International Journal of Toxicology最新文献

The Expert Panel for Cosmetic Ingredient Safety (Panel) considered whether the safety of Glyceryl Isostearates and Glyceryl Stearate/Acetate as used in cosmetics should be reassessed. The Panel reviewed newly available safety data related to these ingredients. The Panel concluded, based on the available data contained in the report, that these two ingredients are safe as cosmetic ingredients in the present practices of use and concentration as described in the report.

Advances in the delivery and safety of nucleic acid-based therapeutics are enabling tissue-selective targeting and broadening the reach of genetic medicines. In addition to GalNAc-conjugated oligonucleotides, newer modalities-predominantly antibody- and peptide-conjugated oligonucleotides-combine innovative components with complex and often multimodal mechanisms of action. These constructs may require tailored nonclinical testing strategies to evaluate pharmacology, biodistribution, and component- and construct-driven toxicities. Here, we review the current state of these molecules, collectively termed here as bioconjugated oligonucleotide (BCO) therapeutics, summarize key safety liabilities across the protein scaffold, linker, and oligonucleotide payload, and highlight nonclinical approaches, including predictive safety assessments and in vivo toxicity studies that can support human clinical trials. We also discuss risk-based regulatory considerations that may differ from traditional biologics or small molecules.

The Expert Panel for Cosmetic Safety (Panel) assessed the safety of 8 naturally-sourced clay ingredients, of which 6 were previously reviewed, as used in cosmetic formulations. All of these ingredients are reported to function in cosmetics as absorbents and bulking agents; other cosmetic functions are also reported. The Panel reviewed all relevant data and concluded that Kaolin is safe in cosmetics in the present practices of use and concentration described in this safety assessment. The remaining 7 naturally-sourced clay ingredients are safe in cosmetics in the present practices of use and concentration, with the exception that the available data are insufficient to make a determination that these ingredients are safe in products that may be incidentally inhaled.

Quercetagetin (QG) is a naturally occurring flavonoid found in marigold (Tagetes erecta). It has garnered attention for its potential to support immune health, regulate blood sugar levels, and enhance metabolism. Yet, unlike the closely related compound quercetin (QC), QG has an extra hydroxyl (-OH) group at the C-6 position of the flavonoid A-ring, whereas quercetin has only a hydrogen atom at that position, which has raised safety concerns. QG has not been thoroughly studied for long-term safety. To fill this gap, we conducted a 90-day study in rats to assess the response to repeated oral doses of QG. The QG-administered group of animals received 500, 1000, or 3000 mg/kg bw per day, and we monitored a wide range of health indicators, from body weight and food intake to blood chemistry, hormone levels, and indicators of organ health. The results were reassuring as there were no changes in the urine parameters, deaths, clinical signs, or changes in growth or eye health. Changes were non-adverse and/or of no significant toxicological concern in blood, and organ weight differences were minor and not associated with any tissue damage. Based on these findings, the No Observed Adverse Effect Level (NOAEL) was established at 3000 mg/kg bw/day, the highest dose tested.We also tested QG for mutagenicity/clastogenicity using standard genotoxic assays, including bacterial mutation tests and micronucleus assays in CHO-k1 cells (in vitro) and Swiss albino mice (in vivo). Across all systems, QG showed no evidence of mutagenicity and/or clastogenicity.

Nalmefene is an opioid antagonist used in OPVEE^® nasal spray approved for use in patients 12 years of age and older. To support future clinical studies in younger pediatric populations, 2 GLP juvenile rat studies were conducted to assess the safety of nalmefene and its associated systemic exposure. Nalmefene was administered daily via intranasal instillation from postnatal day (PND) 7 to PND 28 (corresponding to birth through approximately 3 years) with recovery to PND 91, or from PND 22 to PND 70 (2 years to adolescent) with recovery to PND 114. Exposures on PND 7 were 28-40 times higher than those on PND 28, and exposures on PND 22 were 3-5 times higher than those on PND 70. Exposures on PND 28 were comparable to those on PND 70, attaining adult levels. Considering the extensive metabolism and urinary clearance of nalmefene, these findings are consistent with the maturation of metabolic and urinary clearance pathways during early development. No effects were observed on clinical signs, ophthalmology, food consumption, femur length, sperm parameters, immune responses, or neurodevelopment as assessed by neurohistopathology and neurobehavioral testing for locomotor activity, sensory function, or learning and memory. There were no macroscopic or microscopic findings indicative of target organ, systemic, or neurotoxicity. The NOAELs were 4.25 mg/dose, the highest doses tested. On PND 28, C_max (224 ng/mL) and AUC (311 ng·hr/mL) were 21- and 8-fold higher than those reported in human adults, respectively. The AUC-based safety margins in pediatric patients were estimated to range from 1.5 to 12, depending on the age group (birth-12 years; 3-40 kg).

To evaluate the safety of Metabolyte™ (sodium dodecanedioate) for human consumption, results from in vitro and in vivo studies are reported, including a bacterial reverse mutation assay, an in vitro mammalian chromosome aberration test, an in vivo mammalian bone marrow micronucleus test, an in vivo mammalian bone marrow chromosome aberration test, and a 28-day repeat-dose oral toxicological evaluation. Metabolyte™ was not mutagenic in the in vitro and in vivo studies. In the 28-day study, Wistar rats were administered Metabolyte™ by gavage at doses of 0 (G1), 3250 (G2), 6500 (G3), and 13,100 (G4) mg test article/kg bw/day. Histological examination did not reveal any test item related lesions. In the G3 and G4 dose groups, significantly altered electrolyte levels and decrease in sodium and chloride levels in males, and increase in calcium and phosphorous in females, are indicative of possible kidney malfunction. The observed significant increase in triglycerides in G4 males and G3 and G4 females and bile acid in G3 and G4 males and G4 females, decrease in globulin and concurrent increase in albumin/globulin ratio in G4 males, and increase/decrease in ALT in G4 males and females indicate liver malfunction. Significant alterations in motor activity were observed, along with an increase in alkaline phosphatase, in G3 and G4 female animals. Significant changes in absolute relative weight of kidney and liver were detected in G4 females. The NOAEL was considered to be 3250 mg/kg bw/day, as at this dose there were no toxicologically relevant treatment-related findings in male or female rats.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, was first approved by the US FDA as KETALAR® for induction and maintenance of general anesthesia. Ketamine has been used off-label for depression treatment, while its S-enantiomer, esketamine (SPRAVATO®), is approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior. High doses of ketamine have been linked to neurotoxicity. The effects of acute ketamine exposure on brain development during childhood and adolescence in humans remain poorly understood. To better characterize the safety of ketamine, we treated juvenile (postnatal day (PND) 21, 30, 35) and adult rats (PND 90) with a single subcutaneous dose of ketamine (50, 75, and 100 mg/kg). Seventy-two hours later, tissue samples were collected. Tissue samples were processed, mounted as 5-µm-thick sections, and stained with H&E for neurohistopathological evaluation. Additionally, key pharmacokinetic parameters of ketamine were determined. Neuronal necrosis was detected in the retrosplenial cortex in adult female rats treated with ketamine (100 mg/kg), while no histological changes were observed in any other groups. These data are the first to demonstrate that acute ketamine can cause neuronal necrosis in adult animals and do not support juvenile rats as having an increased susceptibility to ketamine-induced neuronal death. Adult female rats showed a marked increase in norketamine, the primary metabolite of ketamine in serum. We hypothesize that the elevated levels of norketamine may contribute to these sex- and age-specific histopathological changes.

Siamenoside I, a cucurbitane glycoside 300 times sweeter than sucrose, is found in monk fruit (Siraitia grosvenorii). The triterpene glycosides in monk fruit, such as mogroside V, siamenoside I, and mogroside III, comprise around 1% of the fruit flesh. These mogrosides share a core structure, mogrol, with varying numbers of glucose units attached to carbon-3 of the cucurbitane backbone and/or carbon-24 of the triterpene side chain. Previous in vitro fecal homogenate metabolism and in vivo pharmacokinetic research indicated that mogrosides are deglycosylated to a common metabolite, the aglycone mogrol, by intestinal flora prior to absorption. This study was conducted using a purified siamenoside I produced via fermentation and a monk fruit extract in an in vitro human fecal homogenate system to confirm the deglycosylation of siamenoside I by intestinal microflora to the common metabolic intermediate, mogrol. The rates of deglycosylation of siamenoside I and monk fruit extract showed essentially complete metabolism to mogrol within 8 h at 0.2 mg/mL and 2 mg/mL for siamenoside I, and 8 h at 0.2 mg/mL and 16 h at 2 mg/mL for monk fruit extract, in both male and female pooled fecal homogenates with no apparent sex differences. Overall, no difference was observed in the deglycosylation rates of purified siamenoside I or siamenoside I present in monk fruit extract to the mogrol metabolite further confirming the deglycosylation of mogrosides in the lower gastrointestinal tract.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 8 Melaleuca alternifolia (tea tree)-derived ingredients as used in cosmetic formulations; 5 of these ingredients are reported to function in cosmetics as skin-conditioning agents. Because final product formulations may contain multiple botanicals, each containing the same constituents of concern, formulators are advised to be aware of these constituents and to avoid reaching levels that may be hazardous to consumers. Industry should use good manufacturing practices to minimize impurities that could be present in botanical ingredients. The Panel noted that oxidized tea tree oil could be a sensitizer, and stated that industry should employ methods to minimize oxidation of the oil in the final cosmetic product. The Panel considered all the data and concluded that these ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment when formulated to be non-sensitizing.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Basic Yellow 87, which is reported to function as a hair dye in cosmetic products. The Panel reviewed the available data to determine the safety of this ingredient. The Panel concluded that Basic Yellow 87 is safe for use as a hair dye ingredient in the present practices of use and concentration described in this safety assessment.