According to BPR Article 19 and Annex II, information on analytical methods is required

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1 Date of draft: 1 (5) Definition of relevant impurities Introduction ECHA is currently working on a revision of the Guidance on Technical Equivalence a (TE Guidance). Among other things, it is necessary to clarify the definition of a relevant impurity. In the current document, SECR presents some relevant information and seeks the views of the WG members on an appropriate definition based on two alternative options. In addition to the TE Guidance, the definition will be relevant to other guidance documents where the term is used. Current definitions Current BPR guidance on information requirements and TE Guidance defines relevant impurities as follows: An impurity/additive considered being of toxicological and/or ecotoxicological relevance. An impurity may be relevant even if it occurs in a quantity <1g/kg (e.g. very toxic substances like dioxin). The relevant impurity should be identified and quantified if technically possible and included in the substance specification, with stated maximum concentration. Relevant impurities may be defined as (#DG SANCO, 2012) substances including, but not limited to, meeting the criteria to be classified as hazardous in accordance with CLP Regulation (EC) No. 1272/2008, or the available information (e.g. from (Q)SARs) indicates that the impurity has an (eco)toxicological hazard. Relevant impurities have the inherent capacity to cause harmful/unacceptable effects within the meaning of Article 19(1)(b) of the BPR. Compared to the active substance, relevant impurities show additional (comparable or more severe) toxic properties (in the sense of the definition above). The current definition does not specify whether the definition should rely solely on hazardous properties of the impurity or whether it should take into account also the concentration at which the impurity is present. A related term significant impurity is defined in the TE Guidance as follows: An impurity is regarded as significant if it occurs or potentially occurs in a quantity 1 g/kg in the substance as manufactured. The limit of 1 g/kg applies to the dry technical material (TC) and therefore for technical concentrates (TK) the limit will apply to theoretical dry material and hence impurities below this limit if they are 1 g/kg on a dry weight basis, must also be determined. The impurity should be identified and quantified if technically possible and included in the substance specification, with stated maximum concentration. A significant impurity may be considered relevant or non-relevant depending, in particular, on its known toxicological and eco-toxicological properties. The current definition of significant impurity is considered clear and no further elaboration is necessary. Consequences for relevant impurities According to BPR Article 19 and Annex II, information on analytical methods is required a Guidance on the Biocidal Products Regulation Volume V, Guidance on applications for technical equivalence Version 1.1 March 2017

2 2 (5) concerning the determination of the active substance, isomers, impurities and residues of the starting materials and additives (e.g. stabilisers), which are of toxicological or ecotoxicological concern (i.e. which are relevant for risk assessment) or which are present in quantities 1 g/kg in the active substance as manufactured. The same requirement concerns biocidal products (Annex III of BPR). Relevant impurities should be reported as part of the non-confidential specification of the active For technical equivalence, it is crucial to know which impurities of the active substance are relevant as an increase in concentration of these impurities means that the substance is not technically equivalent at Tier I and it is necessary to perform a Tier II assessment. In addition, Article 64 of BPR, which refers to the use of data when data protection has expired, states that the nature of any relevant impurities should be included as part of the evidence that the active substance is technically equivalent to the active substance for which the data protection period has expired. Clarifying the definition of relevant impurity To clarify the current definition, two options are initially presented below. For both options, whether an impurity is considered relevant or not would depend on the properties of both the active substance and the impurity. Consequently, a specific impurity (at a given concentration) could be considered relevant for one substance and non-relevant for another Nevertheless, any impurity with PBT/vPvB properties should always be regarded as a relevant impurity b. Please also note that this document concerns only the definition of relevant impurities and does not concern the assessment on whether the (eco)toxicity test batches are covered by the reference specification, or the implications for technical equivalence. 1. Definition based on hazard properties The definition of a relevant impurity in this option is based on the hazard properties of the impurity, without considering the concentration at which the impurity is present. An impurity should be considered relevant if, based on any available information, it is reasonable to assume that the impurity has an (eco)toxicological hazard, which is additional, comparable or more severe in comparison to the active As an example, lead would always be a relevant impurity in the active substance copper, regardless of its concentration, due to its comparable or more severe ecotoxicological hazard profile and more severe toxicological hazard profile in comparison to copper. 2. Definition based on hazard properties and concentration In addition to the hazard properties, the definition of a relevant impurity would take into account the concentration at which it is present. A relevant impurity affects the hazardous properties of the active substance at the concentration at which it is present, i.e. the hazard classification would become more stringent or the reference values such as AELs and PNECs would be affected. In deciding on the relevance, existing information on reference values, such as specific or generic concentration limits for classification and risk based values such as AELs or NOAELs for human health and EC 50 /NOEC values for the environment should be taken into consideration. In practice, it would be necessary to agree on a threshold below which the impurity would not be considered relevant (see Annex 1 Introduction and the quotation from the WHO/FAO manual below under Related guidance ). Some impurities could have an b Note, this is not to be confused with an impurity relevant for the PBT assessment. According to the REACH R.11 guidance impurities should normally be considered in the PBT assessment ( relevant for the PBT assessment ) when they are present in concentration of 0.1% (w/w). (Guidance on Information Requirements and Chemical Safety Assessment Chapter R.11: PBT/vPvB assessment Version 3.0 June 2017)

3 3 (5) intrinsic property (hazard) that is comparable or more severe in comparison to the active substance, but would be present below the threshold level and would therefore not be identified as relevant impurities. As an example, lead would be a relevant impurity in the active substance copper only if its concentration is sufficiently high to affect the hazard properties of the active substance (i.e. concentration is above an agreed threshold level). Related guidance Regarding the two options, related guidance should be noted. SANCO guidance for plant protection products c The definition in the SANCO guidance for plant protection products was used as the basis for the biocides guidance and is not explicit with respect to whether the concentration should be considered. Option 1 could be interpreted to be more in line with the definition in the SANCO guidance: Considering the Regulation, the following definition is proposed for relevant impurities: such substances include, but are not limited to, substances meeting the criteria to be classified as hazardous in accordance with Regulation (EC) No. 1272/2008 [extract from Art. 3(4)] or the available information (e.g. (Q)SAR, genotoxicity) indicates that the impurity has a toxicological hazard. Relevant impurities have the inherent capacity to cause harmful/unacceptable effects within the meaning of Article 4(2) and (3). Compared to the active substance, relevant impurities show additional (or more severe) toxic properties (in the sense of the above given properties). WHO/FAO manual for pesticides d The concentration of an impurity is taken into account in the WHO/FAO Manual on development and use of FAO and WHO Specifications for Pesticides, and with this respect option 2 is more in line with the WHO/FAO manual: As a default, an impurity becomes relevant when its concentration in the TC equals or exceeds 10% of the maximal acceptable limit as determined above. Thus skin and eye irritants, become relevant at a concentration of 1 g/kg, sensitizing chemicals, mutagens, carcinogens, and reproductive toxicants at the level of 0.1 g/kg. Action required Please provide your comments on this document by 9 August In particular, please indicate which option you would prefer in defining relevant impurities. Furthermore, the members are requested to provide input regarding further consequences or implications of identifying an impurity as c Guidance document on the assessment of the equivalence of technical materials of substances regulated under Regulation (EC) No 1107/2009. SANCO/10597/2003 rev. 10.1, 13 July d FAO plant production and protection paper 228. Manual on development and use of FAO and WHO Specifications for Pesticides. First edition - third revision, rd_amendment_jmps_manual.pdf

4 4 (5) Annex 1. Examples Introduction For comparison of toxicity (no) effect levels, as in examples a) and b), it could be necessary to agree on a threshold level of e.g. 10 % of the toxicity of the active As an example, this would mean that an impurity which has the same toxicity profile as the active substance would be allowed at 10 % of the active substance concentration, while an impurity which is 100- fold more toxic would be allowed at a concentration 1000-fold below that of the active Such calculations could obviously only be performed regarding threshold effects where there is sufficient information on the NOAEL/LOAEL. The examples below were calculated assuming this 10% limit on the basis of the WHO/FAO manual for pesticides c. Examples Example Option 1. Based on hazard properties a) The acute oral LD50 of an impurity is 100 mg/kg bw and that of the active substance is 1000 mg/kg bw. The level of impurity is 0.5% and the minimum purity of the active substance is 92%. b) The lowest reliable NOAEL short-term of the impurity is 4 mg/kg bw/day. The AEL shortterm of the active substance is based on a NOAEL of 450 mg/kg bw/day. The level of impurity is 0.1% and the purity of the active is 99%. since it has a comparable or more severe hazard compared to the active since it has a comparable or more severe hazard compared to the active Note that the impurity would be relevant regardless of whether the effect is the same. If the NOAEL for both the impurity and the active substance is based on the same effect, then the toxicity is comparable or more severe. If the effect is different for the impurity and the active substance, then the impurity may have additional toxicity. Option 2. Based on hazard properties and concentration The level at which this impurity becomes relevant would be calculated as follows: 0.1 e 92% (1000 mg/kg bw / 100 mg/kg bw) = 0.92% The concentration of the impurity (0.5%) is below 0.92%. Conclusion: the impurity is not relevant (for this active substance at the given concentration) The level at which this impurity becomes relevant would be calculated as follows: 0.1 d 99% (4 mg/kg bw/day / 450 mg/kg bw/day) = 0.088% The level of impurity is 0.1%, which is higher than 0.088%. Conclusion: the impurity is e The calculations shown for Option 2 depend on a generic agreement on how much additional toxicity would trigger the relevance of an impurity in comparison to the toxicity of the active The calculations are made assuming that the impurity would be allowed to reach 10 % of the toxicity of the active substance before being considered relevant (0.1 in the equations).

5 5 (5) c) Classification of the active substance is STOT RE2. The impurity meets the criteria for STOT RE1 for which the generic concentration limit is 1%. The level of impurity is 0.4%. d) There is no information available on the impurity in the literature. The QSAR analysis shows an alert for genotoxicity. The active substance is not genotoxic. The level of impurity is % and the AEL of the active substance is 4 mg/kg bw/day. since it has an additional hazard property compared to the active since it is reasonable to assume that it has an additional hazard property compared to the active If the TTC approach is applied, there is a threshold level which is compared to AEL as in Option 2. The impurity concentration 0.4% would not trigger classification of the active Conclusion: the impurity is not The TTC of µg/kg bw/day f applies as the impurity has a genotoxicity alert. The maximum exposure for the impurity would be mg/kg bw/day = µg/kg bw/day that is above the TTC. Conclusion: the impurity is f Review of the Threshold of Toxicological Concern (TTC) approach and development of new TTC decision tree. EFSA Supporting publication 2016:EN