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Regulatory approach of the dietary risk assessment of biocidal products
Abstracts / Toxicology Letters 189S (2009) S57–S273
successfully proposed to IMI-JU a new type, high quality and sustainable programme for education and training in Safety Sciences for Medicines. This programme will fulfil the needs of pharmaceutical industry, regulatory authorities and academia. The tailor-made training courses will encompass the safety, ethical, regulatory and societal aspects in all phases of drug development, with emphasis on integrative, translational and 3Rs aspects of drug safety assessment. Individual safety professionals who wish to address specific knowledge gaps will be able to follow single courses. The modular set up also provides an excellent opportunity for dedicated subsets of courses, to be accredited for Continuing Professional Development (CPD) and an accredited Master of Advanced Safety Sciences of Medicines (MAS2M). 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.874 Regulatory Toxicology X01 Analysing discordant local lymph node assay datasets: Implications for reach David Basketter 1 , Nicolas Ball 2 , Stuart Cagen 3 , Juan-Carlos Carrillo 4 , Hans Certa 5 , Dorothea Eigler 6 , Harald Esch 7 , Christine Garcia 8 , Cynthia Graham 9 , Carl Haux 10 , Reinhard Kreiling 11 , Annette Mehling 12,∗ 1
DABMEB Consultancy Ltd., Sharnbrook, United Kingdom, 2 The Dow Chemical Company, Horgen, Switzerland, 3 Shell Health, Houston, Texas, United States, 4 Shell International B.V., Den Haag, Netherlands, 5 SASOL Germany GmbH, Marl, Germany, 6 Evonik Goldschmidt GmbH, Essen, Germany, 7 BASF Aktiengesellschaft, Ludwigshafen, Germany, 8 SEPPIC, Castres, France, 9 Huntsman LLC, The Woodlands, United States, 10 Akzo Nobel Surface Chemistry AB, Stenungsund, Sweden, 11 Clariant Produkte (Deutschland) GmbH, Sulzbach, Germany, 12 Cognis GmbH, Duesseldorf, Germany The local lymph node assay (LLNA) is the assay of choice in European regulatory toxicology. As with other toxicology/sensitisation assays, it has a potential for false results, the anionic surfactant sodium lauryl sulphate (SLS) representing a classic example. In the work reported here, examples of false positives in the LLNA are compared to published benchmarks such as SLS. Clear false positives (e.g. oleic acid) are also contrasted with examples where data interpretation is more challenging. As the LLNA will be applicable to >30,000 chemicals under REACH, and in the light of animal welfare considerations to do no more than the absolute minimum of animal testing, results from a single LLNA often represent the only available data on sensitisation. This reinforces the need to ensure data from this assay are interpreted intelligently, using scientific analysis of results and considering the weight of evidence, before decisions are made on which substances should be classified as representing a skin sensitisation hazard. In chemical classes where the LLNA has been shown to be an inappropriate assay other standardised methods (e.g. the Buehler or Magnusson and Kligman guinea pig tests [OECD 406]) should be employed as the first choice assays. doi:10.1016/j.toxlet.2009.06.830
S267
X02 Information resources for disaster response from the US National Library of Medicine Jeanne Goshorn National Library of Medicine/NIH, HHS, Bethesda, MD, United States The Toxicology and Environmental Health Information Program was established at the US National Library of Medicine (NLM) in 1967. Since that time many well-known databases have been developed and maintained, with improved access provided to an ever wider group of users as computer and communications technology evolved. Most recently, NLM has focused on disaster information, and a Disaster Information Management Research Center (DIMRC) has been established to help with national preparedness and response to disasters of natural, accidental, or deliberate origin. NLM resources have evolved to meet the needs of disaster response. The information in the Hazardous Substances Data Bank (HSDB) provides content for the Wireless Information System for Emergency Responders (WISER), which works in standalone mode for handheld devices and can also deploy information over the Internet. HSDB also provides background information for a comprehensive tool in response to radiation emergencies, the Radiation Event Medical Management system (REMM). A similar tool for the management of chemical exposure emergencies is under development. The Disaster Information Response Research Center at NLM provides a focal point for health information related to disasters and a mechanism for development of education and training tools and communications interoperability technologies for providing access to important health resources in the event of a large-scale emergency. doi:10.1016/j.toxlet.2009.06.831
X03 Regulatory approach of the dietary risk assessment of biocidal products Michel Bouvier d’Yvoire ∗ , Erik van de Plassche Joint Research Centre, IHCP – Chemical Assessment and Testing Unit, Ispra (VA), Italy The pattern of use of some biocidal products may cause secondary dietary exposure of consumers to biocidal substances. For example, the use of insecticides in animal housing facilities may lead to the presence of the biocidal substance or its residues in the animal food products, i.e. meat, milk, and eggs. The corresponding dietary risk assessment is required by the Biocidal Products Directive 98/8/EC (BPD). A tiered approach is being developed to be applied at the stage of inclusion of the biocidal substances into Annex 1 of the BPD. The exposure of the food-producing animals to the substance can be estimated and refined, and compared to a trigger value derived from the practice of the EFSA for pesticides. If the trigger value is exceeded, then a complete dietary risk assessment will take place. The first steps of exposure estimation and dietary risk assessment will be performed by the rapporteur Member State (RMS), based on the hazard characterisation profile of the substance and on the use pattern of the product(s) associated to the substance for inclusion into Annex 1 of the BPD. Where indicated, a further step of evaluation of the need for setting maximum residue levels (MRLs), including the request for complementary studies, is foreseen to take place under the responsibility of the EMEA and/or
S268
Abstracts / Toxicology Letters 189S (2009) S57–S273
EFSA, in close co-operation with the RMS. Where necessary, the dietary risk assessment of later products containing the same substance should be done under the responsibility of the Member State Competent Authority receiving the application, on the basis of the initial assessment done at the substance inclusion stage. doi:10.1016/j.toxlet.2009.06.832
X04 Comparison of LLNA and GPMT results for the identification of skin sensitizing potentials of the category of non-ionic sugarlipid surfactants Christine Garcia 1,∗ , Nicholas Ball 2 , Stuart Cagen 3 , Juan Carlos Carrillo 4 , Hans Certa 5 , Dorothea Eigler 6 , Harald Esch 7 , Cynthia Graham 8 , Carl Haux 9 , Reinhard Kreiling 10 , Annette Mehling 11 1
SEPPIC, Regulatory Department, Castres, France, 2 The Dow Chemical Company, Horgen, Switzerland, 3 Shell Health, Houston, United States, 4 Shell International B.V., Den Haag, Netherlands, 5 SASOL GERMANY GmBH, MARL, Germany, 6 Evonik Goldschmidt GmBH, Essen, Germany, 7 BASF Aktiengesellschaft, Ludwigshafen, Germany, 8 Hunstman LLC, The Woodlands, Germany, 9 AKZO NOBEL Surface Chemistry AB, Stenungsund, Germany, 10 CLARIANT Produkte GmbH, Sulzbach, Germany, 11 COGNIS GmBH, Germany The Local Lymph Node Assay (LLNA, OECD 429, adopted 2002) is the preferred test for the identification of skin sensitizing potentials of chemicals in Europe and also the first choice method within REACH. In other countries, such as the US and Japan, the Guinea Pig Maximization Test (GPMT, OECD 406, adopted 1992) is still available and considered the preferred conventional test. Some classes of chemicals, such as surfactants, were insufficiently represented in the LLNA validation process and SDS was identified as a false positive in this test. In this study, 10 non-ionic sugarlipids used as emulsifiers were tested both in LLNA and GPMT as well as in 50 human volunteers according to the conventional method of Human Repeat Insult Patch Test (Marzulli & Maibach). Of the 10 non-ionic sugarlipids tested in LLNA, five showed stimulation indices (SI) above 3.0. Three of five positive reactions were concomitant with signs of skin irritation as indicated by an increase in ear thickness. In GPMT, all test products fulfilled the criteria as non-sensitizers. In human volunteers, no skin reactions were reported adding to the weight of evidence. In conclusion, the LLNA over-classifies this category of surfactants and is not appropriate for labelling and classification. In some cases, the false positive result in LLNA is related to the irritant effect of the product. For this category of surfactants, LLNA lacks the predictive potential to discriminate between allergens and irritants. GPMT is the more appropriate test to evaluate sensitizing potential in this class of chemicals. doi:10.1016/j.toxlet.2009.06.833
X05 Substances with endocrine disrupting properties under new EU plant protection product regulation—Establishment of assessment and decision criteria Philip Marx-Stoelting 1,∗ , Ibrahim Chahoud 2 , Tomas Moeller 1 , Rudolf Pfeil 1 , Roland Solecki 1 , Beate Ulbrich 1 , Karen Ildico Hirsch-Ernst 1 1 Federal Institute for Risk Assessment, Safety of Substances and Preparations, Berlin, Germany, 2 Charite, Berlin, Germany
In the past decades substances with a potential to modulate the hormonal system have been subject to intensive public and scientific debates. The new EU plant protection regulation names endocrine disrupting properties as one of the cut-off criteria for the approval of active substances which are aimed to be used in plant protection products. While the regulation clearly states that an active substance, safener or synergist shall only be approved if it is not considered to have endocrine disrupting properties that may cause adverse effects in humans, unless the exposure of humans under realistic proposed conditions of use is negligible, it fails to provide conclusive scientific criteria for risk assessment. Measures concerning specific scientific criteria for the determination of endocrine disrupting properties are to be presented by the commission within four years. To address this need, the Federal Institute for Risk Assessment is suggesting scientific criteria for the assessment of substances with potential adverse effects on the endocrine system. Furthermore, a framework for evaluating the likely relevance of potentially adverse endocrine effects for humans under realistically assumed exposure conditions will be proposed. Central aspects considered within the framework include dose-dependency, severity and selectivity of effects on the endocrine system, establishment of a mode of action in animals, and qualitative and quantitative comparison of key mechanistic events between experimental animals and humans. Here we present an overview on the assessment and decision criteria for substances with endocrine modulating properties under the new plant protection legislation. doi:10.1016/j.toxlet.2009.06.834
X06 Chlorpyrifos and neurodevelopmental toxicity: Critical assessment and expert elicitation Brooke Magnanti 1,∗ , Sara Correia Carreira 1 , Margaret Saunders 1 , Alena Bartonova 2 , Martin Von Krauss 3 1
Haematology and Oncology Centre, Biophysics, Bristol, United Kingdom, 2 Norwegian Institute for Air Research (NILU), Centre for Ecological Economics, Kjeller, Norway, 3 World Health Organisation, European Centre for Environment and Health, Copenhagen, Denmark Organophosphate (OP) compounds are used worldwide for pest control, in agriculture and gardening and also in residential and indoor settings. OPs act by inhibiting acetylcholinesterase, thus affecting nerve function in insects, humans and other animals. Most of the animal and human studies published between 2000 and 2007 refer to the OP chlorpyrifos (CPF). There are concerns about the safety of CPF in the environment. While previous studies have shown levels of CPF that are safe in adult animals, recent evidence indicates young animals and humans may be more sensitive to CPF toxicity. In young animals,
successfully proposed to IMI-JU a new type, high quality and sustainable programme for education and training in Safety Sciences for Medicines. This programme will fulfil the needs of pharmaceutical industry, regulatory authorities and academia. The tailor-made training courses will encompass the safety, ethical, regulatory and societal aspects in all phases of drug development, with emphasis on integrative, translational and 3Rs aspects of drug safety assessment. Individual safety professionals who wish to address specific knowledge gaps will be able to follow single courses. The modular set up also provides an excellent opportunity for dedicated subsets of courses, to be accredited for Continuing Professional Development (CPD) and an accredited Master of Advanced Safety Sciences of Medicines (MAS2M). 夽 Selected for Oral Presentation. doi:10.1016/j.toxlet.2009.06.874 Regulatory Toxicology X01 Analysing discordant local lymph node assay datasets: Implications for reach David Basketter 1 , Nicolas Ball 2 , Stuart Cagen 3 , Juan-Carlos Carrillo 4 , Hans Certa 5 , Dorothea Eigler 6 , Harald Esch 7 , Christine Garcia 8 , Cynthia Graham 9 , Carl Haux 10 , Reinhard Kreiling 11 , Annette Mehling 12,∗ 1
DABMEB Consultancy Ltd., Sharnbrook, United Kingdom, 2 The Dow Chemical Company, Horgen, Switzerland, 3 Shell Health, Houston, Texas, United States, 4 Shell International B.V., Den Haag, Netherlands, 5 SASOL Germany GmbH, Marl, Germany, 6 Evonik Goldschmidt GmbH, Essen, Germany, 7 BASF Aktiengesellschaft, Ludwigshafen, Germany, 8 SEPPIC, Castres, France, 9 Huntsman LLC, The Woodlands, United States, 10 Akzo Nobel Surface Chemistry AB, Stenungsund, Sweden, 11 Clariant Produkte (Deutschland) GmbH, Sulzbach, Germany, 12 Cognis GmbH, Duesseldorf, Germany The local lymph node assay (LLNA) is the assay of choice in European regulatory toxicology. As with other toxicology/sensitisation assays, it has a potential for false results, the anionic surfactant sodium lauryl sulphate (SLS) representing a classic example. In the work reported here, examples of false positives in the LLNA are compared to published benchmarks such as SLS. Clear false positives (e.g. oleic acid) are also contrasted with examples where data interpretation is more challenging. As the LLNA will be applicable to >30,000 chemicals under REACH, and in the light of animal welfare considerations to do no more than the absolute minimum of animal testing, results from a single LLNA often represent the only available data on sensitisation. This reinforces the need to ensure data from this assay are interpreted intelligently, using scientific analysis of results and considering the weight of evidence, before decisions are made on which substances should be classified as representing a skin sensitisation hazard. In chemical classes where the LLNA has been shown to be an inappropriate assay other standardised methods (e.g. the Buehler or Magnusson and Kligman guinea pig tests [OECD 406]) should be employed as the first choice assays. doi:10.1016/j.toxlet.2009.06.830
S267
X02 Information resources for disaster response from the US National Library of Medicine Jeanne Goshorn National Library of Medicine/NIH, HHS, Bethesda, MD, United States The Toxicology and Environmental Health Information Program was established at the US National Library of Medicine (NLM) in 1967. Since that time many well-known databases have been developed and maintained, with improved access provided to an ever wider group of users as computer and communications technology evolved. Most recently, NLM has focused on disaster information, and a Disaster Information Management Research Center (DIMRC) has been established to help with national preparedness and response to disasters of natural, accidental, or deliberate origin. NLM resources have evolved to meet the needs of disaster response. The information in the Hazardous Substances Data Bank (HSDB) provides content for the Wireless Information System for Emergency Responders (WISER), which works in standalone mode for handheld devices and can also deploy information over the Internet. HSDB also provides background information for a comprehensive tool in response to radiation emergencies, the Radiation Event Medical Management system (REMM). A similar tool for the management of chemical exposure emergencies is under development. The Disaster Information Response Research Center at NLM provides a focal point for health information related to disasters and a mechanism for development of education and training tools and communications interoperability technologies for providing access to important health resources in the event of a large-scale emergency. doi:10.1016/j.toxlet.2009.06.831
X03 Regulatory approach of the dietary risk assessment of biocidal products Michel Bouvier d’Yvoire ∗ , Erik van de Plassche Joint Research Centre, IHCP – Chemical Assessment and Testing Unit, Ispra (VA), Italy The pattern of use of some biocidal products may cause secondary dietary exposure of consumers to biocidal substances. For example, the use of insecticides in animal housing facilities may lead to the presence of the biocidal substance or its residues in the animal food products, i.e. meat, milk, and eggs. The corresponding dietary risk assessment is required by the Biocidal Products Directive 98/8/EC (BPD). A tiered approach is being developed to be applied at the stage of inclusion of the biocidal substances into Annex 1 of the BPD. The exposure of the food-producing animals to the substance can be estimated and refined, and compared to a trigger value derived from the practice of the EFSA for pesticides. If the trigger value is exceeded, then a complete dietary risk assessment will take place. The first steps of exposure estimation and dietary risk assessment will be performed by the rapporteur Member State (RMS), based on the hazard characterisation profile of the substance and on the use pattern of the product(s) associated to the substance for inclusion into Annex 1 of the BPD. Where indicated, a further step of evaluation of the need for setting maximum residue levels (MRLs), including the request for complementary studies, is foreseen to take place under the responsibility of the EMEA and/or
S268
Abstracts / Toxicology Letters 189S (2009) S57–S273
EFSA, in close co-operation with the RMS. Where necessary, the dietary risk assessment of later products containing the same substance should be done under the responsibility of the Member State Competent Authority receiving the application, on the basis of the initial assessment done at the substance inclusion stage. doi:10.1016/j.toxlet.2009.06.832
X04 Comparison of LLNA and GPMT results for the identification of skin sensitizing potentials of the category of non-ionic sugarlipid surfactants Christine Garcia 1,∗ , Nicholas Ball 2 , Stuart Cagen 3 , Juan Carlos Carrillo 4 , Hans Certa 5 , Dorothea Eigler 6 , Harald Esch 7 , Cynthia Graham 8 , Carl Haux 9 , Reinhard Kreiling 10 , Annette Mehling 11 1
SEPPIC, Regulatory Department, Castres, France, 2 The Dow Chemical Company, Horgen, Switzerland, 3 Shell Health, Houston, United States, 4 Shell International B.V., Den Haag, Netherlands, 5 SASOL GERMANY GmBH, MARL, Germany, 6 Evonik Goldschmidt GmBH, Essen, Germany, 7 BASF Aktiengesellschaft, Ludwigshafen, Germany, 8 Hunstman LLC, The Woodlands, Germany, 9 AKZO NOBEL Surface Chemistry AB, Stenungsund, Germany, 10 CLARIANT Produkte GmbH, Sulzbach, Germany, 11 COGNIS GmBH, Germany The Local Lymph Node Assay (LLNA, OECD 429, adopted 2002) is the preferred test for the identification of skin sensitizing potentials of chemicals in Europe and also the first choice method within REACH. In other countries, such as the US and Japan, the Guinea Pig Maximization Test (GPMT, OECD 406, adopted 1992) is still available and considered the preferred conventional test. Some classes of chemicals, such as surfactants, were insufficiently represented in the LLNA validation process and SDS was identified as a false positive in this test. In this study, 10 non-ionic sugarlipids used as emulsifiers were tested both in LLNA and GPMT as well as in 50 human volunteers according to the conventional method of Human Repeat Insult Patch Test (Marzulli & Maibach). Of the 10 non-ionic sugarlipids tested in LLNA, five showed stimulation indices (SI) above 3.0. Three of five positive reactions were concomitant with signs of skin irritation as indicated by an increase in ear thickness. In GPMT, all test products fulfilled the criteria as non-sensitizers. In human volunteers, no skin reactions were reported adding to the weight of evidence. In conclusion, the LLNA over-classifies this category of surfactants and is not appropriate for labelling and classification. In some cases, the false positive result in LLNA is related to the irritant effect of the product. For this category of surfactants, LLNA lacks the predictive potential to discriminate between allergens and irritants. GPMT is the more appropriate test to evaluate sensitizing potential in this class of chemicals. doi:10.1016/j.toxlet.2009.06.833
X05 Substances with endocrine disrupting properties under new EU plant protection product regulation—Establishment of assessment and decision criteria Philip Marx-Stoelting 1,∗ , Ibrahim Chahoud 2 , Tomas Moeller 1 , Rudolf Pfeil 1 , Roland Solecki 1 , Beate Ulbrich 1 , Karen Ildico Hirsch-Ernst 1 1 Federal Institute for Risk Assessment, Safety of Substances and Preparations, Berlin, Germany, 2 Charite, Berlin, Germany
In the past decades substances with a potential to modulate the hormonal system have been subject to intensive public and scientific debates. The new EU plant protection regulation names endocrine disrupting properties as one of the cut-off criteria for the approval of active substances which are aimed to be used in plant protection products. While the regulation clearly states that an active substance, safener or synergist shall only be approved if it is not considered to have endocrine disrupting properties that may cause adverse effects in humans, unless the exposure of humans under realistic proposed conditions of use is negligible, it fails to provide conclusive scientific criteria for risk assessment. Measures concerning specific scientific criteria for the determination of endocrine disrupting properties are to be presented by the commission within four years. To address this need, the Federal Institute for Risk Assessment is suggesting scientific criteria for the assessment of substances with potential adverse effects on the endocrine system. Furthermore, a framework for evaluating the likely relevance of potentially adverse endocrine effects for humans under realistically assumed exposure conditions will be proposed. Central aspects considered within the framework include dose-dependency, severity and selectivity of effects on the endocrine system, establishment of a mode of action in animals, and qualitative and quantitative comparison of key mechanistic events between experimental animals and humans. Here we present an overview on the assessment and decision criteria for substances with endocrine modulating properties under the new plant protection legislation. doi:10.1016/j.toxlet.2009.06.834
X06 Chlorpyrifos and neurodevelopmental toxicity: Critical assessment and expert elicitation Brooke Magnanti 1,∗ , Sara Correia Carreira 1 , Margaret Saunders 1 , Alena Bartonova 2 , Martin Von Krauss 3 1
Haematology and Oncology Centre, Biophysics, Bristol, United Kingdom, 2 Norwegian Institute for Air Research (NILU), Centre for Ecological Economics, Kjeller, Norway, 3 World Health Organisation, European Centre for Environment and Health, Copenhagen, Denmark Organophosphate (OP) compounds are used worldwide for pest control, in agriculture and gardening and also in residential and indoor settings. OPs act by inhibiting acetylcholinesterase, thus affecting nerve function in insects, humans and other animals. Most of the animal and human studies published between 2000 and 2007 refer to the OP chlorpyrifos (CPF). There are concerns about the safety of CPF in the environment. While previous studies have shown levels of CPF that are safe in adult animals, recent evidence indicates young animals and humans may be more sensitive to CPF toxicity. In young animals,