Subject(s)
Odorants , Perfume , Monoterpenes , Perfume/toxicity , Phenylacetates/toxicity , Registries , Risk AssessmentABSTRACT
The existing information supports the use of this material as described in this safety assessment. Phenethyl phenylacetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that phenethyl phenylacetate is not genotoxic. Data provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog benzyl benzoate (CAS # 120-51-4) provide an MOE >100 for the developmental toxicity endpoint. The fertility and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to phenethyl phenylacetate is below the TTC (0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from analog benzyl phenylacetate (CAS # 102-16-9) show that there are no safety concerns for phenethyl phenylacetate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV/Vis spectra; phenethyl phenylacetate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; phenethyl phenylacetate was found not to be PBT as per the IFRA Environmental Standards and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.
Subject(s)
Acetates/toxicity , Environmental Exposure/adverse effects , Odorants/analysis , Perfume/toxicity , Phenols/toxicity , Phenylacetates/toxicity , Safety , Academies and Institutes/standards , Acetates/analysis , Animals , Dermatitis, Photoallergic , Dermatitis, Phototoxic , Endpoint Determination , Europe , Fertility/drug effects , Humans , Mutagenicity Tests , North America , Perfume/chemistry , Phenols/analysis , Phenylacetates/analysis , Registries , Reproduction/drug effects , Respiratory System/drug effects , Risk Assessment , Skin/drug effects , Toxicity TestsABSTRACT
Primary mouse hepatocytes isolated from genetically defined and/or diverse lines and disease models are a valuable resource for studying the impact of genetic and environmental factors on drug response and disease. However, standard monolayer cultures result in a rapid decline in mouse hepatocyte viability and functionality. Therefore, we evaluated 3D spheroid methodology for long-term culture of primary mouse hepatocytes, initially to support investigations of drug-induced liver injury (DILI). Primary hepatocytes isolated from male and female C57BL/6J mice were used to generate spheroids by spontaneous self-aggregation in ultra-low attachment plates. Spheroids with well-defined perimeters were observed within 5 days after seeding and retained morphology, ATP, and albumin levels for an additional 2 weeks in culture. Global microarray profiling and quantitative targeted proteomics assessing 10 important drug metabolizing enzymes and transporters demonstrated maintenance of mRNA and protein levels in spheroids over time. Activities for 5 major P450 enzymes were also stable and comparable to activities previously reported for human hepatocyte spheroids. Time- and concentration-dependent decreases in ATP and albumin were observed in response to the DILI-causing drugs acetaminophen, fialuridine, AMG-009, and tolvaptan. Collectively, our results demonstrate successful long-term culture of mouse hepatocytes as spheroids and their utility to support investigations of DILI.
Subject(s)
Chemical and Drug Induced Liver Injury , Models, Biological , Acetaminophen/toxicity , Adenosine Triphosphate/metabolism , Albumins/metabolism , Animals , Arabinofuranosyluracil/analogs & derivatives , Arabinofuranosyluracil/toxicity , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/metabolism , Cytochrome P-450 Enzyme System/metabolism , Female , Hepatocytes/metabolism , Male , Mice, Inbred C57BL , Phenylacetates/toxicity , Proteomics , Spheroids, Cellular/metabolism , Sulfonamides/toxicity , Tolvaptan/toxicity , TranscriptomeSubject(s)
Phenylacetates/chemistry , Phenylacetates/toxicity , Registries , Animals , Databases, Chemical , Humans , Perfume/chemistry , Perfume/toxicity , Risk AssessmentSubject(s)
Perfume/toxicity , Phenylacetates/toxicity , Animals , Ecotoxicology , Endpoint Determination , Environmental Pollutants/chemistry , Environmental Pollutants/toxicity , Humans , Odorants , Perfume/chemistry , Phenylacetates/chemistry , Risk Assessment , Salmonella typhimurium/drug effectsSubject(s)
Monoterpenes/toxicity , Perfume/toxicity , Phenylacetates/toxicity , Animals , Ecotoxicology , Endpoint Determination , Escherichia coli/drug effects , Humans , Monoterpenes/chemistry , Odorants , Perfume/chemistry , Phenylacetates/chemistry , Risk Assessment , Salmonella typhimurium/drug effectsSubject(s)
Perfume/toxicity , Phenylacetates/toxicity , Animals , Ecotoxicology , Endpoint Determination , Humans , Odorants , Perfume/chemistry , Phenylacetates/chemistry , Risk AssessmentABSTRACT
Crop plants face a multitude of diverse abiotic and biotic stresses in the farmers' fields. Although there now exists a considerable knowledge of the underlying mechanisms of response to individual stresses, the crosstalk between response pathways to various abiotic and biotic stresses remains enigmatic. Here, we investigated if the cytotoxic metabolite methylglyoxal (MG), excess of which is generated as a common consequence of many abiotic and biotic stresses, may serve as a key molecule linking responses to diverse stresses. For this, we generated transgenic rice plants overexpressing the entire two-step glyoxalase pathway for MG detoxification. Through assessment of various morphological, physiological and agronomic parameters, we found that glyoxalase-overexpression imparts tolerance towards abiotic stresses like salinity, drought and heat and also provides resistance towards damage caused by the sheath blight fungus (Rhizoctonia solani) toxin phenylacetic acid. We show that the mechanism of observed tolerance of the glyoxalase-overexpressing plants towards these diverse abiotic and biotic stresses involves improved MG detoxification and reduced oxidative damage leading to better protection of chloroplast and mitochondrial ultrastructure and maintained photosynthetic efficiency under stress conditions. Together, our findings indicate that MG may serve as a key link between abiotic and biotic stress response in plants.
