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

Substance name: 4-tert-butylphenol
CAS number: 98-54-4
EC number: 202-679-0

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

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. 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 

General comments on the SVHC proposal
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4729
2016/10/20	GIFAS,
Industry or trade association,
France	Please refer to the Attachment	Thank you for your information about the intermediate use of Bisphenol A and 4-tert-Butylphenol for manufacturing reaction products in the field of aeronautics and space applications. We will consider it when considering further risk management options.	
		Attachment: 4729_20020-Letter GIFAS-SVHC -consultation ECHA-20 oct 2016.pdf
		
4747
2016/10/20	ASD,
Industry or trade association,
Belgium	Bisphenol  A and 4-tert-Butylphenol  are widely used substances in the Aerospace and Defence Industry for manufacturing various advanced polymeric and composites materials. Known principal uses in the Aerospace and Defence industry and its supply chain include amongst other specific possible reported uses as additives:

• Intermediate use to manufacture  TBBPA, the most commonly used flame retardant in PCB’s
• Intermediate use to manufacture   Epoxy resin e.g. BADGE (Bisphenol A diglycidyl ether):
o Epoxy resins for composite materials for structural components for weight and CO2 emission saving
o Epoxy resins as potting compounds for the majority of electrical components used on printed circuit boards
o Epoxy adhesives for modern manufacturing techniques
o Epoxy paints and varnishes for long-lived products
• Intermediate use to manufacture polycarbonate is a high valued construction material for windows and other transparent objects with excellent properties for these to function in the harsh environment like high altitudes or combat situations. Parts produced out of polycarbonate include:
o Windows for Airplanes
o Covers for position lights etc.
o Personal protection equipment for civil and military usage (goggles, visors of helmets)
o Electrical insulation
o Modern communication with optical technology

Whilst there may be potential alternatives for many of these uses, ASD notes that the time required for the aerospace and defence industries to validate viable alternatives in the wide range of applications could be decades. Many alternatives listed in the dossier have not been studied to the same level as Bisphenol A and 4-tert-Butylphenol but from what is known are unlikely to prove viable as alternatives, indeed some are not yet in full production.

Considering the main usage as an intermediate in the sense of the REACH regulation and under the light of the new restriction of Bisphenol A in thermal papers – banning effectively the only relevant consumer exposure – we would like to draw your attention to the potential effect on the aerospace industry the inclusion of Bisphenol A and 4-tert-Butylphenol substances in the candidate list would have. Additionally, any induced obligation of tracking of these substances in articles as a consequence of their incorporation in the candidate list could not be enforced without the relevant set of standardised analytical methodologies appropriate to the various substrates in which these substances would have to be identified and quantified, including also qualified laboratories.	Thank you for your information about the use of Bisphenol A and 4-tert-Butylphenol. We will consider it when discussing further risk management options.	
		Attachment: 4747_ASD comments on BPA being identification SVHC V2[2].docx
		
4757
2016/10/21	Norway,
Member State	-	Thank you for the information on monitoring data. We will consider them when discussing further risk management options.	
		Attachment: 4757_4-tert-butylphenol.xlsx
		
4768
2016/10/21	BASF SE,
Company,
Germany	Please see attached document	Thank you for your comment, however we do not agree with the conclusion by BASF that the substance is not an endocrine disruptor and that the equivalent level of concern is not justified. See our more specific responses to comments below
1a) Scientific criteria not met: The following adverse effects which are considered population relevant have been observed for BP: change in sex-ratio.this is supported by a read across to other alkylphenols
1b)Eloc assessment missing: Please refer to chapter 6.3.2.  Potency is not part of the Eloc assessment in our point of view.
1c) Studies unreliable: Only Klimisch 1 or 2 studies were used for the conclusions
2) no effects at env relevant concentrations: Please note, that exposure is not considered for SVHC identification
3) uses are not in the scope of SVHC identification: thank you for your information which is how ever not relevant for the actual SVHC identification itself.
For the sake of clearity,specific comments on the Demska-Zakes study are copied in the previous column and answered in detail.

We agree that analytical measurements would be preferable. However, if cross-contamination occurred, this would probably lead to inconsistent results. In this case results are very consistent (e.g. consistent dose-response curves), and thus likelihood of cross-contamination seems to be low

Abiotic parameters including temperature are measured regulary, in line with the OECD guideline (see Annex II, Tab 24 for details):

Numbers estimated from graphs were used to illustrate results. Statistical significance was performed by the authors using the raw data. Additional information on statistics was included in the dossier.

According to an email correspondence the purity of 4-tert-butylphenol is about 97%. This is now included in the dossier.  Due to the low concentrations it cannot be expected that they significantly influence results.

Please note, that stocking density as described in OECD 234 refers to the species described in the guideline and a different rearing conditions. In this study a flow through system with biological filtering was used. According to Schmidt & Kühn (2013): the stocking density is in the range or only slightly above the values suggested for aquaculture. 

As described in Annex II of the dossier, mean values were based on 30 fish for each treatment and d 88 or d 144 respectively. The number in brackets provide the standard deviation (which is indicated in the study for some tables but nut for all. It was checked that this information is provided in the support document

Differences in body weight gain are very small. Only outliers were sorted out.

We agree that no number of fish at termination is provided. However, it seems reasonable that all fish which disappeared are included in the number of dead fish. Even if this is not the case we wonder how this would influence the effects observed.

Although the selection of individuals does not follow the procedure set out in OECD 234, we cannot see how the selection could have influenced the results. Only outliers were deselected. A biased selection should result in inconsistencies also in controls however the sex ratio in controls was 1:1.

The fact was confirmed by the author in a personal communication. This information is now included in the support document.

The fish showed a gain in body weight and length which indicates good rearing conditions.

The amount of food is high indeed. However, no influence on water quality was observed (see below) and feaces and remaining food were removed on a daily basis.

Ammonia and nitrite concentrations are in the range recommended for aquaculture of Sander (Schmidt  Kühn, 2013): Ammonium (NH4) < 0,5 mg/L, Nitrit < 2 mg/L. At pH tested (7.65- 7.96) only low amounts of NH3 are expected.

Constant illumination is often used in aquaculture to increase growth. No influence on fish health are reported. 
In general we would like to point out that rearing conditions were similar in treatments, control and solvent control. Thus effects observed cannot be a result of different rearing conditions.

The reliability was reassessed but remained 2.	
		Attachment: 4768_EC_202-679-0_Comments on Annex XV report CAS 98-54-4 BASF SE.pdf

Analytical measures needed to detect possible cross-contaminations

Abiotic measurements needed

There are no precise numbers given for the effect levels in the Annex XV dossier. Numbers were estimated from the figures. the raw data are no longer available and no re-evaluation of the data is possible in light of a flaw statistical analysis.

The purity and supplier of the test substance CAS 98-54-4 is not given in the study.

The stocking density is too high which induces stress to the test species

Table 13 of Demska-Zakes 2005 only gives the mean values for fish length. However, it is not clear how this mean values has been derived.
Also, the meaning of the number in brackets next to the mean value is not stated.

Overall, large differences in body length gain throughout the whole study has to be assumed out of the fact that fish had to be sorted for equal body length at the start of exposure.

Also, no data on numbers of fish after termination of the experiment are given. Only mortality is given but no conclusion can be drawn whether fish have been lost due to cannibalism.

The selection of fish inserted into the aquaria is biased based on sex due to selection of fish according to size

We disagree with the MSCA in the point that the solvent has been unquestionably equally concentrated in the solvent control and in the exposure conditions.

Rearing conditions are inadequate for fish health. The condition coefficient in table 13 of Demska Zakes 2005 does not increase over time or remains constant, as one would expect

High amount of food

Water quality criteria are not met

constant illumination is also not recommended

Barse et al should be reliability 2		
4770
2016/10/21	United Kingdom,
Member State	• Overall summary (p. 5) and Section 6.3 (p. 47-): The dossier states that reduced reproduction and growth fit with an endocrine mode of action, and that data show no evidence that they are caused by systemic toxicity. However, non-endocrine modes of action cannot be ruled out either, and we think the text needs to more clearly distinguish between equivocal and unequivocal evidence, both positive and negative. This example would be equivocal supporting evidence only in our view.

Similarly, the statement in Section 5.2.2.4.1 on p. 44 that “it is very plausible that [reduced growth/reduced male fertility] are caused by an estrogenic mode of action” is not objective. For example, what is the evidence that this specific substance causes reduced fertility after male exposure? The Medaka test is considered unreliable, and none of the other studies with 4-tert-butylphenol investigated male fertility as such. If this statement is based on data for an analogue, this should be described more clearly bearing in mind differences in potency and bioaccumulation potential. We should avoid poorly substantiated or potentially misleading statements.

• Overall summary (p. 5): There are no data on the substance itself to suggest that it causes endocrine disrupting effects on taxa other than fish. Read across from other alkylphenols is complicated by differing degrees of bioaccumulation, and we also note that in vitro potency seems to vary significantly between fish and mammals for this substance (potency for other taxa may therefore be lower too). We therefore suggest that the sentence beginning “Data provide indication…” at the foot of the page is deleted as it is not essential for decision-making. We also suggest modifying or deleting the related statements made in Section 5.2.2.4.2 on p. 45, and Section 6.3.2.1 on p. 48.

• Overall summary (p. 6) and Section 6.3 (p. 47-): The reference to the possibility of effects from transient exposure of sensitive life stages is unclear. What does “transient” mean in this context? We do not think such an argument needs to be made, but if it is kept, we think that the uncertainty in such a statement for this substance needs to be emphasised more.

• Overall summary (p. 6, third bullet point), and Section 6.3.2.1 (p. 48-49) (repeated in Section 6.3.3, p. 50): We would caution against making statements such as it is “nearly impossible” to estimate which species are most sensitive or that it is “difficult” to derive a safe level. A decision on this point should only be made at the relevant policy level or by the Risk Assessment Committee in due course (if needed). We think statements about the potential for thresholds should be deleted from the document. Decisions should be taken on the basis of data that are available.

• Section 3.2.1 (adsorption/desorption) (p. 12): The purpose of this section is unclear as it is not used for in the rest of the document. However, we think it would be very helpful to include a summary of degradability (and bioaccumulation, for read across purposes), which could be adapted from the RAC opinion on the hazard classification.

• Section 5.1.2 (long-term aquatic invertebrate toxicity) (p. 14): Although some invertebrates may be affected by estrogens, this report does not provide any information to substantiate an endocrine mode of action, or compare toxicity with other non-alkylphenolic substances. To avoid misconceptions and because these data are not used for the final decision, we think it would be better just to present them in Table 8 without any accompanying text. We also note that this information was missing from the hazard classification proposal, although would not affect the conclusion (which is driven by fish toxicity).

• Section 5.2.1 (fish toxicokinetics): Since most of the test compounds were linear alkylphenols, it would be helpful to provide a clearer statement about the relevance of the data for branched structures. For example, is there a difference in bioaccumulation potential, and what is the implication of β-oxidation of the linear alkyl chain (e.g. is elimination faster)? It would also be useful to summarise the implications of all of these studies for 4-tert-butylphenol at the end of the section.

• Section 5.2.2.2 (in vitro studies) (p. 18-): As a general remark, it would be useful to know the purity of the test substance and state the actual test concentration (in terms of mg/L) in the various studies. In some cases, the reported effects occurred at concentrations above 1 mg/L so some consideration of relevance to likely tissue concentrations (e.g. based on the toxicokinetic information) would be helpful. Where comparisons are made with other substances, please confirm whether this is based on equimolar concentrations and the same dose spacings (as relevant).

• Section 5.2.2.3.1 (Pimephales promelas study) (p. 31-34): The Krueger et al. (2008) study is given a reliability rating of 1 by the REACH Registrants, so it is not clear why it is rated 2 by the Dossier Submitter. It would be helpful to mention that this was a standard regulatory study conducted to GLP. We agree that this is a supportive study in terms of the purposes of this dossier, since it lacks sufficiently robust apical adverse effects relevant at a population level that are clearly linked to an endocrine mode of action. The summary on p. 34 indicates that delayed development cannot be excluded, and whilst we agree that this fits with an endocrine mode of action, presumably it could also be affected by other forms of toxicity. 
We think the uncertainty in this statement needs more emphasis. Where a comparison is made with 4-tert-pentylphenol, it would be helpful to explain whether there are any differences in the magnitude/timing of the effects.

• Section 5.2.2.4.2 (plausible causal link) (p. 45): In Table 18, the Pike-perch data are said to be “almost certainly” indicative of endocrine disruption. This does not match the statements made elsewhere in the dossier, and it would be more appropriate to amend this to say that it is indicative (if valid).

• Annex II (Demska-Zakęś (2005) RSS): Despite the efforts of the Dossier Submitter to obtain further details from the author, some information is still missing:

- Test substance purity.

- It is difficult to judge the number of fish sampled at each time point for each test concentration/replicate from the information provided – was it 10 per replicate and time point? In contrast, all fish in an OECD TG 234 study would be examined for sex.

- A clear description of how the histopathology was performed should be available, to provide confidence that the correct procedures were followed (e.g. use of blind techniques, appropriate identification of structures, etc.). This seems to be fundamental to the study outcome.

This was an extensive study, involving eleven different substances and twelve tanks per substance, i.e. 132 tanks and 10 560 fish before the controls are considered. Each test lasted 84 days per substance (with 28 days of exposure). Presumably there would have been some overlap between individual tests, but this still implies a total duration of well over a year. It would not be too surprising if the researchers experienced unexpected fish mortality, problems with equipment or dosing, etc., over such a time frame, but no information is provided about this at all. This is a further reason to be cautious over the use of the study. It would be useful to know how the error bars obtained in this study compare with standard fish sexual development tests. 
Sander lucioperca is not a standard laboratory species and there are no ring-test data to indicate how much biological variation exists or how it responds to physico-chemical and other variables in the laboratory environment. It would be very useful to know more about sexual development in this species, and whether this can be influenced by stocking density, seasonality, removal of dominant individuals, etc. This information would seem to be a pre-requisite before the study can be used unreservedly.

Editorial: Section 5.2.2.1 (p. 15 -): We note that some of the general references given in this section (e.g. Kendall et al., 1998) are missing from the reference list at the end (presumably due to cut and paste from a previous report).

Section 5.2.2.3.2 (Sander lucioperca study) (p. 36-38): Please explain what the superscripts a - e mean in Table 14, and what the error bars in Figure 2 & 3 represent (we understand that these indicate the standard deviation). This information is not provided in Annex II.	Thank you for your comment. The text was revised and it is stated that the effects might be caused by other modes of action too but the overall evidence makes it plausible that they are caused by an ED MOA.

The text was revised in order to be more precise on the reasoning for the statement including read across.
With regard to reduced male fertility, a short text was introduced to explain how results were used despite the Klimisch 3 scoring. 

The support document was revised in order to make clear that the statement is based on read across and a sentence was included about the plausibility of the read-across.

The text was revised. 

The text was revised but still revers to the difficulties to derive a safe level. Please note: a general statement, that “it may be difficult (albeit not impossible) to determine a safe threshold with reasonable certainty for endocrine disruptors, taking into consideration all uncertainties related to EDs” has been made on a policy level by the European Commission at CARACAL (Doc. CA/25/2014, March 2014).
Please also note that a similar sentence is included in the MSC Agreement on 4-tert-otcylphenol and 4-nonylphenol branched and linear

A summary on degradability and bioaccumulation was included.

The section was not revised. Data were included in order to get an overview about toxicity for other taxa which might be ED mediated but for which no conclusion is possible.

In section 5.2.1 a sentence on why the data were included was added (for read-across purpose). In annex II the review of the data with regard to read-across was complemented with some discussion of the relevance of data for linear structures. However please note that with regard to 4-tert-butylphenol, the branched structure was tested and in addition data for the branched 4-tert-octylphenol and the technical 4-nonylphenol, which mainly consists of branched isomers is available for comparison. 

The section was revised to provide some further information. Molar concentrations were kept as they allow a better comparison on a molecular level. In vitro studies are used to provide information about a possible mode of action. They are not meant to discuss in vivo effect concentrations. Thus no further information about relevance to tissue concentrations was provided and no additional information about spacing was included. 

The Klimisch score was changed to 1. Additional information that the substance was a GLP and guideline study was included.

A statement about the uncertainty was included. Reference to 4-tert-pentylphenol was deleted

As described in the heading of table 18 the conclusion “almost certain an endocrine disruptor” is based on the OECD GD 150 which states that if a shift in sex-ratio is observed in a fish sexual development test and in vitro data and other in vivo data support the mode of action the substance is almost certain an endocrine disruptor.

Information about the test substance purity was provided by the author via email and the information was included in the dossier.

We verified the information in the text and revised the dossier accordingly: 
Every treatment, the dilution water control (dwc) and the solvent control (sc) was tested in two replicates i.e. two tanks, each containing 80 fish (so in total 160 fish per treatment, dwc, sc were tested).
For the histological examination 30 fish per treatment, dw and sc and time point were examined. 
All examined fish were randomly chosen out of the two replicates.

Some information was included, however unfortunately no information about the actual procedure is available. 

According to personal communication with experts on Sander fish aquaculture, sex determination of Sander is stable against abiotic parameters such as temperature or water quality. 

According to the new information fewer tanks were used. As pikeperch is a commercially relevant species it can be assumed that rearing conditions are well established and control mortality should be low.

References are included now. 

The superscripts a – e were explained under the table: Values with the same superscript in the same column are not significantly different (P>0.05).       
Further information about statistics are included in the dossier as far as available.	
		-		
4773
2016/10/21	Sasol Germany GmbH, as Lead Registrant,
Company,
Germany	-	With regard to the fulfilment of the criteria, environmental relevant concentrations and reliability of tests please see our response to comments provided by BASF.
With regard to ACR, low potency, potentially narcotic effects, PNEC protective for ED effects: We do not agree with the conclusions.
With regard to wildlife data please note that the WHO definition which is used in REACH does not require proving effects in wildlife nor does it state that effects are considered not relevant if monitoring data indicate that effects might not be relevant on a population level. Despite this fact it is our opinion that the information provided by Sasol is not robust enough to prove that effects observed are not relevant on the population level. For instant literature cited for STP effluents include histological changes but not changes in sex-ratio. It is not possible to conclude for the endpoint sex-ratio from these studies.	
		Attachment: 4773_Letter Response to Annex XV Reports_211016_Butylphenol_final.pdf
		
4787
2016/10/21	Health & Environment Alliance (HEAL),
International NGO,
Belgium	HEAL supports the adoption of  4-tert-butylphenol as an SVHC for its endocrine disrupting properties. Although the relevance for human health has not been assessed in this dossier, we believe that the relevance should be assumed unless strong evidence indicates a reason not to do so.	Thank you for your support.	
4794
2016/11/01	Finland,
Member State	ED concern

In general, the Finnish CA agrees that the evidence regarding ED properties of 4-TBP (EC 202-679-0) in respect to the WHO/IPCS criteria is rather convincing, taking into account read-across to stuctural analogues already identified to candidate list (4-Nonylphenol, branched and linear and 4-tert-Octylphenol,  EC 205-426-2) and to the two other analogues (4-tert-Pentylphenol (EC 201-280-9) and 4-tert-Heptylphenol, branched and linear) proposed to be identified as SVHC. Evidence on estrogenic receptor binding and activation has been shown in silico and in vitro, including e.g. vitellogenin expression in rainbow trout hepatocytes.  Negative results have also been reported  from in vivo studies with fish regarding endpoints that indicate adversity (e.g. sex ratio in P. promelas where the examination of the proportion of male by gross internal gonadal sex assessment showed no effects, Krueger et al. 2008). The key study, which shows adverse effects on fish linked to an estrogenic mode of action, is the Demska- Zakęś (2005).

We appreciate the summary in Annex II of the Annex XV report regarding the experimental set-up and results of the key study (Long-term study with Sander lucioperca, Demska-Zakęś 2005). Unfortunately the study has been published only in Polish, which complicates the evaluation of the validity and reliability of the study. Therefore, to enable robust assessment of this study and to facilitate possibly forthcoming discussion in the MSC, we would appreaciate if the whole study report were translated.

While we acknowledge the distinctive estrogenic activity of 4-Butylphenol on fish shown in the study, we would like to bring out some concerns related to the study documentation. Firstly, to understand the statistical power and relevance of the study, clarification on the number of fish and replicates, which were histologically investigated, is crucial. We understand that 80 fish per tank were loaded, but it is not clear whether there were replicate tanks per test concentration. The reporting MSCA assumes that the translated expression "all treatments were repeated twice" means three replicate tanks, which would be important to verify. However, it is said that 30 fish were collected randomly at three occasions (before exposure, day 88 and day 144) from each treatment. 30 fish from each tank of 80 fish would mean 90 fish, which is not possible.

Regarding histological studies we believe that sampling, preparation and analysis should be reported in a sufficiently detailed manner, including the number of fish/samples studied, the applied criteria for intersex and sex determination and inclusion of (at least some) raw data, in order to be able to evaluate the performance of study. This kind of information is lacking from the Annex XV proposal. Please include this information in the proposal.

In addition, we are somewhat concerned of the test set-up of the Demska-Zakęś -study regarding the test solution exchange. We understand that the study was conducted as semi-static meaning 50 % replacement of the test solution per 24 h. In addition flow rates in the recirculation system are given (4 L/min) meaning water circulation of 3-fold tank volume per hour, which seems a rather high circulation rate, especially when the stability of the test substance concentrations were not measured. Only nominal concentrations have been reported and although the reporting MSCA considers them as the worst case situation, we think that the lack of measured concentrations should be taken into account when estimating the validity of the study.

Overall we would welcome general discussion on the validity criteria concerning open literature and non-standard test results when used for regulatory purposes, which may have extensive impacts on the risk management of chemicals.

Other properties relevant for environmental concern

Under Chapter 3 of the Annex XV report it is stated that environmental fate properties are not relevant for the identification of the substance as SVHC in accordance with 57(f) of REACH. We consider that at least persistency and potential for bioaccumulation are important intrinsic properties of a substance and relevant for the evaluation on whether a substance has probable serious effects to the environment giving rise to an equivalent level of concern in accordance with  57(f) of REACH. In order to strengthen the proposal, please add a short discussion and any further information on these properties.

Based on information in the registration dossier (an OECD 301F study), we note that the substance seems to be readily biodegradable, not fulfilling the 10 d window. This result seems similar to results reported for 4-Nonylphenol (branched) (NP) and 4-tert-Octylphenol (OP).1,2 For NP and OP also aquatic simulation degradation results are available that show that the substances have a tendency to dissipate into sediment and have significant persistence in certain environments (sediments, sea water). Could you please include a comparison to NP, OP and other similar alkylphenols regarding degradation.

Regarding bioaccumulation we note that an OECD 305 fish bioaccumulation study is available in the registration dossier. Could you please include this as well as QSAR predictions and a comparison to other similar alkylphenols in the proposal.	
Thank you for your support.

Thank you for the comment. Concerning the translation of the study: So far we have translated the most relevant parts. 

Please see our response to the comments provided by UK. 

See our response to the comments provided by UK.

The flow rate was chosen in light of the aqua cultural procedures and to ensure the water quality.
We agree that the measurement of the test substance concentration would have been very useful. But we think the lack of the measurement do not invalidate the study. We assume that the actual test concentrations were not likely higher than the nominal, but probably lower. The latter is not affecting the results demonstrating clear endocrine effects as the NOEC for decrease in male fish and appearance of intersex species is below the lowest nominal test concentration and therefore also below the assumed actual test concentration

We have included a section on validity of the Demska-Zakes study in the Annex XV dossier. A general discussion would be very useful, but is not substance specific.
Open literature studies can and should be used for assessment of endocrine disruption, if the studies are relevant and reliable. Also in the recently published European Commission’s draft scientific criteria for endocrine disruptors, it is noted that the identification of endocrine disrupting properties for a substance shall be based on all available relevant scientific data.

Some additional information was introduced, but no full comparison with other alkylphenols was included. However please note that neither potency nor degradability or bioaccumulation was considered when identifying 4-nonylphenol branched and linear and 4-tert-octylphenol as substances of very high concern.

The study was included. Comparison with other alkylphenols is provided in Annex II.

Specific comments on the justification
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4621
2016/10/17	ANSES,
Academic institution,
France	The substance 4-tert-butylphenol is considered as part of group of alkylphenols, with a linear or branched alkyl chain in para-position. The assessment of endocrine disruptor properties is mainly based on in vitro and in vivo data for different fish species and supported by a read across to other alkylphenols (4-tert-pentylphenol, 4-heptylphenol, 4-tert-octylphenol, 4-nonylphenol) with regard to the endocrine disrupting properties for the environment.

According with all data presented in the report, there is enough evidence that the substance is an endocrine disruptor for the environment.

Results from in vitro studies in fish such as binding assays and estrogen receptor activation assays (reporter gene assays, vitellogenin induction assay in primary hepatocytes of Oncorhynchus mykiss and MCF-7 cell proliferation assay) showed that the substance binds and activates the estrogen receptor and also binds to sex estrogen binding proteins. Assays with mammalians also revealed this mechanism of action, however the binding and activation was not pronounced as fish. In conclusion, in vitro studies show that 4-tert-butylphenol acts via an estrogenic agonist mechanism of action.
Concerning in vivo studies, four studies are available with different species of fish (P. promelas, S. lucioperca, C. carpio and O. Latipes). The studies were conducted at different levels of response (biomarkers, histology and apical endpoints) allowing to confirm the endocrine mode of action and the adverse effect associated.
• Most of the studies showed positive results (except VTG induction in males of P. promelas), the substance alters the function of the endocrine system in fish via an estrogenic mode of action.

Effects are observed on reproduction parameters such as fertility and fecundity. Histomorphological observations of testis in fish in the study with C.Carpio show a reduction of testicular size, necrosis of spermatozoa, decrease in the number of cells germinales and the germinal epithelium cells were atrophied.  Furthermore, the reproduction study with O.Latipes show a decrease of hatchings and a significant production of egg unfertilized.  These observed adverse effects can be attributed mainly to an estrogenic mode of action although others modes of action can play an additional role. However, considering all other data available it is plausible that the effects are caused by an estrogenic mode of action.

• Concerning sexual development, the studies show changes in sex ratio towards a lower number of males. Results for one fish species show that exposure to 4-tert-butylphenol may result in a complete sex reversal resulting in all female populations. This endpoint is both diagnostic for an endocrine mode of action and an adverse effect. Furthermore, changes in appearance were observed in males fish in the studies with P. promelas, a significant number of male fish did not look like males anymore. These changes in sex ratio and appearance can made difficult the reproduction on fish and leads to consequence in a population level.

The adverse effects reported in the available studies show that the exposition to 4-tert-butylphenol in fish can give negatives consequences in an ecological level. In spite of no data for other taxa such as amphibians or invertebrates are available, it is not possible to exclude the fact that other taxa can be impacted. Results for 4-tert-octylphenol and 4-nonylphenol provide indication that effects in other taxa (invertebrates) may be caused by an estrogen-like mode of action, too.

No data for 4-tert-butylphenol are available to assess long-term effects or even intergenerational effects. However, available data for 4-tertoctylphenol and 4-nonylphenol show that these substances may cause long lasting effects which persist after cease of exposure. Thus, it seems very probable, that such effects could also occur after exposure to 4-tert-butylphenol.

In conclusion, ANSES support the proposition of 4-tert-butylphenol as a substance of very high concern in accordance with Article 57(f) of Regulation (EC) 1907/2006 (REACH) because it is a substance with endocrine disrupting properties for the environment.	Thank you for your support.	
		-		
4629
2016/10/19	Austria,
Member State	For 4-tert-butylphenol in vivo and in vitro data show an estrogenic mode of action.
The available in vivo data for 4-tert-butylphenol provide sufficient evidence that the substance causes adverse population relevant effects like a female biased sex ratio, reduced fecundity or growth in fish.
The link between mode of action and population relevant adverse effects is sufficiently evident.
The observed adverse effects are population relevant, provide indications of irreversibility even after exposure has ended. These effects may adversely affect populations in the longer-term and migratory species not only locally but also in regions where no exposure occurred.
The data fit to the data provided for other alkylphenols in a weight of evidence approach: Two of these substances (4-tert-octylphenol, 4-nonylphenyl, branched and linear) are already identified as endocrine disruptors for the environment.
Therefore, 4-tert-butylphenol is considered to fulfil the WHO definition for endocrine disrupters, the Commission’s proposal for scientific criteria for endocrine disruptors for the Biocidal Products Regulation and the Plant Protection Products Regulation (European Commission, 2016 ) and is of equivalent level of concern to those of other substances listed in points (d) to (e) of Article 57 REACH.
The conclusion that there is scientific evidence that 4-tert-butylphenol causes probable serious effects in the environment which give rise to an equivalent level of concern to those of other substances listed in points (d) to (e) of Article 57 REACH, is fully supported.

A change of the substance identity scope in analogy to 4-nonylphenol, branched and linear, could be envisaged.	Thank you for your support.

With regard to substance identity we think that such an approach is currently not required for this substance since the production process results in a mono-constituent substance which has also been registered as such.	
		-		
4714
2016/10/20	ChemSec,
International NGO,
Sweden	ChemSec supports the identification of 4-tert-butylphenol as a Substance of Very High Concern. The evidence presented in the dossier clearly show the endocrine disrupting effects in fish, wherefore the substance is an endocrine disrupting chemical for the environment. The relevance for human health has not been assessed in this dossier, we believe however it would be of importance to more carefully investigate also the endocrine disrupting properties for human health, as there are indications that this substance could also interfere with mammalian endocrine systems.	Thank you for your support.	
4729
2016/10/20	GIFAS,
Industry or trade association,
France	Please refer to the Attachment	See our response to your general comment.	
		Attachment is embedded in table 1 of Part I: 4729_20020-Letter GIFAS-SVHC -consultation ECHA-20 oct 2016.pdf		
4747
2016/10/20	ASD,
Industry or trade association,
Belgium	-	See our response to your general comment.	
		Attachment is embedded in table 1 of Part I: 4747_ASD comments on BPA being identification SVHC V2[2].docx		
4757
2016/10/21	Norway,
Member State	The Norwegian CA supports that 4-tert-butylphenol fulfills the criteria in Article 57 (f) and should be identified as SVHC based on in vitro and in vivo data. The data demonstrate that the substance is an endocrine disrupting compound in fish, comparable to octylphenol and nonylphenol in the types of effects observed, as well as the concentrations at which effects are elicited, which are widely recognized as ED substances.

4-tert-butylphenol (4-tert-BP) is widely used in paint, plastics, rubber and glue industry. Monitoring studies show that 4-tert-BP is found in rivers and coastal areas in both water (up to 2300 ng/l) and sediments (up to 3.2 mg/kg). (Heemken et al., 2001; Kannan et al., 2001; Remberger et al., 2003; Uguz et al., 2003; Basheer et al., 2004; Brossa et al., 2004; Kawaguchi et al., 2004; Koh et al., 2006). See the attachment for full references.

Several studies have detected relatively high levels of 4-tert-BP (up to 387 ng/m3) in air samples from domestic houses. 4-tert-BP has been detected in water samples from landfill leachate in Sweden (Kalmykova et al., 2013), a few samples of drinking water in France (Colin et al., 2014) as well as aquatic and marine biota (Arp 2013, Norwegian EPA 2014). All these studies can support the proposal.

For more details and full references please see the attachment.	Thank you for your support.	
		Attachment is embedded in table 1 of Part I: 4757_4-tert-butylphenol.xlsx		
4768
2016/10/21	BASF SE,
Company,
Germany	-	See our response to your general comment.	
		Attachment is embedded in table 1 of Part I: 4768_EC_202-679-0_Comments on Annex XV report CAS 98-54-4 BASF SE.pdf		
4770
2016/10/21	United Kingdom,
Member State	• We congratulate the Dossier Submitter on a very thorough and clearly presented Annex XV dossier.

• Contrary to some of the statements made in the Annex XV dossier (e.g. Section 3, p. 12), we believe that persistence, as well as the potency of the effect, are essential considerations for deciding whether a substance poses an equivalent level of environmental concern to CMR and PBT/vPvB substances. In other words, when a substance is being assessed for equivalent concern on environmental grounds, the factors considered under Article 57(d) and 57(e) are still relevant. The recent Risk Assessment Committee opinion on the hazard classification under the CLP Regulation indicates that 4 tert-butylphenol is rapidly degradable. We therefore believe that it is very important to consider the concentration at which the adverse effect occurs in this case.

• The strongest evidence of a relevant adverse apical effect appears to be the virtually complete feminisation of a laboratory population of Pike-perch (Sander lucioperca) (Demska-Zakęś, 2005). We thank the Dossier Submitter for preparing a robust study summary of this important study for the assessment of 4 alkylphenols,
which has additional regulatory implications beyond SVHC identification. For example:

- It would affect the chronic M-factor for this substance under the CLP Regulation. The Risk Assessment Committee opinion was only agreed in June, and the Commission/ECHA will need to consider how to take account of the data before Annex VI of the CLP Regulation is updated.
- The same study obtained results for linear 4-nonylphenol which the UKCA will need to take into account for our Substance Evaluation of the branched substance in due course. This could have consequences for the current environmental quality standard derived for nonylphenol under the Water Framework Directive, for example.
- It raises a question about whether Sander lucioperca might be an alternative model species for endocrine disruption testing. Additional research could be commissioned for comparison with life cycle test data for known potent estrogens. Perhaps an alkylphenol industry trade association would take on this challenge, given the implications for several of their substances.

• Taken at face value, Demska-Zakęś (2005) found no completely male fish at the end of the study at nominal concentrations of 100 µg/L [0.1 mg/L] and above. This was the result of just 28 days’ exposure and is not a “borderline” effect. The response pattern was similar to that obtained with the positive control. Only around 15 % of the fish were fully male at 10 µg/L, and a skewed sex ratio was detected even at the lowest test concentration of 1 µg/L. The study was a semi-static design and the actual exposure concentrations were not confirmed analytically (so could have been lower than the stated nominals, assuming that the dosing was accurate). It can therefore be concluded that a significant population-relevant adverse effect – which is generally recognised as being endocrine-mediated – was occurring below a nominal concentration of 100 µg/L (0.1 mg/L), with an EC10/NOEC highly likely to be below 10 µg/L (0.01 mg/L). This would trigger an Aquatic Chronic 1 hazard classification under the CLP Regulation, signifying the highest level of hazard under EU law. The Fathead Minnow data are supportive though not conclusive in their own right since they do not provide apical data.

• This level of effect would normally be enough for us to agree with SVHC identification on the basis of environmental endocrine disruption. However, whilst the Demska-Zakęś (2005) study appears to be broadly reliable based on the information provided in the dossier, it is concerning that some critical details are missing. If we cannot confirm that a study has been performed to a satisfactory standard, Industry stakeholders should be given an opportunity to provide additional data (e.g. repeating the study under GLP conditions). In this case, we do not know why such a novel and important study was not formally published in the academic literature. We have no information about the peer review process for the habilitation qualification, and there is no audit trail (e.g. as provided by QA/GLP). Since the author appears unable to provide further clarification, we think it would be more appropriate to rate the Demska-Zakęś (2005) study as Klimisch 4 (unknown reliability). This would reduce the weight given to it in the overall assessment, although it could still be relevant as supporting evidence. Further explanation is given in our detailed comments below.

• We therefore think that the case relies more heavily on the reliability of the read across from 4-tert-pentylphenol. We agree that 4-tert-pentylphenol has endocrine disruptive properties in fish that give rise to a level of concern equivalent to PBT/vPvB and CMR substances (see our comments on that substance). 4-tert-Butylphenol differs by a single carbon atom, and the description of the physico-chemical and toxicokinetic data in Annex I suggests that they will be of similar bioavailability to fish tissues 
(although we would prefer to see a more detailed comparison of reliable BCF data). 4-tert-Pentylphenol is relatively data rich, and LOECs (and therefore NOECs) for a change in sex ratio occur below 100 µg/L (0.1 mg/L) for some fish species. In vitro data suggest that these two substances may be equipotent, but the only in vivo comparison that can be made concerns FSDT studies in Fathead Minnow and a reproduction assay in Common Carp. It is difficult to make a direct comparison between the studies, but some of the data suggest that 4-tert-pentylphenol is slightly more toxic, whilst other data suggest the opposite. On balance, it seems reasonable to assume that the substances are of similar toxicity to fish in long-term studies. However, a key difference is that 4-tert-butylphenol is rapidly degradable, which affects the overall level of environmental hazard it poses. The 4-tert-pentylphenol data would trigger an Aquatic Chronic 2 classification for 4-tert-butylphenol on the basis of the sex ratio data. This is not the highest level of concern for chronic aquatic effects, so it is debateable whether a substance should be identified as an SVHC on this basis. We think this is really a policy choice, and such a discussion has not yet been held. We realise that the RAC opinion recommends that 4-tert-butylphenol should be classified as Aquatic Chronic 1, but this is on the basis of a NOEC for growth rate, secondary sexual characteristics and time to hatch, which might not be endocrine-mediated or considered sufficiently adverse for SVHC identification.

• On this basis, we think it might be premature to conclude that 4-tert-butylphenol has endocrine disruptive properties in fish that give rise to a level of concern equivalent to PBT/vPvB and CMR substances. However, we are very interested in other MSCAs’ views on these issues.

• Speculative statements about the lack of a threshold for endocrine disrupting effects are not helpful and we do not think that the final MSC opinion should present an approach that has not been agreed at a policy level, or which might prejudice the Risk Assessment Committee’s analysis of subsequent applications for authorisation or restriction proposals.	

Some consideration of the relative potency was included in the read-across section. However, please note that neither potency nor degradability or bioaccumulation was considered when identifying 4-nonylphenol branched and linear and 4-tert-octylphenol as substances of very high concern.

Thank you for these considerations. We believe that results will be taken up by MS/ECHA responsible for the substances mentioned. With regard to the test being an alternative model species we believe that this could be discussed e.g. by the ED expert group. However we would like to point out, that the test is more extensive compared to a standard FSDT.

Some additional information was provided in the dossier in order to strengthen the good standard and reliability of the study, including information about the peer review process.

Some additional information on BCF data was included in Annex II.

With regard to the effects used for CLP classification by RAC please not that effects on secondary sex characteristics are indeed endocrine mediated. Also growth is endocrine sensitive and it cannot be excluded that the effects are endocrine mediated. Despite this discussion we do not think that chronic 1 classification is a prerequisite for SVHC identification. This is mainly based on the fact that both historical data as well as actual information on other alkylphenols indicate that effets on other taxa as well as non-standard endpoints might be underestimated by results from standard tests. Some additional considerations on this topic were included in the chapter on equivalent concern. 

The sentences were revised. Please note that the same argument was used in the support document for the SVHC identification of 4-nonylphenol.
	
		-		
4773
2016/10/21	Sasol Germany GmbH, as Lead Registrant,
Company,
Germany	p. 15 (5.2.2 Endocrine Disruption in fish):  We believe that:
1. The substance does not meet the criteria for Substances with an Equivalent Level of Concern (ELoC)

The evidence set out in the Annex XV document does not support the conclusion that the substance meets the criteria for substances with an equivalent level of concern, as set out at Article 57(f) REACH for the following reasons.

a. The scientific criteria espoused by the European Commission for identification of substances with the potential to pose a risk to human health and wildlife from the adverse effects of endocrine disruption are not met.

b. An Equivalent Level of Concern assessment has not been carried out (considering inter alia potency) to establish that the substance meets the criteria set out in Article 57(f) REACH in accordance with the procedure recommended by ECHA.
In addition:

c. The evidence base as presented is not robust.  Various studies presented are not reliable.  Therefore the findings do not accurately reflect the scientific weight of evidence. A conclusion that the substance meets the criteria for Substances with an Equivalent Level of Concern (in accordance with Article 57(f) REACH) in line with all scientific information is not possible.

2. The weight of scientific evidence does not support the conclusion that substance effects relating to an endocrine mode of action are observed at environmentally relevant concentrations.

There are various studies and lines of reasoning relating to the endocrine activity of this substance, evidence for endocrine disruption effects, and the mode of action for measured apical effects such as reproduction or size.  There is a lack of scientific consensus on these matters.  However, notwithstanding these various possible interpretations or positions, available evidence indicates that endocrine mediated effects, and indeed biomarkers for such effects, are not observed at exposures relating to environmentally relevant concentrations of this substance.

Detailed arguments relating to these points can be found in our attachment.	Please see our response to your general comment and the comments provided by BASF.	
		Attachment is embedded in table 1 of Part I: 4773_Letter Response to Annex XV Reports_211016_Butylphenol_final.pdf		
4781
2016/10/21	CHEM Trust,
National NGO,
United Kingdom	CHEM Trust supports the proposal to include 4-tert-butylphenol as a substance of equivalent concern in the REACH candidate list based on Article 57f. The information provided in the dossier summarizes very well the basis for the assessment. In-vivo fish data and mechanistic in- vitro data support the conclusion that this substance is an endocrine disrupter for the environment which is relevant at the population level. Additionally, in our view it would be important to look into the evidence for impacts on human health.	Thank you for your support	

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

Specific comments on use, exposure, alternatives and risks
Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4618
2016/10/05	Company,
Germany	4-tert-butylphenol is an important coating additive. Currently is none alternative substance with comparable properties available.	Thank you for this information. We will consider it when discussing further risk management options.	
4639
2016/10/20	Company,
United States	We have identified the use of 4-tert-butylphenol in the following preparations: potting compounds/edge sealing materials in interior composite panels and exterior (decorative and component) primers.
Additional investigation will be required to determine whether alternatives exist.	Thank you for this information. We will consider it when discussing further risk management options.	
4729
2016/10/20	GIFAS,
Industry or trade association,
France	Please refer to the Attachment	See our respond to your general comment.	
		Attachment is embedded in table 1 of Part I: 4729_20020-Letter GIFAS-SVHC -consultation ECHA-20 oct 2016.pdf		
4747
2016/10/20	ASD,
Industry or trade association,
Belgium	-	See our respond to your general comment.	
		Attachment is embedded in table 1 of Part I: 4747_ASD comments on BPA being identification SVHC V2[2].docx		
4757
2016/10/21	Norway,
Member State	-	See our respond to your general comment.	
		Attachment is embedded in table 1 of Part I: 4757_4-tert-butylphenol.xlsx		
4768
2016/10/21	BASF SE,
Company,
Germany	-	See our respond to your general comment.	
		Attachment is embedded in table 1 of Part I: 4768_EC_202-679-0_Comments on Annex XV report CAS 98-54-4 BASF SE.pdf		
4770
2016/10/21	United Kingdom,
Member State	• It could be helpful for (future) prioritisation purposes to know whether derivatives have the potential to degrade to the parent 4-alkylphenol in the environment. Monitoring information is available in the risk assessment report under the Existing Substances Regulation suggesting that 4-tert-butylphenol can be widely detected in wastewater treatment plant influent.

• The current proposal only refers to a specific isomer of 4-butylphenol. In line with other 4 alkylphenols, would it be appropriate to ensure that the linear and other branched isomers are included in the SVHC identification, if possible, to avoid regrettable substitutions? We realise that this might require some further discussion of data from other 4-alkylphenols showing the in vivo equivalence of the various isomers.	Thank you for this suggestion. We will consider it when discussing further risk management options.

With regard to substance identity we think that such an approach is currently not required for this substance since the production process results in a mono-constituent substance which has also been registered as such.	
4773
2016/10/21	Sasol Germany GmbH, as Lead Registrant,
Company,
Germany	p. 51 (9 Information on uses of the substance):  We believe that:

The Uses of the Substance are not within the scope of Authorisation.  Therefore proposals to identify the substance as a SVHC cannot be considered efficient or effective policy.

As supported by Part II, Section 9 of the German MSCA Annex XV report, the substance is used as an intermediate or monomer.  No further uses are known to the registrants or indeed covered by the REACH registration.  Intermediate use is explicitly being out of the scope of authorisation under REACH. Therefore authorisation is an ineffective regulatory tool.

That monomers can be considered intermediates is supported by the European Court of Justice adopted opinion on July 07, 2009 of Advocate General J Kokott.	Thank you for your comment. We will consider it when discussing further risk management options.	
		Attachment is embedded in table 1 of Part I: 4773_Letter Response to Annex XV Reports_211016_Butylphenol_final.pdf