List Of Substances Research Articles

Development of the national list of carcinogens, mutagens and reprotoxicants and its implementation in the regulation of the circulation of chemicals over the territory of the Russian Federation and member states of the Eurasian economic union

Introduction. Highly hazardous chemicals that can cause distant and specific effects in the human body and various representatives of natural biota are circulating on the market. To develop effective measures to minimize the risk of chemicals exposure and to inform the general public in the countries of the European Union, the United States and many other countries, national lists of substances that are potentially dangerous due to one or another type of effect on the body are being created. There are no lists of chemicals with reprotoxic and mutagenic effects in the Russian Federation and the Eurasian Economic Union. There is also a need to update the list of substances with carcinogenic properties. The aim of the study. Creation of lists of chemicals with reprotoxic, mutagenic and carcinogenic effects, based on a single international harmonized approach to the assessment, hazard classification and labelling of these highly hazardous substances. Materials and methods. To achieve this goal, an analysis of the information was carried out on about two thousand substances included in the regulatory legal acts of the Russian Federation and the European Union, as well as on a huge array of data from domestic and foreign sources of information, using the principles of evidence-based medicine. Results. Based on the obtained data, lists of chemicals with reprotoxic, mutagenic and carcinogenic were formed. The list of chemicals according to the danger of impact on reproductive function and development of offspring, which consists of substances classified into two classes, as well as compounds that affect through lactation. Seventy-five substances were assigned to class 1, 46 were included in the second class, and 16 substances were allocated to a separate class that influences the newborn through lactation. The list of mutagenic effects included 589 chemical substances, and due to the lack of epidemiological data, the analysis did not allow any of the substances to be attributed to hazard class 1A, 438 substances were classified to hazard class 1B, 151 substances were classified to hazard class 2. As a result of the analysis, a list of carcinogens was formed, among which 133 substances were assigned to the 1st class, and 244 were classified to the 2nd hazard class. Conclusion. These lists, to implement the Technical Regulations of the Eurasian Economic Union “On the Safety of Chemical Products” (TR EAEU 041/2017), were included in Annex No. 7 of the Procedure for Forming and Maintaining the Register of Chemicals and Mixtures of the Eurasian Economic Union, and also formed the basis for coding production and consumption waste according to these effects.

Plant-Derived Pesticides as an Alternative to Pest Management and Sustainable Agricultural Production: Prospects, Applications and Challenges.

Pests and diseases are responsible for most of the losses related to agricultural crops, either in the field or in storage. Moreover, due to indiscriminate use of synthetic pesticides over the years, several issues have come along, such as pest resistance and contamination of important planet sources, such as water, air and soil. Therefore, in order to improve efficiency of crop production and reduce food crisis in a sustainable manner, while preserving consumer’s health, plant-derived pesticides may be a green alternative to synthetic ones. They are cheap, biodegradable, ecofriendly and act by several mechanisms of action in a more specific way, suggesting that they are less of a hazard to humans and the environment. Natural plant products with bioactivity toward insects include several classes of molecules, for example: terpenes, flavonoids, alkaloids, polyphenols, cyanogenic glucosides, quinones, amides, aldehydes, thiophenes, amino acids, saccharides and polyketides (which is not an exhaustive list of insecticidal substances). In general, those compounds have important ecological activities in nature, such as: antifeedant, attractant, nematicide, fungicide, repellent, insecticide, insect growth regulator and allelopathic agents, acting as a promising source for novel pest control agents or biopesticides. However, several factors appear to limit their commercialization. In this critical review, a compilation of plant-derived metabolites, along with their corresponding toxicology and mechanisms of action, will be approached, as well as the different strategies developed in order to meet the required commercial standards through more efficient methods.

Assessment of Trametes versicolor, Isochrysis galbana, and Purple Phototrophic Bacteria for the Removal of Pharmaceutical Compounds in Hospital Wastewater

Hospitals are one of the key contributors of pharmaceutical contaminants of emerging concern to the sewer systems. Hospitals wastewaters contain concentrations of pharmaceutical compounds between 3 and 150, which are higher than urban wastewater streams. However, dedicated treatments of the hospital effluents before discharge to the sewer system are not compulsory. Besides, conventional wastewater treatment plants have not been designed to remove pharmaceutical compounds effectively, and consequently, these micropollutants can reach the aquatic ecosystems. The removal of pharmaceutical compounds in real hospital wastewater was gaged using three different microbial cultures (white rot-fungus Trametes versicolor, microalga Isochrysis galbana, and a mixed culture of non-sulfur purple phototrophic bacteria). Before and after bioassays of the hospital wastewater, environmental hazard quotients were used to evaluate the biological treatment efficiency. Up to 45 out of the 79 compounds included in the analytical method were noticed in the hospital wastewater, with a predominance of analgesics/anti-inflammatories (acetaminophen, ibuprofen, ketoprofen, and naproxen). It was followed by antibiotics (azithromycin, ciprofloxacin, and ofloxacin, out of which the first two are included in the watch list of substances for monitoring in water in 2020) and anti-hypertensive drugs. Isochrysis galbana reached a reduction of 45% of the total concentration of pharmaceuticals, whereas Trametes versicolor and mixed culture of purple phototrophic bacteria improved the reductions up to 69% and 76%, respectively. Moreover, potential environmental risk compounds (antibiotics, particularly ciprofloxacin and ofloxacin) were removed by Trametes versicolor in higher extension, obtaining a total hazard quotient reduction higher than the other two cultures. Removal efficiency and environmental risk assessment of remaining PhACs were used to evaluate the performance of the new biological systems for the treatment of emerging pollutants. According to both criteria, T. versicolor seems the most capable alternative for removing pharmaceutical compounds in hospital wastewater effluents.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Calidad del agua y niveles guía para la protección de la biodiversidad acuática. Interacción entre ciencia y gestión

Argentina has a great diversity of aquatic environments associated with the variety of climatic regions that determine unique characteristics of hydrological basins. This diversity is given by morphological conditions, physicochemical characteristics and the presence of natural and xenobiotic substances derived from anthropic activity. The toxicity of different substances on aquatic biota produces modifications in the quality of the aquatic systems. To maintain the benefits and services that the ecosystems offer, a long time effective management based on its integral management is necessary. Strategies for protection of aquatic biodiversity demand definition of guide levels (NG) for water quality. According to the environmental policy of Argentina, those who manage the water resource consider the NG of water quality as a reference framework for the definition of its aptitude in relation to their uses. The definition of NG is among the incumbencies of the hydrological national authority. With this objective, the Ministry of Environment and Sustainable Development (MAyDS) was linked with the National Scientific and Technical Research Council - Argentina (CONICET) to work in the water quality and to establish NG for the protection of aquatic biodiversity (NG-PBA). Considering the demand from the government sector, the aims of this work were: to obtain a robust methodology that allows determining NG-PBA, to establish criteria for selection and prioritization of substances, and to discuss the regional adaptation of the NG-PBA. The agreed methodology was based on the NG-PBA previously developed by the ex- Secretary of Water Resources (SSRH), updated in terms of the operative sequences, statistic method, and amount and prioritization of species. A preliminary list of substances for which establishing the corresponding NG to derivate was determined. It was recognized the interaction between scientific knowledge and management of natural resources as a synergic tool, and as superlative mechanism for the protection of aquatic biodiversity.

Occurrence and risk assessment of pesticides in a Mediterranean Basin with strong agricultural pressure (Guadiana Basin: Southern of Portugal)

The study aimed to assess the occurrence and the environmental risk of a group of 51 selected pesticides in the Guadiana Basin (a biodiversity hotspot, in the Mediterranean). The most abundant pesticides were bentazone and 2,4-D, while terbuthylazine together with terbutryn constituted the most ubiquitous pesticides. Eighteen out of the 38 pesticides detected are no longer approved in Europe, and 5 of them are included in the list of priority substances. The risk assessment showed that azinphos ethyl, diflufenican, irganol, imidacloprid, and oxadiazon occurred occasionally, but always in concentrations above their respective ecotoxicological threshold value. Contrary, bentazone, terbuthylazine, and terbutryn presented a high risk in most of the sampled locations and periods.The site-specific risk assessment showed a spatial and temporal pattern, with a higher risk occurring mainly in intermittent streams, in the drought period. The presence of pesticides banned from the EU market since 2009 showed the importance of improving the monitoring process, to identify the main sources of pollution and the fate of these emerging compounds. The results showed the need of implementing actions to improve the sustainable use of pesticides in agricultural areas, working with farmers and management entities to reduce the contamination of aquatic ecosystems. Transboundary water governance is also required to solve potential transboundary contamination problems.

Identification and classification of commercially relevant per- and poly-fluoroalkyl substances (PFAS).

Per‐ and poly‐fluoroalkyl substances (PFAS) are a universe of fluorinated organic substances with very different physical, chemical, and biological properties including polymers and non‐polymers; solids, liquids, and gases. Commercial PFAS‐based products have been used in a wide variety of industrial and consumer applications because they have unique performance properties of significant socioeconomic value. The PFAS definition has evolved and expanded over the years. Numerous lists of PFAS, some with thousands of entries, have been compiled, but none have clearly identified which of the substances are commercially relevant. This study is the first to use a bona‐fide “bottom up” approach to identify how many of the 4730 PFAS substances listed in a 2018 OECD/UNEP Report are directly connected to commercial products based on input from three major global producers. This study provides new and valuable insight into the 2018 OECD/UNEP Report list of PFAS substances. The results show that 256, less than 6%, of the 4730 PFAS substances presented in the 2018 OECD/UNEP Report are commercially relevant globally. This study suggests that grouping and categorizing PFAS using fundamental classification criteria based on composition and structure can be used to identify appropriate groups of PFAS substances for risk assessment, thereby dispelling assertions that there are too many PFAS chemistries to conduct proper regulatory risk assessments for the commercially relevant substances. Integr Environ Assess Manag 2021;17:1045–1055. © 2021 The Chemours Company, Beach Edge Consulting, LLC, AGC Chemicals Americas Inc., Daikin America Inc. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Computational study of amiloride – a WADA banned molecule

Amiloride (AMI) is a representative of diuretics. Among other purposes, it is utilized for high blood pressure or swelling induced by heart failure. While it is identified as one of the safest medicines available, it is also listed in the World Anti-doping Agency’s list of substances banned in sport, because it is considered a masking agent. Since it has been abused in sports, methods have been developed to be able to detect it during doping controls. We have computationally investigated selected structural and reactive properties of the AMI molecule in this work, employing density functional theory calculations.

Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy.

Alcohol and medication use are increasingly prevalent in the older population. Concurrent use of alcohol and alcohol-interactive (AI) medication can lead to significant adverse consequences. Three reference works were used to create an explicit list of drug substances for which information about the interaction with alcohol was available in at least one of them. Additional information was extracted from the Summary of Product Characteristics (SPC). The first aim was to generate a list of 256 substances with standardized advice regarding the concurrent use of each drug with alcohol. The second aim was to observe the prevalence of potential drug-alcohol-interactions. The list was applied to a database containing information about alcohol and medication use of 1,016 community-dwelling older patients (≥70years) with polypharmacy. About half of the sample population reported to consume alcohol at least once a week. Around 22% were classified as frequent drinkers (5-7days/week) and 11% as heavier drinkers (>7units/week). Ninety-three percent alcohol consumers in our sample took at least one chronic drug that potentially interacts with alcohol and 42% used at least one chronic drug for which alcohol use is considered contraindicated. We developed an explicit list of potentially drug-alcohol-interactions in older adults, with standardized handling advice. We observed that prevalence of potential drug-alcohol-interactions is substantial in community-dwelling older patients with polypharmacy.

Prevalence of alcohol-drug interactions in community-dwelling older patients with polypharmacy.

Alcohol and medication use are increasingly prevalent in the older population. Concurrent use of alcohol and alcohol-interactive (AI) medication can lead to significant adverse consequences. Three reference works were used to create an explicit list of drug substances for which information about the interaction with alcohol was available in at least one of them. Additional information was extracted from the Summary of Product Characteristics (SPC). The first aim was to generate a list of 256 substances with standardized advice regarding the concurrent use of each drug with alcohol. The second aim was to observe the prevalence of potential drug-alcohol-interactions. The list was applied to a database containing information about alcohol and medication use of 1,016 community-dwelling older patients (≥70years) with polypharmacy. About half of the sample population reported to consume alcohol at least once a week. Around 22% were classified as frequent drinkers (5-7days/week) and 11% as heavier drinkers (>7units/week). Ninety-three percent alcohol consumers in our sample took at least one chronic drug that potentially interacts with alcohol and 42% used at least one chronic drug for which alcohol use is considered contraindicated. We developed an explicit list of potentially drug-alcohol-interactions in older adults, with standardized handling advice. We observed that prevalence of potential drug-alcohol-interactions is substantial in community-dwelling older patients with polypharmacy.

Biological removal processes in aerobic granular sludge exposed to diclofenac

ABSTRACT Diclofenac is a worldwide consumed drug included in the watch list of substances to be monitored according to the European Union Water Framework Directive (Directive 2013/39/EU). Aerobic granular sludge sequencing batch reactors (AGS-SBR) are increasingly used for wastewater treatment but there is scant information on the fate and effect of micropollutants to nutrient removal processes. An AGS-SBR fed with synthetic wastewater containing diclofenac was bioaugmented with a diclofenac degrading bacterial strain and performance and microbial community dynamics was analysed. Chemical oxygen demand, phosphate and ammonia removal were not affected by the micropollutant at 0.03 mM (9.54 mg L–1). The AGS was able to retain the degrading strain, which was detected in the sludge throughout after augmentation. Nevertheless, besides some adsorption to the biomass, diclofenac was not degraded by the augmented sludge given the short operating cycles and even if batch degradation assays confirmed that the bioaugmented AGS was able to biodegrade the compound. The exposure to the pharmaceutical affected the microbial community of the sludge, separating the two first phases of reactor operation (acclimatization and granulation) from subsequent phases. The AGS was able to keep the bioaugmented strain and to maintain the main functions of nutrient removal even through the long exposure to the pharmaceutical, but combined strategies are needed to reduce the spread of micropollutants in the environment.

The effects of the exposure to neurotoxic elements on Italian schoolchildren behavior

Neurodevelopmental disorders are constantly increasing on a global scale. Some elements like heavy metals are known to be neurotoxic. In this cross-sectional study we assessed the neurobehavioral effect of the exposure to trace elements including lead, mercury, cadmium, manganese, arsenic and selenium and their interactions among 299 schoolchildren residing in the heavily polluted Taranto area in Italy. Whole blood, urine and hair were collected for metal analyses, while the Child Behavior Checklist and the Social Responsiveness Scale, administered to the main teacher and the mothers were considered to identify behavioral problems in children. Blood lead mainly influenced social problems, aggressive behavior, externalizing and total problems. Urinary arsenic showed an impact on anxiety and depression, somatic problems, attention problems and rule breaking behavior. A significant interaction between lead and arsenic was observed, with a synergistic effect of the two metals increasing the risk of attention problems, aggressive behavior, externalizing problems and total problems. Overall, we were able to test that higher blood lead, urinary arsenic concentrations and their interaction increase the risk of neurobehavioral problems. This is in line with the U.S. Environmental Protection Agency’s priority list of hazardous substances where arsenic and lead are ranked as first and second respectively.

Review on toxic metal ions removal by using activated carbon prepared from natural biomaterials

Heavy metals has wide range of applications including industrial, domestic, medical, agricultural and technological field. Due to industrialization and urbanization variety of heavy metal ions are released in the environment. Toxicity of heavy metal ions depends on the route of exposure, media of exposure and its dose. Some of the metals, due to its high degree of toxicity are incorporated in CERCLA (Comprehensive Environmental Response, Compensation and Liability Act) priority list of hazardous substances. According to CERCLA, arsenic is the top most toxic metal followed by lead and mercury. These metals are proven to be carcinogens for human beings even at lower concentration. Contamination of water resources by toxic metal ions is a common problem since past years. There exists different methods for removal of toxic metal ions from waste water but adsorption is the most widely used and effective method. There are several adsorbents used for adsorption of toxic metal ions but, adsorbents prepared from low-cost and ecofriendly raw materials like coconut shells, rice husk, sugarcane bagasse, banana peels, potato peels, corncob, wheat straw, neem barks, almond shells and others are capturing researcher’s attention due to its easy availability and effective removal efficiency. This review highlights low cost adsorbents used for elimination of heavy metal ions from waste water and its other usage possibilities based on the literature study. This paper also highlights emerging potential bio-adsorbents which can provide maximum removal efficiency.

Developmental Effects of Amoxicillin at Environmentally Relevant Concentration Using Zebrafish Embryotoxicity Test (ZET)

Amoxicillin (AMX) is an antibiotic that has been added to the watch list of substances by the European Union, through the Water Framework Directive (WFD; 2000/60/EC) and its daughter regulation (Decision 2018/840) for which monitoring data have to be gathered with a possibility for future regulation. Previous studies have demonstrated that this antibiotic generates toxic effects, among which oxidative stress in aquatic organisms is noteworthy. The aim of this study was to evaluate the effect on embryonic development and the teratogenic effects induced by AMX at environmentally relevant concentrations in oocytes and embryos of Danio rerio. Furthermore, oxidative stress biomarkers were evaluated at 72 and 96 hpf. The LC50 was 14.192 μgL−1, EC50 was 7.083 μgL−1, and TI was 2.003. Biomarkers of cellular oxidation and antioxidant enzymes were modified in a concentration-dependent way with respect to the control group (p<0.05). The main malformations identified were tail malformation, pericardial edema, yolk sac malformation, scoliosis, pectoral fin absence, and no hatching. The results allow us to conclude that AMX at environmentally relevant concentrations is capable of inducing embryotoxic and teratogenic effects and oxidative damage. This compound represents a risk to aquatic organisms such as Danio rerio. Not applicable.

Hemp Production Network Effects: Are Producers Tipped Toward Suboptimal Varietal Selection by Their Neighbors?

The 2018 farm bill removed industrial hemp from the Schedule 1 Controlled Substance List. In response, states scrambled to enact hemp legislation. Some hemp flower producers report their hemp fields were cross- pollinated by a neighbor growing a different hemp cultivar. For hemp flower crops, cross- pollination reduces cannabinoid concentration levels within the flower; these concentration levels dictate flower price. We show that in a repeated game, once a sufficiently large percentage of growers decide to plant hemp fiber/seed crops, cross-pollination forces flower growers to convert to fiber/seed to avoid the negative network externality. Over time, a stable, suboptimal Nash equilibrium of reduced flower production results. The most important factor driving this tip to reduced flower production is pollen transmission rates between fields. This factor can be effectively reduced through either an auction-style quota system directed at seed and fiber cultivars or intertemporal zoning laws that dictate when a particular cultivar can be planted. As applications for hemp growing licenses swell, cross- pollination between farmers becomes increasingly likely. If left unchecked by policy, farm-level income and rural economic development will be suppressed.

The Challenges of 21st Century Neurotoxicology: The Case of Neurotoxicology Applied to Nanomaterials.

After a short background discussing engineered nanomaterials (ENMs) and their physicochemical properties and applications, the present perspective paper highlights the main specific points that need to be considered when examining the question of neurotoxicity of nanomaterials. It underlines the necessity to integrate parameters, specific tools, and tests from multiple sources that make neurotoxicology when applied to nanomaterials particularly complex. Bringing together the knowledge of multiple disciplines e.g., nanotoxicology to neurotoxicology, is necessary to build integrated neurotoxicology for the third decade of the 21st Century. This article focuses on the greatest challenges and opportunities offered by this specific field. It highlights the scientific, methodological, political, regulatory, and educational issues. Scientific and methodological challenges include the determination of ENMs physicochemical parameters, the lack of information about protein corona modes of action, target organs, and cells and dose– response functions of ENMs. The need of standardization of data collection and harmonization of dedicated neurotoxicological protocols are also addressed. This article highlights how to address those challenges through innovative methods and tools, and our work also ventures to sketch the first list of substances that should be urgently prioritized for human modern neurotoxicology. Finally, political support with dedicated funding at the national and international levels must also be used to engage the communities concerned to set up dedicated educational program on this novel field.

Inter- and Transgenerational Effects of Paternal Exposure to Inorganic Arsenic.

The rise of metabolic disorders in modern times is mainly attributed to the environment. However, heritable effects of environmental chemicals on mammalian offsprings' metabolic health are unclear. Inorganic arsenic (iAs) is the top chemical on the Agency for Toxic Substances and Disease Registry priority list of hazardous substances. Here, we assess cross‐generational effects of iAs in an exclusive male‐lineage transmission paradigm. The exposure of male mice to 250 ppb iAs causes glucose intolerance and hepatic insulin resistance in F1 females, but not males, without affecting body weight. Hepatic expression of glucose metabolic genes, glucose output, and insulin signaling are disrupted in F1 females. Inhibition of the glucose 6‐phosphatase complex masks the intergenerational effect of iAs, demonstrating a causative role of hepatic glucose production. F2 offspring from grandpaternal iAs exposure show temporary growth retardation at an early age, which diminishes in adults. However, reduced adiposity persists into middle age and is associated with altered gut microbiome and increased brown adipose thermogenesis. In contrast, F3 offspring of the male‐lineage iAs exposure show increased adiposity, especially on a high‐calorie diet. These findings have unveiled sex‐ and generation‐specific heritable effects of iAs on metabolic physiology, which has broad implications in understanding gene‐environment interactions.

High pressure assisted extraction for cadmium decontamination of long rice grain

Cadmium (Cd) ranks seventh in the World Health Organization (WHO) priority list of hazardous toxic substances. In this study, a high-pressure extraction (HPE) method was explored for Cd decontamination in rice, and the process was compared with the traditional washing method. Optimal extraction conditions were achieved with experimental constraints. For washing, the Cd removal efficiency was 66% for intact rice grain and almost 100% for rice flour but only after washing for 20 h at pH 3.0; For HPE, a 600 MPa-10 min treatment at pH 5.5 yielded an extraction efficiency of 43% for rice grain and 82% for rice flour. No major changes in rice quality were observed after the HPE decontamination process. The Cd removal efficiency was further enhanced by multiple HPE cycles, almost reaching the 100% level. The HPE method has several attributes, including efficiency, preservation of rice quality and capability to remove Cd from rice grain and rice flour. This is the first study on HPE decontamination of Cd from rice.

Complexing ability of organic compounds and their influence on the human body (review)

Introduction. Increased content of organic substances in natural waters, expanding the list of input substances to water bodies, owing to industrial and economic activities of a person, and climate changes is an urgent issue. Against this background, compounds with unknown chemical and toxic properties are likely to appear. The purpose of this study is to collect data concerning the ways for organic compounds entering water bodies and the human body, study data on interaction mechanisms of organic substances with metals, reveal the fate of known organic chelators, complexing agents as well as organometallic compound shaped by them inside the body. The literature search was carried out in Scopus, Web of Science, CyberLeninka databases. Sources of organic substances entering water bodies, properties of organic substances. There are three types of organic substances in water bodies, divided by the sources of their occurrence (inflow): terrigenous origin, shaped inside water bodies and coming from man-made sources. Organic compounds may produce soluble and insoluble compounds with metals and colloids. Mechanisms of interaction of organic substances with metals. Bonding of organic substances takes place by the type of chelation and complexation. There are factors for bonding: functional group content, the molecular mass of substances, ion radius, and competitive interaction with binding sites. Substances having binding properties include phenolic compounds, carboxylic acids, polysaccharides, and flavonoids. Considering that phenolic compounds are located in large quantities in plant and animal tissues, this group of compounds has been researched more thoroughly in terms of interactions with metals and toxicometry. Intake of organic and organometallic compounds into the body, their kinetics, metabolism and decay. Organic compounds, chelates, and complexes enter the body with drinking water, food, and drugs. They are also generated in the body, including by replacing ions. Data on biochemical and toxicological studies of currently known compounds is given

The Slow Decrease of Active Substance Candidates for Substitution in the Framework of the European Pesticide Regulation (EC) No 1107/2009

The specific status of active substance candidates for substitution (CfS) is detailed by Article 24 of plant protection Commission Regulation EC No 1107/2009 (PPP Regulation). The criteria of candidates for substitution are now clearly defined: low acceptable daily intake/acute reference dose/acceptable operator exposure level or two persistent, bio-accumulative or toxic criteria, or by nature of the critical effects: non-active isomers, carcinogen 1A/1B, toxic for reproduction 1A/1B or endocrine disruption properties, with these later properties now being well characterised. The total number of active substances CfS has been in constant evolution since 2011, with the first batch of candidates for substitution being published in 2015 and updated since then. After a slow decrease, growth is again observed, with another list of active substances being granted this status. CfS are substances targeted by the PPP Regulation that are supposed to be cancelled or non-renewed at the active substance level or substituted at the market authorisation level. CfS are also supposed to be replaced by substances with better toxicological profiles. However, after five years of implementation of the status, their number, which is intended to decrease, remains high, at sixty residual CfS. We exhibit here their evolution.