Risk Assessment of the Insecticide Plenum 50 WG with the Active Substances Pymetrozine

Plenum is a new insecticide containing the new active substance pymetrozine. Plenum is an insecticide against different pests in ornamentals, lettuce, cucumber and tomato in greenhouse and against pollen beetles in oilseed- and turnip rapes. The risk assessment was finalized at a meeting Mai 29, 2012, by VKM’s Scientific Panel on plant protection products (VKM). The Panel is in particular asked by the Norwegian Food Safety Authority to look at the following: The human health risk for operators related to the properties of the active substance and the product. The Panel is in particular asked to look at the following: o The effects seen in studies on dog and if these effects warrant a classification for chronic toxicity. o The oncogenic effects in liver and lungs o The genotoxicity of metabolite CGA 300407. o The effects on reproduction and if the effects seen in teratology studies and developmental neurotoxicity study warrant a classification for developmental toxicity o The establishment of NOAELs and reference values (ADI, AOEL and ARfD). o The classification and labelling of the active substances and the product. VKM’s conclusion is as follows: The effects reported in the repeated dose toxicity studies with dogs should be considered as adverse. The increased incidence of liver and lung tumors should be considered as relevant for humans. It cannot be excluded that a genotoxic mechanism could be involved in the formation of the liver tumors, which would have implications for risk assessment. It should therefore be considered to test pymetrozine in more sensitive in vivo genotoxic endpoints in liver. The effects reported in the teratogenicity studies in rats and rabbits and in the developmental neurotoxicity study in rats should be considered for a classification of pymetrozine for developmental toxicity. Risk calculations with both the German model and the UK POEM show low risk if personal protection equipment is used. VKM propose: NOAEL of 0.6 mg/kg bw/day for pymetrozine based on the 1-year study in dogs. AOEL of 0.006 mg/kg bw/day for pymetrozine based on the NOAEL value at 0.6 mg/kg bw/day from the one year study in dogs and an UF of 100. ADI of 0.006 for pymetrozine based on the NOAEL value at 0.6 mg/kg bw/day from the one year study in dogs and an UF of 100. ARfD of 0.02 mg/kg bw/day for pymetrozine based on the LOAEL value at 8.1 mg/kg bw/day from the developmental neurotoxicity study and an UF of 500 (10 x interspecies difference, 10 x intraspecies difference, 3 x due to the use of a LOAEL value and 2 x due to the adversity of the neurodevelopmental effects). VKM supports the classification proposal from Norwegian Food Safety Authority.

Risk Assessment of the Insecticide Movento 100 SC with the Active Substance Spirotetramat

Movento 100 SC is a new insecticide containing the active substance spirotetramat. The intended use is in stone fruit, pome fruit, vegetables and ornamentals outdoors, and lettuce, tomatoes and cucumbers in greenhouses. VKM was requested by the Norwegian Food Safety Authority to consider possible health risk for operators related to the properties of Movento 100 SC; in particular the relevance of the effects of spirotetramat on thyroid hormones, brain, thymus and body weight observed in dogs, and the reproductive effects of spirotetramat observed in rats. VKM was also asked to consider the fate and behaviour of Movento 100 SC with the active ingredient spirotetramat in the environment, and the ecotoxicological effects and risks related to its use. The risk assessment was finalized in a meeting on May 24. 2013, by VKM’s Scientific Panel on Plant Protection Products. VKM’s conclusions are as follows: Health: VKM concludes that spirotetramat shows toxic effects in dogs and rats that could be relevant for humans. Thyroid and thymus glands are target organs in the oral subchronic toxicity studies of spirotetramat in dogs, and effects are observed from 19 mg/kg bw/day (600 ppm). Decreases in circulating thyroid hormone levels were detected in all three studies carried out with dogs (28-, 90-days and 1-year) and should be considered toxicologically relevant. The opinion of the Panel is that it cannot be excluded that the observed brain dilatation in dogs is treatment-related, and relevant to humans. Furthermore, VKM concludes that the reproductive effect observed in rats could be relevant for humans. VKM proposes a NOAEL of 5 mg/kg bw/day (200 ppm) for spirotetramat based on a 1- year toxicity study in dogs, and a NOAEL of 100 mg/kg bw/day based on the acute neurotoxicity study in rats. VKM supports/proposes: ADI: 0.05 mg/kg bw/day. AOEL: 0.05 mg/kg bw/day. ARfD: 1 mg/kg bw/day. Risk calculations show minimal risk if personal protective equipment is used. Environment: VKM concludes that spirotetramat and its metabolites are not expected to accumulate in soil. It is not expected that spirotetramat or any of its metabolites will reach concentrations in groundwater above the threshold level of 0.1 μg/L when the formulation Movento 100 SC is applied according to the intended use. VKM concludes that use of Movento 100 SC with the active substance spirotetramat according to the proposed application scheme in Norway represents a minimal risk of adverse effects on terrestrial mammals, birds, earthworms, and soil microorganisms. However, in-field effects on sensitive species of predatory mites in the crop cannot be excluded. The risk of adverse effects on bees is minimal providing that spirotetramat is not used on crops during flowering or when bees are actively foraging. For aquatic organisms in surface water, the risk is considered minimal, provided that a 5 m buffer zone to open water is used.

Risk Assessment of the Growth Inhibitor Bonzi with the Active Substance Paclobutrazol

Bonzi is a new plant growth regulator containing the active ingredient paclobutrazol of the triazole chemical class. Bonzi is for use on ornamental plants, such as Chrysanthemum, Perennial Plants, Bedding Plants, Foliage Plants, Geraniums, Hibiscus and Azaleas, in nurseries and greenhouses. VKM was requested by the Norwegian Food Safety Authority to consider the potential of Bonzi and paclobutrazol to induce reproductive effects in humans; in particular the relative sensitivity and relation between maternal effects and the effects on the offspring; and to what extent cleft palate observed in developmental studies in rat can be regarded as a specific teratogenic effect of relevance for humans. The risk assessment was finalized in a meeting in VKM’s Scientific Panel on Plant Protection Products on May 24. 2013. VKM’s conclusions are as follows: No adverse effect on fertility or reproductive performance was seen in rats. VKM concluded that the incidences of twisted snout observed in the F1 and F2 offspring of paclobutrazol treated rats are not likely to represent a developmental alteration, but rather an unspecific toxic effect. Marked maternal toxicity was seen in rats above 250 mg/kg bw/day, while partially ossified 7th cervical transverse processes and supernumerary 14th ribs were found in the offspring at 10 - 40 mg/kg/day. VKM concluded that the latter should be regarded as a direct teratogenic effect of paclobutrazol. Furthermore, VKM concluded that the data from the developmental toxicity studies are inconclusive regarding the effect on cleft palate development in rat foetuses. VKM proposes a NOAEL of 2.5 mg/kg bw/day for paclobutrazol based on a developmental toxicity study in rats.

Risk Assessment of the Fungicide Talius with the Active Substances Proquinazid

Talius is a new fungicide containing the new active substance proquinazid. Talius is a fungicide against cereal powdery mildew (Blumeria graminis) in cereals and grass seed. The risk assessment was finalized at a meeting Mai 29, 2012, by VKM’s Scientific Panel on plant protection products (VKM). VKM is in particular asked by the Norwegian Food Safety Authority to look at the following: The human health risk for operators related to the properties of the active substance and the product. o The effects seen in studies on dog and if these effects warrant a classification for chronic toxicity. o The oncogenic effects in liver and thyroid. o The establishment of reference values (ADI, AOEL and ARfD). o Dermal absorption. o The classification and labelling of the active substances and the product. • The fate and behaviour in the environment and the ecotoxical effects and risks with regard to the properties of Talius and proquinazid. VKM’s conclusion is as follows: Health: VKM concluded that a less serious effect (dose-related ocular discharge increase) was seen in dogs in both the 90 days study and 1 year-study. The opinion of the Panel is that cholangiocarcinomas is relevant for the classification of cancer and VKM is concerned about these effects. VKM proposes an NOAEL of 1.2 mg/kg bw/day for proquinazid based on the 2 year study with rats. VKM support: The proposed ADI value of 0.01 mg/kg bw/day. • The proposed AOEL value of 0.02 mg/kg bw/day. The proposed ARfD value of 0.2 mg/kg bw/day. • The proposed classification from The Norwegian Food Safety Authority. VKM supports The Norwegian Food and Safety Authority calculations for dermal absorption under Norwegian directions for use (2.6 times higher dilution). Environment: Proquinazid can be persistent under prevailing conditions in Norway and the Panel considers the results from the Finnish PEC calculator to be relevant for Norwegian conditions and expects that repeated annual applications may cause accumulation in soil up to an equilibrium level under Norwegian conditions.The potential for groundwater contamination from leaching of proquinazid and its metabolites are low. There are minimal risks for toxic effects of proquinazid to terrestrial organisms, sediment dwelling organisms, aquatic plants, and algae with the proposed application regime. For fish and invertebrates minimal risks are calculated provided that a 3 m buffer zone is used.

Risk Assessment of the Fungicide Luna Privilege with the Active Substance Fluopyram

Luna Privilege is a new fungicide for use in apples, pears, outdoor and indoor strawberries, outdoor and indoor lettuces, peas, beans and indoor tomatoes, and contains the new active substance fluopyram. VKM was requested by the Norwegian Food Safety Authority to consider the possible health risk for operators related to the properties of Luna Privilege and fluopyram; in particular to evaluate the potential for bioaccumulation, reproductive and neurotoxic effects, and discuss possible mechanisms involved in liver and thyroid tumor formation observed in rats, and the establishment of NOAELs and reference values. VKM was also asked to evaluate the fate and behaviour of fluopyram in the environment, and the ecotoxicological effects and risks related to its use, in particular the potential for groundwater contamination, safety margins and possible effects on birds and aquatic organisms. The assessment was finalized in a meeting on December 13. 2013 by VKM’s Panel on Plant Protection Products. VKM’s conclusions are as follows: Health: It is the opinion of VKM that: The active ingredient fluopyram has low potential for bioaccumulation, and the data do not suggest a sex-specific excretion. An in vivo Comet Assay in rat liver could help to further elucidate the genotoxic potential of fluopyram. It can not be excluded that the reported incidence of “gall bladder absent” is treatment related. NOAEL for the 90-day feeding study in rats should be set to 3.06 mg/kg bw/day, resulting in an AOEL of 0.03 mg/kg bw/day. The “dumb-bell or incomplete ossification and/or bipartite/normal cartilage” should be considered as a malformation and regarded as treatment related. The time points used for neurotoxic measurements are not optimal to detect neurotoxic effects from acute exposure, since the time window between the first and second measurements is too long. The studies where effects of fluopyram and phenobarbital are compared can not be used to exclude human relevance of the tumor-inducing effect of fluopyram in the liver of female rats. The results from the mechanistic studies are insufficient to support the proposed mode of action for the induction of thyroid follicular cell tumors in male mice, and thus the induction of thyroid tumors in male mice could be relevant for humans. VKM proposes: NOAEL of 1.2 mg/kg bw/day based on a 2 year feeding study in rats. ADI: 0.012 mg/kg bw/day AOEL: 0.03 mg/kg bw/day ARfD: 0.25 mg/kg bw/day Risk calculations for field use of Luna Privilege show minimal risk if personal protective equipment is used. The AOEL of fluopyram for greenhouse use is not exceeded, even without protective equipment. Re-entry and bystander exposure is calculated to be well below the AOEL. Environment: It is the opinion of VKM that: Worst case degradation rates from laboratory studies should preferably be used to calculate PECsoil values for fluopyram. Both fluopyram and fluopyram-7-hydroxy have a high potential for groundwater contamination. The efficacy of buffer zones needs to be considered on a case-by-case basis, and further validation of values for efficacy from the model simulation is necessary. It is further the opinion of VKM that all the refinements used in the risk assessment for birds are relevant. Since the TER values estimated for all crops except for orchards are below the trigger following refinements, it is the view of VKM that the data indicate medium risk for strawberries and pulses, and high risk for lettuce in open field. The use of LC50 values for fluopyram in the TER calculations with a TER trigger value of 100 is overly conservative, and a reduction of the acute trigger for both invertebrates and fish from 100 to 10 for such calculations are suggested. The trigger for acute toxicity is not exceeded for any of the crops. For chronic toxicity, VKM concludes that there is a moderate risk for effects on fish when Luna Privilege is applied to beans/strawberries without the use of a vegetated mitigation buffer-strip.

Risk Assessment of the Fungicide Infinito with the Active Substances Fluopicolide and Propamocarb HCL

Infinito is a new fungicide containing the two active substances fluopicolide and propamocarb-HCL. Infinito is a new generation fungicide to protect potatoes against the blight pathogen phytophtora infestans. The risk assessment was finalized at a meeting Mai 29, 2012, by the Panel on plant protection products of the Norwegian Scientific Committee for Food Safety (VKM). The Norwegian Food Safety Authority would like, in this regard, an assessment of the following: The fate and behaviour in the environment and the ecotoxicological effects and risks with regard to the properties of Infinito and the active substances. The Panel is particularly asked to look at the following: o The persistence of fluopicolide and its metabolites. o The leaching potential of fluopicolide and its metabolites. VKM considers both fluopicolide and its main metabolite M-01 (2,6-dichlorobenzamid (BAM)) to be persistent in Norwegian soils and surface waters. Other conclusions from VKM are as follows: Fluopicolide and its main metabolite may have a significant potential for soil accumulation after repeated use under Norwegian conditions.Fluopicolide shows low mobility in both studies and modelling. Metabolite M-01 (BAM) is however highly mobile.There is minimal risk for toxic effects of fluopicolide to terrestrial and aquatic organisms with the proposed application regime.

Risk Assessment of the Fungicide Aviator Xpro EC 225 with the Active Substances Bixafen and Prothioconazole

Aviator Xpro EC 225 is a new fungicide for use in cereals, containing the new active substance bixafen and the already approved active substance prothioconazole. Prothioconazole was assessed by the Norwegian Scientific Committee for Food Safety in 2006, and is therefore not included in this report. VKM was requested by the Norwegian Food Safety Authority to consider the possible health risk for operators related to the properties of bixafen used in Aviator Xpro EC 225; in particular to evaluate the relevance of the effects of bixafen on liver and coagulation parameters observed in rats and mice, thyroid tumours and reproductive effects observed in rats, and the establishment of NOAELs and reference values. VKM was also asked to evaluate the fate and behaviour of bixafen in the environment, and the ecotoxicological effects and risks related to its use. The risk assessment was finalized in a meeting on May 24. 2013 by VKM’s Scientific Panel on Plant Protection Products. VKM’s conclusions are as follows: Health: VKM concluded that the liver effects reported in sub-chronic and chronic studies in rats, dogs and mice exposed to bixafen, as well as the effects on coagulating parameters, should be considered adverse and of relevance to humans. It is the opinion of VKM that the thyroid follicular cell tumours reported in female rats exposed to bixafen is not sufficient to suggest that bixafen has a tumour inducing potential. It is further the opinion of VKM that it cannot be excluded that the reduced pup weight during lactation in the two-generation study is mediated by bixafen via the milk, and that bixafen has a direct effect on the number of stillborn pups in the F1 and F2 generation. Finally, the pup developmental variants and anomalies reported in the teratogenicity study are considered treatment related, and not as secondary effects related to maternal toxicity. VKM proposes a NOAEL of 2.0 mg/kg bw/day based on a 2 year feeding study in rats. VKM support/propose: ADI: 0.02 mg/kg bw/day AOEL: 0.13 mg/kg bw/day ARfD: 0.2 mg/kg bw/day Risk calculations show minimal risk if personal protective equipment is used. Environment: Bixafen is shown to be persistent in soil. VKM considers the results from a field study on a German site and the Finnish PEC calculator to be relevant and concludes that repeated annual applications can cause accumulation in soil under Norwegian conditions. There is also a potential for groundwater contamination from leaching of the metabolite M44. VKM has concluded that the use of bixafen as an ingredient in Aviator Xpro EC 225 with the proposed application regime in Norway will represent a minimal risk for toxic effects to terrestrial organisms. The toxicity of bixafen to aquatic organisms is high, and minimal risk of effects in surface waters can be achieved only if risk mitigation measures with bufferzones of 10 m are applied.

Risk Assessment of the Biological Plant Protection Products Nemasys G and Nemasys H with the Active Organism Heterorhabditis Bacteriophora

Nemasys G and Nemasys H with the nematode Heterorhabditis bacteriophora as the active organism is applied for as a plant protection product in Norway. Nemasys G is intended for use against the garden chafer (Phyllopertha horticola) in lawns and Nemasys H against black vine weevil (Otiorhynchus sulcatus) in strawberries and ornamentals. VKM was requested by the Norwegian Food Safety Authority to consider the possible health and environmental risk related to the properties of Nemasys G and Nemasys H; in particular to evaluate if the nematode is naturally occurring in Norway, the potential for establishing and spreading under Norwegian conditions, possible taxonomic challenges and assessment of the health risk related to its use. The assessment was finalized in October 2014 by VKM’s Panel on Plant Protection Products. VKM’s conclusions are as follows: Natural occurrence of the nematode: The nematode Heterorhabditis bacteriophora has not been observed in Norway, but is widespread world-wide in regions with continental and Mediterranean climates. In Europe it has been isolated in France, Germany, Hungary, Italy, Moldavia, Spain, Switzerland and the UK. Potential for establishing and spreading of the nematode under Norwegian conditions: The thermal preference of H. bacteriophora restricts its establishing. Short term establishment in the growing season is possible in parts of Norway. This nematode has however poor long term survival in soil, especially in the absence of suitable hosts, and the potential for long term establishment in Norway is considered to be low. Taxonomic challenges: There are no taxonomic challenges related to assessment of this nematode. Human health risk for operators: Exposure of user is considered to be low. The use of plant protection products containing Heterorhabditid nematodes against insects has not been associated with health effects on humans. The symbiotic bacteria Photorhabdus luminescens has not been linked to pathogenic effects in humans. It is therefore the view of VKM that the use of the nematode Heterorhabditis bacteriophora with the symbiotic bacteria Photorhabdus luminescens will have minimal health risk for operators.

Risk Assessment of the Biological Control Product «Gulløyelarver» with the Active Organism Chrysoperla Carnea

Gulløyelarver (green lacewing larvae, Chrysoperla carnea) is a product for biological control. The application is for use against aphids in green-houses and tunnels. Gulløyelarver was used in Norway from 1985-1993. An assessment in 2001 concluded however that the use of products with Chrysoperla carnea could represent an environmental risk since it was not known if the species in the products were the same as the ones with natural occurrence in Scandinavia. In this regard, The Norwegian Food Safety Authority would like VKM to perform an assessment of possible risks related to health and environment in light of possible new data. VKM’s conclusions are as follows: Health: The larvae of Chrysoperla carnea have hollow jaws through which they can inject digestive enzymes into their prey. In contact with humans, the larvae are capable of delivering painful bites which may cause local swelling. Such bites are however not considered dangerous, and can be avoided with preventive measures. Allergic asthma and rhino conjunctivitis has been reported in persons working in the production of biological agents with Chrysoperla carnea, but it is the opinion of VKM that such effects are not likely to be relevant for users of the agents. Environment: A previous assessment in 2001 concluded that the use of products with Chrysoperla carnea represented an environmental risk because of the risk of genetic interference with natural populations of the species in Norway. Lacewings belonging to the Chrysoperla carnea complex are considered established and indigenous in Norway, and a recent study by the Norwegian Institute for Agricultural and Environmental Research (Bioforsk) strongly suggests that the lacewings in the commercial products belong to the same cryptic species complex as individuals sampled in Norway. In case the species in the products is different from those present in Norway, any genetic interference with local populations in Norway is prevented by differences in duetting songs. If an invertebrate biological control agent is indigenous and has limited direct or indirect effect on the environment, it is the opinion of VKM that it could be authorized for release in greenhouses or plastic tunnels. Chrysoperla carnea is polyphagous and cannibalistic. They prefer aphids, but may also consume other insects and mites. It is however the opinion of VKM that the environmental risk from this will be minimized in greenhouses and tunnels where the release will be in a contained environment and directed against aphid colonies. Establishment, host range and dispersal ability should be carefully reviewed, even if the species is indigenous. Chrysoperla carnea may establish in the greenhouse and plastic tunnels and may also possess the ability to disperse and survive in the field. However, it is the opinion of VKM that the direct and indirect effects of this are at most moderate, although it cannot be completely excluded that Chrysoperla carnea species in the products might also have properties that have not been reviewed.

Evaluation of the Arguments in the Appeal from Bayer Crop Science of the Decision Made by the Norwegian Food Safety Authority on the Fungicide Infinito with the Active Substances Fluopicolide and Propamocarb

Infinito is a new fungicide containing the two active substances fluopicolide and propamocarb-HCl intended to protect potatoes against the blight pathogen Phytophtora infestans. Fluopicolide is a new active substance in Norway, while propamocarb-HCl is already approved in several products. The risk assessment of Infinito was finalized in a meeting on 29. May 2012 by the Panel on Plant Protection Products of the Norwegian Scientific Committee for Food Safety (VKM). The main conclusions from the risk assessment of Infinito were: VKMs opinion is that both fluopicolide and its main metabolite M-01 (2,6- dichlorobenzamid (BAM)) are persistent in Norwegian soils and surface waters. Fluopicolide and its main metabolite M-01 may accumulate in Norwegian soils. The metabolite M-01 is highly mobile, while fluopicolide shows lower mobility in both studies and modelling. Based on the environmental properties pointed out in the risk assessment, The Norwegian Food Safety Authority (Mattilsynet) turned down the application for use of Infinito in Norway. The decision made by Mattilsynet has been appealed by the applicant, Bayer Crop Science. No new studies have been presented. Mattilsynet has asked VKM to consider the arguments in the appeal from Bayer Crop Science on the risk assessment of Infinito. The appeal and arguments were discussed in a meeting in VKMs Panel on Plant Protection Products on 13. December 2013. The conclusions were as follows: VKM maintains the previous conclusion on the risk assessment on persistence, accumulation and mobility of fluopicolide and one of the metabolites M-01. Our conclusion is further strengthened by additional documentation on: Persistence of M-01 as indicated by data from the National Monitoring program (JOVA) and international studies Accumulation as related to results from 4 year field studies and model calculations using the Finnish PEC calculator Mobility of M-01 as identified by FOCUS PELMO, FOCUS PEARL and MACRO simulations using Swedish and Norwegian scenarios in addition to monitoring results from groundwater in Norway Opinion from EFSA indicating that model simulations and risk of leaching to groundwater from row crops are under-estimated by a factor of six, and should be revised in the new FOCUS scenarios. Half-life calculations based on field studies of mobile substances should be avoided as some of the substances could have escaped to deeper layers and therefore showing artificially high degradation rates.

Risk Assessment of the Pesticide Centium with the Active Substance Clomazone

Centium is a new product in Norway containing the active substance clomazone. The product is applied for use as a herbicide in potato, carrot, cabbage, brussel sprout, swedes, oil seed rape, pea and bean. The Norwegian Institute for Agricultural and Environmental Research recommend approval in potato, carrot, swedes and pea. They do not recommend approval in oil seed rape, cabbage and bean because of lacking documentation on efficacy. The Norwegian Scientific Committee for Food Safety (VKM) was asked by the Norwegian Food Safety Authority to perform a risk assessment on human health and environmental fate of the active substance and the product. The risk assessment of the product was finalized at a meeting May 18, 2011, by VKM’s Scientific Panel on plant protection products (Panel 2). VKM Panel 2’s conclusion is as follows: The active ingredient clomazone is of moderate acute toxicity after oral and inhalation exposure and of low dermal toxicity. The product Centium is of low acute toxicity after oral exposure, by skin contact or by inhalation; however the product may contain a co-formulant, monomeric isocyanate, with sensitizing properties. Due to the lack of documentation on the monomer content, the Panel cannot evaluate the risk of sensitization. UK Poem model estimation of exposure show that exposure to operator is below AOEL and the health risk is therefore minimal. The effects observed in the dog study were considered due to the exposure of clomazone and should therefore be used to determine the NOAEL value. The fertility index used in the two-generation study in rats is not considered relevant as a measure of critical effect. The Panel suggests to use 4000 ppm (354 mg/kg bw/day) which is the highest dose tested in the study. Dose dependent responses were not always evident in the rat teratology study, but significant effects were found at the two highest dose levels (300 and 600 mg/kg bw/day). The observed effects were considered adverse. The proposed NOAEL of 100 mg/kg bw/day was therefore supported. The teratology study with rats is considered relevant for determination of acute reference dose (ARfD) since skeletal malformations can be induced after short exposure periods if the exposure is taking place during a sensitive period of foetal development. The Panel also concludes that based on the results from modeling with MACRO (4.4.2) using the Nordic groundwater scenarios and the input parameters agreed upon in the EU there is a potential for contamination of groundwater exceeding the trigger value of 0.1µg/L for the active ingredient following prescribed usage.

Risk Assessment of the Pesticide Envidor with the Active Substance Spirodiclofen

Envidor is a new product in Norway containing the active substance spirodiclofen. The product is applied for use as an insecticide and acaricide in fruit, berries and ornamentals (field, glasshouses and tunnels). The Norwegian Scientific Committee for Food Safety (VKM) was asked by the Norwegian Food Safety Authority to perform a risk assessment on human health, environmental fate and ecotoxicological effects of the active substance and the product. The risk assessment of the product was finalized at a meeting November 25, 2010, by VKM’s Scientific Panel on plant protection products (Panel 2). VKM Panel 2’s conclusion is as follows: Both Envidor and the active substance spirodiclofen showed low acute oral -, dermal - and inhalation toxicities in animal studies, but showed skin sensitising properties. The estimated risk for operators is assessed as minimal provided adequate use of personal protective equipment. Spirodiclofen may have endocrine disrupting effects, but the in vivo data are not sufficient to make a firm conclusion at this point. Adrenals and other organs of the endocrine system, including the reproductive system, are target organs for chronic toxicity of spriodiclofen. Males seem to be more sensitive than females for adverse reproductive effects of spirodiclofen. Decreased testes and epididymides sizes, testes atrophy and decreased number of sperm were seen both in the parental and subsequent generation of rats. No teratogenic effect of spirodiclofen was seen. The disturbances in the endocrine system may account for the carcinogenic potential of spirodiclofen as evidenced by tumours in testicles, uterus and liver of animals. Spirodiclofen is not considered genotoxic. The Panel regards spirodiclofen to be carcinogenic and toxic to the reproduction in laboratory animals. Both spirodiclofen and its metabolites are rapidly degraded in soil, but while spirodiclofen has a low mobility due to high soil sorption, its metabolites are highly mobile. Use of Envidor with the proposed application regime implies a very high risk for adverse effects on bees and non-target arthropods due to exposure to the active substance spirodiclofen. The risk for adverse effects of spirodiclofen on other terrestrial organisms, and on aquatic organisms provided that a buffer zone of 30 m to surface water is applied, is considered to be minimal.

Risk Assessment of the Insecticide/Acaricide Milbeknock with the Active Substance Milbemectin

Milbeknock is a new insecticide/acaricide containing the new active substance milbemectin, which is a microbial fermentation product of Streptomyces. It is applied for control of mites and leafminers. The intended use is as a foliar spray in fruits (apples/pears), strawberries (only after harvest) and in ornamental plants growing in greenhouse and outdoors. The risk assessment was finalized at a meeting November 24, 2011, by VKM’s Scientific Panel on plant protection products (Panel 2). Panel 2 is in particular asked by the Norwegian Food Safety Authority to look at the following: 1) The human health risk for operators related to the properties of the active substance and the product. 2) The degree of oral absorption. 3) Acute toxicity. 4) The reproduction and developmental toxicity. 5) Establishment of reference values (ADI, AOEL and ARfD). 6) The fate and behaviour in the environment and environmental risk with regard to the properties of Milbeknock and milbemectin. 7) Bioavailability of milbemectin. 8) The microcosm study. VKM Panel 2’s conclusion is as follows: Health: Panel 2 proposes to set the absorption to 50%, which is in agreement with the EU DAR report (propose 47%). For acute toxicicity, Panel 2 concludes that milbemectin probably has a LD50 for dogs between 100 and 200 mg/kg body weight (bw)/day. Dogs seem to be the most sensitive experimental species and should be considered for hazard classification purposes. With respect to reproduction and developmental toxicity, Panel 2 concludes that the documentation of the role of the P-glycoprotein transporter is not convincing, and that the CF1 mice study cannot be used to support the argumentation of no developmental toxicity put forward by the applicant. The following reference values have been estimated: ADI of 0.03 mg/kg bw/day; AOEL of 0.015 mg/kg bw/day and ARfD of 0.067 mg/kg bw/day for milbemectin. Provided that personal protection equipment is used, the AOEL for operators is not exceeded. Environment: With respect to environmental fate, the opinion of the Panel is that the relatively rapid degradation in soil indicates a significant bioavailability in both soil and water-sediment systems. Further it concludes that 0.058µg/L should be regarded as NOECpopulation for the microcosm study. Panel 2 concludes that there is a medium risk of toxic effects on aquatic organisms due to exposure of milbemectin sprayed in fruits with the proposed application regime, provided that a buffer zone of 30 meters to surface water is applied. There are minimal risks of toxic effects on aquatic organisms with sufficient buffer zones in other applied crops. Panel 2 further considers the risk for foliage dwelling non-target predators and parasitoids to be high, and the risk to earthworms to be medium. The strong sorption to soil suggests that the bioavailability in soil may be limited. However, the opinion of the Panel is that the relatively rapid degradation in soil indicates a significant bioavailability. Also, for a substance with such a high log Kow the reported water solubility is relatively high, which will contribute to the availability for biological uptake. The toxicity observed in the microcosm study indicates high bioavailability also in a water/sediment system.

Risk Assessment of the Pesticide Coragen 20 SC with the Active Substance Chlorantraniliprole

Coragen 20 SC is a new product in Norway containing the active substance chlorantraniliprole. It is applied for use in apples against codling moth (Cydia pomonella), apple fruit moth (Argyresthia conjugella) and free leaf living larvae. The Norwegian Scientific Committee for Food Safety (VKM) was asked by the Norwegian Food Safety Authority to perform a risk assessment on human health, environmental fate and ecotoxicological of the active substance and the product. The risk assessment of the product was approved at a meeting 11th of May 2010 by VKMs Scientific Panel on Pesticides (Panel 2). VKMs Panel 2 concludes as following: The product and the active substance have low acute oral, dermal and inhalation toxicities. Both are non-irritating to the skin, and no allergenic potential by skin contact were shown. Coragen was non-irritating to the eyes, while chlorantraniliprole showed a weak irritating potential. Chlorantraniliprole is not shown to have any genotoxic or carcinogenic potential, or to be teratogenic or toxic to the reproduction of female animals. The potential for testicular toxicity of chlorantraniliprole is unclear because the study design and the limited number of young dogs (2/sex/group) do not provide basis for a firm conclusion. No particular target organ for toxicity in any species in the sub-chronic and chronic toxicity studies was seen. The observed dose- and time dependent increased degree of microvesiculation in the zona fasiculata of the adrenal cortex in male rats, is however of uncertain biological significance. All test species (rat, mice, dog) showed physiological adaption to chlorantraniliprole administration (increased liver metabolism with induction of cytochrome P450 enzymes) which was manifested as increased liver weight and hepatocellular hypertrophy. In the chronic toxicity study in mice, the increased liver weight and hepatocellular hypertophy was accompanied with eosinofilic foci, which was assessed as an adverse effect. The no observed effect level (NOAEL) derived from this study serves as basis for calculations of values for acceptable daily intake (ADI) and acceptable operator exposure level (AOEL). In Panel 2‘s opinion a sub-chronic study (90 days) with the technical material (E2Y45-282) including relevant concentration of the impurity IN-G2S78 should be performed. This would bring information on possible influence of the impurity on the toxicological profile of the technical material, and consequently on the assessment of the NOAELs in the various toxic studies. The estimated risk for operator and for bystanders or for workers re-entering treated crops is assessed as minimal. Chlorantraniliprole is persistent in soil with half live of about 1 year. The long half life indicates high potential for accumulation in soil after repeated use, which is confirmed by both model simulations and field studies. The Panel considers field data from the south of Europe not to be relevant for the Nordic conditions based on different climate conditions and soil properties contributing in different directions. The Panel considers that the existing documentation is not sufficient for a firm conclusion on the use of normalised field data for modelling purposes. However, the substance is persistent and expected to accumulate in soil. The Panel concludes that there is minimal risk for toxic effects on mammals, birds, bees, and microorganisms in soil due to chlorantraniliprole exposure with the proposed exposure regime. Panel concludes that there is “very high risk” for effects on in-field non target arthropods from chlorantraniliprole exposure. For soil living invertebrates, earthworms seem rather insensitive to chlorantraniliprole and the Panel considers the toxic effects to be minimal. Panel considers the risk for toxic effects on soil living arthropods to be high. Crustaceans and insects larvae are the aquatic organisms most sensitive to chlorantraniliprole. The Panel concludes that there is a minimal risk of toxic effects on aquatic organisms due to exposure to chlorantraniliprole with the proposed application regime provided that a buffer zone of 30 m to surface water is applied.

Re-Assessment of the Plant Protection Product PROMAN – with the Active Ingredient Metobromuron [Edition 2]

Proman is a broad spectrum selective herbicide for potatoes grown outdoors, containing the active substance metobromuron. VKM’s Panel on Plant Protection Products has previously discussed questions concerning Proman raised by The Norwegian Food Safety Authority, and stated its opinion in a report of 21. January 2015 (http://www.vkm.no/dav/3c64afe035.pdf). Following this report, The Norwegian Food Safety Authority turned down the application to register Proman as a plant protection product in Norway. The applicant filed a complaint on this decision, and the VKM Panel has been asked to reassess its previous opinion in light of the information given by the applicant in the complaint. The VKM Panel has discussed the arguments put forward in the complaint. The arguments did not change the Panel’s main conclusions in the original assessment. Some changes in the wording of the conclusions were however done, in order to put more emphasis on areas of uncertainty. These are the standing conclusions of VKM’s Panel on Plant Protection Products: On the relevance of the carcinogenic effects observed in the rat carcinogenicity study; fibrosarcomas in females and pheochromocytomas and Leydig cell tumours in males: It is the opinion of VKM’s Panel for Plant Protection Products that the relevance of the observed incidences of mammary gland tumours and Leydig cell tumours in the rat carcinogenicity study is strengthened by the fact that the increases in tumours associated with exposure to metobromuron are observed in hormone responsive tissues. The panel concludes that the carcinogenic effects observed in the rat carcinogenicity study could be relevant for tumour induction in humans. Higher incidences of still dumbbell-shaped centres of thoracic vertebrae and nonossification of the 13th rib observed in the rat developmental toxicity study and whether these are considered to be malformations: VKM’s Panel on Plant Protection Products has discussed the classification of the different types of incomplete ossifications and concluded that incomplete ossification of sternebrae and non-ossification of the 13th rib in rats should by itself be considered to be variations, and not adverse developmental effects. On the other hand, the Panel agrees with ECHA that the “thoracic vertebral centres still dumbbell-shaped” should be considered as malformations, due to limited data and understanding of the mechanism underlying the observed slow reversal of these anomalies. Furthermore, it is the view of the Panel that the different types of retarded ossification induced by the exposure should be considered as a whole when assessing for developmental effects. Establishment of the NOAEL for the developmental toxicity study in rats and the reference value (ARfD): VKM’s Panel on Plant Protection Products supports the proposal of an ADI value of 0.008 mg/kg bw/day based on a NOAEL of 0.8 mg/kg bw/day from the 2-year study in mouse, and AOEL of 0.016 mg/kg bw/day based on the NOAEL of 1.6 mg/kg bw/day from the 1-year feeding study in dog. The panel suggests an alternative ARfD value of 0.03 mg/kg bw based on a LOAEL of 10 mg/kg bw /day for the observations of incomplete ossification in the rat developmental study. The anti-androgenic potential of metobromuron: The rat carcinogenicity study indicates that metobromuron may interact with the endocrine system. The data from the Hershberger in vivo rat study, the in vitro studies, as well as the comparison with demonstrated effects and mechanisms for flutamide and linuron is suggestive of an anti-androgenic effect. Thus, it is the opinion of the VKM Panel on Plant Protection Products that an anti-androgenic effect of metobromuron cannot be excluded.

Risk Assessment of the Fungicide Bontima with the Active Substances Cyprodinil and Isopyrazam

Bontima is a new fungicide containing the two active substances isopyrazam and cyprodinil. Bontima is a fungicide against the most important diseases in winter and spring barley. Isopyrazam is a new active ingredient with new mechanisms of action that may delay the development of fungicide resistance in treated crops. The risk assessment was finalized at a meeting May 29, 2012, by the Panel on plant protection products of the Norwegian Scientific Committee for Food Safety (VKM). The Norwegian Food Safety Authority would like, in this regard, an assessment of the following: The fate and behaviour in the environment and the ecotoxicological effects and risks with regard to the properties of Bontima and the active substances. The Panel is particularly asked to look at the following: o The persistence of isopyrazam and its metabolites. o The leaching potential of isopyrazam and its metabolites. VKM’s conclusion is as follows: Fate-related issues Isopyrazam is likely to be persistent in Norwegian soils with an associated risk of accumulation after repeated use. Isopyrazam exhibits low mobility in soil and is not expected to reach groundwater, however the two main metabolites are likely to exceed the EUs drinking water limit of 0.1 g/L in groundwater. Since drainage and runoff, as well as drift, contributes to concentrations in surface water the risk assessment have to consider all these sources. In the EU DAR step 4 calculations, buffer zones of 20 m have been used to reduce runoff levels contributions by 80 %. VKM does not accept the use of these buffer zone modifications for Norwegian topographic conditions (with e.g. steeper agricultural areas). Risk to the environment There is minimal risk for toxic effects of isopyrazam to terrestrial organisms. For the aquatic compartment, there is a high risk for toxic effects of isopyrazam to aquatic organisms with the proposed application regime. This is based on calculations of runoff without buffer zone modifications, from which the resulting TER calculations show high risk of acute effects on fish and a medium risk of acute effects on invertebrates. A minimal risk for toxic effects was calculated for sediment dwelling organisms, aquatic plants, and algae.

Opinion on the Safety of BioProtein® by the Scientific Panel on Animal Feed of the Norwegian Scientific Committee for Food Safety

BioProtein® (BP) is a trademark for single cell (bacteria) protein, based on conversion of methane, with the addition of ammonia and oxygen, to a protein source. BP is produced by Norferm AS in Norway, and has been authorized by the EU as a protein source in animal feeds since 1995, for fattening pigs (8%), calves (8%) and salmon (19-33%). Significant immune effects were revealed in a toxicity study performed in rats fed a nucleic acid reduced BP product (NABP) and thereafter, similar, but less severe effects were also found after feeding with untreated BP. Additional studies confirmed increased mesenteric lymph node weights in cats and foxes. Due to the undesirable effects and also due to applications for extended use, BP has been assessed by the Scientific Committee on Animal Nutrition (SCAN) and EU’s Scientific Committee on Food (SCF) in 1995, by SCAN in 2001 and 2003 and by the European Food Safety Authority (EFSA) in 2005. The EU memberstates United Kingdom, France and Finland have also conducted assessments. The EU approval from 1995 remains unchanged. The Norwegian Food Safety Authority requested the Norwegian Scientific Committee for Food Safety (VKM) to assess the risk of using BP as a protein source in feedingstuffs, both for the animal categories already authorized and for extended use to pet animals, chickens and pigs from weaning to slaughter. The Norwegian Scientific Committee for Food Safety was asked to consider all existing documentation. Based on all documentation enclosed with the request from the Norwegian Food Safety Authority and published scientific articels, an opinion on the safety of BP assessed by the VKM panel on Animal Feed was published on 20 March 2006 (05/608-final-rev1). The Producer made a complaint regarding this opinion and claimed that not all documents on BP had been evaluated. The Norwegian Food Safety Authority then requested VKM to revise its opinion on the risk of using BP as a protein source in feedingstuffs, based on 17 documents previously not available to VKM, in addition to the 20 documents included in the opinion published on 20 March 2006. BP is composed of a protein with a somewhat different amino acid compostion compared with fish meal, but BP and fish meal have more similarities in amino acid content than soybean meal. BP has relatively high level of nucleic acids, phospholipids, lipopolysaccarides and minerals. Effect studies with BP have been conducted in rats/mice, pigs, chicken, cats, foxes, and salmon. Most of the concern regarding the side effects of BP in feed is related to the immune response. The main findings include changes in weight and morphology of mesenteric lymph nodes, followed by induction of specific antibodies. Histopathological examination after feeding with NABP also revealed changes in the intestines and several internal organs indicating systemic effects. The Producer claims that the immune response seen in BP-fed mice/rats is most likely a normal response to ingestion of large doses of a foreign antigen, and further, that oral tolerance towards this protein is induced over time. However, these interpretations are not adequately supported by the supplied documentation. A tendency towards adaption might be indicated in some of the studies, other results argue against tolerance induction. It is unclear whether the content of phospholipids, lipopolysaccarides, nucleic acids or the protein structure, or the combination of these compounds is responsible for the immunological changes observed. However, the particulate structure of BP has been shown to influence the observed immune response as the systemic immune response was avoided by ingestion of BP free of whole cells. The studies conducted in target species have not included adequate examinations of the immune effects from ingestion of BP. Concerning terrestrial species, no histopathological effects were revealed in the pig, chicken, cat or fox studies. However, increased mesenteric lymph nodes were reported in cats and foxes fed BP. In the remaining studies the main focus has been on production parameters; weight gain, feed intake, feed efficiency, metabolism of nutrients, observation of clinical health, and product quality. When the contents of amino acids were balanced, the inclusion of low levels of BP (9%) tended to stimulate growth in pigs and the same tendency was found in chicken with 6% BP. Higher feed levels of BP tended to cause a reduction in growth. In salmon, a dose dependent improvement of growth was reported in a short term experiment (8 weeks). However, in longer term experiments with salmon, depressed growth and increased liver weight were observed in freshwater at 19% BP with no-effect-level at 10%. In seawater studies, a tendency of reduced growth was found in salmon fed with 20% BP in the diet, and BP levels of 27% and higher levels resulted in significantly reduced body weight. Furthermore, levels of 27% BP and above in fish feed reduced specific immune responses, but increased lymphocyte response, and also tended to improve the survival after bacterial and viral infections. At 37% BP in the diet histopathological changes in the distal intestine, and reduced storage of glycogen and increased lipid deposition and liver weight were observed. No negative effects were seen in salmon in seawater at a feed level of 13.5% BP. The results indicate negative effects in salmon at BP levels in fish feed considerably lower than those currently approved (19 and 33%, in feed for salmon in fresh and sea water, respectively). To conclude, in terrestrial target species documented effects of BP include reduced weight gain and increased weight of mesenteric lymph nodes. In the more thoroughly studied species the rat, findings incluse histopathologic effects in mesenteric lymph nodes, changed humoral immune responses, increased weight of other lymphoid tissue (spleen), increased level of neutrophile granulocytes, and slight leakage of hepatic and renal tubuli enzymes. In terrestrial target species, 6% BP in the feed is considered to be the highest inclusion level not to cause such effects. The results from the rat studies show a similar no-effect-level. In salmon, reduced weight gain, liver storage effects, changed humoral and celluar immune responses and histopathological effects in the intestine are documented. A 10% level of BP in fish feed is the highest level tested without causing such effects. There are relatively few valid studies for the risk assessment of BP in target species, and the designs of the assessed studies are very variable. Thus, there are qualitative and quantitative uncertainties concerning the effects of BP in target species. The Panel on Animal Feed is of the opinion that an inclusion level of BP of 6% in the diets to terrestrial target animals and a 10% maximum inclusion level in salmon feed (both for fresh- and seawater stages) would reduce the risk of potentially adverse effects in the animals. The risk associated with the human consumption of products from animals fed on BP is considered negligible. However, the production of single cell protein for feed production represents a relatively new scientific approach which implies precautionary handling.

Human Health Risk Assessment of the Pesticide Simplex with the Active Substances Aminopyralid and Fluroxypyr

Simplex is a new herbicide in Norway containing the active substances aminopyralid and fluroxypyr. Aminopyralid is a new active substance in Norway, but fluroxypyr is found in several authorized products. The application concerns use in established grassland for forage, established ley and pasture and in grass at the first year of sowing. The Norwegian Scientific Committee for Food Safety (VKM) has on a request from the Norwegian Food Safety Authority performed a risk assessment on human health of the active substance and the product. The risk assessment of the product was approved at a meeting May 11 2010 by VKMs Scientific Panel on Pesticides (Panel 2). VKM’s Panel 2 concludes as following: Both Simplex and the active substance aminopyralid are characterized as extremely irritating to the eye based on persistent irritation to the eyes of rabbits. The product Simplex is also found irritating to the rabbit skin. Aminopyralid has low acute toxicity and is not shown to have genotoxic potential, or to be teratogenic or toxic to the reproduction in animals. There may however be a carcinogenic effect of aminopyralid based on an increased number of uterine sarcomas in mice. The main target organs for sub-chronic and chronic toxicity were the caecum (rats), the stomach (dogs, inflammation) and the liver (dogs, hyperthropy). No adverse effects for chronic toxicity were seen in mice. Rabbit was the most sensitive species for toxicity and the no observed effect levels (NOAELs) derived from studies in this species serve as base for calculations of values for acceptable daily intake (ADI) and acceptable operator exposure level (AOEL). The estimated risk for operator is assessed as minimal both by use of boom spraying (46% of AOEL) and knapsack sprayers (81% of AOEL). However, as a result of the hazard classification, a faceshield and gloves are necessary personal protective equipment (PPE) to be worn during mixing and loading operations, due to the risk of serious damage to the eyes and skin irritation.

Environmental Risk Assessment of the Pesticide Simplex with the Active Substances Aminopyralid and Fluroxypyr

Simplex is a new herbicide in Norway containing the active substances aminopyralid and fluroxypyr. Aminopyralid is a new active substance in Norway, but fluroxypyr is registered in several authorized products. The intended use of the plant protection product is in established grassland for forage, established ley and pasture and in grass at the first year of sowing. During the spring of 2010, the Norwegian Scientific Committee for Food Safety (VKM) performed a human health risk assessment of the active substance aminopyralid and the product on request from the Norwegian Food Safety Authority. On further request from the Norwegian Food Safety Authority, VKM has performed a risk assessment on the fate and the behaviour in the environment and the environmental risk with regard to the properties of the active substance aminopyralid and the product Simplex, which was finalized at a meeting of VKM’s Scientific Panel on plant protection products (Panel 2) on November 25, 2010. VKM Panel 2’s conclusion is as follows: Aminopyralid is highly mobile in soil and the substance is very likely to reach ground water at concentrations above the threshold of 0.1 µg/L. Experimental data (watersediment studies) suggest that aminopyralid is persistent. However, aminopyralid concentrations in surface water are expected to decrease rapidly due to photolytic degradation. The overall risk for adverse effects on terrestrial and aquatic organisms following the proposed application of Simplex is considered to be minimal.

Assessment of the Potential Risks Associated with the Proposed Use of Composted Waste from the Production of Bacitracin as a Soil Additive

Bacitracin is a hexapeptide antibiotic, with a substituted thiazolidine nucleus, produced by some strains of B. licheniformis. It is mainly active against Grampositive bacteria, although many differences in susceptibility exist among the bacterial species. Alpharma A.S. Norway has produced bacitracin for use in human medicine since 1954. Until 1998, the fermentation waste from the production of bacitracin was added to animal feed in some European countries, including Norway, to promote growth of pigs and domestic fowl. In 1998, fermentation waste containing bacitracin as a food additive was banned by the EU to reduce the risk of developing bacitracin-resistant bacteria in animals, and the subsequent possible transfer of such bacteria to humans via the food chain. Use of fermentation waste containing bacitracin as a feed additive has not been officially banned in Norway, but it is no longer used for this purpose. Alpharma is therefore actively seeking alternative uses for their production waste. As the waste material is rich in nutrients, the company proposes that it could be developed as a soil additive by fermenting it with chipped bark and lime. The Norwegian Food Safety Authority (Mattilsynet) commissioned the Panel on Biological Hazards of the Norwegian Scientific Committee for Food Safety (Vitenskapskomitéen for mattrygghet) to develop a risk assessment regarding the use of composted waste material from Alpharma’s production of bacitracin, as a soil additive. In response, an ad hoc Working Group of experts was appointed with the mandate to draft a risk assessment which should include the following elements: assessment of risk to human health and/or the environment in relation to residual content of bacitracin in the finished soil additive product and assessment of the risk in relation to dissemination of the production strain and antimicrobial resistance genes. The Panel on Biological Hazards concludes that the risks to human health and the environment posed by residual bacitracin present in the finished product are minimal. Furthermore, as Bacillus licheniformis is considered essentially non-pathogenic, occurring rarely as an opportunistic pathogen, the risk posed by this bacterium to human health or the environment is very low. It is reasonable to assume that during the early composting process horizontal transfer of bacitracin and erythromycin resistance genes, from the B. licheniformis producer strain to environmental bacteria, will exceed background levels. However, this is considered to represent a low risk to human health and the environment.