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Food Safety

Scientific Committees Scientific Committee on Plants Outcome of discussions Plant Protection Products

Opinion of the Scientific Committee on Plants regarding the evaluation of Paecilomyces fumosoroseus in the context of Council Directive 91/414/EEC concerning the placing of plant protection products on the market (opinion adopted by the Scientific Committee on Plants on 30 November 2000)

1. TITLE

OPINION OF THE SCIENTIFIC COMMITTEE ON PLANTS REGARDING THE EVALUATION OF PAECILOMYCES FUMOSOROSEUS IN THE CONTEXT OF COUNCIL DIRECTIVE 91/414/EEC CONCERNING THE PLACING OF PLANT PROTECTION PRODUCTS ON THE MARKET

(Opinion adopted by the Scientific Committee on Plants on 30 November 2000)

2. TERMS OF REFERENCE

The Scientific Committee on Plants (SCP) is requested to respond to the following questions in the context of the Commission's work on the implementation of Council Directive 91/414/EEC concerning the placing of plant protection products on the market.

1) Is the issue of residue levels in food and feed adequately addressed in relation to the safety requirements of Article 5 of Council Directive 91/414/EEC?

2) Given the absence of models for assessing operator exposure for microbial pesticides - has this issue been adequately addressed in relation to Article 5 of Council Directive 91/414/EEC?

3) With regard to possible hazard to humans, should repeated dosing be part of the primary data set?

4) It is known that certain health problems can arise from working with microbial pesticides e.g. allergies developed when glasshouse workers were exposed to attenuated strains of tobacco mosaic virus (TMV). Would a post authorisation requirement to monitor the health of workers (blood testing etc.) be a prudent measure? If so, what measures would the Committee recommend?

3. BACKGROUND

The draft Commission Directive for inclusion of Paecilomyces fumosoroseus in Annex I to Directive 91/414/EEC 1 concerning the placing of plant protection products on the market was submitted to the Committee for their opinion. The Committee had been supplied with documentation comprising a monograph prepared by the Rapporteur Member State (Belgium) based on a dossier submitted by the notifier (Biobest), a review report prepared by the Commission and the Recommendations of the ECCO 2 Peer Review Programme.

Paecilomyces fumosoroseus is a fungus intended for use with glasshouse food crops (tomato, cucumbers) to control whiteflies in conjunction with other forms of biological control.

4. OPINION

4.1 Question 1

"Is the issue of residue levels in food and feed adequately addressed, in relation to the safety requirements of Article 5 of Council Directive 91/414/EEC?"

Opinion of the Committee:

In view of the biological properties and the mode of use of this product, the information provided is sufficient to establish that no adverse effects are expected from residues in food or feed. Consequently the SCP is of the opinion that the safety requirements of Article 5 of Council Directive 91/414/EEC have been adequately addressed.

Scientific background on which the opinion is based:

4.1.1 General considerations

Unlike chemicals added to biological systems where any residues detected are the parent compound or its metabolites, living organisms introduce higher levels of organisation and this is reflected in the nature of any retained material. Material retained is more likely to consist of the organism itself, either in an active metabolic state or in some form of resting stage, non-viable cells, or fragments of the organism. In addition the added organism may produce metabolites at any stage of its production or final use which may then be further transformed by other micro-organisms and/or the host. Any assessment of safety must consider the possibility and consequences of the added organisms entering and remaining with the food chain as well as the fate of any metabolites.

4.1.2 Paecilomyces fumosoroseus

Paecilomyces fumosoroseus Apopka 97 is a representative of a group of entomopathogenic hyphomycetes with no known perfect stage (perfect stage of related strains is Byssochlamys). It is marketed in the form of water-dispersible granules containing 20% mycelium and blastospores. The other ingredients of the final product only include ingredients approved for food use by the US EPA 3 .

4.1.3 Survival on the treated plant

Blastospores, which form the bulk of the active components of the final product, germinate only in the presence of living insects or debris derived from insects. Any further contamination of plant surfaces by conidiospores released from the mycelium following invasion of the insect host is minimal compared to the initial treatment.

Treatment is limited to a maximum of three applications /crop and the product is to be used only on vegetative plants. However, immature fruits may be exposed. There is no evidence of the fungus germinating in the absence of insect hosts and becoming established on or in the plant. Any residues on mature fruit would derive from such incidental exposure to fungal spores, thus mature tomatoes and cucumbers should normally be free of the fungus.

4.1.4 Toxicity of viable spores

Three acute toxicity tests were carried out in rats each involving the delivery of approximately 2 x 10 6 cfu 4 to each animal (~10 8 cfu kg -1 body weight) respectively by oral, peritoneal and respiratory (intra-tracheal) route. All animals survived and no clinical abnormalities were recorded.

No invasion of tissues occurred following oral administration and spores disappeared from blood samples within two days (the earliest observation time) following intra-peritoneal injection.

Following intra-tracheal instillation, the lung homogenates were heavily infected on day one. But viable spores were found only in the lungs of a single animal at day four and none thereafter. Spores were also detected in the caecum of four animals after day four but this was probably due to a secondary ingestion.

These results establish the absence of any toxic effects following exposure to a high dose of the fungus in the form of conidiospores.

4.1.5 Pathogenicity

There are no reports of P. fumosoroseus as a pathogen of humans or livestock.

Other Paecilomyces species are saprophytic and widely distributed in soils, in decaying vegetation and as airborne contaminants. Despite their ubiquity , saprophtyic Paecilomyces species are rarely a cause of fungal infections in humans. Only two species, P. lilacinus and P. variotii, are reported to be occasional pathogens of human and animals. They are most commonly associated with ocular infections but also with infections occurring via a respiratory route (bronchopulmonary mycosis).

P. lilacinus is a known source of toxins including leucostatins triggering an inflammatory response and paecilotoxins with strong uncoupling activity towards mitochondria.

4.1.6 Production of metabolites

The absence of significant levels of contamination and outgrowth on the plant makes the in situ production of metabolites, toxic or otherwise, virtually impossible. Any metabolites occurring in anything other than trace amounts would have to derive from the fermentation process and be incorporated in the final product.

P. fumosoroseus Apopka 97 is known to produce beauverolides, a group of compounds showing some insecticidal activity. Beauverolides are said not to be present in the rapidly grown commercial product and only to accumulate in the filtrates of cultures grown under condition of low oxygen tension for extended periods. Although the growth conditions during the industrial production of the micro-organism, are unfavourable to the production of beauverolides, the method proposed by the notifier to monitor the presence of beauverolides in the fermentation broths can be used to ensure the absence of beauverolides in the commercial products.

4.1.7 Conclusion

Given the very limited probability of germination in the absence of an insect host, residues consist of only very low levels of blastospores and conidiospores incidentally deposited on the immature fruits. Normal washing before sale would further reduce or remove this minor contamination. Even in the absence of this risk management step, there is no evidence to suggest that the exposure of consumers to the spores of P. fumosoroseus Apopka 97 at concentrations far greater than would be encountered as a consequence of their intended use has any deleterious effects.

4.2 Question 2:

"Given the absence of models for assessing operator exposure for microbial pesticides - has this issue been adequately addressed in relation to Article 5 of Council Directive 91/414/EEC?"

Opinion of the Committee:

In spite of the absence of specific and validated methods to assess exposure to micro-organisms used as PPPs 5 , the risk estimates derived from the application of the methods adopted for chemical PPPs indicate the presence of a sufficient margin of safety for the operators, bystanders, and agricultural workers in the intended uses of Paecilomyces fumosoroseus.

Scientific background on which the opinion is based:

4.2.1 General considerations

In analogy to chemical substances, intake of microbiological PPPs by the operators can occur by inhalation, ingestion and skin penetration. In the case of inhalation, the size of the micro-organism-bearing particles is important to determine the site of the airways where they may deposit and the route of absorption. Assuming a behaviour similar to that of inhalable dust, particles greater than 20-30 m m would only be inhaled in minimal amounts, while particles from 20 to 5 m m would mostly deposit in the upper airways, and particles less than 5 m m would reach the smaller bronchioles and deeply penetrate into the lungs. The particles deposited in the nose, larynx and pharynx can successively be ingested. The penetration of the micro-organism through intact skin is likely to occur to a very limited (if any) extent, except when the micro-organism can colonise the epidermis and become established.

Specific models to assess operator exposure to biological PPPs are not available and the experience in this area is rather limited. Since operator exposure has to be in any case assessed, the SCP is of the opinion that the methods and the models used for the chemical PPPs can be adapted to this purpose. This assumes that a microbial propagule is quantitatively comparable to a mass of chemical molecules and the quantitative contamination created by spraying suspensions of micro-organisms is analogous to that generated by chemical PPPs. Such a procedure allows the dose expected to reach the operator to be estimated and, after conversion in terms of micro-organism mass, to compare the exposure values with the inoculum concentrations used in the toxicity studies or, when available, with NOAELs 6 .

Similar considerations apply to bystander exposure and to agricultural workers exposure, although the differences in adherence and skin penetration between chemical and biological PPPs may be large.

As indicated above, it has to be recognised that operator exposure assessment for micro-organisms used as PPPs is currently far from accurate and that any proposed method of assessment can only provide a general, approximated estimate of risk. Thus a sufficiently large margin of safety has to be present in order to ensure compliance with the provisions of Article 5 of the Directive 91/414/EEC. Moreover, while the quantitative assessment of exposure to micro-organisms is relevant to the assessment of the toxic and infection risk, other potential adverse effects such as allergic reactions cannot be adequately predicted and assessed with this method [this issue is addressed below under question 4].

4.2.2 Paecilomyces fumosoroseus

Operator exposure to P. fumosoroseus was not adequately assessed in the dossier submitted by the notifier. However, an assessment was provided by the RMS 7 at the ECCO meeting. According to the RMS, exposure by inhalation during mixing/loading of the WG formulation and hand-held application (calculated with the German model) amounts to 0.002 mg a.s./person for 1 kg active substance applied. If the product is applied to 1 ha at the maximum rate of 600g blastospores/ha, 0.0012 mg - corresponding to 10 4 spores - could be inhaled. Toxicity studies with P. fumosoroseus have been conducted with the intratracheal administration of 10 6 conidia/animal and, in Sprague-Dawley rats with 10 8 and 10 9 conidia/animal, which represent worst case scenarios, without detecting any adverse effects. Higher doses have not been tested. Thus the resulting margin of safety can be estimated to be greater than 10 2-10 5 and, as such, sufficient.

With respect to bystander exposure, since the product is intended for use only in glasshouses, the possibility of inadvertent presence of bystanders can be reasonably excluded.

Exposure of operators during harvesting has been considered to be negligible as a significant inhalation exposure from dispersion of dislogeable residues would only potentially occur in the presence of strong wind - a condition very unlikely in glasshouses - and skin exposure is not relevant due to the skin barrier to penetration.

4.2.3 Conclusion

In spite of the absence of specific and validated methods to assess exposure to micro-organisms used as PPPs, the estimates provided by applying the methods adopted for chemical PPPs indicate the presence of a sufficient margin of safety for the operators in the intended uses of P. fumosoroseus. No significant exposure is expected either for bystanders or for agricultural workers at harvesting.

4.3. Question 3:

"With regard to possible hazard to humans, should repeated dosing be part of the primary data set?"

Opinion of the Committee:

The SCP is of the opinion that repeated dosing should in general be part of the primary data set, but repeated dosing can be omitted provided that adequate justification can be offered based on the biological properties of the micro-organism and the results of acute toxicity and pathogenicity studies. In the specific case of Paecilomyces fumosoroseus, and in the light of the results of the available studies, the SCP is of the opinion that repeated dosing is not necessary to assess hazard to humans.

Scientific background on which the opinion is based:

4.3.1 General considerations

In general, it is advisable to perform repeated dose studies in order to get a proper insight into the ability of micro-organisms to cause adverse effect in mammals. However, repeated dosing may not be necessary when knowledge of the biological properties of the agent and the results from acute toxicity studies are sufficiently clear to conclude that the agent is non-toxic. If, on the basis of acute toxicity data or for other reasons, doubt remain, repeated dosing should be performed.

Repeated dosing is also not deemed necessary when the results of the acute toxicity and pathogenicity studies enable to conclude in the absence of infectivity and of toxicity due to toxins or metabolites produced by the micro-organism.

4.3.2 Paecilomyces fumosoroseus

The results of the acute toxicity studies are clear enough to conclude in the absence of toxicity or pathogenicity induced by P. fumosoroseus. Moreover, P. fumosoroseus is not able to grow at temperatures higher than 32°C and will therefore not develop in mammals.

Therefore repeated dosing is not considered to be necessary.

4.3.3 Conclusion

Based on results of the acute toxicity studies, it is concluded that in the case of Paecilomyces fumosoroseus, repeated dosing is not necessary to evaluate hazard to humans.

4.4 Question 4

"It is known that certain health problems can arise from working with microbial pesticides e.g. allergies developed when glasshouse workers were exposed to attenuated strains of tobacco mosaic virus (TMV). Would a post authorisation requirement to monitor the health of workers (blood testing, etc.) be a prudent measure? If so, what measures would the Committee recommend?"

Opinion of the Committee:

The possibility of occurrence of allergic reactions resulting from agricultural exposure to Paecilomyces fumosoroseus cannot be excluded. Greater confidence on the absence of allergenic response in humans can only be provided by direct observation on subjects exposed to it in its production or use.

Therefore the SCP considers that monitoring the health of producers and users would be a prudent measure. In the case of an allergic reaction being recorded in these subjects, the causative agent should be identified and notified to the competent authority of the relevant Member State. The results of the monitoring should be made available for future re-assessment.

Scientific background on which the opinion is based:

4.4.1 Generalities on allergy

The term allergy denotes a condition of hyper-reactivity of the immune system of an organism which may be the cause of pathological reactions of clinical significance on repeated contact with substances (allergens) against which the organism is hypersensitive. Since food allergy is a particular phenomenon involving the gastro-intestinal immune system and the oral exposure for workers is likely to be negligible, the issue of food allergy is not addressed.

The substances acting as allergens, possess a variety of chemical structures. This fact makes it difficult to predict the allergenic potential of a substance based on its structural or chemico-physical properties. Many substances of biological origin, in particular proteins and glycoproteins, have the potential to act as allergens, although the (genetic) predisposition of the host plays a determinant role in the onset of the allergic reaction. Heterologous animal testing of a substance to predict the allergenic risk for man has limited value because of interspecies differences in allergic reactivity and inability of these tests to predict the inter-individual human variability in response.

4.4.2 Allergic responses to microbial aerosols

Allergic reactions induced by fungi in man may take the form of allergic interstitial pneumonitis, a syndrome caused by inhalation of organic dust and characterised by granulomatous infiltrates in the lungs and symptoms such as fever and cough. In allergic interstitial pneumonitis the hypersensitivity reaction results in a granulomatous reaction in alveolar septums, with collection of lymphocytes, plasma cells and epithelioid cells. Ordinarily eosinophils (which are common in diseases such as hay rhinitis and asthma) are not part of the cellular infiltrate. In most instances, the antigens appear to be products of bacterial and fungal growth in stored vegetable materials. Precipitating antibodies to the inciting antigen occur in most patients and appear to mediate the reaction. In these conditions the period of exposure required to establish the specific sensitivity is uncertain, but once sensitisation is established, inhalation exposure to the antigen commonly leads to a moderately acute illness in a matter of hours.

In the case of Farmer's lung, agricultural workers may develop chills, fever, cough, and dyspnea rapidly, a few hours after exposure to mouldy organic dusts (hay, grain, corn, tobacco, etc.). Mouldy hay is rich in thermophilic actinomycetes ( Micropolyspora faeni and Micromonospora vulgaris) as well as a number of fungal species ( Aspergillus, Cladosporium, Mucor, Penicillium, and Humicola). The serum of patients with Farmer's lung contains precipitating antibodies against extracts of mouldy hay dust but none to clean hay dust. Furthermore, when inhaled by aerosol, extracts of mouldy hay or cultures of the actinomycetes will produce typical attacks.

In the case of Maple bark disease, sawmill or logging workers may develop typical attacks of interstitial pneumonitis after shaving or peeling bark from maple logs that have been stored for some time after cutting. Examination of the logs reveals heavy growth of the sporulating mould Cryptostroma corticale. Lung biopsies may show a number of inhaled spores; these spores have not germinated or grown mycelium, but by their presence, they initiate a strong hypersensitivity reaction. Similar syndromes occur after exposure to redwood or elm sawdust and are due to sensitivity to fungi of the genus Graphium.

Hypersensitivity pneumonitis has also been observed after exposure to organic dust in buildings. The agents responsible for these forms have included thermophilic actinomycetes, Pullularia, Cladosporium cladosporoides, Penicillium species, and endotoxins.

Humidifier fever is an influenza-like illness characterised by headache, myalgia, lethargy, fever and dyspnea occurring the first day back at work after a break, usually resolving within 24 hours and not recurring despite continued exposure to the polluted environment until a further period away from work. The specific cause(s) of humidifier fever are not known, however postulated causes include allergens from protozoans, Bacillus subtilis and bacterial or fungal endotoxins.

4.4.3 Allergenic potential of Paecilomyces fumosoroseus

No cases of allergic reactions have been observed amongst the limited number of operators monitored for adverse effects and no case has been reported in the USA where this product has been authorised as an active ingredient since 1998 8 . Occasional cases of infectious allergic bronco-pneumonitis have been reported after primary and secondary infection with fungi of the Paecilomyces genus such as P. variotii.

The allergenic potential of exposure to P. fumosoroseus following a large-scale use in agriculture is difficult to assess on a theoretical base. The possibility of occurrence of these reactions cannot be excluded, given the scarce knowledge available and the limited experience of use. A greater confidence on the absence of allergenic potential of this micro-organism in humans can only be obtained by direct observation of a significant number of subjects exposed to it in its production or use.

Given the fact that individual susceptibility is of great importance in allergic responses and allergic reactions usually concern a minority of the human population, a sufficiently large number of subjects need to be kept under observation in order to draw valid conclusions about the absence of allergic responses.

4.4.4 Conclusion

The possibility of occurrence of allergic reactions to P. fumosoroseus cannot be excluded, given the scarce knowledge available and the limited experience of use.

Therefore the SCP considers that monitoring the health of producers and users would be a prudent measure. In the case of an allergic reaction being recorded in these subjects, the causative agent should be determined and the competent authority of the relevant Member State notified. The results of the monitoring should be made available for future re-assessment.

5. DOCUMENTATION MADE AVAILABLE TO THE COMMITTEE

1. Terms of reference "Evaluation of Paecilomyces fumosoroseus in the context of Council Directive 91/414/EEC concerning the placing of plant protection products on the market" (Doc. SCP/PAECIL/001).

2. Evaluation table Doc. 6866/VI/98 rev.3 (Doc. SCP/PAECIL/003-Rev.1).

3. Draft review report Doc. 4203/VI/98-rev.2 (Doc. SCP/PAECIL/005).

4. Appendices to Evaluation of Paecilomyces fumosoroseus in the context of Council Directive 91/414/EEC concerning the placing of plant protection products on the market - 14 January 2000 (Doc. SCP/PAECIL/006).

5. Response from the notifier to the question (SCP/PAECIL/004) raised by the SCP (Doc. SCP/PAECIL/007).

6. Reply from the notifier to the SCP following the request for information concerning the reasons for the non-authorisation of the substance on food crops in the USA (Doc. SCP/PAECIL/008).

7. Monograph prepared in the context of inclusion of Paecilomyces fumosoroseus Strain Apopka 97 in Annex I of Council Directive 91/414/EEC - Ministère des classes moyennes et de l'agriculture - Belgium (Volumes 1 to 4 - December 1997).

6. ACKNOWLEDGEMENTS

The Committee wishes to acknowledge the contributions of the working groups that prepared the initial draft opinion.

Micro-organism plant protection products Working Group: Prof. O'Gara (Chairman) and Committee Members Dr. Delcour-Firquet, Prof. Maroni, Dr. Meyer, Prof. Silva Fernandes, Dr. Speijers, invited experts: Dr. Alabouvette, Dr. Chesson, Prof. Defago, Prof. Gismondo, Prof. Nuti, Dr. Stead and Prof. von Wright.

Toxicology Working Group: Prof. Maroni (Chairman), and Committee Members Dr. Delcour-Firquet, Dr. Meyer, Dr. Moretto, Prof. Silva Fernandes, Dr. Speijers, Prof. Savolainen and invited expert Dr. Fait.

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1 OJ N° L 230 of 19. 8.1991, p. 1.

2 European Community Co-ordination.

3 US Environment Protection Agency.

4 Colony forming units (unit of measurement of viable micro-organisms).

5 Plant Protection Products.

6 No observed adverse effect level.

7 Rapporteur Member State.

8 Source EPA http://www.epa.gov/oppbppd1/biopesticides/factsheets/fs115002e.htm

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