Corp)
was identified as the
source of the test
substance.
Low
3
1
3

3. Test Substance
Purity
Purity such that effects
due to test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were used.
High
1
2
2
Test Design
5. Positive Controls
See footnote at end of
page.1
High
1
1
1

6. Randomized
Allocation
Animals allocated by
random number
Medium
2
1
2

assignment sheet.

7. Preparation and
Storage of Test
Substance
Preparation and storage
were not reported.
Low
3
1
3

8. Consistency of
Exposure
Administration
Test material was rubbed
into the skin. Dosing
volume, diluent or
dilution factor were not
described. It is unclear
Low
3
1
3
Exposure
Characterization
whether doses were
administered
consistently.

9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Exposure duration and
frequency were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and dose spacing were
reported and justified.
High
1
1
1
1 Metric that received a "High" rating met the criteria as discussed in the Applications of Systematic Review for
TSCA Risk Evaluation.
60

-------
N-Methylpyrrolidone
Study reference:
Intl Specialty, Prods (1979). INITIAL SUBMISSION: TERATOLOGICAL DOSE RANGE-FINDING
STUDY WITH N-METHYLPYRROLIDONE IN SPRAGUE-DAWLEY RATS (FINAL REPORT) WITH
ATTACHMENTS AND COVER LETTER DATED 022792

HERO ID: 4214125





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

12. Exposure Route
and Method
The route and method of
exposure were
appropriate.
High
1
1
1

13. Test Animal
Characteristics
The source, strain, sexual
state, sex, and initial
body weight were
reported. Health status
and specific numeric age
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Temperature, lighting,
and humidity were not
reported.
Medium
2
1
2

15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Treatment did not extend
throughout the period of
organogenesis.
Medium
2
2
4

17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
Outcome
Assessment
18. Sampling
Adequacy
Sampling was adequate
for the outcomes of
interest.
High
1
1
1

19. Blinding of
Assessors
Blinding was not
required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables in test design
and procedures were
noted.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposures
were observed.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
described and
appropriate.
High
1
1
1
24. Reporting of
Data
Data were presented for
all outcomes.
High
1
2
2

Sum of scores:

29
44
61

-------
N-Methylpyrrolidone
Study reference:
Intl Specialty, Prods (1979). INITIAL SUBMISSION: TERATOLOGICAL DOSE RANGE-FINDING
STUDY WITH N-METHYLPYRROLIDONE IN SPRAGUE-DAWLEY RATS (FINAL REPORT) WITH
ATTACHMENTS AND COVER LETTER DATED 022792
HERO ID: 4214125
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.5172
Overall Score:
Nearest *:
1.5
Overall Quality Level:
High
62

-------
N-Methylpyrrolidone
4.5. Animal toxicity evaluation results of Exxon Biomedical 1991 for a
multigeneration reproductive toxicity study on rats - reproductive, growth
(early life) and developmental outcomes
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535

HERO ID: 3809420

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified as N-
methylpyrrolidone by
name in the study title
(CASRN not provided).
The test substance is
referred to as MRD-
89-365 throughout the
study report.
High
1
2
2
Test Substance
2. Test Substance
Source
The study report indicates
that the synthesis,
fabrication, and/or
derivation of the test
substance were
the responsibility of the
sponsor (GAF
Corporation).
The batch number is
identified (I), but the
manufacturer (if
applicable) was not
explicitly identified.
Although the materials
and methods reference a
certificate of analysis, it
was not included in the
study report (i.e., not
found in an appendix).
Medium
2
1
2

3. Test Substance
Purity
The study report indicates
that the test substance was
assumed 100% pure for
the purposes of dosing.
Purity was not reported
explicitly, but given other
information (i.e., analyses
of the test substance in
feed mixtures), this was
not expected to
substantially impact the
study results.
Medium
2
1
2
63

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535

HERO ID: 3809420

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

4. Negative and
Vehicle Controls
The study authors
reported using an
appropriate concurrent
negative control group
(conditions the same
except for treatment).
Controls were given the
same rodent chow as
treated animals (minus
addition
of the test substance).
High
1
2
2
Test Design
5. Positive Controls
Positive control not
indicated by study type.
Not Rated
NA
NA
NA
6. Randomized
Allocation
The study report indicates
that rats (F0 generation)
were selected using a
computer-generated
sorting program so that
weight variations were
within 20% of the group
mean body weight. Rats
were randomly allocated
to groups by computer
(with an attempt to nearly
equalize initial body
weights).
High
1
1
1
Exposure
Characterization
7. Preparation and
Storage of Test
Substance
The test substance was
thoroughly mixed into the
diet; jars containing the
feed were replaced at least
weekly. Homogeneity,
stability, and
concentration analyses
were performed.
Homogeneity samples
(top, middle, and bottom
for the low- and high-dose
groups only) were within
7% of the target values;
stability analyses
indicated the test
substance was stable for at
least one month.
High
1
1
1
64

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535

HERO ID: 3809420

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported and exposure
were administered
consistently across
groups. All groups of rats
were administered the test
substance in the diet
(offered ad libitum).
High
1
1
1

9. Reporting of
Doses/
Concentrations
Target doses were 0, 50,
160, and 500 mg/kg-day.
Concentrations of the test
substance in the diet were
adjusted during pre-
mating, and maintained
constant thereafter (i.e.,
during mating, gestation,
and lactation). Based on
measured data, doses were
generally within 20% of
target levels during
premating and gestation.
Although no test
substance intake
information was available
during mating, the
current guideline indicates
that test substance intake
data are required except
during cohabitation .The
study notes that males
were dosed at lower than
target dose levels during
this period (as dosing
based on female body
weight/food consumption
data). Test substance
intake was inconsistent
during
lactation. Doses were
higher than target levels
from PND 4 on, reaching
2 to 3x target levels by
PND 21. In general, body
weight and food
consumption data were
available to enable
calculations.
Medium
2
2
4
65

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535

HERO ID: 3809420





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

10. Exposure
Frequency and
Duration
The exposure frequency
and duration were
reported
and appropriate for the
study type/outcomes of
interest.
Animals were dosed
during pre-mating,
mating, gestation,
lactation, and/or until
weaning of the F2b litter.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The target doses were
based on data for a
previously conducted
dose-probe study. The
high-dose was sufficient
to induce treatment-
related effects (i.e.,
selected
doses enable evaluation ol
dose-response effects).
However, the target dose
intervals were slightly
more than 3-fold (current
guideline suggests that for
dietary studies, the dose
interval should not be
more than 3-fold).
High
1
1
1

12. Exposure Route
and Method
The route and method of
exposure were reported
and were suited to the test
substance. Based on
homogeneity and stability
analyses, the test
substance was non-
volatile in the diet.
High
1
1
1
66

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535
HERO ID: 3809420
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Organism
13. Test Animal
Characteristics
The test animal species,
strain, sex, health status,
age, and initial body
weights were reported.
Rats used in the study
were obtained from a
commercial source. The
test species and strain
were an appropriate
model; the study report
indicates that rats have
historically been used for
multi-generation
reproduction
studies (rats are the
preferred species based on
OECD guideline).
High
1
2
2
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were reported and were
generally considered
adequate. Some
differences in conditions
were noted (occasions in
which room temperature
and/or humidity were out
of range), but all dose
groups were presumably
affected by these
deviations,
and they are not expected
to substantially impact the
study results.
Medium
2
1
2
15. Number per
Group
The number of
animals/group
(30/sex/generation) was
reported and was
appropriate for the study
type (guideline
recommendation of no
fewer than 20 pregnant
females at or near
parturition).
High
1
1
1
67

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535
HERO ID: 3809420
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Outcome
Assessment
16. Outcome
Assessment
Methodology
In general, the outcome
assessment methodology
addressed/
reported the intended
outcomes of interest;
reproductive/
developmental parameters
were evaluated over the
course of two generations.
However, several
endpoints recommended
by current guidelines were
not evaluated, including
organ weights, estrous
cycle parameters
(normality), and sperm
parameters (motility and
morphology) in parental
animals.
Medium
2
2
4
17. Consistency of
Outcome
Assessment
The timing/methods of
outcome assessments
were reported and
appeared to be consistent
across treatment groups.
High
1
1
1
18. Sampling
Adequacy
In general, details
regarding sampling were
reported. However, it
appears that mean fetal
body weight data are
based on n = number of
fetuses (i.e., the litter was
not the basis for analysis).
Although
histopathological
examinations were
performed for
low- and high-dose groups
only (which is acceptable
as per the current
guideline), additional dose
groups were examined
when histopathological
findings were
observed at the high dose
(e.g., in the ovaries and
uterus of female rats).
Medium
2
1
2
68

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535

HERO ID: 3809420





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

19. Blinding of
Assessors
The study report included
a quality assurance
statement with respect to
histopathology
examinations, indicating
that evaluations were
performed according to
standard operating
procedures, audited., and
based on good laboratory
practice. Other endpoints
evaluated in the study
were not subjective.
High
1
1
1

20. Negative Control
Response
The biological responses
of the negative control
group were adequate.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
There were no significant
differences among study
groups with respect to
initial body weights or
food consumption rates.
High
1
2
2
Confounding /
Variable Control
22. Health Outcomes
Unrelated to
Exposure
There were no outcomes
reported unrelated to
exposure. There were only
a few unscheduled deaths
(which were considered
incidental). Effects
observed in
histopathological
examinations that were
not treatment-related were
considered spontaneous
(not attributed to a cause
like infection).
High
1
1
1
69

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535
HERO ID: 3809420
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data Presentation
and Analysis
23. Statistical
Methods
The body of the study
report indicates that mean
body weights and food
consumption were
analyzed statistically for
significant differences.
However, the discussion
references other
"statistically significant
effects" (e.g., on fertility
and fecundity indices);
these are not marked as
statistically significant in
the corresponding data
tables. While sufficient
data (n, mean, and
measure of variance) are
provided in
most cases, some of these
data would have to be
obtained from data tables
on individual animals.
Appendix AQ indicates
that most data were not
analyzed statistically
(including fertility
indices).
Low
3
1
3
70

-------
N-Methylpyrrolidone
Study reference:
Exxon Biomedical (1991). Multiseneration Rat ReDroduction Studv with N-MethvlDvrrolidone. Project
Number 236535
HERO ID: 3809420
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

24. Reporting of
Data
Data for treatment-related
findings were reported for
most, but not all,
outcomes appropriately.
For example, reproductive
indices were reported, but
the numbers used for
calculating these indices
were not
explicitly provided.
However, these data could
be pieced together by
evaluating individual
reproduction
data (available in
appendices). Data for
gestation length are also
available based on
individual data only.
Similarly, necropsy data
were not presented in a
summary table, but
individual data were
available.
Medium
2
2
4
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Sum of scores:

30
42
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.400
Overall Score:
Nearest *:
1.4
Overall Quality Level:
High
71

-------
N-Methylpyrrolidone
4.6. Animal toxicity evaluation results of Exxon 1992 for a developmental toxicity
study in rats on growth (early life) and development outcomes
Study reference:
Exxon (1992). INITIAL SUBMISSION: DEVELOPMENTAL TOXICITY STUDY IN RATS WITH N-
METHYLPYRROLIDONE (DRAFT REPORT) WITH ATTACHMENTS AND COVER LETTER DATED
041092

HERO ID: 3563347 and 4214126




Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name.
Characterization and
analysis of the test article
were reported to be
documented by the
sponsor, but no details
were provided.
Medium
2
2
4
Test Substance
2. Test Substance
Source
The batch number was
provided. The source
was of the test substance
was not provided but
reported as sponsor.
Medium
2
1
2

3. Test Substance
Purity
The purity was assumed
to be 100%, however no
data was provided for
support.
Medium
2
1
2

4. Negative and
Vehicle Controls
A concurrent vehicle
control was included.
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Method of allocation was
based on confirmed
mating.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Test substance
preparation and storage
were reported. Stability
and concentration were
reported.
High
1
1
1
Exposure
Characterization
8. Consistency of
Exposure
Administration
Doses were administered
consistently.
High
1
1
1

9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Duration and frequency
were reported.
High
1
1
1
72

-------
N-Methylpyrrolidone
Study reference:
Exxon (1992). INITIAL SUBMISSION: DEVELOPMENTAL TOXICITY STUDY IN RATS WITH N-
METHYLPYRROLIDONE (DRAFT REPORT) WITH ATTACHMENTS AND COVER LETTER DATED
041092

HERO ID: 3563347 and 4214126




Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were not
justified but were
sufficient to show results
relevant to the outcome
of interest.
Medium
2
1
2

12. Exposure Route
and Method
The exposure route and
method were appropriate.
High
1
1
1

13. Test Animal
Characteristics
The source, species,
strain, sex, health status,
and initial body weight
were reported.
High
1
2
2
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported.
High
1
1
1

15. Number per
Group
The number of animals
per group was
appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
described and
appropriate.
High
1
2
2
Outcome
17. Consistency of
Outcome
Assessment
Outcome assessment was
consistent.
High
1
1
1
Assessment
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding not required in
this assay.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
Distribution by mating
confirmation resulted in
4 non-pregnant control
animals, but there were a
sufficient number of
offspring available for
comparison.
Medium
2
2
4

22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were observed.
High
1
1
1
73

-------
N-Methylpyrrolidone
Study reference:
Exxon (1992). INITIAL SUBMISSION: DEVELOPMENTAL TOXICITY STUDY IN RATS WITH N-
METHYLPYRROLIDONE (DRAFT REPORT) WITH ATTACHMENTS AND COVER LETTER DATED
041092

HERO ID: 3563347 and 4214126




Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
well described and
appropriate.
High
1
1
1
24. Reporting of
Data
Data were reported for
all outcomes.
High
1
2
2


Sum of scores:

29
37
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.2759
Overall Score:
Nearest *:
1.3
Low: >=2.5 and <=j







Overall Quality Level:

High

74

-------
N-Methylpyrrolidone
4.7. Animal toxicity evaluation results of Lee et al 1987 for an inhalation
developmental study on growth (early life) and development outcomes
Study reference:
Lee. K. P..Chromev. N. C..Culik. R..Barnes. J. R.Schneider. P. W. (1987). Toxicity of N-methvl-2-
pyrrolidone (NMP): teratogenic, subchronic, and two-year inhalation studies Fundamental and Applied
Toxicology, 9(2), 222-235

HERO ID: 3539878





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Chemical structure,
established
nomenclature, and
physiochemical
properties were reported
High
1
2
2
Test Substance
2. Test Substance
Source
The source was not
reported. However, the
concentration of
exposures were measured
by IR spectrometry and
gas chromatography.
Medium
2
1
2

3. Test Substance
Purity
The compound was
stated to be 100% pure
without support for the
statement. The
concentration of
exposures were measured
by IR spectrometry and
gas chromatography.
Thus effects are likely
due to the test substance.
Medium
2
1
2
Test Design
4. Negative and
Vehicle Controls
A concurrent control
group was included
High
1
2
2
5. Positive Controls
Positive controls not
required
Not Rated
NA
NA
NA
75

-------
N-Methylpyrrolidone
Study reference:
Lee. K. P..Chromev. N. C.,Culik. R.,Barnes. J. R.Schneider. P. W. (1987). Toxicity of N-methvl-2-
pyrrolidone (NMP): teratogenic, subchronic, and two-year inhalation studies Fundamental and Applied
Toxicology, 9(2), 222-235

HERO ID: 3539878

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

6. Randomized
Allocation
Pregnant females were
randomly assigned.
However, the article
states, "In the experiment
for teratogenicity, the
pregnant female rats
were assigned at random
into the three groups, but
random distribution was
not obtained. Five of
twenty-five females in
the 0.1 mg/liter exposure
group were not
impregnated. Two of
twenty pregnant females
had only four and one
corpora lutea,
respectively, and one
implantation each. If
these two females were
removed from the group,
the calculated mean
value of parameters
measuring the
reproduction capability
would be similar to those
of the control group."
The NOAEC was 0.36
mg/L.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
Aerosol generation
system was described
and appropriate.
High
1
1
1

8. Consistency of
Exposure
Administration
Exposures were
consistent across groups
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
The particle size
distribution was not
determined and there was
uncertainty about
whether analytical or
nominal concentration
was reported.
Low
3
2
6

10. Exposure
Frequency and
Duration
Exposed GD6-15 for 6
h/day
High
1
1
1
76

HERO ID: 3539878

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
Rationale was not
provided, but very little
impact on results. Only 2
doses were used.
Exposures were not high
enough to cause toxicity
in females or fetuses.
Medium
2
1
2

12. Exposure Route
and Method
Dynamic chambers were
used
High
1
1
1

13. Test Animal
Characteristics
Age and overall health
status were not reported
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry was not
adequately reported.
Low
3
1
3

15. Number per
Group
The number of
animals/group was
sufficient for outcome
analysis
High
1
1
1

16. Outcome
Assessment
Methodology
The outcomes of interest
were addressed by the
methodology
High
1
2
2
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
18. Sampling
Adequacy
Adequate sampling for
the outcomes of interest
was conducted
High
1
1
1

19. Blinding of
Assessors
Subjective outcomes
were not assessed
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative controls
responded appropriately
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
However, NMP is an
irritant. Breathing rates
and body temperature
measurements were not
made to rule our reflex
bradypnea.
Medium
2
2
4
77

-------
N-Methylpyrrolidone
Study reference:
Lee. K. P..Chromev. N. C.,Culik. R.,Barnes. J. R.Schneider. P. W. (1987). Toxicity of N-methvl-2-
pyrrolidone (NMP): teratogenic, subchronic, and two-year inhalation studies Fundamental and Applied
Toxicology, 9(2), 222-235

HERO ID: 3539878





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

22. Health Outcomes
Unrelated to
Exposure
The article states "In the
experiment for
teratogenicity, the
pregnant female rats
were assigned at random
into the three groups, but
random distribution was
not obtained. Five of
twenty-five females in
the 0.1 mg/liter exposure
group were not
impregnated. Two of
twenty pregnant females
had only four and one
corpora lutea,
respectively, and one
implantation each. If
these two females were
removed from the group,
the calculated mean
value of parameters
measuring the
reproduction capability
would be similar to those
of the control group."
The NOAEC was 0.36
mg/L.
Medium
2
1
2
Data Presentation
and Analysis
23. Statistical
Methods
The described statistical
methods were
appropriate
High
1
1
1
24. Reporting of
Data
Data were reported for
outcomes
High
1
2
2


Sum of scores:

29
44
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.517
Overall Score:
Nearest *:
1.5
Low: >=2.5 and <=j







Overall Quality Level:

High

78

-------
N-Methylpyrrolidone
4.8. Animal toxicity evaluation results of Saillenfait et al 2002 for an oral
developmental rat and maternal effects study on growth (early life),
development, and reproductive outcomes
Study reference:
Saillenfait. A. M..Gallissot. F.Xangonne. L.Sabate. J. P. (2002). Develomnental toxicity of N-methvl-2-
pyrrolidone administered orally to rats Food and Chemical Toxicology, 40(11), 1705-1712

HERO ID: 3551103

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name only.
Medium
2
2
4
Test Substance
2. Test Substance
Source
Source identified by
name.
Medium
2
1
2

3. Test Substance
Purity
The reported purity was
such that effects likely
due to the test substance.
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
controls were included.
High
1
2
2

5. Positive Controls
Positive controls not
required.
Not Rated
NA
NA
NA
Test Design
6. Randomized
Allocation
Stratified randomization
was used so mean body
weights were similar
among groups on
gestation day 0.
Medium
2
1
2

7. Preparation and
Storage of Test
Substance
limited details on
preparation were
reported. Frequency of
preparation and storage
were not reported.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposures were
administered
consistently.
High
1
1
1
Exposure
Characterization
9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of groups
and spacing were based
on dose-range finding
studies.
High
1
1
1

12. Exposure Route
and Method
The route and method
were appropriate.
High
1
1
1
79

-------
N-Methylpyrrolidone
Study reference:
Saillenfait. A. M..Gallissot. F.Xangonne. L.Sabate. J. P. (2002). Develomnental toxicitv of N-methvl-2-
pyrrolidone administered orally to rats Food and Chemical Toxicology, 40(11), 1705-1712

HERO ID: 3551103

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Organism
13. Test Animal
Characteristics
The source, species,
strain, sex, and initial
body weight were
reported. Health status
and age were not
reported.
Medium
2
2
4
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported except
room air changes were
reported.
Medium
2
1
2

15. Number per
Group
The number of dams per
group was appropriate.
High
1
1
1

19. Blinding of
Assessors
Blinding not applicable.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were observed.
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical analysis was
conducted and
appropriate.
High
1
1
1
24. Reporting of
Data
Data were reported for
all outcomes.
High
1
2
2

Sum of scores:

29
38
mgn: >-i ana =1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.3103
Overall Score:
Nearest *:
1.3
80

-------
N-Methylpyrrolidone
Study reference:
Saillenfait. A. M..Gallissot. F.Xangonne. L.Sabate. J. P. (2002). Develomnental toxicitv of N-methvl-2-
pyrrolidone administered orally to rats Food and Chemical Toxicology, 40(11), 1705-1712
HERO ID: 3551103
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

Overall Quality Level:
High
81

-------
N-Methylpyrrolidone
4.9. Animal toxicity evaluation results of Saillenfait et al 2003
Study reference:
Saillenfait. A. M..Gallissot. F..Morel. G. (2003). Develomnental toxicity of N-methvl-2-Dvrrolidone in rats
following inhalation exposure Food and Chemical Toxicology, 41(4), 583-588

HERO ID: 3551104

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Nomenclature and
CASRN were reported
High
1
2
2
Test Substance
2. Test Substance
Source
Source reported
High
1
1
1

3. Test Substance
Purity
Purity (99.5%) such that
effects likely due to test
substance
High
1
1
1

4. Negative and
Vehicle Controls
Concurrent negative
control animals were
included
High
1
2
2
Test Design
5. Positive Controls
Positive controls were
not required
Not Rated
NA
NA
NA

6. Randomized
Allocation
Females were randomly
assigned to exposure
groups
High
1
1
1

7. Preparation and
Storage of Test
Substance
Method of generation
and equipment used were
reported; however,
storage was not.
Medium
2
1
2

8. Consistency of
Exposure
Administration
Exposures were
administered consistently
High
1
1
1

9. Reporting of
Doses/Concentration
s
Target and analytical
concentrations were
reported. The analytical
method was reported and
appropriate.
High
1
2
2
Exposure
Characterization
10. Exposure
Frequency and
Duration
Exposures occurred 6
hr/d on GD 6-20.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The purpose was to set a
definitive NOAEL for
developmental toxicity,
and although not
explicitly stated,
concentrations appeared
to be based on a 2-gen
toxicity study in which
fetal weights were
reduced. The
concentrations used were
appropriate for the
purposes of the study.
Medium
2
1
2
82

-------
N-Methylpyrrolidone
Study reference:
Saillenfait. A. M.,Gallissot. F..Morel. G. (2003). Develomnental toxicity of N-methvl-2-Dvrrolidone in rats
following inhalation exposure Food and Chemical Toxicology, 41(4), 583-588

HERO ID: 3551104

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

12. Exposure Route
and Method
Methodological
information provided,
including an evaluation
of aerosol formation
(e.g., temperature,
humidity). Exposures
were conducted in
dynamic chamber;
however, aerosol particle
size was not reported.
Low
3
1
3

13. Test Animal
Characteristics
Age, and health status
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
Husbandry conditions
were reported and
appropriate
High
1
1
1

15. Number per
Group
The number of
females/group 25-26 was
appropriate for the study
type and outcomes.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology for
maternal and fetal
evaluations addressed the
outcomes of interest;
however, breathing
rate/body temperature
was not measured.
Low
3
2
6
Outcome
Assessment
17. Consistency of
Outcome
Assessment
Outcome assessment was
carried out consistently
among groups
High
1
1
1

18. Sampling
Adequacy
Sampling details were
reported and were
adequate
High
1
1
1

19. Blinding of
Assessors
No subjective outcomes
were assessed.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were
appropriate
High
1
1
1
83

-------
N-Methylpyrrolidone
Study reference:
Saillenfait. A. M..Gallissot. F..Morel. G. (2003). Develomnental toxicity of N-methvl-2-Dvrrolidone in rats
following inhalation exposure Food and Chemical Toxicology, 41(4), 583-588

HERO ID: 3551104





Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were reported.
However, NMP is an
irritant and no measures
were made to assess
changes in breathing rate
or body temperature. The
possibility of reflex
bradypnea is not
eliminated but the results
of the study are
consistent with oral and
dermal study effects on
fetal body weight.
Low
3
2
6

22. Health Outcomes
Unrelated to
Exposure
No health differences
unrelated to exposure
were reported
High
1
1
1
Data Presentation
and Analysis
23. Statistical
Methods
Statistical methods were
described and
appropriate for the
dataset
High
1
1
1

24. Reporting of
Data
Data for all outcomes
were reported.
High
1
2
2


Sum of scores:

29
42
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.4483
Overall Score:
Nearest *:
1.4
Low: >=z.J ana <=j







Overall Quality Level:

High

84

-------
N-Methylpyrrolidone
4.10. Animal toxicity evaluation results of Sitarek et al 2008 for a reproductive-
male study on reproductive outcomes
Study reference:
Sitarek. K..Stetkiewicz. J. (2008). Assessment of reDroductive toxicity and sonadotoxic Dotential of N-methvl-
2-pyrrolidone in male rats International Journal of Occupational Medicine and Environmental Health, 21(1),
73-80

HERO ID: 3540734

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High, Medium,
Low,Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
The test substance was
identified by name and
CASRN.
High
1
2
2
Test Substance
2. Test Substance
Source
Source identified by
name.
Medium
2
1
2

3. Test Substance
Purity
Purity not reported.
Analytical grade test
substance used.
Low
3
1
3

4. Negative and
Vehicle Controls
Concurrent negative
control animals were
included.
High
1
2
2
Test Design
5. Positive Controls
Positive control animals
not required.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Method of randomization
for animal allocation was
not reported.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Limited preparation
details were provided,
and no storage
information was
provided. It is unclear
whether dosing solutions
were prepared daily.
Since NMP degrades
under aerobic conditions,
this could have a
substantial impact on
results.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
It is unclear whether
doses were administered
consistently, as dosing
volumes were not
reported.
Low
3
1
3

9. Reporting of
Doses/Concentration
s
Doses were reported.
High
1
2
2

10. Exposure
Frequency and
Duration
Frequency and duration
were reported.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
No justification provided
for the number of groups
and dose spacing.
Method
2
1
2
85

-------
N-Methylpyrrolidone
Study reference:
Sitarek. K.,Stetkiewicz. J. (2008). Assessment of reDroductive toxicity and sonadotoxic Dotential of N-methvl-
2-pyrrolidone in male rats International Journal of Occupational Medicine and Environmental Health, 21(1),
73-80

HERO ID: 3540734

Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High, Medium,
Low,Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

12. Exposure Route
and Method
The route and method
were appropriate.
High
1
1
1

13. Test Animal
Characteristics
The source, species,
strain, sex, and age were
reported. Initial body
weight and health status
were not reported.
Medium
2
2
4
Test Organism
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
except air changes were
reported.
Medium
2
1
2

15. Number per
Group
The number per group
was appropriate.
High
1
1
1

16. Outcome
Assessment
Methodology
Outcome assessment
methodology was
reported.
High
1
2
2
Outcome
17. Consistency of
Outcome
Assessment
Outcomes were assessed
consistently.
High
1
1
1
Assessment
18. Sampling
Adequacy
Sampling was adequate.
High
1
1
1

19. Blinding of
Assessors
Blinding not required.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were adequate.
High
1
1
1
Confounding /
Variable Control
21. Confounding
Variables in Test
Design and
Procedures
No confounding
variables were observed.
High
1
2
2
22. Health Outcomes
Unrelated to
Exposure
No health outcomes
unrelated to exposure
were reported.
High
1
1
1

23. Statistical
Methods
Statistical analysis was
described and
appropriate.
High
1
1
1
Data Presentation
and Analysis
24. Reporting of
Data
Data were presented, but
severity and incidence
data for histopathological
findings were not
included.
Low
3
2
6

Sum of scores:

29
47
86

-------
N-Methylpyrrolidone
Study reference:
Sitarek. K.,Stetkiewicz. J. (2008). Assessment of reDroductive toxicity and sonadotoxic Dotential of N-methvl-
2-pyrrolidone in male rats International Journal of Occupational Medicine and Environmental Health, 21(1),
73-80
HERO ID: 3540734
Domain
Metric
Eval Comment
Qualitative
Determination
[i.e., High, Medium,
Low,Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.6207
Overall Score:
Nearest *:
1.6
Overall Quality Level:
High
87

-------
N-Methylpyrrolidone
4.11. Animal toxicity evaluation results of Sitarek et al 2012 for a single
generation reproductive toxicity assessment in rats exposed orally study on
hematological and immune, respiratory, endocrine, hepatic, renal,
Study reference:
Sitarek. K.. Stetkiewicz. J..W (2012). Evaluation of reDroductive disorders in female rats exDOsed to N-
methyl-2-pyrrolidone Birth Defects Research, Part B: Developmental and Reproductive Toxicology, 95(3),
195-201

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Test substance identified
by name and CASRN
High
1
2
2
Test Substance
2. Test Substance
Source
Test substance obtained
from commercial source
but without certification
or analytical verification
of identity.
Medium
2
1
2

3. Test Substance
Purity
Purity reported to be
>98%
High
1
1
1
Test Design
4. Negative and
Vehicle Controls
Negative controls were
sham-treated with tap
water; however, report
did not specify whether
water was the vehicle for
NMP.
Medium
2
2
4
5. Positive Controls
Positive controls not
typical for this study
type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Study did not report how
animals were allocated to
groups.
Low
3
1
3

7. Preparation and
Storage of Test
Substance
Test material prep and
storage were not
reported.
Low
3
1
3
Exposure
Characterization
8. Consistency of
Exposure
Administration
Most exposure details
were reported, but time
of day of gavage
administration was not
reported. No
inconsistencies in
exposure administration
were reported.
Medium
2
1
2

9. Reporting of
Doses/Concentration
s
Gavage doses were
reported in mg/kg bw;
initial body weight was
not reported.
Medium
2
2
4

10. Exposure
Frequency and
Duration
Frequency and duration
were reported and suited
to the study time.
High
1
1
1
88

-------
N-Methylpyrrolidone
Study reference:
Sitarek. K.. Stetkiewicz. J..W (2012). Evaluation of reDroductive disorders in female rats exDOsed to N-
methyl-2-pyrrolidone Birth Defects Research, Part B: Developmental and Reproductive Toxicology, 95(3),
195-201

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
Three nonzero doses
ranging ~7-fold were
selected based on
fractions of the LD50.
Effects were seen at all
doses, so it is not clear
that the low dose was
low enough.
High
1
1
1

12. Exposure Route
and Method
Study does not report
whether compound
administered neat or in a
vehicle. Controls were
given tap water, so it is
possible that water was
the vehicle.
Medium
2
1
2
Test Organism
13. Test Animal
Characteristics
The test animal species,
strain, sex, life stage, and
source (laboratory-
maintained colony) were
reported. Starting age
and body weight were
not reported. Test
animal was appropriate
to the outcome; however,
only females were
exposed, so effects
through the male line
could not be assessed.
Medium
2
2
4

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All animal husbandry
conditions were reported
and appropriate.
High
1
1
1

15. Number per
Group
22 to 28 females/group
tested.
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
Endpoints relevant to
these outcomes were
limited to organ weights,
histopathology, and
hematocrit.
Low
3
2
6
89

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

17. Consistency of
Outcome
Assessment
Females of the high dose
group that were not
pregnant were sacrificed
on day 25 post mating,
while remaining females
were sacrificed after 3
weeks of lactation (the
latter had longer
exposure durations).
Medium
2
1
2

18. Sampling
Adequacy
All animals were
evaluated for all
outcomes.
High
1
1
1

19. Blinding of
Assessors
Subjective outcomes not
evaluated.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were reported
and adequate.
High
1
1
1

21. Confounding
Variables in Test
Design and
Procedures
No potentially
confounding factors were
noted by the authors or
apparent in the study.
High
1
2
2
Confounding /
Variable Control
22. Health Outcomes
Unrelated to
Exposure
There were 2 deaths of
nonpregnant females at
the high dose, and
pneumonia was
diagnosed, suggesting
possible gavage errors,
but the authors did not
draw a conclusion with
respect to cause of death.
This attrition was
reported and unlikely to
impact the results.
Medium
2
1
2
Data Presentation
and Analysis
23. Statistical
Methods
Statistical analysis was
described and conducted;
however, it is not clear
that all offspring
analyses considered the
effect of litter size.
Medium
2
1
2

24. Reporting of
Data
Histopathology data were
reported qualitatively.
Low
3
2
6

Sum of scores:

28
50
90

-------
N-Methylpyrrolidone
Study reference:
Sitarek. K.. Stetkiewicz. J..W (2012). Evaluation of reDroductive disorders in female rats exDOsed to N-
methyl-2-pyrrolidone Birth Defects Research, Part B: Developmental and Reproductive Toxicology, 95(3),
195-201
HERO ID: 3043651
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.7857
Overall Score:
Nearest *:
1.8
Overall Quality Level:
Medium
91

-------
N-Methylpyrrolidone
4.12. Animal toxicity evaluation results of Sitarek et al 2012 for single
generation reproductive toxicity assessment in rats exposed orally study on
reproductive outcomes
Study reference:
Sitarek. K.. Stetkiewicz. J..W (2012). Evaluation of reDroductive disorders in female rats exDOsed to N-
methyl-2-pyrrolidone Birth Defects Research, Part B: Developmental and Reproductive Toxicology, 95(3),
195-201

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

6. Randomized
Allocation
Study did not report how
animals were allocated to
groups.
Low
3
1
3

9. Reporting of
Doses/Concentration
s
Gavage doses were
reported in mg/kg bw;
initial body weight was
not reported.
Medium
2
2
4

10. Exposure
Frequency and
Duration
Frequency and duration
were reported and suited
to the study time.
High
1
1
1
92

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

11. Number of
Exposure Groups
and Dose Spacing
Three nonzero doses
ranging ~7-fold were
selected based on
fractions of the LD50.
Effects were seen at all
doses so it is not clear
that the low dose was
low enough.
High
1
1
1

14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All animal husbandry
conditions were reported
and appropriate.
High
1
1
1

15. Number per
Group
22 to 28 females/group
tested.
High
1
1
1
Outcome
Assessment
16. Outcome
Assessment
Methodology
See footnote at end of
page1
High
1
2
2
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic
Review for TSCA Risk Evaluation.
93

HERO ID: 3043651

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

18. Sampling
Adequacy
All animals were
evaluated for all
outcomes.
High
1
1
1

19. Blinding of
Assessors
Subjective outcomes not
evaluated.
Not Rated
NA
NA
NA

20. Negative Control
Response
Negative control
responses were reported
and adequate.
High
1
1
1

24. Reporting of
Data
See footnote at end of
page1
High
1
2
2

Sum of scores:

28
45
1 Metrics that received a "High" rating met the criteria as discussed in the Applications of Systematic
Review for TSCA Risk Evaluation.
94

-------
N-Methylpyrrolidone
Study reference:
Sitarek. K.. Stetkiewicz. J..W (2012). Evaluation of reDroductive disorders in female rats exDOsed to N-
methyl-2-pyrrolidone Birth Defects Research, Part B: Developmental and Reproductive Toxicology, 95(3),
195-201
HERO ID: 3043651
Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
High: >=1 and <1.7
Medium: >=1.7 and <2.3
Low: >=2.3 and <=3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.6071
Overall Score:
Nearest *:
1.6
Overall Quality Level:
High
95

-------
N-Methylpyrrolidone
4.13. Animal toxicity evaluation results of Solomon et al 1995 for a 2-generation
reproduction/developmental study, inhalation study on reproductive, growth
(early life), and development outcomes
Study reference:
Solomon. H. M., Burgess. B. A.. Kennedv. G. L.. Jr.. StaDles. R. E. (1995). l-methvl-2-Dvrrolidone (NMP):
Reproductive and developmental toxicity study by inhalation in the rat. Drug and Chemical Toxicology, 18(4),
271-293

HERO ID: 2761868

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

1. Test Substance
Identity
Clearly identified
High
1
2
2
Test Substance
2. Test Substance
Source
Test substance source
was reported. No lot or
batch number was
reported, but this
omission of details is not
likely to have a
substantial impact on
results.
Medium
2
1
2

3. Test Substance
Purity
Purity reported (99.9%).
Impurities were
identified and present in
quantities that would not
influence the results.
High
1
1
1

4. Negative and
Vehicle Controls
A concurrent negative
control was used and
appears to be sham-
exposed.
High
1
2
2
Test Design
5. Positive Controls
This metric is not
rated/applicable for this
study type.
Not Rated
NA
NA
NA

6. Randomized
Allocation
Rats were distributed
randomly into control
and treated groups using
a randomized block
design based on body
weight.
High
1
1
1
Exposure
7. Preparation and
Storage of Test
Substance
The test substance
preparation, method, and
equipment used to
generate the vapor were
reported and appropriate.
High
1
1
1
Characterization
8. Consistency of
Exposure
Administration
Details of exposure
administration were
reported and
administered consistently
across study groups.
High
1
1
1
96

-------
N-Methylpyrrolidone
Study reference:
Solomon. H. M.. Burgess. B. A.. Kennedv. G. L.. Jr.. StaDles. R. E. (1995). l-methvl-2-Dvrrolidone (NMP):
Reproductive and developmental toxicity study by inhalation in the rat. Drug and Chemical Toxicology, 18(4),
271-293

HERO ID: 2761868

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

9. Reporting of
Doses/Concentration
s
Target and analytical
concentrations were
reported. The analytical
high dose was reported
as 116.4 ppm (target
dose was 130 ppm). It
was reported that
technical restraints
(condensation on the
inside of the high dose
chambers) prevented
attainment of the target
dose (130 ppm).
Medium
2
2
4

10. Exposure
Frequency and
Duration
The exposure frequency
and duration of exposure
were appropriately
identified.
High
1
1
1

11. Number of
Exposure Groups
and Dose Spacing
The number of exposure
groups and
concentrations were not
justified by the study
authors in the report.
This is unlikely to impact
results, as the number of
exposure groups and
spacing of the exposures
were adequate to show
results relevant to the
outcome of interest.
Medium
2
1
2

12. Exposure Route
and Method
A dynamic whole-body
chamber was used for
vapors that may
condense. The high-
concentration target of
130 ppm was not attained
due to condensation on
the inside of the high
dose chambers; the
actual high-concentration
exposure level was
measured as 116.4 ppm.
The number of air
changes/hour was
reported to be 12-15.
Medium
2
1
2
97

-------
N-Methylpyrrolidone
Study reference:
Solomon. H. M.. Burgess. B. A.. Kennedv. G. L.. Jr.. StaDles. R. E. (1995). l-methvl-2-Dvrrolidone (NIVIP):
Reproductive and developmental toxicity study by inhalation in the rat. Drug and Chemical Toxicology, 18(4),
271-293

HERO ID: 2761868

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score
Test Organism
13. Test Animal
Characteristics
The test animal species,
strain, sex, age, and
starting body weight
were reported and
obtained from a
commercial source. The
rats were weighed, and
clinical signs were taken
on all rats upon arrival
and 2 times more before
exposure.
High
1
2
2
14. Adequacy and
Consistency of
Animal Husbandry
Conditions
All husbandry conditions
were reported, were
adequate, and were the
same for control and
exposed groups.
High
1
1
1

15. Number per
Group
The number of animals
per study group was
reported and appropriate
for the study type and
outcome analysis.
High
1
1
1

16. Outcome
Assessment
Methodology
The outcome assessment
methodology was
reported and addressed
the intended outcomes of
interest.
High
1
2
2

17. Consistency of
Outcome
Assessment
Details of the outcome
assessment protocol were
reported and outcomes
were assessed
consistently across study
groups.
High
1
1
1
Outcome
Assessment
18. Sampling
Adequacy
Sampling was reported
and adequate for the
outcomes of interest.
High
1
1
1

19. Blinding of
Assessors
The study report reported
that investigators
assessing outcomes of
the developmental were
not aware of the
exposure group to which
any of the dams or
offspring belonged to.
High
1
1
1

20. Negative Control
Response
The biological responses
of the negative control
groups were adequate.
High
1
1
1
98

HERO ID: 2761868

Domain
Metric
Eval Comment
Qualitative
Determination [i.e.,
High, Medium,
Low, Unacceptable,
or Not rated]
Metric
Score
Metric
Weighting
Factor
Weighted
Score

21. Confounding
Variables in Test
Design and
Procedures
There were no reported
differences among the
study groups in initial
body weight, but
respiratory rates were not
reported; this lack of
reporting is not likely to
have a significant impact
on results.
Medium
2
2
4
Confounding /
Variable Control
22. Health Outcomes
Unrelated to
Exposure
Details regarding animal
attrition and health
outcomes unrelated to
exposure was reported.
It was reported that 2
animals in the control
group died during the
reproduction phase of the
study; one of these
deaths was due to a
handling injury. There
were no differences
among groups that would
influence the outcome
assessment.
High
1
1
1

23. Statistical
Methods
Statistical methods were
clearly described and
appropriate.
High
1
1
1
Data Presentation
and Analysis
24. Reporting of
Data
The data for all outcomes
were reported by
exposure group, sex, and
generation and described
adequately. Continuous
data included means and
the respective standard
error.
High
1
2
2

Sum of scores:

30
37
High: >=
Medium: >=
1 and <1.7
=1.7 and <2.3
Overall Score = Sum of Weighted Scores/Sum
of Metric Weighting Factors:
1.2174
Overall Score:
Nearest *:
1.2
Low: >=2.5 and <=j

Overall Quality Level:

High

-------
N-Methylpyrrolidone
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101

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