Risk Assessment of the Plant Protection Product PROMAN – with the Active Ingredient Metobromuron

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.

Risk Assessment of the Active Plant Protection Product Ingredient MCPA (4-chloro-2-methylphenoxyacetic acid): AOEL and ADI Determination

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.

Risk Assessment of the Metabolite M44 of Bixafen, One of the Active Substancesin Aviator Xpro EC225

Aviator Xpro EC 225 containing the active substance bixafen was assessed by VKM in spring 2013, and it was concluded that the metabolite M44 has potential for groundwater contamination. Furthermore, VKM assessed in late 2013 the relevance of this metabolite in accordance with the EU guidance document on metabolites in groundwater, and concluded that the malformations observed in rabbits exposed to the metabolite should be considered treatment related. VKM also concluded that the data presented to evaluate the possible genotoxic properties of the metabolite was insufficient to reach a conclusion. Based on this, the Norwegian Food Safety Authority rejected the approval of Aviator Xpro EC 225. The applicant has now submitted results from an in vivo study to strengthen the basis for assessment of genotoxic properties, and also submitted new historical controls in relation to the experimental studies on foetal developmental effects in rabbits. The VKM Panel on Plant Protection Products has discussed the questions raised by The Norwegian Food Safety Authority on the basis of the new data, and has the following opinion: On the assessment of genotoxic properties of the M44 metabolite of bixafen, one of the active ingredients of Aviator Xpro EC 225. It is the view of VKM Panel on Plant Protection Products that the new in vivo mouse micronucleus study, supplemented together with a separate study demonstrating bioavailability, overrides the results of the in vitro clastogenicity studies. Taken together, it is the opinion of VKM that under the conditions studied, M44 should be considered as non-genotoxic. On the assessment of the relevance of the foetal malformations in M44 exposed animals. VKMs Panel on Plant Protection products has assessed the arguments and new historical control data presented by the applicant, intended to show that metabolite M44 is not teratogenic. It is however the opinion of the Panel that the arguments and the new historical data provided by the applicant do not alter the panel’s previous conclusion; that the malformations observed in rabbits exposed to the metabolite M44 should be considered treatment related.

Risk Assessment of Malakite with the Active Substances Dithianon and Pyrimenthanil

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.

Genotoxic Assessment of the Metabolite M-11 of Mepanipyrim, the Active Ingredient in the Plant Protection Product FRUPICA SC

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.

Degradation and Mobility of Pesticides in Norwegian Soils

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.

Comparison of Organic and Conventional Food and Food Production Part V: Human Health – Pesticide Residues

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.