Chapter 30

Registration of Plant Protection Products: Comparison of the U.S. and EU Models

Héctor F. Galicia1 and Ronald J. Breteler2

1Springborn Laboratories (Europe) AG, CH-9326 Horn, Switzerland 2Springborn Laboratories Inc., 790 Main Street, Wareham, MA 02571

Registration of plant protection products (PPPs) is going through major changes world wide. The European Union (EU) and the North American Free Trade Association (NAFTA) pursue harmonization of their registration requirements, e.g., efforts in the EU have resulted in the 91/414/EEC Council Directive for the Registration of Agrochemicals. However, success is limited, since only one list of PPPs has been published and its assessment has been delayed by about 4 years. In the Americas, with the passage of the US Food Quality Protection Act (FQPA) in 1996, the concept of a uniform "reasonable certainty of no harm" standard and newly adopted risk assessment criteria will require more than 8,000 tolerances to be reviewed over the next decade. In 1996, the NAFTA technical group for pesticides agreed to pilot joint reviews of applications to register low-risk pesticides. The harmonization procedure must take place at different levels to achieve its objectives. A comparison of the EU and the U.S. models points out some of the factors that ought to be taken into account in the process of mutual acceptability.

Regulatory schemes have been designed to reduce to a minimum the risk that use of man made products represent to individuals. Pressure on government institutions is driven by technological advances and increased public awareness and thus a new perception of risk (7). Legislative and regulatory assumptions made years ago are repeatedly challenged as technological advances allow more sensitive measurement of toxic substances to be made. On occasion, novel risks appear, such as, endocrine disrupters and genetically modified food. As the use of science in policy arenas

© 1999 Amer ican Chemica l Society 253

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increases, there is a corresponding pressure to enact laws that keep pace with the science upon which the policy is based.

This process has taken place in several countries, and it has resulted in national regulatory law. Globalisation processes and the advantages of the creation of free trade zones, e.g., the EU, NAFTA and MERCOSUR, that have taken place in recent years have promoted the unification of nations having different national regulatory laws. Efforts to harmonize the regulatory procedures are reflected in the 91/414/EEC directive, which aims to regulate the registration and re-registration of new and existing plant protection products (PPPs) in the EU. Similar trends have been observed in North and South America and in Asia. In North America, NAFTA started a program in 1996 for member states to come together to develop requirements and or adopt those already in existence for the regulation of PPPs.

The EU harmonization experience started four years ago and the progress made is a matter of controversy. It is certainly accepted among state members that within the EU a high level of understanding and cooperation have been reached. On the other hand, the objectives set in 1991 have not been fulfilled and still several issues, such as, data protection, remain open to discussion.

The following sections compare the EU and the US regulatory systems and point out at which levels harmonization is possible at the scientific level and at which levels political decisions should take over. Harmonization within the EU and NAFTA ought to be the prerequisite to global harmonization between the two regulatory systems.

Mutual Acceptability

The road to mutual acceptability can be smooth or bumpy and straight or winding. The ease of traverse strongly depends on the similarities and differences of the different regulatory systems being considered. Identification of the likely obstacles in this road will facilitate an analysis as to their potential contribution to mutual acceptability.

The following factors are proposed to be essential in a harmonization procedure and thus should be given high priority, though no claim is made as to the completeness of the selected items. The factors can be of a political and of a scientific nature.

Regulatory Basis: Risk Perception and Legislation. For practical purposes, the discussion is limited to the EU and US regulatory systems; other countries' systems will be discussed in detail in other chapters in this book. Harmonization is certainly a world wide process and thus in Asia, although the Japanese regulatory system is very similar to the EU and US systems, the JMAFF only decided in 1997 to ask for GLP studies for their own reregistration program.

Most of the environmental laws and regulations can be postulated to rest upon a single often non-stated concept, namely the negative default (2). This means that for any given environmental risk, it must be assumed that the worst case scenario will happen, and then an attempt has to be made to prove that a less severe situation will

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actually prevail. In agriculture, the application of a PPP will have effects on the pest(s) to be eliminated or controlled. The non-target crops and organisms are then assumed to be protected from harm. The producer and the formulator of agrochemicals will be asked to prove that at the intended use rate, and given a worst case scenario, the risk involved will be below any unacceptable exposure level.

In order to perform an environmental risk assessment, it has to be accepted that absolute certainty cannot be attained if costs are to be kept at a reasonable level. Present regulatory systems, e.g., EU and US, rely on the premise that it is not possible to give 'proof of zero risk existence', i.e., an absolute zero risk in the use of PPPs. By the same token, the concept of 'zero tolerance' is automatically excluded from present agricultural practices. The latter concept would imply zero use of pesticides in agriculture (no exposure) and thus a zero risk. Integrated Pest and Crop Management practices (IPM and ICM, respectively) are steps being taken in the direction of attaining lower risk. An additional step in the zero tolerance approach is biological control of pests, and the ultimate step is the zero use of PPPs as envisaged by the so called 'biological' (organic) growers. Conseq sntly, a regulatory system is self-regulating by the need to make decisions with the highest certainty possible to assure minimal risk. To do this, governments rely on risk assessment, on the one hand, and the cost that an agrochemical company can bear in preparing the data package, on the other. The concept of reducing the use of PPPs so that the risk decreases to acceptable levels has taken the form of mitigation measures, i.e., risk management. A thorough essay on alternative approaches and the extent to which each approach may be useful can be found in (5).

Risk assessment consists of a) hazard identification, b) dose-response assessment, and c) the actual environmental risk assessment. Hazard identification is the process of identifying which living being or environmental compartment will negatively be affected by the use of a PPP.

The dose-response assessment is necessary to define the likelihood of an effect to be observed at a higher concentration or an increased exposure. Finally, the environmental risk assessment deals with the associated probability that a substance causes damage and attempts to predict the extent of this probable damage. An additional complication is the relationship between the risk in question and other unknown risk factors, as well as the risk within a selected habitat, e.g., synergy or effect in the population dynamics.

Based on the above, a better approach to "risk assessment" would be a "harm assessment", which implies having complete and adequate data, and thus an accurate assessment of the harmful effects caused by a PPP could be conducted. Consequently, neither overestimation nor underestimation of the toxic effects could take place. The cost of obtaining (if at all possible) such information is exponentially high, and the time needed to do so probably will be too long for practical purposes. It follows that regulatory agencies are confronted with making decisions from the results of risk assessments with large associated uncertainties. The mistakes that may take place will be made either when defining the hazard or the dose-response relationship. For hazard assessments, false positive and false negative mistakes can be made. The former

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occurs when a toxic effect is wrongly attributed to a substance, and the latter, when a substance is not attributed a toxic effect although it affects one.

In assessing the dose-response and estimating the need of regulation, the error involved can be defined as overregulation or underregulation of PPPs. Overregulation takes place when a PPP is regulated in accordance with a particular statute too severe for the kind and degree of harm it might cause. The PPP may cause no harm or much less harm than the regulatory authorities may have thought. On the other hand, underregulation will occur when a substance is regulated under a particular regulatory scheme to a lesser degree than it should have been.

A system based on making scientific judgments only when all the sufficient facts are available so no mistakes are made will be inherently slow. Efforts such as these will avoid mainly false positives although false negatives are logically of greater importance.

The US Food Quality Protection Act (1996) (FQPA) (4) adopted a standard with the concept of "reasonable certainty of no harm" and with newly adopted risk assessment criteria. This legislation acknowledges the problem of achieving a 100% certainty, mentioned above, and thus proceeds with a less stringent regulatory system. In this respect, the EU and US systems are following similar objectives, and consequently, they may be considered as comparable at the present time. An effort must be made to develop joint concepts in their assessment models since these models are the fundamental principles in their regulatory thinking. It is essential that their definition of scientific uncertainty and the reasonable certainty of no harm remain similar, otherwise mutual acceptability would become unattainable.

The fact that the EU and US approaches are similar can be confirmed by several recent initiatives between the EU and the US to exchange knowledge and to establish working groups in all disciplines involved in the regulatory process. The experience gained by the US EPA during the reregistration of old pesticides was certainly taken into account by European authorities (5). It can be concluded that the present regulatory system and approach are themselves not in question; alternative systems are rarely discussed. In the Food and Drug Administration (FDA) regulatory system, recent proposals for an alternative approach have been issued (6).

GLP in the Regulatory Process. Taking into account the previous discussion, an improvement was achieved when it was decided to establish a guarantee for integrity and quality in data packages, and the process is well under way but is not yet complete. The implementation of the GLP principles inherently reduced the uncertainty in the quality of the data submitted, and thus in the risk assessment process, i.e., reducing the likelihood of false positives and false negatives. In principle, an overregulation did not take place because of the introduction of the GLP standards since the risk was reduced without increasing the number or complexity of studies needed but rather increasing the quality of the data collection in the studies themselves.

Both the EU and US regulatory systems, aside from some exceptions, require GLP studies. In the EU not all studies submitted to evaluate a substance will have been performed according to the GLPs; however, for new active ingredients, all

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studies will have been conducted under GLPs. In the Americas, with the exception of the US and Canada, there are no definitive GLP programs; however, there are initiatives to implement them. The absence of these programs obviously slows down the process of assessment of PPPs in the Americas, and more importantly, it may prevent harmonization and the implementation of uniform principles within NAFTA and between the US and Canada and other nations in the American continent. Alternative roads, i.e., recent efforts to aid international harmonization through ISO guidelines will be addressed in this book. At this stage, it is apparent that the road to mutual acceptability is to pass through the GLP crossroad.

The publication of the revised OECD GLP guidelines (7), prepared with an initial input from the US EPA will certainly be a milestone toward mutual acceptance between the US (by extension NAFTA) and the EU. Moreover, it will open the way to the adoption of laboratory accreditation programs in the US, as it has happened in some EU member states and Switzerland. This will ensure better data integrity and higher standards for the agrochemical industry.

A subject of discussion for the future ro)~ of GLP standards in the regulatory process may be the implementation of these principles in the conduct of risk assessments, as it is now required in the US (8).

Test Guidelines. These are essential in the road to mutual acceptability. Countries wishing to take part in an international harmonized system may be better off by not going their own way and investing limited resources in developing their own testing guidelines if the principles of their regulatory systems do not include innovation or allow alternatives to the existing tests. Experience has shown that present regulatory approaches cannot guarantee a virtual zero risk society. These national agencies may profit more if they were to step into the vehicle which is already way far ahead and participate in the efforts taking place in the EU and in the initiatives started in NAFTA.

National regulatory laws have based their requirements on test guidelines, which, in their turn, have been developed at the national level (FIFRA, BBA), in professional societies (ASTM, API, CIPAC), in international organizations (FAO, OECD, ISO, EPPO), or in scientific societies (SETAC, ACS). These organizations have given themselves a mission to generate test guidelines which have been adopted by different regulatory bodies or have been used as a basis for improved guidance.

After analyzing all these test guidelines, it can be stated that there appear to be more similarities than differences among them. Sometimes minor differences in requirements may make impossible the design of a harmonized study protocol. It could be assumed that discussion among the different regulators and organizations, including the agrochemical industry, would produce harmonized guidelines. Unfortunately, this is often not the case, even within the EU.

Freedom to select test guidelines should be preserved for each nation. More important is that studies are not rejected based on the difference in requirements. Regulators, the agrochemical industry, and academia must agree on the interpretations of results from different studies. International expert groups should continue to promote the exchange of information to reach such a level of harmonization. Mutual

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acceptability should not mean uniformity nor hegemony of one single scientific approach.

Much work has been carried out in the past years on risk assessment, and it would seem that more effort should be invested in the risk assessment schemes presently used rather than in increasing the requirements for more studies for they will marginally aid in improving the regulatory decisions taken.

The Regulatory System in the US. The regulatory system in the US has been described in some detail in previous chapters. A brief overview is presented here.

The Federal Insecticide, Fungicide and Rodenticide ACT (FIFRA). The US law regulating the registration of PPP is the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) which was enacted in 1947 and amended in 1988 (9). FIFRA was originally promulgated to support farmers in order to have efficacious products for agriculture. Now FIFRA's major objectives are the protection of the consumer, the agriculture worker, the producer of the PPP, and the environment.

In 1970, Congress transferred the administration of FIFRA to the newly created Environmental Protection Agency (EPA). Currently, EPA regulates approximately 22,000 pesticide products on the basis of a little over 400 distinct active ingredient groups. In fact, in the US a state may have its own pesticide regulations, as is the case of California with its so called 'state registrations'. The latter consists of a completely separate registration data review system mandated by state law; however, this certification program must still be approved by the EPA, for states cannot have less strict laws than EPA. For example, California's proposition 65, a fairly rigid state initiative dealing with carcinogens, is an example of a very good 4state registration' initiative that was implemented in a fair manner.

In the pesticide regulatory program at the EPA, a rigid regulatory approach has been taken, and it has prevented the EPA from taking a number of innovative approaches to regulation. EPA has labored, chemical by chemical, and submission by submission, over the last two decades, and it still faces major backlogs in reviewing currently registered pesticides. The EU is facing the same problems after 4 years of reregistration efforts.

Residue Tolerances (Maximum Residue Levels, MRLs). Residue tolerances are the basis for export and import of crops and consequently, are a major factor in mutual acceptability. The US residue tolerances, or MRLs in the EU, established by the EPA, are based on the Food, Drug and Cosmetic Act signed in 1938 and amended in 1962 (10). The enforcement of the residue tolerances is conducted by the FDA for fruits, vegetables, and grains and by the US department of Agriculture (USDA) for meat, seafood, etc.

Reregistration (FIFRA f88). In 1972, EPA began reregistering PPPs already in the market, using current scientific and regulatory standards. A Registration Standard summarized EPA's evaluation of the available data on an existing chemical, identified and required submission of additional data, and set forth other conditions a

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registrant had to meet in order for EPA to reregister pesticide products containing the active ingredient. The growing public concern about how long it would take to reassess the potential hazards of existing pesticides, particularly those used on food crops, spurred Congress to enact a series of amendments to FIFRA in 1988 to substantially change EPA's approach to reregistration. Under these amendments, EPA developed a five-phase reregistration process to complete, over approximately a 9-year period, the review of each registered product containing any active ingredient registered before November 1, 1984. This reregistration process has been dubbed "FIFRA-88". This "FIFRA-88" process has obvious similarities to the reregistration process undertaken by the EU in the past five years.

The results of Phase 5 reviews (still in progress) are contained in Reregistration Eligibility Decision (RED) documents. Through the reregistration process, EPA is ensuring that older PPPs meet contemporary health and safety standards, that their labeling is improved, and that their risks are reduced.

The Pesticide Evaluation Process. The EPA is responsible for assessing the risks of all pesticides used or sold in the U.S. to human health or to the environment. The EPA bases registration decisions for new pesticides on its evaluation of test data provided by registration applicants. Applicants for pesticide registration obtain these data from tests that are specified by the EPA. The tests must be performed according to specified protocols.

When a registered pesticide shows evidence of posing a potential human health or environmental safety problem, a Special Review may be triggered. In this Special Review, the pesticide is subjected to an intensive risk/benefit analysis in which all interested parties (environmentalists, manufacturers, users, scientists, the USDA, and the general public) can comment. In a Special Review, EPA may implement various regulatory options to reduce risks associated with a pesticide's use, such as, restricting its use to certified applicators, requiring protective clothing, and prohibiting certain application methods in certain areas only or on certain commodities. EPA may also decide to simply continue its registration if mitigation measures are found unnecessary.

In the mid-nineties, EPA began to recognize the need for harmonized testing guidelines in order to minimize variations among the testing procedures that must be performed to meet data requirements under the Toxic Substances Control Act and the Federal Insecticide, Fungicide and Rodenticide Act. Increase globalization and the initiation of a pesticide reregistration process in the EU lead to the inclusion of guidelines issued by the Organization for Economic Cooperation and Development (OECD) in the guideline harmonization process. To date, only half of the guidelines have been finalized. Twenty five percent more are in draft form. The completion of the harmonized guidelines has been delayed due to enhancement of the Food Quality Protection Act (FQPA).

Food Quality Protection Act (FQPA). Under FQPA, which became effective on August 3, 1996, EPA must also consider the potential for increased susceptibility of infants and children to the toxic effects of pesticides. FQPA requires

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registered pesticides to meet current safety standards. The Agency also must reassess existing tolerances (MRLs in food), considering aggregate exposure to pesticide residues from many sources and the cumulative effects of pesticides and other compounds with common mechanisms of toxicity. The passage of the Food Quality Protection Act has mandated that a screening and testing program for endocrine disrupters be developed by EPA. Specifically, the FQPA requires that: 1) EPA develop a peer review screening and testing program by mid-1998; 2) EPA implement the program within three years; and, 3) EPA report progress to Congress within 4 years.

The screening and testing program must include estrogenic effects, human health effects, and pesticide active ingredients. However, the screening and testing program could include other reproductive and non-reproductive effects, ecological effects, certain drinking water contaminants, pesticide inert ingredients, anything on the TSCA inventory, and any other environmental agent.

The enactment of the US Food Quality Protection Act in 1996 addresses the above as the concept of a uniform "reasonable certainties of no harm" standard with its newly adopted risk assessment criteria.

In short, the US registration procedure basically consists of the submission of a full data package to the EPA for the active ingredient and the formulated product. Then an iterative procedure is started in which the EPA authorities will ask the applicant to provide them with any additional information on specific concerns, and the applicant's answers are implemented into the evaluation processes. Upon complete review of the data, which may take up to about 2 years, the final decision is made on product registration with its intended uses and the residue tolerances. The resulting decision is published in the Federal Register, which is the US official journal.

The US registration procedure is thus an iterative process which normally involves queries from the EPA on the full data package (issue of dossier completeness in the EU). Responses are expected from the scientists who conducted the studies or the representatives of the agrochemical producer (Figure 1).

The Regulatory System in the EU. The regulatory system in the EU has been presented in detail in other chapters in this book. Therefore, in this chapter, only the highlights will be pointed out.

The Registration Procedure and the 91/414/EEC Commission Directive. Commission Directive 91/414/EEC (77) set the path to the reregistration effort in Europe. This commission directive includes Annexes II A and Π Β for chemical and microbial PPPs, respectively; as well as Annexes ΠΙ A and ΠΙ Β for their corresponding formulated products. The main step in the registration of a PPP, according to this directive, is the periodic publication of a list of active ingredients which are to be reassessed. The agrochemical producers communicate to the rapporteur country that they will submit a complete dossier containing the data requirements for the inclusion of the active substances into Annex I.

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Figure 1. Comparison of the US and EU Registration Models.

US Application

Full Data Package Active Ingredient and Formulated Product

Submission to EPA

Requests, Questions

Answers by Agrochemical Producer

EPA Evaluation

Decision on: - Product Registration - Residue Tolerances

Publication in the Federal Register

US Official Journal

Product Registration State by State

EU Application

Completeness Check Annex II: Active Ingredient Annex III: Formulated Product

Evaluation

At E U -Member State Level

Monograph Preparation

I Advisory

Committee

At EU-Level

Provisional Authorisation or Extended Registration

European Commission

EC-Co-ordinating (EC-CO) Group Evaluation

Evaluation in tripartite Meetings

Evaluation by the EC Working Group and Legislation: Recommendation

Standing Committee on Plant Health Emmitting a Qualified Majority Voting

Annex I Listing

Product Registration or Re-registration in one Member State

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Thereafter, the regulatory authorities of the corresponding rapporteur country conduct a completeness check and if satisfied, they proceed to an evaluation of the data submitted. Once all data requirements have been answered, including additional queries or demand for higher tier studies, the rapporteur country prepares and submits a monograph for that active ingredient to the advisory committee. At this stage, a request for provisional authorization may be granted. The advisory committee takes the case to the European Commission where an ECCO (EC-Coordinating) group evaluates the findings, and through tripartite meetings and also at the EC Working Group level, the evaluation is terminated. A recommendation is given to the Standing Committee on Plant Health, which reports a qualified majority vote. If the decision is positive, the active ingredient is listed in Annex I, and product registration or reregistration for sale in one member state can proceed (Figure 1). This procedure, in contrast with FIFRA '88, strongly depends on the conclusions and risk assessments conducted by the applicant.

Other Stops on the Road to Mutual Acceptability. Discussion of the experiences gained by the EPA and the EU in the past few years has pointed out the need to concentrate on several that need attention. Some of these issues are noted in the following paragraphs:

The National Regulatory Structures. Some of the member states in the EU and most of the countries in Latin America will struggle to implement similar regulatory systems as those established by the US, UK and Germany (72). Their staffs are either limited in number or have not been exposed to similar evaluation schemes. Implementation of GLP accreditation programs, evaluation of test guidelines and assessment of data packages, all at the same time, must involve very careful planning and use of resources. The EU experience has shown that this may lead to a concentration of power in a few, better prepared member states. The contrasts among countries in the Americas are more pronounced, and the danger of absorbing a nation's regulatory process by an established, stronger one, is imminent.

Applicants and Data Protection. The EU experience has shown that a difference exists between the approach followed by multinational and local agrochemical companies, or by proprietary and generic producers. A likely harmonization between the EU and the US will have to take into consideration data protection, since mechanisms are different between the two regions.

Data Interpretation - Comparison of Zones, Regions and Scenarios. The larger the trade zone where harmonization is meant to take place the more different the geographic and climatic regions and, therefore, the more scenarios needed to be considered. Mutual acceptability in the EU, based on the proliferation of climatic scenarios resembling more those found in Northern Europe, will pose problems to state members located in the southern part of the EU.

The extension can be made to the use of soil types, sediments, surface waters, groundwater, aquatic and terrestrial organisms, birds (yearly migration), and crops

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(e.g., bananas in Spain, Canary Islands and Mexico). It is certainly difficult for an applicant to perform a study with a soil that may fully correspond to his application but that may not match the standards set by the regulatory bodies. Within the EU, the mutual recognition of authorizations is in the implementation process and will address the following sectors: Efficacy, Human Health (exposure to the PPP), Human Health (exposure to PPP residues), Fate and Behavior in the Environment and Impact on Non-target Species (73). It is expected that the differences in all species and abiotic components of an ecosystem will be overcome by choosing realistic worst cases and not those of abuse. The process requires preparation of working documents with review and revision. This aspect is certainly one of the most difficult ones since it presupposes trust in the PPP assessment by other member state. Mutual recognition between the EU and the US would certainly profit from the experience to be gained in the EU.

EU and US Regulatory Systems: Differences and Similarities. Some common features and differences are:

• The objective of the EU and US systems is to reduce false positive and false negative mistakes, to increase the certainty in the risk assessment, and to avoid under- or overregulation.

• The present development may give the impression that the EPA may have started to follow a more pragmatic approach, "reasonable certainty of no harm", whereas the EU may be following the strategy of acquiring more data to reduce uncertainties. The question, in fact, is which regulatory system at present demands more studies, and how are they evaluated?

• In the EU and in the U.S., the registration process is centrally organized (Brussels, Washington). However, in the EU it is not centrally evaluated. In the EU, each member state prepares a monograph for an allocated substance. In the US, a similar situation takes place in the states which have their own registration data review, as is the case of California.

• In the EU, each member state will accept the requirements set by the EU unless the directive 91/414/EC has not been implemented into their law, as is the case in Germany. In the US, a state may have its own 'state registrations' (e.g., California) and thus may not necessarily accept an EPA decision. California has a separate registration data review system that is mandated by state law; however, it still needs to be approved by the EPA.

• Data protection in the US provides for a 15-year data compensation for all data submitted to the EPA, whereas in the EU,there are 5 years' data protection for data concerning the active ingredient and no additional protection for supplementary data submitted for the formulated product.

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• In the EU, industry is asked to submit a dossier including risk assessment and recommendations on the substance of interest; whereas in the US, this risk assessment is performed by the EPA authorities themselves (obviously agrochemical producers in the US conduct their own risk assessment anyhow).

• Both the EU and the US have as their top priority sound scientific judgment for evaluation of the data for each PPP and follow the so called scientific approach.

• One of the most difficult areas for evaluation is the area of carcinogenicity, and this will be one of the essential factors in mutual acceptability and, consequently, a main topic in the harmonization efforst between the EU and the US.

Conclusions

The EU and US systems are considered to follow similar objectives, and they may be considered to be similar at the present time. It was pointed out that an effort must be made to develop joint concepts in the assessment models in order to have common, fundamental principles in their regulatory thinking. It is essential that their definition of scientific uncertainty and the reasonable certainty of no harm remain similar, otherwise mutual acceptability would become unattainable.

The implementation of GLP principles into regulatory testing may not have reduced the scientific uncertainty in the data submitted; but, in combination with study guidelines, it has eliminated unreliable data and thus aided the risk assessment process for the registration of PPPs. Therefore, the inclusion of GLP requirements in harmonization procedures can only be desirable.

A major aspect for mutual acceptability is that studies should not be rejected based on the difference in national testing requirements. Regulators, the agrochemical industry, and academia must agree on interpretations of results from the same type of study with slightly different testing requirements. It is suggested that international expert groups continue to promote scientific exchange to reach such a level of harmonization.

It has been assumed here that the input of the US and Canadian regulatory systems will be the driving force in the NAFTA effort, and thus by extension, the argument presented for the US EPA ought to be valid for the North American continent. Other regulatory authorities on the continent will profit from the disclosure of these efforts. A global harmonization, EU-NAFTA, is now an ambitious vision that many contemplate as the ultimate step. If the harmonization processes within the EU and NAFTA are as smooth as could be expected, global harmonization will be attainable before long.

Acknowledgments

We wish to thank the reviewers for the useful comments to improve the contents presented herein.

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