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TTC and herbal preparations
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Abstracts / Toxicology Letters 258S (2016) S39–S53
all chemicals including natural compounds. Finally, the combined use of structural information with in vitro testing (Ames test) was suggested. Taken together, there is an enormous interest in TTC. However, un-coordinated and widely diverse concepts, methodologies and interpretations weaken the method. It is suggested that guidelines similar to the existing guidelines for toxicological testing are developed which prevent TTC from becoming a bunch of arbitrary risk assessment tools. http://dx.doi.org/10.1016/j.toxlet.2016.06.1266 W06-2 TTC and “unknowns”, e.g. in food contact materials Benoit Schilter Nestlé Research Center, India Currently, there is no consensus on how to evaluate the safety of food packaging. Therefore a new approach is being developed. It starts with migration studies using simulants reflecting the food to be packed. Then, the migration extracts are analyzed using analytical chemistry. This includes the identification and quantification of the Intentionally Added Substances (IAS) used for packaging production (e.g. monomers, antioxidants, plasticizers), but also the so-called Non Intentionally Added Substances (NIAS) originating from impurities in starting materials as well as from chemical reactions and degradations over packaging manufacturing, storage and use. Many NIAS appear as peaks in chromatograms but are not structurally identified. Standard risk assessment can be applied to establish the safety of identified chemicals. This is however not possible for the NIAS which cannot be structurally characterized. Recently, it has been proposed to apply the threshold of toxicological concern (TTC) concept to address unidentified chemicals. This first requires to exclude the presence of a number of chemicals-chemical classes, including high-potency genotoxic (e.g., aflatoxin-like, N-nitroso and azaoxy), and non-genotoxic (steroids, dioxins, polyhalogenated furans) chemicals, as well as proteins and polymers. In addition, to apply the Cramer class III TTC evidence of an absence of genotoxic substances and acetylcholine esterase inhibitors must be provided. A stepwise approach has been proposed to cope with these exclusion criteria. It is based on knowledge of the sample source, targeted and untargeted analytics and the application of specific bioassays. The TTC approach may therefore be a pragmatic way to set up priorities regarding the need for identification and safety assessment of unknown NIAS in migration extracts. Current limitations are the potential for combined effects and the fit for purposeness of analytical and biological methods. http://dx.doi.org/10.1016/j.toxlet.2016.06.1267 W06-3 TTC and herbal preparations Olavi Pelkonen Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland The TTC is a pragmatic risk assessment tool, based on conservative, screening-level exposure limits to chemicals of known structure, classified with the help of comparison with chemicals of measured toxicological potentialities. In principle, on the basis
of chemical structure and known exposure, a TTC dose with low concern of systemic toxicity can be set for any substance even in the absence of substance specific toxicity data. However, there are many points in the decision tree linked with a need of an actual toxicity study. Complex plant-derived herbal products contain components of toxicological concern. Unlike impurities in synthetic drugs, such substances in plant-derived products are natural constituents, about which usually only scanty toxicological data at all is available. Due to the complex nature of products, proper analytics is indispensable for all steps of toxicity evaluation, from authentication of composition to identification of active and toxic constituents to hazard and risk assessment. The TTC concept was developed for single individually identified chemical entities using databases consisting of various chemical domains and toxicity outcomes. It is obvious that the applicability of the TTC concept to complex herbal products is not straightforward and needs solution of a large number of practical and theoretical problems. Currently in the EMA guidelines on herbal medicines, the TTC concept is explicitly mentioned only in the context of genotoxicity tests. However, a wider adoption of the TTC concept and decision tree(s) and in silico (QSAR) tools may be beneficial for risk assessment. Some examples of the use of the TTC-based approaches for more complex preparations are cosmetics, consumer products, food flavouring agents, impurities in pharmaceutical products (ICH M7), and chemicals under REACH. It is possible to apply TTC for individual chemicals of concern in herbal preparations. However, full use of (any) threshold concepts in risk assessment of herbal preparations is dependent on comprehensive use of proper analytics, in silico tools, read-across and in vitro testing. It is also useful to keep in mind that herbal medicines are under EU pharmaceutical legislation even allowing for their peculiar complex composition and other characteristics. http://dx.doi.org/10.1016/j.toxlet.2016.06.1268 W06-4 Is the use of a default TTC for impurities warranted? Lutz Mueller F. Hoffmann-La Roche, Switzerland The TTC has been installed as a default approach for assessment and control of genotoxic impurities in pharmaceuticals internationally with the ICH M7 guideline, which is in operation since 2016. It serves as a reference basis for toxicologists and technical specialists to set limits in pharmaceutical that can be accepted by health authorities in all parts of the world. However, alternatives to the default TTC can be applicable in special situations, e.g. if an impurity is also formed as a metabolite or in case of degradation products. In such cases, the means to control risk by purification, change of synthesis and other means are limited. Alternative ways to assess risk need to be evaluated. Departing from the TTC is justifiable as the TTC set for genotoxic impurities is giving lower boundaries of intervention with very high safety margins so that no benefit/risk dispute should occur between industry and health authorities. Alternatives to the default TTC set in ICH M7 for genotoxic impurities may be using a statistical benchmark approach, threshold of effect models, urgent medical need, severity of the disease, cancer risk of the treated patient population and others. This presentation will elaborate on these types of alternatives to the generic TTC for setting limits for genotoxic impurities in pharmaceuticals. http://dx.doi.org/10.1016/j.toxlet.2016.06.1269
Abstracts / Toxicology Letters 258S (2016) S39–S53
all chemicals including natural compounds. Finally, the combined use of structural information with in vitro testing (Ames test) was suggested. Taken together, there is an enormous interest in TTC. However, un-coordinated and widely diverse concepts, methodologies and interpretations weaken the method. It is suggested that guidelines similar to the existing guidelines for toxicological testing are developed which prevent TTC from becoming a bunch of arbitrary risk assessment tools. http://dx.doi.org/10.1016/j.toxlet.2016.06.1266 W06-2 TTC and “unknowns”, e.g. in food contact materials Benoit Schilter Nestlé Research Center, India Currently, there is no consensus on how to evaluate the safety of food packaging. Therefore a new approach is being developed. It starts with migration studies using simulants reflecting the food to be packed. Then, the migration extracts are analyzed using analytical chemistry. This includes the identification and quantification of the Intentionally Added Substances (IAS) used for packaging production (e.g. monomers, antioxidants, plasticizers), but also the so-called Non Intentionally Added Substances (NIAS) originating from impurities in starting materials as well as from chemical reactions and degradations over packaging manufacturing, storage and use. Many NIAS appear as peaks in chromatograms but are not structurally identified. Standard risk assessment can be applied to establish the safety of identified chemicals. This is however not possible for the NIAS which cannot be structurally characterized. Recently, it has been proposed to apply the threshold of toxicological concern (TTC) concept to address unidentified chemicals. This first requires to exclude the presence of a number of chemicals-chemical classes, including high-potency genotoxic (e.g., aflatoxin-like, N-nitroso and azaoxy), and non-genotoxic (steroids, dioxins, polyhalogenated furans) chemicals, as well as proteins and polymers. In addition, to apply the Cramer class III TTC evidence of an absence of genotoxic substances and acetylcholine esterase inhibitors must be provided. A stepwise approach has been proposed to cope with these exclusion criteria. It is based on knowledge of the sample source, targeted and untargeted analytics and the application of specific bioassays. The TTC approach may therefore be a pragmatic way to set up priorities regarding the need for identification and safety assessment of unknown NIAS in migration extracts. Current limitations are the potential for combined effects and the fit for purposeness of analytical and biological methods. http://dx.doi.org/10.1016/j.toxlet.2016.06.1267 W06-3 TTC and herbal preparations Olavi Pelkonen Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland The TTC is a pragmatic risk assessment tool, based on conservative, screening-level exposure limits to chemicals of known structure, classified with the help of comparison with chemicals of measured toxicological potentialities. In principle, on the basis
of chemical structure and known exposure, a TTC dose with low concern of systemic toxicity can be set for any substance even in the absence of substance specific toxicity data. However, there are many points in the decision tree linked with a need of an actual toxicity study. Complex plant-derived herbal products contain components of toxicological concern. Unlike impurities in synthetic drugs, such substances in plant-derived products are natural constituents, about which usually only scanty toxicological data at all is available. Due to the complex nature of products, proper analytics is indispensable for all steps of toxicity evaluation, from authentication of composition to identification of active and toxic constituents to hazard and risk assessment. The TTC concept was developed for single individually identified chemical entities using databases consisting of various chemical domains and toxicity outcomes. It is obvious that the applicability of the TTC concept to complex herbal products is not straightforward and needs solution of a large number of practical and theoretical problems. Currently in the EMA guidelines on herbal medicines, the TTC concept is explicitly mentioned only in the context of genotoxicity tests. However, a wider adoption of the TTC concept and decision tree(s) and in silico (QSAR) tools may be beneficial for risk assessment. Some examples of the use of the TTC-based approaches for more complex preparations are cosmetics, consumer products, food flavouring agents, impurities in pharmaceutical products (ICH M7), and chemicals under REACH. It is possible to apply TTC for individual chemicals of concern in herbal preparations. However, full use of (any) threshold concepts in risk assessment of herbal preparations is dependent on comprehensive use of proper analytics, in silico tools, read-across and in vitro testing. It is also useful to keep in mind that herbal medicines are under EU pharmaceutical legislation even allowing for their peculiar complex composition and other characteristics. http://dx.doi.org/10.1016/j.toxlet.2016.06.1268 W06-4 Is the use of a default TTC for impurities warranted? Lutz Mueller F. Hoffmann-La Roche, Switzerland The TTC has been installed as a default approach for assessment and control of genotoxic impurities in pharmaceuticals internationally with the ICH M7 guideline, which is in operation since 2016. It serves as a reference basis for toxicologists and technical specialists to set limits in pharmaceutical that can be accepted by health authorities in all parts of the world. However, alternatives to the default TTC can be applicable in special situations, e.g. if an impurity is also formed as a metabolite or in case of degradation products. In such cases, the means to control risk by purification, change of synthesis and other means are limited. Alternative ways to assess risk need to be evaluated. Departing from the TTC is justifiable as the TTC set for genotoxic impurities is giving lower boundaries of intervention with very high safety margins so that no benefit/risk dispute should occur between industry and health authorities. Alternatives to the default TTC set in ICH M7 for genotoxic impurities may be using a statistical benchmark approach, threshold of effect models, urgent medical need, severity of the disease, cancer risk of the treated patient population and others. This presentation will elaborate on these types of alternatives to the generic TTC for setting limits for genotoxic impurities in pharmaceuticals. http://dx.doi.org/10.1016/j.toxlet.2016.06.1269