Analysis on Global Registrations, Formulas and Market Situation of Prothioconazole Products

By Yating Jiang¹, Jianghui Yin²
(1. AgroPages; 2. Shanghai E-Tong Chemical Co., Ltd.)

In the broad global market of cereals, soybean, rape and other crops, Prothioconazole plays a vital role because of its multiple outstanding advantages.

It has been used in more than 60 countries and is very popular among growers in Brazil, Germany, Britain, France, etc. Since its commercialization in 2004, Bayer has  developed a wide variety of compound products based on Prothioconazole, which has dramatically increased its sales, expanded its application scope and helped it to establish a strong market position.

The patents of Prothioconazole in China, the United States and Europe expired in 2015, so its "Golden Age" is coming. However, while Europe and the United States are thriving, there are very few registrations in China. But rough waves surge beneath the seemingly calm surface. The authors will analyze the registrations, dosage forms, formulas and market situation of Prothioconazole.

Analysis on Dosage Forms and Formulas of Fox Xpro™ and Delaro Complete™

In its financial report of the second quarter of 2021, Bayer said, “The sales of its agricultural business (Crop Science Division) increased by 10.6%, partly due to the increase in the sales of fungicides. The sales of Fox Xpro™ (Prothioconazole + Trifloxystrobin + Bixafen) launched in Latin America and Delaro Complete™ (Prothioconazole + Trifloxystrobin + Fluopyram) launched in North America, particularly showed an increasing trend.” Let us start with the two star Prothioconazole products.

Bayer's Fox Xpro™ and Delaro Complete™ fungicides are ternary compound suspending agents (SC) containing Prothioconazole. Table 1 shows details of its application methods, crops and disease control.

Table 1 Interpretation of Labels of Fox Xpro and Delaro Complete Fungicides

Review on Global Registrations of Prothioconazole Compound Products

Since its listing as a new active ingredient in the list of registered active ingredients in the European Union (EU) Pesticide Registration Regulation (1107/2009) in 2008, Prothioconazole has been marketed in over 60 countries/regions around the world. After the expiration of the patents of the Prothioconazole compounds, major companies such as Syngenta, BASF and ADAMA are scrambling to conduct research and development of this product. At present, Prothioconazole ranked third in global fungicide sales and became the largest product in cereal fungicide market and the fourth-largest product in the soybean fungicide market.

Main active ingredients compounded with Prothioconazole include Fluoxastrobin, Tebuconazole, Trifloxystrobin, Bixafen, Penflufen, Solatenol, Spiroxamine, Boscalid, Fluopyram, Metalaxyl and Clothianidin. Prothioconazole’s main registered dosage forms include a suspending agent, a suspending seed treatment agent, emulsifiable concentrate and suspension emulsion.

European Market:

In 2004, Prothioconazole was registered and marketed in Great Britain and Germany for the first time. Cereals (wheat) and rape are the main crops grown in Europe. Bayer has launched multiple fungicides and seed treatment agents containing Prothioconazole for cereal and rape crops. Detail information is shown in Table 2. In recent years, BASF and ADAMA have also launched products containing Prothioconazole in Great Britain and Germany, etc.

Table 2 Summary of Mainstream Prothioconazole Products Launched by Bayer in Europe (Incomplete Statistics)

Australian Market:

In 2006, Prothioconazole was registered and marketed in Australia for the first time. Wheat and rape are the main crops grown in Australia. Bayer has introduced fungicide products containing Prothioconazole for wheat and rape crops, as shown in Table 3. In 2016, Bayer and Sumitomo Chemical launched Aviator Xpro (Prothioconazole + bixafen) fungicide in Australia.

Table 3 Summary of Mainstream Prothioconazole Products Launched by Bayer in Australia (Incomplete Statistics)

 
North American Market:

In 2007, Prothioconazole was registered and marketed in the United States and Canada. Wheat, soybean and corn are the main crops grown in North America. Bayer launched multiple Prothioconazole products in the United States and Canada, including fungicides and seed treatment agents. Detailed information is shown in Table 4. In addition, in 2021, BASF launched Sphaerex (Prothioconazole + Metconazole) fungicide in the United States, which is used to prevent and control wheat scab and DON.

Table 4 Summary of Mainstream Prothioconazole Products Launched by Bayer in North America (Incomplete Statistics)

South American Market:

In 2007, Prothioconazole was registered in Brazil. Soybean, corn and wheat are the main crops grown in South America. Bayer has launched multiple fungicides containing Prothioconazole in Brazil and Argentina. Detailed information is shown in Table 5. These products are mainly used to prevent and control soybean Asian rust and wheat scab in South America.

Table 5 Summary of Mainstream Prothioconazole Products Launched by Bayer in South America (Incomplete Statistics)

Indian Market:

In 2014, Bayer launched a seed treatment agent, Raxil Easy (Prothioconazole + Tebuconazole + Metalaxyl), in India, used to prevent and control wheat loose smut.

Market Applications of Prothioconazole

According to the statistics of Phillips McDougall, the global sales of Prothioconazole exceeded US$1.2 billion in 2019. In 2005 (the second year of its commercialization), 2009 and 2014, the global sales were $113, $421 and $855 million, respectively. Prothioconazole is consumed mainly in Europe, South America and North America, including Brazil, Germany, Great Britain, France, Canada, the United States, Russia, Ukraine, Poland, Romania and other countries (Figure 1).

Figure 1 Prothioconazole consumption distribution (2019)

Brazil is the largest Prothioconazole user. It consumed about 2,600 tons in 2019, accounting for more than 40% of the total global consumption. Soybean is the crop with the highest consumption of Prothioconazole in Brazil, accounting for 87%. Other crops consuming prothioconazole include corn, cotton and cereals. Bayer is a major exporter and importer of Prothioconazole to Brazil. At present, Brazil has approved the registrations of nine technical products and 11 formulated products. Enterprises holding technical concentrate registrations include Bayer, ADAMA, UPL, Syngenta, Albaugh and Rainbow, etc. Enterprises holding formulation registration certificates include ADAMA, BASF, UPL, Bayer, Syngenta and Corteva, etc. In addition, currently, eight Prothioconazole products have entered the final analysis stage in Brazil, involving ADAMA, UPL, Nufarm and other companies, and 70 Prothioconazole products are in line for registration, involving some Chinese companies, such as Rotam, YONON and Pilarquim. At present, most of the market players are multinational companies. However, Prothioconazole has become a much sought-after chemical based on its popularity of product registration among many companies, and the Brazilian market will face intense competition in the future.

Great Britain, Germany and France are the three largest users of Prothioconazole in Europe. Unlike Brazil, more than 80% of the product is used for cereals, and the same goes for other European countries. According to the statistics in 2018, all Prothioconazole used in France and Germany are mixtures. In the wheat treatment areas of 7.5 million hectares in France and six million hectares in Germany, half of them were applied with Prothioconazole once a season. In Germany, rape crop was applied with a compound formulation (Prothioconazole + Tebuconazole) that can be used twice a season. A total of 3,450 tons of formulations were used in Germany and 2,935 tons in France. In Great Britain, wheat and rape were sprayed with 160 tons and 120 tons of single-dose product respectively, and the rest were compound Formulations. Prothioconazole was applied on 100% of British wheat and 2,770 tons of Formulations were consumed. Other countries consumed 1,909 tons of Prothioconazole Formulations, and some wheat and mostly rape can use Prothioconazole twice a year. Single-dose Prothioconazole consumed in the European Union totaled 349 tons.

More than 60% of Prothioconazole is applied to cereals in the United States agricultural market, and only 13.60% and 4.01% to soybean and corn. In Canada, cereals and rape are the two main crops using Prothioconazole, accounting for 51.35% and 41.05%, respectively, while a small amount is applied to corn, soybean and other crops.

Synthetic Routes of Prothioconazole (Supported by Jiangsu BioGuide Laboratory Co., Ltd.)

Four synthetic routes of Prothioconazole are showed as follows.

Route I: O-chlorobenzyl chloride and 1-chloro-1-acetyl cyclopropane are used as starting materials on this route. The target product is obtained through five steps, including chlorination, Grignard reaction, triazole substitution, and sulfuration, etc.

Route Ⅱ: In this route, o-chlorobenzyl chloride and 1-chloro-1-acetyl cyclopropane are also used as starting materials. The target product is obtained through five steps, including chlorination, triazole substitution, Grignard reaction, sulfuration, etc. Compared with route I, route II only adjusted the order of triazole substitution.

Route Ⅲ: This route uses o-chlorobenzyl chloride and 1-chloro-1-chloroformyl cyclopropane as starting materials. The target product is obtained through four steps, including Zinc Grignard reaction, epoxidation, triazole substitution and sulfuration.

Route Ⅳ: This route also uses o-chlorobenzyl chloride and 1-chloro-1-acetyl cyclopropane as starting materials. The target product is obtained through six steps including chlorination, Grignard reaction, hydrazine hydrate substitution, cyclization, sulfuration, etc.

The related impurities that must be tested in Prothioconazole technical concentrate are desulfurization impurities (limit: 0.5 g/kg) and dechlorination impurities. The two impurities are also a critical issue in the application for Prothioconazole registration. At present, the mainstream production process of Prothioconazole in China is Route IV, and desulfurization impurities can be completely avoided during the process.

Prothioconazole Faces both Challenges and Opportunities

Challenge I: Health Problem

Although Prothioconazole is safe for bees, birds, fish, algae, etc., its secondary metabolite (desulfurization-prothioconazole) is highly toxic to mammals. The major health problem of Prothioconazole is the potential harm to the female reproductive system leading to female infertility. Compared with advanced pesticide application technologies, highly professional application personnel and perfect protective measures in Europe and America, relatively low application technologies, application personnel’s lack of professionalism and insufficient safety protection measures are among factors limiting Prothioconazole application in China. Therefore, it is critical to take steps to ensure the health and safety of the application personnel to promote Prothioconazole products. The measures include using sealed machinery and UAV to apply pesticides, providing professional training to application personnel, and applying pesticides only after personnel obtain relative work certificate.

Challenge II: Resistance Problem

The primary dosage forms of Prothioconazole are suspending agent, emulsifiable concentrate, suspension emulsion, suspending seed treatment agent, etc. At present, some resistant mutants of pathogenic fungi have appeared. Mutations in the target site of Prothioconazole lead to moderate resistance risk. Therefore, to delay the generation and development of Prothioconazole resistance in the global market, it is necessary to maintain its market vitality. Binary and multicomponent compound products of Prothioconazole compounded with Triazole, Methyl Methoxyacrylate, Pyrazolamide and SDHI fungicides and insecticidal amine insecticides have been developed. These products have produced the highest level of disease-control effect and excellent yield-increasing effect.

Opportunity I: Technological Upgrade

In recent years, with the improvement of land circulation and intensification in China, pesticide application methods have witnessed numerous changes. UAV spraying and large-scale mechanized spraying have been popularized. Accordingly, the unified prevention and control area has been gradually expanded. Pesticide application personnel now have professional protective clothing and safety devices. Therefore, the risk of harm to the human body caused by Prothioconazole is controllable, and its problem of risk assessment will be solved. It is believed that soon China’s Prothioconazole market will be fiercely competitive.

Opportunity II: High Incidence of Scab

Wheat scab is getting severe in many places around the world, and it becomes harder to control the disease year by year. The consumption and cost of available pesticides are increasing, and the resistance of scab to pesticide products is also escalating. Scab has become one of the major diseases that harm wheat crops. At the same time, when scab infects wheat, its grains will produce DON and the wheat quality will be debased, leading to a decrease in its economic value. In addition, after people eat wheat containing DON, toxic symptoms are easy to develop. At present, good results have been achieved in foreign countries in the treatment of wheat scab and other diseases with Prothioconazole products. Therefore, Prothioconazole plays an important role in the control of scab and other major diseases.

Question: Reasons of Few Registrations in China

According to a relative investigation, China has approved more than 100 Prothioconazole products to conduct field efficacy trials as of 2017. The products compounded with Prothioconazole include Azoxystrobin, Pyraclostrobin, Trifloxystrobin, Picoxystrobin, Fluoxastrobin, Tebuconazole, etc. The crops for field trials include wheat, banana, rice, cucumber, etc. However, it is noteworthy that until September 2021, only two technical products and three formulated product were finally approved for registration. Both Anhui Jiuyi Agriculture Co., Ltd. and Hailir Pesticides and Chemicals Group registered the technical product and formulated product in early 2019. Why couldn’t many more Prothioconazole products not get registered, resulting in no newly registered products for more than two years?

Special thanks to Shanghai E-Tong Chemical Co., Ltd. for its professional support to this paper. The company has rich operation experience in pesticide products, including Prothioconazole, and is able to provide stable, high-quality and professional support from raw materials to formulation customization to overseas market registration and operation. To learn more, please visit www.etongchem.com