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Toxicological risk assessment of micro-organisms used as active substances in plant protection products
Abstracts / Toxicology Letters 258S (2016) S62–S324
determine transfer efficiency in order to adjust the dose volume applied to the septum ensuring the appropriate test concentration on the skin. After dose transfer, a standard DA study was performed according to OECD 428 TG. Results from 10 compounds indicated the methodology of creating and transferring DFR onto skin surfaces can be incorporated in a standard OECD 428 TG study. These data also indicated the DA from DFR was lower than that from the equivalent spray. The DA generated with this methodology is relevant for performing/refining the re-entry worker risk assessments for agrochemicals. http://dx.doi.org/10.1016/j.toxlet.2016.06.2048 P22-005 EPA’s methodology to inform TSCA premanufacturing notification decision-making: A critical analysis based on chemicals regulated by consent order R. Borotkanics ∗ , P. Locke Background: Regulatory toxicology has emerged as a necessary discipline to ensure the chemicals introduced into commerce are safe. In the United States, a number of federal laws guide regulatory toxicology, including the Toxic Substances Control Act (TSCA). The New Chemicals program is administered by US Environmental Protection Agency (EPA). This program evaluates premanufacture notifications (PMNs) of new chemicals or significant new uses of existing chemicals. PMN submitters are not required to include human health or environmental effects data, nor are they required to undertake any toxicity testing. These statutory restrictions place constraints on the EPA with respect to the basic data available to inform decisions, and the EPA has only 90 days to make regulatory decisions on PMN substances. Using publically available information about decisions on new chemicals, we sought to determine the methodology used by the TSCA New Chemicals Program, including data proffered or generated, to inform such regulatory decisions; specifically, consent order decisions. Results: The consent order regulatory decisions evaluated in this study applied analog analyses, or in silico methods to inform two-thirds of the decisions. For these decisions, no new in vivo or in vitro tests were carried out by EPA or at the direction of EPA. PMN submissions included testing data about one half of the time, which informed one third of the decisions to regulate by consent order. More broadly, test results submitted by PMN submitters were often not aligned to the health concerns identified by the EPA. Multiple human (3 or more) and environmental health concerns were associated with decisions to regulate. Discussion: Because of the way in which TSCA is written and implemented, the EPA must operate in a data poor information environment. In response, the EPA has developed alternative testing methods, which by definition include non test methods, to inform and assist in PMN regulatory decision making. This demonstrates that TSCA has resulted in the utilization of these alternative methods, demonstrating that laws can provide an opportunity for innovation and efficiencies even if explicit incentives are not designed into the law. TSCA is not the only law to promote such innovation. For instance, the European Commission required the phase out of animal tests in cosmetics. The adoption of alternative testing methods is consistent with the National Academies vision of toxicity testing in the 21st century. This study and findings are important for other regulators in the potential adoption of alternative testing methods to inform regulatory decisions going forward. http://dx.doi.org/10.1016/j.toxlet.2016.06.2049
S307
P22-006 Toxicological risk assessment of micro-organisms used as active substances in plant protection products C. Ochoa-Campuzano 1 , S. Seehase 2,∗ , R. Hauschild 2 , J. Süß 3 , W. Pfau 2 1 GAB Consulting Spain S.L.U., Av. Cortes Valencianas, No. 39, 8B, 46015 Valencia, Spain 2 GAB Consulting GmbH, Ottenbecker Damm 10, 21684 Stade, Germany 3 GAB Consulting GmbH, Heinrich-Fuchs-Str. 94, 69126 Heidelberg, Germany
Plant protection products containing micro-organisms like bacteria, fungi or viruses as active substances are regarded as sustainable and environmentally safe tools to manage pests in agriculture. The pesticidal activity of these naturally occurring micro-organisms is mostly mediated by mechanisms highly specific to the target species, including infection, parasitism or competition for nutrients, which are usually not relevant to humans. In order to ensure a safe use for humans of microbial based plant protection products, a comprehensive toxicological assessment is required. This comprises not only the conduction of studies in vertebrates as for chemical active substances and studies addressing the infectivity and pathogenicity, but also a deep knowledge of the taxonomy, biology, physiology and the mode of action of each particular micro-organism. In addition, the critical assessment of data from the peer-reviewed literature regarding reported cases of infections or allergies as well as on the production of secondary metabolites and toxins is a valuable tool in the evaluation process. Micro-organisms used in plan protection are regulated in the EU according to Regulation (EC) No. 1107/2009 and Regulations (EU) No. 283/2013 and No. 284/2013. Although these regulations have been adapted to better meet the requirements to assess micro-organisms, discussion is ongoing on how to improve the methodology. In this work, we discuss the current testing requirements under EU regulation regarding the unique characteristics of micro-organisms used in plant protection, based on our experience in the approval of microbial strains as active substances and in the registration of microbial biopesticides in the EU. http://dx.doi.org/10.1016/j.toxlet.2016.06.2050 P22-007 Negative prediction of chemical carcinogenicity using short-term effects T. Hill III 1,∗ , M. Nelms 1 , S.W. Edwards 2 , C.E. Wood 2 1
Oak Ridge Institute for Science and Education participant at the National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (EPA), Research Triangle Park, NC 27709, USA 2 National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709, USA The long-term rodent bioassay has served for decades as a cornerstone for identifying and assessing chemical carcinogens. However, high resource demands make this test unfeasible for the vast majority of environmental chemicals. To help address this issue and improve methods to screen and prioritize compounds for potential carcinogenic risk, here we evaluated the negative predictivity of short-term risk factors for tumor outcomes and
determine transfer efficiency in order to adjust the dose volume applied to the septum ensuring the appropriate test concentration on the skin. After dose transfer, a standard DA study was performed according to OECD 428 TG. Results from 10 compounds indicated the methodology of creating and transferring DFR onto skin surfaces can be incorporated in a standard OECD 428 TG study. These data also indicated the DA from DFR was lower than that from the equivalent spray. The DA generated with this methodology is relevant for performing/refining the re-entry worker risk assessments for agrochemicals. http://dx.doi.org/10.1016/j.toxlet.2016.06.2048 P22-005 EPA’s methodology to inform TSCA premanufacturing notification decision-making: A critical analysis based on chemicals regulated by consent order R. Borotkanics ∗ , P. Locke Background: Regulatory toxicology has emerged as a necessary discipline to ensure the chemicals introduced into commerce are safe. In the United States, a number of federal laws guide regulatory toxicology, including the Toxic Substances Control Act (TSCA). The New Chemicals program is administered by US Environmental Protection Agency (EPA). This program evaluates premanufacture notifications (PMNs) of new chemicals or significant new uses of existing chemicals. PMN submitters are not required to include human health or environmental effects data, nor are they required to undertake any toxicity testing. These statutory restrictions place constraints on the EPA with respect to the basic data available to inform decisions, and the EPA has only 90 days to make regulatory decisions on PMN substances. Using publically available information about decisions on new chemicals, we sought to determine the methodology used by the TSCA New Chemicals Program, including data proffered or generated, to inform such regulatory decisions; specifically, consent order decisions. Results: The consent order regulatory decisions evaluated in this study applied analog analyses, or in silico methods to inform two-thirds of the decisions. For these decisions, no new in vivo or in vitro tests were carried out by EPA or at the direction of EPA. PMN submissions included testing data about one half of the time, which informed one third of the decisions to regulate by consent order. More broadly, test results submitted by PMN submitters were often not aligned to the health concerns identified by the EPA. Multiple human (3 or more) and environmental health concerns were associated with decisions to regulate. Discussion: Because of the way in which TSCA is written and implemented, the EPA must operate in a data poor information environment. In response, the EPA has developed alternative testing methods, which by definition include non test methods, to inform and assist in PMN regulatory decision making. This demonstrates that TSCA has resulted in the utilization of these alternative methods, demonstrating that laws can provide an opportunity for innovation and efficiencies even if explicit incentives are not designed into the law. TSCA is not the only law to promote such innovation. For instance, the European Commission required the phase out of animal tests in cosmetics. The adoption of alternative testing methods is consistent with the National Academies vision of toxicity testing in the 21st century. This study and findings are important for other regulators in the potential adoption of alternative testing methods to inform regulatory decisions going forward. http://dx.doi.org/10.1016/j.toxlet.2016.06.2049
S307
P22-006 Toxicological risk assessment of micro-organisms used as active substances in plant protection products C. Ochoa-Campuzano 1 , S. Seehase 2,∗ , R. Hauschild 2 , J. Süß 3 , W. Pfau 2 1 GAB Consulting Spain S.L.U., Av. Cortes Valencianas, No. 39, 8B, 46015 Valencia, Spain 2 GAB Consulting GmbH, Ottenbecker Damm 10, 21684 Stade, Germany 3 GAB Consulting GmbH, Heinrich-Fuchs-Str. 94, 69126 Heidelberg, Germany
Plant protection products containing micro-organisms like bacteria, fungi or viruses as active substances are regarded as sustainable and environmentally safe tools to manage pests in agriculture. The pesticidal activity of these naturally occurring micro-organisms is mostly mediated by mechanisms highly specific to the target species, including infection, parasitism or competition for nutrients, which are usually not relevant to humans. In order to ensure a safe use for humans of microbial based plant protection products, a comprehensive toxicological assessment is required. This comprises not only the conduction of studies in vertebrates as for chemical active substances and studies addressing the infectivity and pathogenicity, but also a deep knowledge of the taxonomy, biology, physiology and the mode of action of each particular micro-organism. In addition, the critical assessment of data from the peer-reviewed literature regarding reported cases of infections or allergies as well as on the production of secondary metabolites and toxins is a valuable tool in the evaluation process. Micro-organisms used in plan protection are regulated in the EU according to Regulation (EC) No. 1107/2009 and Regulations (EU) No. 283/2013 and No. 284/2013. Although these regulations have been adapted to better meet the requirements to assess micro-organisms, discussion is ongoing on how to improve the methodology. In this work, we discuss the current testing requirements under EU regulation regarding the unique characteristics of micro-organisms used in plant protection, based on our experience in the approval of microbial strains as active substances and in the registration of microbial biopesticides in the EU. http://dx.doi.org/10.1016/j.toxlet.2016.06.2050 P22-007 Negative prediction of chemical carcinogenicity using short-term effects T. Hill III 1,∗ , M. Nelms 1 , S.W. Edwards 2 , C.E. Wood 2 1
Oak Ridge Institute for Science and Education participant at the National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency (EPA), Research Triangle Park, NC 27709, USA 2 National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709, USA The long-term rodent bioassay has served for decades as a cornerstone for identifying and assessing chemical carcinogens. However, high resource demands make this test unfeasible for the vast majority of environmental chemicals. To help address this issue and improve methods to screen and prioritize compounds for potential carcinogenic risk, here we evaluated the negative predictivity of short-term risk factors for tumor outcomes and