Hazard Assessment Of Chemicals Research Articles

Bioaccumulation of Organic Contaminants in Humans: A Multimedia Perspective and the Importance of Biotransformation

Bioaccumulation is an important component of the exposure hazard assessment and risk assessment of organic chemicals. Screening criteria for chemical hazard used in national and international regulations are based on the paradigm that partitioning properties are the primary chemical determinants of bioaccumulation. We use a holistic multimedia perspective to evaluate the partitioning property paradigm with respect to assessing human bioaccumulation. Multimedia bioaccumulation factors (mmBAFs) for humans were modeled for hypothetical chemicals with a wide range of physical-chemical properties. Varying partitioning properties over 12 orders of magnitude (a plausible range for nonionizing organics) resulted in only modest changes in mmBAFs (a factor of ∼ 10) for all but very volatile or hydrophilic chemicals. In contrast, varying biotransformation rate constants over 6 orders of magnitude resulted in substantial differences in mmBAFs (greater than a factor of 10(9)). Our model results are supported by empirical observations of well characterized pollutants, which demonstrate that chemicals with similar partitioning properties can have very different bioaccumulation behavior. Susceptibility to biotransformation clearly determines bioaccumulation in humans for many chemicals. We conclude that a holistic multimedia perspective for bioaccumulation assessment is necessary to develop regulations, criteria, and policies that are protective of human health and the environment.

The double value of toxicokinetics: Improved chemical hazard and risk assessment plus reduction and refinement of animal use

The double value of toxicokinetics: Improved chemical hazard and risk assessment plus reduction and refinement of animal use

Thesaurus for histopathological findings in publically available reports of repeated-dose oral toxicity studies in rats for 156 chemicals

Because histopathological findings are often conclusive indicators of the toxicities of chemicals, standardization of nomenclature and construction of a thesaurus for histopathological findings are important for the comparative evaluation of histopathological data from repeated-dose toxicity studies (RTS). However, terms for histopathological findings have not been standardized and different technical terms are used to indicate almost the same thing in RTS. The present study was conducted to construct an easy-to-use thesaurus for histopathological findings in order to facilitate hazard assessments of untested chemicals by the category approach using knowledge of the toxicity of analogue chemicals. We used reports of 28-day RTS, conducted on rats by gavage, which were posted on the websites of the National Institute of Health Sciences (NIHS) and the National Institute of Technology and Evaluation (NITE). The histopathological data were from 156 reports on RTS conducted by 13 institutions in Japan. As a result of this study, major parts of the thesaurus were devoted to the findings in the liver, kidney, stomach, adrenal, thyroid and testis; the first three organs are known to be the main targets of chemicals. We also decided that findings such as swelling and enlargement of hepatocytes should be categorized as synonyms for terms meaning hypertrophy. Our thesaurus will be helpful in assessing or screening new untested chemicals by the category approach using knowledge of the toxicities of analogues of the new chemical. The RTS database with this thesaurus will be made publically available in 2012.

Erratum : Thesaurus for histopathological findings in publically available reports of repeated-dose oral toxicity studies in rats for 156 chemicals

Because histopathological findings are often conclusive indicators of the toxicities of chemicals, standardization of nomenclature and construction of a thesaurus for histopathological findings are important for the comparative evaluation of histopathological data from repeated-dose toxicity studies (RTS). however, terms for histopathological findings have not been standardized and different technical terms are used to indicate almost the same things in RTS. The present study was conducted to construct and easy-to-use thesaurus for histopathological findings in order to facilitate hazard assessments of untested chemicals by the category approach using knowledge of the toxicity of analogue chemicals. We used reports of 28-day RTS, conducted on rats by gavage, which were posted on the websites of the National Institute of health Sciences (NIHS) and the National Institute of Technology and Evaluation (NITE). The histopathological data were from 156 reports on RTS conducted by 13 institutions in Japan. As a result of this study, major parts of the thesaurus were devoted to the findings in the liver, kidney, stomach, adrenal, thyroid and testis; the first three organs are known to be the main targets of chemicals. We also decided that findings such as swelling and enlargement of hepatocytes should be categorized as synonyms for terms meaning hypertrophy. Our thesaurus will be helpful in assessing or screening new untested chemical by the category approach using knowledge of the toxicities of analogues of the new chemical. The RTS database with this thesaurus will be made publically available in 2010.

Bioaccessibility studies of ferro‐chromium alloy particles for a simulated inhalation scenario: A comparative study with the pure metals and stainless steel

The European product safety legislation, REACH, requires that companies that manufacture, import, or use chemicals demonstrate safe use and high level of protection of their products placed on the market from a human health and environmental perspective. This process involves detailed assessment of potential hazards for various toxicity endpoints induced by the use of chemicals with a minimum use of animal testing. Such an assessment requires thorough understanding of relevant exposure scenarios including material characteristics and intrinsic properties and how, for instance, physical and chemical properties change from the manufacturing phase, throughout use, to final disposal. Temporary or permanent adverse health effects induced by particles depend either on their shape or physical characteristics, and/or on chemical interactions with the particle surface upon human exposure. Potential adverse effects caused by the exposure of metal particles through the gastrointestinal system, the pulmonary system, or the skin, and their subsequent potential for particle dissolution and metal release in contact with biological media, show significant gaps of knowledge. In vitro bioaccessibility testing at conditions of relevance for different exposure scenarios, combined with the generation of a detailed understanding of intrinsic material properties and surface characteristics, are in this context a useful approach to address aspects of relevance for accurate risk and hazard assessment of chemicals, including metals and alloys and to avoid the use of in vivo testing. Alloys are essential engineering materials in all kinds of applications in society, but their potential adverse effects on human health and the environment are very seldom assessed. Alloys are treated in REACH as mixtures of their constituent elements, an approach highly inappropriate because intrinsic properties of alloys generally are totally different compared with their pure metal components. A large research effort was therefore conducted to generate quantitative bioaccessibility data for particles of ferro-chromium alloys compared with particles of the pure metals and stainless steel exposed at in vitro conditions in synthetic biological media of relevance for particle inhalation and ingestion. All results are presented combining bioaccessibility data with aspects of particle characteristics, surface composition, and barrier properties of surface oxides. Iron and chromium were the main elements released from ferro-chromium alloys upon exposure in synthetic biological media. Both elements revealed time-dependent release processes. One week exposures resulted in very small released particle fractions being less than 0.3% of the particle mass at acidic conditions and less than 0.001% in near pH-neutral media. The extent of Fe released from ferro-chromium alloy particles was significantly lower compared with particles of pure Fe, whereas Cr was released to a very low and similar extent as from particles of pure Cr and stainless steel. Low release rates are a result of a surface oxide with passive properties predominantly composed of chromium(III)-rich oxides and silica and, to a lesser extent, of iron(II,III)oxides. Neither the relative bulk alloy composition nor the surface composition can be used to predict or assess the extent of metals released in different synthetic biological media. Ferro-chromium alloys cannot be assessed from the behavior of their pure metal constituents.

Analyzing Cytotoxic Effects of Selected Isothiazol-3-one Biocides Using the Toxic Ratio Concept and Structure−Activity Relationship Considerations

To demonstrate how baseline toxicity can be separated from other more specific modes of toxic action and to address possible pitfals when dealing with hydrophobic substances, the four isothiazol-3-one biocides N-methylisothiazol-3-one (MIT), 5-chloro-N-methylisothiazol-3-one (CIT), N-octylisothiazol-3-one (OIT), and 4,5-dichloro-N-octylisothiazol-3-one (DCOIT) as an example for reactive electrophilic xenobiotics were tested for their cytotoxic effects on the human hepatoblastoma cell line Hep G2, on the marine bacterium Vibrio fischeri, and on the limnic green alga Scenedesmus vacuolatus. In each of the three test systems, toxic effects were observed in a consistent pattern. The two chlorinated compounds and OIT were found to be significantly more toxic than MIT. As compared to baseline toxicants, the small and polar MIT and CIT exhibited pronounced excess toxicity in each of the three test systems that is presumably triggered by their intrinsic reactivity toward cellular thiols. In contrast, OIT and DCOIT showed mainly toxicities that could be explained by their hydrophobicity. Analyzing and comparing these results using the toxic ratio concept and with data that indicate a dramatic depletion of cellular glutathione levels after incubation with DCOIT reveals that for highly hydrophobic substances, baseline level toxicity in an assay for acute toxicity can lead to an oversight of other more specific modes of toxic action that may cause significant effects that might be less reversible than those caused by unreactive baseline toxicants. This possibility should be taken into account in the hazard assessment of chemicals that are both hydrophobic and reactive.

Evaluating the Community Health Legacy of WWI Chemical Weapons Testing

Spring Valley, Washington, DC, was built over a World War I chemical weapons development site. Test- ing activities caused wide dispersal of arsenic in soil and waste disposal resulted in localized subsurface contami- nation. Spring Valley presents an interesting case study, a contaminated physical environment, but a strongly health- protective social environment. To address a possible ''healthy community'' bias we selected a nearby compari- son community with similar health-protective characteris- tics. Our study included a community health assessment, a spatial analysis of disease clustering and a chemical hazard assessment. Community health in Spring Valley is good. Rates of major causes of mortality and incidence of selected cancers are 20-70% lower than the nation's. Rates of hypertension and related kidney disease mortality and certain potentially arsenic-related cancers are slightly ele- vated in Spring Valley over a comparison community. Registry-confirmed cancers are not more likely to cluster in higher contamination areas, odds ratio (95% Confidence Interval) = 0.60 (0.30, 1.11). Chemicals detected in dis- posal pits are associated with cancer, kidney, neurological and blood effects. In context of a healthy community, the elevated rates of certain mortality and cancer outcomes warrant continued monitoring. Follow-up on kidney, neu- rological and blood diseases was recommended. Urban environments are complex with close proximity of resi- dents to a wide variety of commercial and government activities, past and present. Each community will have a mix of health-damaging and health protective factors. Our assessment combined descriptive and analytical epidemi- ology and environmental risk analyses and represents a flexible tool kit adaptable to unique community conditions.

Effects of Nutrient Pre-Exposure on Atrazine Toxicity to Vallisneria americana Michx. (Wild Celery)

Accelerated eutrophication is common to many freshwater and marine environments and often co-occurs with the presence of anthropogenic chemicals. However, the toxic effects of common chemical stressors such as herbicides in the presence of elevated nutrients are not well understood for most aquatic flora, particularly vascular species. To provide insight, field-collected Vallisneria americana Michx. (wild celery) were sequentially exposed to three nutrient concentrations for 3 months and then to nominal 11 and 110 microg L(-1) atrazine for 96 h. Nutrient concentrations (combined NH(4)(+), NO(2)(-), NO(3)(-), PO(4)(-)) were based on ambient concentrations in the St. Johns River (FL) and ranged from 0.013 to 0.668 mg L(-1). Nutrient pretreatment potentiated the toxicity of atrazine as determined by chlorophyll fluorescence activity. Electron transport rates (ETR) were significantly less (48-59%) for plants pretreated with low and ambient nutrient levels in the presence of an average of 107.5-128.1 microg L(-1) atrazine. Significant ETR reductions were also observed for plants exposed to an average of 11.4 microg L(-1) atrazine after exposure to nutrients three times the ambient concentration in the St. Johns River. The results indicate the importance of considering the presence of nutrients in chemical hazard assessments, particularly for phytotoxicants and nontarget vascular plants.

Surfactants Used in Food Industry: A Review

The understanding of the formation, structures, and properties of emulsions is essential to the creation and stabilization of structures in food. The increasing use of surfactants, the identification of compounds with low toxicity and good surface activity properties is of great interest. The relevance of the major end points specified in the Organisation for Economic Co-operation and Development (OECD) guidelines for the hazard assessment of food chemicals is critically analyzed and main parameters are acute toxicity, subacute repeated studies, allergy, reproductive toxicity, long-term studies, and mutagenicity tests. We focus this article on surfactant association structures and food colloids. There is almost infinite number of combinations are organized and arranged in very complex internal microstructures with various types of assemblies such as dispersions, emulsions, foams, gels, etc. Low-mass surfactants are very mobile at the interface and they are particularly efficient reducing the interfacial tension. As a result, they rapidly coat the freshly created oil-water interface during emulsification. In this category, we mainly mentioned monoglycerides, lecithins, glycolipids, fatty alcohols and fatty acids. High-mass surfactants cover protein and polysacharide groups. The protein molecule may interpenetrate in the lipid phase to various degrees. The specific binding is predominantly electrostatic: The headgroups of the surfactants bind to groups of opposite charge on the protein. The saturation binding for anionic surfactants is pH-independent and seems to be controlled by the cooperative hydrophobic interactions. Polysaccharides and smallmolecule surfactants are two of the predominant groups of amphiphilic materials that have been explored for the stabilization of emulsions. One of the most important aspects of polymer-surfactant systems is their ability to control stability and rheology over a wide range of composition. Biocompatible, biodegradable, and/or nontoxic emulsion-based formulations have great potential for applications in the food. The combination of particular characteristics such as emulsifying, anti-adhesive and antimicrobial activities presented by biosurfactants suggests potential application as multipurpose ingredients or additives.

Risk-relevant indices for the characterization of persistence of chemicals in a multimedia environment

The present research study proposes a new set of appropriately defined indices for the characterization of persistence of chemicals in a multimedia environment that prominently figures as a key exposure-based indicator within contemporary frameworks of chemical hazard and risk assessment, as well as recent international regulatory initiatives. Effectively overcoming some of the limitations associated with traditional approaches that could lead to a potential misclassification of chemical substances, the proposed set of persistence indices retain also a conceptually insightful and computational appeal. Conceptually inspired by certain measures/indices for the characteristic time found in classic dynamic systems theory, and technically relying on notions and methods from the theory of matrices, the new performance indices can be easily calculated on the basis of a dynamic multimedia environmental model and the aid of a software package such as MATLAB. In particular, an extension of the notion of equivalence width as a quantitative proxy of overall persistence is introduced, that captures the dynamic history of the chemical's environmental behavior, while remaining independent of the particular release pattern and discharge conditions (thus overcoming the standardization difficulties encountered when a large number of chemicals need to be first screened and classified in a tiered hazard assessment methodology). Furthermore, a second persistence index is introduced whose value can be analytically calculated through the solution of a simple Lyapunov matrix equation bearing some resemblance to certain measures of system resilience used in theoretical biology and ecology, yet inspired by system-theoretic notions associated with the Lyapunov framework of analysis in systems science. Furthermore, for both persistence measures a comparison is made with the slowest time-constant associated with the specific chemical dynamics in a multimedia environment, and upper and lower bounds are established. Finally, the proposed persistence indices are calculated on the basis of a standard dynamic multimedia environmental model for various representative cases involving chemicals of particular interest.

TOX 21: New Dimensions of Toxicity Testing

On the ground floor of the National Institutes of Health Chemical Genomics Center (NCGC) in Rockville, Maryland, a $10-million automated laboratory spends all day and night screening chemicals at speeds no team of human researchers could ever match. In a week, depending on the nature of the assay, it can yield up to 2.2 million molecular data points derived from thousands of chemicals tested at 15 concentrations each.

Occupational asthma to gel flux containing dodecanedioic acid

Most occupational asthma from electronic solder fluxes is due to colophony (1, 2). We report the first case of occupational asthma to electronic colophony-free gel flux predominantly containing dodecanedioic acid. The patient worked as an electronics instructor from 1999; he initially used solder wire and a separate flux (both colophony). In 2002, he changed to a colophony-free solder wire (predominantly palmitic acid) and a separate gel flux. In 2004, he developed work-related stuffy nose and dyspnoea. This became worse in 2005 when he woke up twice a night and had a blocked nose, wheeze and sputum for the first 2 h after waking. He was worse in the evening after soldering or the night following soldering. He had no asthma, hay fever or eczema in childhood. His father had occupational asthma from corn dust, but his sister had no asthma. He smoked seven to 10 cigarettes per day since age 17 and gave up 6 weeks before being seen in clinic. He had negative skin tests to all common environmental allergens. He completed serial peak expiratory flow (PEF) measurements every 2 h for a total of 4 weeks. When plotted in Oasys (3), the record showed large deteriorations in PEF (declining up to 120 l/min from mean rest PEF) when he visited the soldering bays and intermittent smaller deteriorations when working in the office. The record was scored by the Oasys work effect index (3) as 3.00 (probable occupational asthma; a score of >2.50 has a sensitivity of 75% and specificity of 94%; 3). The area between the curves (ABC) plot (4) in Oasys analysed the two exposures separately and gave an ABC from waking score of 56 l/min/h in the soldering bay and 5 l/min for the office work (an ABC score of ‡15 l/min/h has a sensitivity of 69% and specificity of 100% for occupational asthma diagnosis; 4). His mean work day diurnal variation was 21% and mean rest day diurnal variation was 12%. His exhaled nitric oxide (FENO) level while exposed was 14.3 ppb (Aerocrine Niox at 50 ml/s). He was admitted for specific inhalation challenge testing to both solder wires and fluxes. He melted approximately 5 m of solder wire (using an iron heated to 370 C) spread over three challenges totalling 70 min. For the fluxes, he dipped the soldering iron into the flux approximately every 10 s, letting it fume into the challenge chamber after each insertion. For the colophony flux, he did this over three challenges totalling 17 min and for only 8 min when using the colophony-free gel flux. Figure 1 shows the results of the colophony and dodecanedioic acid fluxes. His forced expiratory volume in 1 s (FEV1) fell by a maximum of 23% from baseline when he was exposed to the dodecanedioic acid flux. He was negative to the colophony wire and wire containing predominantly palmitic acid. His nonspecific reactivity was >4800 lg of methacholine (via the Yan method) prechallenge, becoming measurable postchallenge at 3490 lg. Two years after removal from exposure and while working as an apprenticeship manager without soldering exposure, his asthma continues, but is no longer work-related and his FENO remains normal at 10.7 ppb. Dodecanedioic acid has an asthma hazard index of 0.94 using the chemical asthma hazard assessment programme (5); a value >0.5 has a high probability of being an asthmagen. Other noncolophony based fluxes such as palmitic acid and adipic acid (previously described in a pharmaceutical worker; 6) also have high hazard indexes (0.92 and 0.75 respectively).

Development of a flow-through system for the fish embryo toxicity test (FET) with the zebrafish ( Danio rerio)

The acute fish test is still a mandatory component in chemical hazard and risk assessment. However, one of the objectives of the new European chemicals policy (REACH – Registration, Evaluation, Authorization and Restriction of Chemicals) is to promote non-animal testing. For whole effluent testing in Germany, the fish embryo toxicity test (FET) with the zebrafish ( Danio rerio) has been an accepted and mandatory replacement of the fish test since January 2005. For chemical testing, however, further optimization of the FET is required to improve the correlation between the acute fish test and the alternative FET. Since adsorption of the test chemical to surfaces may reduce available exposure concentrations, a flow-through system for the FET using modified commercially available polystyrene 24-well microtiter plates was developed, thus combining the advantages of the standard FET with those of continuous delivery of test substances. The advantages of the design presented include: small test footprint, availability of adequate volumes of test solution for subsequent chemical analysis, and sufficient flow to compensate for effects of non-specific adsorption within 24 h. The flow-through test system can also be utilized to conduct longer-term embryo larval fish tests, thus offering the possibility for teratogenicity testing.

Using chemical categories to fill data gaps in hazard assessment

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 assessment of organic chemicals with the use of artificial neural networks

A procedure for assessing the hazard class of chemicals is developed based on the use of artificial neural networks. The structure of a neural network is founded on the structural analysis of chemical compounds. Training and testing were carried out within the computer database of chemical structures.

The Process of JSET-establishment and Inevitability of Filed Investigations for Environmental Assessment of chemical Hazards.

The Process of JSET-establishment and Inevitability of Filed Investigations for Environmental Assessment of chemical Hazards.

Pollution‐induced community tolerance as a measure of species interaction in toxicity assessment

1 The assessment of the environmental hazards posed by chemical pollutants typically results from single-species tests that are extrapolated to ecosystems. The aim of the present study was to compare this type of extrapolation for a herbicide with the chronic effects that may be observed at a community level and to evaluate currently applied risk assessment strategies for their ability to predict chemical effects on complex communities. 2 Freshwater periphyton communities, grown in indoor aquaria, were exposed to the pollutant diuron for 3 months. Acute toxic effects of diuron were detected as photosynthesis inhibition using quenching analysis of chla-fluorescence. Chronic effects of the herbicide were observed in terms of changes in biomass and algal class composition as well as pollution-induced community tolerance (PICT). The PICT concept is based on a chemical exerting selection pressure on a community and therefore eliminating sensitive species. As a result, the measured community tolerance increases. 3 Short-term effects of diuron arise from 4–9 µg L−1 as half-maximal effect concentration (EC50). It is further shown that diuron concentrations down to 0·08 µg L−1 caused chronic effects in two independent microcosm studies. The observed threshold concentration of 0·08 µg L−1 still caused changes in biomass and class composition as well as an increased community tolerance. The determined EC50 values increased by a factor of 2–3 in diuron-exposed periphyton communities. This threshold value could not be predicted by advanced extrapolation methods such as species sensitivity distribution or acute-to-chronic effect ratios. 4 Synthesis and applications. The chronic community-level effects of the pollutant diuron were not predictable from single-species tests. However, regulations such as the EC Water Framework Directive or the EC-REACH process (Registrations, Evaluation and Authorisation of Chemicals) rely on this type of information. The management of chemicals in the environment should be based upon higher-tier assessment tools. Species interaction, detectable and quantifiable by the PICT methodology, may serve as a prognostic tool in chemical hazard assessment when extrapolating effects from single-species tests to community level.

Can the unit world model concept be applied to hazard assessment of both organic chemicals and metal ions?

A unit world model that has the potential to be used for the hazard assessment of both metal ions and organic chemicals is described and discussed, with an emphasis on the problems that arise when treating metal ions. It is based on the steady-state equilibrium criterion model that is designed to simulate the fate of organic chemicals in a 100,000-km(2) region and comprises four well-mixed compartments: Air, water, soil, and sediment. To be applicable to metal ions, modifications are required. The single soil and sediment layers should be replaced by two layers to accommodate aerobic and anaerobic conditions. The more complex and variable partitioning of metals resulting from dependence on pH, redox conditions, ionic oxidation state, and presence of sulfide also must be addressed, but preferably in a separate geochemical model, because these factors can result in nonlinearity. For metals, a dynamic as well as a steady-state model is desirable. It is shown that the resulting model can be applied to both organics and metals. Rather than seeking to apply the hazard criterion of persistence to metal ions, the model can be used to deduce a critical loading that results in a defined toxic end point, thus integrating the hazard criteria of persistence, toxicity, and possibly, bioaccumulation. This approach is applied illustratively to naphthalene as a typical organic substance and to four environmentally relevant metal ions. Results are discussed and recommendations made for further development. Specifically, the absence of metal degradation can result in large, steady-state quantities in soils and sediments corresponding to residence times of many centuries. Consequently, the dynamic calculations are more relevant for fate assessments of metals over a period of years, and more focus on the aquatic environment is justified.

Assessment of Chemical, Physical, and Safety Hazards in Paper Industry in Dammam

Assessment of Chemical, Physical, and Safety Hazards in Paper Industry in Dammam

Development of the HarsMeth methodology for hazard assessment of highly reactive systems: HarsMeth new process

This paper presents the evolution of the HarsMeth methodology for the assessment of chemical reactive hazards in process plants. This tool is intended to help small and medium enterprises with the safety analysis of their chemical processes, and it is a result of the European Commission funded network HarsNet, which was active between 1998 and 2002, when the latest version of HarsMeth was published. The methodology has been improved by adapting its structure to the logical evolution in the development of a chemical process. The objective is to perform the assessment on a step-by-step basis, starting with the preliminary analysis of different synthesis paths, followed by a bench scale analysis of the selected route at the laboratory, and finishing with the necessary safety considerations in order to implement the process at plant scale. The methodology has been tested with a real process in order to check its efficiency. The reaction chosen is the production of macrocyclic peroxides from catalytical oxidation of cyclohexanone with hydrogen peroxide. Recent investigations have determined the conditions under which this reaction may lead to a runaway, which makes it suitable to determine how HarsMeth can help in the assessment of such reactions.