Developing new chemical crop protection agents is an expensive and lengthy process. Globally, only six companies invest in exploratory research and each year only five to 10 new agents reach the market. Anke Hubenthal looks at the market

Developing new chemical crop protection agents is an expensive and lengthy process. Globally, only six companies invest in exploratory research and each year only five to 10 new agents reach the market. Anke Hubenthal looks at the market

Licensing new plant protection agents is regulated extensively, not even pharmaceuticals have to undergo such thorough testing before being approved. As a result, it takes an average of eight to 10 years before a new agent reaches the market. ’Each year we test a six-figured number of compounds  to see whether they are active against pathogenic fungi, insects, or weeds,’ explains Bernd Gerling from BASF’s plant protection and food division. 

These first tests are carried out in greenhouses. In addition, BASF uses molecular in vitro systems to identify groups of biologically active compounds. Researchers at Bayer CropScience use a miniaturised and automated greenhouse screening (in vivo or ultra high throughput screening (UHTS)) to test whether, and in what way, substances are active against pathogens. In a complementary approach known as target screening (in vitro UHTS), the compounds are tested at the molecular recognition sites. 

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’If a biological effect is demonstrated, the optimisation of the lead structure begins in the lab and in the field,’ says Gerling. ’In parallel to the development of the new agent,’ says Hannelore Schmid of the German agricultural industry association, IVA, ’the manufacturers carry out investigations into the toxicology, ecotoxicology and environmental fate.’ 

Tough testing

The costly testing procedures reduce the number of potential agents considerably. ’Due to the tough testing conditions, only one out of over 50 000 compounds synthesised makes it through to become a marketable product,’ explains Norbert Lemken of Bayer CropScience. Around 30 years ago, the chance was one in 10 000. If the UHTS experiments are included in the calculation, only one in 140 000 new substances meet the requirements. Therefore, development has to follow economic criteria as well as biological and ecological ones. 

High development costs for plant protection agents have shaped the market. According to IVA records, there are globally only six companies left that invest in research and development of new agents, namely BASF, Bayer CropScience, Dow Agro, DuPont de Nemours, Monsanto and Syngenta. In 1990 there were 13. 

The market is still moving. These six companies buy and sell individual products, or entire product lines, between each other, as well as to and from third parties. For example, BASF sold its phenoxy herbicides to the Australian company Nufarm in 2004 and acquired the insecticide fipronil along with selected fungicides from Bayer CropScience. 

Like everybody else, BASF has to respond to the market. ’To be able to grow profitably in the long term, we invest in research aimed at finding new substances, especially in the areas of fungicides and insecticides,’ Gerling explains. Last year, BASF invested ?273 million (?185 million), or 8.1 per cent of the plant protection and food turnover, in R&D. This investment has remained constant in relation to turnover over five years and it is paying off. BASF is introducing seven plant protection agents to the market - three fungicides for cereals, soy beans, and speciality seeds; three herbicides for cereals and maize; and one insecticide. The pipeline contains herbicide tolerant soy beans and products to protect seeds using established agents. 

Bayer CropScience is well-positioned, especially in the insecticides market, partly due to its acquisition of Aventis’ (now Sanofi-Aventis) plant protection division in 2002. Bayer’s researchers also work on new formulations of already approved substances, to use them for new applications and thus prolong their life cycle. In 2004, Bayer invested ?679 million in crop protection and plant biotechnology R&D. It obtained licences for two fungicides and expects to get another in 2005 for an insecticide to be used for vegetables, fruit, cotton, maize, beans or tea.

Syngenta invested $809 million (?460 million) in plant protection, seed and plant science R&D in 2004. Like Bayer CropScience, Syngenta banks on established products. ’Continuously improving already approved agents makes sense and it is necessary because of the growing legal requirements,’ explains Peter Hefner of Syngenta Agro. 

Reacting to new pests

New or imported diseases and pathogens can drive new developments. Because it takes a long time to develop and authorise a new agent, researchers have to anticipate what pests will trouble farmers in 15 years time.   

As this is rarely predictable, researchers and farmers often have to face new pathogens without much preparation.   

A recent example is the outbreak of black rot attacks on vines in vineyards in the Moselle, Nahe, and middle Rhine regions in Germany over the last couple of years. If left unchecked, the pathogen Guignardia bidwellii infects grapes before they are ripe, and all green parts of the plant, reducing the yield by up to 80 per cent.   

Growers cannot simply use one of the products already licensed in Germany to fight the fungus. The licences are specific for the pests the products are targeted at, so manufacturers will need to apply for the licence to be extended to the new application.   

Tests are currently under way to see whether products against Oidium  and Peronospora are active against black rot and if they could possibly obtain approval for this application.    

Changing licensing procedures

Licensing and registration has not yet been standardised across EU member states. In the long term, a European directive (91/414/EWG), which regulates the ’placing of plant-protection products on the market’ across the EU, should lead to laws being harmonised.

For example, under this directive, since 1993 every new agent has had to undergo a uniform testing protocol throughout the EU. If a given compound passes this test, it is included in the EU’s ’positive list’. This licence is limited to 10 years and can be withdrawn at any time, for example if undesirable side effects become apparent. In addition, manufacturers have to seek approval for the complete product formulation from each EU member state. 

’Over the last five years, we received around 30-40 applications per year for the licensing of new products and around 50 for the renewal of existing ones,’ explains Jochen Heimberg of the BVL, the government authority in charge of licensing in Germany. On top of that, there are applications for additional uses of existing products. Among the applications for new licences, there are around 10-15 products with an agent that is still being tested for the EU positive list. In such cases, the BVL can grant a licence for three years. 

"Since 1993, around 110 new agents have entered the EU-wide licensing procedure"

’Since 1993, around 110 new agents have entered the EU-wide licensing procedure,’ says Heimberg. Among them are 10 microorganisms, such as the bacterium Bacillus thuringiensis ssp. aizawei, the Adoxophyes orana granulosis virus, and the fungus Coniothyrium minitans - biological plant protection agents, which must be licensed the same way as chemical ones. 

In the UK, the Pesticide Safety Directorate has to approve new plant protection agents, while in Northern Ireland it is the Department for Agriculture and Rural Development. In the UK, manufacturers can seek approval for new products on the basis of the 1986 control of pesticides regulations (COPR) or the 2003 plant protection products regulations. The latter was introduced as part of the EU-wide harmonisation of regulations and will eventually replace COPR. 

Harmonisation within the EU

EU member states can mutually recognise each other’s licences, as long as the active ingredient of a product is included in the EU’s positive list, explains BASF’s Gerling. 

As the number of agents on that list stands at about 110 and is still rising, mutual recognition becomes more and more important. However, there are certain limits, as Heimberg warns: ’It is essential that the conditions for agriculture, plant protection and the environment are comparable in both member states.’ Thus, mutual recognition between Spain and Sweden is practically impossible, because any studies concerning the degradation of an agent in the field, if conducted in Spain, would not be transferable to the evironmental conditions in Sweden. 

Therefore, the European commission is planning to divide the EU area into large zones, so that manufacturers can get approval of new plant protection products for a complete zone in a single process. The commission favours dividing the area into central, northern and mediterranean zones but will have to agree the details with the industry and individual member states. 

Furthermore, this year the European parliament wants to pass a directive for EU-wide harmonisation of maximum residual amounts, a decision from which both producers and consumers can benefit. So far, different limits apply for substances in various EU countries. This may depend on the overall quantities in which a given agent is used in a country. For example, if a substance is rarely used in the UK, the limits may be quite low, while they are higher in other EU countries with a more frequent use. 

In addition to EU-wide measures, Germany is launching a programme to reduce chemical crop protection, developed by the federal ministry for consumer protection, food and agriculture. Consumer, environment and farmers’ organisations, as well as the IVA, representing the industry, were involved in developing the programme. Its core is educating farmers because improved know-how should ensure the legal limits will be exceeded less often and chemical measures can be dropped or replaced by non-chemical alternatives. 

In March 2005, the agricultural ministers of Germany’s federal and state governments agreed to reduce the use of chemical plant protection agents by 15 per cent in the next 10 years. 

According to German plant protection laws, the use of chemical products must be a last resort, as the ’integrated plant protection’ principle should be applied. Farmers should preferentially protect their crops using appropriate crop alternation, biological, or biotechnological measures, before resorting to chemical products. Predatory insects, for example, that feed off plant pathogens can serve as biological plant protection agents. 

Pheromone traps can protect vineyards and maize crops because they stop flying insects from reproducing, because it’s often the larvae that create the greatest damage. In enclosed areas, such as greenhouses, predatory insects work well but liberating them in fields or vineyards would make little sense. Manufacturers that want to sell pheromone traps must isolate the active ingredient and get a licence for it, just as they would for a fully synthetic compound, with the same costs and limitations. 

Searching for new substances 

The last real blockbuster of the plant protection industry was the herbicide glyphosate, which was licensed in Germany in 1995. Monsanto, which markets it under the name Round-Up in combination with glyphosate-resistant seeds, has come to dominate the US herbicide market with the product.   

Bayer’s imidacloprid, the best selling insecticide, has been on the market since 1991 and the patents run out in 2006. Therefore, the plant protection industry is looking for new classes of substances. The most important discovery of the 1990s were the strobilurins. Like the insecticide imidacloprid, this class of fungicides is based on a natural compound: the fungus Strobilurus tenacellus uses a strobilurin to fight competitors. While the lead structure itself is sensitive to light, synthetic analogues have a high specificity and effectiveness against phytopathogenic fungi.   

Several companies, including Syngenta, Bayer CropScience and BASF, produce synthetic analogues of the strobilurin lead structure, which have in the last two years played an important role in the fight against the Asian soy rust, which posed a major threat to crops in Brazil. However, first resistances have occurred already and agriculture experts recommend only using strobilurins once a year and switching to azoles if there is any doubt about their efficiency.   

Only Bayer CropScience can boast a completely new class of substances for crop protection: the ketoenoles. This year, a new insecticide from this group, namely spiromesifen, is due to come on the market.   

Transgenic plants

Like biological agents, genetically modified plants with in-built resistance against pests can be used as an alternative to chemical crop protection products. However, an economically successful stragegy has been to use plants with herbicide-resistant genes in combination with herbicides. 

For example, Monsanto produces seeds for soya, maize, and cotton, among other plants, that are resistant to the total herbicide glyphosate. This agent accounted for 59 per cent of the company’s gross earnings in plant protection last year and dominates the herbicide market in the US. 

"Nearly 60 per cent of the acreage farmed with transgenic plants is in the US"

So far, relatively little acreage is farmed with transgenic plants. Globally, it amounted to 81 million hectares in 2004, according to the International Service for the Acquisition of Agro-Biotech Applications. Nearly 60 per cent of this is in the US, where transgenic maize, herbicide tolerant soya bean, and transgenic cotton are the main cultivates. 

Other countriues with considerable acreage include Argentina (16.2 million hectares), Canada (5.4 million), Brazil (5 million), China (3.7 million) and Paraguay (1.2 million). The only EU member state with more than 50 000 hectares used for transgenic plants is Spain, where farmers grow Bt-maize, a variety that contains a gene of the bacterium Bacillus thuringiensis producing an insecticide. With a global acreage of 11.2 million hectares, Bt-maize is the second most common transgenic plant. The leader is herbicide tolerant soya bean, whose global acreage amounts to 48.4 million hectares. Farmers in Argentina cultivate almost exclusively the genetically manipulated variety of soya bean. 

Gene technology legislation

In Germany, the cultivation of transgenic plants is hardly on the agenda. The industry blames the gene technology law, that came into force at the beginning of this year. It states that farmers are liable if, for example, genetically modified pollen is transferred to neighbouring, conventionally cultivated fields, by insects or wind. 

According to Norbert Lemken, of Bayer CropScience, this has given a negative signal for Germany as a research location: ’We in Germany are missing the opportunity to develop the potential of this key technology.’ Nevertheless, Bayer CropScience is going to continue its involvement in plant biotechnology, because the company believes in its advantages. In locations like Belgium or France, researchers from the bioscience department investigate, for example, stress tolerant plants, seed improvements or potatoes with an extremely high starch content. 

BASF also conducts research into starch-rich potatoes which are being considered as a renewable resource for the paper, glue, and textile industries. Furthermore, BASF researchers would like to transfer genes from Arabidopsis thaliana into crop plants like maize, soya, or wheat, to improve their drought resistance. Both Bayer CropScience and BASF are testing the modified potatoes in field trials, but will not reveal where. 

Anke Hubenthal is a freelance science writer based in Karlstein, Germany. 
Translated by Michael Gross

RSC and GDCh cooperate

As part of the RSC and the German chemical society’s (GDCh) collaborative work, Chemistry World and Nachrichten aus der Chemie are publishing a series of articles simultaneously in both magazines. This article continues the series.