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

Substance name: Ethylenediamine
CAS number: 107-15-3
EC number: 203-468-6

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

Disclaimer: Comments provided during public consultation are made available as submitted by the commenting parties. It was the commenting parties own responsibility to ensure that their comments do not contain confidential information. The Response to Comments table has been prepared by the competent authority of the Member State preparing the proposal for identification of a substance of very high concern. RCOM has not been agreed by the Member State Committee nor has the document been modified as result of the MSC discussions. The table does not contain any confidential information.

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

General comments on the SVHC proposal

Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
5006
2018/04/19	Freiberger Compound Materials GmbH,
Company,
Germany	-	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
		Attachment: 5006_2018_04_18 Freiberger - comments for EDA to the ECHA consultation on inclusion in candidate list.pdf
		
5071
2018/04/23	Ethylene Amines REACH consortium,
Other contributor,
United Kingdom	The conclusion from the Annex XV report stated that ‘It is beyond doubt that the substance is a respiratory sensitiser based on findings in animals and humans. Moreover, EDA has a harmonised classification for respiratory sensitisation.’

Conclusion Industry: We counter that this conclusion is misleading since it shows a lack of understanding of respiratory sensitisation and the clinical evidence presented.
Firstly, we do not question here the classification as such but there are no respiratory sensitization findings in animals (there is no validated and/or widely accepted test method available for this endpoint), so there is no non-human information presented in the dossier. The dermal sensitization studies in guinea pigs are inappropriate to conclude about respiratory allergy.

Secondly, the findings in humans do not conclusively point at respiratory sensitization as irritant-induced asthma and/or work-aggravated asthma cannot be excluded. EDA may act as an asthmagen, in which case adverse effects are caused by non-immunological mechanisms (Kimber et al., 2001). There is a real need to understand whether chemicals that are associated with respiratory effects in the workplace are true allergens that induce immunological priming and allergic sensitisation, or whether the symptoms recorded are due to some other non-allergic mechanism such as work-aggravated or irritant-induced asthma. In regulatory terms there is a clear distinction between skin sensitisation resulting in allergic contact dermatitis (H317), and irritant contact dermatitis that is not associated with, or dependent upon, allergic sensitisation (H315). A similar clear distinction between chemical respiratory allergens and asthmagens that induce effects through non-immunological mechanisms is in our opinion long overdue. Thus, if a substance has a harmonized classification for respiratory sensitization, it may be an asthmagen but not necessarily a respiratory allergen based on the current criteria for harmonized classification and labelling.

In addition, the clinical diagnosis of chemical respiratory allergy should be addressed: the appearance of respiratory symptoms in those working with EDA may be consistent with occupational asthma. However, the information available is not sufficient to support a diagnosis of allergic asthma. Not all cases of occupational asthma are associated with immunological sensitisation and allergy. As stated above, the term occupational asthma embraces (a) sensitiser-induced asthma (allergic asthma), (b) irritant-induced asthma (non-allergic, including Reactive Airways Dysfunction Syndrome (RADS)), or (c) work-exacerbated asthma (pre-existing asthma unrelated to work that is made worse by a workplace exposure) (Vandenplas, 2011; Tarlo and Lemiere, 2014). In order to confirm a definite diagnosis of allergic occupational asthma the following criteria must be met: (1) diagnosis of asthma by a physician, (2) an association between the symptoms of asthma and work, (3) workplace exposure to an agent or process previously associated with work-related asthma, and at least two of the following three criteria: (4) significant work-related changes in spirometry, (5) significant work-related changes in non-specific airway hyperresponsiveness, and (6) a positive response to an inhalation provocation with the specific agent to which the individual is exposed at work (Klees et al., 1990).
In view of these criteria, the Annex XV dossier does not describe the evidence in sufficient detail to allow a critical review of the diagnostics employed in the worker studies and case reports and make a judgment on whether they are appropriate. It can, in addition, be questioned whether the cases reported would meet modern diagnostic criteria; we note for example the UK is currently revisiting its clinical diagnostic guidelines. Thus considering the available worker studies and case reports collectively, it is not possible to conclude with certainty that EDA has the potential to induce immunologically mediated respiratory allergy in humans.

On a mechanistic basis there is significant evidence that respiratory sensitizers bind preferentially to lysine moieties whereas skin sensitizers bind both to cysteine and lysine (Sullivan et al., 2017). The absence of peptide depletion (only 0.7%) using lysine with 18.6% peptide depletion using cysteine (Bauch et al., 2012) would support EDA not being a true respiratory sensitizer but a skin sensitizer only.

The evidence presented in the Annex XV report seems to suggest that 63 out of 400 workers have developed respiratory allergy and that they have developed serious health conditions at concentrations as low as 1 ppm (2.5 mg/m3). In one study 337 workers were examined, in which 38 workers showed respiratory reactions; in the other worker/case studies there was an additional number of ca. 25 workers with respiratory reactions. Together this would be a total number of ca. 400 workers. However, the total number of workers exposed to EDA will have been much larger. Moreover, as indicated above it is also questioned whether these cases would meet modern diagnostic criteria.
Also, in the study that reported measured concentration levels (Aldrich et al., 1987), air concentrations exceeded 1 ppm (1.1-25% of the samples) in all years measured, and in 3 of these years concentrations exceeded 10 ppm (0.1-4.8%). Note that these are the percentages of air samples exceeding 1 or 10 ppm; maximum concentrations, however, were not indicated. Aldrich et al. (1987) concluded that ‘increased risk of EDA sensitization might be expected when workplace air concentrations of EDA exceeded 1 ppm’ but they also considered presence of excursions. In the study by Ng et al. (1995) levels of 4.8 and 10.5 ppm were reported. However, it is generally recognized that in most cases it is likely peak exposures (and not a concentration*time such as an 8-h TWA) may result in respiratory reactions, which in the case of EDA may have resulted in irritant-induced or work-aggravated asthma.
Moreover, based on the fact that there are no more recent cases reported in view of the workforce exposed, it can be concluded that the current OEL of 10 ppm did not result in a substantial number of new cases during more than 2 decades, if at all, since the most recent study dates from 1995. This strongly indicates that current occupational hygiene standards and practices are sufficiently protective. It is therefore questionable whether proposing EDA as SVHC really would be of similar societal concern to e.g. chemicals causing cancer or developmental effects.
In addition, whilst reactions may become more severe upon repeated exposure, it is highly unlikely in practice since a person will not repeatedly put himself in a position whereby he experiences significant & repeated symptoms. This also means irreversible, pathological changes in the airways do not develop and the effect on overall quality of life is not minimized. Indeed, in several of the studies presented it was reported that respiratory symptoms cleared and individuals became asymptomatic after removal from the work environment, thus the effects were not permanent nor irreversible, did not lead to a decreased quality of life and did not require long-term medication. It is indeed better to remove people with hypersensitive airways (e.g. in case of work-aggravated or irritant-induced asthma) from exposure but this is not different from ‘removing’ asthmatics away from areas where they can experience hyperreactivity reactions from exposure to irritants.
According to the legal text, the evidence for nomination as SVHC in accordance with Article 57f should be presented on a case by case basis. However, the Annex XV dossier has only presented general information on respiratory sensitization and no evidence specifically that EDA is a current health or economic burden to society. Moreover, as indicated above it is not conclusively shown that EDA induces irreversible and permanent respiratory allergy, and secondly, the current studies do not indicate that many exposed workers have been affected and had to leave their job. Therefore, the currently available scientific information and the number of cases in view of the workforce possibly exposed do not support the observation or conclusion that EDA should be regarded as giving rise to an equivalent level of concern to those substances listed in points (a) to (e) of Article 57 REACH.
Finally, since no real societal concern is demonstrated in the Annex XV dossier, would the supposed benefit to society be proportional to the regulatory burden placed on industry and thus be acting in the interest of proper functioning of the internal market, so contrary to Articles 1 and 55 of REACH?

In summary, the currently available scientific information and the number of cases in view of the workforce possibly exposed does not support this observation or conclusion. According to Article 57f, the evidence for nomination of a substance as having equivalent level of concern should be presented on a case by case basis. In the specific case of EDA the dossier submitter has clearly failed to provide sufficient evidence since:
1) Conclusive scientific evidence that exposure to EDA alone causes respiratory sensitisation and allergy is lacking
2) Evidence that the effects observed are irreversible is lacking, since a number of reports describe complete restoration of lung function in previously symptomatic individuals
3) Evidence that thresholds do not exist is not provided, since the lack of cases reported following imposition of current OELs would indicate that current limits are protective of worker health
4) Evidence that the burden to society is significant is missing, no new cases in more than 20 years would indicate minimal societal burden both from a health concern or economic concern
5) Furthermore, there is no specific evidence with respect to societal concern presented for EDA which should be a prerequisite when nomination as SVHC in accordance with the law is ‘on a case by case basis’.
On the basis of the evidence provided and discussed, Industry therefore disagrees strongly with the dossier submitter’s proposal that EDA be considered SVHC in accordance with Article 57f of REACh.	Thank you for your comments.

The reference to animals has been removed from the conclusion.

As pointed out in your comment, such a distinction does not exist in the CLP Regulation for respiratory sensitisation, therefore this point cannot be further addressed in the report. 

As mentioned above, as a distinction between immunological and non-immunological mechanisms does not exist in the CLP Regulation for respiratory sensitisation, this does not preclude EDA from being identified as an SVHC on the basis that it presents as equivalent level of concern to CMR (PBT/vPvB) substances.

Regarding the mechanistic basis Sullivan et al., (2017) note that experimental work has suggested that some respiratory sensitisers appear to preferentially bind to lysine; however, it is also noted that an in chemico analysis of a larger set of respiratory sensitisers indicates a lack of a simple division between the reactivity preferences of the two types of sensitisers, showing that certain classes displayed a lysine preference, for example, anhydrides, whereas others, such as diisocyanates, do not. The aim of Bauch et al., (2012) was to combine in vitro methods to test for skin sensitising potentials. Respiratory sensitisers are not discussed per se in the paper, apart from Section 3.5 “Incorrect predictions”, where the high number of false negatives are detailed. 

The sentence regarding the number of workers has been modified.

The support document can only detail studies that are available in the literature. It cannot postulate or hypothesise on what changes in clinical practice might mean for past cases as the raw data is not available for such an analysis.

Despite the fact that maximum concentrations were not indicated in the studies mentioned and considering that the exposures detailed may have been peak exposures, rather than 8-h TWA, it remains clear from the AEGL assessment that it is not possible to derive a “non-disabling” dose of EDA, irrespective of whether it was a 10 minute exposure or an 8-h TWA. While occupational hygiene standards and practices may have improved in recent years, it is possible that some systems are designed around a particular threshold, i.e. to ensure exposure stays below a particular limit, in this case 10 ppm.  As this limit may not be sufficiently protective, further action such as identification of EDA as an SVHC is warranted.

Repeated exposure may easily occur as the first phase of sensitisation (induction) presents no physical symptoms. Typically, by the time physical symptoms are visible in the second phase (elicitation), the person is irreversibly sensitised. The irreversibility of the first phase and its relevancy for SVHC identification have been recognised by the Court (see paragraph 59 of Case T-134/13). Further, the second phase can lead to irreversible effects, such as lung damage, which are also relevant for SVHC identification (see paragraphs 61-62 of Case T-134/13). In addition, the fact that the negative effects associated with the use of a substance can be controlled adequately does not preclude its identification as a substance of very high concern (see paragraphs 61 and 68 of Case T-134/13). The support document provides sufficient evidence based on which it can be decided whether  EDA should be regarded as giving rise to an equivalent level of concern to those substances listed in points (a) to (e) of Article 57 REACH.

Please find responses to your further comments in the attachment below: 

		Attachment: EDA SVHC Annex XV Comments- final_20 April.pdf

Specific comments on the justification

Number / Date	Submitted by (name, submitter type, country)	Comment	Responses	
4969
2018/04/12	ChemSec,
International NGO,
Sweden	ChemSec supports the inclusion of Ethylenediamine on the Candidate List based on its classification as a respiratory sensitizer and the evidence presented in the dossier.	Thank you for your support.	
4995
2018/04/18	Finland,
Member State	The Finnish CA supports identification of ethylenediamine (ethane- 1,2-diamine) as a SVHC according to Article 57(f) of Regulation (EC) No 1907/2006 (REACH) based on its respiratory sensitising properties. For this hazard class, ethylenediamine has a harmonised classification Resp. Sens. 1; H334: “May cause allergy or asthma symptoms or breathing difficulties if inhaled”. The Finnish CA agrees with the equivalent level of concern (ELoC) assessment presented in the Annex XV report. There is scientific evidence of probable serious effects to human health which gives rise to ELoC.

The Finnish CA notes that Risk Management Option Analysis (RMOA) conclusion document has been published on the ECHA website. According to the RMOA the substance is considered to meet the SVHC Roadmap to 2020 criteria.	Thank you for your support.	
5006
2018/04/19	Freiberger Compound Materials GmbH,
Company,
Germany	-	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
		See the corresponding embedded attachment in table 1 of Part I: 
5006_2018_04_18 Freiberger - comments for EDA to the ECHA consultation on inclusion in candidate list.pdf		
5009
2018/04/19	Sweden,
Member State	The Swedish CA agrees that ethylene diamine (EDA) can be considered as a Substance of Very High Concern according to article 57(f).
EDA has a harmonised classification as Resp. Sens. 1 and data show that a considerable portion of workers become sensitised and develop serious health conditions such as expiratory wheezing (a symptom of asthma) at low air concentrations (approx. 1 ppm). In the proposal there are some epidemiological and case studies demonstrating the irreversibility of the induction phase of the sensitisation as well as the seriousness of asthma due to EDA exposure. Although these data are relevant for the ELoC assessment of EDA, we do not consider that it should always be necessary to have such data from the substance under evaluation in order to be able to conclude on general aspects of sensitisation (i. e. that the induction phase is irreversible) or that asthma is associated with severe health effects.  We thus agree with the statement in section “Irreversibility of health effects” that “Asthma is clearly a serious and irreversible condition and brings with it the risk that any asthma attack can be fatal”. In our view, the sections “Effects on quality of life” and “Societal concern” clearly indicate that EDA exposure can reduce the quality of life for an individual and can be considered of high concern for society as a whole even though the data provided are from respiratory sensitisers as a group.	Thank you for your support. We note your additional comments on the level of data required to be able to conclude on general aspects of sensitisation and that asthma is associated with severe health effects. We recognise  such information has been used to conclude on SVHC identification (see Court judgement in case T-134/13). However, as all proposals made under Article 57(f) are considered on a case-by-case basis, it is noted that there may be differences in the type of information reported and the specific considerations, depending on the case.	
5024
2018/04/20	Norway,
Member State	Norway supports that ethylendiamine (EDA) should be identified as a substance of very high concern and should be included in the Candidate list. EDA has a harmonised classification as a respiratory sensitiser. EDA gives rise to an equivalent level of concern based on several case studies where a considerable proportion of workers became respiratory sensitised to EDA at airborne concentrations as low as 1 ppm with serious irreversible health conditions and permanent impairment of lung function as a consequence. It is not possible to derive a no effect level, and a safe concentration cannot be derived. EDA meets the criteria for inclusion on the Candidate list in Article 57 f) in REACH.	Thank you for your support.	
5033
2018/04/20	Germany,
Member State	The German CA supports the SVHC identification of EDA due to its sensitizing properties.
However, since cross-reactivity between different ethyleneamines is mentioned in section 

4.1.1, please explain why ECHA did not follow a grouping approach by including all relevant congeners?

Section 1.3: The statement regarding the irrelevance of metabolites seems to be in contradiction with the statement in section 4.1:
„It is unlikely that EDA undergoes direct reaction with protein residues, but rather is metabolised to the electrophilic glyoxal aldehyde (oxidative deamination) to form a Schiff base that can undergo substitution to form a hapten-protein complex of sufficient size to be antigenic.“
Therefore, glyoxal aldehyde should be listed under section 1.3.

Section 4.1
P 10: Para 1
Please replace „…results in adverse feelings of poor health…“ with: „...results in less severe adverse effects on health…“. The term „feelings“ would seem to imply that these effects are only of a subjective or even psychosomatic nature, which obviously is not the case.

Paras 3, sentence 2 („In the process of…“)  – 5
It would be helpful if the mechanistic information mentioned in this section could be anchored in the proposed Adverse Outcome Pathways (AOP) for skin and respiratory sensitisation.

Section 4.1.1. p 11.
It is suggested to report the results from Leung & Aletta in more detail: Which test in which species was used, what was the basic outcome? This would also explain what is meant by „the same animal model“ in the following paragraph.

Section 4.1.1.1. p 11.
Para 2, last sentence
Please change „dermal“ to „intradermal“.

Section 6.3.2.1
p. 16/17:  Sub-section on type and severity of effects
It might be added that respiratory sensitisation is a hazard of particular concern which is underscored by the fact that it is the only endpoint other than CMR for which CLP Art. 36 requires harmonised classification.

p. 21/22: Sub-section „Is derivation of a ‚safe concentration possible?“
This sub-section should maybe start by mentioning that a) it is as yet unclear what a „safe concentration“ for respiratory sensitisation would mean (in terms of an acceptable residual risk) and b) due to the nature of the effect, the absence of validated and accepted animal models, and the limitations of epidemiological data, in general setting safe levels for respira-tory sensitisers is not possible.	Thank you for your support.

4.1.1 ECHA agrees that a grouping approach, i.e. including all relevant congeners is in general  preferable. However, on this occasion, a grouping approach was not followed and data was gathered on the basis of the substance itself (EDA) and not on a group basis to allow assessment of the congeners. As it is not possible to augment the report with further substances at this stage, it is planned to proceed on the basis of EDA itself.

Section 1.3 As some uncertainties remain about the precise metabolism of EDA, glyoxal aldehyde has not been added to Section 1.3. The text has been modified to reflect the uncertainty.

Section 4.1, P 10: Para 1
The text has been modified as follows “results in adverse effects on health” as it was not found reasonable to consider difficulty breathing as a less severe effect.

Paras 3, sentence 2 („In the process of…“)  
As there is currently no internationally agreed AOP for respiratory sensitisation for organic low molecular weight chemicals, a reference to a recent paper on the topic is included instead.

Section 4.1.1. p 11.
Leung & Auletta. Further information from the Leung & Auletta study has been added to the Support Document.

Section 4.1.1.1. p 11.
Para 2, last sentence
The text has been changed accordingly.

Section 6.3.2.1
p. 16/17:  Sub-section on type and severity of effects.
This suggestion is included in the Support Document.

p. 21/22: Sub-section „Is derivation of a ‚safe concentration possible?“
This suggestion is included in the Support Document.	
		-		
5070
2018/04/23	CHEM Trust,
National NGO,
United Kingdom	CHEM Trust supports the inclusion of ethylene diamine   in the REACH candidate list as a substance of equivalent concern according to article 57f due to its properties as a respiratory sensitizer. We note in particular the fact that the derivation of a no effect level was not possible based on available data described in the Annex XV dossier. Moreover, the type and severity of the relevant health effects can lead to irreversible and long term impacts which illustrates the societal concern.	Thank you for your support.	
5071
2018/04/23	Ethylene Amines REACH consortium,
Other contributor,
United Kingdom	See our main comments in "Further comments on Annex XV report"
See the corresponding embedded attachment in table 1 of Part I: Attachment: EDA SVHC Annex XV Comments- final_20 April.pdf	Please see our responses in the corresponding embedded attachment in table 1 of Part I:	
5081
2018/04/23	Jotun A/S,
Company,
Norway	P.18 indicates that the health effects are irreversible. This does not seem to be true. This page already declares that the effects "cleared after removal from an EDA work environment". It also says that "once a person is sensitised, continued exposure can result in permanent damage to the lungs and increasingly severe symptoms". According to our knowledge EDA is only present in industrial products meaning any health effects would/should be discovered and managed before symptoms would become "increasingly severe".

P.19 states "By the time the damage has occured, removal from the exposure situation will have no impact on the outcome". If the outcome is defined as health effects then this would not be true as cessation of exposure will clear the effects/symptoms. The person will be sensitised to EDA but effects will not be manifested without exposure. Also; all chemicals may cause a delay in health effects - it will depend on dose and exposure time how delayed the effects will be.

P.20-21 indicates occupational asthma causes a worse quality of life (psychiatric syndromes) than non-occupational asthma. This is quite speculative and not substantiated with any explanation.

P.21 links societal concern to leaving "their place of employment or get relocated". This situation is not specific to EDA but could be an effect due to numerous factors, e.g. ergonomics (back pain etc) and psycho-social work environment. The statement that an "employee may have to leave a well-paid job for a less paid one" is quite speculative and adds to the impression that one is really trying to look for arguments supporting that EDA should be proposed as a SVHC.

P.24-25 mention that the OELs in Europe are to high. The text also says the effects of EDA "limit the person's possibility of living a normal working and private life." As the effects of EDA, once a person is sensitised, are reversible upon cessation of exposure it would be possible to live a normal working and private life even if relocation would be necessary. If the OELs are to high they should be lowered. Also; health surveillance programs in the companies using the substance would prevent occupational asthma to develop. Risk can be managed by enforcement of the requirements in the Chemical Agents Directive. Proposing EDA as a substance of equivalent level of concern as CMRs 1A/B and possibly as a candidate for authorisation does seem to be disproportionate to its hazardous properties.	Thank you for your comments.

P.18-19: Repeated exposure may easily occur as the first phase of sensitisation (induction) presents no physical symptoms. Typically, by the time physical symptoms are visible in the second phase (elicitation), the person is irreversibly sensitised. The irreversibility of the first phase and its relevance for SVHC identification have been recognised by the Court (see paragraph 59 of Case T-134/13 P). Given that EDA may also cross-react with a number of chemicals, elicitation may be invoked by exposure to a number of chemicals, increasing the likelihood of irreversible effects such as permanent lung damage.

P.20-21: The methodology and reasoning for these findings can be read in more detail in the original publications:
Yacoub et al. (2007)
http://erj.ersjournals.com/content/29/5/889 and
Lowery et al. (2007)
https://link.springer.com/article/10.1007/s11136-007-9274-5

P.21: The statement regarding relocation is made with exposure to respiratory sensitisers in mind, not other causes such as ergonomics or psycho-social issues. Given that EDA is known to cross-react with other substances, removal/relocation may be even more necessary 

P.24-25: As effects have been recorded at exposure levels ~10 times lower than the current (most common) OEL, this indicates the difficulty in defining a safe level of exposure for EDA. In addition, the fact that the negative effects associated with the use of a substance can be controlled adequately does not preclude its identification as a substance of very high concern (see paragraph 61 of Case T-134/15). The support document provides sufficient evidence based on which it can be decided whether  EDA should be regarded as giving rise to an equivalent level of concern to those substances listed in points (a) to (e) of Article 57 REACH.	
		-		
5095
2018/04/23	Austria,
Member State	The Austrian CA wants to thank ECHA for the Elaboration of the Annex XV dossier on EDA based on its respiratory sensitizing property. We agree with the conclusion that EDA shall be identified as an SVHC meeting the ELoC-criteria as laid down in the ECHA document” Potential of sensitisers to be identified as SVHCs under the ‘equivalent level of concern’ route (Article 57(f))”.

In a publication by FoBiG (2010) the hardener EDA was ranked as chemical with high potency (category HS). The ranking was based on all available data including in vitro tests.

Measures for further Epoxy Resin Amines should be considered also keeping in mind that other short-chain amines with similar toxicological properties may be used as alternatives.

Reference:
FOBIC (2010) http://www.bgbau.de/gisbau/fachthemen/epoxi/downloads/Gesamtbericht.pdf 	Thank you for your support and the additional information.	
5135
2018/04/23	ANSES,
National NGO,
France	Based on its harmonised classification and the available human data, EDA is a respiratory sensitiser that may cause occupational asthma in humans.

In relation to the demonstration of its ELoC necessary for identification as an SVHC according to 57(f), the following points are noted :
- On severity, it is acknowledged that described symptoms include serious symptoms such as wheezing, breathlessness, dyspnea and significantly decreased FEV.
- On irreversibility, sensitisation in itself is an irreversible process and it is expected that the effects will continue if sensitised subjects are maintained exposed. No data examine whether the respiratory function is permanently affected in EDA-sensitised subjects when the exposure is stopped. However, it is noted that worsening of effects across time is observed in one case report (Lam & Chan-Yeung 1980) with symptoms also present during weekends whereas the source of exposure is occupational. Although it does not demonstrate irreversibility, it shows that prolonged effects after cessation of exposure that support that the effects are of very high concern.  In addition, it is considered that prolonged inflammatory reactions in the lung induced by asthma are expected to result in remodeling of lung airways. What is not assessed neither is the cross-sensitisation rendering subjects more sensitive to other sensitisers.
- The impact of occupational asthma on the quality of life is recognised and well established in the SVHC dossier by appropriate studies showing that the quality of life is significantly decreased by asthma and in particular by occupational asthma.
- The societal concern linked to occupational asthma is also supported.
- ANSES agrees that a safe concentration cannot be established at this point. In particular, it is recognised that for EDA, the database is particularly limited with no experimental data and a limited number of human data. Therefore, in this particular case, lack of data may have an important impact on the impossibility to characterise a safe concentration. The only quantification of levels of exposure responsible for asthmatic reactions is approximately 1 ppm. It is a low level but it is reported to correspond to exposure levels when handling pure or solutions of 50% of EDA. In addition, it is not clear whether there are recent cases of respiratory sensitisation with EDA that could illustrate that while exposure probably have decreased over years, it may still induce asthma in occupationally exposed subjects and therefore support that a safe level cannot be established. At the same time, it is recognised that occupational asthma is often underreported and underestimated. In general, setting a safe concentration for a respiratory sensitiser is considered difficult because once sensitised, the elicitation thresholds may be very low and highly dependent from one sensitised subject to another.
On the basis on these considerations, ANSES is in support for the identification of EDA as an SVHC fulfilling 57(f) criteria due to its respiratory sensitization properties and would welcome scientific discussions on how to overcome the difficulties pointed out in these comments that do not attend to prevent identification.	Thank you for your support	
		-		
5158
2018/04/23	Aerospace Industries Association,
Industry or trade association,
United States	Ethylenediamine (EDA) is a monomer used in diverse applications in the aerospace sector.  There are no direct replacements for ethylenediamine in many critical applications listed below, and replacement would likely involve significant redesign and/or attendant requalification and recertification activities.	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	

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	
5006
2018/04/19	Freiberger Compound Materials GmbH,
Company,
Germany	See the corresponding embedded attachment in table 1 of Part I: 
5006_2018_04_18 Freiberger - comments for EDA to the ECHA consultation on inclusion in candidate list.pdf	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
5033
2018/04/20	Germany,
Member State	Uses and exposure:
Information on uses is kept to a minimum in the report by just listing the registered uses in table 9. No further information on exposure is given. Although this information is not necessary for the identification of EDA as SVHC, it is important for subsequent regulatory activities (prioritisation etc.).Therefore it might be beneficial to include a more detailed exposure assessment in this report as well.

Furthermore, the German CA would find it beneficial to have estimates on the number of exposed employees for the various reported uses of EDA.

In addition, although EDA is not registered for consumer uses, publicly available sources indicate that the substance is an ingredient in several consumer products, e.g. the SPIN database („one or several uses indicate a very probable exposure“).

Alternatives:
In as far as uses of EDA are determined by its high reactivity, substitutes are likely to have similar issues.	Thank you for your comment.
As you noted, the justification for SVHC is based on intrinsic properties of the substance, not on use, exposure or risk. The information on uses and exposure (i.e. Part II of the Annex XV report) is not considered during the agreement seeking phase of the SVHC identification process and has therefore not been updated. 	
5034
2018/04/20	Individual,
Switzerland	We use in our company, for 15 years, ethylenediamine to manufacture electroplating products. Ethylenediamine is processed in our sites and does not remain in our sales products. For our factories, our procedures on Exposure are straightforward and protect efficiently our teams which does not lead do any sensitization issue for our employees since we begun using ethylenediamine.	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.	
5071
2018/04/23	Ethylene Amines REACH consortium,
Other contributor,
United Kingdom	The ethylene amines consortium undertook a use survey for EDA and assessed that 92% was used as intermediate. While response to the survey was not complete, the consortium believes that potential non-intermediate uses are closed uses at industrial sites, and a very limited amount used by professional workers.	Thank you for your comment and the information provided. The justification for SVHC is based on intrinsic properties of the substance, not on use, exposure and risk. Comments regarding use, exposure, alternatives and risks may, when relevant, be considered at later stages of the risk management process of the SVHC dossier.