Combined Risk Assessments
As part of the authorisation process under Regulation 1107/2009, the risk to non-target organisms from the product must be considered. The risk arising from the product may be greater than from the active substance alone due to the effect of other substances in the formulation. When a product contains more than one active substance, it is necessary to consider any potential additive effects of the active substances present in the product as well as the influence of any co-formulants. Similarly, if the active substance and metabolite(s) are likely to co-occur then this risk should also be considered.
This guidance introduces the combined risk assessment of pesticides containing more than one active substance or situations where active substances and metabolites are likely to co-occur from a Fate and Behaviour perspective. It will be necessary to consider the ecotoxicological database of endpoints to determine the appropriate endpoints to use and the level of assessment required. The calculation for formulation PECs is addressed in Soil and PECsw via spraydrift. The following provides guidance on the calculation of PECs for exposure to multiple active substances from the same product covering the environmental compartments of soil, groundwater and surface water.
Soil exposure from all the actives in a product and any co-formulants present is assessed using an Initial PECsoil for the formulation value (See Soil for guidance on the calculation of soil and formulation PECs). For multiple application GAPs it is considered sufficient to calculate an initial PECsoil value for the formulation from a single application, since the individual components of the formulation are expected to disperse between applications such that exposure to the intact formulation will only occur from a single application. Care should be taken when reporting a formulation PECsoil value, to ensure that it is clear that the concentration is expressed as mg formulation/kg dry weight soil, to ensure that the correct ecotoxicological endpoints are used in the risk assessment.
If the active substance(s) produce a common metabolite, that also trigger a soil risk assessment (for example, the metabolite is listed as an ecotoxicologically relevant metabolite in the EFSA conclusions), a summation of the initial PECsoil values calculated for the formation of the metabolite from each active substance provides a conservative assessment, as it assumes the maximum formation of the metabolite from each active substance occurs at the same time.
By providing standard PECsoil values for each active substance for the individual risk assessments, the fate assessment will also provide the necessary input values for any additional combined active substance risk assessment (for example, for more persistent or accumulating substances where the risk may not be fully assessed by the initial formulation PECsoilvalue).
A combined assessment for groundwater is only necessary if the active substances produce a common metabolite. Summation of the PECGW values for each scenario provides a conservative first tier assessment as it assumes the maximum formation of each metabolite from each active substance occurs at the same time.
Core Zonal Applications
Combined risk assessments are dependent on Member State specific approaches or using theGuidance on tiered risk assessment for plant protection products for aquatic organisms in edge-of-field surface waters (EFSA Journal 2013; 11(7):3290. Therefore, for Core Zonal applications, calculation of FOCUS PECsw/sed for each active substance present in the formulation must be presented within the same Draft registration Report. (Please refer to FOCUSsw calculations for guidance on FOCUS PECsw/sed and Other Calculations for calculation of formulation PECsw using FOCUS models). Although Member State (MS) approaches for Combined Risk Assessments in surface water are MS specific, applicants will need to include calculations for formulation PECsw/sed within the core dossier of a zonal request (with STEP4 FOCUSsw calculations presented in the relevant MS National Addendum).
UK Specific Requirements
Surface water exposure from all the active substances in a product and any co-formulants present is assessed using Initial PECSW resulting from spray drift of the formulation.(see PECsw via spraydrift). For multiple application GAPs it is considered sufficient to calculate an initial PECSW drift value for the formulation from a single application, since the individual components of the formulation are expected to disperse between applications such that exposure to the intact formulation will only occur from a single application. Care should be taken when reporting a formulation PECsw value, to ensure that it is clear that the concentration is expressed as mg or μg formulation/l, to ensure that the correct ecotoxicological endpoints are used in the risk assessment.
If the active substances produce a common metabolite that also triggers a surface water risk assessment (for example, the metabolite is listed as an ecotoxicologically relevant metabolite in the EFSA conclusions), a summation of the initial PECSW values calculated for the formation of the metabolite from each active substance provides a conservative assessment as it assumes the maximum formation of the metabolite from each active substance occurs at the same time. By providing standard PECsw values for each active substance for the individual risk assessments, the fate assessment will also provide the necessary input values for any additional combined active substance risk assessment. For example, for multiple application GAPs with more persistent substances where carry over of residues between spray applications may result in higher PECsw values and where the risk may not be fully assessed by the initial formulation PECsw value.
If surface water exposure via drain flow is relevant then it is considered unlikely that the active substance and all the co-formulants will remain intact in drain flow therefore no assessment of combined risk from the formulation via drain flow is required.
The principal risk of combined exposure via drain flow will therefore be due to multiple active substances and/or ecotoxicologically relevant metabolites that may co-occur in water. To simplify this potentially complex area, it should be considered whether the risk is being driven by one active substance. If all the active substances within the formulation pass the 1st tier risk assessment with a margin of safety then the need for further assessment of combined exposures and effects will be limited. Further Ecotoxicology guidance.
Please refer to first tier drainflow PECsw for guidance on the calculation of 1st tier PECsw from drain flow.
The simplest way to assess the possible effects from combined exposure is to compare the sum of individual PECsw values with the lowest appropriate RAC from all substances of interest (Equation 1). This is the most simple and conservative approach, because it assumes all substances are equally toxic.
If this 1st tier assessment does not result in an acceptable exposure, the combined exposure in drain flow can be refined to take into account the differences in toxicity and/or relative exposure concentrations of each substance (see Approach 1 and 2 below). Each should result in the same regulatory decision, however, depending on the situation; one approach may be preferable over another.
For metabolites; if a metabolite passes the drain flow assessment at the first tier, it is not necessary to consider it further in the combined assessment. If the active substances produce a common metabolite, then a combined assessment as outlined in Equation 1 is necessary. If the combined metabolites assessment passes at the first tier then it is not necessary to include the combined metabolite levels in the combined active assessment. However, if the metabolite and the active substances go to the higher tier assessment, both active substances and metabolites should be included in the higher tier combined assessment.
PECSW(combined, drain flow) = PECSW(A) + PECSW(B) + ....
Where: PECSW(X) is the 1st tier PECSW(drain flow) for substance X
Compare PECSW(combined, drain flow) to the lowest RAC for all substances.
Approach 1 (Toxic Equivalents Approach)
The simplest way to address the combined risk in a more refined way is to calculate a PECSW for the total combined active substance concentration, taking into account the differences in the relative toxicities of the active substances. This is done by comparing the toxicity end points for the same type of organism. Such an approach may not be suitable for comparing end points from higher tier studies, eg mesocosm studies. Further Ecotoxicology guidance.
Approach 2 (Finney Equation)
For acute assessments, the Finney equation can be used to determine the combined toxicity of the mixture of substances in the first tier drain flow exposure calculation. When using the Finney equation it is important to use the fractions of the substances in drain flow, not the fraction in the original formulation, since the ratios of the substances in the receiving water body can change significantly as a result of drain flow. Further information is provided here.
1/RAC(A+B+...) = f(A)/RAC(A) + f(B)/RAC(B) + ....
RAC(A+B+...) is the combined regulatory acceptable concentration
RAC(X) is the regulatory acceptable concentration of substance X
f(X) is the fraction of substance X in the mixture calculated from:
f(X) = PECSW(X)/PECSW(combined, drain flow)(Equation1)
RAC(A+B+...X) should be compared with the simple additive PECSW(combined, drain flow)derived from Equation 1.
Higher Tier Drain Flow
Higher tier drain flow assessments will be required if the first tier exposure assessment fails. Please refer to higher tier drainflow from webfram and higher tier drainflow from MACRO for guidance on carrying out higher tier drain flow assessments and the scenario years approach.
Combined exposure following higher tier drain flow modelling with MACRO follows a staged approach outlined below. For all stages, if the combined PECsw, drain flow) for each soil/climate combination are less than the lowest RAC, no further exposure assessment is required. The scenario years approach is used where some exceedances occur. If the overall exceedances are <10% overall and <60% for each individual soil/climate combination, then no further consideration is required (assuming higher plants are the most sensitive aquatic species). If the most sensitive aquatic species is not higher aquatic plants, then the acceptable number of scenario years for which exceedances are permitted will be fewer and further consideration from Ecotoxicology on a cases by case basis, will be required.
Combine the annual maximum drain flow concentration for each substance, for each of the 30 simulation years, in each soil and climate combination and compare against the lowest RAC. This assumes that the maximum concentration for each substance occurs at the same time and as such is probably an overestimate bearing in mind the different degradation and sorption behaviour for each substance. If an acceptable risk assessment is achieved at this stage, then no further exposure assessment is required.
The annual maximum drain flow concentration for each substance are adjusted (weighted) to take account of the different toxicities (toxicity equivalents approach, see Equation 2) and the weighted concentrations are then combined in the same way as in Stage 1 and compared against the appropriate toxicological endpoint. If an acceptable risk assessment is achieved at this stage, then no further exposure assessment is required.
If substance A has the lowest RAC:
PECSW(combined, drain flow) = PECSW(A) + [RAC(A)/RAC(B)]* PECSW(B) +....
PECSW(X) is the 1st tier PECSW(drain flow) for substance X
RAC(X) is the regulatory acceptable concentration for substance X
Compare PECSW(combined, drain flow)to the RAC for substance A ie the lowest RAC.
Combine the daily individual drain flow concentrations for each substance, for each of the 30 simulation years and for each of the soil/climate combinations and compare against the lowest RAC. This calculation would allow for the different degradation and sorption behaviours producing a more realistic exposure assessment. If an acceptable risk assessment is achieved at this stage, then no further exposure assessment is required.
The daily concentrations for each substance are adjusted (weighted) to take account of the different toxicities (toxicity equivalents approach, see Equation 2) and the weighted daily concentrations are then combined in the same way as in Stage 3 and compared against the appropriate toxicological endpoint.
If at stage 4 the overall exceedances are >10% or the individual soil/climate scenario years exceedances are >60%, the use may be unacceptable. At this stage Applicants are advised to consider the timing, magnitude and duration of the exposure(s) above the RAC, along with consideration of the extent of the crop in the UK landscape etc.
Webfram is a web-based tool aimed at incorporating variability and uncertainty into regulatory environmental risk assessments using a probabilistic approach. The basic output from the drain flow module of Webfram is in the form of an exposure distribution that accounts for variability and uncertainty. It therefore represents a very different type of exposure assessment compared to the standard deterministic exposure assessments at either the 1st tier or higher tier using MACRO. Approaches to combined exposure assessments using Webfram are under development using the same basic principles as outlined above for other 1st tier and higher tier approaches see higher tier drainflow from webfram.
Metabolites in higher tier drain flow assessment
In theory it is possible that the aquatic environment will be exposed to a combination of active substance(s) and their metabolites at the same time. Whilst it would be possible to treat the metabolite(s) as if they were another active substance for inclusion in the full combined risk assessment, in most cases it will be appropriate to take a much simpler approach.
When either the active substance(s) or metabolite(s) pass the simple first tier drain flow assessment, no further consideration of combined exposure and effects is required. This is because at this first tier the absolute peak occurrence level of either the active substance or metabolite will have been calculated. Since the active substance must degrade in order to generate the metabolite at the peak levels assumed at the first tier, it is unlikely that both substances will occur at the same high levels for the purposes of the combined assessment. The margins of safety associated with the simple first tier calculations are considered sufficient to cover any combined risks from the substances at the lower concentrations that would occur in reality.
The only time that a detailed consideration of combined risks from active substances and metabolites is required is when the substances under consideration go to the higher tier drain flow assessment. At this assessment level the model will be based on simultaneous degradation of parent and formation of metabolites and the combined concentrations are expected to be reflective of actual concentrations in drainage ditches. Combined assessments should follow the stages outlined above.