Toxicological data analysis to support grouping of pesticide active substances for cumulative risk assessment of effects on liver, on the nervous system and on reproduction and development

Regulation (EC) No. 396/2005 on Maximum Residue Levels (MRLs) of pesticides in or on food and feed provides that cumulative and synergistic effects of pesticides should be taken into account for dietary risk assessment when appropriate methodologies are available. Regulation (EC) No. 1107/2009 concerning the placing of plant protection products on the market also provides that the residues of the plant protection products shall not have any harmful effects on human health, taking into account known cumulative and synergistic effects where the scientific methods accepted by the Authority to assess such effects are available. EFSA and the PPR Panel have started the development of such methodologies in 2007. The implementation of the methodologies requires also the establishment of cumulative assessment groups (CAGs) of pesticides on the basis of their toxicological properties. To support this activity EFSA’s Pesticides Unit outsourced preparatory work under the Grant Agreement CFP/EFSA/PPR/2009/01. This project was carried out by the Technical University of Denmark, DTU. The project explored the existing data on pesticide active substances in order to identify the toxicological effects and endpoints and where possible data on mechanism or mode of action that can be the basis of a cumulative risk assessment. The final report by DTU contains proposals for cumulative assessment groups of pesticides having specific identified effects and their related endpoints. EFSA concluded that further consolidation of the outcome of the DTU report needed to be carried out, in particular in the area of neurotoxicity, liver toxicity and toxicity on reproduction and development. Thus, as a follow up of the project carried out by DTU, EFSA launched a call for tender “Toxicological data analysis to support grouping of pesticide active substances for cumulative risk assessment (CRA) of effects on the liver, on the nervous system and on reproduction and development”(CFT/EFSA/PRAS/2012/07). In order to consolidate the outcome of the report drawn up by DTU, in the present project all the pesticides identified as having effects on reproduction and development, the liver and the nervous system were re-evaluated by the consortium. In addition, all pesticides added to Annex I in the period 31-05-2009 to 31-12-2011, and three pesticides (flurtamone, oxadiargyl and pyridate) not screened by DTU in the absence of DARs, were also evaluated for these effects. Toxicological analysis of the available regulatory studies provided in support of their approval has been performed for reproductive and developmental toxicity, neurotoxicity and for effects on liver and gallbladder. In total 257 substances were found to have reproductive and developmental toxicity, 67 substances were found to be neurotoxic, and 244 substances to cause effects on the liver and biliary system, including the gallbladder. All the findings (endpoints) that were indicated in the contract as indicative for those effects have been reported for each substance, with their respective NOEL/LOELs. The selection of NOELs and LOELs was performed, as requested by EFSA, without any interpretation on whether an effect is to be considered adverse or not adverse. The identification of key effects appropriate for the establishment of common assessment groups was also not required and therefore not undertaken. It was in fact considered that the establishment of CAGs should be agreed upon by a group of experts rather than be based on the opinion of an individual contractor. However, the data presented in this report provide the basis for addressing both the issue of adversity versus non adversity, and the definition of CAGs. Critical to these activities is the identification, whenever possible, of the MoA. In the report, established or postulated MoAs have been reported, as well as reference to possible sources of information in this respect, which mostly included the open literature. No in-depth analysis of proposed or postulated MoAs was performed. In conclusion, this report provides a comprehensive database that would allow EFSA to access the relevant toxicological information necessary to define the CAGs according to the toxicological criteria that will be adopted. It is recommended that the data provided in this report be interpreted against information on MoA and the presence of other systemic toxicological effects. Given the present toxicological knowledge, the definition of CAGs will necessarily be the result of an expert weight-of-evidence judgment.