Responses to Comments for NMP Work Plan Risk Assessment

Summary of External Peer Review and

Public Comments and Disposition

This document summarizes the public and external peer review comments that the EPA’s Office 

of Pollution Prevention and Toxics (OPPT) received for the draft work plan risk assessment for 

n-Methylpyrrolidone (NMP). It also provides EPA/OPPT’s response to the comments received 

from the public and the peer review panel.

EPA/OPPT appreciates the valuable input provided by the public and peer review panel. The 

input resulted in numerous revisions to the risk assessment.

Peer review charge questions1 are used to categorize the peer review and public comments 

into specific issues related to the five main themes. 

• General Issues on the Risk Assessment Document

• Worker Exposure Assessment

• Consumer Exposure Assessment

• Hazard and Dose-Response Assessment

• Use of PBPK Model

• Risk Characterization

1 These are the questions that EPA/OPPT submitted to the panel to guide the peer review process.

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Responses to Comments for NMP Work Plan Risk Assessment

General Issues on the Risk Assessment Document

Charge Question 1-1: Please comment on whether the risk assessment provides a clear and logical summary of EPA’s analysis. 

Please provide specific suggestions for improving the clarity and transparency of the risk assessment document. 

Charge Question 1-2: Please comment on whether appropriate background information is provided and accurately characterized. 

Please provide any other relevant literature, reports, or data that would be useful to support the risk assessment.

# Summary of Peer Review and Public 

Comments for Specific Issues Related to 

Charge Questions 1-1 and 1-2

EPA/OPPT Response

1 Several public and peer review commenters 

stated that the document is not clear about 

the overall objectives of the risk assessment.

EPA/OPPT has added language to clarify the objectives of the risk assessment. 

Specifically see the Executive Summary and Introduction (section 1.1)

2 A public commenter requested that the 

exposure estimates be clarified and refined, 

specifically the information contained in 

Table 3-7 and Table D-4.

EPA/OPPT has updated the description of exposure assessment methodology. 

All tables have been updated and exposure estimates have been refined. 

Please see Tables 2-1 through 2-5 and Appendices D & E.

3 Peer reviewers and several public 

commenters advocated the use of a PBPK 

model in the risk assessment.

The final risk assessment integrates a revised PBPK model. Section 1.2.4, 

Analysis Plan, describes how the PBPK model was used in the assessment. 

Section 2.1.2 describes the PBPK model input parameters for the derivation of 

occupational exposure estimates. Section 2.2.3 describes the PBPK model 

input parameters for the derivation of consumer exposure estimates. Section 

3.2.2 describes how PBPK-derived internal doses were used to determine 

PODs. Appendix I includes a description of both the rat and human PBPK 

models.

4 Several public commenters and peer review 

panelists noted that EPA’s small shop focus 

may not be warranted, suggesting that 

statements about lack of glove use at small 

shops and the assumption that the small 

shops have exposures that are less 

EPA/OPPT improved the focus descriptions in the Executive Summary, sections 

1.1.1 and 1.1.3. EPA/OPPT found that there were limited readily available data 

to support the original assumption and removed the assumption that small 

shops have < 10 workers. Therefore, even though the interest is for small 

shops, the occupational exposure analysis retains data and analyses for all 

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Responses to Comments for NMP Work Plan Risk Assessment

controlled and monitored than those seen in 

large-scale industrial operations are not well 

supported.

industries and shop sizes. EPA/OPPT cannot rule out that any of these 

industries may have small shops engaging in paint stripping jobs. 

In addition, EPA/OPPT revised the occupational exposure assessment to 

include a scenario approach that considers the use of respirators to control 

exposures. Section 2.1.1 contains information about the occupational 

scenarios examined in the final risk assessment.

5 Public commenters requested additional 

information to explain the use of different 

models in different work plan assessments.

The selection of exposure models for use in risk assessment depends on the 

data that are available for use in the exposure model. For example, MCCEM 

was used for DCM and NMP because there were chamber test emission data 

suitable for fitting this higher tier model. Data for use in MCCEM modeling 

were not available for TCE. Thus, E-FAST2/CEM were used in the TCE’s 

consumer exposure model, as these models do not require emission data.

6 A number of public commenters suggested 

that the assessment is using screening-level 

methodology that may not be appropriate 

for risk assessment for regulatory decisionmaking (e.g., TCE, DCM and NMP)

EPA/OPPT disagrees with this comment. This assessment incorporates both 

measured data and modeling to estimate exposures under a number of 

different scenarios. For conducting Work Plan assessments EPA/OPPT may use 

a variety of appropriate available models to estimate parameters needed to 

calculate risks when measured data are unavailable.

For example, EPA/OPPT has incorporated a revised PBPK model has been used 

to estimate internal doses, which allows for the effective use of toxicological 

data based on different routes of exposure for more robust dose-response 

assessments. 

7 Public commenters noted that there was no 

clear framework to prioritize specific uses 

scenarios.

As described in section 1.2.3, EPA/OPPT considered the range of TSCA uses 

including petrochemical processing, engineering plastics, coatings (resins, 

paints, finishes, inks, and enamels), paint stripping, agricultural chemicals, 

electronic cleaning and industrial/ domestic cleaning. Narrowing of the scope 

required exclusion of some uses based on comparative judgments relative to 

paint stripping. These comparative judgments considered potential exposure 

among the primary uses identified (e.g., percent content relative to potential 

exposure).

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Responses to Comments for NMP Work Plan Risk Assessment

This assessment focused on the use of NMP in paint strippers because NMP 

with expected to have the highest potential exposures to both consumers and 

workers. In addition, NMP is a potential substitute for DCM in paint stripping 

applications, which was recently assessed as a work plan chemical. EPA/OPPT 

considered it prudent to evaluate NMP as a likely replacement.

8 Several commenters suggested that 

EPA/OPPT employ a systematic process for 

the evaluation of the quality of the studies 

used in the assessment.

EPA/OPPT used a systematic, weight of evidence approach to evaluating 

available data and data quality. 

EXPOSURE:

For occupational exposure data, EPA has added descriptions of the literature 

search strategy and quality criteria to Appendix D.

Section 2.2 and Appendix E now include a more detailed description of the 

approach taken to developing consumer exposure estimates. Consumer 

exposure data is extremely limited. No measurements of the concentrations 

of these chemicals from actual use by consumers in their homes are

available. Also, no emission data are available for consumer products. A

chamber study conducted by MRI (EPA, 1994), although there were 

calibration errors that had to be investigated, was deemed sufficient for 

estimating NMP air concentrations from paint stripping activities.

Usage amounts came from survey information cited in EPA’s Exposure 

Factors Handbook (EFH) (EPA, 2011) and to a small degree from other 

surveys. The data in the EFH has previously been peer reviewed.

HAZARD

Section 3.1 describes the approach and methodology EPA/OPPT used to 

evaluate toxicity data. Appendix F includes a description of literature 

collection, data quality evaluation and study selection. In summary, publicly 

available toxicity data were identified, starting with a survey of existing 

assessments. Additional studies suggested by peer reviewers and public 

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Responses to Comments for NMP Work Plan Risk Assessment

commenters were added. Outcomes were evaluated for sensitivity and 

consistency. This resulted in the selection of developmental toxicity 

endpoints as the basis for the risk assessment.

9 One commenter suggested that EPA address 

OSHA authorities to regulate occupational 

exposures.

EPA/OPPT consulted with OSHA and NIOSH during the development of the 

NMP risk assessment. OSHA and NIOSH comments and suggestions were 

incorporated into the final risk assessment.

10 One public commenter suggested that the 

risk assessment should be classified as a 

Highly Influential Scientific Assessment

(HISA)

This assessment was identified as an Influential Scientific Product (ISA). The 

peer review process for this ISA product was not different from that

prescribed for a HISA.

11 Several commenters expressed concern that 

many of the documents cited in the risk 

assessment are not in the public domain.

EPA/OPPT encourages owners of studies and reports considered to be 

confidential business information to release as much information as possible. 

All of the data that form the basis of the quantitative risk assessment are from 

public sources.

12 Exposures should be estimated for women 

and children, including female children aged 

16 - 21.

The selection of the lifestage of interest was driven by the identification of the 

most sensitive hazard endpoints (section 3.1.3.4). Although EPA/OPPT 

identified a number of hazard concerns (e.g., reproductive toxicity, 

neurotoxicity, liver and kidney toxicity), developmental endpoints were the 

most consistent, robust and sensitive. Therefore, pregnant women and

women of childbearing age who may become pregnant, were selected as a 

focus for the risk estimates (section 4.1). However, EPA/OPPT considered 

potential risks to other lifestages and subpopulations, based on concern for 

other endpoints, but assumed that exposures that do not result in 

unacceptable risks for these particular lifestages would also be protective of 

other receptors, including children and adult males (section 4.1).

13 EPA should make an attempt to estimate 

oral exposure and incorporate the data into 

the aggregate exposure analysis if possible. 

If there are no data, this should be clearly 

identified as a data gap that could result in 

an underestimation of exposure.

EPA identifies in the section describing uncertainties (4.3) that exclusion of 

oral exposure will underestimate exposure, but this underestimation is not 

expected to contribute significantly to aggregate exposure, given occurrence 

and use patterns.

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Responses to Comments for NMP Work Plan Risk Assessment

Worker Exposure Assessment

Charge Question 2-1: Please comment on the approach used and provide any specific suggestions or alternative approaches, 

models or information that should be considered by the Agency for improving its assessment of the workplace inhalation exposure, 

including specific citations (if available) of data sources characterizing occupational inhalation exposures.

Charge Question 4-1: Please comment on the approach used and provide any specific suggestions or recommendations for 

alternative approaches, models or information that should be considered by the Agency for improving its assessment of the 

workplace dermal exposure, including specific citations (if available) of data sources characterizing occupational dermal exposures. 

Please comment on the strengths and weaknesses of the evaluation and the choice of assumptions/input parameters for generating 

estimates of the NMP’s dermal exposure.

Charge Question 4-2: Please comment on the approach used and provide any specific suggestions or recommendations for 

alternative approaches, models or information that should be considered by the Agency for improving its assessment of the 

consumer dermal exposure, including specific citations (if available) of data sources characterizing dermal exposures in a residential 

setting. As part of the review, please comment on the strengths and weaknesses of the evaluation and the choice of 

assumptions/input parameters for generating estimates of the NMP’s dermal exposure.

Charge Question 4-3: Please comment on the assumptions used by the Agency regarding film thickness for the assessment, 

including any additional data on film thickness with which to assess dermal exposure to NMP for both consumers and workers.

# Summary of Peer Review and Public 

Comments for Specific Issues Related to 

Charge Questions 1-1 and 1-2

EPA/OPPT Response

14 Panel members suggested that the literature 

search strategy should be described and 

recommended additional references as 

containing potentially relevant exposure 

data.

Also, a public commenter asked why the 

occupational exposure assessment did not 

consider exposure monitoring data for 

graffiti workers reported in WHO (CICAD 

document).

EPA/OPPT has added descriptions of the literature search strategy and quality 

criteria to Appendix D

EPA/OPPT reviewed the additional exposure-relevant references 

recommended by the public and peer review panel. The WHO data are 

included but have been expanded to include more data from the WHO 

primary references (Anundi et al., 2000; Anundi et al., 1993). A small amount 

of new inhalation data was identified, but all values were within the ranges of 

the original data sets. The additional data have been added to the data sets in 

Appendix D.

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Responses to Comments for NMP Work Plan Risk Assessment

15 Regarding worker dermal exposure 

modeling and parameters, several issues 

were raised:

a) Lack of consideration of glove use, 

particularly since dermal exposure estimates 

may not represent real world conditions 

based on the corrosive properties of NMP. 

EPA’s assessments should be based on 

intended uses in accordance with label 

instructions.

b) Differences in dermal exposure between 

the residential applicator and the worker 

applicator are substantial with the reason 

not clear, including film thicknesses. Also, 

one episode of dermal contact/ day is not 

conservative and is an uncertainty. Some 

parameters only use a single value that is 

too conservative.

c) A sensitivity analysis of film thickness 

parameters and surface density is needed.

(This comment also applies to the consumer 

exposure assessment)

a) Literature information on gloves and prevalence of their use has been 

presented, characterized and used for the dermal analyses in Appendix D. The 

updated assessment corrects the original erroneous statements indicating 

NMP as corrosive. EPA’s assessments are based on intended uses in 

accordance with label instructions but also take into account scenarios where 

label instructions, particularly regarding use of gloves made of optimal 

material for protection against NMP are not followed as survey data has found 

applies to a significant fraction of workers.

b) and c) The models used have changed from thin film to PBPK, reducing the 

number of parameter inputs. Two highly uncertain parameters, film thickness 

and number of episodes of dermal contact/ day are no longer used in the 

assessment. Dermal uptake is predicted based on the surface area exposed, 

concentration of NMP in contact (assumed to be equal to the formulation) and 

permeability constant which was derived from human PK studies. While 

dermal uptake is very sensitive to these parameters, the degree of uncertainty 

in them is fairly low. The fraction of total absorption by this route depends on 

the particular scenario and particularly glove use. The parameters have been 

harmonized for workers and consumers except for scenario specific 

differences in duration of contact and NMP concentrations in products. These

differences are explained in Appendix D and E. And EPA has improved upon 

the composite range approach by including statistical values (e.g., 50th

percentile, arithmetic mean) where possible. When statistical values cannot be 

provided, midpoints are provided as central tendency substitutes along with 

ranges.

16 Regarding worker inhalation monitoring 

data and its use in generating ADCs, several 

interrelated issues were raised:

a) EPA/OPPT further considered IMIS data and found no solid criteria for 

determining which IMIS data are associated with use of NMP-containing 

strippers. Thus, EPA has concluded that the original preference for literature 

data over IMIS is valid. EPA/OPPT has bolstered the text in Appendix D

indicating that the IMIS data are excluded from use in risk estimation since 

7 | Page
Responses to Comments for NMP Work Plan Risk Assessment

a) More OSHA IMIS data should be used for 

estimating risks.

b) Reliance on graffiti workers as the sole 

source of workplace exposure 

concentrations creates a large uncertainty 

and potential for underestimation of 

exposure.

c) Data presentation and transparency 

should be improved, including being more 

statistical, using central tendencies, or 

developing a probabilistic approach rather 

than using only composite ranges. Exclusion 

of some data shown in the appendix is not 

clear.

d) Exposure controls are neglected.

literature data were available and preferred due to their known applicability to 

paint stripping, while IMIS data may not be due to NMP-based strippers. 

b) EPA/OPPT has broadened the data used and created two assessed 

populations in the assessment. These populations are expected to cover the 

entirety of categories of workers who may be exposed to NMP-based strippers 

and NMP-based graffiti remover products.

c) Data presentation, transparency, statistics (including central tendencies)

and exposure controls are particularly interrelated for assessment purposes. 

EPA/OPPT has improved on the composite range approach by including 

statistical values (e.g., 50th percentile, arithmetic mean) where possible. When 

statistical values cannot be provided, midpoints are provided as central 

tendency substitutes along with ranges. EPA/OPPT bolstered the data 

summaries in tables and text to include numbers of studies, numbers of data 

points and study dates, along with adding more data to the summaries for 

completeness. EPA/OPPT determined that modeling or probabilistic 

approaches are inappropriate for this assessment due to the lack of statistical 

data for most of the parameters. These issues are discussed in Appendix D. 

Also, some previously excluded data have been included. The remaining 

excluded data are discussed, but these exclusions have no impact on the risk 

analyses.

d) EPA/OPPT has included model runs with and without respirators and gloves. 

The relative prevalence of use of personal protective equipment is not known 

to EPA/OPPT. Readily available data were insufficient for quantifying exposure 

impacts due to other exposure control measures such as local ventilation, 

although anecdotal examples of such controls, where available, are included in 

the discussions in Appendix D.

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Responses to Comments for NMP Work Plan Risk Assessment

17 Peer review panel members suggested that 

the assessment does not adequately address 

occupational non-users of NMP.

The updated risk assessment clarifies exposure issues for occupational nonusers. Section 2.1.1.2 describes the general approach. Section 2.1.1.3 explains 

that each exposure scenario also included a nearby worker not directly 

working with NMP (non-user), who was assumed to not be wearing a 

respirator but to only have incidental dermal contact equal to 1% of the skin 

area. 

18 Public commenters suggested that the US 

census data are too weak to be used to 

calculate worker population estimates.

EPA/OPPT considered other data sources such as EPA’s National Emission 

Standards for Hazardous Air Pollutants (NESHAP) for Paint Stripping. NESHAP 

data were usable for postulating estimates of the total population of workers 

involved in the DCM-based paint stripping operations for all industries 

combined. This estimate for DCM-based stripping was assumed to be an upper 

bound for NMP-based stripping. Please see Appendix D for further discussion. 

EPA/OPPT also made revisions to Appendix D to clearly show the estimates of 

number of workers per shop in each of the industries.

19 A public commenter asked why the 

occupational exposure assessment did not 

consider the use of NMP-based graffiti 

removers by other occupations.

Data for other such occupations were not found. The updated assessment 

notes in Appendix D that such occupations may have exposures but these 

would be expected to be lower than the exposures of those whose occupation 

is graffiti remover.

20 A public commenter asked why the 

occupational exposure assessment did not 

consider other NMP-based paint strippers.

EPA/ OPPT is not aware of other NMP-based paint strippers that are not 

considered.

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Responses to Comments for NMP Work Plan Risk Assessment

21 A peer review panelist requested that 

EPA/OPPT include more information on 

label instructions, common industry 

practices and high-end or extremes in 

stripper use.

Also, a public commenter requested that a 

more robust description of the assumptions 

made regarding PPE and gloves in the 

occupational setting be included in the 

assessment.

Appendix D incorporated additional information about common industry 

practices when available. EPA/OPPT could not find data on high-end and 

extreme stripper use rates. Information on labeling instructions was not 

incorporated in the final risk assessment because such instructions would be 

anecdotal. With the exception of respirator use, all of these types of 

information and data suggested for inclusion would not impact exposure 

estimates used in the risk analyses. The expected prevalence of respirator use 

and gloves are discussed qualitatively in Appendix D.

22 Discussion of uncertainties and limitations 

should be improved for the worker exposure 

assessment. Directional impact on risk 

should be included and the discussion 

should be more complete and robust.

EPA/OPPT determined gaps in the discussion and completed improvements in

section 4.3.1, including to directional impact on risk when possible and also 

making the discussion more complete and robust.

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Responses to Comments for NMP Work Plan Risk Assessment

Consumer Exposure Assessment

Charge Question 3-1: Please comment on the approach used and provide any specific suggestions or recommendations for 

alternative approaches, models or information that should be considered by the Agency for improving its assessment of consumer 

inhalation exposure, including specific citations of data sources characterizing consumer emission profiles of NMP-based paint 

strippers. As part of the review, please also evaluate the sensitivity analysis conducted for the assessment and comment on the 

strengths and weaknesses of the evaluation of different exposure scenarios and the choice of assumptions/input parameters for 

generating central tendency and upper-end NMP air concentrations.

# Summary of Peer Review and Public 

Comments for Specific Issues Related to 

Charge Questions 1-1 and 1-2

EPA/OPPT Response

23 A panelist suggested expanding the paint 

stripping protocol description and insert same 

in body of document.

As stated in section 2.2.1.2 of the body of the report, Section E-3 of 

Appendix E discusses label instructions for ventilation and user location 

during the wait period. The application method and times per step are 

described adequately for the zone modeling that is used. Additional 

considerations such as effects of containers left open, methods to loosen 

paint and cleanup procedures did not have available data sufficient for 

quantification.

24 A peer review panelist and a public 

commenter stated that the presentations in 

Table 3-7 and D-4 for user and non-user are 

confusing.

The confusion results because the scenarios are labeled as upper-end for 

the user or non-user based on changes in parameters shown to be more 

sensitive for the user or non-user—this does not mean that the results are 

not upper-end for the other exposure group. For example, all of the 

scenarios where the most sensitive parameters for the non-user were 

made upper-end resulted in exposures for the user that were higher than 

the scenarios run as upper-end for the user; this is because the effect of 

higher chemical mass plus low rest-of-house ACH to increase exposures 

for the user was greater than the lower-exposure impact of user location 

in rest-of-house instead of workshop (the user location was the most 

sensitive parameter for short exposures but much less sensitive at longer 

exposure times). EPA/OPPT has edited the tables, now table 2-4 and 2-5 

and their associated text in sections 2.2 to clarify these points.

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Responses to Comments for NMP Work Plan Risk Assessment

25 A panelist and public commenter stated that 

the Executive Summary and toxicology 

sections present contradictory information 

regarding NMP corrosivity; one states that it is 

corrosive, the other that it is an irritant, but 

not corrosive.

The hazard summary has been revised to state that NMP is not corrosive. 

See section 3.1.2.

26 A peer review panelist commented that the 

role of human behavior in responding to 

irritating substances by increasing ventilation, 

leaving the area, or other actions does not 

seem to have been incorporated in extreme 

exposure scenarios or models.

EPA/OPPT assumes that this comment is related to the incorrect 

description of NMP as corrosive. As discussed in the response to comment 

15, the corrosive description has been corrected in the revised 

assessment. Note that in the extreme exposure (because of large tub 

area, low ventilation and small zone volumes) bathtub stripping scenarios 

that the user leaves the work area during the wait period.

27 A peer review panelist pointed out that there 

is a discrepancy in the reporting of the vapor 

pressure in Table 2-1 versus Table D-6.

EPA/OPPT will only refer to the peer reviewed value of 0.19 mmHg at 25°C 

that was in Table 1-1 (previous Table 2-1). The MCCEM saturation 

concentration scenarios affected by this change have been revised in the 

final assessment.

28 A public commenter stated that EPA/OPPT’s 

assumptions for the importance of 

volatilization are internally inconsistent. NMP 

was developed as a low-volatile alternative to 

methylene chloride for paint stripping 

applications. Volatilization of NMP is not 

expected to be significant during normal use. 

Based on its Henry's Law constant (4.45X10-8

atm-cu m/mole), NMP is expected to be 

essentially nonvolatile from water and soil 

(HSDB, 2012). This conclusion is consistent 

with the results of the fugacity modeling 

presented in Table 2-4 of EPA/OPPT’s draft 

assessment, which indicate that only 0.1% of 

NMP released to the environment will be 

The release fraction of 0.26 for brush-on NMP is the theoretical upper 

bound of the release over an infinite period of time based on measured 

concentration data collected during chamber studies in EPA (1994). The 

assessment states that about 4.7% (a 0.047 fraction) of the brush-on NMP 

would be released in three hours, which is the scenario with longest time 

frame. Emissions are truncated at the end of the scenarios because 

scrapings are assumed to be removed from the house. Also, the EPA 

(1994) chamber data were collected over approximately a 4.5-hr period 

for the brush-on stripper. Because modeled emissions in all cases are over 

a shorter time period than the collected measurement data, there is a 

high degree of confidence in the emission profiles used in the modeling 

study. 

In addition, the comparison of these predictions to fugacity estimates 

must be made with caution due to the underlying assumptions of each 

12 | Page
Responses to Comments for NMP Work Plan Risk Assessment

found in air. In contrast, EPA/OPPT has 

assumed air release fractions of 0.26-0.52 for 

NMP during normal use (i.e., 26-52% of the 

mass of NMP applied will volatilize during use.

method. The fugacity model is predicated on equilibrium, with the Level III 

model incorporating steady-state behavior together with multimedia 

transport. The modeling study used a dynamic mass-balance model, 

incorporating time-varying emission rates and accounting for transport 

and removal processes. The fugacity ratio of 0.1% assumes transport rates 

that are almost certainly different than those assumed in the modeling 

study.

29 A public comment stated that all the exposure 

scenarios were indoor and asked whether 

there was consideration of product use 

outside.

It is correct that the assessment is of indoor use only, so the assessment 

exposure descriptors refer only to a range of indoor exposures. The risk 

assessment was edited to more clearly reflect this.

30 A peer review panelist suggested that 

monitored radon concentration differences 

according to floor of home could be used as a 

check of ROH estimates in consumer 

inhalation modeling for non-users.

EPA/OPPT does not think that the suggested radon concentration ratios 

are appropriate for the NMP analysis because they are slowly changing, 

virtual steady-state conditions, whereas the stripper use generates rapid 

changes in NMP concentration. 

31 A peer review panelist and a public 

commenter suggested that differences in 

worker and consumer dermal exposure 

scenarios should be harmonized or better 

explained.

EPA/OPPT has developed a harmonized approach to replace the original 

worker and consumer dermal exposure scenarios.

32 Peer review panelists and a public commenter 

suggested that the consumer inhalation 

modeling results be compared to data from 

the MRI and occupational exposure studies.

Comparison of the MCCEM results to the MRI study results was 

complicated by an apparent discrepancy between the concentration 

values reported in graphical plots versus those for the same test reported 

in time-integrated tables; this is discussed in section D.1 of Appendix D of 

the revised assessment.

33 A peer review panelist commented that the 

EPA 1994 chamber test of consumer 

exposures is referred to as an occupational 

study in that section of the assessment—it 

EPA/OPPT acknowledges this error and has incorporated the 

recommendation.

13 | Page
Responses to Comments for NMP Work Plan Risk Assessment

should be referred to consistently as a 

chamber test throughout the report.

34 A peer review panelist commented that the 

consumer application and scraping times 

seem unrealistically low. Since they were 

derived from a chamber test using flat panels 

they do not account for more intricate work 

pieces; perhaps doubling the 

application/scrape times could be used for 

upper-end scenarios.

As stated in the Stripping Sequence of the Inhalation Exposure Scenario 

Inputs section of the Consumer Exposure Assessment Appendix E-3, the 

application and scraping times were assumptions that fit the overall times 

reported for the EPA (1994) scenarios. It is possible that these times could 

be greater or smaller by an unknown amount; however, the stripping 

sequence was done twice for all scenarios, thus doubling all the exposure 

times. Also, because the sensitivity analysis indicated that User Location 

was the most sensitive exposure parameter, one of the upper end 

workshop scenarios designated the wait location of the user to be in the 

room-of-use, so the user was exposed to the NMP concentrations within 

the workshop for the entire stripping period (apply/wait/scrape).

35 A peer review panelist commented that there 

is evidence in the Riley et al. (2001) survey 

that a substantial proportion of users do not 

open windows. Sensitivity analysis shows that 

workshop ACH is a strong determinant of user 

and non-user exposures, so consider extra 

scenarios with closed windows (lower ACH in 

room of use).

Excluding the users in other locations or with ventilation, the Riley et al. 

(2001) survey indicated approximately 20% of users are indoors without

open windows. Regarding the impact of the workshop ACH—it is less 

sensitive than user location, chemical mass and rest-of-house ACH. With 

the exception of the bathroom scenario, which replicates very low 

ventilation conditions from an actual DCM stripper scenario so NMP 

exposures can be compared under those conditions, all the consumer 

scenario parameter choices are supported by label suggestions for 

ventilation (open windows) and/or by preponderance of information on 

indoor user behavior in (Abt Associates (1992); Pollack-Nelson (1995)) and 

Riley et al. (2001). This information is presented in detail in the Inhalation 

Exposure Scenario Inputs section of Appendix E-3: Consumer Exposure 

Assessment

36 A peer review panelist commented that the 

spray-on product is only modeled in workshop 

scenarios; consider adding another scenario 

for use of spray-on product in the bathroom.

EPA/OPPT has edited the spray-on product scenarios for the revised 

assessment, primarily because the MRI chamber tests ((US EPA, 1994)

that served as a basis for emission profiles did not include any applications 

involving NMP-containing spray-on strippers. Given the assumptions used

for the spray-on scenario, expanded modeling was not performed.

14 | Page
Responses to Comments for NMP Work Plan Risk Assessment

Emission parameters for the spray applied product were not available, so 

upper and lower estimates were developed to estimate exposures. The 

lower estimate was based on the brush applied data and the upper 

estimate was set as ten times higher based on professional judgment for 

the relationship between brush and spray applied products. The 

uncertainty of these estimates precludes performing a highly refined 

estimate as reliable input data is a prerequisite for a detailed modeling 

assessment. Thus the spray scenario is presented as an estimate of 

potential exposures.

37 A peer review panelist commented that use of 

the term “application rate” for g/ft2 is 

confusing because rate implies the pace 

(amount per time frame), whereas this is the 

amount per surface.

Although in the exposure assessment field rate typically represents the 

ratio of a mass or quantity to time (e.g., emission rate or air flow rate), 

rate is more generally defined as the ratio of one quantity against 

another. Therefore the use of rate to describe mass per area is correct, as 

is the use of rate to describe mass per time. The report is careful to define 

the units in places where the term can be confused; as there is no better 

terminology for amount of product applied per area, the use of the term 

is appropriate.

38 A peer review panelist commented that 

dermal exposure should be estimated 

separately for women, using female-specific 

body weight and hand size.

EPA/OPPT has adopted this recommendation.

39 A peer review panelist commented that the 

consumer dermal analysis would be improved 

by a more formal set of distributional 

representations of variability and uncertainty.

The consumer dermal analysis applies all the available distributional data 

(NMP product weight fraction and density), but considerable uncertainty 

remains in the factors lacking data that are based on professional 

judgment (exposed skin surface area and frequency of exposure). 

Reducing this uncertainty by acquiring data that is representative of the 

distributions for these parameters is beyond the scope of this assessment.

40 A peer review panelist requested an 

explanation of the differences in hand surface 

areas and film thicknesses between worker 

and consumer dermal exposure assessments. 

In the revised assessment the worker and consumer user dermal 

scenarios have been harmonized across common exposure factors, such 

as hand surface area. 

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Responses to Comments for NMP Work Plan Risk Assessment

41 a) A peer review panelist commented that a 

probabilistic approach could prove much 

more informative than the varying point 

estimate approach used for consumer 

inhalation assessment. It would be useful to 

clearly state which risks would not occur or be 

less likely if recommended safety precautions 

were taken. 

b) A peer review panelist and a public 

commenter recommended using Riley et al. 

(2001) and Abt Associates (1992) survey data 

to present information on degree of consumer 

compliance to manufacturer instructions.

c) A public commenter stated that some of 

EPA/OPPT’s estimated air concentrations are 

bounding; also, air modeling is not needed for 

assessing consumer inhalation exposures—

compare to monitoring data.

d) A public commenter recommended that 

EPA/OPPT construct scenarios based on 

recommended product use and labeling 

precautions, not on product misuse, 

suggesting that EPA/OPPT has overstated risk 

via the use of worst case scenario assessment.

a) A probabilistic approach would be a higher tier (more sophisticated) 

effort that requires additional input data that are currently not available. 

b) With the exception of the bathroom scenario, which replicates very low 

ventilation conditions from an actual DCM stripper scenario so NMP 

exposures can be directly compared under those conditions (which are 

characterized as high-end to bounding), all the consumer scenario 

parameter choices are supported by label suggestions for ventilation 

(open windows) and/or by preponderance of information on indoor user 

behavior (Abt Associates, 1992; Pollack-Nelson, 1995; Riley et al., 2001). 

However, these references are not NMP-specific, so degree of compliance 

or other quantitative details cannot be determined from them. More 

details are presented in detail in the Inhalation Exposure Scenario Inputs 

section of Appendix E-3: Consumer Exposure Assessment.

c) The characterization of the bathroom scenarios is high-end to bounding 

because it replicates a DCM CDC/NIOSH case. This scenario was included 

here if NMP is selected as a substitute for DCM by consumers. However, 

the workshop scenarios were designed to be considered plausible, in fact, 

the upper end amount of stripper product used in the assessment is only 

about the 80th percentile value from the Abt Associates (1992) survey, so 

yields a lower exposure estimate than the higher amounts from that 

survey. The higher amounts were not used because their occurrence is 

less likely, so the resulting scenarios would be considered less plausible.

d) All the consumer scenario parameter choices are supported by label 

suggestions for ventilation (open windows) and/or by preponderance of 

information on indoor user behavior in Abt Associates (1992), PollackNelson (1995) and Riley et al. (2001). The scenarios evaluated considered 

use with and without PPE.

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Responses to Comments for NMP Work Plan Risk Assessment

42 A public commenter stated that if users took 

breaks outside, as mentioned in the 

assessment on page 109, it is not clear why 

this scenario was not modeled.

The referenced sentence on page 109 of the draft assessment presents 

examples of break activities mentioning both indoor, e.g., making a 

sandwich in kitchen and outdoor, e.g., yard work, activities. The revised 

assessment makes clear that it is an indoor assessment only.

43 Public commenters made the following 

suggestions: 

a) EPA/OPPT should use the appropriate body 

weight from EPA’s Exposure Factors 

Handbook for target population of women of 

child-bearing age and discuss effects to infants 

and children.

b) Justify the differences of hand’s surface 

area and thin film contact between consumers 

and workers.

c) EPA/OPPT should include other possibilities 

than just one thin film with each exposure 

event.

a) In the revised assessment, harmonized worker and consumer dermal 

exposure scenarios shared common exposure factors, e.g., body weight, 

hand size. Selection of these parameters are justified in the document. 

b) Since the risk assessment was based on fetal effects, the exposure 

assessment focused on women of childbearing age and pregnant women. 

Since there are other hazard endpoints of interest (section 3.1.2), the risk 

characterization also discussed potential concerns for other lifestages and 

subpopulations, but concluded that EPA/OPPT expects risks to these 

lifestages and subpopulations to be lower, for a variety of reasons. See 

sections 3.2.5 and 4.1 for specific details.

c) The occupational assessment assumes that the scenario-specific surface 

area for liquid contact is exposed to the liquid for the entire time that the 

worker is on the task. For the full work-day exposure this is two periods of 

4 h separated by a 30-min lunch break. The concentration in the liquid is 

assumed to be constant at the formulation concentration for the entire 

time. So it is not assumed that a single “film” is applied at the beginning of 

exposure and no more is deposited.

44 A public commenter urged EPA/OPPT not to 

use the professional judgment value for the 

thin film thickness used in the consumer 

exposure assessment; instead, use the less 

conservative approach used for the worker 

exposure estimates.

The revised assessment has harmonized occupational and consumer 

dermal assessments and uses the concentrations of NMP (weight 

fractions) identified by surveying MSDS’s of NMP-containing paint 

strippers for both worker and consumer exposure estimates.

45 A peer review panelist recommended that the 

consumer inhalation modeling be redone 

The response to this comment merits a detailed explanation of the 

approach used to estimate consumer inhalation. Please see the Extended 

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Responses to Comments for NMP Work Plan Risk Assessment

because the derivation of the emission rates 

was done incorrectly. More specifically, the 

panelist suggested that the parameters used 

for the emission rate modeling reported in 

Table D-3 of the NMP Risk Assessment 

document are incorrect and cannot be used to 

obtain the results shown in Figure D-5 and 

that the k value for the first exponential is 

unrealistically high. 

Response to this comment, titled “NMP Memo FINAL – Response to 

Armstrong Comments 18Feb2014” included in the public docket (Docket: 

EPA-HQ-OPPT-2012-0725).

46 A peer review panelist recommended that the 

modeling for the bathtub stripping scenario 

be based on either a different modeling 

equation than that in the MCCEM model, or 

on emission rates from appropriate lab scale 

experiments. This recommendation is based 

on the following: the MCCEM model that is 

properly fitted to MRI emission data should be 

appropriate for flat surface scraping, but the 

commenter states that a thin saturated NMP 

vapor layer, i.e., “backpressure,” due to the 

concave shape of bathtub is not adequately 

represented by the flat surfaces in the MRI 

chamber test, so it is likely that the MCCEM 

modeling significantly overestimates the NMP 

concentration in air.

EPA/OPPT acknowledges that there is uncertainty about the application of 

the emission factors derived from the flat panels in the MRI chamber test 

to the concave surface of a bathtub. However, it is not clear that a 

backpressure condition would occur or have a significant impact, for the 

following reasons: 1) the majority of the paint stripping time for a tub 

(64%) consists of user brush-on and scraping of the stripper, which would 

create air turbulence disrupting conditions necessary for backpressure, 2) 

MCCEM predicts that NMP concentrations in the source cloud would be at 

the saturation concentration for almost the entire stripping time, so a 

small decrease in mass-transfer rate might delay reaching the saturation 

concentration but have a negligible impact after saturation was reached, 

3) the source cloud assumption is based on estimates of room airflow 

velocities. If the surface velocities are expected to be low, such that a 

boundary layer inhibits mass transfer, this would imply that the sourcecloud ventilation would also be lower, tending to increase the NMP 

concentrations in the source cloud. 

The uncertainties in these parameters may very well dwarf the potential 

impacts of low air velocities and subsequent backpressure layer 

formation. Monitoring of NMP concentrations in targeted laboratory or 

field studies would best address the potential impact of a backpressure 

layer, but are beyond the scope of this assessment.

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Responses to Comments for NMP Work Plan Risk Assessment

47 A public commenter noted that the sensitivity 

analyses are presented for model predictions 

for 1-hour and 24-hour averages. Because 

neither of these time points is used in the risk 

assessment, EPA/OPPT should present 

sensitivity results corresponding to the 4-hour 

predictions used in the risk assessment.

The updated risk assessment relies on PBPK modeling that uses 24 hours 

of indoor air data generated by the exposure model (MCCEM). For the 

workplace scenario the internal dose metric used is the (average) 24-hour 

blood AUC and for the consumer scenarios the internal dose metric used 

is the peak blood concentration (Cmax). Therefore the sensitivity analysis 

was performed for the 1 hour and 24 hour averages. Sensitivity of the 

1 hour average was also evaluated since it is more representative of peak 

blood levels for residential uses.

48 A peer reviewer recommended a correction to 

the near field (source cloud) assessment for 

bathtub scenario and further recommended 

that all the inhalation modeling utilize the 

near field approach; also, that there be an 

expanded discussion of the MCCEM model.

The source cloud (near field) mathematical error and associated exposure 

estimates have been corrected for the bathtub stripping scenario; 

however, near field modeling was not considered as appropriate in the 

workshop consumer exposure scenarios, so this was not done. Please see 

extensive discussion in Appendix E, section E-3.

49 A peer review panelist commented that the 

bathtub scenario did not consider use of an 

exhaust fan.

As stated in the Description of Exposure Scenarios portion of Section 

2.2.1.2 of the risk assessment, the bathtub stripping scenarios were 

developed to simulate use conditions similar to those reported in a 

CDC/NIOSH occupational-exposure case for a DCM-containing paint 

stripper (CDC, 2012a, 2012b); an exhaust fan was not used in that case. 

The designation of no fan use for these scenarios is also presented in 

Table 2-5.

50 A public commenter urged EPA/OPPT to not 

rely on saturated vapor concentrations for the 

worst case inhalation scenario, because 

saturation typically only occurs under 

experimental conditions. Instead, assume the 

EPA 1994b study’s monitoring data as worst 

case.

The upper end to bounding bathtub stripping exposures are from a 

scenario that replicates an actual CDC/NIOSH case for DCM use. The 

greater stripper amount and lower ventilation and room of use volume for 

the bathtub scenario than the chamber test make it a more conservative 

scenario. The two different bathtub scenarios reflect changes in plausible 

humidity levels, which have a substantial effect on NMP volatilization, so 

should be in the assessment. If left out, the predicted exposure levels 

would have been even higher.

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Responses to Comments for NMP Work Plan Risk Assessment

51 A public commenter noted that NMP-based 

products are often formulated with other 

organic solvents that could increase dermal 

absorption; this should be discussed.

The revised risk assessment discusses this uncertainty in the dermal 

absorption rate (see Section 4.3) but does not attempt to quantitatively 

estimate the effect of different solvents on skin absorption of NMP.

52 A public commenter suggested discussion of

use of various other NMP-based products, 

e.g., graffiti removers, by custodial staff and 

public works employees. 

The assessment of risks to workers associated with the use of graffiti 

removers was included in this risk assessment. 

53 A peer review panelist and public commenters 

suggested that the assessment be revised to 

address inhalation and dermal exposures as a 

combined total dose.

The revised assessment includes PBPK modeling of the combined 

inhalation, dermal and vapor-through-skin exposures.

54 Public commenters recommended that 

EPA/OPPT should attempt to estimate oral 

exposure to NMP in pesticides used for food 

crops, because NMP is allowed unregulated in 

pesticides applied to food.

Estimating and adding this exposure is beyond the scope of this

assessment.

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Responses to Comments for NMP Work Plan Risk Assessment

Hazard/Dose-Response Assessment

Charge Question 5-1: Please comment on EPA’s use of the identified developmental studies and POD to assess acute inhalation 

exposures to NMP use in paint strippers. As part of the review, provide your input on the appropriateness of using an acute POD 

based on fetal body weight decrements that were observed in the presence of maternal body weight decrements following 

exposure to NMP during gestational days 6 to 13. Please comment on whether the maternal no-observed-adverse-effect level 

(NOAEL) of 122 mg/m3 (Saillenfait et al. 2001, 2003) should be analyzed in the MOE calculations along with the fetal body weigh 

decrements. Please specify any other endpoints that should be considered for the hazard evaluation of acute inhalation exposures. 

Please provide relevant data or documentation and rationale for including other studies and endpoints for consideration. 

Charge Question 6-1: Please comment on EPA’s use of the identified developmental studies and POD to assess chronic inhalation 

exposures. As part of the review, please comment on the appropriateness of using a developmental toxicity endpoint and the 

identified effects to assess chronic inhalation exposures to NMP-based paint strippers. Please specify any other toxicological 

endpoints that should be considered for the hazard evaluation of acute inhalation exposures. Also, please provide relevant data or 

documentation and rationale for including other studies and endpoints for consideration.

Charge Question 7-1: Please comment on EPA’s use of the identified developmental study and POD to assess acute and chronic 

dermal exposures. As part of the review, provide your input on the appropriateness of using a developmental toxicity endpoint and 

the identified effects to assess acute and chronic dermal exposures to NMP-based strippers. Please specify any other endpoints that 

should be considered for the hazard of acute or chronic dermal exposures. Please provide relevant data or documentation and 

rationale for including other studies and endpoints for consideration.

# Summary of Peer Review and Public 

Comments for Specific Issues Related to 

Charge Questions 1-1 and 1-2

EPA/OPPT Response

55 A number of public commenters and peer 

review panelists suggested studies that 

should be considered in the risk assessment.

A public commenter suggested review of 

two additional studies that focused on male 

and female reproductive toxicity in rats.

EPA/OPPT incorporated the results of an expanded review of studies identified 

by commenters. The final risk assessment includes a discussion of studies that 

identify male and female reproductive effects. See section 3.1.2.

56 A peer review panelist indicated that human 

ethics reviews should be conducted for the 

EPA/OPPT completed a human ethics review for each intentional dosing study 

used to support the PBPK model. The reviews are available in Appendix G.

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Responses to Comments for NMP Work Plan Risk Assessment

intentional dosing human studies used to 

support PBPK model. 

57 Several commenters requested additional 

information on the determination that 

reproductive toxicity was not the basis for 

the risk assessment. It was also noted that 

the draft report relied heavily and almost

exclusively on a 2007 OECD SIDS Initial

Assessment Report for NMP toxicological

information. It did not cite or discuss

different scientific opinions by EPA/OPPT,

Cal/EPA, WHO and others related to 

information in the OECD report.

The final risk assessment incorporates information based on multiple 

toxicological reviews and includes consideration of a number of additional 

toxicological studies. In addition, the final risk assessment describes a range of 

hazard concerns, including reproductive toxicity, neurotoxicity and liver and 

kidney toxicity and explains the rationale for the selection of developmental 

endpoints as the basis for risk calculations.

58 EPA/OPPT should calculate how much 

parent compound and metabolites are 

remaining in the body after 24 hr exposure.

The metabolism of NMP is considered a detoxification and NMP metabolites 

are not known to have significant toxicity. NMP is rapidly metabolized in vivo

with a half-life of approximately 2.5 hours. Therefore NMP is not expected to 

bioaccumulate. Some NMP metabolites may bioaccumulate in an individual 

repeatedly exposed to high doses but they are not expected to have adverse 

health effects.

59 A public commenter suggested that 

EPA/OPPT’s use of dermal extrapolation 

methods (from rat to human data) was 

inappropriate. Specifically that EPA/OPPT 

did not take into account the innate 

difference in absorption rate of substances 

across rodent skin versus human skin, as 

described in the EPA Dermal Exposure 

Assessment guidelines (Interim Report) 

(EPA, 1992).

EPA/OPPT is now using PBPK modeling for the interspecies extrapolation.

Specifically the rat and human dermal absorption parameters were obtained 

from species-specific pharmacokinetic experiments, so do represent the 

species-specific absorption rates. The human parameters also distinguish 

absorption for 100% vs. diluted NMP, which were observed to differ.

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Responses to Comments for NMP Work Plan Risk Assessment

60 Several commenters suggested using 

benchmark dose modeling for deriving the 

POD.

Several public commenters asserted that the 

minimal effects on fetal body weight do not 

warrant use of BMR of 5% and instead 

recommended the use of a BMR of 1 SD.

One public commenter recommended the 

use of a BMR of 1SD (approximately 7.7%)

for fetal BW effects based on the combined

control data reported by the Saillenfait 

studies (Saillenfait et al., 2002; Saillenfait et 

al., 2003) where the mean and standard 

deviation (SD) are 5.70 g and 0.44, 

respectively.

A peer review panelist recommended the 

use of a BMR of 1%

EPA agreed that the BMD approach was most appropriate for derivation of the 

POD, when the data supported this approach.

A BMR of 5% decreased fetal body weight was used because in the absence of 

knowledge as to what level of response to consider adverse, it has been 

suggested to consider a 5% change relative to the control mean for 

developmental endpoints (Kavlock et al., 1995). A BMR of 1% was used for 

increased resorptions/fetal mortality to address the relative severity of this 

endpoint (EPA, 2012). BMD modeling results for a BMR of 1 SD are presented 

for comparison in the BMD analysis Appendix H.

A BMR of 1% for increased resorptions/fetal mortality was used to address the 

relative severity of this endpoint (EPA, 2012).

62 A peer review panelist suggested that the 

selection of an acute POD based on a 

developmental toxicity study is overly 

conservative. Citing Van Raaij et al. (2003), 

the commenter suggested that the average 

NOAEL from repeat dose studies is 3.4 times 

higher and the average LOAEL is 4.76-fold 

higher in the single (acute) studies. The 

commenter recommends that this analysis 

supports the use of 2- 4-fold factor in going 

from the rat developmental studies to an 

The revised risk assessment considers a different set of endpoints for the 

calculation of risks associated with acute exposures. Specifically, EPA/OPPT 

focused on increased resorptions, fetal mortality and skeletal malformations, 

as these endpoints are more plausibly associated with short-term (acute) 

exposure periods (Van Raaij et al., 2003). 

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Responses to Comments for NMP Work Plan Risk Assessment

acute POD rather than the conservative no 

adjustment approach.

63 A peer review panelist questioned Selection 

of BMD models, noting that the model with 

the lowest AIC was not always selected.

The benchmark dose modeling has been revised for the selection of PODs for 

both chronic and acute exposures. Of the models that fit the data adequately 

(chi-square goodness of fit p-value) and when the BMD:BMDL ratio was less 

than 3 for all adequate models, the best fitting model was selected based on 

the model with the lowest AIC value. 

64 A number of commenters questioned the 

basis for the calculation of PODs used in the 

draft risk assessment:

A public commenter suggested that 

decrements in fetal body weight should not 

be used to set the POD for acute exposure 

risk calculations.

A public commenter recommended the use 

of a quantitative risk assessment approach

to identify hazard valuesfor NMP that is 

consistent with the approach used by

Cal/EPA Limit. 

A public commenter criticized the use of the 

Becci et al. (1982) study for the derivation of 

the POD, indicating that in the study the rats 

were dermally exposed to NMP during 

gestation days (GD) 6-15, an exposure 

duration that is inconsistent with the longer 

exposure period (GDs 6-20) of current 

guidelines and does not permit an adequate 

In the revised risk assessment, EPA/OPPT considered a wider selection of 

studies and analyses than in the original assessment. The selection of studies 

for the basis of the risk calculations considered the appropriateness of 

endpoints for the different exposure durations and scenarios and the 

consistency of outcome among the different studies. 

The revised risk assessment for chronic exposure is based on decreased fetal 

body weights, observed in the DuPont (1990), Saillenfait et al. (2002), 

Saillenfait et al. (2003) and Becci et al. (1982). The POD is based on the BMR of 

5% from Saillenfait et al. (2003), which EPA/OPPT judged to be the most 

sensitive and robust of the studies. 

The revised risk assessment for acute exposure is based on fetal resorptions, 

observed in Saillenfait et al. (2002), Saillenfait et al. (2003) and Becci et al. 

(1982). The POD is based on the BMR of 1% from the combined Saillenfait et 

al. (2002) and (Saillenfait et al. (2003)), which resulted in a similar effect level, 

that EPA/OPPT judged to be the most sensitive and robust of the studies. 

While maternal stress has been noted in some studies, EPA guidance (EPA, 

1991) precludes using maternal stress to discount fetal effects.

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Responses to Comments for NMP Work Plan Risk Assessment

characterization of the developmental 

endpoints.

A public commenter asserted that 

incomplete vertebral ossification (Becci et 

al., 1982) is an inappropriate endpoint for 

repeated dose toxicity. EPA/OPPT should 

instead use fetal body weight reported by

Saillenfait et al. (Saillenfait et al., 2002; 

Saillenfait et al., 2003).

A public commenter suggested that the

acute BMDL05 for skeletal malformations

should be based on the pooled Saillenfait

(2002; 2003) data, without the result at

the highest internal dose where extreme

toxicity was noted.

A public commenter recommended against 

pooling the fetal BW of Saillenfait and Becci 

due to maternal stress factors. EPA should 

use the inhalation fetal BW as a health 

protective POD

65 A peer reviewer noted the absence of 

epidemiological data and asked if 

epidemiological data were included in the 

literature search.

A single case report was identified (Solomon et al., 1996). The study was 

included in the hazard identification and weight of evidence discussions.

66 Several commenters noted errors in the 

exposure section of the draft risk 

assessment:

a) This sentence is removed and a more informative description of absorption 

via dermal and inhalation exposures is given in section 3.2.2.

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Responses to Comments for NMP Work Plan Risk Assessment

a) pp. 44-46: Statement that dermal 

exposure is “(≤100 %) depending on 

conditions” is not very informative. The 

contrast with the 40-60 percent range given 

for inhalation exposures seems to imply that 

dermal is more efficient than inhalation 

exposure in leading to absorption. This 

implication should be removed.

b) p. 151: Caption to Figure F2 refers to data 

in Table D-1 when it should be F-1.

c) pp.152-3 Captions in the figures refer to 

dose in mg/m3 but dose is actually stated in 

ppm.

d) The plots show results of exponential 

models 2 and 3, but the AICs for the Hill and 

linear models are both listed as lower than 

these in Table F-2. The BMCL for the Hill 

model, with the lowest AIC is listed as

130.19—much less than the 300-odd mg/m3

shown for the linear and exponential models 

2 and 3 that appear to have been chosen as 

the basis of the BMD determination.

e) Also, the final paragraph on page 45, 

reproduced here, seems incomplete: “It is 

interesting to note that there is evidence to 

support that absorption and effect are very 

similar by oral and dermal routes. Oral LD50 

b) Figure F-2 – BMD Appendix plot of mean response by dose with fitted curve 

has been replaced by new BMD modeling (Appendix H).

c) The captions in BMD modeling have been updated based on internal dose 

metrics with the appropriate units.

d) The basis of BMD determinations for the updated BMD modeling are 

explained in the BMD Analysis Appendix H.

e) The sentence comparing LD50 values across routes was removed. This 

section was re-written.

f) All instances of the word rationale are now correctly spelled.

g) The table of data in the BMD appendix H (Table H-1) was updated to 

correctly indicate the number refers to the number of litters examined and not 

number of fetuses.

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Responses to Comments for NMP Work Plan Risk Assessment

values were 4,150, 3,914 and 3,605 mg/kg in 

rats (Ansell and Fowler, 1988; Bartsch et al., 

1976; BASF AG, 1963; as cited in OECD,

2007, respectively) and 7,725 and 4,050 

mg/kg in mice (Bartsch et al., 1976; 

Weisbrod and Seyring, 1980; Weisbrod, 

1981; as cited in OECD, 2007) to dermal 

dose levels.”

f) And on page 49, in this heading, “Rational 

for Study and Endpoint Selection for Acute 

PODs.” “Rational” should be “Rationale.”

g) In Table F-1, the column heading refers to 

“fetuses,” but the data are actually numbers 

of litters examined.

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Responses to Comments for NMP Work Plan Risk Assessment

Hazard Assessment: Use of PBPK Model

Charge Question 8-1: Please review the model and comment on the Poet et al. (2010) analysis as well as EPA’s evaluation of the 

revised model. Please comment on whether the model is clearly and transparently described and technically and scientifically 

adequate for supporting OPPT’s work plan risk assessment for NMP-based paint strippers. Specifically, please address the structure 

of the PBPK model, parameter calibration and model predictions of the available in vivo data.

Charge Question 8-2: Please comment on the appropriateness of using the selected dose metric for chronic inhalation and dermal 

exposures based on the maternal blood concentration of the parent compound expressed as the area under the curve (AUC). Please 

comment on whether the maternal dose metric is a reasonable surrogate for a fetal dose metric in the absence of fetal metabolism 

data.

Charge Question 8-3: Please comment on whether the selected dose metric for acute inhalation and dermal exposures should be 

reported as the maternal blood AUC of the parent compound and/or the maximum concentration (Cmax) in maternal blood.

Charge Question 8-4: Please comment on whether the BMD analysis should be conducted with the PBPK-derived internal doses or 

the external air concentrations (standard approach) reported in Saillenfait et al. 2003. Please specify whether the BMD calculations 

(Appendix F of draft risk assessment) were appropriately conducted and documented.

# Summary of Peer Review and 

Public Comments for Specific 

Issues Related to Charge 

Questions 8-1 through 8-4

EPA/OPPT Response

67 Several reviewers suggest that 

glove use and effectiveness of 

gloves should be discussed. 

The PBPK model simulates scenarios where gloves are or are not used. EPA/OPPT 

evaluated a range of exposed surface area for brush-on application, 460, 665 and 890

cm2, to represent the palm-side of two hands, the palm size of two hands and part of the 

back of hand, and both sides of both hands, respectively. EPA/OPPT assumed that the 

surface area was reduced by the glove effectiveness factor of 90% when appropriate 

gloves were used. The remaining (10%) exposed surface area is an approximation that is 

intended to account for accidental exposures outside of the hands, glove failure and 

ineffectual gloves. A nominal surface area of 1 cm2 representing a finger-tip was assumed 

to become wetted for spray-on application. Again this is reduced by 90% when gloves are 

used.

68 A peer reviewer noted in one 

human exposure study (Bader and 

Van Thiel, 2006) the measured 

Evaluation of individual subject data with the PBPK model found decreased amounts of 

NMP in blood and its metabolite 5HNMP in blood and urine. If metabolism had been 

induced, the amount of 5HNMP in blood and urine would have increased. Further, this 

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Responses to Comments for NMP Work Plan Risk Assessment

NMP blood level AUCs relative to 

exposure concentrations were 

decreased, which might suggest 

induction of metabolism. 

change only occurred in 4 of the 8 subjects. This evidence is not supportive of the 

proposed metabolic induction and may suggest differences in absorption. The PBPK 

model was refit to the low-concentration data to avoid under-estimating internal doses 

and adequately fits the data in to multiple data sets shown in the PBPK Appendix I.

69 A peer reviewer expressed 

concern about the adequacy of 

using the well mixed assumption 

for representing absorption of 

NMP in the skin during after 

dermal exposures.

The PBPK model was re-fit to the human dermal data sets. Specifically, the model has 

now been fit separately to data for neat vs. 50% diluted NMP, which exhibit different 

absorption efficiencies. Unfortunately blood levels of NMP were not measured during the 

human dermal studies, but blood and urinary 5-HNMP was. Fits to these data, shown in 

the PBPK Appendix I, are considered adequate and do not justify changes in the model 

structure. For NMP the clearance rate is more rate-limiting than absorption, so a detailed 

dermal model structure is not as important as for other chemicals. 

70 Peer reviewers noted the method 

of calculating dermal absorption 

for workplace and residential 

exposures were different.

The PBPK dermal model is now applied in the same way to both workplace and consumer 

exposures.

71 PBPK model:

Legacy code in model

A clean revised version of the PBPK model is included in the public docket (Docket: EPAHQ-OPPT-2012-0725).

72 Peer reviewers noted absorption 

of 50% diluted NMP was less than 

neat NMP and suggested 

evaluation of the dermal 

absorption model with data from 

Akrill et al., 2002.

The PBPK model the permeability constant has now been fit separately to the neat and 

50% diluted NMP blood and urine time course data (Akesson et al., 2004) since NMP 

diluted in water has reduced dermal absorption. Two other studies Akrill et al. 2002 and 

Kenner et al., 2007 have dermal exposures to NMP and measured total 5HNMP in urine. 

Comparison of these data with the PBPK model is discussed in the PBPK Appendix I. The 

mechanism of the nonlinearity in absorption is unknown there is not sufficient 

information to describe absorption across all possible dilution levels. The permeability for 

neat absorption was used to workplace applications involving undiluted NMP. The 

permeability estimated from 50% diluted NMP was used for residential and workplace 

applications with diluted NMP, which ranged from 25-53% concentration (i.e., 75-47% 

dilution).

73 Re-running residential exposures 

for MOEs

The internal dose estimates and MOEs have been recalculated with the updated PBPK 

models.

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74 A peer reviewer suggested the 

assessment should more clearly 

explain the dermal absorption 

model and rate constants.

The PBPK model has dermal absorption of liquid and vapor NMP which both were fit to 

data from human exposure studies and the description of the PBPK dermal model was 

improved and presented in the PBPK Appendix I.

75 A peer reviewer suggested that it 

is unclear that PBPK model 

predictions are adequate for the 

dermal exposure route

The PBPK model has dermal absorption of liquid and vapor NMP which both were fit to 

data from human exposure studies and the model fits of the EPA/OPPT modified PBPK 

model are presented in the PBPK Appendix I. (See also, response to question #76.)

76 A peer reviewer stated they could 

not determine that the PBPK 

model performs adequately for 

dermal vapor and inhalation 

exposures

The model fits of the EPA/OPPT modified PBPK model are adequate for dermal vapor and 

inhalation exposures and are presented in the PBPK Appendix I. Data to fully characterize 

the extent to which normal clothing acts as a barrier to NMP dermal vapor absorption are 

not available, hence this is an uncertainty in the modeling that cannot be resolved. 

However it is discussed in the PBPK Appendix I and since the human model is calibrated 

against whole-body exposures, we believe that vapor absorption and uptake are 

appropriately characterized. The development and application of the internal dose 

metrics are described in the PBPK Appendix I and the human health assessment section 

3.2.2.

77 The peer reviewers agreed with 

the choice of the AUC as the 

internal dose metric for fetal BW 

PODs.

The NMP AUC is the chosen dose metric for evaluating reduced fetal body weight which is 

the most sensitive, consistent effect in repeated dose studies. The uncertainty is selection 

of dose metrics is discussed further in section 4.3.3.

78 The peer reviewers supported the 

choice of BMD analysis with 

internal doses from the PBPK 

model rather than the external,

administered concentrations.

When sufficient information was available BMD analysis was applied for calculation of 

PODs in rats. The PODs in rats were converted to internal doses with the PBPK model. In 

studies with sufficient similarities the exposures were combined across routes using 

internal doses to provide a more extensive characterization of the dose response curve. 

MOEs were calculated by comparing internal doses in rats and humans this allowed MOEs 

to be calculated for combined inhalation and dermal exposures in human exposure 

scenarios. 

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Responses to Comments for NMP Work Plan Risk Assessment

Risk Assessment

Charge Question 9-1: Please comment on the assumptions, strengths and weaknesses of the MOE approaches used to estimate the 

acute inhalation risks to consumers of NMP-based products and to bystanders/non-users (e.g., children, women of childbearing 

age), including the standard MOE approach presented in the document as well as MOEs calculated with PBPK-derived internal doses 

instead of HECs. Please comment on the selection of composite uncertainty factors that were used as benchmark MOEs to 

determine the acute inhalation risks. 

Charge Question 9-2: Please comment on the assumptions, strengths and weaknesses of the MOE approaches used to estimate the 

chronic inhalation risks to workers using NMP-based products, including the standard MOE approach presented in the document as 

well as MOEs calculated with PBPK-derived internal doses instead of HECs. Please also comment on the selection of composite 

uncertainty factors that were used as benchmark MOEs to determine the chronic inhalation risks.

Charge Question 9-3: Please comment on the assumptions, strengths and weaknesses of the MOE approaches used to estimate the 

acute dermal risks to consumers of NMP-based products, including the standard MOE approach presented in the document as well 

as MOEs calculated with PBPK-derived internal doses instead of HEDs. Please also comment on the selection of composite 

uncertainty factors that were used as benchmark MOEs to determine the acute dermal risks. 

Charge Question 9-4: Please comment on the assumptions, strengths and weaknesses of the MOE approaches used to estimate the 

chronic dermal risks to workers of NMP-based products, including the standard MOE approach presented in the document as well 

as MOEs calculated with PBPK-derived internal doses instead of HEDs. Please also comment on the selection of composite 

uncertainty factors that were used as benchmark MOEs to determine the chronic dermal risks.

Charge Question 9-4: Please comment on whether the risk assessment document has adequately described the uncertainties and 

data limitations in the methodology used to assess risks to allow the EPA to reduce risks to human health from NMP. Please 

comment on whether this information is presented in a transparent manner.

# Summary of Peer Review and Public 

Comments for Specific Issues Related to 

Charge Questions 1-1 and 1-2

EPA/OPPT Response

79 A public commenter suggested that the 

Margins of Exposure (MOE) for 

occupational and residential exposure

scenarios should be calculated by summing

the MOE for the inhalation exposure and

the MOE for the pooled exposures from all 

other relevant routes.

The MOEs for occupational and consumer scenarios are calculated for the 

combined inhalation and dermal exposures. The assessment was updated to 

include a description of how the MOEs are calculated in Section 1.2.4

Conceptual Model and shown in Figure 1-3.

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Responses to Comments for NMP Work Plan Risk Assessment

80 A peer review panelist agreed that the MOE 

of 30 appears to be appropriate, but 

indicated that there has not been a 

comprehensive data gap analysis to 

determine whether substantial uncertainties 

exist in the database. For example and most 

relevant to the acute scenario, we have no 

data regarding acute irritation or CNS 

effects. The workplace literature on NMP 

may give some idea of whether it elicits an 

acute response and at what level. 

Laboratory animals cannot tell the 

investigator when they have a headache. 

The low odor threshold relative to the 

modeled concentrations suggest that 

applicators and residential bystanders will 

detect the NMP odor which in some 

individuals may trigger an irritation 

response. These considerations can be part 

of a data gap analysis. 

The target MOE of 30 will be retained and the justification has been provided 

in section 4.1.

EPA/OPPT agrees that there are uncertainties due to data gaps. There were no 

reports of adverse effects, such as headaches or neurotoxicity, following the 

intentional human exposures, reviewed in Appendix G. Laboratory animal 

studies identified effects that might be suggestive of neurotoxicity, however 

the data are limited. A discussion of this uncertainty was added to section 

4.3.3.

81 A peer review panelist suggested that 

EPA/OPPT improve risk communication.

Quantitative probabilistic characterization 

of variability or uncertainty is not necessary 

in every risk assessment and in the current 

case, given the range of exposure and 

modeling scenarios run, it is likely that a 

reasonable array of different risks have 

been presented. This includes different user 

behaviors and different levels of protection 

The revised risk assessment now identifies which scenarios and behaviors 

create the greatest risks:

For occupational scenarios, the variables that were associated with elevated 

risks include:

1. Longer duration of worker contact time(4 or more hours)

2. Not using appropriate gloves

3. Higher concentration of NMP in the product. 

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Responses to Comments for NMP Work Plan Risk Assessment

(gloves on or off, respiratory protection or 

not). Presenting the results of MOE analyses 

on all these exposure and modeling options 

could result in a potentially confusing array 

of risks. Therefore, it will be important for 

EPA/OPPT to communicate these clearly 

and perhaps sort thru the results to 

highlight 1) what scenarios and behaviors 

create the greatest risk; 2) what may 

represent the most likely risks; 3) what are 

the greatest contributors to risk (e.g., 

inhalation vs. dermal vapor vs. dermal liquid 

contact).

Dermal exposures without gloves produces the highest internal doses, hence 

drive risks and use of appropriate gloves will greatly reduce exposures in the 

occupational environment.

Inhalation absorption is the second largest contributor to internal dose. Clearly 

this can be mitigated by use of a respirator and/or good ventilation.

While dermal absorption of NMP vapor through the skin also contributes 

significantly, especially in the absence of liquid contact, the risks from this 

pathway alone are minimal.

82 Given the importance of dermal exposure, 

the lack of chronic toxicology studies by the 

dermal route represents a data gap but this 

may be considered minor relative to the 

availability of other types of dermal and 

inhalation testing.

Uncertainties regarding dermal exposure are addressed in 4.3. 

83 Discussion of how assumptions, parameters, 

etc. lead to the under or over-estimation of 

risks

USEPA/OPPT can consider an over/under 

approach in which best professional 

judgment is used to state whether a given 

uncertainty is likely a source of overestimation, under-estimation or unclear 

(toxicology data gaps). This could help the 

reader understand whether overall, the 

assumptions and uncertainties tend to go in 

EPA/OPPT incorporated a more detailed elucidation of the consequences of 

the assumptions used and decisions made and how they affect the risk 

assessment. See the “Key sources of Uncertainty and Data Limitations” section 

4.3.

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Responses to Comments for NMP Work Plan Risk Assessment

one direction or the other. Another 

approach is to identify the risk drivers (e.g., 

time spent actually doing the stripping) and 

describing the range of values used vs. the 

range of all values possible and the 

uncertainty in the underlying data.

84 Document did not fully address all of the 

uncertainties:

a) Potential for the bystander exposure to 

be a young child, with attendant greater skin 

surface area, respiratory rate and slower 

NMP metabolism. 

b) Potential toxicological data gaps or 

uncertainties presented by the underlying 

data as described in preceding sections. For 

example, the acute neurotoxic potential of 

NMP is not discussed. Given the relatively 

high concentrations simulated, much higher 

than the NMP odor threshold, it is possible 

that there could be acute irritation and 

neurological effects. This possibility should 

be considered from the perspective of 

surveys and reports from the workplace and 

any other studies or clinical reports. 

c) The rationale for the extrapolation

between gestational developmental data to 

acute exposure scenarios could be improved 

a) In the final risk assessment, EPA included calculations based on a young 

child near to the consumer user. This was described in section 4.1.

b) Revisions were made the uncertainties section, including a description of 

uncertainties associated with neurotoxicity. Also, although NMP is reported to 

be irritating, there were no reports of irritating effects in the intentional 

human studies, used for validating the PBPK model and described in appendix 

G.

c) The revised risk assessment includes a more detailed description of the 

rationale for the use of developmental toxicity studies in the evaluation and 

selection of key endpoints for acute exposure scenarios (Section 3.1.3.4) and 

the van Raiij reference and others are cited.

d) This comment is no longer applicable because contact/per day was not used 

in the harmonized approach to exposure assessment.

e) EPA/OPPT has broadened the inhalation data used in the occupational 

exposure assessment and created two assessed populations in the 

assessment. These populations are expected to cover the entirety of 

categories of workers who may be exposed to NMP-based strippers and NMPbased graffiti remover products. Therefore, the use of the broader data 

negates the need to consider modeling of worker inhalation exposures.

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Responses to Comments for NMP Work Plan Risk Assessment

and the van Raiij reference is an excellent 

resource for this purpose.

d) EPA/OPPT identifies one episode of 

dermal contact/day as an uncertainty. It 

would seem that the uncertainty of this 

assumption could be addressed in more 

depth. 

e) The air concentrations assumed for 

workers are based upon a limited amount of 

data for outdoor graffiti removal workers. 

These air estimates are considerably lower 

than the air estimates for the residential 

scenario, even the non-user. This 

discrepancy may be due to the 

indoor/outdoor exposure differences. 

However, there would appear to be many 

workers that would be handling NMP 

indoors. Thus, the use of graffiti workers as 

the occupational basis would present a 

rather large uncertainty and potential for 

underestimation.

85 Uncertainties in the assumption of one 

exposure per day to the hands (both 

occupational and consumer exposure 

assessments)

The harmonized consumer and occupational assessments assume continuous 

exposure to NMP when working with the paint stripper. The occupational 

dermal exposure is assumed to be continuous for the duration of the work 

period (section 2.1.1.3). For consumer dermal exposure use patterns reported 

in the literature were used (section 2.2.1.1). 

86 A peer review panelist suggested that the 

draft risk assessment contained misleading 

conclusions about risks to consumers. 

The final risk assessment, which refined the exposure assessment by 

incorporating a PBPK model, and included a range of exposure durations, and 

product concentrations. The outcome of the risk assessment demonstrates 

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Responses to Comments for NMP Work Plan Risk Assessment

Specifically, the conclusion on page 64 state

that “Consumers may have potential risks of 

concern from inhalation exposure if 

exposed for more than 4 hours at lower 

ventilation rates.” This is misleading 

because a) MOEs were not calculated for <4 

hours inhalation exposure, so it should be 

made clear that this doesn’t imply that 

shorter duration exposures are safe; and b) 

It’s a bit ambiguous to say the risk is “at 

lower ventilation rates.” The MOE for 

scenario 4 (spray application, central 

tendency scenario) was <30 and this was at 

the higher ventilation rate modeled. 

Scenario 2 also had an MOE <30 for the user

and was at the higher ventilation rate. 

Furthermore, every scenario except 7 & 8 

assumed open windows (relatively good 

ventilation), whereas there is evidence 

suggesting that a substantial proportion of 

users do not open the windows when using 

paint strippers (Riley 2001). So, the message 

should not be that risk occurs at lower 

ventilation rates, since that implies that risk 

is only at low ventilation rates.

that duration of use and product concentration are both important drivers of 

risk. Short term (e.g., 1-2 hour) exposures to products with low concentrations 

of NMP (e.g., 25% or less) result in no risks. However, the use of higher 

concentration products that can readily be purchased by both consumers and 

workers may result in risks. The risk assessment was revised throughout to 

more clearly explain a number of considerations, including that dermal 

exposure is the more important exposure route, and that use of appropriate 

gloves would significantly reduce dermal exposures and risks. 

87 A peer review panelist noted that the 

potential for children to receive a higher 

dose due to increased surface area and 

respiratory rate per body weight, as well as 

the potential for slower metabolism of 

parent compound, has not been evaluated.

While a child’s metabolic capacity is developing in the first months of life, the 

data we’ve reviewed indicate that it’s at essentially adult levels (consistent 

with allometric scaling) by 1 year of age if not sooner. Simulations were run for 

a 9-kg, 75 cm tall person which is the approximate weight and height for a 1-

year-old girl from the exposure factors handbook Air concentrations for the 

“rest of house” consumer scenarios were used as inputs. While children have 

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Responses to Comments for NMP Work Plan Risk Assessment

faster respiration/BW and higher skin SA/BW, once they are metabolic 

competent that metabolism is also expected to be relatively faster based on 

allometric scaling. The resulting simulations predict that while peak 

concentrations in the child would be 22-34% higher than a 74 kg adult woman, 

the blood AUC would actually be 0.6 to 2.4% lower than the adult.

While these simulations indicate only moderate variation in internal dose 

between children and adults, it must be kept in mind that the minimum MOE 

includes a factor of 10 for intra-human variability which is specifically intended 

to protect sensitive populations. It is generally assumed that this factor is a 

combination of a 3-fold factor for PK variability and 3-fold for PD. The 

simulations above indicate that absent reduced metabolic capability, 

children’s internal doses are well within this 3-fold factor, hence it is unlikely 

that even the youngest infants would exceed that factor. Further, the 

simulations for rest-of-house residential exposures showed a MOE that well 

exceeded the benchmark MOE.

In addition, the MOEs in this assessment are based on fetal endpoints. 

Toxicological endpoints that may be relevant to children (e.g., systemic 

effects) tend to occur in laboratory animals at higher doses.

Considering that residential use is only expected to occur for a single day at a 

time and the large MOEs estimated for nonusers, the effect of this exposure 

on the developing child is not expected to be of concern. The greatest acute 

risk is to the fetus and impacts on growth would only be expected for more 

long-term exposures.

88 A public commenter suggested the use of 

the OSHA PEL to evaluate risks.

The Occupational Safety and Health Administration (OSHA) has not established 

regulatory exposure limits for NMP.

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Responses to Comments for NMP Work Plan Risk Assessment

89 A public commenter questioned the decision 

to exclude acute exposure risk estimates for 

workers and occupational bystanders.

EPA/OPPT included in the final report the assessment of acute exposure risks 

for workers and nearby non-users.

90 Peer review panel members suggested that 

the uncertainties and data limitations 

discussion for worker exposures could be

improved, particularly related to directional 

impact on risk and making the discussion 

more complete and robust. Also please add 

more consideration of uncertainties 

regarding glove use.

EPA/OPPT determined gaps in the discussion and completed improvements in 

section 4.3.1. The discussion was made more complete and robust, although 

directional impacts on risk could not be determined for any of the 

uncertainties so could not be included. Glove use information was also made 

more robust and included in Appendix D.

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