Frederique Istace

Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC

Glyphosate is the most widely used herbicide worldwide. It is a broad spectrum herbicide and its agricultural uses increased considerably after the development of glyphosate-resistant genetically modified (GM) varieties. Since glyphosate was introduced in 1974, all regulatory assessments have established that glyphosate has low hazard potential to mammals, however, the International Agency for Research on Cancer (IARC) concluded in March 2015 that it is probably carcinogenic. The IARC conclusion was not confirmed by the EU assessment or the recent joint WHO/FAO evaluation, both using additional evidence. Glyphosate is not the first topic of disagreement between IARC and regulatory evaluations, but has received greater attention. This review presents the scientific basis of the glyphosate health assessment conducted within the European Union (EU) renewal process, and explains the differences in the carcinogenicity assessment with IARC. Use of different data sets, particularly on long-term toxicity/carcinogenicity in rodents, could partially explain the divergent views; but methodological differences in the evaluation of the available evidence have been identified. The EU assessment did not identify a carcinogenicity hazard, revised the toxicological profile proposing new toxicological reference values, and conducted a risk assessment for some representatives uses. Two complementary exposure assessments, human-biomonitoring and food-residues-monitoring, suggests that actual exposure levels are below these reference values and do not represent a public concern.

Peer review of the pesticide risk assessment for the triazole derivative metabolites in light of confirmatory data submitted

Abstract The conclusions of EFSA following the peer review of the initial risk assessment carried out by the competent authority of the rapporteur Member State, the United Kingdom, for the pesticide risk assessment for the triazole derivative metabolites are reported. The context of the peer review was that requested by the European Commission following the submission and evaluation of confirmatory data in relation to mammalian toxicology, metabolism and residue data. The conclusions were reached on the basis of the evaluation of various uses for a number of triazole fungicides. Recommendations are proposed. Missing information identified as being required by the regulatory framework is listed. Concerns are identified.

Peer review of the targeted hazard assessment of the pesticide active substance quinoxyfen

Abstract The conclusions of EFSA following the peer review of the initial assessments carried out by the competent authorities of the rapporteur Member State, the United Kingdom, and co‐rapporteur Member State, Austria, for the pesticide active substance quinoxyfen 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 information targeted at the assessment of the potential persistent, bioaccumulative and toxic (PBT), very persistent and very bioaccumulative (vPvB) and persistent organic pollutant (POP) properties of quinoxyfen according to Article 11(2) of Regulation (EC) No 1107/2009. The reliable end points, appropriate for use in these regulatory hazard cut off assessments are presented. Missing information identified as being required by the regulatory framework is listed. The concern is identified that quinoxyfen may be considered to exhibit the hazard properties of both a PBT and vPvB substance considering the triggers specified in Annex II of Regulation (EC) No 1107/2009.

Peer review of the pesticide risk assessment of the active substance pethoxamid

Abstract 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, Austria, and co‐rapporteur Member State, the Czech Republic, for the pesticide active substance pethoxamid 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 pethoxamid as a herbicide on maize and soya bean. 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 identified.

Peer review of the pesticide risk assessment of the active substance mepanipyrim

Abstract The conclusions of 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 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 identified.

Peer review of the pesticide risk assessment for the active substance terbuthylazine in light of confirmatory data submitted

Abstract The conclusions of EFSA following the peer review of the initial risk assessment carried out by the competent authority of the rapporteur Member State, the United Kingdom, for the pesticide active substance metazachlor are reported. The context of the peer review was that requested by the European Commission following the submission and evaluation of confirmatory data regarding the groundwater exposure of metabolites and their toxicological relevance triggering an assessment. The conclusions were reached on the basis of the evaluation of the representative uses of metazachlor as a herbicide on winter and spring rapeseed and on ornamental trees and shrubs. The reliable endpoints concluded as being appropriate for use in regulatory risk assessment, derived from the available studies and literature in the dossier peer reviewed, are presented. Concerns are identified.

Response to the reply by C. J. Portier and P. Clausing, concerning our review “Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC”

commenting rounds and the public consultation (EFSA 2015b). Although our response will be restricted to the EFSA assessment presented in Tarazona et al. (2017), it is worth noting the similarities in term of complementarity and transparency between the EFSA process under the pesticides regulation and the ECHA process under Regulation (EC) No 1272/2008. Germany as RMS under the Regulation (EC) No 1107/2009 (Germany 2015) and Dossier Submitter under the Regulation (EC) No 1272/2008 (BAuA 2016) expresses the views of the German experts, while EFSA (2015a, b) reports the view of the experts involved in the EFSA peer-review. The RAC Opinion (ECHA 2017) represents the view of the ECHA Committee for Risk Assessment. Portier and Clausing (2017) are suggesting apparent contradictions between the different views regarding the evaluation of study N. But in our opinion, this participates to the strength of the EU complementarity value. Different approaches for the weight of evidence are presented in a transparent way, allowing the scrutiny by the scientific community and interested groups. Even more important, despite different views on how to approach specific issues such as the reliability and relevance of study N, the weights of evidence converge and there is full consensus on the final conclusion, thus confirming that including or excluding study N does not change the overall assessment. EFSA decided to exclude study N due to concerns on the health status of the animal population, identified by US EPA (USEPA 2016), and confirmed by EFSA experts. Viral infections were not investigated by the study authors; therefore, EFSA’s confirmation focused on the health status and was based on indirect indications in the study report, supported by complementary evidence. The GLP status of the study (mandatory for industry-sponsored studies) implies that the test system should be free of any disease or condition that might interfere with the purpose or conduct of We welcome the opportunity for having an evidence-based scientific discussion on glyphosate’s carcinogenicity. We note that all of the findings in Table 1 of the Reply by Portier and Clausing (2017) have been available in the public domain in the supplemental data tables published by Greim et al. (2015; available online since February 2015). In addition, some of these findings were also raised in the report by IARC, but were not considered further. Although not explicitly mentioned by Portier and Clausing, it is relevant to indicate that, following a request to access to documents by four Members of the European Parliament, both authors got access to the findings and raw data of the unpublished industry sponsored studies on the carcinogenicity and genotoxicity of glyphosate submitted to EFSA; and even more important, that this information will be provided, under request, to any other person interested in scrutinizing the EFSA assessment and weight of evidence presented in our review. Two basic values of the EU assessments on pesticides are complementarity and transparency. The first is based on the peer-review principle, with an initial assessment by experts of the rapporteur member state (RMS), which is peer-reviewed by EFSA in close collaboration with experts from other Member States, and resulting in the EFSA Conclusion (EFSA 2015a). Transparency is ensured by publishing all assessments in a peer review report, which includes the comments and responses received during the different

Peer review of the pesticide risk assessment of the active substance azadirachtin (Margosa extract)

Abstract 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, Germany, for the pesticide active substance azadirachtin 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 additional representative use of azadirachtin as an acaricide on greenhouse ornamentals. Conclusions are also represented for the representative use evaluated for the approval of azadirachtin, which was as an insecticide on potatoes. 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 identified.

Peer review of the pesticide risk assessment of the active substance Bacillus subtilis strain IAB/BS03

Abstract 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 the Netherlands, for the pesticide active substance Bacillus subtilis strain IAB/BS03 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 B. subtilis strain IAB/BS03 as a fungicide on field lettuce, orchards and protected cucurbits. 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 identified.

Peer review of the pesticide risk assessment of the active substance tolclofos‐methyl

Abstract 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, Sweden, and co‐rapporteur Member State, Denmark, for the pesticide active substance tolclofos‐methyl 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 tolclofos‐methyl as a fungicide on potatoes, lettuce and ornamentals. 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 identified.