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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.

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.

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.

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.

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.

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.

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.

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.

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 \(\mu\)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.

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.

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.

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.

Air pollutions are shown to increase the occurrence of cardiovascular diseases and ischemic stroke. These effects imply an indirect exposure of secondary organs downstream of the respiratory system as the primary target of exposure. Mechanistic studies of air pollution on secondary organs have traditionally been performed on organ specific monocultures at submerged conditions. Direct exposure to organ specific cells secondary exposed to air pollution have the drawback that it does not imply realistic exposure conditions. In this study we have indirectly exposed organ specific cells to particulate matter via exposure of a bronchial lung model at the air liquid interphase (ALI). The lung model was exposed to a model diesel particle (DEP) and an equivalent dose of an acetone extract of the DEP. The DEP induced induction of IL-6 formation of which the DEP was more potent than the DEP extract. The DEP extract inhibited CXCL8 formation, which appeared contradictory since both the DEP and DEP-extract increased expression of CXCL8 mRNA. Our results showed a substantial increased expression of CyP1A1 and CyP1B1 in both epithelial and endothelial cells in the lung model of which no differences were observed between the DEP and DEP-extract. However, the solvent extract induced the CYPs with a higher potency in the secondary exposed HepG2 liver cells, probably due to faster permeation of dissolved substances in the DEP extract through the lung barrier. Thus, organ specific cell models can be combined to achieve a more realistic so-called body-specific model to study secondary effects.

Combustion-derived particles constitute an important part of the fine fraction of particulate matter with aerodynamic diameter less than 2.5 microns (PM2.5) and are considered central for the adverse effects of air pollution. Understanding the mechanisms of combustion particle toxicity may shed light on the components and characteristics of outdoor air PM driving adverse health effects. This may also enable more targeted and efficient policies to improve air quality and promote health and wellbeing. The aryl hydrocarbon receptor (AhR) is a ligand dependent transcription factor, originally discovered for its ability to bind polycyclic aromatic hydrocarbons (PAHs) and dioxin-like compounds and regulate PAH metabolism. It is now clear that AhR regulates a variety of biological and toxicological responses, overlapping to a considerable degree with the effects of combustion PM and ambient PM2.5. Studies from our lab and others also suggest that AhR activation is among the most sensitive responses to combustion PM exposure, induced at orders of magnitude lower concentrations than many other endpoints. This talk will discuss the potential role of the AhR and PAHs in combustion PM toxicity based on previous and ongoing work, with a main focus on intracellular signalling and regulation of inflammatory reactions in lung epithelial cells and vascular endothelial cells.

Ambient particulate matter (PM) is one of the leading environmental mortality risk factors worldwide. PM is not a single entity but consists of a complex and variable mixture of particles from multiple sources. Nevertheless, there is a paucity of experimental studies assessing the potential combinatory effects of different types of particles, and most focus on the effects of individual PM components or mixed PM samples. In the present study, the pro-inflammatory effects of combined exposure to road wear particles and diesel exhaust particles (DEP), two important constituents of traffic-derived PM, were assessed in vitro. Human bronchial epithelial cells (HBEC3-KT) and differentiated THP-1 macrophage-like cells were exposed to road wear particles and two different samples of DEP under submerged conditions, both alone and in combination. Particle-induced release of pro-inflammatory cytokines (CXCL8 and IL-1β) was measured by enzyme-linked immunosorbent assay. The results show that combined exposure to road wear particles and DEP induced enhanced release of pro-inflammatory cytokines compared with the effects of the individual particle samples. The combinatory effects appeared to depend on properties of the DEP samples and also differed between the HBEC3-KT cells and THP-1 macrophage-like cells. This study shows that the effects of combined exposure to different types of particles may surpass the effects anticipated by the effects of the individual particulates. These combinatory effects between types of particles could have implications when assessing measures to reduce PM-induced health effects.

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.

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.

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.

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.

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.

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.

Background People are exposed to ambient particulate matter (PM) from multiple sources simultaneously in both environmental and occupational settings. However, combinatory effects of particles from different sources have received little attention in experimental studies. In the present study, the pro-inflammatory effects of combined exposure to diesel exhaust particles (DEP) and mineral particles, two common PM constituents, were explored in human lung epithelial cells. Methods Particle-induced secretion of pro-inflammatory cytokines (CXCL8 and IL-1β) and changes in expression of genes related to inflammation (CXCL8, IL-1α, IL-1β and COX-2), redox responses (HO-1) and xenobiotic metabolism (CYP1A1 and CYP1B1) were assessed in human bronchial epithelial cells (HBEC3-KT) after combined exposure to different samples of DEP and mineral particles. Combined exposure was also conducted using lipophilic organic extracts of DEP to assess the contribution of soluble organic chemicals. Moreover, the role of the aryl hydrocarbon receptor (AhR) pathway was assessed using an AhR-specific inhibitor (CH223191). Results Combined exposure to DEP and mineral particles induced increases in pro-inflammatory cytokines and expression of genes related to inflammation and redox responses in HBEC3-KT cells that were greater than either particle sample alone. Moreover, robust increases in the expression of CYP1A1 and CYP1B1 were observed. The effects were most pronounced after combined exposure to α-quartz and DEP from an older fossil diesel, but enhanced responses were also observed using DEP generated from a modern biodiesel blend and several stone particle samples of mixed mineral composition. Moreover, the effect of combined exposure on cytokine secretion could also be induced by lipophilic organic extracts of DEP. Pre-incubation with an AhR-specific inhibitor reduced the particle-induced cytokine responses, suggesting that the effects were at least partially dependent on AhR. Conclusions Exposure to DEP and mineral particles in combination induces enhanced pro-inflammatory responses in human bronchial epithelial cells compared with exposure to the individual particle samples. The effects are partly mediated through an AhR-dependent pathway and lipophilic organic chemicals in DEP appear to play a central role. These possible combinatory effects between different sources and components of PM warrant further attention and should also be considered when assessing measures to reduce PM-induced health effects.

A major challenge in nanoparticle (NP) research is to elucidate how NPs activate initial targets in cells, leading to cytotoxicity and inflammation. We have previously shown that silica (Si)NPs induce pro-inflammatory responses in bronchial epithelial cells (BEAS-2B) via mechanisms involving transforming growth factor (TGF)-α release, and activation of MAP-kinase p38 and JNK besides NF-κB (p65). In the present study, the roles of scavenger receptors (SRs) in SiNP-induced cytokine responses in BEAS-2B cells were examined by siRNA silencing. Cells exposed to Si10 and Si50 (nominal sizes 10 and 50 nm) showed marked interleukin (IL)-6, CXCL8, IL-1α, IL-1β responses. Transient knockdown of SR-B1, LOX-1 and CXCL16 reduced the Si10- and Si50-induced cytokine responses, to a different magnitude dependent on the particle size, SR and cytokine. Si10-induced TGF-α responses were also markedly reduced by knockdown of SR-B1 and CXCL16. Furthermore, the role of SR-B1 in Si10-induced phosphorylations of p65 and MAP-kinases p38 and JNK were examined, and no significant reductions were observed upon knockdown of SR-B1. In conclusion, LOX-1 and CXCL16 and especially SR-B1 seem to have important roles in mediating cytokine responses and TGF-α release due to SiNP exposure in BEAS-2B cells, without a down-stream role of MAP-kinase and NF-κB.

Background Respirable stone- and mineral particles may be a major constituent in occupational and ambient air pollution and represent a possible health hazard. However, with exception of quartz and asbestos, little is known about the toxic properties of mineral particles. In the present study, the pro-inflammatory and cytotoxic responses to six stone particle samples of different composition and with diameter below 10 μm were assessed in human bronchial epithelial cells (HBEC3-KT), THP-1 macrophages and a HBEC3-KT/THP-1 co-culture. Moreover, particle-induced lysis of human erythrocytes was assessed to determine the ability of the particles to lyse biological membranes. Finally, the role of the NLRP3 inflammasome was assessed using a NLRP3-specific inhibitor and detection of ASC oligomers and cleaved caspase-1 and IL-1β. A reference sample of pure α-quartz was included for comparison. Results Several stone particle samples induced a concentration-dependent increase in cytotoxicity and secretion of the pro-inflammatory cytokines CXCL8, IL-1α, IL-1β and TNFα. In HBEC3-KT, quartzite and anorthosite were the most cytotoxic stone particle samples and induced the highest levels of cytokines. Quartzite and anorthosite were also the most cytotoxic samples in THP-1 macrophages, while anorthosite and hornfels induced the highest cytokine responses. In comparison, few significant differences between particle samples were detected in the co-culture. Adjusting responses for differences in surface area concentrations did not fully account for the differences between particle samples. Moreover, the stone particles had low hemolytic potential, indicating that the effects were not driven by membrane lysis. Pre-incubation with a NLRP3-specific inhibitor reduced stone particle-induced cytokine responses in THP-1 macrophages, but not in HBEC3-KT cells, suggesting that the effects are mediated through different mechanisms in epithelial cells and macrophages. Particle exposure also induced an increase in ASC oligomers and cleaved caspase-1 and IL-1β in THP-1 macrophages, confirming the involvement of the NLRP3 inflammasome. Conclusions The present study indicates that stone particles induce cytotoxicity and pro-inflammatory responses in human bronchial epithelial cells and macrophages, acting through NLRP3-independent and -dependent mechanisms, respectively. Moreover, some particle samples induced cytotoxicity and cytokine release to a similar or greater extent than α-quartz. Thus, these minerals warrant further attention in future research.

Proman is a new product containing the active substance metobromuron. The intended use is as a broad spectrum selective herbicide for potatoes grown outdoors. VKM’s Panel on Plant Protection Products has discussed the questions raised by The Norwegian Food Safety Authority in the Terms of reference and has stated the following opinion: 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 incidence in mammary gland tumours and Leydig cell tumours in the rat carcinogenicity study is strengthened by the fact that the tumours are observed in hormone responsive tissues. The panel concludes that the carcinogenic effects observed in the rat carcinogenicity study are likely to be relevant for tumours that are influenced by the endocrine system, also in humans. On the 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 of metobromuron should be considered as a whole when assessing for developmental effects. On the 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 VKM Report 2015: 03 5. 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. An UF of 100 is applied. The panel suggests on the other hand an ARfD of 0.03 mg/kg bw based on a LOAEL of 10 mg/kg bw /day with the observations of incomplete ossification in the rat developmental study. An UF of 300 is applied. On the possible anti-androgenic potential of metobromuron: It is the view of the Panel that the rat carcinogenicity study suggests that metobromuron may possess endocrine disrupting potency. The data from the Hershberger in vivo rat study and the in vitro studies is also suggestive of a weak 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.

Reactive oxygen species (ROS) is regarded as a critical denominator in nanoparticle toxicology and inflammation. Previously, we have shown that silica nanoparticles sized 50 nm (Si50) induce release of CXCL8 and IL-6 from BEAS-2B cells, via mechanisms involving NFκB, p38 MAP kinase and TGF-α-activated EGF receptor. In the present study, the role of ROS-mediated mechanisms in the concentration-dependent Si50 induction of CXCL8 and IL-6 responses was examined. Si50 (200 µg/mL) induced a time-dependent ROS formation and a postponed increase in expression of haem oxygenase (HO-1) mRNA and protein. Pre-treatment with the ROS inhibitors N-acetyl cysteine (NAC) and diphenyleneiodonium (DPI) partially attenuated CXCL8 and IL-6 responses to 200 µg/mL, but not to 100 µg/mL Si50. The release of TGF-α induced by Si50 (200 µg/mL) was significantly reduced by NAC, but not by DPI nor siRNA against NADPH oxidase DUOX-1 (siDUOX-1). Furthermore, siDUOX-1 reduced Si50-induced CXCL8, but not IL-6. Both p38 and p65 phosphorylations were inhibited by siDUOX-1, but for NAC only p65 phosphorylation reached a significant reduction. Neither NAC nor DPI reduced Si50-induced CXCL8 and IL-6 gene expressions. In conclusion, Si50-induced CXCL8 and IL-6 involved both ROS-dependent and ROS-independent mechanisms. Notably, the role of ROS seemed restricted to effects of higher concentrations of Si50 and not mediated via the gene expression.

Background Respirable mineral particles represent a potential health hazard in occupational settings and ambient air. Previous studies show that mineral particles may induce cytotoxicity and inflammatory reactions in vitro and in vivo and that the potency varies between samples of different composition. However, the reason for these differences is largely unknown and the impact of mineralogical composition on the biological effects of mineral dust remains to be determined. Methods We have assessed the cytotoxic and pro-inflammatory effects of ten mineral particle samples of different composition in human bronchial epithelial cells (HBEC3-KT) and THP-1-derived macrophages, as well as their membranolytic properties in erythrocytes. Moreover, the results were compiled with the results of recently published experiments on the effects of stone particle exposure and analysed using linear regression models to elucidate which mineral components contribute most to the toxicity of mineral dust. Results While all mineral particle samples were more cytotoxic to HBEC3-KT cells than THP-1 macrophages, biotite and quartz were among the most cytotoxic in both cell models. In HBEC3-KT cells, biotite and quartz also appeared to be the most potent inducers of pro-inflammatory cytokines, while the quartz, Ca-feldspar, Na-feldspar and biotite samples were the most potent in THP-1 macrophages. All particle samples except quartz induced low levels of membranolysis. The regression analyses revealed associations between particle bioactivity and the content of quartz, muscovite, plagioclase, biotite, anorthite, albite, microcline, calcite, chlorite, orthopyroxene, actinolite and epidote, depending on the cell model and endpoint. However, muscovite was the only mineral consistently associated with increased cytotoxicity and cytokine release in both cell models. Conclusions The present study provides further evidence that mineral particles may induce cytotoxicity and inflammation in cells of the human airways and that particle samples of different mineralogical composition differ in potency. The results show that quartz, while being among the most potent samples, does not fully predict the toxicity of mineral dust, highlighting the importance of other particle constituents. Moreover, the results indicate that the phyllosilicates muscovite and biotite may be more potent than other minerals assessed in the study, suggesting that this group of sheet-like minerals may warrant further attention.

Epidemiological studies have found strong associations between air pollution and respiratory effects including development and/or exacerbation of asthma and chronic obstructive pulmonary disease (COPD) as well as increased occurrence of respiratory infections and lung cancer. It has become increasingly clear that also polycyclic aromatic hydrocarbons (PAHs) may affect processes linked to non-malignant diseases in the airways. The aim of the present paper was to review epidemiological studies on associations between gas phase and particle-bound PAHs in ambient air and non-malignant respiratory diseases or closely related physiological processes, to assess whether PAH-exposure may explain some of the effects associated with air pollution. Based on experimental in vivo and in vitro studies, we also explore possible mechanisms for how different PAHs may contribute to such events. Epidemiological studies show strongest evidence for an association between PAHs and asthma development and respiratory function in children. This is supported by studies on prenatal and postnatal exposure. Exposure to PAHs in adults seems to be linked to respiratory functions, exacerbation of asthma and increased morbidity/mortality of obstructive lung diseases. However, available studies are few and weak. Notably, the PAHs measured in plasma/urine also represent other exposure routes than inhalation. Furthermore, the role of PAHs measured in air is difficult to disentangle from that of other air pollution components originating from combustion processes. Experimental studies show that PAHs may trigger various processes linked to non-malignant respiratory diseases. Physiological- and pathological responses include redox imbalance, oxidative stress, inflammation both from the innate and adaptive immune systems, smooth muscle constriction, epithelial- and endothelial dysfunction and dysregulated lung development. Such biological responses may at the molecular level be initiated by PAH-binding to the aryl hydrocarbon receptor (AhR), but possibly also through interactions with beta-adrenergic receptors. In addition, reactive PAH metabolites or reactive oxygen species (ROS) may interfere directly with ion transporters and enzymes involved in signal transduction. Overall, the reviewed literature shows that respiratory effects of PAH-exposure in ambient air may extend beyond lung cancer. The relative importance of the specific PAHs ability to induce disease may differ between the biological endpoint in question.

Background Silica nanoparticles (SiNPs) are among the most widely manufactured and used nanoparticles. Concerns about potential health effects of SiNPs have therefore risen. Using a 3D tri-culture model of the alveolar lung barrier we examined effects of exposure to SiNPs (Si10) and crystalline silica (quartz; Min-U-Sil) in the apical compartment consisting of human alveolar epithelial A549 cells and THP-1-derived macrophages, as well as in the basolateral compartment with Ea.hy926 endothelial cells. Inflammation-related responses were measured by ELISA and gene expression. Results Exposure to both Si10 and Min-U-Sil induced gene expression and release of CXCL8, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1α (IL-1α) and interleukin-1β (IL-1β) in a concentration-dependent manner. Cytokine/chemokine expression and protein levels were highest in the apical compartment. Si10 and Min-U-Sil also induced expression of adhesion molecules ICAM-1 and E-selectin in the apical compartment. In the basolateral endothelial compartment we observed marked, but postponed effects on expression of all these genes, but only at the highest particle concentrations. Geneexpressions of heme oxygenase-1 (HO-1) and the metalloproteases (MMP-1 and MMP-9) were less affected. The IL-1 receptor antagonist (IL-1RA), markedly reduced effects of Si10 and Min-U-Sil exposures on gene expression of cytokines and adhesion molecules, as well as cytokine-release in both compartments. Conclusions Si10 and Min-U-Sil induced gene expression and release of pro-inflammatory cytokines/adhesion molecules at both the epithelial/macrophage and endothelial side of a 3D tri-culture. Responses in the basolateral endothelial cells were only induced at high concentrations, and seemed to be mediated by IL-1α/β released from the apical epithelial cells and macrophages.

Background Exposure to traffic-derived particulate matter (PM), such as diesel exhaust particles (DEP), is a leading environmental cause of cardiovascular disease (CVD), and may contribute to endothelial dysfunction and development of atherosclerosis. It is still debated how DEP and other inhaled PM can contribute to CVD. However, organic chemicals (OC) adhered to the particle surface, are considered central to many of the biological effects. In the present study, we have explored the ability of OC from DEP to reach the endothelium and trigger pro-inflammatory reactions, a central step on the path to atherosclerosis. Results Exposure-relevant concentrations of DEP (0.12 μg/cm2) applied on the epithelial side of an alveolar 3D tri-culture, rapidly induced pro-inflammatory and aryl hydrocarbon receptor (AhR)-regulated genes in the basolateral endothelial cells. These effects seem to be due to soluble lipophilic constituents rather than particle translocation. Extractable organic material of DEP (DEP-EOM) was next fractionated with increasing polarity, chemically characterized, and examined for direct effects on pro-inflammatory and AhR-regulated genes in human microvascular endothelial (HMEC-1) cells and primary human endothelial cells (PHEC) from four healthy donors. Exposure-relevant concentrations of lipophilic DEP-EOM (0.15 μg/cm2) induced low to moderate increases in IL-1α, IL-1β, COX2 and MMP-1 gene expression, and the MMP-1 secretion was increased. By contrast, the more polar EOM had negligible effects, even at higher concentrations. Use of pharmacological inhibitors indicated that AhR and protease-activated receptor-2 (PAR-2) were central in regulation of EOM-induced gene expression. Some effects also seemed to be attributed to redox-responses, at least at the highest exposure concentrations tested. Although the most lipophilic EOM, that contained the majority of PAHs and aliphatics, had the clearest low-concentration effects, there was no straight-forward link between chemical composition and biological effects. Conclusion Lipophilic and semi-lipophilic chemicals seemed to detach from DEP, translocate through alveolar epithelial cells and trigger pro-inflammatory reactions in endothelial cells at exposure-relevant concentrations. These effects appeared to be triggered by AhR agonists, and involve PAR-2 signaling. Electronic supplementary material The online version of this article (10.1186/s12989-018-0257-1) contains supplementary material, which is available to authorized users.

In this report the following topic of pesticides and fate in Norway has been outlined covering: 1. Factors influencing degradation of pesticides. 2. Description and update of datasets on soil and climate in agricultural areas. 3. Normalization of field degradation data as input for modelling fate. 4. Use of degradation data from Norway in model scenarios. Norwegian laboratory degradation studies indicate that increased soil organic carbon content enhances degradation rates of pesticides that show low sorption (e.g. metalaxyl, bentazone) ,due to increased microbial activity. Whereas pesticides that sorb moderately to strongly to soil (e.g. boscalid, propiconazole), display reduced degradation as organic carbon increases as a consequence of sorption and reduced bioavailability. Recent DegT50 field studies display a large variation in fungicide degradation rates from Klepp in the south to Tromsø in the north. For the mobile herbicide bentazone, no effect of climate was observed, as degradation rates were coherent at all sites, probably due to rapid leaching. The climate (temperature) seems to be more determinate for fungicide degradation rates than the soil type. Fungicide degradation was slow at two northern sites having low soil temperatures, even though microbial biomass was hugely different at the sites. How soil temperature and moisture affects microbial activity and diversity in various soils, climates and crops is important for the understanding of degradation capacity in Norwegian soils and fields. Microbial activity could be related to both soil, climate and crops/cropping regime – as well as to the nature of the soil organic matter. The fact that DegT50 values are very much shorter than laboratory values at the same reference conditions, may point to some systematic error in the normalization procedure (e.g. the default simplifications in the Walker and Arrhenius equations), or that the parameters affecting degradation in the laboratory are different from the parameters that affect degradation in the field. Consequently, lab-derived and field-derived DegT50matrix values should be compared and interpreted with care. The large variations in normalized DegT50 values obtained in field studies in Norway as well as in other regions in Norway cannot be explained by differences in the associated parameters characterizing the soil and microbial community. It is therefore not possible to determine if a certain field study is more or less representative for “Norwegian conditions”. As a conservative approach, the highest, normalized DegT50 from the European field studies should be selected for the Norwegian risk assessment independent on geographic vicinity. As an alternative, when a sufficient number of data are available, a high percentile (e.g 80 or 90-percentile) should be used rather than the geomean. Each agricultural region in Norway is dominated by one specific soil type for each region. Albeluvisol, Cambisol, Umbrisol, Stagnosol and Histosol in respectively Eastern Norway south, Eastern Norway north, Rogaland, Trøndelag and North of Norway. New updates for Norway include especially Umbrisols and Histosols rich in organic matter. Albeluvisols, Cambisols and Stagnosols are representing the main soil types in the agricultural area in Norway. These are also included in the groundwater (Rustad and Heia) and surface water scenarios (Syverud) developed for Norway. Experience from pesticide fate in the organic rich soils on the south west coast and north of Norway is limited. Compared to the “normal” temperature and precipitation from 1961 to 1990 with a “new normal” from 1991 to 2014, the climate has changed. For the five described agricultural areas in Norway, annual temperature has increased in average 1 degrees for all five regions and seasons for the new normal. The rainfall has increased for all seasons and regions except for the Northern Norway (Holt in Tromsø) and summer season at Kvithamar (Trøndelag) with lower precipitation in June to September. Annually the precipitation has increased approximately 100 mm in average. The existing Norwegian scenarios in groundwater and surface water seem to be representative in the meaning of covering the main soil types in the central agricultural areas in South Eastern Norway. However there are no scenarios covering areas of South West and North of Norway containing soil with high organic content, slow degradation and heavy rainfall. Vulnerable areas are not included in these scenarios as the idea of the representativity of soil was to include the main soil types covering the most of the agricultural production areas. The vulnerable areas deals with smaller areas and has to be treated separately. Vulnerable areas are areas with high groundwater levels and sandy soil and mobile pesticides. Hilly areas with clay soil represent high risk of surface runoff with strongly sorbed pesticides. We are lacking experience from areas with high content of organic matter causing slow degradation, combined with heavy rainfall. A database with representative soils and climates for various crops should be established in Norway and utilized in a targeted risk assessment approach. Then, the degradation of pesticides to be used in for example fruit/berry cropping, could be evaluated in respect to representative and vulnerable soils and climates in fruit/berry regions in Norway. A correct risk assessment of pesticide degradation in Norwegian agricultural soils should take the varying climatic zones, the diversity in agricultural soils and crops in Norway into consideration before formulated pesticides are approved. Risk assessment should be based on soils and climates most prevalent for the crop to which the pesticide is to be applied, in addition, vulnerable areas with slow degradation and/or high leaching/runoff risk should be recognized.

The plant protection product Malakite (BAS 669 01 F), containing the active substances dithianon and pyrimethanil, is a fungicide against scab in pome fruits. Products containing these active plant protection substances are approved in Norway, but not with both substances in the same product. The Swedish Chemicals Agency (KemI) has as zonal Rapporteur Member State (zRMS) of the Northern Zone evaluated the product Malakite and decided on non-approval due to the observation of unacceptable effects in exposed birds, aquatic organisms, non-target arthropods and earthworms. On request from The Norwegian Food Safety Authority, the VKM Panel on Plant Protection Products has discussed the available data and the report prepared by KemI, and has concluded as follows on the questions raised: On the refinement of DT50 in long term risk assessment for birds: It is the view of the VKM panel that the refinement is not acceptable because the analysis using first order kinetics seems not in line with a realistic and sufficiently conservative approach for the data provided. Furthermore, field studies from more sites are required. On the long term cumulative effects of the active substances on birds: VKM shares the view of KemI, that the combined sub-lethal and reproduction effects should be assessed because the mode of action of the two ingredients has only been shown in fungi, and since the mechanisms in birds could be different. On the reduction of assessment factor for fish: VKM opposes to the reduction of assessment factor for dithianon in fish because the data from acute toxicity tests cannot be extrapolated to chronic toxicity, and because the factor should reflect not only the variation in interspecies sensitivity, but also the uncertainty involved in extrapolation from laboratory tests to the field situation. On the choice of end point in risk assessment for fish: The VKM panel considers the NOEC of dithianon for fish determined from the study at pH 7.9 not to be adequate for the more acidic Norwegian surface waters, and recommends using the data from the test performed at pH 6.5. On the formulation studies for aquatic organisms: It is the opinion of the VKM panel that the formulation studies may be used together with corresponding studies with the active ingredients as long as the studies compared are performed and evaluated according to the same principles. However, VKM notes that the formulation tests as well as the tests of the active ingredients have been performed at high pH values, which are not representative to most Norwegian surface waters. Thus, the toxic effect of dithianon shown in these tests are likely to be lower than expected under typical conditions in Norway. On the assessment factors for concentration addition in fish: It is the opinion of the VKM panel that a reduction in assessment factor for one component in a mixture cannot be used for a formulation containing components for which a similar reduction has not been accepted. On effect studies of active substances and formulations on non-target arthropods: The VKM panel shares the view of KemI that the risk assessment should be based on all available information, including the studies presented for the active substances. On the endpoint in earthworm risk assessment: VKM supports the view of KemI that the observed effects of pyrimethanil on reproduction of earthworms should be considered in the risk assessment of Malakite.

The present report is based on data from the 2010 EFSA Report on pesticide residues in food, the Norwegian monitoring programmes 2007-2012 and data from peer reviewed literature and governmental agencies. It is a challenge to perform quantitative estimates and comparative studies of residue levels due to large variation in the measured levels, and the large number of different pesticides present in the samples. Thus, the focus is on the frequency of observed contaminations in relation to regulatory limits and to present examples to illustrate the variation in residue values and number of detected substances. Pesticide residues in conventional and organic products: Of the 12,168 samples (plant- and animal products) in the 2010 EU-coordinated programme, 1.6% exceeded the respective maximum residue level (MRL) values, and 47.7% had measurable residues above the limit of quantification (LOQ), but below or at the MRL. Of the 1168 samples analysed in Norway in 2012 (from both imported and domestic products), 1.9% exceeded MRL and 53% contained measurable pesticide residues. Direct comparison of these values is however not possible, since they contain different types of food samples, and are analysed for a different number of pesticides. When organic and conventional samples from fruit, vegetables and other plant products in the 2010 EU-coordinated programme were compared, 4.2% of the conventional and 1.0% of the organic samples exceeded the MRL values, while 43.2% of the conventional and 10.8% of the organic samples had measurable residues below or at the MRL value. Most of the pesticide residues detected in organic samples are not permitted for use in organic farming. Of the 624 organic samples analysed in Norway 2007 - 2012, 0.2% (one sample) had residues exceeding MRL, while measurable residues were detected in 1.8% of the samples (11 samples). Conventional products were often found to contain different pesticides while most organic samples were found to contain few or only one type of pesticide. Lack of data on pesticide residue levels of organic samples in the EU-coordinated programme, and few Norwegian samples do not allow for a quantitative comparison of pesticide residue levels in organic and conventional samples. Comparative estimation of pesticide residues faces a number of challenges and uncertainties. However, it seems unquestionable based on available data that organic plant products contain fewer and substantially lower amounts of pesticide residues than conventional products. Health risk associated with pesticide residues: The general level of pesticide residues in both conventional and organic food is low, and well below what is likely to result in adverse health effects. This conclusion is based on the comparison of estimated dietary exposure with toxicological reference values i.e. acceptable daily intake (ADI) for chronic effects, and acute reference dose (ARfD) for acute effects. The finding of pesticide residues that exceeds established regulatory limits in a minority of tested samples is not considered to represent a health risk. When dietary exposure that was estimated in six different food commodities in the 2010 EUcoordinated programme was compared with their relevant reference values, EFSA concluded that for 79 of 18243 conventionally grown fruit and vegetable samples, a short-term acute consumer health risk could not be excluded. The conclusion was based on the exceeding of ARfD. None of these 79 samples were organic. It is important to also consider that the exceeding of the acute reference value only occurred in 0.4% of the samples and that the scenario used for acute intake assessment is conservative, suggesting that the toxicological implications are limited. This is also reflected in the chronic exposure assessment, where none of the samples were found to exceed the toxicological reference value ADI. Dietary exposure assessments on the basis of Norwegian samples of apples, tomatoes, carrots, strawberries and lettuce did not show an exceeding of any toxicological reference value. Combined exposure and cumulative risk assessment of pesticide residues: No generally accepted methodology is at present established for cumulative risk assessment of combined exposure to pesticide residues. Available data suggest however that combined exposure is not likely to result in increased human health risk.

MCPA (4-chloro-2-methylphenoxyacetic acid) is the active ingredient in several registered herbicides. VKM concluded in 2006 that the effects observed in experiments with dogs were of little relevance to humans, and an AOEL value of 0.036 mg/kg bw/day was proposed, based on renal effects in a 90-day study in rats. The manufacturer is of the opinion that AOEL should be set to 0.11 mg/kg bw/day, and ADI to 0.05 mg/kg bw/day, based on the view that since a 90-day and 2-year study in rats were conducted in the same lab using the same rat strain, it is reasonable to eliminate effects which are not reproduced in both sets of data. The Norwegian Food Safety Authority has therefore requested VKM’s Panel for Plant Protection Products for an opinion on the determination of NOAEL values based on the 90-day and 2-year studies in rats, and consider if it is acceptable to use the manufacturer's approach for an overall consideration of the submitted studies. The Panel has discussed the findings in the two rat studies and concluded that it is not considered acceptable that individual studies separated by several years, in this case studies performed in 1985 and 1988, are taken together and data not reproduced in both sets eliminated. The Panel is still of the opinion that both AOEL and ADI for MCPA should be set to 0.036 mg/kg bw/day based on a NOAEL of 3.6 mg/kg bw/day (50 ppm) from assessment of the renal effects in the 90-day study in rats. The manufacturer has also requested a reconsideration of the present values for dermal absorption which was set by the Norwegian Food Safety Authority during the administrative review of the product MCPA 750 Liquid in 2013. VKM’s Panel on Plant Protection Products supports the conclusion of the Norwegian Food Safety Authority concerning the determination of values for dermal absorption of MCPA. This includes the consideration of remaining substance in skin after washing as part of the absorbed dose in the in vitro studies, and the use of the same experimental time period in the in vitro and in vivo experiments as a basis for the so-called “Triple-pack-approach” for determination of human dermal absorption.

Asbestos (Mg-hydrosilicate; chrysotile) is known to cause pleural diseases, pulmonary fibrosis and lung cancers, via mechanisms strongly depending on diameter-length ratio and possibly metal content. A critical question is whether synthetic hydrosilicate nanotubes (NTs) of short length possess little toxic potential compared to chrysotile. Five Mg- and two NiNTs of different lengths were assessed for cytotoxicity and pro-inflammatory responses in THP-1 macrophages and human bronchial epithelial lung cells (HBEC3-KT), in comparison with chrysotile. NT lengths/diameters were characterized by TEM, surface areas by BET- and BJH analysis, and chemical composition by XRD. The different Mg- and NiNTs induced little cytotoxicity in both cell models, in contrast to chrysotile that induced marked cytotoxicity. The two longest synthetic MgNTs, with median lengths of 3 and 5 µm, induced increased levels of pro-inflammatory cytokines in THP-1 macrophages, but much less than chrysotile (median length 15 µm) and silica nanoparticles (Si10). The shortest NTs did not induce any increase in cytokines. In HBEC3-KT cells, all synthetic NTs induced no or only small changes in cytokine responses, in contrast to chrysotile and Si10. The synthetic NTs induced lower TGF-β responses than chrysotile in both cell models. In conclusion, the pro-inflammatory responses were associated with the length of synthetic hydrosilicate NTs in THP-1 macrophages, but not in HBEC3-KT cells. Notably, the shortest NTs showed no or little pro-inflammatory activity or cytotoxicity in both cell models. Such a safety by design approach is important for development of new materials being candidates for various new products.

Different transition metals have been shown to induce inflammatory responses in lung. We have compared eight different metal ions with regard to cytokine responses, cytotoxicity and signalling mechanisms in a human lung epithelial cell model (BEAS-2B). Among the metal ions tested, there were large differences with respect to pro-inflammatory potential. Exposure to Cd(2+), Zn(2+) and As(3+) induced CXCL8 and IL-6 release at concentrations below 100μM, and Mn(2+) and Ni(2+) at concentrations above 200μM. In contrast, VO4(3-), Cu(2+) and Fe(2+) did not induce any significant increase of these cytokines. An expression array of 20 inflammatory relevant genes also showed a marked up-regulation of CXCL10, IL-10, IL-13 and CSF2 by one or more of the metal ions. The most potent metals, Cd(2+), Zn(2+) and As(3+) induced highest levels of oxidative activity, and ROS appeared to be central in their CXCL8 and IL-6 responses. Activation of the MAPK p38 seemed to be a critical mediator. However, the NF-κB pathway appeared predominately to be involved only in Zn(2+)- and As(3+)-induced CXCL8 and IL-6 responses. Thus, the most potent metals Cd(2+), Zn(2+) and As(3+) seemed to induce a similar pattern for the cytokine responses, and with some exceptions, via similar signalling mechanisms.

The toxicity of some per- and polyfluoroalkyl substances (PFASs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) has been studied thoroughly, showing that systemic PFASs targets the lungs. However, regulators lack data to assess the impact of other PFASs on the lungs and alternative methods to test substances for lung toxicity are needed. We combined two in vitro models to assess toxicity to the respiratory system; i) a lung surfactant (LS) function assay to assess the acute inhalation toxicity potential, and ii) a cell model with human bronchial epithelial cells to study pro-inflammatory potential and modulation of inflammatory responses. We tested salts of four PFASs: perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), PFOS, and PFOA as well as the fluorotelomer 8:2 FTOH. The results show that PFHxS, PFOA and PFOS can inhibit LS function. High PFOS concentrations induced a pro-inflammatory response, measured as increased IL-1α/β release. Moderate concentrations of PFOS suppressed release of the chemokines CXCL8 and CXCL10, whereas both PFOS and PFOA stimulated the release of the pro-inflammatory cytokine IL-1β in immune stimulated human bronchial epithelial cells. These findings support the concern that some PFASs may increase the risk of acute lung toxicity and of airway infections.

The VKM Panel for plant protection products considered Frupica SC in a meeting on 25.11.2010, and found the active ingredient problematic with regard to carcinogenic effects and possible genotoxicity. M11 is a metabolite of mepanipyrim which is the active ingredient the plant protection product Frupica SC. The Norwegian Food Safety Authority has asked the applicant for further assessment of the genotoxic potential of the metabolite M11. The applicant has submitted a rat liver in vivo Comet assay of the metabolite, and the panel has been requested to consider if the genotoxic properties of mepanipyrim and the metabolite M11 is adequately documented. The metabolite M11 caused positive findings in in vitro studies for bacterial mutation and chromosomal aberrations. Three in vivo studies (Micronucleus, unscheduled DNA synthesis and Comet assay) did not show evidence of genotoxicity. Based on the documentation available, VKMs Panel on Plant Protection Products concludes that mepanipyrim and the metabolite M11 should not be considered genotoxic in vivo. The lack of demonstrated in vivo genotoxicity makes it likely that mepanipyrim induces liver tumors in rats and mice by a mechanism that involves a threshold below which tumors are not expected to develop. This conclusion is strengthened by the finding of a promoter-like behavior of mepanipyrim for induction of gamma-glutamyl-transpeptidase positive foci in rat liver.