COMMENTS ON AN ANNEX XV DOSSIER FOR IDENTIFCATION OF A SUBSTANCE AS SVHC AND RESPONSES TO THESE COMMENTS

Substance name:	1-methyl-2-pyrrolidone	
CAS number:	872-50-4	
EC number:	212-828-1	

Reason of the submission of Annex XV:  Article 57(c) of the REACH Regulation

Note: The Response to Comments table (RCOM) has been prepared by the European Chemicals Agency in consultation with the European Commission. The comments were received during the public consultation of the Annex XV dossier. RCOM has not been agreed by the Member State Committee nor has the document been modified as a result of MSC discussions.

PART I: Comments and responses to comments on the SVHC proposal and its justification

General comments on the SVHC proposal
Number	Date	Submitted by (name, Organisation/
MSCA)	Comment	Response	
40	2011/04/07	International NGO
Health and Environment Alliance
Belgium	We support the inclusion of 1-methyl-2-pyrrolidone on the candidate list, on the basis of information in the Annex XV dossier.	Thank you for providing your opinion.	
38	2011/04/07	Industry or trade association
European Semiconductor Industry Association (ESIA)
Belgium	Section 2.1 - Overview of Uses page 17 
Section 2.5.3 - Quantities Involved page 28 
Section 3.6 - Environmental releases and exposure page 55

These sections utilise a derivation of a global total of OECD data for NMP in 2005 based on ‘electronics’ sector to extrapolate use amounts for Europe. The semiconductor or microelectronic sector manufactures semiconductor components. This sector is not the same as the electronics sector and it is not possible to use the terms interchangeably. It is therefore not accurate to characterise the use in ‘electronics’ or ‘electronic equipment manufacture’ as being the same amount used in semiconductor manufacturing. One cannot therefore extrapolate on the OECD global figures and provide a speculative analysis to come up with European figures. The semiconductor industry produces ‘microchips/semiconductor devices’ not electronic equipment. 

For the semiconductor industry in Europe the very highest aggregated maximum use range for the sector was up to 270 tonnes per year. This is the sum of the maximum use case scenarios for the sector based on information already given to the consultants who prepared the questionnaire for the NMP Annex XV dossier. The report does not include the range of values that was submitted to the ECHA consultant’s questionnaire by the semiconductor industry. This table is included below. Table 9 on page 17 of the dossier attributes between 2,000-10,000 tonnes as being used by the electronics industry in Europe. These figures are based on incorrect extrapolations of the historic global level use in ‘electronics’ not semiconductor manufacturing and are used repeatedly in the dossier. (On page 17, (table 9) page 28 and page 55 (table 20) in terms of environmental release estimations).  It is not accurate to label semiconductor manufacturing as electronics and to then use and emphasis incorrect figures which represent several orders of magnitude higher than the figures that were submitted by the user industry. Thank you to correct these inaccuracies so that a clear and representative picture is reflected in the dossier.
	Thank you for the additional information on the use and regulation of NMP in the semiconductor industry. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

The use of NMP in semiconductor industry will be considered separately from the use in electronics, given the clarifications on uses and exposure outlined in your comment.  
	
			See also:
Comment 38 attachment (ESIA response to Annex XV dossier consultation on NMP 1 Methyl 2 Pyrrolidone  Final.pdf).pdf		
37	2011/04/07	International organisation
European Federation of Pharmaceutical Industries and Associations (EFPIA)
Belgium	NMP is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and associated intermediates.  Existing regulation under the Solvent Emissions Directive means that use of NMP within pharmaceutical manufacturing is restricted to those applications where there is no feasible alternative.  A lack of alternative solvents without the same hazards as NMP means that placing NMP on the SHVC Candidate List and potential prioritisation for inclusion in Annex XIV would, in certain circumstances, push the pharmaceutical industry towards using alternatives that present a higher risk to both worker health and the environment than NMP.  
 
The facts presented below lead EFPIA to the conclusion that it would be inappropriate for NMP to be considered for inclusion in Annex XIV.  In the context of pharmaceutical manufacturing, the proposal is based purely on hazard, with no account of any exposure scenario that allows translation to the risk presented by NMP.  Whilst we do not, and cannot, disagree with the current classification of NMP, we would strongly argue that to propose NMP for prioritization for inclusion into annex XIV is to ignore the relative risks associated with NMP and some of it’s obvious alternatives (DMF and DMAc), where the associated risk is higher.

The regulation of pharmaceutical manufacturing under the Solvent Emissions Directive currently provides a more effective regulatory framework than the SVHC proposal for NMP: use of NMP, DMF and DMAc are collectively ruled out unless there is no feasible alternative.  Where no feasible alternative exists, the legislation allows for their use if risks are adequately controlled, and, unlike this proposal, would tend to steer one towards use of NMP if possible, as it presents the lowest risk.  Inclusion of NMP in the SVHC candidate list and potential prioritisation for inclusion in Annex XIV, would push the pharmaceutical manufacturing industry, in circumstances where an alternative was not feasible, towards using the higher risk solvents DMAc and DMF.  This would appear illogical and consequently EFPIA disagrees with the proposal.
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
36	2011/04/07	International organisation
Council of Europe, Directorate for the Quality of Medicines and HealthCare
France	We consider that the article 56(3) of the Regulation (EC) No 1907/2006 corr applies to analytical use. Irrespectively, 1-methyl-2-pyrrolidone (or N-Methylpyrrolidone) should remain on the market for the convention on the elaboration of the European Pharmacopoeia (European Treaty Series 50) and the protocol to the elaboration of the European Pharmacopoeia, which are necessary for the implementation of the Directive 2001/82/EC on the community code relating to veterinary medicinal products and Directive 2001/83/EC on the community code relating to medicinal products for human use. 	Thank you for providing your opinion.	
35	2011/04/07	Other contributor

United Kingdom	1-methyl-2-pyrrolidone  (NMP) is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and  associated intermediates.  Existing regulation under the Solvent Emissions Directive means that use of NMP within pharmaceutical manufacturing is restricted to those applications where there is no feasible alternative.  A lack of alternative solvents without the same hazards as NMP means that placing NMP on the SHVC Candidate List and potential prioritisation for inclusion in Annex XIV would, in certain circumstances, push the pharmaceutical industry towards using alternatives that present a higher risk to both worker health and the environment than NMP.  

The facts presented below lead ABPI  to the conclusion that it would be inappropriate for NMP to be considered for inclusion in Annex XIV.  In the context of pharmaceutical manufacturing, the proposal is based purely on hazard, with no account of any exposure scenario that allows translation to the risk presented by NMP.  Whilst we do not, and cannot, disagree with the current classification of NMP, we would strongly argue that to propose NMP for prioritization for inclusion into annex XIV is to ignore the relative risks associated with NMP and some of it’s obvious alternatives (DMF and DMAc), where the associated  risk is higher.

The regulation of pharmaceutical manufacturing under the Solvent Emissions Directive currently provides a more effective regulatory framework than the SVHC proposal for NMP: use of NMP, DMF and DMAc are collectively ruled out unless there is no feasible alternative.  Where no feasible alternative exists, the legislation allows for their use if risks are adequately controlled, and, unlike this proposal, would tend to steer one towards use of NMP if possible, as it presents the lowest risk.  Inclusion of NMP in the SVHC candidate list and potential prioritisation for inclusion in Annex XIV, would push the pharmaceutical manufacturing industry, in circumstances where an alternative was not feasible, towards using the higher risk solvents DMAc and DMF.  This would appear illogical and consequently ABPI disagrees with the proposal.

Our detailed comments below are largely relevant to the following sections of the explanatory dossier accompanying the consultation:
-	Section 2.7 - Use #6 ‘Pharmaceuticals’
-	Section 3.4.9 – ‘Use of NMP in the prepartionof pharmecuticals’
-	Section 4 – ‘Current knowledge on alternatives – downstream users’
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
33	2011/04/07	International NGO
WWF European Policy Office
Belgium	WWF supports the inclusion of this substance in the candidate list owing to its classification as toxic for reproduction 1 B.	Thank you for providing your opinion.	
29	2011/04/07	Company

France	The use of 1-methyl-2-pyrrolidone as a synthesis solvent in the manufacture process of active ingredients for pharmaceutical and cosmetic applications was not very described in the dossier.
This type of use only concern industrial users and is very controlled : limitation of emissions because of the process type and protection of employees in relation with chemical substances on workplace European directive.
It doesn’t exist equivalent substitution solvent which is not dangerous.
As a consequence, the interdiction of use of NMP in chemistry would limit the number of chemical reactions and would not permit the manufacturing of some active ingredients for pharmaceutical or cosmetic applications.
We ask ECHA to exclude uses of NMP as synthesis solvent in organic chemistry in case of inclusion of NMP in Annexe XIV or to evaluate the alternative of the restriction procedure for this substance for the uses identified as dangerous for workers and consumers.
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
28	2011/04/07	Member State
Germany	The German CA supports the proposal to identify N-methyl-2-pyrrolidone as SVHC.

Page 14:  For the synthesis of 1-methyl-2-pyrrolidone Wikipedia has been cited and the authors do not make any reference to acknowledged primary sources. It is therefore recommended to refer to a reliable primary source, e.g Kirk Othmer -Encyclopedia of Chemical Technology, Volume 13, p. 1060.
	Thank you for providing your opinion.

Provided that the substance is identified as SVHC, the additional information on manufacture, use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
27	2011/04/06	Company
Gaylord Chemical Company
United States	The document is well written, and agrees with our understanding of the concerns associated with N-methyl pyrollidone use. 	Thank you for the information regarding dimethyl sulfoxide as alternative substance to NMP.
Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
 	
			See also:
Comment 27 attachment (DMSO as NMP alternative.pdf).pdf		
25	2011/04/06	Company
Shasun Pharma Solutions Ltd
United Kingdom	p.17 Uses of the substance	See reply below.	
23	2011/04/06	Industry or trade association

United States	The National Electrical Manufacturers Association (NEMA), representing manufacturers of electrical and medical imaging equipment, appreciates the opportunity to comment on behalf of its Magnet Wire Section on the current consultation for proposed substances of very high concern (SVHCs). Magnet wire is absolutely integral to the efficient production, conversion, and management of electrical energy. Some of the most advanced insulations for magnet wire rely on use of NMP as a raw material input. Reducing accessibility of NMP could negatively impact magnet wire production, which would be entirely counterproductive to the ongoing worldwide drive for more intelligent management of energy.	Thank you for the additional information. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
24	2011/04/06	Member State
Norway	The Norwegian CA supports that  1-methyl-2-pyrrolidone should be identified as a substance of very high concern and should be included in the Candidate list.	Thank you for providing your opinion.
	
22	2011/04/06	Member State
Netherlands	The NL-CA supports the proposal to include 1-methyl-2-pyrrolidone in the candidate list of substances of very high concern.	Thank you for providing your opinion.
	
20	2011/04/06	Company

France	Ipsen Pharma SAS agrees and supports with the Astra Zeneca comments on the proposal not to include 1-Methyl-2-pyrrolidone [N-methyl pyrrolidone, CAS 872-50-4] on the REACH SVHC Candidate List for the use of NMP as a solvent as described in the Annex XV Dossier. 

NMP is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and associated intermediates.  Existing regulation under the Solvent Emissions Directive means that use of NMP within pharmaceutical manufacturing is restricted to those applications where there is no feasible alternative.  A lack of alternative solvents without the same hazards as NMP means that placing NMP on the SHVC Candidate List and potential prioritisation for inclusion in Annex XIV would, in certain circumstances, push the pharmaceutical industry towards using alternatives that present a higher risk to both worker health and the environment than NMP.  

(Source Astra Zeneca)
(Refer to Astra Zeneca position paper)	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

			See also:
Comment 20 CONFIDENTIAL attachment 		
17	2011/04/06	Company
Mitsubishi Chemical Corporation
Japan	P.12 Part I 2 HARMONISED CLASSIFICATION AND LABELLING
We have no comment on the hazard assessment/classification content of the Annex XV dossier, but consider there are important omissions in sections 2 and 4.	See reply below.	
16	2011/04/06	Company
Teijin Aramid BV
Netherlands	None.	-	
15	2011/04/06	Company
Teijin Aramid BV
Netherlands	None.	-	
14	2011/04/06	Company

France	Functions of the substance as excipient not covered in the Annex XV Dossier (section 2.7 page 30) 

Please refer to the Ipsen Pharma SAS’s attachment for further explanations.

Focus seems to be given to the use of NMP as a solvent engaged in manufacturing processes (extraction, purification and crystallization) in the Annex XV Dossier but not as an “inactive ingredient” or excipient. 
The use of NMP as excipient for injectable drug products is not correctly covered in the Annex XV Dossier. 

In Pharmaceutical products, the NMP is currently used as an “inactive ingredient” / excipient in different drug products aimed to treat relevant diseases. The formulations for human use include a controlled-release gel for  the  subcutaneous  injection  of  leuprolide  acetate (Eligard®) and  a  subgingival form of doxycycline hyclate (Atridox®), both of which contain NMP and are currently marketed. 

NMP is then used as an excipient in drug-delivery. 

The Jouyban paper does not accurately address the specific use of NMP as an excipient but rather merges the 2 functional uses of NMP in one as a “standard solvent”. 
Ipsen wants to address a specific and limited use of this substance within the Pharmaceutical industry as an excipient. 

Moreover, as the main focus is given to the use of NMP as a solvent engaged in industrial processes (coating, cleaning, agrochemicals, ….) in the Annex XV Dossier, the section 3.5, “Consumer releases and exposure” does not address the medical use of drug product by the patient.

Conclusion 

Ipsen pharma SAS principally uses NMP as an excipient in formulation of its own proprietary Active Pharmaceutical Ingredients (API) because of its extremely useful physical properties as polar aprotics. 

As an interested party, Ipsen takes the opportunity to provide further information to the Agency on the use of NMP as an excipient, the potential exposure, alternatives and risks in order not to place on the REACH SVHC Candidate List the uses of NMP as an excipient in pharmaceuticals.
 
As NMP is a polar aprotic substance, and without misrepresenting the NMP toxicity profile, Ipsen requests ECHA to reconsider the use of NMP in Pharmaceuticals as an excipient. 

NMP can enhance drug formulations, and thus increase the Risk/Benefit ratio in favour of patient care. Other polar aprotic substances exist, which have similar or more adverse toxicity profiles, and these alternatives will not, nevertheless, achieve the goal of optimized formulation of drugs and may require Ipsen to use materials representing higher risks, e.g. in industrial hygiene towards workers or sustainable development. In addition, this would lead Ipsen to conduct long & costly development and clinical studies of 5 to 10 years for a new drug product, which is against the improvement of patient convenience and care by delaying or removing effective and safe treatments for serious medical conditions.
 
Considering the arguments cited above, Ipsen pharma SAS strongly recommends that 1-Methyl-2-pyrrolidone should not be placed on the REACH SVHC Candidate List for the uses of NMP as an excipients in pharmaceuticals, because sufficient controls established by other legislation are already in place. 

This specific use of NMP as an excipients need to be exempted from authorisation, should the listing of NMP be made for other uses.   	Thank you for the information on the use and regulation of NMP as an excipient in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
			See also:
Comment 14 attachment (NMP comments - V10 - 6 April 11 - Final.pdf).pdf		
13	2011/04/06	Industry or trade association
CEFIC
Belgium	 
									6 April 2011

Comments of the Annex XV Identification Dossier of 1-METHYL-2-PYRROLIDONE (NMP) as SVHC on behalf of the members of the Cefic 1,4-Butanediol & Derivatives Sector Group (BDO).
Introduction
In general the industry view is in accordance with that presented in the Annex XV Identification dossier. It is our belief that the following comments should be emphasised to allow the correct prioritisation of NMP. In particular, it should be noted that almost all uses of NMP are industrial and there are no significant consumer applications the industry is aware of. Good industrial hygiene practice will therefore be effective in controlling potential exposures and risk.  In conclusion there is no need for any prioritization of NMP.

Comments:
1)	Technical feasibility of substitution
The dossier clearly points out the difficulties of substituting NMP and we would support the ECHA view that the only technically feasible alternative that has been identified is 1-ethyl-2-pyrrolidone (NEP): “For the main uses of NMP in coatings, electronics and cleaning products, the most frequently identified potential alternative is NEP. Whilst there would still be challenges in replacing NMP with NEP (due to customer approvals, further testing, etc.), it appears that this substance has the greatest potential in technical and economic terms as a replacement for NMP….. However, many of the companies responding have highlighted the potential future classification of NEP as a reproductive toxicant. ……However, none of these seem to be able to replace NMP in as many applications as NEP and it is clear that some companies do not currently have a solution identified in the event that they are no longer able to use NMP or NEP” (dossier p.58-60).
NEP has recently come under greater toxicological scrutiny; please see the comments in section 2.
The dossier also suggests: “It is understood that the labeling requirements related to classification as a category 1B reproductive toxicant would not apply when the concentration of NMP is below 5 %. Some of the coating products are expected to include NMP at concentrations below 5 % so it is considered feasible that use may continue in those applications” (dossier p.20).
The table in Annex A highlights the technical issues for all potential or partial substitutes, which were mentioned in the Annex XV Identification Dossier and the industry is aware of to date.

2)	Toxicology
Whilst it is recognised that NMP has a category 1B reproduction classification, it should be noted that many of the substances suggested as potential or partial substitutes are also classified as reprotoxic (e.g. DMF, DMAC) and some have a greater/other  degree of toxicity than NMP (e.g. some hydrocarbon solvents, gamma butyrolactone or 1,3-dimethyl-2-imidazolidinone). Brief comments are listed in the table in Annex A.

3)	Uses of NMP
The major uses of NMP are industrial and there is no direct contact required with NMP. As a cat. 1b substance it is already restricted by EU-regulations 94/60/EEC for marketing to the general public (e.g. paints, pickling agents, brush-cleaning solvents). NMP containing products were removed from the European DIY market in 2005 and there is “advice against use” in the cosmetics industry.

Coatings – NMP has use as a solvent for professional products. There is a potential for consumers to be exposed where NMP is used as a solvent in water borne parquet floor finishes. During the drying process, NMP can evaporate in to the air. It is recommended that safety precautions such as longer ventilation times after application and before rooms are re-inhabited are included in safety instructions. The industry also believes that substitution should be possible in this application.

Electronics – use as a solvent for circuit board strippers, and cleaners, solvent for polymeric battery separators in Lithium ion batteries. These manufacturing environments are already tightly controlled.

Pharmaceuticals – use as a solvent during pharmaceutical manufacturing, again the environments are controlled. There is also a use as a pharmaceutical penetration enhancer; however this use is not covered by REACH and should be considered in the corresponding pharmaceutical regulations.

Graffiti removal – graffiti can be removed by products containing NMP in spray, brush or scraper products. This is normally carried out under professional conditions with workers wearing appropriate protective clothing and in screened off areas. Clearly, there is a potential in the case of spray on products for aerosols to build up that could, potentially be inhaled by unprotected persons. It is recommended that safety precautions should be strengthened to emphasise that spray based products should not be used where a build up of aerosol concentrations could occur.

4)	Other comments
The great majority of uses of NMP are industrial and are in industries where control of exposure and contamination is well-understood and practiced. Good industrial hygiene and air quality are essential in these industries and we are unaware of any applications where there is a need for direct contact with NMP. Risks associated with the use of NMP are therefore adequately controlled.
It is our conclusion that the Annex XV dossier over emphasises the use of NMP by the general public.  To the best of our knowledge all registrants have registered NMP for uses limited to industrial processes or uses by professional workers. As a result we feel that this report is biased toward the potential risk and exposure to the general public as consumers in comparison to the use in industrial settings or the use by professional workers.

Conclusion
In summary, the Cefic 1,4-Butanediol & Derivatives Sector Group would like to highlight:

1)	Exposure is primarily expected to occur in industrial and professional settings where risk is already adequately controlled
2)	The industry has undertaken significant efforts to look for alternatives to NMP
3)	ECHA recognises that the only feasible technical alternative is NEP
4)	There are no, good alternatives to NMP from a technical and toxicological viewpoint

It is therefore our opinion that, based on the existing Annex XV dossier, the insertion of NMP in the SVHC candidate list is postponed until a real alternative (with respect to technical and toxicological properties) to NMP becomes available. 
Annex A: Technical and Toxicological Limitations of Substitution
a) Coatings, Annex XV dossier p. 58
name	CAS RN	Toxicology	Technical limitations
NEP	2687-91-4	Currently being reviewed for reproduction toxicity	Less effective solvent

Waterborne polyurethane dispersion paint w/o solvents			Lower surface tension, needs solvent addition downstream
DMSO	67-68-5	Not CMR tested to OECD 414	High melting point, chemical reactivity leading to breakdown above 150°C to sulphur oxides – odor and residual garlic taste on exposure.
Hydro carbon solvent		n-Hexane, CAS 10-54-3 a mild irritant and CNS depressant in acute exposure.
legal: GHS Repro 2, H361f***; Asp Tox 1, H304; STOT RE2*, H373**, Skin Irrit. 2, H315; STOT SE3, H336
n-pentane, CAS 109-66-0 of lower toxicity, effects might require gross exposures
GHS Asp Tox1, H304; STOT SE 3, H336	Poor solvents

Ketone solvent			Lower viscosity, boiling point ~ 85°C
Glycolether (> 30 substancers)		Some are classified as reprotoxic: EGEE, EGEEA, EGME, EGMEA, EGDME, DEGDME, TEGDME	Low solvent power, limited solubility with water and chemicals

DMF, Dimethylformamide	68-12-2	Annex VI CLP: Repro 1B, H360D***
	
DMAC, Dimethylacetamide	127-19-5	Annex VI CLP: Repro 1B, H360D***	
Alcoxy alkyl amid			Not chemically inert in many applications
Gamma butyrolactone	96-48-0	Potential for misuse as a recreational drug 	Hydrolyses in water

1,3-Dimethyl-2-imidazolidinone	80-73-9	CNS depressant (Lien 1982 + 1986) not at all biodegradable, not enough toxicological data for profound evaluation	Too expensive
2-pyrrolidone	616-45-5	GHS Eye Irrit. Cat 2, H319	Solid at room temperature and solubility parameter not as broad as aprotic solvents.  Labile hydrogen.

b) Electronics, p. 62
name	CAS RN	Toxicology	Technical limitations
Polyimides: 
- n-formyl-piperidine, 2591-86-8
-Dimethylpropionamide, 758-96-3, legal: 
- 1,3-diemthyl-2- imidazolidinone, 80-73-9
- 1,1,3,3, tetramethyl-urea, 632-22-4			Chemically unstable

DMSO, GBL, PGMEA, glycol ether		See above	

c) Cleaning Products, p. 63
name	CAS RN	Toxicology	Technical limitations
NEP	2687-91-4	See above	

d) Agrochemicals
name	CAS RN	           Toxicology	       Technical limitations
NEP	2687-91-4	See above	
Methyl diproxitol butyldiglycol			Reactive hydroxyl groups, poor on hydrophobic and aromatic soils

Hydro carbon solvent			Not effective on water soluble or hydrophilic soils

Contact: 
Walter Cremers, BDO Secretary General 
wcr@cefic.be	Thank you for this detailed additional information. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
11	2011/04/06	National Authority
Allgemeine Unfallversicherungsanstalt
Austria	We support 1-methyl-2-pyrrolidone being identified as a substance of very high concern.	Thank you for providing your opinion.	
8	2011/04/05	Member State
Belgium	Belgium supports the identification of 1-methyl-2-pyrrolidone as SVHC according to article 57(c).	Thank you for providing your opinion.
	
7	2011/04/05	Member State
Sweden	The Swedish CA agrees that 1-methyl-2-pyrrolidone, being classified as Repr. 1B, meets the criteria according to Article 57(c) in REACH and is thus eligible for identification as a substance of very high concern.	Thank you for providing your opinion.	
4	2011/04/01	Company

France	Use of NMP as solvent in the production of pharmaceuticals:

p30 (2-7-1)
p43 (3-4-9-1)		
			See also:
Comment 4 CONFIDENTIAL attachment 		
5	2011/03/31	Company

Germany	The required quantity in our coating products amounts less than 0,2 %. To this time we assume that no effects appear to workers and the environment	Thank you for the additional information. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
2	2011/03/15	Trade union
European Trade Union Confederation
Belgium	ETUC supports the identification of 1-methyl-2-pyrrolidone as SVHC.	Thank you for providing your opinion.	

Specific comments on the justification
Number	Date	Submitted by (name, Organisation/
MSCA)	Comment	Response	
37	2011/04/07	International organisation
European Federation of Pharmaceutical Industries and Associations (EFPIA)
Belgium	None	-	
35	2011/04/07	Other contributor
industry association
United Kingdom	None	-	
29	2011/04/07	Company

France	No comment on this part.	-	
20	2011/04/06	Company

France	None	-	
			See also:
Comment 20 CONFIDENTIAL attachment 		
17	2011/04/06	Company
Mitsubishi Chemical Corporation
Japan	No comment	-	
16	2011/04/06	Company
Teijin Aramid BV
Netherlands	Page 12:
In Table 6 and Table 7 the reprotoxic concentration limit for NMP is given as >= 5%. This should also be the threshold for NMP as SVHC.
	The specific concentration limit of 5 % is indicated in the classification according to part 3 of Annex VI, Table 3.1 ((list of harmonised classification and labelling of hazardous substances) of Regulation (EC) No 1272/2008. Therefore the use of mixtures where the substance is present below this specific concentration limit would not require an authorisation. 	
15	2011/04/06	Company
Teijin Aramid BV
Netherlands	Page 12:
In Table 6 and Table 7 the reprotoxic concentration limit for NMP is given as >= 5%. If the reproductive effect of NMP is >= 5%, the threshold as SVHC in REACH should be >= 5%.	Provided the substance is identified as SVHC and included in Annex XIV, the specific concentration limit (SCL) of 5 % stipulated in part 3 of Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation) will affect the authorisation requirement as follows: The use of the substance on its own or in a mixture above the SCL will require authorisation whereas the use of mixtures containing the substance in concentrations below the SCL will not. Please note that identification as SVHC will trigger the notification obligation for substances in articles in accordance with Article 7(2). The concentration limit of 0.1% weight by weight for a substance in an article set out in Article 7(2) as one of the criteria triggering the notification obligation is however affixed and not dependent on SCLs set in Annex VI of the CLP Regulation. 	
14	2011/04/06	Company

France	None	- 	
			See also:
Comment 14 attachment (NMP comments - V10 - 6 April 11 - Final.pdf).pdf		
8	2011/04/05	Member State
Belgium	p.12 (under Table 6): Repr. 1B, H360D***4 "May damage fertility or the unborn child" has to be replaced by "May damage the unborn child".	Thank you for this information. The support document has been updated accordingly. 	
6	2011/04/04	Member State
Ireland	1-methyl-2-pyrrolidone is classified as Repr. 1B according to Regulation EC No. 1272/2008, and therefore the Irish CA agrees that the substance meets the criteria for identification as an SVHC in accordance with Article 57 (c) of REACH.	Thank you for providing your opinion.	
2	2011/03/15	Trade union
European Trade Union Confederation
Belgium	1-methyl-2-pyrrolidone is included in the Trade Union Priority List for REACH authorisation (entry No 169)
see http://www.etuc.org/a/6023	Thank you for providing your opinion.	

PART II: Comments and responses to comments on uses, exposures, alternatives and risks

Specific comments on use, exposure, alternatives and risks
Number	Date	Submitted by (name, Organisation/MSCA)	Comment	Response	
38	2011/04/07	Industry or trade association
European Semiconductor Industry Association (ESIA)
Belgium	Specific comments on Part II 'Information on Use, Exposure, Alternatives and Risks':

On the basis of the following extensive section of EU legislation that regulates semiconductor factory operations, the semiconductor industry believes that any potential future nomination or inclusion in the candidate list of NMP for semiconductor usage should identify an exemption for the semiconductor sector from an authorisation for usage as being the most effective and appropriate measure. 
EU. Indicative Exposure Limit Values in Directives 91/322/EEC, 2000/39/EC, 2006/15/EC, 2009/161/EU, thru OJ (L 338) 87, 17 Dec 2009)
EU. Directive 98/24/EC on the protection of workers from the risks related to chemical agents, Art. 2(b)(i), OJ (L 131) 11, 5 May 1998 (updated thru table 3.2 of Annex VI to CLP, 5 Sep 2009)
EU. Directive 92/85/EEC on pregnant workers and workers who have recently given birth or are breastfeeding, O.J. (L 348) 1, 28 Nov 1992 (updated thru table 3.2 of Annex VI to CLP, 5 Sep 2009)

EU. Directive 94/33/EC on young people at work, OJ (L 216) 12, 20 Aug 1994, as amended by Directive 2007/30/EC, OJ (L 165) 21, 27 Jun 2007 (updated thru table 3.2 of Annex VI to CLP, 5 Sep 2009)

CE Marking Directives (Machinery 2006/42/EC, Electromagnetic (EMC) 2004/108/EC, Low Voltage (LVD) 2006/95/EC)
Regulation 1272/2008 CLP of substances and mixtures
Solvent Emissions Directive 1999/13/EC
IPPC Directive 2008/1/EC
Water Framework Directive 2000/60/EC
Waste Directive 2006/12/EC

The highly sophisticated and detailed risk management measures employed in the semiconductor industry  in Europe for this substance alongside the highly controlled workplace environment and the relevant industrial hygiene measurements used in the semiconductor industry, and the de minimis environmental emissions to air ensure a rigorous and strictly managed usage of NMP

Section 2.1 - Overview of Uses page 17 
Section 2.5.3 - Quantities Involved page 28 
Section 3.6 - Environmental releases and exposure page 55

These sections utilise a derivation of a global total of OECD data for NMP in 2005 based on ‘electronics’ sector to extrapolate use amounts for Europe. The semiconductor or microelectronic sector manufactures semiconductor components. This sector is not the same as the electronics sector and it is not possible to use the terms interchangeably. It is therefore not accurate to characterise the use in ‘electronics’ or ‘electronic equipment manufacture’ as being the same amount used in semiconductor manufacturing. One cannot therefore extrapolate on the OECD global figures and provide a speculative analysis to come up with European figures. The semiconductor industry produces ‘microchips/semiconductor devices’ not electronic equipment. 

For the semiconductor industry in Europe the very highest aggregated maximum use range for the sector was up to 270 tonnes per year. This is the sum of the maximum use case scenarios for the sector based on information already given to the consultants who prepared the questionnaire for the NMP Annex XV dossier. The report does not include the range of values that was submitted to the ECHA consultant’s questionnaire by the semiconductor industry. This table is included below. Table 9 on page 17 of the dossier attributes between 2,000-10,000 tonnes as being used by the electronics industry in Europe. These figures are based on incorrect extrapolations of the historic global level use in ‘electronics’ not semiconductor manufacturing and are used repeatedly in the dossier. (On page 17, (table 9) page 28 and page 55 (table 20) in terms of environmental release estimations).  It is not accurate to label semiconductor manufacturing as electronics and to then use and emphasis incorrect figures which represent several orders of magnitude higher than the figures that were submitted by the user industry. Thank you to correct these inaccuracies so that a clear and representative picture is reflected in the dossier.

Table of European Semiconductor Manufacturing Industry usage of NMP as submitted to consultants who drafted Annex XV dossier
Member State	Uses	Quantity (tonnes)
France	Carrier solvent, cleaner/stripper 	<5 tpa
Italy 	Carrier solvent, cleaner/stripper	3-5 tpa
Ireland 	Carrier solvent, cleaner/stripper	10-100 tpa
Netherlands	Carrier solvent, cleaner/stripper	<20 tpa
Germany 	Carrier solvent, cleaner/stripper	< 10-100 tpa 
UK	Carrier solvent, cleaner/stripper	10-20 tpa
Austria	Carrier solvent, cleaner/stripper	<20 tpa

Section 2.5.2.3 page 28
Dossier states that “In semiconductor process, it is understood that about 90-95 % of the solvent used is collected for offsite incineration, 5-10 % evaporates and <0.5 % is discharged to waste water9 (ECHA 2010b).”page 28 Dossier
This is copied from on the ESIA/ECHA exposure scenario document and the solvent utilized under example C. 5-10% evaporation to air is not accurate for NMP. As submitted to the consultants who drafted the ECHA dossier less than 5% evaporates to air. This is a very conservative figure in most cases evaporation to air is a lot less than <5%.

Section 2.5.2.3 page 28 and section 3.4.5.1 page 41
The dossier list the processes involved on page 28 and 41 as, 
“The following main processes are understood to be undertaken:
• loading/unloading of wafers to/from automatic enclosed equipment;
• loading/unloading of wafers into partially enclosed equipment;
• maintenance and cleaning of equipment;
• handling and connection of containers;
• sampling.

These terms seems to be a copy from the ESIA/ECHA Exposure scenario examples of substance C ie..tasks and events where there may be potential for exposure. They are not accurate semiconductor manufacturing processes steps for which to classify the use of NMP. See potential uses as listed in the table below under column heading Process Step. 

Exposure information

Section 3.4.5.2 Releases of the Substance page 41

Information presented on page 41 appears to be based on apparent industry measurement information from 1991. 
Please utilise the table below which includes current semiconductor industry information and is based on actual industry measurements of NMP in the fabrication plants.

 Semiconductor Industry Measurement Data for NMP
Process Step	Measurement levels of NMP recorded	Worker exposure	Basis for figures
Photoresist stripping/Photolithography
Fully closed process tool no exposure. 	Below detection limit	None in normal operations 	Air concentration measurements based on personnel monitoring/ in the breathing zone
Photoresist stripping/Photolithography
Semi-closed process tool: minimal exposure	All measurements showed <1ppm. Majority<.01 ppm	Negligible in normal operations 	Air concentration measurements based on personnel monitoring/ in the breathing zone
Chemicals storage and delivery area- ambient air	Below detection limit  	None	Air concentration measurements
Maintenance (not normal operations)	Up to 1,7 ppm	Typically much less than measurement levels due to specific wearing of PPE	Air concentration measurements based on personnel monitoring/ in the breathing zone
Cleaning ‘bath’	<2ppm	Typically much less than measurement levels due to specific wearing of PPE	Air concentration measurements based on personnel monitoring/ in the breathing zone

The semiconductor industry undertakes frequent monitoring of manufacturing process equipment (tools) where NMP is used. NMP is typically used in totally closed process systems well below detection limits. The above table shows the different scenarios of potential use.

Additional information on the industry risk management measures in place

All semiconductor manufacturing process equipment (tools) are designed in accordance with SEMI S2 (semiconductor industry standards), safety standards which go far beyond European community equipment safety legislation. SEMI S2 safety standards require semiconductor process equipment manufacturers (equipment tool suppliers) to conduct chemical exposure assessment for all preventive maintenance activities during the design of the process equipment. All process equipment is equipped with local exhaust ventilation. (LEV) the LEV is checked routinely, the ducts have visual gauges to indicate flow, PPE is worn anytime there is a potential for an accidental splash. All workers are trained in chemical handling.    

The vast majority of European production sites of semiconductor devices have strict ESH management systems in place (ISO14001, OHSAS18001 EMAS or equivalent). All sites have a permit to operate from their national and local authorities. 

Many risk management measures (safety controls) are in place in the semiconductor industry, most of which are industry standards. There are ESH standards related with the construction of a fab and the production of auxiliary equipment (in conformance to the Semiconductor Equipment and Materials International (SEMI) “ESH Guideline for Semiconductor Manufacturing Equipment”, which generally goes far beyond regulatory requirements). There are many internal semiconductor industry standards related with safety, and many technical environmental protection measures are in place. Continuous improvement programs to enhance ESH are conducted based on actual sampled data.
Core elements: work place related risk assessment (chain)
The typical FAB (fabrication facility) in which microchips are manufactured has an environment that is tightly controlled with regard to temperature, humidity and particle contamination in the air.  A tolerance of only 100 particles with a diameter of 1/10000 of a millimeter or larger per cubic meter is the typical standard; this is thousands of times cleaner than a hospital operating room.  Uncontrolled chemical vapors and gases are equally unacceptable for obvious ESH reasons and from a production standpoint because of their potential for contaminating wafers, 

Because of the considerable measures of control within a semiconductor manufacturing facility, under normal operating conditions, workers are not exposed to chemicals.  Risk management measures such as local exhaust, process enclosures and automation create a barrier between workers and the process.  In many cases, there is secondary and even tertiary redundancy to these controls to ensure that, in the event that one control fails, others will continue to provide the necessary protection.  Numerous voluntary guidelines developed by the industry promote manufacturing equipment design that minimizes risk to workers whether during normal operation or during maintenance procedures.  When equipment maintenance is performed and workers must bypass normal risk management measures, they utilize additional means of protection such as personal protective equipment to ensure their safety.  This personal protective equipment is typically precautionary only, as, even with equipment in an opened or disassembled state, maintenance workers are typically never exposed to chemical levels above the applicable occupational exposure limits.

The following are a small sampling of the many semiconductors manufacturing Risk Management Methods currently in normal operating practice across the industry.  

Exhaust systems are designed to processes and equipment and are typically segregated to ensure proper handling and treatment, and to prevent reactions between incompatibles (e.g., acids, bases, solvents).  Where necessary, exhaust abatement systems are incorporated into the exhaust scheme to treat the exhaust to prevent undesired emissions to the environment.  In this way, emissions to the air environment are controlled and kept below permitted levels.  Similar systems and controls exist for management of liquid wastes as well, preventing untreated liquids from entering the water environment

Environmental Spill Prevention methods include protective design features such as double-containment spill control in manufacturing and chemical distribution areas, and double-walled piping.  Potential exposure routes to the soil are unlikely due to diligent disposal of all solid hazardous waste through proper methods 
Automation is also used to separate workers from the processes.  The typical large modern manufacturing fab has a high degree of automation for most of the production equipment, minimizing workers’ risk of exposure to chemicals.  Wafers are typically handled by automated systems that feed them into, and remove them from an enclosed process.  

In modern Fabs, chemicals are typically delivered to a process by an automated chemical delivery system, often from a remote location.  In the case of the most commonly used process chemicals, Bulk Chemical Delivery Systems (BCDS), minimize the need for chemical handling and eliminate the hazards of manually pouring chemicals at process stations.  

Section 3.6 Environmental release and exposure page 55
 
In the dossier page 55 table 20, 600-3000 tonnes per year are estimated to be released to the air. These figures are again based on the extrapolation of use figures for the whole electronics global sector. They are completely inaccurate, not transferable nor applicable for European semiconductor manufacturing. Thank you to correct these inaccuracies so that a clear and representative picture is reflected in the dossier.

In semiconductor manufacturing in Europe as submitted to the ECHA consultant directly the picture is rather different. NMP is 1 constituent of organic emissions in level of operating permit with a VOC treatment system in place.  As submitted to the consultants who drafted the ECHA dossier less than 5% evaporates to air. This is a very conservative figure in most cases evaporation to air is a lot less than <5%. There is no emission to surface water and soil. Process related waste water (<0.5%)). NMP is collected as solvent waste then incinerated/fuel blended

Information on alternative substances and techniques

Section 4.3.2 page 62

Potential alternatives are being tested and checked in collaboration with materials suppliers. Up to now the potential alternatives have not the required level of performance necessary in the process to be implemented. Many of the potential alternatives also have higher or equivalent negative health and environmental characteristics than NMP. This is not a simplistic process and there are no drop in replacements, any potential alternatives have to be tested to work in the individual processes and this may require new process systems and many requalification rounds.

The paragraph below identified below in section 4.3.2 page 62, does not make complete sense and may be a misinterpretation. Polyimides is  a standard  photolithographic process and not an alternative substance. As submitted by ESIA previously , NMP is an important solvent for polyimides.  Polyimides are important for the performance of the final article.  Replacement requires requalification for the entire supply chain.  

“One electronics company which uses NMP in mixtures for removal of photoresist in the
semiconductor manufacturing process noted that other solvent alternatives are available for the sector, notably polyimides, which are solvent based alternatives and are under evaluation. These can be used as photoresist strippers and casting solvents for polyimide resin based formulations.These substances are reportedly not yet commercially available and have not yet been fully tested|”
	Please see reply in the first section. 

Thank you for the additional information. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

			See also:
Comment 38 attachment (ESIA response to Annex XV dossier consultation on NMP 1 Methyl 2 Pyrrolidone  Final.pdf).pdf		
37	2011/04/07	International organisation
European Federation of Pharmaceutical Industries and Associations (EFPIA)
Belgium	p. 30, Section 2.7 - Use #6 ‘Pharmaceuticals’
p. 44, Section 3.4.9 – ‘Use of NMP in the preparation of pharmaceuticals’
p.58, Section 4 – ‘Current knowledge on alternatives – downstream users’

Use of NMP in the Pharmaceutical Industry - background 

N-methyl pyrrolidone, or NMP, is one of a class of extremely useful solvents designated as polar aprotics. The physical properties of these solvents make them an attractive choice from a chemistry perspective in the synthesis of Active Pharmaceutical Ingredients (APIs) and associated intermediates.  Advantages of NMP include:
•	NMP offers generally high solubility of many APIs and intermediates, which often  have very poor solubility in less polar solvents.  This facilitates processes that require minimal solvent quantities, compared with the much larger volumes of other solvents that may be required.
•	NMP additionally offers sufficient solubility of many inorganic reagents (e.g. acids & bases) that facilitates chemical reactions that would not be practicable or robust in many other organic solvents.
•	Reaction rates of certain reactions (e.g. nucleophilic substitution) are substantially enhanced due to the solvent polarity.
•	The use of these solvents can be essential (due to their relatively low acidity) when strong bases are employed as these materials would be completely consumed by side reactions if protic solvents were used.  
•	Water miscibility – for example facilitating precipitation, and subsequent isolation, of products from reaction liquors through the addition of water as an anti-solvent.
•	A high boiling point (202oC) – allowing reactions to be carried out at much higher temperatures than would be achievable in many organic solvents, without the need to operate under pressure (often not operationally feasible in typical pharmaceutical reactors, and inherently of greater operational hazard).  An additional benefit is that the potential for solvent emissions associated with processing is less than those associated with many other solvents.

NMP is therefore used within pharmaceutical research and development laboratories, development manufacturing pilot plants and commercial manufacturing plants.

Regulation of NMP under the Solvent Emissions Directive (European Community Directive 1999/13/EC as amended by Directive 2004/42/EC)

As a result of the properties described above, NMP had become a ‘solvent of choice’ for the pharmaceutical industry.  However, this changed in 2009 when NMP was assigned the Risk-phrase R61 (May cause harm to the unborn child.).  This meant that use of NMP fell under the control of the Solvent Emissions Directive (SED) within the EU. This requires specific industries, including the pharmaceutical manufacturing industry, to apply the ‘replace, control and limit’ requirements of the Solvent Emissions Directive within the shortest possible time from the date at which NMP became designated as a specified risk phrase material.  

In effect, the SED already requires that alternatives to NMP be utilised within the pharmaceutical industry, unless no feasible and reasonably practicable alternative can be found.  The major problem for industry presented by the assignment of the R61 phrase to NMP, and its subsequent regulation under the SED, is that the most frequently used and feasible alternatives, have the same reprotoxic health risks associated with them, and hence also fall within the ‘replace’ obligations of the SED.

In cases where it is not possible to substitute NMP, the SED requires very strict air emission limits to be complied with (≤10 g/h or ≤2 mg/m3) for the protection of the local environment and population.  Use in modern, contained pharmaceutical manufacturing plants, allow NMP to be safely handled under conditions that maintain exposure levels below relevant occupational exposure standards and thus adequately protect worker health, without out the need to employ ‘special’ equipment/precautions.

Alternative Polar Aprotic Solvents to NMP

A key point of consideration for the pharmaceutical industry is the regulatory implications that may be associated with changing the solvent used in any stage of a commercial manufacturing process that is registered with the appropriate regulatory health authorities.  Changes to such processes invariably require extensive redevelopment of processes and associated interaction/authorisation from health authorities in order to ensure product quality, efficacy and patient safety is not compromised.  Typically, changing a commercial process would necessarily involve a long lead time, large amounts of work and significant associated costs.  

There are a number of solvents that could potentially be used in place of NMP in some API manufacturing syntheses.  The most common ‘direct’ alternatives used within the pharmaceutical industry are highlighted in the ECHA dossier: DMF (N, N-dimethylformamide, CAS 68-12-2) and DMAc (dimethylacetamide, CAS 127-19-5).  Also noted in the dossier, these alternatives carry essentially the same health hazard (R61) as NMP.  However, the risk associated with using DMF or DMAc is greater – they have higher volatility (i.e. lower boiling point) than NMP, meaning that the risk of worker or environmental exposure through use of these solvents is generally higher.  This point is illustrated in the table below, where a ‘vapour hazard ranking’ has been assigned for DMF, DMAc and NMP by dividing the saturated concentration of the solvent (at 20 oC) by the UK 8 hour TWA Occupational Exposure Standard.  NMP can clearly be seen to be the lowest risk of these 3 solvents.

Solvent	UK Long-term exposure 
limit (8-hour TWA) [ppm]	Vapour pressure [mmHg at 20 oC]	Ratio (vapour pressure/8hr  TWA LTEL) [mmHg/ppm]	Vapour hazard ranking
DMF	10	2.9	0.29	1
DMAc	10	2.7	0.27	2
NMP	25	0.33	0.013	3

Other alternative polar aprotic solvents exist, a number of which are listed and commented on below.  As can be seen from the comments on these solvents below, there are other limitations associated with these alternatives may prevent their use in specific circumstances.  Whilst a more detailed, circumstance specific, consideration is of course required in the context of a particular chemical process, these comments serve to illustrate that finding a feasible alternative to NMP (or DMF, DMAc) may not be possible.

•	Dimethyl sulfoxide (DMSO), CAS 67-68-5.  DMSO) is a potentially reactive chemical and thermal instability can be induced by a range of chemicals / impurities.  Many incidents have been reported involving this solvent .  From a safety point of view alone alternative solvents should be investigated before choosing DMSO as a reaction solvent. This can also be the case with other aprotic solvents such as dimethyl formamide (DMF), dichloromethane (DCM), etc.  NMP is a much more thermally stable solvent and appears to have a lower potential for hazardous interactions with other reagents based on a number of compatibility tests undertaken .
•	Dichloromethane (DCM), CAS 75-09-2.  In addition to the potential reactive hazards noted in the previous bullet, DCM presents significant health hazards as a Category 2 carcinogen (under CLP (EC)1272/2008).  As such, it is also controlled by the Solvent Emission Directive (albeit not subject to the same ‘replace’ obligations). It’s very high volatility (BP 37 oC) means that, using the same vapour hazard ranking as above, it is substantially higher risk than NMP, DMF or DMAc, with a ratio of 3.5 mmHg/ppm. 
•	Sulfolane, CAS 126-33-0.  Sufolane has a high melting point (range ~ 20 – 26 oC oC)  and consequently may often prove operationally impracticable.
•	Acetone (CAS 67-64-1) and Acetonitrile (CAS 75-05-8).  Neither of these solvents possess the high solvating power of NMP, DMF and DMAc, nor the high boiling point to facilitate higher temperature reactions
•	DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, CAS 7226-23-5), DMI (2,3-dimethyl 2-imidazolidione CAS 80-73-9), TMU (Tetramethylurea, CAS 632-22-4). These solvents are relatively new and have been the subject of recent evaluation within one of our member companies.  Whilst they appear to offer some opportunity as alternatives to NMP, their commercial availability is currently questionable, and security of supply for a manufacturing process could present a risk.  They additionally add no or limited benefits with regards to the health hazard properties. SDSs for DMPU and TMU state that these substances are toxic for reproduction. No information on the reprotoxic properties of DMI was found at the time for the evaluation but it is reasonable to assume that DMI is also reprotoxic based on the chemical similarity with NMP and the other solvents in this group

Other Pharmaceutical Uses
 
We are also aware of some uses of this material as an excipient in finished product and similar issues around substitution and reformulation would be encountered	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
36	2011/04/07	International organisation
Council of Europe, Directorate for the Quality of Medicines and HealthCare
France	The quality of medicines including their containers and raw materials may be compromised, if 1-methyl-2-pyrrolidone is withdrawn from the market. Monograph (1675) controls the quality of N-Methylpyrrolidone. It is also used as a reagent for determining the quality of amphotericin B and pyrrolidone. 	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
35	2011/04/07	Other contributor

United Kingdom	Use of NMP in the Pharmaceutical Industry - background 

N-methyl pyrrolidone, or NMP, is one of a class of extremely useful solvents designated as polar aprotics. The physical properties of these solvents make them an attractive choice from a chemistry perspective in the synthesis of Active Pharmaceutical Ingredients (APIs) and associated intermediates.  Advantages of NMP include:
•	NMP offers generally high solubility of many APIs and intermediates, which often  have very poor solubility in less polar solvents.  This facilitates processes that require minimal solvent quantities, compared with the much larger volumes of other solvents that may be required.
•	NMP additionally offers sufficient solubility of many inorganic reagents (e.g. acids & bases) that facilitates chemical reactions that would not be practicable or robust in many other organic solvents.

•	Reaction rates of certain reactions (e.g. nucleophilic substitution) are substantially enhanced due to the solvent polarity.
•	The use of these solvents can be essential (due to their relatively low acidity) when strong bases are employed as these materials would be completely consumed by side reactions if protic solvents were used.  
•	Water miscibility – for example facilitating precipitation, and subsequent isolation, of products from reaction liquors through the addition of water as an anti-solvent.
•	A high boiling point (202oC) – allowing reactions to be carried out at much higher temperatures than would be achievable in many organic solvents, without the need to operate under pressure (often not operationally feasible in typical pharmaceutical reactors, and inherently of greater operational hazard).  An additional benefit is that the potential for solvent emissions associated with processing is less than those associated with many other solvents.

NMP is therefore used within pharmaceutical research and development laboratories, development manufacturing pilot plants and commercial manufacturing plants.

Regulation of NMP under the Solvent Emissions Directive (European Community Directive 1999/13/EC as amended by Directive 2004/42/EC)

As a result of the properties described above, NMP had become a ‘solvent of choice’ for the pharmaceutical industry.  However, this changed in 2009 when NMP was assigned the Risk-phrase R61 (May cause harm to the unborn child.).  This meant that use of NMP fell under the control of the Solvent Emissions Directive (SED) within the EU. This requires specific industries, including the pharmaceutical manufacturing industry, to apply the ‘replace, control and limit’ requirements of the Solvent Emissions Directive within the shortest possible time from the date at which NMP became designated as a specified risk phrase material.  

In effect, the SED already requires that alternatives to NMP be utilised within the pharmaceutical industry, unless no feasible and reasonably practicable alternative can be found.  The major problem for industry presented by the assignment of the R61 phrase to NMP, and its subsequent regulation under the SED, is that the most frequently used and feasible alternatives, have the same reprotoxic health risks associated with them, and hence also fall within the ‘replace’ obligations of the SED.

In cases where it is not possible to substitute NMP, the SED requires very strict air emission limits to be complied with (≤10 g/h or ≤2 mg/m3) for the protection of the local environment and population.  Use in modern, contained pharmaceutical manufacturing plants, allow NMP to be safely handled under conditions that maintain exposure levels below relevant occupational exposure standards and thus adequately protect worker health, without out the need to employ ‘special’ equipment/precautions.

Alternative Polar Aprotic Solvents to NMP

A key point of consideration for the pharmaceutical industry is the regulatory implications that may be associated with changing the solvent used in any stage of a commercial manufacturing process that is registered with the appropriate regulatory health authorities.  Changes to such processes invariably require extensive redevelopment of processes and associated interaction/authorisation from health authorities in order to ensure product quality, efficacy and patient safety is not compromised.  Typically, changing a commercial process would necessarily involve a long lead time, large amounts of work and significant associated costs.  

There are a number of solvents that could potentially be used in place of NMP in some API manufacturing syntheses.  The most common ‘direct’ alternatives used within the pharmaceutical industry are highlighted in the ECHA dossier: DMF (N, N-dimethylformamide, CAS 68-12-2) and DMAc (dimethylacetamide, CAS 127-19-5).  Also noted in the dossier, these alternatives carry essentially the same health hazard (R61) as NMP.  However, the risk associated with using DMF or DMAc is greater – they have higher volatility (i.e. lower boiling point) than NMP, meaning that the risk of worker or environmental exposure through use of these solvents is generally higher.  This point is illustrated in the table below, where a ‘vapour hazard ranking’ has been assigned for DMF, DMAc and NMP by dividing the saturated concentration of the solvent (at 20 oC) by the UK 8 hour TWA Occupational Exposure Standard.  NMP can clearly be seen to be the lowest risk of these 3 solvents.

Solvent	UK Long-term exposure 
limit (8-hour TWA) [ppm]	Vapour pressure [mmHg at 20 oC]	Ratio (vapour pressure/8hr  TWA LTEL) [mmHg/ppm]	Vapour hazard ranking
DMF	10	2.9	0.29	1
DMAc	10	2.7	0.27	2
NMP	25	0.33	0.013	3

Other alternative polar aprotic solvents exist, a number of which are listed and commented on below.  As can be seen from the comments on these solvents below, there are other limitations associated with these alternatives may prevent their use in specific circumstances.  Whilst a more detailed, circumstance specific, consideration is of course required in the context of a particular chemical process, these comments serve to illustrate that finding a feasible alternative to NMP (or DMF, DMAc) may not be possible.

•	Dimethyl sulfoxide (DMSO), CAS 67-68-5.  DMSO) is a potentially reactive chemical and thermal instability can be induced by a range of chemicals / impurities.  Many incidents have been reported involving this solvent .  From a safety point of view alone alternative solvents should be investigated before choosing DMSO as a reaction solvent. This can also be the case with other aprotic solvents such as dimethyl formamide (DMF), dichloromethane (DCM), etc.  NMP is a much more thermally stable solvent and appears to have a lower potential for hazardous interactions with other reagents based on a number of compatibility tests undertaken .
•	Dichloromethane (DCM), CAS 75-09-2.  In addition to the potential reactive hazards noted in the previous bullet, DCM presents significant health hazards as a Category 2 carcinogen (under CLP (EC)1272/2008).  As such, it is also controlled by the Solvent Emission Directive (albeit not subject to the same ‘replace’ obligations). It’s very high volatility (BP 37 oC) means that, using the same vapour hazard ranking as above, it is substantially higher risk than NMP, DMF or DMAc, with a ratio of 3.5 mmHg/ppm. 
•	Sulfolane, CAS 126-33-0.  Sulfolane has a high melting point (range ~ 20 – 26 oC oC)  and consequently may often prove operationally impracticable.
•	Acetone (CAS 67-64-1) and Acetonitrile (CAS 75-05-8).  Neither of these solvents possess the high solvating power of NMP, DMF and DMAc, nor the high boiling point to facilitate higher temperature reactions.

•	DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, CAS 7226-23-5), DMI (2,3-dimethyl 2-imidazolidione CAS 80-73-9), TMU (Tetramethylurea, CAS 632-22-4). These solvents are relatively new and have been the subject of recent evaluation within one of our member companies.  Whilst they appear to offer some opportunity as alternatives to NMP, their commercial availability is currently questionable, and security of supply for a manufacturing process could present a risk.  They additionally add no or limited benefits with regards to the health hazard properties. SDSs for DMPU and TMU state that these substances are toxic for reproduction. No information on the reprotoxic properties of DMI was found at the time for the evaluation but it is reasonable to assume that DMI is also reprotoxic based on the chemical similarity with NMP and the other solvents in this group

Other Pharmaceutical Uses

We are also aware of some uses of this material as an excipient in finished product and similar issues around substitution and reformulation would be encountered
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
32	2011/04/07	Company

Ireland	2 Uses of the substance
2.7.1 Use 6# Pharmaceuticals [page 30]
N-methyl pyrrolidone, or NMP, is one of a class of extremely useful solvents designated as polar aprotics. The physical properties of these solvents make them an attractive choice from a chemistry perspective in the synthesis of Active Pharmaceutical Ingredients (APIs) and associated intermediates.  Advantages of NMP include:

a) NMP offers generally high solubility of many APIs and intermediates, which often  have very poor solubility in less polar solvents.  This facilitates processes that require minimal solvent quantities, compared with the much larger volumes of other solvents that may be required.
b) NMP additionally offers sufficient solubility of many inorganic reagents (e.g. acids & bases) that facilitates chemical reactions that would not be practicable or robust in many other organic solvents.
c) Reaction rates of certain reactions (e.g. nucleophilic substitution) are substantially enhanced due to the solvent polarity.
d) The use of these solvents can be essential (due to their relatively low acidity) when strong bases are employed as these materials would be completely consumed by side reactions if protic solvents were used.  
e) Water miscibility – for example facilitating precipitation, and subsequent isolation, of products from reaction liquors through the addition of water as an anti-solvent.
f) A high boiling point (202oC) – allowing reactions to be carried out at much higher temperatures than would be achievable in many organic solvents, without the need to operate under pressure (often not operationally feasible in typical pharmaceutical reactors, and inherently of greater operational hazard).  An additional benefit is that the potential for solvent emissions associated with processing is less than those associated with many other solvents.

NMP is therefore used within pharmaceutical research and development laboratories, development manufacturing pilot plants and commercial manufacturing plants.

4. Current knowledge on alternatives [page 57]
A key point of consideration for the pharmaceutical industry is the regulatory implications that may be associated with changing the solvent used in any stage of a commercial manufacturing process that is registered with the appropriate regulatory health authorities.  Changes to such processes invariably require extensive redevelopment of processes and associated interaction/authorisation from health authorities in order to ensure product quality, efficacy and patient safety is not compromised.  Typically, changing a commercial process would necessarily involve a long lead time, large amounts of work and significant associated costs.  

There are a number of solvents that could potentially be used in place of NMP in some API manufacturing syntheses.  The most common ‘direct’ alternatives used within the pharmaceutical industry are highlighted in the ECHA dossier: DMF (N, N-dimethylformamide, CAS 68-12-2) and DMAc (dimethylacetamide, CAS 127-19-5).  Also noted in the dossier, these alternatives carry essentially the same health hazard (R61) as NMP.  However, the risk associated with using DMF or DMAc is greater – they have higher volatility (i.e. lower boiling point) than NMP, meaning that the risk of worker or environmental exposure through use of these solvents is generally higher.  

Other alternative polar aprotic solvents exist, a number of which are listed and commented on below.  As can be seen from the comments on these solvents below, there are other limitations associated with these alternatives may prevent their use in specific circumstances.  Whilst a more detailed, circumstance specific, consideration is of course required in the context of a particular chemical process, these comments serve to illustrate that finding a feasible alternative to NMP (or DMF, DMAc) may not be possible.

* Dimethyl sulfoxide (DMSO), CAS 67-68-5.  DMSO) is a potentially reactive chemical and thermal instability can be induced by a range of chemicals / impurities. DMSO decomposes always and the decomposition is depending on temperature. Decomposition is accompanied by a high release of heat (~600 J/g) an high gas formation (runaway). The decomposition of DMSO is not only self-accelerating but also a accelerated by both acids and bases, particularly with even trace amounts of organic and inorganic halogenides. DMSO decomposes via an autocatalytic mechanism following two paths. First path leading to formaldehyde (gives rise to a violent polymerization reaction to paraformaldehyde) and methylsulfide. Second path via disproportionation into dimethylsulfon and dimethylsulfide. Many incidents have been reported involving this solvent (Bretherick’s Handbook of Reactive Chemical Hazards (6th Edn. P336). From a safety point of view alone alternative solvents should be investigated before choosing DMSO as a reaction solvent. This can also be the case with other aprotic solvents such as dimethyl formamide (DMF), dichloromethane (DCM), etc.  NMP is a much more thermally stable solvent and appears to have a lower potential for hazardous interactions with other reagents based on a number of compatibility tests undertaken.
* Dichloromethane (DCM), CAS 75-09-2.  In addition to the potential reactive hazards noted in the previous bullet, DCM presents significant health hazards as a Category 2 carcinogen (under CLP (EC)1272/2008).  As such, it is also controlled by the Solvent Emission Directive (albeit not subject to the same ‘replace’ obligations). It’s very high volatility (BP 37 oC) means that, using the same vapour hazard ranking as above, it is substantially higher risk than NMP, DMF or DMAc, with a ratio of 3.5 mmHg/ppm. 
* Sulfolane, CAS 126-33-0.  Sufolane has a high melting point (range ~ 20 – 26 oC oC)  and consequently may often prove operationally impracticable.
* Acetone (CAS 67-64-1) and Acetonitrile (CAS 75-05-8).  Neither of these solvents possess the high solvating power of NMP, DMF and DMAc, nor the high boiling point to facilitate higher temperature reactions.

Regulation of NMP under the Solvent Emissions Directive (European Community Directive 1999/13/EC as amended by Directive 2004/42/EC)
As a result of the properties described above, NMP had become a ‘solvent of choice’ for the pharmaceutical industry.  However, this changed in 2009 when NMP was assigned the Risk-phrase R61 or hazard statement H360D (May cause harm to the unborn child.).  This means that use of NMP is regulated by the Solvent Emissions Directive (SED) within the EU. This requires specific industries, including the pharmaceutical manufacturing industry, to apply the replace, control and limit requirements of the Solvent Emissions Directive within the shortest possible time from the date at which NMP became designated as a specified risk phrase material.  

In effect, the SED already requires that alternatives to NMP be utilised within the pharmaceutical industry, unless no feasible and reasonably practicable alternative can be found.  The major problem for industry presented by the assignment of the H360D statement or R61 phrase to NMP, and its subsequent regulation under the SED, is that the most frequently used and feasible alternatives, have the same reprotoxic health risks associated with them, and hence also fall within the ‘replace’ obligations of the SED.

In cases where it is not possible to substitute NMP, the SED requires very strict air emission limits to be complied with (≤10 g/h or ≤2 mg/m3) for the protection of the local environment and population.  Use in modern, contained pharmaceutical manufacturing plants, allow NMP to be safely handled under conditions that maintain exposure levels below relevant occupational exposure standards and thus adequately protect worker health, without out the need to employ ‘special’ equipment/precautions.

Summary
NMP is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and associated intermediates.  Existing regulation under the Solvent Emissions Directive means that use of NMP within pharmaceutical manufacturing is restricted to those applications where there is no feasible alternative.  A lack of alternative solvents without the same hazards as NMP means that placing NMP on the SHVC Candidate List and potential prioritisation for inclusion in Annex XIV would, in certain circumstances, push the pharmaceutical industry towards using alternatives that present a higher risk to both worker health and the environment than NMP	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
31	2011/04/07	Company

Belgium	2 Uses of the substance
2.7.1 Use 6# Pharmaceuticals [page 30]
N-methyl pyrrolidone, or NMP, is one of a class of extremely useful solvents designated as polar aprotics. The physical properties of these solvents make them an attractive choice from a chemistry perspective in the synthesis of Active Pharmaceutical Ingredients (APIs) and associated intermediates.  Advantages of NMP include:

a) NMP offers generally high solubility of many APIs and intermediates, which often  have very poor solubility in less polar solvents.  This facilitates processes that require minimal solvent quantities, compared with the much larger volumes of other solvents that may be required.
b) NMP additionally offers sufficient solubility of many inorganic reagents (e.g. acids & bases) that facilitates chemical reactions that would not be practicable or robust in many other organic solvents.
c) Reaction rates of certain reactions (e.g. nucleophilic substitution) are substantially enhanced due to the solvent polarity.
d) The use of these solvents can be essential (due to their relatively low acidity) when strong bases are employed as these materials would be completely consumed by side reactions if protic solvents were used.  
e) Water miscibility – for example facilitating precipitation, and subsequent isolation, of products from reaction liquors through the addition of water as an anti-solvent.
f) A high boiling point (202oC) – allowing reactions to be carried out at much higher temperatures than would be achievable in many organic solvents, without the need to operate under pressure (often not operationally feasible in typical pharmaceutical reactors, and inherently of greater operational hazard).  An additional benefit is that the potential for solvent emissions associated with processing is less than those associated with many other solvents.

NMP is therefore used within pharmaceutical research and development laboratories, development manufacturing pilot plants and commercial manufacturing plants.

4. Current knowledge on alternatives [page 57]
A key point of consideration for the pharmaceutical industry is the regulatory implications that may be associated with changing the solvent used in any stage of a commercial manufacturing process that is registered with the appropriate regulatory health authorities.  Changes to such processes invariably require extensive redevelopment of processes and associated interaction/authorisation from health authorities in order to ensure product quality, efficacy and patient safety is not compromised.  Typically, changing a commercial process would necessarily involve a long lead time, large amounts of work and significant associated costs.  

There are a number of solvents that could potentially be used in place of NMP in some API manufacturing syntheses.  The most common ‘direct’ alternatives used within the pharmaceutical industry are highlighted in the ECHA dossier: DMF (N, N-dimethylformamide, CAS 68-12-2) and DMAc (dimethylacetamide, CAS 127-19-5).  Also noted in the dossier, these alternatives carry essentially the same health hazard (R61) as NMP.  However, the risk associated with using DMF or DMAc is greater – they have higher volatility (i.e. lower boiling point) than NMP, meaning that the risk of worker or environmental exposure through use of these solvents is generally higher.  

Other alternative polar aprotic solvents exist, a number of which are listed and commented on below.  As can be seen from the comments on these solvents below, there are other limitations associated with these alternatives may prevent their use in specific circumstances.  Whilst a more detailed, circumstance specific, consideration is of course required in the context of a particular chemical process, these comments serve to illustrate that finding a feasible alternative to NMP (or DMF, DMAc) may not be possible.

* Dimethyl sulfoxide (DMSO), CAS 67-68-5.  DMSO) is a potentially reactive chemical and thermal instability can be induced by a range of chemicals / impurities. DMSO decomposes always and the decomposition is depending on temperature. Decomposition is accompanied by a high release of heat (~600 J/g) an high gas formation (runaway). The decomposition of DMSO is not only self-accelerating but also a accelerated by both acids and bases, particularly with even trace amounts of organic and inorganic halogenides. DMSO decomposes via an autocatalytic mechanism following two paths. First path leading to formaldehyde (gives rise to a violent polymerization reaction to paraformaldehyde) and methylsulfide. Second path via disproportionation into dimethylsulfon and dimethylsulfide. Many incidents have been reported involving this solvent (Bretherick’s Handbook of Reactive Chemical Hazards (6th Edn. P336). From a safety point of view alone alternative solvents should be investigated before choosing DMSO as a reaction solvent. This can also be the case with other aprotic solvents such as dimethyl formamide (DMF), dichloromethane (DCM), etc.  NMP is a much more thermally stable solvent and appears to have a lower potential for hazardous interactions with other reagents based on a number of compatibility tests undertaken.
* Dichloromethane (DCM), CAS 75-09-2.  In addition to the potential reactive hazards noted in the previous bullet, DCM presents significant health hazards as a Category 2 carcinogen (under CLP (EC)1272/2008).  As such, it is also controlled by the Solvent Emission Directive (albeit not subject to the same ‘replace’ obligations). It’s very high volatility (BP 37 oC) means that, using the same vapour hazard ranking as above, it is substantially higher risk than NMP, DMF or DMAc, with a ratio of 3.5 mmHg/ppm. 
* Sulfolane, CAS 126-33-0.  Sufolane has a high melting point (range ~ 20 – 26 oC oC)  and consequently may often prove operationally impracticable.
* Acetone (CAS 67-64-1) and Acetonitrile (CAS 75-05-8).  Neither of these solvents possess the high solvating power of NMP, DMF and DMAc, nor the high boiling point to facilitate higher temperature reactions.

Regulation of NMP under the Solvent Emissions Directive (European Community Directive 1999/13/EC as amended by Directive 2004/42/EC)
As a result of the properties described above, NMP had become a ‘solvent of choice’ for the pharmaceutical industry.  However, this changed in 2009 when NMP was assigned the Risk-phrase R61 or hazard statement H360D (May cause harm to the unborn child.).  This means that use of NMP is regulated by the Solvent Emissions Directive (SED) within the EU. This requires specific industries, including the pharmaceutical manufacturing industry, to apply the replace, control and limit requirements of the Solvent Emissions Directive within the shortest possible time from the date at which NMP became designated as a specified risk phrase material.  

In effect, the SED already requires that alternatives to NMP be utilised within the pharmaceutical industry, unless no feasible and reasonably practicable alternative can be found.  The major problem for industry presented by the assignment of the H360D statement or R61 phrase to NMP, and its subsequent regulation under the SED, is that the most frequently used and feasible alternatives, have the same reprotoxic health risks associated with them, and hence also fall within the ‘replace’ obligations of the SED.

In cases where it is not possible to substitute NMP, the SED requires very strict air emission limits to be complied with (≤10 g/h or ≤2 mg/m3) for the protection of the local environment and population.  Use in modern, contained pharmaceutical manufacturing plants, allow NMP to be safely handled under conditions that maintain exposure levels below relevant occupational exposure standards and thus adequately protect worker health, without out the need to employ ‘special’ equipment/precautions.

Summary
NMP is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and associated intermediates.  Existing regulation under the Solvent Emissions Directive means that use of NMP within pharmaceutical manufacturing is restricted to those applications where there is no feasible alternative.  A lack of alternative solvents without the same hazards as NMP means that placing NMP on the SHVC Candidate List and potential prioritisation for inclusion in Annex XIV would, in certain circumstances, push the pharmaceutical industry towards using alternatives that present a higher risk to both worker health and the environment than NMP	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
30	2011/04/07	Industry or trade association
CONCAWE
Belgium	Page 42 - Section 3.4.6 Petrochemical Processing
1-methyl-2-pyrrolidone (NMP) is used by some petroleum refineries (i.e., industrial facilities), employing a high level of process containment, as an extraction solvent in the production of lubricant base oils to remove aromatic hydrocarbons (e.g PAHs) and other polar components. This extraction process leads to improved lubricating oils with lower impact to human health and the environment.
This use of NMP  is acknowledged in the Integrated Pollution Prevention and Control (IPPC) Reference Document on Best Available Techniques for Mineral Oil and Gas Refineries (February 2003) as Best Available Technology. The environmental benefits cited in the BREF include reduction of in refinery effluents of more toxic solvents such as phenols and sulphur dioxide and a lower consumption of energy. NMP is recovered and recycled in closed systems. There is no exposure to professionals or consumers; hence, there is no wide dispersive use.
	Thank you for the information on the use and regulation of NMP in petrochemical processing. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
29	2011/04/07	Company

France	2 – Uses of the substance
2.7 Use #6 - Pharmaceuticals
2.7.1 Functions of the substance (p.30)
We use the 1-methyl-2-pyrrolidone as a synthesis solvent in the manufacture process of active ingredient for pharmaceutical and cosmetic applications.

The 1-methyl-2-pyrrolidone belongs to the class of dipolar aprotic solvents which is essential in organic chemistry in the reactions including anionic nucleophiles.
The majority of the solvents of this class present disadvantages and toxicological alerts.
One of the best solvent (selectivity, yield) in this class is Dimethylformamide which is also reproductive toxicant. DMF has been progressively replaced by industrials by 1-methyl-2-pyrrolidone because it was the only solvent able to substitute it in good conditions in a lot of reactions.

2.7.2 Sectors of use (p.30)
It’s important to note that for these uses as synthesis solvent, the 1-methyl-2-pyrrolidone is not present in the active ingredients nor in the final product. 
The sector of use is active ingredient manufacturer which means only industrial sector.
The 1-methyl-2-pyrrolidone is used in close vessels (tanks, filter dryer,…).

2.7.3 Quantity involved (P.31)
We use less than 300 t/year of the 1-methyl-2-pyrrolidone.

3 – Releases from uses
3.4.9 – Uses of NMP in the preparation of pharmaceuticals (or cosmetic active ingredient)(p.44)

The release of NMP during this type of industrial application is very low since the process is most of the time close process (filling by pipes, reaction in close vessels, drying of the product in closed filter dryer,…). During the few operations that could emit NMP, the emission is controlled with local ventilation and extra individual protection for employees (respiratory and dermal protections).
It’s important to note that the boiling point of NMP is quite high (204°C) compared to other process solvent.
Moreover, we confirm that there is no consumer release and exposure associated to the use of NMP as synthesis solvent since it is not present in the final active ingredient.

4 - Current knowledge on alternatives (p.57)

As already explained, the majority of dipolar aprotic solvents present disadvantages and toxicological alerts. NMP was today the best alternative to Dimethylformamide.
The only one in this class that is non toxic is Dimethyl Sulfoxide (DMSO) but it can not be used in all the cases for instance because of chemical incompatibility hazards, or because of its physical chemistry properties. Moreover, when it can be used the selectivity of the reaction is worse and as a consequence the purity of active ingredient as well.
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
28	2011/04/07	Member State
Germany	Pages 35 and 38 refer to „hand application“ or “finger paint” in the framework of professional use. Such terms suggest unprotected contact with formulations containing NMP (and probably other solvents). This seems strange in the field of industrial use. Please clarify.

E. ANNEX 5, p 86-112: The tables which describe the predicted levels of occupational exposures (table 35-36, 38-51) are ambiguous, since both of the columns are labelled in the same way as “Predicted inhalatory exposure (ppm) Predicted dermal exposure (mg/kg bw/day)”. An unambiguous description of the exposure (inhalative or dermal) would be desirable as well as the consistent application of the same dimension for the sake of comparability (ideally mg/kg bw/day plus mg/m³ or ppm in case of inhalative exposure). Since dermal exposure may play an important role for this substance, the total exposure (inhalative + dermal) should be summarized in an additional column for each scenario as well.  This would allow for assessing the total risk adequately.

The estimates made with ECETROC-TRA are not traceable since the assumptions made for the respective exposure scenarios are not explicated. Some of the values appear implausible in this context (e.g. table 42: it is not clear and not self-evident why the predicted exposure for scenario 9 “Material transfers. Drum/batch transfers.” is higher than that for scenario 13 “Manual. Spraying. Indoor”, the same applies to table 43:  scenario 10 and 13).

Page 45-55, 3.5 Consumer releases and exposure
Chronic consumer exposures from uses in coatings and cleaners are calculated by considering use frequencies of 1/year or 2/year. Given the fast metabolisation of NMP, these calculations may not be appropriate. (Reproductive risks also may arise from short time exposures of pregnant women to NMP.)

Assuming 5 % (w/w) of NMP as co-solvent in waterborne wall paint seems unrealistic as 1-2 % is assumed in the cited reference (Bremmer and van Engelen 2007).

Information on alternative substances and techniques:
Page 60 mentions 10 resp 15% as extra cost for using NEP as an alternative.  Page 62 mentions for NEP and 1,3-dimethyl-2-imidazolidinone a cost 10 times that of NMP. Such a large discrepancy seems unlikely to be correct, at least as far as NEP is concerned. This detail should be clarified.	Thank you for providing your comments. The issues will be clarified and provided that the substance is identified as SVHC considered in the follow-up stages of the risk management process. 
	
27	2011/04/06	Company
Gaylord Chemical Company
United States	We believe that the document does not fully consider Dimethyl Sulfoxide (DMSO)as a strong alternative to N-Methyl Pyrollidone (NMP). DMSO has many chemical properties (polarity, comparable Hansen Solubility Parameters, solubility properties) to suggest its use as an alternative to NMP in Paint removal, microelectronic manufacturing, and pharmaceutical synthesis. 
 	See reply to comment 27 above.
	
			See also:
Comment 27 attachment (DMSO as NMP alternative.pdf).pdf		
26	2011/04/06	Industry or trade association
Arkema
France	The main long-term alternative to NMP available on the market is dimethylsulfoxide (DMSO). Whilst DMSO certainly is not a drop-in substitute for all applications, it has a broad spectrum of uses in which it could replace NMP, with significantly reduced environment and/or health risk.

-	There is a extensive physico-chemical, environmental and toxicological database available on DMSO demonstrating that DMSO is of low concern for the environment and the human health. (SIDS dossier available at http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=4C5A1A36-54BC-41C3-950F-AE4171BDA7F5).
-	DMSO, like NMP, belongs to the class of aprotic polar solvents. It is a powerfull organic solvent which is well established in the industry, with dissolving properties for binder polymers (including PVDF, PAI, PUs, acrylics, ..) identical to NMP.
-	DMSO is widely available. Arkema manufactures DMSO in Europe. Two other manufacturers have registered DMSO in 2010 (REACH registration number 01-2119431362-50-0000). Global DMSO manufacturing capacity is estimated to be 80,000mT.  

In Coatings Applications:
-	DMSO can substitute 1:1 NMP for liquid rheology additives for aqueous coatings, pigment concentrates additives, for solvent-borne and solvent-free systems. http://www.crayvallac.com/TDS/CRAYVALLAC_LA-150_en.pdf, http://www.crayvallac.com/TDS/CRAYVALLAC_LA-250_en.pdf
-	Laboratory testing has demonstrated that DMSO can substitute 1:1 NMP as a coalescing agent and adhesion promoter in waterborne paints for most automotive and industrial uses.  Customer approval are ongoing.

In Industrial and Consumer cleaners

DMSO is a powerfull solvent and has a high solvating power for plastics, resins, oil and grease. DMSO and DMSO based formulations are widely used in paint removers, floor strippers, graffiti remover, industrial degreasing and equipment cleaning application.
http://www.rhodia.com/en/markets_and_products/new_products/Novecare_Rhodiasolv_STRIP.tcm
http://www.dodconf.swri.org/2003Papers/Dishart.pdf

In Agricultural chemicals
The powerful solvent properties of DMSO allow for high actives loading, resulting in highly concentrated formulations. In addition DMSO is used to aid systemic transport of active pesticides, growth initiators and nutrients. DMSO is the preferred formulation solvent for Imidacloprid, a general use pesticide.

In electronic applications: 

DMSO is available at the required purity level to meet the stringent requirement of the semiconductor industry. This is a well establish application field for DMSO. High purity electronic grades of DMSO are used as a major component in bulk photoresist stripping formulations, and as an additive in specialized post-etch cleaning products and edge bead removers. DMSO performance is similar to NMP.
http://www.microchemicals.com/remover_stripper.html
http://cleanconcept.eu/clean_concept_english/images/clean_concept/Datasheet_OPS976.pdf
	Thank you for the information regarding dimethyl sulfoxide as alternative substance to NMP.
Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
			See also:
Comment 26 CONFIDENTIAL attachment 		
25	2011/04/06	Company
Shasun Pharma Solutions Ltd
United Kingdom	The Annex XV report on N Methyl Pyrrolidone, (NMP), EC 212-828-1, does not address the use of NMP as a solvent in industrial intermediate pharmaceutical and fine chemical synthesis. We have no quantitative data on this use in the EU, but we believe that it likely to be significant as NMP has highly desirable properties as a dipolar aprotic solvent and as a substitute for methylene chloride (MDC) EC 200-838-9. Note – this use as a substitute for MDC is documented in Table 21 of the Annex XV report.

Shasun Pharma Solutions Ltd uses NMP as a solvent in the manufacture of several Intermediates for a number of Active Pharmaceutical Ingredients (API’s). These API’s are regulated by the FDA and MHRA and are used in the treatment of Hepatitis C, of Schizophrenia, and of Essential Thrombocythemia, and there would be a considerable socio-economic impact, to patients and to the cost of research and subsequent regulatory approval, if NMP was not available for use as a solvent in the manufacturing process for the API’s.

Shasun Pharma Solutions Ltd suggests that relevant information on the use of NMP as a solvent in the manufacture of pharmaceutical intermediates be added to the Annex XV report, or presented as additional information, on uses of the substance, to the European Commission, such that it can be considered in the recommendation to the Commission regarding inclusion of NMP as an Annex XIV SVHC.

Shasun Pharma Solutions Ltd  further suggests that should NMP be included in Annex XIV, then the use of the substance as a solvent in industrial intermediate pharmaceutical and fine chemical synthesis should be exempt from any restriction or authorisation as such manufacture is controlled by regulatory agencies such as FDA and MHRA and manufacture is operated under ‘Strictly Controlled Conditions’ as defined by the EC REACH regulation, in closed systems with negligible inhalation or dermal exposure, and low emission of the substance to the environment.	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
21	2011/04/06	Company

Ireland	1-methyl-2-pyrrolidone (NMP) is used as part of a batch process in the manufacture of a polymer.  The solvent is extracted during the manufacturing process and waste solvent is either recovered or disposed of as hazardous waste for incineration. 

Alternatives are currently not available and it will require considerable resources to trial and validate alternatives, if at all possible.

In addition, our customers in the pharmaceutical industry who have validated the use of our polymer through governmental agencies such as the European Medicines Agency (EMEA) or the United States Food and Drug Administration (FDA) will be forced to undergo a lengthy revalidation process to continue manufacturing the therapeutics they produce using our polymer products.

Exposure of workers:
The process is contained with local exhaust ventilation and area monitoring completed on a regular basis.  Operators are trained and adequate personal protective equipment is worn where required.

Exposure to the environment/public:
Waste solvent is disposed according to all applicable regulations.  Areas of use are equipped with spill barriers (bunded) and containment programmes are in place.

Exposure to the customer:
The vast majority of our customers are in the pharmaceutical industry, so validation of the polymer is often required, including approval by government agencies such as the EMEA or FDA.	Thank you for the information on the use of NMP in the manufacture of polymers. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
20	2011/04/06	Company

France	Refer to Astra Zeneca position paper	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
			See also:
Comment 20 CONFIDENTIAL 		
18	2011/04/06	Company

Germany	USES:   
Use of the Substance / Preparation: Process additive for the petrochemical industry
Function: Polymerization inhibitor for monomers.
The 1-methyl-2-pyrrolidone (NMP) is used as solvent/co-solvent in the production of petrochemical additives.

HANDLING AND STORAGE
Handling
Precautions for safe handling
Observe the rules usually applicable when handling chemicals.
Wear personal protective equipment; see section 8.
Advice on protection against fire and explosion
Take precautionary measures against static charges, keep away from sources of ignition.
Explosion protection equipment required.

Storage
Conditions for safe storage, including any incompatibilities
Keep container tightly closed.
Keep in a well-ventilated place.
Keep in a cool place.
Advice on common storage
Keep separate from foodstuffs, luxury foods, feedstuffs.
Risk Management Measures (RMM´s):
EXPOSURE CONTROLS/PERSONAL PROTECTION
Control parameters
1-methyl-2-pyrrolidone
CAS-No. 872-50-4 EC-No. 212-828-1
Control parameters 25 ppm
103 mg/m3
Time Weighted Average (TWA):(EH40 WEL)
Control parameters 75 ppm
309 mg/m3
Short Term Exposure Limit (STEL):(EH40 WEL)
Control parameters Skin designation:(EH40 WEL)
Can be absorbed through the skin.
Control parameters 10 ppm Time Weighted Average (TWA):(EU ELV)
40 mg/m3
Indicative
Control parameters 20 ppm
80 mg/m3
Short Term Exposure Limit (STEL):(EU ELV)
Indicative
Control parameters Skin designation:(EU ELV)
Can be absorbed through the skin.

Personal protective equipment
Respiratory protection
Use suitable respiratory protection where aerosols/vapours are generated.
If workplace exposure limit is exeeded apply respirator with ABEK-P3 combination filter.
Note time limit for wearing respiratory protective equipment.

Hand protection

Recommendation:
suitable protective gloves
Glove material nitrile rubber, butyl-rubber, Fluorinated rubber (Viton), Remember that the
useful time per day of a chemical protection glove may be much shorter than
the permeation time determined according to EN 374 due to the many
different influential factors involved (e.g. temperature)., The rupture time and
material thickness data are guideline values! Exact rupture time / material
thickness data can be obtained from the protective glove manufacturer.
Material thickness 0.5 - 0.85 mm
Method DIN EN 374

Eye protection
close-fitting protective goggles (e.g. closed goggles)

Skin and body protection
suitable protective clothing - Use disposable clothing if appropriate.

Hygiene measures
Avoid contact with skin and eyes.
Wash off immediately in the event of contact with the skin (rinsing agent: glycol polyethylene 400), rinse off
afterwards with copious amounts of water.
No eating, drinking, smoking, or snuffing tobacco at work. Wash face and/or hands before break and end of
work.
Take off clothing and shoes contaminated with product. Clean before reuse.

Protective measures
The personal protective equipment used must meet the requirements of directive 89/686/EEC and
amendments (CE certification).
	Thank you for the information on the use and regulation of NMP in petrochemical processing. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
19	2011/04/06	Company

Belgium	NMP is a particularly useful solvent frequently used in the chemical synthesis of Active Pharmaceutical Ingredients and associated intermediates.

The physical properties of NMP make it an attractive solvent in the synthesis of Active Pharmaceutical Ingredients (APIs) and associated intermediates (e.g. high solubility of many APIs and intermediates, sufficient solubility of many inorganic reagents, enhanced reactions due to the solvent polarity, water miscibility, high boiling point,...).

The most feasible alternatives (e.g. SED, DMF, DMAc, DMSO, DCM, acetone,....) have identical or even additional hazards as NMP or have other limitations in the context of the particular chemical process concluding these alternatives are not feasible.

In addition, introduction of alternatives require extensive redevelopment of processes and associated interaction/authorisation from health authorities.

Inclusion into Annex XIV, purely based on hazard, not taking into account the specific measures in place during pharmaceutical manufacturing is neither acceptable. 

Due to a lack of alternative solvents, the pharmaceutical industry would be pushed towards using alternatives that present a higher risk to both worker health and the environment than NMP.

Considering above comments, as well the more detailed argumentation drawn up by Astra Zeneca, do us conclude the inclusion of NMP in Annex XIV would be inappropriate.	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

	
			See also:
Comment 19 attachment (AZ comments_NMP SVHC_18_03_11 (2).pdf).pdf		
17	2011/04/06	Company
Mitsubishi Chemical Corporation
Japan	P.17 PartII 2 USE OF THE SUBSTANCE
Mitsubishi Chemical Corporation, a manufacturer of NMP (cas. 872-50-4) in Japan, hereby provides our comments for the proposal Annex XV dossier.  Our main claim is that further restriction of industrial use for NMP has the serious potential to make a substantial negative impact on industry and global society: many industrial uses and no suitable alternative to NMP have been identified.

NMP has been industrially used for coating solvents for the synthetic resins and reaction solvents for engineering plastics (e.g. polyphenylene sulfide resin, polyimide resin) because NMP is a very stable, highly effective solvent for synthetic resins.
Specifically we note that the important uses of NMP as a solvent for manufacture of lithium ion batteries and in liquid crystal display panels are not directly addressed in the Annex XV dossier.
We would like to provide the information on use of NMP for manufacture of lithium ion batteries.  An electrode in a lithium ion battery determines capacity and life of the battery, so the electrode is one of the most important parts of the battery.  In the manufacturing process of the electrode, NMP has been used as a solvent for binder resins between a metal foil and an active material for positive/negative electrode agents.  From the point of view of proper performance of the electrode, it is essential for a solvent to dissolve PolyVinylidene DiFluoride (PVdF) of the binder sufficiently, and the solvent with the active material need to be dispersed uniformly on the metal foil with the binder resin. In addition, it is indispensable for the solvent to be vaporized and completely removed from the electrode after coating. From our long investigation about an alternative solvent for NMP, we have not found any alternative but we have now concluded NMP is essential for industrial use and has no alternative for such processes as the manufacturing of the battery. 

World market scale of the lithium ion secondary battery would be 10 billion euro in 2010, and is now estimated to be 27.8 billion euro in 2020. In addition, market scale of lithium ion secondary battery for electric vehicle is only starting up at this time, and is estimated to grow 12.0 billion euro in 2015. (Yano research institute ltd. (2010/10/6)). If NMP were to become an SVHC substance, it is predictable that this would seriously and very badly influence the market for lithium ion secondary batteries.
The increased use of these products across all regions of the world will make a positive contribution to the wellbeing of human society, to the environment and to energy saving, thus contributing to a reduction or cessation of global warming. Demands for such products are increasing, not only in Asia but across the world: no suitable alternative to NMP for production of lithium ion batteries and liquid crystal display panels has been identified and the manufacturing processes employed use high-level containment to ensure occupational exposure is minimised.

In addition, lithium ion secondary batteries and liquid crystal display panels are expected to contribute greatly to energy saving, to combating global warming and to the climate change issue. We would like to provide our Life Cycle Assessment (from the manufacturing stage of cars to disposal stage after 100000 km driving) for the contribution of electric cars as below.

[Comparison of estimation of amount of CO2 emission per a vehicle: t= tonnes]
-	gasoline powered vehicle : 33 t-CO2 / LC(manufacturing: 2.7t-CO2, driving:29t-CO2)
-	battery vehicle: 16 t-CO2 / LC(manufacturing: 9.2t-CO2, driving: 7t-CO2)

Meanwhile, the amount of CO2 discharged by consumption of fossil fuel is around 30 billion tonnes in 2010. Of this total, 20% is derived from transportation, and light duty vehicles account for 50% of transportation. This means the CO2 emissions of light duty vehicle are 10% of the total emissions of CO2 from fossil fuel (Sustainable Mobility 2030 (WBCSD)). If all of battery vehicle replaced gasoline powered vehicle, it is possible to reduce by 5% the total CO2 discharged by consumption of fossil fuels.    

Regarding an alternative issue, NEP (cas. 2687-91-4) was introduced as an alternative to NMP mainly in EU, but at this moment NEP has been reported to have reproductive toxicity and the French CA has now issued a proposal for harmonised C&L of NEP which recommends classification as Reprotoxicity Cat.1B under the CLP regulation. 

In conclusion, we can to some extent understand that concern could arise in connection with consumer use of NMP, given the fact that there are objective test data. However we note that the important uses of NMP as a solvent for manufacture of lithium ion batteries and in liquid crystal display panels are not directly addressed in the Annex XV dossier, and no suitable alternative to NMP for these products has been identified.  At the work place high-level containment of NMP in manufacturing processes ensures that occupational exposure for workers is minimised. In addition these products are expected to contribute greatly to energy saving which will help global warming and climate change issues. Therefore further restriction of industrial use for NMP has the serious potential to make a substantial negative impact on industry and global society.
	Thank you for the information on the use and regulation of NMP in batteries and display panels. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

16	2011/04/06	Company
Teijin Aramid BV
Netherlands	Page 14 to 31:
1. According to the dossier, NMP is a substance that is manufactured and used in relatively small amounts. Consequently, many importers may not yet have registered this substance and the uses known to them. If at this point in time, NMP is prioritised for authorisation, their uses may not have been registered yet and they will largely be caught unaware. 

2. As an example of point 1 above may serve the as yet unregistered use of NMP as a processing aid in the production of poly-aromatic polymers such as (but not exclusively) poly-paraphenylenediamine- terephthalic acid (PPTA, para-aramid). This polymer is subsequently used for the production of high-tensile yarns (e.g. Twaron®). 
In this particular patented application, NMP is the only known solvent in which the monomers for the polymer can be simultaneously dissolved and polymerized. 
Up to and including polymerization, this use can be considered as fully controlled, but after polymerization, the resultant polymer still contains traces of NMP that may evaporate during the production process and may cause worker exposure. Documented exposure is lower than 1 mg/m3 under current conditions. 

Related polymer powders and yarns may also contain some residual NMP, e.g. PPTA-copolymers (e.g. Technora®) and meta-aramid yarns (e.g. Teijinconex®). 
	1. Given that NMP fulfils the classification criterion “toxic for reproduction”, all manufacturers and importers of NMP in volumes higher than 1 tonne/year had according to Art. 23.1(a) of Regulation No 1907/2006 (REACH Regulation) the obligation to register the substance by the registration deadline of December 2010. 

2. Thank you for the information on the use of NMP in the manufacture of polymers. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
15	2011/04/06	Company
Teijin Aramid BV
Netherlands	Page 14 to 31:
1. NMP is indispensable for the production of meta-aramid fibers (e.g. Teijinconex®) used as industrial materials and as protective clothing material, and cannot be replaced. 
2. Moreover, it is impossible to adjust the amount of remaining NMP to less than 0.1%. 
3. It becomes impossible to produce meta-aramid-fibers when NMP cannot be used. It will have an extensive influence on the supply of industrial materials and protective clothing materials. 
	Thank you for providing information on the use of NMP in the production of meta-aramid fibers.

If the substance will be identified as SVHC and included in Annex XIV (list of substances subject to authorisation), this would not mean that NMP cannot be used anymore. It just would mean that its use would require authorisation. If in an authorisation application it can be shown that the risks arising from the intrinsic properties specified in Annex XIV are adequately controlled or that the socio-economic benefits outweigh the risk to human health and the environment arising from the use of the substance an authorisation may be granted 

To us it is not clear what is meant under # 2. of the comment, please refer also to the reply to your comments in the previous sections. If the substance is identified as SVHC, you will have the opportunity to further clarify the issues around # 2. in potential  follow-up stages of the risk management process.  
	
14	2011/04/06	Company

France	Arguments for reconsidering the use of NMP in Pharmaceutics 
 
Please refer to the Ipsen Pharma SAS’s attachment for further explanations.

1.	Functions of the substance as excipient not covered in the Annex XV Dossier (Annex XV Dossier - section 2.7 page 30)

Focus seems to be given to the use of NMP as a solvent engaged in manufacturing processes (extraction, purification and crystallization) in the Annex XV Dossier but not as an “inactive ingredient” or excipient.

2.	NMP characteristics & usage at Ipsen Pharma SAS (Annex XV Dossier - section 2.7.1 page 30)
•	Unique polar aprotic characteristics of NMP (Annex XV Dossier - section 2.7.1 page 30)

Ipsen Pharma SAS uses NMP for its unique intrinsic characteristics as a polar aprotic substance which gives specific properties and allows the preparation of sustained released formulations of drugs. No equivalent is identified at this time.

•	NMP quantities used in Pharmaceuticals (Annex XV Dossier - section 2.7.3 page 31)

As NMP is used as excipient and for its unique polar aprotics characteristics, Ipsen Pharma SAS assumes to use no more than 500 kg of NMP per year.

3.	Manufacturing  processes  in  the  pharmaceutical sector are tightly  controlled (Annex XV Dossier – section 3.3 page 33 & section 3.4.9.1 page 44)
•	High level of requirements and traceability in the pharmaceutical sector
•	Final Drug approval process: specific application for a marketing authorization for pharmaceuticals
•	Medicinal products are exempted from Reach
•	Strong international regulations 

4.	High level of requirements toward industrial hygiene at the workplaces (Annex XV Dossier – section 3.4.9.1 page 44)

5.	Very limited environmental releases from Ipsen Pharma SAS’s process (Annex XV Dossier – section 3.6 page 55)

6.	Current knowledge on alternatives : lack of alternatives (Annex XV Dossier – section 4 page 57)

Other technologies (e.g. micropsheres) could be considered to produce these new formulations, but they would use even more toxic solvents, such as dichloromethane, and in huge amounts for manufacturing (and then required industrial hygiene prevention plan and air emission (COV) monitoring & surveillance). In addition, they would produce a pharmacokinetic profile with  major side effects related to a significant  burst release of these formulations.

7.	Risks (Annex XV Dossier – section 3.5 page 44)

As the main focus is given to the use of NMP as a solvent engaged in industrial processes (coating, cleaning, agrochemicals, ….) in the Annex XV Dossier, the section 3.5, “Consumer releases and exposure” does not address the medical use of drug product by the patient.

•	Impact on drug development
As there is no alternative to NMP to improve these formulations, it means that Ipsen Pharma SAS will have to conduct long & costly research studies (5-10 years for a new formulation) and complete new pharmacology and toxicology studies to prove the same quality, efficacy  and safety of the drug product to the detriment of the Patient.

•	Patient benefit
Patients are expecting new injectable formulations with reduced side effects, improved tolerability, safety profile and efficacy. NMP is used by Ipsen Pharma SAS to develop new formulations that will bring longer exposure of the patient to the drug with less injection to cover the same treatment period. These formulations will significantly improve the quality of life of the patients.

Conclusion

Considering  the  arguments  cited  above,  Ipsen Pharma SAS  strongly  recommends  that  1-Methyl-2-pyrrolidone should not be placed on the REACH SVHC Candidate List 
for  the  uses  of  NMP  as  an  excipients  in  pharmaceuticals,  because  sufficient 
controls established by other legislation are already in place. 

This  specific  use  of  NMP  as  an  excipients  need  to  be  exempted  from authorisation, should the listing of NMP be made for other uses.  
 
As  NMP  is  a  polar  aprotic  substance,  and  without  misrepresenting  the  NMP toxicity  profile,  Ipsen Pharma SAS  requests  ECHA  to  reconsider  the  use  of  NMP  in Pharmaceuticals as an excipient.  
 
NMP can enhance drug formulations, and thus increase the Risk/Benefit ratio in favour of patient care. Other polar aprotic substances exist, which have similar or more adverse toxicity profiles, and these alternatives will not, nevertheless, achieve the goal of optimized formulation of drugs and may require Ipsen Pharma SAS to use materials representing higher risks, e.g. in industrial hygiene towards workers or sustainable development. 

In addition, this would lead Ipsen Pharma SAS to conduct long & costly development and clinical studies of 5 to 10 years for a new drug product, which is against the improvement of patient convenience and care by delaying or removing effective and safe treatments for serious medical conditions.
	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
			See also:
Comment 14 attachment (NMP comments - V10 - 6 April 11 - Final.pdf).pdf		
12	2011/04/06	Company
CARLO ERBA REACTIFS - SDS
France	P16 : Chapt 1.5.1 : purification steps by distillation or percolation are performed by downstream users : Use in closed batch process (RMM are the same as the manufacture)
P30 : Chap 2.7.1 NMP is also used as solvent during the manufacturing process for peptide synthesis (vaccine, amino acid, diagnosctic product).
Chap 2.7.2.1 : sector of use : could you delete "presumably" ? because these sectors of use are real.
Chap 2.7.2.3 : manufacturing in closed system, closed batch (existing RMM for charging, sampling, discharge, maintenance)
P31 Other uses 2.8.2 use in laboratories
NMP is used as solvent for peptides synthesis, as solvent for dissolving before gas chromatography or HPLC analysis.
NMP is used as standard in GC analysis (determination of impurities, residual solvents) according European Pharmacopeia, US Pharmacopeia or other standard.
Sector of use : Industrial (as pharmaceutical and cosmetic industries, R & D, chemical industries...) Professional (as Official laboratories) Public domain (Universities, research)
For all uses, there are existing RMM.

Thank you
Best regards	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
11	2011/04/06	National Authority
Allgemeine Unfallversicherungsanstalt
Austria	p 31, 2.8.2 Use in laboratories
Due to its excellent solvent properties NMP is widely used especially in organic research an development. R&D is up to 1 t/a exempted from REACH regulation. Therefore this cannot be a hindering reason for a stricter regulation of this substance.

p 36 ff
NMP is not only used in relatively safe closed systems. In some sectors of use it is used in a wide and dispersive way, e.g. on construction sites or in the cleaning business. These uses – especially under higher temperatures – lead to relatively high exposures up to air concentrations above the OEL.
Furthermore OELs might be over-run if NMP is handled in open equipment, as well.
P18 Table
As described in the dossier NMP is mostly used in industrial sites but still partly in consumer products. This is on more reason to regulate this substance
	Thank you for the additional information on NMP.

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 

10	2011/04/05	Company
Germany
	Comments
Page 44: Use of NMP in the preparation of pharmaceuticals

NMP is used in our company as an important solvent in the chemical synthesis of active pharmaceutical ingredients (APIs) and corresponding intermediates.

As a polar aprotic solvent NMP shows several advantages in this field:
- Good solubility of APIs, intermediates and reagents,
- Solvent polarity enhances reaction rates,
- High boiling point allowing higher reaction temperatures,
- Lower vapor pressure with reduced volatility minimizing potential emissions

NMP is only used by well trained workers in closed reactor systems. Filling is done by vacuum transfer, emptying directly and closed in used solvent containers. So emissions to workers or environment are reduced as far as possible.

Page 57: Alternatives

Following alternatives have been examined:
- DMF: As NMP was chosen as an alternative solvent for DMF regarding its reproductive toxicity. Therefore DMF is no suitable alternative.
- NEP: When testing N-ethylpyrrolidone as an alternative solvent NEP showed in the respective pharmaceutical synthesis a significant increase of a critical impurity. So NMP is also no suitable alternative solvent. On the other hand NEP is also in discussion due to its potential reproductive toxicity. 
- DMSO: Showed also negative properties in the use as alternative solvent to NMP.

Conclusion:
Considering the above mentioned facts and our experiences we come to the conclusion that it would be inappropriate to set NMP on the SVHC candidate list for inclusion in Annex XIV.
Inclusion in Annex XIV might force our company to use solvents with higher risk like DMF. Regarding the protection of persons and environment this makes no sense and is in fact disadvantageous.	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
9	2011/04/05	Company

Germany	NMP as solvent in fine chemical and GMP pharma synthesis

General description of the reaction
NMP is used in different batch processes as a solvent in a chemical synthesis. 

In addition smaller amounts of NMP are used in batch cleaning procedures when special persistent impurities have to be removed.

Most of the batch processes are highly contained. In few cases open handling steps are accompanied by the use of PPE and LEV. The solvent is removed from the product by extraction and/or crystallization. The waste solvent is incinerated or recycled. According to the specification of the final product NMP is not allowed in the highly purified fine chemical products. NMP is listed as class 2 residual solvent in the ICH Guideline Q3C. Therefore, a limit value for NMP as impurity in a final drug product exists. Customers of the products are located in the electronic and pharmaceutical industry. 
Neither professionals nor consumers are exposed to NMP concerning the use in electronic industry. 
Some consumers need the pharmaceutical product for treatment. During the approval of the pharmaceutical product the product is tested as it is produced in a standardised production process. Therefore, all health aspects are tested with the residual solvent NMP and are evaluated during the approval.

Exposure of workers
Well-trained industrial workers are using NMP. The exposure of the industrial workers is estimated to be negligible to low. The personal protection equipment is adapted to the risk requirements. In cases of occurrence of vapours a gas mask is worn in addition to standard personal protection equipment.

Exposure of environment
The exposure of the environment with NMP due to this use is negligible. All waste is incinerated or recycled by a qualified contractor.	Thank you for the additional information on the use and regulation of NMP in pharmaceuticals. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
7	2011/04/05	Member State
Sweden	Section 3.4.1 (p.33-34): 
Please recalculate the 8-hr-shift exposure calculation, based on the OEL of 10 ppm (40 mg/m3). 10 m3 x 40 mg/m3 = 400 mg. Assuming a body weight of 70 kg this equals 400/70 = 5.7 mg/kg/day.

Section 3.5.2.2 (p.45-46):
The Tier 1 approach appears to give an unrealistically high exposure considering the low vapor pressure of 1-methyl-2-pyrrolidone.

Section 3.5.4, Table 19 (p.53):
Please delete the so called “chronic” exposure values from the Table. It is not appropriate to average the exposure on the day of the event (taking place once a year) with the no exposure the other 364 days of the year, in particular when used in a risk assessment for reprotoxic effects.
	Thank you for providing your opinion.

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 	
5	2011/03/31	Company

Germany	p 58 The main alternative N-ethylpyrrolidone (NEP, CAS Number 2687-91-4) is actually classified as repr.cat 1B, too. 

p 60 Other alternatives like Dimethyl sulfoxide (DMSO) are not classified.  Yet we have not enough experience, whether DMSO is suitable as an alternative to NMP and NEP. DMSO is able to dissolve and transport other substances trough gloves and skin. Based on this fact the use of DMSO as alternative to NMP is dubious.	Thank you for providing your opinion.

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process.	
3	2011/03/24	Company
Cheminova A/S
Denmark	In our opinion, if 1-methyl-2-pyrrolidone (NMP) will be included in Annex XVII, use of NMP as formulation ingredient in products for agriculture should be exempt from requiring authorisation, because of the following three reasons:

1. Risk is negligible because of low exposure

The substance is to be a substance of very high concern because of its effects on reproduction. These effects occur at exposure levels of 100 – 150 mg/kg bw/day. No effects were found at lower exposure levels. Risk assessment shows that these exposure levels are unlikely both for workers in formulation industry and for agricultural workers in the field. In most cases, risks arising from the active ingredients are more severe.

Depending on the model used, exposure to NMP for agricultural workers typically is around 1 – 2 mg/kg bw/day without the use of personal protection equipment.

2. Agricultural uses have been approved by national authorities already

Agricultural products are registered by national authorities before being placed on the market. Risk assessment is a part of the registration process. The properties of NMP have been known for some time and have been assessed as a part of these processes. Since the products have been registered, the evaluations by the national authorities have shown that the risks are acceptable. 

3. Substitution is costly

Registration of agricultural products is a costly affair. Substitution will require new registrations. New registrations will also require new animal tests.

In the preamble to Reg. 1907/2006 it is stated in (22) that socio-economic considerations should be taken into account. It is our opinion that substitution will not be economically viable for many agricultural products containing NMP registered at the moment.	Thank you for the information on the use and regulation of NMP in agricultural products. 

Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
2	2011/03/15	Trade union
European Trade Union Confederation
Belgium	1-methyl-2-pyrrolidone is among the substances or group of substances related with diseases suspected of being occupational in origin.
See Annex II from the Commission Recommendation (19/09/2003) concerning the European schedule of occupational diseases. C(2003)3297 final.	Thank you for providing your opinion.	
1	2011/03/08	Company

France	It is mentioned p. 60 concerning the alternative substance dimethylsulfoxide (DMSO) :
“Another company which uses NMP for printing as part of a formulated screen ink, noted that DMSO has been shown to have higher environmental and/or health risk than NMP”. 
According to the available environmental and toxicological data on DMSO, this statement is wrong. There is a extensive physico-chemical, environmental and toxicological database available on DMSO which have been reviewed in the frame of the OECD SIDS program and for the REACH registration dossier. According to these reliable informations, DMSO is not classified for any end-points according to CLP or DSD criteria and the SIDS evaluation (SIDS dossier available at http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=4C5A1A36-54BC-41C3-950F-AE4171BDA7F5) concluded that DMSO is of low concern for the environment and the human health.
Another company suggested “that DMSO is of much greater concern than NEP, owing to the ability to dissolve and transport other substances through gloves and skin, potentially increasing systemic exposures to other substances”.
It is true that DMSO is absorbed by dermal route. A reliable skin penetration study in human volunteers indicated a skin absorption of ca. 30% of the dose (1 g/kg bw) based on the urinary excretion of DMSO and DMSO2 (Hucker et al., 1967). 
However, according to the available data summarized in the NMP SIDS dossier (http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=996F9CEA-4B30-4E70-9E54-8DEF28E023EB), NMP is also extensively absorbed by dermal route (<=100% depending on conditions, according to the SIDS dossier). A comparative skin penetration study with split human skin on different commercial solvents showed a permeation rate of NMP of 171 g/m²/h, similar to that of DMSO, 176 g/m2.h (Ursin et al., 1995). 
DMSO, as NMP, could facilitate the penetration of many other substances across skin and membranes. In a study performed to evaluate the risk due to the penetration of residual paint components dissolved by paint stripper formulations, the extent of absorption of lead (a classical substance found in old paint films) was assessed after application of different paint stripper formulations (DMSO-, N-methylpyrrolidone-based formulations) or paint stripper components (DMSO and N-methylpyrrolidone) to excised human dermatomed skin (0.9 cm²) mounted in static diffusion cells (DMSO SIDS dossier, 2008). DMSO alone resulted in low level of lead penetration, well below than of NMP (0.8 vs. 2.1 ng/cm²/h). As well as for the DMSO- compared to the NMP-based paint stripper formulations (4.3 vs. 9.9 ng/cm²/h).

In conclusion, DMSO is of low concern for the environment and the human health and is not classified according to CLP and DSD criteria. Pure DMSO and NMP seem to have a similar skin penetration potential and both can facilitate the penetration of exogenous substances across the skin.

Reference
Hucker HB, Miller JK, Hochberg A, Brobyn RD, Riordan FH, and Calesnick B (1967) Studies on the absorption, excretion and metabolism of dimethylsulfoxide in man. J. Pharm. Exp. Ther., 155/2, 309-317.

Ursin C, Hansen CM, Van Dyk GW, Jensen PO, Christensen IJ and Ebbehoej J (1995) Permeability of commercial solvents through living human skin. American Industrial Hygiene Association Journal, 56, 651-660.	Thank you for the information regarding dimethyl sulfoxide as alternative substance to NMP.
Provided that the substance is identified as SVHC, the information on use, exposure and availability of alternatives will be taken into account at later stages of the risk management process. 
	
			See also: Comment 1 attachment (SIAP DMSO.pdf).pdf		

Attachments

Comment number	Public attachment	Confidential attachment	
1	
Comment 1 attachment (SIAP DMSO.pdf).pdf		
4		
Comment 4 CONFIDENTIAL attachment c	
14	
Comment 14 attachment (NMP comments - V10 - 6 April 11 - Final.pdf).pdf		
19	
Comment 19 attachment (AZ comments_NMP SVHC_18_03_11 (2).pdf).pdf		
20		
Comment 20 CONFIDENTIAL attachment 	
26		
Comment 26 CONFIDENTIAL attachment 	
27	
Comment 27 attachment (DMSO as NMP alternative.pdf).pdf		
34	
Comment 34 attachment (20014-2011- ECHA_Gifas-methyl pyrrolidone.pdf).pdf		
38	
Comment 38 attachment (ESIA response to Annex XV dossier consultation on NMP 1 Methyl 2 Pyrrolidone  Final.pdf).pdf		
39	
Comment 39 attachment (20014-2011- ECHA_Gifas-methyl pyrrolidone (6).pdf).pdf