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## 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 inh alation 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 NMP

based product (also referred to as bystanders or non

- users).



### General Q uestion on the R isk A ssessment 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

ri sk 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. P lease provide specific suggestions for improving the clarity and transparency of

the risk assessment document.

Question 1

- 2: Please comment on whet her 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 E xposure 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 : Pl ea se c o mm e nt on t he a pp r o ac h u s e d a nd p r ov i de a n y sp e c i f i c sug g e s ti ons or

r ec o mm e n d a ti ons f

or a lt er n a ti ve a p p r o ac h e s
, m o d e l s or i n f o r m a ti on th a t shou l d be c ons i d ere d b y t he

A g e n c y f or im p r ov i n g its assessment of t he w o r kp l a c e inhalation e x posu r e , 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

centra l tendency and upper

- end NMP air concentrations.

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Question 3

- 1 : Pl ea se c o mm e nt on t he a pp r o ac h u s e d a nd p r ov i de a n y sp e c i f i c sug g e s ti ons or

r ec o mm e n d a ti ons f

or a lt er n a ti ve a p p r o ac h e s, m o d e l s or i n f o r m a ti on th a t shou l d be c ons i d ere d b y t he

A g e n c y f or im p r ov i n g its assessment of consumer inhalation e x posu r e , 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 t he 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 re sidential 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 lab oratory tests of surrogate film materials

. The film thickness value for consumer exposures w as based on the professional judgment of a chemist employed in a paint stripp ing company

.

Question 4

- 1 : Pl ea se c o mm e nt on t he a pp r o ac h u s e d a nd p r ov i de a n y sp e c i f i c sug g e s ti ons or

r ec o mm e n d a ti ons f

or a lt er n a ti ve a p p r o ac h e s, m o d e l s or i n f o r m a ti on th a t shou l d be c ons i d ere d b y t he

A g e n c y f or im p r ov i n g its assessment of t he w o r kp l a c e dermal e x posu r e
, including specific citations (if available) of data sources characterizing occupational dermal exposures

. P lease 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 : Pl ea se c o mm e nt on t he a pp r o ac h u s e d a nd p r ov i de a n y sp e c i f i c sug g e s ti ons or

r ec o mm e n d a ti ons f

or a lt er n a ti ve a p p r o ac h e s, m o d e l s or i n f o r m a ti on th a t shou l d be c ons i d ere d b y t he

A g e n c y f or im p r ov i n g its assessment of t he consumer dermal e x posu r e, 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 an d 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.

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Questions on the Hazard Assessment

Issue 5 . EPA chose a point of departure (POD) from developmental inhalation stud ies in rats reported by Saillenfait et al. ( 2001, 2003) 1 to 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 th e Saillenfait studies , EPA chose a POD based on fetal body weight decrement s to represent the effects of single acute inhalation exposur e.

Question 5

- 1 : Please comment on EPA’s use of th e identified developmental stud ies 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 s pecify any other endpoints that sh ould be

considered for the hazard evaluation of acute inhalation exposures. P lease provide relevant data or documentation and rationale for including other studies and endpoints for consider ation

.

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

et al. ( 2001, 2003) to evaluate the chronic occupational inhalation exposure s . It was assumed that the repeated nature of exposure to NMP during pregnancy could produce adverse developmental

effects . From th ese 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 specif y any other toxicological endpoints that sh ould

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 consider ation

.

1 Saillenfait, A. M., Gallissot, F., Langonne, I., Sabate, J. P., and Morel, G. (2001). Dev elopmental toxicity of N

methyl

- 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

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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 iden tified effects to assess acute and chronic dermal exposures to NMP

- based strippers. Please specify any other endpoints that

sh ould be considered for the hazard of acute or chronic dermal exposures. P lease provide relevant

data or documentation and rationa le for including other studies and endpoints for consider ation

.

Issue 8. EPA evaluated whether a p hysiologically

- based p harmacokinetic ( 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 benchmar k d ose ( 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 uncerta inties 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 th e 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 suppor ting 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 matern al dose met ric

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 (C

max ) in maternal blood.

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

.

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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 exposure s to NMP

- based paint strippers. The new preferred approach consist s 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

POD internal dose to the Exposure internal dose . MOE ca lculations 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 be nchmark 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 r i sk c h a r a c t er i z a t i o n also provides a discussion of the un cert a in t i e s s u rr o und i n g
t h e r i sk c a l c u la t i o n s.

Q u e s t ion 9

- 1: Pl ea se c o mm e nt on t he assumptions

, s t re n g t hs a nd wea kn e s s e s of t he M OE

a pp r o a c h es us e d t o e s tim a t e t he ac u t e inhalation r i sks t o consumers of NMP

- based products and to bystanders/

non

- u s er s (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

.

Q u e s t ion 9

- 2: Pl ea se c o mm e nt on t he assumptions

, s t re n g t hs a nd wea kn e s s e s of t he M OE

a pp r o a c hes us e d t o e s tim a t e t he chronic inhalation r i sks t o 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 composit e uncertainty factors that were used as benchmark MOEs to determine the chronic inhalation risks.

Q u e s t ion 9

- 3: Pl ea se c o mm e nt on t he assumptions

, s t re n g t hs a nd wea kn e s s e s of t he M OE

a pp r o a c hes us e d t o e s tim a t e t he ac u t e dermal r i sks t o 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 us ed as benchmark MOEs to determine the acute dermal risks.

Question 9

- 4: Pl ea se c o mm e nt on t he assumptions

, s t re n g t hs a nd wea kn e s s e s of t he M OE

a pp r o a c hes us e d t o e s tim a t e t he chronic dermal r i sks t o 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 risk s.

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.