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Overview of the existing regulations and testing programs for endocrine active chemicals
Abstracts / Toxicology Letters 221S (2013) S59–S256
alternative data, followed, if necessary, by in vivo testing. The latter does not need to be conducted if there is information indicating that the substance should be classified for sensitisation or corrosivity, if the substance is a strong acid or base or if the substance is flammable in air at room temperature. In terms of in vivo testing, the Murine Local Lymph Node assay (LLNA) is considered to be the first choice. This presentation will describe approaches as currently applied by REACH consortia to the skin sensitization assessment of chemicals. It will discuss the ‘tool box’ of non-animal and animal methodologies available for chemical registrations under REACH and look at its practical application based on case studies. Focus will be on illustrating how non-animal approaches (e.g., QSAR; readacross; grouping/category assessments; WoE analyses) are used to avoid unnecessary animal testing but examples will also be provided where animal testing is still unavoidable. http://dx.doi.org/10.1016/j.toxlet.2013.05.494
P18-19 Non-experimental alternative methods for the hazard evaluation of cosmetics and chemicals Carole Charmeau ∗ , Nathalie Ledirac, Laëtitia Fiévez-Fournier, Muriel Danten, Aurélie Sevestre CEHTRA, France Since 11th March 2013, the use of animal testing on vertebrates for the evaluation of cosmetic ingredients has been prohibited in Europe. Only a few alternative methods, which fully exclude the use of living animals, have been validated by the ECVAM and could be used in regulatory submissions, such as cosmetic or REACH regulations. However, these validated methods do not provide all the requested data needed for regulatory hazard assessments. In this context, non-experimental alternative methods, which take advantage of existing data, without the use of additional animals, are promising. Quantitative Structure Activity Relationships (QSAR) methods use large databases of known substances to predict the toxicity of untested chemicals. They can be used as key studies or to support other scientific approaches like read-across, which consist of using the properties of substances with similar biological activities or modes of action to extrapolate to other substances. These QSAR methods are complex and rely on databases which must be evaluated in terms of chemical structure, relevance and study quality, and require specific expertise to provide robust predictions. However, animal testing is still required to evaluate the effect of substances on complex systems (especially when no experimental data is available on similar substances), or on specific substances such as nanomaterials. Despite these limitations, the development of in silico models, together with the progress of in vitro toxicology, will be a key element to conduct hazard evaluation within the framework of the regulations. http://dx.doi.org/10.1016/j.toxlet.2013.05.495
P18-20 Overview of the existing regulations and testing programs for endocrine active chemicals Simon Warren 1,∗ , Elaine Freeman 1 , Julian Reddy 2 1 Center for Chemical Regulations and Food Safety, Exponent Inc., Washington, DC, USA, 2 Center for Chemical Regulations and Food Safety, Exponent Inc., Derby, UK
S209
We present a global perspective of the regulation of endocrineactive chemicals, giving an overview of the existing global regulations and testing requirements from several authorities. The World Health Organization defines an endocrine disruptor as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)-populations” and this is widely accepted. The majority of national regulatory authorities have policy statements which state that endocrine disruption is considered during the risk assessment process (including but not limited to US, Canada, Hong Kong, and Australia). The European Union has stringent legislation covering the regulatory acceptability of endocrine disrupting chemicals, but has not yet agreed the precise circumstances in which the legislation will apply. Japan has issued a list of potential endocrine disruptors; however legislation is not available to determine the testing paradigm necessary to test for endocrine disruptors. The United States (US) Endocrine Disruptor Screening Program (EDSP) is currently the only program requiring specific protocols for potential endocrine testing; other jurisdictions accept OECD guideline rodent studies as appropriate screening procedures. The US has stated that the results of the TIER I EDSP testing are strictly for screening purposes and will not be utilized for risk management. However, the TIER I EDSP test results will be available to other regulatory authorities so may potentially trigger stringent regulation of potential endocrine active compounds. The implications of EDSP testing in regard to global chemical registrations are discussed. http://dx.doi.org/10.1016/j.toxlet.2013.05.496
P18-21 Ranking of epoxy resin compounds based on their sensitising potency Ulrike Schuhmacher-Wolz 1,∗ , Karin Heine 1 , Johannes Geier 2 , Fritz Kalberlah 1 1
FoBiG, Freiburg, Germany, 2 IVDK, Göttingen, Germany
Occupational contact allergy to compounds in epoxy resin systems is frequently observed. A priority approach to reduce the risk of contact allergies would be the substitution of strong skin sensitising compounds by substances with a lower sensitising potency, if technically feasible. Thus, a research project aimed at developing a ranking method regarding the sensitising potency of epoxy resin components. The project was funded by the German Social Accident Insurance. A semi-quantitative assessment of 51 sensitising compounds commonly used in epoxy resin systems was performed using a weight-of-evidence approach. A minimal data set required to classify the sensitisation potency was defined based on the current mechanistic understanding of contact allergy. There were three categories: “very high sensitising potency” (SHS), “high sensitising potency” (HS) and “low or moderate sensitising potency” (GMS). The project focussed on data from in vitro experiments and in silico calculations, due to the lack of sufficient in vivo data in a lot of cases (e.g., LLNA studies or human experience/testing). Up to now, approximately 50% of the substances could be assigned to a specific sensitising potency category, whereas for the remaining substances only default assumptions could be made based on insufficient data (leading to default “HS” classification). In order to facilitate substance selection in epoxy resin product formulations based on toxicological aspects, the results will be publicly accessible on an Internet platform.
alternative data, followed, if necessary, by in vivo testing. The latter does not need to be conducted if there is information indicating that the substance should be classified for sensitisation or corrosivity, if the substance is a strong acid or base or if the substance is flammable in air at room temperature. In terms of in vivo testing, the Murine Local Lymph Node assay (LLNA) is considered to be the first choice. This presentation will describe approaches as currently applied by REACH consortia to the skin sensitization assessment of chemicals. It will discuss the ‘tool box’ of non-animal and animal methodologies available for chemical registrations under REACH and look at its practical application based on case studies. Focus will be on illustrating how non-animal approaches (e.g., QSAR; readacross; grouping/category assessments; WoE analyses) are used to avoid unnecessary animal testing but examples will also be provided where animal testing is still unavoidable. http://dx.doi.org/10.1016/j.toxlet.2013.05.494
P18-19 Non-experimental alternative methods for the hazard evaluation of cosmetics and chemicals Carole Charmeau ∗ , Nathalie Ledirac, Laëtitia Fiévez-Fournier, Muriel Danten, Aurélie Sevestre CEHTRA, France Since 11th March 2013, the use of animal testing on vertebrates for the evaluation of cosmetic ingredients has been prohibited in Europe. Only a few alternative methods, which fully exclude the use of living animals, have been validated by the ECVAM and could be used in regulatory submissions, such as cosmetic or REACH regulations. However, these validated methods do not provide all the requested data needed for regulatory hazard assessments. In this context, non-experimental alternative methods, which take advantage of existing data, without the use of additional animals, are promising. Quantitative Structure Activity Relationships (QSAR) methods use large databases of known substances to predict the toxicity of untested chemicals. They can be used as key studies or to support other scientific approaches like read-across, which consist of using the properties of substances with similar biological activities or modes of action to extrapolate to other substances. These QSAR methods are complex and rely on databases which must be evaluated in terms of chemical structure, relevance and study quality, and require specific expertise to provide robust predictions. However, animal testing is still required to evaluate the effect of substances on complex systems (especially when no experimental data is available on similar substances), or on specific substances such as nanomaterials. Despite these limitations, the development of in silico models, together with the progress of in vitro toxicology, will be a key element to conduct hazard evaluation within the framework of the regulations. http://dx.doi.org/10.1016/j.toxlet.2013.05.495
P18-20 Overview of the existing regulations and testing programs for endocrine active chemicals Simon Warren 1,∗ , Elaine Freeman 1 , Julian Reddy 2 1 Center for Chemical Regulations and Food Safety, Exponent Inc., Washington, DC, USA, 2 Center for Chemical Regulations and Food Safety, Exponent Inc., Derby, UK
S209
We present a global perspective of the regulation of endocrineactive chemicals, giving an overview of the existing global regulations and testing requirements from several authorities. The World Health Organization defines an endocrine disruptor as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, its progeny, or (sub)-populations” and this is widely accepted. The majority of national regulatory authorities have policy statements which state that endocrine disruption is considered during the risk assessment process (including but not limited to US, Canada, Hong Kong, and Australia). The European Union has stringent legislation covering the regulatory acceptability of endocrine disrupting chemicals, but has not yet agreed the precise circumstances in which the legislation will apply. Japan has issued a list of potential endocrine disruptors; however legislation is not available to determine the testing paradigm necessary to test for endocrine disruptors. The United States (US) Endocrine Disruptor Screening Program (EDSP) is currently the only program requiring specific protocols for potential endocrine testing; other jurisdictions accept OECD guideline rodent studies as appropriate screening procedures. The US has stated that the results of the TIER I EDSP testing are strictly for screening purposes and will not be utilized for risk management. However, the TIER I EDSP test results will be available to other regulatory authorities so may potentially trigger stringent regulation of potential endocrine active compounds. The implications of EDSP testing in regard to global chemical registrations are discussed. http://dx.doi.org/10.1016/j.toxlet.2013.05.496
P18-21 Ranking of epoxy resin compounds based on their sensitising potency Ulrike Schuhmacher-Wolz 1,∗ , Karin Heine 1 , Johannes Geier 2 , Fritz Kalberlah 1 1
FoBiG, Freiburg, Germany, 2 IVDK, Göttingen, Germany
Occupational contact allergy to compounds in epoxy resin systems is frequently observed. A priority approach to reduce the risk of contact allergies would be the substitution of strong skin sensitising compounds by substances with a lower sensitising potency, if technically feasible. Thus, a research project aimed at developing a ranking method regarding the sensitising potency of epoxy resin components. The project was funded by the German Social Accident Insurance. A semi-quantitative assessment of 51 sensitising compounds commonly used in epoxy resin systems was performed using a weight-of-evidence approach. A minimal data set required to classify the sensitisation potency was defined based on the current mechanistic understanding of contact allergy. There were three categories: “very high sensitising potency” (SHS), “high sensitising potency” (HS) and “low or moderate sensitising potency” (GMS). The project focussed on data from in vitro experiments and in silico calculations, due to the lack of sufficient in vivo data in a lot of cases (e.g., LLNA studies or human experience/testing). Up to now, approximately 50% of the substances could be assigned to a specific sensitising potency category, whereas for the remaining substances only default assumptions could be made based on insufficient data (leading to default “HS” classification). In order to facilitate substance selection in epoxy resin product formulations based on toxicological aspects, the results will be publicly accessible on an Internet platform.