Predicting human neurotoxicity of propylene glycol methyl ether (PGME) by implementing in vitro neurotoxicity results into toxicokinetic modelling.

Although organic solvents have been associated with CNS toxicity, neurotoxicity testing is rarely a regulatory requirement. We propose a strategy to assess the potential neurotoxicity of organic solvents and predict solvent air concentrations that will not likely produce neurotoxicity in exposed individuals. The strategy integrated an in vitro neurotoxicity, an in vitro blood-brain barrier (BBB), and an in silico toxicokinetic (TK) model. We illustrated the concept with propylene glycol methyl ether (PGME), widely used in industrial and consumer products. The positive control was ethylene glycol methyl ether (EGME) and negative control propylene glycol butyl ether (PGBE), a supposedly non-neurotoxic glycol ether. PGME, PGBE, and EGME had high passive permeation across the BBB (permeability coefficients (Pe) 11.0 × 10-3, 9.0 × 10-3, and 6.0 × 10-3 cm/min, respectively). PGBE was the most potent in in vitro repeated neurotoxicity assays. EGME's main metabolite, methoxyacetic acid (MAA) may be responsible for the neurotoxic effects reported in humans. No-observed adverse effect concentrations (NOAECs) for the neuronal biomarker were for PGME, PGBE, and EGME 10.2, 0.07, and 79.2 mM, respectively. All tested substances elicited a concentration-dependent increase in pro-inflammatory cytokine expressions. The TK model was used for in vitro-to-in vivo extrapolation from PGME NOAEC to corresponding air concentrations (684 ppm). In conclusion, we were able to predict air concentrations that would not likely result in neurotoxicity using our strategy. We confirmed that the Swiss PGME occupational exposure limit (100 ppm) will not likely produce immediate adverse effects on brain cells. However, we cannot exclude possible long-term neurodegenerative effects because inflammation was observed in vitro. Our simple TK model can be parameterized for other glycol ethers and used in parallel with in vitro data for systematically screening for neurotoxicity. If further developed, this approach could be adapted to predict brain neurotoxicity from exposure to organic solvents.

Comparative evaluation of mutagenic, genotoxic, cytotoxic, and antimicrobial effects of flavour and fragrance aldehydes, ketones, oximes, and oxime ethers.

Despite the large number of odoriferous compounds available, new ones with interesting olfactory characteristics are desired due to their potentially high commercial value. Here, we report for the first time mutagenic, genotoxic, and cytotoxic effects, and antimicrobial properties of low-molecular fragrant oxime ethers, and we compare their properties with corresponding oximes and carbonyl compounds. 24 aldehydes, ketones, oximes, and oxime ethers were evaluated for mutagenic and cytotoxic effects in Ames (using Salmonella typhimurium strains TA 98 with genotype hisD3052, rfa, uvrB, pKM101, and TA100 with genotype hisG46, rfa, uvrB, pKM101, concentration range: 0.0781-40 mg/mL) and MTS (using HEK293T cell line concentration of tested substances: 0.025 mM) assays. Antimicrobial evaluation was carried out against Bacillus cereus (ATCC 10876), Staphylococcus aureus (ATCC 6538), Enterococcus hirae (ATCC 10541), Pseudomonas aeruginosa (ATCC 15442), Escherichia coli (ATCC 10536), Legionella pneumophila (ATCC 33152); Candida albicans (ATCC 10231) and Aspergillus brasiliensis (ATCC 16404) with concentration range of tested substances 9.375 - 2.400 mg/mL. Furthermore, 5 representatives of carbonyl compounds, oximes, and an oxime ether (stemone, buccoxime, citral, citral oxime, and propiophenone oxime O-ethyl ether) were evaluated for genotoxic properties in SOS-Chromotest (concentration range: 7.8·10-5 - 5·10-3 mg/mL). All of the tested compounds did not exhibit mutagenic, genotoxic, or cytotoxic effects. Oximes and oxime ethers showed relevant antimicrobial activity against pathogenic species (P. aeruginosa, S. aureus, E.coli, L. pneumophila, A. brasiliensis, C. albicans) in the MIC range 0.075 - 2.400 mg/mL compared to the common preservative methylparaben with the MIC range 0.400-3.600 mg/mL. Our study shows that oxime ethers have the potential to be used as fragrant agents in functional products.

Hematological variations in healthy participants exposed 2 h to propylene glycol ethers under controlled conditions.

Glycol ethers are solvents used in a plethora of occupational and household products exposing the users to potential toxic effects. Several glycol ethers derived from ethylene glycol induce hematological toxicity, such as anemia in workers. The exposure effects on blood cells of glycol ethers derived from propylene glycol are unknown in humans. The aim of our study was to evaluate blood parameters indicative of red blood cell (RBC) hemolysis and oxidative stress in participants exposed to propylene glycol (propylene glycol monobutyl ether (PGBE) and propylene glycol monomethyl ether (PGME)), two extensively used propylene glycol derivatives worldwide. Seventeen participants were exposed 2 h in a control inhalation exposure chamber to low PGME (35 ppm) and PGBE (15 ppm) air concentrations. Blood was regularly collected before, during (15, 30, 60, and 120 min), and 60 min after exposure for RBC and oxidative stress analyses. Urine was also collected for clinical effects related to hemolysis. Under the study conditions, our results showed that the blood parameters such as RBCs, hemoglobin concentration, and white blood cells tended to increase in response to PGME and PGBE exposures. These results raise questions about the possible effects in people regularly exposed to higher concentrations, such as workers.

Amended Safety Assessment of Butyl Polyoxyalkylene Ethers as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 46 butyl polyoxyalkylene ethers that share a common structural motif, namely a butyl chain (4 carbon alkyl chain) bound to a polyoxyalkylene (PPG, PEG, or both); 23 of these ethers were previously reviewed by the Panel, and 23 are reviewed herein for the first time. Most of the butyl polyoxyalkylene ethers have several functions in cosmetics, but the most common reported functions include hair conditioning agent and skin conditioning agent, and many reportedly function as solvents. Upon review of new data, including frequency and concentration of use, and data from previous Panel reports and on read-across analogs, the Panel concluded that these ingredients are safe in the present practices of use and concentration in cosmetics when formulated to be non-irritating.

Blood absorption toxicokinetics of glycol ethers after inhalation: A human controlled study.

Glycol ethers are organic solvents present in countless products for professional and domestic use. The main toxicological concerns are hematotoxicity, respiratory and reproductive toxicity. The general population can be exposed when using products containing one or several glycol ethers that evaporate or if sprayed, generate aerosols that can be inhaled. The rate at which glycol ethers enters blood following inhalation exposure are unknown in humans, and chemical risk assessors only rely on animal and in vitro toxicity studies. Propylene glycol monomethyl ether (PGME) and propylene glycol monobutyl ether (PGBE) are two examples of glycol ethers used worldwide. Our study aimed to provide human toxicokinetic data after inhalation exposure of low PGME and PGBE concentrations tested alone or in mixture. Healthy participants (n = 28) were exposed to 35 ppm (131 mg/m3) of PGME and 15 ppm (i.e., 83 mg/m3) of PGBE for 2 or 6 h. Blood was regularly collected during the exposure sessions. PGME and PGBE were immediately bioavailable in blood during exposure, and the mean absorption rates were up to 13 µg/L/min and 2.45 µg/L/min, respectively. Maximum mean blood concentration (Cmax) was 2.91 mg/L and 0.41 mg/L for PGME and PGBE. The cumulative internal doses over time (area under the curve, AUC) were 11 mg∗h/L and 1.81 mg∗h/L for PGME and PGBE. PGME and PGBE total blood uptake could possibly be higher in physically active individuals, such as workers. We recommend that glycol ethers present on the market undergo toxicological testing with the internal doses we found in our toxicokinetic study.

Acute Toxicity of Gambierone and Quantitative Analysis of Gambierones Produced by Cohabitating Benthic Dinoflagellates.

Understanding the toxicity and production rates of the various secondary metabolites produced by Gambierdiscus and cohabitating benthic dinoflagellates is essential to unravelling the complexities associated with ciguatera poisoning. In the present study, a sulphated cyclic polyether, gambierone, was purified from Gambierdiscus cheloniae CAWD232 and its acute toxicity was determined using intraperitoneal injection into mice. It was shown to be of low toxicity with an LD50 of 2.4 mg/kg, 9600 times less toxic than the commonly implicated Pacific ciguatoxin-1B, indicating it is unlikely to play a role in ciguatera poisoning. In addition, the production of gambierone and 44-methylgambierone was assessed from 20 isolates of ten Gambierdiscus, two Coolia and two Fukuyoa species using quantitative liquid chromatography-tandem mass spectrometry. Gambierone was produced by seven Gambierdiscus species, ranging from 1 to 87 pg/cell, and one species from each of the genera Coolia and Fukuyoa, ranging from 2 to 17 pg/cell. The production of 44-methylgambierone ranged from 5 to 270 pg/cell and was ubiquitous to all Gambierdiscus species tested, as well as both species of Coolia and Fukuyoa. The relative production ratio of these two secondary metabolites revealed that only two species produced more gambierone, G. carpenteri CAWD237 and G. cheloniae CAWD232. This represents the first report of gambierone acute toxicity and production by these cohabitating benthic dinoflagellate species. While these results demonstrate that gambierones are unlikely to pose a risk to human health, further research is required to understand if they bioaccumulate in the marine food web.

Comparative analysis of the physicochemical, toxicokinetic, and toxicological properties of ether-PFAS.

Perfluoropolyethers, also known as ether-PFAS, are linear or branched alkyl ether polymers, where the substituent hydrogens on the carbon atoms in the chain have been fully replaced by fluorine atoms. Some of these molecules may have a carboxylate functional group attached to one of the terminal carbon atoms to form an ether-PFAS carboxylate. Perfluoropolyethers are used as processing aids in the manufacture of various types of perfluorinated polymeric materials which are used in a variety of consumer applications. Although the physicochemical and toxicological properties of certain perfluoropolyether compounds have been extensively studied, data are relatively sparse for some members of this class of compounds. Moreover, the physicochemical, toxicokinetic, and toxicological properties of ether-PFAS as a class have not been elucidated in previous comprehensive review articles. This article reviews the nomenclature and uses of ether-PFAS and compares the physicochemical properties, toxicokinetic characteristics, apical effects in toxicological studies, and dose-response profiles across four specific ether-PFAS compounds. This comparison, including a description of identified data gaps should help to inform the design of studies to further elucidate the characteristics of ether-PFAS and to propose potential read-across assessment strategies for members of this class.

Revisiting the toxin profile of Alexandrium pseudogonyaulax; Formation of a desmethyl congener of goniodomin A.

During a survey of the production of goniodomin A (GDA) by Alexandrium pseudogonyaulax in Danish coastal waters, Krock et al. (2018) obtained mass spectral evidence for the presence of a truncated congener, herein termed GD754, having a molecular weight 14 Da lower than GDA and assigned it as goniodomin B (GDB). An erroneous structure of GDB involving deletion of a methylene group between rings B and D had previously been reported by Espiña et al. (2016) but without experimental details. HPLC properties reported by Krock for GD754 point to it being a homolog of GDA. Comparison of mass spectral fragmentation data reported for GD754 with fragmentation data for GDA, show it to be a truncated form of GDA with the deletion involving a CH2 group from ring F or one of the two methyl substituents on ring F, not elsewhere on the molecule. On biosynthetic grounds, the GD754 congener is proposed to be 34-desmethyl-GDA. Further experimental work will be required to confirm this hypothesis.

A Mediterranean Alexandrium taylorii (Dinophyceae) Strain Produces Goniodomin A and Lytic Compounds but Not Paralytic Shellfish Toxins.

Species of the dinophyte genus Alexandrium are widely distributed and are notorious bloom formers and producers of various potent phycotoxins. The species Alexandrium taylorii is known to form recurrent and dense blooms in the Mediterranean, but its toxin production potential is poorly studied. Here we investigated toxin production potential of a Mediterranean A. taylorii clonal strain by combining state-of-the-art screening for various toxins known to be produced within Alexandrium with a sound morphological and molecular designation of the studied strain. As shown by a detailed thecal plate analysis, morphology of the A. taylorii strain AY7T from the Adriatic Sea conformed with the original species description. Moreover, newly obtained Large Subunit (LSU) and Internal Transcribed Spacers (ITS) rDNA sequences perfectly matched with the majority of other Mediterranean A. taylorii strains from the databases. Based on both ion pair chromatography coupled to post-column derivatization and fluorescence detection (LC-FLD) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis it is shown that A. taylorii AY7T does not produce paralytic shellfish toxins (PST) above a detection limit of ca. 1 fg cell-1, and also lacks any traces of spirolides and gymnodimines. The strain caused cell lysis of protistan species due to poorly characterized lytic compounds, with a density of 185 cells mL-1 causing 50% cell lysis of cryptophyte bioassay target cells (EC50). As shown here for the first time A. taylorii AY7T produced goniodomin A (GDA) at a cellular level of 11.7 pg cell-1. This first report of goniodomin (GD) production of A. taylorii supports the close evolutionary relationship of A. taylorii to other identified GD-producing Alexandrium species. As GD have been causatively linked to fish kills, future studies of Mediterranean A. taylorii blooms should include analysis of GD and should draw attention to potential links to fish kills or other environmental damage.

Toxic effect and genotoxicity of carvacrol ethers in Drosophila melanogaster.

The present study investigated the effect of four carvacrol ethers (propyl-, butyl, octyl- and benzyl) on the viability, level of dominant lethal mutations of Drosophila melanogaster and their influence on the multiplication of the nuclear genome in salivary gland cells. The fertility and viability of fruit flies were assessed after oral administration (0.05 % to culture medium) and inhalation exposure (5 mg per 1 cm2 of polyvinyl alcohol film) of compounds 1‒4 and initial carvacrol. The influence of terpenoid and its ethers on the degree of chromosomes polyteny in salivary gland cells of D. melanogaster larvae has been revealed. Among all tested compounds, carvacrol exhibited the most significant impact on frequency of dominant lethal mutations, fecundity and insect survival when inhaled or adding to the culture medium. Oral administration of ethers 1‒4 was found to decrease the average level of chromosome polyteny degree (366 C-500 C) while pure carvacrol adding to culture medium had the opposite effect (763 C) compared to control (695 C). The possible mechanism of action for carvacrol and its ethers is discussed.

Nontargeted mass-spectral detection of chloroperfluoropolyether carboxylates in New Jersey soils.

The toxicity and environmental persistence of anthropogenic per- and poly-fluoroalkyl substances (PFAS) are of global concern. To address legacy PFAS concerns in the United States, industry developed numerous replacement PFAS that commonly are treated as confidential information. To investigate the distribution of PFAS in New Jersey, soils collected from across the state were subjected to nontargeted mass-spectral analyses. Ten chloroperfluoropolyether carboxylates were tentatively identified, with at least three congeners in all samples. Nine congeners are ≥(CF2)7 Distinct chemical formulas and structures, as well as geographic distribution, suggest airborne transport from an industrial source. Lighter congeners dispersed more widely than heavier congeners, with the most widely dispersed detected in an in-stock New Hampshire sample. Additional data were used to develop a legacy-PFAS fingerprint for historical PFAS sources in New Jersey.

Toxic response of the bacterium Vibrio fischeri to sodium lauryl ether sulphate residues in excavated soils.

Sodium lauryl ether sulphate (SLES) is the main chemical component in several lubricant products used for soil conditioning in the mechanized excavation industry using Earth Pressure Balance-Tunnel Boring Machines. During the tunnelling process, huge amounts of excavated soil are produced and the SLES presence can affect the subsequent re-use of this material as a by-product. Currently, there is still no regulatory indication of reliable and sensitive bioassays for monitoring soil quality during the excavation process. The main objective of this work was to verify if the Vibrio fischeri screening test was suitable as a consistent and precautionary tool for this specific purpose. Firstly, the ecotoxicity (EC20 and EC50) of the SLES standard solution and three commercial products (SLES content from 10 to 50%) were evaluated to select the most environmental friendly product. Subsequently, soil samples from about 2 years of tunnelling in a real construction site, conditioned with the selected product, were evaluated for their environmental compatibility with the prescriptions of an Italian site-specific protocol. The latter established 2 mg/L as a threshold value for SLES concentration in soil water extracts and a no toxic response (≤20%) for the Vibrio fischeri test. The comparison of the bacterium bioluminescence inhibition values (%) with analytical determinations showed an ecotoxicity when SLES was >2 mg/L. The toxicity was directly related to SLES concentration, indicating that the V. fischeri test and the SLES analyses are suitable tools for assessing excavated soil as a by-product, ensuring its safe reuse in accordance with a green production process (circular economy).

Carcinogenicity of butyl 2,3-epoxypropyl ether in rats and mice by whole body inhalation for two years.

Butyl 2,3-epoxypropyl ether (CAS No. 2426-08-6, synonym: n-butylglycidyl ether, BGE) was exposed by whole body inhalation to F344 rats and BDF1 mice of both sexes (50 animals per group) 6 hours per day, 5 days per week for 104 weeks at targeted concentrations of 0, 10, 30 or 90 ppm (v/v) for rats and 0, 5, 15 or 45 ppm for mice. In rats, 90 ppm of BGE increased the incidences of nasal squamous cell carcinomas in both sexes. Nasal adenomas and splenic mononuclear cell leukemia were increased in male rats exposed to 30 ppm. Splenic mononuclear cell leukemia was increased in female rats by trend test. Non-neoplastic nasal lesions, such as squamous cell hyperplasia with atypia, squamous cell metaplasia and the inflammation of the respiratory region and atrophy of the olfactory epithelium were increased in both sexes in a dose-dependent manner. In mice, the incidences of histiocytic sarcomas of the uterus in female mice were increased in a dose-dependent manner and the incidences of nasal hemangiomas in both sexes were increased in a dose-dependent manner. Nasal squamous cell carcinoma, a rare tumor, was observed, although not statistically significant, in both sexes. Non-neoplastic lesions such as nodular hyperplasia of the transitional epithelium and cuboidal changes of the respiratory epithelium in the nasal cavity, were increased both in males and females in a dose-dependent manner. The present study demonstrated clear evidence of carcinogenicity of BGE in both rats and mice by the 2-year whole body inhalation exposure.

Perfluoropolyether carboxylic acids (novel alternatives to PFOA) impair zebrafish posterior swim bladder development via thyroid hormone disruption.

Perfluoropolyether carboxylic acids (PFECAs, CF3(OCF2)nCOO-, n = 2-5) are novel alternatives to perfluorooctanoic acid (PFOA) and are widely used in industrial production. However, although they have been detected in surface water and human blood, their toxicities on aquatic organisms remain unknown. We used zebrafish embryos to compare the developmental toxicities of various PFECAs (e.g., perfluoro (3,5,7-trioxaoctanoic) acid (PFO3OA), perfluoro (3,5,7,9-tetraoxadecanoic) acid (PFO4DA), and perfluoro (3,5,7,9,11-pentaoxadodecanoic) acid (PFO5DoDA)) with that of PFOA and to further reveal the key events related to toxicity caused by these chemicals. Results showed that, based on half maximal effective concentrations (EC50), toxicity increased in the order: PFO5DoDA > PFO4DA > PFOA > PFO3OA, with uninflated posterior swim bladders the most frequently observed malformation. Similar to PFOA, PFECA exposure significantly lowered thyroid hormone (TH) levels (e.g., T3 (3,5,3'-L-triiodothyronine) and T4 (L-thyroxine)) in the whole body of larvae at 5 d post-fertilization following disrupted TH metabolism. In addition, the transcription of UDP glucuronosyltransferase 1 family a, b (ugt1ab), a gene related to TH metabolism, increased dose-dependently. Exogeneous T3 or T4 supplementation partly rescued PFECA-induced posterior swim bladder malformation. Our results further suggested that PFECAs primarily damaged the swim bladder mesothelium during early development. This study is the first to report on novel emerging PFECAs as thyroid disruptors causing swim bladder malformation. Furthermore, given that PFECA toxicity increased with backbone OCF2 moieties, they may not be safer alternatives to PFOA.

Research Progress in the Biosynthetic Mechanisms of Marine Polyether Toxins.

Marine polyether toxins, mainly produced by marine dinoflagellates, are novel, complex, and diverse natural products with extensive toxicological and pharmacological effects. Owing to their harmful effects during outbreaks of marine red tides, as well as their potential value for the development of new drugs, marine polyether toxins have been extensively studied, in terms of toxicology, pharmacology, detection, and analysis, structural identification, as well as their biosynthetic mechanisms. Although the biosynthetic mechanisms of marine polyether toxins are still unclear, certain progress has been made. In this review, research progress and current knowledge on the biosynthetic mechanisms of polyether toxins are summarized, including the mechanisms of carbon skeleton deletion, pendant alkylation, and polyether ring formation, along with providing a summary of mined biosynthesis-related genes. Finally, future research directions and applications of marine polyether toxins are discussed.

Multi-dimensional in vitro bioactivity profiling for grouping of glycol ethers.

High-content screening data derived from physiologically-relevant in vitro models promise to improve confidence in data-integrative groupings for read-across in human health safety assessments. The biological data-based read-across concept is especially applicable to bioactive chemicals with defined mechanisms of toxicity; however, the challenge of data-derived groupings for chemicals that are associated with little or no bioactivity has not been explored. In this study, we apply a suite of organotypic and population-based in vitro models for comprehensive bioactivity profiling of twenty E-Series and P-Series glycol ethers, solvents with a broad variation in toxicity ranging from relatively non-toxic to reproductive and hematopoetic system toxicants. Both E-Series and P-Series glycol ethers elicited cytotoxicity only at high concentrations (mM range) in induced pluripotent stem cell-derived hepatocytes and cardiomyocytes. Population-variability assessment comprised a study of cytotoxicity in 94 human lymphoblast cell lines from 9 populations and revealed differences in inter-individual variability across glycol ethers, but did not indicate population-specific effects. Data derived from various phenotypic and transcriptomic assays revealed consistent bioactivity trends between both cardiomyocytes and hepatocytes, indicating a more universal, rather than cell-type specific mode-of-action for the tested glycol ethers in vitro. In vitro bioactivity-based similarity assessment using Toxicological Priority Index (ToxPi) showed that glycol ethers group according to their alcohol chain length, longer chains were associated with increased bioactivity. While overall in vitro bioactivity profiles did not correlate with in vivo toxicity data on glycol ethers, in vitro bioactivity of E-series glycol ethers were indicative of and correlated with in vivo irritation scores.

Copper-catalyzed synthesis of 2,2,2-trifluoroethyl selenoethers and their insecticidal activities.

A simple and efficient protocol for the copper-catalyzed synthesis of aryl or alkyl 2,2,2-trifluoroethyl selenoethers has been developed. This reaction proceeded smoothly in the presence of CuI/phen as the catalyst, with elemental selenium, 1,1,1-trifluoro-2-iodoethane, and NaBH4 as reagents in DMF with a broad scope of functionalized (hetero)aryl or alkyl halides. Different functional groups were tolerated and moderate to excellent yields of 2,2,2-trifluoroethyl selenoethers were obtained. Some of the synthesized compounds exhibited promising insecticidal activities.

Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers.

Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non-haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long-term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.