Note for discussion with Competent Authorities for Biocidal Products
This document is an attempt to provide guidance in the interest of consistency, and has been drafted by the Commission services responsible for biocidal products with the aim of finding an agreement with all or a majority of the Member States' Competent Authorities for biocidal products. Please note, however, that Member States are not legally obliged to follow the approach set out in this document, since only the Court of Justice of the European Union can give authoritative interpretations on the contents of Union law.
Subject: Substances of Concern – Proposed Human Health (Toxicology) Assessment Scheme for Authorisation of Biocidal Products
The following document addresses exclusively the identification and evaluation of substances of concern in relation to human health (toxicological) endpoints. Guidance concerning substances of concern in relation to physical-chemical and environmental endpoints is under development and will be published at a later time point.
Identification of Substances of Concern
A substance of concern (SoC) is defined in Art 3(f) of Regulation (EU) No. 528/2012/EC or the Biocidal Product Regulation (BPR) as follows:
(f) ‘substance of concern’ means any substance, other than the active substance, which has an inherent capacity to cause an adverse effect, immediately or in the more distant future, on humans, in particular vulnerable groups, animals or the environment and is present or is produced in a biocidal product in sufficient concentration to present risks of such an effect.
Such a substance would, unless there are other grounds for concern, normally be:
a substance classified as dangerous or that meets the criteria to be classified as dangerous according to Directive 67/548/EEC, and that is present in the biocidal product at a concentration leading the product to be regarded as dangerous within the meaning of Articles 5, 6 and 7 of Directive 1999/45/EC, or
— a substance classified as hazardous or that meets the criteria for classification as hazardous according to Regulation (EC) No 1272/2008, and that is present in the biocidal product at a concentration leading the product to be regarded as hazardous within the meaning of that Regulation,
— a substance which meets the criteria for being a persistent organic pollutant (POP) under Regulation (EC) No 850/2004, or which meets the criteria for being persistent, bio-accumulative and toxic (PBT) or very persistent and very bio-accumulative (vPvB) in accordance with Annex XIII to Regulation (EC) No 1907/2006;
Therefore, a SoC is a co-formulant in a biocidal product which meets at least one of the conditions specified in Art 3(f), i.e. a classified co-formulant present in the biocidal product above the respective specific or generic concentration limit of Directive 1999/45/EC and/or the CLP Regulation and thus, leading to its classification. However, as it can be seen from Art 3(f), the legal text is vague on what constitutes a SoC on the basis of “other grounds for concern”. It has been proposed that in addition to the three cases (three indents) of clearly defined SoCs specified in Art 3(f), the following co-formulants present in a biocidal product should be considered as SoCs:
Classified substances that are taken into consideration when determining the classification of the product according to Directive 1999/45/EC, Article 3(3) or according to CLP, Article 11(2). It should be noted that impurities might affect the classification of any such substances. This criterion partly overlaps with the requirements of Art 3(f) of the BPR. Ultimately, this criterion will additionally identify classified co-formulants that contribute, by additivity, to the classification of the biocidal product. It is noted that since the additivity principle of Directive 1999/45/EC or CLP Regs applies only to acute toxicity and irritation/corrosivity, SoCs identified by this criterion would be co-formulants classified for these endpoints, which are present in the biocidal product at concentrations insufficient to trigger the classification of the product by themselves, but that together with other co-formulants/active substance(s) contribute to the classification of the product. Conversely, as the additivity principle of Directive 1999/45/EC or CLP Regs does not apply to the other toxicological hazards under the scope of these legislations, co-formulants classified for these other hazards, which are present in the biocidal product at concentrations insufficient to trigger the classification of the product by themselves are not considered SoCs on the basis of this criterion. Concentrations for classified substances taken into consideration when determining the classification of the product are specified in the relevant legislation (Directive 1999/45/EC and CLP Regs).
Active substances, other than those included in Annex I of the BPR, for which a draft final Competent Authority Report -CAR (with agreed reference values) is available (including draft final CARs for Product Types other than the one of the actual biocidal product under evaluation). This criterion identifies other active substances in the biocidal product that act as co-formulants (e.g. in-can preservatives). It is noted that active substances (acting as co-formulants in a product) should be regarded as SoCs because, due to their intrinsic biological activity, they are likely to possess toxicological activity. It is also noted that as many active substances do not hold harmonised classifications under the CLP Regs, they may fail to be identified as SoCs by indents 1 and 2 of Art 3(f) of the BPR. These substances should be considered SoCs if they are present in the biocidal product at a concentration ≥ 0.1%.
Substances that enhance the effect of the active substance in the product, e.g. synergists. For such substances, critical information/data shall relate to the interaction between the active substance and the synergist, not only to the synergist itself. In such situations, an appropriate evaluation of the risks posed by the active substance in the presence of the synergist rather than an evaluation of the risks posed by the synergist itself should be undertaken. A generic concentration cut-off value (for their presence in a product) applicable to all synergists cannot be specified. On a case-by-case basis, a synergist should be considered a SoC, if it is present at a concentration that enhances the toxicity of the active substance, as indicated by the available data.
Substances that have been included in the list (candidate list) established in accordance with the REACH Regulation, Article 59(1) or fulfil the criteria for inclusion in the candidate list, if not already covered by the criteria of Article 3(f) of the BPR. These substances should be considered SoCs if they are present in the biocidal product at a concentration ≥ 0.1%. It is noted this criterion will ultimately capture, over and above the clearly-defined SoCs specified in Art 3(f) of the BPR, endocrine disruptors (EDs) and substances with hazards of equivalent concern to CMR 1A or 1B (under CLP Regs).
Substances for which there are Community workplace exposure limits. A generic concentration cut-off value (for their presence in a product) applicable to all such substances cannot be specified. This should be determined on a case-by-case basis depending on the hazard profile, potency and exposure potential of the substance.
Evaluation of identified SoCs
Annex VI of the BPR lays down the common principles for the evaluation of dossiers for biocidal products. The following is stated at paragraphs 3, 4, 5, 6, 7, 14, 16 and 17 of this Annex:
3. In order to ensure a high and harmonised level of protection of human health, animal health and the environment, any risks arising from the use of a biocidal product shall be identified. To achieve this, a risk assessment shall be carried out to determine the acceptability or otherwise of any risks that are identified. This is done by carrying out an assessment of the risks associated with the relevant individual components of the biocidal product, taking into account any cumulative and synergistic effects.
4. A risk assessment on the active substance(s) present in the biocidal product is always required. This risk assessment shall entail hazard identification, and, as appropriate, dose (concentration) - response (effect) assessment, exposure assessment and risk characterisation. Where a quantitative risk assessment cannot be made a qualitative assessment shall be produced.
5. Additional risk assessments shall be carried out, in the same manner as described above, on any substance of concern present in the biocidal product. Information submitted in the framework of Regulation (EC) No 1907/2006 shall be taken into account where appropriate.
6. In order to carry out a risk assessment, data are required. These data are detailed in Annexes II and III and take account of the fact that there are a wide variety of applications as well as different product-types and that this has an impact on the associated risks. The data required shall be the minimum necessary to carry out an appropriate risk assessment. The evaluating body shall take due consideration of the requirements of Articles 6, 21 and 62 in order to avoid duplication of data submissions. Data may also be required on a substance of concern present in a biocidal product. For in-situ generated active substances, the risk assessment includes also the possible risks from the precursor(s).
7. The results of the risk assessments carried out on the active substance and on the substances of concern present in the biocidal product shall be integrated to produce an overall assessment for the biocidal product itself.
14. A risk assessment on the active substance present in the biocidal product shall always be carried out. If there are, in addition, any substances of concern present in the biocidal product then a risk assessment shall be carried out for each of these.
16. For each active substance and each substance of concern present in the biocidal product, the risk assessment shall entail hazard identification and the establishment of appropriate reference values for dose or effect concentrations.
17. The results arrived at from a comparison of the exposure to the appropriate reference values for each of the active substances and for any substances of concern shall be integrated to produce an overall risk assessment for the biocidal product. Where quantitative results are not available the results of the qualitative assessments shall be integrated in a similar manner. Therefore, the BPR requires that a risk assessment is performed for all active substances and SoCs in a biocidal product. Clearly paragraph 5 of Annex VI of the BPR implies that a risk assessment should be conducted for SoCs in the same manner as it is performed for the active substance. However, the text in the Regulation contains several caveats. Paragraph 4 of Annex VI indicates that qualitative rather than quantitative risk assessments may be performed where a quantitative one cannot be produced. The ‘where’ part of paragraph 4 is important as, in certain circumstances, it allows applicants to demonstrate that the risk is likely to be acceptable with qualitative arguments or more simplistic calculations (e.g. Tier I exposure assessment).
Performing full risk assessments for every SoC in every formulation is not only impractical, unworkable and unsustainable but also not justified from a scientific point of view. A tiered approach is therefore required to assess the risks posed by SoCs in a proportionate manner.
It should be noted that the onus is on applicants to identify SoCs, provide appropriate information/data and perform risk assessments, if necessary. To identify SoCs, applicants should take into account all available information, including data in the open literature and information from predictive approaches such as (Q)SAR ((quantitative) structural activity relationship), read-across from structural analogues and category approaches. It should also be noted that although SDSs (Safety Data Sheets) for individual co-formulants represent the primary source of hazard information on potential SoCs, useful information could also be obtained from a number of specialised databases and portals such as the eChemPortal, the C&L Inventory, ECHA dissemination website (database of registered substances under REACH), R4BP 3 (Register for Biocidal Products), Annex VI of the CLP Regulation and cosmetic databases. It should be noted that, wherever relevant data for the assessment is covered by proprietary rights, it is the responsibility of the applicant to obtain the right to use these data.
The following toxicological assessment scheme for SoCs is proposed to be used together with ECHA Guidance for Human Health Risk Assessment (Volume III, Part B). The scheme takes into account the nature (quantitative or qualitative) and severity of the hazard classification of the SoC, the concentration/percentage of the SoC in the biocidal product, the relative toxicity of the SoC compared to that of the active substance and the relative ratio between the active substance concentration and the SoC concentration in the biocidal product. The approach has been developed to be initially applicable to those (toxicological) SoCs clearly defined in Art 3(f), i.e. classified co-formulants present in a biocidal product at concentrations leading or contributing to the classification of the product according to Directive 1999/45/EC or the CLP Regs. Ecotoxicological SoCs identified in accordance with Art 3(f) because of their POP, PBT and/or vPvB properties are outside the scope of this paper and are to be addressed by the environmental risk assessment of the biocidal product.
The proposal requires that for each SoC, the classification of the product triggered by the classified SoC is determined first. The SoC is then assigned to one of four possible product hazard classification bands (from A to D) of increasing evaluation and risk management requirements. If the SoC can be assigned to more than one band, the evaluation/risk management requirements of the higher band will apply. Less severe hazards and/or hazards for which, normally, the available dose-response information tends to be qualitative or semi-quantitative are assigned to the lower bands; more severe hazards and/or hazards for which, normally, the available dose-response information tends to be quantitative are assigned to the higher bands.
It should not be forgotten that products classified as Toxic, Very Toxic or C (Carcinogenic), M (Mutagenic) or R (Toxic for Reproduction) Cat 1 or 2 under Directive 1999/45/EC or classified for Acute Toxicity Category 1, 2 or 3 or as C or M or R category 1A or 1B under the CLP Regs cannot be used by the general public (Art 19(4) of the BPR), regardless of whether the classification is triggered by the active substance or by one or more SoCs in the product. It should also not be forgotten that if, for the general public, the wearing of personal protective equipment would be the only possible method for reducing exposure to an acceptable level, the product shall not normally be authorised (Annex VI, para 63 of BPR).
Regardless of band, for SoCs classified for the same endpoint, the potential exists that they act additively with other SoCs and/or with the active substance(s) and that a combined risk assessment would be required. However, as there is little experience of applying such methodology at present, it has been proposed that for the time being a combined risk assessment should only be applied to multiple (2 or more) active substances (including those identified as SoCs under criterion (2)) within a product, and not to SoCs. When sufficient experience has been gained, the combined risk assessment methodology could be extended to include SoCs.
The proposed scheme utilises both the classification and labelling elements of Directive 67/548/EEC and the CLP Regs. The table below outlines the main features of the proposed banding scheme.
Banding evaluation scheme for classified SoCs leading to the classification of the biocidal product
Acute Tox 4 (H332, H312, H302)
STOT SE 2 (H371)
Asp Tox 1 (H304), EUH066, STOT SE 3 (H336)
Eye Irrit 2 (H319), STOT SE 3 (H335), Skin Irrit 2 (H315)
Application of S-phrases/P-statements normally associated with concerned R-phrases/H statements
R23, R24, R25
R39/23, /24, /25
R26, R27, R28
R39/26, /27, /28
R34, R35, R41
Acute Tox 3 (H331, H311, H301)
STOT SE 1 (H370)
Acute Tox 2 (H330, H310, H300), Acute Tox 1 (H330, H310, H300)
STOT SE 1 (H370)
Skin Corr 1A, 1B, 1C (H314), Eye Dam 1 (H318)
Skin Sens 1 (H317), Resp Sens 1(H334)
Qualitative exposure and risk assessment to determine whether S-phrases/P-statements normally associated with concerned R-phrases/H statements are sufficient or whether other risk mitigation measures should be applied
Use of such SoCs to be discouraged; however, if essential and no safer alternatives available, a full risk assessment should be conducted against EU IOELVs (when available), DNELs, DMELs, other references values (e.g. AELs and AECs) or in qualitative manner
BAND A – This band includes SoCs which trigger products to be classified for moderate acute toxicity, including narcosis, and/or mild irritation. It should be noted that for these hazards, a fully quantitative risk assessment is not usually performed because only qualitative or semi-quantitative dose-response information is normally available. It is proposed that for these SoCs, appropriate risk mitigation measures, in the form of the safety (S)-phrases triggered by the relevant risk (R)-phrases under Directive 67/548/EEC or the precautionary (P)-statements normally associated with the concerned hazard (H)-statements under the CLP Regs, should be applied. If acute toxicity and/or irritation studies on the formulation are available, these should be considered to verify whether the predicted hazard(s) (by the calculation method of Directive 1999/45/EC and CLP Regs) are confirmed. If the predicted hazards are not confirmed by the formulation test data, then the product is no longer classified for acute toxicity/irritation and there is no need to perform an evaluation of the initial SoC. If the predicted hazards are confirmed, then the evaluation/risk management requirements associated with this band should be applied.
BAND B - This band includes SoCs which trigger products to be classified for severe or very severe acute toxicity, corrosion and/or sensitisation. As for the hazards in band A, a fully quantitative risk assessment is not usually performed for these properties because only qualitative or semi-quantitative dose-response information is normally available. It is proposed that for these SoCs only a qualitative risk assessment is performed. This should consider the potential for exposure to the SoC, by taking into account the physical-chemical properties of the SoC (e.g. dustiness, volatility), the concentration of the substance in the product and the use pattern of the product. If exposure is regarded to be significant, in addition to the S-phrases/P-statements normally associated with the concerned R-phrases/H-statements, further risk mitigation measures, as appropriate, should be considered.
Similarly to the SoCs in band A, if acute toxicity, irritation and/or sensitisation studies on the formulation are available, these should be considered to verify whether the predicted hazard(s) (by the calculation method of Directive 1999/45/EC and CLP Regs) are confirmed. If the predicted hazards are not confirmed by the formulation test data, then the product is no longer classified for acute toxicity/irritation/sensitisation and there is no need to perform an evaluation of the initial SoC. If the predicted hazards are confirmed, then the evaluation/risk management requirements associated with this band should be applied.
BAND C - This band includes SoCs which trigger products to be classified for repeated dose toxicity, lactation effects and/or carcinogenicity, mutagenicity (when a threshold approach can be taken) or reprotoxicity in the lowest category. Since for these hazards quantitative dose-response information is normally available, it is proposed that a fully quantitative risk assessment is performed according to ECHA Guidance for Human Health Risk Assessment (Volume III, Part B). This will entail for each SoC a comparison of the exposure estimates with appropriate toxicological reference dose levels. Wherever possible, no additional animal testing on the SoC should be conducted simply for the purposes of establishing a reference dose value for the SoC within the scope of the BPR. Every effort should be made by the applicant to avoid further vertebrate testing and to gain access to available data/information. It can be reasonably assumed that as a minimum the information that has triggered the classification of the SoC must exist. If the applicant is unable to obtain access to the available data, other evaluation options should be discussed with the regulatory authority.
For SoCs for which Community workplace exposure limits (IOELVs – Indicative Occupational Exposure Limit Values) have been set, a quantitative inhalation risk assessment for the professional operator against the IOELV should always be conducted. If the IOELV is associated with a “skin notation” and is driven by systemic effects (rather than local effects), then route-to-route extrapolation should be performed (using standard parameters for body weight and ventilation rate) to derive a dermal or a systemic IOELV. This should then be used to conduct a dermal quantitative risk assessment for the professional operator. If the extent of dermal absorption for the SoC is not known, a default, worst-case dermal absorption value should be used (according to Guidance on Dermal Absorption; EFSA Journal 2012; 10(4):2665). If a risk assessment for members of the general public is also required, it should be considered whether the IOELV is appropriate for such use or whether it should be lowered by the application of an assessment factor to take account of vulnerable groups.
For SoCs for which IOELVs have not been set or are not appropriate (e.g. for non-professional users), the existence of other possible reference values should be explored. As it is most likely that the majority of co-formulants used in biocidal products fall within the scope of REACH registration, it is proposed that DNELs (Derived No Effect Levels) stipulated within the Chemical Safety Assessment (CSA) of registration dossiers are used as reference values. DNELs for specific substances can be retrieved from the dissemination website of ECHA, but also from the extended SDSs (Safety Data Sheets) accompanying such substances. DNELs for different routes of exposure and for different populations (workers and general public) should normally be available. Relevant DNELs for different SoC exposure scenarios should be selected as appropriate. It is noted that DNELs are derived by registrants and actors in the chemical supply chain. At present, only a very small minority of these DNELs has been validated by the regulatory system (ECHA or Member States). Therefore, if a national authority has concerns about the validity of any such DNELs for a specific SoC, alternative and more stringent reference values could be set, as appropriate.
With regard to the exposure assessment of the SoC, a Tier II evaluation should be undertaken only if unacceptable risks are identified at Tier I.
BAND D – This band includes SoCs which trigger products to be classified for carcinogenicity and reprotoxicity in the highest two categories and for mutagenicity in all three categories, including the lowest category (the latter only when a non-threshold approach is taken). These are serious hazards which, with the exception of mutagenicity in the lowest category, meet the exclusion criteria for approval (Art (5) of the BPR) when expressed by the active substance. It is therefore proposed that the use of such co-formulants/SoCs in biocidal products should be discouraged. This approach is in accordance with Annex III of Regulation (EC) No 1107/2009 (unacceptable co-formulants). However, if an applicant shows that they are essential in the formulation and there are no safer alternatives, then a full risk assessment should be performed to determine whether or not they pose an unacceptable risk. Similarly to the SoCs in Band C, the risk assessment of these SoCs should be performed against an IOELV, when available, or a DNEL (for threshold effects), DMEL –Derived Minimal Effect Level (for non-threshold genotoxic carcinogens) or in a more qualitative manner (for non-threshold effects for which suitable quantitative dose-response information is not available).
As explained above, the proposed banding evaluation scheme applies to those (toxicological) SoCs clearly defined in Art 3(f), i.e. classified co-formulants present in a biocidal product at concentrations leading to the classification of the product according to Directive 1999/45/EC or the CLP Regs.
With regard to the additional SoCs identified through the “other grounds for concern” route, the principles of the scheme can be adapted to be applicable to these substances as well. Therefore, the following is proposed in terms of evaluation/risk management requirements:
SoCs meeting criterion (1) – This criterion will ultimately capture, over and above the clearly-defined SoCs specified in Art 3(f), co-formulants classified for acute toxicity and/or irritation/corrosion, which are present in the biocidal product at concentrations insufficient to trigger the classification of the product by themselves, but that together with other co-formulants/active substance(s) contribute to the classification of the product. Depending on the severity of the hazard classification, the requirements of band A or B (appropriate risk mitigation measures/qualitative risk assessment) should apply to these SoCs.
SoCs meeting criterion (2) – This criterion identifies other active substances in the biocidal product that act as co-formulants (e.g. in-can preservatives). Reference values (i.e. AELs – Acceptable Exposure Levels and AECs – Acceptable Exposure Concentrations) will normally be available for these SoCs. Therefore, the requirements of band C (i.e. a fully quantitative risk assessment) should apply to these SoCs.
SoCs meeting criterion (3) – This criterion identifies synergists. For these substances, an appropriate evaluation of the risks posed by the active substance in the presence of the synergist rather than an evaluation of the risks posed by the synergist/SoC itself should be undertaken. The principles of band C (i.e. a fully quantitative risk assessment) should apply to this scenario.
SoCs meeting criterion (4) – This criterion will ultimately capture, over and above the clearly-defined SoCs specified in Art 3(f), endocrine disruptors (EDs) and substances with hazards of equivalent concern to CMR 1A or 1B (under CLP Regs). These are serious hazards, and in the case of EDs, they meet the exclusion criteria for approval (Art (5) of the BPR) when expressed by the active substance. Therefore, the requirements of band D (full risk assessment) should apply to these SoCs.
SoCs meeting criterion (5) – This criterion identifies substances for which there are EU IOELVs. The requirements of band C should apply to these SoCs.