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Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. p-Tolyl isobutyrate was evaluated for genotoxicity, repeated dose... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. p-Tolyl isobutyrate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analogs ethyl p-tolyl carbonate (CAS # 22,719-81-9) and p-tolyl acetate (CAS # 140-39-6) show that p-tolyl isobutyrate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to p-tolyl isobutyrate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; p-tolyl isobutyrate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; p-tolyl isobutyrate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33515619
DOI: 10.1016/j.fct.2021.112028 -
Journal of the American Chemical Society Jul 2023To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Phphen)(OH)], was conjugated to the...
To investigate the potential of tumor-targeting photoactivated chemotherapy, a chiral ruthenium-based anticancer warhead, Λ/Δ-[Ru(Phphen)(OH)], was conjugated to the RGD-containing Ac-MRGDH-NH peptide by direct coordination of the M and H residues to the metal. This design afforded two diastereoisomers of a cyclic metallopeptide, Λ-[]Cl and Δ-[]Cl. In the dark, the ruthenium-chelating peptide had a triple action. First, it prevented other biomolecules from coordinating with the metal center. Second, its hydrophilicity made []Cl amphiphilic so that it self-assembled in culture medium into nanoparticles. Third, it acted as a tumor-targeting motif by strongly binding to the integrin ( = 0.061 μM for the binding of Λ-[]Cl to αβ), which resulted in the receptor-mediated uptake of the conjugate . Phototoxicity studies in two-dimensional (2D) monolayers of A549, U87MG, and PC-3 human cancer cell lines and U87MG three-dimensional (3D) tumor spheroids showed that the two isomers of []Cl were strongly phototoxic, with photoindexes up to 17. Mechanistic studies indicated that such phototoxicity was due to a combination of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) effects, resulting from both reactive oxygen species generation and peptide photosubstitution. Finally, studies in a subcutaneous U87MG glioblastoma mice model showed that []Cl efficiently accumulated in the tumor 12 h after injection, where green light irradiation generated a stronger tumoricidal effect than a nontargeted analogue ruthenium complex []Cl. Considering the absence of systemic toxicity for the treated mice, these results demonstrate the high potential of light-sensitive integrin-targeted ruthenium-based anticancer compounds for the treatment of brain cancer .
Topics: Animals; Humans; Mice; Ruthenium; Prodrugs; Integrins; Peptides, Cyclic; Peptides; Brain Neoplasms; Cell Line, Tumor; Coordination Complexes; Antineoplastic Agents
PubMed: 37379365
DOI: 10.1021/jacs.3c04855 -
Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. Glyceryl monooleate was evaluated for genotoxicity, repeated dose... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. Glyceryl monooleate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that glyceryl monooleate is not genotoxic. Data on glyceryl monooleate provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for reactive materials (64 μg/cm); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; glyceryl monooleate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to glyceryl monooleate is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; glyceryl monooleate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Dose-Response Relationship, Drug; Glycerides; Humans; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33460703
DOI: 10.1016/j.fct.2021.111992 -
Cutis Feb 2022
Topics: Dermatitis, Phototoxic; Humans; Methoxsalen; Photosensitizing Agents; Ultraviolet Rays
PubMed: 35659812
DOI: 10.12788/cutis.0462 -
European Journal of Ophthalmology May 2023
Topics: Humans; Pupil; Visual Acuity; Dermatitis
PubMed: 36567500
DOI: 10.1177/11206721221149070 -
Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. 3,4,4a,5,8,8a (Or... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. 3,4,4a,5,8,8a (Or 3,4,4a,7,8,8a)-Hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the threshold of toxicological concern (TTC) for a Cramer Class III material, and the exposure to 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3,4,4a, 5,8,8a (Or 3,4,4a,7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33249051
DOI: 10.1016/j.fct.2020.111885 -
Food and Chemical Toxicology : An... Oct 2020The existing information supports the use of this material as described in this safety assessment. Decanoic acid was evaluated for genotoxicity, repeated dose toxicity,... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. Decanoic acid was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data on the target material and from read-across analog nonanoic acid (CAS # 112-05-0) show that decanoic acid is not expected to be genotoxic. Data on read-across analog octanoic acid (CAS # 124-07-2) provide a calculated MOE >100 for the repeated dose and reproductive toxicity endpoints. Based on the existing data, decanoic acid does not present a concern for skin sensitization under the current, declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; decanoic acid is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to decanoic acid is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; decanoic acid 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.
Topics: Animals; Decanoic Acids; Dermatitis, Phototoxic; Humans; Mutagenicity Tests; Perfume; Registries; Risk Assessment
PubMed: 32640335
DOI: 10.1016/j.fct.2020.111465 -
Food and Chemical Toxicology : An... Mar 2021The existing information supports the use of this material as described in this safety assessment. 3-Octanol was evaluated for genotoxicity, repeated dose toxicity,... (Review)
Review
The existing information supports the use of this material as described in this safety assessment. 3-Octanol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 3-hexanol (CAS # 623-37-0) show that 3-octanol is not expected to be genotoxic. Data on 3-octanol provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity endpoint. Data on read-across analog 2-octanol (CAS # 123-96-6) provide a calculated MOE >100 for the reproductive toxicity endpoint and show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3-octanol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 3-octanol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.
Topics: Animals; Dose-Response Relationship, Drug; Humans; Octanols; Odorants; Quantitative Structure-Activity Relationship; Reproduction; Risk Assessment; Toxicity Tests
PubMed: 33220393
DOI: 10.1016/j.fct.2020.111868 -
Toxicology Sep 2022Pyrimethamine (PYR) is used to treat parasitic infections including toxoplasmosis, pneumonia and cystoisosporiasis in HIV patients. Various oral medicines have shown...
Pyrimethamine (PYR) is used to treat parasitic infections including toxoplasmosis, pneumonia and cystoisosporiasis in HIV patients. Various oral medicines have shown phototoxicity therefore, we aimed to study the phototoxicity of PYR and its molecular mechanism involving stress responsive lysosomal protein Lamp2 and mitochondrial mediated signaling pathway under normal UVA/B exposure. We found that photodegradation and subsequent photoproduct formation was evident through LCMS/MS analysis. Photosensitized PYR produces ROS that cause damage to DNA, cell membrane and membrane bound organelles in human keratinocytes. PYR triggered cytotoxicity and phototoxicity that was evident through MTT and NRU assay respectively. Intracellular ROS generation caused phosphatidyl serine (PS) translocation in cell membrane, lysosome membrane permeabilization (LMP) and mitochondrial membrane potential (MMP) collapse that was further validated through caspase3 activation. DNA damage was measured as tail DNA formation and cell cycle arrest in G1 phase. Photosensitized PYR induces oxidative stress in the form of overexpression of Lamp2 that ultimately led to cellular apoptosis. Moreover, the effects of UVB were higher than UVA, probably due to its direct interaction with various macromolecules. We propose that photoexcited PYR may be harmful to human health even at normal sunlight exposure. Therefore, protective procedures should be practiced during PYR medication.
Topics: Dermatitis, Phototoxic; HIV Infections; Humans; Keratinocytes; Lysosomes; Phosphatidylserines; Pyrimethamine; Reactive Oxygen Species; Signal Transduction; Sunlight; Ultraviolet Rays
PubMed: 36108988
DOI: 10.1016/j.tox.2022.153320 -
The Science of the Total Environment Dec 2023The increased use of agrochemicals raises concerns about environmental, animal, and mainly human toxicology. The development of New Approach Methodologies (NAMs) for...
The increased use of agrochemicals raises concerns about environmental, animal, and mainly human toxicology. The development of New Approach Methodologies (NAMs) for toxicological risk assessment including new in vitro tests and in silico protocols is encouraged. Although agrochemical mutagenicity testing is well established, a complementary alternative approach may contribute to increasing reliability, with the consequent reduction of false-positive results that lead to unnecessary use of animals in follow-up in vivo testing. Additionally, it is unreasonable to underestimate the phototoxic effects of an accidental dermal exposure to agrochemicals during agricultural work or domestic application in the absence of adequate personal protection equipment, especially in terms of photomutagenicity. In this scenario, we addressed the integration of in vitro and in silico techniques as NAMs to assess the mutagenic and phototoxic potential of agrochemicals. In the present study we used the yno1 S. cerevisiae strain as a biomodel for in vitro assessment of agrochemical mutagenicity, both in the absence and in the presence of simulated sunlight. In parallel, in silico predictions were performed using a combination of expert rule-based and statistical-based models to assess gene mutations and phototoxicity. None of the tested agrochemicals showed mutagenic potential in the two proposed approaches. The Gly and 2,4D herbicides were photomutagenic in the in vitro yeast test despite the negative in silico prediction of phototoxicity. Herein, we demonstrated a novel experimental approach combining both in silico and in vitro experiments to address the complementary investigation of the phototoxicity and (photo)mutagenicity of agrochemicals. These findings shed light on the importance of investigating and reconsidering the photosafety assessment of these products, using not only photocytotoxicity assays but also photomutagenicity assays, which should be encouraged.
Topics: Humans; Animals; Mutagens; Saccharomyces cerevisiae; Agrochemicals; Reproducibility of Results; Risk Assessment; In Vitro Techniques
PubMed: 37748613
DOI: 10.1016/j.scitotenv.2023.167320