EFSA Journal 2014;12(4):3675 REASONED OPINION Reasoned opinion on the dietary risk assessment for proposed temporary maximum residue levels (MRLs) of didecyldimethylammonium chloride (DDAC) and benzalkonium chloride (BAC) 1 ABSTRACT European Food Safety Authority 2 European Food Safety Authority (EFSA), Parma, Italy EFSA was requested by the European Commission to perform a dietary exposure assessment for the proposed temporary maximum residue levels (MRLs) for didecyldimethylammonium chloride (DDAC) and benzalkonium chloride (BAC) (0.1 mg/kg, respectively, for all food commodities covered by the EU MRL legislation). Based on the information, EFSA did not identify potential consumer health risks for these proposed MRLs. Thus, the proposed MRLs are considered to be sufficiently protective. However, due to the limited data available, the risk assessments are affected by a high degree of uncertainty. European Food Safety Authority, 2014 KEY WORDS didecyldimethylammonium chloride (DDAC), benzalkonium chloride (BAC), temporary MRLs, Regulation (EC) No 396/2005, consumer risk assessment, quaternary ammonium compounds (QAC) 1 On request from the European Commission, Question No EFSA-Q-2013-01000, approved on 16 April 2014. 2 Correspondence: pesticides.mrl@efsa.europa.eu Suggested citation: European Food Safety Authority, 2014. Reasoned opinion on the dietary risk assessment for proposed temporary maximum residue levels (MRLs) of didecyldimethylammonium chloride (DDAC) and benzalkonium chloride (BAC). EFSA Journal 2014;12(4):3675, 23 pp. doi:10.2903/j.efsa.2014.3675 Available online: www.efsa.europa.eu/efsajournal European Food Safety Authority, 2014
SUMMARY In the framework of quality controls performed by food business operators, residues of didecyldimethylammonium chloride (DDAC) and benzalkonium chloride (BAC) were identified which exceeded the permitted legal limit of 0.01 mg/kg (default MRL established in Article 18(1)(b) of Regulation (E)C No 396/2005). The source of DDAC and BAC residues in food is not fully elucidated but is probably liked to the use of these substances in biocidal products. Since DDAC and BAC were used as pesticides in the past, they fall under the provisions of Regulation (EC) No 396/2005. In 2012 the European Commission and Member States agreed on an enforcement level of 0.5 mg/kg as a proportionate risk management measure on a temporary basis. At the same time a monitoring programme was set up which should allow to get a better understanding of the source and the magnitude of DDAC and BAC residues in food. Based on the results of the monitoring data generated by EU Member States, European Commission derived a proposal to set a temporary MRL at the level of 0.1 mg/kg. EFSA was requested to assess in the framework of Article 43 of Regulation (EC) No 396/2005 whether these proposed temporary MRLs for DDAC and BAC are sufficiently protective for consumers. EFSA bases its assessment on the health assessments performed by German Bundesinstitut für Risikobewertung (BfR) on DDAC and BAC, the background documents provided by the European Commission, such as guidelines of the European Commission, the review report for didecyldimethylammonium chloride, EFSA conclusion on DDAC, the technical report on monitoring of residues of DDAC and BAC and a previously issued reasoned opinion of EFSA on an import tolerance request. For the dietary risk assessment EFSA used the ADI and ARfD values derived by the BfR (ADI for both DDAC and BAC: 0.1 mg/kg bw per day, ARfD for both compounds: 0.1 mg/kg bw). These values are considered as indicative, since no full toxicological dossiers are available for the compounds. It is noted that in the framework of a previously submitted MRL application an indicative ARfD of 0.61 mg/kg was derived for DDAC. The European Commission proposed to set the temporary MRLs for DDAC for all products covered by Annex I of Regulation (EC) No 396/2005 for the following enforcement residue definition: DDAC (mixture of alkyl-quaternary ammonium salts with alkyl chain length of C8, C10 and C12). The estimation of the chronic and acute exposure to DDAC is based on the proposed temporary MRLs, except for citrus fruit, where the residues resulting from a pesticide treatment in South Africa, assessed by EFSA in 2013 were taken into account, as requested in the mandate of the European Commission. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 7.2 % of the indicative ADI (related Dutch children). The contribution of residues in milk to the total consumer exposure accounted for a maximum of 4 % of the ADI (French toddler). A potential acute consumer risk could not be ruled out in relation to the residues in oranges (132.6% of the tentative ARfD 3 ) while for the remaining citrus fruit no risk was identified. It is noted that in the framework of the import tolerance request EFSA performed the risk assessment with the ARfD agreed in the expert meeting. In this case the short-term exposure accounted for 34 % of the ARfD 4. Since in September 2013 the SCoFCAH took a decision not to amend the MRL for citrus, the risk assessment performed in the framework of the import tolerance request is of no relevance. For the other crops for which temporary MRL should be established, the short term exposure assessment did not identify an acute consumer health risk. The calculated maximum exposure for the proposed temporary MRLs (expressed in percent of the indicative ARfD of 0.1 mg/kg bw) was 15 % for potatoes, 15 % for 3 Indicative ARfD 0.1 mg/kg bw derived by BfR (2012a). 4 ARfD of 0.61 mg/kg bw agreed in the EFSA expert meeting (EFSA, 2013b). EFSA Journal 2014;12(4):3675 2
melons and 13 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. For BAC the following residue definition was proposed by the European Commission: Mixture of alkylbenzyldimethylammonium chlorides with alkyl chain lengths of C8 to C18. EFSA proposes to specify that the residue definition comprises only benzalkonium chlorides with alkyl-rests with an even chain length (i.e. C8, C10, C12, C14, C16 and C18). EFSA also identifies the need to clarify with the EURL if the available analytical methods allow to measure the total residues (sum of BAC with alkyl chain lengths of C8, C10. C12, C14, C16 and C18) with an LOQ that is equal or lower than the proposed temporary MRL of 0.1 mg/kg. The dietary acute and chronic exposure to BAC was calculated with the EFSA PRIMo using the proposed temporary MRLs as input values. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 6.8 % of the indicative ADI (related UK infants). The contribution of residues in milk to the total consumer exposure accounted for a maximum of 4 % of the ADI (French toddler). No acute consumer risk was identified. The calculated maximum exposure in percentage of the indicative ARfD was 15.4 % for potatoes, 15.2 % for melons and 13.3 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. Based on the results of the dietary risk assessments for DDAC and BAC EFSA concludes that the proposed temporary MRL of 0.1 mg/kg for all food commodities covered by the EU MRL legislation for DDAC and BAC is expected to be sufficiently protective for European consumers. For oranges the MRL proposal derived in the framework of an import tolerance request leads to an exceedance of the indicative ARfD of 0.1 mg/kg for DDAC. However, using the ARfD agreed with Member State Experts, no short-term exposure risk was identified. Due to the limited information available, the risk assessments for DDAC and BAC are affected by a high degree of uncertainty, in particular related to the lack of detailed information on the toxicological studies, other possible sources of exposure which may contribute to the overall consumer exposure and the lack of information on the nature and magnitude of residues in processed products. The risk assessment was performed for the two compounds separately. In case DDAC, BAC and other quaternary ammonium compounds share the same toxicological mechanism/effects, a comprehensive cumulative exposure assessment would be required to conclude if the proposed temporary MRLs are sufficiently protective. However, currently data on the toxicological mode of action are not available. Taking all these uncertainties, the risk assessment performed by EFSA is only indicative. EFSA Journal 2014;12(4):3675 3
TABLE OF CONTENTS Abstract... 1 Summary... 2 Table of contents... 4 Background... 5 The active substance and its use pattern... 7 Assessment... 11 1. Assessment of DDAC... 11 1.1. Mammalian toxicology - DDAC... 11 1.2. Residue definition for risk assessment and enforcement purpose -DDAC... 12 1.3. Proposed temporary MRLs - DDAC... 12 1.4. Consumer risk assessment - DDAC... 12 2. Assessment of BAC... 14 2.1. Mammalian toxicology - BAC... 14 2.2. Residue definition for risk assessment and enforcement purpose -BAC... 14 2.3. Residue concentrations - BAC... 15 2.4. Consumer risk assessment - BAC... 15 Conclusions and recommendations... 16 References... 18 Appendices... 19 Appendix A. Pesticide Residue Intake Model (PRIMo) - DDAC... 19 Appendix B. Pesticide Residue Intake Model (PRIMo) - BAC... 21 Abbreviations... 23 EFSA Journal 2014;12(4):3675 4
BACKGROUND Didecyldimethylammonium chloride (DDAC) is a quaternary ammonium compound, which in the EU was previously authorised as a plant protection product for use on ornamental crops (according to the period of grace the use of plant protection products containing DDAC was permitted until 20 March 2014); DDAC remains authorised as a biocide for disinfection. Benzalkonium chloride (BAC) is not approved under Regulation (EC) No 1107/2009 5, but it is covered by the biocides review programme of Regulation (EU) No 528/2012 6 within the product type "food and feed area disinfectants". Maximum residue levels (MRLs) for both substances have been set at the default level of 0.01 mg/kg according to Article 18(1)(b) of Regulation (EC) No 396/2005 7 because these uses were not expected to result in any residues in food. The European Commission has been informed by food business operators and later by Member States that various food products may contain residue levels of DDAC and BAC higher than 0.01 mg/kg. Food business operators and Member States have been investigating the reason(s) for this unexpected presence of residues. To allow further monitoring and investigation, the Standing Committee on the Food Chain and Animal Health (SCoFCAH) has agreed guidelines on DDAC and BAC in July 2012, last modified on 5 October 2012 (EC, 2012a, 2012b). Based on statements of the German Bundesinstitut für Risikobewertung (BfR) (BfR, 2012a, 2012b) and a risk assessment performed by BfR with the EFSA PRIMO model, the SCoFCAH considered that the current default MRLs for DDAC and BAC are not a health standard and that it is appropriate to agree on an enforcement level of 0.5 mg/kg, as a proportionate risk management measure on a temporary basis, ensuring a high level of consumer protection in the European Union. Furthermore, Member States agreed to put in place a monitoring programme to have a clear understanding of the levels of DDAC and BAC in all food and feed of plant and animal origin and to communicate the results to the Commission and to EFSA of the monitoring programmes and investigations by the end of February 2013, with a view to taking any necessary measure under Regulation (EC) No 396/2005. Further to the submission of monitoring data, the Commission asked EFSA to analyse them to allow risk managers to have an informed discussion on possible future steps. The Commission sent a request for an evaluation of monitoring data on residues of DDAC and BAC to EFSA. EFSA accepted that mandate and delivered a technical report on 5 September 2013 (EFSA, 2013a). On the basis of EFSA's evaluation of monitoring data, and in view of the use of DDAC and BAC in biocidal products and possible exposure of consumers to residues of these substances, the Commission considers that it is appropriate to set t-mrls at the level of 0.1 mg/kg each for both substances and across all products of plant and animal origin listed in groups 1 through 10 of Annex I to Regulation (EC) No 396/2005. Before taking further steps, the Commission seeks to ascertain whether the proposed t-mrls are sufficiently protective for consumers. The request was submitted to EFSA on 26 November 2013. EFSA accepted the mandate and included it in the EFSA Register of Questions with the reference number EFSA-Q-2013-01000 and the following subject: Didecyldimethylammonium chloride (DDAC) and benzalkonium chloride (BAC) - Dietary exposure assessment for the proposed temporary MRLs 5 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, 24.11.2009, p. 1-50. 6 Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products. OJ L 167, 27.06.2012, p. 1 123. 7 Regulation (EC) No 396/2005 of the Parliament and of the Council of 23 February 2005 on maximum residue levels of pesticides in or on food and feed of plant and animal origin and amending Council Directive 91/414/EEC. OJ L 70, 16.03.2005, p. 1-16. EFSA Journal 2014;12(4):3675 5
TERMS OF REFERENCE EFSA is requested, according to Article 43 of Regulation (EC) No 396/2005, to assess whether t- MRLs proposed by the Commission on the basis of EFSA's evaluation of monitoring data on residues of DDAC and BAC obtained according to the guidelines of the Standing Committee on the Food Chain and Animal Health (section pesticides residues) are sufficiently protective for consumers in view of their possible exposure to residues of these substances due to the use in biocidal products. The proposed t-mrls refer to the unprocessed raw agricultural products. The exposure assessment should be carried out separately for DDAC and BAC. The Commission's proposal is to set t-mrls of 0.1 mg/kg each for both substances and across all products of plant and animal origin listed in groups 1 through 10 of Annex I to Regulation (EC) No 396/2005. As agreed toxicological reference values are still pending under the biocides review programme, the Commission considers it appropriate to apply the acceptable daily intake (ADI) and acute reference dose (ARfD) values used by BfR in its evaluations of DDAC and BAC that formed the basis for the Guideline documents agreed by the SCoFCAH in 2012. For DDAC, an ADI of 0.1 mg/kg bw per d and an ARfD of 0.1 mg/kg bw, as the most conservative of the two values considered should be applied. For BAC, an ADI of 0.1 mg/kg bw per d and an ARfD of 0.1 mg/kg bw should be applied. For the purposes of the requested assessment, the following residue definitions should be used: DDAC: mixture of alkyl-quaternary ammonium salts with alkyl chain lengths of C8, C10 and C12. BAC: mixture of alkylbenzyldimethylammonium chlorides with alkyl chain lengths of C8-18. To obtain the most conservative assessment, residue data from the application to set an import tolerance for DDAC in citrus should be taken into account (EFSA, 2013b). Background and Terms of Reference provided by the European Commission The agreed deadline for providing the reasoned opinion was 31 March 2014. EFSA Journal 2014;12(4):3675 6
THE ACTIVE SUBSTANCE AND ITS USE PATTERN Didecyldimethylammonium chloride (DDAC) is a mixture of alkyl-quaternary ammonium salts with typical alkyl chain lengths of C8, C10 and C12. Benzalkonium chloride (BAC) is a mixture of benzyl alkyl dimethylammonium chlorides, containing alkyl chains with a varying chain length between C8 and C18 (only even numbered alkyl chain lengths). Since both substances are a mixture of compounds, no unique IUPAC names have been allocated. The chemical structures of the molecules are reported below. DDAC BAC R Cl - CH 3 N + R CH 3 R = alkyl chain H3 with typical lengths of C8, C10 and C12 BAC and DDAC belong to the class of alkyl-quaternary ammonium compounds. Other pesticides belonging to this class are chlormequat and mepiquat. DDAC regulatory background on the pesticide assessments According to the Draft Assessment Report (DAR) prepared by the Rapporteur Member State (The Netherlands, 2007) in support of the Annex I inclusion of DDAC under Council Directive 91/414/EEC, DDAC inhibits the growth and kills phytopathogenic fungi, phytopathogenic bacteria and algae in hydroponic systems, on hard surfaces, glasshouse walls and pavements, and equipments. Uses as post-harvest treatment on citrus fruits, pome fruits and some fruiting vegetables were also reported. The DAR of DDAC has been peer reviewed by EFSA (EFSA, 2008). The representative uses evaluated were disinfection of horticulture vessels, equipments (e.g. knives) and surfaces. In the EFSA conclusion a series of data gaps was identified, many of them linked to the lack of information on the exact composition of the active substance, necessary to derive a specification and a minimum purity for the technical DDAC. Since no clear specifications could be established and since the representative uses were referring to non-edible crops only, it was concluded that the setting of toxicological reference values is not necessary (EFSA, 2008). DDAC was included in Annex I of this Directive by Directive 2009/70/EC 8 which entered into force on 1 January 2010. According to this directive, only indoor uses for ornamental plants as bactericide, fungicide, herbicide and algaecide were permitted. The minimum purity of the technical concentrate was defined in this directive as 70 % with more than 90 % of the alkyl-chains being C10. Directive 2009/70/EC specified that the notifier had to submit further confirmatory data on the specification of the active substance. In accordance with Commission Implementing Regulation (EU) No 540/2011 9 DDAC was approved under Regulation (EC) No 1107/2009, repealing Council Directive 91/414/EEC. 8 Commission Directive 2009/70/EC of 25 June 2009 amending Council Directive 91/414/EEC to include difenacoum, didecyldimethylammonium chloride and sulphur as active substances, OJ L 164, 26.06.2009, p. 59-63. 9 Commission Implementing Regulation (EU) No 540/2011 of 23 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, 11.06.2011, p. 1-186. EFSA Journal 2014;12(4):3675 7
In 2013 a decision to withdraw the approval for DDAC was taken (Regulation (EU) No 175/2013 10 ) since the notifier failed to provide the confirmatory information specified in Directive 2009/70/EC. Since no authorisations for DDAC were in place on food crops, the default MRL of 0.01 mg/kg according to Article 18(1)(b) of Regulation (EC) No 396/2005 was considered appropriate. According to the provisions of the legislation on biocidal products (Directive 98/8/EC, replaced by Regulation (EC) No 528/2012), dossiers were submitted for DDAC for different product types. So far a decision has been taken on the approval of DDAC as product type 8 (wood preservative) (Directive 2013/4/EU 11 ). The assessment of product type 1-4 (food and feed area) is still ongoing. In 2012, the European Commission has been informed by food business operators and several Member States that various food products were found containing levels of DDAC higher than the default level of 0.01*mg/kg. The origin of these residues was not clearly identified; possible sources were, among others, the use of DDAC in biocidal products, plant strengtheners, DDAC containing fertilisers or coformulants used in plant protection products. On 9 July 2012, modified on 21 January 2013, the German Federal Institute for Consumer Protection and Food Safety issued a statement containing a toxicological assessment of DDAC (BfR, 2012a), 2012b). The ADI proposed by the BfR is 0.1 mg/kg body weight per day, based on a 1 year dog study. The same study was used to derive an ARfD of 0.1 mg/kg body weight. BfR also performed a dietary exposure assessment, which was based on the median and maximum residue concentrations reported by German enforcement laboratories for citrus, pome fruit, stone fruit, berries and other small fruit, tropical fruit, root and tuber vegetables, solanacea, cucurbits, brassica vegetables, fresh herbs, legume vegetables and milk and milk products. The exposure was calculated with German risk assessment models reflecting German food consumption data and with the EFSA PRIMo (EFSA, 2007). The results of the risk assessment provided some evidence that the DDAC exposure via food does not pose a chronic or acute consumer health concern (BfR, 2012a). In the Standing Committee on Food Chain and Animal Health held in July 2012 an exchange of views on the available information and on the results of the risk assessment provided by the BfR took place. It was agreed that Member States should carry out investigations on the causes of the contamination and put in place a monitoring programme with a view to have a clear understanding of the levels of DDAC in food and feed. In addition, it was agreed that food and feed with a level of DDAC higher than 0.5 mg/kg should not be placed on the market and be withdrawn from the market and safely disposed of. In October 2012 the recommended guidelines were slightly modified to avoid ambiguities in enforcement (EC, 2012a). At the same time, Member States were invited to set up a specific national control programme on DDAC in citrus fruit, pome fruit, miscellaneous fruit, root and tuber vegetables, fruiting vegetables and dairy products in both, conventional and organic products. The results had to be reported to the European Commission and to EFSA by the end of February 2013. In 2013, EFSA issued a technical report which summarised the results of the national control programmes (EFSA, 2013a). Taking into account these findings, the European Commission is of the opinion that it is appropriate to set a temporary MRL at the level of 0.1 mg/kg for DDAC in all food products of plant and animal origin listed in Annex I of Regulation (EC) No 396/2005, provided that the dietary risk assessment confirms that these MRLs do not pose a consumer health risk. It is noted that DDAC has not been reviewed by JMPR and therefore, no CXLs are established at Codex level. In addition, it should be mentioned that in 2013, EFSA issued a reasoned opinion on the 10 Commission Implementing Regulation (EU) No 175/2013 of 27 February 2013 amending Implementing Regulation (EU) No 540/2011 as regards the withdrawal of the approval of the active substance didecyldimethylammonium chloride. OJ L 56, 28.2.2013, p. 4-5. 11 Commission Directive 2013/4/EU of 14 February 2013 amending Directive 98/8/EC of the European Parliament and of the Council to include Didecyldimethylammonium Chloride as an active substance in Annex I thereto. OJ L 44, 15.02.2013, p. 10 13. EFSA Journal 2014;12(4):3675 8
setting of an import tolerance for DDAC in citrus (EFSA, 2013b), reflecting a post-harvest treatment of citrus. Based on the EFSA reasoned opinion, in the meeting of the Standing Committee on the Food Chain and Animal Health (SCoFCAH) of 16/17 September 2013 a decision was taken not to amend the MRLs for DDAC in citrus. BAC regulatory background on the pesticide assessments In the past, BAC was used in plant protection products. However, since no manufacturer made a commitment to provide a dossier in support of the assessment in the framework of Directive 91/414/EEC, a decision was taken not to include the active substance in Annex I of this Directive (Regulation (EC) No 2076/2002 12 ). As a consequence, all authorisations of plant protection products containing this active substance had to be withdrawn by 25 July 2003. Since no uses are authorised for plant protection products containing BAC, the setting of specific MRLs was not considered necessary and therefore the default MRL of 0.01 mg/kg is applicable. In the framework of quality controls performed by food business operators, BAC was quantified in concentrations exceeding the default MRL. The source of these residues has not been identified beyond doubts, but it may also be the result of BAC used in plant strengtheners, fertilizer or the use in biocides. The assessment of a dossier in the framework of the biocide active substance review programme is ongoing. It is noted that several different active substances which fall under the general class of benzalkonium chloride are distinguished, depending on the composition of the mixture of the alkyl chains (i.e. ADBAC, BKC). ADBAC has been approved so far for product type 8 (wood preservatives) (Directive 2013/7/EU 13 ). Decision on other product types and BAC related substances are still pending. On 13 July 2012 the German Federal Institute for Consumer Protection and Food Safety issued a statement containing a toxicological assessment of BAC and a dietary risk assessment (BfR, 2012b). The exposure assessment was based on the median and maximum residue concentrations reported by German enforcement laboratories in citrus fruit, pome fruit, stone fruit, berries and other small fruit, tropical fruit, solanacea, cucurbits, brassica vegetables, fresh herbs, legume vegetables and milk and milk products. The exposure was calculated with German risk assessment models reflecting German food consumption data and with the EFSA PRIMo (EFSA, 2007). BfR concluded that the long-term dietary intake of benzalkonium chloride residues is unlikely to present a public health concern. For most of the products BfR concluded that the expected short-term exposure will not exceed the toxicological reference value of 0.1 mg/kg. However, for pineapple a slight exceedance of the ARfD was calculated (101% of the ARfD), which was considered as being of no concern, considering that the residues are likely to be removed with the peel. For milk and milk products the calculated intake exceeded the ARfD for several consumer groups (maximum exposure for bovine milk calculated for German children accounting for 310 % of the ARfD); thus, a potential consumer health risk could not be ruled out for milk containing residues at the highest concentration reported (6.6 mg/kg) (BfR, 2012b). In July 2012, similar to the guidelines for DDAC, the Standing Committee on Food Chain and Animal Health agreed that Member States should investigate the sources of the contamination and put in place a monitoring programme to better understand the reasons of the BAC findings in food and feed; the 12 Commission Regulation (EC) No 2076/2002 of 20 November 2002 extending the time period referred to in Article 8(2) of Council Directive 91/414/EEC and concerning the non-inclusion of certain active substances in Annex I to that Directive and the withdrawal of authorisations for plant protection products containing these substances. OJ L 319, 23.11.2002, p. 3-11. 13 Commission Directive 2013/7/EU of 21 February 2013 amending Directive 98/8/EC of the European Parliament and of the Council to include Alkyl (C 12-16 ) dimethylbenzyl ammonium chloride as an active substance in Annex I thereto. OJ L 49, 22.02.2013, p. 66 69. EFSA Journal 2014;12(4):3675 9
monitoring programmes should focus on citrus fruit, pome fruit, miscellaneous fruit, root and tuber vegetables, fruiting vegetables and dairy products in both, conventional and organic products. In addition, it was agreed that food and feed with a level of BAC higher than 0.5 mg/kg should not be placed on the market. In October 2012 the recommended guidelines were slightly modified to avoid ambiguities in enforcement (EC, 2012b). Based on the results of the national control programmes collected between July 2012 and February 2013 which were summarised in the technical report of EFSA (EFSA, 2013a), the European Commission proposed to set a temporary MRL at the level of 0.1 mg/kg for BAC in all food products of plant and animal origin listed in Annex I of Regulation (EC) No 396/2005, provided that the dietary risk assessment confirms that these MRLs do not pose a consumer health risk. EFSA Journal 2014;12(4):3675 10
ASSESSMENT EFSA bases its assessment on the health assessments performed by BfR on didecyldimethylammonium chloride and benzalkonium chloride (BfR, 2012a, 2012b), the background documents provided by the European Commission, such as guidelines of the European Commission (EC, 2012a, 201b), the review report for didecyldimethylammonium chloride (EC, 2009), EFSA conclusion on DDAC (EFSA, 2008), the technical report on monitoring of residues of DDAC and BAC (EFSA, 2013a) and a previously issued reasoned opinion of EFSA on an import tolerance request (EFSA, 2013b). Considering the different profiles of the substances, EFSA performed a separate assessment for DDAC (Section 1) and BAC (Section 2). 1. Assessment of DDAC 1.1. Mammalian toxicology - DDAC In the framework of the peer review under Directive 91/414/EEC (EFSA, 2008) no toxicological reference values were derived. Toxicological studies were provided by the applicant; the studies were performed with alcoholic/aqueous solutions containing 50 to 80 % of DDAC but the applicant could not provide a confirmation that the composition of the material used in these studies is comparable to the technical material in the plant protection products. In the framework of an MRL application, the EMS (the Netherlands) reconsidered the toxicological data initially presented in the DAR (The Netherlands, 2007) and derived chronic and acute reference values for DDAC (see Table 1-1). These toxicological reference values were discussed with Member State experts in May 2013 (Pesticides Peer Review expert meeting 103). The experts on mammalian toxicology confirmed the values proposed by the EMS. However, it was highlighted that the toxicological reference values should be considered as indicative only since the concerns raised on the specification of the active substance and on the representativeness of the test material used in toxicological studies have not yet been addressed (EFSA, 2013b). In its mandate the European Commission recommended to base the dietary risk assessment on the toxicological reference values derived by BfR in its assessment performed in 2012 (BfR, 2012a). The values are also reported in Table 1-1. Table 1-1: Overview of the toxicological reference values Source Year Value Study relied upon Safety factor Didecyldimethylammonium chloride (DDAC) 14 ADI NL 2012 0.1 mg/kg bw per day 1 year dog 100 ARfD NL 2012 0.61 mg/kg bw 13-week rat & 2-generations rat 100 ADI BfR 2012 0.1 mg/kg bw per day 1 year dog 100 ARfD BfR 2012 0.1 mg/kg bw 1 year dog 100 EFSA concludes that the ADI values derived by the Netherlands and the BfR are identical and can be used for the indicative dietary risk assessment. As regards the ARfD, the value proposed by the European Commission is more conservative than the value derived in the framework of the MRL 14 The identity/composition of the batches used for the toxicological studies was not specified. EFSA Journal 2014;12(4):3675 11
application. Using the ARfD of 0.1 mg/kg body weight introduces an additional conservatism which should be borne in mind. For both the ADI and the ARfD the uncertainties resulting from the lack of information on the composition of the DDAC residues found in the commodities under assessment are noted. The indicative toxicological reference values should be re-considered as soon as the assessment of DDAC in the framework of the biocides assessment is finalised. 1.2. Residue definition for risk assessment and enforcement purpose -DDAC The European Commission proposed to define the residue as follows: DDAC: Mixture of alkyl-quaternary ammonium salts with alkyl chain lengths of C8, C10 and C12. This residue definition shall be used for enforcement and risk assessment purpose. EFSA is of the opinion that the proposed residue definition is sufficiently clear to give guidance to enforcement laboratories regarding which molecules should be analysed in routine food control. Also for risk assessment the residue definition is acceptable on provisional basis. According to the information available on the website of EU Reference Laboratories for Residues of Pesticides (EURL) validated analytical methods based on LC/MS are available for different matrices (acidic, dry, high oil content, high sugar content, high water content); the achievable LOQ is between 0.01 mg/kg and 0.083 mg/kg 15. Thus, the proposed residue definition can be enforced in practice in all food products for which temporary MRLs should be established. 1.3. Proposed temporary MRLs - DDAC The European Commission proposed to set the temporary MRLs for the abovementioned residue definition at the level of 0.1 mg/kg for all food commodities listed in group 1 to 10 of Annex I of Regulation (EC) No 396/2005. The proposed temporary MRLs were derived from the monitoring results submitted by Member States in 2013. It is noted that the proposed temporary MRL corresponds to the 99 th percentile of the results reported for fruits, vegetables, and baby food, the maximum residue concentration measured in cereals and other plant products. For animal products occasionally higher residue concentrations were reported; these results most likely refer to dried milk powder, a processed product where during the dehydration process a concentration might have occurred (EFSA, 2013a). 1.4. Consumer risk assessment - DDAC EFSA performed the consumer risk assessment with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo). This exposure assessment model contains the relevant European food consumption data for different sub-groups of the EU population 16 (EFSA, 2007). For the calculation of chronic exposure, EFSA used the proposed temporary MRLs (0.1 mg/kg) for all commodities listed in group 1 to 10 of Annex I to Regulation (EC) No 396/2005), except for citrus fruit, where according to the mandate the exposure calculations should take into account residues resulting from a pesticide treatment in South Africa, for which a MRL application was assessed by EFSA in 2013 (EFSA, 2013b). Thus, for citrus pulp, the median residue concentration of 0.22 mg/kg derived on the basis of the data submitted in support of the import tolerance request was used as input value 15 DataPool of EURLs, (http://www.eurl-pesticides-datapool.eu/default.aspx?ziel=asp/en/validation.aspx) 16 The calculation of the long-term exposure (chronic exposure) is based on the mean consumption data representative for 22 national diets collected from MS surveys plus 1 regional and 4 cluster diets from the WHO GEMS Food database; for the acute exposure assessment the most critical large portion consumption data from 19 national diets collected from MS surveys is used. The complete list of diets incorporated in EFSA PRIMo is given in its reference section (EFSA, 2007). The exposure assessments are based on the methodology developed by JMPR (FAO, 2009). EFSA Journal 2014;12(4):3675 12
Since only few samples were reported in the framework of the monitoring performed between July 2012 and February 2013 that contained higher residues, the choice of the input values is considered to be sufficiently conservative. The acute exposure was calculated with the proposed temporary MRL, including a variability factor accounting for the inhomogeneous distribution on the individual items consumed for food products with a unit weight greater than 25 g. For citrus fruit the exposure was calculated for the highest residue measured in citrus pulp treated according to the data submitted in the framework of the import tolerance request (EFSA, 2013b). The acute risk assessment approach is considered sufficiently conservative, but it is noted that as long as the source of the DDAC residues are not fully clarified, it cannot be excluded that food containing higher residues than the legal limit might be available to European consumers. These cases are therefore not covered by the risk assessment. The input values for the dietary consumer exposure assessment are summarised in Table 1-2. Table 1-2: Input values for the consumer dietary exposure assessment DDAC Commodity Chronic exposure assessment Acute exposure assessment Input value Comment Input value Comment Risk assessment residue definition: DDAC: Mixture of alkyl-quaternary ammonium salts with alkyl chain lengths of C8, C10 and C12. Citrus fruit 0.22 Median residue in pulp, EFSA, 2013b 1.0 Highest residue in pulp, EFSA, 2013b Orange juice - not relevant 0.54 Median whole fruit *PF, EFSA, 2013b Other commodities of plant and animal origin 0.1 Proposed temporary MRL 0.1 Proposed temporary MRL The results of the intake calculation are presented in Appendix A to this reasoned opinion. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 7.2 % of the indicative ADI (related Dutch children). Milk was found to be the main contributing food commodity (maximum of 4 % of the ADI in French toddler diet). A potential acute consumer risk could not be ruled out in relation to the residues in oranges (132.6% of the tentative ARfD 17 ) while for the remaining citrus fruit no risk was identified. It is noted that in the framework of the import tolerance request EFSA performed the risk assessment with the ARfD agreed in the expert meeting (see Table 1-1). In this case the short-term exposure accounted for 34 % of the ARfD 18. Since in September 2013 the SCoFCAH took a decision not to amend the MRL for citrus, the risk assessment performed in the framework of the import tolerance request is of no relevance. For the other crops for which temporary MRL should be established, the short term exposure assessment did not identify an acute consumer health risk. The calculated maximum exposure for the proposed temporary MRLs (expressed in percent of the indicative ARfD of 0.1 mg/kg 17 Indicative ARfD 0.1 mg/kg bw derived by BfR (2012a). 18 ARfD of 0.61 mg/kg bw agreed in the EFSA expert meeting (EFSA, 2013b). EFSA Journal 2014;12(4):3675 13
bw) was 15 % for potatoes, 15 % for melons and 13 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. EFSA concludes that the proposed temporary MRLs of 0.1 mg/kg for DDAC are not expected to pose a consumer health risk. Due to the limited information available, the risk assessment is affected by a high degree of uncertainties (see end of section 2.4). 2. Assessment of BAC 2.1. Mammalian toxicology - BAC In its mandate the European Commission recommended to base the dietary risk assessment on the toxicological reference values derived by BfR in its assessment performed in 2012 (BfR, 2012b). The values are reported in Table 2-1. Table 2-1: Overview of the toxicological reference values Benzalkonium chloride (BAC) 19 Source Year Value Study relied upon Safety factor ADI BfR 2012 0.1 mg/kg bw per day 52 weeks dog 100 ARfD BfR 2012 0.1 mg/kg bw 1 year dog 100 EFSA agrees to use the ADI and the ARfD values derived by the BfR for the indicative dietary risk assessment. For both the ADI and the ARfD the uncertainties resulting from the lack of information on the composition of the BAC residues found in the commodities under assessment and the composition of BAC used in toxicological studies are noted. It would be desirable to have a clear specification of the test material used in animal studies to compare it with the residues occurring in food. The indicative toxicological reference values should be re-considered as soon as the assessment of BAC in the framework of the biocides assessment is finalised. 2.2. Residue definition for risk assessment and enforcement purpose -BAC The European Commission proposed to define the residue as follows: BAC: Mixture of alkylbenzyldimethylammonium chlorides with alkyl chain lengths of C8 to C18. This residue definition shall be used for enforcement and risk assessment purpose. According to the information available on the website of the EU Reference Laboratories for Residues of Pesticides (EURL) validated analytical methods based on LC/MS are available for benzalkonium chloride with chain length C8, C10, C12, C14, C16 and C18. The LOQs reported for the individual substances ranged from 0.01 mg/kg to 0.083 mg/kg. In order to decide whether the available analytical methods are appropriate for enforcement purposes, it should be clarified with the EURL if the LOQ for the total residues (sum of BAC with alkyl chain lengths of C8, C10. C12, C14, C16 and C18) is equal or lower than the proposed temporary MRL of 0.1 mg/kg. EFSA also proposes to specify that the residue definition comprises only benzalkonium chlorides with alkyl-rests with an even chain length (i.e. C8, C10, C12, C14, C16 and C18) in order to avoid unnecessary efforts in method validation for BAC with odd chain lengths. 19 The specification of the test material was not reported in the assessment of the BfR (BfR, 2012b). EFSA Journal 2014;12(4):3675 14
2.3. Residue concentrations - BAC Dietary risk assessment for temporary MRLs for DDAC and BAC The European Commission proposed to set the temporary MRLs for BAC at the level of 0.1 mg/kg for all food commodities listed in group 1 to 10 of Annex I of Regulation (EC) No 396/2005. The proposed temporary MRLs were derived from the monitoring results submitted by Member States in 2013 (EFSA, 2013). It is noted that a number of monitoring samples of fruits, vegetables, animal products, baby food and other products contained residues in higher concentrations than the proposed temporary MRL. It is also noted that the monitoring results were not always consistent with the proposed residue definition; many of the results referred to the individual BACs (separate results for BAC C8, C10, C12, C14, C16 or C18, respectively) or for the sum of BAC C10 to BAC C16, while results for the total residue definition (BAC C8 to BAC C18) were lacking. 2.4. Consumer risk assessment - BAC EFSA performed the consumer risk assessment with revision 2 of the EFSA Pesticide Residues Intake Model (PRIMo) as described in section 1.4 for DDAC. For the calculation of chronic exposure, EFSA used the proposed temporary MRLs (0.1 mg/kg for all commodities listed in group 1 to 10 of Annex I to Regulation (EC) No 396/2005). Although some samples were reported in the framework of the monitoring performed between July 2012 and February 2013 that contained higher residues, the choice of the input values is considered to be sufficiently conservative for the long-term exposure assessment. The acute exposure was calculated with the proposed temporary MRL, including a variability factor accounting for the inhomogeneous distribution on the individual items consumed for food products with a unit weight greater than 25 g. The approach is affected by some uncertainties related to the lack of information on the total BAC residues in the individual samples (C8, C10, C12, C14, C16 or C18). The monitoring data provided some evidence that food containing higher residues than the proposed legal limit might be available to European consumers. Thus, it should be highlighted that the acute risk assessment performed in the framework of this assessment does not cover the exposure to residues above the proposed temporary MRLs. The results of the intake calculation are presented in Appendix B to this reasoned opinion. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 6.8 % of the indicative ADI (related UK infants). The contribution of residues in milk to the total consumer exposure accounted for a maximum of 4 % of the ADI (French toddler). No acute consumer risk was identified in relation to the proposed temporary MRL. The calculated maximum exposure in percentage of the indicative ARfD 20 was 15.4 % for potatoes, 15.2 % for melons and 13.3 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. Based on the results of the indicative dietary risk assessment EFSA concludes that the proposed temporary MRL of 0.1 mg/kg for all food commodities covered by the EU MRL legislation for BAC are expected to be sufficiently protective for European consumers. However, due to the limited information available, the risk assessments described in section 1.4 and 2.4 for DDAC and BAC, respectively are affected by a high degree of uncertainties, which are resulting from the following issues: - Appropriateness of the toxicological reference values used in the indicative risk assessment (see section 1.1 and 2.1); 20 Tentative ARfD 0.1 mg/kg bw (BfR, 2012b). EFSA Journal 2014;12(4):3675 15
- Actual residue concentrations occurring in food might be higher than the proposed temporary MRLs. (Since the sources of the DDAC and BAC residues are not fully elucidated, it cannot be completely ruled out that higher residues are present in certain food products for which no monitoring data are available at the moment); - Nature of residues in food (i.e. composition of DDAC and BAC residues regarding different chain lengths, and the influence of the chain length on the toxicity of the substance); A possible impact of processing on the nature of residues was not assessed (e.g. formation of toxicological relevant degradation products formed during heat treatment or other technological processes). - The occurrence of higher residues than 0.1 mg/kg in processed food for which no data are available cannot be fully excluded. - Other non-dietary sources of exposure may contribute to the overall exposure of consumers, considering the wide use spectrum of DDAC and BAC (e.g. use of DDAC or BAC as skin antiseptics, pharmaceutical uses, preservative for pharmaceutical products, wet wipes, use as algaecide in swimming pools, other biocidal uses which lead to residues in food or feed). - Cumulative exposure of DDAC, BAC and other quaternary ammonium compounds: In order to decide if substances belonging to the same chemical class (quaternary ammonium compounds) share the same toxicological mode of action, further data would be required. Thus, the current risk assessment which is based on the two individual compounds would not be sufficient to estimate the consumer health risk resulting from the exposure to several quaternary ammonium compounds. CONCLUSIONS AND RECOMMENDATIONS CONCLUSIONS EFSA bases its assessment on the health assessments performed by German Bundesinstitut für Risikobewertung (BfR) on DDAC and BAC, the background documents provided by the European Commission, such as guidelines of the European Commission, the review report for didecyldimethylammonium chloride, EFSA conclusion on DDAC, the technical report on monitoring of residues of DDAC and BAC and a previously issued reasoned opinion of EFSA on an import tolerance request. For the dietary risk assessment EFSA used the ADI and ARfD values derived by the BfR (ADI for both DDAC and BAC: 0.1 mg/kg bw per day, ARfD for both compounds: 0.1 mg/kg bw). These values are considered as indicative, since no full toxicological dossiers are available for the compounds. It is noted that in the framework of a previously submitted MRL application an indicative ARfD of 0.61 mg/kg was derived for DDAC. The European Commission proposed to set the temporary MRLs for DDAC for all products covered by Annex I of Regulation (EC) No 396/2005 for the following enforcement residue definition: DDAC (mixture of alkyl-quaternary ammonium salts with alkyl chain length of C8, C10 and C12). The estimation of the chronic and acute exposure to DDAC is based on the proposed temporary MRLs, except for citrus fruit, where the residues resulting from a pesticide treatment in South Africa, assessed by EFSA in 2013 were taken into account, as requested in the mandate of the European Commission. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 7.2 % of the indicative ADI (related EFSA Journal 2014;12(4):3675 16
Dutch children). The contribution of residues in milk to the total consumer exposure accounted for a maximum of 4 % of the ADI (French toddler). A potential acute consumer risk could not be ruled out in relation to the residues in oranges (132.6% of the tentative ARfD) while for the remaining citrus fruit no risk was identified. It is noted that in the framework of the import tolerance request EFSA performed the risk assessment with the ARfD agreed in the expert meeting. In this case the short-term exposure accounted for 34 % of the ARfD. Since in September 2013 the SCoFCAH took a decision not to amend the MRL for citrus, the risk assessment performed in the framework of the import tolerance request is of no relevance. For the other crops for which temporary MRL should be established, the short term exposure assessment did not identify an acute consumer health risk. The calculated maximum exposure for the proposed temporary MRLs (expressed in percent of the indicative ARfD of 0.1 mg/kg bw) was 15 % for potatoes, 15 % for melons and 13 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. For BAC the following residue definition was proposed by the European Commission: Mixture of alkylbenzyldimethylammonium chlorides with alkyl chain lengths of C8 to C18. EFSA proposes to specify that the residue definition comprises only benzalkonium chlorides with alkyl-rests with an even chain length (i.e. C8, C10, C12, C14, C16 and C18). EFSA also identifies the need to clarify with the EURL if the available analytical methods allow to measure the total residues (sum of BAC with alkyl chain lengths of C8, C10. C12, C14, C16 and C18) with an LOQ that is equal or lower than the proposed temporary MRL of 0.1 mg/kg. The dietary acute and chronic exposure to BAC was calculated with the EFSA PRIMo using the proposed temporary MRLs as input values. No long-term consumer intake concerns were identified for any of the European diets incorporated in the EFSA PRIMo. The total calculated intake accounted for up to 6.8 % of the indicative ADI (related UK infants). The contribution of residues in milk to the total consumer exposure accounted for a maximum of 4 % of the ADI (French toddler). No acute consumer risk was identified. The calculated maximum exposure in percentage of the indicative ARfD was 15.4 % for potatoes, 15.2 % for melons and 13.3 % for oranges. Also for milk, watermelons and pineapples the short term exposure accounted for more than 10 % of the ARfD. Based on the results of the dietary risk assessments for DDAC and BAC EFSA concludes that the proposed temporary MRL of 0.1 mg/kg for all food commodities covered by the EU MRL legislation for DDAC and BAC is expected to be sufficiently protective for European consumers. For oranges the MRL proposal derived in the framework of an import tolerance request leads to an exceedance of the indicative ARfD of 0.1 mg/kg for DDAC. However, using the ARfD agreed with Member State Experts, no short-term exposure risk was identified. Due to the limited information available, the risk assessments for DDAC and BAC are affected by a high degree of uncertainty, in particular related to the lack of detailed information on the toxicological studies, other possible sources of exposure which may contribute to the overall consumer exposure and the lack of information on the nature and magnitude of residues in processed products. The risk assessment was performed for the two compounds separately. In case DDAC, BAC and other quaternary ammonium compounds share the same toxicological mechanism/effects, a comprehensive cumulative exposure assessment would be required to conclude if the proposed temporary MRLs are sufficiently protective. However, currently data on the toxicological mode of action are not available. Taking all these uncertainties, the risk assessment performed by EFSA is only indicative. EFSA Journal 2014;12(4):3675 17