Substances Of Very High Concern Research Articles

A critical review to identify data gaps and improve risk assessment of bisphenol A alternatives for human health.

Bisphenol A (BPA), a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins, has been associated with a variety of adverse effects in humans including metabolic, immunological, reproductive, and neurodevelopmental effects, raising concern about its health impact. In the EU, it has been classified as toxic to reproduction and as an endocrine disruptor and was thus included in the candidate list of substances of very high concern (SVHC). On this basis, its use has been banned or restricted in some products. As a consequence, industries turned to bisphenol alternatives, such as bisphenol S (BPS) and bisphenol F (BPF), which are now found in various consumer products, as well as in human matrices at a global scale. However, due to their toxicity, these two bisphenols are in the process of being regulated. Other BPA alternatives, whose potential toxicity remains largely unknown due to a knowledge gap, have also started to be used in manufacturing processes. The gradual restriction of the use of BPA underscores the importance of understanding the potential risks associated with its alternatives to avoid regrettable substitutions. This review aims to summarize the current knowledge on the potential hazards related to BPA alternatives prioritized by European Regulatory Agencies based on their regulatory relevance and selected to be studied under the European Partnership for the Assessment of Risks from Chemicals (PARC): BPE, BPAP, BPP, BPZ, BPS-MAE, and TCBPA. The focus is on data related to toxicokinetic, endocrine disruption, immunotoxicity, developmental neurotoxicity, and genotoxicity/carcinogenicity, which were considered the most relevant endpoints to assess the hazard related to those substances. The goal here is to identify the data gaps in BPA alternatives toxicology and hence formulate the future directions that will be taken in the frame of the PARC project, which seeks also to enhance chemical risk assessment methodologies using new approach methodologies (NAMs).

Machine Learning-Based Toxicological Modeling for Screening Environmental Obesogens.

The emerging presence of environmental obesogens, chemicals that disrupt energy balance and contribute to adipogenesis and obesity, has become a major public health challenge. Molecular initiating events (MIEs) describe biological outcomes resulting from chemical interactions with biomolecules. Machine learning models based on MIEs can predict complex toxic end points due to chemical exposure and improve the interpretability of models. In this study, a system was constructed that integrated six MIEs associated with adipogenesis and obesity. This system showed high accuracy in external validation, with an area under the receiver operating characteristic curve of 0.78. Molecular hydrophobicity (SlogP_VSA) and direct electrostatic interactions (PEOE_VSA) were identified as the two most critical molecular descriptors representing the obesogenic potential of chemicals. This system was further used to predict the obesogenic effects of chemicals on the candidate list of substances of very high concern (SVHCs). Results from 3T3-L1 adipogenesis assays verified that the system correctly predicted obesogenic or nonobesogenic effects of 10 of the 12 SVHCs tested, and identified four novel potential obesogens, including 2-benzotriazol-2-yl-4,6-ditert-butylphenol (UV-320), 4-(1,1,5-trimethylhexyl)phenol (p262-NP), 2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethanol (OP1EO) and endosulfan. These validation data suggest that the screening system has good performance in adipogenic prediction.

Reducing sample size by clustering: A way to make risk assessment feasible for large groups of organic compounds?

This research addresses the presence of substances of very high concern (SVHCs) confronting the drinking water sector. Responding adequately to the potential hazards by SVHCs, knowledge of emission pathways, toxicity, presence in drinking water sources, and removability during water production is crucial. As this information cannot be received for each compound individually, we employed a detailed clustering approach based on chemical properties and structures of SVHCs from lists with over 1,000 compounds. Through this process, 915 substances were divided into 51 clusters. We tested this clustering in risk assessment. To assess the risks, we developed toxicity prediction models utilizing random forests and multiple linear regression. These models were applied to make toxicity predictions for the list of compounds. This study shows that clustering is a viable approach to reducing sample size. In addition, the toxicity models provide insights into the potential human health risks. This research contributes to more informed decision-making and improved risk assessment in the drinking water sector, aiding in the protection of human health and the environment. This principle is generally applicable. If in a group a suitable representative is found, data from experiments with this compound can be used to gauge the behaviour of chemicals in this group.

Steering responsible innovation: the impact of EU REACH legislation on the novelty and toxicity of chemical inventions

ABSTRACT This study investigates the influence of EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation on the technological trajectory of the chemical industry. Focusing on the Substances of Very High Concern (SVHC) list, this study used a novel dataset of chemical patents and structures filed at the European Patent Office (EPO) over the period from 1990 to 2016. A staggered difference-in-differences approach with inverse probability weights was used to measure the impact of the SVHC list on the novelty and toxicity of chemical patents. The analysis revealed a substantial increase in the chemical novelty of patents after the introduction of the SVHC list. Simultaneously, a significant decrease in the toxicity of these patents was observed, underpinning the legislative intent of REACH. These findings highlight the ability of regulatory frameworks to strategically steer innovation, reinforcing the alignment between technological advancement and the overarching goals of responsible and sustainable development.

Glycidyl methyl ether: A safer alternative to ethylene oxide for designing ethoxy-free non-ionic surfactants

Ethoxylated surfactants have recently raised alarm because small amounts of dioxane, a Substance of Very High Concern (SVHC), are formed during their synthesis and degradation, with some of it ending up as traces in drinking water. This awareness has prompted a quest for alternative non-ionic surfactants free of ethoxylates yet offering a tuneable molecular structure and amphiphilic behaviour akin to polyethoxylated alcohols, CiEj. In this perspective, we performed oligomerization of Glycidyl Methyl Ether (GME) on fatty alcohols to yield branched isomers of CiEj surfactants. The amphiphilic properties of the resulting well-defined ethoxy-free surfactants were systematically compared to their polyethylene glycol counterparts. The introduction of branching in the polar head led to decreased hydrophilicity, as quantified by PIT-slope measurements. Furthermore, these branched surfactants exhibited cloud points with a reduced dependence on the oligomerization degree and lower Critical Micelle Concentrations (CMC). Consequently, these findings position them as promising alternatives to ethoxylated non-ionic surfactants. Finally, the COSMO-RS theory was strategically applied for the first time to rigorously rationalize the amphiphilic properties exhibited by these novel surfactants by precisely quantifying hydrophilic-lipophilic tendencies.

The Compliance Risk Assessment of EU REACH SVHC in Articles of IC Package by Studies of Analysis Methodology

Companies may have legal obligations resulting from the inclusion of the Candidate List of substances of very high concern (SVHC) in a concentration above 0.1% w/w in an Article, as defined under EU REACH Regulation and Waste Framework Directive (SCIP Database) if they place articles on the EU market. Only a few studies have so far been made on how to determine the contents of the Chemical in Product (CiP). The approach to identifying the risk associated with the SVHC in the IC package is mainly to collect and review large information from the supplier chain or by chemical analysis. This article tries to discuss the current challenges for data collection and identifying risks with chemical substances in the IC package. Based on the chemical test results of 2-benzyl-2-dimethylamino-4’-morpholinobutyrophenone and bisphenol A, it was found that the test results of SVHC could be affected by numerous factors such as tested sample form (e.g., powder or flaky shaped), tested sample curing conditions, and chemical analytical methods. Although chemical analysis provides more accurate information for SVHC, when utilizing chemical analysis for checking legal compliance, we still need to compare and analyze the result of chemical substances analysis with the materials self-declaration provided by suppliers to judge whether the data are reasonable.

Uptake, accumulation and metabolism of UV-320 in vegetables and its impact on growth and quality

UV-320 is classified as a Substance of Very High Concern (SVHC) by the European Chemicals Agency and has attracted significant attention due to its presence in the environment. Understanding the uptake, translocation and metabolic patterns of UV-320 in vegetables is essential for assessing their ability to bioaccumulate and potential risks to human health. In this study, we investigated the uptake and translocation of UV-320 in lettuce and radish by hydroponic experiments. The results showed that the root concentration factors (Croot/Csolution, RCF) of lettuce and radish were in the range of 47.9 to 464 mL/g and 194 to 787 mL/g, respectively. The transfer factors (Cshoot/Croot, TF) were observed to be 0.001–0.012 for lettuce and 0.02–0.05 for radish. Additionally, non-targeted screening identified twelve phase I and one phase II metabolites of UV-320 in vegetables, which were confirmed based on their molecular formulas and structures. The metabolic pathways involving oxidation, ketonylation and deamination were proposed in vegetables. Also, we have observed that UV-320 inhibits the growth of vegetables. Meanwhile, we evaluated the health risk of UV-320 in lettuce and radish and found that the consumption of lettuce is relatively safe, while the consumption of radish has a risk of HQ >1 for both adults and children, which should be seriously considered. This study provides valuable insights into the behavior and ecological risks of UV-320 in the environment.

Electrochemical Deposition in Vertical Tubes : An Hydrodynamic and Mass Transfer Study

The present work is part of the research project NXCHROME led by IRT M2P. It concerns the chemical engineering of metallic hard chromium coatings on internal surface of large tubular parts. These parts are intended to be used in several sectors of activity (aeronautics, armament, energy...). Thus, taking into account severe specifications related to these applications, the parts will be very strongly solicited thermomechanically during their use, which requested high performances to increase substrate's life. In the current process, tubes are treated vertically, by electrodeposition from a hexavalent chromium salt based (chromic acid) electrolyte. These electrolytes have the advantage of being efficient, easy to use, with well known functions. However, they have a low faradic yield (<20%), leading to an important production of bubbles (cathodic and anodic).These bubbles create the fluid motion, and eventually govern hydrodynamic, liquid flow and mass transfer of the species in the tube.It is important to note that the use of CrVI salts has been prohibited since 2017 (except for authorizations for applications without alternatives) by the European regulation REACh (Registration, Evaluation, Authorization and restriction of Chemicals). Indeed, hexavalent chromium is classified in Appendix XIV among SVHC (substances of very high concern), due to its high toxicity (CMR compound : Carcinogenic, Mutagenic and Reprotoxic) and the high danger it represents for coworkers using this compound. The objective of NXCHROME is to find a alternative process with a "REACh compatible" electrolyte based on an innovative trivalent chromium. The modus operandi and the electrochemical mechanisms involved are completely different and less well known, compared to the former electrolyte. Nevertheless, it keeps this low faradic yield and the liquid agitation mode in tubular parts will remains identical.Nevertheless, this change is a good opportunity for a deep investigation in the "bubble induced hydrodynamic" which occurs during plating time, and to collect all reliable information on fluids behavior. Then, two main research axis have been considered. The first one is done via the numerical simulation of the secondary current distribution, i.e. taking into account the electrical phenomena in the electrolyte (ohmic drop), the geometry of the system and the kinetics of the electrochemical reactions. This part is in collaboration with HIVELIX company. The second one trhought the design and elaboration of a large size experimental set-up in stainless steel and PMMA (φ = 40mm, L = 3000mm) Figure 1. This ste-up includes electrochemically active cathode parts (production of bubbles by hydrolysis), and transparent parts (windows of observations of the bubbles, according to the height of the tube). As it is the bubble production which puts in movement the fluid with their vertical displacement towards the surface, informations on their size and behavior are of primary importance. Their speed is determined by their size (depending on the distance covered and the coalescence) and the liquid physical properties.To mimic the chromium electrolyte, a transparent saline solution has been chosen and prepared by adjusting its parameters to be identical to the industrial electrolyte (viscosity, conductivity...), while allowing bubble production on the central electrode surface.Data collection and order of magnitude are done by various means, namely flow rate measurements, gas retention within the liquid and high frequency camera shots (bubble size, bubble velocity, coalescence...). Figure 1

The implementation of the substitution principle in European chemical legislation: a comparative analysis

BackgroundThe substitution of hazardous chemicals with safer alternatives is an important objective in European chemical policy, but implementation has been slower than expected. We conduct a comprehensive analysis and comparison of the implementation of the substitution principle in European regulations for pesticides, biocides, and industrial chemicals. Specifically, we examine and compare the criteria and processes associated with the identification of candidates for substitution and the assessment of alternatives.ResultsWe find only minor differences in the criteria applied to identify candidates for substitution amongst pesticides, biocides, and industrial chemicals, but larger differences concerning the processes used. While all substances that are to be approved as a pesticide and biocide are systematically evaluated against the established criteria for substitution, the substitution process for industrial chemicals only focuses on those substances identified as substances of very high concern. The main reason candidates for substitution remain on the market is the lack of identified safer chemical alternatives and the insufficient consideration of non-chemical alternatives, caused, at least to a large extent, by the comparatively weak incentives provided by current regulations.ConclusionsThe systematic approach for the identification of industrial substances of very high concern (SVHC) under ECHAs “Integrated Regulatory Strategy” is much welcome. However, no final conclusion on SVHC properties or the need for regulatory action has been drawn for approximately 90% of the REACH-registered substances, as often even basic hazard and exposure data are missing. Hence, at least a screening-level evaluation of SVHC properties should become a mandatory part of the substance registration under REACH. To reduce the risk of strategic behaviour in the search for alternatives to industrial chemicals identified as SVHC, a setup in which regulatory authorities play a larger role as information and knowledge brokers should be considered. Investments in innovation as well as improved sharing of information and a better distribution of the workloads amongst European authorities might also improve the identification of safer alternatives. However, without stronger incentives, making it more costly for companies to continue using hazardous substances relative to safer alternatives, initiatives to promote substitution are likely to have limited success.

Screening and prioritising persistent, mobile and toxic chemicals: development and application of a robust scoring system

BackgroundLately scientific and societal concern has emerged about persistent (P), mobile (M) and toxic (T) chemicals. Such chemicals, like some polyfluoroalkyl acids (PFAAs), are of concern due to their high mobility and persistence in aquatic compartments which relates to long-term biotic exposure and difficult removal from drinking water. In this study, a screening approach for identification of PMT chemicals was developed and applied to 6158 diverse chemicals.ResultsChemicals are given a continuous score for P, M and T potential based on the modelled indicators (low to moderate potential is a score of 0–0.33, high potential is a score of 0.33–0.5 and very high potential a score of 0.5–1). The P score was based on the estimated aquatic environmental half life and the M score on the chemical’s organic carbon/water partition coefficient (Koc) using respectively the BIOWIN3 and KocWIN QSAR models of EPISuite™. The T score was based on the indicators for five human health endpoints: carcinogenicity (c), mutaganicity (m), reprotoxicity (r), endocrine disruption (ED) and general repeated dose systemic toxicity. Structural alerts for these endpoints taken from the OECD QSAR Toolbox™ and Toxtree™ were used as indicators of potential (human) toxicity. Chemical similarity values to Substances of Very High Concern (SVHC) with c, m and/or r properties were also included. Value functions were developed to translate the presence of alerts and similarity to the existing SVHCs to values between 0 and 1. Subsequently, all values were also aggregated to an overall PMT score, again ranging from 0 to 1. Applying the approach to chemicals from the Inventory of Existing Commercial chemical Substances, which are also REACH registered, resulted in 15% of the chemicals receiving high scores (≥ 0.33) for all three (P-, M- and T-) indicators and 4% getting very high scores (≥ 0.5) for both the P- and M-indicators.ConclusionsThe approach confirmed the properties of chemicals classified as SVHC due to PMT properties (e.g. 1,4-dioxane), illustrating the ability of the approach to identify PMT chemicals of concern. Water regulators, drinking water suppliers and others can use this approach to identify potential PMT/vPvM chemicals that need further investigation.

Hazardous properties of plasticisers that may hinder the recycling of plastics

Plasticisers transform rigid polymers, especially PVC, into flexible and useful material, typically at 10-35% concentration. Four phthalate plasticizers are now banned in the EU (maximum concentration in products of 0.1%). Are other plasticisers, used in concentrations that make a product waste, unsafe? The hazardous properties of plasticisers used in the EU (Plastic Additives Initiative list) were collected from the ECHA registration site. Eight plasticizers (=12% of 69) are either skin sensitizers (2 substances) and under evaluation by ECHA (7 substances), with a potential ban at the end of the evaluation for persistence, bioaccumulation and toxicity (PBT), endocrine disruption (ED) and as substances of very high concern (SVHC). Seventeen (=25% of 69) are used at a concentration that makes the plastic hazardous when it becomes waste. The sorting and management options of these additivated plastics are discussed. The recycling of these hazardous wastes is not prohibited. In the short-term recycling phase in modern industrial plants, there is a low emission of these additives, which is controlled by occupational safety and environmental regulations. On the other hand, the long-term low-quality management such as littering (with weathering and fragmentation) and landfilling (with the emission of degradable products in case of phthalates) scatter these substances. The plastics containing “legacy” banned additives must be phased out. But the plastics with compounds at hazardous concentration should be recycled in controlled recycling loop. They should be managed by a risk approach, like the products they were and the new products that they will become.

Economic interests cloud hazard reductions in the European regulation of substances of very high concern

Here we investigate how the conflicts between hazard reduction and economic interests have shaped the regulation of substances of very high concern (SVHCs) under the Authorization program of the European chemical regulation Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH). Since regulation starts with listing SVHCs on the Candidate List, we analyze the relative importance of toxicological properties, economic motivations, and available scientific knowledge on the probability of inclusion on the Candidate List. We find that the most important factor in whether a substance is listed is whether it is being produced in, or imported into, the European Economic Area (EEA), with the regulators less likely to place a substance on the list if it is currently being produced or imported in the EEA. This evidence suggests that regulators have listed chemicals of secondary importance leading to lesser than anticipated hazard reductions, either because production and imports had already ceased before the listing, or because the compound has never been produced or imported in the EEA at all.

Commentary: Labelling of Synthetic Endocrine Disrupting Chemicals (S-EDCs) as Substances of Very High Concern (SVHC)

Commentary: Labelling of Synthetic Endocrine Disrupting Chemicals (S-EDCs) as Substances of Very High Concern (SVHC)

Overview: Polycarbonates via Ring-Opening Polymerization, Differences between Six- and Five-Membered Cyclic Carbonates: Inspiration for Green Alternatives.

This review aims to cover the topic of polycarbonate synthesis via ring-opening polymerization (ROP) of cyclic carbonates. We report a wide variety of ROP-initiating systems along with their detailed mechanisms. We focus on the challenges of preparing the polymers; the precise control of the properties of the materials, including molecular weight; the compositions of the copolymers and their structural characteristics. There is no one approach that works for all scales in cyclic carbonates ROP. A green process to produce polycarbonates is a luring challenge in terms of CO2 utilization and the targeted domains for application. The main resolution seems to be the use of controlled incorporation of functional/reactive groups into polymer chains that can tailor the physicochemical and biological properties of the polymer matrices, producing what appears to be an unlimited field of applications. Glycerol carbonate (GC) is prepared from renewable glycerol and considered as a CO2 fixation agent resulting in GC compound. This family of five-membered cyclic carbonates has attracted the attention of researchers as potential monomers for the synthesis of polycarbonates (PCs). This cyclic carbonate group presents a strong alternative to Bisphenol A (BPA), which is used mainly as a monomer for the production of polycarbonate and a precursor of epoxy resins. As of December 2016, BPA is listed as a substance of very high concern (SVHC) under the REACH regulation. In 2006, Mouloungui et al. reported the synthesis and oligomerization of GCs. The importance of GCs goes beyond their carbonate ring and their physical properties (high boiling point, high flash point, low volatility, high electrical conductivity) because they also contain a hydroxyl group. The latter offers the possibility of producing oligo and/or polycarbonate compounds that have hydroxyl groups that can potentially lead to different reaction mechanisms and the production of new classes of polycarbonates with a wide range of applications.

Quantitative Analysis of Thyroid Nodules’ Severity and Changes in the Voice Box

Voice is the most natural way to express one’s thoughts, but thyroid disease degrades the quality of one’s voice. Thyroid nodules are lumps of thyrocytes in the thyroid gland that may press the voice box, which results in voice change. To visualize the growth in the thyroid gland, the modified 3D Level Set Volumetric Segmentation (3D LSVS) techniques were used. Thyroid nodules’ severity can be measured based on the volume of the lump. An inferential statistic occurs with confidence intervals between the substance of very high concern (SVHC), Systemic Viral Infection (SVI), STMW and SVHD using Multivariate analysis (MVA) and testing. Acoustic analysis measured the voice changes. Different prevalent methods are compared concurrently and the results of quantitative analysis are better.

ZZS similarity tool: The online tool for similarity screening to identify chemicals of potential concern.

Screening and prioritization of chemicals is essential to ensure that available evaluation capacity is invested in those substances that are of highest concern. We, therefore, recently developed structural similarity models that evaluate the structural similarity of substances with unknown properties to known Substances of Very High Concern (SVHC), which could be an indication of comparable effects. In the current study the performance of these models is improved by (1) separating known SVHCs in more specific subgroups, (2) (re‐)optimizing similarity models for the various SVHC‐subgroups, and (3) improving interpretability of the predicted outcomes by providing a confidence score. The improvements are directly incorporated in a freely accessible web‐based tool, named the ZZS similarity tool: https://rvszoeksysteem.rivm.nl/ZzsSimilarityTool. Accordingly, this tool can be used by risk assessors, academia and industrial partners to screen and prioritize chemicals for further action and evaluation within varying frameworks, and could support the identification of tomorrow's substances of concern.

Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA

GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.

Global evaluation of the chemical hazard of recycled tire crumb rubber employed on worldwide synthetic turf football pitches

Social and environmental concern about the use of crumb rubber from end-of-life car tires in the construction of different sport and recreational facilities is increasing due to the presence of hazardous compounds. The aim of this research was the assessment of 42 organic chemicals, including polycyclic aromatic hydrocarbons (PAHs), phthalates, adipates, antioxidants and vulcanisation agents in a large number of infill samples (91) from synthetic turf football pitches of diverse characteristics and geographical origin. Samples were taken worldwide, in 17 countries on 4 continents, to show the global dimension of this problem. Ultrasound assisted extraction was employed to extract the target compounds, followed by gas chromatography coupled to tandem-mass spectrometry (UAE-GC–MS/MS). Seventy-eight crumb rubber samples as well as thirteen samples of alternatives materials, such as cork granulates, thermoplastic elastomers and coconut fibre, were analyzed. The results highlight the presence of all target PAH in most rubber samples at concentrations up to μg g−1, including the eight ECHA (European Chemicals Agency) PAHs considered as carcinogenic, and anthracene (ANC), pyrene (PYR) and benzo[ghi]perylene (B[ghi]P), catalogued as substances of very high concern (SVHC). Endocrine disruptors such as some plasticizers (mainly phthalates), and other compounds like benzothiazole (BTZ) and 2-mercaptobenzothiazole (MBTZ) were found reaching the mg g−1 level. This confirms the presence of the hazardous substances in the recycled crumb rubber samples collected all around the world. Three crumb rubber samples exceeded the limit of 20 μg g−1 for the sum of the eight ECHA PAHs. Regarding the chemical composition of other infill alternatives, cork appears to be adequate, while the thermoplastic elastomers contained high levels of some plasticizers. In addition, the plastic infill as well as the crumb rubber both are microplastics. Microplastics are considered contaminants of emerging concern since they do not biodegrade and remain in the environment for a long time.

Persistent, mobile and toxic (PMT) and very persistent and very mobile (vPvM) substances pose an equivalent level of concern to persistent, bioaccumulative and toxic (PBT) and very persistent and very bioaccumulative (vPvB) substances under REACH

BackgroundUnder the EU chemicals regulation REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals EC 1907/2006), registrants are not obliged to provide information related to intrinsic substance properties for substances that pose a threat to the drinking water resources. In 2019, perfluorobutane sulfonic acid (PFBS) and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoic acid (HFPO-DA trade name GenX) were demonstrated to have an equivalent level of concern (ELoC) to persistent, bioaccumulative and toxic or very persistent and very bioaccumulative (PBT/vPvB) substances owing to their persistent, mobile and toxic (PMT) substance properties and very persistent and very mobile (vPvM) substance properties, respectively. They were both subsequently identified as substances of very high concern (SVHC) applying Article 57(f) in REACH. This work follows up on this regulatory decision by presenting a science based, conceptual level comparison that all PMT/vPvM substances pose an ELoC to PBT/vPvB substances. Using the two cases named above, as well as 1,4-dioxane, 16 categories were developed to evaluate a) serious effects on human health, b) serious effects on the environment and c) additional effects. 1,4-dioxane has recently been proposed to be classified as Carcinogenic 1B by the Committee for Risk Assessment (RAC). The aim was to enable an objective and scientifically justified conclusion that these classes of substances have an equivalent level of concern for the environment and human health.ResultsIn all of the categories related to human health, the environment and other effects, the PMT/vPvM case study substances exhibited comparable effects to PBT/vPvB substances. A difference in the human and environmental exposure pathways of PMT/vPvM and PBT/vPvB substances exists as they vary temporally and spatially. However, effects and impacts are similar, with PMT/vPvM substances potentially accumulating in (semi-)closed drinking water cycles and pristine aquatic environments, and PBT/vPvB substances accumulating in humans and the food chain. Both PMT/vPvM and PBT/vPvB substances share the common difficulty that long term and long-range transport and risk of exposure is very difficult to determine in advance and with sufficient accuracy.ConclusionThe registration process of substances under REACH should reflect that PMT/vPvM substances pose an equivalent level of concern to PBT/vPvB substances.

Evaluating chemical similarity as a measure to identify potential substances of very high concern

Due to the large amount of chemical substances on the market, fast and reproducible screening is essential to prioritize chemicals for further evaluation according to highest concern. We here evaluate the performance of structural similarity models that are developed to identify potential substances of very high concern (SVHC) based on structural similarity to known SVHCs. These models were developed following a systematic analysis of the performance of 112 different similarity measures for varying SVHC-subgroups. The final models consist of the best combinations of fingerprint, similarity coefficient and similarity threshold, and suggested a high predictive performance (≥80%) on an internal dataset consisting of SVHC and non-SVHC substances. However, the application performance on an external dataset was not evaluated.Here, we evaluated the application performance of the developed similarity models with a ‘pseudo-external assessment’ on a set of substances (n = 60–100 for the varying SVHC-subgroups) that were putatively assessed as SVHC or non-SVHC based upon consensus scoring using expert elicitations (n = 30 experts). Expert scores were direct evaluations based on structural similarity to the most similar SVHCs according to the similarity models, and did not consider an extensive evaluation of available data. The use of expert opinions is particularly suitable as this is exactly the intended purpose of the chemical similarity models: a quick, reproducible and automated screening tool that mimics the expert judgement that is frequently applied in various screening applications. In addition, model predictions were analyzed via qualitative approaches and discussed via specific examples, to identify the model's strengths and limitations.The results indicate a good statistical performance for carcinogenic, mutagenic or reprotoxic (CMR) and endocrine disrupting (ED) substances, whereas a moderate performance was observed for (very) persistent, (very) bioaccumulative and toxic (PBT/vPvB) substances when compared to expert opinions. For the PBT/vPvB model, particularly false positive substances were identified, indicating the necessity of outcome interpretation. The developed similarity models are made available as a freely-accessible online tool.In general, the structural similarity models showed great potential for screening and prioritization purposes. The models proved to be effective in identifying groups of substances of potential concern, and could be used to identify follow-up directions for substances of potential concern.