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

Disclaimer: Comments provided during the consultation are made available as submitted by the commenting parties. It is 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. 

Substance name: reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)morpholine and 2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine
CAS number: -
EC number: 473-390-7

The substance is proposed to be identified as meeting the following SVHC criteria set out in Article 57 of the REACH Regulation: vPvB (Article 57e)

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

Table 1 - General comments on the SVHC proposal

Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
5624
2022/10/12	Norway,
Member State	The Norwegian CA supports that the reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)morpholine and 2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine should be identified as a substance of very high concern and should be included in the Candidate List.	We thank the Norwegian CA for reviewing the annex XV SVHC dossier for EC 473-390-7 and we note that Norway supports the identification of this substance as SVHC based on article 57(e) of REACH.	
5714
2022/10/17	3M,
Company,
Belgium	Attachment: 5714_3M Comments on EC 473-390-7.pdf
	Thank you for your comments. Detailed answers are provided in response to your specific comments in Table 2 (see page 4 to 15) of this RCOM document.	

Table 2 - Specific comments on the justification

Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
5638
2022/10/14	Germany,
Member State	The German CA supports the identification of EC 473-390-7 as SVHC based on its vPvB properties.

With regard to the substance identity, we would like to point out the following: The Annex XV report was prepared for a multi-constituent substance that consists of two main constituents, the isopropyl and the n-propyl species. Regarding the applicability of the Annex XV report page 6 of the report states "the vPvB assessment performed for EC 473-390-7 is also valid for the two individual constituents.". Yet, from a legal point of view, the two main constituents, considered as individual substances, are not covered by the entry proposed at present. Therefore, in addition to the multi-constituent substance the Annex XV report should also identify the individual substances (2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine (CAS 1704-69-4) and 2,2,3,3,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)morpholine (CAS 1600-71-1) as SVHC in separate entries. Only in this way the two main constituents are legally identified as SVHCs and the applicability of the assessment for the constituents mentioned in the report is implemented.
	We thank the German CA for reviewing the annex XV SVHC dossier for EC 473-390-7 and we note that Germany supports the identification of this substance as SVHC based on article 57(e) of REACH.

The current annex XV dossier only intends to identify EC 473-390-7 as SVHC. Provided the SVHC dossier for EC 473-390-7 is accepted, we will consider whether there is need or added value to also identify the 2 main constituents as vPvB substances in separate entries.	
5646
2022/10/14	Sweden,
Member State	The Swedish CA thank Belgium for this proposal and agrees that EC 473-390-7 meets the criteria according to Article 57(e) in REACH and is thus eligible for identification as a substance of very high concern.	We thank the Swedish CA for their efforts to review the annex XV dossier that we have drawn up for EC 473-390-7and we note that Sweden supports the identification of this substance as SVHC based on article 57e of the REACH Regulation.	
5680
2022/10/17	ANSES,
National Authority,
France	ANSES supports the proposal of identification of reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)morpholine and 2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine and as SVHC according to articles 57e.

The Substance is expected to undergo no or very limited degradation in the environment due to the stability of C-F bonds, resulting in a stable substance that cannot be broken under environmental conditions. This is supported by the lack of degradation of the Substance observed in screening test and the already vP conclusion of several perfluorinated compounds.
Regarding bioaccumulation properties, a fish study via aqueous exposure is available. Some difficulties to keep the substance stable in the medium were observed, due to its high volatility. However, considering the lower limit of the 95% confidence interval associated to the BCFk value calculated (i.e., 5492) and the estimation of the minimal steady-state BCFss (i.e., 8418 L/kg), the substance exhibits a high potential of bioaccumulation in fish , the BCF values are higher that the threshold value of 5000.

On this basis, ANSES agrees that the substance meets the criteria for a vPvB substance in accordance with Annex XIII of the REACH Regulation and a SVHC identification under article 57e is justified.	We thank the French CA for their efforts to review the annex XV dossier that we have drawn up for EC 473-390-7.

It is correct that it was very difficult to maintain a stable test item concentration in water in the OECD 305 study. Consequently, the uncertainties around the BCFk are reported in the Annex XV report and we have demonstrated that the lower limit of the 95% confidence interval is greater than the vB threshold for aquatic organisms and thus we consider it is appropriate to conclude that the vB criterion is met. Considering the way the BCFss is determined, it is appropriate to conclude that the value (8418 L/kg) represents a minimum value. The real BCFss can only be greater and this observation confirms that the vB criterion is met.

We note that France supports the identification of this substance as SVHC based on Article 57e of the REACH Regulation.
	
5702
2022/10/17	ChemSec,
International NGO,
Sweden	ChemSec supports the identification of the substance/s as SVHC based on the evidence presented in the dossier.	We thank ChemSec for their efforts to review the Annex XV dossier that we have drawn up for EC 473-390-7 and we note that ChemSec supports the identification of this substance as SVHC.
	
5710
2022/10/17	CHEM Trust Europe,
International NGO,
Germany	CHEM Trust supports the inclusion of reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)morpholine and 2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine (FC-770) in the REACH candidate list due to its vPvB properties based on article 57 (e). The dossier presents a convincing weight-of-evidence determination according to the provisions of Annex XIII of REACH.	We thank CHEM Trust for their efforts to review the Annex XV dossier that we have drawn up for EC 473-390-7 and we note that CHEM Trust supports the identification of this substance as SVHC based on article 57e of the REACH Regulation.	
5714
2022/10/17	3M,
Company,
Belgium	Substance does not meet the vPvB criteria set out in Annex XIII of REACH. In particular, as further explained in our comments attached, there is insufficient and unreliable evidence to conclude that the Substance is vB.

	Thank you for your comments. Specific responses to the various remarks are provided below.
After detailed analysis of all the remarks that were put forward by the registrant, the dossier submitter remains of the opinion that sufficient evidence is available to conclude that EC 473-390-7 meets the vPvB criteria as set out in Annex XIII of the REACH Regulation.	
		See the corresponding embedded attachment in table 1 of Part I: 5714_3M Comments on EC 473-390-7.pdf
(The content of the PDF is reproduced below (please refer to the PDF for appropriate layout and footnotes)):
3M Comments on the Annex XV Report regarding the Proposal for identification of EC 473-390-7 as a substance of very high concern 
3M submits these comments in the context of the public consultation for the Proposal for identification of reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3- heptafluoropropan-2-yl)morpholine and 2,2,3,3,5,5,6,6-octafluoro4-(heptafluoropropyl)morpholine (“EC 473-390-7” or “the Substance” or “FC-770”) as very persistent and very bioaccumulative (vPvB) according to Article 57(e) of Regulation (EC) No 1907/2006 (REACH), and therefore as a substance of very high concern (SVHC) (“the Proposal”). 
3M considers that the Substance does not meet the vPvB criteria set out in Annex XIII of REACH. In particular, as further explained below, there is insufficient and unreliable evidence to conclude that the Substance is vB.		
		1.	The available experimental data does not allow the derivation of a reliable bioconcentration factor (BCF) in aquatic organisms
Pursuant to Section 1.2.2 of Annex XIII of REACH a substance “fulfils the ‘very bioaccumulative criterion (vB) when the bioconcentration factor in aquatic species is higher than 5000”. This condition has not been met in the present case.
The Proposal concludes that the Substance has a bioconcentration factor (BCF) above 5.000 L/kg for aquatic organisms and qualifies as vB in line with Section 1.2.2 exclusively based on the results of one non-GLP pilot bioaccumulation study in fish conducted following a Substance Evaluation (SEv) decision of 21 August 2018 against a very stringent schedule (“the Pilot Study”). This Pilot Study was however not intended for the derivation of a BCF but only to test and validate a methodology for the conduct of a final study. It could not be used to reach a conclusion on the bioaccumulation potential of the Substance. 
The Substance is characterised as hydrophobic and volatile, which makes it very difficult to dissolve, retain and test in water in accordance with the OECD Test Guideline No. 305 on ‘Bioaccumulation in Fish: Aqueous and Dietary Exposure’ (‘OECD TG 305’) - requested by the SEv decision in 2018. The Pilot Study needed to progressively implement several adaptations, as requested in the SEv decision, which led to fundamental deviations from the protocols in OECD TG 305, non-compliance with the validity requirements for the test and, ultimately, to completely unreliable results. Both the apparatus and test protocol followed, pursuant to the SEv decision, were vastly different in configuration and operating conditions than these provided for in OECD TG 305. As a result the following fundamental abnormalities were observed:	

Based on a detailed analysis of the results of the only BCF study that is available for EC 473-390-7, the dossier submitter has calculated both a kinetic and a steady-state BCF and also a depuration rate constant k2. Both the kinetic and the steady-state BCF turn out to be greater than 5000. Moreover, the depuration rate constant is less than the vB threshold value (i.e. 0.0788 d-1) that can be derived from the indications in ECHA’s Guidance on IR & CSA, Chapter R.7c. (page 37). So, all 3 quantitative approaches demonstrate that the vB criterion for aquatic organisms is met and no quantified counterargument demonstrating the contrary is at hand or is presented by the registrant.

Whether the pilot study was initially intended or not to derive a BCF is not relevant in this framework. Taking into account the way the study was executed, we see no reason to reject the results or to question the intrinsic reliability of the derived values.

It is correct that it is very difficult to maintain the nominal EC 473-390-7 concentration in water during the study, but the BCF calculation is not based on the nominal concentrations. On the contrary, the real exposure concentrations in the various test bottles were effectively measured and we used those measured values to determine the BCFs.
The requirements mentioned in the SEv decision (e.g. EC 473-390-7 concentration to be applied) were intended to avoid incorrect measurements and should certainly not be considered as ‘fundamental deviations’ from the protocol.
Considering the description of the execution of the test in the study report, we conclude that bioconcentration of EC 473-390-7 was examined here in a correct way and the results are sufficiently reliable to come to a definitive conclusion on the (v)B character for EC 473-390-7.
	
		•	Significant fish mortality and morbidity
The Pilot Study showed very high fish mortality and morbidity in both the test and the control chambers, as well as important morphological anomalies in the surviving fish. In practice, at the end of the test almost all the fish was either dead or very sick. This cannot be considered compliant with the test validity criteria in OECD TG 305, according to which the mortality from other adverse effects/disease in both control and treated fish should be less than 10% at the end of the test.
The observed fish mortality and morbidity can be only explained by the test conditions applied during the Pilot Study to comply with the requirements of the SEv decision and the OECD TG 305. On this matter it should be observed that fish from the same ‘batch’ or ‘lot’, which was used by other companies in the conduct of other studies unrelated to the Substance, did not experience any similar mortality and morbidity.
In particular, the Pilot Study used a very high flow rate to adapt the OECD TG 305 test protocols to the hydrophobic and volatile nature of the Substance. As a result, the fish experienced severe levels of stress and exhaustion. When a fish is stressed by environmental challenges it responds with a series of adaptive neuro-endocrine adjustments, metabolic and behavioural changes. Prolonged stress leads to reduced growth and other dysfunctions. Tissue disruptions at the gill surface could have led to unrealistically high uptake of the substance across the gill membrane and lead to artificially high BCF values.	

It is correct that the mortality observed in both the control and in treated fish was on average higher than the 10% criterion as recommended in the OECD 305 Guideline. However, the >10% level of mortality observed in the test does not mean that the study would automatically become invalid or uninterpretable. The dossier submitter has further examined to what extent the non-compliance in terms of mortality level influences the correctness and reliability of the study results.

It is to be noted that EC 473-390-7, like all PFASs, is extremely stable and therefore it is highly unlikely that fish are able to metabolize this substance, irrespective of their health condition. Therefore, there are no grounds to claim that illness of the fish or reduced metabolic activity is the cause of the high BCF that is found in the study. In the article by Huntingford et al. there is no explanation whatsoever why sick fish would show unrealistically high uptake of chemical compounds.

Further it is observed that in 3 test chambers (test chambers where fish were exposed for 7, 14 and 21 days respectively) 0% mortality was found. If only the results from these specific test chambers are used in the calculation of the BCF and thus excluding the mortality factor. Proceeding in this way one comes to an average BCF of 7281 L/kg. So, based on this alternative BCF determination EC 473-390-7 still meets the vB criterion.	
		•	High variability in test concentration and fundamental uncertainties as regard exposure
The Pilot Study also showed high variability in test concentration between the test chambers and over time in each individual chamber, despite 3M’s attempts to regulate and normalize this aspect by adapting the test conditions. The Pilot Study did not comply with the validity criteria of OECD TG 305 for consistency of exposure (±20%). This also prevented the use of the Pilot Study for the determination of a BCF.
First, the Pilot had to be conducted in a closed system to account for the specific physico-chemical properties of the Substance (hydrophobic and volatile). The fish in all test chambers were observed to be fighting each other for access to the limited headspace in each test chamber. When an individual fish got access, they were observed to be “gasping” for air at the surface of the water. As the headspace above the test chamber was saturated with an unknown concentration of the Substance, there were actually multiple exposure routes for the fish. The total exposure concentration was unknown that, once again, prevented the determination of an adequate BCF.
Second, the concentration could not be maintained at a stable level in each test chamber over time and it could also not remain comparable between the test chambers, as required by the OECD TG 305. This added additional uncertainties for the determination of the BFC with significant margins for errors. Further, the sampling was conducted open to the air, which dropped the Substance’s concentration, leading to potentially large underestimates of the test concentration within the chamber and corresponding overestimates of BCF.	

In this study the EC 473-390-7 concentration in the different test chambers varies a lot and it is transparently reported in the Annex XV report. However, the concentration in water is effectively measured in all the test chambers and at all sampling points. Because of the availability of these measured data, one may still calculate BCFs and we consider them to be meaningful and sufficiently reliable. 

According to the full study report (page 15), headspace was ‘minimal’ and in the robust study summary (page 5) it is indicated that there is no headspace and the chambers are completely filled with test water.
Consequently, it is not appropriate to claim that fish are also exposed via saturated air. Furthermore, it is well know that fish are not air-breathing organisms. One may reasonably assume that exposure only occurs via water and because the EC 473-390-7 levels in water are always experimentally measured the total exposure concentration is effectively known.

In the full study report we could not find an indication that concentrations within a test chamber were not stable over time. We only found diverging concentrations between the various test chambers.

Sampling was conducted open to air but as the water was not supersaturated it is reasonable to assume that volatilization out of the water was limited provided due care was taken to carry out the sampling in a quick, efficient manner.	
		•	Unknown/ unassessed lipid content of the fish
The Pilot Study did (or “could”) not identify the lipid content of the fish, as it was not designed for that purpose. Once again this is an important deviation from OECD TG 305, according to which the “[f]ish lipid content should be measured so that BCF can be expressed on a 5% lipid content basis”. Indeed, for substances accumulating by a lipid-partitioning mechanism, such as the Substance, the lipid content has a strong impact on the bioaccumulation potential and must be taken into account. It is standard practice to normalize BCF to fish lipid content of 5% (that is multiplying by the ratio of 5%/actual fish lipid content). The lack of this standard correction leads to unreliable results.
In the light of the above and, specifically, given the observed deleterious effects on the test fish and very high variability in concentration, the registrant (3M) requested consultation with the evaluating Member State (Belgium, ‘BE’) to assess further steps in order to comply with the SEv decision. 3M had concluded that it would be technically very challenging to conduct a final study in compliance with the SEv decision and the validity criteria of OECD TG 305. Also, ethical questions could be construed in conducting such final study under the adapted conditions.	

In the study that is available considerable uptake of the test item is observed. As stated in the summary of the test report (page 8), the BCFk was determined to be 9585 and so it is concluded that the threshold value for vB is clearly exceeded.
It is correct that the lipid content of fish that are used in bioconcentration studies is an important element. As the lipid content of the fish is not mentioned in the report, the dossier submitter asked for further clarifications, either by measuring afterwards the lipid content of the fish that were used in the test, either by providing indications that would allow to assess the ’typical’ lipid content of Lepomis macrochirus used in this type of tests. Unfortunately, no clarification was received.
Considering the result of the study at hand (BCFk = 9585) and the legal vB threshold (BCF = 5000) we note that EC 473-390-7 would not meet the vB criterion if the lipid content of the fish would have been 9.585% or higher. That is highly unlikely to be the case, certainly if one takes into account the unfavourable health conditions of the fish.
In absence of other elements, the dossier submitter thus remains of the opinion that the vB criterion is met for aquatic organisms.  	
		2.	The Proposal fails to take into account the scientific weaknesses of the Pilot Study and to draw appropriate conclusions about the vB potential of the Substance
The Proposal points to most of the above scientific weaknesses and faults but fails to draw the appropriate conclusion from them, i.e., that the Pilot Study results are totally unreliable and could not be used to derive a BCF and draw conclusions on the vB potential of the Substance. In particular the Proposal is vitiated by errors at least in the following respects:

-	The Proposal creates a misleading impression that a final study has actually been conducted. For example, on page 22 it distinguishes between (i) the pilot BCF study, and (ii) the actual BSF study carried out with freshwater under flow-through conditions. A final study has not been conducted.
-	Furthermore, the Proposal addresses on page 25 the fish mortality and morbidity issue by saying that “it is reasonable to assume that fish mortality is not caused by the test item but is triggered by the experimental set-up”. The Proposal fails to clarify how this interpretation validates the test conditions as required by OECD TG 305 and allow the appropriate derivation of a BFC. To the contrary, this statement shows one of the many reasons why the test results must be considered to be unreliable. In the same vein, the Proposal observes that “it was in practice not possible to find out the lipid content of the fish used in this tests” but proceeds by assuming that it is “highly unlikely” that it impacts the final conclusion. Again, this statement shows that the test was not in compliance with OECD TG 305 and that the results must be considered to be unreliable.	

The dossier submitter denies that the study contains fundamental faults and that the results would be per se unreliable. The available study clearly demonstrates that uptake in fish is substantial and that elimination in the depuration phase is slow. The uncertainties relating to the exact exposure concentration, the fish health condition and the fish lipid content do not form a reasonable ground to reject the study or to claim that it cannot be used to examine bioconcentration of EC 473-390-7 in aquatic organisms.

The word ‘actual’ is the Proposal on page 22 is inappropriate and it will be deleted.
Whether the available study is a final study or not is not relevant. The available study demonstrates in a sufficient way that EC 473-390-7 meets the vB criterion and performing another ‘final’ bioconcentration study would only lead to the same conclusion.

In the study some fish died and that phenomenon is triggered by the experimental set-up as it was found that the mortality did not associate with measured exposure concentrations. It is worth noting that only the data from fish that did not die are used to determine the BCF and so the mortality of some fish does not constitute a solid ground to invalidate the results derived from surviving fish.

In the available study report the lipid content of the fish is not given while measuring this property in the fish used in this study or in the same fish used in similar studies can be carried out. In absence of reasonable proof that the lipid content of the test fish was higher than 9.585%, it remains appropriate to conclude that the vB criterion is met.
	
		The Proposal is therefore only based on assumptions and shortcomings. 

In this regard, it should also be noted that doubts regarding the identification of the Substance as vB were also raised in the PBT Expert Group (PBTEG) meeting on 13-14 May 2020. The evaluating Member State (BE) acknowledged that “they would not expect more reliable results from the definitive [actual] study given the technical difficulties” and expressed concerns about the public consultation,

the Netherlands stated that this would be a difficult case,
while ECETOC mentioned that the aquatic environment might not be relevant at all (p.9 of the PBTEG meeting draft minutes).

Finally, 3M acknowledges that the Pilot Study was referred to in the updated registration dossier as ‘reliable with restrictions’ - instead of as ‘unreliable’ as it should have been. This was a mistake made in the context of the imminent deadline set by the SEv Decision at the time when the Pilot Study was conducted (28 November 2019). 3M was led to believe by an external consultant that (i) it cannot lawfully include in its registration dossier, to address a specific end-point, a study qualified as ‘unreliable’, and (ii) the only way to avoid non-compliance with the SEv Decision was to identify the Pilot Study as ‘reliable with restrictions” in its updated registration dossier. However, this does not reflect the actual position of 3M - which is explained above.	The dossier submitter firmly rejects the view that the proposal is only based on assumptions. It is impossible to deny that in the available study substantial EC 473-390-7 levels are found in fish (up to 133 mg/kgww) and that the elimination rate in the depuration phase is low (0.0633 d-1, i.e. lower than the vB threshold value of 0.0788 d-1). It is to be noted that the shortcomings in the study only relate to the uptake phase and not to the depuration phase. So, the low elimination rate is a reliable indication that the vB criterion is met and it demonstrates that the calculated BCFs are not biased by the experimental conditions.

The BE CA acknowledges that because of the intrinsic EC 473-390-7 properties there are technical difficulties that hinder that all validity criteria in a bioaccumulation study are met. In our opinion the currently available data are sufficiently meaningful and performing the study again would not have delivered added value with respect to the assessment of the bioaccumulation potential of EC 473-390-7.
It is to be noted that the following ‘summary and overview of opinions’ is stated in the minutes of the 24th PBT EG meeting: Discussion focused on the pilot OECD 305 (aqueous exposure) study which was provided following a request made under substance evaluation. There was general support that the substance is vB.

We acknowledge the difficulties that relate to the execution of the study but these difficulties do not prevent a meaningful interpretation of the study results.

The ECETOC comment on the relevancy relates to the use of the substance and the distribution into the environment, but not to the intrinsic properties of EC 473-390-7.

Indeed, the available study was referred to in the updated registration dossier as ‘reliable with restrictions’ and in our view that is a correct qualification.

In the conclusion of the study report (page 24), it is stated that the BCFk is 9585. In the comments on the same page, it is noted that there are technical issues with this type of study but the correctness of the obtained BCF is not questioned.	
		3.	The conducted weight-of-evidence determination fails to take into account all relevant and available information
According to Annex XIII of REACH (second paragraph) the identification of substances as PBT or vPvB should be based on “weight-of evidence determination using expert judgement […] by comparing all relevant and available data”. Annex XIII specifies (third paragraph) that the weight of evidence determination should be based on “all the available information” including results of monitoring and modelling, suitable in vitro tests, animal data, QSAR results, etc. It says that the “quality and consistency of the data shall be given appropriate weight. The available results regardless of their individual conclusions shall be assembled together in a single weight-of evidence determination”.
In this regard ECHA explains that “it is underlined, that in addition to BCF values, other relevant information should be considered. The REACH Annex XIII Introduction requires all other available bioaccumulation data to be taken into account in an integrated manner and applying a Weight-of-Evidence approach using expert judgement to derive the conclusion. If BCFs seem not coherent with other data or there are very different BCF-values available, it is important to address the reasons for inconsistency and discuss in which way this inconsistency impacts the overall conclusions on bioaccumulation potential”.
More specifically, Section 3.2.2 of Annex XIII addresses the assessment of the B and vB properties and lists examples of data that should be considered within a weight-of-evidence approach, beyond the bioconcentration or bioaccumulation studies in aquatic species. This list includes, by way of example, results from a bioaccumulation study in terrestrial species, the assessment of the toxicokinetic behaviour of the substance, etc.
As explained, the Proposal exclusively relies upon one Pilot Study in aquatic species to derive a BCF and reach the conclusion that the Substance is vB. It fails to conduct a comprehensive weight-of-evidence (WoE) determination of all the available data at hand. In particular:
-	The QSAR estimations referred to in the Proposal are not considered as they “do not provide reliable information on the bioaccumulation potential of the Substance”. However, the reasoning behind this statement is not given nor is the data, apparently, considered in the WoE determination.
-	The available test data on bioaccumulation in terrestrial organisms from two reliable toxicokinetic studies in Sprague-Dawley strongly supports that “…that the bioaccumulation potential […] is very low.” This is only vaguely mentioned in the Proposal but there is no indication that the results from these studies have been considered in the WoE determination.	

The dossier submitter comes to the conclusion that EC 473-390-7 meets the vB criterion (BCF >5000) for aquatic organisms as set out in Annex XIII. This BCF criterion is also the only quantitative criterion for bioaccumulation that is specified in Annex XIII and so the BCF is the key parameter to decide on the bioaccumulation potential. For EC 473-390-7 both the kinetic and the steady-state BCF is greater than 5000.
Another metric that is used in our assessment of the bioaccumulation potential is the elimination rate constant. Based on the instructions given in ECHA’s Guidance documents R.11.7c and R.11, one may determine a (v)B threshold in terms of an elimination rate constant. In this specific case the elimination rate constant k2 (0.0633 d-1) is less than the threshold (0.0788 d-1) and this adds to the weight-of-evidence determination of the bioaccumulation potential of EC 473-390-7  for aquatic organisms.

One can only conclude that the calculated BCFs are coherent with the elimination rate constant and there are no inconsistencies in this B assessment.

The dossier submitter is of the opinion that EC 473-390-7 is very bioaccumulative for aquatic organisms. The two single oral dose experiments with male Sprague-Dawley rats do not allow to conclude on the bioaccumulation potential of the substance in mammals. Indeed, the outcome of these studies is considered to be uncertain as the total recovered dose is unknow or insufficient and other tissues than the one reported were not measured. In particular, the concentration in fat tissues and expired air were not measured. However, a text has been added to the support document as regards the conclusion for the B/vB assessment (and as part of the WoE) in order to reflect the outcome of the data for air-breathers as this information was missing. 
In principle, a substance should be identified as (v)B if there are sufficient indications based on reliable information for one type of organisms and that is clearly the case here for aquatic organisms. 

As indicated in § 3.4.1.,QSAR estimations, of the support document, the various QSARs (EPI Suite, VEGA, Catalogic) do not provide conclusive information because there is a lack of data on similar PFAS and in fact EC 473-390-7 is not in the applicability domain of the QSARs.

As reported above, the outcome of the toxicokinetic data remains uncertain and these studies do not allow to conclude on the bioaccumulation potential of the substance in mammals. 	
		Given its non-ionic nature, the Substance is not anticipated to have interactions with biological matrices once ingested. The two toxicokinetic studies specifically demonstrated an absence of uptake and metabolism of Substance after oral administration and, in particular, the absence of uptake into the blood after a bolus dose. This precludes the Substance from entering the systemic circulation and distribution to organs for metabolism or bioaccumulation.
In addition to blood, the absence of bioaccumulation potential was further supported by the absence of quantifiable amount of the Substance or (unlikely) morpholino ring-related metabolites in liver or urine. These data supported that the Substance cannot be absorbed (to bioaccumulate) and it does not undergo metabolic biotransformation.
The Proposal refers on page 25 one study in Sprague-Dawley rats (instead of two) concluding that it does not “provide a full picture” of the bioaccumulation potential of the Substance in mammals. First, this conclusion is incorrect. Second, it is irrelevant in a WoE determination. The very purpose of a WoE determination is especially to consider all available information in coming to a conclusion based on a careful consideration of the quality and consistency of all the available data.
The Proposal also states that the available information on toxicological and pharmacokinetic studies in mammals cannot fully confirm the screening information “as uncertainties remain regarding available toxicokinetic data”. It does not provide any justification for that conclusion. Furthermore, even if the available data cannot provide a “full picture” and has “uncertainties” all available information must be taken into account in a WoE determination on the bioaccumulation potential of the Substance.
A correct assessment of all the available data would have come to the conclusion that the Substance is not bioaccumulative for air-breathing organisms. When this is taken into account in a WoE determination with the above observations on the Pilot Study, the only appropriate conclusion should be that the Substance does not qualify as vB.	

In § 3.4.2. of the support document we pointed out that no quantifiable levels of EC 473-390-7 were retrieved in serum, liver and urine, indicating that uptake and bioaccumulation is unlikely in air-breathers. We stated that these tests do not provide a ‘full picture’ of the bioaccumulation potential because only 27% of the administered dose is retrieved in the faeces (what happened with the other 73%, exhaled?; OECD TG 417 recommends that the recovered dose is >90% total recovery), EC 473-390-7 is not measured in fat tissues and in expired air. Furthermore, we are dealing here with a single dose test.

For the reasons given in the above paragraph, we think it is appropriate to conclude that some uncertainties remain regarding the toxicokinetic data. 

These toxicological and pharmacokinetic studies only provide information relative to air-breathers. So, this information is not relevant for aquatic organisms.

The dossier submitter remains of the opinion that
- EC 473-390-7 is very bioaccumulative for aquatic organisms and
- The toxicokinetic studies do not allow to conclude on the bioaccumulation potential of the substance in mammals.	
5729
2022/10/17	European Environmental Bureau (EEB),
International NGO,
Belgium	The EEB supports the proposal by Belgium to identify the reaction mass of 2,2,3,3,5,5,6,6-octafluoro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl) morpholine and 2,2,3,3,5,5,6,6-octafluoro-4-(heptafluoropropyl)morpholine as a Substance of Very High Concern due to its vPvB properties (REACH article 57(e)). The dossier submitter demonstrated convincingly that the substance meets the vPvB criteria based on a weight of evidence assessment.	We thank the EEB for their efforts to review the annex XV dossier that we have drawn up for EC 473-390-7 and we note that the EEB supports the identification of this substance as SVHC.	
5736
2022/11/02

	Netherlands,
Member State	NL supports the proposal to include EC 473-390-7 in the candidate list of SVHC in accordance with Article 57(e) of REACH, due to its very persistent and very bioaccumulative properties	We thank the Dutch CA for their efforts to review the annex XV dossier that we have drawn up for EC 473-390-7 and we note that the Netherlands supports the identification of this substance as SVHC based on article 57e of the REACH Regulation.

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

Table 3 - Specific comments on use, exposure, alternatives and risks

Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
5702
2022/10/17	ChemSec,
International NGO,
Sweden	A number of PFAS alternatives are available on the ChemSec Marketplace: https://marketplace.chemsec.org/alternatives/chemical/382-28-5	Thank you for this information.	
5714
2022/10/17	3M,
Company,
Belgium	See the corresponding embedded attachment in table 1 of Part I: 5714_3M Comments on EC 473-390-7.pdf	Responses are provided in Table 2 of this RCOM.