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

Substance name: 4,4'-isopropylidenediphenol (bisphenol A, BPA)
CAS number: 80-05-7
EC number: 201-245-8

The substance is proposed to be identified as meeting the following SVHC criteria set out in Article 57 of the REACH Regulation: Endocrine disrupting properties (Article 57(f) - human health)

Disclaimer: Comments provided during public consultation are made available 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. The RCOM has not been agreed by the Member State Committee, nor has the document been modified as result of the MSC discussions.  

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

Table 1 - General comments on the SVHC proposal
Reference number	Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
1.		4805
2017/04/20	Merck PM GmbH,
Company,
Germany	On page 176 of the Annex XV Dossier of BPA/Equivalent Concern are uses described and an evaluation is given whether the use is within the scope of Authorisation. This evaluation requires refinement.
If BPA is used for manufacture of polymers like polycarbonate it is a use outside the scope of authorization (Titel VII) of REACH according to Article 2, (8).
In Article 3, (15) an intermediate is defined as a substance that is manufactured for and consumed in or used for chemical processing in order to be transformed into another substance. The substance BPA is transformed into another substance, e.g. the polymer polycarbonate, during the chemical synthesis.	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
2.		4806
2017/04/20	Merck KGaA,
Company,
Germany	p 176
On page 176 of the Annex XV Dossier of BPA/Equivalent Concern are uses described and an evaluation is given whether the use is within the scope of Authorisation. This evaluation requires refinement.

If a substance is used within scientific R&D this use is exempted from authorization by Article 56, (3).
Q&As 585 and 1030 provide further guidance on the scope of the exemption.

REACH Regulation
Article 56, (3)
“3. Paragraphs 1 and 2 shall not apply to the use of substances in scientific research and development. Annex XIV shall specify if paragraphs 1 and 2 apply to product and process orientated research and development as well as the maximum quantity exempted.”

https://echa.europa.eu/de/support/qas-support/qas
FAQ 585
FAQ 1030	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
1.				-		
3.		4807
2017/04/20	American Chemistry Council,
Industry or trade association,
United States	Since formatting and footnotes may be lost in the comments submitted through the text box, a complete set of comments is provided in the attached file. This file contains all submitted information along with a cover letter.	Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 of the RCOM document.	
1.				Attachement: 
 		
1.		4808
2017/04/21	Individual,
China	All material provided to the customer does not contain the above substances
	Noted.	
4.		4811
2017/04/21	GIFAS,
Industry or trade association,
France	Please refer to attached document ref.N°20004/17/GIFAS (The content of the PDF is reproduced below (please refer to the PDF for appropriate layout and footnotes)):

Dear Sir,
The European Chemicals Agency published a proposal to identify two chemicals as Substances of Very High Concern including 4,4’-isopropylidenediphenol (Bisphenol A/ BPA, CAS n° 80-05-7) for its endocrine disrupting properties (Article 57(f) - human health).	Thank you for your comment. Responses are provided below:	
5.				Bisphenol A has already been included in the candidate list since January 2017 for its toxic for reproduction properties (Article 57c). In the frame of the related consultation in 2016, the French Aerospace Industries Association (GIFAS)1 provided comments on the intermediate use of Bisphenol A for manufacturing reaction products in the field of aeronautics and space applications.
These comments were the following:
 The direct usage of Bisphenol A in aerospace and defence industry is rather low, only some special products, especially hardeners, are of concern and already subject to substitution processes. In some products the presence of Bisphenol A is an impurity by the used raw material. We are in intensive contact with our suppliers in the chemical industry to improve the situation in these cases.
 However, there is a huge concern about the usage of Bisphenol A in the chemical industry. This substance is a vital raw material for the production of epoxy compounds and Polycarbonate.
 Epoxy compounds manufactured from Bisphenol A, mainly Bisphenol A diglycidyl ether (BADGE or DGEBA2, CAS n° 1675-54-3) and the pre-polymerised product Bisphenol A diglycidyl ether resin (CAS n° 25068-38-6) are vital for a large range of applications, including but not limited to:
- Epoxy resins for composite materials for structural components (weight reduction and CO2 emission saving),
- Epoxy Adhesives for modern manufacturing techniques,
- Epoxy Paints and varnishes for product durability.
 Polycarbonate is a high valued construction material for windows and other transparent objects with excellent properties for these to function in harsh environments such as high altitude or combat situations. Parts produced out of polycarbonate include: windows for airplanes, covers for position lights, personal protection equipment for civil and military usage (e.g. helmet visors), electrical insulation, modern communication with optical technology.	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
6.				In the frame of the current consultation, as the Endocrine disrupting properties (Article 57(f) - human health) criteria are currently not agreed upon within the European Commission, the demonstration of safe use for authorisation may be difficult not knowing the acceptance criteria.
For this substance, the restriction appears as a better risk management option, (as processed for the thermal paper) and permits to ban the only relevant consumer exposure. For our industry, we would like to draw your attention to the negative impact in case of potential unavailability of these essential materials.
We remain at your disposal for any information you may require.
Yours faithfully,
Pierre-Stéphane BENATI
Leader of GIFAS REACH Working Group
of the GIFAS Environment Commission	We take note of this comment although it is not directly relevant for SVHC identification which is based on the intrinsic properties of the substance. Risk management options will be addressed at the next steps.	
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7.		4813
2017/04/21	CHEM Trust,
National NGO,
United Kingdom	Chapter 6.3: The following article could additionally be used as supportive information in the context of a reduced quality of life under Chapter 6.3.2 Assessment of equivalent level of concern.
J.R. Rochester: Bisphenol A and human health: A review of the literature, Reproductive Toxicology, Volume 42, December 2013, Pages 132–155,  http://dx.doi.org/10.1289/ehp.1408989 	Thank you for your comment. We acknowledge that the ED related effects of BPA may be wider than those described in the Annex XV dossier. Rochester’s review illustrates very well the range of effects that may be at stake on the basis of recent human studies. The link with a potential ED MoA is however not discussed and is of limited relevance in this regard. 	
					
8.		4815
2017/04/21	HUNTSMAN,
Company,
Belgium	Please refer to the PDF document attached. Thank You	Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 of the RCOM document.

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
1.				Attachment:
		
9.		4816
2017/04/21	Individual,
Spain	In page 128 when commenting about Alonso-Magdalena et al 2010, the summary says “ The authors noted that bromodeuxyuridine.......incorporation into insulin producing beta cells was reduced, yet their surface was unchanged”. The phrase ...”yet their surface was unchanged.” must be a mistake and should be deleted.
Following the same paragraph: “However, the latter results, although very likely, should not be considered with caution, since they were obtained with cultured cells from exposed individuals. Therefore, taking into account isolation and culturing methods, cultured cells have different phenotypes than in situ cells”.
It is important to note that we used instant analysis after rapid fixation and treatment of the tissue (Pancreata were removed from F1 mice at the time of sacrifice (6 months of age) and fixed overnight in 4% paraformaldehyde. Subsequently, pancreatic tissue was embedded in paraffin, and 5-µm sections were prepared). Therefore, this analysis should be considered relevant.	Thank you for your comments. Based on your explanations as an author of the publication, we agree to delete the second part of the sentence “yet their surface was unchanged.” And also the end of the paragraph   : “However, the latter results, although very likely, should not be considered with caution, since they were obtained with cultured cells from exposed individuals. Therefore, taking into account isolation and culturing methods, cultured cells have different phenotypes than in situ cells”.	
10.		4817
2017/04/21	Stichting Wemos,
National NGO,
Netherlands		Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 and 3 of the RCOM document.	
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1.		4820
2017/04/21	PC/BPA Group of PlasticsEurope cosigned by BPA REACH Consortium and Epoxy Resins Committee of PlasticsEurope ,
Industry or trade association,
Belgium	Attachement: 
	Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 and 3 of the RCOM document.	
11.		4823
2017/04/23	Health and Environment Alliance (HEAL),
International NGO,
Belgium	This dossier is clearly carefully constructed. It contains an impressive amount of relevant information regarding the MoA of BPA actions to substantiate the link between BPA exposure and adverse effects on (female) fertility, mammary gland development, cognitive function and metabolism. Additional information has been provided by the rapporteur on data gaps and uncertainties that were noted in previous assessments and evaluations of BPA, for example by RAC and EFSA.

The Annex XV report provides convincing evidence that BPA is able to disrupt estrogenic pathways, consequently leading to adverse effects on reproductive function, mammary gland development, cognitive function and metabolism. The ultimate effect depends on the timing of exposure, but all four health effects can be considered irreversible and serious and leading to reduced quality of life. The societal concern is indisputably demonstrated, and given the effects, is clearly of equivalent concern to carcinogenicity, mutagenicity and reproductive toxicity.

Therefore, HEAL fully agrees with the rapporteur that BPA should be identified as an SVHC according to article 57(f) for effects on human health exerted through an ED MoA.	Thank you for your support.	
1.				-		
12.		4824
2017/04/23	Individual,
United States	I appreciate the opportunity to provide feedback on this report. Overall, I found it to be well-researched, well-written, and provide a balanced view of the published literature. As noted in my comments below, the conclusions this review draws about the effects of BPA on the mammary gland are similar to conclusions that have been drawn by others. This subset of data are strong and consistent, and this consistency is even more striking considering the different animal models (mouse, rat, rhesus monkey), strains, doses, routes of exposure, and windows of exposure that have been evaluated.
Considering the strength of the data, and the conclusions reached by a number of different groups of experts, it is clear that there is scientific consensus that BPA alters the developing mammary gland. Based on mechanistic studies, including in vitro evaluations of mammary epithelial cells and 3D cultures, it is clear that BPA acts as an endocrine disruptor. As the report notes, BPA’s actions as an estrogen have been known since the 1930s (pg 21) and only more recently, through the development and use of modern molecular techniques, have studies revealed the more complex pathways altered by this compound. In a review of more than 300 compounds, an analysis conducted by the US EPA found that BPA had the third highest toxicological profile index (ToxPI) score, indicative of its ability to bind to many different receptors (Reif DM, et al. Endocrine profiling and prioritization of environmental chemicals using ToxCast data. Environ Health Perspect 2010;118(12):1714-20). The endocrine disrupting effects of BPA have been documented at length by a number of experts including the UNEP/WHO (UNEP/WHO. State of the science of endocrine disrupting chemicals - 2012. An assessment of the state of the science of endocrine disruptors prepared by a group of experts for the United Nations Environment Programme (UNEP) and WHO, available from: http://www.who.int/iris/bitstream/10665/78101/1/9789241505031_eng.pdf), the Endocrine Society (Diamanti-Kandarakis E, et al. Endocrine-disrupting chemical: an Endocrine Society scientific statement. Endocr Rev 2009;30:293-342; Gore AC, et al. EDC-2: The Endocrine Society's Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocr Rev 2015;36(6):E1-150), expert panels assembled by the US National Institutes of Health (vom Saal FS, et al. Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod Toxicol 2007;24(2):131-8; Vandenberg LN, et al. Low dose effects of Bisphenol A: An integrated review of in vitro, laboratory animal and epidemiology studies. Endocrine Disruptors 2013;1(1):e25078; Peretz J, et al. Bisphenol a and reproductive health: update of experimental and human evidence, 2007-2013. Environ Health Perspect 2014;122(8):775-86; Seachrist DD, et al. A review of the carcinogenic potential of bisphenol A. Reprod Toxicol 2016;59:167-82), and expert evaluations conducted for the European Commission (Kortenkamp A, et al. State of the Art Assessment of Endocrine Disruptors, Final Report. Brussels: European Commission, 2011 available from: http://ec.europa.eu/environment/chemicals/endocrine/pdf/ sota_edc_final_report.pdf), among others (Vandenberg LN, Colborn T, Hayes TB, et al. Hormones and endocrine-disrupting chemicals: low-dose effects and nonmonotonic dose responses. Endocr Rev 2012;33(3):378-455). Thus, it is widely accepted and acknowledged that BPA is an endocrine disrupting chemical.
With regard to the effects of BPA on the developing mammary gland, we evaluated the entirety of published data on this topic in 2013 (Vandenberg LN, et al. Low dose effects of Bisphenol A: An integrated review of in vitro, laboratory animal and epidemiology studies. Endocrine Disruptors 2013;1(1):e25078), and drew similar conclusions to those described in this report. Based on studies available at that point, we noted five studies that demonstrated a causal link between BPA and preneoplastic and neoplastic lesions, and four additional studies demonstrating that low dose BPA exposures increase the response of the mammary gland to carcinogenic challenges later in life. We noted striking consistency across studies conducted in different laboratories, using different species, strains, doses, and routes of exposure. We drew the conclusion that there is strong evidence for adverse effects of BPA on this organ.
I note a few errors or omissions in the Annex XV report with regard to the mammary gland studies that were reviewed. These are described below.

1) There are two different studies with Markey as the first author that examined the mammary gland:
• Markey CM, Luque EH, Munoz De Toro M, et al. In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland. Biol Reprod 2001;65(4):1215-23. This was the first study to describe effects of perinatal BPA exposure on the developing mammary gland. Mammary glands were evaluated in developmentally exposed female mice on postnatal day 10, postnatal day 30, and 6 months of age. The most striking effects of BPA were observed in adulthood, where BPA-exposed females had phenotypes consistent with early- or mid-pregnancy.

• Markey CM, Coombs MA, Sonnenschein C, et al. Mammalian development in a changing environment: exposure to endocrine disruptors reveals the developmental plasticity of steroid-hormone target organs. Evolution and Development 2003;5(1):67-75. This manuscript provides a follow-up to the animals evaluated in the 2001 study. Here, animals exposed during the perinatal period were maintained until 9 months of age, and a number of organs including the mammary glands were evaluated.

A third study is cited in the text, and this study focused on the effects of BPA on the female reproductive tract rather than the mammary gland.

• Markey CM, Wadia PR, Rubin BS, et al. Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract. Biology of Reproduction 2005;72(6):1344-51. This study characterized the effects of developmental BPA exposure on the adult uterus.

2) The doses evaluated in the Markey studies were 25 and 250 ng/kg/day, not 25 and 250 μg/kg/day. The correct doses were published in errata. Thus, based on these studies, the LOAEL dose for mammary gland effects is not 25 μg/kg/day, but 25 ng/kg/day. For effects related to preneoplastic lesions, the LOAEL dose is 250 ng/kg/day. A NOAEL has not yet been identified.

3) The review of the Acevedo 2013 study is incomplete, and does not mention that carcinomas (and not just neoplasias) were observed in BPA-treated animals. Although the incidence of these carcinomas was not statistically significant using a Chi Square test, it cannot be ignored that these carcinomas are exceedingly rare in this rat strain and were only observed in BPA-treatment groups.

4) The report should consider including one of our studies showing that BPA exposures also alter development of the male mammary gland.

• Vandenberg LN, Schaeberle CM, Rubin BS, et al. The male mammary gland: a target for the xenoestrogen bisphenol A. Reprod Toxicol 2013;37:15-23.	Thank you for your support.

Reference from Markey et al., 2001 is now added in the ref. list and quoted in the relevant paragraph.

Reference from Markey et al., 2003 is now added in the ref. list. 

Reference from Markey et al., 2005 has now been removed from the mammary gland section.

Thank you for this comment. However, since we did not identify this Errata, we are not in a position to amend the supportive document accordingly.

Table 16 of the SVHC report, already mentioned neoplasia as well Ductal Carcinoma in situ (DCIS). The further information is now added. 

The report has been amended accordingly.
	
			-		
13.		4832
2017/04/24	ClientEarth,
International NGO,
United Kingdom	Attachement: 
	Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 of the RCOM document.	

Table 2 - Specific comments on the justification
Reference number	Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
14.		4807
2017/04/20	American Chemistry Council,
Industry or trade association,
United States	Comments of the American Chemistry Council
on the Proposal for Identification of a Substance of Very High Concern
On the Basis of the Criteria Set Out in REACH Article 57
Substance Name:  Bisphenol A
Submitted by France on February 3, 2017	Thank you for your comment. Responses are provided below:	
15.				1. Executive Summary of Comments
On February 3, 2017, the French Member State Competent Authority (MSCA) submitted an Annex XV dossier  to the European Chemicals Agency (ECHA).  The dossier proposes to identify bisphenol A (BPA) as a Substance of Very High Concern (SVHC) based on the criteria set out in REACH Article 57.  The dossier was released by ECHA for comments from interested parties on March 9, 2017.  These comments are responsive to that request. 
The dossier proposes to identify BPA as an SVHC on the basis that it meets the requirements of Article 57(f) due to endocrine disrupting properties of BPA.  Consistent with that basis, the dossier extensively discusses various scientific aspects of BPA that are relevant to endocrine disruption.
However, endocrine disrupting properties per se do not provide an adequate basis to conclude that any substance is an SVHC.  The dossier confuses endocrine disrupting properties with the operative requirements of Article 57(f).
The actual operative requirements of Article 57(f) are 1) scientific evidence of probable serious effects and 2) an equivalent level of concern to substances identified in Article 57(a)-(e).  These requirements are independent from endocrine disrupting properties, and all substances considered under Article 57(f) must meet these requirements regardless of whether a substance does or does not display endocrine disrupting properties.
As discussed in detail in the comments below, the dossier fails to make the case that BPA meets the operative requirements of Article 57(f).  In fact, upon close examination, it is clear that the dossier argues against itself by explicitly referring to European authoritative bodies that have independently evaluated the scientific evidence with standards comparable to those in Article 57(f).  The conclusions of both the European Food Safety Authority (EFSA) and the ECHA Risk Assessment Committee (RAC) clearly do not support a conclusion that BPA meets the operative requirements of Article 57(f), which requires “scientific evidence of probable serious effects” and “an equivalent level of concern.”
For these fundamental reasons, the proposal to identify BPA as an SVHC on the basis of endocrine disrupting properties should be rejected by the Member State Committee.	A sufficient level of evidence has been used as a strict condition for selection of the adverse effects of BPA to be considered for their ED MoA in the Annex XV dossier. It was indeed considered that an adverse effect is identified with a sufficient level of evidence when acknowledged in previous regulatory EU discussions, i.e. by either a harmonised classification or by consideration of the effect in the process of risk assessment by RAC in the context of restriction.
For the effects selected, the database supporting the identification of the adverse effect is described and discussed in dedicated sections (4.2.2, 4.3.3, 4.4.2, 4.5.2.1 and 4.5.3.1, respectively).
We agree that the substance also has to show an Equivalent Level of Concern (ELoC) to fulfill the SVHC criteria according to Art 57(f) and the Annex XV report discusses in detail in section 6.3.2 (in conformity with the Annex XV template) how BPA fulfils an ELoC.

Every requirement of article 57(f) is therefore fully addressed in the dossier and is met by BPA.	
16.				2. Article 57 Sets High Standards To Identify A Substance As An SVHC
a. The High Standards Of Article 57(a)-(e) Are Explicitly Described
The requirements for identifying a substance as an SVHC under Article 57(a)-(e)  are readily apparent from the straightforward language of the regulation.  Sections (a)-(c) precisely identify CMR substances in hazard class categories 1A or 1B as substances that may be included in Annex XIV.  Similarly, sections (d)-(e) precisely identify substances with certain persistent and bioaccumulative properties as substances that may also be included in Annex XIV.
In each of sections (a)-(c), a high standard is set for identification of a substance as an SVHC.  Category 1A sets a high standard for “known” hazards and is based primarily on human evidence.  Category 1B for “presumed” hazards sets an equally high standard that can be based largely on animal evidence.
Importantly, Article 57 does not authorize substances with CMR hazard category 2 to be identified as SVHCs.  Category 2 refers to “suspected” hazards with limited evidence, which is not sufficient under Article 57(a)-(c).
b. The Operative Requirements Of Article 57(f) Build On The High Standards of Article 57(a)-(c) With Equally High Standards
Article 57(f) specifies that substances 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 sections (a)-(c) may also be identified as SVHCs.  The two operative requirements of Article 57(f) are thus: 1) scientific evidence of probable serious effects and 2) an equivalent level of concern.
“(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 fulfil 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 59.” (emphasis added)
The explicit reference to sections (a)-(c) indicates that the same high standard applied to substances identified in sections (a)-(c) also applies to substances identified in section (f).  Application of the same high standard is reinforced by the explicit requirements for evidence of probable serious effects (i.e., not suspected) and an equivalent level of concern (i.e., not a lower level of concern).  Article 57(f) does not set a lower standard of evidence to identify a substance as an SVHC compared to Article 57(a)-(c).
c. Endocrine Disrupting Properties Are Not An Operative Requirement of Article 57(f) Per Se And Cannot Be Used As The Criterion To Identify An SVHC
Substances with endocrine disrupting properties are mentioned as examples (i.e., “such as”) of substances that may be considered in Article 57(f).  The examples provided are not exclusive (i.e., other unnamed types of substances might be considered) and classification of a substance as having endocrine disrupting properties is not specifically required or sufficient to identify a substance as an SVHC under Article 57(f).  Endocrine disrupting properties are not an operative requirement of Article 57(f) and may not be used as the criterion to identify an SVHC.
For example, ECHA has previously published a discussion paper on factors to consider for evaluation of sensitizers as SVHCs under Article 57(f).   One of the two key considerations to identify a sensitizer as an SVHC explicitly refers to meeting the criteria of Article 57(a)-(c), indicating that the requirements of these sections serve as a benchmark for evaluation of other substances.
“Assessment of the hazard properties of the substance and comparison of their potential impact on health and other factors and additional considerations with the impacts potentially elicited by carcinogenic, mutagenic or reprotoxic substances meeting the criteria of Article 57 (a-c).” (Footnote 4, page 2)
The discussion paper further notes that classification of a sensitizer is insufficient to identify the substance as an SVHC.  Instead, the operative requirements of Article 57(f) must be met.  Formal classification is not required although it is recommended, which again indicates that the same high standards applicable to “known” or “presumed” CMR substances are also applicable to identification of other substances under Article 57(f).
“Therefore, classification of a substance as a sensitiser in itself is not enough in order to identify it as a SVHC under article 57(f). The substance must also be of ‘equivalent level of concern’.  It is recommended that any SVHC identification of sensitisers under article 57(f) should only be undertaken for substances already classified as sensitisers however” (Footnote 4, page 2)
Accordingly, substances with endocrine disrupting properties do not have any special status under Article 57; they are merely examples that reflect a current topic of interest.  All substances, including those with endocrine disrupting properties, must meet the same operative requirements identified above in order to be identified as an SVHC under Article 57(f).
Notably, the two operative requirements of Article 57(f) are independent of the definition of an endocrine disruptor.  Regardless of the definition, a substance must meet the operative requirements for probable serious effects and an equivalent level of concern in order to be identified as an SVHC under Article 57(f).	For each of the four effects included in the Annex XV dossier, we consider that the available experimental database provides sufficient evidence to identify an adverse effect. Uncertainties exist on the dose-response relationship as also emphasised by the RAC opinion on BPA’s restriction. However, for each effect, there are several converging studies showing an effect. Based on weight of evidence assessment of strengths and limitations of all studies available, induction by BPA of the four adverse effects described cannot be refuted. In absence of conclusive human studies but considering the relevance for humans of the effects observed on animals, these effects can be considered as “presumed” for humans. 

How these adverse effects of BPA are considered of ELoC is discussed in section 6.3.2. of the Annex XV dossier. ECHA’s 2012 discussion paper quoted by ACC in its comment recommends a list of factors to be considered in the ELoC assessments. In the absence of guidance, it is generally accepted that these factors (namely: type, irreversibility, and delay of health effects, impact on quality of life, societal concern, possibility to derive ‘safe concentration’ possible) constitute the high standards put forward by ACC in its comment. They constitute the framework of assessment of ELoC and Art. 57(f) requirements that has been used in the SVHC assessment of substances that were added since then in the candidate list for an ELoC for human health (cadmium compounds, ADCA). All of these factors are included in our ELoC analysis and ED-related effects of BPA give rise to concern on the basis of each of them.

Therefore, there is no basis that the high standard necessary for SVHC identification according to Art. 57(f) is not properly addressed in the Annex XV dossier and met by BPA as presented.	
17.				3. The Annex XV Dossier Does Not Support Identification Of BPA As An SVHC
a. Endocrine Disrupting Properties Are Not A Sufficient Basis To Identify An SVHC
The Annex XV dossier identifies four endpoints that are asserted to support identification of BPA as an SVHC.  Each of the four endpoints is discussed at length in the context of various endocrine-related aspects.  For example, the summary section begins with the paragraph shown below, which specifically relates these endpoints to an “endocrine disruptive pathway” and an “ED MOA” (endocrine disruptor mode of action).
“6.3.1 Summary of the data on the hazardous properties
This dossier has summarised the available evidence that BPA can affect a number of physiological functions and systems of mammalian organisms through an endocrine disruptive pathway. In particular, BPA can alter reproductive function, mammary gland development, cognitive function and metabolism through ED MoA.” (Annex XV dossier page 154, emphasis added)
But as noted above, endocrine disrupting properties are not an operative requirement of Article 57(f) per se and cannot be used as the criterion to identify an SVHC.  To be identified as an SVHC, the two operative requirements in Article 57(f) must be met, regardless of whether a substance does or does not have endocrine disrupting properties.
b. The Annex XV Dossier Does Not Make The Case That The Article 57(f) Operative Requirements Have Been Met
The Annex XV dossier is quite long with approximately 150 pages devoted to a discussion of the four endpoints.  As noted above, much of this discussion is in the context of reputed endocrine disrupting properties.
But looks can be deceiving and the reader should not be misled by the sheer length of the dossier.  If the discussion on endocrine disrupting properties is removed, it becomes clear that the extensive discussion on endocrine disrupting properties is little more than a distraction from the key question that must be addressed.  What remains simply does not make the case, based on the actual operative requirements of Article 57(f), that BPA is an SVHC.
In fact, what does become clear is that the dossier argues against itself.  As clearly documented by the authoritative European expert bodies to which the dossier itself points, the scientific evidence for BPA does not and cannot meet the operative requirements of Article 57(f).	Same argument, see our detailed response above.
Identification of the effects and its ED MoA was indeed addressed in detail as required by the size and complexity of the database. But the other SVHC requirement, i.e. ELoC, was also appropriately assessed.	
18.				4. Conclusions Of Authoritative European Bodies Do Not Support Identification Of BPA As An SVHC Under Article 57(f)
a. Both RAC And EFSA Have Evaluated The Scientific Evidence Relevant To Identification of BPA As An SVHC Under Article 57
The three health endpoints included in Article 57(a)-(c) are specifically covered by harmonized classifications for carcinogenicity, mutagenicity and reproductive toxicity.  Of the four endpoints discussed in the Annex XV dossier, only one is covered by a harmonized classification.
“It is noted that the three last effects are not acknowledged by an harmonized classification. … However, these additional effects were included in a previous restriction analysis and already discussed by RAC.” (Annex XV dossier, page 22)
However, as noted in the dossier, scientific evidence pertaining to the three additional endpoints was reviewed by RAC and documented in its REACH restriction opinion.   In fact, all four endpoints were reviewed and documented by RAC in its opinion.
The Annex XV dossier also notes that EFSA has reviewed the same scientific evidence in the same timeframe.  As discussed in the following sections, the views of EFSA and RAC are consistent and the conclusions of both authoritative expert bodies do not support a conclusion that BPA is an SVHC.
b. The RAC And EFSA Experts Applied High Standards Comparable To Those Of Article 57 In Their Reviews
As discussed above, Article 57 applies high standards for identifying a substance as an SVHC.  Specifically, according to Article 57(a)-(c), a substance must be “known” or “presumed” to cause one of the health effects covered in these sections.
As further discussed above, these same high standards are incorporated into Article 57(f) by explicit reference to Article 57(a)-(c).  The high standards are reinforced by the explicit language of the operative requirements of Article 57(f), in particular by setting requirements for “probable serious effects” and “an equivalent level of concern,” both of which are in reference to Article 57(a)-(c).  Conversely, Article 57(f) does not apply a lower standard for identifying a substance as an SVHC compared to the standards in Article 57(a)-(c).
The most recent EFSA review of BPA was published in January 2015.   The EFSA expert panel that conducted the review followed a systematic approach to evaluate all scientific evidence relevant to their mission of evaluating the human health risks from exposure to BPA.  Of particular relevance for identification of an SVHC under Article 57(f) is the first step in the risk assessment process, which is hazard identification.
EFSA applied a Weight of Evidence approach to evaluate all relevant scientific evidence to reach conclusions on whether BPA is associated with various health endpoints including the four endpoints raised in the Annex XV dossier.  Conclusions were summarized in the form of categories based on the overall experimental evidence for the endpoint.
For each endpoint examined, conclusions were categorized with a standard set of terms shown below.  EFSA stressed that these categories apply solely to BPA hazard identification and not to the assessment of human risks from BPA exposure.  Accordingly, the categories are directly relevant to consideration of BPA as an SVHC under Article 57(f), since that process is also hazard based.
Box 1. Set of standard terms used for expressing the overall likelihood in the WoE tables.
Likelihood
Very likely
Likely
From “-as likely as not- to likely”
As likely as not
From “unlikely to –as likely as not-”
Unlikely
Very unlikely
(EFSA Opinion, page 15)
From the terminology used by the EFSA experts, it is apparent that the category “very likely” is comparable to the “known” and “presumed” categories used for Article 57(a)-(c) for human and animal evidence, respectively.  The high standards applied in Article 57 would not be met by the remaining categories with decreasing likelihood.
The RAC experts also reviewed the same scientific evidence and documented their opinion in 2015.5  As discussed in the next section, the RAC opinion presents its own independent evaluation of the scientific evidence in detail and also notes where the RAC and EFSA experts agree/disagree.
c. The RAC And EFSA Experts Agree That The Evidence Does Not Satisfy The High Standards Of Article 57(f) For Identification Of Bisphenol A As An SVHC
As noted above, the EFSA experts summarized their conclusions on the likelihood of various health endpoints in categories from “very likely” to “very unlikely.”  Similarly, the RAC experts summarized their conclusions and noted whether their conclusions agreed or disagreed with the EFSA expert conclusions.  The EFSA category conclusions and the RAC statement on agreement with EFSA for the four endpoints in Annex XV are summarized in the table below.
Annex XV Endpoint EFSA 2015 RAC 2015
Reproductive function As likely as not  Agrees with EFSA
Mammary gland development  Likely  Agrees with EFSA
Cognitive function As likely as not  Agrees with EFSA
Metabolism As likely as not  Agrees with EFSA

It is very clear from this summary that the conclusions of the EFSA experts and the RAC experts do not support a conclusion that the scientific evidence meets the stringent standards of Article 57(f) for identification of BPA as an SVHC.  At best, the health endpoints identified in the Annex XV dossier might be considered as “suspected,” which is not sufficient to identify BPA as an SVHC according to Article 57.	Regarding EFSA’s assessment, it is noted that the category of likelihood called “as likely as not” corresponds to a probability range from 33% and up to 66% (as defined in the Table 59 of the EFSA’s Scientific Opinion – Part II) and therefore encompasses effects with very different level of evidence. We consider that these effects deserve consideration.

In addition, it is also emphasised that EFSA’s assessment was published in 2015 on the basis of the literature collected up to December 2012 and some additional studies up to March 2014 (closing date of public consultation of Part II). However, a substantial number of publications were published very recently: when looking at studies listed in the summary tables for each endpoint, a significant proportion was published in 2013 or later: 27% for alteration of cycles, 37% for effects on the mammary gland, 56% for alteration of learning and memory and 81% for metabolism. Although not all studies report effects of BPA, altogether they provide further support to the effects.

More importantly, RAC has adopted in March 2014 (https://echa.europa.eu/documents/10162/777918ff-33b5-46ff-be89-2bdc406d34fa) an opinion to classify BPA in category 1B for reproductive toxicity – adverse effect on sexual function and fertility (“Presumed human reproductive toxicant”). There is therefore no doubt that this effect is established with a sufficient level of evidence that satisfies high standards.

It also illustrates very well that RAC’s later agreement with EFSA conclusions relates to the consideration of the effects as a basis for risk assessment and not only to identification of the effect per se. These conclusions were indeed produced in the context of RAC’s opinion on BPA restriction (ECHA, 2015) and not on classification. Our understanding is that RAC concurs in particular with EFSA’s assessment that these endpoints cannot be used as starting point for DNEL derivation considering uncertainties on the dose-response. The exact quotes of the conclusions of RAC are as follows:
-Female reproductive system (page 11): “RAC in principle agrees with EFSA’s conclusion on effects on the female reproductive system. Since effects on the reproductive system have been observed at and below the range where kidney effects occur, RAC considers it prudent to take them into account in hazard and risk assessment and in health impact assessment. RAC however acknowledges that the available information does not allow a quantification of the dose-response relationship and therefore this endpoint will be accounted for in the setting of Assessment Factors.” [emphasis added]
- Mammary gland (page 16): “RAC agrees that BPA has been shown to have a proliferative effect on mammary tissue at doses below the doses causing general toxicity (such as kidney weight changes).
RAC in principle agrees with EFSA’s conclusion on mammary gland effects. The effects on mammary gland development should be taken into account in hazard and risk assessment and in health impact assessment. In line with EFSA (2015), no individual study is however considered robust enough by RAC to serve as critical study for the identification of a starting point for DNEL derivation. Therefore the effects will be accounted for in the setting of Assessment Factors.”
- Brain and behaviour (page 10-11): “RAC in principle agrees with EFSA’s conclusion on effects on brain and behaviour. Since effects on brain and behaviour have been observed at and below the range where kidney effects occur, RAC considers it prudent to take them into account in hazard and risk assessment and in health impact assessment. RAC however acknowledges that the available information does not allow a quantification of the dose-response relationship, therefore this endpoint will be accounted for in the setting of Assessment Factors.”
- Metabolism (page 12): “RAC in principle agrees with EFSA’s conclusion on metabolism and obesity. Although RAC is of the opinion that the studies described are not sufficiently convincing for quantifying the dose-response, RAC considers it prudent to take the metabolic effects into account in hazard and risk assessment (by accounting for them in the setting of Assessment Factors) and in health impact assessment.”
RAC has therefore acknowledged the four effects included in the Annex XV dossier. 	
19.				d. Ongoing Research To Be Reported Soon Will Extinguish Remaining Uncertainties
As discussed above, the EFSA and RAC opinions on BPA were both published in 2015.  Although research on BPA has continued since that time, studies published since 2015 do not by themselves, or in combination with previous studies, support identification of BPA as an SVHC under the high standards of Article 57.
However, significant new information that will be of high relevance to consideration of BPA as an SVHC will be available in the near future.  Starting about 6 years ago, the U.S. Food and Drug Administration (FDA), in conjunction with the U.S. National Toxicology Program (NTP), designed a robust research program to answer key scientific questions and resolve uncertainties about the safety of BPA.
The program was intended to provide a sound scientific basis for FDA’s regulatory decisions on BPA, but the results will be equally relevant for regulatory decisions worldwide.  In fact, EFSA plans to reevaluate BPA in the near future, primarily based on the results from this program.
To date, FDA scientists have published 20 studies in the peer-reviewed scientific literature.  Included are a series of pharmacokinetic studies, which evaluate what happens to BPA when it enters the body and its potential to cause toxicity.  In addition, NTP scientists have published a high-quality human pharmacokinetic study to confirm in humans what has been learned from the series of studies on laboratory animals.
Most recently, FDA scientists published the largest toxicity study ever conducted on BPA.  Notably, no effects were found at any of the seven low doses examined, which are of most importance for evaluating BPA.  These results confirm the prediction from the pharmacokinetic studies that BPA is expected to have low toxicity.  The results also provide no support for the proposal that BPA is an SVHC under Article 57(f).
Overall, the studies build on one another to provide a comprehensive understanding of the potential hazards and risks of BPA.  Now nearing completion by FDA scientists is a chronic toxicity study that will determine whether BPA presents any hazards with exposure over a full lifetime.    The results of this study, known as CLARITY-BPA, are expected later in 2017.  The results will provide highly relevant information for consideration of BPA as an SVHC as proposed in the Annex XV dossier and should be included in this and any future consideration of BPA as an SVHC.
5. Conclusions
For the reasons discussed above, the Annex XV dossier proposing to identify BPA as an SVHC on the basis of endocrine disrupting properties should be rejected by the Member State Committee.  Endocrine disrupting properties per se do not provide an adequate basis to conclude that any substance is an SVHC.
The dossier fails to make the case that BPA meets the operative requirements of Article 57(f), which are 1) scientific evidence of probable serious effects and 2) an equivalent level of concern.  These requirements are independent from endocrine disrupting properties, and all substances considered under Article 57(f) must meet these requirements regardless of whether a substance does or does not display endocrine disrupting properties.
The dossier also argues against itself by explicit reference to European authoritative experts that have independently evaluated the scientific evidence with high standards comparable to those established by Article 57(f).  The conclusions of both EFSA and RAC clearly do not support a conclusion that BPA meets the operative requirements of Article 57(f) as proposed by the Annex XV dossier.
Based on the information provided in the Annex XV dossier and the comprehensive reviews conducted independently by EFSA and RAC, it is clear that BPA does not and cannot meet the high standards set by Article 57 for identification as an SVHC.

	As mentioned above, additional recent studies were included in the weight of evidence and several of them provide additional support for the identification of the adverse effects.

We are aware of the on-going studies performed under the CLARITY-BPA program. The first results obtained in the CLARITY-BPA study have been considered and discussed in the Annex XV dossier: 

-	Johnson et al. (2016) is included in the neurobehaviour section and provides indications of a reduced performance in learning/memory in the Barnes maze.

-	Delclos et al. (2014) is discussed in the reproductive toxicity, the mammary gland and the metabolism sections. 
It is noted that this study presents an important shortcoming related to low dose investigation. Examination of the internal dosimetry detailed in the paper of Churchwell et al. 2014 reveals that the controls (both naïve and vehicle) show some degrees of internal exposure to BPA and that in some instances it can be as high, or even higher, than the low dose groups. For example at PND21 and PND80, BPA aglycone in the vehicle controls was in average similar to the level recorded in the 80 µg/kg/day dose group. At the same time, it appears that total BPA maximal concentrations (aglycone + gluc) seemed to be linearly correlated to the doses between 25 µg/kg/d and 300 mg/kg/day, while they were very similar between controls and the 2.5 and 8 µg/kg/d groups. It can be concluded that the negative controls are totally inadequate as compared to the low dose groups up to 80 µg/kg/day. Thus, from those data, it seems impossible to conclude that those low doses had no effect. 
Therefore, it is considered that this study is not sufficient to overrule effects observed in particular on the mammary gland at low doses in other studies. 
For female reproductive toxicity, increased incidences of abnormal cycles were observed at the highest doses from 100 mg/kg. 
The study did not specifically deal with metabolism and obesity as such. The effect on adipose tissue (reduction of mean weight) was confined to the highest dose tested in both males and females F1. 
Regarding clinical chemistry measured at post-natal day 90, in females, the 100,000 µg/kg bw/d dose significantly depressed cholesterol and triglycerides by 16 and 30%, respectively, but there was no effect on these endpoints at 300,000 µg/kg bw/d. Leptin was significantly decreased (56%) in the highest BPA dose group. In males, 100,000 µg/kg bw/d and 300,000 µg/kg bw/d reduced cholesterol by 16 and 21%.

Additional studies from the CLARITY program were mentioned during the public consultation. Some of them are not directly relevant as they do not address the endpoints described: neurobehavioural tests performed in Rebuli (2015) don’t address alteration of learning/memory. Patel (2017) reports results on ovarian histology and hormones but cyclicity was not reported.
The following studies were however relevant and added in the Support Document: Camacho (2015) on mammary gland and Arambula (2016) on gene expression in different brain areas.

Overall, it is however important to stress that the database that is already available for BPA is very substantial. The CLARITY-BPA program will provide an additional line of information but the conclusion on BPA’s effects needs to be based on all lines of evidence together in a weight of evidence approach, considering the strengths and limitations of each study. 
Although not all studies are consistent, a number of studies repeatedly report the effects of BPA on the four endpoints and it is considered the four effects are established with a sufficient level of evidence. An additional line of evidence is not expected to modify substantially a weight of evidence that is established on an important number of studies.	
			See the corresponding embedded attachment in table 1 of Part I:                                                                    4807_ACC Comments on Annex XV Dossier - April 20 2017.pdf		
20.		4808
2017/04/21	Individual,
China	All material provided to the customer does not contain the above substances	Noted.	
21.		4811
2017/04/21	GIFAS,
Industry or trade association,
France	Please refer to attached document ref.N°20004/17/GIFAS	Please see Table 1 for response to this comment	
1.				See the corresponding embedded attachment in table 1 of Part I: 4811_20004_LetterGIFAS-SVHC_Consultation_ECHA-April 2017_V4.pdf		
22.		4813
2017/04/21	CHEM Trust,
National NGO,
United Kingdom	CHEM Trust considers that the dossier is of very high quality, and provides good evidence for adverse effects mediated by an endocrine disrupting mode of action.

We agree that on the basis of the available evidence for effects on reproductive function, mammary gland development, cognitive function and metabolism, BPA can be considered to be an endocrine disruptor relevant for human health.

It needs to be recognised that the endocrine system includes many pathways, several of which converge, and there is often ‘cross-talk’ between the different pathways.  Therefore, many endocrine disruptors do not exhibit just ‘classical’ estrogenic or classical anti-androgenic actions but have different actions in different tissues. This means that data should be viewed as a whole, and it should not be unexpected to see effects related to oestrogen disruption and perhaps also thyroid disruption from exposure to one compound.

CHEM Trust considers that for a chemical to be called an endocrine disruptor there must be a plausible link between the adverse effects and the endocrine mode of action, and that this is fulfilled in the case of BPA.  It should not be necessary to fully elucidate the mechanisms of action, which could take decades and would require pointless animal testing.  Moreover, we consider that given the irreversible effects, the requirement that a SVHC designated under Article 57(f) must give rise to probable serious effects equivalent to those of a CMR substance is fulfilled.

In short, we concur with the conclusion of the rapporteur that it is generally considered that the effects of BPA result from complex mechanisms that are most probably interacting together. Not all of them are fully understood.  However, the overall database shows that an alteration of the regulation of estrogens is an essential pattern of the mode of action.	Thank you for your comment and support.	
			-		
23.		4815
2017/04/21	HUNTSMAN,
Company,
Belgium	Please refer to the PDF document attached . Thank You 
See the corresponding embedded attachment in table 1 of Part I:                                                                          
(The content of the PDF is reproduced below (please refer to the PDF for appropriate layout and footnotes)):

Response of Huntsman Corporation regarding the proposal for
identification of Bisphenol A as a substance of very high concern on
the basis of the criteria (endocrine disruption) set out in REACH
Article 57.
Executive summary
On the 9th March 2017 the French Member State Competent Authority (MSCA) proposed
identification of Bisphenol A (BPA) as a substance of very high concern on the basis of
criteria (endocrine disruption) set out in REACH Article 57.
Huntsman Corporation strongly disagrees with both SVHC proposals (reproductive and
endocrine disruption) from the French MSCA. This disagreement is based on the foundations
listed below:
1) Business continuity within the EU
2) Implementation of policy
3) Scientific weight of evidence
4) Business impact throughout the supply chain
5) Economic impact for Europe
The following document is the consolidated response of Huntsman Corporation to the
proposal.	Thank you for your comment. Specific responses are provided below.	
24.				Business continuity within the EU
The Annex XV process which may lead to the inclusion of substances on the Candidate List and prioritization under Authorisation brings severe uncertainty to the supply chain, particularly where end-use applications for the automotive and aerospace industries require a minimum of 5-10 years qualification time to replace existing products. These complex innovation projects require dedicated resources working hand-in-hand with customers. The current lack of predictability in the listing and prioritization process means such long-term projects cannot be started with the knowledge that alternative chemicals will not also be subject to risk management measures. The expected minimum 10 years qualification time would most probably accumulate to an indefinite amount of time needed to demonstrate that a possible technically acceptable alternative would be safe with respect to all the endpoints investigated for BPA.
Although many of the uses of BPA as an intermediate would be excluded from eventual Authorisation, the uncertainty and "labelling" of substances as SVHC is sufficient for many users to stop their activities in applications, even in strategic ones, which were proven safe for use and application. For many applications a technical alternative is not available, if a valid alternative were identified it is expected to take a minimum of 10 years to develop and qualify before a direct exchange could take place.
Coordination regarding risk management processes should be urgently reviewed to ensure that all risk management options, whether CLH, restrictions or Authorisations follow a linear process based on the conclusions of substance evaluation and be coordinated by ECHA.
Parallel processes for one substance of CLH, restrictions, authorisation, which allow a second Annex XV dossier to be proposed undermines the likelihood of proportionate and consistent risk management measures and prevent authorities from focusing on addressing the most important risks for society. It also undermines industry’s ability to invest in product innovation in collaboration with downstream industries.	The comment is noted. 
It is however not directly relevant in relation to the criteria for SVHC 57(f) identification which are exclusively based on the intrinsic properties of the substance.	
25.				Implementation of policy
Huntsman believes there is an inconsistent implementation of EU chemicals policy at national level and this is undermining the principles of the Single Market. During the REACH process it is clearly evident that a minority of Member States (Such as France proposing two SVHC intentions within 9 months for BPA) go beyond the interpretation of definitions and legislation.
The EU and its Member States should work hand in hand and take steps to build a Single Market for chemicals. This means avoiding unconstructive national initiatives which undermine economies of scale as well as the legal certainty which should come from a market of 500 million people.
As described previously, qualification time for alternative substances, new chemistries and products takes a minimum of 10 years without inclusion of the regulatory process of testing, hazard/risk assessment and evaluation. Potential alternatives to BPA-based epoxy (including acrylic-based epoxy) currently being investigated require different manufacturing process technologies, and have significantly higher prices than BPA-based epoxy.
On the one hand intermediate uses are in principle out of scope of any authorisation process. However this additional Annex XV report, combined with the inclusion of the manufacturing and use of polycarbonates in the list of uses in the scope of the former Annex XV report issued in August 2016 due to the classification of BPA as reprotoxicant, create a considerable amount of uncertainty on the legal status of intermediates, monomers and polymers, thus resulting in an unpredictable environment for strategic investments in the EU. Alternatives to BPA in polycarbonates are in the very early stages of being assessed. However, the vast majority of known alternatives have a similar if not less favourable hazard profile when compared to BPA1. Due to the numerous types of components involved across products (with each having its own set of functional requirements), it is likely that multiple alternative materials would have to be identified in order to meet the appropriate safety and technical requirements of each product. Replacement of epoxies using BPA as an intermediate, if possible, would take several years (for one product) to reach the regulatory approval stage, require major changes in infrastructure, supply chain and there would be significant impact on current technologies and composites.
SVHC proposals such as those made by France will impact on applications that contribute to the European Commission’s 2020 growth strategy goals e.g. low-carbon economy, climate/energy, sustainability in research and innovation. In addition, the current national initiatives to target certain industries using the REACH process is not constructive and proposals from one member state could potentially destabilise the economy of other member states whereby industry/substance specific businesses are located.	The comment is noted. 
It is however not directly relevant in relation to the criteria for SVHC 57(f) identification which are exclusively based on the intrinsic properties of the substance.	
26.				Scientific Weight of Evidence
Huntsman accepts that the molecular structure of BPA has similarity to estrogen, and scientific evidence indicates that the substance is able to interact with relevant nuclear receptors in in-vitro tests but these tests represent highly conservative, isolated scenarios without inclusion of in-vivo detoxification and metabolic processes. It is also well documented that the potency of BPA is 37,000 times less effective than estradiol and several orders of magnitude less potent than the synthetic human contraceptive diethylstilbestrol.
	The conclusion that BPA exerts ED-related effects relies on a weight of evidence in which interaction with receptors is only one part, non-decisive on its own.
It is correct to say that the affinity of BPA to some estrogen receptors is observed at high concentrations that cannot explain the effects observed in in vivo studies in particular at lower doses. However, the interaction of BPA with other receptors (extranuclear estrogen receptors, ERRγ, GPER) may explain the estrogenic effects of BPA at low doses as explained in the Annex XV dossier and as emphasized by several Scientists (see comments 4816 and 4822) and NGO (see comments 4833) in this public consultation.	
27.				Huntsman also agrees that based on scientific evidence exposure to BPA at high doses has adverse health effects in laboratory animals but sufficient real world exposure would not occur for humans. 
Huntsman strongly disagrees that there is sufficient high quality evidence identifying a plausible link between adverse effects and an endocrine mode of action specific to BPA in humans using realistic exposure scenarios.	Exposure considerations are of no relevance as SVHC is based on hazard identification and not risk assessment
In addition, there is a number of studies for each endpoint that also report effects at low doses, as discussed in section 6.3.2 of the Annex XV dossier, so that there is considerable uncertainty on dose-response and low dose effects cannot be dismissed.	
28.				A key point for consideration is the fact that between 2008 and 2015 the following key reports and conclusions were published regarding BPA:
1) U.S. Department of Health and Human Services, National Toxicology Programme, NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A, NIH Publication 08-5995, (2008)
2) Toxicological and Health Aspects of Bisphenol A, Report of joint FAO/WHO Expert Meeting, World Health Organisation, (2010)
3) US-FDA Hazard Assessment of Bisphenol A for use in food contact applications, USFood and Drug Administration Joint Emerging Science Working Group, (2014)
4) Scientific Opinion on the risks to public health related to the presence of Bisphenol A in foodstuffs, EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF), European Food Safety Authority, (2015)
The US NTP (2008) concluded minimal concern related to effects on the mammary gland and female puberty, negligible concern that exposure of pregnant women to BPA will result in fetal or neonatal mortality, birth defects, or reduced birth weight and growth in their offspring and finally negligible concern that exposure to BPA will cause reproductive effects in non-occupationally exposed adults and minimal concern for workers exposed to higher levels in occupational settings. The expert meeting of the World Health Organisation (2010) concluded no health concerns for the endpoints assessed, studies on developmental and reproductive toxicity in which conventional endpoints were evaluated and only identified effects at high doses, if at all. The conclusion of the US-FDA report (2014) is that an adequate margin of safety exists for BPA at current levels of exposure from food contact uses. EFSA (2015) also concluded that there are no health concerns for any age group from dietary exposure and low health concern from aggregated exposure. The CEF panel noted considerable uncertainty for non-dietary sources, whilst uncertainty around dietary estimates was relatively low.

In addition to the historical conclusions described above, a robust report from the U.S. National Toxicology Programme (CLARITY-BPA) is expected to be published between 2017 and 2018. EFSA and the US-EPA have publically announced that both organisations are taking a pragmatic approach and will re-evaluate BPA again when the results of the CLARITY-BPA project are available. This project will determine chronic effects of BPA exposure and investigate reproductive toxicity, neurobehavioural effects, immune dysfunction, metabolic disease, obesity, cardiovascular effects, thyroid effects and cancers associated with mammary glands, uterus and prostate. The results of this project will provide valuable scientific evidence in the areas of concern proposed by France (e.g. reproductive function, mammary gland development, cognitive function and metabolism).
As a consequence of the thorough review of literature conducted by the WHO, US-FDA, NTP and EFSA it is our scientific opinion based on all of the relevant data published prior to March 2015 that a consensus regarding the effects and safety of BPA had been agreed. However, following a review of the two recent SVHC proposals of France based on reproductive toxicity (30th August 2016) and endocrine disruption (9th March 2017) the competent authority has drawn upon historic publications pre-dating 2015 which were likely to be used in the conclusions of the WHO, US-FDA, NTP and EFSA.
Following a review of the new SVHC proposal from France it should be noted that in total Part 1 of the document references 440 publications. Only 11% of these publications are new (e.g. post 2015 EFSA conclusion) and specific to BPA, thereby indicating that this proposal has been submitted based on limited new evidence since the conclusion of EFSA. Huntsman believes that the SVHC proposals are premature and unjustified due to relying mainly on data that has (i) previously been assessed and considered (ii) presentation of limited new evidence specific to BPA and therefore minimal non-guideline data should not be used in isolation to drive regulatory decisions.
Although the FDA, EFSA, NTP and WHO plus other organisations have determined that BPA is safe at current exposure levels, the safety of BPA continues to be debated and is frequently used as the “poster-child” for political leverage and by scientific research groups to secure funding and publicity. This continuous debate acts as a catalyst driving conflicting messages to the public, industry and fuelling confusion.	It is noted that several of these reports and the NTP conclusions that are highlighted in ACC comments relate to risk considerations that are not relevant for SVHC consideration.

In addition, many of these reports and NTP (2008) in particular do not consider the recent considerable extension of the database. As discussed in a previous comment, a substantial number of publications were published very recently: when looking at studies listed in the summary tables for each endpoint, a significant proportion was published in 2013 or later: 27% for alteration of cycles, 37% for effects on the mammary gland, 56% for alteration of learning and memory and 81% for metabolism. Although not all were positive, they altogether provide further support to the effects.

Please also see our detailed response to comment 19 above in relation to the on-going studies performed under the CLARITY-BPA program.	
29.				Huntsman would like to take this opportunity to reassert our disagreement on the interpretation and use of some data and information in the SVHC process.
i) The proposal recommends questionable routes of exposure e.g. intradermal and intraperitoneal. This approach is considered to be outside the proposed uses. Oral exposure should be considered most appropriate
	Only one study was performed by intraperitoneal route and is presented for comprehensiveness but was not decisive for the conclusions.

The subcutaneous route has been used in a number of BPA studies because the daily dose can be controlled with greater accuracy. 
Compared to oral route, subcutaneous administration bypasses the digestive barrier and most importantly the enterohepatic circulation and first-pass effect. The data collected in rodents show significantly higher proportions of unconjugated BPA after subcutaneous administration compared to oral administration. 
Consideration of subcutaneous studies for risk assessment would therefore require dose correction.

However, other non-artificial routes of exposure such as the dermal route also bypass hepatic first pass. In addition, in rodents, and to a lesser extent in humans, the hepatic metabolism capacity in newborns is limited, resulting in a reduced hepatic first-pass effect. 

The subcutaneous route of exposure is therefore considered fully relevant for the purpose of the present analysis, that is hazard identification and MoA considerations, in particular when developmental or perinatal exposure is considered. 	
30.				ii) There is inconsistency of effects and discrepancies between studies. The proposal is biased and glosses over these unless a negative effect can be associated whereby it is then considered
	It is acknowledged in the Annex XV dossier that divergent results are reported across studies for all endpoints and these discrepancies were discussed. Most of the effects seem indeed to be highly sensitive to many factors across studies, including the level of doses, period of exposure, species, sex and strain differences. Due to variations in the combination of these factors in the different experimental studies available, as well as to variations in the endpoints investigated and sometimes to experimental limitations (limited group size), it is very difficult to capture the specific influence of each parameter on the effect. However, considering the respective limitations and strengths of the different studies available, as well as the reproducibility of effects in different studies for each endpoint, the toxicity of BPA has been established with a sufficient weight of evidence.

This is acknowledged by a harmonised classification in category 1B for reproductive toxicity (fertility) and by RAC’s conclusion not to dismiss the effects on mammary gland, brain and behaviour and metabolism in the context of BPA’s restriction proposal.	
31.				iii) Certain human/epidemiological studies considered to have serious methodological flaws have been used to draw a conclusion
	Human studies are fully relevant and were presented in the Annex XV dossier and discussed for their strengths and limitations. In particular, the difficulty to appropriately evaluate BPA exposure and potential bias are identified and none of them was decisive for the conclusions.
In absence of specific comments from Huntsman in relation to its assertion it is difficult to provide a more detailed response.
For none of the 4 endpoints investigated, epidemiological studies were considered conclusive. In vivo animal data provide the highest level of evidence of a causal link between BPA exposure and these effects which were also considered relevant for human. 	
32.				iv) There is no clear evidence of direct effects of BPA on human reproduction and a severe lack of data linking causality and effect
	The evidence of an effect of BPA on fertility and its relevance for humans is endorsed by its harmonised classification in category 1B for reproductive toxicity (fertility).	
33.				v) Many studies refer to the measurement of BPA in urine samples, whilst this may identify exposure, it simply indicates that BPA passes through the appropriate detoxification systems in-vivo. There is no evidence to claim that any residual BPA accumulates	See response to point iii) above. There is not any claim in the Annex XV dossier that BPA accumulates.	
34.				vi) Although the proposal aims to consider the quality of the available data using ToxRtool, the weight of evidence analysis within the proposal refers to substantial amounts of data that was not considered adequate (e.g. only those studies shaded in grey within summary tables were rated K1 or K2) it is recommended that only studies of appropriate quality are discussed
	We would like to clarify that studies that are not shaded in grey were not assessed with the ToxRtool. Therefore, it is not correct to say that they are not adequate.
It was not considered appropriate to score all the studies with ToxRtool. It was indeed considered most relevant to follow a weight of evidence (WoE) approach for the analysis. In addition, many studies are research publications. All provide an informative piece of information and every study was considered for its strength and limitations in the WoE analysis. 
ToxRtool was only used in a final step to confirm in a transparent way that the most informative (grey-shaded) studies supporting conclusions were reliable.	
35.				vii) The body of the proposal identifies effects related to BPA however, the doses at which these effects are evident are not discussed or related to expected human exposure levels, claims are made without clearly linking to the dose causing the response
viii) There is a strong focus on effects from high unrealistic exposure doses	See response above regarding exposure/risk considerations (comment 27).	
36.				ix) The proposal submitted relied heavily on a literature review by Rochester (2013)2 which we believe requires further quality assessment 

x) Research noted by Rochester (2013) was weighted towards plasma data collected from IVF and fertility clinics therefore focused on a specific cohort with limited reference to controls or global background plasma levels. This was also noted as a limitation of the studies reviewed	This publication is not used or even quoted in the Annex XV dossier. It is a review of epidemiological studies.

See also response to point v) above for comments on human studies. 	
37.				xi) Rochester (2013) cross references Caserta et al. (2013)3 and states that infertile women were significantly more likely to have detectable serum BPA and measured plasma concentrations of other substances (PFOS, PFOA, MEHP and DEHP) were not significant within the same patients. Rochester (2013) fails to note that MEHP was also found in a similarly high percentage of the infertile women when compared with BPA and therefore infertility could be correlated to MEHP exposure
xii) The publication of Rochester also references studies by Li et al (2010 a4, b5) measuring BPA in the urine of male workers within BPA and epoxy resin industries in China. The authors claim that sexual dysfunction correlated with measured BPA however, it is well known that air quality is poor and therefore the data should be considered invalid due to a lack of cause and effect. This information was also omitted by the dossier submitter.	Rochester, which is a review of epidemiological studies, is not cited in our dossier. 
Caserta is not cited in our dossier. This study is descriptive and did not take into account any specific counfounding factors. The exposure is based on a single spot measure. It reflects the 24h exposition prior to the sampling.  Therefore, this publication has not been included in our report, although it could have served our purpose: the percentage of women with BPA concentrations above the limit of detection is significantly higher in infertile women than in controls.

xii) the study of Li does not specify the air quality but it can be assumed that if workers were exposed to a relatively high concentration of BPA, there was no ventilation exhaust in place. There is no indication of the air quality in the factory. The unexposed workers come from the same city where the BPA-exposed workers were recruited. The selection of control factories is based on different criteria among which the fact that workers from the control factories were not exposed to known reproductive toxicants.
To have better representation, the control factories came from a variety of industries including construction material manufacturers, water supply factories, machinery factories, garment factories, a textile factory, manufacturers of electronics, machinery factories, fire stations and trade and commerce firms. 

Therefore, the air quality, although not assessed, is taken into account in a satisfying manner	
38.				xiii) Many claims within the proposal are based on speculation that requires the use of both adequate and inadequate data Huntsman has reviewed all available data and assessed the most relevant studies for BPA in the determination of a hazard classification. Huntsman remain of the opinion that the previous change in classification to Reprotoxic Category 1B6 was not supported by suitable scientific evidence. Huntsman disagrees that sufficient data is available and therefore disputes the proposal for identification of Bisphenol A as a substance of very high concern on the basis of the criteria (endocrine disruption) set out in REACH Article 57
Furthermore, associated risk management measures are sufficient to ensure the safety of workers and downstream users during industrial and professional operations and subsequently the product life cycle.	Noted.	
39.				Business impact throughout the supply chain
If possible to identify a suitable alternative to BPA for all epoxy systems the impacts on the supply chain would be two fold. This is due to epoxy systems being composed of two parts resin and hardener both of which utilise BPA. It is anticipated that replacement of BPA in epoxy hardeners would stimulate an increase in raw material costs between 30% and 500%. Alternatives for use in BPA based resins would require significant capital investment to modify or rebuild plants followed by extremely high qualification costs (several $10m) to qualify alternative resins across all markets where BPA epoxy is used today. This modification/rebuild and qualification would resonate throughout the supply chain.
Since there is currently no alternative epoxy resin with equivalent/comparable technical profile the increase in raw material costs cannot be estimated. The increased raw materials costs would exceed the costs estimated previously for replacement in the epoxy hardeners.
For each new substance developed, there would be significant European/global regulatory costs associated with registration and toxicology studies. The REACH process alone would be in the order of $0.5- $1M per substance.
In general terms epoxy resins would be replaced by more expensive and lower performing alternatives which have not yet been tested for health and environmental hazards, while the European Food Safety Agency (EFSA) and the US Food Safety Agency (FDA) have assessed BPA as safe for use in all current applications.
Since there is no current perspective of suitable technical alternative to BPA epoxy resins, any restricted use would result in the destruction of the associated business for Huntsman (resins and hardeners) across the European territory. Potentially 450 mio USD/ 800 FTE.	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
40.				Economic impact for Europe
It should also be noted that BPA based epoxy resins are used in products that help Europe tackle its most significant energy and environmental challenges. These resins play a role in supporting the development of alternative sources of energy and in the construction and transportation industries, where innovative products are helping customers conserve and use energy more efficiently contributing to sustainability in the EU. Moving away from these resins would impact the greater goals of the European Union in the following areas:
Wind energy
Moving to alternatives could include adverse effects on technical and economic feasibility of large/long wind turbine blades, which may mean contemporary wind turbine blades would have to become smaller. Moreover, reduced longevity of protective coatings on internal components and exposed parts would result in increases in operational and maintenance costs borne by the turbine operators.
Energy and electrical
A proportion of downstream users may be able to use alternatives in low voltage applications. This would not be the case in most medium and high voltage applications where there would be a loss of performance. Subsequently there would be a reduction in the lifetime of components, stimulating higher operating costs due to more frequent inspection and replacement. At worst, more frequent component failure will affect reliability of electricity supply and increase the likelihood of temporary blackouts. This would impose direct repair costs on electricity distribution companies.
Food sector
In food canning, the technical characteristics of alternatives is expected to result in reduced product shelf lives of the cans and hence their contents - likely to result in increased waste of food as producers and consumers throw away spoiled or out of date cans. This may also require modification of acceptable food lifetime standards in at least some canned produce and it is likely that certain food substances would no longer be canned. Sales of canned foods may decrease. Any alternative substances/techniques would also need to undergo the relevant safety tests, which could take decades to obtain knowledge equal to that currently available for BPA.
Water pipes and infrastructure
A consequence of the loss of epoxy products in this application is increased duration and frequency of repairs to water leaks or pipes. Epoxy resin are used within a repair ‘sock’ that is inserted into pipes providing a durable repair to breaks or cracks. The durability of BPA epoxy also protects from breaks/cracks or corrosion damage for longer periods. Many of these pipes are underground. Increased need for repairs and for excavation would impose additional costs on water companies.
Transport
Loss of epoxy resins is expected to lead to a loss of performance in specific components in aircraft, cars and marine vehicles. The range of components is diverse, however in broad terms, the implications include loss of resistance to environmental degradation/corrosion and effects on aircraft/car weights achieved through the use of composite components.
Aircraft Fuel and CO2 Emissions
A significant advantage of epoxy resins is the weight savings that can be achieved in aircraft without loss of strength and performance through their use in composite components. A loss of epoxy resins would adversely affect existing designs and would be likely to increase the weight of aircraft Airlines would face increased fuel costs and CO2 emissions would rise. For many manufacturers, significant costs would be associated with the need for new manufacturing plant to be set up to produce parts based on alternative materials
Automotive and CO2 Emissions
The use of epoxy resins contributes towards reduced weight and hence fuel consumption and CO2 emissions, alongside increasing operational life and reliability.	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
			See the corresponding embedded attachment in table 1 of Part I: 4815_HUN comments_French SVHC_ED_final.pdf		
41.		4816
2017/04/21	Individual,
Spain	Comments by Angel Nadal, Professor of Physiology, Miguel Hernández University of Elche, Spain, on the Proposal for Identification of 4, 4’ isopropylidenediphenol  (Bisphenol A /BPA) as a Substance of Very High Concern (SVHC)on the Basis of the Criteria Set Out in Reach Article 57
Having carefully read the dossier, I found it to give a balance perspective giving information of high quality selected by a clear methodology. Remarkably, it uses most of the information published in the scientific literature during these last years in a very balanced manner.
The dossier gives clear scientifically-based evidence that BPA acts through an endocrine mode of action. It is stated that BPA can work at low concentrations via extranuclearly located estrogen receptors, ERalpha and ERbeta, as well as through other receptors such as estrogen related receptor gamma (EERgamma) and the G-protein couple estrogen receptor (GPER). This is an important information that reveals how BPA can act at low doses (100pM-10 nM) having estrogenic effects. Different from the classic mechanism of binding to ERs and subsequently acting as transcription factors attaching to estrogen response elements in the DNA. These new extranuclearly located pathways activated by estrogens are known for years in the field of estrogen signaling. There are fully accepted by the scientific community.
The weight of evidence in cellular and animal studies, together with epidemiological studies, on reproductive function, mammary gland development, nervous system development and metabolic disorders highly indicate that BPA is an endocrine disruptor relevant for human health.
In the case of BPA there is a clear relation between adverse effects in lipid and glucose metabolism-involved organs of mice, and an endocrine mode of action.   Many details about the molecular mechanism used, particularly in pancreatic beta cells and in adipocytes (including human beta cells and human adipocytes) are already known.  I am aware that more details about mode of action are involved to explain the complex actions of BPA on energy balance and diabetes mellitus etiology. However, I consider that there is no need for further mechanistic details to identify BPA as a SVHC.	Thank you for your comments

Affinity of BPA to estrogen receptor is observed at high concentrations that cannot explain the effects observed in in vivo studies, in particular at lower doses. However we agree with your comment that the interaction of BPA with other receptors (extranuclear estrogen receptors, ERRγ, GPER) may explain the estrogenic effects of BPA at low dose as explained in the Annex XV dossier and as emphasized by several Scientists (see comments 4816 and 4822) and NGOs (see comments 4833) in this public consultation.	
			-		
42.		4817
2017/04/21	Stichting Wemos,
National NGO,
Netherlands	Wemos considers that the French dossier is of very high quality, and provides good evidence for adverse effects mediated by an endocrine disrupting mode of action.	Thank you for your support.	
1.				See the corresponding embedded attachment in table 1 of Part I:                                                                       4817_20170421 BPA tabel ECHA comments.pdf		
43.		4819
2017/04/21	Epoxy Resins Committee (PlasticsEurope),
Industry or trade association,
Belgium	Response of The Epoxy Resin Committee regarding the proposal for identification of Bisphenol A as a substance of very high concern on
the basis of the criteria (endocrine disruption) set out in REACH Article 57

Executive summary

On the 9th March 2017 the French Member State Competent Authority (MSCA) proposed the identification of Bisphenol A (BPA) as a substance of very high concern on the basis of the criteria (endocrine disruption) set out in REACH Article 57.

While the Epoxy Resin Committee (ERC) agrees with the aim of REACH to ensure a high level of protection of human health and the environment, and its regulatory measures to propose substances as “substance of very high concern” with the aim of substitution, the ERC strongly disagrees with both SVHC proposals (reproductive and endocrine disruption) for Bisphenol-A from the French MSCA.
This disagreement is based on the foundations listed below:

1) Implementation of policy
2) Scientific weight of evidence
3) Business continuity within the EU
4) Business impact throughout the supply chain
5) Economic impact for Europe

The following document is the consolidated response of the Epoxy Resin Committee to the proposal.	See answers given above to comments 24 to 40 made by Huntsman.

Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
44.				1) Implementation of policy
The ERC believes there is an inconsistent application of EU chemicals policy at national level and this is undermining the principles of the Single Market. During the REACH process it is clearly evident that a minority of Member States (such as France proposing two SVHC intentions and one restriction within 9 months for BPA) disregard the legal text of REACH Article 57. BPA should not be identified as an SVHC under Article 57(f) based on equivalent concern (ED to human health) when it has already been identified as an SVHC due to its classification as CMR (Article 57 (c)). Their initiatives take place while the RMOA resulting out of the German MSCA Substance Evaluation, the formal process for setting regulatory adequate measures, is still in progress.

Unpredictable and overlapping regulatory processes (substance evaluation, reclassification, RMOA, 3 ANNEX XV dossiers in 9 month for BPA) significantly increase insecurities on continuous use of BPA but also lead to confusion about the target of potential regulatory measures and therefore also violate potential substitution considerations within industries.

Coordination regarding risk management processes should be urgently reviewed to ensure that all risk management options, whether CLH, restrictions or authorisations follow a linear process based on the conclusions of substance evaluation and be coordinated by ECHA.
The EU and its Member States should work hand in hand and take steps to build a Single Market for chemicals. This means avoiding unconstructive national initiatives which undermine economies of scale as well as legal security within a market of 500 million people.

In addition, using the REACH process to target certain industries is not constructive and proposals from one member state could potentially destabilise the economy of other member states where industry/substance specific businesses are located.

Epoxy manufacturing is to a vast majority an intermediate use and intermediate use is out of scope of any authorisation process. Already the Annex XV report issued in August 2016 to propose inclusion of BPA into the candidate list, which included manufacturing and use of polycarbonates in the list of uses in scope, created a considerable amount of uncertainty on the legal status of intermediates, monomers and polymers. This additional Annex XV report adds further to an unpredictable environment for strategic investments in the EU.

Replacement of epoxy products using BPA as an intermediate, if possible, would take several years (for one product) to reach the regulatory approval stage, require major changes in infrastructure, supply chain and there would be significant impact on current technologies and composites.

SVHC proposals such as those made by France will impact applications that contribute to the European Commission’s 2020 growth strategy goals e.g. low-carbon economy,
climate/energy, sustainability in research and innovation.	See response to comment 25.	
45.				2) Scientific Weight of Evidence
The ERC accepts that the molecular structure of BPA has similarity to estrogen, and scientific evidence indicates that the substance is able to interact with relevant nuclear receptors in in-vitro tests but these tests represent highly conservative, isolated scenarios without inclusion of in-vivo detoxification and metabolic processes. It is also well documented that the potency of BPA is 37,000 times less effective than estradiol and several orders of magnitude less potent than the synthetic human contraceptive diethylstilbestrol.  The ERC also agrees that based on scientific evidence exposure to BPA at high doses has adverse health effects in laboratory animals but real world exposure levels would not be adequate for such effects to occur in humans.

The ERC strongly disagrees that there is sufficient high quality evidence identifying a plausible link between adverse effects and anthropogenic exposure. Although theoretically plausible, such effects are clearly limited to high dose exposures without consideration of risk management measures. The ERC believes that no adequate high quality evidence supporting any such plausible link exists between an endocrine mode of action specific to BPA in humans under realistic exposure conditions.

A key point for consideration is the fact that between 2008 and 2015 the following key reports and conclusions were published regarding BPA:

1) U.S. Department of Health and Human Services, National Toxicology Programme,NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A, NIH Publication 08-5995, (2008);

2) Toxicological and Health Aspects of Bisphenol A, Report of joint FAO/WHO Expert Meeting, World Health Organisation, (2010);

3) US-FDA Hazard Assessment of Bisphenol A for use in food contact applications, USFood and Drug Administration Joint Emerging Science Working Group, (2014);

4) Scientific Opinion on the risks to public health related to the presence of Bisphenol A in foodstuffs, EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF), European Food Safety Authority, (2015).

The US NTP (2008) concluded minimal concern related to effects on the mammary gland and female puberty, negligible concern that exposure of pregnant women to BPA will result in fetal or neonatal mortality, birth defects, or reduced birth weight and growth in their offspring and finally negligible concern that exposure to BPA will cause reproductive effects in non-occupationally exposed adults and minimal concern for workers exposed to higher levels in occupational settings. The expert meeting of the World Health Organisation (2010) concluded no health concerns for the endpoints assessed, studies on developmental and reproductive toxicity in which conventional endpoints were evaluated and only identified effects at high doses, if at all. The conclusion of the US-FDA report (2014) is that an adequate margin of safety exists for BPA at current levels of exposure from food contact uses. EFSA (2015) also concluded that there are no health concerns for any age group from dietary exposure and low health concern from aggregated exposure. The CEF panel noted considerable uncertainty for non-dietary sources, whilst uncertainty around dietary estimates was relatively low.

In addition to the historical conclusions described above, a robust report from the U.S.National Toxicology Programme (CLARITY-BPA) is expected to be published between 2017 and 2018. EFSA and the US-EPA have publically announced that both organisations are taking a pragmatic approach and will re-evaluate BPA again when the results of the
CLARITY-BPA project are available. This project will determine chronic effects of BPA exposure and investigate reproductive toxicity, neurobehavioural effects, immune dysfunction, metabolic disease, obesity, cardiovascular effects, thyroid effects, and cancers associated with mammary glands, uterus, and prostate. The results of this project will provide valuable scientific evidence in the areas of concern proposed by France (e.g., reproductive function, mammary gland development, cognitive function, and metabolism).

As a consequence of the thorough review of literature conducted by the WHO, US-FDA,
NTP, and EFSA, it is our scientific opinion, based on all of the relevant data published prior to
March 2015, that a consensus regarding the effects and safety of BPA had been agreed.
However, following a review of the two recent SVHC proposals of France based on reproductive toxicity (30th August 2016) and endocrine disruption (9th March 2017), the competent authority has drawn upon earlier publications pre-dating 2015 which were likely used in the conclusions of the WHO, US-FDA, NTP, and EFSA.

Following a review of the new SVHC proposal from France, it should be noted that in total
Part 1 of the document references 440 publications. Only 11% of these publications are new (e.g., post 2015 EFSA conclusion) and specific to BPA, thereby indicating that this proposal has been submitted based on limited new evidence since the conclusion of EFSA. The ERC believes that the SVHC proposals are premature and unjustified due to relying mainly on data that has (i) previously been assessed and considered or (ii) presentation of limited new evidence specific to BPA, and therefore provides minimal non-guideline data that should not be used in isolation to drive regulatory decisions.

Although the FDA, EFSA, NTP, and WHO, plus other organisations, have determined that BPA is safe at current exposure levels, the safety of BPA continues to be debated and is frequently used as the “poster-child” for political leverage and by scientific research groups to secure funding and publicity. This continuous debate acts as a catalyst driving conflicting messages to the public and industry, fuelling confusion.

The ERC would like to take this opportunity to reassert our disagreement on the interpretation and use of some data and information in the SVHC process.

i) The proposal recommends relying on data from routes of exposure with questionable relevance (e.g., > 70% of the post-2015 data is from in-vitro, intradermal and intraperitoneal exposures). This approach is considered to be outside the proposed uses. Oral exposure should be considered most appropriate.
ii) There are inconsistency of effects and discrepancies between/across studies. The proposal is biased and glosses over these inconsistencies and discrepancies unless a negative (toxic) effect can be associated, whereby it is then considered.
iii) Certain human/epidemiological studies considered to have serious methodological flaws have been used to draw a conclusion.
iv) There is no clear evidence of direct effects of BPA on human reproduction, and there is a severe lack of data linking causality and effect in humans.
v) Many studies refer to the measurement of BPA in urine samples, whilst this may identify exposure, it simply indicates that BPA passes through the appropriate detoxification systems in-vivo. There is no evidence to claim that any residual BPA accumulates.
vi) Although the proposal claims to consider the quality of the available data using ToxRtool, the weight of evidence (WOE) analysis within the proposal refers to substantial amounts of data that were not considered adequate (e.g., only those studies shaded in grey within summary tables were rated K1 or K2). It is recommended that only studies of appropriate quality be discussed and considered/included in the WOE analysis.
vii) The body of the proposal identifies effects related to BPA; however, the doses at which these effects are evident are not discussed or related to expected human exposure levels, and claims are made without clearly linking to the dose causing the response.
viii) There is a strong focus on effects from high unrealistic exposure doses that are not relevant to human exposure scenarios.
ix) The proposal submitted relied heavily on a literature review by Rochester (2013)2 which we believe requires additional quality assessment.
x) Research noted by Rochester (2013) was weighted towards plasma data collected from IVF and fertility clinics; therefore focused on a specific (abnormal, identified with impaired fertility, non-average) cohort, with limited reference to controls or global background plasma levels. This was also noted as a limitation of the studies reviewed.
xi) Rochester (2013) cross references Caserta et al. (2013)3 and states that infertile women were significantly more likely to have detectable serum BPA, and that measured plasma concentrations of other substances (PFOS, PFOA, MEHP and DEHP) were not significant within the same patients. Rochester (2013) fails to note that MEHP was also found in a similarly high percentage of the infertile women when compared with BPA, and therefore, based on their correlation approach, infertility could equally be correlated to MEHP exposure.
xii) The publication of Rochester also references studies by Li et al. (2010 a4, b5) measuring BPA in the urine of male workers within BPA and epoxy resin industries in China. The authors claim that self-reported sexual dysfunction correlated with measured BPA; however, it is well known that air quality in these workplaces is poor and therefore the data should be considered invalid due to a lack of cause and effect. In addition, self-reported information, particularly on sexual dystunction in males, is generally of limited reliability , . This information was also omitted by the dossier submitter
xiii) Many claims within the proposal are based on speculation that requires the use of both adequate and inadequate data.

The ERC has reviewed all available data and assessed the most relevant studies for BPA in the determination of a hazard classification. The ERC remains of the opinion that the previous change in classification to Reprotoxic Category 1B6 was not supported by suitable scientific evidence. The ERC disagrees that sufficient quality data are available and therefore disputes the proposal for identification of Bisphenol A as a substance of very high concern on the basis of the criteria (endocrine disruption) set out in REACH Article 57.

Furthermore, associated risk management measures are sufficient to ensure the safety of workers and downstream users during industrial and professional operations and subsequently the product life cycle.	See response to comments 26 to 38.	
46.				3) Business continuity within the EU

The Annex XV process which may lead to the inclusion of substances on the Candidate List and prioritization under Authorisation brings severe uncertainty to the supply chain, particularly where end-use applications for the automotive and aerospace industry are involved.  SVHC labeling leads to high uncertainty in a broad number  of industries, such as the above. Most industries are not even affected by a potential authorisation as the use of BPA as starting monomer of Epoxy products is an intermediate use, so exempt from a potential Authorisation. However due to its inclusion into the candidate list, BPA is for example included into the GASDL for the automotive industry on 1st of February. The GADSL only covers substances that are expected to be present in a material or part that remains in a vehicle at point of sale. However, the industry, knowing that BPA is used as stating material, is concerned and might deselect high performance Epoxy products in favor of other less functional materials. This despite the fact that there is virtually no BPA in the final epoxy product.

Although many of the uses of BPA as an intermediate would be excluded from eventual Authorisation, the identification of BPA as SVHC (as starting substance or additive in an intermediate production step) is sufficient for many users to stop their activities in applications, even in strategic ones, which were proven safe for use and application.

If substitution would be considered, qualification time for alternative substances, new chemistries and products could take up to 10 years and more without inclusion of the regulatory process of testing, hazard/risk assessment and evaluation. For many applications a technical drop-in alternative is not available, if a valid alternative were identified therefore it is expected to take up to 10 years or more to develop and qualify before a direct exchange could take place.

Potential alternatives to BPA-based epoxy products (including acrylic-based epoxy) currently being investigated require different manufacturing process technologies, and have significantly higher prices than BPA-based epoxy.

These complex innovation projects require dedicated resources working hand-in-hand with customers.

The current lack of predictability in the listing and prioritization process could potentially further delay projects with the knowledge that alternative chemicals will not also be subject to risk management measures. Potential substitutes might turn out to be unsafe tomorrow, if it has to be demonstrated that possible technically acceptable alternative would be safe with respect to all the endpoints investigated for BPA.

Parallel processes for one substance of CLH, restrictions and authorisation, allowing 3
Annex XV dossiers to be proposed in a short period of time, while in parallel an RMOA is in progress based on a different concern (environmental ED) does not allow sufficient stakeholder involvement due to short and overlapping commenting periods, undermines the likelihood of proportionate and consistent risk management measures and prevent authorities from focusing on addressing the most important risks for society. It also undermines industry’s ability to invest in product innovation in collaboration with downstream industries.	See response to comment 24.	
47.				4) Business impact throughout the supply chain

If possible to identify a suitable alternative to BPA for all epoxy systems, the impacts on the supply chain would be two fold. This is due to epoxy systems being composed of two parts resin and hardener both of which utilise BPA. It is anticipated that replacement of BPA in epoxy hardeners would stimulate an increase in raw material costs between 30% and 500%.
Alternatives for use in BPA based resins would require significant capital investment to
modify or rebuild plants followed by extremely high qualification costs (several $10m) to
qualify alternative resins across all markets where BPA epoxy is used today. This
modification/rebuild and qualification would resonate throughout the supply chain.
Since there is currently no alternative epoxy resin with equivalent/comparable technical
profile the increase in raw material costs cannot be estimated. The increased raw materials costs would exceed the costs estimated previously for replacement in the epoxy hardeners.
For each new substance developed, there would be significant European/global regulatory costs associated with registration and toxicology studies. The REACH process alone would be in the order of $0.5- $1M per substance.
In general terms epoxy resins would be replaced by more expensive and lower performing alternatives which have not yet been tested for health and environmental hazards, while the
European Food Safety Agency (EFSA) and the US Food Safety Agency (FDA) have assessed BPA as safe for use in all current applications.
Since there is no current perspective of suitable technical alternative to BPA epoxy resins, any restricted use would result in the destruction of the associated business for Huntsman (resins and hardeners) across the European territory. Potentially 450 mio USD/ 800 FTE.	See response to comment 39.	
48.				5) Economic impact for Europe

It should also be noted that BPA based epoxy resins are used in products that help Europe tackle its most significant energy and environmental challenges. These resins play a role in supporting the development of alternative sources of energy and in the construction and transportation industries, where innovative products are helping customers conserve and use energy more efficiently contributing to sustainability in the EU. Moving away from these resins would impact the greater goals of the European Union in the following areas:

Wind energy
Moving to alternatives could include adverse effects on technical and economic feasibility of large/long wind turbine blades, which may mean contemporary wind turbine blades would have to become smaller. Moreover, reduced longevity of protective coatings on internal components and exposed parts would result in increases in operational and maintenance costs borne by the turbine operators.

Energy and electrical
A proportion of downstream users may be able to use alternatives in low voltage applications. This would not be the case in most medium and high voltage applications where there would be a loss of performance. Subsequently there would be a reduction in the lifetime of components, stimulating higher operating costs due to more frequent inspection and replacement. At worst, more frequent component failure will affect reliability of electricity supply and increase the likelihood of temporary blackouts. This would impose direct repair costs on electricity distribution companies.

Food sector
In food canning, the technical characteristics of alternatives is expected to result in reduced product shelf lives of the cans and hence their contents - likely to result in increased waste of food as producers and consumers throw away spoiled or out of date cans. This may also require modification of acceptable food lifetime standards in at least some canned produce and it is likely that certain food substances would no longer be canned. Sales of canned foods may decrease. Any alternative substances/techniques would also need to undergo the relevant safety tests, which could take decades to obtain knowledge equal to that currently available for BPA.

Water pipes and infrastructure
A consequence of the loss of epoxy products in this application is increased duration and frequency of repairs to water leaks or pipes. Epoxy resin are used within a repair ‘sock’ that is inserted into pipes providing a durable repair to breaks or cracks. The durability of BPA epoxy also protects from breaks/cracks or corrosion damage for longer periods. Many of these pipes are underground. Increased need for repairs and for excavation would impose additional costs on water companies.

Transport
Loss of epoxy resins is expected to lead to a loss of performance in specific components in aircraft, cars and marine vehicles. The range of components is diverse, however in broad terms, the implications include loss of resistance to environmental degradation/corrosion and effects on aircraft/car weights achieved through the use of composite components.

Aircraft Fuel and CO2 Emissions
A significant advantage of epoxy resins is the weight savings that can be achieved in aircraft without loss of strength and performance through their use in composite components. A loss of epoxy resins would adversely affect existing designs and would be likely to increase the weight of aircraft Airlines would face increased fuel costs and CO2 emissions would rise. For many manufacturers, significant costs would be associated with the need for new manufacturing plant to be set up to produce parts based on alternative materials.

Automotive and CO2 Emissions
The use of epoxy resins contributes towards reduced weight and hence fuel consumption and CO2 emissions, alongside increasing operational life and reliability.	See response to comment 40.	
49.		4820
2017/04/21	PC/BPA Group of PlasticsEurope cosigned by BPA REACH Consortium and Epoxy Resins Committee of PlasticsEurope ,
Industry or trade association,
Belgium	COMMENTS PART I OF THE ANNEX XV SVHC DOSSIER

* The attached PDF includes the emphasis that has been added to various references
The PC/BPA Group of PlasticsEurope welcomes the opportunity to comment on the Annex XV dossier proposing to identify Bisphenol A (BPA) as a substance of very high concern (SVHC) in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH). The PC/BPA Group opposes the French dossier on the basis of the legal interpretation of the REACH Regulation for identifying BPA under Article 57(f) and on the basis of the non-conclusive scientific evidence and the weakness in the scientific argumentation brought forward by the French authorities in the dossier.	Thank you for your comment. Detailed responses are provided below.	
50.				1. GIVEN THE PROVISIONS OF ARTICLE 57, A SUBSTANCE SHOULD NOT BE IDENTIFIED AS AN SVHC UNDER ARTICLE 57(f) WHEN IT HAS ALREADY BEEN IDENTIFIED AS AN SVHC UNDER ARTICLE 57(c)
The submission of a second SVHC dossier by the French authorities represents a misuse of Article 57 of the REACH regulation. Only substances that do not fall within the CMR, PBT and vPvB hazard categories specifically identified by the legislature as being of very high concern pursuant to Article 57(a) to (e), may be identified as SVHC pursuant to Article 57(f). BPA can therefore not be identified as an SVHC under Article 57(f) based on its alleged endocrine disrupting properties when it has already been identified as an SVHC by virtue of its hazard under Article 57(c).
According to Article 57 of REACH, the following substances may be included in Annex XIV: “(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 fulfil 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 59”.
On 8 August 2016, France submitted an Annex XV Report to propose BPA for identification as an SVHC on the grounds of its harmonized classification as toxic for reproduction (ref.1)  Subsequently, on 12 January 2017, BPA was included in the Candidate list as an SVHC, toxic for reproduction pursuant to Article 57(c) of REACH, based on a decision of ECHA of 4 January 2017 in line with the unanimous agreement of the Member State Committee (MSC) of 2 December 2016.
The PC/BPA Group highlights that Article 57(f) of REACH targets specifically substances – such as those having endocrine disrupting properties – which give rise to an equivalent level of concern to those other substances which do not fulfil any of the criteria under Article 57(a) to (e). Consequently, only substances that do not fall within the CMR, PBT and vPvB hazard categories specifically identified by the legislature as being of very high concern pursuant to Article 57(a) to (e), could be identified as SVHC pursuant to Article 57(f).
The PC/BPA Group notes that, in a recent judgement, the Court of Justice of the European Union (ref.2) stated that Article 57(f) should only be used to propose substances for identification as SVHCs, that do not fulfil any of the criteria in Article 57(a) to (e) (emphasis added in the pdf attachment).
Specifically, the Court noted in Case C-324/15 P, Hitachi Chemical Europe GmbH and Polynt SpA v ECHA (ref.3) that Article 57(f) of REACH:
“[…] covers all other substances which do not fulfil any of the foregoing criteria but ‘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 59’.”
By way of example, the provision mentions substances which have endocrine disrupting properties, or substances which have PBT or vPvB properties, when these do not fulfil the criteria for inclusion under points (d) or (e) of Article 57.
To this purpose, Article 57(f) provides for an independent mechanism that makes it possible to identify substances as SVHCs which have not already been designated as such pursuant to the other criteria under Article 57 (a-e).
Consequently, given that BPA has already been identified as an SVHC based on its reproductive toxicity properties under Article 57(c), a further submission based on alleged endocrine disrupting properties for human health with a rationale as provided in the second SVHC dossier under Article 57(f) can in principle not be supported based on the legal requirements as laid down under REACH.
	On regulatory and practical grounds:
As it has been established through decision "implementing identification of bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl phthalate (DIBP) as substances of very high concern according to Article 57(f) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council" (adopted during Reach Committee in February 2017), "Article 57 does not forbid identifying a substance as being of very high concern several times based on more than one intrinsic property causing the same effect on human health".
Co-legislators did choose not to prevent SVHC listing of a substance for intrinsic properties causing the same effect as a hazard that has already allowed its SVHC identification, and that it is possible to include such substances for all possible identification criteria, as many examples of regulatory impacts as below prove it: 
- Transparency provides clear information on the dangers of the substances present in the articles, hence the need to identify the SVHC substances for all of the SVHC hazard properties.
- In the event that an Annex XIV substance is identified for new SVHC hazard properties under Article 57 (f), in addition to 57 (a or c), this would imply new consequences as soon as the Commission modifies the corresponding entry in Annex XIV to include these new hazard properties. In particular, all of the SVHC properties will have to be considered in the assessment of risks and/or impacts of the substance as well as in their mitigation and control in any future applications for authorisation.
- If a new property for SVHC identification as 57 (f) for endocrine disruption should be included for substances listed in Annex XIV, a concentration limit of 0.1% would be applicable under Article 56.6.a of the REACH Regulation to determine whether the use of the mixture containing this substance is to be the subject of an application for authorization, whereas at present a higher concentration limit of 0.3% applies for substances identified only for reproductive toxic properties (Article 56.6.b of the REACH Regulation).
 
On legal grounds : 
Indeed, Article 57 specifies, by categories, the nature of the "Substances to be included in Annex XIV".
In support of its argument, Plastics Europe Association also relies on the judgment in Case C-324/15 P - Hitachi Chemical Europe and Polynt v ECHA of 15 March 2017.
Firstly, it should be observed that the same substance may have effects within several categories mentioned in the various subparagraphs of Article 57, including (f).
Secondly, the judgment in which the action for annulment of a judgment of the Court of First Instance of 30 April 2015 in Case T-135/13 dismissing Hitachi Chemical Europe's action against the decision ED / 169/2012 of the European Chemicals Agency of 18 December 2012, including MHHPA in the list of substances of very high concern, did not directly address the issue raised: the legal issue was whether Article 57 (f) of REACH Regulation requires an analysis of the intrinsic properties of the substances concerned, excluding any consideration of human exposure data.
Lastly, the recall made by the CJEU on an incidental basis cannot have the consequences that PlasticsEurope association would like to draw: indeed, if point (f) seems to be intended as a 'broom arrangement', so as, to encompass the scope of the Regulation for substances not meeting the criteria referred to in points (a) to (e) does not mean that the classification of a substance in Annex XIV under a heading prohibits it under another. 
This is the approach adopted by ECHA in practice: in particular, Bis (2-ethylhexyl) phthalate, is identified as a substance of very high concern, both under Article 57 (c) (as reprotoxic) and under point (f):
https://echa.europa.eu/documents/10162/30b654ce-1de3-487a-8696-e05617c3173b  
and
https://echa.europa.eu/documents/10162/c2ecc989-445d-40b9-a054-28671849b092 	
51.				2. ANY IDENTIFICATION OF BPA AS AN SVHC BECAUSE OF ALLEGED ENDOCRINE DISRUPTING (ED) PROPERTIES  IS PREMATURE AND UNJUSTIFIED
The French proposal to identify BPA as an SVHC because of alleged endocrine disrupting properties is premature in light of the ongoing US NCTR/NTP study (CLARITY Study). The CLARITY study is widely acknowledged, by regulators and authorities at European level, including EFSA and ECHA, to be the definitive study for the assessment of the alleged endocrine disrupting properties of BPA. To conclude, any proposal for identification of BPA as an endocrine disruptor for human health taken before the publication (and appropriate consideration) of final results from the CLARITY study has to be considered premature. Hence, any Annex XV proposal could not be considered to be fully substantiated, until the study is taken into account.
In the REACH Substance Evaluation decision on BPA (ref.4), ECHA acknowledged the relevance of a still outstanding major study (the “CLARITY study” (ref.5)) for the assessment of alleged endocrine disrupting properties of BPA, by stating that any need for further testing may depend on the results from that study and other relevant new information. On these grounds, the evaluating German Competent Authority deemed necessary to exclude the assessment of endocrine disrupting properties (human health) from the scope of its evaluation, and postpone it to a later stage.
Similar statements on the relevance of the upcoming CLARITY study were made by EFSA (ref.6) and the German BfR (ref.7) in 2015: In its scientific opinion of 2015, EFSA acknowledged that the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF panel) will re-evaluate the BPA database, taking also into account endocrine related endpoints after the CLARITY study becomes publicly available:
“The CEF Panel designated the TDI as temporary, pending the outcome of the long-term study in rats involving prenatal as well as postnatal exposure to BPA, currently being undertaken by NTP/FDA. This study will help resolve the uncertainties in the database”. (Ref.6)
The CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA) study is a cooperative program, conducted under the auspices of the US National Toxicology Program (NTP). It comprises a core chronic Good Laboratory Practices, guideline-compliant study performed at US FDA’s National Centre for Toxicological Research (NCTR) as well as 13 NIEHS-funded university-based research projects. (For detail see Heindel et al., 2015 (ref.5) and Schug et al., 2013 (ref.8)). The in-life phase of the core chronic study was completed in January 2015. The publication of the core chronic study is expected in 2018. It will be a major additional building block for the overall assessment of BPA.
Once finalized, the chronic core study will further help to assess the coherence of observations related to assumed MoA(s) and consistency amongst different studies. The central hypothesis of the Annex XV dossier is that BPA exerts adverse effects by “…disruption of the estrogenic pathway and estrogenic regulation.” As the CLARITY study includes the reference estrogen ethinyl estradiol (EE2) as a positive control, it will help to assess also the specificity of potential effects (endocrine related versus non-endocrine related, especially related to estrogen related activities).	Please see our detailed response to comment 19 above in relation to the CLARITY-BPA program.	
52.				Criteria for the identification of Endocrine Disruptors are not yet adopted in the EU
The PC/BPA Group notes that criteria for the identification of substances with endocrine disrupting properties under Article 57(f) of REACH have not yet been adopted by European Union institutions. Furthermore, the definition of criteria for the identification of endocrine disruptors in other European regulatory frameworks (respective regulations on Biocides and Plant Protection Products) is currently ongoing, but not yet finalised. Thus, also for this reason, it would be premature to identify BPA as an endocrine disruptor (by SVHC identification on the basis of alleged endocrine disruption).

In summary, at this stage, any identification of BPA as an endocrine disruptor for human health has to be considered premature and could not be regarded as fully substantiated before the publication (and appropriate consideration) of the CLARITY study and before the definition of criteria for the identification of endocrine disruptors in an EU regulatory context.	As noted in your comment the criteria currently in discussion by the European institutions relate to the Biocides and Plant Protection Products regulations. The REACH text does neither refer to, nor require, criteria for inclusion of endocrine disruptors in the candidate list on a case-by-case basis. This process has already been applied for other substances identified as endocrine disruptors fulfilling criteria 57(f).	
53.				3. THE ARGUMENTATION AND ANALYSIS PUT FORWARD BY THE FRENCH AUTHORITIES IS BASED ON WEAK EVIDENCE AND IS CONFLICTING WITH EARLIER CONCLUSIONS OF DIFFERENT AUTHORITIES
An Annex XV dossier proposing SVHC identification pursuant to Article 57(f) of REACH should meet two requirements 1) scientific evidence of probable serious effects and 2) an equivalent level of concern. Both of these requirements should be met, whether a substance is identified for its endocrine disrupting properties or for others.
Regarding endocrine disrupting properties, the World Health Organisation (WHO) defines an endocrine disruptor as an “exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations.”
A. The French dossier lacks a convincing defined mechanism or mode of endocrine disrupting action. There is no clear hypothesis provided, instead the dossier is reliant on a description of individual observations “in the context of endocrine disruption”. The French authority’s scientific argumentation is quite vague. It does not provide sufficient “scientific evidence of probable serious effects to human health” as demanded by Article 57(f).
The French dossier provides a definition for mode of action (MoA) and indicates that there is a clear distinction between the terms MoA and mechanism of action. The dossier specifies on pages 21-22 that:
“The mechanism of action is typically defined as the totality of mechanistic steps, whereas the MoA refers to a less detailed sequence of key events […]. For the purpose of the present analysis, the following definition is retained for MoA: “A sequence of key cellular and biochemical events with measurable parameters that result in a toxic effect” (emphasis added in the pdf attachment).
Taking into account the less detailed MoA definition, the PC/BPA Group notes that the dossier does not elaborate any consistent or specific MoA. This is illustrated by the following examples in the dossier: 

• Page 48: “Thus, we conclude that it is quite likely that BPA may alter the ovarian cycle in humans through the disruption of the endocrine activity of the ovarian follicle” (emphasis added in the pdf attachment).
• Page 51: “In conclusion, it is generally considered that the effects of BPA result from complex mechanisms that are most probably interacting together. Not all of them are fully understood. However, the overall database shows that an alteration of the regulation of estrogens is an essential pattern of the MoA” (emphasis added in the pdf attachment).
• Page 75: “All data presented here support the possibility that BPA, through interaction with the nuclear ERs, or GPER (which may also play a role, see Filardo et al., 2006), and indirectly with PR, modulates estrogenic- and progestin agonist activities” (emphasis added in the pdf attachment).	The Annex XV dossier aims to summarise and transparently discuss the overall evidence that BPA has ED-mediated effects as well as its uncertainties as pointed out in your comment. Indeed, FR considers it as important to base the ED and SVHC identification of BPA on a rigorous and critical scientific assessment. This effort for a balanced analysis should not be seen as a weakness of the dossier but definitely as its strength.

Requirements of the WHO/IPCS definition and its agreed European interpretation (JRC, 2013) involve demonstration that the adverse effects are plausibly caused by an alteration of the endocrine function. There is therefore no requirement to understand the whole mode of action at stake.
This has been done in the Annex XV dossier for each of the four endpoints and uncertainties on the exact sequence of events does not prevent the identification of the essential involvement of endocrine disruption for induction of the effects.
Similarly, the possibility that other modes of action may occur simultaneously does weaken the key role of modulation of the estrogenic pathway. 

FR disagrees with the way of presenting the work “emphasizes associations and philosophical assumptions about the possibility that the proposed mode(s) of action leads to adverse effects”. In different cases, studies associating estrogen inhibitors with BPA are described. In the mammary gland, they show no adverse effect on acini structures (Marchese and Silva, 2012), prevented partially the BPA-induced effects on 11-bHSD1 mRNA levels (Wang et al., (2013). For neurobehavioral effects, ER inhibitor reversed the effect of BPA on both learning/memory performance and molecular and structural changes (Xu, 2015b). Regarding the reproductive toxicity endpoint the apical endpoint (cell cyclicity) is in itself endocrine disruption, as it is for the effects on insulin secretion or resistance considered in the metabolism section. 	
54.				• Page 152: “Most importantly, although the steps of the respective mechanisms of action are specific for each effect, the disruption of the estrogenic pathways is a common MoA consistently involved in each of the four effects. The primary target of BPA is however still not known with certainty. BPA binds to estrogen receptors (ER) but with a weak affinity. In addition, BPA binds also to other types of ER such as GPER or ERR-γ with a higher affinity and then, these receptors may also be involved in BPA mediated effects, particularly at low doses” (emphasis added in the pdf attachment).
The dossier emphasizes associations and philosophical assumptions about the possibility that the proposed mode(s) of action leads to adverse effects. The PC/BPA Group notes that “associating” an effect to an endocrine related MoA does not provide sufficient evidence to fulfil the criteria for Article 57(f) since associations between two aspects alone do not prove evidence that “key cellular and biochemical events […] result in a toxic effect”. On different occasions, the French authorities admit that such conjecture does not provide a sufficient basis for firm conclusions. For example on page 43 it is stated that:
“These data clearly indicate that BPA developmental exposure can be associated in animal models with an altered development of the neuroendocrine component of the gonadal axis. From a physiological point of view, it is legitimate to assume that most of these alterations can possibly lead to disruption of estrous cyclicity later in life. However, the majority of these studies did not monitor cyclicity, which precludes any definitive conclusion regarding a potential functional link between these developmental neuroendocrine alterations and perturbation of estrous cyclicity in adults” (emphasis added in the pdf attachment).
In the overall conclusion of the human health hazard assessment (Chapter 4.6), it is summarised that according to the French authorities the primary target of BPA is still not known, multiple MoAs may interact and other findings also point towards alternative elements involved in BPA-mediated effects. It states on page 152 that:
“Most importantly, although the steps of the respective mechanisms of action are specific for each effect, the disruption of the estrogenic pathways is a common MoA consistently involved in each of the four effects. The primary target of BPA is however still not known with certainty. BPA binds to estrogen receptors (ER) but with a weak affinity. In addition, BPA binds also to other types of ER such as GPER or ERR-γ with a higher affinity and then these receptors may also be involved in BPA-mediated effects, particularly at low doses. The complexity of the toxic response to BPA also suggests multiple MoA that may interact. However, some evidence detailed in each section of this report for each effect specifically enables to establish that the estrogenic pathway is central and common in the MoA. Other findings also point toward alternative elements involved in BPA-mediated effects, e.g. epigenetic modifications. It is not known whether these modifications may be estrogen-dependent but the potential role of additional mechanistic pathways does not contradict the importance of the estrogenic pathways in the BPA-mediated effects” (emphasis added in the pdf attachment).
Different hypotheses need to be taken into account and critically assessed and the resulting evidence needs to be weighted to reach a conclusion on which one is the primary and biological relevant MoA. If the hypothesis is that there are “additional mechanistic pathways”, there is a need to assess also the alternative hypothesis that these effects are not biologically linked. The statement that “the potential role of additional mechanistic pathways does not contradict the importance of the estrogenic pathways” is therefore not sufficient to define a MoA for ED under Article 57(f).	FR disagrees with the way of presenting the work “emphasizes associations and philosophical assumptions about the possibility that the proposed mode(s) of action leads to adverse effects”. In different cases, studies associating estrogen inhibitors with BPA are described and show no adverse effect on acini structures (Marchese and Silva, 2012), prevented partially the BPA-induced effects on 11-bHSD1 mRNA levels (Wang et al. (2013)). Regarding the reproductive toxicity endpoint the apical endpoint is in itself endocrine disruption, as it is for metabolism (insulin secretion and insulin resistance). The comment discusses the certainty of the association of each step of the mode of action together with the adverse outcome. However, when considering the definition of an ED, this association is defined as a biologically plausible link. Indeed, the studies displaying an altered development by BPA of the neuroendocrine component on gonadal axis can not evaluate their effect on the perturbation of estrous cyclicity in adults: indeed, animals can only be killed once. The link between the two spatio-temporal events can only be theoretically demonstrated and it CANNOT be expected to be demonstrated by an experiment.	
55.				The dossier fails to evaluate potential alternative MoA; e.g., the proposal did not take into account an alternative mechanism for the reduction in aromatase activity reported at supra-physiological (µM) concentrations in the in vitro studies. Based on the very high BPA concentrations investigated and the reduction in all parameters mentioned in table 9 (page 54 of the dossier), it would be reasonable to assume that BPA shows cytotoxicity at these high concentrations.	1. Zhou et al. (2008) Mol Cell Endocrinol, 283:12-18.
Model: culture of follicular cells isolated from mature SD rat
The negative effect of high doses of BPA on aromatase mRNA level and estradiol production in the culture of granulosa cells observed in this paper cannot be attributed to a general cytotoxicity for the following reasons:
1) In this paper, 0.1 to 100 µM BPA increased the steroidogenic activity in the cultured theca-interstitial cells (Fig 1 and 2). To our knowledge, no paper demonstrates that the susceptibility to cytotoxic compounds of the granulosa cells is higher than that of the theca-interstitial ones.
2) If the decrease in estradiol produced by the granulosa cells in the response of 1 and 10 µM BPA was the result of a general toxicity, the production of progesterone by these cells should also decrease. On the contrary, it was increased by these BPA concentrations (Fig 3). 
3) If the decrease in aromatase expression produced by the granulosa cells in response to 1 and 10 µM BPA was the result of a general toxicity, the expression of P450scc in these cells should also decrease. On the contrary, it was increased by these BPA concentrations (Fig 4). 
4) If the decrease in aromatase expression in the granulosa cells in response to 100 µM BPA was the result of a general toxicity, the expression of StAR in these cells should not be increased by this BPA concentration as it is observed (Fig 4). 

2. Peretz et al. (2011) Toxicol Sci, 119:209-217.
Model: culture of isolated mouse antral follicle
The negative effect of 44 µM BPA on estradiol and estrone production by the mouse antral follicle in culture for 4 days (Fig 2) cannot result from a cytotoxic effect since the follicular growth throughout the culture period is not affected by BPA (Fig 1). 

3. Mlynarcikova et al. (2005) Mol cell Endocrinol, 244:57-62.
Model: culture of granulosa cells isolated from porcine ovary
A non-specific cytotoxicity cannot explain why 1 and 10 µM BPA reduced the production of estradiol (Fig 2A) and did not affect that of progesterone (Fig 1A). 

4. Kwintkiewicz et al. (2010) Environ Health Perspect, 118:400-406.
Model: culture of KGN granulosa-like tumor cell line
In this model, BPA reduced the expression of aromatase in a dose-dependent manner with the tested concentrations range (from 40 to 100 µM). 
The effect of 10 to 100 µM BPA on cell metabolic activity was measured using the MTS assay. A dose-dependent reduction of this metabolic activity was observed from 30 to 100µM of BPA with a maximum effect achieved at 50 μM (- 31 ± 3%) without further changes at higher concentrations. 
The reduction of aromatase expression cannot be attributed to a general cytotoxic effect for the following reasons:
1) It is misleading to write that the MTS assay is a cell viability assay. The MTS assay is a colorimetric assay for assessing cell metabolic activity, and more precisely, the NAD(P)H-dependent cellular oxidoreductases activities. In this assay, these enzymes, via an intermediate electron acceptor, reduce the tetrazolium dye (MTS) into formazan, which has a purple color which is measured. Thus, it is important to keep in mind that having a positive MTS could be due to the fact that one compound may reduce this reductase metabolic activity without affecting the cell viability.
2) In this paper, if the reduction of aromatase expression in response to BPA was the result of a general toxicity of high doses of BPA, the expression of all the genes should be reduced. However, the expression of CREB remained unaffected and that of PPARgama was increased by BPA. 
3) A comparative analysis of the dose-responses curves of the effect of BPA on the aromatase expression (Fig 1B) and on the metabolic cell activity (Fig 4B) shows that these curves do not fit together. Specifically, there was a reduction by half in the aromatase expression from 60 to 100 µM while the MTS assay showed no change between 50 and 100 µM.
4) The authors bring data in favour of a plausible biological pathway to explain how BPA reduces aromatase expression. They observed that BPA reduces the expression of GATA4 and increases that of PPARgama. GATA4 and PPARgama are known to be positive and negative regulators of aromatase expression respectively. To test the hypothesis that BPA act on aromatase expression via an increase in PPAR gama, they over-expressed PPARgama in these cells and observed a reduction in aromatase mRNA levels with increasing concentration of the transfected PPARgama expression.

5. Watanabe et al. (2010) Toxicol letters, 210:95-99.
Model: culture of KGN granulosa-like tumor cell line

Both aromatase mRNA level and activity were reduced by all the concentrations of BPA tested (35 µM for mRNA and 5, 25, 50, 100 µM for the activity). The authors bring data in favour of a plausible biological pathway to explain how BPA reduces aromatase expression. The specific ovarian promoter II of aromatase was transfected into KGN and its activity was measured. The activity of promoter II was down-regulated in the presence of all the concentrations of BPA tested (5, 25, 50 µM BPA) showing that BPA acts specifically on the activity of the promoter of aromatase. 
6. Mansur et al. (2016) Human reprod, 31:1562-1569.
Model: Primary culture of human granulosa cells
If the reduction of aromatase expression observed here in response to 8.8 and 88 µM BPA was the result of a general toxicity of high doses of BPA, the expression of all the genes should be reduced. This is not the case, since 8.8 and 88 µM BPA did not affect the expression of StAR and 17β-hydroxysteroid dehydrogenase in this model.
Note : New data recently published (Pérez-Albaladejo E, Fernandes D, Lacorte S, Porte C, 2017, Toxicol in vitro, 38 :41-48) 
In this recent paper, the cytotoxicity and the inhibition on aromatase activity in response to various BPA doses were compared using JEG-3 cells, derived from a human placental carcinoma. Cytotoxic effect of BPA was measured using 5-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM) to evaluate cell membrane integrity. Aromatase activity was determined by measuring the amount of 3H2O formed during the aromatization of [1β-3H] androstenedione. In this cell type, the EC50 for cytotoxicity was higher than the IC50 for aromatase diminution (218 ± 14 µM v.s.93.7 ± 1.8 µM in JEG-3 cells or 71 ± 7 in S9 fraction isolated from JEG-3 cells).
Conclusions
The data provided above show that high doses of BPA decrease the expression and/or the activity of aromatase in the granulosa cells in all the papers although the authors used various in vitro models. The assumption that this inhibition could result from the cytotoxicity of high doses of BPA is invalidated by the data of all these papers.	
56.				The dossier does not establish the key biochemical, cellular, and molecular events in the proposed MoA, nor does it explain the temporal and dose-response concordance between them; rather, it merely hypothesizes their existence. The dossier does not provide any data demonstrating that BPA produces a sufficient magnitude of response at any of the key events to propagate the MoA. Just “an effect” e.g., on estrous as health effect without demonstration of a consistent defined biological response (e.g., type of irregularity) is not specific enough to be linked to a specific MoA or mechanism of action and therefore does not create sufficient evidence as demanded by Article 57(f). Similarly, “alteration of organ/function” is a very broad term and is not specific enough to be linked to a specific MoA or mechanism of action.
To fulfil the criteria of Article 57(f) for an SVHC-identification based on endocrine disruption, a conclusive demonstration of a respective MoA or mechanism of action that is relevant for an observed adverse effect would be needed. This means that weak evidence of an adverse effect (e.g. as RAC concluded for estrous cyclicity; see page 30 of the French dossier) together with weak and/or not conclusive evidence of an endocrine mechanism (without a demonstrated MoA or mechanism of action) does not create sufficient evidence for Article 57(f).
The French dossier fails to show that there is any agreed specific adverse effect with a conclusively demonstrated endocrine related MoA. The database is not strong enough to support the conclusion of an equivalent level of concern in addition to the already existing classification.	On one of the adverse outcomes, reproductive effects, it was recognized that it is difficult to establish a dose-response relationship. The database showed a relative consistency in the reproductive effects seen at doses > 100 mg/kg bw/d whereas no statistically significant effects or contradictory effects are seen in lower doses. The contradictory effects observed in different scientific publications cannot be explained so far, as animals or even strains, doses and time of exposure vary from one study to another. Therefore, consistency on a dose-response relationship cannot be established from the database used in the previous CLH report. This state of play is true for the other adverse outcomes and even more complex for their earlier events.
It should be emphasized that the complexity and variations in sex hormone regulation in different species, strains, sexes, organs and at different life-stages render the mode of action very sensitive to many parameters. At the time-being, it is therefore anticipated that the effects exerted by BPA may differ at different dose levels and/or period of exposure, rendering any tentative of dose-response concordance of the different key events impossible.	
57.				B. The French dossier follows an apparently inconsistent and selective approach in assessing the relative weight of specific scientific studies. It includes an inconsistent and non-transparent use of the ToxRTool, used to assign relative importance to particular studies. Often studies that have been deemed as not reliable by other authorities are considered as most relevant studies in the dossier (highlighted in grey). It remains unclear why these studies are ranked so highly by ANSES. Hence the dossier cannot be deemed an appropriate weight of evidence approach.

In principle, the PC/BPA Group appreciates the use of the Toxicological data Reliability assessment Tool (ToxRTool) to support a weight of evidence approach. However, for the appropriate use of the ToxRTool, it is important that underlying information is provided and that there is sufficient transparency on how scores have been derived.
On page 24 of the dossier, it is briefly mentioned that the ToxRTool was used to score the reliability of individual studies:
“In order to provide further support and transparency to the robustness of the conclusions, ToxRtool was used to assess the reliability of the experimental studies that were considered as the most informative to reach the conclusions. ToxRtool12 was developed by the European Commission's Joint Research Center in 2009 (Segal et al., 2015) and builds on Klimisch categories by providing additional criteria and guidance for assessing the reliability of toxicological studies. It is applicable to various types of experimental data, endpoints and studies (study reports, peer-reviewed publications)” (emphasis added in the pdf attachment).
“The rating of the most informative studies to reach the conclusions resulted in a reliability score of 1 (reliable without restriction) or 2 (reliable with restriction) according to ToxRtool. They are identified by a grey shade in the summary tables in each section” (emphasis added in the pdf attachment).
The ToxRTool provides reliability assessment EXCEL templates with specific questions to be answered for each study. However, the PC/BPA Group notes that no information on the assessment of the individual questions or the rationale to derive final scores is given for any study throughout the dossier.	Please see our detailed response to comment 34 above in relation to the use of ToxRtool.	
58.				In addition, studies mentioned in the dossier as “most informative” or “key” studies are described as having limitations by other expert committees. For example, the study by Rubin (2001) (ref.9), assessed as “most informative” study by ANSES, was also discussed by EFSA (2015) (ref.6), SCOEL (2014) (ref.10) and CERHR (2008) (ref.11). All concluded that there were shortcomings in the study conduct. The number of mated dams (n=6) was low, and it was not reported whether the litter was used as statistical unit.
It is furthermore remarkable that comprehensive studies (as Tyl 2002 (ref.12), 2008 (ref.13), Ema 2000 (ref.14), Delclos 2014 (ref.15)) acknowledged as key studies by other regulatory bodies such as RAC, EFSA, SCOEL or in the EU Risk Assessment are not mentioned in the dossier as “most informative” studies, and are thus not taken into account with the same weight in the French dossier. These comprehensive studies have been used for example by:
• ECHA (2015) (ref.16): “adverse effects, such as disturbances in the oestrous cycle, at a dose of 600 mg/kg bw/day (Tyl et al., 2008) and at a dose of 100 mg/kg bw/day (Delclos et al., 2014).” (emphasis added in the pdf attachment)
• SCOEL (opinion of 2014) (ref.10) which stated that: “The effects of BPA on fertility and reproductive performance have been investigated in three good quality 3-generation and 2-generation studies in rats or mice, and one older continuous breeding study in mice.” [Tyl 2002, 2008 and Ema 2000]
• The EU Risk Assessment Report of 2008 (ref.17) which stated that: “… we consider this investigation by Tyl et al. (2007) as the gold-standard, definitive study of the reproductive toxicity of BPA (for the endpoints examined)…”
The PC/BPA Group is also concerned that numerous studies are not cited in the dossier and/or important information is not identified for individual studies. Some examples are given below (for further details and additional information see background document):
• There are numerous studies not cited in the dossier which show no effect on the discussed endpoints. For example, ovarian cycle is a common endpoint measured in many studies and in some studies information on ovarian cycle, in particular absence of effects, is only briefly mentioned (Goodman (2009 (ref.18), 2006 (ref.19)), Gray (2004 (ref.20)), CERHR (2008 (ref.11)), EFSA (2015 (ref.6)), SCOEL (2014 (ref.10))).	The reproductive toxicity endpoint is not re-discussed here as it has been classified by RAC. However, Rubin is cited among others because it has evaluated the impact of BPA on oestrous cyclicity. Contrary to the comment, Tyl 2002 (ref.12), and Delclos 2014 (ref.15) are cited: “Several studies fail to reveal an effect of BPA on the estrous cycle (Tinwell et al., 2002; Kwon et al., 2000; Tagaki et al., 2004; Yoshida et al., 2004; Ferguson et al., 2014; Tyl et al., 2002) while others report alterations of cycles after perinatal (Rubin et al., 2001; Delclos et al., 2014))”

Altered patterns of estrous cycle in the female offspring of dams exposed during gestation and/or lactation have been reported in several studies. In most cases, BPA treatment induces significantly longer estrous cycle. It has been demonstrated that not only extended periods of estrus were seen, but also extended period of diestrus (Rubin et al., 2001; Mendoza-Rodriguez et al., 2011; Nikaido et al., 2004; Honma et al., 2002; Tyl et al., 2008). Another study revealed also premature anestrus (Adewale et al., 2009).
Similarly, Mendoza-Rodriguez et al., observed in 79.2% of female rats exposed perinatally from GD6 through PND21 to 1.2 mg/kg bw/d of BPA irregular estrous cycles characterized by predominant persistent estrus or persistent diestrus (Mendoza-Rodriguez et al., 2011). Mendoza-Rodríguez et al. showed that oral exposure of female Wistar rats to BPA during gestation and lactation induces:
- in the 4 months old female offspring a modification of the estrous cyclicity and 
- a down regulation of the protein Estrogen Receptor α (ERα) in uterine cells on estrus day as evaluated by immunohistochemistry (Mendoza-Rodríguez et al., 2011). 

Estrous cycle alteration characterized by an elongated cycle length of 3 days on average (p < 0.01) due to prolonged diestrus phase (p < 0.01) and reduced age at puberty was also reported by Nikaido et al. on CD-1 mice exposed in utero for four days from GD15 to GD 19 to 0.5 or 10 mg/kg/day of BPA via subcutaneous injections in pregnant dams (Nikaido et al., 2004).
In contrast, 2 studies failed to reveal significant differences in patterns of estrous cycle after perinatal exposure to high levels of BPA (Kwon et al., 2000), or after a prepubertal exposure (Nikaido et al., 2005). Kwon et al. hypothesize that this lack of effect may be due to insensitivity of Sprague-Dawley rats to endocrine-mediated toxicity. This is confirmed by the Tyl et al. study (Tyl et al., 2002 or Ema et al., 2001) but contradicted by one of our key studies (Lee et al., 2013a). Similarly, ICR mice have been described as being insensitive to estrogen (Nagao et al., 2002) but not in another study (Honma et al., 2002). Therefore, the available publications show that BPA affects estrous cycle under certain conditions.
Ema and Tyl have been added to the text of the support document.

All the references cited here are reviews of existing data that are all incorporated in the dossier. The analysis performed earlier by other bodies are not mixed with the raw data for the sake of clarity. Moreover, these reviews or report are deemed to identify threshold values based on known hazard while our report aims to demonstrate a new hazard: the endocrine disrupting property of BPA.	
59.				The publications by Hass (2016 (ref.21)) and Vandenberg (2008 (ref.22)) are mentioned in the chapters on brain development and mammary gland, respectively, but it is not mentioned that these studies investigated also estrous cyclicity and reported no effects on this endpoint.	See response to comment number 81 below. 	
60.				• Publications by one research group are mentioned in the dossier to support the hypothesis that alterations in EZH2 gene-expression is crucial in the BPA dependent mammary gland carcinogenesis MoA (Bhan, 2014a (ref.23), 2014b (ref.24); Hussain, 2015 (ref.25)). The French dossier did not mention that gene expression of EZH2 and other genes were investigated in other studies, e.g., in the comprehensive US National Center for Toxicological Research (US FDA/NCTR) one-generation 90-day study by Delclos (2014 (ref.15)) conducted under the auspices of NTP. No effect on EZH2 gene-expression was reported in this comprehensive study for BPA or EE2 in any tissue investigated, including female mammary glands (Camacho 2015; supplementary data (ref.26)).
• All studies highlighted as “most informative” (marked grey in the French dossier) in the chapter on mammary gland carcinogenesis were already included in the comprehensive review by EFSA (2015 (ref.6)). EFSA reported notable limitations for these studies. The reasoning for this deviating evaluation is not given in the French dossier.	Thank you for the reference from Camacho et al., 2015. The summary table has now been amended and results from Camacho et al., are now included.

See below the response to comment 83 for further details.
	
61.				The French authorities highlight the study by Xu, 2010 (ref.27) as “most informative” for the endpoint brain development and cognitive function. EFSA evaluated this study and three additional studies reported by the same laboratory and concluded: “Overall, the studies by Xu et al. in mice showed an inconsistent change in hippocampal NMDAR subunits between age and sex after exposure to BPA, and no conclusion can be drawn from these findings.” (EFSA, 2015; emphasis added in the pdf attachment).

In summary, while the use of the ToxRTool in principle is appreciated, its non-transparent application in the French dossier and the specific discrepancies with earlier assessments of the same studies by regulatory bodies is concerning. Therefore it´s result cannot be regarded an appropriate weight of evidence.	It is reminded that the conclusions are based on WoE on the whole database and not only on a limited number of selected studies.

It is an important finding of the series of studies performed by Xu et al. in mice that the effects of BPA are sex-specific. Both males and females were tested in two studies (Xu, 2011b and Xu, 2013b) and both studies observed an alteration of learning and memory in males whereas no effect was significant for this parameter in females. Another study was performed in males only and reported similarly an alteration of spatial learning and memory (Xu, 2010b).
A similar pattern was observed for regulation of the expression of hippocampal NMDAR subunit that were down-regulated in all studies that investigated this parameter in males (Xu, 2010b, Xu, 2012, Xu, 2013a, Xu, 2013b).
In addition, the concomitant effects on memory and NMDAR are perfectly coherent and are supported by more than 30 years of studies on the involvement of NMDAR in learning and memory process, especially in long-term memory. The fact that the effects observed may be age and sex-dependent is also not surprising at all. Sex and age differences are known for a very long time in toxicology. Thus, we think that it is not legitimate to evoke such differences to disqualify a study. 

In females, a recent additional study investigated BPA’s effect in ovariectomised females and interestingly observed that BPA suppresses the effect induced by estrogen supplementation in ovariectomised animals (Xu, 2015a). The same was also observed for the modification of synaptic interface and the modification of the expression of synapsin I, PSD-95 and NMDA receptor GluN2B.

Altogether, this database is therefore indeed quite consistent in showing an effect that is expressed differently according to the sex. In terms of MoA, sex-specifity and results on ovariectomised mice support that interaction with sex hormones and in particular estrogenic pathway may be involved in the effect. Given than the MoA involves estrogenic pathways, it is also not surprising to observe a difference of effect in the different sexes.

It is also noted that in Xu (2010b) the number of animals used for testing is known (n=10/group on PND21 and 10/group on PND 56) and there is no specific element raising questions on the dosing protocol. The level of information provided in the paper conforms to what is expected in a publication of good quality and does not compromise the validity of its results.	
62.				C. The European Food Safety Authority (EFSA) discussed the ED question with respect to BPA and came to the clear conclusion that, based on the WHO criteria, BPA is not an endocrine disruptor. This is the opposite from what is proposed by the French authorities. Such a fundamental divergence demonstrates that it is impossible to conclude that there is “scientific evidence of probable serious effects to human health” as demanded by Article 57(f).
The European Food Safety Authority (EFSA) evaluated BPA in a comprehensive review taking into account all relevant information and published its scientific opinion in 2015 (ref.6). EFSA endorses the World Health Organisation (WHO)’s definition on endocrine disruptors and concluded on the question “Is BPA an “endocrine disruptor” as follows:
“In their 2015 opinion on BPA, EFSA’s experts reviewed all literature on potential endocrine-related effects of BPA. They concluded that there is no single clearly-defined explanation that substantially completes scientific understanding of the potential effects of BPA in humans. Therefore, based on the WHO criteria, it is not possible to conclude that BPA is an endocrine disruptor” (emphasis added in the pdf attachment).

	It is emphasized that defining whether BPA is an endocrine disruptor has never been the purpose of EFSA assessment.
In addition, the exact EFSA quote mentioned in Plastic Europe’s comment has not been located in EFSA’s opinion.
It is correct to quote EFSA’s conclusion on the absence of a single clearly-defined explanation but the last sentence “Therefore, based on the WHO criteria, it is not possible to conclude that BPA is an endocrine disruptor” is NOT part of EFSA’s opinion but in its FAQ 

In this FAQ, which is rather short, EFSA refers to 2015 opinion and to “causal relationship”. They also conclude “The effects of BPA on fertility and reproduction and the endocrine system have been subject to much scientific debate” when RAC has adopted in March 2014 (https://echa.europa.eu/documents/10162/777918ff-33b5-46ff-be89-2bdc406d34fa) an opinion to classify BPA in category 1B for reproductive toxicity – adverse effect on sexual function and fertility (“Presumed human reproductive toxicant”). Our dossier is not based on the same database than EFSA, although we have no precise indication on the database used for this FAQ (potentially literature collected up to December 2012). Finally, when considering the definition of an ED, the association between adverse effect of MOA is defined as a biologically plausible link and not a causal relationship. 

In contrast, RAC mentioned in its opinion on classification of BPA for reproductive toxicity (ECHA 2014): “Both oestrogenic and anti-oestrogenic effects of BPA were described and not all expected oestrogenic effects were observed. However, RAC concluded that the observed pattern of effects on the female reproductive tract suggest an overall oestrogen-like response in vivo.”
This illustrates well that the MoA is most probably complex but that estrogenic pathways are preponderant. In addition, it provides support from a European regulatory body to our analysis. 	
63.				D. The current prevailing scientific literature does not provide any scientific evidence of probable serious effects to human health via an ED related mode of action (MoA) across the 4 different endpoints identified by the French authorities. Thus it does not fulfil the requirements set by Article 57(f).
The information provided in the French dossier to be indicative of an endocrine MoA is not plausible. There is also no consistent description of adverse effects and not all available information is included in the dossier. 
Regarding the 4 different endpoints identified by the French authorities, the PC/BPA Group notes that:	Please see response to more specific comments below.	
64.				• Estrous cyclicity: The studies mentioned in the French dossier indicate that levels of BPA detected in the ovarian follicle, blood and urine do not result in negative effects on granulosa cell steroidogenesis in vitro. Reported in in vitro observations at unrealistically high (µM) concentrations should be considered as supra-physiological and consequently not relevant for animals or humans in vivo. In addition, the observations reported in in vivo studies including the selected “key-study” by Lee (2013 (ref.28)) are not consistent with the proposed MoA.	It is difficult to compare doses of short-term in vitro studies with those showing effects after long-term exposure in vivo. We agree that a dose concordance will help but comparison of dose response relationship in in vitro models with in vivo data is challenging.
Without further details on the comment of Lee, it is difficult to understand why this study is judged inconsistent. On the contrary, we consider that “This work is in accordance with in vitro data described above. It shows that one clear-cut primary target of BPA is the reduction of the expression of aromatase. BPA first decreases estradiol levels by disturbing P450arom protein expression. Then, it is likely that the prolonged status of reduced estradiol subsequently provokes decreased feedback regulation of LH, lengthening of the estrous cycle as well as ovarian cell apoptosis”. See below comment number 81 for further response to your comment 	
65.				• Mammary gland: Acute studies in adult animals are mentioned in the French dossier. However, there are chronic carcinogenicity studies in rats and mice available, which did not show any carcinogenic effect, but these are not mentioned or cited. The authors of the comprehensive one-generation 90-day study by Delclos (2014 (ref.15)), including naıve and vehicle controls, conducted at NCTR/FDA concluded that there is no robust evidence for duct hyperplasia in mammary gland tissue.	Refering to the BPA carcinogenicity studies, it should be reminded that these studies were conducted with a very limited number of dose levels (only two dose levels) and at quite high dose levels: 1000 and 5000 ppm in rats and 1000 and 5000 ppm in mice. Lastly these studies were not carried out during the right window of exposure, a reason why these studies were not included in the SHVC report.

Regarding the results from Delclos et al., 2014, these results and the design of this study was already included in our report. 

The effects of chronic exposure to BPA from gestation day 6 (GD6) on rat mammary glands were studied by Delclos et al. (2014) in juvenile and adult animals. These results are already included in the BPA SVHC report see section 4.3.3 and see Table 16.

Ductal hyperplasia, as defined by the authors, was observed in this study as well as one mammary adenocarcinoma at the lowest tested dose level only (2.5 µg/kg bw/day, oral route). 

Due to some methodological uncertainties (which, in particular, limit the sensitivity of this study) made it difficult to assess the doses from which BPA causes hyperplastic ductal lesions. A dedicated opinion published by ANSES is available on the following link :
https://www.anses.fr/fr/system/files/SUBCHIM2015sa0001.pdf	
66.				• Brain and behaviour: No defined adverse effect or MoA is established for the endpoint. Studies mentioned as “most informative” in the French dossier are evaluated by EFSA as “inconsistent change” and “no conclusion can be drawn from these findings.” In addition, studies conducted by US FDA/NCTR were available and evaluated by EFSA: “Overall the CEF Panel noted that this robust well conducted study shows very limited effects of BPA on neurobehavioural endpoints, with the positive control EE, showing more marked, but not substantial changes.” (EFSA 2015 (ref.6); emphasis added in the pdf attachment). Initial information from the CLARITY study does not report robust adverse effects on brain or behaviour or an endocrine, specifically estrogenic, MoA.	This comment summarises Plastic Europe’s criticisms that are detailed in the next document below (“Scientific background document on the comments to the French Annex XV dossier on Bisphenol A (BPA) – ED”). Please see detailed response to these comments 84 to 88 below. 
In particular, it is emphasized that the results obtained within the CLARITY-BPA program and related to learning/memory performance are described in Johnson (2016) that is included in the Annex XV dossier. It provides some indications of altered spatial navigational learning and memory. 	
67.				• Metabolism and obesity: No consistent adverse effect and no MoA is established for the endpoint metabolism and obesity. The French dossier mentions data from individual studies without deriving a MoA. Cross-sectional human studies are taken to establish a MoA for insulin resistance although cross-sectional studies in general are discussed in the dossier as follows: “cross-sectional studies are not designed to assess a causal link and therefore were not further considered. Only prospective studies may be used to discuss a causal link.”
	Anses considered that cross sectional studies are not appropriate to investigate a causal link between exposure to BPA and a health effect, due to concomitant measurement of the exposure and the effects. Cohort studies would be more appropriate to show an association between exposure to BPA and an effect and to investigate a causal link. However due to methodological constraints such as the delay between exposure and the development of an effect, the lack of sensitive biomarker of effects for ED associated effects, the co-exposure to other chemicals etc.   it is anticipated that epidemiological studies will rarely be able to provide robust evidence that could be used in a weight of evidence approach to identify ED. However, negative results (i.e. no significant association) of epidemiological studies are not sufficient to conclude on the lack of effects in humans. That is why, based on animal data and without any good argument to exclude that this could happen in humans, we consider that the adverse effects observed in rodents are also relevant for humans.	
68.				The PC/BPA Group notes that there are numerous studies not cited in the French dossier which investigated endpoints as e.g., estrous cyclicity at different life stages, and the majority of studies show no effect on estrous cyclicity using human relevant exposure (Goodman, 2009 (ref.18), 2006 (ref.19); Gray, 2004 (ref.20); CERHR, 2008 (ref.11); EFSA, 2015 (ref.6); SCOEL, 2014 (ref.). Taking into account and weighing all relevant data, BPA should not be considered as an endocrine disruptor.	All the references cited here are reviews of existing data that are all incorporated in the dossier. The analysis performed earlier by other bodies are not mixed with the raw data for the sake of clarity. Moreover, these reviews or report are deemed to identify threshold values based on known hazard while our report aims to demonstrate a new hazard: the endocrine disrupting property of BPA.	
69.				Also the CLARITY study contains endpoints relevant to the evaluation of estrous cyclicity, potential mammary gland carcinogenesis, brain and behaviour, and metabolism. Taking into account information from exploratory studies within this study, the hypothesis of endocrine disrupting properties of BPA (adverse effects related to an endocrine, specifically estrogen, MoA) is not confirmed with the currently available data from the CLARITY-BPA study.	Please see detailed response to the comments related to the CLARITY study above. 	
70.				It is further concerning that the French dossier does not take into account the OECD document 150 “Guidance Document on Standardized Test Guidelines for Evaluating Chemicals for Endocrine Disruption” and considered in vivo experiments in ovariectomized rodents as “most informative studies” although comprehensive level 5 multi-generation studies are available.
	The purpose of the Annex XV dossier is to establish both adverse effects as well as their ED MoA. In this perspective, it is fully justified that studies using ovariectomised animals are identified as very informative in particular for MoA considerations.
It is also noted that the studies by Xu (2015b) and Inagaki (2012) also include intact animals in their protocol in addition to ovariectomised animals.	
71.				In the attached scientific background document, the PC/BPA Group provides more detailed scientific information on the 4 individual endpoints described in the French dossier.	Detailed responses to this document are provided below.	
72.				4. THE ANNEX XV DOSSIER PROPOSED BY THE FRENCH AUTHORITIES DOES NOT FOLLOW THE ACCEPTED PROCEDURE FOR DEVELOPING A RISK MANAGEMENT MEASURE
The submission of a second SVHC dossier by the French authorities has been undertaken without the completion of an accepted Risk Management Option Analysis (RMOA). The RMOA should be completed before taking further actions under the relevant processes of REACH, based on ECHA’s duties of sound administration and in respect of legitimate expectations.
Several ECHA documents (ref. 29) and guidance refer to the need to develop an RMOA prior to adopting risk management measures (“RMMs”). The purpose of the RMOAs is to identify the best regulatory option to manage any identified risk, either in REACH (authorisation, restriction or substance evaluation) or outside of REACH (with other legislation). The identification of a substance as an SVHC under REACH is one option that authorities performing the RMOA can consider recommending as the best way forward.
A RMOA for BPA based on its CMR classification appears to have been finalized by France, with the conclusion “[a]ppropriate to initiate regulatory risk management action”, and follow-up “SVHC” (ref.30) which apparently has been the basis of the Annex XV dossier proposal under Article 59 of REACH by France, culminating in the identification of BPA as an SVHC under that provision, on 12 January 2017. The respective RMOA has to-date not been made publicly available and no stakeholder consultation has taken place, according to industry’s knowledge.
Under a different PACT (Public Activities Coordination Tool) entry, included by France on 13 October 2016, ED properties are listed as the scope of a hazard assessment for BPA. Until the publication of the Annex XV dossier, this assessment was still categorised as “under development” and there was “no suggestion yet” as for the RMM to be adopted (ref.31). The PACT entry was only updated on 13 April 2017, a month after the publication of the Annex XV dossier, and now indicates that according to the French authority’s assessment, BPA is considered an ED in accordance with the WHO/IPCS definition. It is proposed under the same PACT entry to carry out an RMOA as a follow up.
By this, even the French authorities themselves acknowledge that the SVHC proposal is premature as SVHC identification as a RMM can only be one of the possible conclusions of an RMOA. Hence, this initiative ultimately compromises the agreed SVHC Roadmap 2020.
________________________________________________
See the corresponding embedded attachment in table 1 of Part I: 4820_Attachments PCBPA comments Annex XV dossier.zip	Your comment is noted although not directly related to BPA 57(f) identification.

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
73.				Content of the attached document “Scientific background document on the comments to the French Annex XV dossier on Bisphenol A (BPA) – ED” is reproduced below (please refer to the PDF for appropriate layout and footnotes) 	Please see below detailed response on each section of the comment.	
74.				Executive summary:
1) General aspects
a) The OECD Conceptual Framework document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” is not taken into account
The French dossier does not take into account the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” and considered in vivo experiments in ovariectomized rodents as “most informative studies” (OECD 2012) although comprehensive level 5 multi-generation studies are available. Taking into account and weighing all relevant data, BPA should not be considered as an endocrine disruptor. This conclusion is consistent with the EFSA evaluation on BPA in 2015 which indicated; “Therefore, based on the WHO criteria, it is not possible to conclude that BPA is an endocrine disruptor.” (EFSA 2015).
b) The French proposal is premature in light of the ongoing US NCTR/NTP study (CLARITY Study).
Once finalized, the chronic core study will further help to assess the coherence of observations related to assumed MoA(s) and consistency amongst different studies. The central theme of the Annex XV dossier is that BPA exerts adverse effects by “…disruption of the estrogenic pathway and estrogenic regulation.” As the CLARITY study includes the reference estrogen ethinyl estradiol (EE2) as a control, it will help to assess the specificity of effects (endocrine related versus nonendocrine related, especially related to estrogen related activities).
c) The French dossier does not discuss human relevance of observations in general 
Much of the French dossier is devoted to a detailed description of the physiology of estrus cycle regulation and ovulation in rodents, and the scant in vivo data cited for the mode of action comes from studies in rodents, not humans or non-human primates.
2) Estrus Cyclicity:
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible
The studies mentioned in the French dossier indicate that levels of BPA detected in the ovarian follicle, blood and urine do not result in negative effects on granulosa cell steroidogenesis in vitro.
In vitro observations at μM concentrations should be considered as supra-physiological concentrations not relevant for animals or humans in vivo. In addition, the observations reported in in vivo studies including the selected “key-study” by Lee (2013) are not consistent with the proposed hypothesis that aromatase is a primary target of BPA.
b) Evidence for a neuroendocrine basis to BPA-induced disruption of estrous cyclicity following developmental exposure is inconsistent
The French dossier did not elaborate a MOA but summarised results from individual studies with contradictory and/or inconsistent individual observations.
c) No consistent adverse effect on estrus cyclicity is described and not all available information is mentioned
There are numerous studies not cited in the French dossier which investigated estrus cyclicity at different life stages and the majority of studies show no effect on estrus cyclicity using human relevant exposure level (Goodman 2009, 2006, Gray 2004, CERHR 2008, EFSA 2015, SCOEL 2014). Taking into account and weighing all relevant data BPA should not be considered as an endocrine disruptor related to estrus cyclicity.
d) The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool
The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool and fails to explain the major differences and inconsistencies between the selection and scoring of individual studies compared to EFSA (2015).
e) The OECD Conceptual Framework document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” is not taken into account
The French dossier does not take into account the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” and considered in vivo experiments in ovariectomized rodents as “most informative studies” although comprehensive level 5 multi-generation studies are available.
f) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
The CLARITY study contains endpoints relevant in the evaluation of estrus cyclicity.
3) Mammary gland
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible
Acute studies in adult animals are mentioned to discuss a specific mammary gland carcinogenesis MoA in adult animals. Chronic carcinogenicity studies in rats and mice are available, but not mentioned or cited. The chronic studies did not show any carcinogenic effect.
The comprehensive one-generation 90 day study by Delclos (2014), including naıve and vehicle controls, conducted at NCTR/FDA, concluded that there is no robust evidence for duct hyperplasia in mammary gland tissue.
b) The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool
The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool and fails to explain the major differences and inconsistencies between the selection and scoring of individual studies compared to EFSA (2015).
c) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
The CLARITY study contains endpoints relevant in the evaluation of potential mammary gland carcinogenesis.
4) Brain and behaviour:
a) The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool
The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool and fails to explain the major differences and inconsistencies between the selection and scoring of individual studies compared to EFSA (2015).
b) No consistent adverse effect is reported and comprehensive information is not mentioned in the French dossier.
No defined adverse effect or MoA is established for this endpoint. Studies mentioned as “most informative” in the French dossier are evaluated by EFSA as “inconsistent change” and “no conclusion can be drawn from these findings.” In addition, studies conducted by US FDA/NCTR were available and evaluated by EFSA: “Overall the CEF Panel noted that this robust well conducted study shows very limited effects of BPA on neurobehavioural endpoints, with the positive control EE, showing more marked, but not substantial changes.” (EFSA 2015 ; emphasis added)
c) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
Initial information from the CLARITY study does not report robust adverse effects on brain or behaviour or an endocrine, specifically estrogenic, MoA.
5) Metabolism and obesity
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible
Cross-sectional human studies are taken to establish a MoA for insulin resistance. Cross-sectional studies in general are discussed in the dossier as follows: “cross-sectional studies are not designed to assess a causal link and therefore were not further considered. Only prospective studies may be used to discuss a causal link.”
b) No MoA is established for the endpoint metabolism and obesity
The French dossier mentions data from individual studies without deriving a MoA.
	Please see below detailed response on each section of the comment.	
75.				1) General aspects:
a) The OECD Conceptual Framework document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” is not taken into account
According to the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” (OECD 2012) all available data should be considered during an evaluation. The conceptual framework consists of 5 levels:
Level 1: Existing Data and Non-Test Information
Level 2: In vitro assays providing data about selected endocrine mechanism(s) / pathways(s) (Mammalian and non mammalian methods)
Level 3: In vivo assays providing data about selected endocrine mechanism(s) / pathway(s)
Level 4: In vivo assays providing data on adverse effects on endocrine relevant endpoints
Level 5: In vivo assays providing more comprehensive data on adverse effects on endocrine relevant endpoints over more extensive parts of the life cycle of the organism
Although level 5 multi-generation studies are available the French dossier cites, in the context of estrus cyclicity, lower-level studies as “most informative” studies.
The OECD framework describes that level 3 studies indicate a possibility that level 4 and 5 studies will show adverse effects, but positive outcome in level 3 studies per se should not be taken as adverse effects. “A positive outcome (i.e. a statistically significant change(s) in an ED-specific endpoint) of Level 3 assays indicates a possibility for adverse effects in the reproductive and developmental studies at Levels 4 and 5 and may in certain cases (UT assay) indicate effects in immature animals (which may be considered of concern).” (OECD 2012)
Overall, the French dossier does not take into account the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” and considered in vivo experiments in ovariectomized rodents as “most informative studies” although comprehensive level 5 multi-generation studies are available.
Taking into account and weighting all relevant data BPA should not be considered as an endocrine disruptor. 
	First, it is reminded that the purpose of the Annex XV dossier is also to establish both adverse effects as well as their ED MoA. 
In this perspective, it is fully justified that studies using ovariectomised animals are identified as very informative in particular for MoA considerations.
It is also noted that the studies by Xu (2015b) and Inagaki (2012) also include intact animals in their protocol in addition to ovariectomised animals.

More importantly, the OECD document 150 mentions important notes in the definition of the conceptual framework (annex 1.4 of OECD document 150 on page 385-387) that are not reported in Plastic Europe’s comment:
-	note to Level 3: “Some assays may also provide some evidence of adverse effects.”
-	general note to the conceptual framework: “Note 2: The assessment of each chemical should be made on a case by case basis, taking into account all available information.” 
The framework therefore clearly mentions that information on adverse effects is not only obtained in level-5 studies but also in level 4 (as defined by its title) and sometimes level-3 studies.
The OECD conceptual framework is therefore fully consistent with the weight of evidence approach that has been used in the Annex XV dossier, in which every study was considered for its strength and limitation. This methodology has been applied on the one hand for identification of the adverse effects and on the other hand for ED MoA considerations for each endpoint.
It is also noted that some of the adverse effects discussed in the dossier are not fully addressed in standard protocols and that level-5 studies are not gold-standard for these endpoints. In both the 2-generation and the extended one-generation studies:
-	testing of learning/memory performance is not a standard requirement (unless the DNT cohort of the EOGRT is included in the design)
-	glucose or insulin tolerance tests are not included in the protocol
-	Whole mount examination of the mammary gland is not yet included in this protocol whereas some recommandations about further examination of the mammary gland are given in the OECD Guidance Document 151.
It is therefore not surprising nor questionable from a methodological point of view that the most informative studies are not level-5 studies according to OECD conceptual framework.	
76.				This conclusion is consistent with the EFSA evaluation on BPA in 2015, which indicated; “Therefore, based on the WHO criteria, it is not possible to conclude that BPA is an endocrine disruptor.” (EFSA 2015)	As mentioned before, this quote from EFSA has not been located in its 2015 opinion, see reponse to comment 62.	
77.				b) The French proposal is premature in light of the ongoing US NCTR/NTP study (CLARITY Study).
The CLARITY study is widely acknowledged, by regulators at European level, including ECHA, to be the definitive study for the assessment of the endocrine disrupting properties of BPA. As stated by both EFSA (2015) and the German BfR in 2015 (BfR 2015), it is necessary to wait for the comprehensive CLARITY study. In its scientific opinion of 2015, EFSA acknowledged that the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) panel will reevaluate
the BPA database, taking also into account endocrine related endpoints after a
comprehensive Consortium Linking Academic and Regulatory Insights on BPA (CLARITY-BPA)
study becomes available:
“The CEF Panel designated the TDI as temporary, pending the outcome of the long-term study in rats involving prenatal as well as postnatal exposure to BPA, currently being undertaken by NTP/FDA. This study will help resolve the uncertainties in the database”
(EFSA 2015)
The CLARITY-BPA program is a cooperative agreement, conducted under the auspices of the National Toxicology Program (NTP), between NIEHS-funded university-based researchers, staff at the NIEHS National Toxicology Program (NTP) and Division of Extramural Research and Training (DERT), and staff at the FDA’s National Centre for Toxicological Research (NCTR). (For detail see Heindel (2015) and Schug (2013). The in-life phase of the core chronic study was completed in January 2015. The publication of the core chronic study is expected in 2018 and will be a major building block for the overall assessment of BPA.
The core chronic Good Laboratory Practice study is being performed at NCTR and contains the essential elements of a guideline-compliant study (e.g. standard protocols and endpoints typically considered by regulatory agencies in hazard identification and risk assessment). The core chronic CLARITY study is a “Level 5” study in accordance with OECD Conceptual Framework document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption”. The study is comprehensive and even goes beyond the scope of other level 5 studies.
The core chronic study is a perinatal 2 year chronic study in Sprague Dawley rats with 14 treatment groups covering a large range of BPA doses including very low oral doses (2.5 to 25,000 μg BPA/kg/day and positive as well as negative control groups; overall nearly 1900 animals allocated).
Because BPA binds to the estrogen receptor and many of its reported effects have been hypothesized to be due to modulation of estrogen signalling. Two dose levels of the reference estrogen ethinyl estradiol (EE2) are also included. The study assesses early lifetime (perinatal) exposure and late outcome (not covered by current guideline testing) covering the full range of organ toxicity as well as carcinogenicity.
Thirteen academic researchers, funded by NIEHS, were provided with animals and/or tissues or serum from animals taken from the core chronic study for exploratory research to addresses questions from earlier exploratory studies.
Once finalized, the chronic core study will further help to assess the coherence of
observations related to assumed MoA(s) and consistency amongst different studies. The central theme of the Annex XV dossier is that BPA exerts adverse effects by “…disruption of the estrogenic pathway and estrogenic regulation.” As the CLARITY study includes the reference estrogen ethinyl estradiol (EE2) as control, it will help to assess the specificity of effects (endocrine related versus non-endocrine related, especially related to estrogen related activities).	Please also see our detailed response to comment 19 above in relation to the CLARITY-BPA study.	
78.				c) The French dossier does not discuss human relevance in general
Much of the French dossier is devoted to a detailed description of the physiology of estrus cycle regulation and ovulation in rodents, and the scant in vivo data cited for the mode of action comes from studies in rodents, not humans or non-human primates. Only cursory discussion is given on human relevance without clear conclusions; e.g.:
“There are therefore indications that this MoA may be relevant to humans during developmental exposure.” (emphasis added) 
“Even if available epidemiological studies are inconclusive, these effects are considered relevant for humans because similarities exist in homeostatic regulation of insulin production and sensitivity between animals and humans and because of in vitro experimental data using human cells or tissue.” (emphasis added)
	BPA is classified in category 1B for reproductive toxicity. Human relevance is a parameter to be considered in classification and is supported in RAC’s opinion, also considering its MoA:
“Disruption of oestrogenic signalling was considered to be the main mode of action for the effects of BPA on fertility, based on current knowledge. The hormonal systems are well conserved between mammalian species, and the effects observed in rodents are therefore also relevant for humans.”

In the same way, human relevance has also not been questioned by RAC for the 3 other endpoints discussed in the restriction opinion.

It is further highlighted that human relevance is discussed for each endpoint in a dedicated section.
	
79.				Conspicuously, the French dossier fails to cite a relevant critical review of these process in rodents versus humans, which explains why many MoAs underlying disruption of estrus cyclicity and ovulation in rodent species are unlikely to have relevance for human reproduction (Plant, 2012).
	For each of the endpoints, we have worked on objectively establishing the human relevance, i.e. we have identified the commonalities together with the differences between species: see numerous paragraphs in the support document (paragraphs 4.2.3.3.3, 4.3.7, 4.4.3.4, table7,…) . We have cited all available published epidemiological studies we found and mentionned their limitations. None of them is strong enough to allow a definitive conclusion in one direction or the other. In absence of epidemiological data allowing concluding, we had to base our demonstration on experimental data and their relevance for humans.
Regarding estrous cyclicity, the review cited (Plant, 2012) mentions that there are two points of view regarding the role of the hypothalamus in the ovulatory surge of LH: a ‘‘permissive role” with the main role played by the pituitary, which was based on the work of Knobil’s group (Krey et al., 1975) and a ‘‘deterministic one”.
First, in our dossier we have mentioned the potential role of the pituitary in the steroid-induced feedback on the HPG axis.
Second, since the studies of de Roux et al. (2003) and Seminara et al. where the implication of kisspeptine is well demonstrated by the infertility induced in the subjects carrying the mutation of GPR54 (kisspeptin receptor), more and more studies point out the key role of hypothalamic neuropeptides (kisspeptin and GnRH system) in the regulation of female fertility (reviewed in Singapore Med J 2015; Cortes et al., J Pediatr Adolesc Gynecol 2015; Clarke & Dhillo, J. Endocrinol 2016…).
Finally, in a recent paper of Plant’s laboratory (Trujillo et al.,
2016) performed in female Rhesus Monkey, it was found that imposition of an increment in circulating E2 concentrations early in the follicular phase resulted in an increase in the number of immunoreactive kisspeptin neurons in the anteroventral periventricular nucleus of the hypothalamic preoptic area, in association with the initiation of a premature LH surge. According to the authors, “this result supports the earlier finding of Smith et al. (2010) and reinforces the view that the population of kisspeptin neurons in the preoptic area of the primate hypothalamus plays a role in mediating the positive feedback action of E2 that elicits the preovulatory surge of LH in the normal menstrual cycle.”, although the role of the pituitary has also to be taken into account.	
80.				There are no human estrogens with estrogenic potencies at ERα or ERβ 10,000 times lower than the primary endogenous hormone 17β-estradiol. If there were, the French dossier should have identified these, as this would have been a compelling line of indirect evidence that BPA’s extremely weak estrogenic potential could have relevance for humans. In Section 4.1 [page 25], the French dossier notes that BPA is ten-thousand times less potent than the endogenous primary estrogenic hormone, 17β-estradiol at estrogen receptors (ERα and ERβ). However, it fails to put this potency into context with the synthetic estrogen DES, to which BPA was related just a few pages prior. DES is equipotent or in some assays, more potent than 17β-estradiol, making it at least 10,000 times more potent than BPA.	It is correct to say that the affinity of BPA with estrogen receptor is weak (in particular compared to DES) and cannot explain the effects observed in in vivo studies in particular at lower doses. However, the interaction of BPA with other receptors (extranuclear estrogen receptors, ERRγ, GPER) may explain the estrogenic effects of BPA at low dose as explained in the Annex XV dossier and as emphasized by several Scientists (see comments 41 and 135-139) and NGO (see comments 121-123) in this public consultation.	
81.				2) Estrus Cyclicity:
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible:
in vitro:
The French dossier provided information indicative of the endocrine activity of BPA and concluded:
“BPA reduces the estrogen production by granulosa cells in vitro by reducing the aromatase expression in all species studied including in humans.” All in vitro experiments mentioned (Table 9;page 54) were conducted at unrealistic high, supra-physiological concentrations between 1 to 100μM BPA concentrations1.
The French dossier did not take into account an alternative mechanism for the reduction inaromatase activity reported at supra-physiological (μM) concentrations in the in vitro studies. Basedon the very high BPA concentrations investigated and the reduction in all parameters mentioned in table 9 (page 54) it would be reasonable to assume that BPA shows cytotoxicity at these high concentrations.
There is only one study which used human cells. The authors used human granulosa cells and discuss their “supra-physiological“ data as follows (Mansur 2016): “As the aim of this proof-ofconcept study was to assess the effect of BPA on the steroidogenic pathway, we also treated the cells with high and supra-physiological concentrations of BPA. These concentrations were similar to or even lower than the concentrations tested in previous studies. Although the highest doses of BPA seem supra-physiological, the level of the chemical actually taken up by the cells remains unclear. In conclusion, our results suggest that levels of BPA detected in the ovarian follicle, blood and urine do not result in negative effects on granulosa cell steroidogenesis in vitro. These conclusions seem reassuring for women trying to conceive as exposure to BPA is ubiquitous, but further clinical studies are needed to replicate these in vitro results.” (Emphasis added)
In vivo:
The French dossier indicates “Lee et al. (2013a) developed a key study using adult female Sprague-Dawley rats” and indicated “This work is in accordance with in vitro data described above. It shows that one clear cut primary target of BPA is the reduction of the expression of aromatase.”(Emphasis added)
In the recent OECD TG 407 (sub-acute study) validation process one aromatase inhibitor: CGS 18320B was included as a reference compound. As reported in the validation report (OECD 2006) there are several severe effects reported for the aromatase inhibitor, including increase in body weight in female rats; “the limited impact on male body weights and the dramatic increase in
female body weights at all doses used in the studies.”…” In females, the dramatic increases in body weights at all doses need to be taken into account.” Consequently, “dramatic” increase in female body weight would be conclusive for a “primary target aromatase inhibitor”. Unfortunately, the Lee study reported in Material and Methods some body weights at the beginning of the study but did not mention body weight in the results. Since the study by Lee investigated adult rats and exposed the adult animals sub-chronically for 90 days the discrepancy between effects observed with a primary aromatase inhibitor in the OECD TG 407 validation process and observations reported in the Lee study do not support the hypothesis that BPA is an aromatase inhibitor. In addition a comprehensive OECD TG 407 study is available for BPA. No increase in body weight is reported at any dose tested in this study (Yamasaki 2002).
Since no consistent effect on fertility is reported at 1 - 100 μg/kg (the dose level investigated by Lee 2013a) in comprehensive multi-generation studies dosing adult animals (i.e. F0 generation), expert evaluations concluded that there is no consistent or reproducible effect at these dose levels (Hengstler 2011, EFSA 2015, ECHA 2014).
Overall, the studies mentioned in the French dossier indicate that levels of BPA detected in the ovarian follicle, blood and urine do not result in negative effects on granulosa cell steroidogenesis in vitro. In vitro observations at μM concentrations should be considered* as supra-physiological concentrations not relevant for animals or humans in vivo. In addition the observations reported in in vivo studies including the selected “key-study” by Lee (2013a) are not consistent with the proposed hypothesis that aromatase is a primary target of BPA.

b) Evidence for a neuroendocrine basis to BPA-induced disruption of estrous cyclicity following developmental exposure is inconsistent 
The French dossier indicates:
“The limited number of studies and differences in doses and analyses do not allow to conclude whether developmental exposure to BPA inhibits or increases neuropeptide expression. It seems, however, that neonatal and early postnatal exposure diminishes, while a longer exposure time starting from gestation until weaning increases, kisspeptin expression.” (page 43; emphasis added)
“It is noteworthy however, that based on available data it is sometimes difficult to state
whether those endocrine alterations are the primary mode of action or just
consequences of a non-endocrine related mechanism such as meiotic alteration or
epigenetic modifications in the oocytes and/or other follicular cell types. This is typical
of the regulatory loop systems that are the basis of endocrinology.” (page 43:
emphasis added)
Overall, the French dossier did not elaborate a MOA but summarised results from individual studies with contradictory and/or inconsistent individual observations.
c) No consistent adverse effect on estrus cyclicity is described and not all available information is mentioned
There are numerous studies not cited in the French dossier which investigated estrus cyclicity at different life stages. Ovarian cycle is a common endpoint measured in many studies. In some studies this endpoint is briefly mentioned in the text if no effect on ovarian cycle is observed; e.g. Betancourt 2010, Kubo 2001, Noda 2005, Adewale 2009, Yamasaki and Ishii 2012.
The publications by Hass 2016 and Vandenberg 2008 are mentioned in the French dossier in the chapters on brain development and mammary gland, respectively, but it is not mentioned that these studies also investigated estrus cyclicity and reported no effect.
A study by Lee (2013a) is considered in the French dossier as a “key study” study for estrus cyclicity. A second study by the same laboratory with a different experimental setting is not mentioned but reported “the mean duration of the estrus cycle in females did not differ” (Lee 2013b).
Overall, there are numerous studies not cited in the French dossier which investigated estrus cyclicity at different life stages and the majority of studies show no effect on estrus cyclicity using human relevant exposure (Goodman 2009, 2006, Gray 2004, CERHR 2008, EFSA 2015, SCOEL 2014). Taking into account and weighing all relevant data BPA should not be considered as an endocrine disruptor related to estrus cyclicity.
studies with contradictory and/or inconsistent individual observations.

c) No consistent adverse effect on estrus cyclicity is described and not all available information is mentioned
There are numerous studies not cited in the French dossier which investigated estrus cyclicity at different life stages. Ovarian cycle is a common endpoint measured in many studies. In some studies this endpoint is briefly mentioned in the text if no effect on ovarian cycle is observed; e.g. Betancourt 2010, Kubo 2001, Noda 2005, Adewale 2009, Yamasaki and Ishii 2012.
The publications by Hass 2016 and Vandenberg 2008 are mentioned in the French dossier in the chapters on brain development and mammary gland, respectively, but it is not mentioned that these studies also investigated estrus cyclicity and reported no effect.
A study by Lee (2013a) is considered in the French dossier as a “key study” study for estrus cyclicity. A second study by the same laboratory with a different experimental setting is not mentioned but reported “the mean duration of the estrus cycle in females did not differ” (Lee 2013b).
Overall, there are numerous studies not cited in the French dossier which investigated estrus cyclicity at different life stages and the majority of studies show no effect on estrus cyclicity using human relevant exposure (Goodman 2009, 2006, Gray 2004, CERHR 2008, EFSA 2015, SCOEL 2014). Taking into account and weighing all relevant data BPA should not be considered as an endocrine disruptor related to estrus cyclicity.	See the response provided above on this question of cytotoxicity as alternative MoA for aromatase inhibition. 

Regarding the comment on the Mansur’s study, it is difficult to compare doses of short-term in vitro studies with those showing effects after long-term exposure in vivo. We agree that a dose concordance will help but all toxicologists know the limitation of in vitro models in terms of dose concordance with in vivo data. The effects described by Mansur are also described in other in vitro models (different cell lines) and in vivo by Lee, 2013. Therefore, the reassuring conclusion of Mansur’s study is not endorsed in our dossier: one of the assumptions of toxicology is that effects identified at higher doses in specific models should be assumed relevant for humans at lower doses-longer time exposure unless the contrary is proven.

Aromatase inhibition

Effects on body weight of aromatase inhibitors depleting a whole organism on estrogen have been under scrutiny for a few years (G. J. van Londen et al., 2011). 
CGS 18320B is a global and strong aromatase inhibitior leading to oestrogen depletion. However, the Lee study describes a more subtle effect of BPA, which is not a “systemic/ general” nor a complete aromatase inhibitior, but a partial inhibitior in Granulosa cells in particular. 

In addition, it should be noted that in a recent publication by Hass (2016), in which pregnant Wistar rats (n = 17–21) were gavaged from gestation day 7 to pup day 22 with bisphenol A doses of 0, 25 µg, 250 µg, 5 mg or 50 mg/kg bw/day, it is noted that exposure to 25 µg/kg bw/day bisphenol A  in the female offspring,  resulted in increased body weight late in life.

Based on the current knowledge and thanks to your remark, the support document has been modified to be precise that data allow to claim for an aromatase inhibition in certain cells only, such as granulosa.

b) As mentionned before, the dossier tries to describe all the data available at the time of evaluation with no a priori on the outcome. In the case of the neuroendocrine basis to BPA-induced disruption of estrous cyclicity following developmental exposure, a biological plausible link can be set up, based on the state of science although contradicting results exist that ANSES was not able to explain.

c) Betancourt, 2010; Kubo, 2001; Vandenberg, 2008; Yamasaki and Ishii 2012 or Noda 2005; Lee, 2013b are indeed not cited in our dossier for estrous cycle and do report no modification in estrous cyclicity. They are all prenatal or perinatal studies performed for other endpoints. The data on estrous cycle are not reported (data not shown is mentioned in all the abovementionned papers). In some of them, even the method used is not reported. Without further details, these papers were judged not qualitative enough to be mentioned. Furthermore, the details do not help analysing the origin of discrepancies with other studies.

Hass (2016) reports that only around 60% of the control animals were still regularly cycling at 1 year of age. Somewhat lower frequencies ranging from 32 to 44% were seen in the BPA-dosed animals. Statistical analysis showed, however, that none of the dosed groups were significantly different from the control group (p = 0.11 or higher) of oestrus cyclicity at 1 year of age. The study was not added in our dossier after your comment as these results are equivocal and would not change our conclusion one way or the other.
	
82.				d) The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool
No information on the assessment of the individual questions provided in the ToxRTool or the rational to derive final scores is given for any study throughout the French dossier.
It is not explained why the French dossier did not take into account limitations on individual studies discussed by other expert committees. The following information is discussed by different expert committees on the Rubin 2001 study: EFSA 2015: “There were some shortcomings in the study performance. The number of mated dams (n=6) was low, and it was not reported whether the litter was used as statistical unit.”
SCOEL 2014: “Both of these studies [ Rubin 2001, Salian 2009] used, however, a limited number of parental animals and did not, for example, describe whether the litter effect was taken into account in the analysis of the results or not.”
CERHR 2008: “Strengths/Weaknesses: This study incorporates a range of basic developmental and gross functional reproductive endpoints, but the sample sizes are small (6 dams/group) and the statistical approach does not appear to use litter as the unit. Actual exposures are poorly defined, particularly postnatally. The plausibility of the estrous cycle changes is a strength. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process, based on a lack of adequate control for litter effects”
Overall, the French dossier is inconsistent and non-transparent concerning the application of the ToxRTool and fails to explain the major differences and inconsistencies between the selection and scoring of individual studies compared to other European expert committees.
e) The OECD Conceptual Framework document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” is not taken into account Although level 5 multi-generation studies are available the French dossier mentions lower-level studies as “most informative” studies. The study by Monje (2010) used ovariectomized rats supplemented with E2 implants. According to the OECD framework this study design should be considered a level 3 study: “These assays are designed to provide alerts to chemicals with possible endocrine disrupting properties, and detect alterations in endocrine-sensitive tissues. Therefore
they are of deliberately high responsiveness (e.g. use in some cases of castrated/immature animal models without an intact HPG axis, which are therefore unable to compensate fully for endocrine perturbations)”
The OECD framework further describes that level 3 studies indicate a possibility that level 4 and 5 studies will show adverse effects, but positive outcome in level 3 studies per se should not be taken as adverse effects.
“Overall, the French dossier does not take into account the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” and considered in vivo experiments in ovariectomized rodents as “most informative studies” although comprehensive level 5 multi-generation studies are available.
f) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
As mentioned above and stated by both EFSA and the German BfR in 2015, it is necessary to wait for the comprehensive CLARITY study. In its scientific opinion of 2015, EFSA acknowledged that the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) panel will re-evaluate the BPA database, taking also into account endocrine related endpoints after the CLARITY-BPA study becomes available:
“The CEF Panel designated the TDI as temporary, pending the outcome of the long-term study in rats involving prenatal as well as postnatal exposure to BPA, currently being undertaken by NTP/FDA. This study will help resolve the uncertainties in the database”.
The CLARITY study contains endpoints relevant in the evaluation of estrus cyclicity.	d) See response to comment 34  above to the same topic

e) See response to comment 75  above to the same topic
	
83.				3) Mammary gland
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible
The French dossier concluded in chapter 4.3.8 (Summary and conclusion) on mammary gland carcinogenesis: “Emerging epigenetic studies have reported changes related to estrogendependent genes (such as EZH2 and HOTAIR), as well as HOX genes (involved in embryogenesis and post-natal development) associated with the BPA induced abnormal development and cancer increased susceptibility of mammary gland.”
The studies by one research group mentioned in the dossier to support this conclusion used an inappropriate study design. Adult female rats were dosed by two subcutaneous injections (s.c.) with 25 μg/kg BPA 24h and 4h prior to sacrifice and observations on gene-expression are reported (Bhan 2014a, 2014b, Hussain 2015). Based on s.c. dosing, the acute exposure 24h and 4h prior to sacrifice and the use of adult animals these observations should not be considered relevant. This is even mentioned on page 23 of the French dossier where it is indicated: “… Therefore, the effects observed after subcutaneous exposure are considered relevant when the exposure has taken place during the developmental period. Studies with BPA subcutaneous administration in which the exposure took place in adults were only considered to be informative during the identification of the MoA of BPA.” (emphasis added) The French dossier did not mention that gene expression of EZH2 and other genes were investigated in other studies such as the comprehensive US National Center for Toxicological Research (US FDA/NCTR) One-Generation 90-day study by Delclos (2014). The authors investigated mammary gland apical histopathology, intraductal hyperplasis and gene-expression.
No effect on EZH2 or HOX gene-expression was reported in this comprehensive study for BPA or EE2 in any tissue investigated, including female mammary glands (Camacho 2015; supplementary data).
In addition, although the French dossier cites studies with exposure of adult animals, it is not mentioned that comprehensive chronic carcinogenicity studies are available in two species F344 rats and B6C3F1 mice (NTP, 1982). The EU-RAR (2008) concluded on these studies: “A small increased incidence of leukaemias was seen in male and female F344 rats along with increases in the frequency of mammary gland fibroadenomas in male rats. These increases were not statistically significant, were slight and in a strain prone to these tumours….Consequently, it is concluded that bisphenol-A was not carcinogenic in this study in both species.”

b) The French dossier is inconsistent and non-transparent concerning the application of the
ToxRTool
No information on the assessment of the individual questions provided in the ToxRTool or the
rational to derive final scores is given for any study throughout the French dossier.
The comprehensive study by Delclos (2014) is not considered as “most relevant” information although the study was considered as relevant by EFSA.
EFSA evaluated the above mentioned comprehensive NCTR study based on the peer-reviewed publication and the full study report with the individual data (US FDA/NCTR, 2013 and Delclos et al., 2014). In the study, animals were administered BPA by oral gavage from GD 6 through the start of labour and then directly to pups from PND 1 until termination at PND 90 at the doses of 0, 2.5, 8, 25, 80, 260, 840, 2 700, 100 000 and 300 000 μg/kg bw per day. Microscopic evaluation of the mammary gland was performed at PND 21 and PND 90. An increase in the incidence of mammary duct hyperplasia in females was observed at both times, with statistically significant effects at the BPA doses of 2 700 and 100 000 μg/kg bw per day at PND 21 and at the doses of 2 700, 100 000 and 300 000 μg/kg bw per day at PND 90. The severity of the duct hyperplasia was minimal in all dose groups.
The authors concluded: “The incidence of mammary gland ductal hyperplasia was variable across the dose range, including naıve and vehicle controls,…” “There were no other BPA-induced significant effects on the mammary gland in females…”
As is typical for NTP-sponsored studies, all pathological observations were subjected to extensive quality control procedures, including a re-reading of slides by a second internal pathologist, followed by a second set of review by outside pathologists, and finally a Pathology Working Group was convened during which consensus was reached on all diagnoses prior to release of the Final Pathology Report. The independent review of the data concluded: “Taking the incidences, statistical testing results, and all pathologist and study author opinions together, we conclude that the evidence for duct hyperplasia in the mammary gland of females on either PND 21 or 90 is weak. We consider it to be an equivocal finding that may be a reflection of normal biological variability and/or a reflection of limits in tissue processing. We agree with the study authors that there were no clearly adverse effects in the low-dose range. However, we also believe that this conclusion will be tested by the results of the chronic toxicity study with BPA, for which the current study served primarily as a dose-range finding study.” (Memorandum by Gu and Mitkus 2013) A second independent memorandum concluded: ”Therefore, we agree with the toxicologist that there are no significant mammary gland effects at the low does BPA range including the 2700 dose group as stated in the overall summary conclusion of the toxicology report (reference 2, pg. 9): “In conclusion, BPA in the dose region between 2.5 and 2700 μg/kg bw/day did not exhibit clear adverse effects in either sex under the conditions of this study”. (Memorandum by Mog and Francke 2013)
This study also investigated also intraductular hyperplasia and carcinoma in situ following the method of Murray (2007). Reprod Toxicol. 23:383-390. The NCTR reported high variability of the method and “no apparent BPA treatment effects was discerned”. Consequently, the data reported by the Soto Laboratory in rats were not confirmed by this study (NCTR GLP/NTP Technical Report 2013).

EFSA concluded the following strength and weaknesses on the Delclos (2014) study:
“The CEF Panel identified the following strengths/weaknesses the study:
Strengths:
- Large sample size
- Both naïve and vehicle controls available
- Adequate positive controls included
- Measurement of BPA concentration in the serum
- Number of doses (≥3)
- Oral administration by via gavage
- Phytoestrogen-free diet
- Use of non-PC cages
- Study performed according to OECD guidelines, under GLP US FDA/NCTR, 2013 and
Delclos et al., 2014
Weaknesses:
- Unintended exposure of the control groups (see Churchwell et al, 2014)”
(EFSA 2015)
Overall, the comprehensive study by Delclos (2014) conducted at NCTR/FDA concluded that the incidence of mammary gland ductal hyperplasia was variable, including naıve and vehicle controls, and there is no robust evidence for duct hyperplasia in mammary gland tissue.
All studies highlighted as “most informative” (marked gray in the French dossier) in the chapter mammary gland carcinogenesis were already included in the comprehensive review by EFSA (2015). It is not explained why the French dossier did not take into account limitations on individual studies discussed by EFSA; e.g.:
Durando 2007: The CEF Panel identified the following strengths and weaknesses in this
study:
“Strengths:
- Use of non-PC cages and of non plastic bottles
Weaknesses:
- Single dose level study
- Animal diet and phytoestrogen content not measured
- Low No of animals tested for histological examination”
(EFSA 2015)
Jenkins 2009: “In conclusion, the shortcomings in the study design, and the absence of a significant dose: response, the uncertainty regarding the exposure of the offspring to BPA, and the limitations in reporting preclude these results to be used for risk assessment of BPA and the re-evaluation of the existing TDI. However, the CEF Panel noted that a dose-related response of BPA on cell proliferation and apoptosis in the mammary gland was reported in the study and this deserves further considerations. Consistent finding: cell proliferation was increased and apoptosis decreased by BPA at PND 50 but not after PND 21 days. The CEF Panel concluded that the present study cannot be used for the assessment of cancer risk but as supporting evidence of the induction of proliferation by BPA following lactational as well as in utero exposure.” (EFSA 2015; emphasis added) Tharp 2013: “The CEF Panel acknowledged that a primate study is judged to have particular relevance for humans however also noted that very little is known about the mammary gland at birth in rhesus monkeys. So few individuals were used in this study and the variability among the measurements was such that it seems inappropriate to conclude the results were the result of BPA administration and not simply individual biological variation within the context of a high and changing endogenous sex hormone environment. …The mammary tissue was collected 1-3 days after birth, which is sufficiently non-standardised to represent another uncertain variable. Gestation periods may vary by a day or two between pregnancies and organ development may have been slightly different between the animals used. The results therefore can only be considered very preliminary and their relevance for the assessment of carcinogenic potential of BPA cannot be assessed. The CEF Panel concluded nonetheless that the results of this study can be used as supportive evidence of the induction of proliferation by BPA.” (EFSA 2015; emphasis added) Ayyanan 2011: “Two other new rodent studies reviewed used complex protocols in which the morphology, cell proliferation and other characteristics of mammary tissue were studied in offspring of mothers treated with BPA (Ayyanan et al., 2011; Kass et al., 2012). The CEF Panel considered that the morphological endpoints examined in these studies have no clear link to the development of mammary cancer in adult rodents or humans, although they provide some support for the hypothesis that BPA causes proliferative changes in the mammary gland. However the complexity of these studies, the limited numbers of animals,
the likely experimental and inter-animal variability as well as lack of any exposure data in
these studies hamper the clear interpretation of the data.”...“In contrast the study of Ayyanan et al. (2011) did not demonstrate an increased incidence of mammary tumours following exposure to BPA over a 1-year period. Overall, however, the CEF Panel concluded that based on the WoE evaluation and the experimental deficiencies in the studies, the findings in these studies do not provide convincing evidence that BPA is carcinogenic in animals when exposed pre- or perinatally.” (EFSA 2015; emphasis added)

c) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
As mentioned above and stated by both EFSA and the German BFR in 2015, it is necessary to wait for the comprehensive CLARITY study. In its scientific opinion of 2015, EFSA acknowledged that the Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) panel will re-evaluate the BPA database, taking also into account endocrine related endpoints after the CLARITY-BPA study becomes available:
“The CEF Panel designated the TDI as temporary, pending the outcome of the long-term
study in rats involving prenatal as well as postnatal exposure to BPA, currently being
undertaken by NTP/FDA. This study will help resolve the uncertainties in the database”.
(EFAS 2015)
The CLARITY study contains endpoints relevant in the evaluation of potential mammary gland carcinogenesis.	Results from Camacho et al., 2015 study are now included in our report.

Results on EZH2 are well reported in the supplementary data (Table Excel supplement table 5) but appears to be related to an evaluation conducted at PND4 and not at PND 90. Moreover, in this experiment, Esr2 is not modulated by EE2 and Esr1 is upregulated by a low dose of EE2 and slightly downregulated by higher doses of EE2: single probe analysis is not informative enough and need to be validated by further qPCR. Consequently those results cannot negate the results obtained on EZH2 and HOTAIR in adult animals in Bhan, (2014a, 2014b) or Hussain (2015). The Camacho study has been added to the support document for its conclusion: suggested that the effect of the high BPA dose level at the genome-wide gene expression overlapped to some extent with that of the low dose EE2, in particular in the female mammary gland.

Regarding the use of studies conducted with ovariectomized animals, these type of results can be used in order to document a MoA which was the case in our SVHC report.

Regarding Delclos et al., 2014 study, where the effects of chronic exposure to BPA from gestation day 6 (GD6) on rat mammary glands were studied in juvenile and adult animals, these results are already included in the BPA SVHC report (see section 4.3.3 and Table 16).

Ductal hyperplasia, as defined by the authors, was observed in this study as well as one mammary adenocarcinoma at the lowest tested dose level only (2.5 µg/kg bw/day, oral route). Some methodological uncertainties (which, in particular, limit the sensitivity of this study) made it difficult to assess the doses from which BPA causes hyperplastic ductal lesions. A dedicated opinion published by ANSES is available on the following link : https://www.anses.fr/fr/system/files/SUBCHIM2015sa0001.pdf 
Moreover even if this study was conducted according to GLP standard and NTP standard, a very limited number of mammary gland slides was made for each gland.

84.				4) Brain and behaviour:
a) The French dossier is inconsistent and non-transparent concerning the application of the ToxRTool
No information on the assessment of the individual questions provided in the ToxRTool or the rational to derive final scores is given for any study throughout the French dossier.
The French dossier highlights the study by Xu 2010b as “most informative”. EFSA evaluated this study and three additional studies reported by the same laboratory and concluded:
“Three new papers by Xu and co-workers (Xu et al. 2012, 2013a, 2013b) have examined the effect of BPA in the dose range 0.04 to 40 mg/kg bw on behaviour and brain, and have addressed the same hippocampal NMDAR subunits NR1 as Xu et al., 2010b in ICR mice of the same age… Overall, the studies by Xu et al. in mice showed an inconsistent change in hippocampal NMDAR subunits between age and sex after exposure to BPA, and no conclusion can be drawn from these findings.” (emphasis added)
The studies in mice by Xu 2013a and 2013b are cited within in the French dossier; the study by Xu 2012 is not cited.
Overall, taking into account the individual studies and the studies combined no conclusions can be drawn from these findings as indicated by EFSA.
The study by Xu (2010b) is ranged “most informative” in the French dossier. This study is also evaluated by EFSA with the following conclusion/limitations:
“Comments from the CEF Panel:
The CEF Panel identified the following strengths/weaknesses in the study:
Strengths:
- Number of doses (4)
- Phytoestrogen-free diet
Weaknesses:
- Test performed in one sex only (only male offspring)
- Insufficient study reporting (reproductive outcome not shown, e.g. maternal bw, no preweaning body weight data shown; information about type of bedding and water bottles missing; no indication of the number and the identity of the animals used for testing)
- Insufficient BPA-exposure assessment (unknown if constant during pregnancy and lactation and or adjusted daily to body weight, see line above).”(EFSA 2015)
	It is reminded that the conclusions are based on WoE on the whole database and not only on a limited number of selected studies.

The Support Document has been updated further to your comment to add Xu (2012). However, in contrast to what is said in your comment this study is consistent with the other pieces of the database.
Indeed, it is an important finding of the series of studies performed by Xu et al. in mice that the effects of BPA are sex-specific. Both males and females were tested in two studies (Xu, 2011b and Xu, 2013b) and both studies reported an alteration of learning and memory in males whereas no effect was significant for this parameter in females. Another study was performed in males only and reported similarly an alteration of spatial learning and memory (Xu, 2010b).
A similar pattern was observed for regulation of the expression of hippocampal NMDAR subunit that was down-regulated in all studies that investigated this parameter in males (Xu, 2010b, Xu, 2012, Xu, 2013a, Xu, 2013b).
In addition, the concomitant effects on memory and NMDAR are perfectly coherent and are supported by more than 30 years of studies on the involvement of NMDAR in learning and memory process, especially in long-term memory. The fact that the effects observed may be age and sex-dependent is also not surprising at all. Sex and age differences are known for very long time in toxicology. Thus, we think that it is not legitimate to evoke such differences to disqualify a study. 

In females, a recent additional study investigating BPA’s effect on ovariectomised females interestingly observed that BPA suppresses the effect induced by estrogen supplementation (Xu 2015a). The same was also observed for the modification of synaptic interface and the modification of the expression of synapsin I, PSD-95 and NMDA receptor GluN2B.

Altogether, this database is therefore indeed quite consistent in showing an effect that is expressed differently according to the sex. In terms of MoA, sex-specifity and results on ovariectomised mice support that interaction with sex hormones and in particular estrogenic pathway may be involved in the effect. Given than the MoA involves estrogenic pathways, it is also not surprising to observe a difference of effect in the different sexes.

It is also noted that in Xu (2010b) the number of animals used for testing is known (n=10/group on PND21 and 10/group on PND 56) and there is no specific element raising questions on the dosing protocol. The level of information provided in the paper conforms to what is expected in a publication of good quality and does not compromise the validity of its results.	
85.				The study by Inagaki (2012) is ranged “most informative” in the French dossier. This study is also evaluated by EFSA with the following conclusion/limitations:
“Comments from the CEF Panel:
The CEF Panel identified the following strengths/weaknesses in the study:
Strengths:
- BPA measurement in biological samples (serum)
Weaknesses:
- Single acute dose administration
- Test performed in one sex only
- Insufficient study reporting (study design, doses and number of animals used in the various tests appears unclear; except from feed content, no information of environmental contamination of BPA is given, i.e. cages, water bottles, or bedding)
- Inappropriate statistics (considerations of repeated measures of the same animal were not included in the statistical analyses, neither multiple endpoint within a test)
Overall the CEF Panel noted that handling and administration of the rats in connection with testing may influence the test results.” (EFSA 2015)
b) No consistent adverse effect is reported and comprehensive information is not mentioned in the French dossier.
Taking into account the EFSA evaluation and the study design the above mentioned study by Inagaki (2012) is not reliable and should not be rated as “most reliable” information. Female Sprague Dawley rats were administered BPA at levels from 0.4 μg/kg to 400 μg/kg by subcutaneous injection. Two types of hippocampal-dependent memory tasks, object placement and object recognition, were done. Ovariectomized rats (n=6-8 per dose level) received BPA 30 min to 4 h before testing.
According to the OECD framework the study by Inagaki should be considered a level 3 study according to the OECD document 150 “Guidance Document on Standardised test Guidances for evaluating Chemicals for Endocrine disruption” (2012) since the authors used acute dosing of ovariectomized adult rats.
	It is not considered that the design of this study (single dose and only female tested) compromise the validity of the results obtained in these specific experimental conditions. More generally, the result of any experimental study needs to be interpreted in relation to its specific test conditions and its relevance but this does not affect its reliability or robustness. The use of a single acute dose cannot be used to reject a study. This study merely reveals that acute effects, and at low dose, can occur, which is considered very important information. Hence, a chronic exposure is not necessarily required to induce adverse effects.
Concerning the investigation of one sex only, rejecting a study based on the use of only one sex appears as a rather fallacious argument. With such a rationale, studies on one age or a given developmental period should also be rejected. Thus; even if the study is focused on one sex, it provides very important information on the potential effect of BPA on the individuals of this sex.

The lack of investigation on multiple endpoints is not disqualifying. The study is focused on specific aspect of BPA toxicity and only methodological arguments should be raised.

It is also noted that one part of the study was performed on 18 intact females and not only in ovariectomised animals. In addition, the purpose of the Annex XV dossier is to demonstrate an effect as well as to analyse mode of action considerations. The study by Inagaki is therefore of major interest for demonstration that the action of BPA on memory is mediated through estrogen-dependent pathways as it provides evidence that BPA inhibited E2-induced memory enhancing effects in ovariectomised animals. Intact animals were tested at the different phases of the estrous cycle and inhibition of object recognition performance was observed in intact females only during the proestrus phase of the cycle when E2 levels are the highest.	
86.				The comprehensive DNT study by Stump (2010), a level 5 study, investigated brain histopathology and developmental neurototoxicity endpoints, including but not limited to learning and memory, open field, auditory startle, and motor activity. No compound related developmental neurotoxicity effects were reported at any dose tested in any endpoint investigated, including in the Biel maze test.
Other comprehensive level 5 studies also do not indicate effects on brain development and cognitive function:
Tyl (2002, 2008) did not indicate from the clinical observations any signs of neurotoxicity to rats or mice from the multigeneration reproduction studies. No effects on neurobehavioral observations or learning and memory were reported in a comprehensive 2-generation reproduction study in rats following BPA exposure from 0.2 to 200 μg/kg/day (Ema 2001).
Additional studies are conducted by US FDA/NCTR (Ferguson 2014 and 2012). The study by Ferguson 2012 is not cited within the French dossier. In both studies pregnant Sprague-Dawley rats (n=11-12/group) were gavaged daily with vehicle, 2.5 or 25.0 μg/kg BPA, or 5.0 or 10.0 μg/kg ethinyl estradiol (EE2) on gestational days 6-21. Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose their dam received. Postweaning, one offspring/sex/litter (n=11-12/sex/group) was assessed for the typical behaviors measured in developmental neurotoxicology studies (Ferguson 2012). Adolescent play, running wheel activity, flavored solution intake, female sex behavior, and manually-elicited lordosis were assessed in the second study by Ferguson (2014). The authors concluded “Although EE2 treatment caused pubertal delays and decreased testosterone levels in males, their behaviors were within the range of control males. Conversely, BPA treatment did not alter any measured endpoint. Similar to our previous reports (Ferguson et al. 2012; 2011), the BPA doses and design used here produced few alterations.” (Ferguson 2014)
EFSA concluded on the Ferguson 2014 study:
“Comments from the CEF Panel:
The CEF Panel identified the following strengths/weaknesses in the study:
Strengths:
- Large sample size
- Both naïve and vehicle controls available (to account for the handling of the animal)
- Adequate positive controls included
- Use of non-PC cages and of glass water bottles
Weaknesses:
- Study design not appropriate to the scope (only low doses BPA used)”
“Overall the CEF Panel noted that this robust well conducted study shows very limited effects of BPA on neurobehavioural endpoints, with the positive control EE, showing more marked, but not substantial changes.” (EFSA 2015; emphasis added)	The study of Stump (2010) is included in the Annex XV dossier and considered in the weight of evidence. It is however noted that animals were fed with a diet containing phytoestrogens which may therefore compromise the interpretation of results at low doses. 
The studies by Tyl (2002) and Tyl (2008) did not investigate any specific parameters related to neurobehaviour and it is therefore not relevant to include and discuss these studies in the Neurobehavioural section of the Annex XV report.

We take note of EFSA’s assessment of Ferguson (2014) as a robust study but this study does not include testing of memory/learning function.
The study by Ema (2001) is not further considered in the analysis as the results are not shown in the publication and cannot be evaluated. 
It is noted that Ferguson (2012) observed no effect of BPA on spatial learning and memory in a study of good quality.

However, the conclusions of our assessment are based on the repeated observations of an alteration of this function in several independent studies that cannot be dismissed by this additional negative study.

The Support Document has been updated to include the study Ferguson (2012) and take note of this conclusion.
 	
87.				No convincing evidence and controversial results can be concluded from available studies about an ED-related MOA causal link. Nakamura (2010), Watanabe (2012), and Lee (2013a) demonstrated that BPA exposure reduced testosterone content and down-regulated the expression of cytochrome P450 aromatase. While increased aromatase expression in rat testicular Leydig cells and prefrontal cortex the presence of BPA were determined in studies by Kim (2010) and Castro (2013).
	The effects considered are based on alteration of learning and memory in relation to an estrogenic action. In this regard, the study by Xu (2014b) provides strong evidence by reversing the effect of BPA with co-administration of an ER antagonist. This was further supported by Xu (2015b), Inagaki (2012) and Leranth (2008) that showed BPA’s interference with estrogens effect. 
Your comment is noted but does not contradict evidences of an estrogenic-mediated alteration of learning and memory. 

As noted in the Annex XV dossier, the detailed mechanism of action is not known and it is not excluded that other ED (or non ED) MoAs contribute to the complex response of BPA but they are not established with a sufficient level of evidence.
As discussed in the reproductive toxicity section, a reduction of estrogen production through aromatase down-regulation is consistently observed in the ovary of adult females. The observation of a different modulation of the aromatase in other experimental conditions and tissues (brain prefrontal cortex and testicular Leydig cells investigated respectively in Castro, 2013, and Kim, 2010) is therefore not unexpected considering the differences and complexity in sex hormone regulation in different sexes, organs and ages.	
88.				c) The French proposal is premature in light of the ongoing US NCTR/ NTP study (CLARITY Study).
As outlined above, the CLARITY study is widely acknowledged, by regulators at European level, including ECHA, to be the definitive study for the assessment of the endocrine disrupting properties of BPA.
As mentioned above in chapter 1 b The core chronic study is a perinatal 2 year chronic study in Sprague Dawley rats with 14 treatment groups covering a large range of BPA doses including very low oral doses (2.5 to 25,000 μg BPA/kg/day and two levels of the reference estrogen ethinyl estradiol (EE2) as well as a negative control group. Thirteen academic researchers, funded by NIEHS, were provided with animals and/or tissues or serum from animals taken from the core chronic study for exploratory research to addresses questions from earlier exploratory studies.
Certain initial publications from exploratory laboratories have already been released and they show no consistent effects for BPA on brain development or cognitive function. There is only a limited overlap with observations related to the estrogenic positive control ethinyl estradiol (EE2). An overview of the information that has been published so far:
Patel (2017) concluded on potential ovarian toxicity: “Collectively, these data indicate that BPA exposure at some doses and time-points affects ovarian follicle numbers and sex steroid levels, but these effects are different than those observed with ethinyl estradiol exposure and some previous studies on BPA” (emphasis added).
Concerning potential effects on exploratory and anxiety behavior Rebuli (2015) concluded: “No consistent effects of BPA were observed for any endpoint, in either sex, at either age compared to vehicle controls; however, significant differences between BPA-exposed and EE-exposed groups were identified for some endpoints” (emphasis added).
Concerning potential effects on spatial navigational learning and memory Johnson (2015) concluded: “Our current findings though suggest that the BPA-induced behavioral effects may be due to an estrogen receptor-independent manner” (emphasis added).
Arambula (2016) concluded on potential effects on the Neonatal Rat Hypothalamic and Hippocampal Transcriptome: “The present studies found limited effects of BPA on the PND1 rat hypothalamus and hippocampus…” (emphasis added).
Overall, based on the information from these exploratory studies, the hypothesis of endocrine disrupting properties of BPA (adverse effects related to an endocrine, specifically estrogen, MoA) is not confirmed with the available data from the CLARITY-BPA study. The core chronic CLARITY study also contains endpoints relevant for brain and behaviour; these data are not yet published.	Please see above the general response related to the CLARITY study to come. 

From the references quoted here as initial results from the CLARITY-BPA program:
-	The studies from Patel (2017) and Rebuli (2015) are not relevant in the discussion of the section in the Annex XV dossier dedicated to alteration of memory and learning as Patel (2017) relates to ovarian toxicity and behavioural tests performed while Rebuli (2015) relates to anxiety and locomotor activity.
-	The study from Johnson (2015) is quoted and described in the Annex XV dossier under its appropriate reference. Johnson (2016) indeed provides indications of a reduced performance in learning/memory in the Barnes maze.
-	The study by Arambula (2016) is very recent and was not considered in the Annex XV dossier but concluded that “BPA-related transcriptional changes were mainly confined to the hypothalamus. Consistent with prior observations, BPA induced sex-specific effects on hypothalamic ERα and ERβ (Esr1 and Esr2) expression and hippocampal and hypothalamic oxytocin (Oxt) expression. These data demonstrate prenatal BPA exposure, even at doses below the current no-observed-adverse-effect level, can alter gene expression in the developing brain.” It therefore provides additional indication that BPA exposure alters estrogenic signaling pathways, in a sex-specific manner. Effects in the hippocampus were limited but tissues were examined very early at PND1. It does not exclude that effects in hippocampus may appear later in life, as it was observed in a similar study where tissues were examined at PND28 (Kundakovic, 2013). 
	
89.				5) Metabolism and obesity
a) Information provided in the French dossier to be indicative of an endocrine MOA is not plausible
Information on the use of individual studies within the French dossier is not consistent throughout.
E.g. cross-sectional human studies “were not further considered” in one paragraph and in another paragraph one cross-sectional study “established that BPA acts on the efficiency of insulin on its target cells, and thus via an ED MoA”.
In chapter 4.5.3.3 (Summary of the plausible link between adverse effects and endocrine MoA:
Effects of BPA on insulin sensitivity; page 138) the French dossier reads:
“Finally, a study performed on 141 obese children concluded that there was a strong inverse association between BPA and adiponectin (Menale et al., 2016). Taken together, using distinct animal models and a cohort of obese children, these 3 recent studies established that BPA acts on the efficiency of insulin on its target cells, and thus via an ED MoA.” (emphasis added). Menale (2016) described their study design as cross-sectional; “Our study design was an observational cross-sectional one.”
Later on page 141 in the dossier cross-sectional studies are discussed as follows: “cross-sectional studies are not designed to assess a causal link and therefore were not further considered. Only prospective studies may be used to discuss a causal link.”
Consequently, the evaluation process for individual studies is not consistently followed within the dossier.
b) No MoA is established for the endpoint metabolism and obesity
The French dossier mentions data from individual studies without deriving a MoA and concluded in chapter 4.5.5 (General conclusion on metabolism and obesity)
“In conclusion, based on animal studies (rodents and non-rodents) after prenatal and/or perinatal or adult exposure, there is now evidence that BPA may increase the incidence of type-2 diabetes via an ED MoA. In particular, BPA has been shown to alter insulin secretion and/or release by β-pancreatic cells, or insulin signalisation (signaling mechanisms) within insulin-sensitive organs (i.e., liver, muscle, adipose tissues). This resulted in variations in the expression levels of hepatic or adipose tissue markers which are indicative of a state of insulin resistance. These effects are considered by the experts as hallmarks of endocrine disruption mechanisms, especially if there is a combination of effects each leading to insulin resistance within the different insulin-sensitive tissues. In addition, while most studies were performed on males, a few studies have also examined the impact of BPA either on both sexes or on females. However, more studies should be
undertaken before one can conclude on a sex specificity or not of the metabolic impact of BPA.”(emphasis added)
The French dossier did not develop a MoA but highlights effects reported in different studies “may” indicate that the MoA is “insulin secretion and/or release by β-pancreatic cells, or insulin signalization”. Further on it is mentioned that “effects are considered by the experts as hallmarks of endocrine disruption mechanisms” but it is not mentioned which effects are seen as “hallmarks” nor any quantitative relationship between in vitro and in vivo responses, since the dossier relies heavily on in vitro data to support the MoA.
In the next paragraph another hypothesis is mentioned: “Recent experimental in vivo and in vitro studies indicate that these effects may involve ERα, ERβ or GPR30 pathways. Other hormones such as leptin and adiponectin, which are involved in resistance to insulin and lipogenesis, are also modified following BPA exposure. This shows that BPA could interfere in the balanced interplay between insulin secretion and insulin action that controls glycaemia.”…” Overall, it is suggested that the pancreas is targeted by BPA exposure and that mechanisms could differ depending on whether exposure occurs during the fetal life or in adulthood.” (emphasis added) Again, the French dossier did not develop a MoA but highlights effects reported in different studies “may” involve ERα, ERβ, GPR30 pathways or other hormones.
In the following paragraph the French dossier mentions a third hypothesis: “Moreover, most of the in vitro studies showing adverse effects of BPA on adipocyte differentiation and function point to alteration of endocrine mechanisms (e.g., adiponectin release, insulin signaling cascade effectors).
It is not clear whether BPA activates PPARγ and/or other nuclear receptors. Cross-talk between nuclear receptors may explain these uncertainties.” (emphasis added)
Again, the French dossier did not develop a MoA but highlights effects reported in different studies and conclude “It is not clear whether BPA activates PPARγ and/or other nuclear receptors.”
Overall, no MoA is established.
Finally, the French dossier concluded in the same paragraph 4.5.5 (General conclusion on metabolism and obesity):”Even if available epidemiological studies are inconclusive, these effects are considered relevant for humans because similarities exist in homeostatic regulation of insulin production and sensitivity between animals and humans and because of in vitro experimental data using human cells or tissue.” (emphasis added)
Overall, it is not comprehensible that inconclusive human data should be considered relevant “because similarities exist in homeostatic regulation of insulin production and sensitivity between animals and humans and because of in vitro experimental data using human cells or tissue.” (emphasis added)	Anses considered that cross sectional studies are not appropriate to investigate a causal link between exposure to BPA and an health effect, due to concomitant measurement of the exposure and the effects. Cohort studies would be more appropriate to show an association between exposure to BPA and an effect and to investigate a causal link. However due to methodological constraints such as the delay between exposure and the development of an effect, the lack of sensitive biomarker of effects for ED associated effects, the co-exposure to other chemicals etc.   it is anticipated that epidemiological studies will rarely be able to provide robust evidence that could be used in a weight of evidence approach to identify ED. However, negative results (i.e. no significant association) of epidemiological studies are not sufficient to conclude on the lack of effects in humans. That is why, based on animal data and without any good argument to exclude that this could happened in humans, we consider that the adverse effects observed in rodents are also relevant for humans.

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NCTR GLP/NTP Technical Report for Project No. 2176.01. PI K. Barry Delclos – May 2013
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0495.1000e109.php?aid=8413		
91.				Content of the attached document “Legal considerations concerning Article 57(f) of the REACH Regulation in the framework of the Annex XV proposal for the identification of Bisphenol A as a Substance of Very High Concern (SVHC) based on its alleged endocrine disruptor properties” by Steptoe is reproduced below ((please refer to the PDF for appropriate layout and footnotes)		
92.				Legal considerations concerning Article 57(f) of the REACH Regulation in the framework
of the Annex XV proposal for the identification of Bisphenol A as a Substance of Very High
Concern (SVHC) based on its alleged endocrine disruptor properties
Note: the legal arguments summarised in the present document have been prepared for PlasticsEurope AISBL. The relevant definitions, as provided for by Regulation (EC) No 1907/2006 (“REACH” or “REACH Regulation”), are included in the Annex to this summary for reference.
A substance may not be identified as an SVHC under Article 57(f) when it has already been identified as an SVHC pursuant to Article 57(a) to (e).
For the purpose of identifying the substances that may be included on the candidate list (and eventually on the Annex XIV to REACH, as substances subject to authorisation), Article 57 of REACH provides for different criteria, listed in different entries from (a) to (f).
Article 57(a) to (c) cover substances meeting the criteria for classification in the hazard classes carcinogenicity, mutagenicity or reproductive toxicity (“CMR”) category 1A or 1B, in accordance with sections 3.5 to 3.7 of Annex I to Regulation (EC) No 1272/2008. Article 57(d) and (e) cover substances which are persistent, bioaccumulative and toxic (“PBT”) and those which are very persistent and very bioaccumulative (“vPvB”), in accordance with the criteria set out in Annex XIII to REACH.
Article 57(f) of REACH “covers all other substances which do not fulfil any of the foregoing criteria but ‘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 59’.”1 (emphasis added).
By way of example, the provision mentions substances which have endocrine disrupting properties, or substances PBT or vPvB properties, when these do not fulfil the criteria for inclusion under points (d) or (e) of Article 57.
The provision clearly reads that Article 57(f) is meant to cover all other substances which do not fulfil any of the criteria under Article 57(a) to (e).
This is further confirmed in a recent Judgement of the Court of Justice of the European Union (“CJEU”), which states that Article 57(f) of REACH targets specifically all other substances which do not fulfil any of the criteria under Article 57(a) to (e). Only substances that do not fall within the CMR, PBT and vPvB hazard categories specifically identified by the legislature as being of very high concern pursuant to Article 57(a) to (e), may be identified as SVHC pursuant to Article 57(f).2
The Court held that:
The criteria laid down under Article 57 of REACH for identification of substances on the grounds listed from (a) to (e) are “based on the assessment of the hazards presented by those substances”.3
“Article 57 provides, at point (f), for an independent mechanism that makes it possible to identify, as being of very high concern, substances which have not already been designated as such under that provision.”4 (emphasis added)
The Court therefore held that, where a substance has been already identified as an SVHC pursuant to Article 57(a) to (e), it may not be identified as an SVHC pursuant to Article 57(f).
Therefore, it must be inferred that BPA may not be identified as an SVHC under Article 57(f) when it has already been identified as an SVHC under Article 57(c).

Annex: Relevant Articles of the REACH Regulation
Article 57(f)
The following substances may be included in Annex XIV in accordance with the procedure laid down in Article 58: […] (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 fulfil 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 59.	On regulatory and practical grounds:
As it has been established through decision "implementing identification of bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl phthalate (DIBP) as substances of very high concern according to Article 57(f) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council" (adopted during Reach Committee in February 2017), "Article 57 does not forbid identifying a substance as being of very high concern several times based on more than one intrinsic property causing the same effect on human health".
Co-legislators did choose not to prevent SVHC listing of a substance for intrinsic properties causing the same effect as a hazard that has already allowed its SVHC identification, and that it is possible to include such substances for all possible identification criteria, as many examples of regulatory impacts as below prove it: 
- Transparency provides clear information on the dangers of the substances present in the articles, hence the need to identify the SVHC substances for all of them SVHC hazard properties.
- In the event that an Annex XIV substance is identified for new SVHC hazard properties under Article 57 (f), in addition to 57 (a or c), this would imply new consequences as soon as the Commission modifies the corresponding entry in Annex XIV to include these new hazard properties. In particular, all of the SVHC properties will have to be considered in the assessment of risks and/or impacts of the substance as well as in their mitigation and control in any future applications for authorisation.
- If a new property for SVHC identification as 57 (f) for endocrine disruption should be included for substances listed in Annex XIV, a concentration limit of 0.1% would be applicable under Article 56.6.a of the REACH Regulation to determine whether the use of the mixture containing this substance is to be the subject of an application for authorization, whereas at present a higher concentration limit of 0.3% applies for substances identified only for reprotoxic properties (Article 56.6.b of the REACH Regulation).
 
On legal grounds: 
Indeed, Article 57 specifies, by categories, the nature of the "Substances to be included in Annex XIV".
In support of its argument, Plastics Europe Association also relies on the judgment in Case C-324/15 P - Hitachi Chemical Europe and Polynt v ECHA of 15 March 2017.
Firstly, it should be observed that the same substance may have effects within several categories mentioned in the various subparagraphs of Article 57, including (f).
Secondly, the judgment in which the action for annulment of a judgment of the Court of First Instance of 30 April 2015 in Case T-135/13 dismissing Hitachi Chemical Europe's action against the decision ED / 169/2012 of the European Chemicals Agency of 18 December 2012, including MHHPA in the list of substances of very high concern, did not directly address the issue raised : the legal issue was whether Article 57 (f) of REACH Regulation requires an analysis of the intrinsic properties of the substances concerned, excluding any consideration of human exposure data.
Lastly, the recall made by the CJEU on an incidental basis cannot have the consequences that PlasticsEurope association would like to draw : indeed, if point (f) seems to be intended as a 'broom arrangement', so as, to encompass the scope of the Regulation for substances not meeting the criteria referred to in points (a) to (e) does not mean that the classification of a substance in Annex XIV under a heading prohibits it under another. 
This is the approach adopted by ECHA in practice: in particular, Bis (2-ethylhexyl) phthalate, is identified as a substance of very high concern, both under Article 57 (c) (as reprotoxic) and under point (f) :
https://echa.europa.eu/documents/10162/30b654ce-1de3-487a-8696-e05617c3173b   
and
https://echa.europa.eu/documents/10162/c2ecc989-445d-40b9-a054-28671849b092 	
93.		4821
2017/04/22	United Kingdom,
Member State	We thank France for their proposal to identify BPA as an SVHC according to Article 57(f) and have the following comments.

The dossier submitter concludes that on the basis of evidence available in relation to alteration of reproductive function, mammary gland development, cognitive function and metabolism, BPA can be considered an endocrine disruptor for human health.

We consider these effects and the evidence used to support this proposal below.
	Thank you for your comment.	
94.				Reproductive effects
We agree that the effects on reproduction are most likely the consequence of disruption of oestrogen regulation. Accepting that these effects are endocrine mediated, the arguments of severity and irreversibility are considered to be sufficient for equivalent level of concern (ELoC) establishment. 	We thank UK for their support	
95.				Mammary gland development
The effects on mammary gland development were not considered in the RAC discussions on the classification of BPA for reproductive effects so are not taken into account in the candidate listing according to Article 57(c). Our comments on the ELoC assessment are given below;

Type of Effects
We agree that there is some evidence that BPA has caused changes in mammary gland structure, in experimental animals exposed pre- and peri-natally, and that such changes are likely related to an ED MoA.  However, there are many uncertainties and questions about the reliability of these findings, especially because similar effects were not seen in several high-quality multi-generational studies.  It is also unclear what the functional significance of these histopathological changes is.

It has been suggested that these mammary gland changes may predispose individuals to cancer development. However, we note that there is no evidence in experimental animals that BPA is a carcinogen, with no tumours (including breast tumours) seen in standard cancer studies in rats and mice.  The evidence provided to support that BPA is a tumour promoter is unclear and the underlying studies are not reported in the dossier in much detail, so there is uncertainty regarding their quality.  

Irreversibility of Effects
Although we agree that the observed changes in mammary gland structure in experimental animals are irreversible per se, there are more fundamental questions about the reliability, reproducibility, functional and adverse consequences of these findings.

Quality of Life Affected/ Societal Concern
We agree with the dossier submitter that any human cancer, including breast and prostate is a serious concern for an individual and society as a whole.  However, we do not agree that any convincing evidence has been presented to support the hypothesis that in utero or peri-/post-natal exposure to BPA will increase the risk of breast/prostate cancer in humans.  We note that no specific estimate for the breast-cancer burden related to BPA is available.

Therefore, for the reasons highlighted above, we consider that the observed mammary gland changes in experimental animals do not support inclusion of BPA on Annex XV under Article 57(f). 

	Regarding the mammary gland evaluation, it should be highlighted that mammary gland structure evaluation is not currently covered either in multi-generational or chronic studies. There is no accepted test guideline to cover this adverse effect.
The relevance of these structural effects in terms of increased sensitivity of the breast tissue to carcinogenicity has to be considered instead of functional significance.

As indicated in your comments, these mammary gland changes may predispose individuals to cancer development (see also the literature review and for example the publications from Russo and Russo, Fenton or Brisken et al.). These structure changes usually occur following pre-natal or post-natal exposure whereas the standard cancer studies do not permit to test the life-long effects of prenatal exposure. Studies available with BPA (rat and mice) did not cover this period of development. Moreover, these BPA carcinogenicity studies were conducted with a limited number of dose levels (only two dose levels: 1000 and 5000 ppm in rats and 1000 and 5000 ppm in mice) and these dose levels were quite high. Overall, these two data sets cannot be compared nor be considered as conflicting data as they do not have the good design.
Lastly, the studies conducted with DMBA such as Jenkins et al., 2009 and Betancourt et al., 2010, are reported in Table 16 of the SVHC report.

Please refer to the above mentionned text in the same response when we already discuss on reliability, reproducibility, functional and adverse consequences of these findings.

To our knowledge, only three epidemiological studies have studied the relationship between exposure to BPA and the risk of breast cancer. These studies focused their attention on breast cancer risk after BPA exposure in adulthood. In one study, BPA exposure was indirectly assessed from occupational women’s self-report (Aschengrau et al., 1998). In the two others studies, exposure was estimated using biomarkers in a single spot urine or blood sample at the time of the study (Trabert et al., 2014, Yang et al., 2009). The authors of these works do not observe associations between BPA exposure and breast cancer risk. Unfortunately, such conclusions are greatly impaired by the limitations of exposure assessments and consequently it is impossible to conclude in one direction or another. A fourth study, limited to studying mammary density (and not formally breast cancer) in postmenopausal women consulting for mammography screening, was not considered (Sprague et al., 2013). 
No epidemiological studies have been published to date focusing on the prenatal period as exposure window. It is important to keep in mind that such studies are complex and will require repeated measurements of exposure during pregnancy (to reduce intra-individual variability) and a follow-up of girls for a minimum of 40 years.
Overall, the available epidemiological studies covered only adult exposure with a BPA exposure evaluated at the time of the study whereas the effects looked at are long-term outcomes (namely breast cancer) appearing more than 40 years after exposure. Due to the absence of reliable exposure in any previous critical window, added to the short half-life of BPA in the body, these human data cannot provide evidence of no adverse effect for human breast cancer. 
It should be kept in mind that the guideline studies in toxicology or epidemiological studies do not allow to identify such long-life effects. This is a basic for the acceptance of the level of proof necessary.	
96.				Cognitive function and metabolism
We do not think that a case has been made that BPA causes effects on metabolism and cognitive function that are either endocrine mediated or of ELoC. There is conflicting evidence in the literature about the potential effects of BPA on cognitive functions and metabolism. The effects do not appear to be reproducible. In some cases, non-physiological routes of exposure have been used bypassing the normal detoxification process of BPA. In many cases, effects are reported at very low dose levels and then they disappear at higher doses - this is not biologically plausible. The findings are inconsistent with those of gold-standard, GLP regulatory studies including several guideline DNT studies where low and high doses have been tested. It is also not biologically plausible that a rather weak oestrogen chemical as BPA causes all these different effects. As such we think the level of evidence is insufficient to include these effects in this proposal.
	Concerning effects of BPA on metabolism, we consider that, based on animal studies (rodents and non-rodents) after prenatal and/or perinatal or adult exposure, there is sufficient evidence that BPA may increase the incidence of type-2 diabetes via an ED MoA. In particular, BPA has been shown to alter insulin secretion and/or release by β-pancreatic cells, or insulin signalisation (signaling mechanisms) within insulin-sensitive organs (i.e., liver, muscle, adipose tissues). This resulted in variations in the expression levels of hepatic or adipose tissue markers which are indicative of a state of insulin resistance. These effects are considered as hallmarks of endocrine disruption mechanisms, especially if there is a combination of effects each leading to insulin resistance within the different insulin-sensitive tissues. We do recognize that some data published in the literature may be seen as conflicting data but there are a few studies performed with similar design differences in window of exposure, doses, route of exposure, sex, species and strains which may explain these apparent discrepancies (see table 25 in the support document). For example, most studies were performed on males and a few studies only have also examined the impact of BPA either on both sexes or on females. 

Concerning alteration of learning and memory more specifically, a large majority of the numerous studies investigating this endpoint report an effect following exposure to BPA. Not all the studies were consistent in the observation of the effect but considering the repetitions of the results in several independent studies, it is considered to be established with a sufficient level of evidence. This is further supported by observation of molecular and structural changes that may underlie the impaired performances. 
Differences in response in males and females should not be seen as inconsistencies in the database. In particular, several studies have provided evidence that the effect is mediated through an estrogenic pathway. In this respect, the study by Xu (2014a) provides strong evidence by reversing the effect of BPA with co-administration of an ER antagonist. 
This was further supported by two studies in ovariectomised females that interestingly observed that BPA suppresses the effect induced by estrogen supplementation in ovariectomised animals (Xu, 2015a, Inagaki, 2012). The same was also observed for the modification of synaptic interface and the modification of the expression of synapsin I, PSD-95 and NMDA receptor GluN2B (Xu, 2015b) in mice and for modification of synaptogenesis in monkeys (Leranth, 2008).

It is acknowledged that many studies were performed by subcutaneous route. 
The subcutaneous route has been used in a number of BPA studies because the daily dose can be controlled with greater accuracy. 
Compared to oral route, subcutaneous administration bypasses the digestive barrier and most importantly the enterohepatic first-pass effect. The data collected in rodents show significantly higher proportions of unconjugated BPA after subcutaneous administration compared to oral administration. 
Consideration of subcutaneous studies for risk assessment would therefore require dose correction but these data can be considered for hazard identification.
Although artificial, it should be kept in mind that other non-artificial routes of exposure such as the dermal or inhalation route also bypass hepatic first pass. In addition, in rodents, and to a lesser extent in humans, the hepatic metabolism capacity in newborns is limited, resulting in a reduced hepatic first-pass effect. 
The subcutaneous route of exposure is therefore considered fully relevant for the purpose of the present hazard identification and MoA considerations, in particular when developmental or perinatal exposure is considered.
In addition, the alteration of learning/memory further to BPA exposure has been largely reported in studies performed by oral route (Xu 2010b, Jasarevic 2011, Jasarevic 2013, Kumar 2014, Kubo 2001, Poimenova 2010, Goncalves 2010, Kuwahara 2013, Wang 2014b, Wang 2016, Johnson 2016, Hass 2016, Kim 2011, Xu 2011b, Jain 2011, Kuwahara 2014, Xu 2013b, Zhang 2014, Fan 2013).
Regarding your reference to the DNT study, you might refer to the Stump study. If this is the case, please see our answer to the comment 86.

It should be emphasized that the complexity and variations in sex hormone regulation in different species, strains, sexes, organs and at different life-stages render the mode of action very sensitive to many parameters. At the time being, it is therefore anticipated that the effects exerted by BPA may differ at different dose levels and/or period of exposure, rendering any tentative of dose-response of the different key events impossible. 

Finally, it is correct to say that the affinity of BPA with some estrogen receptors is weak and cannot explain all the effects observed in in vivo studies in particular at lower doses. However, the interaction of BPA with other receptors (e.g. extranuclear estrogen receptors, ERRγ, GPER) may explain the estrogenic effects of BPA at low dose as explained in the Annex XV dossier and as emphasized by several scientists (see comments 4816 and 4822) and NGO (see comments 4833) in this public consultation.	
97.				Additionally we disagree that there is robust evidence to support the lack of thresholds, low-dose effects and non-monotonic dose response of BPA. Therefore, we do not support these as valid considerations for ELoC establishment.
	The argument that we want to address in the ELoC assessment is that a number of studies have identified effects on these endpoints at doses below the point of departure used by RAC for DNEL derivation, which is factually difficult to reject.
This piece of evidence is sufficient to raise uncertainties on the dose-response characterisation and setting of safe levels.
References to concepts of low-dose effects, non-monotonic dose-response and absence of threshold are not necessary in this aim and the Support Document has been updated to remove these terms.	
98.				In conclusion if it is agreed that a substance can be included on the candidate list as SVHC according to Article 57 (c) and 57(f) for the same effects, then we can agree that BPA meets the criteria for 57(f) in relation to its ED-mediated effects on reproduction/fertility. If however SVHC listing according to Article 57(c) and 57(f) for the same effect is not possible, then we consider that the additional identification of BPA as an SVHC under Article 57(f) is not justified on the basis of the evidence presented in the dossier.	FR considers it important to identify the different SVHC properties of a substance so that all of them are considered in the assessment process of potential applications for authorisation if further prioritised. 
In addition, it is noted that a previous case of identification as SVHC 57(c) as well as 57(f) as an endocrine disruptor relevant for human health has been recently endorsed for some phthalates by the REACH committee. 
Indeed, it has been established through decision "implementing identification of bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl phthalate (DIBP) as substances of very high concern according to Article 57(f) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council" (adopted during Reach Committee in February 2017), "Article 57 does not forbid identifying a substance as being of very high concern several times based on more than one intrinsic property causing the same effect on human health".	
99.		4823
2017/04/23	Health and Environment Alliance (HEAL),
International NGO,
Belgium	P23. Not using Klimisch scores is justified in this analysis. Studies were qualitatively weighed based on expert judgement for their relevance, reliability and adequacy for the analysis. Additionally, ToxRTool was used to obtain reliability scores. This approach allows transparent and weighed decisions on validity of studies. Most informative studies are identified in the tables provided, clearly showing the vast amount of reliable studies that was used to support the argumentation.	Thank you for your comment.
Your support is noted.	
100.				P27. The statement “The effects observed after sc exposure are considered relevant when the exposure has taken place during the developmental period” requires some specification. Is sc exposure considered the only relevant route to assess in utero exposure? It should also be noted here that for each of the assessed endpoints, the “developmental period” is different, or be specified as “in utero” if that is what is meant here.	The subcutaneous route has been used in a number of BPA studies because the daily dose can be controlled with greater accuracy. 
Compared to oral route, subcutaneous administration bypasses the digestive barrier and most importantly the enterohepatic first-pass. The data collected in rodents show significantly higher proportions of unconjugated BPA after subcutaneous administration than in the case of an oral administration. 
In rodents and to a lesser extent in humans, the hepatic metabolism capacity in newborns is limited, resulting in a reduced hepatic first-pass effect. Consideration of subcutaneous studies is therefore directly relevant when developmental exposure is considered. ‘Developmental’ is here used in its wide meaning and covers in utero as well as early postnatal development.

In addition, other non-artificial routes of exposure such as the dermal route or inhalation also bypass hepatic first pass. Although dose correction would be required in the context of risk assessment, the subcutaneous route of exposure is therefore considered relevant for the purpose of the present analysis that is to say hazard identification and MoA considerations.	
101.				P45. In light of species differences in endocrine control of the ovarian cycle in adults, it might be relevant to address the effects of BPA on prolactin (PRL). In rats, PRL has a luteotropic function (corpus luteum regresses in absence of PRL) and is negatively regulated by estrogens. Similarly to estradiol, BPA exposure has been shown to (directly) increase PRL secretion (e.g. Steinmetz et al. 1997 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627028/). Thereby stimulating progesterone production and inhibiting estrogen production. In humans, PRL does not have a luteotropic action, which might explain some of the species differences observed in BPA effects on cycle length. Still, BPA has been linked to higher PRL and progesterone levels in adult females as well (e.g. Miao et al. 2015 https://www.ncbi.nlm.nih.gov/pubmed/9112368).	We do not describe any species differences of BPA effects on cycle length: in our dossier, there is only one epidemiological study: “Based on this single study, no robust conclusion can be drawn on the effect of BPA on the estrous cycle in women.” of the support document (see 4.2.2.2). Moreover, PRL should act on corpus luteus and not on follicle, and thus should increase the length of diestrus, which is not discussed in our dossier for identifying BPA as ED.
	
102.				P66. When addressing relevant doses of BPA for effects on mammary gland development it is relevant to note that in the study by Tharpe et al. (2012) BPA exposure was assessed in serum. The internal doses used in that study are similar to human systemic doses of unconjugated BPA. Consequently, this should study should be considered extremely relevant for human risk assessment.
	Thank you for this comment. In the detailed Table 14, the indication about seric measurement was mentioned. And now the text in this table has been expanded as well as the section 4.3.3. in adding: “Noticing that the non-human primates study from Tharp et al., 2012 assessed unconjugated BPA serum measurement showing internal doses used similar to human systemic doses of unconjugated BPA.“	
103.				P160. Based on all data provided and careful weighing and consideration of the data, the overall conclusion that BPA alters reproductive function, mammary gland development, cognitive functions and metabolism through an ED MoA, more specifically through disruption of the estrogenic pathways, is justified.	Thank you for your support.	
104.				P170. For effects on brain and behavior, it would be relevant to note that when deriving a “safe concentration” sex differences should be considered.	Noted.	
105.				P170. As extensively discussed, critical windows of exposure are extremely relevant for the observed effect for all described endpoints. Although difficult to translate that into population-relevant safe levels (as mentioned on P168), it is extremely important that this is acknowledged and taken into account when establishing “safe levels”.	Noted.	
106.		4827
2017/04/24	Center for International Environmental Law,
International NGO,
United States	The Center for International Environmental Law (CIEL) supports the dossier for the proposed identification of Bisphenol A as a substance of very high concern in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) based on its endocrine disrupting properties.

Primarily, CIEL supports the consideration that all available data should be considered without limitation to the estrogenic or anti-androgenic actions; secondly, CIEL supports the use of “biologically plausible causal link” between the adverse health effects and the endocrine mode of action to support the listing of Bisphenol A.

The available evidence for the effects on reproductive function, mammary gland development, cognitive function, and metabolism shows that Bisphenol A should be considered as an endocrine disruptor relevant for human health.

Additionally, the permanence and irreversibility of the effects is an indication of the serious effects of Bisphenol A, amounting to an equivalent level of concern than for those substances listed in Article 57 REACH points (a) to (e).

Therefore, CIEL supports the conclusion of the dossier to consider Bisphenol A an endocrine disruptor for human health on the basis of available evidence.	Thank you for your comment and support.	
1.				-		
107.		4828
2017/04/24	Sweden,
Member State	We thank the French CA for submitting a dossier on bisphenol A (BPA) aimed at the inclusion on the candidate list as a SVHC based on its endocrine disrupting properties.

We find that BPA fulfills the WHO/IPCS definition of an endocrine disruptor, and the substance can be considered an endocrine disruptor for human health. The Swedish CA agrees that BPA should be identified as an SVHC according to article 57(f) in REACH.	Thank you for your comment and support.	
108.				We noted that the following studies were published after development of the dossier, and may add to the strength of the presented evidence.
Mammary gland:
Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats. Gomez et al. Horm Cancer. 2017 Apr;8(2):78-89. doi: 10.1007/s12672-016-0282-1. Epub 2017 Jan 11.
Low-dose effects of bisphenol A on mammary gland development in rats. Mandrup K et al. Andrology. 2016 Jul;4(4):673-83. doi: 10.1111/andr.12193. Epub 2016 Apr 18.	Thank you for these additional references. This study is now included in the revised document.
	
109.				Neurodevelopment:
Low-dose effect of developmental bisphenol A exposure on sperm count and behaviour in rats. Hass U et al. Andrology. 2016 Jul;4(4):594-607. doi: 10.1111/andr.12176. Epub 2016 Apr 18.
Bisphenol A Exposure Disrupts Neurotransmitters Through Modulation of Transaminase Activity in the Brain of Rodents. Zalko D et al. Endocrinology. 2016 May;157(5):1736-9. doi: 10.1210/en.2016-1207.
	The study by Hass (2016) is already included and discussed in the Annex XV dossier.
The study by Zalko (2016) consists of a reanalysis of the study by Cabaton (2013) investigating metabolomics in particular in the brain of pups exposed to BPA from GD8 to PND 16. The reanalysis provided support for GABA being a key determinant of BPA effects on neuroendocrine maturation.
GABA modulation is associated with modulation of transaminases involved in the synthesis and production of L-glutamate. Although data supporting this hypothesis based on experimental studies involving xeno-estrogens are lacking, it should be stressed that estradiol and ageing were previously found to decrease transaminase activity in rat brains.
This study therefore provides indications on how BPA may affect the neuroendocrine maturation. Its direct implication for alteration of learning and memory more specifically needs to be established. In particular, the different parameters were measured on whole brain without distinction of specific areas and its interpretation is therefore limited in the context of our assessment and has not been included.	
110.				Metabolism:
Perinatal BPA exposure alters body weight and composition in a dose specific and sex specific manner: The addition of peripubertal exposure exacerbates adverse effects in female mice. Rubin BS et al. Reprod Toxicol 2017 Mar,68:130-144. doi: 10.1016/j.reprotox.2016.07.020.  Epub 2016 Aug 2.
Bisphenol A exposure increases liver fat in juvenile fructose-fed Fischer 344 rats. Rönn M et al. Toxicology. 2013 Jan 7;303:125-32. doi: 10.1016/j.tox.2012.09.013. Epub 2012 Nov 8. (An older paper not included in the dossier)	Thank you for your comments, the study of Rubin et al. (2017) has now been added in the support document. Concerning the effects of BPA on liver fat, this effect has not been specificaly considered in the assessment and therefore the study from Ronn et al. (2013) was not added.	
111.		4829
2017/04/24	ChemSec,
International NGO,
Sweden	ChemSec supports the identification of BPA as an endocrine disrupting chemical, in addition to the earlier identification as toxic to reproduction. The evidence in the dossier is very well presented.
In addition to the refered studies we also recommend the following studies:
Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environmental Health Perspectives doi: 10.1289/ehp.1408989.
Rochester JR. 2013. Bisphenol a and human health: a review of the literature. Reproductive Toxicology 42C:132-155.	Thank you for your comment and support.
The additional references are noted.

The 2015 review by Rochester illustrates very well the range of effects that may be at stake on the basis of recent human studies. The link with a potential ED MoA is however not discussed and has therefore not been considered relevant for this dossier in this regard.

The 2013 review raises valid questions of the safety of BPA alternatives. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
1.				-		
112.		4831
2017/04/24	Belgium,
Member State	Belgium would like to thank France for the preparation and submission of this annex XV dossier. We acknowledge the huge work done!
The adverse effects and the link to the ED mode of action are clearly reported. The animal data are relevant and sufficient to conclude that the substance meets the WHO definition of an ED. Moreover, the equivalent level of concern to CMRs is clearly demonstrated.
Based on the provided data/arguments, Belgium supports the identification of BPA as SVHC in accordance with art.57(f) for ED effects in relation to human health.	Thank you for your comment and support.	
113.		4832
2017/04/24	ClientEarth,
International NGO,
United Kingdom	Please see the uploaded document for our full comments. Many thanks
----------------------------
See the corresponding embedded attachment in table 1 of Part I.  The content of the attached document is reproduced below (please refer to the PDF for appropriate layout and footnotes)	Thank you for your comment. 	
114.				 Comments on Annex XV SVHC report: identification of Bisphenol A as SVHC due to endocrine disrupting properties (Article 57(f) - human health) 
Scientific contribution of Dr Olwenn V. Martin, Research Fellow at Brunel University London

The Annex XV report proposing the identification of Bisphenol A (BPA) as a substance of very high concern (SVHC) for its endocrine properties prepared by ANSES is well evidenced, logical and sufficiently robust from a scientific point of view. In accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH), the report gathers scientific evidence of probable serious effects to human health which gives rise to an equivalent level of concern (ELoC) to those of CMR PBT or vPvB, i.e. “so serious and [that] cannot normally be reversed so that such effects have to be prevented rather than remedied”.1 
In support of the identification of BPA as SVHC for its endocrine disrupting properties, we provide: 
Additional evidence showing probable serious effects of BPA which give rise to ELoC; 
Comment on plausible link between the mode of action and the serious effect; 
Comment on the notion of “secondary toxicity”. 	Thank you for your support. Detailed responses are provided below.	
115.				1) Additional evidence of probable serious effects giving rise to ELoC 
The scientific evidence provided below reveals additional probable serious effects of BPA on human health within the meaning of Article 57(f) of REACH, which reinforce the evidence gathered in the report. 
It also shows that these effects give rise to an ELoC to those of CMR, PBT or vPvB, in particular because of their irreversibility, the consequences of those effects for society and impact of those effects on the lives of persons affected. It confirms, in addition, the difficulty of adequately assessing the risk due for example to the delayed effects of BPA. 
Crosstalk between sex steroid hormones and thyroid hormones 
The report itself clarifies2 that its focus on the estrogenicity of BPA as an endocrine mode of action should not preclude the consideration of other (endocrine) mechanisms. There is also no reason to limit the assessment to the binding affinity of BPA to estrogen receptors (ERs). We therefore provide additional evidence of an endocrine mode of action beyond the estrogenicity. 
An important mode of action that has not been considered in this report is the disruption of the Hypothalamus-Pituitary-Thyroid (HPT) axis. Thyroid hormones (THs) are involved in at least three of the adverse effects considered, namely reproductive function, neurodevelopment and metabolism. Indeed, THs are known to regulate sex steroid synthesis and action in both the brain and gonads. The crosstalk between these two endocrine axes was recently reviewed by Duarte-Guterman et al (2014).
BPA is known to be able to disrupt several important processes along the HPT axis (Wu et al 2016; Zoeller et al 2005). Additionally, some cross-sectional studies in humans have detected associations between exposure to BPA and THs (e.g. Sriphrapradang et al 2013; Wang et al 2013) in adults. More recently, two case-control studies have found associations between BPA exposure and incidence of thyroid nodular disease in adult women (Andrianou et al. 2016), or thyroid volume and structure in school children (Wang et al. 2015). Notwithstanding the limitations of such study designs, there is more crucially evidence of an effect of BPA exposure on maternal hypothyroidism in both humans (Chevrier et al 2013) and pregnant ewes, an animal model very relevant to humans due to its long pregnancy (Viguié et al 2013). The relationship between maternal hypothyroidism during pregnancy and subsequent suppressed psychomotor development and lower IQs in their children is established. 
Therefore, disruption of TH action by BPA can contribute to adverse effects on neurobehaviour (e.g. Somogyi et al. 2016) and fat metabolism (Ahmed 2016).	This comment supports that several endocrine MoA may be involved and explain the complex response of BPA. 
The Annex XV dossier focusses on the strongest evidence of ED-mediated effects and the database is considered strongest in favour of interference with estrogenic pathways.
A reference to evidence of involvement of thyroid hormone disruption has been added in the Support Document further to your comment. 	
116.				Neurobehaviour 
Several epidemiological studies investigating the association between prenatal BPA exposure and neurobehavioural effects in children were not considered in this report (Braun et al 2009; Braun et al 2011; Evans et al 2014; Harley et al 2013; Miodovnik et al 2011; Roen et al 2015). All but one of these studies, that measured urinary BPA metabolites during the third trimester of pregnancy, detect positive associations between prenatal BPA exposure and behavioural effects in children. Moreover, an experimental study in mice found that effects could be observed in the third, and therefore never exposed, generation (Wolstenholme et al 2013). The transgenerational nature of BPA action on behaviour further emphasizes the irreversibility of such effects. 
Autism Spectrum Disorders 
Autism is a spectrum of disorders that comprise a group of lifelong conditions characterised by impaired social interaction and communication, with stereotyped and repetitive behaviours, and some level of intellectual impairment in around 75% of cases. It is of great societal concern due to a recent dramatic increase in diagnoses considered by some as an epidemic. Recent epidemiological studies suggest an association between autism spectrum disorder and BPA exposure (Arbuckle et al 2016; Kardas et al 2016; Kondolot et al 2016; Stein et al 2015), and as such this endpoint should also be considered. 
Neurodegenerative diseases 
Another area of emerging concern that ought to be mentioned are the potential effects of BPA exposure in neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease or dementia. This is crucially socially relevant in the ageing European population. Although this is currently understudied, there are indications that BPA exposure has an effect on neurodegenerative processes both through an estrogenic pathways or disruption of TH action (Preciados et al 2016; Jiang et al 2016; Boxian et al 2014).	Thank you for this comment. 
It was decided to focus in the Annex XV dossier on the effects that fulfilled both the criteria of a well-established effect and evidence of an ED-mediated effect. Such a conjunction of evidence is considered to be available for alteration of learning and memory function and was therefore detailed in the report. We have however taken note in the dossier that the overall database points toward additional indications for effects of BPA on neurobehaviour and highlight that ED-mediated effects of BPA analysed in the Annex XV dossier may underestimate the spectrum of effects. However, the level of evidence is considered lower at this point in time than for alteration of memory/learning.
The Support Document has been updated to further insist on these uncertainties.	
117.				Cardiovascular diseases 
Cardiovascular disease is a major contributor to mortality and morbidity worldwide. The epidemiological, experimental and mechanistic evidence for effects of BPA exposure on cardiovascular were recently reviewed by Gao et al (2014) who suggested that the underlying molecular mechanisms may involve estrogen receptor rapid signalling. 
Several epidemiological studies indicate that BPA exposure in adult populations is associated with increased risk for CV diseases, including coronary artery heart disease, angina, heart attack, hypertension, and peripheral artery disease (e.g. Bae et al 2015; Lang et al 2008; Melzer et al 2010; Melzer et al 2012a; Melzer et al 2012b; Shankar et al 2012; Romano et al 2015). 
More recently, a study detected an association between prenatal BPA exposure and higher diastolic blood pressure in children (Bae et al 2017) suggesting that BPA may also have delayed developmental effects on cardiovascular health. 
Experimental studies suggest BPA exposure could affect the physiological functioning of CV system (Gao et al 2014). Of note, maternal BPA exposure has been found to affect the fetal heart transcriptome in non-human primates (Chapalamadugu et al 2014). There is also evidence in the zebrafish, an animal model considered relevant to humans in the clinical setting, that effects on cardiovascular function may be transgenerational (Lombo et al 2015). 	Similarly, this endpoint has not been included in the Annex XV dossier as the level of evidence is considered lower. 
The Support Document has been updated to recognize a potential underestimation of ED-related effects of BPA.	
118.				Metabolism/fetal exposure 
Studies in the sheep (Corbel et al 2015) and non-human primates (VandeVoort et al 2016) indicate that rapid maternal metabolism of BPA does not alleviate exposure to the developing fetus. This evidence on potential fetal exposure increases further the level of concern. 
References 
Ahmed RG (2016) Maternal bisphenol A alters fetal endocrine system: Thyroid adipokine dysfunction. Food And Chemical Toxicology 95: 168-174. 
Andrianou XD, Gangler S, Piciu A et al (2016) Human Exposures to Bisphenol A, Bisphenol F and Chlorinated Bisphenol A Derivatives and Thyroid Function. PLOS ONE 11(10): e0155237. 
Arbuckle TE, Davis K, Boylan K et al (2016) Bisphenol A, phthalates and lead and learning and behavioral problems in Canadian children 6–11 years of age: CHMS 2007–2009. Neurotoxicology 54:89–98. 
Bae S, Hong Y-C (2015) Exposure to Bisphenol A From Drinking Canned Beverages Increases Blood Pressure Randomized Crossover Trial. Hypertension 65(2): 313-319 
Bae SY, Lim YH, Lee YA et al (2017) Maternal Urinary Bisphenol A Concentration During Midterm Pregnancy and Children's Blood Pressure at Age 4. Hypertension 69(2):367-374.
Boxian H, Chunyan J, Jian L et al (2014) Maternal exposure to bisphenol A may increase the risks of Parkinson's disease through down-regulation of fetal IGF-1 expression. Medical Hypotheses 82(3):245-249. 
Braun JM, Kalkbrenner AE, Calafat AM et al (2011) Impact of early-life bisphenol A exposure on behavior and executive function in children. Pediatrics 2011, 128, 873–882. 
Braun JM, Yolton K, Dietrich KN, Hornung R et al. (2009) Prenatal bisphenol A exposure and early childhood behavior. Environ. Health Perspect. 117:1945–1952. 
Chapalamadugu KC, VandeVoort CA, Settles ML et al (2014) Maternal Bisphenol A Exposure Impacts the Fetal Heart Transcriptome. PLoS ONE 9(2): e89096 
Chevrier J, Gunier RB, Bradman A et al (2013) Maternal Urinary Bisphenol A during Pregnancy and Maternal and Neonatal Thyroid Function in the CHAMACOS Study. Environmental Health Perspectives 121(1):138-144. 
Corbel T, Perdu E, Gayrard V et al (2015) Conjugation and Deconjugation Reactions within the Fetoplacental Compartment in a Sheep Model: A Key Factor Determining Bisphenol A Fetal Exposure. Drug Metabolism and Disposition 43(4): 467-476. 
Duarte-Guterman P, Navarro-Martín L, Trudeau VL (2014) Mechanisms of crosstalk between endocrine systems: regulation of sex steroid hormone synthesis and action by thyroid hormones. General and Comparative Endocrinology 203:69-85. 
Evans SF, Kobrosly RW, Barrett ES et al (2014) Prenatal bisphenol A exposure and maternally reported behavior in boys and girls. Neurotoxicology 45:91-99. 
Harley KG, Gunier RB, Kogut K et al (2013) Prenatal and early childhood bisphenol A concentrations and behavior in school-aged children. Environ. Res. 126:43–50. 
Jiang W, Cao L, Wang F et al (2016) Accelerated reduction of serum thyroxine and hippocampal histone acetylation links to exacerbation of spatial memory impairment in aged CD-1 mice pubertally exposed to bisphenol-A. AGE 38(5-6): 405-418. 
Kardas F, Bayram AK, Demirci E et al (2016) Increased Serum Phthalates (MEHP, DEHP) and Bisphenol A Concentrations in Children With Autism Spectrum Disorder: The Role of Endocrine Disruptors in Autism Etiopathogenesis. Journal of Child Neurology 31(5):629-635. 
Kondolot M, Ozmert EN, Ascı A et al (2016) Plasma phthalate and bisphenol a levels and oxidant-antioxidant status in autistic children. Environ. Toxicol. Pharmacol. 43:149–158. 
Lang IA, Galloway TS, Scarlett A, et al (2008) Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. JAMA. 300(11):1303-1310.
Lombo M, Fernandez-Díez C, Gonzalez-Rojo S et al (2015) Transgenerational inheritance of heart disorders caused by paternal bisphenol A exposure. Environmental Pollution 206:667–678. 
Melzer D, Rice NE, Lewis C, et al (2010) Association of urinary bisphenol A concentration with heart disease: evidence from NHANES 2003/06. PLoS ONE 5(1):e8673. 
Melzer D, Gates P, Osborne NJ, et al. (2012a) Urinary bisphenol a concentration and angiography-defined coronary artery stenosis. PLoS ONE 7(8):e43378. 
Melzer D, Osborne NJ, Henley WE, et al. (2012b) Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women. Circulation 125(12): 1482-1490. 
Miodovnik A, Engel SM, Zhu C et al (2011) Endocrine disruptors and childhood social impairment. Neurotoxicology 32:261–267. 
Preciados M, Yoo C and Roy D (2016) Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases. Int. J. Mol. Sci. 17: 2086, 62pp. 
Roen EL, Wang Y, Calafat AM et al (2015) Bisphenol A exposure and behavioral problems among inner city children at 7–9 years of age. Environ. Res. 142:739–745. 
Romano ME, Webster GM, Vuong AM et al (2015) Gestational urinary bisphenol A and maternal and newborn thyroid hormone concentrations: The HOME Study. Environmental Research 138:453-460. 
Shankar A, Teppala S, Sabanayagam C. (2012) Bisphenol A and peripheral arterial disease: results from the NHANES. Environ Health Perspect. 120(9):1297-1300. 
Sriphrapradang C, Chailurkit L, Aekplakorn W et al (2013) Association between bisphenol A and abnormal free thyroxine level in men. Endocrine 44(2): 441-447. 
Stein TP, Schluter MD, Steer RA et al (2015) Bisphenol A Exposure in Children With Autism Spectrum Disorders. Autism Research 8(3): 272-283. 
Somogyi V, Horvath TL, Toth I et al (2016) bisphenol a influences oestrogen- and thyroid hormone-regulated thyroid hormone receptor expression in rat cerebellar cell culture. Acta Veterinaria Hungarica 64(4):497–513. 
VandeVoort CA, Gerona RR, vom Saal FS et al (2016) Maternal and Fetal Pharmacokinetics of Oral Radiolabeled and Authentic Bisphenol A in the Rhesus Monkey PLOS One 11(12): e0165410 
Viguié C, Collet SH, Gayrard V et al (2013) Maternal and Fetal Exposure to Bisphenol A Is Associated with Alterations of Thyroid Function in Pregnant Ewes and Their Newborn Lambs. Endocrinology 154(1): 521-528.
Wang N, Zhou Y, Fu C et al (2015) Influence of Bisphenol A on Thyroid Volume and Structure Independent of Iodine in School Children. PLOS ONE 10(10): e0141248 
Wang T, Lu J, Xu M et al (2013) Urinary Bisphenol A Concentration and Thyroid Function in Chinese Adults. Epidemiology 24(2): 295-302. 
Wu Y, Beland FA, Fang J-L (2016) Effect of triclosan, triclocarban, 2,2 ',4 ',-tetrabromodiphenyl ether, and bisphenol A on the iodide uptake, thyroid peroxidase activity, and expression of genes involved in thyroid hormone synthesis. Toxicology in Vitro 32:310-319. 
Zoeller RT, Bansal R, Parris C (2005) Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. Endocrinology 146(2): 607-612. 	This information is noted and support that the first pass metabolism by oral route does not fully protect the fetus from BPA exposure and subcutaneous route is in particular relevant when developmental exposure is considered in the context of hazard (and MoA) identification. Support Document has been updated in this respect.	
119.				2) Comment on plausible link between the mode of action and the serious effect 
The report includes sections dedicated to the evidence of a plausible link between an estrogenic mode of action and each adverse effect considered. These typically start with a statement on whether such link has been observed experimentally in the same study. Observing both mechanism and effect in the same study, however, should not be considered a requirement for identification as a SVHC for endocrine disrupting properties as it would be far too high a burden of proof. As mentioned in the report, a link may not be observed in one and the same study due to the latency between exposure and effect, or because of experimental practicalities. This does not call into question the plausibility of the link. 
This notion of 'plausible link' should rather be defined following the approach of Bradford Hill (1965): 
“It will be helpful if the causation we suspect is biologically plausible. But this is a feature I am convinced we cannot demand. What is biologically plausible depends upon the biological knowledge of the day. […] In short, the association we observe may be one new to science or medicine and we must not dismiss it too light-heartedly as just too odd. As Sherlock Holmes advised Dr. Watson, ‘when you have eliminated the impossible, whatever remains, however improbable, must be the truth.’” (emphasis added) 
In light of this, assessing the plausible link should be done by considering the body of evidence within the context of the current state-of-knowledge, as opposed to looking at whether the body of evidence itself internally demonstrates a plausible link. In that regard, the report (background information and human relevance) contains sufficient information showing a plausible link between the endocrine mode of action and the serious adverse effects. 
References 
Austin Bradford Hill (1965) The Environment and Disease: Association or Causation? 
Proceedings of the Royal Society of Medicine 58:295-300.	FR fully supports the comment of Client Earth. The detailed analysis provided in the Annex XV dossier results from the exceptional size of the database and the complexity and multiplicity of the effectsto the whole database available on BPA illustrate that ED substances may induce a large spectrum of effects and raise uncertainties in terms of risk characterisation that fully justify their SVHC identification.	
120.				3) Comment on the notion of “secondary toxicity” 
In the context of endocrine disruption, the term ‘secondary toxicity’ was probably first used in the WHO/IPCS 2002 State-of-the Art report (IPCS, 2002) when describing criteria for attribution to an endocrine mode of action. It was introduced as follows: 
“Dose–response observations that indicate the perturbance of the endocrine system is a critical response of the organism, and not the secondary result of general systemic toxicity” (emphasis added) 
Kortenkamp et al (2012) noted that the WHO/IPCS definition leaves the interpretation of which modes-of-action should be considered to “alter the function of the endocrine system” relatively open. The concept of endocrine disruption first developed when it was observed that some environmental chemicals were able to mimic the action of the sex hormones oestrogens and androgens. This notion has now evolved to encompass a range of mechanisms incorporating the many hormones secreted directly into the blood circulatory system by the glands of the endocrine system and their specific receptors, transport proteins and associated enzymes. The definition does not explicitly address the issue of indirect endocrine toxicity, or when an effect on endocrine function is observed secondarily to overt toxicity in other organs or systems. This is related to what is referred to as “specificity” or sometimes also “lead toxicity”, to describe the requirement for endocrine disruption to occur at lower doses than other mechanisms of toxicity. 
As such, 'secondary toxicity' refers to overt systemic toxicity resulting from toxic effects to other organs that are eventually reflected in changes in hormone levels. Subtle changes such as meiotic alterations and (epi)genetic changes that disrupt the programming and ultimately the functioning of the endocrine communication system should therefore not be described as ‘secondary toxicity’ but rather as a endocrine disrupting mechanism (as stated on page 43 of the report). 
Reference 
International Programme on Chemical Safety. 2002. Global Assessment of the State-of-the-Science of Endocrine Disruptors. Geneva: World Health Organization. 
Kortenkamp A, Martin OV Faust M et al (2012) State of The Art Assessment of Endocrine Disrupters. Brussels: European Commission.
With the scientific contribution of: 
Dr Olwenn V. Martin 
Research Fellow at Brunel University London Institute for the Environment, Health and Societies 
+44(0)1895 274000 olwenn.martin@brunel.ac.uk 	The comment is noted. None of the adverse effects described in the Annex XV dossier are considered to result from secondary toxicity. 	
			See the corresponding embedded attachment in table 1 of Part I: 4832_ClientEarth (Dr V. Martin) Comments on BPA Annex XV SVHC report.pdf		
121.		4833
2017/04/24	Breast Cancer UK,
National NGO,
United Kingdom	Breast Cancer UK is a charity which aims to prevent breast cancer by reducing public exposure to carcinogenic and other hazardous chemicals in the environment. We are especially concerned about the potential role of exposures to environmental chemicals such as bisphenol A (BPA) in increasing breast cancer risk. We appreciate the opportunity to comment on the proposal to identify BPA as a substance of very high concern (SVHC), in relation to its endocrine disrupting mode of action.

Breast Cancer UK welcomes the comprehensive and well researched dossier prepared by France which presents strong and convincing evidence that BPA should be listed as a SVHC due to its endocrine disrupting properties. We fully support this proposal.	Thank you for your comment and support.	
122.				The dossier is based on literature searches up to May 2016. Since that time, there have been numerous articles which provide further evidence that low dose exposure to BPA is endocrine disrupting and detrimental to human health. We agree there is sufficient evidence for effects on reproductive function, alteration of mammary gland development, alteration of brain development and cognitive function, and alterations in metabolic function. Increasing evidence suggests that BPA may also affect the immune system (e.g. 1,2,3).

Strong and convincing evidence presented in the dossier demonstrates BPA affects oestrogen signaling pathways by binding to ER alpha, GPR30 and ERR gamma receptors and prevents ligand binding to ER beta and androgen receptors. The dossier also suggests BPA may activate other receptors and pathways, although binding has not been established. We concur with this view; there is increasing evidence that BPA affects several endocrine pathways through oestrogen signaling, and possibly through direct binding to other nuclear receptors, such as progesterone (4) and glucocorticoid receptors (5). The endocrine system is associated with a series of pathways, which often interact with one another. It is highly likely endocrine disrupting chemicals will affect multiple pathways, resulting in a range of health effects.	Immunotoxicity is identified in the dossier as a potential additional ED-effect of BPA but was not investigated in detail and the dossier doesn’t aim to be exhaustive in this regard.

Recent studies providing additional evidence for binding to progesterone and glucocorticoid have been added in the Support document. They further support the potential of BPA’s multiple interactions.
	
123.				We at Breast Cancer UK are especially concerned that early exposures to BPA may induce or predispose humans to an increased risk of breast cancer, as well as other cancers (6). The dossier highlights potential effects caused by BPA through nuclear receptor signaling and epigenetic changes to oestrogen-dependent genes and those involved in embryogenesis and post-natal development. Recent studies highlight further the role of BPA in inducing epigenetic alterations (e.g. 7,8). These, along with the effects of BPA on oestrogen receptors (and other nuclear receptors)may affect mammary gland development which may increase susceptibility to breast cancer later in life.

In summary Breast Cancer UK support the dossier’s conclusion BPA can affect a number of physiological functions and systems in mammalian organisms through an endocrine disruptive pathway, and can alter reproductive function, mammary gland development, cognitive function and metabolism through an ED MoA and so should be classified as a SVHC due to its ED properties.

References
1. Gear, R. B. and Belcher, S. M. (2017). Impacts of Bisphenol A and Ethinyl Estradiol on Male and Female CD-1 Mouse Spleen. Science Reports 7(1):856
2. Qiu, W. et al. (2016). The potential immune modulatory effect of chronic bisphenol A exposure on gene regulation in male medaka (Oryzias latipes) liver. Ecotoxicology and Environmental Safety 130: 146-154.
3. https://www.efsa.europa.eu/en/press/news/160426a?utm_content=hl&utm_source=EFSA+Newsletters&utm_campaign=3bd764133f-HL_20160428&utm_medium=email&utm_term=0_7ea646dd1d-3bd764133f-63626997
4. Rehan, et al. (2015). Androgen and Progesterone Receptors are Targets for Bisphenol A (BPA), 4-Methyl-2,4-bis-(P-Hydroxyphenyl)Pent-1-Ene— A Potent Metabolite of BPA, and 4-Tert-Octylphenol: A: Computational Insight. PLoSOne 10(9): e0138438.
5. Zhang, J. et al. (2017). In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor. Analytical and Bioanalytical Chemistry 409(8): 2239-2246.
6. Seachrist, D. D. et al. (2016). Title: A Review of the Carcinogenic Potential of Bisphenol A. Reproductive Toxicology 59: 167-182.
7. Jorgensen, E. M. et al. (2016). Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol-A) exposure. FASEB Journal 30: 3194-3201.
8. Romagnolo, D. F. et al. (2016). Epigenetics of breast cancer: Modifying role of environmental and bioactive food compounds. Molecular Nutrition and Food Research 60(6): 1310-29.	Thank you for your support.

Thank you. For your notice, this review was well considered in our Support Document.

Thank you. This reference is now added in the revised section dedicated to the mammary gland.	
124.		4835
2017/05/05	Finland,                Member State	We want to thank the French CA for the comprehensive SVHC dossier. The French proposal to identify 4,4’-isopropylidenediphenol (bisphenol A, BPA) as SVHC according to Art. 57 (f) is based on the following effects: 
1. Effect on the reproductive function
2. Alteration on mammary gland development
3. Alteration of brain development and cognitive function 
4. Metabolic alterations	Thank you for your comment.	
125.				The Finnish CA agrees that bisphenol A meets the criteria as SVHC according to Article 57(f) as giving rise to an equivalent level of concern because of its endocrine disrupting properties on reproductive function and scientific evidence of probable serious effects to human health. Bisphenol A has a harmonised classification for the hazard class reproductive toxicity category 1B (H360F ‘May damage fertility’) based on effects on reproductive function and it is identified recently as SVHC according to Article 57(c). 	We thank Finland for its support.	
126.				The Finnish CA considers, however, that the added value of the identification of bisphenol A as SVHC according to article 57(f) in relation to risk management is not evident. The identification of bisphenol A as a SVHC in accordance with article 57 (c) appears to cover endocrine disrupting properties because an estrogenic mode of action seems to be one of the mechanistic backgrounds for the reproductive toxic effects, which are the basis for Repr. 1B classification.
	It is noted that this consideration is not directly relevant for the SVHC identification that is exclusively based on the intrinsic properties of the substance and not on risk management considerations. However, the Finnish concern is acknowledged and we would like to explain the motivations of our proposal.

FR considers it important to identify the different SVHC properties of a substance so that all of them are considered in the assessment process of potential applications for authorisation (if further prioritised). 
It is also noted that additional SVHC properties may have consequences on the obligations linked to SVHC and/or Annex XIV status (e.g. concentration threshold to be considered).
For BPA, it is correct that the ED MoA is involved in the effect that is the basis of 57(c) previous identification. 
However, the ED MoA of BPA, as demonstrated in this dossier is involved in several adverse effects that will need to be considered when granting an authorisation under Art. 60.3. BPA’s ED MoA also raises important uncertainties on dose-response and on the possibility to define reliable safe levels. This is critical for the assessment of potential future applications for authorisation that the uncertainties linked to BPA’s ED-MoA are fully considered in the choice of the route of authorisation as well as in the scope of ED-related effects covered in the assessment. 
Finally, it is noted that a previous case of identification as SVHC 57(c) as well as 57(f) as an endocrine disruptor relevant for human health has been recently endorsed for some phthalates by the REACH committee. Indeed, it has been established through decision "implementing identification of bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), benzyl butyl phthalate (BBP) and diisobutyl phthalate (DIBP) as substances of very high concern according to Article 57(f) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council" (adopted during Reach Committee in February 2017), "Article 57 does not forbid identifying a substance as being of very high concern several times based on more than one intrinsic property causing the same effect on human health".

Please also see response to comment 50 in relation to legal issues. 	
127.				The Finnish CA considers that there are significant uncertainties regarding the relevance and adversity of other effects to human health (i.e. alterations to mammary gland development, brain development and cognitive function, and metabolism). For instance, we hesitate to agree that the increased cancer susceptability of the mammary gland can be regarded as serious a concern as actual CMR cat. 1 effects. Therefore, unlike the French CA, the Finnish CA considers that it is questionable whether these alterations give rise to an equivalent level of concern to those of CMR cat. 1. These effects should be treated as supportive information in the SVHC identification and could be taken into account in the risk assessment (by accounting for them in setting assessment factors and DNELs) rather than as a basis for the SVHC identification.	For mammary gland effects, the structural changes observed in mammary glands in rodents and also in non-human primates and the increase susceptibility of the mammary gland to carcinogenicity represent a serious societal concern because of the increased prevalence of breast cancer. 
For neurobehavioural effects, it is noted that alterations in the cognitive abilities, i.e. learning and memory functions may have large consequences at a populational level. Neurobehavioural disorders represent a serious societal concern because of their increasing prevalence. Any alteration of neurobehaviour, as seen with BPA, should be considered as a relevant adverse effect.
Concerning effects of BPA on metabolism, it is also anticipated that alteration of glucose homeostasis due to effects of BPA on insulin secretion and insulin resistance may lead to Type 2 diabetes. Knowing the large incidence of this pathology in the human population and the lack of knowledge on the role of chemical exposure in the etiology of diabetes and obesity, it represents a serious societal concern.	

PART II: Comments and responses to comments on uses, exposures, alternatives and risks
Table 3 - Specific comments on use, exposure, alternatives and risks
Refernce number	Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
128.		4807
2017/04/20	American Chemistry Council,
Industry or trade association,
United States	See the corresponding embedded attachment in table 1 of Part I:           4807_ACC Comments on Annex XV Dossier - April 20 2017.pdf	Thank you for your comments. Detailed answers are provided in response to your specific comments displayed in the Table 2 of the RCOM	
129.		4808
2017/04/21	Individual,
China	All material provided to the customer does not contain the above substances	Noted	
130.		4811
2017/04/21	GIFAS,
Industry or trade association,
France	Please refer to attached document ref.N°20004/17/GIFAS	Please see Table 1 for response to this comment	
1.				See the corresponding embedded attachment in table 1 of Part I:                                                                               4811_20004_LetterGIFAS-SVHC_Consultation_ECHA-April 2017_V4.pdf		
131.		4813
2017/04/21	CHEM Trust,
National NGO,
United Kingdom	Additional comment on BPA exposure and BPA alternatives:
BPA exposure is nearly ubiquitous as we highlighted in our recent CHEM Trust report `No Brainer – The impact of chemicals on children`s brain development: a cause for concern and a need for action´. (http://www.chemtrust.org.uk/brain/) BPA has been found in people`s urine worldwide, with most studies showing a detection frequency of over 90%. (Covaci et al, Urinary BPA measurements in children and mothers from six European member states: Overall results and determinants of exposure, Environ Res, 141:77-85, 2015)

A study published by the German Environment Agency in 2009 found BPA in the urine of 591 out of 599 children between the age of 3 and 14 years.
Becker et al., Umweltbundesamt (UBA), Kinder-Umwelt-Survey (KUS) 2003/06, Human-Biomonitoring-Untersuchungen auf Phthalat- und Phenanthrenmetabolite sowie Bisphenol A (German and English summary) https://www.umweltbundesamt.de/sites/default/files/medien/376/publikationen/umwelt_und_gesundheit_04_2009_kurzfassung_1.pdf

Chapter 11.2 Alternatives:
For some uses, BPA has been replaced with bisphenol S (BPS), a substitution that may have similar or worse health effects. However, it should be noted that recent studies found BPS and other similar bisphenols in humans, and research suggests they may exhibit developmental neurotoxicity in animals(Chen et al. 2016, Qui et al. 2016, Thayer et al. 2016).  One study has found initial indications that BPS exposure during development may affect maternal behaviour in mice (Catanese et al).  In 2015 Rochester and Bolden carried out a systematic review to compare the hormonal activity of BPS and BPF.

Chen D, Kannan K, Tan H, Zheng Z, Feng Y, Wu Y, Widelka M, Bisphenols analogues other than BPA. Environmental occurrence, human exposure, and toxicity—A review. Environmental Science and Technology 50:5438-5453, 2016

Qui W, Zhao Y, Yang M, Farajzadeh M, Pan C, Wayne NL, Actions of bisphenol A and bisphenol S on the reproductive neuroendocrine system during early development in zebrafish, Endocrinology 157:636-647, 2016

Thayer KA, Taylor KW, Garantziotis S, Schurman S, Kissling GE, Hunt D, Herbert B, Church R, Jankowich, R, Churchwell MI, Scheri RC, Birnbaum LS, Bucher JR, Bisphenol A, bisphenol S, and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP) in urine and blood of cashiers, Environmental Health Perspectives 124:437–444, 2016

Catanese, MC, & Vandenberg, LN, Bisphenol S (BPS) alters maternal behavior and brain in mice exposed during pregnancy/lactation and their daughters, Endocrinology, 2016-1723

Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environ Health Perspect 123:643–650; http://dx.doi.org/10.1289/ehp.1408989  	Your comment is noted although not directly related to BPA 57(f) identification.

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
			-		
132.		4815
2017/04/21	HUNTSMAN,
Company,
Belgium	Please refer to the PDF document attached. Thank You	Responses are provided in Table 2 above	
1.				See the corresponding embedded attachment in table 1 of Part I:                                                                                 4815_HUN comments_French SVHC_ED_final.pdf		
133.		4817
2017/04/21	Stichting Wemos,
National NGO,
Netherlands	The Wemos Foundation is highly concerned about human exposure to BPA and related health effects. Two of our studies support this claim.

Firstly, we found residues of BPA in human urine in four out of four participants. This sample consisted out of four female politicians. It is concerning that these four women who attempt to live in a sustainable manner and limit exposure to chemicals still had residues in their urine. It appears as if exposure to BPA is unavoidable by consumers. The research was executed in collaboration with the Vrije Universiteit Amsterdam. Detailed results can be found attached.

Secondly, we tested five food products for presence of BPA. We found that four out of five products were contaminated with BPA. This included corn from a can, a small apple juice pack, frankfurters sausages (knakworstjes) from a can and tuna from a can. In the smoked sausage (rookworst) we did not find traces of BPA. The widespread contamination of our food with BPA is highly concerning. Detailed results can be found attached.

Lastly, we stress that we are highly concerned about similar alternatives to BPA such as BPS and BPF but not excluding other similar chemicals. To avoid more harm to human health and the environment, BPA should be solely replaced with alternatives safe to human health and the environment. Moreover, when BPA is classified as a threat for human health, so should similar chemicals be classified.	Thank you for your comment. It raises valid questions of the safety of BPA alternatives.
Your comment is noted although not directly related to BPA 57(f) identification. 
Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
1.				See the corresponding embedded attachment in table 1 of Part I:                                                                            4817_20170421 BPA tabel ECHA comments.pdf		
134.		4820
2017/04/21	PC/BPA Group of PlasticsEurope cosigned by BPA REACH Consortium and Epoxy Resins Committee of PlasticsEurope ,
Industry or trade association,
Belgium	COMMENTS PART II OF THE ANNEX XV SVHC DOSSIER
The PC/BPA Group of PlasticsEurope wants to make key legal comments with regards to the uses of BPA as identified by the French authorities, supporting its overall position that the Annex XV proposed by France is unjustified and disproportionate:
1. THE ANNEX XV DOSSIER IS DISPROPTIONATE GIVEN THAT THE VAST MAJORITY OF USES OF BPA ARE AS AN INTERMEDIATE WHICH FALL OUTSIDE THE SCOPE OF TITLE VII OF REACH

A. As also supported by Section 9 of the French dossier, in the vast majority of cases, BPA is used as an intermediate, and consequently exempt from authorisation, in accordance with Article 2 (8)(b) of REACH. Hence, given the very limited non-intermediate uses, an SVHC identification of BPA is not proportionate.
In the vast majority of cases, BPA is used as a monomer, which meets the definition of an on-site/transported isolated intermediate in the manufacture of polycarbonate and other polymers. Pursuant to Article 2(8)(b) of REACH, such intermediate uses are exempted from the entire Title VII (Articles 55 to 66 of REACH) and cannot, therefore, be identified as SVHCs under Article 59 of REACH. Indeed, it has been acknowledged by the French Competent Authority in the framework of the proposal for identification of BPA as an SVHC on the grounds of its reprotoxic properties “that a monomer is considered as an intermediate that cannot be subject to authorisation under REACH” (ref.32).
The uses, which clearly meet the definition of “intermediate” under Article 3(15) of REACH, far outweigh the uses of BPA as an additive (which would subsequently be within the scope of authorisation), for example in the production of thermal paper. Given the use of BPA in thermal paper is already the focus of a targeted restriction under REACH, also triggered by the French authorities, the ultimate merits and relevance of an SVHC process for the remaining non-intermediate uses of BPA does not seem proportionate. The French dossier in fact confirms that only a limited portion of the uses of BPA is non-intermediate.
In summary, such low volume and adequately controlled uses should not result in the prioritisation of BPA for inclusion in Annex XIV based on the Article 58(3) criteria of REACH; hence, identifying BPA as an SVHC for these very limited applications only is not proportionate.

2. THE POTENTIAL RELEASE OF A SUBSTANCE IDENTIFIED AS SVHC GENERATED AS A RESULT OF DEGRADATION DURING THE INTENDED USE OF ITS POLYMERS CANNOT BE CONSIDERED WITHIN THE SCOPE OF AUTHORISATION OF THE SUBSTANCE
The PC/BPA Group of PlasticsEurope notes the question the French authorities raised in their dossier: “…hydrolysis of the polymer can occur at high temperature and alkaline pH, a reaction that can release BPA (ANSES, 2011). In this case, the status of BPA released from polycarbonate is questionable in relation to Authorisation.”
The PC/BPA group responds as follows:
The use of a substance as a monomer in the manufacturing of polymers falls outside the scope of Authorisation because it meets the definition of “intermediate” under Article 3(15) of REACH. Polymers are further defined as separate substances within REACH. Hence any potential degradation of the polymer cannot be considered relevant for the Authorisation of the initial substance.
The release of any substance formed as a result of the potential degradation of a polymer during its intended uses also does not meet the requirements for Authorisation as laid down under Article 56 of REACH. Specifically, ‎Article 56(1) of REACH addresses the scope of the Authorisation procedure in that “[a] manufacturer, importer or downstream user shall not place a substance on the market for a use or use it himself if that substance is included in Annex XIV […]” (emphasis added in the pdf attachment).
Accordingly, the status of traces of BPA potentially released from hydrolysis of polycarbonate cannot be considered in scope of potential Authorisation of BPA.

See the corresponding embedded attachment in table 1 of Part I:                                
4820_Attachments PCBPA comments Annex XV dossier.zip	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
135.		4822
2017/04/22	Individual,
United States	Comments by Frederick S. vom Saal, Curators’ Distinguished Professor of Biology, University of Missouri-Columbia, USA, on the Proposal for Identification of bisphenol A (4, 4’ isopropylidenediphenol) as a Substance of Very High Concern (SVHC) on the Basis of the Criteria Set Out in REACH Article 57.

Overall, this is a very well balanced review of scientific findings showing that bisphenol A (BPA) is an endocrine disrupting chemical that can disrupt endocrine function at very low concentrations, particularly when exposure occurs during vulnerable periods in development.
Regarding potency, findings that BPA can cause effects via non-classical estrogen receptors that are located outside of the cell nucleus (these receptors are associated with the outer membrane of cells) are extremely important, since doses of BPA below the part-per-trillion range can disrupt normal cell function (and have the same potency as estradiol) via these receptors; recent findings show that these receptors are critical for normal development of the reproductive system (Nanjappa MK, et al. Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice. Endocrinology. 2016;157(7):2909-19. doi: 10.1210/en.2016-1085). In addition, it is via these membrane-associated estrogen receptors that BPA stimulates insulin secretion in both mouse and human pancreatic beta cells (Alonso-Magdalena P et al. Bisphenol-A acts as a potent estrogen via non-classical estrogen triggered pathways. Mol Cell Endocrinol. 2012;355(2):201-7. doi: 10.1016/j.mce.2011.12.012).
We have also shown that via the classical nuclear estrogen receptor alpha, BPA at doses equivalent to concentrations of bioactive (unconjugated) BPA in human serum in the high part-per-trillion range, stimulates an increase in both androgen receptor and estrogen receptor 1 (ERalpha) gene expression, and the increase in gene expression is blocked by the nuclear estrogen receptor inhibitor tamoxifen, demonstrating a nuclear estrogen-mediated mode of action (Richter CA, et al. Estradiol and bisphenol A stimulate androgen receptor and estrogen receptor gene expression in fetal mouse prostate cells. Environ Health Perspect. 2007;115:902-8; Taylor JA, et al. Dose-Related Estrogen Effects on Gene Expression in Fetal Mouse Prostate Mesenchymal Cells. PLoS ONE. 2012;7(10). doi: 10.1371/journal.pone.0048311).	Thank you for your comment and support.

Your comment provides further support to the important role on non-classical estrogen receptors in explaining the effects observed at low doses.	
136.				It has also been shown that the induction of androgen receptors in fetal mice by estradiol or BPA is permanent, leading to dramatically increased prostatic androgen receptors (vom Saal FS, et al. Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses. Proc Nat Acad Sci. 1997;94(5):2056-61; Gupta C. Reproductive malformation of male offspring following maternal exposure to estrogenic chemicals. Proc Soc Exp Biol Med. 2000;224(2):61-8. PubMed PMID: 10806412). A dramatic increase in androgen receptors in prostate cells results in a marked increase in the sensitivity of the adult prostate to hormonal stimulation, which is associated with prostate enlargement and pre-cancerous celular abnormalities (metaplasia) (Ogura Y, et al. Bisphenol A induces permanent squamous change in mouse prostatic epithelium. Differentiation. 2007;75(8):745-56. PubMed PMID: 17459086).	It was decided to focus the Annex XV dossier on the effects that fulfilled both the criteria of a well-established effect and evidence of ED-mediated effects. We have however taken note in the dossier that the overall database points toward additional indications for effects of BPA and highlight that ED-mediated effects of BPA analysed in the Annex XV dossier may underestimate the spectrum of effects. 
The Support Document has been updated to further recognize a potential underestimation of ED-related effects of BPA that includes increased susceptibility for prostate cancer.	
137.				We have also shown in a published study (not reviewed in the report; Hormann AM et al. Holding thermal receipt paper and eating food after using hand sanitizer results in high serum bioactive and urine total levels of bisphenol A (BPA). PLoS ONE. 2014;9(10):e110509. doi: 10.1371/journal.pone.0110509) that women had a dramatic, rapid increase in serum BPA (twice that found in men) after holding a thermal receipt containing BPA (men have a more effective dermal barrier than women). Thus, exposure models that assume that all human BPA exposure is from food and beverage containers are clearly greatly underestimating actual human exposure to BPA.	This comment raises valid questions on BPA’s exposure assessment and your comment is noted although not directly related to BPA 57(f) identification. 
Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
138.				The followinng are some additional comments concerning two of the studies reviewed in the report that had flaws that were not discussed in the report.

Page 42: The study by Delclos et al, 2014 is discussed: “In the study from Delclos et al. (2014) issued from the BPA-clarity initiative (Heindel et al., 2015), effects on estrous cyclicity were conclusive in the higher dose group after periconceptional and all life-long exposure.” However, not cited in the review is a companion article (Churchwell MI, et al. Comparison of life-stage-dependent internal dosimetry for bisphenol A, ethinyl estradiol, a reference estrogen, and endogenous estradiol to test an estrogenic mode of action in Sprague Dawley rats. Toxicol Sci. 2014;139(1):4-20. doi: 10.1093/toxsci/kfu021). In this companion article reporting the serum levels of BPA in animals used in the Delclos et al. 2014 study, Churchwell et al. 2014 identify that in the Delclos et al 2014 study, all groups administered doses of BPA in the microgram/kg body weight range had the same serum levels of unconjugated BPA as the vehicle negative controls, which the FDA scientists attributed to inadvertent contamination of the negative controls (the lack of the expected dose-related increase in BPA in low-dose treatment groups may have been due to confusión by staff when dosing animals in the different groups). Contaminated negative controls would make it impossible to find effects in the low-dose range and thus explains why in the Delclos et al 2014 study only doses of BPA in the milligram/kg body weight (high-dose) range showed significant effects relative to the negative controls contaminated with BPA.	Thanks for your comment. The support document has been updated accordingly.	
139.				Page 128: The results from a study by Ryan et al (2010) are discussed. Not identified by Ryan in their publication, and not discussed in the report, is that Ryan et al used an animal feed that had been shown in multiple studies to result in a dramatic increase in body fat in the CD-1 mouse strain used by Ryan (Cederroth CR, Vinciguerra M, Kühne F, Madani R, Klein M, James RW, et al. A phytoestrogen-rich diet increases energy expenditure and decreases adiposity in mice. Environ Health Perspect. 2007;115(10):1467-73; Ruhlen RL, et al. Low phytoestrogen levels in feed increase fetal serum estradiol resulting in the "fetal estrogenization syndrome" and obesity in CD-1 mice. Environ Health Perspect. 2008;116(3):322-8. PubMed PMID: 18335098). As predicted by these prior studies, the negative control mice in the Ryan et al. 2014 study had dramatically higher amounts of fat relative to negatiive control mice in our studies, and the lack of an effect of a very low dose of BPA on glucose tolerance in mice in the Ryan et al 2010 study relative to their metabolically disrupted negative controls was not surprising; Ryan et al. 2010 also housed the animals in polycarbonate cages and provided wáter in polycarbonate bottles, which we and others have shown to have the potential to significantly contaminate all animals with BPA (Howdeshell KL, et al. Bisphenol A is released from used polycarbonate animal cages into water at room temperature. Environ Health Perspect. 2003;111(9):1180-7. PubMed PMID: 12842771; Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Hagan A, Voigt RC, et al. Bisphenol A causes meiotic aneuploidy in the female mouse. Current Biol. 2003;13:546-53). In contrast, as discussed in the report (P 133), when maintained on a feed that did not result in negative controls being obese (and housed in polypropylene cages with glass bottles containing purified BPA-free water), fetal exposure to low doses of BPA resulted in widespread metabolic disruption in CD-1 mice, inclusing impaired glucose tolerance (Angle BM, et al. Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation. Reprod Toxicol. 2013;42:256-68. doi: 10.1016/j.reprotox.2013.07.017).	Thanks for your comment. We were well aware that in the study from Ryan et al. (2010), mice were fed with high-fat diet but we considered that BPA under these conditions has an effect on glucose intolerance. More recent studies such as Moon et al. (2015) support these observations (see table 25 in the support document).	
			-		
140.		4823
2017/04/23	Health and Environment Alliance (HEAL),
International NGO,
Belgium	- The high tonnage status of BPA (P174), the known ubiquitous use and application of this compound (P174-187) as well as the unknown applications all contribute to wide-spread exposure of the entire population to this compound (e.g. RIVM (2014) Bakker J et al. Bisphenol A: Part 1. Facts and figures on human and environmental health issues and regulatory perspectives. http://www.rivm.nl/dsresource?objectid=9c10974c-f3d2-4bd2-8cf0-436c40fe9f70&type=org&disposition=inline ). This includes unborn children, who are even more susceptible for BPA adverse health effects, as described in this dossier. Together, this certainly warrants risk management actions, which will be facilitated by listing BPA on the SVHC list.

- Even though the relevance of alternatives to reduce risks has not been assessed (P187), it is important to acknowledge that some alternatives that are mentioned, such as BPF and BPS (P192), also display estrogenic activity and are not necessarily safer than BPA.

For example:
Rochester JR, Bolden AL. 2015. Bisphenol S and F: a systematic review and comparison
of the hormonal activity of bisphenol A substitutes. Environ Health Perspect 123:643–650: http://dx.doi.org/10.1289/ehp.1408989 

Eladak et al. 2015. A new chapter in the bisphenol A story: bisphenol S and bisphenol F are not safe alternatives to this compound. Fertility and Sterility 103(1): http://dx.doi.org/10.1016/j.fertnstert.2014.11.005 	Thank you for your comment and the information provided. 

Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.
	
			-		
141.		4832
2017/04/24	ClientEarth,
International NGO,
United Kingdom	See the corresponding embedded attachment in table 1 of Part I:                                4832_ClientEarth (Dr V. Martin) Comments on BPA Annex XV SVHC report.pdf	See RCOM in table 2.	
142.		4833
2017/04/24	Breast Cancer UK,
National NGO,
United Kingdom	BPA is widespread in the environment and is routinely found in freshwater, seawater and landfill leachates. It has been detected in human urine, blood, amniotic fluid, breast milk, fat tissue and the placenta (9). Urinary BPA has been detected in people from many different countries, with most studies showing over 90% of individuals tested have BPA in their urine (e.g. 10, 11) and several reporting higher levels in children compared to adults.

We at Breast Cancer UK are concerned that compounds used as substitutes for BPA may have similar endocrine disrupting properties. Bisphenols, such as bisphenol S (BPS), bisphenol F (BPF) and Bisphenol AF (BPAF) are used in the production of polycarbonate plastics and epoxy resins. Alternative bisphenols have been detected in human urine (12) and a recent study suggests BPF, BPAF, BPS, BPB and BPZ are all oestrogenic (13).

References
9. Vandenberg, L. N. et al. (2010). Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A. Environmental Health Perspectives 118 (8): 1055-1070.
9. Vandenberg, L. N. et al. (2010). Urinary, Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A. Environmental Health Perspectives 118 (8): 1055-1070.
10. Covaci et al. (2015). Urinary BPA measurements in children and mothers from six European member states: Overall results and determinants of exposure. Environmental Research 141: 77-85.
11. Choi, J. et al. (2017). Identification of exposure to environmental chemicals in children and older adults using human biomonitoring data sorted by age: Results from a literature review. International Journal of Hygiene and Environmental Health 220(2A): 282–298.
12. Chen, D, et al. (2016). Bisphenols analogues other than BPA. Environmental occurrence, human exposure, and toxicity—A review. Environmental Science and Technology 50:5438-5453, 2016
13. Mesnage, R. et al. (2017). Transcriptome profiling reveals bisphenol A alternatives activate estrogen receptor alpha in human breast cancer cells. BioRxiv preprint posted March 2, 2017. http://biorxiv.org/content/early/2017/03/02/112862 	Thank you for your comment. It raises valid questions on exposure to BPA and the safety of BPA alternatives.
Your comment is noted although not directly related to BPA 57(f) identification. 
Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.