Toxicological Reassessment: Anvisa Aims for Transparency and Dialogue in Brazil

reavaliações toxicológicas

“Toxicological reassessment is not a process that is exclusive to Brazil. Other countries and blocks that are international references on the subject also adopt similar procedures…”

Maria Augusta Carvalho Rodrigues is the coordinator of pesticide reassessment at Anvisa’s General Toxicology Management.

Rodrigues graduated in biochemistry from the Federal University of Alfenas, with a M.Sc and a Ph.D in toxicology from the Faculty of Pharmaceutical Sciences at USP in Ribeirão Preto.

Maria Carvalho, coordinator of pesticide reassessment at Anvisa

AgriBrasilis – Why can toxicological reassessment result in a product being banned?

Maria Carvalho – Unlike other products regulated by the National Agency of Sanitary Monitoring (Anvisa), the registration of pesticides has no legal provision for renewal or revalidation. Once granted, a pesticide registration is valid indefinitely.

Thus, Decree No. 4074, of 2002, provided that the Ministries of Agriculture, Health and the Environment, within the scope of their respective areas of competence, must promote the reevaluation of the pesticide registration when there is an alert for risks, contraindication of the use of certain pesticides by other authorities or new signs of risks that advise against the use of registered products.

These signs may place the pesticide in one of the prohibitive registration categories, listed in Article 31 of the aforementioned Decree: being teratogenic, carcinogenic, mutagenic, causing hormonal disorders, more dangerous to humans than demonstrated in animal tests, in addition to the identified absence of deactivation methods and absence of antidotes.

When new evidence indicates that the pesticide complies to a criterion that would not allow registration, without the possible determination of a safe threshold, the reevaluation is concluded by banning the active ingredient.

AgriBrasilis – Can all molecules registered in the country be subjected to this process? Does the registration approval process not guarantee the security?

Maria Carvalho – All active ingredients of registered pesticides are subject to reevaluation. Even though safety was assessed at the time of registration, the technical-scientific knowledge about these products is constantly evolving and new aspects and risks can be identified.

Toxicological reassessment is not a process that is exclusive to Brazil. Other countries and blocks that are international references on the subject also adopt similar procedures, aiming to protect the population.

Considering the advancement of scientific knowledge, the new evidence of health risks, which were not detected at the time of the pesticide’s registration, cannot be neglected.

AgriBrasilis – What is considered sufficient evidence to initiate a reevaluation process? What makes Anvisa prioritize the reevaluation of certain molecules?

Maria Carvalho – The reevaluation process begins with the indication of an active ingredient. The indication may occur when there are alerts from international organizations; by the initiative of Anvisa itself, when new signs of risk to human health are detected; or also by a person or institution, as long as it is formalized using the form available on the reevaluation page.

The indication must be accompanied by technical-scientific evidence that suggests the possible classification of the active ingredient in the prohibitive registration criteria or in others with potential risk to human health.

Among the indications submitted, Anvisa frames and selects the active ingredients that will be subject to reevaluation based on the risks to human health, considering: evidence that the pesticide meets the prohibitive registration criteria; evidence of health risks, with extrapolation of dietary and occupational reference parameters; relevance of exposure to pesticides for humans, assessed through marketing data, human poisoning data, monitoring of pesticide residues in water, food and biological samples; etc.

The selection criteria that resulted in the last published list of pesticides intended for reassessment, created in 2019, used a risk matrix that scored various evidence of health risk and exposure, for example: dietary risk, marketing data and operator exposure scenarios , etc. The list and scores achieved are available on the reassessment electronic portal, and can be accessed at this page.

AgriBrasilis – If the reevaluated molecule is not banned, what types of restrictions can it suffer?

Maria Carvalho – The reevaluation process is not automatically linked to the prohibition or restriction of the use of a specific pesticide active ingredient. The reassessment analyzes the evidence of health risks and may conclude that the active ingredient and its products must be maintained, with or without registration changes, or maintained with the adoption of health risk mitigation measures, prohibition or suspension of use.

AgriBrasilis – What is the history of toxicological reevaluation in Brazil?

Maria Carvalho – Anvisa has carried out toxicological reassessments since its creation. Until 2006, when it was decided to reevaluate a certain pesticide by decision of the Board of Directors, a meeting was held with representatives from Anvisa, Ministry of Agriculture, Cattle and Supplying (MAPA), Brazilian Institute of the Environment (Ibama) and the union representing pesticide producers for discussion and immediate conclusions on the reevaluation process.

After 2006, technical notes were published with a brief introduction, summary of toxicological data, discussion, referrals and references.

In 2008, RDC No. 10 was published, which defined the reevaluation of the following pesticides: Abamectin, Acephate, Carbofuran, Cyhexatin, Endosulfan, Phorate, Phosmet, Glyphosate, Lactofem, Methamidophos, Paraquat, Methyl Parathion, Tiram and Trichlorfon. At the time of this publication, there was still no definition of procedures for conducting a reassessment process. This resulted in the subsequent publication of RDC nº 48, which provided for administrative procedures for the toxicological re-evaluation of technical and formulated products, based on active ingredients that raise health concerns, and amended provisions of RDC nº 10, of 2008.

In 2016, Anvisa restructured the toxicology area, seeking to strengthen its actions. It was possible to review the pesticide reevaluation process and dedicate a specific team to this activity in the General Toxicology Management, resulting in the creation of the Reevaluation Coordination (CREAV), which was structured to strengthen activities related to the pesticide post-market and to reorganize and optimize work processes, including the reassessment of pesticides.

Since the creation of CREAV, improvements have been made to the work processes and standardization of analyses, such as the elaboration of partial opinions for each analysis carried out or each toxicological aspect of a reassessment, allowing details on the steps overcome and those still pending during the process reevaluation.

Based on the experience acquired by Anvisa in the pesticide re-evaluation process, a proposal for regulatory action was prepared, which resulted in the publication of RDC No. 221, of 2018. The regulation provides for the criteria and procedures for the toxicological re-evaluation process of pesticides within the scope of Anvisa and revoked RDC No. 48, of 2008, providing greater objectivity, clarity, transparency and effectiveness to the reevaluation procedures, so that they correspond to the real needs and purpose of the activity.

The difference in RDC No. 221 is precisely the inclusion of the initial stages of the process, namely: indication, selection and definition of the scope of the reassessment. The standard establishes that Anvisa will evaluate the evidence of health risks of active ingredients permitted in Brazil, and will establish which ones should be reassessed first, based on the risk that pesticides actually pose to health. This is important since there will always be indications of health risks for various pesticides, but public institutions need to rationalize the use of their resources.

Therefore, since 2006, when the reevaluation procedures were improved, Anvisa completed the reevaluation of 20 active ingredients. Thirteen of them were banned, six were kept with registration restrictions, and one was kept without changes to the register.

AgriBrasilis – How is the economic impact analysis carried out in the event of a ban, as recently occurred with carbendazim?

Maria Carvalho – Once the reevaluation is completed, if it is necessary to implement measures such as prohibition or maintenance of registration with restrictions, Anvisa must hold meetings with MAPA and Ibama before its final decision, to discuss restrictive measures that may be applicable and the adaptation deadlines, within the scope of their respective areas of competence.

Discontinuation deadlines and mitigation measures vary according to the active ingredient, and consider: environmental impact, in which Ibama decides between incineration or depletion of stocks; agronomic impact, in which MAPA and Embrapa evaluate available alternatives; impact on food production, in which MAPA considers the possibility of shortages.

In the case of carbendazim, the discontinuation periods were gradual, initially prohibiting imports by pesticide manufacturing industries, granting three months until production was banned, six months for the commercialization ban, and 12 months for the export ban, allowing the products purchased by end users to run out. Therefore, mitigation and discontinuation measures and deadlines are expected to be in balance with the economic impacts of the ban.

AgriBrasilis – Is sufficient time guaranteed for companies to prepare for product withdrawal?

Maria Carvalho – Anvisa prioritizes transparency and dialogue. In this sense, there are efforts to allow the predictability of the active ingredients that will be reevaluated.

Anvisa carries out the selection and prioritization stages of active ingredients through the preliminary assessment of indications for reassessment regarding their relevance and possibility of being eligible for this. The result of this procedure is the publication of a list of selected substances on the Anvisa Website, to disclose the selected active ingredients and the order in which they will be reevaluated.

Publicizing the list in advance of the start of the reevaluation process is necessary to guarantee transparency and predictability for society, to the pesticide production sector and to the users of these products [the farmers]. Thus, farmers and the production sector will have adequate predictability to collect data and studies regarding the substance to be reevaluated and also to begin the search for alternatives to active ingredients that may be restricted or banned after reevaluation.

After publishing the selection list of active ingredients, the reevaluation begins with the publication of the call notice, convening companies with registered products to discuss the documents to be filed within 180 days. After this period, the technical analysis is carried out and the preliminary Technical Note is prepared, which, in turn, receives contributions through a Public Consultation. Only after evaluating the contributions and necessary diligence with other entities is the final decision published, which still includes discontinuation deadlines.

Reevaluation is an extensive, transparent process, and involves social participation, which allows preparation for a possible withdrawal of products or programming of substitutes.

The last list of active ingredients selected for reevaluation was released in 2019. Since then, one active ingredient has had its reevaluation completed (carbendazim), four are undergoing technical analysis (procymidone, chlorpyrifos, epoxiconazole and thiophanate-methyl) and two (linuron and chlorthalonil) are still awaiting the publication of a notice to begin the reevaluation.

The reevaluation of the active ingredients that are in the technical analysis stage (procymidone, chlorpyrifos, epoxiconazole and methyl thiophanate) is in the phase of documentation evaluation – filed by the companies – and preparing opinions/analyses that will support the preparation of the Preliminary Technical Note.

AgriBrasilis – Can banning molecules from the market increase illegal trade or encourage the adoption of worse practices in the field?

Maria Carvalho – Bans of active ingredients of pesticides through toxicological safety reassessments aim to protect the health of the Brazilian population. The process is complex, extensive, transparent and widely discussed. Therefore, it is expected that there will be an understanding that the illegal use of these products results in a risk to human health and that alternatives will be offered to farmers in order to avoid harmful practices.



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