Plant protection products (PPPs) are in most countries extensively regulated and a huge bundle of required studies needs to be submitted to receive a country registration.
Before a plant protection product is submitted to an authority to be registered, it undergoes up to 10 years of testing and safety evaluation by Bayer. Before submission, Bayer evaluates the tests and makes risk assessments. Once we are satisfied that it is a safe and effective product, we submit all our data to the authorities. They can spend up to 2 years reviewing and making their own safety assessments before granting registration. After a product is registered, authorities continue to monitor the use of the product to ensure continued safe use. In many countries, authorities do a complete re-review of the product data every 10-15 years to be confident of the product’s safety, often asking for updated or extended data.
In fact, safety standards and requirements have never been as high as they are today.
After registration is granted:
Authorities (Monitoring)
After registration, authorities frequently monitor for residues of plant protection products on domestic & traded goods. Foodstuffs that have residues above the maximum allowable limit are not allowed to be sold and can be either destroyed or sent back to the country of origin.
Farmer & Suppliers
Farmers and suppliers use plant protection products according to product labels (recommendations made by Bayer and endorsed by the regulators) and keep records of all treatments. Finally, Bayer interacts with farmers and other users to ensure the product is being used safely (i.e. as recommended by Bayer).
A lot of different studies need to be provided to grant a registration for a plant protection product. Besides safety studies for the environment, ecosystems, and workers also the safety of consumption of treated food is an important area of investigation. Besides trade enabling and support activities, the Bayer Dietary Safety department focuses on the safe use of plant protection products and their residues in food.
The studies steered by this department investigate the type and levels of residue that humans or animals might be exposed to when they consume foods derived from commodities treated with a plant protection product.
Traces of crop protection products or their metabolism/decomposition products might still be present in or on food at harvest. These are called residues.
To evaluate the exposure of humans to crop protection products, their residues in crops for human consumption are investigated.
Before a plant protection product can be approved for use in agriculture, its residues are measured in all types of food that you can buy in a grocery store:
- In raw food
- In foods grown in fields where pesticides have been used previously (rotational crops)
- In foods that have been processed in any way (cooked, peeled, etc.)
- In foodstuffs from animals (eggs, milk, meat, etc.) that have eaten treated crops
Types of food
Primary Crops
These are the crops that have directly been treated with a plant protection product. Residues from that treatment are measured.
For the tests, the products are applied to relevant crops in line with Good Agricultural Practice, and this is repeated in 8 to 24 individual trials (learn more).
Residue Trial Planning
Testing does not necessarily need to be done on each crop. In international guidelines a system of crop grouping is given, along which we can extrapolate from one crop to another or to a whole group. For example, in the EU residues of orange can be extrapolated to the whole citrus group or apple can be extrapolated to pome fruits.
With the trials the agricultural worst case needs to be covered. So, the GAP parameters theoretically leading to the highest residues are chosen. Highest application rates, maximum number of applications and shortest pre-harvest intervals or latest growth stages at application, are probably the most important factors but also the intervals between applications or the spray concentrations have a certain influence on the residues.
Looking at the crop varieties we also need to choose the most critical ones so for example cherry tomatoes instead of normal-sized ones, open-leaf lettuce instead of a closed-head variety, or hanging strawberries instead of traditionally grown ones.
Also, for seasonal varieties like winter or spring wheat, we need to choose the more critical one.
We also need to consider if the intended crop is a major or a minor crop. The definition for a major crop in the EU is dietary intake contribution above 7.5 g and/or a cultivation area above 100 000 ha and a production of more than 200 000 t/year. For major crops, a higher number of residue trials per indication needs to be conducted.
Often also uses outside the EU are to be covered. There different crop grouping and extrapolation systems are used.
Approximately 50% of the trials are usually planned as harvest trials meaning sampling takes place only at day zero (day of application) and at harvest.
The second half of the trials are planned as decline trials. With this sampling regime, additional sampling events take place between day zero and harvest with the aim to show how the active substance declines, and individual metabolites are formed and decline.
There is one additional sampling regime, which is only applied in special cases named reverse decline. With this sampling regime parallel plots are treated at different PHIs and then harvested at the same time and therewith show residue levels in commodities harvested at exactly the same stage of ripeness. This sampling regime only makes sense in certain crops. It is used when detailed understanding is needed on the relation between PHI and residues.
Samples of appropriate food and feed products are taken at various intervals and are analyzed for their residue levels (learn more).
The analytical work for our residue studies are done in special internal or external residue analysis laboratories. Residue studies intended for dossier submission need to be done in a certified laboratory under the provisions of GLP (Good Laboratory Practice).
With residue studies the analytical specialists perform trace analysis, meaning they quantify residue levels of 5/1.000.000.000 part of the sample (0.005 mg/kg) or below. This is comparable to a determination of four lumps of sugar in an Olympic swimming pool. The only difference is that the pool is not filled with water, but it is filled with organic material.
Residue analysis is mostly done via HPLC (high-performance liquid chromatography) with mass spectrometric detection (MS or MS/MS). The HPLC separates the different ingredients in the sample whereas the mass spectrometric detector selectively detects specific compound masses. After the chromatographic separation, only some compounds enter the detector at the same time. There these molecules are ionized. After ionization, the different compounds are split according to their mass to charge ratio by a magnetic field. The detector itself cannot differentiate between the different masses. Via fast modulation of the magnetic field, the different masses are detected one after another. As this is trace analysis only a few molecules of the analytical target reach the magnetic field, and the detector needs to continuously monitor the target mass so as to not miss a peak while scanning the other masses. Therefore screening (looking for everything present at the same time) is not possible in trace analysis.
As the decline of residues during storage could lead to an underestimation of the residue values in the samples, storage stability data has to be generated. This laboratory study can start as soon as the analytical method is available. Not every crop needs to be investigated. The matrix groups which need to be covered are described in international guidelines.
For this study type untreated sample material is "spiked" with all components of the residue definition separately. The samples are then placed in the freezer in the same way as normal residue samples. Samples are thawed and analyzed at several intervals up to 2 years of storage.
If the stability of the analytes cannot be appropriately demonstrated the storage time of samples from residue trials may have to be adopted.
Afterwards, the data are evaluated to better understand the residue behavior of the pesticide.
When a product is registered, all the GAP information is included on the product label. Farmers using the product must comply with the instructions on the label.
But how do you know which residues to look for?
Residues in plants are first investigated through metabolism studies conducted under controlled greenhouse conditions.
In these studies, biological systems (such as plants, animals, and soil) are exposed to a plant protection product. Scientists then examine the metabolites — these are any potential breakdown products that occur during metabolism (learn more).
As soon as the plant protection product is taken up by the plant the natural detoxification processes in the plant start to modify and degrade the molecules. Via these processes, different metabolites and degradation products of the active substance are created over time and for example sugar conjugates or even more natural compounds. Since residue analysis is a trace analysis for which you need to know the exact chemical structure of the different residue components, scientists need to find out exactly which metabolites are generated by the plant.
For this purpose, the compound of interest is radiolabeled (by the inclusion of a radioactive isotope into the molecule, usually 14C) in up to three different positions. Considering the intended GAP the labeled compounds are applied onto plants placed in a container. The plants are grown in the greenhouse and harvested at different growth stages. The remaining residue is extracted from the resulting sample material and the extracts are subject to chromatography with radio-detection. The generated compounds detected with this procedure are separated and identified as far as possible. Metabolites, which occur at high levels in different plant parts or are of possible toxicological concern might be taken up in the residue definition for data generation. The metabolites of this residue definition are then synthesized and certified before the analytical laboratory can start work on method development.
Another important piece of information derived from these studies is the extractability of the metabolites. This is important to know as residues in plant matrices do behave differently than freshly spiked metabolites which are used for method development and validation. Therefore, the analytical methods use extraction procedures which were identified to be effective in the metabolism studies.
With this information, scientists can identify the main residue components that need to be monitored during field residue studies (learn more).
As soon as the data from the metabolism studies are available the metabolism expert and the residue expert jointly define a residue definition for data generation.
For these metabolites, an analytical method is developed and is used for all plant residue trials as well as for the storage stability studies.
Based on the results of the field residue trials and the toxicological considerations, the residue definition for risk assessment (the components included in dietary risk assessment evaluations) is proposed by Bayer and confirmed or challenged by the authorities.
For enforcement purposes, which means for monitoring of the MRLs, the residue definition is usually defined as a parent plus a commonly present major metabolite or, for substances where the parent is the major component in the residue or where no residues are to be expected at all the residue definition for monitoring might be a parent only. For the metabolites included in the residue definition for monitoring independent laboratory validations and/or multi-method testing for example for the Quechers method take place.
If, during the evaluation of a dossier the residue definition changes; for example, a regulatory agency is of the opinion that a metabolite should be considered for risk assessment which was not part of the residue definition for data generation (meaning residue data for this metabolite are not available) then risk assessment cannot be finalized. Therefore, the experts do their evaluation carefully, according to scientific principles, trying to anticipate and address questions or concerns authorities might have.
Substance-related study information for primary crops can be found in the summary documents for residue studies on our website.
Rotational Crops
Farmers often rotate crops to preserve the quality of their soil. This means that they plant different types of crops in the same field in succeeding seasons.
Rotational crops are crops that have been planted in a field where a plant protection product has been applied to a previous plantation. For example, a farmer plants soybean and treats them for insects, later he plants corn in the same field. Will the corn have residues of the insecticide used previously on the soybean crop?
Despite not having been treated themselves, rotational crops are tested for residue levels that they may have been taken up from the soil from past plant protection product use (learn more).
After harvest, a field may still contain residues of the used product either in the soil or in plowed in plant parts from the preceding crop.
The potential for the transfer of these residues to subsequent cultures needs to be investigated.
As these residues are taken up via the soil the nature of residue may differ from those of the primary crop.
Therefore, the nature of residue in rotated crops is determined in a confined rotational crop study (CRC study) with radiolabeled material labeled in as many positions as necessary. This study is the basis for the residue definition in rotated crops and consequently, this may differ from the residue definition in primary crops.
If with the CRC study residues ≥ 0.01 mg/kg are found in food or ≥ 0.05 mg/kg in feed field rotational crop studies need to be initiated as a higher Tier study.
These field rotational crop studies are done on non-labeled compounds.
If, in this limited field rotational crop study, the trigger values are reached a third-tier study may be necessary. For every tier, up to 36 months are needed to finalize the study. In case this third tier is necessary the timeline is critical for developmental compounds. Additionally, complexity increases significantly with every tier. Up to 60 trials might be necessary for a third-tier study.
Also, with rotational crop studies, the worst case should be covered. Therefore, application needs to be done at the maximum annual dose rate to bare soil. For slower degrading compounds also the soil accumulation plateau level might need to be taken into account.
For confined rotational crop studies at least 3 crop groups need to be tested with one representative crop per group. The number of crops to be investigated increases with higher-tier studies.
For every crop 3 plant-back intervals need to be tested.
One for plants seeded at 7-30 days after application representing crop failure, for 60-270 days after application representing a second crop in the same year, and 270-365 days after application representing the next year of cultivation.
The results of these studies might be used to set MRLs on rotated crops.
These tests are done for plants seeded from 30 days until up to one year after application of the pesticide.
Substance-related study information for rotational crops can be found in the summary documents for residue studies on our website.
Processed Foods
Many foods are not only eaten raw, but also in a processed form, for example, fruit or vegetable juices, or ketchup containing tomatoes, beer made from barley, and oil made from soybeans.
To assess what happens to residues during processing, scientists process raw agricultural commodities like tomatoes or cereal grain using typical industrial or household practices, for example, frying, boiling, baking, fermenting, or pressing. The final products are then analyzed for their residue content (learn more).
The aim of residue studies is to determine the level of residues in Raw Agricultural Commodities (RAC).
Many harvested commodities undergo a processing step such as fermenting, smoking, drying, cooking, or brewing before they are consumed.
The aim of processing studies is to determine if a residue might be concentrated or diluted through the processing procedure.
The result of processing studies is evaluated via the ratio of residue levels in the processed product compared to those in the RAC. This ratio is called transfer factor and may be used as a multiplier in dietary risk assessment.
In a processing hydrolysis study, the effect of model processes on the nature of the residues is investigated in the metabolism laboratory. The results of this may have an influence on the residue definition for the analysis of the processed samples.
Raw agricultural commodities (RAC) from residue studies are subjected to typical processes representing household or industrial practice for the respective RAC. The residues cannot simply be spiked to sample material as it is done for storage stability studies because age inherent residues behave differently to spiked residues during processing. The final processing products and some by-products are analyzed for their residue levels.
The processing types to be covered and the sample materials to be investigated are listed in international guidelines.
Often residue levels in some processed commodities are very low and therefore no meaningful transfer factors can be calculated. To compensate the RACs used for processing are often applied at exaggerated rates.
Substance-related study information for processed food can be found in the summary documents for residue studies on our website.
Animal Products
Animals may be fed with crops that have been treated with a plant protection product. We investigate all the residues that could be transferred to animal products such as milk, meat, and eggs.
Scientists, therefore, conduct studies where animals ingest the plant protection product and/or its decomposition product at levels that are relevant to normal farm animal feed. The resulting animal products are then analyzed for their residue levels (learn more).
If residues are found in feed items like straw, forage, or apple pomace the effects of feeding those residues to food-relevant animals must be examined. With this type of study, the residue definition for the analysis of animal tissues is derived from the relevant farm animal metabolism studies.
Observed residue levels in feedstuffs from field residue trials are filled into theoretical animal diet tables derived from national or international guidelines ("feeding tables"). The tables include typical worst-case dietary consumption of various commodities for beef and dairy cattle, poultry, swine, and sheep. From this, a "dietary burden“ for farm animals is calculated.
A dietary burden above 0.004 mg/kg bw/day will trigger the conduct of animal feeding studies.
For the feeding study, the calculated worst-case dietary burden is used as 1x level, three feeding levels are required. We usually do the 1x; 3x and 10x levels. Sometimes for certain reasons an additional feeding level can be added.
In such studies, three cows or 10 hens per dose group are used plus at least one untreated animal and an additional depuration dose group. This depuration group is included to investigate the decline of residues in animal tissues after the end of dosing.
With such studies, the animals are dosed over a certain period of time. During the in-life phase samples of milk or eggs are taken usually twice a day. After euthanization of the animals' samples of meat, fat, liver, kidney, and other tissues are taken and analyzed according to the residue analytical method for animal commodities. The determined residues in tissues and products can then be included in the human dietary risk assessment and MRLs for animal tissues, milk and eggs can be proposed.
Besides these residue studies in farm animal products also residues in honey are investigated (learn more).
In October 2018 the EU COM published the final version of the “Technical guidelines for determining the magnitude of pesticide residues in honey and setting Maximum Residue Levels (MRL) in honey”.
The guidelines will apply as from 1 January 2020, therefore applicants currently generate experimental residue data on honey.
The document gives guidance to evaluate the necessity for such a study and discusses the derivation of a residue definition in honey.
And it also gives some experimental guidance. Within Bayer, the studies currently are run externally with bee experts as, so-called semi-field tunnel studies. To ensure that the bees are adequately fed during the course of the study, the model crop phacelia is used.
The results also are included in the dietary risk assessment (intake of honey according to intake figures) and will be used for the setting of an MRL in honey.
Substance-related study information for animal products can be found in the summary documents for residue studies on our website.
Ready for a surprise?
Did you know that plants and other food ingredients can be harmful if consumed raw or in large amounts?
Rhubarb leaves are inedible as they contain toxic anthraquinones |
Coffee contains caffeine and other chemicals that can cause heart and nervous system problems. |
Raw cashew nuts contain urushiol, which is a toxin. They must be cooked before eating. |
57g of salt can be deadly to a small child. |
How safe is my food?
Your food is safe.
With the information gained in the described residue studies and official consumption data (government gathered data on what people eat in a country or region), scientists calculate the theoretically possible highest intake of residues with their daily diet for different population groups (e.g. adults, toddlers, elderly...) and different regional habits.
In another bundle of studies, the susceptibility of animals is investigated to determine which amounts of a plant protection product or its degradation products can be tolerated without negative impact to different species. The amounts determined to be safe are divided by certain safety factors (typically 100) and then established as official safety limits. This means the dose allowed to be consumed is 100 times less than the dose that caused no observable harmful effects (NOAEL) in animal tests.
Scientists then compare the determined maximum intake by diet with the established safety limits. Only uses which do not compromise the established safety limit can be approved. Compliance with these safety limits is strictly monitored at regular intervals by government authorities.
Authorities’ Role
Registration authorities evaluate all processes happening before registration. Then, if a product is deemed acceptable — and ONLY then — they publish the official MRL.
This official MRL is a legal limit meaning that food containing residues above the official MRL are not allowed to be traded. Such food commodities have either to be sent back or to be destroyed (learn more).
Depending on the climatic zone, the soil, and other conditions the GAP for a product might need to be adapted to each country. Every country is setting its own MRLs based on trials relevant to its national GAP. Additionally, every authority decides which residue components need to be included when an MRL is calculated. Therefore, even though the OECD MRL calculator is globally used as a calculation tool for MRLs, in different countries different MRLs for the same crop/active combination might be set. Bayer intensively tries to harmonize the MRLs globally but in some cases, these efforts fail. In this case, the different MRLs can be a trade barrier. If a farmer in Brazil grows a crop according to Brazilian GAP and in compliance with the Brazilian MRL which is higher than the EU MRL, he will not be able to export his crops to the EU. Therefore, Bayer is working together with local grower associations to make them aware of actual or upcoming trade barriers and support them in solving these problems.
Public and NGOs pressure forces supermarkets to require residues substantially lower than the MRL which is the official measure for a legal product. This is a problem for growers because they need to deliver food at that lower residue level although the MRLs are based on the recommended GAP. These required lower levels are called “secondary standard”.
To support the growers as our customers Bayer conducts trials to determine the GAPs needed to fulfill secondary standards. This is a tricky issue as too low application rates foster resistance development. Therefore, it might be difficult to recommend the secondary standards for some actives.
These trials are not always conducted and reported according to the same level of detail as we do for the guideline trials. For example, these trials do not need to be done under GLP.
These trials are not for registration purposes.
Remark: A MRL is not a safety limit, the safe limit is at least 100 fold higher!
Exceedances of an MRL is not synonymous with a health risk. Quite often the risk assessment calculations revealed that also higher MRLs would be possible, but governments want the MRL levels to be only as high as needed to cover the recommendations for the intended use.
Can you imagine eating 850 apples in one day? Although this is a typical example, the numbers shown are not always this high. But large safety factors are always included in dietary risk assessment to ensure that the crop protection residues that may be found in food will not pose a risk to the consumer.
So, what about food safety?
Farmers must comply with Good Agricultural Practice (GAP), following a basic principle of using crop protection: As little as possible and only when necessary. Also, the potential residues on harvested crops are regulated by maximum residue levels (MRLs).
This ensures the safety of your food
Do I have to do something?
When it comes to residues in food, there is nothing you need to do, because it is the job of professionals to keep your next meal safe.
But there are some things that are always good to consider while handling raw food to follow general food hygiene and nutrition rules.
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Wash raw foods under running water. This allows the reduction of surface impurities, such as dirt, bacteria, or residues |
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Dry produce with a clean cloth towel or paper towel where possible. |
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Scrub firm fruits and vegetables, like melons and root vegetables |
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Eat a variety of fruits and vegetables. |