European Food Safety Authority (EFSA)

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1 ] TECHNICAL REPORT APPROVED: 05 April 2018 doi: /sp.efsa.2018.en-1407 Outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for extract from tea tree in light of Abstract European Food Safety Authority (EFSA) The European Food Safety Authority (EFSA) was asked by the European Commission to provide scientific assistance with respect to the risk assessment for an active substance in light of requested following approval in accordance with Article 6(1) of Directive 91/414/EEC and Article 6(f) of Regulation (EC) No 1107/2009. In this context EFSA s scientific views on the specific points raised during the commenting phase conducted with Member States, the applicant and EFSA on the and their use in the risk assessment for extract from tea tree are presented. The current report summarises the outcome of the consultation process organised by the rapporteur Member State Latvia and presents EFSA s scientific views and conclusions on the individual comments received. European Food Safety Authority, 2018 Keywords: extract from tea tree, peer review,, risk assessment, pesticide, fungicide Requestor: European Commission Question number: EFSA-Q Correspondence: pesticides.peerreview@efsa.europa.eu EFSA Supporting publication 2018:EN-1407

2 Suggested citation: EFSA (European Food Safety Authority), Technical report on the outcome of the consultation with Member States, the applicant and EFSA on the pesticide risk assessment for extract from tea tree in light of. EFSA supporting publication 2018:EN pp. doi: /sp.efsa.2018.en-1407 ISSN: European Food Safety Authority, 2018 Reproduction is authorised provided the source is acknowledged. 2 EFSA Supporting publication 2018:EN-1407

3 Summary Extract from tea tree was included in Annex I to Directive 91/414/EEC on 1 January 2009 by Commission Directive 2008/127/EC, and has been deemed to be approved under Regulation (EC) No 1107/2009, in accordance with Commission Implementing Regulation (EU) No 540/2011, as amended by Commission Implementing Regulation (EU) No 541/2011. It was a specific provision of the approval that the applicant was required to submit to the European Commission by 30 April 2016 further studies on: (a) the plant metabolism and consumer exposure; (b) the toxicity of the compounds that constitute the extract and the relevance of possible impurities other than methyl eugenol; (c) the groundwater exposure for the less strongly adsorbed components that constitute the extract and for potential soil transformation products; (d) the effects on biological methods of sewage treatment. In accordance with the specific provision, the applicant, Biomor Europe Ltd, submitted an updated dossier in April 2016, which was evaluated by the designated rapporteur Member State (RMS), Latvia, in the form of addenda to the draft. In compliance with guidance document SANCO 5634/2009-rev.6.1, the RMS distributed the addenda to Member States, the applicant and EFSA for comments on 1 December The RMS collated all comments in the format of a reporting table, which was submitted to EFSA on 9 March EFSA added its scientific views on the specific points raised during the commenting phase in column 4 of the reporting table. The current report summarises the outcome of the consultation process organised by the RMS, Latvia, and presents EFSA s scientific views and conclusions on the individual comments received. Extract from tea tree is the essential oil obtained by steam distillation of the foliage and terminal branchlets of Melaleuca alternifolia. The oil obtained should conform to the requirements given in the International Standard ISO 4730:2004 Oil of Melaleuca, terpinen-4-ol type (Tea Tree oil), standard revised by ISO 4730:2017 (Essential oil of Melaleuca, terpinen-4-ol type (Tea Tree oil)), which sets maxima and/or minima for 15 components of the oil. Extract from tea tree from Melaleuca alternifolia contains various mono- and sesquiterpenes as well as aromatic compounds. The natural content of the individual terpenes in extract from tea tree may vary considerably depending on the Melaleuca alternifolia population used, the climate, the leaf maceration, the age of the leaves and the duration of distillation. Its major constituents are presented in Appendix B. The representative formulation was Timorex containing 660 g/kg of tea tree oil. The representative uses assessed were spray applications as a fungicide on potato, carrots, herbs, cucumber, watermelon, tomato, pepper and ornamentals. The batches used in the toxicological studies support the technical specification; however the toxicological relevance of the individual impurities present in the technical specification has not been appropriately addressed and their potential impact on the toxicity of the technical material cannot be assessed. From this point of view, it is considered that the second requirement has not been addressed. Extract from tea tree is unlikely to be genotoxic, however other toxicological endpoints would need to be further discussed. Taking into consideration that adverse effects have been observed on the testes, sperm and epididymides, an endocrine mediated mode of action cannot be ruled out. A consensus was reached during the commenting to derive the acceptable daily intake (ADI) at 0.03 mg/kg bw per day based on a NOAEL of 30 mg/kg bw per day for adverse effects observed on the male reproductive system in a 90-day dietary toxicity study in rats and developmental toxicity (increased incidence of skeletal variations) in the presence of maternal toxicity in a developmental toxicity study in rats. An additional uncertainty factor (UF) of 1000 is proposed to account for the limited database available. No consensus was reached regarding the UF to be used in setting other toxicological reference values. It is therefore proposed to set provisional values using a conservative UF of 1000 to derive the acute reference dose (ARfD), the acceptable operator exposure level (AOEL) and the acute acceptable operator exposure level (AAOEL) at the same level as the ADI. The RMS agreed with this approach, however the estimation of operator exposure was calculated against the applicant s AOEL proposal of 0.3 mg/kg bw per day (using an UF of 100). Adjusting the exposure estimates to the provisionally agreed AOEL, operator exposure exceeds the AOEL (around 3 EFSA Supporting publication 2018:EN-1407

4 600% of the AOEL) even when operators wear gloves, coverall and boots as personal protective equipment according to the IVA 1 model for greenhouse applications (Mich G, 1996). No exposure assessment of workers, bystanders and residents has been provided. While bystanders and residents exposure would not be relevant in case of applications in permanent greenhouse structures, worker exposure needs to be addressed. Data gaps were identified for plant metabolism studies to derive residue definitions for monitoring and risk assessment when extract from tea tree is applied according to the representative uses and for sufficient and acceptable residue trials to address the magnitude of the relevant compounds included in the residue definitions for the crops under consideration. Considering the representative uses on potatoes and carrots and in the absence of an agreed plant residue definition for risk assessment it is not possible to calculate the total livestock dietary burden and to assess the potential for the occurrence of significant residues in food of animal origin. The submitted were therefore not sufficient to perform a comprehensive consumer dietary risk assessment. Using the submitted, it was possible to confirm that for the representative uses assessed, the active substance components terpinen-4-ol and α-terpineol have the potential to be present in annual average recharge concentrations leaving the top 1 m of soil above the parametric drinking water limit, applied to groundwater of 0.1µg/L. The groundwater exposure potential of soil transformation products of the active substance components: terpinene-4-ol, α-terpineol and 1,8- cineole was addressed in as far as they were demonstrated to be readily biodegradable in guideline OECD ready biodegradability experiments or published peer reviewed scientific literature studies. An assessment was not available for the soil transformation products of the major active substance components: gamma-terpinene and alpha-terpinene. A reliable study was provided demonstrating the low toxicity of extract from tea tree to organisms involved in the biological methods of sewage treatment. Consequently, for ecotoxicology the requirement has been addressed. 1 Industrieverband Agrar 4 EFSA Supporting publication 2018:EN-1407

5 Table of contents Abstract... 1 Summary Introduction Background and Terms of Reference as provided by the requestor Interpretation of the Terms of Reference Assessment... 7 Documentation provided to EFSA... 7 References... 7 Abbreviations... 8 Appendix A Collation of comments from Member States, applicant and EFSA on the pesticide risk assessment for the active substance extract from tea tree in light of and the conclusions drawn by EFSA on the specific points raised... 9 Appendix B Used compound codes Appendix C List of endpoints updated parts following assessment EFSA Supporting publication 2018:EN-1407

6 1. Introduction 1.1. Background and Terms of Reference as provided by the requestor Extract from tea tree was included in Annex I to Directive 91/414/EEC 2 on 1 January 2009 by Commission Directive 2008/127/EC 3, and has been deemed to be approved under Regulation (EC) No 1107/2009 4, in accordance with Commission Implementing Regulation (EU) No 540/2011 5, as amended by Commission Implementing Regulation (EU) No 541/ EFSA previously finalised a Conclusion on this active substance on 16 December 2011 (EFSA, 2012). It was a specific provision of the approval that the applicant was required to submit to the European Commission by 30 April 2016 further studies on: (a) the plant metabolism and consumer exposure; (b) the toxicity of the compounds that constitute the extract and the relevance of possible impurities other than methyl eugenol; (c) the groundwater exposure for the less strongly adsorbed components that constitute the extract and for potential soil transformation products; (d) the effects on biological methods of sewage treatment. In accordance with the specific provision, the applicant, Biomor Europe Ltd, submitted an updated dossier in April 2016, which was evaluated by the designated rapporteur Member State (RMS), Latvia, in the form of addenda to the draft (Latvia, 2018). In compliance with guidance document SANCO 5634/2009-rev.6.1, the RMS distributed the addenda to Member States, the applicant and EFSA for comments on 1 December The RMS collated all comments in the format of a reporting table, which was submitted to EFSA on 9 March EFSA added its scientific views on the specific points raised during the commenting phase in column 4 of the reporting table. The current report summarises the outcome of the consultation process organised by the RMS, Latvia, and presents EFSA s scientific views and conclusions on the individual comments received Interpretation of the Terms of Reference On 22 December 2014 the European Commission requested EFSA to provide scientific assistance with respect to the risk assessment of following approval of an active substance in accordance with Article 6(1) of Directive 91/414/EEC and Article 6(f) of Regulation (EC) No 1107/2009. specific points raised during the commenting phase conducted with Member States, the applicant and EFSA on the risk assessment of for extract from tea tree are presented. To this end, a technical report containing the finalised reporting table is being prepared by EFSA. The deadline for providing the finalised report is 9 April On the basis of the reporting table, the European Commission may decide to further consult EFSA to conduct a full or focused peer review and to provide its conclusions on certain specific points. 2 Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market. OJ L 230, , p Commission Directive 2008/127/EC of 18 December 2008 amending Council Directive 91/414/EEC to include several active substances. OJ L 344, , p Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC. OJ L 309, , p Commission Implementing Regulation (EU) No 540/2011 of 25 May 2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p Commission Implementing Regulation (EU) No 541/2011 of 1 June 2011 amending Implementing Regulation (EU) No 540/2011 implementing Regulation (EC) No 1107/2009 of the European Parliament and of the Council as regards the list of approved active substances. OJ L 153, , p EFSA Supporting publication 2018:EN-1407

7 2. Assessment The comments received on the pesticide risk assessment for the active substance extract from tea tree in light of and the conclusions drawn by the EFSA are presented in the format of a reporting table. The comments received are summarised in column 2 of the reporting table. The RMS considerations of the comments are provided in column 3, while EFSA s scientific views and conclusions are outlined in column 4 of the table. The finalised reporting table is provided in Appendix A of this report. The parts of the list of endpoints that have been updated following the assessment of the are presented in Appendix C. Documentation provided to EFSA 1. Latvia, 2018a. Addenda to the on extract from tea tree, B6, B7, B8, B9,, March Available online: 2. Latvia, 2018b. Reporting table, comments on the pesticide risk assessment for extract from tea tree in light of, March References EFSA (European Food Safety Authority). Conclusion on the peer review of the pesticide risk assessment of the active substance extract from tea tree. EFSA Journal 2012;10(2):2542, 48 pp. doi: /j.efsa European Commission, Guidance document on the procedures for submission and assessment of confirmatory information following approval of an active substance in accordance with Regulation (EC) No 1107/2009. SANCO 5634/2009-rev. 6.1 Mich, G, Operator Exposure in greenhouse during practical use of plant protection product ECON Forschungs-und Bewertungskonzepte für Umwelt und Gesundheitssicherheit GmbH Ingelheim. Unpublished. 7 EFSA Supporting publication 2018:EN-1407

8 Abbreviations ADI AOEL ARfD a.s. DAR GAP DG SANCO EU HCD MRL NESTI NOAEL PEARL PBI PEC PEC sed PEC soil PEC sw PELMO PRIMo RMS TMDI acceptable daily intake acceptable operator exposure level acute reference dose active substance draft good agricultural practice European Commission Directorate General Health and Consumers European Union Historical control data maximum residue level national estimated short-term intake no observed adverse effect level Pesticide Emission Assessment at Regional and Local Plant-back interval predicted environmental concentration predicted environmental concentration in sediment predicted environmental concentration in soil predicted environmental concentration in surface water Pesticide Leaching Model Pesticide Residue Intake Model rapporteur Member State theoretical maximum daily intake 8 EFSA Supporting publication 2018:EN-1407

9 Appendix A Collation of comments from Member States, applicant and EFSA on the pesticide risk assessment for the active substance extract from tea tree in light of and the conclusions drawn by EFSA on the specific points raised 1. Physical/Chemical Properties; Details of Uses and Further Information; Methods of Analysis Identity 1(1) Addendum to Vol.4, C.1.1 Composition of toxicological batches, p. 3 EFSA: the batches XK 23, XK37 and KC1069- RMS (LV): Agreed used in toxicological studies are all complying with the proposed specification for extract from tea treeand the content of the components are representative to the production. Addressed. 9 EFSA Supporting publication 2018:EN-1407

10 2. Mammalian toxicology Short-term toxicity 2(1) Vol. 3, B Development toxicity, Tea Tree Oil: 90-Day Repeated Dose Toxicity Study in Wistar Rats, p EFSA: it is noted that the study is not a developmental toxicity study (as referred in the title), but a 90-day short term toxicity study, including FOB tests. The study belongs to Annex IIA, 5.3, short term toxicity. Table B is unclear to us; we miss the information on body weight change over the full study and dose levels, and the absolute body weights to assess the adversity of the effects. It is mentioned in the text that no treatment-related variations in bw were measured, but the table indicates significant increases in cumulative bw gains between days and in G3. Please clarify. The NOAEL of 30 mg/kg bw per day should be discussed further considering the clinical signs and body weight changes (to be clarified). RMS (LV): Noted. Missing information added to the updated DAR addendum. Addressed. The information provided clarifies the body weight changes that are not considered adverse EFSA Supporting publication 2018:EN-1407

11 Short-term toxicity 2(2) B days rat study AT: We agree to set the NOAEL of the study at 30 mg/kg bw/d. Based on the observed effects on male reproductive organs and sperm parameters at 60 and 120 mg/kg bw/d, in absence of severe systemic toxicity, the concern for potential ED properties is raised. Based only on available data, it might be questioned if tee tree oil would even fulfil the cut-off criteria. AT propose to discuss the effects on male reproductive organs and sperm parameters, as well as the potential consequence, in an expert consultation. RMS (LV): Agreed to set NOAEL of 30 mg/kg bw/d. Regarding ED Extract from tea tree is now submitted for the renewal procedure, and according applicant uncertainties regarding ED properties and effects on male reproductive organs and sperm parameters, as well as the potential consequence will be addressed during renewal procedure. Although a NOAEL of 30 mg/kg bw per day may be agreed for the 90-day study in rats, the endocrine disrupting properties of extract from tea tree should be further discussed, considering the effects observed on male reproductive organs and sperm parameters EFSA Supporting publication 2018:EN-1407

12 Genotoxicity 2(3) B.6.4 Genotoxicity Applicant: the specific request raised by EFSA (2012) in the frame of Directive 91/414/EEC was fulfilled. Further data required according to Regulation (EC) 1107/2009 was prepared and will be submitted in the frame of AIR 4 renewal programme. All study results indicate that Extract from tea tree is not genotoxic. The belonging data will be provided upon request. Note: the request on Extract from tea tree under Commission Implementing Regulation (EU) 154/2014 does not list this requirement. 2(4) Vol. 3, RMS overall conclusion regarding : genotoxicity, p. 43 EFSA: an in vivo micronucleus test was provided and considered acceptable at the time of the peer review; no further data on clastogenicity had been requested. According to the confirmatory data requirement, the genotoxicity assessment may be considered as addressed. RMS (LV): According to the requirement, the genotoxicity assessment is considered as addressed. RMS (LV): According to the requirement, the genotoxicity assessment is considered as addressed Addressed: Extract from tea tree is unlikely to be genotoxic. Addressed: Extract from tea tree is unlikely to be genotoxic EFSA Supporting publication 2018:EN-1407

13 Genotoxicity 2(5) B Genotoxicity + Conclusion of the whole assessment, page 43 AT: RMS concluded that genotoxicity has not been adequately addressed since only in vitro gene mutation assay has been provided as Confirmatory data. AT cannot support RMS s opinion for following reasons: 1) In the first submission notifier provided already an AMES test and an in vivo MN assay 2) In the EFSA Conclusion, following expert consultation, the only data gap for genotoxicity was set for gene mutation in mammalian cells Therefore, AT concludes that the applicant fulfilled the request for regarding genotoxicity. Since all studies are negative, there is no concern for genotoxicity based on available information. RMS (LV): Noted. RMS agrees that genotoxicity package is fully addressed. Addressed: Extract from tea tree is unlikely to be genotoxic EFSA Supporting publication 2018:EN-1407

14 Long-term toxicity and carcinogenicity 2(6) 6.5 Long-term toxicity and carcinogenicity Applicant: No such request was explicitly raised by EFSA (2012) and Commission Implementing Regulation (EU) 154/2014 in the frame of Directive 91/414/EEC. For derivation of an ADI a long-term study is not necessarily required (see No. 2(27)). In addition, a waiver was provided by the applicant addressing the non-necessity of long-term and carcinogenicity studies, including the information that in animal studies with TTO components no carcinogenic effects were observed. An updated version of the waiver will be provided upon request. Furthermore, natural exposure via food consumption is significantly higher than the negligible exposure via treated crops; therefore long-termtoxicity from exposure from treated crops is unlikely. RMS (LV): We are still on the opinion that carcinogenicity could not be assessed as no carcinogenicity studies were submitted. Carcinogenicity potential of Extract from tea tree could not be excluded. However by increasing uncertainty factor in setting the toxicological reference values could resolve the issue. See 2(7) 14 EFSA Supporting publication 2018:EN-1407

15 Long-term toxicity and carcinogenicity 2(7) Vol. 3, RMS overall conclusion regarding : carcinogenicity, p. 44 EFSA: it is agreed that a carcinogenic RMS (LV): Agreed potential cannot be excluded for Tea tree oil. This uncertainty could however be taken into account using an increased uncertainty factor in setting the toxicological reference values. The RMS proposes to set reference values adding an additional uncertainty factor of 1000 to account for the limited database. This approach is agreeable for EFSA as a worst case, however the approach and value to be used should be discussed during an experts consultation. See also 2(6) Reproductive toxicity 2(8) Vol. 3, B Development toxicity, Prenatal Developmental Toxicity Study of Extract from tea tree in Wistar Rats by Oral Route, p EFSA: it is noted that the study belongs to Annex IIA, 5.6, reproductive toxicity. Regarding the setting of the developmental NOAEL, it should take into consideration the significant increases in skeletal variations observed at the mid- and top dose levels (in the presence of maternal RMS (LV): Noted. HCD has been presented from applicant. Addendum to DAR has been updated accordingly. Justification from applicant: As per literature, variation is a divergence beyond the usual range of structural constitution (including the ossification variations) but which will not EFSA and AT are of the opinion that the developmental NOAEL should be lowered to 30 mg/kg bw per day while the RMS maintain that it should be 60 mg/kg bw per day. These diverging views would not have an impact on the setting of the 15 EFSA Supporting publication 2018:EN-1407

16 Reproductive toxicity toxicity). adversely affect survival, development or function. Skeletal variations in this study consisted predominantly of delays in ossification, statistically significant at the highest dose levels. In the high dose group, ossification delay is typically seen in the presence of maternal / foetal toxicity and does not have teratological significance because it does not interfere with viability or function and it is considered secondary to maternal toxicity. Therefore, although there is dose response/ treatment related effect (maternal stress) and some parameters which were marginally higher than historical data value, the significant increase in normal variants were not considered to be of any biological significance as these normal variants are routinely observed. toxicological reference values, however this could be discussed during an experts consultation. See also 2(9) 16 EFSA Supporting publication 2018:EN-1407

17 Reproductive toxicity 2(9) B Developmental study in rats AT: We agree with the RMS to set the NOAEL for maternal toxicity at 30 mg/kg bw/d. For developmental effects we would, however, propose the NOAEL also at 30 mg/kg bw/d (and not at 60 mg/kg bw/d), based on several skeletal findings (variations) observed at 60 and 120 mg/kg bw/d. RMS (LV): Skeletal ossifications do not have teratological significance because it does not interfere with viability or function (of foetuses RMS) and it is considered secondary to maternal toxicity. This justification together with historical data is accepted by RMS and NOAEL of 60 mg/kg bw/d supported, however this question could be discussed further in the Peer review meeting or during renewal process. See 2(8) 17 EFSA Supporting publication 2018:EN-1407

18 Other toxicological studies & Medical data 2(10) 6.8 Endocrine disruption effects 2(11) Vol. 3, RMS overall conclusion regarding : endocrine disrupting properties, p. 44 Applicant: Endocrine disruption is not a specific issue under Directive 91/414. Correspondingly, the request by EFSA (2012) did not specifically address this point. Two guideline studies were prepared for AIR 4 submission under Regulation 1107/2009. Study results and a Weight of Evidence approach do not indicate that Extract from tea tree has a potential for endocrine disruption. EFSA: we agree with the conclusion of the RMS that an ED mode of action cannot be excluded for the effects observed on the testes, sperm and epididymides, in the 90-day toxicity study in rats. RMS (LV): We are on the opinion that an ED mode of action cannot be excluded for the effects observed on the testes, sperm and epididymides. However, this question will be fully addressed during renewal process that is already ongoing. Considering the adverse effects observed on the testes, sperm and epididymides, an endocrine mediated mode of action cannot be ruled out; this should be further discussed. See also 2(11) RMS (LV): Agreed See 2(10) 18 EFSA Supporting publication 2018:EN-1407

19 Summary of mammalian toxicology and setting of ADI, AOEL and ARfD 2(12) B.6.10 ADI Applicant: A 90-d repeated dose toxicity study in Wistar rats and a developmental toxicity study in rat were submitted as. Currently, there is no harmonised and internationally agreed guidance for setting the acceptable daily intake of the a.i. for the inclusion in Annex I of Directive 91/414/EEC or approval under Regulation (EC) 1107/2009. For the derivation of ADI a long-term study may be used, however, other exposure studies, e.g. 90-drepeated dose toxicity studies and/or developmental toxicity studies are also appropriate (HSE, 20137, e.g. p. 17) in conjunction with an additional safety factor (REACH 20068, p ). Consequently, the data provided is deemed sufficient for the derivation of an ADI. The applicant provided a waiver which suggested an ADI of 0.03 mg/kg bw/day based on a conservative safety factor of 1000 based on NOEL = 30 RMS (LV): Agreed to set ADI of 0.03 mg/kg. See 2(14) 7 Chemicals Regulation Directorate, Health & Safety Executive, UK; Investigation of the state of the art on identification of appropriate reference points for the derivation of health-based guidance values (ADI, AOEL and AAOEL) for pesticides and on the derivation of uncertainty factors to be used in human risk assessment. Supporting Publications 2013; 10(4):EN-413. [169 pp.]. doi: /sp.efsa.2013.en REACH, Regulation (EC) No 1907/2006; Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health; EFSA Supporting publication 2018:EN-1407

20 Summary of mammalian toxicology and setting of ADI, AOEL and ARfD mg/kg bw from both studies. However, dietary intake calculations indicate that exposure from natural occurrence clearly exceeds exposure from intended uses (see 3(25)) EFSA Supporting publication 2018:EN-1407

21 Summary of mammalian toxicology and setting of ADI, AOEL and ARfD 2(13) ARfD Applicant: The ARfD cannot be derived from standard acute toxicity studies as in these studies not all relevant parameters are assessed. It can, however, be derived from the submitted 90-d repeated dose exposure study (EC, p. 6). The derived NOEL was supported by the outcome of the also submitted developmental toxicity study in rat, in both studies NOEL = 30 mg/kg. The outcome of both studies demonstrates the need of an ARfD (maternal effects, target organ effects male reproductive tissues, reversible effects on spermatogenesis). The ARfD, based on a standard safety factor of 100, would therefore be 0.3 mg/kg bw. However, dietary intake calculations indicate that exposure from natural occurrence clearly exceeds exposure from intended uses (see 3(25)). RMS (LV): We are on the opinion that in the absence of acute toxicity study safety factor of 1000 would be more appropriate as a conservative approach; however this issue should be further discussed during renewal procedure or in the peer review expert meeting. See 2(14) 9 European Commission, /VI/99; Draft Guidance Document Guidance for the setting of an acute reference dose (ARfD); EFSA Supporting publication 2018:EN-1407

22 Summary of mammalian toxicology and setting of ADI, AOEL and ARfD 2(14) Vol. 3, RMS overall conclusion regarding : toxicological reference values, p. 44 Vol. 3, B.6.2, Operator exposure, Toxicological endpoints (Annex IIIA 7.2.1), p. 40 EFSA: the studies presented could provide a basis for establishing toxicological reference values (ADI, AOEL, ARfD and AAOEL) using additional uncertainty factors to account for the missing studies and additional uncertainty (egg. if based on a LOAEL or lack of oral absorption data). The use of an additional uncertainty factor of 10 as proposed by the applicant to derive the ADI (position paper, p. 58) could be supported, but the standard uncertainty factor of 100 to derive the AOEL (p. 40) is not agreed with. Since it is unknown whether the adverse effects observed in male reproductive system may be due to a single administration, the setting of ARfD/AAOEL could be based on the same effects as for the ADI/AOEL. RMS (LV): We support to add uncertainty factor of 1000 for setting ADI, ARfD and AAOEL which result ADI, ARfD and AAOEL of 0.03 mg/kg bw. We are on the opinion that AOEL value should be further discussed during peer review meeting. There seem to be a consensus on the setting of the ADI using an UF of 1000 due to the limited toxicological database available. The setting of other toxicological reference values was not agreed during the commenting, and different views were received regarding the uncertainty factor to be applied to the AOEL, ARfD or AAOEL. EFSA proposes to use provisionally the most conservative uncertainty factor of 1000 as supported by the RMS, to derive all reference values. Accordingly, the ADI, AOEL, ARfD and AAOEL may be set at 0.03 mg/kg bw per day based on the 90-day study in rats (and developmental toxicity study in rats) showing a NOAEL of 30 mg/kg bw per day and applying an uncertainty factor of 1000 to account for the limited data base. It is proposed to discuss these values during an experts consultation. See also 2(12, 13, 15) 22 EFSA Supporting publication 2018:EN-1407

23 Summary of mammalian toxicology and setting of ADI, AOEL and ARfD 2(15) Conclusion, page 44 AT: RMS concluded that based on the available data no reference values can be derived. AT is of the opinion that based on the fact that tee tree oil is a compound with reduced data requirements, reference values could be set. As a starting point, we could propose as follows: AOEL: 0.03 mg/kg bw/d (based on the NOAEL from 90-days rat study and developmental rat study, and applying a SF of 1000) ADI = same as AOEL. ARfD = 0.3 mg/kg bw/d, based on the maternal NOAEL in rat developmental study and SF of 100. The ARfD is proposed based on bw loss in dams in days 5-8 of the study. AT propose to discuss the necessity of ADI and ARfD (pending on the evaluation of residue section on natural background data), as well as the setting of an AOEL and AAOEL in an expert consultation. RMS (LV): We agree that on the basis of See 2(14) submitted data reference values could be derived, and reference values should be further discussed in expert consultation EFSA Supporting publication 2018:EN-1407

24 Other comments 2(16) Addendum to vol. 4, C.1.1, composition of extract from tea tree(tto) batches used in toxicology studies, p. 3 EFSA: It is agreed that the batches used in the toxicity studies are within the ISO standard 4730 range. Regarding the assessment of the relevance of the individual components of TTO, the applicant provided some Regulatory data under other frameworks (cosmetics, flavouring) which do not allow to establish upper limits or establish hazard properties of these components, including their carcinogenic potential. It is however noted that toxicological data including genotoxicity data are available in the open literature on some of the components of TTO and a systematic search for this literature should have been performed by the applicant. RMS (LV): Agreed that batches used in the toxicity studies are within the ISO standard 4730 range. Applicant did not submit any literature data for the TTO as a whole composition. The batches used in the toxicity studies are in agreement with the ISO standard 4730 range. The toxicological relevance of the individual impurities has not been addressed and a systematic review of the open literature needs to be performed to address this issue. With respect to the relevance of the individual impurities, it is considered that the requirements have not been addressed EFSA Supporting publication 2018:EN-1407

25 3. Residues Metabolism in plants 3(1) B.7.1 Metabolism in plants Applicant: A study on metabolism in plants was conducted. Results indicate that no detectable residues occur in the edible part of the crop 1 d after application. In addition, in fruit no significant metabolites were found. In the nonedible part of the plant the only compound detected > LOQ was p- Cymene. Terpinene-4-ol was detected to occur below LOQ of 0.05 mg/kg and 4 metabolites above trigger values, accounting for 46.8 % of the TRR or mg eq./kg. The final report is scheduled for 02/2018 and will be provided upon request. RMS: Metabolism data in plants has not been submitted. The data gap identified during the peer review for plant metabolism data to support the representative uses is not addressed. However, applicant have conducted new metabolism in plants study which will be submitted for the renewal of Extract from tea tree (TTO). The submitted do not address the data gap identified for plant metabolism studies to identify the relevant residues in plants following application of extract from tea tree according to the representative uses EFSA Supporting publication 2018:EN-1407

26 Metabolism in plants 3(2) Addendum to Volume 3- Annex B, Confirmatory data, B.7.1. Metabolism, distribution and expression of residues, B Plants EFSA: RMS agrees with EFSA - the data gap The submitted position paper (Taya, A., 2016) provides the occurrence of the different components of extract from tea identified during the peer review for plant metabolism data to support the representative uses is not addressed. tree in edible crops and does not However, applicant has informed that new address the fate and behaviour of these compounds in plants following the use of extract from tea tree as a plant protection product according to the representative uses. EFSA is of the metabolism study has been performed for renewal of active substance. Report will be finalized in 02/2018 and will be submitted to RMS Poland for renewal of TTO. opinion that the data gap identified during the peer review for plant metabolism data to support the representative uses is not addressed. See 3(1) 26 EFSA Supporting publication 2018:EN-1407

27 Residue definition 3(3) Addendum to Volume 3- Annex B, Confirmatory data, B.7.2. Residue definition 3(4) Addendum to Volume 3- Annex B, Confirmatory data, B.7.2. Residue definition EFSA: RMS agrees with this comment, as regards The extract from tea tree is applied as a foliar, metabolism data in plants spray on the crops. The comparison of is still missing. the application rates of the extract from However, applicant has informed that new tea tree used as a plant protection metabolism study has been performed for product with the environmental renewal of active substance. Report will be emissions of the components of this finalized in 02/2018 and will be submitted to active substance cannot be used as a RMS Poland for renewal of TTO. valid waiver to metabolism data and to the establishment of a residue definition in plants. EFSA: RMS agrees with this comment. The need to derive a residue definition for animal matrices should be reconsidered pending upon potential significant transfer of extract from tea tree components in animal matrices since potatoes and carrots are feed items. A robust plant residue definition for monitoring and risk assessment will be reconsidered based on the outcome of the requested plant metabolism studies compliant with the representative uses. Considering the representative uses on potatoes and carrots and in the absence of an agreed plant residue definition for risk assessment it is not possible to calculate the total livestock dietary burden and to assess the potential for the occurrence of significant residues in food of animal origin EFSA Supporting publication 2018:EN-1407

28 Use pattern, critical GAP, residues trials 3(5) Addendum to Volume 3- Annex B, Confirmatory data, B.7.1. Metabolism, distribution and expression of residues, B Plants EFSA: RMS agrees with this comment. Reference is made to the residue trials submitted in the DAR (October, 2007) Applicant is planning to submit new residue analysing for several components of trials on sweet peppers, tomato and extract from tea tree (terpinene-4-ol, cucumbers (performed according to new gamma-terpinene, 1,8-cineole) in GAP) for renewal of active substance. tomatoes and cucumbers only. The validity of these trials is questionable in terms of compliance with the representative uses on these crops, lack of storage stability data since these compounds are assumed to be highly volatile and whether these compounds are actually the relevant residue markers to be monitored in absence of metabolism data. EFSA also disagrees on the assumption made that a no-residue situation is expected in crops because of the high volatility of the components of tea tree oil. Finally residue trials to support the other representative uses on potatoes, carrots, herbs, watermelon and peppers were not provided. EFSA notes. The residue trials should comply with the representative uses and should address the magnitude of the relevant residues included in the plant residue definition for monitoring and risk assessment. These trials should be supported by acceptable storage stability data. See also 3(1), 3(3) 28 EFSA Supporting publication 2018:EN-1407

29 MRLs related issues and Consumer Risk Assessment 3(6) 7.15 Consumer exposure Applicant: The dietary exposure of consumers RMS: Noted via natural occurrence of the Metabolism data in plants is still missing to components and via exposure from draw conclusions on consumer exposure. treated crops was extrapolated and assessed. Worst case calculations reveal that the natural exposure to the TTO components is substantially higher than the exposure via treated crops (chronic exposure 1: 682, acute exposure 1 : 55). With natural exposure being far higher than can be from application, the applicant is of the opinion that a consumer risk assessment (i.e. comparing the exposure in mg/kg bw(/day) to ADI and ARfD) as opposed to exposure calculations (evaluating consumer exposure in mg/kg bw(/day)) is not meaningful. The calculations will be provided upon request. 3(7) Addendum to Volume 3- Annex B, Confirmatory data, B.7.3. Consumer risk assessment EFSA: RMS agrees with this comment. Considering the identified data gap for metabolism data, the consumer risk assessment cannot be conducted. However, applicant has informed that new metabolism study has been performed for renewal of active substance. Report will be finalized in 02/2018 and will be submitted to RMS Poland for renewal of TTO. See 3(7) The submitted were not sufficient to perform a comprehensive consumer dietary risk assessment. See 3(1), 3(3), 3(4), 3(5) 29 EFSA Supporting publication 2018:EN-1407

30 4. Environmental fate and behaviour Route and rate of degradation in soil DAR (vol., point, page) 4(1) Study of Tchere Kakia (2016) 4(2) Study of Schemmel (2016) Comments from Member States or applicant AT: AT supports the decision of RMS LV not to consider the results of this modelling study. We also refer the considerable differences between modelling results of PELMO and PEARL to a different handling of volatilization in the uppermost soil compartment in the model codes. To our experience, these differences are known to occur for substances with high vapour pressures (here: 5.7 Pa estimated). Another shortcoming of the study is that all physical key-input properties (i.e., solubility, vapour pressure, KOC and DT50) have not been measured but have been only estimated by EPI. In the opinion of AT, this approach might not be justified if a toxicological relevance assessment is triggered due to the modelling results. AT: AT does not agree with the conclusion of RMS LV stating that the Terpinen-4-ol and α-terpineol can be handled as nonrelevant metabolites since these substances do occur naturally. Study designs should either consider or Evaluation by (RMS) rapporteur and - if available - (Co-RMS) Co-rapporteur Thank you for comment! RMS: Two new laboratory studies on aerobic degradation of some Extract from tea tree Components in soil have been conducted and submitted to RMS. Addressed The original submission did not adequately address the potential for the active substance components Terpinen-4-ol and α- Terpineol to be present in groundwater above the parametric drinking water 30 EFSA Supporting publication 2018:EN-1407

31 Route and rate of degradation in soil DAR (vol., point, page) Comments from Member States or applicant exclude the natural background concentration in agricultural soils. It is the opinion of AT, that major (active) substances such as Terpinen-4-ol and α- Terpineol must not be assessed as (relevant or non-relevant) metabolites but as active substances. As a consequence, AT considers the conclusion to accept a threshold of 10 µg/l as not applicable to Terpinen-4-ol and α-terpineol. Despite this aspect, in the opinion of the AT efate section, a toxicological relevance assessment for these substances is required. Evaluation by (RMS) rapporteur and - if available - (Co-RMS) Co-rapporteur Refined PECgw calculations have been performed by applicant using new experimental laboratory DT50soil values. These PECgw calculations demonstrate that leaching above 0.1 µg/l of Terpinen-4- ol, α-terpineol and 1,8-Cineole into groundwater is not expected from the intended GAP-use of the product for both permanent and non-permanent covered crop structures. RMS consider acceptable the new modelling. limit of 0.1 µg/l. The RMS received additional experimental studies and groundwater exposure assessments for Terpinen-4-ol which the RMS presented in an update to their assessment. Degradation rate was only available in a single soil. The data requirements specify that this information should be provided for a minimum of 4 soils. A QSAR based soil adsorption value was used for α-terpineol (to satisfy the data requirements soil adsorption needs to have been investigated in 4 soils). This updated assessment did not include any new substance input values for α-terpineol. It was assumed that modelling substance input values for α-terpineol might be extrapolated from Terpinen-4-ol (results from one soil only). For the uses in permanent glasshouses the RMS assessment of the available groundwater simulations was understandable (though a soil half life of 4.2 and not 3 days would have been selected following the logic presented?), even if the approach was based on a too small data set and an 31 EFSA Supporting publication 2018:EN-1407

32 Route and rate of degradation in soil DAR (vol., point, page) Comments from Member States or applicant Evaluation by (RMS) rapporteur and - if available - (Co-RMS) Co-rapporteur unjustified extrapolation of substance properties from Terpinen-4-ol to α- Terpineol. However for the groundwater modelling for non permanent covered crop structures (low plastic tunnels and plastic shelters) the RMS assessment contains insufficient details to understand what was done. In conclusion satisfactory information was not available on the potential for groundwater exposure by the active ingredient components Terpinen-4-ol and α-terpineol EFSA Supporting publication 2018:EN-1407

33 PEC in surface water and in ground water 4(3) PECgw Table B EFSA: The selected soil DT50 for the groundwater simulations is not in line with evaluation practice using ECHA guidance when there is evidence that the substances being assessed are readily biodegradable. The ECHA guideline value of soil DT50 30 days is for a reference temperature of 12 C. The FOCUS reference temperature is 20 C. Therefore the relevant DT50 is 14.1 days (for simulations using standard FOCUS scenarios for semi permanent glasshouses) and 141 days (for the permanent glasshouse GEM modelling). Both values normalised from 12 to 20 C using a Q10 of Lower PEC gw values would be derived using this approach of using the shorter DT50. RMS: the PECgw simulations was updated by applicant considering the EFSA comment. RMS consider acceptable the updated modelling. Addressed Note when this approach was followed Terpinen-4-ol and α-terpineol were predicted to be present in groundwater at concentrations above the parametric drinking water limit of 0.1µg/L EFSA Supporting publication 2018:EN-1407

34 PEC in surface water and in ground water 4(4) RMS conclusion in the RMS comment box following Table B EFSA: We do not understand the basis for the conclusion: However, as the constituents of TTO are naturally occurring the concentrations in leachate may be influenced by natural background level of compounds. Thus, the trigger of 10 µg/l as it is used for non-relevant metabolites of synthetic active substances is considered more appropriate trigger in this situation. To address the confirmatory requirement fully, more extended non-relevance assessment of Terpinen-4-ol and α-terpineol would be needed. A non relevance assessment is not possible for constituents making up the active substance. Their being natural has no bearing on the 0.1 µg/l trigger for active substances which applies to active substance components for decision making, whilst extract from tea treeis approved as a plant protection product active substance. RMS: see comment under 4 (2) See comment 4(2). Satisfactory information was not available on the potential for groundwater exposure by the active ingredient components Terpinen-4-ol and α-terpineol EFSA Supporting publication 2018:EN-1407

35 Other comments 4(5) EFSA: The RMS has not provided a list of endpoints that contains the new endpoints resulting from the evaluation of this submission. Please could the RMS provide the relevant sections of the list of endpoints that need to be part of the EFSA technical report. RMS: the relevant sections of the list of endpoints has been updated. Addressed Note the only new fate and behaviour information considered reliable that had the potential to have been provided in accordance with the Commission s submission deadline was evidence that 1,8-cineole, δ-cadinene were readily biodegradable EFSA Supporting publication 2018:EN-1407