Agrochemicals Registration in Brazil - Equivalent Technical-Grade Products

Written by Paulo M. Silva and Edivan Tonhi

In 1989 the called “Agrotoxics Law” was enacted (Law n. 7.802, July 11, 1989) in Brazil, which was regulated by the Decree-Law n. 4.074 of January 4, 2002, that determined the rules for agrochemicals registration, where the results of the required previous studies are evaluated for this purpose regarding the aspects of agronomic efficiency and potential environmental and public health impacts. The Decree-Law n. 4.074 of January 4, 2002, was updated by the Decree-Law n. 5.981 of December 6, 2006.

The rules and the evaluations of the agrochemicals registrations are controlled by three Brazilian governmental agencies: Ministry of Agriculture and Supply – MAPA, National Health Surveillance Agency – ANVISA (affiliated to the Ministry of Health) and The Brazilian Institute for the Environment and Natural Resources – IBAMA (affiliated to the Ministry of Environment).

In Brazil, the technical-grade products registration can be obtained in two ways:

    a) Full Dossier: presentation of all physical-chemistry, ecotoxicological, toxicological and mutagenic studies cited in the Regulatory Ordinance No. 84/1996 on October 15, which was updated with the Regulatory Ordinance No. 6/2012 on May 17; and

    b) Equivalence: simplified presentation of studies, considering the register as Equivalent Technical-Grade Product, according to the Decree-Law n. 4.074/2002 and the Interministerial Normative Instruction n. 49 of August 20, 2002. This process is composed by three phases:

    Phase I – Analysis of the Chemical Profile;

    Phase II – Analysis of the Acute Toxicological and Mutagenic Profile;

    Phase III – Analysis of the Toxicological with repeated doses and Ecotoxicological Profile.

The studies of Phase I should be initially presented for the registration of the Equivalent Technical-grade Product, which are:

Physical-chemistry studies
GLP Study	Suggestion of Internationally Recognized Guidelines
Five Batch Analysis	OPPTS 830.1000, OPPTS 830.1700, OPPTS 830.1800
Vapour Pressure	OECD 104, OPPTS 830.7950, ASTM E 1194
Melting (solid) or Boling (liquid) point	OECD 102, OPPTS 830.7200, OECD 103, OPPTS 830.7220
Solubility (solid) or Miscibility (liquid)	OECD 105, OPPTS 830.6319, OPPTS 830.7860,
Partition Coefficient n-Octanol/Water	OECD 107, OECD 117, OPPTS 830.7560, OPPTS 830.7570
Physical Chemistry Certificate	ABNT NBR 8510
Validation of Analytical Methods for Active Ingredient	ABNT NBR 14029

The Five Batch study is crucial on the evaluation of the Equivalent Technical-grade Products because it presents the complete chemical composition of the candidate product to equivalent. The product will be considered equivalent in the Phase I if presents similarity with the product taken as a reference taking into account the physical-chemistry properties and the chemical composition. If it is equivalent the registration is granted.

When the equivalence with the product taken as a reference is not granted in the Phase I, criteria are set for performing the toxicological studies based on the quantity of the impurity and specificity of the studies. The studies that may be required for evaluation of the Phase II are shown below:

Toxicological and Mutagenic studies
GLP Study	Suggestion of Internationally Recognized Guidelines
Acute Oral Toxicity in Rat	OECD 423
Acute Inhalation Toxicity in Rat	OECD 403
Acute Dermal Toxicity in Rat	OECD 402
Acute Dermal Irritation/Corrosion	OECD 404
Acute Eye Irritation/Corrosion in Rabbit	OECD 405
Skin Sensitization	OECD 406
Bacteria Reverse Mutation Test (AMES Test)	OECD 471
Mammalian Erythrocyte Micronucleus Test	OECD 474

In Phase II, the studies of Structure-Activity Relationship (SAR) and Quantitative Structure-Activity Relationship (QSAR) may be also required, with the objective of evaluate the toxicological relevance of the impurities.

The products will be considered equivalents in the Phase II when:

    - The new impurities and/or incremented impurities do not present warnings from QSAR different from those obtained for the active ingredient;
    - The toxicological data do not go over the factor 2 in relation to the result of the reference product; and
    - The results are negative for mutagenesis and skin sensitization or as the same compared with the reference product.

If the Equivalence of the Technical-grade Product is also not granted in the Phase II, then the following additional studies may be required for the evaluation on the Phase III:

    - Toxicological studies with repeated doses (from sub-acute to chronic) and toxicological studies for evaluating the teratogenicity, carcinogenicity, neurotoxicity and hormonal effects;
    - Ecotoxicological studies with toxicity to aquatic and terrestrial organisms (fish, daphnia, algae, birds, bees, microorganisms or soil organisms), according to the intended usage of the product.

The products will be considered equivalents in the Phase III when:

    - The toxicological data do not go over the factor 2 in relation to the result of the reference product as long as the affected organs are the same;
    - The “No-Observed-Effect-Level (NOELs)” and the “No-Observed-Adverse-Effect-Level (NOAEL)” do not differ more than the difference from the used dose levels;
    - There should be no changes on the evaluation of the studies that produce positive or negative results; and
    - Equivalence from the ecotoxicological profiles for the technical product (if corresponds to the proposed usage). The ecotoxicological profile will be considered equivalent when compared to the reference profile, and they do not differ from a factor greater than 5, when determined using the same species (or from a factor greater than the increment of the dose, if it is greater than 5).

When a technical product is not considered equivalent after passing through the evaluation from Phases I, II and III of the Equivalent Technical-grade Products, it can continue in process as long as it complies every requisites for the registration of a conventional technical product (Full Dossier), as it is described in the Regulatory Ordinance 84 of October 15, 1996 and Regulatory Ordinance n. 6 of May 17, 2012.

About Bioagri:

Bioagri – a Mérieux NutriSciences Company is the biggest private laboratory of Latin America and it is in operation since 1991 in the conduction of studies for agrochemicals registration. The majority of studies in evaluation by the Brazilian authorities were conducted by Bioagri as well as the majority of the registration in place in Brazil was obtained with studies conducted at Bioagri. In that way, the authorities that evaluate the studies are very familiar with Bioagri reports. Furthermore, Bioagri has the best knowledge of the quality expectation of the studies by the Brazilian authorities. Bioagri has highly qualified and experienced professionals as well as state-of-the-art pieces of equipment for the conduction of the studies (Five Batch, Physical-Chemistry, Toxicological, Ecotoxicological and Mutagenesis in Agrochemicals).

Bioagri has conducted more than 650 Five Batch studies contemplating more than 70 different molecules. Bioagri has also conducted more than 30.000 Physical-Chemistry studies, 3.821 Ecotoxicological studies, 6.315 Toxicological studies and 2.200 Mutagenic studies. The studies performed by Bioagri can be used for agrochemicals registration in Brazil as well as in the world once the company has the GLP accreditation by the OECD, which Brazil is considered a member since May, 2011.

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