Determination and risk assessment of UV filters and benzotriazole UV stabilizers in wastewater from a wastewater treatment plant in Lüneburg, Germany.

UV filters and benzotriazole UV stabilizers are considered emerging contaminants in the environment. LC-MS/MS and GC-MS methods, involving a single solid phase extraction protocol, were developed and validated to determine eight UV filters and seven UV stabilizers, respectively in wastewater from a wastewater treatment plant (WWTP) in Lüneburg, Germany. The LC-MS/MS method exhibited extraction recoveries of ≥ 71% at six different fortification levels with limits of detection (LODs) range of 0.02 ng mL-1 - 0.09 ng mL-1. Extraction recoveries of 47 to 119% at six different fortification levels were obtained for the GC-MS method with LODs range of 0.01 - 0.09 ng mL-1. Among the UV filters, the highest mean concentration was determined for octocrylene (OCR) in influent (3.49 ng mL-1) while the highest mean concentration was measured for 2-hydroxy-4-octyloxybenzophenone (UV 531) in influent (0.44 ng mL-1) among the UV stabilizers. Potential risk to aquatic organisms was assessed by the risk quotient approach. Only OCR presented a high risk to aquatic invertebrates whereas 2-ethylhexyl 4-methoxycinnamate (EHMC) and 2-ethylhexyl salicylate (EHS) posed high risks to algae. Benzotriazole UV stabilizers presented negligible risks to aquatic invertebrates and fish. This work reports the detection of rarely studied 4-aminobenzoic acid (PABA) and UV 531 in WWTP influent and effluent. The occurrence and risk assessment of target benzotriazole UV stabilizers in wastewater from a German WWTP was demonstrated for the first time.

Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development.

Biodegradation of flavonoids - Influences of structural features.

Flavonoids, a class of natural products with a variety of applications in nutrition, pharmacy and as biopesticides, could substitute more harmful synthetic chemicals that persist in the environment. To gain a better understanding of the biodegradability of flavonoids and the influence of structural features, firstly, the ultimate biodegradation of 19 flavonoids was investigated with the Closed Bottle Test according to the OECD guideline 301 D. Secondly, regarding the fast abiotic degradation reported for several flavonoids with severe concentration decrease within hours and its possible impacts on the processes behind the ultimate biodegradation, primary degradation of 4 selected flavonoids was compared at conditions representing biodegradation, abiotic degradation, and mixed substrates by monitoring the flavonoids' concentrations with HPLC-UV/vis. Our results showed that 17 out of the 19 tested flavonoids were readily biodegradable. Structural features like a hydroxy group at C3, the C2-C3 bond order, a methoxy group in the B ring, and the position of the B ring in regard to the chromene core did not affect biodegradation of the tested flavonoids. Only flavone without any hydroxy groups and morin with an uncommon 2',4' pattern of hydroxy groups were non-readily biodegradable. Monitoring the concentration of 4 selected flavonoids by HPLC-UV/vis revealed that biodegradation occurred faster than abiotic degradation at CBT conditions with no other carbon sources present. The presence of an alternative carbon source tends to increase lag phases and decrease biodegradation rates. At this condition, abiotic degradation contributed to the degradation of unstable flavonoids. Overall, as a first tier to assess the environmental fate, our results indicate low risks for persistence of most flavonoids. Thus, flavonoids could represent benign substitutes for persistent synthetic chemicals.

Analysis of environmental biodegradability of cellulose-based pharmaceutical excipients in aqueous media.

Pharmaceutical cellulosic polymers will inevitably reach natural water systems if they are not removed after entering wastewater. Biodegradation of organic chemicals in sewage or in the aquatic environment is an important removal mechanism. In this study, we investigated the environmental biodegradation of 14 cellulose derivatives commonly utilized as pharmaceutical excipients using three different test systems that are based on the closed bottle test (OECD 301D) and the manometric respirometry test (OECD 301F). For the different cellulose derivatives tested, we observed varying degrees of biodegradation ranging from 0 to 20.4 % chemical oxygen demand (COD). However, none met the criteria for classification as 'readily biodegradable'. In addition, 10 out of 14 cellulose derivatives and/or their possible transformation products formed during the experiments, may exhibit possible toxic inhibitory effects on the inoculum. This includes one or several derivatives of hydroxy propyl methyl cellulose, hydroxy propyl cellulose, methyl cellulose, ethyl cellulose, and hydroxy ethyl cellulose. Based on the results obtained, we have developed a graded classification score ('traffic light system') for excipient biodegradation. This could help streamline the assessment and classification of cellulose derivatives concerning risk of persistence and potential adverse environmental effects, thereby assisting in the prioritization of more favorable compounds. In the long term, however, excipients should be designed from the very beginning to be biodegradable and mineralizable in the environment ('benign by design').

How data on transformation products can support the redesign of sulfonamides towards better biodegradability in the environment.

Sulfonamide antibiotics (SUAs) released into the environment can affect environmental und human health, e.g., by accelerating the development and selection of antimicrobial resistant bacteria. Benign by Design (BbD) of SUAs is an effective risk prevention approach. BbD principles aim for fast and complete mineralization or at least deactivation of the SUA after release into the aquatic environment. Main objective was to test if mixtures of transformation products (TPs) generated via photolysis of SUAs can be used as an efficient way to screen for similarly effective but better biodegradable SUA alternatives. Six SUAs were photolyzed (Hg ultraviolet (UV) light), and generated UV-mixtures analysed by high performance liquid chromatography coupled to an UV and tandem mass spectrometry detector. UV-mixtures were screened for antibiotic activity (luminescence bacteria test, LBT, on luminescence and growth inhibition of Aliivibrio Fischeri) and environmental biodegradability (manometric respirometry test, MRT, OECD 301F) using untreated parent SUAs in comparison. Additionally, ready environmental biodegradability of three commercially available hydroxylated sulfanilamide derivatives was investigated. SUA-TPs contributed to acute and chronic bacterial luminescence inhibition by UV-mixtures. LBT's third endpoint, growth inhibition, was not significant for UV-mixtures. However, it cannot be excluded for tested TPs as concentrations were lower than parents' concentrations and inhibition by most parental concentrations tested was also not significant. HPLC analysis of MRT samples revealed that one third of SUA-TPs was reduced during incubation. Three of these TPs, likely OH-SIX, OH-SMX and OH-STZ, were of interest for BbD because the sulfonamide moiety is still present. However, hydroxylated sulfanilamide derivatives, tested to investigate the effect of hydroxylation on biodegradability, were not readily biodegraded. Thus, improving mineralization through hydroxylation as a general rule couldn't be confirmed, and no BbD candidate could be identified. This study fills data gaps on bioactivity and environmental biodegradability of SUAs' TP-mixtures. Findings may support new redesign approaches.

Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development.

Active pharmaceutical ingredients (APIs), their metabolites and transformation products (TPs) are found as pollutants in the environment. They can impact human and environmental health. To address this issue, an efficient, long-term prevention strategy could be the design of APIs that have less impact on the natural environment, i.e. the design of greener APIs, by the implementation of environmental parameters into the drug discovery and development process (also abbreviated R&D for 'research and development'). Our study aimed to evaluate the feasibility of the design of greener APIs based on insights from drug design experts working in large, research-based pharmaceutical companies. The feasibility evaluation also identified needs and incentives for process modification. For this purpose, 30 R&D and environmental experts from seven globally active pharmaceutical companies were interviewed along a structured questionnaire. Main findings are that the interviewed experts saw manifold opportunities to include properties rendering APIs greener in different stages along the R&D process. This implementation would be favoured by the fact that the pharmaceutical R&D process is very flexible and relies on balancing multiple parameters. Furthermore, some API properties that reduce environmental risks were considered compatible with common desirable properties for application. Environmental properties should be considered early during R&D, i.e. when molecules are screened and optimized. It has been found that availability of suitable in silico models and in vitro assays is crucial for this environmental consideration. Their attributes, e.g. throughput and costs, determine at which process stage they can be successfully applied. An intensified exchange between R&D and environmental experts within and outside companies would push the industrial application of the benign by design approach for APIs forward. Collaboration across pharmaceutical companies, authorities, and academia is seen as highly promising in this respect. Financial, social, and regulatory incentives would support future design of greener APIs.

Learning from Safe-by-Design for Safe-and-Sustainable-by-Design: Mapping the current landscape of Safe-by-Design reviews, case studies, and frameworks.

With the introduction of the European Commission's "Safe and Sustainable-by-Design" (SSbD) framework, the interest in understanding the implications of safety and sustainability assessments of chemicals, materials, and processes at early-innovation stages has skyrocketed. Our study focuses on the "Safe-by-Design" (SbD) approach from the nanomaterials sector, which predates the SSbD framework. In this assessment, SbD studies have been compiled and categorized into reviews, case studies, and frameworks. Reviews of SbD tools have been further classified as quantitative, qualitative, or toolboxes and repositories. We assessed the SbD case studies and classified them into three categories: safe(r)-by-modeling, safe(r)-by-selection, or safe(r)-by-redesign. This classification enabled us to understand past SbD work and subsequently use it to define future SSbD work so as to avoid confusion and possibilities of "SSbD-washing" (similar to greenwashing). Finally, the preexisting SbD frameworks have been studied and contextualized against the SSbD framework. Several key recommendations for SSbD based on our analysis can be made. Knowledge gained from existing approaches such as SbD, green and sustainable chemistry, and benign-by-design approaches needs to be preserved and effectively transferred to SSbD. Better incorporation of chemical and material functionality into the SSbD framework is required. The concept of lifecycle thinking and the stage-gate innovation model need to be reconciled for SSbD. The development of high-throughput screening models is critical for the operationalization of SSbD. We conclude that the rapid pace of both SbD and SSbD development necessitates a regular mapping of the newly published literature that is relevant to this field.

Impact of green and blue-green light on the growth, pigment concentration, and fatty acid unsaturation in the microalga Monoraphidium braunii.

The spectral composition of light is an important factor for the metabolism of photosynthetic organisms. Several blue light-regulated metabolic processes have already been identified in the industrially relevant microalga Monoraphidium braunii. However, little is known about the spectral impact on this species' growth, fatty acid (FA), and pigment composition. In this study, M. braunii was cultivated under different light spectra (white light: 400-700 nm, blue light: 400-550 nm, green light: 450-600 nm, and red light: 580-700 nm) at 25°C for 96 h. The growth was monitored daily. Additionally, the FA composition, and pigment concentration was analyzed after 96 h. The highest biomass production was observed upon white light and red light irradiation. However, green light also led to comparably high biomass production, fueling the scientific debate about the contribution of weakly absorbed light wavelengths to microalgal biomass production. All light spectra (white, blue, and green) that comprised blue-green light (450-550 nm) led to a higher degree of FA unsaturation and a greater concentration of all identified pigments than red light. These results further contribute to the growing understanding that blue-green light is an essential trigger for maximized pigment concentration and FA unsaturation in green microalgae.

Status quo on identified transformation products of organic ultraviolet filters and their persistence.

Organic micropollutants of concern-including organic UV filters (UVF)-are getting increasing attention. Personal care products such as sunscreens or cosmetic articles often contain large quantities of UVF. These substances enter the environment either directly (during outdoor activities) or indirectly (via sewages from households). Therefore, the removal or degradation of UVF by natural or technical treatment processes is important to understand. UVF are often incompletely removed and transformed to side products of incomplete mineralization by abiotic and biotic processes. An extensive overview on transformation products (TPs) is essential to systematically identify knowledge gaps and to derive research needs. While there are many reviews on the UVF themselves, the number of reviews which focus on their TPs is limited. Consequently, this review gives an overview on the latest findings regarding TPs of UVF. In this publication, known TPs of UVF, which were formed during abiotic and biotic processes, are reviewed. Target substances were defined and a literature database was reviewed for studies on TPs of the target substances. The first list of studies was shortened stepwise, thus generating a final list of studies which contained only the relevant studies. Since biodegradation is one of the most important pathways for removal of organic compounds from the environment, this review presents an overview on known TPs of organic UVF and their biodegradability, which determines their environmental fate. In this way, all identified TPs of UVF were listed and checked for information on their biodegradability. A total of 2731 records of studies were assessed. Forty-two studies, which assessed 46 processes that lead to the formation of identified TPs, were included in this review. One hundred and seventyseven different TPs resulting from 11 different UVF were identified. Little to no data on the biodegradability was found for TPs. This indicates a severe lack of data on the biodegradability of TPs of organic UVF substances. Since most TPs lack information on biodegradability, further research should provide information on both-identity and biodegradability-of formed TPs to be able to assess their hazardousness for the environment.

Les micropolluants organiques préoccupants, y compris les filtres UV organiques (UVF), font l'objet d'une attention croissante. Les produits de soins personnels tels que les écrans solaires ou les articles cosmétiques contiennent souvent de grandes quantités de filtres UV. Ces substances pénètrent dans l'environnement soit directement (lors d'activités de plein air), soit indirectement (via les eaux usées ménagères). Il est donc important de comprendre l'élimination ou la dégradation des UVF par des processus de traitement naturels ou techniques. Les UVF sont souvent éliminés de manière incomplète et transformés en produits secondaires de minéralisation incomplète par des processus abiotiques et biotiques. Il est essentiel de disposer d'une vue d'ensemble des produits de transformation pour identifier systématiquement les lacunes dans les connaissances et déterminer les besoins en matière de recherche. S'il existe de nombreuses études sur les UVF eux-mêmes, le nombre d'études portant sur leurs produits de transformation est limité. Par conséquent, cette étude donne un aperçu des dernières découvertes concernant les produits de transformation des UVF. Dans cette publication, les TP connus des UVF, qui ont été formés au cours de processus abiotiques et biotiques, sont passés en revue. Des substances cibles ont été définies et une base de données bibliographiques a été examinée pour trouver des études sur les PT des substances cibles. La première liste d'études a été raccourcie progressivement, ce qui a permis d'obtenir une liste finale d'études qui ne contenait que les études pertinentes. La biodégradation étant l'une des voies les plus importantes pour l'élimination des composés organiques de l'environnement, cette étude présente une vue d'ensemble des PT connus des UVF organiques et de leur biodégradabilité, qui détermine leur devenir dans l'environnement. Ainsi, tous les PT identifiés d'UVF ont été répertoriés et des informations sur leur biodégradabilité ont été vérifiées. Au total, 2731 enregistrements d'études ont été évalués. Quarante-deux études, qui ont évalué 46 processus conduisant à la formation des polluants organiques persistants identifiés, ont été incluses dans cette analyse. Cent soixante-dix- sept TP différents résultant de 11 UVF différents ont été identifiés. Peu ou pas de données sur la biodégradabilité ont été trouvées pour les PT. Cela indique un manque important de données sur la biodégradabilité des produits finis des substances UVF organiques. Étant donné que la plupart des PT manquent d'informations sur la biodégradabilité, les recherches futures devraient fournir des informations sur l'identité et la biodégradabilité des PT formés afin de pouvoir évaluer leur dangerosité pour l'environnement.

Are Si-C bonds formed in the environment and/or in technical microbiological systems?

Organosiloxanes are industrially produced worldwide in millions of tons per annum and are widely used by industry, professionals, and consumers. Some of these compounds are PBT (persistent, biaccumulative and toxic) or vPvB (very persistent and very bioaccumulative). If organosiloxanes react at all in the environment, Si-O bonds are hydrolyzed or Si-C bonds are oxidatively cleaved, to result finally in silica and carbon dioxide. In strong contrast and very unexpectedly, recently formation of new Si-CH3 bonds from siloxanes and methane by the action of microorganisms under mild ambient conditions was proposed (in landfills or digesters) and even reported (in a biotrickling filter, 30 °C). This is very surprising in view of the harsh conditions required in industrial Si-CH3 synthesis. Here, we scrutinized the pertinent papers, with the result that evidence put forward for Si-C bond formation from siloxanes and methane in technical microbiological systems is invalid, suggesting such reactions will not occur in the environment where they are even less favored by conditions. The claim of such reactions followed from erroneous calculations and misinterpretation of experimental results. We propose an alternative explanation of the experimental observations, i.e., the putative observation of such reactions was presumably due to confusion of two compounds, hexamethyldisiloxane and dimethylsilanediol, that elute at similar retention times from standard GC columns.

Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.

Are Si-C bonds cleaved by microorganisms? A critical review on biodegradation of methylsiloxanes.

Methylsiloxanes, compounds that contain H3C-Si-O subunits in their molecular structure, are emerging ubiquitous pollutants now detected in many environmental compartments. These compounds and generally Si-C bonds do not occur in living nature, but are industrially produced worldwide in millions of tons per annum and are widely used, resulting in their release to the environment. It is an open question whether or to what extent microorganisms are able to decompose these compounds. The presence of methylsiloxanes in many biogases adds to the economic relevance of this question. We here review and critically discuss, for the first time, the evidence obtained for and against degradation of methylsiloxanes by microorganisms, and in particular for microbial cleavage of Si-CH3 bonds. As a result, no convincing demonstration of Si-C cleavage by native environmental microorganisms has been found.

Environmental degradation of human metabolites of cyclophosphamide leads to toxic and non-biodegradable transformation products.

The present study assessed the ready biodegradability of the prodrug cyclophosphamide (CPA) and its stable human metabolites in the closed bottle test (CBT). The results of the CBT showed that only the main human metabolite, carboxyphosphamide (CXP), was biodegradable to a certain extent (23 ± 2.4 % ThODNH3). All other metabolites showed neither biodegradation under these conditions nor were any toxic effects on the inoculum observed. Yet, HRMSn results revealed partial primary elimination of all human metabolites and formation of 25 new transformation products. Abiotic degradation via SNi and SN2 reactions was proposed as the main degradation pathway during the CBT. The main degradation products were assigned as 3-(2-chloroethyl)oxazolidin-2-one (COAZ), cytotoxic N-2-chloroethylaziridine (CEZ) and nor­nitrogen mustard (NNM), an analogue of the chemical warfare agent HN2. While the acute ecotoxicity of the detected products is widely unknown, many have already been reported in medical literature to be either mutagenic, genotoxic, cytotoxic or carcinogenic and may therefore cause a greater risk than their precursors. QSAR models predicted that 16 of them are mutagenic and genotoxic, thus classifying the majority of the chemicals as potential environmental hazards. The central intermediates during the degradation process were proposed as CEZ and its corresponding aziridinium ion. However, other degradation products may occur depending on the type and strength of nucleophiles present in the matrices. Overall, the results demonstrated the importance to include human metabolites in the evaluation of the environmental fate of pharmaceuticals and their risk assessment especially when investigating prodrugs. The results underline the importance of identifying possible degradation products of metabolites, as they can be more toxic than related parent compounds and metabolites and can cause a greater risk to the environment and humans.

Designing benign molecules: The influence of O-acetylated glucosamine-substituents on the environmental biodegradability of fluoroquinolones.

Antibiotics are detected worldwide in the aquatic environment, with continuously rising concentrations. Antibiotics in the environment have the potential to damage ecosystems and contribute to the development of resistance. Whilst a few antibiotics, such as some ß-lactams, are eliminated by effluent treatment, others, such as fluoroquinolones, are not or just partially removed and enter the environment. Therefore, approaches are needed to tackle those problems at the compound level. Benign by design (BbD), an important part of green pharmacy, has the goal to integrate environmental fate and end-of-use considerations at the very beginning, i.e., into the design of active pharmaceutical ingredients. Hence, pharmaceuticals should be designed to be sufficiently active and stable during storage and usage but should degrade after excretion into the environment, so that they cannot cause any adverse effects. Fluoroquinolones (FQs) are important broad-spectrum antibiotics. They are known to be persistent in the environment and to be neither inactivated nor degraded or even mineralized during sewage treatment. The addition of new substituents via amidation, like glucosamine moieties, at the carboxylic group of FQs, led to better antimicrobial activity compared to its parent compounds against various microorganisms. To investigate if the addition of sugar moieties could improve the overall environmental biodegradability of FQs, eight novel quinolone and fluoroquinolone analogs conjugated with 1,3,4,6-Tetra-O-acetyl-ß-d-glucosamine and 2-deoxy-d-glucopyranose have been investigated regarding their ready biodegradability (OECD 301D/F) and their degradation pathways have been analyzed. According to the OECD 301D test, none of the substances could be classified as readily biodegradable. However, the O-acetyl analogs did undergo a partial degradation of the O-acetyl glucosamine moiety, via stepwise deacetylation and the degradation of the whole glucosamine moiety. The degradation resulted in Fluoroquinolone-3-carboxamide derivatives. Those insights could be further used as input for fragment-based design of benign APIs that will degrade once they reached the environment.

Ionic liquids vs. ethanol as extraction media of algicidal compounds from mango processing waste.

The race for environmentally-safe pesticides and biocides has been showing solutions ranging from pest-pathologic microorganisms to safer botanical extracts that can be incorporated in several formulations. Often linked to high biological activities, fruit residues can be recovered from food processing factories to obtain complex extracts enriched with several bioactive chemicals. Mango (Mangifera indica) fruits are processed into food products in high volumes across the globe and generate a consistent residue that contains, among others, the xanthonoid mangiferin and the flavonoid hyperoside. Both compounds have been linked to several pharmacological and pesticidal activities, although not yet studied for algicidal applications, a current concern specially for antifouling and harmful algae blooms control products. The challenge lies, however, not only on the degree of activity of the natural compounds, but also on the processes necessary to separate, isolate and formulate the bioactive compounds in order to obtain an effective final product. The solvent choice plays an important part regarding the selectivity of the separation and isolation of the main bioactive compounds from the solid waste matrix. Ethanolic mixtures in water have been consolidated recently as a promising extraction medium for flavonoids and xanthonoids, although hindered by solubility limitations. In this paper, aqueous solutions of ionic liquids (ILs) were tested, screened and optimized using Box-Behnken design and Response Surface Methodology to obtain mangiferin and hyperoside-enriched extracts. Results showed a greater concentration of mangiferin and hyperoside with 1-octyl-3-methylimidazolium chloride ([C8MIm] Cl), when compared to choline acetate and ethanolic extracts using optimized parameters. In terms of sufficiency, solvent selection between ILs and ethanolic extraction media was discussed considering economic and environmental factors. Ethanol/water mango waste extracts were then studied for their activity against Raphidocelis subcapitata microalgae, which showed a higher growth inhibition in comparison to standard solutions of mangiferin and hyperoside, either individually and in a 1:1 mixture. A EC50 value was found in relative low concentrations of mangiferin and hyperoside (0.015 mg L-1) detected in the extract, showcasing a promising approach to the direct use of residuary plant extracts in biocidal formulations.

GREENER Pharmaceuticals for More Sustainable Healthcare.

Medicines are essential to human health but can also impact the aquatic and terrestrial environment after use by patients and release via excreta into wastewater. We highlight the need for a GREENER approach to identify and meet important environmental criteria, which will help reduce the impact of medicinal residues on the environment. These criteria include effect reduction by avoiding nontarget effects or undesirable moieties, exposure reduction via lower emissions or environmental (bio)degradability, no PBT (persistent, bioaccumulative, and toxic) substances, and risk mitigation. With all of these criteria, however, patient health is of primary importance as medicines are required to be safe and efficacious for treating diseases. We discuss the feasibility of including these criteria for green by design active pharmaceutical ingredients in the process of drug discovery and development and which tools or assays are needed to accomplish this. The integrated GREENER approach can be used to accelerate discussions about future innovations in drug discovery and development.

Repurposing chemical waste: Sustainable chemistry for circularity beyond artificial intelligence.

Generating considerable amounts of industrial waste requires rethinking chemistry for circularity in a broader picture. We discuss the study by Wolos et al. (2022) showing that the critical application of artificial intelligence on chemical reactivity can help us trace an unprecedented number of syntheses to novel responsible uses of waste.

Blue-green light is required for a maximized fatty acid unsaturation and pigment concentration in the microalga Acutodesmus obliquus.

Blue-green light is known to maximize the degree of fatty acid (FA) unsaturation in microalgae. However, knowledge on the particular waveband responsible for this stimulation of FA desaturation and its impact on the pigment composition in microalgae remains limited. In this study, Acutodesmus obliquus was cultivated for 96 h at 15°C with different light spectra (380-700 nm, 470-700 nm, 520-700 nm, 600-700 nm, and dark controls). Growth was monitored daily, and qualitative characterization of the microalgal FA composition was achieved via gas chromatography coupled with electron impact ionization mass spectrometry (GC-EI/MS). Additionally, a quantitative analysis of microalgal pigments was performed using high-performance liquid chromatography with diode array detection (HPLC-DAD). Spectra that included wavelengths between 470 and 520 nm led to a significantly higher percentage of the polyunsaturated fatty acids (PUFA) 18:3 and 16:4, compared to all other light conditions. However, no significant differences between the red light cultivations and the heterotrophic dark controls were observed for the FA 18:3 and 16:4. These results indicate, that exclusively the blue-green light waveband between 470 and 520 nm is responsible for a maximized FA unsaturation in A. obliquus. Furthermore, the growth and production of pigments were impaired if blue-green light (380-520 nm) was absent in the light spectrum. This knowledge can contribute to achieving a suitable microalgal pigment and FA composition for industrial purposes and must be considered in spectrally selective microalgae cultivation systems.

Transformation products of sulfonamides in aquatic systems: Lessons learned from available environmental fate and behaviour data.

Sulfonamides (SUAs) and their transformation products (TPs) contribute to environmental pollution. Importance of research on TPs' properties has been emphasised, e.g. allowing a comprehensive environmental risk assessment of their parent compounds. However, TPs' properties have been discussed in reviews on SUAs only marginally, if at all. For the first time, a scientific literature review aims to discuss the current state of knowledge on SUA-TPs including research gaps, and commonalities of SUA-TPs and TPs in general. Literature on SUA-TPs was consulted systematically to collect data on occurrence, physicochemical properties, degradability, and (eco)toxicity. TPs of 14 SUAs were reviewed, and aspects applicable for TPs in general were identified to guide future handling of TPs as a complex category of compounds. The data of sulfamethoxazole (SMX), the main representative, was analysed in more detail to discuss insights on a chemical level. Literature search resulted in 607 SUA-TPs reported in 222 publications. Only for 4%, 31%, and 35% of these TPs, data on occurrence in aquatic systems, on degradation, and (eco)toxicity, respectively, was found. Several mixtures of SUA-TPs were more ecotoxic than their parent compounds, e.g. 10 of 15 mixtures of SMX-TPs. Only few TPs were tested as single substance. Although several TPs could be eliminated experimentally, their mineralisation rate remained often unknown. Thus, further transformation to persistent TPs could not be ruled out. Standardised biodegradability tests of individual TPs would monitor their mineralisation rate, but are almost completely lacking. Reasons are likely poor availability of TPs, but also the focus on abiotic water treatment. Data assessment demonstrated that data of high significance according to standard methods, e.g. OECD methods for chronic (eco)toxicity and ready biodegradability, is needed to assess environmental risks of prioritised TPs, but also to redesign their parent pharmaceutical for complete environmental mineralisation in a long-term (Benign by Design).

Inventory of biodegradation data of ionic liquids.

Ionic liquids (ILs) are increasingly of interest for environmentally open applications. Therefore, completely mineralising ILs are highly desirable. We reviewed the current state of knowledge on ILs' environmental biodegradability and identified research needs. Literature data were evaluated as for applied standard methods (e.g. OECD, ISO, APHA) for biodegradation of ILs in order to get an overview on the validity of the test results received and ILs' biodegradability. 109 studies were evaluated. The ILs were categorised based on the cation's core structure. The biodegradation data was classified according to a traffic light system (red: 0-19% degradation, amber: 20-59% degradation, green: ≥ 60% degradation). Not all studies could be assessed for compliance with the test guidelines due to missing test parameters. Moreover, no study discussed all validation criteria as defined by the test guidelines. Consequently, the reliability and quality of the existing biodegradation data is restrained. With regard to the different cations classified for ≥ 60% biodegradability, phosphonium ILs are the least biodegradable, followed by imidazolium ones. The most ILs that were biodegradable are cholinium ILs. The results indicate the need for more and qualitatively better testing according to standard methods including application and reporting of all validation criteria in order to get reliable data that enables the comparison of the test data and a comprehensive understanding of ILs' biodegradability. Moreover, reliable data allows the selection of sufficiently environmentally biodegradable ILs if an introduction into the environment during use cannot be excluded.