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

Substance name:	4-Nonylphenol, branched and linear, ethoxylated [substances with a linear and/or branched alkyl chain with a carbon number of 9 covalently bound in position 4 to phenol, ethoxylated covering UVCB- and well-defined substances, polymers and homologues, which include any of the individual isomers and/or combinations thereof]	
CAS number:	-	
EC number:	-	

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
Number	Date	Submitted by (name, Organisation/MSCA)	Comment	Response	
17	2013/05/03	Member State Finland	We agree that 4-nonylphenol, branched and linear, ethoxylated (4-NPE) should be added to the candidate list as an SVHC according to article 57(f) in REACH. We think that the information submitted by Germany provides sufficient scientific evidence that 4-NPE degrade to 4-nonylphenol (4-NP), branched and linear, either already in wastewater treatment plants, or via further degradation processes in sediments (e.g. of aquatic bodies receiving the wastewater effluents) and soils (e.g. receiving sewage sludge). We agree that the equivalent level of concern is based on the degradation to 4-NP which has already been included in the candidate list.    

The Finnish CA considers that after inclusion of substances identified based on article 57 (f) in the candidate list it still needs to be further considered which risk management measures would be the most appropriate. The coverage of existing measures shall be taken into account.	Thank you for your support.	
12	2013/04/18	International NGO
Health and Environment Alliance
Belgium	HEAL strongly supports this substance being adopted as an SVHC, especially given that its degradation product 4 nonylphenol is already adopted on the Candidate List	Thank you for your support.	
11	2013/04/18	Industry or trade association
European Council for Alkylphenols and Derivatives
Belgium	6.0  	Nomination of NPEO polymers as SVHC because one of their degradation intermediates, NP,  has been identified as a SVHC, circumvents the intention of SVHC under REACH and the need for Commission consideration of policy regarding polymers  under REACH

The Annex XV Report argues that “to be consistent with the approach implemented in Annex XIII of REACH for PBT substances, it seems reasonable to conclude that any substance, which may result in a relevant exposure to a SVHC  (i.e., due to degradation to this substance under environmental conditions) should be considered as SVHC itself as it results in the same equivalent level of concern”.

A revision to REACH Annex XIII regarding the assessment of PBT and vPvB properties was published under COMMISSION REGULATION (EU) No 253/2011. This revision added consideration of a weight of evidence approach and the condition that the identification of PBT/vPvB substances “shall also take account of the PBT/vPvB-properties of relevant constituents of a substance and relevant transformation and/or degradation products.” The fact that Annex XIII went through a revision process that included Commission consideration and approval highlights the uniqueness of this provision. 

In contrast, Article 57 lists the criteria for SVHC candidates for authorisation and there is no mention in Article 57 that SVHC designation should be applicable any substances other than those that meet one or more of those hazard criteria.   There is also no intention expressed anywhere in the REACH regulations that polymers or substances that degrade to a SVHC should also be considered an SVHC. Development of such a policy on a case-by-case basis through SVHC nominations circumvents the need for Commission consideration of such an important policy under REACH. 

10.0 	The very low estrogenic potency, multiple modes of action, and low environmental occurrence and concentrations for NP and NPEOs do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to substances meeting the criteria of Article 57(a) through (f).

Categorization as SVHC should be reserved for substances for which the weight-of-evidence supports a finding of both probable serious effects from that specific substance. Data supporting the hazards of a substance nominated for SVHC should be specific and sufficient to support that substance as meeting criteria listed under Article 57.  The available data for NPEO do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to those of other substances meeting the criteria of Article 57. 

The Annex XV Report for NPEO is based on assumptions that these polymeric compounds are contributing to probable serious effects in aquatic species due to their degradation to NP in the environment.  As discussed previously, NP, at most, has weakly estrogenic activity, low mole NPEOs have even weaker estrogenic activity and higher mole NPEOs have no estrogenic activity. NP and NPEO have estrogenic activity that is orders of magnitude less than the natural (E2) and synthetic (EE2) estrogens based on in vitro and in vivo tests. Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action and affect acute lethality and chronic reproduction, growth and development endpoints very differently than E2 or EE2.  Comparison of studies examining NPEO, NP and E2 and EE2 demonstrates that there are great differences between the effects that they cause to aquatic organisms.  While the estrogenic mode of action is clearly the lead, or most predominant, mode of action impacting adverse effects from E2 and EE2, this is not clearly the case for NP or low mole NPEO, which have other co-occurring modes of toxicity (i.e., narcosis) that result in adverse effects observed among fish population, Endocrine activity alone is not sufficient justification for equivalent concern under Article 57(f).  Without evidence of probable serious adverse effects that are primarily the consequence of that mode of action the compound does not rise to a level of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds.

Consideration of exposure and risk are inherent in determining probable serious effects.    In the case of NP and NPEOs, concentrations in European waters are generally well below NOEC and LOEC values for adverse apical effects found in studies on NP in aquatic species and have dropped significantly since 2003 when the M & U Directive on dispersive uses of NP and NPEO was implemented. Concentrations of NP are typically below EQS established for this compound under the Water Framework Directive.  In addition, as discussed in earlier in these comments, studies that examine estrogenically active substances in wastewater treatment plant effluent found that if detected, NP, NPEOs and alkylphenols generally, contributed only minimally to the aggregate estrogenicity. 

NPEO and NP are not considered “persistent” or “very persistent” according to Annex XIII criteria and the presence of NP in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

Perhaps most importantly, the criteria listed under Article 57  list specific  hazard-based  adverse effects criteria that should apply to SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those criteria.  The proposal in the Annex XV Report for NPEO to designate these polymers that degrade to a SVHC compound to also be SVHC based on the argument that the polymer is an environmental source of the degradant  circumvents the need for Commission consideration of this significant policy determination under REACH. In addition, there are other regulatory instruments in place in the EU to control emissions of NPEO, which based on current monitoring data in the EU should preclude the need for further prioritization of these compounds. 

For all of these reasons APERC and CEPAD recommend rejection of the Annex XV Report on NPEO. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT	Thank you for your comment.

6.0 
As mentioned in the comment 57(f) considers substances for which there is scientific evidence  of probable serious effects which give rise to an equivalent level of concern to those of substances listed under 57(a) – (e).
57(f) does not specify the type of concern and thus any substance property which may cause serious effects which are of equivalent concern can in principle be considered under 57(f). 
In the case of degradation to a SVHC the effects considered are the effects of the degradation product which are already confirmed to be of very high concern.
We therefore consider the proposal to be in line with the legal text. It is in line with the proposal for PBT substances in Annex XIII and in line with a proposal by the EU Commission to consider substances degrading to SVHC as SVHC themselves.

10.0
Please note that the dossier proposes to nominate 4-nonylphenol ethoxylates due to their degradation to 4-nonylphenol for which probable serious effects which are of equivalent concern have been already approved. 4-nonylphenol was identified as SVHC in December 2012.

Please also note, that exposure considerations are not part of a SVHC identification.
	
			See also:
Comment 11 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
10	2013/04/18	Industry or trade association
Alkylphenols & Ethoxylates Research Council
United States	6.0  	Nomination of NPEO polymers as SVHC because one of their degradation intermediates, NP,  has been identified as a SVHC, circumvents the intention of SVHC under REACH and the need for Commission consideration of policy regarding polymers  under REACH

The Annex XV Report argues that “to be consistent with the approach implemented in Annex XIII of REACH for PBT substances, it seems reasonbale to conclude that any substance, which may result in a relevant exposure to a SVHC  (i.e., due to degradation to this substance under environmental conditions) should be considered as SVHC itself as it results in the same equivalent level of concern”.

A revision to REACH Annex XIII regarding the assessment of PBT and vPvB properties was published under COMMISSION REGULATION (EU) No 253/2011. This revision added consideration of a weight of evidence approach and the condition that the identification of PBT/vPvB substances “shall also take account of the PBT/vPvB-properties of relevant constituents of a substance and relevant transformation and/or degradation products.” The fact that Annex XIII went through a revision process that included Commission consideration and approval highlights the uniqueness of this provision. 

In contrast, Article 57 lists the criteria for SVHC candidates for authorisation and there is no mention in Article 57 that SVHC designation should be applicable any substances other than those that meet one or more of those hazard criteria.   There is also no intention expressed anywhere in the REACH regulations that polymers or substances that degrade to a SVHC should also be considered an SVHC. Development of such a policy on a case-by-case basis through SVHC nominations circumvents the need for Commission consideration of such an important policy under REACH. 

10.0 	The very low estrogenic potency, multiple modes of action, and low environmental occurrence and concentrations for NP and NPEOs do not support a conclusion of probable serious environmental effects  giving rise to an equivalent level of concern to substances meeting the criteria of Article 57(a) through (f).

Categorization as SVHC should be reserved for substances for which the weight-of-evidence supports a finding of both probable serious effects from that specific substance. Data supporting the hazards of a substance nominated for SVHC should be specific and sufficient to support that substance as meeting criteria listed under Article 57.  The available data for NPEO do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to those of other substances meeting the criteria of Article 57. 

The Annex XV Report for NPEO is based on assumptions that these polymeric compounds are contributing to probable serious effects in aquatic species due to their degradation to NP in the environment.  As discussed previously, NP, at most, has weakly estrogenic activity, low mole NPEOs have even weaker estrogenic activity and higher mole NPEOs have no estrogenic activity. NP and NPEO have estrogenic activity that is orders of magnitude less than the natural (E2) and synthetic (EE2) estrogens based on in vitro and in vivo tests. Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action and affect acute lethality and chronic reproduction, growth and development endpoints very differently than E2  or EE2.  Comparison of studies examining NPEO, NP and E2 and EE2 demonstrates that there are great differences between the effects that they cause to aquatic organisms.  While the estrogenic mode of action is clearly the lead, or most predominant , mode of action impacting adverse effects from E2 and EE2, this is not clearly the case for NP or low mole NPEO, which have other co-occurring modes of toxicity (i.e., narcosis) that result in adverse effects observed among fish population, Endocrine activity alone is not sufficient justification for equivalent concern under Article 57(f).  Without evidence of probable serious adverse effects that are primarily the consequence of that mode of action the compound does not rise to a level of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds.

Consideration of exposure and risk are inherent in determining probable serious effects.    In the case of NP and NPEOs, concentrations in European waters are generally well below NOEC and LOEC values for adverse apical effects found in studies on NP in aquatic species and have dropped significantly since 2003 when the M & U Directive on dispersive uses of NP and NPEO was implemented. Concentrations of NP are typically below EQS established for this compound under the Water Framework Directive.  In addition, as discussed in earlier in these comments, studies that examine estrogenically active substances in wastewater treatment plant effluent found that if detected, NP, NPEOs and alkylphenols generally, contributed only minimally to the aggregate estrogenicity. 

NPEO and NP are not considered “persistent” or “very persistent” according to Annex XIII criteria and the presence of NP in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

Perhaps most importantly, the criteria listed under Article 57  list specific  hazard-based  adverse effects criteria that should apply to SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those criteria.  The proposal in the Annex XV Report for NPEO to designate these polymers that degrade to a SVHC compound to also be SVHC based on the argument that the polymer is an environmental source of the degradant  circumvents the need for Commission consideration of this significant policy determination under REACH. In  addition, there are other regulatory instruments in place in the EU to control emissions of NPEO, which based on current monitoring data in the EU should preclude the need for further prioritization of these compounds. 

For all of these reasons APERC and CEPAD recommend rejection of the Annex XV Report on NPEO. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT	Thank you for your comment. See response to comment number 11.	
			See also:
Comment 10 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
1	2013/04/12	Member State
United Kingdom	Editorial remarks:
Section 1.3 (physico-chemical properties): Information on vapour pressure of a short chain ethoxylate is given in Section 3.1.1.2.1, statements about trends in vapour pressure are given in Section 3.2.2 and QSAR predictions are used in Sections 3.2.1 and 3.2.3. We note that it is explicitly stated that no evaluation has been performed, because this information is not essential for the dossier. However, it is relevant in terms of environmental distribution, and we think it would have been more transparent to summarise such information in either the phys-chem section, or perhaps an appendix, ideally with an indication of the validity of the predictions. 
	Thank you for your comment. A table summarizing calculated physic-chemical properties for NPEO with different grades of ethoxylation was included in section 1.3. However no indication of validity was included as the information is not essential for the final conclusion which is based on experimental data.	

Specific comments on the justification
Number	Date	Submitted by (name, Organisation/MSCA)	Comment	Response	
16	2013/04/26	Member State
France	FR MSCA agrees that 4-Nonylphenol, branched and linear, ethoxylated (4-NPnEO) are substances with endocrine disrupting properties for which there is scientific evidence of probable serious effects to the environment which gives rise to an equivalent level of concern to those of other substances listed in points [(a) to (e)] of article 57 of REACH. Therefore 4-Nonylphenol, branched and linear, ethoxylated (4-NPnEO) should be identified as SVHC according to Article 57 (f) of REACH. 
Indeed, according to the degradation pathways well described in the annex XV-SVHC dossier, 4-Nonylphenol, branched and linear, ethoxylated (4-NPnEO) degrade in sewage treatment plants and in the environment to 4NP, NP1EO, or NP2EO that are known to have endocrine disrupting properties. Nonylphenol is mainly formed in anaerobic conditions. Monitoring studies show that degradation in nonylphenol (NP) occurs in sewage treatment plants (STP) as concentration of NP increases during the treatment. Additionally, partial degradation of 4-NPnEO in STP leads to release of metabolites which can be further degraded either directly to NP in the environment, or first to NP1EO or NP2EO which are then degraded to NP. 	Thank you for your support.	
15	2013/04/18	Industry or trade association
ASD
Belgium	None	See response to your comment at part ”Specific comments on use, exposure, alternatives and risks”	
			See also:
Comment 15 attachment (ASD Letter.docx).docx		
14	2013/04/18	International NGO
Women in Europe for a Common Future
France	The classification of 4-nonylphenol as substance of equivalent level of concern having probable serious effects to the environment (Article 57 f) seems relevant. A body of scientific evidence exists to support this classification: 
Effects of 4-nonylphenol and/or diisononylphthalate on THP-1 cells: impact of endocrine disruptors on human immune system parameters. Bennasroune A, Rojas L, Foucaud L, Goulaouic S, Laval-Gilly P, Fickova M, Couleau N, Durandet C, Henry S, Falla J. Int J Immunopathol Pharmacol. 2012 Apr-Jun;25(2):365-76.
An evaluation on combination effects of phenolic endocrine disruptors by estrogen receptor binding assay. Li Z, Zhang H, Gibson M, Li J. Toxicol In Vitro. 2012 Sep;26(6):769-74. doi: 10.1016/j.tiv.2012.05.017. Epub 2012 Jun 9.
Effects of some endocrine disruptors on cell cycle progression and murine dendritic cell differentiation. Pisapia L, Del Pozzo G, Barba P, Caputo L, Mita L, Viggiano E, Russo GL, Nicolucci C, Rossi S, Bencivenga U, Mita DG, Diano N. Gen Comp Endocrinol. 2012 Aug 1;178(1):54-63. doi: 10.1016/j.ygcen.2012.04.005. Epub 2012 Apr 17.
Potential hazards to embryo implantation: A human endometrial in vitro model to identify unwanted antigestagenic actions of chemicals. Fischer L, Deppert WR, Pfeifer D, Stanzel S, Weimer M, Hanjalic-Beck A, Stein A, Straßer M, Zahradnik HP, Schaefer WR. Toxicol Appl Pharmacol. 2012 May 1;260(3):232-40. doi: 10.1016/j.taap.2012.02.016. Epub 2012 Mar 6.
Effects of 4-nonylphenol on proliferation of AGS gastric cells. Manente L, Sellitti A, Lucariello A, Laforgia V, De Falco M, De Luca A. Cell Prolif. 2011 Oct;44(5):477-85. doi: 10.1111/j.1365-2184.2011.00774.x.
Does the oestrogen receptor encourage oestrogenicity in environmental pollutants? The case of 4-nonylphenol. Graham LA, Shaw IC. SAR QSAR Environ Res. 2011 Jun;22(3):329-50. doi: 10.1080/1062936X.2011.569899.
Endocrine disrupting chemicals bind to a novel receptor, microtubule-associated protein 2, and positively and negatively regulate dendritic outgrowth in hippocampal neurons. Matsunaga H, Mizota K, Uchida H, Uchida T, Ueda H. J Neurochem. 2010 Sep 1;114(5):1333-43. doi: 10.1111/j.1471-4159.2010.06847.x. Epub 2010 Jun 7.
[Study on the levels of the bisphenol A, octylphenol, 4-nonylphenol in serum of precocious girls]. Qiao L, Zheng L, Cai D. Wei Sheng Yan Jiu. 2010 Jan;39(1):9-12. Chinese. 	Thank you for the additional information.	
13	2013/04/18	International NGO
ChemSec, the International Chemical Secretariat
Sweden	We fully support the identification of the substance group as an SVHC:
- Based on the evidence laid out in the dossier that the ethoxylated forms do degrade into 4-nonylphenol in the environment.
 -Based on the previous inclusion of 4-nonylphenol on the candidate list. 
	Thank you for your support.	
11	2013/04/18	Industry or trade association
European Council for Alkylphenols and Derivatives
Belgium	Executive Summary

The European Council for Alkylphenols and Derivatives (CEPAD) and the Alkylphenols & Ethoxylates Research Council (APERC) jointly submit these comments in objection to the Annex XV Report proposing to identify Nonylphenol, branched and linear, ethoxylated (NPEO) as a Substance of Very High Concern (SVHC). 

The Annex XV Report suggests that NPEOs meet the criteria for SVHC under Article 57(f) of the Registration, Evaluation, Authorisation and Restriction of Chemicals Regulation (EC) 1907/2006 (REACH), which states:

“(f) substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 

The Annex XV Report proposes to identify NPEs as SVHC primarily based on the argument that due to their degradation they are “an environmental source” of nonylphenol (NP), which was previously designated as SVHC.   CEPAD and APERC continue to disagree with the SVHC determination of NP (CEPAD and APERC, 2012); however even recognizing this designation for NP, the assumption that degradation of a polymer to an intermediate that is designated as SVHC also warrants designation of the polymer as SVHC is inconsistent with the requirements and intention of Article 57 and, as discussed further below, circumvents the need for Commission consideration of this significant policy determination under REACH.

The Annex XV Report further justifies designating NPEOs as SVHC on the basis that: 
“… available information for NPnEO indicate that short chain ethoxylates (NP1EO and NP2EO) show endocrine activity themselves: Results for Onchorhynchus mykiss and Oryzias latipes with NPE1EO and NPE2EO indicate that the in vivo and in vitro endocrine activity is nearly as high (factor 10) or similar to the endocrine activity of 4-nonylphenol. These tests do not include adverse endpoints. Hence, it is not possible to conclude whether 4-NP1EO and 4-NPE2EO are endocrine disruptors themselves, or not. However due to the similar in vivo endocrine activity and information available for 4-NP it seems possible that these substances may cause endocrine disrupting adverse effects.” (emphasis added) 
 The Annex XV Report for NPE speculates that NPEO1 and NPEO2 may cause endocrine disrupting adverse effects, while at the same time acknowledging that “it is not possible to conclude whether 4-NP1EO and 4-NPE2EO are endocrine disruptors themselves.”   The precautionary principle is intended to apply to situations where there is considerable scientific uncertainty; it is not a substitute for evaluating potential environmental effects when sufficient information exists. The comments below will provide a review of the data available for NP and NPEO in comparison with data for the natural estrogen, 17β-estradiol (E2) and synthetic (EE2) estrogen to show that NPEO and NP have a very different mode of action profile than these potent estrogens and should not be presumed to have comparable adverse effects based on an estrogenic mode of action.  
In addition to the above mentioned scientific concerns with the arguments in the Annex XV Report for NPE, these comments will also raise policy concerns.  The Annex XV Report for NPEO proposes a basis for determining probable serious environmental effects from an endocrine mode of action even as the European Commission has activities underway to develop a definition of endocrine disruptors. These activities include discussion about an endocrine disruptor hazard categorization scheme and consideration of the potency, adversity of effects and requirement to review the weight-of-evidence for endocrine disruptors (Kortenkamp, A., 2011). 

Also, the Annex XV Report proposes to identify NPEO polymers as SVHC because they are a source of NP, which has been identified as a SVHC, in the environment. The criteria under Article 57  list specific  hazard-based properties that should apply to the SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those hazard criteria.  In addition, in this case, environmental concentrations of NP in EU waters are for the most part below Environmental Quality Standards (EQS) for this compound and do not support concern for probable serious effects in the environment from  either NPEO or NP. 
 
The Annex XV Report for NPEO cites  the revision of REACH Annex XIII regarding the assessment of PBT and vPvB properties, which was published under COMMISSION REGULATION (EU) No 253/2011 as justification to designate NPEO polymer as the SVHC because NP is already a SVHC.  The revision to Annex XIII added the condition that the identification of PBT/vPvB substances “shall also take account of the PBT/vPvB-properties of relevant constituents of a substance and relevant transformation and/or degradation products”. The process of revising Annex XIII to include this change highlights the uniqueness of this provision within REACH. There is no such requirement to consider transformation and/or degradation products in the assessment of any other hazard under Article 57. Application of such a provision should require the consideration of the Commission and revision of the regulations as was done with Annex XIII.  Therefore, any assessment of NPEO as SVHC should be based solely on consideration of the hazard properties of the polymer relative to the criteria listed under Article 57. The proposal to include  polymers that degrade to an  intermediate that is a SVHC circumvents the need for Commission consideration of this significant policy determination under REACH. 

As discussed in more detail below, Article 57(f) states that scientific evidence of probable serious effects to human health or the environment, which give rise to an equivalent level of concern to those of substances that meet the criteria under Article 57(a) to (e) is necessary to classify a substance as a SVHC. The very low to non-existent estrogenic potency of NPEO, along with their low environmental occurrence and concentrations, do not support a conclusion of probable serious environmental effects from these compounds in the EU.  In addition, neither NPEO nor NP is persistent or increasing in EU waters.  Furthermore, an indication that a compound has some estrogenic activity should not be considered as of equivalent concern to the criteria under Article 57 (a)-(e), since endocrine activity is not an effect and is not necessarily adverse. Rather, endocrine activity is a mode of action, which may or may not be linked to any sort of adverse effect in an intact organism.  The criteria listed under Article 57 (a) to (c) are clearly based on adverse effects while those in (d) and (e) are linked to environmental fate.  Simple mode of action evidence for compounds, i.e. endocrine activity, therefore does not meet the requirement of equivalent concern under Article 57(f) without evidence of consequent and probable serious adverse effects.  Concentrations of NP from peer-reviewed publications indicate that environmental concentrations in EU waters are generally below levels of concern for any type of adverse effects in environmental organisms.  Thus, there is no evidence for NP or NPEO of probable serious effects to human health or the environment, which give rise to an equivalent level of concern under Article 57.

Moreover, the adverse effects of NPEO and NP on aquatic organisms are already controlled through existing regulatory instruments in the EU such as the Water Framework Directive, which has established an Environmental Quality Standard (EQS) for NP, and the Integrated Pollution Prevention and Control (IPPC) Directive.  More importantly, there is a long-standing EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  The M&U Directive for NP and NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP and NPEO in wide dispersive uses most likely to result in emissions to the aquatic environment. Considering these existing regulatory instruments in the EU, there does not appear to be a need to further prioritize for NPEOs as SVHC on the basis of concern for the toxicity to the environment.

The following comments elaborate on these points and demonstrate that while some degradation intermediates of NPEO may have weak estrogenic activity, neither NP nor NPEO demonstrate adverse environmental effects that give rise to an equivalent level of concern as CMR, PBT or vPvB compounds. 

1.0  	NPEOs do not meet the clearly defined hazard criteria for classification as an SVHC under the sections Article 57a through 57e. 

Article 57 of REACH very specifically lists the following hazard-based criteria for substances to be candidates to be included in Annex XIV. 

(a) substances meeting the criteria for classification as carcinogenic category 1 or 2 in accordance with Directive 67/548/EEC; 
(b) substances meeting the criteria for classification as mutagenic category 1 or 2 in accordance with Directive 67/548/EEC; 
(c) substances meeting the criteria for classification as toxic for reproduction category 1 or 2 in accordance with Directive 67/548/EEC; 
(d) substances which are persistent, bioaccumulative and toxic in accordance with the criteria set out in Annex XIII of REACH; 
(e) substances which are very persistent and very bioaccumulative in accordance with the criteria set out in Annex XIII of REACH; and 
f) substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 
	
As noted in the Annex XV report for NPEO, these polymers are not classified according to Annex VI of Regulation (EC) No. 1272/2008 (the CLP Regulation). However, NPEO were not assessed in the Annex XV Report relative to the criteria under Article 57 (a) – (e).  This section of these comments  summarizes assessments that confirm that NPEO and NP are not carcinogenic, mutagenic or reproductive toxicants (CMR).  Nor ar they persistent, bioaccumulative and toxic (PBT) or very persistent and very Bioaccumulative (vPvB) compounds.  

1.1	Neither NPEO nor its degradation intermediates, including NP, meet the criteria for carcinogen, mutagen or reproductive toxicants category 1 or 2 in accordance with REGULATION (EC) No 1272/2008 (the CLP Regulation).
While the Annex XV Report for NPEO did not assess NPEO for CMR properties, it is useful to note that the European Chemicals Bureau (ECB) Risk Assessment on NP states that NP is not mutagenic and that there is low concern for carcinogencity by a non-genotoxic mechanism. It also concludes that there was no evidence of functional changes in reproduction and any changes that were seen occurred at exposure levels in excess of the LOAEL for repeated dose toxicity (ECB, 2002).  

In addition, US EPA conducted an assessment of the human safety of NPEO and approved their use as inert ingredients in pesticide formulations after considering risk to infants and children and finding “reasonable certainty of no harm”. (US EPA OPPTS, 2006)  Assessments of chemicals by US EPA under the Food Quality Protection Act (FQPA) are conducted based on informed multiple risk exposure scenarios, which allows meaningful, risk-based priority setting and activity planning. In 2006, EPA conducted an assessment on the use of NPEOs as inert ingredients in pesticide products. The assessment of NPEO by US EPA was conducted as part of a reassessment of all inert ingredients as mandated by FQPA, which has a primary focus on children’s health. FQPA assessments require the use of reliable data and must make a “reasonable certainty of no harm” finding to exempt an inert ingredient from the requirement of tolerance levels in pesticide products.  The US EPA inert reassessment on NPEO concluded there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to NPEO when used as an inert ingredient in pesticide products when considering dietary exposure and all non-occupational exposures. The US EPA reassessment acknowledged several multi-generation reproduction studies on NP in rats that demonstrate no adverse effects on reproductive function. US EPA found that in NPEO developmental toxicity studies in rats and mice, there was no incidence of developmental toxicity in the absence of maternal toxicity. The Agency concluded that neither NP nor NPEO are carcinogenic and that human exposure to NPEO via food, drinking water, and residential exposure pathways is orders of magnitude less than the No Observed Effect Levels (NOELs) and No Observed Adverse Effect Levels (NOAELs) in animal studies including chronic, repeat-dose, developmental and carcinogenicity studies. Finally, US EPA concluded no concern for increased sensitivity to infants and children from NPEOs. 

In 2001, Environment Canada and Health Canada conducted a Risk Assessment for NP and NPEOs pursuant to the Canadian Environmental Protection Act (CEPA), which determined that NP and NPE are not CMRs (EC & HC, 2001).

1.2 	Neither NPEO nor its degradation intermediates, including NP,  
are PBT or vPvB.

The European Commission determined NP is not persistent or bioaccumulative. (ECB PBT WG, 2003).  In 2006, Environment Canada completed a review of NP and NPEO along with octylphenol (OP) and octylphenol ethoxylates (OPE) as part of a categorization assessment under the Canadian Environmental Protection Act (CEPA), which required an assessment of all substances on the Canadian Domestic Substances List (DSL) with respect to persistence, bioaccumulation and inherent toxicity (PBiT) characteristics. Environment Canada concluded that none of these alkylphenol and ethoxylate compounds are persistent or bioaccumulative (Environment Canada, 2006). 

Subsequent to these governmental assessments, Klecka et al (2008) conducted a comprehensive review of the literature and conducted a weight-of-evidence based assessment of the persistence and bioaccumulation potential of C-8 and C-9 alkylphenol ethoxylates (APE) along with their degradation intermediates and metabolic by-products.  The authors found that the commercial APE products and their degradation intermediates do not meet any national or international criteria for identifying these compounds as PBT or vPvB substances.

2.0	NPEOs and NP have not been shown to cause probable serious effects that are of equivalent concern to those under Article 57 (a)-(e) and adverse effects from these compounds on aquatic species cannot be clearly attributed to an endocrine mode of action obscuring the relevance of Article 57(f) to these compounds.  

Article 57 (f) states:  “substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 

The Annex XV Report for NPEOs does not provide sufficient scientific evidence that these polymers or their degradation intermediate NP pose probable serious effects in the environment from an endocrine mode of action.  Rather, the Report relies on presumptions of “possible” effects of an equivalent concern to CMR and PBTs. NPEO polymers (NPEO≥4) are not estrogenic and the Annex XV Report for NPEO overstates the estrogenic potency of low mole NPEO and NP.  Estrogenic potency should certainly be a consideration when assessing whether there is scientific evidence of probable serious effects to human health or the environment under Article 57(f). 

Also, as discussed in more detail below, the data from NPEO and their breakdown intermediates, including NP, indicate that there are likely multiple modes of action occurring within the same exposure concentration ranges. Therefore any adverse effects from NPEO or their breakdown intermediates on aquatic species cannot be clearly attributed to an endocrine mode of action obscuring the relevance of Article 57(f) to these compounds

2.1	Higher mole NPEO are not estrogenic and low mole NPEO (NPEO1, NPEO2) and NP are considerably less potent than the natural estrogen, 17β-estradiol (E2) and synthetic (EE2) estrogen based on in vitro estrogen activity screening tests as well as endpoints from in vivo tests.

Information about the potency of endocrine active compounds relative to the known potent estrogens E2 and EE2 are provided by various in vitro screening tests and in vivo tests with intact organisms. Relative potencies from these studies can be approximated by concentrations of NP and E2 or EE2 used as a positive control that gave comparable results. Overall, the data show that NP is approximately one thousand to one million-fold less potent than the endogenous estrogen E2 or the synthetic estrogen EE2, depending on the species and endpoint investigated (Jobling and Sumpter 1993; Lee and Lee 1996; Islinger et al. 1999; Metcalfe et al. 2001; Dussault et al. 2005; Balch and Metcalfe 2006; Lin and Janz 2006; Zha et al. 2007, 2008).

From in vitro studies, relative potencies of NPEO1 and NPEO2, tested singly or as a mixture, ranged from 1.5 to 8300-fold less than NP (Jobling and Sumpter, 1993; Metcalfe et al., 2001; Isidori et al., 2006). Using test material of confirmed purity and composition, yeast screening assays conducted with higher mole NPEO (NPEO≥6) showed negligible activity or gave no response. The toxicity of NPEO relative to E2 from in vivo assays is lower than for NP. Balch and Metcalfe (2006) reported effects on secondary sex characteristics in fathead minnow exposed for 100 days to NP and NPEO1, but no response with nonylphenol monoether carboxylate (NPEC1) or NPEO4, or NPEO9. Dussault et al (2005) measured vitellogenin induction in rainbow trout and reported that NPEO1 and NPEC1 were 5 to 33-fold less potent than NP. Miles-Richardson et al. (1999) and Nichols et al. (2001) exposed breeding pairs of fathead minnow to NPEO9 for 42 days and reported no significant effects on reproduction, vitellogenin, serum testosterone or E2 levels, gonadal histopathology or secondary sex characteristics. 

2.2	Examination of the estrogenic potency and aquatic toxicity of natural estrogen (E2) and synthetic estrogen (EE2) provides an understanding of the adverse effects profile that result from a highly potent estrogen.

The Annex XV Report for NPEO emphasizes the estrogenic activity of NPEO as the basis for “equivalent concern” in its assessment of the compound’s aquatic toxicity. In light of this concern, it is of use to first examine effects on aquatic organisms from known endocrine active substances for which the mode of action is indisputable – natural estrogen (E2) and a synthetic and therapeutic estrogen (EE2). Relevant studies are summarized in Table I below.  

SEE TABLE I SUMMARY OF AQUATIC TOXICITY STUDIES FOR 17 α -ETHYNYLESTRADIOL (EE2) AND 17β -ESTRADIOL (E2) IN ATTACHED SUBMISSION DOCUMENT

The estrogenic potencies of E2 and EE2 have been found to be generally similar to each other. EE2/E2 ratios range from 0.19 to 1.9 depending on the screen used (Kidd et al., 2007).  E2 and EE2 are especially potent when compared to the weak estrogenic activity of NP.

The natural and synthetic estrogens E2 and EE2, respectively, cause significant and severe effects on freshwater and saltwater fish. As described in more detail below, a signature set of estrogenically mediated aquatic effects from E2 and EE2 may include:  complete feminization of male gonads; induced failure to differentiate into males; reduced reproduction capabilities; severe histological effects on gonadal tissues; and even collapse of whole populations in a lake continuously dosed with EE2 for three years.

As noted in Table I above, a  series of short term reproduction assays showed that survival, reproduction, fertilization, spawning and hatch success, and sex ratio can be significantly altered at estrogen concentrations down to 0.005 µg/L. Secondary endpoints (which are more focused on determining mode of action rather than adverse effect), such as gonadal weights and histopathology, testis-ova, and kidney lesions were affected at even lower concentrations, down to 0.0002 µg/L. Life cycle studies with fathead minnow and zebra fish that included exposure to EE2 over the full life cycle showed similar effects at 0.001 to 0.016 µg /L and 0.0003 to 0.010 µg /L, respectively. Second generation NOEC were seen at concentrations as low as 0.0002 to 0.0003 µg/L (Lange R., 2001; Wenzel et al., 2001). Secondary endpoints, including secondary sex characteristics, testis-ova, gonadal histopathology, and VTG, had NOEC in the 0.001 to 0.004 µg/L range. In both studies, and presumably due to the strong estrogenic potencies of these compounds, essentially complete feminization of males and/or male characteristics was reported.

In order to differentiate the relationship of endpoint effects caused by a narcotic mode of action and those mediated by an estrogenic mode of action, Wenzel et al (2001) examined the ratio of the acute LC50 of EE2 (1,700 µg /L) and the most significant reproduction NOEC (fertilization success, NOEC 0.0003 µg /L). The acute-to-chronic ratio of the two is 5.73 million. This very high ratio is indicative of the specific mode of action (i.e. estrogenic activity) associated with the synthetic estrogen EE2 in relation to the acute toxicity of EE2 based on mortality.  It is clear for EE2 that the reproduction, growth and development endpoints are affected by a different mechanism of action (estrogenic activity) than the acute lethality (narcosis) endpoints. Given the potency of natural and synthetic estrogens, this is expected, and hence the very high ratio is understandable. The acute to chronic ratio for EE2 is very different from the ratios that are calculated with NP (22 to 116) as is discussed below.

In a whole lake study, Kidd (2007) and colleagues dosed a whole lake with EE2 (0.005 to 0.006 µg/L) for 3 years. Fathead minnow populations became completely feminized, reproduction halted, and the population collapsed. The abundance of pearl dace fish was also decreased. These two species of fish were previously predominant in the lake. As noted in laboratory studies, severe effects on gonadal tissues were found. Male gonadal tissue development was stunted or halted, edema was noted in ovarian tissues and lesions were found in kidney tissue.
 
In summary, the effects on aquatic organisms by potent estrogenic substances such as E2 and EE2 collectively add up to a predictable, cohesive signature of effects, which are consistent with the known mechanism of action for these compounds. Natural development of male gonadal tissue is halted, differentiation into male characteristics is blocked, male secondary sex characteristics are prevented from developing, and gonadal tissues are severely compromised and damaged, reproduction within natural populations can be halted, and effects that are mediated by estrogenic activity occur at concentrations that are millions of times lower than those where narcotic effects occur. As a scientifically rigorous review of relevant studies shows (see Section 2.3 below), the profile of effects of NPEO and NP on aquatic organisms are very different from the effects from potent estrogens.

2.3	NPEO and NP affect acute lethality and chronic reproduction, growth and development endpoints very differently than natural (E2) or synthetic (EE2) estrogens.

At typical environmental concentrations, the primary mode of toxicity for conventional toxicity endpoints for NP and the lower chain length NPEO and NPECs appears to be narcosis. (Servos, 2000, Talmage, 1994, Staples, 2004)  Narcosis is a form of non-selective toxicity and is a result of general disruption of cell membrane and/or protein function. (Rand, 1995)  In numerous instances, NP and associated NPEO metabolites have been observed to affect cellular membranes of exposed organisms.  The observed toxicity via this mode of action in NPEO and its metabolites has been reviewed by several authors and agencies. (US EPA, 2005; EC and HC, 2001; Staples, 2004; Talmage, 1994).

Comparison of studies examining NPEO, 4-NP and natural (E2) and synthetic (EE2) estrogens demonstrates that there are great differences between the effects that they cause to aquatic organisms (see Table II).Estrogenic activity within intact aquatic organisms due to exposure to the natural and synthetic estrogens E2 and EE2 occurs at concentrations that are orders of magnitude below the threshold for systemic toxicity. These exposures result in a suite of responses that are collectively linked to the estrogenic mode of action. In a life cycle study with EE2 and zebrafish, Wenzel et al. (2001) reported the 96-h LC50 (narcosis-based toxicity) for EE2 to be 1700 µg/L and the NOEC for fertilization success to be 0.0003 µg/L. The authors calculated the ratio of the two values to be 5.73 x 106. Therefore, these data indicate that the estrogenic mode of action is the lead, or most predominant, mode of action impacting adverse effect for E2 and EE2.  

NP does not affect the same endpoints in aquatic organisms in the same way that natural and synthetic estrogens act. Data from three studies with NP demonstrate that the reproduction, growth and development endpoints are mainly indicative of narcosis-type mode of action, possibly coupled or concurrent with a very weakly estrogenic mode of action.  Using rainbow trout, Brooke et al. (1993) reported a 96-h LC50 of 221 µg/L. Ackermann et al. (2002) reported a no observed effect concentration (NOEC) from a one year exposure to embryonic, larval, and juvenile rainbow trout of 10.17 µg/L based on hatching success and sex ratio. The ratio of the lethal effect concentration (221 µg/L) to the reproductive NOEC of 10.17 µg/L is 22. Using fathead minnows, Brooke et al. (1993) reported a 96-h LC50 of 128 µg/L. Giesy et al. (2000) reported a NOEC of 1.6 µg/L based on egg production with fathead minnows. The ratio of the acute lethal concentration of 128 µg/L and the NOEC of 1.6 µg/L for the reproductive endpoint is 80. Using Japanese medaka, Kashiwada et al. (2002) reported a 96-h LC50 of 950 µg/L. Yokota et al. (2001) conducted a 1.5 generation test with Japanese medaka reporting a lowest NOEC for F1 sex ratio of 8.2 µg/L. The ratio of the acute lethal effect concentration of 950 µg/L and the NOEC of 8.2 µg/L is 116. Thus, the ratio of acute lethality LC50 values and the NOEC of the lowest apical NOEC for reproduction, growth or development endpoints are fairly consistent across the species rainbow trout, fathead minnows, and Japanese medaka. Across the three species, the ratios range from 22 to 116, which are approximately 50,000- to 260,000-fold lower than the ratio of 5.73 million calculated for EE2.

A similar comparison of acute LC50 values and chronic NOEC can be made for a range of higher and lower mole NPEO, as well as the biodegradation intermediates NPEC1. Such data are available for four species of fish and an invertebrate species. Johnson (2001) conducted partial life cycle studies with the sheepshead minnow and reported a 96-h acute LC50 of 93,000 µg/L and a lowest chronic NOEC of 1000 µg/L yielding a ratio of 93. Dorn et al. (1993) conducted studies with NPEO9 and adult fathead minnows and reported a 96-h LC50 of 4600 µg/L NPEO9 and a short-term growth NOEC of 1000 µg/L, giving a ratio of 5. Jobling et al. (1996) exposed adult male rainbow trout for 21 days to NPEO2 reporting effects on testis weight at 38.3 µg/L. With an acute 96-h LC50 range of 4500 to 5900 µg/L for NPEO “biodegradation products” (Talmage, 1994), a ratio of about 117 to 150 is obtained. Balch and Metcalfe (2006) exposed Japanese medaka fish to NPEO1-9 for 100 days, measuring survival, growth, and sex ratio. The authors reported a NOEC of 300 µg/L for NPEO1. Using a 96-h LC50 for NPEO1 of 3000 µg/L (Yoshimura, 1986), a ratio of 10 is obtained. Using Ceriodaphnia dubia, Isidori et al. (2006), conducted 48-h survival tests and 7-d reproduction tests with NPEO1-10 and NP. Ratios of acute and chronic EC50 values were 50, 14, 3, and 28 for NPEO10, NPEO6, NPEO1,2, and NP. Thus for NPEO, there is a similar span of concentrations from acute lethality and chronic reproduction, growth, and development NOEC as was found for NP (i.e., 3 to 150 for all NPEO and 22 to 116 for NP). The acute to chronic ratios for NPEO are 38,000 to 1.9 million fold lower than obtained with EE2.

Together these data show that NPEO and NP have a very different mode of action than the natural and synthetic estrogens with effects on survival resulting from narcosis being at least as critical to the organisms exposed to NPEO and NP as other modes of toxicity. While biomarkers such as an increase in male fish VTG indicate that estrogen receptor binding is occurring while exposed to low mole NPEO and NP, the endpoints related to growth, development, and reproduction are only a factor of 3 to 150 for NPEO and 22 to 116 for NP from short term acute toxicity and in the same range as caused by longer term lethality.  Hence it is possible that effects on growth, development, and reproduction for NPEO and NP are more indicative of narcosis-type mode of action, possibly coupled with a very weakly estrogenic mode of action with low mole NPEO and NP. Taken together, the acute and chronic datasets for NPEO/NP and EE2 are very different. This conclusion is supported by the assertion by Schwaiger et al. (2000) based on laboratory exposures of common carp (Cyprinus carpio) to NP, “…4-NP-induced general toxic effects might outbalance the relatively weak estrogenic effects of this compound…” as ecologically relevant endpoints such as reproduction may be “…also due to toxic effects leading to an impairment of the general health condition of the fish.” A similar conclusion is logically drawn from the aquatic toxicity data for NPEO. 

SEE TABLE II STUDIES USED TO COMPARE ACUTE LETHALITY ENDPOINTS WITH LOWEST CHRONIC NOEC IN ATTACHED SUBMISSION DOCUMENT 

2.4	Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action. 

While low mole NPEO and NP have weak estrogenic activity that is 1000 to 1,000,000 fold less potent than 17ß-estradiol (E2) and 17α-ethynylestradiol (EE2) (Coady et al., 2010), adverse apical effects caused by the NPEO or NP are not clearly endocrine mediated.   The assumption that effects on biologically complex, apical endpoints, such as reproduction, are mediated by a single mode of action, in this case one that is endocrine mediated via the estrogen receptor, is not reasonable for NP or NPEO.  In estrogenic mixture studies with estrogens and alkylphenols, the phenomenon of decreased fish reproduction due to alkylphenol exposure alone was clearly not solely attributed to estrogen-like activity (Brian et al., 2007). 

Investigations using gene array technologies to specifically compare NP and estradiol (E2) gene transcription profiles have established that NP has additional modes of action that are independent of the estrogen receptor (Larkin et al., 2002; Ruggeri et al., 2008; Watanabe et al., 2004).  Molecular evidence in both mammalian and fish models have demonstrated that the alkylphenols influence a greater suite of genes than estrogens (Ruggeri et al., 2008; Watanabe et al., 2004).  For example, 425 genes were differentially expressed in liver tissue from zebrafish exposed to 10-7 M NP, while 153 genes were differentially expressed in liver tissue from zebrafish exposed to 10-7 M E2 (Ruggeri et al., 2008).  Of the 30 most differentiated genes affected by NP compared to controls, only 1/3 of these genes were also altered among E2-exposed fish, and then not all in the same direction of change (Ruggeri et al., 2008). In mice, NP activated more genes than E2 in liver tissue, and the activated genes in the livers of NP-exposed mice were distinct from estrogen-responsive genes (Watanabe et al., 2004).  These molecular studies of gene activation illustrate that NP has multiple modes of action, of which weak estrogenic activity is one, and the apical effects noted on aquatic organisms, such as decreased growth, survival and reproduction, are not necessarily directly or solely attributed to NP’s weak estrogen receptor binding activity.  

In summary, estrogenicity does not appear to be the sole mechanism of action for NP and NPEO in aquatic species and neither of these compounds have been shown to have endocrine disrupting properties that cause probable serious effects that are of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds in aquatic species, therefore they do not meet the criteria under REACH Article 57(f).

2.5	Findings on genistein, a naturally occurring estrogenically active compound, provide a realistic perspective on the importance of considering estrogenic potency and lead or predominant  mode of toxicity when assessing whether a compound poses probable serious effects to human health or the environment that give rise to an equivalent level of concern to those of other substances that meet the criteria in Article 57 (a)-(e).

To put the toxicity and estrogenicity findings of NP and NPEOs into perspective, similar toxicity information was examined for another known estrogenically active compound, which is naturally occurring. This compound is the isoflavone genistein which is found in certain plants such as soybeans and soy products like tofu.  Genistein and other isoflavones have been shown to interact with animal and human estrogen receptors.  In a study on genistein Wenzel et al (2001) reported an acute LC50 of >1900 µg/L (solubility) and a NOEC (fertilization success) of 1.3 µg/L. The ratio of these two values is >1460, which falls between  the ratios for EE2 and NP indicating that perhaps genistein is moderately active relative to EE2, but not just like EE2.  These findings on genistein are useful in providing a realistic perspective on the importance of considering the estrogenic potency of a compound as well as the lead or predominant mode of toxicity when assessing whether it poses probable serious effects to human health or the environment that give rise to an equivalent level of concern to those of other substances that meet the criteria in Article 57 (a)-(e).   The genistein findings raise the question of whether genistein, a phytoestrogen that occurs in common foods, is present in the aquatic environment, and is more estrogenically potent than NP should also be assessed and considered an SVHC. This is the suggestion based on the rationale that is presented for NP/NPEO in the Annex XV Report for NPEO. 

3.0     The adverse apical endpoints raised in the Annex XV Report for NP and attributed to an estrogenic mode of action were reproductive or developmental effects in aquatic organisms; however the rationale for the leap between findings of weak NP estrogenic activity and reproductive effects seen in some fish studies is not well founded, and the same concerns apply to NPEO.

The endpoints that are considered to indicate an estrogen agonist mode of action are summarized in the Annex XV Report for NP on page 49 (Table 18). (ECHA, 2012).  Several of these endpoints are more apical in nature and can be observed naturally and also under various stressful conditions for fish.  Oocyte atresia normally occurs in fish as a part of the natural reproductive cycle, so an understanding of the normal background level of this phenomenon is important. Oocyte atresia and testicular degeneration also occur in fish when exposed not only to an estrogenic compound, but also in response to compounds with known androgenic or anti-androgenic modes of action (USEPA, 2007).  Therefore it appears that oocyte atresia and testicular degeneration, in and of themselves, are not indicative of a particular endocrine mode of action  (i.e. estrogen receptor agonism).  It is also established that stressful situations resulting in sustained increases in a fish’s cortisol levels can depress sex steroid concentrations, which in turn can cause delayed gonadal development, lowered VTG levels, and depressed secondary sex characteristics in fish (Milla et al., 2009; Aluru and Vijayan,  2009).  Therefore, these endpoints are not necessarily specific to an endocrine mediated mode of action, but will respond when fish are stressed, whatever the cause may be.

In various studies with medaka fish, increased VTG was observed in males at concentrations of NP ≥ 5.4 µg/L, altered histopathology of the gonads (specifically occurrence of testis-ova) generally occurred at concentrations of NP ≥ 8.2 µg/L.  The occurrence of testis-ova in the gonads was more marked when fish were exposed during the time period of sexual differentiation, which occurs before hatch.  Incidences of ova-testis were less frequent and occurred at higher concentrations when exposure to NP was initiated post-hatch.  Sex ratios in medaka fish were altered toward a greater proportion of females at concentrations of NP ≥ 17.7 µg/L. These results indicate that effects noted in medaka may be due to the weak estrogen binding activity of NP.  However, the apical effects that have a relevance to medaka populations (i.e. altered sex ratio), occur at concentrations well above the current Environmental Quality Standard (EQS) of 0.3 µg/L for NP in surface waters under the Water Framework Directive as well as above the Predicted No Effect Concentration (PNEC) of 0.6 µg/L that is listed in the REACH Dossier for NP and was based on a species sensitivity distribution model (ECHA, 2012).  

In studies with fathead minnows of various ages, increased VTG was observed at concentrations of NP ≥ 8.1 µg/L, altered histopathology of the gonads and altered secondary sex characteristics generally occurred at concentrations of NP ≥ 1.6 µg/L.  Apical endpoints, such as reproduction and survival, were affected among fathead minnows, including early life stages, at concentrations of-NP ≥ 14 µg/L.  While behavioral effects of NP exposure on male fathead minnows were described by Schoenfuss et al., 2008, namely nest holding behavior, the magnitude of the noted effects among NP-exposed fish was low (i.e. 5-10% of 4-NP-exposed fish were outcompeted by control males) and arguably not of biological relevance.  The biological relevance of such a small effect is questionable, especially for an endpoint as variable as nest holding behavior, which has not been validated in a standardized fish testing guideline.  Also notable in the Schoenfuss et al., 2008 study is the fact that patchy and high mortality rates were observed among tested fish at concentrations of NP that are lower than those known to result in fish mortality (i.e. 58% survival in 0.15 µg/L NP treatment group), thus questioning the husbandry practices for the fish in this study.  Again, the apical effects that have a relevance to fathead minnow populations (i.e. reproduction and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

A quote from the section on fathead minnow results in the Annex XV Report for NP (page 64) states, “Although apical effects started at similar or even lower concentrations compared to biomarker responses, it seems very likely that they are estrogen mediated.” (ECHA, 2012)  There really is no support for this statement, since NP has multiple modes of action apart from weak estrogen receptor binding, as has been demonstrated by several gene array and other molecular based mode of action studies with NP (see section 2.4).  There is no definitive link with the weak estrogenic effects noted among fathead minnows (i.e. effects on VTG and reproductive tissues) and the effects on apical endpoints (i.e.  reproduction and survival) which occur at overlapping concentrations.  The most sensitive apical effect for fathead minnows that was statistically different from controls in a validated study was based on mortality in an ELS study (Ward and Boeri, 1991).   There is no clear link in this study with fathead minnow mortality and an estrogenic mode of action.

A total of four NP exposure studies with zebrafish were examined in the report, however, 3 of the 4 studies were deemed a Klimisch score 3, which indicates that these studies are “not reliable” (Klimisch, 1997).  However, the endpoints from these studies are still used in a weight of evidence evaluation of the effects of NP on zebrafish.  With inappropriate controls included in the test design and high control mortality rates, the study endpoints are compromised and should not be included in a weight of evidence approach for determining the effects of NP on zebrafish.  From the one study determined acceptable for consideration (Lin and Janz, 2006), VTG was increased among male and female fish at 100 µg/L NP, testicular tissue was skewed to earlier stages at 10 µg/L 4-NP, and the effects of 1) no detectable males based on gonadal histology and 2) decreased swim up success were noted at 100 µg/L NP.  Altered sex ratios compared to controls were also observed at 10 µg/L NP (58% females at 10 µg/L NP vs 30% females in controls), however since the sex ratio was skewed in the control group, the meaningfulness of this observation is questionable. The effects that have a relevance to zebrafish populations (i.e. altered sex ratio and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

Various studies with rainbow trout exposed to 4-NP were summarized, and effects on increased VTG levels were noted at concentrations as low at 1.05 µg/L.  Effects on gonadal tissues were noted at concentrations of NP ≥ 30 µg/L, and effects on apical endpoints including growth and survival, were noted at concentrations of NP ≥ 10.3 µg/L.  Additionally, the effect of reduced sperm volume was noted in one study (Lahnsteiner et al., 2005) starting at concentrations of NP ≥ 0.13 µg/L; however, reproduction was not assessed in this study, so it is unknown if this decrease in sperm volume affected reproduction levels in rainbow trout. In addition, this endpoint is not well-studied, therefore the usefulness of the endpoint for predicting effects for population health is not known.  The lowest apical endpoint noted in among the toxicity studies with rainbow trout was the reduced growth of rainbow trout at 10.3 µg/L in an early life stage test (Brooke, 1993).   This apical endpoint is not clearly related to an estrogenic mode of action.  Fish growth can be affected by various modes of action and reductions or delays in growth are not necessarily estrogen-mediated.  In fact, the OECD Guidance Document on the Assessment of Chemicals for Endocrine Disruption states, “… an effect solely on growth or survival, while potentially of concern from the viewpoint of environmental risk assessment, would not lead to a conclusion that the chemical is an ED in fish.” (OECD, 2011).  Again, the apical effects that have a relevance to rainbow trout populations (i.e. growth and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

In studies with guppies and mosquito fish, NP exposure resulted in similar findings with increased VTG at concentrations of NP ≥ 10 µg/L, changes in gonadal tissues at concentrations ≥ 0.5 µg/L, and effects on apical endpoints at concentrations of NP ≥ 5 µg/L.  While skewed sex ratios were noted at concentrations of NP ≥ 50 µg/L, significant effects on growth were noted at lower concentrations of 5 µg/L.  As stated previously, decreased growth is not specific to an estrogenic mode of action.  As seen with the other fish species, apical effects that have a relevance to viviparious fish populations (i.e. growth), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

Taken together, the fish studies do indicate that NP has a mode of action that is consistent with a relatively weak binding affinity to the estrogen receptor when compared to the endogenous ligand, E2.  Increased levels of VTG, alterations in gonadal histopathology, and altered sex ratios in fish are consistent with this mode of action.  However, the most sensitive apical endpoints among fish toxicity studies with NP are based on decreased growth and survival, particularly of early life stage fishes.  These endpoints for NP are not clearly linked to an endocrine mode of action, and are not estrogen agonist specific.  There are other modes of action associated with NP as is evidenced in Section 2.4 of these comments by the suite of genes that are differentially activated in gene array and other molecular based investigations of the mode of action of NP.  

Again, the data do not support a rationale that connects NPEO or NP exposures to probable serious effects in the environment (i.e., reproductive or developmental effects in fish), which are attributable primarily to an estrogenic mode of action.  

4.0   	The Annex XV Report for NPEO overstates the importance of NP as degradation intermediate of NPEO.  

While the assessment of the biodegradation data for NP in the Annex XV Report for NPEO is generally correct in stating that the primary biodegradation pathway of the NPEO released to surface waters is to their ether carboxylates, the summary of this characteristic incorrectly concludes that NP and NPEO are not extensively mineralized. 

After release into surface waters, Jonkers et al. (2001, 2003, 2005) demonstrated with laboratory and field studies that high mole APEOs break down via an oxidative hydrolytic pathway to higher ether carboxylates, then lower ether carboxylates, and subsequently to further metabolites (not the alkylphenol). Low mole ethoxylates break down to lower ether carboxylates and subsequently to further metabolites (also not the alkylphenol).  The field studies conducted by Jonkers et al. (2005) showed that biodegradation of APEO proceeded via this pathway and the authors further determined that first order biodegradation half-lives for APEO, APEC, and AP were 10 to 41 days. The laboratory and field studies by Jonkers and colleagues served as key information in the fuller elucidation of the biodegradation pathways of NPEO surfactants as developed by Staples et al. (2008) and Klecka et al. (2008), which describe rapid degradation of APEO to short chain APEO and NPEC, which in turn degrade ultimately to carbon dioxide and water.  Naylor et al, (2006) evaluated the aerobic biodegradation of [14C] Ring-Labeled NPEO and found that the aromatic ring does break down. Staples et al, 2008 note that APEO degrade more slowly under anaerobic conditions.  

In summary, NPEO are not persistent and they degrade through low mole NPEO and NPEC compounds with NP as a lesser degradation intermediate, which ultimately mineralizes under aerobic conditions.  

5.0  	The Annex XV Report overstates the significance of releases of NP and of low mole NPEOs from sediment to the risk of aquatic organisms. 

The Annex XV Report for NPEO expresses concern that NP and low mole NPEOs may accumulate in sediment and thereby become a permanent source in the environment.   This line of thinking seems in conflict with the intention of the PBT and vPvB criteria for SVHC.  Adsorption to sediment does not constitute persistence nor does it represent a “permanent source”.   

While NP has been found to biodegrade more slowly under anoxic conditions, many organic compounds degrade more slowly under low temperature, nutrient-poor or oxygen-limited conditions (see for example Boethling and Mackay, 2000). The data for NP are consistent with the findings for other such substances.  NP does degrade in the environmental compartments in which organisms reside. These compartments include freshwater and marine water and sediment and soil. 

While NP and NPEO are likely to persist if buried in sediment under anaerobic conditions; many other compounds are also persistent and are not bioavailable for microbial degradation or to pose toxicity under these conditions. In addition, should NP or low mole NPEOs be scoured up due to a flood or high water, as speculated in the Annex XV Report, they would resume their normal aerobic biodegradation pathway through their ether carboxylates ultimately to carbon dioxide and water. 

Since NPEO and NP aerobically biodegrade in all relevant and bioavailable environmental compartments, they are not expected to build up and pose a concern to aquatic organisms as would be expected by truly long lasting and persistent substances.  NPEO and NPE are not considered “persistent” or “very persistent” according to Annex XIII criteria and their presence in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

7.0  	There are other regulatory instruments in place in the EU to control emissions of NPE, which have decreased the use and release of these compounds in Europe.  

The following regulations are already in place in the EU to control emissions and environmental risks from NP and NPEO. 

7.1	The Water Framework Directive (Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy)

The Water Framework Directive requires the Members States to measure aquatic concentrations of compounds relative to established Environmental Quality Standards (EQS) and to take action in case this value is exceeded.  An EQS value of 0.3 µg/L has been established for NP. 

7.2	The EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  

The M&U Directive for NP/NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP/NPEO in the wide dispersive uses most likely to result in emissions to the aquatic environment. 

7.3	 The Integrated Pollution Prevention and Control (IPPC) Directive 2008/1/EC of the European Parliament and of the Council of 15 January 2008 

The IPPC Directive lays down measures designed to prevent or, where that is not practicable, to reduce emissions to air, water and land from the activities mentioned in Annex I to the Directive, including measures concerning waste.

Given that the concern expressed in the Annex XV Report for NPEO is actually for NP, consideration should be given to these existing regulatory instruments, which are in place and already control emissions of NP in the EU. 

9.0 	Contribution of NPEO1 and NPEO2 and NP to the measured estrogenicity of wastewater effluents is negligible and not likely to result in probable serious effects to the aquatic environment. 

Analysis of data on the contribution of NP and NPEO and other APEOs indicates that the contribution from these compounds to the overall estrogenicity of wastewater effluents is negligible. This further supports a conclusion that these compounds are not likely resulting in probable serious effects in the receiving aquatic environment. 

Numerous studies have examined the extent to which measurable estrogenic activity in wastewater treatment plant (WWTP) effluents is attributable to natural and synthetic hormones (e.g., E2 and EE2) or to other constituents (e.g., NP, NPEO or other AP/APEOs). Desbrow et al. (1998) used a sample fractionation system to isolate fractions of WWTP effluent samples that were tested for estrogenicity using a YES assay. Estrogenic fractions were found to contain natural and synthetic hormones including E2, estrone, and EE2.  Alkylphenolic compounds were not detectable in the estrogenic fractions. 

Most studies employed in vitro screening assays such as YES assays and concentration measurements from whole effluents to assess relative contributions to estrogenicity. Korner et al. (1999) and Aerni et al. (2004) reported that the contribution of NP in German WWTP effluents was <3% and 2%, respectively, of the total estrogenicity. In WWTP effluents in the US, Drewes et al. (2005) reported that nearly all of the estrogenic activity was attributable to natural and synthetic hormones. Similar findings have been reported for WWTP effluents in Australia, New Zealand, and China, with estrogenic contributions from NP of 0.04 to 3.9% (Leusch et al., 2006; Jin et al., 2007; Lu et al., 2011).  

Considering that high mole NPEO (EO ≥ 4) are not estrogenic and the estrogenicity of NPEO1 and NPEO2 is even weaker than that for NP, it is reasonable to conclude that NPEO are not contributing significantly to the estrogenicity of WWTP effluent and therefore not likely to result in probable serious effects to the aquatic environment. 

10.0 	The very low estrogenic potency, multiple modes of action, and low environmental occurrence and concentrations for NP and NPEOs do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to substances meeting the criteria of Article 57(a) through (f).

Categorization as SVHC should be reserved for substances for which the weight-of-evidence supports a finding of both probable serious effects from that specific substance. Data supporting the hazards of a substance nominated for SVHC should be specific and sufficient to support that substance as meeting criteria listed under Article 57.  The available data for NPEO do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to those of other substances meeting the criteria of Article 57. 

The Annex XV Report for NPEO is based on assumptions that these polymeric compounds are contributing to probable serious effects in aquatic species due to their degradation to NP in the environment.  As discussed previously, NP, at most, has weakly estrogenic activity, low mole NPEOs have even weaker estrogenic activity and higher mole NPEOs have no estrogenic activity. NP and NPEO have estrogenic activity that is orders of magnitude less than the natural (E2) and synthetic (EE2) estrogens based on in vitro and in vivo tests. Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action and affect acute lethality and chronic reproduction, growth and development endpoints very differently than E2 or EE2.  Comparison of studies examining NPEO, NP and E2 and EE2 demonstrates that there are great differences between the effects that they cause to aquatic organisms.  While the estrogenic mode of action is clearly the lead, or most predominant, mode of action impacting adverse effects from E2 and EE2, this is not clearly the case for NP or low mole NPEO, which have other co-occurring modes of toxicity (i.e., narcosis) that result in adverse effects observed among fish population, Endocrine activity alone is not sufficient justification for equivalent concern under Article 57(f).  Without evidence of probable serious adverse effects that are primarily the consequence of that mode of action the compound does not rise to a level of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds.

Consideration of exposure and risk are inherent in determining probable serious effects.    In the case of NP and NPEOs, concentrations in European waters are generally well below NOEC and LOEC values for adverse apical effects found in studies on NP in aquatic species and have dropped significantly since 2003 when the M & U Directive on dispersive uses of NP and NPEO was implemented. Concentrations of NP are typically below EQS established for this compound under the Water Framework Directive.  In addition, as discussed in earlier in these comments, studies that examine estrogenically active substances in wastewater treatment plant effluent found that if detected, NP, NPEOs and alkylphenols generally, contributed only minimally to the aggregate estrogenicity. 

NPEO and NP are not considered “persistent” or “very persistent” according to Annex XIII criteria and the presence of NP in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

Perhaps most importantly, the criteria listed under Article 57  list specific  hazard-based  adverse effects criteria that should apply to SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those criteria.  The proposal in the Annex XV Report for NPEO to designate these polymers that degrade to a SVHC compound to also be SVHC based on the argument that the polymer is an environmental source of the degradant  circumvents the need for Commission consideration of this significant policy determination under REACH. In  addition, there are other regulatory instruments in place in the EU to control emissions of NPEO, which based on current monitoring data in the EU should preclude the need for further prioritization of these compounds. 

For all of these reasons APERC and CEPAD recommend rejection of the Annex XV Report on NPEO. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT 	As mentioned in the comment 57(f) considers substances for which there is scientific evidence  of probable serious effects which give rise to an equivalent level of concern to those of substances listed under 57(a) – (e).
57(f) does not specify the type of concern and thus any substance property which may cause serious effects which are of equivalent concern can in principle be considered under 57(f). 
In the case of degradation to a SVHC the effects considered are the effects of the degradation product which are already confirmed to be of very high concern.
We therefore consider the proposal to be in line with the legal text. It is in line with the proposal for PBT substances in Annex XIII and in line with a proposal by the EU Commission to consider substances degrading to SVHC as SVHC themselves.

We agree with the comment, that estrogen activity alone without adverse effects which are mediated by the endocrine activity should not be considered as of equivalent concern according to Art 57(f). However please note that it is not the intention of the dossier to nominate NP1EO and NP2EO as SVHC due to their endocrine disrupting properties. 
The data on the endocrine disrupting properties (i.e. endocrine activity) were added in the dossier as additional information which may increase the concern. 

1.0
We appreciate your analysis. However, the dossier does not aim at suggesting 4-nonylphenol ethoxylates as meet the criteria of Article 57 (a)-(e) of REACH. However, the criterion of Article 57 (f) is met.

1.1 
We appreciate your analysis. However, the dossier does not aim at suggesting 4-nonylphenol ethoxylates as CMR Cat 1A or 1B

1.2 
Thank you for your comment. Please note that the dossier does not aim at identifying 4-nonylphenol ethoxylates as PBT or vPvB substance.

It was also not suggested that 4-nonylphenol meets the P-criteria. However, a slow biodegradation, especially under anaerobic conditions has been proven (Sediment DegT50 = 46.2 days (primary degradation) to no elimination after 703 days; depending on linear and branched isomers).

2.0 
Please note that the dossier does not aim at identifying NPEO of any grade of ethoxylation as SVHC due to their endocrine disrupting properties. The concern is based on their degradation to NP. Please also note, that NP has already been agreed to be a SVHC in December 2012. The reason for the identification of NP as SVHC is described in detail in the support document. But for the sake of transparency some of the aspects you are mentioning with regard to the ED properties of NP are considered in our detailed comments below. 

2.1 
We agree with your analysis of the available information which is included in the dossier. While low mole NPEO show estrogenic activity in vitro and in vivo higher mole NPEO seem not to show such activity based on the data available. But please note that the dossier does not identify NPEO as ED.

2.2 
We agree with your analysis of cohesive signature of effects for potent estrogenic substances. However we disagree that the effects observed for NP are different from that signature.

2.3 Thank you for your summary of acute to chronic ratios for NP and NPEO. Although we agree that acute to chronic ratios are lower than for E2 and EE2 available data clearly indicate that the adverse effects observed in long-term studies are endocrine mediated (see also response to comment 2.4 and 3.0

2.4
Thank you for your analysis of the different possible modes of action of NP and NPEO. We agree that NP may act via different modes of action. However this does not influence the conclusion that the effect pattern observed for NP clearly indicate that the adverse effects are endocrine mediated (see also response to comment 3.0)

2.5 
Thank you for your analysis of the findings for genistein. However we do not fully understand why you think that this analysis would influence the conclusion for NP.

3.0 
Thank you for your analysis of the information available for several fish species which reflects our analysis for NP (see support document for more details). We agree that not all effects observed in all fish species are clearly endocrine mediated and this is reflected in the supporting document. However, as described in your comments and in line with the OECD guidance document on ED assessment, some of the effects in some species(i.e O.latipes, D. rerio, and some viviparous species) are clearly endocrine mediated. Effects observed in other species provide strong evidence that NP is an endocrine disruptor. Whether or not the effects occur above or below the EQS or any PNEC (which is based endocrine mediated endpoints) does not matter for the conclusion that NP is an Endocrine Disruptor causing probable serious effect to the environment.

4.0
We agree with you. Like mentioned in the dossier, 
4-nonylphenol ethoxylates are not persistent. They are degradable under aerobic as well as anaerobic conditions. However, 4-nonylphenol, which is already identified as SVHC, is formulated under anaerobic conditions. 4-nonylphenol itself is a stable metabolite which strongly adsorbs to soil, sludge and sediment. 

5.0 
We agree that 4-nonylphenol ethoxylates might be degraded via aerobic pathways once released to the water body. However, as stated in the report, the half life depends on the environmental conditions. As summarized in the dossier for 4-nonylphenol, even very short exposure times may result in sever long lasting damage of aquatic species.

7.0 
Thank you for the additional information which is considered for further work on choosing the most appropriate risk management option.

9.0 Thank you for this analysis. We agree that other substances may contribute to the overall estrogene activity in waste water treatment plants. However this does not influence the conclusion that there is scientific evidence of probable serious effects to the environment due to the endocrine disrupting properties of NP.

10.0
See response to your general comment above.

	
			See also:
Comment 11 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
10	2013/04/18	Industry or trade association
Alkylphenols & Ethoxylates Research Council
United States	Executive Summary

The European Council for Alkylphenols and Derivatives (CEPAD) and the Alkylphenols & Ethoxylates Research Council (APERC) jointly submit these comments in objection to the Annex XV Report proposing to identify Nonylphenol, branched and linear, ethoxylated (NPEO) as a Substance of Very High Concern (SVHC). 

The Annex XV Report suggests that NPEOs meet the criteria for SVHC under Article 57(f) of the Registration, Evaluation, Authorisation and Restriction of Chemicals Regulation (EC) 1907/2006 (REACH), which states:

“(f) substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 

The Annex XV Report proposes to identify NPEs as SVHC primarily based on the argument that due to their degradation they are “an environmental source” of nonylphenol (NP), which was previously designated as SVHC.   CEPAD and APERC continue to disagree with the SVHC determination of NP (CEPAD and APERC, 2012); however even recognizing this designation for NP, the assumption that degradation of a polymer to an intermediate that is designated as SVHC also warrants designation of the polymer as SVHC is inconsistent with the requirements and intention of Article 57 and, as discussed further below, circumvents the need for Commission consideration of this significant policy determination under REACH.

The Annex XV Report further justifies designating NPEOs as SVHC on the basis that: 
“… available information for NPnEO indicate that short chain ethoxylates (NP1EO and NP2EO) show endocrine activity themselves: Results for Onchorhynchus mykiss and Oryzias latipes with NPE1EO and NPE2EO indicate that the in vivo and in vitro endocrine activity is nearly as high (factor 10) or similar to the endocrine activity of 4-nonylphenol. These tests do not include adverse endpoints. Hence, it is not possible to conclude whether 4-NP1EO and 4-NPE2EO are endocrine disruptors themselves, or not. However due to the similar in vivo endocrine activity and information available for 4-NP it seems possible that these substances may cause endocrine disrupting adverse effects.” (emphasis added) 
 The Annex XV Report for NPE speculates that NPEO1 and NPEO2 may cause endocrine disrupting adverse effects, while at the same time acknowledging that “it is not possible to conclude whether 4-NP1EO and 4-NPE2EO are endocrine disruptors themselves.”   The precautionary principle is intended to apply to situations where there is considerable scientific uncertainty; it is not a substitute for evaluating potential environmental effects when sufficient information exists. The comments below will provide a review of the data available for NP and NPEO in comparison with data for the natural estrogen, 17β-estradiol (E2) and synthetic (EE2) estrogen to show that NPEO and NP have a very different mode of action profile than these potent estrogens and should not be presumed to have comparable adverse effects based on an estrogenic mode of action.  
In addition to the above mentioned scientific concerns with the arguments in the Annex XV Report for NPE, these comments will also raise policy concerns.  The Annex XV Report for NPEO proposes a basis for determining probable serious environmental effects from an endocrine mode of action even as the European Commission has activities underway to develop a definition of endocrine disruptors. These activities include discussion about an endocrine disruptor hazard categorization scheme and consideration of the potency, adversity of effects and requirement to review the weight-of-evidence for endocrine disruptors (Kortenkamp, A., 2011). 

Also, the Annex XV Report proposes to identify NPEO polymers as SVHC because they are a source of NP, which has been identified as a SVHC, in the environment. The criteria under Article 57  list specific  hazard-based properties that should apply to the SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those hazard criteria.  In addition, in this case, environmental concentrations of NP in EU waters are for the most part below Environmental Quality Standards (EQS) for this compound and do not support concern for probable serious effects in the environment from  either NPEO or NP. 
 
The Annex XV Report for NPEO cites the revision of REACH Annex XIII regarding the assessment of PBT and vPvB properties, which was published under COMMISSION REGULATION (EU) No 253/2011 as justification to designate NPEO polymer as the SVHC because NP is already a SVHC.  The revision to Annex XIII added the condition that the identification of PBT/vPvB substances “shall also take account of the PBT/vPvB-properties of relevant constituents of a substance and relevant transformation and/or degradation products”. The process of revising Annex XIII to include this change highlights the uniqueness of this provision within REACH. There is no such requirement to consider transformation and/or degradation products in the assessment of any other hazard under Article 57. Application of such a provision should require the consideration of the Commission and revision of the regulations as was done with Annex XIII.  Therefore, any assessment of NPEO as SVHC should be based solely on consideration of the hazard properties of the polymer relative to the criteria listed under Article 57. The proposal to include  polymers that degrade to an  intermediate that is a SVHC circumvents the need for Commission consideration of this significant policy determination under REACH. 

As discussed in more detail below, Article 57(f) states that scientific evidence of probable serious effects to human health or the environment, which give rise to an equivalent level of concern to those of substances that meet the criteria under Article 57(a) to (e) is necessary to classify a substance as a SVHC. The very low to non-existent estrogenic potency of NPEO, along with their low environmental occurrence and concentrations, do not support a conclusion of probable serious environmental effects from these compounds in the EU.  In addition, neither NPEO nor NP is persistent or increasing in EU waters.  Furthermore, an indication that a compound has some estrogenic activity should not be considered as of equivalent concern to the criteria under Article 57 (a)-(e), since endocrine activity is not an effect and is not necessarily adverse. Rather, endocrine activity is a mode of action, which may or may not be linked to any sort of adverse effect in an intact organism.  The criteria listed under Article 57 (a) to (c) are clearly based on adverse effects while those in (d) and (e) are linked to environmental fate.  Simple mode of action evidence for compounds, i.e. endocrine activity, therefore does not meet the requirement of equivalent concern under Article 57(f) without evidence of consequent and probable serious adverse effects.  Concentrations of NP from peer-reviewed publications indicate that environmental concentrations in EU waters are generally below levels of concern for any type of adverse effects in environmental organisms.  Thus, there is no evidence for NP or NPEO of probable serious effects to human health or the environment, which give rise to an equivalent level of concern under Article 57.

Moreover, the adverse effects of NPEO and NP on aquatic organisms are already controlled through existing regulatory instruments in the EU such as the Water Framework Directive, which has established an Environmental Quality Standard (EQS) for NP, and the Integrated Pollution Prevention and Control (IPPC) Directive.  More importantly, there is a long-standing EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  The M&U Directive for NP and NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP and NPEO in wide dispersive uses most likely to result in emissions to the aquatic environment. Considering these existing regulatory instruments in the EU, there does not appear to be a need to further prioritize for NPEOs as SVHC on the basis of concern for the toxicity to the environment.

The following comments elaborate on these points and demonstrate that while some degradation intermediates of NPEO may have weak estrogenic activity, neither NP nor NPEO demonstrate adverse environmental effects that give rise to an equivalent level of concern as CMR, PBT or vPvB compounds. 

1.0  	NPEOs do not meet the clearly defined hazard criteria for classification as an SVHC under the sections Article 57a through 57e. 

Article 57 of REACH very specifically lists the following hazard-based criteria for substances to be candidates to be included in Annex XIV. 

(a) substances meeting the criteria for classification as carcinogenic category 1 or 2 in accordance with Directive 67/548/EEC; 
(b) substances meeting the criteria for classification as mutagenic category 1 or 2 in accordance with Directive 67/548/EEC; 
(c) substances meeting the criteria for classification as toxic for reproduction category 1 or 2 in accordance with Directive 67/548/EEC; 
(d) substances which are persistent, bioaccumulative and toxic in accordance with the criteria set out in Annex XIII of REACH; 
(e) substances which are very persistent and very bioaccumulative in accordance with the criteria set out in Annex XIII of REACH; and 
f) substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 
	
As noted in the Annex XV report for NPEO, these polymers are not classified according to Annex VI of Regulation (EC) No. 1272/2008 (the CLP Regulation). However, NPEO were not assessed in the Annex XV Report relative to the criteria under Article 57 (a) – (e).  This section of these comments  summarizes assessments that confirm that NPEO and NP are not carcinogenic, mutagenic or reproductive toxicants (CMR).  Nor ar they persistent, bioaccumulative and toxic (PBT) or very persistent and very Bioaccumulative (vPvB) compounds.  

1.1	Neither NPEO nor its degradation intermediates, including NP,  meet the criteria for carcinogen, mutagen or reproductive toxicants category 1 or 2 in accordance with REGULATION (EC) No 1272/2008 (the CLP Regulation).
While the Annex XV Report for NPEO did not assess NPEO for CMR properties, it is useful to note that the European Chemicals Bureau (ECB) Risk Assessment on NP states that NP is not mutagenic and that there is low concern for carcinogencity by a non-genotoxic mechanism. It also concludes that there was no evidence of functional changes in reproduction and any changes that were seen occurred at exposure levels in excess of the LOAEL for repeated dose toxicity (ECB, 2002).  

In addition, US EPA conducted an assessment of the human safety of NPEO and approved their use as inert ingredients in pesticide formulations after considering risk to infants and children and finding “reasonable certainty of no harm”. (US EPA OPPTS, 2006)  Assessments of chemicals by US EPA under the Food Quality Protection Act (FQPA) are conducted based on informed multiple risk exposure scenarios, which allows meaningful, risk-based priority setting and activity planning. In 2006, EPA conducted an assessment on the use of NPEOs as inert ingredients in pesticide products. The assessment of NPEO by US EPA was conducted as part of a reassessment of all inert ingredients as mandated by FQPA, which has a primary focus on children’s health. FQPA assessments require the use of reliable data and must make a “reasonable certainty of no harm” finding to exempt an inert ingredient from the requirement of tolerance levels in pesticide products.  The US EPA inert reassessment on NPEO concluded there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure to NPEO when used as an inert ingredient in pesticide products when considering dietary exposure and all non-occupational exposures. The US EPA reassessment acknowledged several multi-generation reproduction studies on NP in rats that demonstrate no adverse effects on reproductive function. US EPA found that in NPEO developmental toxicity studies in rats and mice, there was no incidence of developmental toxicity in the absence of maternal toxicity. The Agency concluded that neither NP nor NPEO are carcinogenic and that human exposure to NPEO via food, drinking water, and residential exposure pathways is orders of magnitude less than the No Observed Effect Levels (NOELs) and No Observed Adverse Effect Levels (NOAELs) in animal studies including chronic, repeat-dose, developmental and carcinogenicity studies. Finally, US EPA concluded no concern for increased sensitivity to infants and children from NPEOs. 

In 2001, Environment Canada and Health Canada conducted a Risk Assessment for NP and NPEOs pursuant to the Canadian Environmental Protection Act (CEPA), which determined that NP and NPE are not CMRs (EC & HC, 2001).

1.2 	Neither NPEO nor its degradation intermediates, including NP,  
are PBT or vPvB.

The European Commission determined NP is not persistent or bioaccumulative. (ECB PBT WG, 2003).  In 2006, Environment Canada completed a review of NP and NPEO along with octylphenol (OP) and octylphenol ethoxylates (OPE) as part of a categorization assessment under the Canadian Environmental Protection Act (CEPA), which required an assessment of all substances on the Canadian Domestic Substances List (DSL) with respect to persistence, bioaccumulation and inherent toxicity (PBiT) characteristics. Environment Canada concluded that none of these alkylphenol and ethoxylate compounds are persistent or bioaccumulative (Environment Canada, 2006). 

Subsequent to these governmental assessments, Klecka et al (2008) conducted a comprehensive review of the literature and conducted a weight-of-evidence based assessment of the persistence and bioaccumulation potential of C-8 and C-9 alkylphenol ethoxylates (APE) along with their degradation intermediates and metabolic by-products.  The authors found that the commercial APE products and their degradation intermediates do not meet any national or international criteria for identifying these compounds as PBT or vPvB substances.

2.0	NPEOs and NP have not been shown to cause probable serious effects that are of equivalent concern to those under Article 57 (a)-(e) and adverse effects from these compounds on aquatic species cannot be clearly attributed to an endocrine mode of action obscuring the relevance of Article 57(f) to these compounds.  

Article 57 (f) states:  “substances — such as those having endocrine disrupting properties or those having persistent, bioaccumulative and toxic properties or very persistent and very bioaccumulative properties, which do not fulfill the criteria of points (d) or (e) — for which there is scientific evidence of probable serious effects to human health or the environment which give rise to an equivalent level of concern to those of other substances listed in points (a) to (e) and which are identified on a case-by-case basis in accordance with the procedure set out in Article.” (emphasis added) 

The Annex XV Report for NPEOs does not provide sufficient scientific evidence that these polymers or their degradation intermediate NP pose probable serious effects in the environment from an endocrine mode of action.  Rather, the Report relies on presumptions of “possible” effects of an equivalent concern to CMR and PBTs. NPEO polymers (NPEO≥4) are not estrogenic and the Annex XV Report for NPEO overstates the estrogenic potency of low mole NPEO and NP.  Estrogenic potency should certainly be a consideration when assessing whether there is scientific evidence of probable serious effects to human health or the environment under Article 57(f). 

Also, as discussed in more detail below, the data from NPEO and their breakdown intermediates, including NP, indicate that there are likely multiple modes of action occurring within the same exposure concentration ranges. Therefore any adverse effects from NPEO or their breakdown intermediates on aquatic species cannot be clearly attributed to an endocrine mode of action obscuring the relevance of Article 57(f) to these compounds

2.1	Higher mole NPEO are not estrogenic and low mole NPEO (NPEO1, NPEO2) and NP are considerably less potent than the natural estrogen, 17β-estradiol (E2) and synthetic (EE2) estrogen based on in vitro estrogen activity screening tests as well as endpoints from in vivo tests.

Information about the potency of endocrine active compounds relative to the known potent estrogens E2 and EE2 are provided by various in vitro screening tests and in vivo tests with intact organisms. Relative potencies from these studies can be approximated by concentrations of NP and E2 or EE2 used as a positive control that gave comparable results. Overall, the data show that NP is approximately one thousand to one million-fold less potent than the endogenous estrogen E2 or the synthetic estrogen EE2, depending on the species and endpoint investigated (Jobling and Sumpter 1993; Lee and Lee 1996; Islinger et al. 1999; Metcalfe et al. 2001; Dussault et al. 2005; Balch and Metcalfe 2006; Lin and Janz 2006; Zha et al. 2007, 2008).

From in vitro studies, relative potencies of NPEO1 and NPEO2, tested singly or as a mixture, ranged from 1.5 to 8300-fold less than NP (Jobling and Sumpter, 1993; Metcalfe et al., 2001; Isidori et al., 2006). Using test material of confirmed purity and composition, yeast screening assays conducted with higher mole NPEO (NPEO≥6) showed negligible activity or gave no response. The toxicity of NPEO relative to E2 from in vivo assays is lower than for NP. Balch and Metcalfe (2006) reported effects on secondary sex characteristics in fathead minnow exposed for 100 days to NP and NPEO1, but no response with nonylphenol monoether carboxylate (NPEC1) or NPEO4, or NPEO9. Dussault et al (2005) measured vitellogenin induction in rainbow trout and reported that NPEO1 and NPEC1 were 5 to 33-fold less potent than NP. Miles-Richardson et al. (1999) and Nichols et al. (2001) exposed breeding pairs of fathead minnow to NPEO9 for 42 days and reported no significant effects on reproduction, vitellogenin, serum testosterone or E2 levels, gonadal histopathology or secondary sex characteristics. 

2.2	Examination of the estrogenic potency and aquatic toxicity of natural estrogen (E2) and synthetic estrogen (EE2) provides an understanding of the adverse effects profile that result from a highly potent estrogen.

The Annex XV Report for NPEO emphasizes the estrogenic activity of NPEO as the basis for “equivalent concern” in its assessment of the compound’s aquatic toxicity. In light of this concern, it is of use to first examine effects on aquatic organisms from known endocrine active substances for which the mode of action is indisputable – natural estrogen (E2) and a synthetic and therapeutic estrogen (EE2). Relevant studies are summarized in Table I below.  

SEE TABLE I SUMMARY OF AQUATIC TOXICITY STUDIES FOR 17 α -ETHYNYLESTRADIOL (EE2) AND 17β -ESTRADIOL (E2) IN ATTACHED SUBMISSION DOCUMENT

The estrogenic potencies of E2 and EE2 have been found to be generally similar to each other. EE2/E2 ratios range from 0.19 to 1.9 depending on the screen used (Kidd et al., 2007).  E2 and EE2 are especially potent when compared to the weak estrogenic activity of NP.

The natural and synthetic estrogens E2 and EE2, respectively, cause significant and severe effects on freshwater and saltwater fish. As described in more detail below, a signature set of estrogenically mediated aquatic effects from E2 and EE2 may include:  complete feminization of male gonads; induced failure to differentiate into males; reduced reproduction capabilities; severe histological effects on gonadal tissues; and even collapse of whole populations in a lake continuously dosed with EE2 for three years.

As noted in Table I above, a  series of short term reproduction assays showed that survival, reproduction, fertilization, spawning and hatch success, and sex ratio can be significantly altered at estrogen concentrations down to 0.005 µg/L. Secondary endpoints (which are more focused on determining mode of action rather than adverse effect), such as gonadal weights and histopathology, testis-ova, and kidney lesions were affected at even lower concentrations, down to 0.0002 µg/L. Life cycle studies with fathead minnow and zebrafish that included exposure to EE2 over the full life cycle showed similar effects at 0.001 to 0.016 µg /L and 0.0003 to 0.010 µg /L, respectively. Second generation NOEC were seen at concentrations as low as 0.0002 to 0.0003 µg/L (Lange R., 2001; Wenzel et al., 2001). Secondary endpoints, including secondary sex characteristics, testis-ova, gonadal histopathology, and VTG, had NOEC in the 0.001 to 0.004 µg/L range. In both studies, and presumably due to the strong estrogenic potencies of these compounds, essentially complete feminization of males and/or male characteristics was reported.

In order to differentiate the relationship of endpoint effects caused by a narcotic mode of action and those mediated by an estrogenic mode of action, Wenzel et al (2001) examined the ratio of the acute LC50 of EE2 (1,700 µg /L) and the most significant reproduction NOEC (fertilization success, NOEC 0.0003 µg /L). The acute-to-chronic ratio of the two is 5.73 million. This very high ratio is indicative of the specific mode of action (i.e. estrogenic activity) associated with the synthetic estrogen EE2 in relation to the acute toxicity of EE2 based on mortality.  It is clear for EE2 that the reproduction, growth and development endpoints are affected by a different mechanism of action (estrogenic activity) than the acute lethality (narcosis) endpoints. Given the potency of natural and synthetic estrogens, this is expected, and hence the very high ratio is understandable. The acute to chronic ratio for EE2 is very different from the ratios that are calculated with NP (22 to 116) as is discussed below.

In a whole lake study, Kidd (2007) and colleagues dosed a whole lake with EE2 (0.005 to 0.006 µg/L) for 3 years. Fathead minnow populations became completely feminized, reproduction halted, and the population collapsed. The abundance of pearl dace fish was also decreased. These two species of fish were previously predominant in the lake. As noted in laboratory studies, severe effects on gonadal tissues were found. Male gonadal tissue development was stunted or halted, edema was noted in ovarian tissues and lesions were found in kidney tissue.
 
In summary, the effects on aquatic organisms by potent estrogenic substances such as E2 and EE2 collectively add up to a predictable, cohesive signature of effects, which are consistent with the known mechanism of action for these compounds. Natural development of male gonadal tissue is halted, differentiation into male characteristics is blocked, male secondary sex characteristics are prevented from developing, and gonadal tissues are severely compromised and damaged, reproduction within natural populations can be halted, and effects that are mediated by estrogenic activity occur at concentrations that are millions of times lower than those where narcotic effects occur. As a scientifically rigorous review of relevant studies shows (see Section 2.3 below), the profile of effects of NPEO and NP on aquatic organisms are very different from the effects from potent estrogens.

2.3	NPEO and NP affect acute lethality and chronic reproduction, growth and development endpoints very differently than natural (E2) or synthetic (EE2) estrogens.

At typical environmental concentrations, the primary mode of toxicity for conventional toxicity endpoints for NP and the lower chain length NPEO and NPECs appears to be narcosis. (Servos, 2000, Talmage, 1994, Staples, 2004)  Narcosis is a form of non-selective toxicity and is a result of general disruption of cell membrane and/or protein function. (Rand, 1995)  In numerous instances, NP and associated NPEO metabolites have been observed to affect cellular membranes of exposed organisms.  The observed toxicity via this mode of action in NPEO and its metabolites has been reviewed by several authors and agencies. (US EPA, 2005; EC and HC, 2001; Staples, 2004; Talmage, 1994).

Comparison of studies examining NPEO, 4-NP and natural (E2) and synthetic (EE2) estrogens demonstrates that there are great differences between the effects that they cause to aquatic organisms (see Table II).Estrogenic activity within intact aquatic organisms due to exposure to the natural and synthetic estrogens E2 and EE2 occurs at concentrations that are orders of magnitude below the threshold for systemic toxicity. These exposures result in a suite of responses that are collectively linked to the estrogenic mode of action. In a life cycle study with EE2 and zebrafish, Wenzel et al. (2001) reported the 96-h LC50 (narcosis-based toxicity) for EE2 to be 1700 µg/L and the NOEC for fertilization success to be 0.0003 µg/L. The authors calculated the ratio of the two values to be 5.73 x 106. Therefore, these data indicate that the estrogenic mode of action is the lead, or most predominant, mode of action impacting adverse effect for E2 and EE2.  

NP does not affect the same endpoints in aquatic organisms in the same way that natural and synthetic estrogens act. Data from three studies with NP demonstrate that the reproduction, growth and development endpoints are mainly indicative of narcosis-type mode of action, possibly coupled or concurrent with a very weakly estrogenic mode of action.  Using rainbow trout, Brooke et al. (1993) reported a 96-h LC50 of 221 µg/L. Ackermann et al. (2002) reported a no observed effect concentration (NOEC) from a one year exposure to embryonic, larval, and juvenile rainbow trout of 10.17 µg/L based on hatching success and sex ratio. The ratio of the lethal effect concentration (221 µg/L) to the reproductive NOEC of 10.17 µg/L is 22. Using fathead minnows, Brooke et al. (1993) reported a 96-h LC50 of 128 µg/L. Giesy et al. (2000) reported a NOEC of 1.6 µg/L based on egg production with fathead minnows. The ratio of the acute lethal concentration of 128 µg/L and the NOEC of 1.6 µg/L for the reproductive endpoint is 80. Using Japanese medaka, Kashiwada et al. (2002) reported a 96-h LC50 of 950 µg/L. Yokota et al. (2001) conducted a 1.5 generation test with Japanese medaka reporting a lowest NOEC for F1 sex ratio of 8.2 µg/L. The ratio of the acute lethal effect concentration of 950 µg/L and the NOEC of 8.2 µg/L is 116. Thus, the ratio of acute lethality LC50 values and the NOEC of the lowest apical NOEC for reproduction, growth or development endpoints are fairly consistent across the species rainbow trout, fathead minnows, and Japanese medaka. Across the three species, the ratios range from 22 to 116, which are approximately 50,000- to 260,000-fold lower than the ratio of 5.73 million calculated for EE2.

A similar comparison of acute LC50 values and chronic NOEC can be made for a range of higher and lower mole NPEO, as well as the biodegradation intermediates NPEC1. Such data are available for four species of fish and an invertebrate species. Johnson (2001) conducted partial life cycle studies with the sheepshead minnow and reported a 96-h acute LC50 of 93,000 µg/L and a lowest chronic NOEC of 1000 µg/L yielding a ratio of 93. Dorn et al. (1993) conducted studies with NPEO9 and adult fathead minnows and reported a 96-h LC50 of 4600 µg/L NPEO9 and a short-term growth NOEC of 1000 µg/L, giving a ratio of 5. Jobling et al. (1996) exposed adult male rainbow trout for 21 days to NPEO2 reporting effects on testis weight at 38.3 µg/L. With an acute 96-h LC50 range of 4500 to 5900 µg/L for NPEO “biodegradation products” (Talmage, 1994), a ratio of about 117 to 150 is obtained. Balch and Metcalfe (2006) exposed Japanese medaka fish to NPEO1-9 for 100 days, measuring survival, growth, and sex ratio. The authors reported a NOEC of 300 µg/L for NPEO1. Using a 96-h LC50 for NPEO1 of 3000 µg/L (Yoshimura, 1986), a ratio of 10 is obtained. Using Ceriodaphnia dubia, Isidori et al. (2006), conducted 48-h survival tests and 7-d reproduction tests with NPEO1-10 and NP. Ratios of acute and chronic EC50 values were 50, 14, 3, and 28 for NPEO10, NPEO6, NPEO1,2, and NP. Thus for NPEO, there is a similar span of concentrations from acute lethality and chronic reproduction, growth, and development NOEC as was found for NP (i.e., 3 to 150 for all NPEO and 22 to 116 for NP). The acute to chronic ratios for NPEO are 38,000 to 1.9 million fold lower than obtained with EE2.

Together these data show that NPEO and NP have a very different mode of action than the natural and synthetic estrogens with effects on survival resulting from narcosis being at least as critical to the organisms exposed to NPEO and NP as other modes of toxicity. While biomarkers such as an increase in male fish VTG indicate that estrogen receptor binding is occurring while exposed to low mole NPEO and NP, the endpoints related to growth, development, and reproduction are only a factor of 3 to 150 for NPEO and 22 to 116 for NP from short term acute toxicity and in the same range as caused by longer term lethality.  Hence it is possible that effects on growth, development, and reproduction for NPEO and NP are more indicative of narcosis-type mode of action, possibly coupled with a very weakly estrogenic mode of action with low mole NPEO and NP. Taken together, the acute and chronic datasets for NPEO/NP and EE2 are very different. This conclusion is supported by the assertion by Schwaiger et al. (2000) based on laboratory exposures of common carp (Cyprinus carpio) to NP, “…4-NP-induced general toxic effects might outbalance the relatively weak estrogenic effects of this compound…” as ecologically relevant endpoints such as reproduction may be “…also due to toxic effects leading to an impairment of the general health condition of the fish.” A similar conclusion is logically drawn from the aquatic toxicity data for NPEO. 

SEE TABLE II STUDIES USED TO COMPARE ACUTE LETHALITY ENDPOINTS WITH LOWEST CHRONIC NOEC IN ATTACHED SUBMISSION DOCUMENT 

2.4	Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action. 

While low mole NPEO and NP have weak estrogenic activity that is 1000 to 1,000,000 fold less potent than 17ß-estradiol (E2) and 17α-ethynylestradiol (EE2) (Coady et al., 2010), adverse apical effects caused by the NPEO or NP are not clearly endocrine mediated.   The assumption that effects on biologically complex, apical endpoints, such as reproduction, are mediated by a single mode of action, in this case one that is endocrine mediated via the estrogen receptor, is not reasonable for NP or NPEO.  In estrogenic mixture studies with estrogens and alkylphenols, the phenomenon of decreased fish reproduction due to alkylphenol exposure alone was clearly not solely attributed to estrogen-like activity (Brian et al., 2007). 

Investigations using gene array technologies to specifically compare NP and estradiol (E2) gene transcription profiles have established that NP has additional modes of action that are independent of the estrogen receptor (Larkin et al., 2002; Ruggeri et al., 2008; Watanabe et al., 2004).  Molecular evidence in both mammalian and fish models have demonstrated that the alkylphenols influence a greater suite of genes than estrogens (Ruggeri et al., 2008; Watanabe et al., 2004).  For example, 425 genes were differentially expressed in liver tissue from zebrafish exposed to 10-7 M NP, while 153 genes were differentially expressed in liver tissue from zebrafish exposed to 10-7 M E2 (Ruggeri et al., 2008).  Of the 30 most differentiated genes affected by NP compared to controls, only 1/3 of these genes were also altered among E2-exposed fish, and then not all in the same direction of change (Ruggeri et al., 2008). In mice, NP activated more genes than E2 in liver tissue, and the activated genes in the livers of NP-exposed mice were distinct from estrogen-responsive genes (Watanabe et al., 2004).  These molecular studies of gene activation illustrate that NP has multiple modes of action, of which weak estrogenic activity is one, and the apical effects noted on aquatic organisms, such as decreased growth, survival and reproduction, are not necessarily directly or solely attributed to NP’s weak estrogen receptor binding activity.  

In summary, estrogenicity does not appear to be the sole mechanism of action for NP and NPEO in aquatic species and neither of these compounds have been shown to have endocrine disrupting properties that cause probable serious effects that are of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds in aquatic species, therefore they do not meet the criteria under REACH Article 57(f).
2.5	Findings on genistein, a naturally occurring estrogenically active compound, provide a realistic perspective on the importance of considering estrogenic potency and lead or predominant  mode of toxicity when assessing whether a compound poses probable serious effects to human health or the environment that give rise to an equivalent level of concern to those of other substances that meet the criteria in Article 57 (a)-(e).

To put the toxicity and estrogenicity findings of NP and NPEOs into perspective, similar toxicity information was examined for another known estrogenically active compound, which is naturally occurring. This compound is the isoflavone genistein which is found in certain plants such as soybeans and soy products like tofu.  Genistein and other isoflavones have been shown to interact with animal and human estrogen receptors.  In a study on genistein Wenzel et al (2001) reported an acute LC50 of >1900 µg/L (solubility) and a NOEC (fertilization success) of 1.3 µg/L. The ratio of these two values is >1460, which falls between  the ratios for EE2 and NP indicating that perhaps genistein is moderately active relative to EE2, but not just like EE2.  These findings on genistein are useful in providing a realistic perspective on the importance of considering the estrogenic potency of a compound as well as the lead or predominant mode of toxicity when assessing whether it poses probable serious effects to human health or the environment that give rise to an equivalent level of concern to those of other substances that meet the criteria in Article 57 (a)-(e).   The genistein findings raise the question of whether genistein, a phytoestrogen that occurs in common foods, is present in the aquatic environment, and is more estrogenically potent than NP should also be assessed and considered an SVHC. This is the suggestion based on the rationale that is presented for NP/NPEO in the Annex XV Report for NPEO. 

3.0     The adverse apical endpoints raised in the Annex XV Report for NP and attributed to an estrogenic mode of action were reproductive or developmental effects in aquatic organisms; however the rationale for the leap between findings of weak NP estrogenic activity and reproductive effects seen in some fish studies is not well founded, and the same concerns apply to NPEO.

The endpoints that are considered to indicate an estrogen agonist mode of action are summarized in the Annex XV Report for NP on page 49 (Table 18). (ECHA, 2012).  Several of these endpoints are more apical in nature and can be observed naturally and also under various stressful conditions for fish.  Oocyte atresia normally occurs in fish as a part of the natural reproductive cycle, so an understanding of the normal background level of this phenomenon is important. Oocyte atresia and testicular degeneration also occur in fish when exposed not only to an estrogenic compound, but also in response to compounds with known androgenic or anti-androgenic modes of action (USEPA, 2007).  Therefore it appears that oocyte atresia and testicular degeneration, in and of themselves, are not indicative of a particular endocrine mode of action  (i.e. estrogen receptor agonism).  It is also established that stressful situations resulting in sustained increases in a fish’s cortisol levels can depress sex steroid concentrations, which in turn can cause delayed gonadal development, lowered VTG levels, and depressed secondary sex characteristics in fish (Milla et al., 2009; Aluru and Vijayan,  2009).  Therefore, these endpoints are not necessarily specific to an endocrine mediated mode of action, but will respond when fish are stressed, whatever the cause may be.

In various studies with medaka fish, increased VTG was observed in males at concentrations of NP ≥ 5.4 µg/L, altered histopathology of the gonads (specifically occurrence of testis-ova) generally occurred at concentrations of NP ≥ 8.2 µg/L.  The occurrence of testis-ova in the gonads was more marked when fish were exposed during the time period of sexual differentiation, which occurs before hatch.  Incidences of ova-testis were less frequent and occurred at higher concentrations when exposure to NP was initiated post-hatch.  Sex ratios in medaka fish were altered toward a greater proportion of females at concentrations of NP ≥ 17.7 µg/L. These results indicate that effects noted in medaka may be due to the weak estrogen binding activity of NP.  However, the apical effects that have a relevance to medaka populations (i.e. altered sex ratio), occur at concentrations well above the current Environmental Quality Standard (EQS) of 0.3 µg/L for NP in surface waters under the Water Framework Directive as well as above the Predicted No Effect Concentration (PNEC) of 0.6 µg/L that is listed in the REACH Dossier for NP and was based on a species sensitivity distribution model (ECHA, 2012).  

In studies with fathead minnows of various ages, increased VTG was observed at concentrations of NP ≥ 8.1 µg/L, altered histopathology of the gonads and altered secondary sex characteristics generally occurred at concentrations of NP ≥ 1.6 µg/L.  Apical endpoints, such as reproduction and survival, were affected among fathead minnows, including early life stages, at concentrations of-NP ≥ 14 µg/L.  While behavioral effects of NP exposure on male fathead minnows were described by Schoenfuss et al., 2008, namely nest holding behavior, the magnitude of the noted effects among NP-exposed fish was low (i.e. 5-10% of 4-NP-exposed fish were outcompeted by control males) and arguably not of biological relevance.  The biological relevance of such a small effect is questionable, especially for an endpoint as variable as nest holding behavior, which has not been validated in a standardized fish testing guideline.  Also notable in the Schoenfuss et al., 2008 study is the fact that patchy and high mortality rates were observed among tested fish at concentrations of NP that are lower than those known to result in fish mortality (i.e. 58% survival in 0.15 µg/L NP treatment group), thus questioning the husbandry practices for the fish in this study.  Again, the apical effects that have a relevance to fathead minnow populations (i.e. reproduction and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

A quote from the section on fathead minnow results in the Annex XV Report for NP (page 64) states, “Although apical effects started at similar or even lower concentrations compared to biomarker responses, it seems very likely that they are estrogen mediated.” (ECHA, 2012)  There really is no support for this statement, since NP has multiple modes of action apart from weak estrogen receptor binding, as has been demonstrated by several gene array and other molecular based mode of action studies with NP (see section 2.4).  There is no definitive link with the weak estrogenic effects noted among fathead minnows (i.e. effects on VTG and reproductive tissues) and the effects on apical endpoints (i.e.  reproduction and survival) which occur at overlapping concentrations.  The most sensitive apical effect for fathead minnows that was statistically different from controls in a validated study was based on mortality in an ELS study (Ward and Boeri, 1991).   There is no clear link in this study with fathead minnow mortality and an estrogenic mode of action.

A total of four NP exposure studies with zebrafish were examined in the report, however, 3 of the 4 studies were deemed a Klimisch score 3, which indicates that these studies are “not reliable” (Klimisch, 1997).  However, the endpoints from these studies are still used in a weight of evidence evaluation of the effects of NP on zebrafish.  With inappropriate controls included in the test design and high control mortality rates, the study endpoints are compromised and should not be included in a weight of evidence approach for determining the effects of NP on zebrafish.  From the one study determined acceptable for consideration (Lin and Janz, 2006), VTG was increased among male and female fish at 100 µg/L NP, testicular tissue was skewed to earlier stages at 10 µg/L 4-NP, and the effects of 1) no detectable males based on gonadal histology and 2) decreased swim up success were noted at 100 µg/L NP.  Altered sex ratios compared to controls were also observed at 10 µg/L NP (58% females at 10 µg/L NP vs 30% females in controls), however since the sex ratio was skewed in the control group, the meaningfulness of this observation is questionable. The effects that have a relevance to zebrafish populations (i.e. altered sex ratio and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

Various studies with rainbow trout exposed to 4-NP were summarized, and effects on increased VTG levels were noted at concentrations as low at 1.05 µg/L.  Effects on gonadal tissues were noted at concentrations of NP ≥ 30 µg/L, and effects on apical endpoints including growth and survival, were noted at concentrations of NP ≥ 10.3 µg/L.  Additionally, the effect of reduced sperm volume was noted in one study (Lahnsteiner et al., 2005) starting at concentrations of NP ≥ 0.13 µg/L; however, reproduction was not assessed in this study, so it is unknown if this decrease in sperm volume affected reproduction levels in rainbow trout. In addition, this endpoint is not well-studied, therefore the usefulness of the endpoint for predicting effects for population health is not known.  The lowest apical endpoint noted in among the toxicity studies with rainbow trout was the reduced growth of rainbow trout at 10.3 µg/L in an early life stage test (Brooke, 1993).   This apical endpoint is not clearly related to an estrogenic mode of action.  Fish growth can be affected by various modes of action and reductions or delays in growth are not necessarily estrogen-mediated.  In fact, the OECD Guidance Document on the Assessment of Chemicals for Endocrine Disruption states, “… an effect solely on growth or survival, while potentially of concern from the viewpoint of environmental risk assessment, would not lead to a conclusion that the chemical is an ED in fish.” (OECD, 2011).  Again, the apical effects that have a relevance to rainbow trout populations (i.e. growth and survival), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

In studies with guppies and mosquito fish, NP exposure resulted in similar findings with increased VTG at concentrations of NP ≥ 10 µg/L, changes in gonadal tissues at concentrations ≥ 0.5 µg/L, and effects on apical endpoints at concentrations of NP ≥ 5 µg/L.  While skewed sex ratios were noted at concentrations of NP ≥ 50 µg/L, significant effects on growth were noted at lower concentrations of 5 µg/L.  As stated previously, decreased growth is not specific to an estrogenic mode of action.  As seen with the other fish species, apical effects that have a relevance to viviparious fish populations (i.e. growth), occur at concentrations well above the current environmental quality standard of 0.3 µg/L for NP in surface waters under the Water Framework Directive.

Taken together, the fish studies do indicate that NP has a mode of action that is consistent with a relatively weak binding affinity to the estrogen receptor when compared to the endogenous ligand, E2.  Increased levels of VTG, alterations in gonadal histopathology, and altered sex ratios in fish are consistent with this mode of action.  However, the most sensitive apical endpoints among fish toxicity studies with NP are based on decreased growth and survival, particularly of early life stage fishes.  These endpoints for NP are not clearly linked to an endocrine mode of action, and are not estrogen agonist specific.  There are other modes of action associated with NP as is evidenced in Section 2.4 of these comments by the suite of genes that are differentially activated in gene array and other molecular based investigations of the mode of action of NP.  

Again, the data do not support a rationale that connects NPEO or NP exposures to probable serious effects in the environment (i.e., reproductive or developmental effects in fish), which are attributable primarily to an estrogenic mode of action.  

4.0   	The Annex XV Report for NPEO overstates the importance of NP as degradation intermediate of NPEO.  

While the assessment of the biodegradation data for NP in the Annex XV Report for NPEO is generally correct in stating that the primary biodegradation pathway of the NPEO released to surface waters is to their ether carboxylates, the summary of this characteristic incorrectly concludes that NP and NPEO are not extensively mineralized. 

After release into surface waters, Jonkers et al. (2001, 2003, 2005) demonstrated with laboratory and field studies that high mole APEOs break down via an oxidative hydrolytic pathway to higher ether carboxylates, then lower ether carboxylates, and subsequently to further metabolites (not the alkylphenol). Low mole ethoxylates break down to lower ether carboxylates and subsequently to further metabolites (also not the alkylphenol).  The field studies conducted by Jonkers et al. (2005) showed that biodegradation of APEO proceeded via this pathway and the authors further determined that first order biodegradation half-lives for APEO, APEC, and AP were 10 to 41 days. The laboratory and field studies by Jonkers and colleagues served as key information in the fuller elucidation of the biodegradation pathways of NPEO surfactants as developed by Staples et al. (2008) and Klecka et al. (2008), which describe rapid degradation of APEO to short chain APEO and NPEC, which in turn degrade ultimately to carbon dioxide and water.  Naylor et al, (2006) evaluated the aerobic biodegradation of [14C] Ring-Labeled NPEO and found that the aromatic ring does break down. Staples et al, 2008 note that APEO degrade more slowly under anaerobic conditions.  

In summary, NPEO are not persistent and they degrade through low mole NPEO and NPEC compounds with NP as a lesser degradation intermediate, which ultimately mineralizes under aerobic conditions.  

5.0  	The Annex XV Report overstates the significance of releases of NP and of low mole NPEOs from sediment to the risk of aquatic organisms. 

The Annex XV Report for NPEO expresses concern that NP and low mole NPEOs may accumulate in sediment and thereby become a permanent source in the environment.   This line of thinking seems in conflict with the intention of the PBT and vPvB criteria for SVHC.  Adsorption to sediment does not constitute persistence nor does it represent a “permanent source”.   

While NP has been found to biodegrade more slowly under anoxic conditions, many organic compounds degrade more slowly under low temperature, nutrient-poor or oxygen-limited conditions (see for example Boethling and Mackay, 2000). The data for NP are consistent with the findings for other such substances.  NP does degrade in the environmental compartments in which organisms reside. These compartments include freshwater and marine water and sediment and soil. 

While NP and NPEO are likely to persist if buried in sediment under anaerobic conditions; many other compounds are also persistent and are not bioavailable for microbial degradation or to pose toxicity under these conditions. In addition, should NP or low mole NPEOs be scoured up due to a flood or high water, as speculated in the Annex XV Report, they would resume their normal aerobic biodegradation pathway through their ether carboxylates ultimately to carbon dioxide and water. 

Since NPEO and NP aerobically biodegrade in all relevant and bioavailable environmental compartments, they are not expected to build up and pose a concern to aquatic organisms as would be expected by truly long lasting and persistent substances.  NPEO and NPE are not considered “persistent” or “very persistent” according to Annex XIII criteria and their presence in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

7.0  	There are other regulatory instruments in place in the EU to control emissions of NPE, which have decreased the use and release of these compounds in Europe.  

The following regulations are already in place in the EU to control emissions and environmental risks from NP and NPEO. 

7.1	The Water Framework Directive (Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy)

The Water Framework Directive requires the Members States to measure aquatic concentrations of compounds relative to established Environmental Quality Standards (EQS) and to take action in case this value is exceeded.  An EQS value of 0.3 µg/L has been established for NP. 

7.2	The EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  

The M&U Directive for NP/NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP/NPEO in the wide dispersive uses most likely to result in emissions to the aquatic environment. 

7.3	 The Integrated Pollution Prevention and Control (IPPC) Directive 2008/1/EC of the European Parliament and of the Council of 15 January 2008 

The IPPC Directive lays down measures designed to prevent or, where that is not practicable, to reduce emissions to air, water and land from the activities mentioned in Annex I to the Directive, including measures concerning waste.

Given that the concern expressed in the Annex XV Report for NPEO is actually for NP, consideration should be given to these existing regulatory instruments, which are in place and already control emissions of NP in the EU. 

9.0 	Contribution of NPEO1 and NPEO2 and NP to the measured estrogenicity of wastewater effluents is negligible and not likely to result in probable serious effects to the aquatic environment. 

Analysis of data on the contribution of NP and NPEO and other APEOs indicates that the contribution from these compounds to the overall estrogenicity of wastewater effluents is negligible. This further supports a conclusion that these compounds are not likely resulting in probable serious effects in the receiving aquatic environment. 

Numerous studies have examined the extent to which measurable estrogenic activity in wastewater treatment plant (WWTP) effluents is attributable to natural and synthetic hormones (e.g., E2 and EE2) or to other constituents (e.g., NP, NPEO or other AP/APEOs). Desbrow et al. (1998) used a sample fractionation system to isolate fractions of WWTP effluent samples that were tested for estrogenicity using a YES assay. Estrogenic fractions were found to contain natural and synthetic hormones including E2, estrone, and EE2.  Alkylphenolic compounds were not detectable in the estrogenic fractions. 

Most studies employed in vitro screening assays such as YES assays and concentration measurements from whole effluents to assess relative contributions to estrogenicity. Korner et al. (1999) and Aerni et al. (2004) reported that the contribution of NP in German WWTP effluents was <3% and 2%, respectively, of the total estrogenicity. In WWTP effluents in the US, Drewes et al. (2005) reported that nearly all of the estrogenic activity was attributable to natural and synthetic hormones. Similar findings have been reported for WWTP effluents in Australia, New Zealand, and China, with estrogenic contributions from NP of 0.04 to 3.9% (Leusch et al., 2006; Jin et al., 2007; Lu et al., 2011).  

Considering that high mole NPEO (EO ≥ 4) are not estrogenic and the estrogenicity of NPEO1 and NPEO2 is even weaker than that for NP, it is reasonable to conclude that NPEO are not contributing significantly to the estrogenicity of WWTP effluent and therefore not likely to result in probable serious effects to the aquatic environment. 

10.0 	The very low estrogenic potency, multiple modes of action, and low environmental occurrence and concentrations for NP and NPEOs do not support a conclusion of probable serious environmental effects  giving rise to an equivalent level of concern to substances meeting the criteria of Article 57(a) through (f).

Categorization as SVHC should be reserved for substances for which the weight-of-evidence supports a finding of both probable serious effects from that specific substance. Data supporting the hazards of a substance nominated for SVHC should be specific and sufficient to support that substance as meeting criteria listed under Article 57.  The available data for NPEO do not support a conclusion of probable serious environmental effects giving rise to an equivalent level of concern to those of other substances meeting the criteria of Article 57. 

The Annex XV Report for NPEO is based on assumptions that these polymeric compounds are contributing to probable serious effects in aquatic species due to their degradation to NP in the environment.  As discussed previously, NP, at most, has weakly estrogenic activity, low mole NPEOs have even weaker estrogenic activity and higher mole NPEOs have no estrogenic activity. NP and NPEO have estrogenic activity that is orders of magnitude less than the natural (E2) and synthetic (EE2) estrogens based on in vitro and in vivo tests. Low mole NPEO and NP operate under multiple modes of action, not just a weak estrogenic mode of action and affect acute lethality and chronic reproduction, growth and development endpoints very differently than E2  or EE2.  Comparison of studies examining NPEO, NP and E2 and EE2 demonstrates that there are great differences between the effects that they cause to aquatic organisms.  While the estrogenic mode of action is clearly the lead, or most predominant , mode of action impacting adverse effects from E2 and EE2, this is not clearly the case for NP or low mole NPEO, which have other co-occurring modes of toxicity (i.e., narcosis) that result in adverse effects observed among fish population, Endocrine activity alone is not sufficient justification for equivalent concern under Article 57(f).  Without evidence of probable serious adverse effects that are primarily the consequence of that mode of action the compound does not rise to a level of equivalent concern to CMR Cat. 1A or 1B, PBT or vPvB compounds.

Consideration of exposure and risk are inherent in determining probable serious effects.    In the case of NP and NPEOs, concentrations in European waters are generally well below NOEC and LOEC values for adverse apical effects found in studies on NP in aquatic species and have dropped significantly since 2003 when the M & U Directive on dispersive uses of NP and NPEO was implemented. Concentrations of NP are typically below EQS established for this compound under the Water Framework Directive.  In addition, as discussed in earlier in these comments, studies that examine estrogenically active substances in wastewater treatment plant effluent found that if detected, NP, NPEOs and alkylphenols generally, contributed only minimally to the aggregate estrogenicity. 

NPEO and NP are not considered “persistent” or “very persistent” according to Annex XIII criteria and the presence of NP in anoxic sediment does not constitute either a bioavailable or “permanent source” in the environment. 

Perhaps most importantly, the criteria listed under Article 57  list specific  hazard-based  adverse effects criteria that should apply to SVHC candidates for authorisation  and there is no inference under Article 57, or elsewhere in the REACH regulations,  that SVHC candidate chemicals for authorisation under Annex XIV should be anything other than chemicals that meet one or more of those criteria.  The proposal in the Annex XV Report for NPEO to designate these polymers that degrade to a SVHC compound to also be SVHC based on the argument that the polymer is an environmental source of the degradant  circumvents the need for Commission consideration of this significant policy determination under REACH. In  addition, there are other regulatory instruments in place in the EU to control emissions of NPEO, which based on current monitoring data in the EU should preclude the need for further prioritization of these compounds. 

For all of these reasons APERC and CEPAD recommend rejection of the Annex XV Report on NPEO. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT 	Thank you for the comment. See response to comment number 11.	
			See also:
Comment 10 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
9	2013/04/17	National NGO
CHEM Trust
United Kingdom	CHEM Trust supports the inclusion of 4-nonylphenol, branched and linear, ethoxylated in the REACH candidate list according to article 57 f. 

The reasoning for inclusion in the candidate list is well explained and is taken in analogy to the approach for 4-tert octylphenol ethoxylates and 4-tert-octylphenol: 4-NPnEO degrades to  4-nonylphenol in the environment, and 4-nonylphenol has been included as endocrine disrupting SVHC on the REACH candidate list . Sediments will remain a relevant source for 4-NP long after the cessation of exposure of 4-NPnEO.	Thank you for your support.	
8	2013/04/17	Company
Sweden	Uses reported in the Annex XV dossier are:
The registration dossiers of 4-nonylphenol provide some additional information on sectors of use and product types where 4-Nonylphenol, branched and linear, ethoxylated are constituents of mixtures. But these data do not refer to the concentration of 4-Nonylphenol, branched and linear, ethoxylated in the mixtures. The uses in the registration dossiers of 4-nonylphenol are:
- Formulation of paints
- Industrial end-use of paints
- Consumer and professional end-use of products (e.g. paints)
- Use of ethoxylates in emulsion polymerisation

Confidential comment submitted.

The purpose in submitting these comments is to ensure that ECHA is familiar with certain critical uses of 4-Nonylphenol, branched and linear, ethoxylated as described in the fourth identified use aforementioned.

Although our uses of these substances are in limited volumes, the uses are critical for the manufacture of fine chemicals that are used by pharmaceutical and biopharmaceutical industries to manufacture and purify active pharmaceutical ingredients (API). These uses are NOT as medicinal products. However, inability to use 4-Nonylphenol, branched and linear, ethoxylated in the manufacturing processes of the fine chemicals will adversely impact the production of medicinal products and the pharmaceutical and biopharmaceutical industries. There are currently no known substitutes for these uses. 

In the confidential comments uploaded our uses are described in further detail.	Thank you for the additional information on uses. It will be considered for further work on choosing the most appropriate risk management option.	
			CONFIDENTIAL attachment is removed		
7	2013/04/17	National NGO
CHEM Trust
United Kingdom	CHEM Trust supports the inclusion of 4-nonylphenol, branched and linear, ethoxylated in the REACH candidate list according to article 57 f. 

The reasoning for inclusion in the candidate list is well explained and is taken in analogy to the approach for 4-tert octylphenol ethoxylates and 4-tert-octylphenol: 4-NPnEO degrades to  4-nonylphenol in the environment, and 4-nonylphenol has been included as endocrine disrupting SVHC on the REACH candidate list . Sediments will remain a relevant source for 4-NP long after the cessation of exposure of 4-NPnEO.	
Thank you for your support (= comment number 9).	
6	2013/04/16	Member State
Belgium	Belgium supports the proposal to identify these substances as SVHC, based on article 57(f) of the REACH Regulation. There is scientific evidence of probable serious effects to the environment from these substances through their degradation to 4-NP (previously identified as SVHC, due to its endocrine disrupting properties), either directly in wastewater treatment plants or, in sediments and soils. Given the slow degradation rate, exposed sediments and soils are expected to remain a relevant source for 4-NP in the environment long after the cessation of exposure. 	Thank you for your support.	
4	2013/04/16	Member State
Norway	General comments:
Norway will first thank Germany for preparing this document. The Norwegian CA supports the German proposal that the abovementioned substance(s) should be added to the candidate list as SVHC according to REACH article 57(f). 

We support the conclusion that 4-nonylphenol, branched and linear, ethoxylated, should be considered as substance(s) of very high concern because of the endocrine disrupting (ED) properties according to REACH article 57 (f), giving rise to an equivalent level of concern as exerted by CMR or PBT/vPvB substances. 

Justification
We consider that the information submitted by Germany demonstrates the degradation of 4-nonylphenol, branched and linear, ethoxylated, to 4-nonylphenol or other intermediary substances which are sources for degradation to 4- nonylphenol. 

4- nonylphenol has already been identified as a substance of very high concern and included in the Candidate List due to its endocrine disrupting properties which cause probable serious effects to organisms in the environment. 

Hence, we support the conclusion that 4-nonylphenol, branched and linear, ethoxylated, should be included on the candidate list	Thank you for your support.	
3	2013/04/15	Other contributor
Germany	We think it will be appropriate that oligomers ( until 8-mer ) of ethoxylate are to be regulated, and polymers ( >= 9-mer ) are excluded. Is our understanding correct?

	Please note, that the dossier includes all 4-nonylphenol ethoxylates with an ethoxylation grade of ≥ 1. Thus it includes both oligomers (including those with n > 8) and polymers. The reason is that all these ethoxylates degrade to nonylphenol.	
2	2013/04/15	Member State
Sweden	The Swedish CA agrees that 4-nonylphenol, branched and linear, ethoxylated (4-NPE) should be added to the candidate list as an SVHC according to article 57(f) in REACH. We think that the information submitted by Germany provides sufficient scientific evidence that 4-NPE degrade to 4-nonylphenol (4-NP), branched and linear, either already in wastewater treatment plants, or via further degradation processes in sediments (e.g. of aquatic bodies receiving the wastewater effluents) and soils (e.g. receiving sewage sludge). We agree on that the equivalent level of concern is based on the degradation to 4-NP.    
In principle we are of the opinion that for identification of a substance as an SVHC according to article 57(f) due to its endocrine disrupting properties, it will generally be irrelevant whether the concern for probable serious effects to human health or the environment arises from either environmental data or health data or both data pools. Particularly in a case like this, where the endocrine mode of action is via estrogenicity, a hormonal regulatory system relevant for a wide variety of species in the environment and also in humans, all available information including (but not limited to) experimental animal data from the environment and human health data bases should be used. Thus, evidence from the environmental data base should, where relevant, be brought to bear also on the human health assessment and vice versa.
Thus, in our view there is a general concern for endocrine mediated adverse effects for the degradation product 4-NP of 4-NPE. In case they would be recommended for inclusion in Annex XIV,  we consider it to be crucial that both health and environmental concerns have been mentioned as reasons for their SVHC identification, and consequently, that both these aspects would need to be considered in the chemicals safety assessments of possible future applications for, and decisions on, authorization of the substances.
Presently, the Annex XV SVHC dossier for 4-NPE only addresses concerns based on scientific evidence of probable serious effects to the environment due to the endocrine disrupting properties. No corresponding analysis and conclusion for human health concerns have been brought forward in the SVHC dossier.
Notwithstanding the eligibility of 4-nonylphenol, ethoxylated to be identified as a SVHC according to REACH Art. 57(f) as regards the environment, the Swedish REACH CA also believes that the substance warrants identification as a REACH Art. 57(f) SVHC as regards concerns for human health. We suggest that the latter end may be achieved in due course by an update of the SVHC dossier or submission of a separate dossier to cover also the human health concerns and a subsequent revision of the candidate list entry as appropriate.	Thank you for your support.
We appreciate your comment with regard to the human health concern and we agree that in principle human health concerns may be covered in a separate dossier if appropriate.	
1	2013/04/12	Member State
United Kingdom	We agree that 4-nonylphenol ethoxylates (NPEs) are a significant source of an existing SVHC (4-nonylphenol) following environmental degradation. On that basis, it seems appropriate that they should be included on the Candidate List. 	Thank you for your support.	

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

Specific comments on use, exposure, alternatives and risks
Number	Date	Submitted by (name, Organisation/MSCA)	Comment	Response	
15	2013/04/18	Industry or trade association
ASD
Belgium	We can understand the issues of publishing a long list of CAS numbers however we know of no effective way to identify, on the part of a Downstream User, which products these materials would be used for.  Without a CAS number we cannot identify the products!
This is not a helpful position and nullifies any consultative information we may be able to provide.	We understand your concerns. However we would like to emphasise that the substance description does mirror the situation on the marked which includes ethoxylates with varying chain length and often known or unknown distributions of chain length which can not sufficiently be covered by the CAS numbers available. 	
			See also:
Comment 15 attachment (ASD Letter.docx).docx		
14	2013/04/18	International NGO
Women in Europe for a Common Future
France	The following data on exposure and uses should be taken into account:

4-Nonylphenol and bisphenol A in Swedish food and exposure in Swedish nursing women. Gyllenhammar I, Glynn A, Darnerud PO, Lignell S, van Delft R, Aune M. Environ Int. 2012 Aug;43:21-8. doi: 10.1016/j.envint.2012.02.010. Epub 2012 Mar 30.
Recent trends in biomonitoring of bisphenol A, 4-t-octylphenol, and 4-nonylphenol. Asimakopoulos AG, Thomaidis NS, Koupparis MA. Toxicol Lett. 2012 Apr 25;210(2):141-54. doi: 10.1016/j.toxlet.2011.07.032. Epub 2011 Aug 22. Review.
Migration of plasticizers phthalates, bisphenol A and alkylphenols from plastic containers and evaluation of risk. Guart A, Bono-Blay F, Borrell A, Lacorte S. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2011 May;28(5):676-85. doi: 10.1080/19440049.2011.555845.
Simultaneous determination and assessment of 4-nonylphenol, bisphenol A and triclosan in tap water, bottled water and baby bottles. Li X, Ying GG, Su HC, Yang XB, Wang L. Environ Int. 2010 Aug;36(6):557-62. doi: 10.1016/j.envint.2010.04.009. Epub 2010 May 7.	Thank you for the additional information on exposure and uses which is considered for further work on choosing the most appropriate risk management option.
	
13	2013/04/18	International NGO
ChemSec, the International Chemical Secretariat
Sweden	The following alternatives to nonylphenols are available, as presented in the SUBSPORT database:
 
Alternatives in textile production, degumming process:
Polyoxyethylene alkyl ether
CAS No. 9002-92-0 EC No. 500-002-6
Polyoxyethylene tridecyl ether
CAS No. 24938-91-8
Company
In use by Fast retailing co., who provided the case story
Reference
http://www.subsport.eu/case-stories/372-en?lang=
 
Alternatives in textile production, to reduce yellowing
Alcohols, C10-16, ethoxylated
CAS No. 68002-97-1 EC No. 500-182-6
Company
In use by G-Star, who provided the case story
Reference
http://www.subsport.eu/case-stories/370-en?lang=	Thank you for the additional information on alternatives of nonylphenol ethoxylates.	
11	2013/04/18	Industry or trade association
European Council for Alkylphenols and Derivatives
Belgium	7.0  	There are other regulatory instruments in place in the EU to control emissions of NPE, which have decreased the use and release of these compounds in Europe.  

The following regulations are already in place in the EU to control emissions and environmental risks from NP and NPEO. 

7.1	The Water Framework Directive (Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy)

The Water Framework Directive requires the Members States to measure aquatic concentrations of compounds relative to established Environmental Quality Standards (EQS) and to take action in case this value is exceeded.  An EQS value of 0.3 µg/L has been established for NP. 

7.2	The EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  

The M&U Directive for NP/NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP/NPEO in the wide dispersive uses most likely to result in emissions to the aquatic environment. 

7.3	 The Integrated Pollution Prevention and Control (IPPC) Directive 2008/1/EC of the European Parliament and of the Council of 15 January 2008 

The IPPC Directive lays down measures designed to prevent or, where that is not practicable, to reduce emissions to air, water and land from the activities mentioned in Annex I to the Directive, including measures concerning waste.

Given that the concern expressed in the Annex XV Report for NPEO is actually for NP, consideration should be given to these existing regulatory instruments, which are in place and already control emissions of NP in the EU. 

8.0 	Surface water concentrations of NPEO, along with other alkylphenol ethoxylate (APEO) surfactants, and their biodegradation intermediates in EU Waters are below their known toxicity values and Environmental Quality Standards (EQS) and do not indicate that their presence in EU surface water are likely to pose probable serious effects to human health or the environment from any mode of toxicity.  

Since the Market and Use Directive for NP and NPEO was enacted by the European Parliament in 2003, restrictions on the use of these compounds in products and applications most likely to discharge to wastewater treatment plants and/or the aquatic environment have been implemented in the EU.  Therefore, examination of surface water concentrations since that time of NPEO and their aerobic biodegradation intermediates (low mole NPEO and NPECs), as well as NP that is formed during anaerobic digestion processes in wastewater treatment plants, provides a useful assessment of the probability that the presence of these degradants of NPEOs will result serious effects to human health or the environment that give rise to an equivalent level of concern to CMR, PBT or vPvB compounds.

Published studies reporting surface water monitoring for NPEO, and APEO more generally, since the Market and Use restrictions in the EU began are summarized in Table III.

In sampling campaigns conducted in 2003 and 2004 analyzing numerous constituents including NP, Beck et al. (2006) reported concentrations of NP of about 2 to 15 ng/L. Arditsoglou and Vousta sampled numerous locations in the years 2005 and 2006 in and near the Thermaikos Gulf in the North Aegean Sea near Greece. The authors reported concentrations of NPEO1 and NPEO2 ranging overall from 14.6 to 346 ng/L and average NPEO1 and NPEO2 concentrations of 62 to 63 ng/L, respectively.  NP concentrations ranged from 22 to 201 ng/L, averaging 79 ng/L. Jonkers et al. (2010) reported the results from numerous locations sampled in 2006 within the Ria de Aveiro, Portugal area focusing on the shallow lagoon and rivers entering the system. Concentrations of higher mole APEO (APEO3-10) were 0.3 to 314 ng/L, low mole APEO1-2 were 0.2 to 91 ng/L, APEC1-4 were 0.1 to 2660 ng/L, and NP was 13 to 52 ng/L. Micic and Hofman (2009) conducted extensive sampling of water, suspended material, and sediment along the length of the Danube River from Germany to Romania in 2007. The authors measured concentrations of APEC and NP in surface water samples, reporting that NPEO1 and NPEO2 were not detected in any sample (N=19) and that NP was detected in only 3 of 19 samples at concentrations of 100 to 130 ng/L. 

Considering the EQS established for NP under the Water Framework Directive for the protection of inland waters is 0.3 µg/L (300 ng/L), no concentration of NP reported in these studies conducted since Market and Use Directive for NP and NPEO was implemented exceeded the EQS. While there is no EQS for NPEO, the NOEC from Table II for these compounds range from about 38.3 to 1000 µg/L (38,000 to 1,000,000 ng/L). 

In summary, in published monitoring studies of EU surface waters conducted since the Market and Use Directive for NP and NPEO was implemented NPEO were often not detected and when detected concentrations ranged up to a maximum of 346 ng/L, or at least 100-fold lower than the range of known NOEC for NPEO.

SEE TABLE III MONITORING STUDIES OF NPEO, NPEC, NP IN EUROPEAN COASTAL AND ESTUARINE WATERS AND RIVERS ENTERING COASTAL WATERS IN ATTACHED SUBMISSION DOCUMENT. 

In summary, surface water concentrations of NPEO, along with other APEO surfactants, and their biodegradation intermediates in EU Waters are generally below their known toxicity values and Environmental Quality Standards (EQS) and do not indicate that their presence in EU surface water are likely to pose probable serious effects to human health or the environment from any mode of toxicity. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT	7.0 and 8.0
Thank you for the additional information which is considered for further work on choosing the most appropriate risk management option.
	
			See also:
Comment 11 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
10	2013/04/18	Industry or trade association
Alkylphenols & Ethoxylates Research Council
United States	7.0  	There are other regulatory instruments in place in the EU to control emissions of NPE, which have decreased the use and release of these compounds in Europe.  

The following regulations are already in place in the EU to control emissions and environmental risks from NP and NPEO. 

7.1	The Water Framework Directive (Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy)

The Water Framework Directive requires the Members States to measure aquatic concentrations of compounds relative to established Environmental Quality Standards (EQS) and to take action in case this value is exceeded.  An EQS value of 0.3 µg/L has been established for NP. 

7.2	The EU Market and Use Directive (M&U Directive) for Nonylphenol and its Ethoxylates first issued under DIRECTIVE 2003/53/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 June 2003 amending for the 26th time Council Directive 76/769/EEC and now incorporated into the REACH regulation as (EC) No 1907/2006, Annex XVIII.  

The M&U Directive for NP/NPEO was based on concern for the aquatic toxicity of NP and restricted the marketing and use of NP/NPEO in the wide dispersive uses most likely to result in emissions to the aquatic environment. 

7.3	 The Integrated Pollution Prevention and Control (IPPC) Directive 2008/1/EC of the European Parliament and of the Council of 15 January 2008 

The IPPC Directive lays down measures designed to prevent or, where that is not practicable, to reduce emissions to air, water and land from the activities mentioned in Annex I to the Directive, including measures concerning waste.

Given that the concern expressed in the Annex XV Report for NPEO is actually for NP, consideration should be given to these existing regulatory instruments, which are in place and already control emissions of NP in the EU. 

8.0 	Surface water concentrations of NPEO, along with other alkylphenol ethoxylate (APEO) surfactants, and their biodegradation intermediates in EU Waters are below their known toxicity values and Environmental Quality Standards (EQS) and do not indicate that their presence in EU surface water are likely to pose probable serious effects to human health or the environment from any mode of toxicity.  

Since the Market and Use Directive for NP and NPEO was enacted by the European Parliament in 2003, restrictions on the use of these compounds in products and applications most likely to discharge to wastewater treatment plants and/or the aquatic environment have been implemented in the EU.  Therefore, examination of surface water concentrations since that time of NPEO and their aerobic biodegradation intermediates (low mole NPEO and NPECs), as well as NP that is formed during anaerobic digestion processes in wastewater treatment plants, provides a useful assessment of the probability that the presence of these degradants of NPEOs will result serious effects to human health or the environment that give rise to an equivalent level of concern to CMR, PBT or vPvB compounds.

Published studies reporting surface water monitoring for NPEO, and APEO more generally, since the Market and Use restrictions in the EU began are summarized in Table III.

In sampling campaigns conducted in 2003 and 2004 analyzing numerous constituents including NP, Beck et al. (2006) reported concentrations of NP of about 2 to 15 ng/L. Arditsoglou and Vousta sampled numerous locations in the years 2005 and 2006 in and near the Thermaikos Gulf in the North Aegean Sea near Greece. The authors reported concentrations of NPEO1 and NPEO2 ranging overall from 14.6 to 346 ng/L and average NPEO1 and NPEO2 concentrations of 62 to 63 ng/L, respectively.  NP concentrations ranged from 22 to 201 ng/L, averaging 79 ng/L. Jonkers et al. (2010) reported the results from numerous locations sampled in 2006 within the Ria de Aveiro, Portugal area focusing on the shallow lagoon and rivers entering the system. Concentrations of higher mole APEO (APEO3-10) were 0.3 to 314 ng/L, low mole APEO1-2 were 0.2 to 91 ng/L, APEC1-4 were 0.1 to 2660 ng/L, and NP was 13 to 52 ng/L. Micic and Hofman (2009) conducted extensive sampling of water, suspended material, and sediment along the length of the Danube River from Germany to Romania in 2007. The authors measured concentrations of APEC and NP in surface water samples, reporting that NPEO1 and NPEO2 were not detected in any sample (N=19) and that NP was detected in only 3 of 19 samples at concentrations of 100 to 130 ng/L. 

Considering the EQS established for NP under the Water Framework Directive for the protection of inland waters is 0.3 µg/L (300 ng/L), no concentration of NP reported in these studies conducted since Market and Use Directive for NP and NPEO was implemented exceeded the EQS. While there is no EQS for NPEO, the NOEC from Table II for these compounds range from about 38.3 to 1000 µg/L (38,000 to 1,000,000 ng/L). 

In summary, in published monitoring studies of EU surface waters conducted since the Market and Use Directive for NP and NPEO was implemented NPEO were often not detected and when detected concentrations ranged up to a maximum of 346 ng/L, or at least 100-fold lower than the range of known NOEC for NPEO.

SEE TABLE III MONITORING STUDIES OF NPEO, NPEC, NP IN EUROPEAN COASTAL AND ESTUARINE WATERS AND RIVERS ENTERING COASTAL WATERS IN ATTACHED SUBMISSION DOCUMENT. 

In summary, surface water concentrations of NPEO, along with other APEO surfactants, and their biodegradation intermediates in EU Waters are generally below their known toxicity values and Environmental Quality Standards (EQS) and do not indicate that their presence in EU surface water are likely to pose probable serious effects to human health or the environment from any mode of toxicity. 

FULL REFERENCES ARE PROVIDED IN ATTACHED SUBMISSION DOCUMENT	Thank you for your comment. See response to comment number 11.	
			See also:
Comment 10 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf		
9	2013/04/17	National NGO
CHEM Trust
United Kingdom	4-Nonylphenols have been listed as priority hazardous substances under the EU’s water Framework Directive since 2000 and despite some reduction in use, further reductions are urgently needed: A recent Greenpeace study had also highlighted this fact (see report Dirty Laundry: http://www.greenpeace.org/international/Global/international/publications/toxics/Water%202011/dirty-laundry-report-2.pdf)	Thank you for the additional information.	
8	2013/04/17	Company
Sweden	Confidential comment submitted.

4-Nonylphenol, branched and linear, ethoxylated is part of product that is used as an emulsifier during the manufacture of fine chemicals used in the manufacture and purification of active pharmaceutical ingredients. The substance is not part of the final fine chemical.

Between 95-100% of the substance is separated from the process and sent for incineration to an authorized waste vendor. The rest of the substance is sent to our waste water treatment plant. The outgoing water from our waste water treatment plant is sent to the municipal waste water treatment plant and by them we have a written agreement on the allowed total amounts of nonylphenols in our outgoing water. 

Use descriptors for use of 4-Nonylphenol, branched and linear, ethoxylated:
•SU3 Industrial uses: Uses of substances as such or in preparations at industrial sites
•SU9 Manufacture of fine chemicals – C20.5.9 Manufacture of other chemical products n.e.c.
•SU24 Scientific research and development 
•PC0 Other – UCN code O25300 Emulsifier 
•PROC3 Used in closed batch process (synthesis or formulation) 
•PROC4 Use in batch and other process (synthesis) where opportunity for exposure arises.
•PROC9 Transfer of substance or preparation into small containers (dedicated filling line, including weighing)
•PROC15 Use as laboratory reagent
•PC19 Intermediate
•PC21 Laboratory chemicals 
•ERC4 Industrial use of processing aids in processes and products, not becoming part of articles. No release of the substance to air or soil. 	Thank you for the additional information. It will be considered for further work on choosing the most appropriate risk management option.	
			CONFIDENTIAL attachment is removed		
7	2013/04/17	National NGO
CHEM Trust
United Kingdom	4-Nonylphenols have been listed as priority hazardous substances under the EU’s water Framework Directive since 2000 and despite some reduction in use, further reductions are urgently needed: A recent Greenpeace study had also highlighted this fact (see report Dirty Laundry: http://www.greenpeace.org/international/Global/international/publications/toxics/Water%202011/dirty-laundry-report-2.pdf)	Thank you for the additional information (= comment number 9).	
5	2013/04/16	Company
Germany	Nonylphenol, ethoxylated is used in formulations for scientific R&D.
These applications are routine analytical uses in a laboratory within the scope of scientific R&D. The risk for the environment and consumers is very low. Usually the volumes and the concentration of the substance are low. The disposal of the substance is also controlled.
	Thank you for the additional information. It will be considered for further work on choosing the most appropriate risk management option.	
4	2013/04/16	Member State
Norway	Information on Use, Exposure, Alternatives and Risks
A recent Norwegian screening survey investigated the occurrence of the alkylphenolic compounds, nonylphenol (nNP, straight chained isomer and tNP, branched chain mixture), and nonylphenol monoethoxylate (NP1EO in the marine and freshwater aquatic environments, and selected alkylphenols (a. o. nNP, tNP and NP1EO) in Arctic biota. 

The full report can be downloaded here 
http://www.klif.no/publikasjoner/2899/ta2899.pdf

	Thank you for the additional information on occurrence of nonylphenol and nonylphenol ethoxylates in the environment. It will be considered for further work on choosing the most appropriate risk management option.	

Attachments

Comment number	Public attachment	
10	
Comment 10 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf	
11	
Comment 11 attachment (CEPAD-APERC Comments on NPE SVHC(04.17.2013).pdf).pdf	
15	
Comment 15 attachment (ASD Letter.doc).doc