. 2022 Jan 18;20(1):e07032. doi: 10.2903/j.efsa.2022.7032

Table J.2.

Recommended requirements for performance and analysis of higher tier field studies

Criteria	Exposure parameter
*General considerations/Quality*
A GLP compliance certificate.	Human exposure/DFR/TTR
A GLP compliance statement. When the field phase and analytical phase are conducted by separate facilities, the appropriate documentation for the laboratory sub‐contracted to perform the analytical work is expected.	Human exposure/DFR /TTR
QA statement This should provide inspection dates for the key elements of the study (field and laboratory phases).	Human exposure/DFR /TTR
*Study design*
The study includes a review which shows that the study design used is representative of the scenario to be considered (e.g. currently typical cultivation and application methods in Europe, including demonstration of representative climatic conditions, e.g. with Köppen‐Geiger criteria).	Human exposure/DFR /TTR
Representative application methods and application techniques, according to the current agricultural application practices in Europe. Application equipment, tank volume, water volume, pressure, forward speed etc. should be described and reported.	Human exposure/DFR /TTR
Representative crop activities should be tested, reflecting current agricultural practices in Europe. Activities carried out by workers should be described in detail.	Human exposure/DFR /TTR
The test site is clearly defined, including location and positioning of the sampling points/person being exposed.	Human exposure/DFR /TTR
At least three test sites in different locations to capture variation in working/agronomic practices and environmental conditions would be desirable. A justification for the selection of the locations and the working/agronomic practices used in the study shall be provided.	Human exposure/DFR /TTR
The meteorological conditions must be fully reported. As a minimum, this must include temperature, humidity and rainfall (for worker exposure and DFR studies, information about date, duration and amount of rainfall is necessary).	Human exposure/DFR /TTR
Key experimental data must be reported. As a minimum this should be identification of the plant protection substance, formulation, application rate and crop (BBCH, age of the crop). Sprayer description should also be included.	Human exposure/DFR /TTR
It is recommended to consider the worst‐case intended use for each crop investigated (e.g. maximum application rates; multiple applications using the minimum treatment interval; late growth stage).	Human exposure/DFR /TTR
The timing of the applications should bracket the time frames when re‐entry activities are anticipated to occur, with a focus on the timeframes where higher exposure activities occur. Likewise, the transferable residue (e.g. DFR/TTR) samples should be collected accordingly.	Human exposure/DFR /TTR
Agricultural spray adjuvants should not be used unless they are recommended for the respective product (e.g. in cases where the use of adjuvants is mandatory).	Human exposure/DFR /TTR
Only necessary maintenance products (plant protection products and fertilisers) should be used. These products must not interfere with the chemical analysis.	Human exposure/DFR /TTR
For studies designed to provide estimate of TC values, the exposure measurements and DFR determinations should be done concurrently in the same crop and at the same sites.	Human exposure/DFR /TTR
According to OECD Guideline (OECD, 1997), at least 10 subjects are required for each task performed. It is recommended that a sufficient number of measurements be made in different locations to cover the range of use procedures and conditions, including as an example that variation in harvesting work procedures may be substantial, even within the same crop.	Human exposure
Monitoring of professional agricultural operators or workers (e.g. farmers and contractors) working in accordance with Good Agricultural Practices.	Human exposure
Representative workwear and PPE used should be described and reported.	Human exposure
To measure the exposure of uninvolved persons (e.g. residents and bystanders) to spray‐drift, mannequins (other types of dosimeters are also acceptable if the transferability to humans/mannequins is demonstrated) for adults and children/toddler are to be used (i.e. 2D measurements are no longer acceptable). The body surface of the mannequins should be comparable to that described in 2.4.7. Default surface area of body parts. For the total of the trials, at least ten mannequins are to be used for each distance and group (e.g. ten mannequins each for adults and children/toddler).	Human exposure
Mannequins are to be positioned downhill (if applicable) and downwind direction (at application) of the field plots in order to measure the spray‐drift (i.e. ‘worst‐case’ conditions). Thereby, mannequins are to be set up staggered at different distances from the treated culture (e.g. to avoid a ‘spray shadow’).	Human exposure
At the test site one or several field plot(s) and one control plot should be established. In order to obtain representative samples from a field plot, it must be divided into at least 3 subplots. Replicate sample should be taken from the different subplots of a field plot.	DFR/TTR
The control plot will be positioned upslope (if applicable) and upwind (at application) of the field plots to reduce the potential for contamination due to drift. The separation distance between control and field plots should be sufficient to avoid contamination of the control plot while ensuring that the crop, soil and environmental conditions are the same in field and control plots.	DFR/TTR
Since climatic conditions and growing conditions can influence the dissipation rate, studies should be performed at sites representative of the climatic and growing conditions representative of the intended use areas. The Köppen–Geiger criteria may be useful when considering climatic equivalence. (Note: If the intended use is relevant for the entire EU then representativeness of climatic conditions should be covered by multiple field studies, unless comparability of climatic conditions or ‘worst‐case’ conditions for the relevant crop can be justified, based on the residue guidelines (e.g. SANTE/2019/12752) a differentiation for northern and southern studies for outdoor crops should normally be sufficient).	DFR/TTR (DT₅₀)
Individual studies should be conducted in areas where the slowest dissipation of residue is assumed, i.e. representing ‘worst‐case’ conditions. There should be no rainfall for 24 h before and after applying the product. If the precipitation during the sampling period is higher than the typical precipitation at the field location, the study may not be acceptable for the estimation of half‐lives (DT₅₀). However, this should be decided on the basis of the resulting dissipation kinetics.	DFR/TTR
*Sampling parameters*
The sampling approach should be clearly described and be justifiable, representative and appropriate, allowing for a consistent sample collection. It should include sampling time, sampling interval, distance from application to sampling point, sampling height, foliage type, etc.	Human exposure/DFR/TTR
To verify the application rate, and the amount of active substance loaded and applied per tank, tank mix samples should be taken and analysed. Various sampling techniques can be used, e.g. samples can be taken directly from the spray nozzles; from a tap attached to the tank or directly from the tank. It is recommended to take at least three samples (e.g. at the beginning in the middle and at the end of each treatment). The nozzles must be calibrated at the beginning of each treatment. Other sampling techniques can also be used if these methods are appropriate for analysing the concentration of the spray solution.	Human exposure/DFR/TTR
The active substance, or any degradation products relevant to the risk assessment, should be sufficiently stable under field conditions to permit reliable estimation of exposure and other values.	Human exposure/DFR/TTR
It is recommended that the formulation used in the study should be used for fortification experiments when analytics is assumed to be influenced by co‐formulants (e.g. lower extraction efficiency).	Human exposure/DFR/TTR
Worker exposure should only be measured during re‐entry activities. Workers should enter the treated areas only after the foliage has dried off.	Human exposure
Ideally, the exposure duration for a single measurement of exposure or absorbed dose should be representative of the typical working day. Actual exposure duration is to be measured and it is expected to be around at least 4–5 h, up to or even exceeding 8 h for operators and workers. For certain tasks, however, shorter exposure durations can also be considered (e.g. ~ 2 h for crop inspection and irrigation tasks). Duration of tasks should be given.	Human exposure
In order to measure the exposure of uninvolved person to spray‐drift, the entire plot must be treated with the application technique and application rate specified in the list of intended uses (i.e. not only the outer row of the culture). The application should take place in a growth stage according to the intended uses (Note: in general, data in lower growth stages cover later growth stages, as the growth and the changing density of the foliage can directly influence the spray‐drift).	Human exposure
A minimum of three replicate samples should be taken in each field plot and at each sampling interval. However, more are recommended (e.g. four to six) to provide more robust data and a better estimate of the DFR value (see also Criteria below). Where only the minimum are provided, the representative DFR value is likely to be set at the maximum value observed.	DFR/TTR
Replicate samples are to be taken from the areas of the plant where contact with workers is expected. Different approaches are available e.g. non‐directed sampling where field technicians enter a treated area and sample at their own discretion; the Iwata approach (Iwata et al., 1977) for tree crops where samples are collected at 45 degree intervals around the circumference of each sampled tree and at varying heights in the tree; the planned approach for row crops where investigators develop a scheme that predetermines sample collection locations.	DFR
To characterise dissipation rates of dislodgeable residue (DT₅₀), data should be sufficient to cover several half‐lives (e.g. three half‐lives). Typical sampling intervals are 4 h, 12 h, 1, 3, 7, 14, 21, 28, 35 days after treatment (DAT). If the study involves multiple applications, samples should be taken prior to and after each application on the day of application. It is also suggested that samples are taken in the intervals between the application events at least every 7 days after each application.	DFR/TTR
*Sampling techniques*
Samples should be collected and prepared in the field, if necessary, transported and stored according to OECD 1997 (see also EC Guidance 7029/VI/95 rev. 5).	Human exposure/DFR/TTR
Inhalation exposure should be determined with appropriate inhalation fraction samplers (e.g. personal air sampling). Whole body dosimetry for dermal exposure should be selected. Patch data should not be considered unless uniform exposure can be demonstrated. Absorbent gloves method should be prioritised over hand wash or rinse methods unless efficiency of these methods is determined.	Human exposure
For sampling and extracting of leaves, the protocol by Iwata et al. (1977) should be followed. In short, leaf samples should be gathered with a mechanical leaf punch device (equal to ~ 200 cm² single side, or 400 cm² double‐sided). Some crops do not lend themselves to the use of a leaf punch (e.g. some ornamentals and conifers). Determinations of leaf sample surface areas should be addressed on a case‐by‐case basis. Ideally within 4 h and always within 24 h leaves, samples should be extracted by washing the surface of the leaf with a water/surfactant solution (e.g. a 0.01% dioctyl sulfosuccinate, sodium salt solution). The use of organic solvents should be avoided as they may carry surface residue into the leaf tissues or extract penetrated residue. Non‐extracted samples should not be stored freeze or with dry ice.	DFR
For measuring the amount of transferable residue on turf, the protocol by Fuller et al. (2001) should be followed (Modified California Roller Method). In short, a 100% white cotton percale sheet (0.68 m²; 0.58 m² sampling area) is securely attached to a PVC frame and placed on turf‐covered ground. To collect residue, a weighted roller is pushed five times over the sample area. Visible debris (e.g. grass clipping, thatch, granules) are carefully removed before the cotton cloth is placed in a suitable sample container and sent to an analytical laboratory.	TTR
*Sample storage*
Samples should be stored in a manner that will minimise deterioration and loss of analyte(s) between collection and analysis. Sample storage time should be recorded. The study investigator is responsible for demonstrating the stability of the samples under the storage duration and conditions used (for further details see ‘quality assurance/quality control’ below).	Human exposure/DFR/TTR
*Quality assurance/quality control (pre‐field laboratory considerations)*
SANTE/2020/12830, Rev.1, 24. February 2021 should be used when generating and reporting methods of analysis. Any analytical method used to analyse samples from field studies needs to be sufficiently validated regarding all parameters in accordance with the available guidance in force.	Human exposure/DFR/TTR
The stability of analyte(s) should be determined on appropriate sampling matrices under storage conditions similar to those anticipated for storage of field samples. This study is optional if the field recovery samples are stored and analysed with the actual field samples. Storage stability samples should include preparation and analysis of at least three blanks, three low‐level fortifications and three high‐level fortifications. Samples should be stored under the same conditions as planned for field samples and the study duration should be ≥ the likely storage duration of the field samples. These can be done before or in conjunction with the field phase.	Human exposure
*Quality assurance/quality control (in field considerations)*
Valid field recovery data (and thus, the ability to accurately fortify field recovery samples with a known amount of mass ingredient) is essential to the study, to allow the experimental data to be corrected for losses that occur during all phases of sample collection and analysis.	Human exposure/DFR/TTR
Ideally, a complete set of field recovery samples should be collected at each site and on each day of sampling. If it can be shown that the field recovery does not change over the sampling period, then in the case of DFR studies, a complete set of field recovery may not be required for each sampling day. It may be acceptable to collect a single set of field recovery samples if the environmental conditions are similar on each day and/or at each site.	Human exposure/DFR/TTR
A complete set of field recovery samples should include 3 (or more) samples, each blank control samples, low level fortification and high level fortification. The high and low fortification should cover the range of the anticipated level of chemical on the respective matrices. If the highest expected level is more than 100X the lowest spiking level, it is recommended that a midlevel of fortification is included.	Human exposure/DFR/TTR
Field recovery samples should be handled using the same procedures as the actual field samples. They should be collected, handled, transported and stored concurrently with actual field samples. Additionally, field recovery samples should be analysed concurrently with actual field samples to account for residue losses during sample extraction and analysis.	Human exposure/DFR/TTR
Field recovery results less than 95% should be used to correct the results of field samples. However, if field recoveries are below 70% they must be technically justified. Recovery results greater than 95–100% should be noted but not used to correct the data. Actual field samples should be corrected with the closest spiking level obtained from the fortified samples.	Human exposure/DFR/TTR
Blank control field samples indicate whether contamination of the field recovery samples has occurred. The report should provide a valid explanation for the occurrence of residue in control samples when results are higher than 30% of LOQ.	Human exposure/DFR/TTR
Travel recovery samples should be shipped and stored with the field recovery and actual field samples. Travel recovery samples are optional and reflect losses which may occur during shipment and possibly storage. These samples are not used to correct actual field samples but may be useful to determine where losses have occurred.	Human exposure/DFR/TTR
*Quality assurance/quality control (post‐field laboratory considerations)*
Laboratory recovery samples are analysed in the analytical laboratory concurrently with the actual field samples to determine the recovery efficiency of the analyte(s) from the respective matrices. It is recommended that the field recovery samples are used as concurrent laboratory samples whenever possible. When used in this manner, field recovery samples can be used to correct actual field samples for losses that occur both in the field and in the laboratory.	Human exposure/DFR/TTR
*Presenting and analysing results*
Raw data must be provided as well as detailed observations on operators and workers.	Human exposure/DFR/TTR
Results should be reported as absolute values (μg or mg active ingredient per sample) as well as mg or μg active ingredient per kg active ingredient applied.	Human exposure/DFR /TTR
If residues are below the limit of quantification (LOQ) and above the limit of detection (LOD), they should be reported as below LOQ (e.g. < LOQ), but they should be considered as LOQ.	Human exposure/DFR /TTR
If residue are below the limit of detection (LOD), they should be reported below LOD (e.g. < LOD), but they should be considered as LOD.	Human exposure/DFR /TTR
A justification for excluding outliers should be clearly stated in the study report and summary text. Although outliers may be excluded from the analysis if well justified, for technical or procedural reasons e.g. part of the sample extract was lost (note a statistical test alone is not sufficient justification), the data must nevertheless be presented. It should be noted that results treated as outliers should include spuriously low values as well as high values. Expert judgement might ultimately be applied on a case‐by‐case basis to increase values compensating for deficiencies in the quality of the study. Justification for choosing a certain increased value should be provided and fully documented in such cases.	Human exposure/DFR /TTR
Statistical analysis is appropriate and must be provided addressing the variability of the study results.	Human exposure/DFR /TTR
Exposure values must be related to a single intake route (e.g. dermal and inhalation exposure should not be combined).	Human exposure
Suitable data form for model development: separately measured hand, head and body exposure; separate measurements for the different activities (mixing/loading, application, cleaning, etc.) and for inner and outer dosimeters.	Human exposure
Exposure is reported as the amount of active ingredient the individual person receives; amount as excreted from the body (urine samples) will only be used as supplementary information.	Human exposure
When using results of exposure measurements, considering that a sample size as low as 10 subjects is allowed by the respective guideline (OECD No 9, 1997), due consideration should be given to the statistical analysis of such small data set for the purpose of acute risk assessment	Human exposure
Correction for background concentration should not be performed. If the worst‐case intended use for each crop investigated is considered, no correction is needed even in the case of multiple applications. If residue are found before the first application, then consideration should be given to use determined DFR/TTR value without correction or rejecting the study entirely.	DFR/TTR
The highest DFR/TTR value should be used if only 3 replicate samples were taken from a field plot per sampling interval. When ≥ 4 replicate samples are available per field plot and per sampling interval, the use of a mean might be justified. However, if there is significant variation between these replicate samples (i.e. the standard deviation is equal to or larger than 25% of the mean) the standard deviation should be added to the mean value.	DFR /TTR
DT₅₀ values can only be derived from acceptable DFR studies, therefore all validity criteria for DFR studies must be taken into account. For estimation of DT₅₀ the standard procedures recommended by FOCUS (2014) should be followed, including e.g. the general procedure and the assessment of the goodness‐of‐fit. Since calculated DT₅₀ values are used in models for exposure assessments (e.g. determination of the MAF), single first‐order kinetics should generally be used (EFSA, 2014c). More recommendations on the fitting of DT₅₀ data and the statistical validation of the fit can also be found in the EFSA Technical Report (2019).	DFR /TTR (DT₅₀)
In case of multiple applications, when a field study is available, but not considered sufficient for the specific DFR estimation, the following should be considered for the DT₅₀ derivation: a) If appropriate data (adequate sampling points) in between the different applications are available then: – each application (and the following points until the next application) can be considered as a standalone trial – a DT₅₀ is calculated for each application and then the geomean (GM) of the calculated DT₅₀ values, – depending on the amount and variability of the data, use either the GM or the highest DT₅₀ value calculated as a worst case. b) If the sampling points for the in between applications are not adequate for the calculation of single DT₅₀ values, the data set after the last application is to be used.	DT₅₀