Three chromogenic products of AHTN have been detected after photo-oxidation and shown to react with glycine or albumin, giving rise first to a blue color, followed by pink and, finally, a dark green color. The absorption spectrum associated with the late green color showed an increased absorbance in the long wavelength region of the spectrum, similar to the green color extracted from the liver of AHTN-treated animals. The color produced by the chromogenic derivatives of AHTN and by o-diacetylbenzene (a model chromogenic compound) were tightly bound to the protein pellet and resistant to acidic pH, unlike the color from the ninhydrin reaction. The dark green colour produced in the liver by feeding AHTN to rats was also tightly bound to proteins and stable to acidic pH. These results suggest that both the photo-oxidized chromogenic derivatives of AHTN and o-diacetylbenzene, produce colored derivatives with amino acids and proteins by a mechanism unrelated to ninhydrin. They also suggest that a chromogenic derivative of AHTN, produced in vivo during prolonged treatment with high doses of AHTN, may be responsible for the green color of the livers and other tissues from treated animals. The data suggest that the AHTN-derived chromogenic material is metabolite-related rather than representative of a toxic process ...
IDENTIFICATION AND USE: Tonalide is a solid with a musk odor. It is used as a fragrance in cosmetics, detergents, fabric softeners, household cleaning products and air fresheners. HUMAN STUDIES: No irritation was observed after repeated occlusive applications as well as no phototoxic reactions. High concentrations of tonalide can affect steroidogenesis in vitro using the H295R cell line. Tonalide was not genotoxic in the micronucleus test with human lymphocytes in vitro with or without metabolic activation. ANIMAL STUDIES: Tonalide did not produce erythema or edema when tested on the skin of rabbits. In tests for photoirritation in the rabbit clear phototoxicity was seen at 5% in ethanol. Moderate redness and slight to moderate chemosis of the conjunctivae was seen in rabbits in an eye irritation test. A single high dose of tonalide leads to acute hepatic damage in rats. In other experiment, rats were treated with doses 1260, 1588, 2000 or 2520 mg/kg bw and observed for 14 days. The majority of animals showed lethargy, piloerection, hunched position, oscillated movements, shaggy coat and emaciation. Other occasional signs included green urine, hypothermia, half-closed eyes, difficult breathing and increased breathing, prostration and lacrimation. In a 2-week study, groups of 5 male and female rats were administered dietary doses of 0, 33, 88 and 169 mg/kg bw/day for males and 0, 32, 91 and 150 mg/kg bw/day for females. All animals in the high dose group had marked reduction in food consumption and body weight losses. Food consumption and body weight losses were slightly reduced at the mid-dose. In a two generation developmental study in rats, there were no adverse effects to the dams or offspring up to and including the highest dose level (20 mg/kg bw/day). In genotoxicity studies no positive responses were observed except for cells with structural aberrations in the in vitro cytogenetics assay in CHO cells with metabolic activation. ECOTOXICITY STUDIES: In Dreissena polymorpha, tonalide exposure induced lipid peroxidation and increased carbonyl content alone with significant increases in DNA strand breaks, but no fixed genetic damage was observed. Cytochrome P450 isoforms are potentially sensitive targets of synthetic musk substances in fish. There was no observed significant effect on the growth rate of E. fetida after a 28-day tonalide exposure except that at the highest concentration 100 ug/g, whereas a significant decrease of cocoon production was found in earthworms exposed to 50 and 100 ug/g.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。
Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
... In the present study the subchronic hepatotoxicity of AHTN administered to rats at doses within the human exposure range was evaluated. For this purpose female and male juvenile Wistar rats were exposed to AHTN (300 ug/kg body weight per day, i.p.) alone or to a single dose of diethylnitrosamine (DEN) (100 mg/kg body weight, ip) followed by AHTN (1, 10, 100 or 300 ug/kg body weight per day, ip) for 90 days. Thereafter the liver architecture as well as the presence of placental glutathione S-transferase (GST-P)-positive hepatic lesions was assessed. In male animals receiving AHTN alone or in combination with DEN the number of GST-P-positive single hepatocytes was similar to that in untreated rats, while GST-P-positive mini-foci and foci were not observed. In the case of female rats the number of GST-P-positive single hepatocytes and mini-foci in AHTN-treated rats was similar to that in untreated animals ...
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR as necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Aromatic hydrocarbons and related compounds/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/
/MILK/ In a study designed to determine the effects of AHTN on the neonate when exposed through nursing, AHTN (purity 99.3%) was administered at dosages of 0, 2, 6 or 20 mg/kg bw/day once daily by gavage in corn oil to groups of 28 time-mated rats (Crl:CD BR VAF/Plus strain) from Day 14 of pregnancy (end of organogenesis) through to weaning on Day 21 post partum. The females were allowed to litter and rear their young to weaning (litters were standardised to 8 pups on Day 4 post partum). From these litters, selected offspring were retained (24 males and females per group) to maturity and assessed for behavioral changes and reproductive capacity. The F1 generation was only exposed to AHTN in utero during the perinatal phase and through transfer in the milk of the lactating dams. ... AHTN levels in mother's milk up to 1.9 and 25 mg AHTN equivalents (including also metabolite)/L were found at oral doses of 2 and 20 mg 14C-AHTN/kg bw/ day, respectively, to the dams. ... The offspring (F2 generation) were examined for abnormalities at parturition and periodically until day 21 post partum at which time the study was terminated. There were no effects of treatment in any of the treated parent females during pregnancy or lactation. No effects were apparent on development of the F1 generation during the late prenatal phase, or on postnatal growth, no changes in post weaning behavioral tests or mating performance were seen and post mortem examination of F1 males and females, reproductive capacity, litter data and macroscopic post mortem examination of F2 pups did not reveal abnormalities. There were no adverse effects to the dams or offspring up to and including the highest dose level (20 mg/kg bw/day).
Synthetic musks, chemical constituents of personal care products, enter the human body through dermal contact. Elucidation of the mechanisms underlying transdermal permeation of synthetic musks should enhance our understanding of their uptake and distribution in human skin and allow accurate evaluation of associated human exposure. Here, the transdermal permeation dynamics and distribution of galaxolide (HHCB) and tonalide (AHTN) were investigated using an in vitro skin diffusion model. The transdermal permeation amounts of HHCB and AHTN increased rapidly during the first 6 hr. The applied HHCB and AHTN amounts did not affect percutaneous absorption rates. HHCB and AHTN remained primarily in the stratum corneum, accounting for 70.0% and 70.3% of the totals during the 24-hr period, respectively. The percutaneous absorption rate of both chemicals was ~11%. HHCB, AHTN, musk ketone, musk xylene, and Musk-T were detected in 29 personal care products. The average total concentrations of the musks were 3990, 54.0, 17.7, and 9.8 ug/g in perfume, shampoo, lotion, and shower gel, respectively. Among the four product categories, HHCB was dominant (57.4%-99.6%), followed by AHTN. The data clearly indicate that polycyclic and nitro musks are most commonly used in personal care products. The total estimated dermal intake (51.6 ug/kg bw/day) was markedly higher than total dermal uptake (5.9 ug/kg bw/day) when percutaneous absorption rates of the chemicals were added into the calculation. Uptake of HHCB and AHTN via dermal contact of personal care products was significantly higher than that from dust inhalation calculated according to earlier literature data.
Chinese sturgeon (Acipenser sinensis) was listed as a Grade I protected animal in China in 1989, and the observed intersexual phenomenon and sex ratio deviation have suggested that chemicals have posed a risk as environment pollutants. This study analyzed seven musk fragrances in liver, muscle, heart, gonad, stomach, intestines, adipose, gill, pancreas, kidney, gallbladder, and roe from 13 female Chinese sturgeons, and the toxicokinetic behavior of musks were studied and compared with some organochlorines. Of the seven musks, HHCB, AHTN, and musk xylene were detected, and the highest concentrations were observed in adipose tissue: from 33.7 to 62.1 ng/g wet weight (ww), from 1.0 to 5.4 ng/g ww, and from 1.1 to 13 ng/g ww, respectively. Similar to the tissue distribution of DDTs and HCB, musks were detected frequently in high lipid content tissues such as roe, adipose, and liver, suggesting that tissue distribution of musks is controlled by the affinity to lipids. The concentration ratios based on lipid weight between roe and adipose were estimated to be 0.47 for HHCB, 0.58 for AHTN, and 0.51 for musk xylene, and those for the total DDTs and HCB were 0.27 and 0.61, which were relatively low compared with mammals. Relatively high concentrations of p,p'-DDE (68.4-449 ng/g ww) were detected in 10 of total 11 samples, which would cause the feminization of Chinese sturgeons during embryonic development. It was found that lipid-corrected concentrations of HHCB, AHTN, p,p'-DDE, and p,p'-DDD increased with age in female sturgeon, of which the trends were similar to those in fishes and different from those in mammals.
/MILK/ Synthetic musks are used as additives in many household products. After absorption into the human body, they accumulate and their concentrations in human milk reflect both the mother and her infant's exposure level. Concentrations of four synthetic musks, musk xylene (1-tert-butyl-2,6-dimethyl-2,4,6-trinitrobenzene, MX), musk ketone (4-tert-butyl-2,6-dimethyl-3,5-dinitroacetophenone, MK), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[gamma]-2-benzopyran (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyl- 1,2,3,4-tetrahydronaphthalene (AHTN), were determined in human milk samples collected from Shanghai, Wuxi, and Shaoxing in Eastern China. The four synthetic musks were found in most samples analyzed, with HHCB the dominant component followed by MX. The median (mean) values for HHCB, AHTN, MX and MK concentrations were 63 (82), 5 (12), 17 (24) and 4 (9) ng/g lipid weight, respectively. These data suggested the total synthetic musk contamination was low, and the distribution percentage was HHCB > MX > AHTN approximately MK. The relative high ratio of nitro to polycylic musk indicated that nitro musks were still widely used. The musk concentrations in these cities were not significantly different from each other (p > 0.05). Principal components score plots were obtained, which showed similar exposure sources. The amount of total synthetic musks in human milk were not associated with mother's age, although HHCB was significantly correlated with AHTN (p < 0.05). Daily ingestion of HHCB, AHTN, MX and MK for infants from human milk were estimated as (2526 +/- 2926), (370 +/- 524), (7391 +/- 832), and (277 +/- 462) ng/day, respectively. Those doses were 1-2 orders of magnitude below the provisional tolerable daily intakes.
Trienediolates of hexadienoic acids in synthesis. synthesis of retinoic and nor-retinoic acids.
摘要：
Double deprotonation of either (E,E)-3-methyl-2,4-hexadienoic acid 2. or 4,6-dimethyldihydro-2-pyrone 3 generates apparently the same lithium trienediolate, which affords omega-hydroxy acids 9 on reaction with ketones 7. Hydroxy acids 9 arc easily dehydrated to octatrienoic acids 5. which are structurally related to retinoic acid. Similarly, sorbic acid 1 leads to nor-retinoic acid analogs 6.
作者：Haiwen Xiao、Zhonglin Liu、Haigen Shen、Benxiang Zhang、Lin Zhu、Chaozhong Li
DOI：10.1016/j.chempr.2019.02.006
日期：2019.4
Direct trifluoromethylation of C(sp3)–H bonds, especially in late stages, remains a formidable challenge. Herein, we describe the copper-catalyzed benzylicC(sp3)–H trifluoromethylation. With Cu(I) or Cu(II) as the catalyst, (bpy)Zn(CF3)2 (bpy = 2,2′-bipyridine) as the CF3 source, and NFSI (or Selectfluor) as the oxidant, site-selective benzylicC(sp3)–H trifluoromethylation is successfully implemented
method for the α-trifluoromethoxylation of ketones is reported. Enol carbonates react with N-trifluoromethoxy-4-cyano-pyridinium, using the photoredox catalyst 4-CzIPN under 456 nm irradiation, affording the α-trifluoromethoxy ketones in ≤50% isolated yield and complete chemoselectivity. As shown by 29 examples, the reaction is general and proceeds very rapidly under batch (1 h) and flow conditions (2 min)
Transformations of Aryl Ketones via Ligand‐Promoted C−C Bond Activation
作者：Hanyuan Li、Biao Ma、Qi‐Sheng Liu、Mei‐Ling Wang、Zhen‐Yu Wang、Hui Xu、Ling‐Jun Li、Xing Wang、Hui‐Xiong Dai
DOI：10.1002/anie.202006740
日期：2020.8.17
The coupling of aromatic electrophiles (aryl halides, aryl ethers, aryl acids, aryl nitriles etc.) with nucleophiles is a core methodology for the synthesis of aryl compounds. Transformations of arylketones in an analogous manner via carbon–carbon bond activation could greatly expand the toolbox for the synthesis of aryl compounds due to the abundance of arylketones. An exploratory study of this
methodologies and occurs through a trifluoroacyl radical mechanism promoted by a photocatalyst, which triggers a C−O bond fragmentation. Mechanistic studies (kineticisotopeeffects, spectroelectrochemistry, optical spectroscopy, theoretical investigations) highlight the evidence of a fleeting CF3CO radical under photoredox conditions. The trifluoroacyl radical can be stabilized under CO atmosphere, delivering
我们报告了一种温和且操作简单的烯烃三氟酰化策略，该策略利用三氟乙酸酐作为低成本且易于获得的试剂。这种光介导的过程与传统方法有着根本的不同，它通过由光催化剂促进的三氟酰基自由基机制发生，从而触发 CO 键断裂。机理研究（动力学同位素效应、光谱电化学、光谱学、理论研究）突出了转瞬即逝的 CF 3的证据光氧化还原条件下的 CO 自由基。三氟酰基自由基可以在 CO 气氛下稳定，提供具有更高化学效率的三氟乙酰化产物。此外，该方法可以通过简单地改变反应参数变成三氟甲基化协议。除了简单的烯烃外，该方法还允许小分子药物和常见药效团的化学和区域选择性功能化。
[EN] 2-HYDROXY-6-METHYL-HEPTANE DERIVATIVES AS PERFUMING INGREDIENTS<br/>[FR] DÉRIVÉS DU 2-HYDROXY-6-MÉTHYL-HEPTANE EN TANT QUE COMPOSANTS PARFUMANTS
申请人：FIRMENICH & CIE
公开号：WO2011135487A1
公开（公告）日：2011-11-03
The present invention relates to the field of perfumery. More particularly, it concerns some derivatives of formula 5 in the form of any one of its stereoisomers or a mixture thereof, and wherein R1 represents a hydrogen atom, a C1-4 alkyl or alkenyl group, or a (CHR)2OH group, each R being a hydrogen atom or a methyl group; R2 represents a hydrogen atom or a 10 methyl, ethyl or n-propyl group; and R3 represents a hydrogen atom or a methyl group; as well as their use as perfuming ingredients. The present invention concerns also the compositions or articles containing said compounds.
