Peer review of the pesticide risk assessment of the active substance clove oil.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State, Malta, for the pesticide active substance clove oil are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions for the amendment of approval were reached on the basis of the evaluation of the representative use of clove oil as a preharvest nematicide on tomatoes and cucumbers (permanent greenhouse use). The representative use evaluated for the renewal of approval of clove oil was as post-harvest fungicide and bactericide on apples, pears and peaches (indoor uses). The reliable endpoints appropriate for use in regulatory risk assessment are presented. Endpoints not relevant to the scope of the proposed amendment of approval conditions will be addressed in the context of the renewal of approval procedure of clove oil running in parallel (AIR IV, EFSA Q-2016-00809). Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance quinolin-8-ol.

The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Spain, and co-rapporteur Member State, the Netherlands, for the pesticide active substance quinolin-8-ol are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative use of quinolin-8-ol as a fungicide and bactericide against soil-borne pathogens in tomato cultivation in permanent greenhouses applied by drip irrigation. The reliable end points, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Updated peer review of the pesticide risk assessment of the active substance dichlorprop-P and variant dichlorprop-P-2-ethylhexyl.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Ireland, and co-rapporteur Member State, Poland, for the pesticide active substance dichlorprop-P and the variant dichlorprop-P-2-ethylhexyl and the assessment of applications for maximum residue levels (MRLs) are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative uses of dichlorprop-P as a herbicide on cereals, grassland and grass seed crops and of the variant dichlorprop-P-2-ethylhexyl as a plant growth regulator on citrus. MRLs were assessed in mandarin and lemon. The conclusions from 2018 were updated in 2024 following the request from the European Commission with regard to the endocrine-disrupting properties. The reliable end points, appropriate for use in regulatory risk assessment and the proposed MRLs, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Updated peer review of the pesticide risk assessment of the active substance pydiflumetofen.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authority of the rapporteur Member State, France, and co-rapporteur Member State, Austria, for the pesticide active substance pydiflumetofen and the assessment of applications for maximum residue levels (MRLs) are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of the representative uses of pydiflumetofen as a fungicide field application on pome fruits, grapes, potato, fruiting vegetables, cucurbits and Brassica vegetables and updated following the request from Commission to consider additional information submitted and review the risk assessment. The reliable endpoints, appropriate for use in regulatory risk assessment and the proposed MRLs, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

TKPlate 1.0: An Open-access platform for toxicokinetic and toxicodynamic modelling of chemicals to implement new approach methodologies in chemical risk assessment.

This publication is linked to the following EFSA Supporting Publications articles: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8441/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8440/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8437/full.

Peer review of the pesticide risk assessment of the active substance dimoxystrobin.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Hungary, and co-rapporteur Member State, Ireland, for the pesticide active substance dimoxystrobin as well as the assessment of maximum residue levels (MRLs) and confirmatory data following the review of the existing MRLs of dimoxystrobin according to Article 12 of Regulation (EC) No 396/2005 are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. In June 2023, the European Commission sent a mandate confirming the need to adopt and publish a conclusion on the peer review of the pesticide risk assessment of the active substance dimoxystrobin excluding the full assessment of endocrine-disrupting properties, containing all the results of the peer review process related to the renewal of approval as well as the assessment of the application for MRL for oilseed rapeseed, poppy seed, mustard seed and gold of pleasure seed, and the MRL application addressing the confirmatory data identified during the MRL review under Article 12 of Regulation (EC) No 396/2005. The conclusions were reached on the basis of the evaluation of the representative uses of dimoxystrobin as a fungicide on oilseed rape and sunflower. MRLs were assessed in rapeseeds, poppy seed, mustard seed and Gold of pleasure seed. The reliable end points, appropriate for use in regulatory risk assessment and the proposed MRLs, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are presented where identified.

Peer review of the pesticide risk assessment of the active substance metalaxyl-M (amendment of approval conditions).

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Belgium, and co-rapporteur Member State, Greece, for the pesticide active substance metalaxyl-M are reported. The context of the peer review was that required by Regulation (EC) No 1107/2009 of the European Parliament and of the Council. The conclusions were reached on the basis of the evaluation of the representative uses for the amendment to the conditions of approval of metalaxyl-M as a fungicide seed treatment for sunflower and spinach seeds intended to be sown in field and on the basis of data submitted to update the specified level of an impurity in the technical active substance. The reliable endpoints, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance metribuzin.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Estonia, and co-rapporteur Member State, Germany, for the pesticide active substance metribuzin and the assessment of application to amend existing residue definition are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative use of metribuzin as a herbicide on potato and soybean (field use). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance metconazole.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Belgium, and co-rapporteur Member State, the United Kingdom, for the pesticide active substance are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of metconazole as a fungicide on cereals and oilseed rape and as a plant growth regulator on oilseed rape. The reliable end points appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance folpet.

The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Austria and co-rapporteur Member State Italy for the pesticide active substance folpet and of confirmatory data following the MRL review under Article 12 of Regulation (EC) No 396/2005. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of folpet as a fungicide on barley, wheat and wine grape (field uses) and tomato (field and greenhouse uses). The reliable end points, appropriate for use in regulatory risk assessment and the confirmatory data, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance urea.

The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State Greece and co-rapporteur Member State Finland for the pesticide active substance urea and the considerations as regards the inclusion of the substance in Annex IV of Regulation (EC) No 396/2005 are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of urea as an attractant of fruit fly Bactrocera oleae on olive crops. The reliable end points, appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance tritosulfuron.

The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Slovenia, and co-rapporteur Member State, Austria, for the pesticide active substance tritosulfuron are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of tritosulfuron as a herbicide on spring and winter cereals, spring cereals with undersown grasses and maize (field uses). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Updated peer review of the pesticide risk assessment of the active substance mepanipyrim.

The conclusions of the EFSA following the peer review of the initial risk assessments carried out by the competent authorities of the rapporteur Member State, Belgium, and co-rapporteur Member State, Greece, for the pesticide active substance mepanipyrim are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012. The conclusions were reached on the basis of the evaluation of the representative uses of mepanipyrim as a fungicide on table and wine grapes and in field and protected strawberries and tomatoes. The conclusions were updated with regard to the endocrine-disrupting properties following a mandate received from the European Commission in January 2019. The reliable end points appropriate for use in regulatory risk assessment are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Peer review of the pesticide risk assessment of the active substance milbemectin.

The conclusions of the European Food Safety Authority (EFSA) following the peer review of the initial risk assessment carried out by the competent authorities of the rapporteur Member State, Germany, and co-rapporteur Member State, the Netherlands, for the pesticide active substance milbemectin are reported. The context of the peer review was that required by Commission Implementing Regulation (EU) No 844/2012, as amended by Commission Implementing Regulation (EU) No 2018/1659. The conclusions were reached on the basis of the evaluation of the representative uses of milbemectin as an acaricide and insecticide in strawberry (field and greenhouse), berries and black and white currant (field and greenhouse), apple, pear, cherry and plum (field) and ornamentals (field and greenhouse). The reliable end points, appropriate for use in regulatory risk assessment, are presented. Missing information identified as being required by the regulatory framework is listed. Concerns are reported where identified.

Metabolites in the regulatory risk assessment of pesticides in the EU.

A large majority of chemicals is converted into metabolites through xenobiotic-metabolising enzymes. Metabolites may present a spectrum of characteristics varying from similar to vastly different compared with the parent compound in terms of both toxicokinetics and toxicodynamics. In the pesticide arena, the role of metabolism and metabolites is increasingly recognised as a significant factor particularly for the design and interpretation of mammalian toxicological studies and in the toxicity assessment of pesticide/metabolite-associated issues for hazard characterization and risk assessment purposes, including the role of metabolites as parts in various residues in ecotoxicological adversities. This is of particular relevance to pesticide metabolites that are unique to humans in comparison with metabolites found in in vitro or in vivo animal studies, but also to disproportionate metabolites (quantitative differences) between humans and mammalian species. Presence of unique or disproportionate metabolites may underlie potential toxicological concerns. This review aims to present the current state-of-the-art of comparative metabolism and metabolites in pesticide research for hazard and risk assessment, including One Health perspectives, and future research needs based on the experiences gained at the European Food Safety Authority.

Assessment of the in vitro developmental toxicity of diethylstilbestrol and estradiol in the zebrafish embryotoxicity test.

The present study investigated the developmental toxicity of diethylstilbestrol (DES) in the zebrafish embryotoxicity test (ZET). This was done to investigate whether the ZET would better capture the developmental toxicity of DES than the embryonic stem cells test (EST) that was previously shown to underpredict the DES-induced developmental toxicity as compared to in vivo data, potentially because the EST does not capture late events in the developmental process. The ZET results showed DES-induced growth retardation, cumulative mortality and dysmorphisms (i.e. induction of pericardial edema) in zebrafish embryos while the endogenous ERα agonist 17ß-estradiol (E2) showed only growth retardation and cumulative mortality with lower potency compared to DES. Furthermore, the DES-induced pericardial edema formation in zebrafish embryos could be counteracted by co-exposure with ERα antagonist fulvestrant, indicating that the ZET captures the role of ERα in the mode of action underlying the developmental toxicity of DES. Altogether, it is concluded that the ZET differentiates DES from E2 with respect to their developmental toxicity effects, while confirming the role of ERα in mediating the developmental toxicity of DES. Furthermore, comparison to in vivo data revealed that, like the EST, in a quantitative way also the ZET did not capture the relatively high in vivo potency of DES as a developmental toxicant.

Biomonitoring and Subsequent Risk Assessment of Combined Exposure to Phthalates in Iranian Children and Adolescents.

This study aimed to estimate the exposure and related health risks of phthalates, and to assess the health risks from combined exposure to three of the phthalates sharing the same mode of action (anti-androgenicity) in children. We determined the internal exposure of 56 Iranian children and adolescents aged 6 to 18 years by analyzing seven urinary metabolites of five phthalates. The estimated daily intake values derived from the biomonitoring data ranged from 0.01 µg/kg bw/day for butyl benzyl phthalate (BBP), to 17.85 µg/kg bw/day for di(2-ethylhexyl) phthalate (DEHP). The risk assessment revealed that not only the exposure to the individual phthalates, but also the combined exposure to the three anti-androgenic phthalates (DEHP, DBP, BBP) did not raise a safety concern (hazard index values averaged 0.2). The range of maximum cumulative ratio values varied from around 1 for most individuals to around 2 in some individuals, indicating that the combined exposures were dominated by one and in some cases by two of the three anti-androgenic phthalates, especially dibutyl phthalate (DBP) and/or DEHP. Based on biomonitoring data, the overall combined exposure of Iranian children to phthalates does not raise a concern, while reduction of exposure is best focused on DEHP and DBP that showed the highest hazard quotient.

Assessment of acute and chronic toxicity of doxorubicin in human induced pluripotent stem cell-derived cardiomyocytes.

The present study assesses acute and chronic toxicity of doxorubicin in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), with the aim to obtain in vitro biomarkers that can be used as readouts to predict in vivo cardiotoxicity. Possible acute toxicity was investigated by assessing effects on the beating rate and the field potential duration (FPD) of doxorubicin-exposed cardiomyocytes by measuring electrical activity using multi-electrode array (MEA) analyses. No effects on the beating rate and FPD were found at concentrations up to 6µM, whereas at 12µM no electrical activity was recorded, indicating that the cardiomyocytes stopped beating. Acute and chronic effects of doxorubicin on mitochondria, which have been reported to be affected in doxorubicin-induced cardiotoxicity, were assessed using high content imaging techniques. To this end hiPSC-CMs were exposed to 150 or 300nM doxorubicin using both single dosing (3h and 2days) and repetitive dosing (3 times, of 2days each), including washout studies to assess delayed effects (assessment at day 14) and effects on cell number, mitochondrial density, mitochondrial membrane potential, mitochondrial superoxide levels and mitochondrial calcium levels were assessed. No effects of doxorubicin were found on mitochondrial density and mitochondrial superoxide levels, whereas doxorubicin reduced cell survival and slightly altered mitochondrial membrane potential and mitochondrial calcium levels, which was most profound in the washout studies. Altogether, the results of the present study show that concentrations of doxorubicin in the micromolar range were required to affect electrical activity of hiPSC-CMs, whereas nanomolar concentrations already affected cell viability and caused mitochondrial disturbances. Integration of these data with other in vitro data may enable the selection of a series of in vitro biomarkers that can be used as readouts to screen chemicals for possible cardiotoxicity.

Risk assessment for pyrrolizidine alkaloids detected in (herbal) teas and plant food supplements.

Pyrrolizidine alkaloids (PAs) are plant metabolites present in some botanical preparations, with especially 1,2-unsaturated PAs being of concern because they are genotoxic carcinogens. This study presents an overview of tumour data on PAs and points of departure (PODs) derived from them, corroborating that the BMDL10 for lasiocarpine represents a conservative POD for risk assessment. A risk assessment using this BMDL10 and mean levels of PAs reported in literature for (herbal) teas, indicates that consumption of one cup of tea a day would result in MOE values lower than 10 000 for several types of (herbal) teas, indicating a priority for risk management for these products A refined risk assessment using interim relative potency (REP) factors showed that based on the mean PA levels, 7(54%) of 13 types of (herbal) teas and 1 (14%) of 7 types of plant food supplements (PFS) resulted in MOE values lower than 10 000, indicating a priority for risk management also for these products in particular. This includes both preparations containing PA-producing and non-PA-producing plants. Our study provides insight in the current state-of-the art and limitations in the risk assessment of PA-containing food products, especially (herbal) teas and PFS, indicating that PAs in food presents a field of interest for current and future risk management.

Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment.

The currently available techniques for the safety evaluation of candidate drugs are usually cost-intensive and time-consuming and are often insufficient to predict human relevant cardiotoxicity. The purpose of this study was to develop an in vitro repeated exposure toxicity methodology allowing the identification of predictive genomics biomarkers of functional relevance for drug-induced cardiotoxicity in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The hiPSC-CMs were incubated with 156 nM doxorubicin, which is a well-characterized cardiotoxicant, for 2 or 6 days followed by washout of the test compound and further incubation in compound-free culture medium until day 14 after the onset of exposure. An xCELLigence Real-Time Cell Analyser was used to monitor doxorubicin-induced cytotoxicity while also monitoring functional alterations of cardiomyocytes by counting of the beating frequency of cardiomyocytes. Unlike single exposure, repeated doxorubicin exposure resulted in long-term arrhythmic beating in hiPSC-CMs accompanied by significant cytotoxicity. Global gene expression changes were studied using microarrays and bioinformatics tools. Analysis of the transcriptomic data revealed early expression signatures of genes involved in formation of sarcomeric structures, regulation of ion homeostasis and induction of apoptosis. Eighty-four significantly deregulated genes related to cardiac functions, stress and apoptosis were validated using real-time PCR. The expression of the 84 genes was further studied by real-time PCR in hiPSC-CMs incubated with daunorubicin and mitoxantrone, further anthracycline family members that are also known to induce cardiotoxicity. A panel of 35 genes was deregulated by all three anthracycline family members and can therefore be expected to predict the cardiotoxicity of compounds acting by similar mechanisms as doxorubicin, daunorubicin or mitoxantrone. The identified gene panel can be applied in the safety assessment of novel drug candidates as well as available therapeutics to identify compounds that may cause cardiotoxicity.