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Human health risk assessment of ferrosilicon alloys under REACH
S178
Abstracts / Toxicology Letters 211S (2012) S43–S216
hazards, comfort effects, dose–response relationships and suitable exposure indicators. The exposure level at which the risk of adverse health and comfort effects were assessed as minimal was defined by dose–response analysis. The exposure levels achievable by advanced control technology were determined separately for different fields and worksites. The lowest of the health- or technology-based values determined the final target level. Results and conclusions: The proposed target levels of 5 and 20 g/m3 /8 h (elemental carbon, respirable) for above ground and underground worksites, respectively, were based on technical achievability, and were assessed to protect against even the mild respiratory effects of diesel exhaust. These levels are 5 to 20 times lower than the few available OELs. The methodology we present may be a useful tool for defining protective and realistic guideline values to promote the continuous improvement of the work environment. doi:10.1016/j.toxlet.2012.03.641
P29-07 Human health risk assessment of ferrosilicon alloys under REACH Sirpa Huuskonen 1 , Milla Heinälä 1 , Gunilla Herting 2 , Inger Odnevall Wallinder 2 , Tiina Santonen 1 1
Finnish Institute of Occupational Health, Finland, 2 KTH Royal Institute of Technology, Sweden Ferrosilicon (FeSi) are alloys produced by smelting process (carbothermic reduction of ores) with a wide compositional range, registered as multicomponent substances under REACH in 2010. Since no toxicological data for the needs of REACH was available on FeSi, a read-across-based approach was developed to assess potential human health risks. The assessment of alloys was challenging since the intrinsic properties of alloys are different compared to its individual components. Furthermore, the surface oxide composition is different from the bulk composition with barrier properties crucial for the extent of metal release and any potential toxicity. Kinetic bioaccessibility data and in-depth surface characteristics were generated on which the read-across approach was based. Metal release data was generated for FeSi-alloy particles in five synthetic biological media of relevance for human exposures and compared with available data for metals, alloys or compounds of similar surface characteristics. Compositional information of the surface oxide of the FeSi-alloys was hence crucial to find substances suitable for read-across purposes. The surface oxide composition of the FeSi-alloys was different from their bulk content and predominantly composed of silicon oxides and to some extent iron-, and aluminium-rich oxides. All alloys revealed low amounts of released elements, dominated by silicon. Small amounts of strontium and barium were released from some grades and their potential impact on toxicity was taken into account. Generated in vitro dissolution data and surface characteristics were used to identify relevant silicon compounds for read-across. Based on this approach, FeSi-alloys were found to be non-hazardous for human health. doi:10.1016/j.toxlet.2012.03.642
P29-08 Minimizing risk of cross-contamination in control samples of toxicology studies Paolo Angelo Colombo, Maria Teresa Neri, Massimo Breda, Pietro Grossi, Raphaela Schnurbus ACCELERA SRL, Italy Evaluation of systemic exposure to test items and metabolites is part of the assessment of new chemical entities in toxicology studies. These evaluations are performed to define the pharmacokinetic profile, to demonstrate the test system exposure to the drug, and to correlate adverse effects with plasma levels. Unfortunately samples from control animals may also contain levels of test items suggesting that contamination of control animals or samples from control groups occurred. As analytical methods have become more sensitive, the possibility of detecting control contamination has increased over time. In some cases contamination has been considered so relevant (e.g. carcino and reproductive studies) that might led to studies invalidation or even to a negative opinion in Marketing Authorization. Any positive finding in these control samples potentially indicates a misdosage or a subsequent contamination during dosing, collection, storage, sample preparation, or analysis process. It is of paramount importance to make sure that proper procedures are in place before and during the samples analysis to preclude or at least minimize possible contaminations. If the test item is nevertheless detected in control samples, a procedure for conducting an investigation to define the source of contamination must be carried out with appropriate documentation in the report to provide assurance to the regulatory agency reviewers about study integrity. Reviewing data from analysis performed in 2007–2011 period with more than 6000 samples coming from different animal species and study type it is shown that the phenomenon although not eliminable is kept under control (<8% positive). doi:10.1016/j.toxlet.2012.03.643
P29-09 A possible roadmap for systemic toxicity testing Marina Hasiwa 1 , Mardas Daneshian 1 , Marcel Leist 1 , Thomas Hartung 2 1
CAAT-Europe, University of Konstanz, Germany, 2 CAAT-US, Johns Hopkins University, United States Animal testing for the safety assessment of cosmetics is foreseen to be banned in 2013. This has enhanced the development of alternative testing methods, but despite the huge efforts, the areas of toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitization, and reproductive toxicity have been extensively reviewed and further scientific challenges have been identified. In October 2011 an expert workshop, organized by the Centre of Alternatives to Animal Testing (CAAT-Europe) and the TransAtlantic Think Tank of Toxicology (t4) was held, to take a larger perspective regarding the respective areas. A forward looking strategy was discussed, taking into account latest scientific innovations, to develop a roadmap for systemic toxicity testing for cosmetics and other substances. Each area was intensively reviewed and following recommendations were achieved: Existing testing approaches should be evaluated applying an evidence-based approach, to detect useless tests and thrive towards their abolition. Key events should
Abstracts / Toxicology Letters 211S (2012) S43–S216
hazards, comfort effects, dose–response relationships and suitable exposure indicators. The exposure level at which the risk of adverse health and comfort effects were assessed as minimal was defined by dose–response analysis. The exposure levels achievable by advanced control technology were determined separately for different fields and worksites. The lowest of the health- or technology-based values determined the final target level. Results and conclusions: The proposed target levels of 5 and 20 g/m3 /8 h (elemental carbon, respirable) for above ground and underground worksites, respectively, were based on technical achievability, and were assessed to protect against even the mild respiratory effects of diesel exhaust. These levels are 5 to 20 times lower than the few available OELs. The methodology we present may be a useful tool for defining protective and realistic guideline values to promote the continuous improvement of the work environment. doi:10.1016/j.toxlet.2012.03.641
P29-07 Human health risk assessment of ferrosilicon alloys under REACH Sirpa Huuskonen 1 , Milla Heinälä 1 , Gunilla Herting 2 , Inger Odnevall Wallinder 2 , Tiina Santonen 1 1
Finnish Institute of Occupational Health, Finland, 2 KTH Royal Institute of Technology, Sweden Ferrosilicon (FeSi) are alloys produced by smelting process (carbothermic reduction of ores) with a wide compositional range, registered as multicomponent substances under REACH in 2010. Since no toxicological data for the needs of REACH was available on FeSi, a read-across-based approach was developed to assess potential human health risks. The assessment of alloys was challenging since the intrinsic properties of alloys are different compared to its individual components. Furthermore, the surface oxide composition is different from the bulk composition with barrier properties crucial for the extent of metal release and any potential toxicity. Kinetic bioaccessibility data and in-depth surface characteristics were generated on which the read-across approach was based. Metal release data was generated for FeSi-alloy particles in five synthetic biological media of relevance for human exposures and compared with available data for metals, alloys or compounds of similar surface characteristics. Compositional information of the surface oxide of the FeSi-alloys was hence crucial to find substances suitable for read-across purposes. The surface oxide composition of the FeSi-alloys was different from their bulk content and predominantly composed of silicon oxides and to some extent iron-, and aluminium-rich oxides. All alloys revealed low amounts of released elements, dominated by silicon. Small amounts of strontium and barium were released from some grades and their potential impact on toxicity was taken into account. Generated in vitro dissolution data and surface characteristics were used to identify relevant silicon compounds for read-across. Based on this approach, FeSi-alloys were found to be non-hazardous for human health. doi:10.1016/j.toxlet.2012.03.642
P29-08 Minimizing risk of cross-contamination in control samples of toxicology studies Paolo Angelo Colombo, Maria Teresa Neri, Massimo Breda, Pietro Grossi, Raphaela Schnurbus ACCELERA SRL, Italy Evaluation of systemic exposure to test items and metabolites is part of the assessment of new chemical entities in toxicology studies. These evaluations are performed to define the pharmacokinetic profile, to demonstrate the test system exposure to the drug, and to correlate adverse effects with plasma levels. Unfortunately samples from control animals may also contain levels of test items suggesting that contamination of control animals or samples from control groups occurred. As analytical methods have become more sensitive, the possibility of detecting control contamination has increased over time. In some cases contamination has been considered so relevant (e.g. carcino and reproductive studies) that might led to studies invalidation or even to a negative opinion in Marketing Authorization. Any positive finding in these control samples potentially indicates a misdosage or a subsequent contamination during dosing, collection, storage, sample preparation, or analysis process. It is of paramount importance to make sure that proper procedures are in place before and during the samples analysis to preclude or at least minimize possible contaminations. If the test item is nevertheless detected in control samples, a procedure for conducting an investigation to define the source of contamination must be carried out with appropriate documentation in the report to provide assurance to the regulatory agency reviewers about study integrity. Reviewing data from analysis performed in 2007–2011 period with more than 6000 samples coming from different animal species and study type it is shown that the phenomenon although not eliminable is kept under control (<8% positive). doi:10.1016/j.toxlet.2012.03.643
P29-09 A possible roadmap for systemic toxicity testing Marina Hasiwa 1 , Mardas Daneshian 1 , Marcel Leist 1 , Thomas Hartung 2 1
CAAT-Europe, University of Konstanz, Germany, 2 CAAT-US, Johns Hopkins University, United States Animal testing for the safety assessment of cosmetics is foreseen to be banned in 2013. This has enhanced the development of alternative testing methods, but despite the huge efforts, the areas of toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitization, and reproductive toxicity have been extensively reviewed and further scientific challenges have been identified. In October 2011 an expert workshop, organized by the Centre of Alternatives to Animal Testing (CAAT-Europe) and the TransAtlantic Think Tank of Toxicology (t4) was held, to take a larger perspective regarding the respective areas. A forward looking strategy was discussed, taking into account latest scientific innovations, to develop a roadmap for systemic toxicity testing for cosmetics and other substances. Each area was intensively reviewed and following recommendations were achieved: Existing testing approaches should be evaluated applying an evidence-based approach, to detect useless tests and thrive towards their abolition. Key events should