Benzotriazole UV stabilizers disrupt epidermal growth factor receptor signaling in human cells.

Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs.

Insights into the effect of benzotriazoles in liver using integrated metabolomic and transcriptomic analysis.

Benzotriazoles (BTRs) are a class of benzoheterocyclic chemicals that are frequently used as metal-corrosive inhibitors, both in industry and daily use. However, the exposure effect information on BTRs remains relatively limited. In this study, an integrated metabolomic and transcriptomic approach was utilized to evaluate the effect of three BTRs, benzotriazole, 6-chloro-1-hydroxi-benzotriazole, and 1-hydroxy-benzotriazole, in the mouse liver with results showing disrupted basal metabolic processes and vitamin and cofactor metabolism after 28 days. The expression of several genes that are related to the inflammatory response and aryl hydrocarbon receptor pathways, such as Gstt2 and Arntl, was altered by the exposure to BTRs. Exposure to BTRs also affected metabolites and genes that are involved in the immune system and xenobiotic responses. The altered expression of several cytochrome P450 family genes reveal a potential detoxification mechanism in the mouse liver. Taken together, our findings provide new insights into the multilayer response of the mouse liver to BTRs exposure as well as a resource for further exploration of the molecular mechanisms by which the response occurs.

N-(2-Aminobenzoyl)benzotriazole Mediated Synthesis of 3-Acyl-2-alkyl(aryl)-4-hydroxyquinolines and 3-Acylamino-4(3H) quinazolinones.

New methods have been developed for the synthesis of the substituted quinolines and quinazolinones derivatives by utilizing N-(2-aminobenzoyl)benzotriazoles under mild reaction conditions. 3-Acyl-2-alkyl(aryl)-4-hydroxyquinolines were obtained in modarete yields by the reaction of N-(2-aminobenzoyl)benzotriazoles and diketones in the presence of tert-BuOK. 3-Acylamino-4(3H) quinazolinones were obtained in good yields via N-(2-aminobenzoyl)benzotriazoles, orthoester and hyrazides in one-pot.

Spatiotemporal variation, partitioning, and ecological risk assessment of benzothiazoles, benzotriazoles, and benzotriazole UV absorbers in the Yangtze River Estuary and its adjacent area.

The distributions and toxicities of the pollutants benzothiazoles (BTHs), benzotriazoles (BTRs), and benzotriazole ultraviolet stabilizers (BUVs) have attracted much attention, but most research has focused on freshwater environments and few have examined their levels in marine environments. This study, for the first time, investigated the spatial and temporal variability and ecological risks of BTHs, BTRs and BUVs in the Yangtze River estuary and its adjacent area, and further elucidated how environmental factors influence the transport of these contaminants. The concentrations of BTHs, BTRs, and BUVs in seawater showed significant seasonal variability, with the highest concentrations in summer, followed by autumn, and then winter-spring. The spatiotemporal variability in BTHs, BTRs and BUVs in the seawater and sediments samples showed decreasing trends from nearshore to offshore, reflecting the influence of river discharge. Marine debris and continuous discharge from cities were responsible for the high detection frequency of these contaminants in the YRE and its adjacent area. Furthermore, the moderate risk from the presence of BTHs, BTRs, and BUVs as they accumulate in sediments should not be ignored. Our study provides new insights into the fate and ecological risk of BTHs, BTRs, and BUVs in the estuary.

Benzotriazole UV stabilizers (BUVs) as an emerging contaminant of concern: a review.

Benzotriazole UV stabilizers (BUVs) are a group of industrial chemicals used in various consumer products and industrial applications. Due to its large-scale production and use, BUVs have been detected in all environmental matrices. Humans are exposed to BUVs from environmental media, food, personal care products (PCPs), and consumer products. As a result, BUVs are detected in human breast milk, attracting researchers and regulatory bodies worldwide. BUVs such as UV-328 exhibit the characteristics of persistent organic pollutants (POPs); hence, it has been recently listed under Stockholm Convention POP list. The current review focuses on the occurrence of BUVs in the environment with emphasis on persistency, bioaccumulation, and toxicity (PBT). Scarcity of scientific data on BUVs' properties, environmental occurrence, exposure levels, and effects on organisms poses significant challenges to the policymakers and regulatory bodies in adopting management strategies. The need for a science-based integrated framework for risk assessment and management of BUVs is recommended. Considering the potential threat of BUVs to human health and the environment, it is recommended that BUVs should be taken as a subject of priority research. Studies on the degradation and transformation route of BUVs need to be explored for the sound management of BUVs.

Removal of benzotriazole micropollutants using Spirodela polyrhiza (L.) Schleid. And Azolla caroliniana Willd.

Phytoremediation of benzotriazoles (BTR) from waters by floating macrophytes is not well understood, but it seems to have the potential to be used in conjunction with conventional wastewater treatment plants. The effectiveness of removing four compounds from the benzotriazole group by floating plants Spirodela polyrhiza (L.) Schleid. And Azolla caroliniana Willd. From the model solution, was studied. The observed decrease in the concentration of studied compounds was in the range 70.5%-94.5% using S. polyrhiza, and from 88.3% to 96.2% for A. caroliniana. It was determined using chemometric methods that the effectiveness of the phytoremediation process is mainly influenced by three parameters: exposure time to light, pH of the model solution and the mass of plants. Using the design of experiments (DoE) chemometric approach, the optimal conditions for removing BTR were selected: plant weight 2.5 g and 2 g, light exposure 16 h and 10 h, and pH 9 and pH 5 for S. polyrhiza and A. caroliniana, respectively. Studies on the mechanisms of BTR removal have shown that the reduction in concentration is mainly due to the process of plant uptake. Toxicity studies have proved that the tested BTR affected the growth of S. polyrhiza and A. caroliniana and induced changes in the levels of chlorophyllides, chlorophylls as well as carotenoids. More dramatic loss in plant biomass and photosynthetic pigment contents was observed in A. caroliniana cultures exposed to BTR.

Assessment of the bioaccumulation potential of four commonly used phenolic benzotriazoles based on in silico and experimental in vivo data.

Phenolic benzotriazoles (BTZs) are used globally as light stabilizers in various plastic products to protect them from photooxidative degradation. The same physical-chemical properties that confer their functionality, like a sufficient photostability and a high octanol-water partition coefficient, also raise concerns on their potential for environmental persistence and bioaccumulation based on in silico predictive tools. To evaluate their bioaccumulation potential in aquatic organisms, standardized fish bioaccumulation studies according to OECD TG 305 were conducted with four of the most commonly used BTZs: UV 234, UV 329, UV P, and UV 326. The resulting growth- and lipid-corrected BCF values revealed that UV 234, UV 329, and UV P were below the bioaccumulation threshold (BCF ≤ 2000), but UV 326 is considered very bioaccumulative (BCF ≥ 5000) with respect to the bioaccumulation criteria under REACH. Comparing these experimentally derived data with quantitative structure activity related or other calculated values using a logarithmic partitioning coefficient octanol-water (log Pow ) driven mathematical formula revealed significant discrepancies demonstrating the weakness of current in silico approaches for this group of substances. Furthermore, available environmental monitoring data demonstrate that these rudimentary in silico approaches can lead to unreliable bioaccumulation estimates for this chemical class due to considerable uncertainties in underlying assumptions (e.g., concentration and route of exposure). However, using more sophisticated in silico methods (i.e., CATALOGIC base-line model), the derived BCF values were better aligned with the experimentally derived ones.

Assessment of benzothiazoles, benzotriazoles and benzenesulfonamides in environmental waters using an optimized combination of microextraction by packed sorbent with programmed temperature vaporization-gas chromatography tandem-mass spectrometry.

This work proposes a new method for the quantification of benzothiazoles (BTs), benzotriazoles (BTRs), and benzenesulfonamides (BSAs) in tap water, river water, and wastewater. The protocol involved the use of microextraction by packed sorbent (MEPS), applied for the first time for the extraction of the target analytes, combined with programmed temperature vaporization-gas chromatography-triple quadrupole mass spectrometry (PTV-GC-QqQ-MS). Considering the synergism between MEPS extraction and PTV injection, the experimental variables affecting their performance were simultaneously optimized by "experimental design", while principal component analysis (PCA) was used to find the overall optimal working conditions. Response surface methodology was used to gain a comprehensive understanding of the effects of working variables on method performance. The developed method achieved very good linearities and satisfactory intra- and inter-day accuracies and precisions. The protocol permitted the detection of the target molecules with limit of detection (LODs) values between 0.005 and 0.85 µg/L. The green character of the procedure was evaluated using three metrics: "Analytical Eco-Scale", "Green Analytical Procedure Index" (GAPI), and "Analytical Greenness metric for sample preparation (AGREEprep). The satisfactory results obtained with real water samples demonstrate the applicability of the method for monitoring campaigns and exposome studies.

Reduced Graphene Oxide Aerogels Cartridges for Solid Phase Extraction of Benzotriazoles.

UV-benzotriazoles have been identified as water micropollutants that cause serious problems for human health and the environment. Their low concentration in water bodies complicates their detection by direct water analysis, slowing the corrective actions to avoid bioaccumulation. In this regard, the use of graphene-based materials with a high affinity for non-polar molecules has been demonstrated to be a potential tool for the optimal separation and concentration of this type of molecules in solid phase extraction (SPE) processes. This work evaluates the potential of novel reduced graphene oxide aerogels (rGO) as extractants of mixtures of three UV-benzotriazoles in water at low concentrations. These rGO aerogels incorporate graphenic domains into a tough structure of polymeric chains by adding graphene oxide during the synthesis of resorcinol-formaldehyde gels. Aerogels with a different content and ordering of graphenic domains were obtained and characterized using Raman, XRD, SEM and nitrogen adsorption isotherms (-196 °C). The rGO aerogels that performed better as solid phase extractants were those containing 60% rGO. Aerogels with lower rGO contents (40%) required a high-temperature (2000 °C) treatment to render competitive results. The SPE methodology using selected rGO aerogels was optimized by varying the elution solvent, elution time and volume. The best performances, i.e., recoveries of 80-100% and enrichment factors of 12.5-50, were accomplished when using 0.8 mL of tetrahydrofuran (THF) as an elution solvent. As a result, a fast (10 min) and simple extraction method of UV-benzotriazoles in water was attained, achieving a detection limit of 1 ng mL-1. Selected aerogels were finally tested for the SPE of spiked samples of river waters, showing a similar performance to that observed with synthetic mixtures.

Design, Synthesis, and Antiviral Activities of New Benzotriazole-Based Derivatives.

Several human diseases are caused by enteroviruses and are currently clinically untreatable, pushing the research to identify new antivirals. A notable number of benzo[d][1,2,3]triazol-1(2)-yl derivatives were designed, synthesized, and in vitro evaluated for cytotoxicity and antiviral activity against a wide spectrum of RNA positive- and negative-sense viruses. Five of them (11b, 18e, 41a, 43a, 99b) emerged for their selective antiviral activity against Coxsackievirus B5, a human enteroviruses member among the Picornaviridae family. The EC50 values ranged between 6 and 18.5 µM. Among all derivatives, compounds 18e and 43a were interestingly active against CVB5 and were selected to better define the safety profile on cell monolayers by transepithelial resistance test (TEER). Results indicated compound 18e as the hit compound to investigate the potential mechanism of action by apoptosis assay, virucidal activity test, and the time of addition assay. CVB5 is known to be cytotoxic by inducing apoptosis in infected cells; in this study, compound 18e was proved to protect cells from viral infection. Notably, cells were mostly protected when pre-treated with derivative 18e, which had, however, no virucidal activity. From the performed biological assays, compound 18e turned out to be non-cytotoxic as well as cell protective against CVB5 infection, with a mechanism of action ascribable to an interaction on the early phase of infection, by hijacking the viral attachment process.

Mechanistic insight into the degradation of 1H-benzotriazole and 4-methyl-1H-benzotriazole by •OH-based advanced oxidation process and toxicity assessment.

Benzotriazoles (BTs) are highly produced chemicals that are commonly used in the manufacture of aircraft de-icing/antifreeze fluids (ADAFs), coolants, etc. BTs have been detected in a variety of water environments, causing health hazards to aquatic species and humans. In this study, 1H-benzotriazole (BTri) and 4-methyl-1H-benzotriazole (4-TTri) were selected to investigate their degradation mechanisms in the aqueous phase initiated by ·OH using a theoretical calculation method. Addition reactions are the main type of reactions of ·OH with BTri and 4-TTri. The total rate constants for the reactions of BTri and 4-TTri with ·OH at 298 K are 8.26 × 109 M-1 s-1 and 1.81 × 1010 M-1 s-1, respectively. The reaction rate constants increase as the temperature rises, indicating that rising temperatures promote the degradation of BTri and 4-TTri. 7-hydroxy-1H-benzotriazole (1-P1) and 4-hydroxy-benzotriazoles (1-P2) produced via multiple reaction pathways are important transformation products of BTri. After successive reactions with ·OH, 1-P1 and 1-P2 can be successively converted to 4,7-dihydroxy-1H-benzotriazole (1-P7), 4,7-dione-1H-benzotriazole (1-P8), and 1,2,3-triazole-4,5-dicarboxylic acid (1-P9), which is consistent with the product compositions detected in the experiments. The toxicity assessment indicated that the acute toxicity and chronic toxicity of the resulting transformation products are significantly reduced compared to BTri as the degradation process progressed, and ultimately showed no harm to all three aquatic organisms (fish, daphnia, and green algae). Hence, advanced oxidation processes (AOPs) can not only effectively remove BTs from water, but also reduce their toxic effects on aquatic organisms.

Determination of benzothiazoles, benzotriazoles and benzenesulfonamides in seafood using quick, easy, cheap, effective, rugged and safe extraction followed by gas chromatography - tandem mass spectrometry: Method development and risk assessment.

The common use of benzothiazoles, benzotriazoles and benzenesulfonamides has led to widespread ubiquity in several environmental matrices. Their occurrence in edible fish could represent an additional exposure route for the population. The present study aims to develop a method for the simultaneous determination of these three compound families in seafood samples. Based on QuEChERS extraction, different salt combinations and clean-up strategies have been evaluated to achieve the highest recoveries while reducing the matrix effect in low and high lipidic content species. The best results were obtained with the original method salts and the lipid-selective push-through clean-up, which combined with gas chromatography-tandem mass spectrometry led to recoveries between 50 and 112% with negligible matrix effects and method detection limits between 0.15-9.50 ng g-1 dw. The application of the method to commercially available samples confirmed the presence of BTs as well as BSAs, with the latter being determined in seafood for the first time. Exposure and risk assessment calculations indicated a minor risk for the population when consuming fish.

Mechanisms, toxicity and optimal conditions - research on the removal of benzotriazoles from water using Wolffia arrhiza.

In the presented work, phytoremediation with the use of floating plant Wolffia arrhiza (L.) Horkel ex Wimm. was proposed as a method of removing the selected benzotriazoles (BTRs): 1H-benzotriazole (1H-BTR), 4-methyl-1H-benzotriazole (4M-BTR), 5-methyl-1H-benzotriazole (5M-BTR) and 5-chlorobenzotriazole (5Cl-BTR) from water. The efficiency of phytoremediation depends on three factors: daily time of exposure to light, pH of the model solution, and the amount of plans. Using a design of experiment (DoE) methods the following optimal values were selected: plant amount 1.8 g, light exposure 13 h and pH 7 per 100 mL of the model solution. It was found that the loss of BTRs in optimal conditions ranged from 92 to 100 % except for 4M-BTR, for which only 23 % of removal was achieved after 14 days of cultivation of W. arrhiza. The half-life values for studied compounds ranged from 0.98 days for 5Cl-BTR to 36.19 for 4M-BTR. The observed rapid vanishing of 5M-BTR is supposed by the simultaneous transformation of 5M-BTR into 4M-BTR. The detailed study of BTRs degradation pointed that the plant uptake is mainly responsible for the benzotriazoles concentration decrease. Toxicity tests showed that the tested organic compounds induce oxidative stress in W. arrhiza, which manifested among others, in reduced levels of chlorophyll in cultures with benzotriazoles compared to control.

Associations of benzotriazoles and benzothiazoles with estrogens and androgens among pregnant women: A cohort study with repeated measurements.

People are extensively exposed to benzotriazoles (BTRs) and benzothiazoles (BTHs) derivatives, which are environmental pollutants that may possess endocrine-disrupting potential; however, no epidemiological evidence is available on the associations of BTRs and BTHs with estrogens and androgens. This study aimed at investigating the associations of BTRs and BTHs with estrogens and androgens among pregnant women. Based on a prospective cohort study, we included 459 pregnant women who donated a complete serial of urine samples at each trimester and had repeated measurements of four BTRs, four BTHs, three estrogens (estrone, 17ß-estradiol, and estrio), and two androgens (dehydroepiandrosterone and testosterone) in the urine samples. Associations of repeatedly measured BTRs and BTHs with maternal urinary estrogens and androgens were analyzed, and the cross-sectional associations were also analyzed. Tolyltriazole (TTR) (≥59.3%) and benzothiazole (BTH) (≥93.5%) had the highest detection rate among the BTRs and BTHs, respectively. Repeated measurement analysis and cross-sectional analysis consistently found the target BTRs and BTHs were positively associated with 17ß-estradiol, estriol, and testosterone, while the trend of the associations with estrone and dehydroepiandrosterone was inconsistent. Among the positive associations with 17ß-estradiol, estriol, and testosterone, the percent of change in estriol associated with TTR was the most prominent [28.5% (95% confidential interval: 24.2%, 32.9%) for each doubling in TTR]. The significant associations with estrone, estriol, testosterone, and dehydroepiandrosterone were stronger among pregnant women who gave birth to a boy than those who gave birth to a girl. These findings add epidemiological evidence on the endocrine-disrupting potential of BTRs and BTHs and highlight the importance of focusing on the health outcomes of BTRs and BTHs related to disturbed estrogens and androgens. Future studies are needed to validate these findings and explore the underlying mechanisms.

Exploring the adsorption behavior of benzotriazoles and benzothiazoles on polyvinyl chloride microplastics in the water environment.

As a kind of emerging pollutant, microplastics (MPs) play an important role as a carrier for pollutant migration in the water environment. Carried by the MPs, benzotriazoles, and benzothiazoles (collectively referred to as BTs)1 are ubiquitous water contaminants. In this paper, the adsorption behavior of BTs on polyvinyl chloride (PVC) MPs was first studied systematically to explain the adsorptive mechanisms and the consequential pollution caused by the absorption-desorption process. The studies on kinetics, isotherms, and thermodynamics revealed that the adsorption of BTs on PVC MPs was a multi-rate, heterogeneous multi-layer, and exothermic process, which was affected by external diffusion, intra-particle diffusion, and dynamic equilibrium. The factors including pH, salinity, and particle size also influenced the adsorption process. In the multi-solute system, competitive adsorption would occur between different BTs. The desorption of BTs from PVC MPs was positively associated with the increase of adsorption amount. Based on the results, the adsorption mechanisms of PVC MPs were clarified, involving hydrophobic interaction, electrostatic force, and non-covalent bonds. It was demonstrated that BTs in the water environment could most probably be accumulated and migrated through MPs, and eventually carried into organisms, posing an increased risk to the ecological environment.

Equilibrium leaching of selected ultraviolet stabilizers from plastic products.

Despite the importance of (micro)plastics in the release of plastic additives, the leaching mechanism of organic plastic additives from various plastic materials is poorly understood. In this study, the equilibrium leaching of five highly hydrophobic ultraviolet (UV) stabilizers (UV326, UV327, UV328, UV329, and UV531) from three plastics (low-density polyethylene (LDPE), polyethylene terephthalate (PET), and polystyrene (PS)), was investigated employing acetonitrile-water cosolvent systems. Their extrapolated water solubilities were in the 0.15-0.54 µg L-1 range, limiting their transport as "dissolved" in water and (micro)plastics are likely those particulate carriers. The equilibrium leaching of UV stabilizers from plastics was better explained by the Flory-Huggins model incorporating the nonideal behavior caused by the size disparity between UV stabilizers and polymer materials and their compatibility. Specifically, leaching of UV stabilizers from LDPE showed a positive deviation from Raoult's law, whereas slight negative deviations were observed in PET and PS. In addition, the equilibrium concentration of the benzotriazoles in LDPE increased linearly with the volume fraction up to only 0.4%. These observations could be explained by the unfavorable interactions of UV stabilizers with polyethylene, indicating that polymer type should be also important when evaluating the fate of hydrophobic additives. Because equilibrium distribution of additives between (micro)plastics and water is crucial for evaluating the fate and transport of hydrophobic plastic additives, further studies on the leaching equilibrium of various additives from different plastic materials are necessary.

Benzotriazole concentrations in airport runoff are reduced following changes in airport deicer formulations.

A comparison of the presence of additives in airport deicers commonly used in the United States and in airport runoff was conducted with data collected before and after changes in deicer formulations. Three isomers of benzotriazoles (BTs)-4-methyl-1H-benzotriazole (4-MeBT), 5-methyl-1H-benzotriazole (5-MeBT), and 1H-benzotriazole (1H-BT)-are corrosion inhibitors added to some formulations of airport deicers and are reported to be a source of aquatic toxicity in streams receiving airport runoff. Concentrations of BT in aircraft deicers and anti-icing fluids (ADAF) were reduced over time but were not reduced in potassium acetate airfield-pavement deicer material (PDM) that was used throughout the study period. Streams receiving runoff from Milwaukee Mitchell International Airport, Milwaukee, Wisconsin, USA, were monitored from 2004 to 2019 for BTs, with concentrations of 4-MeBT varying from <0.35 to 4600 µg/L, 5-MeBT varying from <0.25 to 6600 µg/L, and 1H-BT varying from <0.25 to 150 µg/L. Median 4-MeBT concentrations at sites downstream from the airport decreased by approximately 74%, 5-MeBT by 69%, and 1H-BT by 82% following reduction in BTs in ADAF formulations, resulting in a reduction in the potential for aquatic toxicity in receiving streams. A change in residuals from regression analysis between freezing point depressants and BTs indicate that the reduction in BT concentrations in airport runoff was a result of BT reduction in ADAF formulations, but PDM may still be a substantial source of BTs in airport runoff. Because BTs are a source of aquatic toxicity in airport deicers, the reductions in BTs in the common deicers observed in this study can be used to demonstrate the potential for a reduction in the effects to aquatic organisms in airport runoff, resulting in greater likelihood of meeting aquatic toxicity requirements in airport stormwater permits, and potentially driving airports, airlines, and permit holders to advocate further reduction or elimination of BTs and other harmful contaminants in airport deicers. Integr Environ Assess Manag 2022;18:245-257. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Determination of contaminants of emerging concern and their transformation products in treated-wastewater irrigated soil and corn.

In many parts of the world, clean water has become increasingly scarce. Irrigation of agricultural land with treated wastewater is commonly used in response to water shortages but there is concern about the environmental fate and transport of contaminants present in the irrigation wastewater. This study aimed to examine the presence of wastewater sourced contaminants in soil and field grown corn (Zea mays) crops spray irrigated with treated wastewater. Soil, corn grain, leaves, and roots were sampled and tested from a long-term wastewater irrigation site as well as a non-irrigated control site in close geographic proximity. Samples were analyzed using comprehensive two-dimensional gas chromatography coupled to time of flight mass spectrometry (GC × GC-TOFMS) and both targeted and non-targeted analyses were conducted to determine chemical differences between the wastewater irrigated and control samples. Target compounds detected and quantified in the samples include herbicides, phthalates, and polycyclic aromatic hydrocarbons. Non-targeted analysis showed chemical differences between each the wastewater irrigated and control samples. Furthermore, new chloro-dimethyl-benzotriazole compounds, which are suspected to be transformation products created by the chlorine disinfection process of the wastewater treatment plant, were tentatively identified in the wastewater effluent. Twenty of these new benzotriazoles were detected and semi-quantified in the wastewater irrigated soil samples at a maximum concentration of 472 ng/g. Eight of the most abundant benzotriazoles were also detected in the corn roots at concentrations up to 56 ng/g.

A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs).

Microtubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 µM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 µM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, ß-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine-9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules.

Phenolic benzotriazoles: a class comparison of toxicokinetics of ultraviolet-light absorbers in male rats.

Phenolic benzotriazoles are ultraviolet-light absorbers used in a variety of industrial and consumer applications. We investigated the toxicokinetic behaviour of 9 compounds, covering unsubstituted, monosubstituted, disubstituted, and trisubstituted compounds, following a single gavage (30 and 300 mg/kg) and intravenous (IV) (2.25 mg/kg) administration in male rats.Following IV administration, no distinct pattern in plasma elimination was observed for the compounds with half-lives ranging from 15.4-84.8 h. Systemic exposure parameters, maximum concentration (Cmax) and area under the concentration time curve (AUC), generally increased with the degree of substitution.Following gavage administration, Cmax and AUC of unsubstituted compound were lower compared to the substituted compounds. Cmax and AUC increased ≤7-fold with a 10-fold increase in the dose except for the AUC of the unsubstituted compound where the increase was 30-fold. Plasma elimination half-lives for the class ranged from 1.57 to 192 h with the exception of 30 mg/kg drometrizole.Oral bioavailability was low with ∼ 6% estimated for unsubstituted compound and 12.8-23% for others at 30 mg/kg dose. Bioavailability was lower following administration of the higher dose.Taken collectively, these data point to low oral absorption of phenolic benzotriazoles. The absorption decreased with increasing dose. Substituted compounds may be less metabolized compared to the unsubstituted.