1

Charge Questions for the Peer Review of the draft Workplan Risk Assessment 

for N-Methylpyrrolidone (NMP)

August 2013

OPPT focused its risk assessment on the use of NMP in paint stripping. There are human health concerns 

for developmental effects related to NMP use-application. Both inhalation and dermal exposures were 

evaluated and risk estimates were calculated for consumers and workers using NMP-based paint strippers. 

Risks also were estimated for individuals physically near the residential user, but not using the NMPbased product (also referred to as bystanders or non-users).

General Question on the Risk Assessment Document

Issue 1. This risk assessment is divided into three chapters with seven appendices. Chapter 1 describes 

the scope for the NMP human health risk assessment. Chapter 2 provides information on chemistry, 

environmental fate and transport, production, and uses. Chapter 3 characterizes exposure, hazard, and 

risk findings as well as the uncertainties of the assessment. Supporting information is provided in the 

appendices. The risk assessment is intended to provide a clear and transparent summary of the Agency’s 

analysis.

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. 

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.

Questions on the Exposure Assessment

--Inhalation Exposures

Issue 2. EPA found limited published data for NMP’s air concentrations in workplace settings 

during use of NMP-based paint strippers. These data were used for estimating occupational 

inhalation exposures to NMP in adult workers (e.g., male and female workers of childbearing age).

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

recommendationsfor 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. 

Issue 3. EPA conducted a literature review and found insufficient data to characterize inhalation 

exposures for residential users (e.g., adult users including women of childbearing age) and 

bystanders/non-users (i.e., children, women of childbearing age). Therefore, EPA used a modeling 

approach to estimate inhalation exposures. EPA found limited data on consumer uses and profiles 

and conducted a sensitivity analysis of model parameters to identify critical parameters essential to 

the inhalation modeling approach. EPA varied the most sensitive input parameters to generate 

central tendency and upper-end NMP air concentrations.
2

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

recommendationsfor 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.

--Dermal Exposures

Issue 4. No data were found for occupational or consumer dermal exposures to NMP-based paint 

strippers. Thus, modeling approaches were used to estimate potential dermal exposures of adult 

users in contact with liquid NMP-based paint strippers at workplace and residential settings. The 

occupational and consumer dermal exposure estimates use similar “thin-film” modeling 

approaches. A primary difference between the approaches is the film thickness assumption. The 

estimates for occupational exposures are based on a range of film thickness values from laboratory

tests of surrogate film materials. The film thickness value for consumer exposures was based on the 

professional judgment of a chemist employed in a paint stripping company.

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

recommendationsfor 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.

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

recommendationsfor 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.

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.
3

Questions on the Hazard Assessment

Issue 5. EPA chose a point of departure (POD) from developmental inhalation studies in rats 

reported by Saillenfait et al. (2001, 2003)1to assess the acute inhalation scenario. It was assumed 

that a single exposure to NMP could be sufficient to produce adverse developmental effects (US 

EPA, 1991; van Raaij et al., 2003)2. From the Saillenfait studies, EPA chose a POD based on fetal 

body weight decrements to represent the effects of single acute inhalation exposure. 

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/m

3

(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. 

Issue 6. EPA also chose to use the developmental inhalation studies in rats reported by Saillenfait 

et al. (2001, 2003) to evaluate the chronic occupational inhalation exposures. It was assumed that 

the repeated nature of exposure to NMP during pregnancy could produce adverse developmental 

effects. From these studies, EPA chose a POD based on decrements in fetal body weight to 

represent the effects of chronic inhalation exposure.

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. 

 

1

Saillenfait, A. M., Gallissot, F., Langonne, I., Sabate, J. P., and Morel, G. (2001). Developmental toxicity of Nmethyl-2-pyrrolidone administered by gavage or inhalation to rats. Poster presented at the 29th Conference of the 

European Teratology Society, 2-5 Sep 2001 Balatonfüred, Hungary.

 Saillenfait, A. M., Gallissot, F., and Morel, G. (2003). Developmental toxicity of N-methyl-2-pyrrolidone in rats 

following inhalation exposure. Food Chem. Toxicol. 41(4), 583-588.

2 US EPA (1991). Guidelines for Developmental Toxicity Risk Assessment. EPA/600/FR-91/00. 

http://www.epa.gov/raf/publications/pdfs/DEVTOX.PDF

van Raaij et al. (2003). The relevance of developmental toxicity endpoints for acute limit setting. RIVM report 

601900004. http://www.rivm.nl/dsresource?objectid=rivmp:16116&type=org&disposition=inline&ns_nc=1
4

Issue 7. EPA chose a developmental dermal study in rats to characterize acute and chronic hazard 

for the dermal exposure scenario. The POD was based on fetal body weight and fetal death to 

represent the effects of acute and chronic dermal exposure.

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. 

Issue 8. EPA evaluated whether a physiologically-based pharmacokinetic (PBPK) model could be 

used in the NMP workplan risk assessment. Poet et al. (2010) constructed a PBPK model to 

describe the toxicokinetics of NMP in pregnant rats and humans after oral, dermal and inhalation 

exposures to NMP. The authors used PBPK and benchmark dose (BMD) methodologies to estimate 

human equivalent concentrations/doses (HEC/HED) based on a POD for fetal body weight. EPA 

evaluated the model during the development of the draft NMP risk assessment, but did not use the 

original model due to uncertainties in the model parameterization. The authors have recently 

revised the model and submitted it to EPA for further consideration. EPA has reviewed the revised 

PBPK model and determined that it is appropriate for risk assessment purposes. A copy of the 

model evaluation report and the model files (including the code) has been posted in the NMP 

docket. EPA intends to use the revised model to evaluate the risks of acute and chronic inhalation 

and dermal exposures to NMP-based paint strippers. 

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 workplan 

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.

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.

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. 

Question 8-4: Please comment on whether the BMD analysis should be conducted with the PBPKderived 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.
5

Questions on the Risk Assessment

Issue 9. The margin of exposure ( MOE) approach used the PODs identified in the 

hazard/dose-response assessment to evaluate risks for the acute and chronic inhalation and 

dermal exposures to NMP-based paint strippers. The new preferred approach consists of 

estimating MOEs based on the PBPK-derived internal doses estimated for the selected POD and

the human exposure level calculated in the occupational or the consumer exposure analysis (refer 

to PBPK modeling appendix and EPA’s overview presentation). The MOE is the ratio of the 

PODinternal dose to the Exposure internal dose. MOE calculations with internal doses facilitate combining 

dermal and inhalation exposures and are thus preferred over the estimation of human equivalent 

concentrations/doses (HEC/HED). MOEs were compared to benchmark MOEs to determine 

whether potential risks were present for the different exposure scenarios. Benchmark MOEs were 

assigned to each exposure scenario depending on the uncertainties of the PODs chosen for the 

analysis. The risk characterization also provides a discussion of the uncertainties surrounding

the risk calculations.

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. 

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.

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 PBPKderived 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.

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 PBPKderived 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.

Question 9-5: 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.