General comments
Ref.	Date/Type/Org.	Comments	
34	Date: 2022/06/16 12:27
Country: Finland
	General Comments:
FI CA considers that for BPF (EC 210-658-2) the criteria for endocrine disruption as defined by the WHO/IPCS (2002) are met for the environment.	
		Submitter response:
Thank you for your support.	
37	Date: 2022/06/17 17:39
Org. type: Other contributor
Org. name: Environment Agency Austria
Org. country: Austria
Country: Austria
	General Comments:
The provided evidence is considered sufficient for an identification as endocrine disruptor for the environment: The adverse effects are relevant for populations, the endocrine activity is sufficiently demonstrated and the link is plausible.
In order to improve the readability of the report, we recommend the following:
•	It would be beneficial if particularly in table 5 the tested substances are mentioned in column “methods” and the column “results” (e.g. BPA is missing in column “method” for Eladak et al., 2015). 
•	The term “or” in the context of reporting the results of substances in table 5 could be removed.
•	For identification of the most relevant studies in table 6 the order of the studies could be changed to list the most important studies first 
•	It should be considered to make another table for the amphibian data
	
		Submitter response:
Thank you for your support to the identification as an endocrine disruptor for the environment.
The proposed improvements will be considered for the update of the report.	
38	Date: 2022/06/20 13:29
Org. type: Industry or trade association
Org. name: Cefic
Org. country: Belgium
Country: Belgium
	General Comments:

1.	BPF is a natural occurring substance in plants (Huang, Danaher, Brüschweiler, Kass, & Merten, 2019) and is also formed through natural food fermentation processes (Federal Food Safety and Veterinary Office FSVO Swiss Confederation, 2017). (Dietrich & Hengstler, 2016)
2.	The German MSCA dossier does not provide evidence that industrial and professional uses of BPF are significant contributors to environmental levels.
3.	The comments brought forward by the German MSCA in its dossier are predominantly based on Level 2 and Level 3 type studies according to OECD 150 Test Guidelines (OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupting Chemicals, 2017). Consequently, the study evidence as produced in the dossier is lacking data on e.g. repeated dose toxicity (OECD TG 407 and TG 408) or reproduction/developmental toxicity screening tests (OECD TG 421 or TG 422). Similarly, Level 5 studies such as an  EOGRTS (OECD TG 443) or a two-generation reproduction toxicity study (OECD TG 416)  providing more comprehensive data on adverse effects (of endocrine-relevant endpoints) over extensive parts of the life cycle of organisms are missing. 
In accordance with OECD 150 Framework Testing Guidelines, unambiguous identification of a substance as an endocrine disruptor should be based on study data which goes beyond Level 2 mechanistic in vitro mode of action assays or Level 3 selected individual endocrine mechanisms or pathways. 
The Framework asks also for the use of validated test methods or additional scrutiny if data from non-validated test methods is used. The German MSCA dossier, apart from the referenced Klimisch rating,  does not scrutinize the data from non-validated methods and laboratories for reproducibility and reliability.
4.	Bisphenol F is used almost exclusively as an intermediate by the epoxy resins industry or is generated as a transient intermediate during the production process of phenolic resole and novolac resins. Both types of intermediates are consumed in subsequent reactions and are converted to new substances which have an entirely different substance profile. It is for that reason that Bisphenol F is only fully registered in the lowest tonnage band (1 – 10 MT/a) under REACH whilst it has an intermediate registration in the highest tonnage band. Consequently, releases from those industrial uses are considered  to be insignificant.
5.	Given the registration status of BPF under REACH and the way it is further processed makes it highly unlikely that the environmental concentration of BPF could reach similar levels as Bisphenol A (BPA). In fact, the German MSCA’s dossier provides  no evidence that environmental concentration in the European environment (surface freshwater and/or marine saltwater, river sediment, or soil) is at a level comparable to the levels of BPA which have been quoted in a number of studies. (Fromme, et al., 2002) report in their paper “Occurrence of phthalates and Bisphenol A and F in the environment” the concentrations of BPA, BPF and phthalates in German surface water, sediment, sewage water treatment plant effluents, sewage sludge, landfill leachate (waste dump water), and liquid manure. It was found that BPF was present at significantly lower levels than BPA from 0.0001 to 0.180 µg/l for surface water samples, whilst concentration of BPA was determined to be in the range of 0.005 – 0.229 µg/l in the same samples. The Fromme et al. study is one of the very few studies reporting environmental concentrations of BPF for European waterways. Studies with a focus on East Asia are reporting similar or slightly higher concentrations of BPF in various aqueous compartments, e.g., (Liu, et al., 2021) “Occurrence, toxicity and ecological risk of BPA analogues in aquatic environment – A review” but cannot be transposed directly to a European context due to different use patterns and quality of emission controls. 
Given the data presented for actual environmental exposure, we are concerned that the scientific evidence used is not enough to warrant the (Dietrich & Hengstler, 2016) identification of BPF as an endocrine disruptor.
Dietrich, D. R., & Hengstler, J. G. (2016). From bisphenol A to bisphenol F and a ban of mustard due to chronic low-dose exposures? Arch Toxicology, 90: 489 - 491.
Federal Food Safety and Veterinary Office FSVO Swiss Confederation. (2017). Bisphenol F in Mustard. Notification by teh Swiss FSVO, 2.
Fromme, H., Küchler, T., Otto, T., Pilz, K., Müller, J., & Wenzel, A. (2002). Occurence of phthalates and bisphenol A and F in the environment. Water Research, 1429 - 1438.
Huang, T., Danaher, L.-A., Brüschweiler, B. J., Kass, G. E., & Merten, C. (2019). Natural occurring Bisphenol F in plants used in traditional medicine. Archives of Toxicology, 93: 1485 - 1490.
Liu, J., Zhang, L., Lu, G., Jiang, R., Yan, Z., & Li, Y. (2021). Occurence, toxicity and ecological risk of Bisphenol A analogues in aquatic environment - A review. Ecotoxicology and Environmental Safety , 208, 111481.	
		Submitter response:
Thank you for your comment.
1., 2., 4., 5.: These comments we understand as dealing with the possible emissions of BPF into the environment and the tonnage band of the registration. As the aim of this report is to provide the hazard data and evidence for the endocrine disrupting properties of BPF, it does not describe the manufacture and use of the substance. There is data provided on the concentrations found in monitoring to demonstrate, that despite the limited use of BPF it is already found in the environment. As BPF is a possible alternative substance for BPA in some uses, the increase of emissions is expected in the near future.
3. As BPF is not registered there are no information requirements under REACH that would allow for requesting a level 5 study like an EOGRTS (OECD TG 443) or a two-generation reproduction toxicity study (OECD TG 416). Furthermore, the identification of an endocrine disruptor is based on the WHO/IPCS criteria. Accordingly, the available relevant and reliable scientific data are analysed with respect to evidence for an ED mode of action, adverse and population relevant effects and a plausible biological link between adversity and ED mode of action. With respect to this also OECD level 3 data can be used to demonstrate population relevant adversity if effects impairing reproductive capacity (e.g. fertility or fecundity) or development (e.g. effects on metamorphosis) can be shown. Furthermore, we would like to point out that elements of hazard characterisation like potency are not taken into account when assessing the ED properties of a substance.	
39	Date: 2022/06/20 15:59
Country: Denmark
	General Comments:
Thank you for the opportunity to submit comments on BPF.
We would like to point your attention to an in vivo zebrafish study by Qui et al. (2019) which could also be included in the assessment. The study shows that long-term exposure to low and environmentally relevant levels of BPF in vivo leads to increased expression of reproductive neuroendocrine-related genes and increased levels of hormones in the zebrafish brain as well as increased levels of vitellogenin in liver. The authors suggest that chronic BPF exposure affects regulation of the reproductive neuroendocrine system through activation of the estrogen receptor.
1.	Qui, Wenhui; Fang, Meijuan; Liu, Jingyu; Fu, Caixia; Zheng, Chunmiao; Chen, Bei and Wang, Ke-Jian (2019): In vivo actions of Bisphenol F on the reproductive neuroendocrine system after long-term exposure in zebrafish. Science of The Total Environment. Volume 665, 15 May 2019, Pages 995-1002. DOI: 10.1016/j.scitotenv.2019.02.154.
	
		Submitter response:
Thank you for drawing attention to the publication. We will consider it for the update of the report.	
41	Date: 2022/06/20 16:23
Org. type: National NGO
Org. name: CHEM Trust Europe eV
Org. country: Germany
Country: Germany
	General Comments:
BPF
https://comments.echa.europa.eu/comments_cms/PublicConsultationED.aspx?RObjectId=0b0236e185700c5d_bpf
General comments:
CHEM Trust strongly supports the development of a restriction proposal to address the risks of BPA and structurally relevant bisphenols to the environment. In our report from 2018 ´ From BPA to BPZ – a toxic soup?´  https://chemtrust.org/toxicsoup/ , we demonstrated the fact that companies are being allowed to replace the well-known hormone disrupting chemical BPA with chemicals having a similar hazardous profile to BPA. Our analysis also highlighted BPF and BPAF as relevant substitutes which need to be addressed as a priority in a group approach.
We have long argued that a group restriction for BPA and structurally related bisphenols is long overdue (https://chemtrust.org/bisphenol_group/). A comprehensive group restriction for the bisphenols would be a very important step forward to increase the protection level. It would also be responding to the EU Chemicals Strategy for Sustainability which commits to a ban of EDCs in consumer products as soon as they are identified and allowing their use only, where it is proven to be essential for society. Thus, any derogation should only be granted in exceptional cases based on well-documented reasons and with a time-limit.
In April this year ECHA published the results of an in-depth evaluation of the regulatory needs on the group of bisphenols (see: https://echa.europa.eu/nl/-/group-assessment-of-bisphenols-identifies-need-for-restriction). ECHA and the Member States have assessed a group of 148 bisphenols and recommended that more than 30 bisphenols need to be restricted due to their potential hormonal or reprotoxic effects.  BPF and BPAF are among those 34 bisphenols recommended for a group restriction.
We support the chosen procedure of asking MSC for an opinion of the ED properties in order to make efficient use of previous ECHA committee assessments and to avoid further delays and duplication of work.
Specific Comments : 
On the evaluation of endocrine disrupting properties for the environment for 4,4'-methylenediphenol (EC 210-658-2, CAS 620-92-8, “Bisphenol F”) (BPF) by Germany.
CHEM Trust supports the evaluation conducted by Germany that BPF has endocrine disrupting properties for the environment. 
Overall, the presented data clearly show that BPF has endocrine disrupting properties. BPF may have several modes of action, EATS; estrogenic, anti-androgenic, thyroidal activity and interference with steroidogenesis, where the estrogenic and anti-androgenic activity can be linked to adverse effects relevant for population levels in fish.  BPF shows clear and consistent adverse effects on reproduction and sexual development in zebra fish that are plausibly linked to the estrogenic and anti-androgenic mode of action. Supportive evidence is also that BPF seems to interfere with the HBT-axis as shown by in vitro and in vivo data from fish and amphibians. In addition, studies in rats show a decrease in serum testosterone levels and a decrease in sperm motility in the offspring of treated female rats, which support the conclusion of an estrogenic/antiandrogenic mode of action. This is further supported by the analogy of BPF to BPA and BPB, both of which have been identified as having endocrine disrupting properties for human health and the environment. 
In conclusion, there is clear evidence that BPF fulfils the WHO/IPCS definition for an ED in line with the 2013 recommendations from the ECHA ED Expert Advisory Group and further, the substance has similar properties as BPA and BPB, both of which have been identified as endocrine disruptors. The substance can thus be identified to have endocrine disrupting properties for the environment as proposed by Germany without the need for any duplication of resource-intensive assessment procedures.  Further, in our opinion, BPF should also be identified as an ED for human health considering the conservation of the hormonal system across species, and the fact that endocrine disrupting effects have also be shown in rat studies. 
	
		Submitter response:
Thank you for your supporting comments.	
43	Date: 2022/06/20 16:37
Country: Norway
Attachment:
	General Comments:
Norwegian comments on endocrine disrupting properties for the environment of bisphenol F, bisphenol AF and 8 salts of BPAF
We thank the German CA for preparing a proposal to restrict bisphenol A, other bisphenols and bisphenols derivatives based on their endocrine disrupting properties for the environment.  
Since the substances bisphenol F, bisphenol AF and eight BPAF salts have not been identified as substances of very high concern, we welcome the elaboration of an MSC opinion whether endocrine disrupting properties for the environment are fulfilled. 
Bisphenols are a group of concern for several hazardous properties and should be regulated as a group. This will also avoid that regulated substances of this group could be substituted with compound with similar hazardous properties. 
The Norwegian CA agrees that bisphenol F, bisphenol AF and eight BPAF salts meet the criteria for an endocrine disrupting substance for the environment as defined by the WHO /IPCS ( 2002).
Bisphenols are used in a wide range of products and with potential exposure of humans and the environment. Monitoring data from Norway demonstrate that bisphenol F, AF and several of their derivates have been detected in environmental compartments and biota. 
Please find a compilation of monitoring data from Norway attached. 	
		Submitter response:
Thank you for your support and for the compilation of monitoring data from Norway. This information will be taken into account in the restriction dossier which will be submitted later this year since the Art. 77(3) report focuses on the hazard properties.	
45	Date: 2022/06/20 16:47
Org. type: Industry or trade association
Org. name: Verband der Chemischen Industrie e.V.
Org. country: Germany
Country: Germany
	General Comments:
Art. 77 c) request supporting information report, page 2:
Decisions and options foreseen to be taken during the restriction process should not be undermined by other arbitrary processes as this is actually intended related to two diphenoles via a mandate from the ECHA director for the MSC: “To avoid that RAC [the ECHA committee in charge of providing an option related to risks (= hazard and exposure) under the restriction procedure] has to prepare an opinion on this [ED properties] and introduce a potential risk of divergent of opinions between ECHA committees, the MSC will be tasked with providing an opinion …, which then can be used in the further deliberation of RAC.” 
Companies need processes that are transparent and predictable with a proper time window for their input. For this, the process for harmonised classification and, in absence of CLP hazard classes for ED, the SVHC identification process are accepted approaches including early alerts (registry of intentions) and consultation options for companies. Bypassing these “hazard identification” steps and prying out the hazard part of the risk identification step in the assessment of the annex XV restriction dossier undermines the role attributed to these processes by the REACH and the CLP regulations.
It sounds strange when there is already the expectation that there might be divergent opinions of MSC and RAC regarding the ED properties assessed by the dossier submitter. It is not foreseen in the REACH legislation that committees (RAC/SEAC) empowered to provide an opinion are excluded on purpose from opinion making on key elements of the restriction dossier (here the hazard assessment as part of the risk assessment). 
Thus, we ask to stick to the processes for hazard identification provided for under REACH and CLP and to avoid shortcuts not foreseen in applicable legislation.
	
		Submitter response:
The Art. 77(c) process allows MSC to provide an opinion on specific issues on the Executive Director’s request. This opinion is valuable here since ED ENV identification issues have been broadly discussed in the MSC. RAC will take note of the MSC Opinion when assessing the restriction proposal. Thus, this process will provide information on the hazard properties for BPF and BPAF and hence on the question whether or not both bisphenols will be covered as “bisphenols of similar concern” in the restriction proposal. If they will be included, issues with regard to risk and appropriate risk management options will be discussed in the restriction dossier. Since for both processes, the Art. 77 (c) as well as the restriction process public consultations are performed, you are able to provide your input on hazard and risk issues and the related legislations and consequences. We would like to draw attento to the Judgement of the General Court in Case T-226/18, paragraph 252, which states “that Article 77(3)(c) of Regulation No 1907/2006 allows the Executive Director of ECHA to obtain the opinion of the MSC concerning the safety of substances on their own, in mixtures or in articles. There is therefore a legal basis for intervention by the MSC in such a context. What is more, no provision of Articles 68 to 73 of Regulation No 1907/2006, or even of Article 77 thereof, excludes the possibility of such intervention by the MSC in addition to the requirements set by the procedure for adopting a restriction.” Consequently, we consider the triggering of Article 77 (3) (c) in this case as legally justified.
	
46	Date: 2022/06/20 17:27
Org. type: Industry or trade association
Org. name: Verband Deutscher Schleifmittelwerke VDS
Org. country: Germany
Country: Germany
Attachment:
	General Comments:
For the reasons listed in our attached “Statement regarding bisphenols in relation to their potential properties as endocrine disruptors”, there is no clear scientific evidence that BPF actually exerts an endocrine function in the environment. Further studies are needed to explore a potential effect of BPF in the environment. For the reasons stated, the classification of BPF as an ED is not justified. BPF must be removed from the list of Bisphenols of similar Concern.
	
		Submitter response:
1.	WHO definition: The use of the WHO/IPCS definition to identify the endocrine disrupting properties of a substance is well agreed among all member states. This procedure is used for all substances suspected to have this property.
2.	Data proving that concentrations found in environment can actually have an effect on aquatic life: This report aims to clarify if BPF has endocrine disrupting properties in the environment. The comparison of the effect with the monitoring concentrations is not the intention. This is the question of risk management and will be discussed in the restriction dossier.
3.	Degradability of BPF: Thank you for this information. As we did not describe the degradability in the report which is limited to the assessment of the environmental ED properties, this information will be integrated in the final restriction dossier.
4.	Concentrations that trigger effects are very high compared to endogenous hormone concentrations: According to point 1. the available relevant and reliable scientific data are analysed with respect to evidence for an ED mode of action, adverse and population relevant effects and a plausible biological link between adversity and ED mode of action. With respect to this also OECD level 3 data can be used to demonstrate population relevant adversity if effects impairing reproductive capacity (e.g. fertility or fecundity) or development (e.g. effects on metamorphosis) can be shown. Furthermore, we would like to point out that elements of hazard characterisation like potency are not considered when assessing the ED potential of a substance.	
47	Date: 2022/06/20 17:34
Org. type: Industry or trade association
Org. name: EDITED
Org. country: Austria
Country: Austria
Attachment:
	General Comments:
There is no clear scientific evidence that BPF actually exerts an endocrine function in the environment. Further studies are needed to explore a potential effect of BPF in the environment. The classification of BPF as an ED is not justified. BPF must be removed from the list of Bisphenols of similar Concern.  We support the argumentation provided in the statement attached.
	
		Submitter response:
In our opinion, we demonstrated in the report that BPF has endocrine disrupting properties for the environment. For the response to the attached statement see comment 46.	
48	Date: 2022/06/20 17:39
Org. type: Industry or trade association
Org. name: European Phenolic Resin Association (EPRA)
Org. country: Germany
Country: Germany
Attachment:
	General Comments:

		Submitter response:
Literature search strategy: 
Thank you for your comment. We will include it in the update of the report.
“A literature search was performed to identify all studies available in open literature relevant for the assessment of endocrine disrupting properties of Bisphenol F in relation to the environment. As the substance is not registered, an assessment of the results presented in study reports from the registration dossier was not possible.
Search strings and number of hits are presented in the table below.
Date of search	
Database	
Search string	
Number of articles	
Comment	

Again on 10.09.2021	
PubMed	
(Bisphenol F) OR (4,4’-methylenediphenyl) OR (620-92-8 OR (210-658-2) AND ((fish OR human OR toxicity) OR (endocrine* OR hormone* OR androgen* OR estrogen* OR thyroid* OR steroid*))	
498 publications

Manual screening narrowed the result to 36 potentially relevant publications

The title and abstracts of the identified articles were screened manually. Expert judgement was also used to determine whether a study was likely to provide information of relevance for the ED assessment. 	

The last PubMed search was performed on September 10th 2021. This resulted in 498 hits.

The quality and reliability of all in vitro and in vivo studies were assessed, and each study was assigned a reliability score based on the Klimisch categories 1, 2, 3 or 4 (Klimisch et al., 1997) combined with an expert judgement statement. • 1: reliable without restriction • 2: reliable with restriction • 3: not reliable or • 4: not assignable”
No full package of data, including OECD level 4/5 studies available: As the substance is not registered under REACH no information requirements exist. Therefore, only literature information could be used for the assessment of the endocrine disrupting properties of BPF.
No two-generation reproductive fish studies are available currently: Yes, this is true. In our opinion there is sufficient information on the ED properties available and it is possible to decide on the ED properties of a substance even if no two-generation reproductive fish study  is available. This was already done in SVHC identifications under REACH for endocrine disruptors in the environment, e.g. for 4-tert-butylphenol (EC 202-679-0), 4-pentylphenol (EC 201-280-9) or 3-benzylidene camphor (EC 239-139-9).
Main in-vivo evidence for BPF was drawn from studies on Danio rerio.: This is correct but there is also evidence from studies on Xenopus laevis.
In summary, while it is acknowledged that there may be a plausible link between observed adverse effects and endocrine activity, and that the available in-vitro/in-vivo data point to agonistic estrogen and anti-androgenic modes of action, […]: Thank you for your support.
[…] we would like to emphasise that the basis of the conclusions in the German submission regarding adverse effects and mode of action are based on two studies carried out in the same laboratory – and only one of those is a guideline study. Coupled with the lack of information on full lifecycle and reproduction toxicity studies, it is clear that a larger data package would be justified in order to draw any firm regulatory conclusion on parallels with BPA.: There is not more data available for the assessment of the ED properties of BPF. SVHC identifications for endocrine disrupting properties in the environment have been agreed upon at EU level based on similarly limited data sets in the past (see above).
Thresholds and exposure (concentration in the environment 1-2 µg/L; observed effects above 10 µg/L): At the moment it is not possible to derive a safe threshold for endocrine disrupting substances in the environment. Therefore, this comparison is essential for the evaluation of the ED properties of BPF. Additionally, it is expected that the amounts used would change in the future as BPF is a possible alternative substance for BPA. This was observed e.g. for BPS subsequent to the restriction of BPA for the use in thermal paper.
DHI Report: Thank you for the inclusion of the two review articles on ED properties of BPF. Rochester and Bolden (2015) was known. As we did not use reviews for the evaluation (but the studies), this review was not cited in our report. This is also true for the second review by Usman et al. (2019). One study included in the Usman-review was missing in our report and we will consider this for the update of our report.	
49	Date: 2022/06/20 18:08
Org. type: European institution
Org. name: Federation of European Producers of Abrasives
Org. country: France
Country: France
Attachment:
	General Comments:

		Submitter response:
Please, see response to comment no. 46.	
50	Date: 2022/06/20 18:54
Org. type: Industry or trade association
Org. name: Verband TEGEWA e.V.
Org. country: Germany
Country: Germany
	General Comments:
Verband TEGEWA is concerned about the way the ECHA director anticipates the process to evaluate effects on human health and the environment by substances via the statement given in the Article 77(3)(c) Request Supporting Information Report on evaluation of endocrine disrupting properties for the environment published April 2022: "To avoid a situation where RAC is required to conclude on whether a substance fulfils the criteria for endocrine disruption for the environment, rather than the MSC, it is anticipated that ECHA will facilitate an ad-hoc process under Article 77(3)(c) of REACH to enable the MSC to give an opinion on the endocrine disrupting properties of the substances identified above, which can then be used by RAC as the basis of their evaluation. This assessment report is submitted to ECHA by the DE CA to be used as the basis for the opinion-making of the MSC."
We are surprised by the proposal of the ECHA Director to deviate from the normal process of a hazard assessment and to skip the RAC for the moment. We would like to see the EU authorities follow the normal and transparent processes of hazard assessment and not make the process arbitrary with the possible intention of anticipating results. We think it is important for the trust in the processes and especially in the authorities that the legal processes are carried out in a transparent and reliable way. Therefore, we ask for predictable and reliable processes and not to exclude the empowered committees (RAC/SEAC) in the REACH legislation to provide an opinion on key elements of the restriction dossier (here the hazard assessment as part of the risk assessment).
	
		Submitter response:
As for SVHC identification process the MSC is in charge to conclude on the endocrine disrupting properties of a substance – to beware a continuity in the assessment – the MSC was also tasked in this process providing an opinion on the endocrine disrupting properties of BPF (and BPAF). Please see also our response to comment no. 45.	
51	Date: 2022/06/20 18:57
Org. type: Industry or trade association
Org. name: Epoxy Europe-Cefic Sector Group
Org. country: Belgium
Country: Belgium
Attachment:
	General Comments:
Comments on the BPF Member State Assessment for the Identification of BPF as an Endocrine Disruptor
1.	BPF is a natural occurring substance in plants (Huang, Danaher, Brüschweiler, Kass, & Merten, 2019) and is also formed through natural food fermentation processes (Federal Food Safety and Veterinary Office FSVO Swiss Confederation, 2017). (Dietrich & Hengstler, 2016)
2.	The German MSCA dossier does not provide evidence that industrial and professional uses of BPF are significant contributors to environmental levels.
3.	The comments brought forward by the German MSCA in its dossier are predominantly based on Level 2 and Level 3 type studies according to OECD 150 Test Guidelines (OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupting Chemicals, 2017). Consequently, the study evidence as produced in the dossier is lacking data on e.g. repeated dose toxicity (OECD TG 407 and TG 408) or reproduction/developmental toxicity screening tests (OECD TG 421 or TG 422). Similarly, Level 5 studies such as an  EOGRTS (OECD TG 443) or a two-generation reproduction toxicity study (OECD TG 416)  providing more comprehensive data on adverse effects (of endocrine-relevant endpoints) over extensive parts of the life cycle of organisms are missing. 
In accordance with OECD 150 Framework Testing Guidelines, unambiguous identification of a substance as an endocrine disruptor should be based on study data which goes beyond Level 2 mechanistic in vitro mode of action assays or Level 3 selected individual endocrine mechanisms or pathways. 
The Framework asks also for the use of validated test methods or additional scrutiny if data from non-validated test methods is used. The German MSCA dossier, apart from the referenced Klimisch rating,  does not scrutinize the data from non-validated methods and laboratories for reproducibility and reliability.
4.	Bisphenol F is used almost exclusively as an intermediate by the epoxy resins industry or is generated as a transient intermediate during the production process of phenolic resole and novolac resins. Both types of intermediates are consumed in subsequent reactions and are converted to new substances which have an entirely different substance profile. It is for that reason that Bisphenol F is only fully registered in the lowest tonnage band (1 – 10 MT/a) under REACH whilst it has an intermediate registration in the highest tonnage band. Consequently, releases from those industrial uses are considered  to be insignificant.
5.	Given the registration status of BPF under REACH and the way it is further processed makes it highly unlikely that the environmental concentration of BPF could reach similar levels as Bisphenol A (BPA). In fact, the German MSCA’s dossier provides  no evidence that environmental concentration in the European environment (surface freshwater and/or marine saltwater, river sediment, or soil) is at a level comparable to the levels of BPA which have been quoted in a number of studies. (Fromme, et al., 2002) report in their paper “Occurrence of phthalates and Bisphenol A and F in the environment” the concentrations of BPA, BPF and phthalates in German surface water, sediment, sewage water treatment plant effluents, sewage sludge, landfill leachate (waste dump water), and liquid manure. It was found that BPF was present at significantly lower levels than BPA from 0.0001 to 0.180 µg/l for surface water samples, whilst concentration of BPA was determined to be in the range of 0.005 – 0.229 µg/l in the same samples. The Fromme et al. study is one of the very few studies reporting environmental concentrations of BPF for European waterways. Studies with a focus on East Asia are reporting similar or slightly higher concentrations of BPF in various aqueous compartments, e.g., (Liu, et al., 2021) “Occurrence, toxicity and ecological risk of BPA analogues in aquatic environment – A review” but cannot be transposed directly to a European context due to different use patterns and quality of emission controls. 
Given the data presented for actual environmental exposure, we are concerned that the scientific evidence used is not enough to warrant the (Dietrich & Hengstler, 2016) identification of BPF as an endocrine disruptor.
Dietrich, D. R., & Hengstler, J. G. (2016). From bisphenol A to bisphenol F and a ban of mustard due to chronic low-dose exposures? Arch Toxicology, 90: 489 - 491.
Federal Food Safety and Veterinary Office FSVO Swiss Confederation. (2017). Bisphenol F in Mustard. Notification by teh Swiss FSVO, 2.
Fromme, H., Küchler, T., Otto, T., Pilz, K., Müller, J., & Wenzel, A. (2002). Occurence of phthalates and bisphenol A and F in the environment. Water Research, 1429 - 1438.
Huang, T., Danaher, L.-A., Brüschweiler, B. J., Kass, G. E., & Merten, C. (2019). Natural occurring Bisphenol F in plants used in traditional medicine. Archives of Toxicology, 93: 1485 - 1490.
Liu, J., Zhang, L., Lu, G., Jiang, R., Yan, Z., & Li, Y. (2021). Occurence, toxicity and ecological risk of Bisphenol A analogues in aquatic environment - A review. Ecotoxicology and Environmental Safety , 208, 111481.	
		Submitter response:
Thank you for your comment. For the response please see comment no. 38.	
52	Date: 2022/06/20 19:33
Org. type: Industry or trade association
Org. name: Federchimica - Aispec - Gruppo abrasivi
Org. country: Italy
Country: Italy
Attachment:
	General Comments:
Gruppo abrasivi represents the Italian abrasive industry, encompassing four product segments, bonded and coated abrasives, superabrasives and (conventional) grains. It represents nearly 1500 employees and 25 companies, and it is one of the 13 product groups of Aispec, the association that represents fine chemicals, specialist products and services for the chemical industry inside Federchimica, the Federation of the Italian Chemical industry.
For our comments, please see the attached document.	
		Submitter response:
Thank you for your comment. For the response please see comment no. 46.	
54	Date: 2022/06/20 21:33
Org. type: International NGO
Org. name: European Environmental Bureau
Org. country: Belgium
Country: Netherlands
	General Comments:
The EEB welcomes the assessment prepared by the German Competent Authority (DE CA) on the endocrine disrupting properties of 4,4’-methylenediphenol (Bisphenol F, BPF) in the environment. We support the conclusion that  BPF meets the criteria for endocrine disrupting substances for the environment as defined by the WHO/IPCS (2002).  
The dossier submitter convincingly demonstrated endocrine activity by BPF both in vitro as well as in vivo studies related to estrogenic and anti-androgenic activity, as well as interference with testosterone production and thyroid activity. The ED activity is biologically plausible linked to adverse and population relevant effects of Bisphenol F (BPF) on reproduction and sexual development in fish, including adverse effects on egg production, hatching and survival of offspring, gonadal development and sex ratio.
The conclusion that BPF meets the definition for an ED substance in the environment is also supported by the structural similarity with BPA and BPB that both have been identified as Substance of Very High Concern under REACH. Overall, the EEB agrees that Bisphenol F acts as an endocrine disruptor in the environment according to the ED criteria of the WHO/IPCS (2002). Bisphenol F should be covered by the restriction proposal for Bisphenol A and other bisphenols exhibiting a similar concern for the environment. 
	
		Submitter response:
Thank you for your support.
	
55	Date: 2022/06/20 23:19
Org. type: Academic institution
Org. name: EuDiCo GmbH Toxicologist
Org. country: Germany
Country: Germany
Attachment:
	
General Comments:
	
		Submitter response:
Please, see also response to comment no. 38.

1.	WHO/IPCS definition also includes non-ED substances: The use of the WHO/IPCS definition to identify the endocrine disrupting properties of a substance is well agreed among all member states. This procedure is used for all substances suspected to have this property.
2.	ED-properties of BPF scientifically questionable: For the clarification of the endocrine disrupting properties of BPF it is not necessary to examine what concentrations actually occur in water bodies.
3.	BPF is readily biodegradable + potency compared to 17ß-estradiol: Bisphenol A as well is readily biodegradable. Non-biodegradability would increase the concern for a substance with ED properties but the ED concern is not solved if a substance is readily biodegradable. The potency of 17ß-estradiol is much higher than for BPF (and also BPA). Therefore, this substance is often used as a positive control in ED tests.