RIFM fragrance ingredient safety assessment, hydroxycitronellal dimethyl acetal, CAS Registry Number 141-92-4.

Hydroxycitronellal dimethyl acetal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that hydroxycitronellal dimethyl acetal is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material and the exposure to hydroxycitronellal dimethyl acetal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from hydroxycitronellal dimethyl acetal and from read-across material hydroxycitronellal diethyl acetal (CAS # 7779-94-4) 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 UV spectra; hydroxycitronellal dimethyl acetal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hydroxycitronellal dimethyl acetal 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.

A 13-week subchronic toxicity study of vanillin propylene glycol acetal in F344 rats.

Vanillin propylene glycol acetal (VPGA) has been used as a flavoring agent. Here, we performed a 13-week subchronic toxicity study of VPGA in F344 rats with oral administration by gavage at doses of 0, 100, 300, and 1000 mg/kg body weight (BW)/day. In the 1000 mg/kg BW group, loss of vigorous activity and listlessness immediately after administration were observed for both sexes throughout the experimental period. Reduction of body weight gain was noted in both sexes at 1000 mg/kg BW. Serum biochemistry demonstrated significant increases in total protein, albumin, total cholesterol, calcium, inorganic phosphorus, and γ-glutamyl transpeptidase in both sexes at 1000 mg/kg BW and increases in the albumin/globulin ratio and urea nitrogen in the male 1000 mg/kg BW group. A significant increase in relative liver weight was detected in both sexes at 1000 mg/kg BW. Histopathologically, centrilobular hepatocellular hypertrophy in the liver was observed in both sexes at 1000 mg/kg BW. In addition, the incidence of fatty changes in hepatocytes in the male 1000 mg/kg BW group was decreased compared with that in the control. Based on these results, the no-observed-adverse-effect level for VPGA was evaluated to be 300 mg/kg BW/day for both sexes in the current study.

pH-Responsive Oxygen Nanobubbles for Spontaneous Oxygen Delivery in Hypoxic Tumors.

Tumor hypoxia is a significant factor leading to the resistance of tumors to treatment, especially for photodynamic therapy and radiotherapy where oxygen is needed to kill cancer cells. Oxygen delivery agents such as oxygen-saturated perfluorocarbon nanoemulsions and lipid oxygen microbubbles have been employed to supply oxygen to hypoxic tumors with ultrasound activation. Such oxygen delivery systems are still associated with several drawbacks, including premature oxygen release and the dependence of external stimuli. To address these limitations, we developed oxygen nanobubbles that were enclosed by the acetalated dextran polymer shells for spontaneous oxygeneration in response to a minor pH drop in the tumor microenvironment. The acetalated dextran polymer shell serves as a robust barrier against gas dissolution in the circulating blood to retain the majority of the oxygen payload, and its pH-responsive property enables an abrupt burst release of oxygen in the mild acidic tumor microenvironment. The acetalated dextran oxygen nanobubbles exhibited excellent stability and biocompatibility. In vitro and in vivo experiments were conducted to investigate the pH-responsive oxygen release. The external stimuli-free supply of oxygen by the acetalated dextran oxygen nanobubbles was evaluated on CNE2 tumor-bearing mice, and the intratumoral oxygen level increased by 6-fold after the administration of the oxygen nanobubbles, manifesting that our pH-responsive oxygen nanobubbles hold great potential as a potent oxygen delivery agent to overcome the hypoxia-induced resistance.

E-cigarettes can emit formaldehyde at high levels under conditions that have been reported to be non-averse to users.

E-cigarette aerosol emission studies typically focus on benchmarking toxicant levels versus those of cigarettes. However, such studies do not fully account for the distinct chemical makeup of e-liquids and their unique properties. These approaches often conclude that there are fewer and lower levels of toxins produced by e-cigarettes than by cigarettes. In 2015, we reported the discovery of new hemiacetals derived from the reaction of formaldehyde and the e-liquid solvents. The main finding was that they constituted a significant proportion of potentially undetected formaldehyde. Moreover, unlike gaseous formaldehyde, the hemiacetals reside in the aerosol particulate phase, and thus are capable of delivering formaldehyde more deeply into the lungs. However, the findings were criticized by those claiming that some of the results were obtained under conditions that are averse to vapers. A "reinvestigation" of our study was recently published addressing this latter issue. However, this reinvestigation ignored major details, including no mention of the formaldehyde hemiacetals. Herein, we isolated both gaseous formaldehyde and formaldehyde hemiacetals at an intermediate power level claimed, in the "reinvestigation", to be relevant to "non-averse," "normal" usage. The results were that both gaseous formaldehyde and formaldehyde from hemiacetals were produced at levels above OSHA workplace limits.

Steroidomimetic aminomethyl spiroacetals as novel inhibitors of the enzyme Δ8,7-sterol isomerase in cholesterol biosynthesis.

Grundmann's ketone is converted to a spiroacetal containing a 5-hydroxymethyl-5-nitro-1,3-dioxane moiety whose hydroxymethyl group can be esterified or directly substituted with primary and secondary amines. Among the resulting aminomethyl spiroacetals, several ones bearing diamino residues were found to be inhibitors of the enzyme Δ8,7-isomerase in cholesterol biosynthesis. The complex bicyclic building block derived from Grundmann's ketone could be replaced by a properly substituted tetraline scaffold, without noteworthy loss in activity. This opens the opportunity to perform further structural modifications for the design of new steroidomimetic inhibitors of human Δ8,7-isomerase.

Total synthesis of pectenotoxin-2.

Pectenotoxin-2 (PTX2) is a shellfish toxin and has a non-anomeric spiroacetal, which is not stabilized by an anomeric effect. The selective construction of the non-anomeric spiroacetal has been a major problem in the synthesis of PTX2. Described herein is the stereoselective total synthesis of PTX2 via the isomerization of anomeric spiroacetal pectenotoxin-2b (PTX2b). The synthesis of PTX2b was achieved by a simple process including sulfone-mediated assembly of spirocyclic and bicyclic acetals and subsequent macrocyclization by ring-closing olefin metathesis. Finally, the selective construction of PTX2 was accomplished by the early termination of a dynamic transition process to equilibrium in the acid-catalyzed isomerization of anomeric PTX2b. [6,6]-Spiroacetal pectenotoxin-2c (PTX2c) was also synthesized from PTX2b. The cytotoxicity assay of the synthetic compounds against HepG2 and Caco2 cancer cells showed a potency of the order: PTX2≫PTX2b>PTX2c.