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Chemicals/CAS: Hazardous Substances

A complex chemical mixture is defined as a mixture that consists of tens, hundreds or thousands of chemicals, and of which the composition is qualitatively and quantitatively not fully known. In contrast, a simple mixture consists of a relatively small number of chemicals, say ten or less, and the composition of which is fully known. In the present paper a number of options for hazard identification and risk assessment of complex chemical mixtures is discussed, and a scheme aimed at selecting the most appropriate approach for each (type of) complex mixture is presented. A conspicuous element of this scheme is the dichotomy of complex mixtures into mixtures that are readily available and mixtures that are virtually unavailable for testing in their entirety. Another characteristic aspect of the scheme is the inclusion of the "top-ten" and "pseudo top-ten" approaches, which in essence are ways to select the, say ten, most risky chemicals or pseudocomponents to be dealt with as a simple chemical mixture.

Procedures for the selection of compounds with high health hazard potential are reviewed, and major aspects of the assessment of health risks associated with exposure to mixtures of chemicals are discussed. Examples are given of additivity and synergism of effects following exposure to mixtures. Using these data from the literature a two-step procedure for the safety evaluation of the mixture of chemicals occurring at a specific workplace is suggested. The first step consists of estimating the relative health risk associated with each chemical; the estimation is based on the ratio between exposure level and degree of toxicity. Those chemicals representing a high risk are then selected for further consideration. The second step comprises the risk assessment, focusing on prediction of the risk associated with exposure to the mixture of selected chemicals. To allow such prediction the (presumable) mode of action of the selected compounds should be considered. A practical way to find out whether exposure to chemicals at a specific workplace is of serious health concern, could be the conduct of both a 4-week toxicity study in rats and 2 different types of genotoxicity studies with the mixture of selected chemicals, using exposure concentrations related to those occurring in practice.

Epidemiologic studies directly contribute data on risk (or benefit) in humans as the investigated species, and in the full food intake range normally encountered by humans. This paper starts with introducing the epidemiologic approach, followed by a discussion of perceived differences between toxicological and epidemiologic risk assessment. Areas of contribution of epidemiology to the risk assessment process are identified, and ideas for tailoring epidemiologic studies to the risk assessment procedures are suggested, dealing with data collection, analyses and reporting of both existing and new epidemiologic studies. The dietary habits and subsequent disease occurrence of over three million people are currently under observation worldwide in cohort studies, offering great potential for use in risk assessment. The use of biomarkers and data on genetic susceptibility are discussed. The paper describes a scheme to classify epidemiologic studies for use in risk assessment, and deals with combining evidence from multiple studies. Using a matrix approach, the potential contribution to each of the steps in the risk assessment process is evaluated for categories of food substances. The contribution to risk assessment of specific food substances depends on the quality of the exposure information. Strengths and weaknesses are summarized. It is concluded that epidemiology can contribute significantly to hazard identification, hazard characterisation and exposure assessment. © 2002 ILSI. Published by Elsevier Science Ltd. All rights reserved. Chemicals/CAS: Biological Markers; Hazardous Substances

IGUS is the International Group of Experts on the Explosion Risks of Unstable Substances. Today, the aim of the group is to exchange information on the behavior of unstable substances and to improve safety in production, storage, transport, and use of these substances. Full members of IGUS work for governments and independent research organizations. Experts from industry can and do attend meetings by invitation. IGUS's 50th anniversary in 2012 gives reason to have a closer look at the questions of how IGUS came to be, what IGUS's aims and objectives were, and how it is organized and working today. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hazard assessments of chemicals have been limited by the availability of test data and the time needed to evaluate the test data. While available data may be inadequate for the majority of industrial chemicals, the body of existing knowledge for most hazards is large enough to permit reliable estimates to be made for untested chemicals without additional animal testing. We provide a summary of the growing use by regulatory agencies of the chemical categories approach, which groups chemicals based on their similar toxicological behaviour and fills in the data gaps in animal test data such as genotoxicity and aquatic toxicity. Although the categories approach may be distinguished from the use of quantitative structure-activity relationships (QSARs) for specific hazard endpoints, robust chemical categories are founded on quantifying the chemical structure with parameters that control chemical behaviour in conventional hazard assessment. The dissemination of the QSAR Application Toolbox by the Organisation for Economic Cooperation and Development (OECD) is an effort to facilitate the use of the categories approach and reduce the need for additional animal testing.

Hazard characterisation of low molecular weight chemicals in food and diet generally use a no-observed-adverse-effect level (NOAEL) or a benchmark dose as the starting point. For hazards that are considered not to have thresholds for their mode of action, low-dose extrapolation and other modelling approaches may be applied. The default position is that rodents are good models for humans. However, some chemicals cause species-specific toxicity syndromes. Information on quantitative species differences is used to modify the default uncertainty factors applied to extrapolate from experimental animals to humans. A central theme for extrapolation is unravelling the mode of action for the critical effects observed. Food can be considered as an extremely complex and variable chemical mixture. Interactions among low molecular weight chemicals are expected to be rare given that the exposure levels generally are far below their NOAELs. Hazard characterisation of micronutrients must consider that adverse effects may arise from intakes that are too low (deficiency) as well as too high (toxicity). Interactions between different nutrients may complicate such hazard characterisations. The principle of substantial equivalence can be applied to guide the hazard identification and hazard characterisation of macronutrients and whole foods. Macronutrients and whole foods must be evaluated on a case-by-case basis and cannot follow a routine assessment protocol. © 2002 ILSI. Published by Elsevier Science Ltd. All rights reserved. Chemicals/CAS: Hazardous Substances; Micronutrients

The methods for the dermal exposure assessment vary in their complexity and are in some sense complementary to each other. The most easy-to-use methods involve a pseudo-skin-approach, such as gloves and removal by washing. In some cases generic modelling appears to be possible. The experimental methods can indicate and even quantitate the presence of chemicals on the skin. This enables studies on the occurrence of local effects in relation to the exposure. When the interest is on systemic effects, the dermal exposure is only of interest if it represents the amount that is available for penetration through the skin. This may vary largely between compounds due to the large variation in dermal absorption. When this degree of absorption is not known, the alternate method may be biological monitoring, at least when it is based on a detailed pharmacokinetic knowledge of that compound. The most sophisticated method, applied to study occupational exposures, is formed by a combination of monitoring on clothing (pseudo-skin), hand washing (removal) and biological monitoring. In any case, the assessment of dermal exposure should be based on a sampling strategy that takes into account the distribution of the contamination on the body, the variation in time of the exposure, the duration of the exposure as well as the degree of skin protection afforded by clothing.

Article 2 of European Community Directive 96/82/EC (known as 'Seveso-II' Directive) also requires consideration in the plant inventory of the dangerous substances 'which it is believed may be generated in the loss of control of an industrial chemical process'. The present study was directed to the further development and assessment of procedures for the identification of products formed in the 'loss of control' of chemical systems caused by exothermic decomposition reactions. The specific aim was the development of procedures for the sampling and identification of products formed in four different scale experimental devices and the comparison of the results obtained. The methodologies developed were tested on ethyl diazoacetate (EDA). The results obtained indicated that sufficient agreement was present in the data obtained for the thermal effects and for the apparent kinetic parameters of the thermal decomposition. On the other hand, the analysis of the decomposition products showed important differences both from the qualitative and quantitative point of view. Operating conditions such as pressure, heating rate, and residence time in the hot zones of the experimental devices may become critical factors if a quantitative analysis of decomposition products formed is required. Therefore, the development of standard experimental procedures seems to be necessary in order to apply Article 2 of the 'Seveso-II' Directive. © 2003 Elsevier Ltd. All rights reserved.

Advancing our knowledge on the toxicology of combined exposures to chemicals and implementation of this knowledge in guidelines for health risk assessment of such combined exposures are necessities dictated by the simple fact that humans are continuously exposed to a multitude of chemicals. A prerequisite for successful research and fruitful discussions on the toxicology of combined exposures (mixtures of chemicals) is the use of defined terminology implemented by an authoritative international body such as, for example, the International Union of Pure and Applied Chemistry (IUPAC) Toxicology Committee. The extreme complexity of mixture toxicology calls for new research methodologies to study interactive effects, taking into account limited resources. Of these methodologies, statistical designs and mathematical modelling of toxicokinetics and toxicodynamics seem to be most promising. Emphasis should be placed on low-dose modelling end experimental validation. The scientifically sound so-called bottom-up approach should be supplemented with more pragmatic approaches, focusing on selection of the most hazardous chemicals in a mixture and careful consideration of the mode of action and possible interactive effects of these chemicals. Pragmatic approaches may be of particular importance to study and evaluate complex mixtures; after identification of the 'top ten' (most risky) chemicals in the mixture they can be examined and evaluated as a defined (simple) chemical mixture. In setting exposure limits for individual chemicals, the use of an additional safety factor to compensate for potential increased risk due to simultaneous exposure to other chemicals, has no clear scientific justification. The use of such an additional factor is a political rather than a scientific choice.

The threat of terrorists using CBRN agents continues to pose a risk of mass casualties and severe disruption of societal functions in Europe. Standardisation of crisis management activities is one important step towards effective national and international interoperability and increased resilience. Understanding which CBRN agents are involved in an incident is vital for appropriate response measures. We applied a system's view on the process of CBRN sample analysis and see three discrete applications; Immediate incident response, Forensics, Post incident monitoring. Together with laboratory experts and policy makers from across Europe we identified needs for quality assurance measures in these three areas. Here, we suggest various harmonisation activities that can facilitate interoperability between all stakeholders concerned with CBRN sample analysis. Foremost, we recommend purpose-oriented laboratory networks, but also minimum performance requirements for First Responders’ detection and sampling capabilities, best practices for sample transport and documentation.

In the scope of a Dutch programme to reinforce the working conditions policy on hazardous substances, an internet-based tool was developed to help small- and medium-sized companies to handle hazardous substances with more care. The heart of this tool, called the Stoffenmanager, is a risk banding scheme. It combines a hazard banding scheme similar to that of COSHH Essentials and an exposure banding scheme based on an exposure model originally presented by Cherrie et al. (1996) and further developed by Cherrie and Schneider (1999). The exposure model has been modified to allow non-expert users to understand and use the model. Exposure scores are calculated based on categorization of determinants of emission, transmission and immission. These exposure scores are assigned to exposure bands. The comparison of exposure bands and hazard bands leads to a risk band or priority band. Following the evaluation of the priority of tasks done with products, generic exposure control measures can be evaluated for their possibility to lower the risks. Relevant control measures can be put into an action plan and into workplace instruction cards. The tool has several other functionalities regarding registration and storage of products. The exposure model in the Stoffenmanager leads to exposure scores. These have been compared with measured exposure levels. The exposure scores correlated well with measured exposure levels. The development of the Stoffenmanager has facilitated a whole range of further developments of useful tools for small- and medium-sized enterprises. © The Author 2008. Published by Oxford University Press on behalf of the British Occupational Hygiene Society. Chemicals / CAS: Hazardous Substances

The mucosal membranes form a weak mechanical barrier, but they are provided with an extensive specific and non-specific defence system. Antigenic stimulation of the mucosal immune system of the oronasal passages induces specific, local immune responses, and activates immune components of mucosae elsewhere as well as the systemic immune system. Nasal lymphocytes are disseminated diffusely in the mucosa or are organised in structures at the entrance of the nasopharynx (nasal-associated lymphoid tissues, NALT). Nasal lymphatics, and possibly NALT, play an important role in drainage of brain fluid, especially in small animals. Little is known about toxicity to the NALT, despite its central role in mucosal immunity. Its strategic position in the nasal passages suggests that it comes easily into contact with inhaled nasal toxicants. Therefore, we recommend to include histopathological examination of NALT in standard guideline-driven inhalation toxicity studies. © 2003 Elsevier Science Ireland Ltd. All rights reserved.

To evaluate risk from dermal exposure, the amount of material on the skin must first be measured. The potential for dermal uptake must then be assessed for the potential health effects from systemic exposure. No standard methods exist for studying these processes, and published data are not comparable because of the different techniques used. Future validated methodology should provide a sound scientific basis for risk assessment. Methods for measuring skin and surface contamination will require development of reference contaminated surfaces and skin as part of quality control procedures. Biological monitoring is a valuable tool in the assessment of dermal absorption, in contributing to the validation of in vitro techniques, and in risk assessment and management. It will be necessary to conduct detailed investigations to support risk assessment for dermal exposure. Ultimately, predictive models will be established for exposure and for dermal absorption to support a generic approach and allow risk assessment strategies appropriate to actual workplace situations. This work is licensed under a Creative Commons Attribution 4.0 International License.

A major challenge for the toxicologist involved in safety evaluation of chemical mixtures is to test the hypothesis that as a rule exposure to mixtures of chemicals at (low) non-toxic doses of the individual chemicals is of no health concern. A series of repeated dose studies in rats with defined mixtures of chemicals with the same or different target organs revealed that exposure to a combination of chemicals compared with exposure to the individual compounds did not constitute an evidently increased hazard, provided each chemical was administered at a level similar to, or slightly lower than, its own 'No-Observed-Adverse-Effect-Level'. The results of subacute oral toxicity studies in rats with defined mixtures of nephrotoxicants with similar mode of action underlined the applicability of the additivity assumption for a mixture of chemicals with simple similar action. Safety evaluation of complex chemical mixtures is a challenge that can be tackled as follows: first, identify the (e.g. ten) most risky chemicals in the mixture, and, second, assess the hazard and the potential health risk of the mixture of the most risky chemicals, using procedures developed for defined mixtures. To identify interactions between individual compounds, a most promising testing strategy appeared to be a statistical approach using a fractional two-level factorial design. A challenge for today and the future is to gradually substitute mixture-oriented (real life-oriented) standard setting for (unrealistic) single chemical-oriented standard setting.

A large release of Carbon Dioxide (CO<inf>2</inf>) is modelled with Computational Fluid Dynamics (CFD), (Fluent v12.1). Special attention is given to the modelling of a neutral atmospheric boundary layer (ABL) with gravity. Both the presence of non-vapour CO<inf>2</inf> and the high density of CO<inf>2</inf> require that the effect of gravity is taken into account. The ABL describes the velocity and turbulence properties as a function of height, these strongly influence the mixing and dispersion of the hazardous substance with the surrounding air. Profiles for the ABL are obtained which are constant over the length of the calculation domain. The CO<inf>2</inf> release is modelled as both a gas release as a twophase release. The results are compared and the effects of the ABL and the single/two phase flow are discussed. In addition the results are compared to results obtained by another CFD code (CFX) and by a Gaussian method. Unfortunately no experiments with CO<inf>2</inf> are available yet to validate the developed model. However, the results from the verification are encouraging to continue the CFD study on CO<inf>2</inf>, with obstacles present. This advanced knowledge of CO<inf>2</inf> release behaviour could be applied to envisage stepwise a virtual accidental release in existing Urban or industrial areas.

Regarding risk evaluation of complex mixtures, the Working Group discussed the following topics: evaluation of the mixture as a whole, fractionation of the mixture, identification of the 'top ten' chemicals, and composite standards. It was concluded that no standard methodology for hazard identification and risk assessment of complex mixtures yet exists, but assessment of complex mixtures must proceed, using all available information,methods, technology, expertise and experience. The development of a decision tree for tackling complex mixtures was recommended, and the need to move forward with instituting standards for mixtures, especially in job-oriented situations, was emphasized.

Objectives: For regulatory risk assessment under REACH a tiered approach is proposed in which the first tier models should provide a conservative exposure estimate that can discriminate between scenarios which are of concern and those which are not. The Stoffenmanager is mentioned as a first tier approach in the REACH guidance. In an attempt to investigate the validity of the Stoffenmanager algorithms, a cross-validation study was performed. Methods: Exposure estimates using the Stoffenmanager algorithms were compared with exposure measurement results (n=254). Correlations between observed and predicted exposures, bias and precision were calculated. Stratified analyses were performed for the scenarios "handling of powders and granules" (n=82), "handling solids resulting in comminuting" (n=60), "handling of low-volatile liquids" (n=40) and "handling of volatile liquids" (n=72). Results: The relative bias of the four algorithms ranged between -9% and -77% with a precision of approximately 1.7. The 90th percentile estimate of one out of four algorithms was not conservative enough. Based on these statistics and analyses of residual plots the underlying algorithm was adapted. Subsequently, the calibration and the cross-validation dataset were merged into one dataset (n=952) used for calibrating the adapted Stoffenmanager algorithms. This new calibration resulted in new exposure algorithms for the four scenarios. Conclusions: The Stoffenmanager is capable of discriminating among exposure levels mainly between scenarios in different companies. The 90th percentile estimates of the Stoffenmanager are verified to be sufficiently conservative. Therefore, the Stoffenmanager could be a useful tier 1 exposure assessment tool for REACH.

The heat load, imposed by air-permeable NBC (nuclear, biological, and chemical)-protective suits, can be reduced by improving the air permeability of the suit. However, increased air permeability will reduce the chemical protective performance, since increasing the air permeability of the NBC-protective material will result in higher air velocities through the material. In this study the relation between the chemical protective performance and air velocity through NBC-clothing is evaluated. A theoretical model was developed that describes the chemical protection of air permeable NBC-protective clothing material under various conditions. The initial breakthrough concentration and the 50% breakthrough time are modeled as function of parameters like the air velocity and the challenge concentration. Using this model, the effect of airflow through the material on the breakthrough concentration of mustard vapor was calculated and compared with results of breakthrough experiments. The predictions of the model are in good agreement with the experimental results. The air velocity through the material and thus the air permeability of the material appear to be parameters of critical importance. High air velocity through the material results in high breakthrough concentrations, and therefore poor protective performance of the material. To describe the total breakthrough curve, a semiempirical model of experimental breakthrough results was made. This model describes the total breakthrough concentration of vapor through NBC-protective material as a function of parameters like the air velocity and the challenge concentration. This model can be used as a tool to optimise the protective performance of NBC-protective clothing material.

The toxicological background for hazard assessment using a simple to use toolkit for assessment and management of health risks from occupational dermal exposure is presented. Hazard assessment is intended to answer the following questions: (i) is the substance under consideration capable of damaging the skin; (ii) is the substance under consideration capable of leading to systemic health effects after having penetrated the skin; (iii) to what extent may the substance become systemically available; (iv) is the hazard influenced by the concentration? Local effects (like irritation or corrosion) and systemic effects (like drowsiness or liver damage) are treated separately, taking into account their possible interrelations. Hazard assessment is performed on the basis of easily available risk phrases, which give a short characterization of the inherent toxicity of a pure chemical or preparation. The information provided by risk phrases and possibly additional data is transformed into a one-dimensional ranking system of intrinsic toxicity (IT) scores. IT scores are expressed in broad categories like low, moderate, high or extreme. This ranking provides plausible information on the relevance of potential skin contact to health effects.