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

Substance name:	Hexahydromethylphthalic anhydride, Hexahydro-4-methylphathalic anhydride, Hexahydro-1-methylphathalic anhydride, Hexahydro-3-methylphathalic anhydride	
CAS number:	25550-51-0, 19438-60-9, 48122-14-1, 57110-29-9	
EC number:	247-094-1, 243-072-0, 256-356-4, 260-566-1	

The substance is proposed to be identified as meeting the following SVHC criteria set out in Article 57 of the REACH Regulation: Equivalent level of concern (Art. 57(f))

Disclaimer: Comments provided during public consultation are made available in this document as submitted by the commenting parties. It was in the commenting parties own responsibility to ensure that their comments do not contain confidential information. The Response to Comments table has been prepared by the competent authority of the Member State preparing the proposal for identification of a Substance of Very High Concern. RCOM has not been agreed by the Member State Committee nor has the document been modified as result of the MSC discussions. The table does not contain any confidential information.
 
PART I: Comments and responses to comments on the SVHC proposal and its justification

General comments on the SVHC proposal
Response to general comments the Netherlands - CA
In our view, the Annex XV report provides sufficient information relating to hexahydromethylphathalic anhydride (MHHPA) as a substance giving rise to an equivalent level of concern, article 57(f) under REACH. 

Initially, general criteria that should be taken into account when considering whether a substance shows an equivalent level of concern to CMRs (cat 1A or 1B) are met:
•	The seriousness of the effects, in terms of serious and permanent organ dysfunction,
•	Irreversibility of health effects
•	Societal concern, in terms of cost of treatment and resulting occupational asthma
•	Difficulty in performing a concentration-based risk assessment
Based on discussion between Member States, Commission and ECHA, there seem to be a common understanding that respiratory sensitizers are in principle fulfilling the criteria above. It should be underpinned that the substance should be included on Annex VI to CLP as a respiratory sensitizer and that potential inclusion in the Candidate list through the equivalent level of concern route is a case-by-case decision.

The following points relating to the specific properties of MHHPA support in our view a justification for equivalent level of concern:
•	The Annex XV dossier provides evidence that MHHPA is one of the most potent cyclic acid anhydrides with respect to sensitisation. 
•	Following on from this, the available data for MHHPA would appear to support the conclusion that a concentration-based risk assessment would be difficult to perform. It is also noted that it was not possible for the Health Council of the Netherlands to derive a risk reference value due to limited data. However, it is noted that MHHPA is considered to be at least as potent as HHPA (hexahydro-2-benzofuran-1,3-dione), for which a concern was found based on the risk levels for HHPA. The estimated exposure levels (worst case scenario) in the registration dossier far exceed the risk levels derived for HHPA and thus indicate that safe use of the substance is not guaranteed.  
•	The Annex XV report indicates that there is some evidence that sensitisation to anhydride conjugates is linked to specific occupational exposures, as no specific sensitisation to these agents was detected in unexposed people. 
•	The Annex XV report provides some evidence of the cross-reactivity of cyclic anhydrides, in particular MHHPA and HHPA.	
No.	Date	Submitted by (name, Organisation/
MSCA)	Comment	Response	
21	2012/10/18	Industry or trade association
The Federation of Finnish Technology Industries
Finland	Taking into account non existing non-relevant environmental exposure (see p. 33, section 8.3,) non-existing consumer or environment risks (see p. 33 sections 10.2 and 10.3) and extremely limited amount of people exposed to acid anhydrides on working environments where the exposure area (controlled working area) is limited and OHS control measures are strict, we do not see reason to add this substance on the candidate list.	Noted	
			See also:
Comment 21 attachment (MHHPA_FFTI_.docx).docx		
20	2012/10/18	Industry or trade association
Aerospace Industries Association
United States	AIA supports the comments filed by both ADS and GIFAS on this substance.	Noted	
18	2012/10/18	International NGO
Health and Environment Alliance
Belgium	We support the nomination and adoption of this chemical to the candidate list.	Thank you for your support	
17	2012/10/18	Industry or trade association
GIFAS
France	PLEASE REFER TO ATTACHED DOCUMENT	Noted	
			See also:
Comment 17 attachment (20017_2012_Echa_54 SVHC consultation.pdf).pdf		
15	2012/10/18	Member State
Austria	The Austrian CA supports the nomination of MHHPA because of its significant sensitizing potential and agree with the conclusion that Article 57 (f) of REACH should be applied. We very much welcome the initiative by The Netherlands and fully support their conclusion that the submitted substance should be regarded as a substance of very high concern following the intensive expert discussions between ECHA and CAs.	Thank you for your support.	
14	2012/10/18	Company
Estonia	In the Annex XV – SVHC Dossier MHHPA – CAS No. 25550-51-0 the substance MHHPA is proposed to be identified as substance of equivalent concern according to Article 57 (f) of the REACH regulation EC No. 1907/2006.

The Cyclic Anhydride Cooperation Group, representing European producers and importers, would like to take the opportunity to provide comments to the Annex XV dossier and provide new data and arguments not addressed or not sufficiently addressed in the SVHC-MHHPA dossier. The information provided below is considered to be important for a re-evaluation of the reported exposure data in the Annex XV dossier, the relevance and the hazards in the context of overall proposal to consider MHHPA as a potential substance of “equivalent level of concern” similar to CMR substances. 

1.	MHHPA is exclusively used as a monomer and intermediate in industry. Commercial use is neither currently registered under REACH nor supported in the EU. Monomers and intermediates are exempted from the authorisation process. If monomers and intermediates are nevertheless identified as a first step in the authorisation process as a SVHC substance then the benefit of a potential/theoretical improvement through legislative risk management measures is doubted for monomers/intermediates as both uses are exempted in the final later authorisation process. Thus, legislative risk management through authorisation will have no effect on monomers and intermediates.
In addition, the SVHC concept is also aimed at the protection of consumers by controlling SVHC substances in articles. Since no consumer uses exist for MHHPA itself and the final articles have no free MHHPA, the current identification process of a substance exclusively used in industry as a monomer and intermediate is not in line with the aim of the SVHC concept of protecting consumers.

2.	As summarized in the Annex XV dossier (page 20), until now there is no specific information available on the prevalence of occupational asthma due to MHHPA exposure alone. In general, data related to MHHPA is very scarce. Only cross-reactions with other cyclic anhydrides were noted. These reported incidents are often more than a decade old and related to single cases with high exposure levels (if known at all) only. 

For MHHPA no reliable threshold value could be calculated on the basis of the limited available data. Read-across from other cyclic anhydrides with different induction patterns to MHHPA is scientifically not valid. Thus any reference values calculated for other substances (e.g. HHPA) cannot form the basis for a realistic risk assessment of MHHPA. 

3.	Available data for respiratory sensitization potential of cyclic anhydrides are, in most of the reported incidents, more than a decade old. Working conditions and diagnostic possibilities have changed tremendously in the last 10 years. Thus, this old data reflect past working conditions and past medical data but not today’s situation.

4.	There is a strong trend in the EU that work-related asthma for almost all potential causative agents decreases in the EU as opposed to the perceived trend of increased skin & respiratory sensitization and asthma in the general population.

5.	 For the last 6-10 years, no new medical data regarding cyclic anhydrides have been reported in literature. A recent comprehensive downstream user survey representing a broad spectrum of approximately 20 European and non European downstream users confirmed that no clinical symptoms of respiratory sensitization have been noted since at least ten years. The European downstream users are evenly spread all over Europe. This finding is attributed to various legal requirements and pro-active product stewardship programs (Occupational Health and Safety systems; Industrial Hygiene measures) resulting in state-of-the art engineering measures and standard operating procedures – classical risk management measures in response to an identified concern.

6.	European industry has one of the highest occupational, health and safety standards and state-of-the art engineering measures in the world. This is not only achieved by a vast variety of legislative programs in the EU and the single Member States but also by voluntary pro-active product stewardship programs in the companies. Regarding the manufacturing and use of cyclic anhydrides in Europe, well educated and trained workers are employed in state-of-the-art plants: Where possible, closed systems prevent exposure to cyclic anhydrides resulting in near zero risk of exposure. Consequently, many processes where exposure was possible in the past have been changed to automated and/or closed processes nowadays. Thus potential exposure time is limited to spot exposure only, for example, when mixing or blending in batch processes and the transfer of substances from vessels/containers. Often only 15 minutes daily or twice a week to a few hours a day is related to handling of cyclic anhydrides. For these potential exposure occasions, exhaust ventilation and mandatory personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. Medical surveillance on a regular basis helps monitoring the health status of the workers with the result that if, despite all measures to minimise exposure, indicators in the blood reveal exposure, workers can be, and are, removed from their workplace to an exposure free workplace to prevent the development of any potential health effects.
 
7.	The sensitization process is a two-phase process with a symptom free first phase of “induction” and after a subsequent exposure, the second phase of “elicitation” with clinical symptoms may follow. New diagnostic methods and medical surveillance allow the monitoring of exposure indicators and early health effects. Thus, further exposure and consequently potentially severe clinical symptoms can be efficiently avoided by removing workers from an exposed working environment. 

8.	For cyclic anhydrides no secondary exposure exists as anhydrides are solely used in industry and no consumer uses exist. Final products do not contain any free anhydrides. Also, even in case of an accidental release to the environment, there is no environmental hazard or potential exposure via the environment due to the hydrolytic instability of anhydrides.
 
9.	Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known respiratory sensitizers but blood indicators (IgE and IgG) are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). IgE and IgG levels drop significantly after removal from exposure. Early studies of respiratory sensitization described progression of symptoms with continuing exposure while recent studies report that after removal from exposure the majority of subjects improve or recover (Tarlo et al. 2008). Due to years of symptomatic exposure, the degree of loss of lung function and increased airway hyperresponsiveness at diagnosis also had a negative influence on outcomes. However, it is clear that early diagnosis and removal from continuing exposure before lung function deteriorates is a very important factor for remission of symptoms.

10.	MHHPA is one example for a chemical causal agent known for its sensitization potential. Many more chemicals and even more natural causal agents (flour, house mites, enzymes, moulds etc.) exist. Among these, the most common is flour used in the baking industry which is responsible for a commonplace inhalative allergy among baking industry workers. 
In Germany, 61 % of the reported work-related diseases in 2009 were related to flour, flour products, bakery & pastry products where exposure is not limited to spot handling steps but occurs over the entire working day and secondary exposure outside the baking industry cannot be excluded. Also in the Netherlands and other countries, high prevalence for work-related asthma, rhinoconjunctivits and sensitization was reported in the baking industry. In addition, persistence of respiratory symptoms was significantly greater with high molecular weight agents (flour, enzymes) than with low molecular weight agents (chemicals including MHHPA).

11.	Conclusion: 
The exposure picture presented in the Annex XV dossier is not in line with today’s situation in European industry. The relevance of work-related asthma due to cyclic anhydrides is not given as frequency and incidents of cases have not been reported. In addition, the general population is not affected through primary or secondary exposure as suggested. Other causative agents of respiratory sensitization are responsible for a high number of work-related asthma. Often, secondary exposure in these cases cannot be avoided (baking industry).
Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known sensitizers but biomarkers are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). Only after repeated/prolonged exposure clinical effects may occur. Some of these are reversible (e.g. urticaria) and only the last stage can be regarded as irreversible (resulting in damage of lung functions).
Based on the available information the Cyclic Anhydride Cooperation Group comes to the conclusion that the properties of MHHPA do not qualify MHHPA as a SVHC substance having an equivalent level of concern as substances with CMR properties. In addition, current risk management measures prove to be appropriate and effective. It should also be considered that the substance is solely used as a monomer and intermediate in industry and, as such, the proposed authorisation process will not be relevant to and cannot change or improve current use practices of MHHPA in Europe.	Noted

1. We do not agree that MHHPA is exclusively used as monomer and intermediate. 

Response to points 2, 3 and 4:
All (publicably) available literature has been taken into account. We acknowledge data for MHHPA is limited but in our view, the risk of sensitization due to MHHPA cannot be excluded based on the available information. Furthermore, it is noted that MHHPA specific IgE was detected in a number of cases, indicating the sensitisation potential of MHHPA. 

2.It has been noted in the annex XV dossier that a reliable threshold for MHHPA could not be derived. In fact, this strengthens our consideration that a concentration-based risk assessment is not possible for this substance. The available literature suggests that MHHPA is one of the most potent cyclic anhydrides, comparable to the potency of HHPA. Since for HHPA there are reasons for concern, based on its reference value derived by the Dutch Health Council and the exposure levels found in the registration dossier, there is sufficiently reason for concern for MHHPA exposure.  

4. In our view, the risk of sensitization due to HHPA exposure cannot be excluded based on the information registration dossier.

5. All (publicly) available literature has been taken into account.

6. See response to general comments the Netherlands – CA.

7. See response to general comments the Netherlands – CA.

8. See response to general comments the Netherlands – CA.

9.  MHHPA-HSA specific IgE indicates that a subject has already gone through the induction phase of sensitisation, possibly already showing effects. Although more severe clinical effects can be avoided using the biological detection (requiring invasive measures), it does not necessarily prevent workers from being sensitized, especially since such monitoring actions cannot be performed frequently (daily to weekly). In this case, relocating subjects from the workplace as RMM does not seem ethically justified. 

10. Noted, however this information is not specific to this case.

11. See response to general comments, the Netherlands – CA.
	
13	2012/10/18	Member State
Norway	The Norwegian CA supports that hexahydromethylphtalic anhydride (MHHPA)fulfill the criteria of article 57 f) since evidence exists of serious effects to humans which give rise to equivalent level of concern as CMR substances. MHHPA is harmonized classified as a strong respiratory sensitizer (Resp. Sens. 1) in the CLP regulation and no "safe" no effect level can be derived as regards to the induction of sensitization. During the elicitation phase, the substance may evoke chronic inflammation of the lungs and this can lead to serious and permanent impairment of the lungs. The induced sensitization is irreversible, and exposure of the substance may result in a considerable increased risk of elicitation of respiratory sensitization of affected persons. This may cause limitations of normal working life and could require long term medication. We support that the criteria of article 57 f) is fulfilled and that this substance is of equivalent level of concern as CMR (Cat. 1 or 2) substances. MHHPA should be identified as a SVHC substance.	Thank you for your support.	
12	2012/10/17	Member State
Sweden	We agree with the argumentation put forward in the Annex XV dossier and therefore consider MHHPA to be a SVHC substance of equivalent level of concern according to Article 57(f). The substance is a classified respiratory sensitizer which may cause severe and irreversible health effects, which clearly affect the quality of life of affected individuals and also high costs for society. It is difficult to establish safe exposure levels for respiratory sensitizers like MHHPA, which is another reason for concern. Further, it is noted that this severe endpoint has not been taken into account by registrants in their chemical safety assessment in the Registration dossier.	Thank you for your support. 	
11	2012/10/17	Company
Austria	General Comments

In the Annex XV – SVHC Dossier MHHPA – CAS No. 25550-51-0 the substance MHHPA is proposed to be identified as substance of equivalent concern according to Article 57 (f) of the REACH regulation EC No. 1907/2006.

The Cyclic Anhydride Cooperation Group, representing European producers and importers, would like to take the opportunity to provide comments to the Annex XV dossier and provide new data and arguments not addressed or not sufficiently addressed in the SVHC-MHHPA dossier. The information provided below is considered to be important for a re-evaluation of the reported exposure data in the Annex XV dossier, the relevance and the hazards in the context of overall proposal to consider MHHPA as a potential substance of “equivalent level of concern” similar to CMR substances. 

1.	MHHPA is exclusively used as a monomer and intermediate in industry. Commercial use is neither currently registered under REACH nor supported in the EU. Monomers and intermediates are exempted from the authorisation process. If monomers and intermediates are nevertheless identified as a first step in the authorisation process as a SVHC substance then the benefit of a potential/theoretical improvement through legislative risk management measures is doubted for monomers/intermediates as both uses are exempted in the final later authorisation process. Thus, legislative risk management through authorisation will have no effect on monomers and intermediates.
In addition, the SVHC concept is also aimed at the protection of consumers by controlling SVHC substances in articles. Since no consumer uses exist for MHHPA itself and the final articles have no free MHHPA, the current identification process of a substance exclusively used in industry as a monomer and intermediate is not in line with the aim of the SVHC concept of protecting consumers.

2.	As summarized in the Annex XV dossier (page 20), until now there is no specific information available on the prevalence of occupational asthma due to MHHPA exposure alone. In general, data related to MHHPA is very scarce. Only cross-reactions with other cyclic anhydrides were noted. These reported incidents are often more than a decade old and related to single cases with high exposure levels (if known at all) only. 

For MHHPA no reliable threshold value could be calculated on the basis of the limited available data. Read-across from other cyclic anhydrides with different induction patterns to MHHPA is scientifically not valid. Thus any reference values calculated for other substances (e.g. HHPA) cannot form the basis for a realistic risk assessment of MHHPA. 

3.	Available data for respiratory sensitization potential of cyclic anhydrides are, in most of the reported incidents, more than a decade old. Working conditions and diagnostic possibilities have changed tremendously in the last 10 years. Thus, this old data reflect past working conditions and past medical data but not today’s situation.

4.	There is a strong trend in the EU that work-related asthma for almost all potential causative agents decreases in the EU as opposed to the perceived trend of increased skin & respiratory sensitization and asthma in the general population.

5.	 For the last 6-10 years, no new medical data regarding cyclic anhydrides have been reported in literature. A recent comprehensive downstream user survey representing a broad spectrum of approximately 20 European and non European downstream users confirmed that no clinical symptoms of respiratory sensitization have been noted since at least ten years. The European downstream users are evenly spread all over Europe. This finding is attributed to various legal requirements and pro-active product stewardship programs (Occupational Health and Safety systems; Industrial Hygiene measures) resulting in state-of-the art engineering measures and standard operating procedures – classical risk management measures in response to an identified concern.

6.	European industry has one of the highest occupational, health and safety standards and state-of-the art engineering measures in the world. This is not only achieved by a vast variety of legislative programs in the EU and the single Member States but also by voluntary pro-active product stewardship programs in the companies. Regarding the manufacturing and use of cyclic anhydrides in Europe, well educated and trained workers are employed in state-of-the-art plants: Where possible, closed systems prevent exposure to cyclic anhydrides resulting in near zero risk of exposure. Consequently, many processes where exposure was possible in the past have been changed to automated and/or closed processes nowadays. Thus potential exposure time is limited to spot exposure only, for example, when mixing or blending in batch processes and the transfer of substances from vessels/containers. Often only 15 minutes daily or twice a week to a few hours a day is related to handling of cyclic anhydrides. For these potential exposure occasions, exhaust ventilation and mandatory personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. Medical surveillance on a regular basis helps monitoring the health status of the workers with the result that if, despite all measures to minimise exposure, indicators in the blood reveal exposure, workers can be, and are, removed from their workplace to an exposure free workplace to prevent the development of any potential health effects.
 
7.	The sensitization process is a two-phase process with a symptom free first phase of “induction” and after a subsequent exposure, the second phase of “elicitation” with clinical symptoms may follow. New diagnostic methods and medical surveillance allow the monitoring of exposure indicators and early health effects. Thus, further exposure and consequently potentially severe clinical symptoms can be efficiently avoided by removing workers from an exposed working environment. 

8.	For cyclic anhydrides no secondary exposure exists as anhydrides are solely used in industry and no consumer uses exist. Final products do not contain any free anhydrides. Also, even in case of an accidental release to the environment, there is no environmental hazard or potential exposure via the environment due to the hydrolytic instability of anhydrides.
 
9.	Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known respiratory sensitizers but blood indicators (IgE and IgG) are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). IgE and IgG levels drop significantly after removal from exposure. Early studies of respiratory sensitization described progression of symptoms with continuing exposure while recent studies report that after removal from exposure the majority of subjects improve or recover (Tarlo et al. 2008). Due to years of symptomatic exposure, the degree of loss of lung function and increased airway hyperresponsiveness at diagnosis also had a negative influence on outcomes. However, it is clear that early diagnosis and removal from continuing exposure before lung function deteriorates is a very important factor for remission of symptoms.

10.	MHHPA is one example for a chemical causal agent known for its sensitization potential. Many more chemicals and even more natural causal agents (flour, house mites, enzymes, moulds etc.) exist. Among these, the most common is flour used in the baking industry which is responsible for a commonplace inhalative allergy among baking industry workers. 
In Germany, 61 % of the reported work-related diseases in 2009 were related to flour, flour products, bakery & pastry products where exposure is not limited to spot handling steps but occurs over the entire working day and secondary exposure outside the baking industry cannot be excluded. Also in the Netherlands and other countries, high prevalence for work-related asthma, rhinoconjunctivits and sensitization was reported in the baking industry. In addition, persistence of respiratory symptoms was significantly greater with high molecular weight agents (flour, enzymes) than with low molecular weight agents (chemicals including MHHPA).

11.	Conclusion: 
The exposure picture presented in the Annex XV dossier is not in line with today’s situation in European industry. The relevance of work-related asthma due to cyclic anhydrides is not given as frequency and incidents of cases have not been reported. In addition, the general population is not affected through primary or secondary exposure as suggested. Other causative agents of respiratory sensitization are responsible for a high number of work-related asthma. Often, secondary exposure in these cases cannot be avoided (baking industry).
Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known sensitizers but biomarkers are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). Only after repeated/prolonged exposure clinical effects may occur. Some of these are reversible (e.g. urticaria) and only the last stage can be regarded as irreversible (resulting in damage of lung functions).
Based on the available information the Cyclic Anhydride Cooperation Group comes to the conclusion that the properties of MHHPA do not qualify MHHPA as a SVHC substance having an equivalent level of concern as substances with CMR properties. In addition, current risk management measures prove to be appropriate and effective. It should also be considered that the substance is solely used as a monomer and intermediate in industry and, as such, the proposed authorisation process will not be relevant to and cannot change or improve current use practices of MHHPA in Europe.	See response to comment no. 14
	
10	2012/10/17	Member State
United Kingdom	From a technical perspective we are open to the idea that  sensitisers could be added to the Candidate List and subsequently added to  Annex XIV, in cases where authorisation is identified as the most appropriate risk management option. However, the debate so far indicates that simply being classified as a sensitiser is not sufficient and that additional factors need to be taken into account. Exactly what these factors should be and the criteria that need to be applied to each factor still needs to be decided. Until this happens it is not possible to decide if MHHPA is of equivalent concern and so is eligible for addition to the Candidate List. 

We think it would be useful to obtain better information on the effectiveness of the risk management measures that are currently in use and on the availability of safer alternatives before this substance is considered for inclusion in Annex XIV.	Thank you for your comments and they are noted.

Please see response to general comments the Netherlands – CA.

The industry has indicated that exposure levels are adequately controlled by the SDS requirement to wear masks during tasks where potential exposure can occur (personal communication) and the Chemical Safety reports should be corrected and updated accordingly. However, exposure levels in the registration dossier show that workers in the current settings are at increased risk of respiratory sensitization due to HPPA exposure. Thus there might still be concern. 

The availability of alternatives will be taken into account in the process of priority setting.	
16	2012/10/17	National NGO
Naturskyddsföreningen, Swedish Society for Nature Conservation (SSNC)
Sweden	The Swedish Society for Nature Conservation (SSNC) supports the proposal to categorise Hexahydromethylphathalic anhydride, Hexahydro-4-methylphathalic anhydride, Hexahydro-1-methylphathalic anhydride, Hexahydro-3-methylphathalic anhydride as a Substance of Very High Concern.
 
The SSNC is the largest and most influential environmental organisation in Sweden, currently with 192,000 members nationwide. The SSNC works to protect the natural environment and human health, and to strengthen global solidarity.	Thank you for your support.	
9	2012/10/17	Other contributor
The Cyclic Anhydride Cooperation
Germany	In the Annex XV – SVHC Dossier MHHPA – CAS No. 25550-51-0 the substance MHHPA is proposed to be identified as substance of equivalent concern according to Article 57 (f) of the REACH regulation EC No. 1907/2006.

The Cyclic Anhydride Cooperation Group, representing European producers and importers, would like to take the opportunity to provide comments to the Annex XV dossier and provide new data and arguments not addressed or not sufficiently addressed in the SVHC-MHHPA dossier. The information provided below is considered to be important for a re-evaluation of the reported exposure data in the Annex XV dossier, the relevance and the hazards in the context of overall proposal to consider MHHPA as a potential substance of “equivalent level of concern” similar to CMR substances. 

1.	MHHPA is exclusively used as a monomer and intermediate in industry. Commercial use is neither currently registered under REACH nor supported in the EU. Monomers and intermediates are exempted from the authorisation process. If monomers and intermediates are nevertheless identified as a first step in the authorisation process as a SVHC substance then the benefit of a potential/theoretical improvement through legislative risk management measures is doubted for monomers/intermediates as both uses are exempted in the final later authorisation process. Thus, legislative risk management through authorisation will have no effect on monomers and intermediates.
In addition, the SVHC concept is also aimed at the protection of consumers by controlling SVHC substances in articles. Since no consumer uses exist for MHHPA itself and the final articles have no free MHHPA, the current identification process of a substance exclusively used in industry as a monomer and intermediate is not in line with the aim of the SVHC concept of protecting consumers.

2.	As summarized in the Annex XV dossier (page 20), until now there is no specific information available on the prevalence of occupational asthma due to MHHPA exposure alone. In general, data related to MHHPA is very scarce. Only cross-reactions with other cyclic anhydrides were noted. These reported incidents are often more than a decade old and related to single cases with high exposure levels (if known at all) only. 

For MHHPA no reliable threshold value could be calculated on the basis of the limited available data. Read-across from other cyclic anhydrides with different induction patterns to MHHPA is scientifically not valid. Thus any reference values calculated for other substances (e.g. HHPA) cannot form the basis for a realistic risk assessment of MHHPA. 

3.	Available data for respiratory sensitization potential of cyclic anhydrides are, in most of the reported incidents, more than a decade old. Working conditions and diagnostic possibilities have changed tremendously in the last 10 years. Thus, this old data reflect past working conditions and past medical data but not today’s situation.

4.	There is a strong trend in the EU that work-related asthma for almost all potential causative agents decreases in the EU as opposed to the perceived trend of increased skin & respiratory sensitization and asthma in the general population.

5.	 For the last 6-10 years, no new medical data regarding cyclic anhydrides have been reported in literature. A recent comprehensive downstream user survey representing a broad spectrum of approximately 20 European and non European downstream users confirmed that no clinical symptoms of respiratory sensitization have been noted since at least ten years. The European downstream users are evenly spread all over Europe. This finding is attributed to various legal requirements and pro-active product stewardship programs (Occupational Health and Safety systems; Industrial Hygiene measures) resulting in state-of-the art engineering measures and standard operating procedures – classical risk management measures in response to an identified concern.

6.	European industry has one of the highest occupational, health and safety standards and state-of-the art engineering measures in the world. This is not only achieved by a vast variety of legislative programs in the EU and the single Member States but also by voluntary pro-active product stewardship programs in the companies. Regarding the manufacturing and use of cyclic anhydrides in Europe, well educated and trained workers are employed in state-of-the-art plants: Where possible, closed systems prevent exposure to cyclic anhydrides resulting in near zero risk of exposure. Consequently, many processes where exposure was possible in the past have been changed to automated and/or closed processes nowadays. Thus potential exposure time is limited to spot exposure only, for example, when mixing or blending in batch processes and the transfer of substances from vessels/containers. Often only 15 minutes daily or twice a week to a few hours a day is related to handling of cyclic anhydrides. For these potential exposure occasions, exhaust ventilation and mandatory personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. Medical surveillance on a regular basis helps monitoring the health status of the workers with the result that if, despite all measures to minimise exposure, indicators in the blood reveal exposure, workers can be, and are, removed from their workplace to an exposure free workplace to prevent the development of any potential health effects.
 
7.	The sensitization process is a two-phase process with a symptom free first phase of “induction” and after a subsequent exposure, the second phase of “elicitation” with clinical symptoms may follow. New diagnostic methods and medical surveillance allow the monitoring of exposure indicators and early health effects. Thus, further exposure and consequently potentially severe clinical symptoms can be efficiently avoided by removing workers from an exposed working environment. 

8.	For cyclic anhydrides no secondary exposure exists as anhydrides are solely used in industry and no consumer uses exist. Final products do not contain any free anhydrides. Also, even in case of an accidental release to the environment, there is no environmental hazard or potential exposure via the environment due to the hydrolytic instability of anhydrides.
 
9.	Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known respiratory sensitizers but blood indicators (IgE and IgG) are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). IgE and IgG levels drop significantly after removal from exposure. Early studies of respiratory sensitization described progression of symptoms with continuing exposure while recent studies report that after removal from exposure the majority of subjects improve or recover (Tarlo et al. 2008). Due to years of symptomatic exposure, the degree of loss of lung function and increased airway hyperresponsiveness at diagnosis also had a negative influence on outcomes. However, it is clear that early diagnosis and removal from continuing exposure before lung function deteriorates is a very important factor for remission of symptoms.

10.	MHHPA is one example for a chemical causal agent known for its sensitization potential. Many more chemicals and even more natural causal agents (flour, house mites, enzymes, moulds etc.) exist. Among these, the most common is flour used in the baking industry which is responsible for a commonplace inhalative allergy among baking industry workers. 
In Germany, 61 % of the reported work-related diseases in 2009 were related to flour, flour products, bakery & pastry products where exposure is not limited to spot handling steps but occurs over the entire working day and secondary exposure outside the baking industry cannot be excluded. Also in the Netherlands and other countries, high prevalence for work-related asthma, rhinoconjunctivits and sensitization was reported in the baking industry. In addition, persistence of respiratory symptoms was significantly greater with high molecular weight agents (flour, enzymes) than with low molecular weight agents (chemicals including MHHPA).

11.	Conclusion 
The exposure picture presented in the Annex XV dossier is not in line with today’s situation in European industry. The relevance of work-related asthma due to cyclic anhydrides is not given as frequency and incidents of cases have not been reported. In addition, the general population is not affected through primary or secondary exposure as suggested. Other causative agents of respiratory sensitization are responsible for a high number of work-related asthma. Often, secondary exposure in these cases cannot be avoided (baking industry).
Compared to CMR substances which trigger irreversible effects, cyclic anhydrides are known sensitizers but biomarkers are available which allow early exposure to be identified. Further exposure can be stopped when a positive biological response is seen, before any clinical symptoms have developed (first sensitization phase). Only after repeated/prolonged exposure clinical effects may occur. Some of these are reversible (e.g. urticaria) and only the last stage can be regarded as irreversible (resulting in damage of lung functions).
Based on the available information the Cyclic Anhydride Cooperation Group comes to the conclusion that the properties of MHHPA do not qualify MHHPA as a SVHC substance having an equivalent level of concern as substances with CMR properties. In addition, current risk management measures prove to be appropriate and effective. It should also be considered that the substance is solely used as a monomer and intermediate in industry and, as such, the proposed authorisation process will not be relevant to and cannot change or improve current use practices of MHHPA in Europe.	See response to comment no. 14
	
7	2012/10/16	National NGO
IEW
Belgium	We support the nomination of this chemical to the Candidate List as a substance of very high concern	Thank you for your support.	
5	2012/10/16	Member State
Belgium	The following items are present in the Annex XV dossiers to substantiate that the substances fulfill the article 57(f) criteria:
•             Serious and permanent organ dysfunction is possible (can cause asthma and  allergic rhinitis/conjunctivitis).
•             The health effects are irreversible
•             The consequences for society are high
•             It is difficult to perform a concentration-based risk assessment
Therefore, the BE MSCA supports the identification of the  substance as SVHCs based on article 57(f) of the REACH regulation.	Thank you for your support.	
3	2012/10/15	Member State
Germany	The German CA supports the proposed identification of MHHPA (and its isomers) as Substance of Very High Concern according to Article 57(f) of the REACH regulation.
It seems that the dossier for MHHPA should cover several substances: individual isomers of MHHPA and all possible mixtures thereof. Hence, it should be considered to use a generic name to cover all possible substances/mixtures with one entry in the candidate list.
	Thank you for your support.

The dossier states which four substances are covered by the single dossier. Therefore we agree that the entry/entries in the Candidate List / Annex XIV should also clearly state the four substances (i.e. all three (valid) CAS / EC numbers and chemical names should be listed). The remaining question of whether the four substances should be listed in one line or split into three lines on the Candidate List / Annex XIV should be further discussed.	
2	2012/10/11	National NGO
Danish Consumer Council
Denmark	The Danish Consumer Council (DCC) supports the inclusion of the substance in the candidate list. The DCC wants dangerous chemicals in consumer products to be banned or at least minimized to the lowest possible levels. The inclusion of this substance to the candidate list is a strong signal to producers that the use of this substance should in time be stopped, and substituted with a less dangerous one.	Thank you for your support.	
1	2012/10/01	Trade union
European Trade Union Confederation
Belgium	ETUC supports the identification of theses substances as SVHC. They are included in the Trade Union Priority List for REACH authorisation. see http://www.etuc.org/a/6023	Thank you for your support.	

Specific comments on the justification
No.	Date	Submitted by (name, Organisation/
MSCA)	Comment	Response	
19	2012/10/18	Member State
Ireland	The Irish CA agrees with the general criteria outlined in the Annex XV dossier for the identification of a substance as meeting the criteria of Article 57(f) for equivalent level of concern to CMRs, namely:
•	Inclusion of the substance on Annex VI to CLP as a respiratory sensitiser
•	The seriousness of the effects, in terms of serious and permanent organ dysfunction
•	Irreversibility of health effects
•	Consequences for society, in terms of cost of treatment and resulting occupational asthma
•	Difficulty in performing a concentration-based risk assessment.

However, the Irish CA notes that these criteria could be applied to all respiratory sensitisers and thus do not allow for identification of specific substances meeting Article 57(f) criteria “on a case-by-case basis”. 
Therefore, the Irish CA considers that the following points relating to the specific properties of MHHPA may particularly support a justification for equivalent level of concern:
•	While it is acknowledged that it is difficult to quantify potency with respect to respiratory sensitisation, the Annex XV dossier provides some evidence that MHHPA is one of the most potent cyclic acid anhydrides with respect to sensitisation.
•	Following on from this, the available data for MHHPA would appear to support the conclusion that a concentration-based risk assessment would be difficult to perform. It is also noted that it was not possible for the Health Council of the Netherlands to derive a risk reference value due to limited data. However, it is noted that MHHPA is considered to be at least as potent as HHPA (hexahydro-2-benzofuran-1,3-dione), for which risk reference values of 0.07 μg HHPA/m3 corresponding to an additional risk of 1% (or 0.007 μg HHPA/m3 corresponding to an additional risk of 0.1% ) due to occupational exposure were derived.
•	The Annex XV report indicates that there is some evidence that sensitisation to anhydride conjugates is linked to specific occupational exposures, as no specific sensitisation to these agents was detected in unexposed people. 
•	The Annex XV report provides some evidence of the cross-reactivity of cyclic anhydrides, in particular MHHPA and HHPA.	Thank you for your supporting remarks and comments.	
			See also: 
Confidential attachment removed.		
14	2012/10/18	Company
Estonia	Referring to section 6.3.1.2 (page 20); 6.3.2, 6.3.3 and table 6.1 (page 23-25)
In the Annex XV dossier (p. 20 ) sensitization (e.g. measured as IgE induction) is “not an adverse effect per se” as it is often without any clinical symptoms and only after repeated and prolonged exposure of a MHHPA-sensitized individual may asthma related symptoms occur. In addition, the Health Council of the Netherlands stated in 2008 in the report “Prevention of work-related airway allergies” that “allergic respiratory condition is always preceded by sensitization for a particular allergen”. Therefore IgE induction can be used as a biomonitoring parameter for sensitization to avoid potential clinical effects after continuous and relevant exposure of sensitized individuals. Arts et al. 2006 also describe a first sensitization phase which is free of symptoms and only if subsequent exposure takes place a second phase with symptoms may follow the first phase. Consequently, sensitization without any clinical symptoms cannot be considered to be life threatening as, for example, is the case with cancer. The two phase process is also stated in the Annex XV – SVHC dossier on MHHPA. With cancer no early blood markers like IgE or IgG exist which allow the protection of an exposed individual by removing that individual from the exposure source. Potential clinical symptoms, especially of the early stages of elicitation (e.g. rhinitis) after exposure of MHHPA and other cyclic anhydrides of sensitized workers are not necessarily irreversible. Literature shows clear reversibility (Welinder, et al. 1998) of clinical effects if the final stage of permanent lung damage has been successfully avoided. Also, the IgE and IgG levels which are exposure indicators drop after decrease/cessation of cyclic anhydride exposure and thus are also considered reversible effects. In summary, with the availability of an early indicator as IgE/G and partly reversible clinical symptoms the final irreversible stage of lung damage can be effectively avoided. Thus the respiratory sensitization potential of MHHPA cannot be equalised with CMR properties of other chemical substances where irreversible clinical effects are evoked possibly after only a single exposure with a CMR substance. 

For MHHPA there is, so far, no information on the prevalence of occupational asthma available (Annex XV SVHC dossier MHHPA, page 20). No specific cases of respiratory allergy for MHHPA alone have ever been reported. At present available literature reports show only single cases of cross-reaction effects following exposure to MHHPA together with other substances. These reported cases are often older than a decade and a recent comprehensive European downstream user survey has confirmed no cases of respiratory sensitization in more than ten years (see also comments to part II). In total, the MHHPA data is not sufficient to derive a sound and scientifically correct threshold value for MHHPA. The Dutch expert Committee on Occupational Safety stated that “no reliable threshold level can be discerned form the available data” (Health Council of the Netherlands 2010, page 87). Due to the scarce data available for MHHPA a reference value was calculated for HHPA and transferred to MHHPA by a read-across approach. While the two cyclic anhydrides may be expected to have the same mechanism of action, for this use of read-across to HHPA to be valid requires that the two substances exhibit similar potency in their ability to bind to proteins and form adducts. Rosqvist et al. 2003 showed different exposure-response relationships between MHHPA and HHPA based on the total plasma protein adducts (TPPA) formed. No correlation between the TPPA of HHPA and the TPPA of MHHPA was found suggesting different IgE/IgG induction patterns of MHHPA and HHPA. Thus, a read-across from HHPA to MHHPA with regard to sensitization potential seems to be scientifically questionable. 

Referring to section 6.3.1.5 Quality of life (page 23)
Removing workers from their workplace in case of an elevated health risk is a standard procedure in the European Union and one which applies to a vast variety of examples to ensure the occupational health and safety of workers/employees in general and is not an exceptional case related to MHHPA exposure. For example pregnant and nursing women are especially protected from potential reprotoxicants for the safety of the (unborn) child. Also, workers with health effects of their backs due to carrying heavy loads/sitting activities will be removed from their workplaces. Thus the removal of an exposed worker for the sake of avoiding clinical symptoms is a standard procedure in industry.

References Part I
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003): Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Tarlo S.M. et al. (2008): Diagnosis and Management of Work-rlated Asthma: American College of Chest Physicians Consensus Statement. Chest. 134;1-41.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148.	Noted

IgE induction is an indicator for sensitisation and is considered to be an adverse toxicological effect. The toxicological mechanism is due to the very long half-life of specific IgE (trigger for immune reaction upon renewed contact) is therefore considered a irreversible effect. If exposure is repeated and prolonged, clinical symptoms will occur, which may progress to permanent lung restructuring. Only due to preventive measures after a worker has been sensitized already, such effects can be avoided. At that stage, the subject is sensitized and will show symptoms after renewed contact. Although it is acknowledged that the first stage is free of symptoms, discrimination between the two stages in practice can be very difficult, as some subject will show clinical symptoms quite soon after sensitisation, while others do not. The discrimination is especially difficult when exposure is continuous for a certain period.

It is acknowledged that MHHPA and HHPA show different patterns in binding enzymes and IgE/IgG induction, although they both show the exact same mechanism of action of binding enzymes and IgE/IgG induction. Only the ratios differ. This having said, their potencies of inducing effects at a certain exposure level do not appear to differ as can be seen from Table 5.2 adopted from WHO 2009. It is agreed that risk levels for HHPA cannot be simply adopted for MHHPA, which was not done for this same reason.  

	
11	2012/10/17	Company
Austria	Comments Part I - Section 4 Human Health Hazard Assessment and Section 6 Conclusions of the SVHC Properties

Referring to section 6.3.1.2 (page 20); 6.3.2, 6.3.3 and table 6.1 (page 23-25)
In the Annex XV dossier (p. 20 ) sensitization (e.g. measured as IgE induction) is “not an adverse effect per se” as it is often without any clinical symptoms and only after repeated and prolonged exposure of a MHHPA-sensitized individual may asthma related symptoms occur. In addition, the Health Council of the Netherlands stated in 2008 in the report “Prevention of work-related airway allergies” that “allergic respiratory condition is always preceded by sensitization for a particular allergen”. Therefore IgE induction can be used as a biomonitoring parameter for sensitization to avoid potential clinical effects after continuous and relevant exposure of sensitized individuals. Arts et al. 2006 also describe a first sensitization phase which is free of symptoms and only if subsequent exposure takes place a second phase with symptoms may follow the first phase. Consequently, sensitization without any clinical symptoms cannot be considered to be life threatening as, for example, is the case with cancer. The two phase process is also stated in the Annex XV – SVHC dossier on MHHPA. With cancer no early blood markers like IgE or IgG exist which allow the protection of an exposed individual by removing that individual from the exposure source. Potential clinical symptoms, especially of the early stages of elicitation (e.g. rhinitis) after exposure of MHHPA and other cyclic anhydrides of sensitized workers are not necessarily irreversible. Literature shows clear reversibility (Welinder, et al. 1998) of clinical effects if the final stage of permanent lung damage has been successfully avoided. Also, the IgE and IgG levels which are exposure indicators drop after decrease/cessation of cyclic anhydride exposure and thus are also considered reversible effects. In summary, with the availability of an early indicator as IgE/G and partly reversible clinical symptoms the final irreversible stage of lung damage can be effectively avoided. Thus the respiratory sensitization potential of MHHPA cannot be equalised with CMR properties of other chemical substances where irreversible clinical effects are evoked possibly after only a single exposure with a CMR substance. 

For MHHPA there is, so far, no information on the prevalence of occupational asthma available (Annex XV SVHC dossier MHHPA, page 20). No specific cases of respiratory allergy for MHHPA alone have ever been reported. At present available literature reports show only single cases of cross-reaction effects following exposure to MHHPA together with other substances. These reported cases are often older than a decade and a recent comprehensive European downstream user survey has confirmed no cases of respiratory sensitization in more than ten years (see also comments to part II). In total, the MHHPA data is not sufficient to derive a sound and scientifically correct threshold value for MHHPA. The Dutch expert Committee on Occupational Safety stated that “no reliable threshold level can be discerned form the available data” (Health Council of the Netherlands 2010, page 87). Due to the scarce data available for MHHPA a reference value was calculated for HHPA and transferred to MHHPA by a read-across approach. While the two cyclic anhydrides may be expected to have the same mechanism of action, for this use of read-across to HHPA to be valid requires that the two substances exhibit similar potency in their ability to bind to proteins and form adducts. Rosqvist et al. 2003 showed different exposure-response relationships between MHHPA and HHPA based on the total plasma protein adducts (TPPA) formed. No correlation between the TPPA of HHPA and the TPPA of MHHPA was found suggesting different IgE/IgG induction patterns of MHHPA and HHPA. Thus, a read-across from HHPA to MHHPA with regard to sensitization potential seems to be scientifically questionable. 

Referring to section 6.3.1.5 Quality of life (page 23)
Removing workers from their workplace in case of an elevated health risk is a standard procedure in the European Union and one which applies to a vast variety of examples to ensure the occupational health and safety of workers/employees in general and is not an exceptional case related to MHHPA exposure. For example pregnant and nursing women are especially protected from potential reprotoxicants for the safety of the (unborn) child. Also, workers with health effects of their backs due to carrying heavy loads/sitting activities will be removed from their workplaces. Thus the removal of an exposed worker for the sake of avoiding clinical symptoms is a standard procedure in industry.

References Part I
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003): Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Tarlo S.M. et al. (2008): Diagnosis and Management of Work-rlated Asthma: American College of Chest Physicians Consensus Statement. Chest. 134;1-41.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148. 	See response to comment no. 14 and general comments the Netherlands – CA.
	
10	2012/10/17	Member State
United Kingdom	We agree that it is not appropriate to use a DNEL derived by route-to-route extrapolation from oral data as a benchmark to assess inhalation exposure for substances that cause local effects in the respiratory tract. 	Thank you for your comment.	
9	2012/10/17	Other contributor
The Cyclic Anhydride Cooperation
Germany	Referring to section 6.3.1.2 (page 20); 6.3.2, 6.3.3 and table 6.1 (page 23-25) and other (page 8-25)

In the Annex XV dossier (p. 20 ) sensitization (e.g. measured as IgE induction) is “not an adverse effect per se” as it is often without any clinical symptoms and only after repeated and prolonged exposure of a MHHPA-sensitized individual may asthma related symptoms occur. In addition, the Health Council of the Netherlands stated in 2008 in the report “Prevention of work-related airway allergies” that “allergic respiratory condition is always preceded by sensitization for a particular allergen”. Therefore IgE induction can be used as a biomonitoring parameter for sensitization to avoid potential clinical effects after continuous and relevant exposure of sensitized individuals. Arts et al. 2006 also describe a first sensitization phase which is free of symptoms and only if subsequent exposure takes place a second phase with symptoms may follow the first phase. Consequently, sensitization without any clinical symptoms cannot be considered to be life threatening as, for example, is the case with cancer. The two phase process is also stated in the Annex XV – SVHC dossier on MHHPA. With cancer no early blood markers like IgE or IgG exist which allow the protection of an exposed individual by removing that individual from the exposure source. Potential clinical symptoms, especially of the early stages of elicitation (e.g. rhinitis) after exposure of MHHPA and other cyclic anhydrides of sensitized workers are not necessarily irreversible. Literature shows clear reversibility (Welinder, et al. 1998) of clinical effects if the final stage of permanent lung damage has been successfully avoided. Also, the IgE and IgG levels which are exposure indicators drop after decrease/cessation of cyclic anhydride exposure and thus are also considered reversible effects. In summary, with the availability of an early indicator as IgE/G and partly reversible clinical symptoms the final irreversible stage of lung damage can be effectively avoided. Thus the respiratory sensitization potential of MHHPA cannot be equalised with CMR properties of other chemical substances where irreversible clinical effects are evoked possibly after only a single exposure with a CMR substance. 

For MHHPA there is, so far, no information on the prevalence of occupational asthma available (Annex XV SVHC dossier MHHPA, page 20). No specific cases of respiratory allergy for MHHPA alone have ever been reported. At present available literature reports show only single cases of cross-reaction effects following exposure to MHHPA together with other substances. These reported cases are often older than a decade and a recent comprehensive European downstream user survey has confirmed no cases of respiratory sensitization in more than ten years (see also comments to part II). In total, the MHHPA data is not sufficient to derive a sound and scientifically correct threshold value for MHHPA. The Dutch expert Committee on Occupational Safety stated that “no reliable threshold level can be discerned form the available data” (Health Council of the Netherlands 2010, page 87). Due to the scarce data available for MHHPA a reference value was calculated for HHPA and transferred to MHHPA by a read-across approach. While the two cyclic anhydrides may be expected to have the same mechanism of action, for this use of read-across to HHPA to be valid requires that the two substances exhibit similar potency in their ability to bind to proteins and form adducts. Rosqvist et al. 2003 showed different exposure-response relationships between MHHPA and HHPA based on the total plasma protein adducts (TPPA) formed. No correlation between the TPPA of HHPA and the TPPA of MHHPA was found suggesting different IgE/IgG induction patterns of MHHPA and HHPA. Thus, a read-across from HHPA to MHHPA with regard to sensitization potential seems to be scientifically questionable. 

Referring to section 6.3.1.5 Quality of life (page 23)
Removing workers from their workplace in case of an elevated health risk is a standard procedure in the European Union and one which applies to a vast variety of examples to ensure the occupational health and safety of workers/employees in general and is not an exceptional case related to MHHPA exposure. For example pregnant and nursing women are especially protected from potential reprotoxicants for the safety of the (unborn) child. Also, workers with health effects of their backs due to carrying heavy loads/sitting activities will be removed from their workplaces. Thus the removal of an exposed worker for the sake of avoiding clinical symptoms is a standard procedure in industry.

References Part I
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003): Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Tarlo S.M. et al. (2008): Diagnosis and Management of Work-rlated Asthma: American College of Chest Physicians Consensus Statement. Chest. 134;1-41.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148. 	See response to comment no. 14 and general comments the Netherlands – CA.

	
8	2012/10/16	Company
Sweden	p.9. It is hypothesized without supporting evidence that MHHPA may cause induction followed by elicitation without triggering the immune system since that has been observed for other LMW. Our experience after 30 years of industrial use of anhydride curing agents, typically more than 100 tons/year, is that induction of sensitization will be detected by IgE markers at regular health controls. If actions are taken to minimize or avoid further exposure to anhydrides, the IgE levels drop and development of symptoms are avoided.
p19 and forward. Experience from our factory indicate that development of symptoms and/or permanent dysfunctions do not occur in industries using proper Risk Management Measures in line with current legislationa and Material Safety Data Sheets, including annual monitoring of IgE levels of potentially exposed workers. The possible adverse health effects of anhydrides became understood more than 20 years ago and then modern RMM's were introduced. Since then sensitization is very rare and no worker has developed symptoms or became unable to continue work within the factory. The argument that MHHPA would be of equivalent level of concern as CMR substances is not valid.	Noted.

See response to general comments, the Netherlands – CA,	
3	2012/10/15	Member State
Germany	The identity of all possible individual substances should be given with EC and CAS-No., at least for those that have been registered. Physico- chemical data could be given for individual substances where available.	Thank you for your comment.

The physicochemical information was taken from the ECHA dissemination site. We have included only information, which is available or relevant. Where we do not have data for the individual isomers, we could have indicated no information on the isomers was available. This will be considered for future dossiers.	

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

Specific comments on use, exposure, alternatives and risks
No	Date	Submitted by (name, Organisation/
MSCA)	Comment	Response	
21	2012/10/18	Industry or trade association
The Federation of Finnish Technology Industries
Finland	The health effects are quite widely described in the Human Health Hazard Assessment chapter (page 8). The main concern is sensitizing IgE mediated allergy leading to symptoms in respiratory system and mucous membranes of nose and eyes. Skin sensitizing is also possible.

HHPA is used in few manufacturing processes in electronical component and electromechanical industry. In these processes the number of people exposed to acid anhydrides is limited as low as possible. Controlled production areas have a negative pressure limiting the possibility to exposure inside the controlled part of the plant, where access is limited. According to experiences, in a population of 30-40 people possibly exposed to the acid anhydrides 0-1 sensitized workers a year are found. It means that by strict control measures the sensitizing of employees is limited. On the other side, if sensitizing happens, the symptoms end by moving the worker outside the controlled area. Usually this means a new job in a new department. Also the sensitization does not limit the life outside of the controlled production area, because the exposure is not available in normal environments.

As a conclusion the risk of allergy is possible to control and the handicap caused by the sensitization is very limited. 

Page 33: Information on alternatives
Since mid 2000, global companies have invested significant R&D resources to find alternative solutions to replace the anhydride hardener used in impregnation process for high voltage electric machines. Despite of all efforts, alternative anhydride free system that could be used to construct e.g. equally high quality high voltage windings has not been found. During the years, these companies have reviewed and tested several state of the art commercially available resin systems. Also new invented resins have been tested and several patens filed. None of the reviewed system results in equally high quality insulation system as anhydride based resins. For high voltage electric machines, the thermal and electric life time of the electric machine constructed with anhydride free resins is not competitive. Medium voltage machines could be constructed with such resins, but then processing times would be multiple compared to anhydride based resins. Small repair shops can use resin systems that need extremely long processing times, but for electric motor manufacturers industrial scale processes are needed. If outside EU machines can be constructed with significantly faster processing times and their quality is higher, machine manufacturers in EU are by no means competitive. This risks the existence of remarkable part of European high voltage motor manufacturing in at least in 4 European countries.	Noted. This information will be taken into account in the process of priority setting for Annex XIV.
	
			See also:
Comment 21 attachment (MHHPA_FFTI_.docx).docx		
20	2012/10/18	Industry or trade association
Aerospace Industries Association
United States	Hexahydromethylphathalic anhydride, Hexahydro-4-methylphathalic anhydride, Hexahydro-1-methylphathalic anhydride, Hexahydro-3-methylphathalic anhydride were identified as substances used in the by several  Aerospace companies.  It is incorporated in articles and critical to some direct manufacturing processes. It is used in the manufacture of electronics. It is a component of epoxy underfill materials and epoxy dam, and encapsulent for high power electronics.   Specific products containing at least one of these substances are HYSOL FP4450 and HYSOL FP4451 Catalyst 17M-1.  Process development and requalifications for some applications would be required.
Industry is not presently aware of qualified and available alternatives for these applications	Noted. This information will be taken into account in the process of priority setting for Annex XIV.
	
14	2012/10/18	Company
Estonia	Referring to section 6.3.1.1 (page 19) and case reports (page 10-14)
Reported cases of sensitization and in some cases clinical symptoms in literature relate to cross-reactions of MHHPA with other anhydrides and are, in most of the cases, 10 years old or older and often no clear conclusion with regard to exposure can be drawn. Even in the Annex XV SVHC dossier for MHHPA it is stated that “most cases date back to the period 1990-2006, cases that are more recent have not been found in literature” (page 19). This is also confirmed by industry: with regard to the recent discussion on potential identification of MHHPA as a SVHC substance the Cyclic Anhydride Cooperation Group carried out a comprehensive survey with representative European and also a few non European downstream users. The European downstream users are distributed all over Europe (from North to South and East to West). Among the approximately 20 downstream users who replied in detail there were no known cases of clinical symptoms in the last 10 years. One downstream user reported cases of elevated IgE levels (with no clinical findings) in the past which were drastically decreased to a few isolated cases after the introduction of standard risk management measures (engineering measures, mandatory use of respiratory masks etc.). 
Due to a variety of risk management measures (engineering/technical measures such as closed systems which reduce the exposure to cyclic anhydrides to near zero and automated processes in ventilated areas) potential exposure to cyclic anhydrides is limited to spot exposures of minutes/hours a day and exposure does not occur during the entire working shift. Consequently, many processes where exposure was possible in the past have these days been changed to automated and/or closed processes. Remaining handling steps with a potential exposure to cyclic anhydrides are, for example, mixing or blending in batch processes, sampling and transfer of substances from vessels/containers. Often only minutes (15-30 minutes) to a few hours (2 hours average) handling of cyclic anhydrides is the standard handling time which is often done sporadically only. For these potential exposure occasions, exhaust ventilation and personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. For example the guaranteed exposure level for a state-of-the-art masks (Mask with P3 dust filter if solid or type A filter for vapours and organic gases with a boiling point > 65°C if molten. (EN 149)) is 5 µg/m³. As medical surveillance allows the detection of early markers of potential sensitization, the subsequent development of clinical symptoms can effectively be avoided by monitoring workers’ health parameters. In plants using potential sensitizing chemicals monitoring IgE levels and other blood parameters (creatinin, liver parameters etc.) and urine parameters as well as spirometry is a standard program on a regular basis. In cases of conspicuous results, effective procedures of immediately removing of the worker from the exposed work-place take place which prevents the airway elicitation. Therefore the current standard risk management measures in place prove to be appropriate and effective. There is thus no need for an additional legislative control of risks through an authorisation process as risks are already controlled effectively by industry by applying appropriate risk management measures, evidenced by no recent respiratory clinical symptoms having been recorded over the last years.

Related to section 7.3 and 8 (page 27-32)
The use of MHHPA is limited to monomeric and intermediate use only. According to the REACH Guidance Document for monomers and polymers (April 2012), page 11 epoxy resin curing agents are considered to be monomers which are used in chemical post-modification in the synthesis of polymer substances. It is evident that in the Annex XV dossier this epoxy resin curing was not considered to be a monomer use. Together with the other known uses, MHHPA is used to a 100 % as a monomer (large majority) and an intermediate (minority).

As monomers and intermediates are not subject to the authorization process the identification of MHHPA as a SVHC will thus not lead to an improved legislative risk management. In addition, no free MHHPA is in the final articles present and thus the articles do not possess any sensitising properties.

In general, work-related asthma decreased in the EU: Data from the French national network of occupational health surveillance and prevention shows a significant decrease over the last decade for any causal agents with the exception of quaternary ammonium compounds (Paris et al. 2012). In Germany, work-related allergic respiratory symptoms have declined since 1993. In total, the Accident Prevention & Insurance Association of the German statutory accident insurance reported 523 incidents 2010. In 2009 with slightly more cases (565) the majority of the reported cases were related to the baking industry (61.1 %), hair dyes (5 %), fruits & legumes (5 %), associated to animals (hair, feathers etc.) (4.4 %), disinfection (3.2 %), natural rubber (latex) (2.5 %) feed and food dust (2.3 %). The remaining is related to moulds (0,5 %), enzymes (0,9 %) and others (15.2 %). As chemicals are not explicitly listed they are probably part of the “others” which would correspond to a maximum of 86 incidents related to chemicals as oppose to 345 related to flour (Raulf-Heimsoth et al. 2012). These figures show the vast variety of causative agents workers may be exposed to. Most of the causative agents are not only associated with a work environment but can also be present in the general population as this is true for natural causative agents lik to flour, flour products, bakery & pastry products. Not only in Germany but also in the Netherlands, roughly 30,000 workers are directly exposed to causative agents in the baking industry. Different studies revealed a sensitization rate due to baking products and raw materials of 2-16 % and 4-14 % respectively. The sensitization rate of atopic people was even higher (23 %). Work-related asthma was reported for 11.5 % and rhinoconjunctivitis for 18 %. High prevalence was found among sensitised workers:  > 50 % for asthma and 34 % for rhinitis (Health Council of the Netherlands, 2008). Many chemical agents causing work-related allergic respiration symptoms are only present in a working environment (industrial use; monomeric/intermediate use; no free substance in final article) and, if exposed, early detection of elevated IgE/G permits identification of exposure and allows such individuals to be removed from their workplace with the result that no additional exposure will take place (as opposed to workers exposed to other causative agents (animals, flour, moulds, enzymes) who will also be exposed in their private lives). 

The monitoring of early blood markers like IgE and other medical parameters (e.g. blood and urine, spirometry) are part of the medical surveillance programs in European plants and industry using sensitizing agents like HHPA and many other. With the regular monitoring of these early blood parameters and with the standard operating procedures, engineering equipment in place, potential exposure to MHHPA can be detected and subsequent measures like removing the worker from an exposed work place can be taken to prevent the possibility of the development of any pronounced clinical symptoms. As MHHPA is only used in industry and not in commercial products (Annex XV dossier, page 33, registration dossiers for MHHPA) and secondary exposure can be excluded outside of the work-place a sensitized worker will never be exposed to MHHPA again after a new task has been assigned to that person without MHHPA exposure.

In summary, MHHPA is considered NOT to possess an equivalent level of concern as CMR substances due to the fact that:
-	sensitization is not comparable to effects of CMR substances;
-	even clinical effects are reversible and only the last stage of damage of lung functions is considered not reversible;
-	blood parameters allow monitoring of exposure to cyclic anhydrides and thus the potential for the elicitation of possible irreversible clinical effects to be identified;
-	MHHPA is used as a monomer and intermediate only in industry;
-	No primary and secondary exposure of the general population exist;
-	Extensive legislative and voluntary product stewardship programs exist;
-	Current Risk Management Measures prove to be appropriate and effective;
-	In the past no cases for exposure only to MHHPA were noted (only cross-reactions with other cyclic anhydrides);
-	Recently, no work-related asthma was reported for cyclic anhydrides;
-	Other potent causative agents with many more incidents exist;

References Part II
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Guidance for the implementation of REACH (2012): Guidance for monomers and polymers. publication no. 2012/04. Version 2.0. 

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Paris C., Ngatchou-Wandji J., Luc A., McNamee R., Bensefa-Colas L., Larabi L., Telle-Lamberton M., Herin F., Bergeret A., Bonneterre V., Brochard, P., Choudat, D., Dupas D., Garnier R., Pairon J-C., M Agius, R., Ameille J. (2012): Work-related asthma in France: recent trends for the period 2001-2009. Online publication: downloaded from oem.bmj.com on 19 March 2012 published by group.bmj.com. 

Raulf-Heimsoth M., van Kampen V., Kespohl S., Sander I., Merget R., Brüning, T. (2012): Inhalationsallergien am Arbeitsplatz, aktuellen Entwicklungen, Bundesgesundheitsblatt 2012, 55:363-372. Online publication: 25. Februar 2012.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003):
Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148.	Noted, see response to general comments, the Netherlands MS-CA

Noted, see response to general comments, the Netherlands MS-CA

This information is not specific to this case.	
11	2012/10/17	Company
Austria	Comments Part II – Information on Use, Exposure, Alternatives and Risks

Referring to section 6.3.1.1 (page 19) and case reports (page 10-14)
Reported cases of sensitization and in some cases clinical symptoms in literature relate to cross-reactions of MHHPA with other anhydrides and are, in most of the cases, 10 years old or older and often no clear conclusion with regard to exposure can be drawn. Even in the Annex XV SVHC dossier for MHHPA it is stated that “most cases date back to the period 1990-2006, cases that are more recent have not been found in literature” (page 19). This is also confirmed by industry: with regard to the recent discussion on potential identification of MHHPA as a SVHC substance the Cyclic Anhydride Cooperation Group carried out a comprehensive survey with representative European and also a few non European downstream users. The European downstream users are distributed all over Europe (from North to South and East to West). Among the approximately 20 downstream users who replied in detail there were no known cases of clinical symptoms in the last 10 years. One downstream user reported cases of elevated IgE levels (with no clinical findings) in the past which were drastically decreased to a few isolated cases after the introduction of standard risk management measures (engineering measures, mandatory use of respiratory masks etc.). 
Due to a variety of risk management measures (engineering/technical measures such as closed systems which reduce the exposure to cyclic anhydrides to near zero and automated processes in ventilated areas) potential exposure to cyclic anhydrides is limited to spot exposures of minutes/hours a day and exposure does not occur during the entire working shift. Consequently, many processes where exposure was possible in the past have these days been changed to automated and/or closed processes. Remaining handling steps with a potential exposure to cyclic anhydrides are, for example, mixing or blending in batch processes, sampling and transfer of substances from vessels/containers. Often only minutes (15-30 minutes) to a few hours (2 hours average) handling of cyclic anhydrides is the standard handling time which is often done sporadically only. For these potential exposure occasions, exhaust ventilation and personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. For example the guaranteed exposure level for a state-of-the-art masks (Mask with P3 dust filter if solid or type A filter for vapours and organic gases with a boiling point > 65°C if molten. (EN 149)) is 5 µg/m³. As medical surveillance allows the detection of early markers of potential sensitization, the subsequent development of clinical symptoms can effectively be avoided by monitoring workers’ health parameters. In plants using potential sensitizing chemicals monitoring IgE levels and other blood parameters (creatinin, liver parameters etc.) and urine parameters as well as spirometry is a standard program on a regular basis. In cases of conspicuous results, effective procedures of immediately removing of the worker from the exposed work-place take place which prevents the airway elicitation. Therefore the current standard risk management measures in place prove to be appropriate and effective. There is thus no need for an additional legislative control of risks through an authorisation process as risks are already controlled effectively by industry by applying appropriate risk management measures, evidenced by no recent respiratory clinical symptoms having been recorded over the last years.

Related to section 7.3 and 8 (page 27-32)
The use of MHHPA is limited to monomeric and intermediate use only. According to the REACH Guidance Document for monomers and polymers (April 2012), page 11 epoxy resin curing agents are considered to be monomers which are used in chemical post-modification in the synthesis of polymer substances. It is evident that in the Annex XV dossier this epoxy resin curing was not considered to be a monomer use. Together with the other known uses, MHHPA is used to a 100 % as a monomer (large majority) and an intermediate (minority).

As monomers and intermediates are not subject to the authorization process the identification of MHHPA as a SVHC will thus not lead to an improved legislative risk management. In addition, no free MHHPA is in the final articles present and thus the articles do not possess any sensitising properties.

In general, work-related asthma decreased in the EU: Data from the French national network of occupational health surveillance and prevention shows a significant decrease over the last decade for any causal agents with the exception of quaternary ammonium compounds (Paris et al. 2012). In Germany, work-related allergic respiratory symptoms have declined since 1993. In total, the Accident Prevention & Insurance Association of the German statutory accident insurance reported 523 incidents 2010. In 2009 with slightly more cases (565) the majority of the reported cases were related to the baking industry (61.1 %), hair dyes (5 %), fruits & legumes (5 %), associated to animals (hair, feathers etc.) (4.4 %), disinfection (3.2 %), natural rubber (latex) (2.5 %) feed and food dust (2.3 %). The remaining is related to moulds (0,5 %), enzymes (0,9 %) and others (15.2 %). As chemicals are not explicitly listed they are probably part of the “others” which would correspond to a maximum of 86 incidents related to chemicals as oppose to 345 related to flour (Raulf-Heimsoth et al. 2012). These figures show the vast variety of causative agents workers may be exposed to. Most of the causative agents are not only associated with a work environment but can also be present in the general population as this is true for natural causative agents lik to flour, flour products, bakery & pastry products. Not only in Germany but also in the Netherlands, roughly 30,000 workers are directly exposed to causative agents in the baking industry. Different studies revealed a sensitization rate due to baking products and raw materials of 2-16 % and 4-14 % respectively. The sensitization rate of atopic people was even higher (23 %). Work-related asthma was reported for 11.5 % and rhinoconjunctivitis for 18 %. High prevalence was found among sensitised workers:  > 50 % for asthma and 34 % for rhinitis (Health Council of the Netherlands, 2008). Many chemical agents causing work-related allergic respiration symptoms are only present in a working environment (industrial use; monomeric/intermediate use; no free substance in final article) and, if exposed, early detection of elevated IgE/G permits identification of exposure and allows such individuals to be removed from their workplace with the result that no additional exposure will take place (as opposed to workers exposed to other causative agents (animals, flour, moulds, enzymes) who will also be exposed in their private lives). 

The monitoring of early blood markers like IgE and other medical parameters (e.g. blood and urine, spirometry) are part of the medical surveillance programs in European plants and industry using sensitizing agents like HHPA and many other. With the regular monitoring of these early blood parameters and with the standard operating procedures, engineering equipment in place, potential exposure to MHHPA can be detected and subsequent measures like removing the worker from an exposed work place can be taken to prevent the possibility of the development of any pronounced clinical symptoms. As MHHPA is only used in industry and not in commercial products (Annex XV dossier, page 33, registration dossiers for MHHPA) and secondary exposure can be excluded outside of the work-place a sensitized worker will never be exposed to MHHPA again after a new task has been assigned to that person without MHHPA exposure.

In summary, MHHPA is considered NOT to possess an equivalent level of concern as CMR substances due to the fact that:
-	sensitization is not comparable to effects of CMR substances;
-	even clinical effects are reversible and only the last stage of damage of lung functions is considered not reversible;
-	blood parameters allow monitoring of exposure to cyclic anhydrides and thus the potential for the elicitation of possible irreversible clinical effects to be identified;
-	MHHPA is used as a monomer and intermediate only in industry;
-	No primary and secondary exposure of the general population exist;
-	Extensive legislative and voluntary product stewardship programs exist;
-	Current Risk Management Measures prove to be appropriate and effective;
-	In the past no cases for exposure only to MHHPA were noted (only cross-reactions with other cyclic anhydrides);
-	Recently, no work-related asthma was reported for cyclic anhydrides;
-	Other potent causative agents with many more incidents exist;

References Part II
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Guidance for the implementation of REACH (2012): Guidance for monomers and polymers. publication no. 2012/04. Version 2.0. 

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Paris C., Ngatchou-Wandji J., Luc A., McNamee R., Bensefa-Colas L., Larabi L., Telle-Lamberton M., Herin F., Bergeret A., Bonneterre V., Brochard, P., Choudat, D., Dupas D., Garnier R., Pairon J-C., M Agius, R., Ameille J. (2012): Work-related asthma in France: recent trends for the period 2001-2009. Online publication: downloaded from oem.bmj.com on 19 March 2012 published by group.bmj.com. 

Raulf-Heimsoth M., van Kampen V., Kespohl S., Sander I., Merget R., Brüning, T. (2012): Inhalationsallergien am Arbeitsplatz, aktuellen Entwicklungen, Bundesgesundheitsblatt 2012, 55:363-372. Online publication: 25. Februar 2012.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003):
Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148. 	See response to comment no. 14
	
9	2012/10/17	Other contributor
The Cyclic Anhydride Cooperation
Germany	Referring to section 6.3.1.1 (page 19) and case reports (page 10-14)

Reported cases of sensitization and in some cases clinical symptoms in literature relate to cross-reactions of MHHPA with other anhydrides and are, in most of the cases, 10 years old or older and often no clear conclusion with regard to exposure can be drawn. Even in the Annex XV SVHC dossier for MHHPA it is stated that “most cases date back to the period 1990-2006, cases that are more recent have not been found in literature” (page 19). This is also confirmed by industry: with regard to the recent discussion on potential identification of MHHPA as a SVHC substance the Cyclic Anhydride Cooperation Group carried out a comprehensive survey with representative European and also a few non European downstream users. The European downstream users are distributed all over Europe (from North to South and East to West). Among the approximately 20 downstream users who replied in detail there were no known cases of clinical symptoms in the last 10 years. One downstream user reported cases of elevated IgE levels (with no clinical findings) in the past which were drastically decreased to a few isolated cases after the introduction of standard risk management measures (engineering measures, mandatory use of respiratory masks etc.). 
Due to a variety of risk management measures (engineering/technical measures such as closed systems which reduce the exposure to cyclic anhydrides to near zero and automated processes in ventilated areas) potential exposure to cyclic anhydrides is limited to spot exposures of minutes/hours a day and exposure does not occur during the entire working shift. Consequently, many processes where exposure was possible in the past have these days been changed to automated and/or closed processes. Remaining handling steps with a potential exposure to cyclic anhydrides are, for example, mixing or blending in batch processes, sampling and transfer of substances from vessels/containers. Often only minutes (15-30 minutes) to a few hours (2 hours average) handling of cyclic anhydrides is the standard handling time which is often done sporadically only. For these potential exposure occasions, exhaust ventilation and personnel protective equipment (PPE) effectively ensure the safe handling of cyclic anhydrides. For example the guaranteed exposure level for a state-of-the-art masks (Mask with P3 dust filter if solid or type A filter for vapours and organic gases with a boiling point > 65°C if molten. (EN 149)) is 5 µg/m³. As medical surveillance allows the detection of early markers of potential sensitization, the subsequent development of clinical symptoms can effectively be avoided by monitoring workers’ health parameters. In plants using potential sensitizing chemicals monitoring IgE levels and other blood parameters (creatinin, liver parameters etc.) and urine parameters as well as spirometry is a standard program on a regular basis. In cases of conspicuous results, effective procedures of immediately removing of the worker from the exposed work-place take place which prevents the airway elicitation. Therefore the current standard risk management measures in place prove to be appropriate and effective. There is thus no need for an additional legislative control of risks through an authorisation process as risks are already controlled effectively by industry by applying appropriate risk management measures, evidenced by no recent respiratory clinical symptoms having been recorded over the last years.

Related to section 7.3 and 8 (page 27-32) and other (pape 3-33)

The use of MHHPA is limited to monomeric and intermediate use only. According to the REACH Guidance Document for monomers and polymers (April 2012), page 11 epoxy resin curing agents are considered to be monomers which are used in chemical post-modification in the synthesis of polymer substances. It is evident that in the Annex XV dossier this epoxy resin curing was not considered to be a monomer use. Together with the other known uses, MHHPA is used to a 100 % as a monomer (large majority) and an intermediate (minority).

As monomers and intermediates are not subject to the authorization process the identification of MHHPA as a SVHC will thus not lead to an improved legislative risk management. In addition, no free MHHPA is in the final articles present and thus the articles do not possess any sensitising properties.

In general, work-related asthma decreased in the EU: Data from the French national network of occupational health surveillance and prevention shows a significant decrease over the last decade for any causal agents with the exception of quaternary ammonium compounds (Paris et al. 2012). In Germany, work-related allergic respiratory symptoms have declined since 1993. In total, the Accident Prevention & Insurance Association of the German statutory accident insurance reported 523 incidents 2010. In 2009 with slightly more cases (565) the majority of the reported cases were related to the baking industry (61.1 %), hair dyes (5 %), fruits & legumes (5 %), associated to animals (hair, feathers etc.) (4.4 %), disinfection (3.2 %), natural rubber (latex) (2.5 %) feed and food dust (2.3 %). The remaining is related to moulds (0,5 %), enzymes (0,9 %) and others (15.2 %). As chemicals are not explicitly listed they are probably part of the “others” which would correspond to a maximum of 86 incidents related to chemicals as oppose to 345 related to flour (Raulf-Heimsoth et al. 2012). These figures show the vast variety of causative agents workers may be exposed to. Most of the causative agents are not only associated with a work environment but can also be present in the general population as this is true for natural causative agents lik to flour, flour products, bakery & pastry products. Not only in Germany but also in the Netherlands, roughly 30,000 workers are directly exposed to causative agents in the baking industry. Different studies revealed a sensitization rate due to baking products and raw materials of 2-16 % and 4-14 % respectively. The sensitization rate of atopic people was even higher (23 %). Work-related asthma was reported for 11.5 % and rhinoconjunctivitis for 18 %. High prevalence was found among sensitised workers:  > 50 % for asthma and 34 % for rhinitis (Health Council of the Netherlands, 2008). Many chemical agents causing work-related allergic respiration symptoms are only present in a working environment (industrial use; monomeric/intermediate use; no free substance in final article) and, if exposed, early detection of elevated IgE/G permits identification of exposure and allows such individuals to be removed from their workplace with the result that no additional exposure will take place (as opposed to workers exposed to other causative agents (animals, flour, moulds, enzymes) who will also be exposed in their private lives). 

The monitoring of early blood markers like IgE and other medical parameters (e.g. blood and urine, spirometry) are part of the medical surveillance programs in European plants and industry using sensitizing agents like HHPA and many other. With the regular monitoring of these early blood parameters and with the standard operating procedures, engineering equipment in place, potential exposure to MHHPA can be detected and subsequent measures like removing the worker from an exposed work place can be taken to prevent the possibility of the development of any pronounced clinical symptoms. As MHHPA is only used in industry and not in commercial products (Annex XV dossier, page 33, registration dossiers for MHHPA) and secondary exposure can be excluded outside of the work-place a sensitized worker will never be exposed to MHHPA again after a new task has been assigned to that person without MHHPA exposure.

In summary, MHHPA is considered NOT to possess an equivalent level of concern as CMR substances due to the fact that:
-	Sensitization is not comparable to effects of CMR substances;
-	Even clinical effects are reversible and only the last stage of damage of lung functions is considered not
        reversible;
-	Blood parameters allow monitoring of exposure to cyclic anhydrides and thus the potential for the elicitation of 
        possible irreversible clinical effects to be identified;
-	MHHPA is used as a monomer and intermediate only in industry;
-	No primary and secondary exposure of the general population exist;
-	Extensive legislative and voluntary product stewardship programs exist;
-	Current Risk Management Measures prove to be appropriate and effective;
-	In the past no cases for exposure only to MHHPA were noted (only cross-reactions with other cyclic anhydrides);
-	Recently, no work-related asthma was reported for cyclic anhydrides;
-	Other potent causative agents with many more incidents exist;

References Part II
Arts J.H.E., Mommers C.M. and  De Heer C. (2006): Dose Response Relationships and Threshold Levels in Skin and Respiratory Allergy, TNO Quality of Life, Zeist, Critical Reviews in Toxicology, The Netherlands 36:219-251.

Guidance for the implementation of REACH (2012): Guidance for monomers and polymers. publication no. 2012/04. Version 2.0. 

Health Council of the Netherlands (2008): Prevention of work-related airway allergies - Recommended occupational exposure limits and periodic screening, The Hague, Health Council of the Netherlands, publication no. 2008/03.

Health Council of the Netherlands (2010): Cyclic acid anhydrides - Health-based recommended occupational exposure limit, The Hague, Health Council of the Netherlands. Publication no. 2010/02OSH.

Paris C., Ngatchou-Wandji J., Luc A., McNamee R., Bensefa-Colas L., Larabi L., Telle-Lamberton M., Herin F., Bergeret A., Bonneterre V., Brochard, P., Choudat, D., Dupas D., Garnier R., Pairon J-C., M Agius, R., Ameille J. (2012): Work-related asthma in France: recent trends for the period 2001-2009. Online publication: downloaded from oem.bmj.com on 19 March 2012 published by group.bmj.com. 

Raulf-Heimsoth M., van Kampen V., Kespohl S., Sander I., Merget R., Brüning, T. (2012): Inhalationsallergien am Arbeitsplatz, aktuellen Entwicklungen, Bundesgesundheitsblatt 2012, 55:363-372. Online publication: 25. Februar 2012.

Rosqvist S., Nielsen J., Welinder H., Rylander L., Lindh C.H. and Jonsson B.A. (2003):
Exposure-response relationships for hexahydrophthalic and methylhexahydrophthalic anhydrides with total plasma protein adducts as biomarkers, Scand J Work Environ Health 29(4): 297-303.

Welinder H., Nielsen J., Bensryd I., Björk B., Strömberg U., Skerfving, S. (1998): Decline in serum antibodies to methyltetrahydrophthalic anhydride after cessation of exposure. Implications for use as a biomarker, Biomarkers 3:141-148. 	See response to comment no. 14
	
8	2012/10/16	Company
Sweden	p33. There are no alternatives identified. Anhydride curing epoxies are widely used for the manufacture of structural composite materials for aerospace, electrical and industrial applications. The material is selected due to a unique combination of processability and chemical/mechanical/thermal and electrical properties and the products realized enable significant energy savings and other benefits for the society and environment. Specific combinations of anhydrides are used to tailor the properties for specific applications. For several applications there are no identified alternatives to MHHPA. When/if such an alternative is developed it is likely that the long term human health hazard and environmental health hazard is much less documented than for MHHPA which experience has shown is safe to use when subject to modern risk management measures.	Noted. This information will be taken into account in the process of priority setting for Annex XIV.
	
6	2012/10/16	Industry or trade association
Switzerland	The substance is used as curing agent and is widely used in the electronic industry for specific sector due to its high performance of heat resistance and electrical properties. After curing the substance is embedded into the polymerized matrix. It is not released from the final article (semiconductor device) under normal conditions of use. More over it would be difficult to identify as distinct substance in the final article according to the rules defined in the SIA guidelines.
No exposure arise to employees during use in semiconductor industry, due to controlled working environment. Substance is delivered in closed containers and used in closed equipment. Waste of spent resin are managed according the hazardous waste management practice. There is no discharge in waste water.      
Total quantity of the substance imported in Europe within article is 1,4 t/y.
Final concentration in article would be considered < 0.4 % w/w	Noted. This information will be taken into account in the process of priority setting for Annex XIV.
	
4	2012/10/15	Industry or trade association
ASD - Aerospace & Defence Industries of Europe
Belgium	HHPA is used in the Aerospace and Defence industries as a hardener in some epoxy resins and in a Low Density Void Filler (LDVF) that has been recently qualified. This void filler replaced 4 others in order to rationalise the number of products and also to reduce Health & Safety effects (Toxicology concern & Raw Material ban): Some of the substances contained in the “old LDVF” were CMR2, CMR3 + DecaBDE. Qualified alternatives do not exist at this time.

This case is a good example of difficulties of substitution and anticipation since this and Cyclohexane-1,2-dicarboxylic anhydride are proposed to be identified as an SVHC according to the criteria of “Equivalent concerned”: experts had no visibility and no chance to anticipate that these 2 substances will become SVHC.	Noted. This information will be taken into account in the process of priority setting for Annex XIV.

Attachments
Comment number	Public attachment	
17	
Comment 17 attachment (20017_2012_Echa_54 SVHC consultation.pdf).pdf	
21	
Comment 21 attachment (MHHPA_FFTI_.docx).docx