Research For The Biotransformation Of The Fluorinated Liquid-crystal Monomer 1-ethoxy-2,3-difluoro-4-(Trans-4-propylcyclohexyl) Benzene

Objective: Liquid crystal displays(LCDs)are commonly used in daily life.Liquid crystal compounds(LCMs)rely on physical filling within LCDs and have potential persistent,bioaccumulative and toxic effects that are widely detected in environmental and human samples.LCMs can undergo oxidation in the atmosphere to produce more toxic intermediates.However,little is known about the biotransformation of LCMs and the accompanying biohazards at the risk of intra-biological exposure.1-Ethoxy-2,3-difluoro-4-(trans-4-propylcyclohexyl)benzene(EDPrB)is a ubiquitous and structurally typical fluorinated liquid crystal monomer,and this study was conducted to explore the uptake,distribution,metabolism,and excretion of this class of compounds in living organisms as an example,In this study,the uptake,distribution,metabolism and excretion of EDPrB in organisms were investigated to assess the potential health risks and biohazards of LCMs to humans.Methods: In vitro metabolism experiments of liver microsomes from humans,rats,pigs,Cyprinus carpio,crucian carp,and Channa argus were first carried out to understand the metabolites and metabolic pathways of EDPrB,and further verify the metabolic transformation of the targets in the organisms by gavage experiments in SD rats.In this paper,the first method for the determination of EDPrB and its metabolites in biological matrices was established by Q-Exactive GC-MS,UHPLC-Q/TOF MS.Thermo Scientific Xcalibur data system and Trace Finder,Quan Browser were used for the QExactive GC-MS data acquisition and data processing.Data from UHPLC-Q/TOF MS were processed by Peak View? and Master View.Chemical structures of EDPrB and its metabolites were drawn with Chem Draw Professional and imported into ECOSAR and T.E.S.T.to predict toxicity.Statistical analysis was performed using SPSS to express the metabolic stability of liver microsomes using the percentage of EDPrB remaining at different time points and the parent’s half-life.One-way ANOVA was used to compare the differences in distribution between male and female tissues.Results: In this study,the metabolites of EDPrB were structurally characterized and their metabolic pathways,stability,toxicity and tissue distribution were characterized.A total of 20 in vitro metabolites were identified among six genera,15 of which were phase I products and 5 were phase II products.The in vitro half-lives of EDPrB ranged from 30.7 to 208.1 h across the six genera,indicating a slow metabolic rate of conversion.The ability to clear the toxicants ranged from porcine > rat > Channa argus >human > crucian carp > Cyprinus carpio.Toxicity predictions indicated that a total of17 metabolites,including phase I products and acetylation products,were classified as toxic,with some exhibiting comparable or greater aquatic toxicity than EDPrB and some exhibiting developmental toxicity and mutagenicity in rats.A total of half of the in vitro metabolites were found in plasma,urine,and fecal samples from the experimental group of SD rats after a single administration of EDPrB,with the most excreted being M5 in urine and M2 in feces.rats were transported to systemic tissues via the bloodstream after ingestion of EDPrB,with peak parental concentrations in plasma at hours 5-7,followed by excretion of parental and metabolites mainly via the intestine.However,higher maternal concentrations were detected in organ tissues after7 days,predicting that EDPrB may be bioaccumulative.In addition,there were also sex differences in the distribution of some tissues between males and females.Conclusion: EDPrB was capable of extensive biotransformation by in vitro and in vivo metabolism,and there were species and sex differences.In in vitro metabolism studies,the degradation half-life of EDPrB was longer in aquatic organisms compared to mammals,and even the aquatic toxicity of some metabolites was stronger than that of the parent compound.When the toxicants enter the body,most of the parent and metabolites were excreted via the intestine,while the rest accumulate in multi-organ tissues.The dealkylated and oxidized metabolite M5 was detected at high concentrations in plasma,urine,and feces,and it can be used as a biomarker of EDPrB contamination.This study clarifies the metabolism and tissue distribution differences of typical fluorinated liquid crystal monomer,which can provide a theoretical basis for the risk of exposure within the population.