CELEX: 
Language: en
Date: 2019-10-16 00:00:00
Title: COMMISSION IMPLEMENTING DECISION on the compliance check of a registration of dimethyl ether, referred by the European Chemicals Agency to the Commission pursuant to Article 51(7) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)

COMMISSION IMPLEMENTING DECISION
            
            
               of 16.10.2019
            
            
               on the compliance check of a registration of dimethyl ether, referred by the European Chemicals Agency to the Commission pursuant to Article 51(7) of Regulation (EC) No 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) 
               
            
                (Only the English text is authentic)
            
            
               THE EUROPEAN COMMISSION,
            
            
               Having regard to the Treaty on the Functioning of the European Union,
            
            
               Having regard to Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC
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               , and in particular Article 51(7) thereof,
            
            
               Whereas:
            
            
               (1)The European Chemicals Agency ('the Agency') carried out a compliance check pursuant to Article 41(1) of  Regulation (EC) No 1907/2006 of a joint registration submitted by Nouryon Industrial Chemicals B.V. ('the lead registrant') on behalf of  a number of co-registrants, for the substance dimethyl ether, CAS number 115-10-6, EC number 204-065-8 ('DME'). 
            
            
               (2)The Agency concluded that the registration dossier submitted for the tonnage band of 1 000 tonnes or more per year, including all relevant information that had been added to the registration by 5 of October 2018, did not comply with the standard information requirement regarding pre-natal developmental toxicity in a second species, as laid down in section 8.7.2 of Annex IX and section 8.7.2 of Annex X to Regulation (EC) No 1907/2006, because the dossier did not contain any information on a second species, and regarding reproductive toxicity as laid down in section 8.7.3 of Annex X to Regulation (EC) No 1907/2006 because the proposed adaptation could not be accepted.
            
            
               (3)The Agency prepared a draft decision in accordance with Article 41(3) of Regulation (EC) No 1907/2006 requiring the registrants to submit information from a pre-natal developmental toxicity study (PNDT, test method: EU B.31/OECD TG 414) in rabbits via the inhalation route in order to address the non-compliance regarding pre-natal developmental toxicity in a second species and to conduct an extended one-generation reproductive toxicity study ('EOGRTS') in rats via the inhalation route (test method: EU B.56/OECD TG 443) in the basic study design, as required by column 1 of section 8.7.3 of Annex X to Regulation (EC) No 1907/2006 in order to address the non-compliance regarding reproductive toxicity and to submit the results of those studies to the Agency.
            
            
               (4)Following the examination of the proposals for amendments, the Agency referred its draft decision together with the amendments proposed to the Member State Committee of the Agency ('the MSC') on 19 January 2017. While the MSC agreed that information concerning the two standard information requirements should be requested, it failed to reach unanimous agreement on the draft decision because of diverging opinions on the design of the EOGRTS. Eight members expressed a minority position by voting against the draft decision, as they were of the opinion that the EOGRTS should include cohorts 2A/2B to address developmental neurotoxicity (DNT) concerns pursuant to the second paragraph of column 2 of section 8.7.3. of Annex X to Regulation (EC) No 1907/2006. The eight members were of the view that the concern for developmental neurotoxicity is justified by narcotic effects observed in a 2-weeks repeated dose inhalation toxicity study and in a rat pre-natal developmental toxicity study on the substance. They further justified the request with human exposure data available on TOXNET
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               , which reports narcotic effects at high doses. In relation to the narcotic effects, they argued that the substance can be expected to act on an organism in the same way as its structural analogue diethyl ether ('DEE') which was previously used as an anaesthetic. As the MSC failed to reach unanimous agreement, the Agency referred the draft decision together with all relevant information to the Commission on 13 July 2017 in order for it to take a decision pursuant to Article 51(7) of Regulation (EC) No 1907/2006.
            
            
               (5)The Commission examined the draft decision of the Agency, the amendments proposed by Member States concerning the design of the EOGRTS, the comments submitted by the lead registrant on behalf the co-registrants on the draft decision of the Agency and the reasons why the MSC could not reach unanimous agreement. After the Agency had carried out the compliance check, other registrants which had registered their substance at any of the tonnage levels covered by Annexes VII to X of Regulation (EC) No 1907/2006 joined the joint registration. Upon request of the Commission, the Agency checked all available information in the dossiers for DME again and informed the Commission that information from a PNDT study in a second species and an EOGRTS was still missing. The Agency also concluded that, based on the available information on the substance, conditions were not met to request those studies at Annex IX level. Consequently, the Agency considered that information from those two studies should be requested to fulfil the standard information requirements for the registrants of this joint registration that are at Annex X level. Therefore, those registrants should provide the missing information and they are the addressees of this Decision.
            
            
               (6)The registrants concerned have submitted comments on the draft decision of the Agency and the draft decision of the Commission arguing that the PNDT study in a second species and the EOGRTS do not need to be conducted on DME in accordance with the specific rules for adaptation provided for in the third indent of the first paragraph of column 2 of section 8.7. of Annex X to Regulation (EC) No 1907/2006. The registrants concerned argue that the conditions for applying the adaptation are met. However, the Commission considers that none of the three conditions provided for in the third indent of the first paragraph of column 2 of Annex X to Regulation (EC) No 1907/2006, which have to be met cumulatively, are met and therefore adaptation from column 1 of section 8.7. of that Annex is not justified. 
            
            
               (7)Firstly, DME induced narcotic effects after repeated administration and caused death in an acute inhalation toxicity study at concentrations higher than 12,1 % (121 000 ppm). In a rat PNDT study, lower body weight gain, reduced foetal body weight and increase in skeletal variations were observed at a concentration of approximately 4% (40 000 ppm). Even though those effects have been observed at high doses, the Agency and the Commission consider that the criterion ‘low toxicological activity (no evidence of toxicity seen in any of the tests available)’ is not met.
            
            
               (8)Secondly, toxicokinetic information in the dossier and comments of the registrants concerned on the Agency’s draft decision support the conclusion that an equilibrium between the concentration of the substance in the organism and in the air is reached through exposure via the inhalation route. In particular, toxicokinetic investigations provided evidence of distribution of the substance within the organism, indicating a rapid increase in concentrations of DME in blood, heart, lung, liver, spleen and kidneys, reaching a steady state after 30 minutes of exposure via the inhalation route before rapidly decreasing. The Agency and the Commission therefore consider that the criterion of no systemic absorption via relevant routes of exposure is not met.
            
            
               (9)Thirdly, DME is used as propellant in many consumer daily-use products like deodorants, hairspray etc., hence there is clearly some human exposure. In its comments to the draft decision of the Agency and to the draft decision of the Commission, the registrants concerned claimed that the criterion of no significant exposure is met, as in its view the risk characterisation ratio (RCR) 0,7 for the industrial or professional use by workers and the RCR of 09 for aggregated inhalation exposure of workers additionally using DME-containing consumer products reported in the registration dossier are overly conservative since they represent peak exposures rather than average daily exposure values. However, the Commission considers that aggregated exposure levels for workers and consumers indicate significant exposure. In addition, maximum possible exposure levels have to be considered for acute effects because even short-term, peak exposure concentrations could cause acute effects. Hence based on the information in the dossier the criterion ‘no or no significant human exposure’ is not met.
            
            
               (10)Consequently, the criteria for adaptation laid down in the third indent of the first paragraph of column 2 of section 8.7. of Annex X to Regulation (EC) No 1907/2006 are not met and therefore  the registration is non-compliant, as also concluded by the Agency.
            
            
               (11)Given that DME is a gas with explosive properties, it must be considered whether it is technically feasible to conduct the required studies without risk of explosion. The registrants concerned have indicated in their comments on the Agency’s draft decision that testing would be feasible up to a concentration of 1,65%, which has been derived from the Lower Explosive Limit (3,3%) based on OECD Guidance Document on Acute Inhalation Toxicity Testing No 39. In addition, in a 2-year chronic inhalation study in rats the highest concentration tested was 2,5%, and concentrations of up to 4% were reached in a PNDT study and up to 5% in a 2-weeks repeated dose study. The available data therefore indicate a possibility to test at concentrations that could produce effects while being safe in relation to the explosive properties.
            
         
         
            
               (12)The Commission further agrees with the Agency that the addressees of this Decision should submit information obtained from a pre-natal developmental toxicity study in rabbits (EU B.31/OECD TG 414) via the inhalation route to fulfil the standard information requirement of section 8.7.2. of Annex X to Regulation (EC) No 1907/2006. 
            
            
               (13)The Commission notes that information from two PNDT studies (in rats and rabbits) on the structural analogue DEE is expected to be submitted by 25 July 2019 pursuant to a decision of the Agency
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               . 
            
            
               According to Annex VI to Regulation (EC) No 1907/2006, registrants have to fulfil standard information requirements. In accordance with Article 41(3) of Regulation (EC) No 1907/2006, the Agency is entitled to require  the registrant to submit any information needed to bring the registration into compliance. This includes information from studies involving vertebrate animals, subject to the rules on adaptation provided for in Annexes VI to XI of that Regulation. A Commission decision referred to in Article 51(7) of Regulation (EC) No 1907/2006, is subject to the same provisions.  The registrants concerned claim that an adaptation based on read-across  from the information that is expected to become available on DEE to DME is warranted. However, the information provided by the registrants concerned does not allow to conclude that a compliant adaptation for the pre-natal developmental toxicity of DME in a second species could be developed based on the data that is expected to become available as a result of the PNDT studies on DEE, mainly because of the differences in metabolism between the two substances. Therefore, the request for information from a PNDT study on DME in rabbits (EU B.31/OECD TG 414) via the inhalation route should be upheld.
            
            
               (14)In addition, the addressees of this Decision should conduct an EOGRTS in rats via the inhalation route (test method: EU B.56/OECD TG 443) to fulfil the standard information requirement of column 1 of section 8.7.3  of Annex X to Regulation (EC) No 1907/2006. The study design should include the cohorts 1A and 1B as well as the cohorts 2A/2B (DNT). The Commission has re-evaluated the existing in-vivo data on the registered substance concerning narcotic effects caused by DME. It was observed that, in an acute inhalation study, DME caused transient narcotic effects at a dose of 8,4%, namely ataxia, anaesthesia, short jerky respirations, head bobbing, paw waiving, roving eyeballs. Five out of ten animals developed lung noise post-exposure, which lasted one to four days at that dose. 
            
            
               (15)The effects were observed after a single exposure and they correspond to some of  the criteria listed in Section 3.8.2.2.2 of Annex I to Regulation (EC) No 1272/2008 of the European Parliament and of the Council 
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                for classifying substances as Specific Target Organ Toxicity-single exposure Category 3 (STOT SE- cat. 3) for narcotic effects. Indications of narcotic-type effects were also observed in a rat PNDT study (OECD TG 414) in the form of reduced responsiveness to sound at a concentration of approximately 2% (20 000 ppm) and of no responsiveness to sound at a concentration of approximately 4% (40 000 ppm). In a rat 2-weeks whole body inhalation study, narcotic-type effects were observed in the form of sluggishness at a concentration of approximately 1% and of impaired coordination and absence of response to noise at approximately 5%.
            
            
               The Commission evaluated data on DEE to check if they would provide supportive evidence for triggering the DNT cohort as provided for in the third indent of the second paragraph of column 2 of section 8.7.3. of Annex X to Regulation (EC) No 1907/2006. Evaluation of supportive evidence submitted in the registration dossier for DEE does not mean that a read-across for developmental toxicity DEE to DME would be accepted. It means that the effects of a structural analogue are considered in the decision to include the DNT cohort based on narcotic effects, in accordance with the Agency’s practice
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               . Structural analogy is a necessary but not a sufficient condition for read-across. Slight anaesthetic effects were observed with DEE at two doses in a 90-day oral study. Further, DEE causes narcotic effects in humans and those effects  correspond to some of  the criteria listed in Section 3.8.2.2.2 of Annex I to Regulation (EC) No 1272/2008 for classifying substances as STOT SE- cat. 3 for narcotic effects. Although no clear signs of neurotoxicity have been observed for DME or DEE, the narcotic effects of DME should be considered as sufficient evidence of adverse effects on the nervous system and therefore as meeting the requirement laid down in the first indent of the second paragraph of column 2 of section 8.7.3 of Annex X to Regulation (EC) No 1907/2006. In addition, the narcotic properties of DEE are considered as supportive evidence as provided for in the third indent of the second paragraph of column 2 of section 8.7.3 of Annex X to that Regulation. 
            
            
               (16)Therefore, the addressees of this Decision should include the cohorts 2A/2B (DNT) in the study design depending on the results of a dose range-finding study. Given the limited available evidence on toxic dose levels for reproduction and the particular physicochemical properties of the substance which may have an impact on the highest technically achievable concentration which can be tested, it is necessary to conduct a dose-range finding study in order to determine the concentrations to be tested in the main study. The inclusion of the cohorts 2A/2B (DNT) in the EOGRTS study design should be conditional on any narcotic-type effects observed in the dose-range finding study.
            
            
               (17)The addressees of this Decision should be given sufficient time to generate the required information, and to submit that information to the Agency and update the registration dossiers. 
            
            
               (18)A draft of this Decision has been notified to the addressees of this Decision, who have been informed of their right to comment within 30 days. Extensive comments have been provided and taken into account. 
            
            
               (19)The measures provided for in this Decision are in accordance with the opinion of the Committee established under Article 133 of Regulation (EC) No 1907/2006,
            
            
               HAS ADOPTED THIS DECISION: 
            
            
               Article 1
            
            
               The registration of the substance dimethyl ether (CAS number 115-10-6, EC number 204-065-8) submitted under Article 6 of Regulation (EC) No 1907/2006 by the lead registrant listed in point (1) of Article 5 of this Decision does not comply with sections 8.7.2. and 8.7.3. of Annex X to that Regulation.
            
            
               Article 2
            
            
               The registrants referred to in Article 5 shall submit information from a pre-natal developmental toxicity study on the substance referred to in Article 1 in order to fulfil the standard information requirement regarding pre-natal developmental toxicity in a second species as laid down in section 8.7.2. of Annex X to Regulation (EC) No 1907/2006. The study shall be conducted in accordance with section 8.7.2. of Annex X to that Regulation (test method: EU B.31/OECD TG 414) in rabbits via the inhalation route.
            
            
               Article 3
            
            
               The registrants referred to in Article 5 shall submit information from an extended one-generation reproductive toxicity study ('EOGRTS') (test method: EU B.56/OECD TG 443) on the substance referred to in Article 1 in order to fulfil the standard information requirement regarding reproductive toxicity as laid down in column 1 of section 8.7.3. of Annex X to Regulation (EC) No 1907/2006. 
            
            
               Before the EOGRTS (OECD TG 443) is started, a dose-range finding study shall be conducted (for example OECD TG 421 or similar) and the animals shall be carefully monitored for any narcotic-type effects. Only in case narcotic-type effects are observed at any concentration chosen for the EOGRTS shall the cohorts 2A/2B (DNT) be included in the study design in accordance with column 2 of section 8.7.3. of Annex X to Regulation (EC) No 1907/2006.
            
            
               The EOGRTS shall be conducted in rats via the inhalation route and in accordance with the following study-design specifications: 
            
            
               (a)ten weeks premating exposure duration for the parental generation;
            
         
         
            
               (b)dose level set to induce some toxicity at the highest dose level;
            
            
               (c)cohort 1A (Reproductive toxicity);
            
            
               (d)cohort 1B (Reproductive toxicity) without extension to include a F2 generation 
            
            
               (e)subject to the second paragraph, cohorts 2A/2B (DNT) which shall include additional testing on learning and memory  according to paragraph 37 of OECD TG 426.
            
            
               Article 4
            
            
               The registrants referred to in Article 5 shall submit an update of their registration dossier to the Agency with the results of the studies conducted in accordance with Article 2 and Article 3, including, where relevant, an update of the chemical safety report, within 36 months from the date of notification of this Decision.
            
            
               Article 5
            
            
               This Decision is addressed to:
            
            
               (1)Nouryon Industrial Chemicals B.V., Velperweg 76, PO Box 60192, 6800 JD Arnhem, The Netherlands;
            
            
               (2)Shell Deutschland Oil GmbH, Suhrenkamp 71-77, 22335 Hamburg, Germany;
            
            
               (3)Knoell NL-OR-S01, Agro Business Park 75, 6708 PV  Wageningen, Netherlands;
            
            
               (4)Grillo-Werke AG, Weseler Straße 1, 47169 Duisburg, Germany;
            
            
               (5)PCC Trade & Service GmbH, Moerser Straße 149, 47198 Duisburg, Germany;
            
            
               (6)Colombus Group s.r.o., Ciruvkova 172/32, 10400 Prague, Czech Republic.
            
            
               Done at Brussels, 16.10.2019
            
            
               
                     For the Commission
               
               
                     Karmenu VELLA
                     Member of the Commission
               
            
            
                     
                        
                           
                     
                  
               
         
         
            
                  
                     (1)
                  
                        OJ L 396, 30.12.2006.
               
               
                  
                     (2)
                  
                        https://toxnet.nlm.nih.gov/cgi-bin/sis/search/a?dbs+hsdb:@term+@DOCNO+354 
               
               
                  
                     (3)
                  
                        Decision CCH-D-2114363810-52-01/F of 18 July 2017
               
               
                  
                     (4)
                  
                        Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 (OJ L 353, 31.12.2008, p. 1).
               
               
                  
                     (5)
                  
                        
                  https://www.echa.europa.eu/documents/10162/13630/eogrts_design_en.pdf/09123723-1df7-43cd-952b-21eb365a5d2c
                  , p.9.