M-toluidine appears as a clear colorless liquid. Flash point below 200°F. Vapors heavier than air. Toxic by inhalation, ingestion, and skin absorption in high concentrations or under prolonged exposures. Used in the manufacture of organic chemicals. Density about 8 lb / gal.
颜色/状态：
Colorless to light yellow liquid
气味：
Aromatic, amine-like odor
蒸汽密度：
3.90 (Air = 1)
蒸汽压力：
0.303 mm Hg at 25 °C
亨利常数：
1.66e-06 atm-m3/mole
自燃温度：
481 °C (898 °F)
分解：
When heated to decomposition it emits highly toxic fumes of /nitroxides/.
Two metabolites, 2-amino-4-methylphenol and 4-amino-2-methylphenol, were identified after hydrolysis of the urine extract /from rats (strain not given)/..
The binding of monocyclic aromatic amines to hemoglobin was studied in vivo. Female Wistar rats were administered aniline, N-methylaniline, N,N-dimethylaniline, o-toluidine, m-toluidine, p-toluidine, 2,4-dimethylaniline, 2,4,5-trimethylaniline, p-chloroaniline 3,4-dichloroaniline, 4-chloro-o-toluidine, 5-chloro-o-toluidine, or 6-chloro-o-toluidine by gavage. Blood samples were collected 24 hr later and the hemoglobin was isolated. The hemoglobin samples were extracted with hexane, hydrolyzed with sodium hydroxide, and the amount of each amine recovered was determined by gas chromatography. The extent of amine/hemoglobin binding was determined by computing hemoglobin binding indices (HBIs) from the administered doses and the amount of amine recovered. Female B6C3F1 mice were administered aniline, o-toluidine, p-chloroaniline, 4-chloro-o-toluidine, or 5-chloro-o-toluidine. The extent of amine/hemoglobin binding was determined as before. Rats were given 2,4-dimethylaniline, aniline, 5-chloro-o-toluidine, 4-aminobiphenyl, or p-chloroaniline, and the extent of methemoglobin formation was determined. In rats hydrolysis of the hemoglobin yielded only one cleavage product, the parent amine, in each case. An additional signal was seen in the chromatogram in the case of 6-chloro-o-toluidine. The hemoglobin binding indices ranged from 0.7 for 2,4,5-trimethylaniline to 569 for p-chloroaniline. The binding of aniline, o-toluidine, p-chloroaniline, 4-chloro-o-toluidine, and 5-chloro-o-toluidine in mice was significantly lower than in rats. The extent of amine/hemoglobin binding in rats correlated well with the maximum concentrations of methemoglobin. /Results indicate/ that determining hemoglobin adducts may be useful for monitoring occupational exposure to amines.
30 min after a single intravenous administration of 0.77 mmol (= 111.1 mg) m-toluidine-HCl/kg bw to dogs, a maximum concentration of 3.5 ug m-nitrosotoluene/mL blood was reached. 5 hours after the injection the concentration of m-nitrosotoluene was still about 1 ug/mL blood. /m-Toluidine hydrochloride/
In vitro, the p-hydroxylation of m-toluidine by rabbit liver microsomes was measured with a specific activity of 0.43 nmol/min and mg microsomal protein.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
人体健康。虽然在大鼠尿液中鉴定出了代谢物2-氨基-4-甲基酚和4-氨基-2-甲基酚，但关于代谢和毒物动力学的信息不足。由于大鼠、小鼠和兔子的口服LD50值为450至1430毫克/千克，所以间甲苯胺的急性毒性较低。这种化学物质对皮肤有轻微刺激性，对眼睛有中等刺激性。目前还没有关于皮肤致敏的信息。根据OECD联合重复剂量和生殖/发育毒性筛选试验[TG 422]，将间甲苯胺以0、30、100、300毫克/千克/天的剂量通过灌胃给予Crj: CD (SD)雄性和雌性大鼠，至少连续给药41天。在100和300毫克/千克剂量下，关键效应是溶血性贫血，表现为红细胞计数和血红蛋白浓度降低，以及肝脏和脾脏中的色素沉积和髓外造血等组织学变化。其他毒性是肾脏管状上皮细胞病变，伴有肾脏中的色素沉积。由于在最低剂量30毫克/千克时，如脾脏中的边缘色素沉积和髓外造血等提示溶血性贫血的证据，可能是由于高铁血红蛋白形成，重复剂量毒性的LOAEL为30毫克/千克/天。在上述筛选试验[OECD TG 422]中，从雄性大鼠交配前14天到交配后14天，从雌性大鼠交配前14天到哺乳期第3天给予间甲苯胺。由于在所有动物中300毫克/千克出现了着床损失，而在100毫克/千克的10只中有2只出现了着床损失，但在30毫克/千克没有发现，因此生殖毒性的NOAEL为30毫克/千克/天。在30和100毫克/千克/天剂量下观察到的所有幼崽死亡或超过一半数量的幼崽死亡被认为是母体毒性的结果，因为有明显证据表明缺乏护理活动，可能是由于贫血，而30和100毫克/千克的所有活后代在4天内都正常发育。因此，发育毒性的NOAEL被认为是100毫克/千克/天。细菌遗传毒性研究在S. typhimurium和E. coli中无论有无代谢活化均显示阴性结果。在中国仓鼠肺(CHL/IU)细胞中进行的OECD TG 473染色体畸变试验中，没有观察到断裂性，但在最高浓度下多倍体显著增加(0.9至1.25%)。然而，这一结果被认为不是阳性，因为它在历史对照和普遍接受的显著性标准(5%)之内。两种体内研究，姐妹染色单体交换和DNA合成抑制，也显示阴性结果。因此，间甲苯胺被认为不具有遗传毒性。在雄性大鼠的饮食研究中，9400 ppm的剂量下没有观察到肿瘤，而在雄性和雌性小鼠中分别为14700和20400 ppm的剂量下也没有观察到肿瘤。然而，啮齿动物的致癌性结论不确定，因为与当前的致癌性测试协议相比，实验条件不足。环境。这种化学物质主要在水体中持久存在，当释放到其他环境隔室时，它将被传输到水体。这种化学物质不易生物降解，其生物积累潜力较低。这种化学物质已在有限数量的水生生物种类中进行了测试。对于藻类，72小时EC50(生物量变化，Selenastrum capricornutum)为17.7毫克/升。对于水蚤，最低急性毒性值为0.73毫克/升(48小时EC50，不动性)，最低慢性值为0.01毫克/升(21天NOEC，繁殖)。对于鱼类，只有急性数据可用，其中最低值为34毫克/升(96小时LC50，Oryzias latipes)。从最低慢性值(NOEC水蚤；0.01毫克/升)使用评估因子100计算出的水生生物的PNEC为0.0001毫克/升。这种化学物质对水生生物的毒性，特别是对水蚤的毒性很高。暴露。1990-1992年间，日本生产的间甲苯胺量少于100吨，1988-1992年间进口量为97-285吨/年，然而1998年日本的生产量和进口量均为0吨。这种化学物质用作颜料、摄影剂等中间体。这种化学物质在中性或碱性溶液中稳定，被归类为“不易生物降解”。预期会发生直接光降解。半衰期估计约为4个月。一个通用的 fugacity模型(Mackey三级)显示这种化学物质主要分布到水中。在1977年对日本一般环境的监测研究中，从地表水和沉积物中检测到了间甲苯胺，但在1999年的监测研究中，水中、沉积物中或空气中均未检测到。根据一家日本制造商的数据，估计每年有400千克间甲苯胺随1 x
Human Health. Although the metabolites, 2-amino-4-methylphenol and 4-amino-2-methylphenol were identified in the rat urine with a small amount of the parent compound, there is not sufficient information on metabolism and toxicokinetics. Acute toxicity of m-toluidine is low because the oral LD50 values in rat, mouse and rabbit are from 450 to 1,430 mg/kg. This chemical is slightly irritating to skin and moderately irritating to eyes. There is no information available on skin sensitization. In accordance with an OECD combined repeat dose and reproductive/developmental toxicity screening test [TG 422], m-toluidine was given to Crj: CD (SD) male and female rats by gavage at doses of 0, 30, 100, 300 mg/kg/day for at least 41 days. The critical effect at 100 and 300 mg/kg is a hemolytic anemia, revealed by reduction of erythrocyte counts and hemoglobin concentration, and histological changes such as pigment deposit and extramedullary hematopoiesis in liver and spleen. Other toxicity is renal tubular epithelium lesions accompanied with pigment deposit in kidney. As there is suggestive evidence of hemolytic anemia such as marginal pigment deposit and extramedullary hematopoiesis in spleen at the lowest dose of 30 mg/kg, probably caused by methemoglobin formation, LOAEL for repeat dose toxicity was 30 mg/kg/day. In the above screening test [OECD TG 422], m-toluidine was given from 14 days before mating to 14 days after mating in males and from 14 days before mating to day 3 of lactation in females. As implantation losses were found in all animals at 300 mg/kg and two of ten at 100 mg/kg but not at 30 mg/kg, NOAEL for reproductive toxicity is 30 mg/kg/day. The death of all pups or more than half the number of pups observed at 30 and 100 mg/kg/day is considered as the result of maternal toxicity because there is clear evidence of the lack of the nursing activity, probably due to anemia, and all live offsprings of 30 and 100 mg/kg had normally developed up to 4 days. Therefore the NOAEL for developmental toxicity is considered to be 100 mg/kg/day. Bacterial genotoxicity studies show negative results in S. typhimurium and E. coli with and without metabolic activation. In chromosomal aberration test conducted in cultured Chinese hamster lung (CHL/IU) cells by OECD TG 473, clastogenicity was not observed but significant increase of polyploidy (0.9 to 1.25 %) was found at the highest concentration. However, this result was considered not to be positive because it was within historical control and generally accepted criteria of significance (5 %). Two kinds of in vivo studies, sister chromatid exchange and inhibition of DNA-synthesis, also show negative results. Therefore m-toluidine is considered not to be genotoxic. Tumors were not observed in dietary study of male rats at 9,400 ppm and male and female mice at 14,700 and 20,400 ppm, respectively. However, the carcinogenicity in rodents is inconclusive because the experimental conditions were insufficient compared to a current carcinogenicity testing protocol. Environment. This chemical is mainly persistent in water and it will be transported to water compartment when released to other environmental compartments. The chemical is not readily biodegradable, and its bioaccumulation potential is low. This chemical has been tested in a limited number of aquatic species. For algae, 72 hr EC50 (biomass change in Selenastrum capricornutum) is 17.7 mg/L. For Daphnia, the lowest acute toxicity value is 0.73 mg/L (48 hr EC50 for immobilization), and the lowest chronic value is 0.01 mg/L (21d NOEC for reproduction). For fish, only acute data were available, the lowest of which is 34 mg/L (96 hr LC50, Oryzias latipes). PNEC of 0.0001 mg/L for the aquatic organisms was calculated from the lowest chronic value (NOEC for Daphnia; 0.01 mg/L) using an assessment factor of 100. Toxicity of this chemical to aquatic organisms, specially against Daphnia, is high. Exposure. The production volume of m-toluidine in Japan was less than 100 tonnes in 1990 - 1992, and imported volume was 97-285 tonnes/year in 1988-1992, however both the production volume and imported volume in Japan in 1998 was 0 ton. This chemical is used as intermediates for pigments, photography agents and others. This chemical is stable in neutral or alkaline solutions, and is classified as "not readily biodegradable". Direct photodegradation is expected. The half-life is estimated to be about 4 months. A generic fugacity model (Mackey level III) shows this chemical would be distributed mainly to water. In the monitoring study of the general environment in Japan in 1977, m-toluidine was detected from surface water and sediment, but in the monitoring study in 1999, it was not detected in water, sediment or air. According to a Japanese manufacturer, 400 kg/year (estimated) of m-toluidine are released with 1 x 10+7 tonnes/year of effluent into bay. Local predicted environmental concentration (PEClocal) is 4.0 x 10-5 mg/L, employing the calculation model. The highest exposure to the general population via the environment would be expected through drinking water processed from surface water. The concentration in drinking water is assumed to be less than 4.0 x 10-5 mg/L. Consumer exposure is negligible because m-toluidine is not contained in consumer products. As m-toluidine is mainly produced in a closed system, occupational exposures at production sites may occur by the inhalation and dermal route. Estimated human exposure for a worker who operates sampling (0.1 hr/day), drum filling (1.5 hr/day), and reaction vessel cleaning (2 day/year) without protective equipment is less than 0.21 mg/kg/day. By wearing chemical cartridge respirator during these operations, and ventilation systems during the filling process, exposure level is lower than the estimation.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌性证据
A4；不可归类为人类致癌物。
A4; Not classifiable as a human carcinogen.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
暴露途径
这种物质可以通过吸入、皮肤接触和摄入被身体吸收。
The substance can be absorbed into the body by inhalation, through the skin and by ingestion.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
After a single oral administration of 500 mg m-toluidine to rats (strain not given), only 2.5% of the unchanged compound was recovered from the urine for 24 hrs and two metabolites, 2-amino-4-methylphenol and 4-amino-2-methylphenol were identified after hydrolysis of the urine extract. However, there is no information on the quantitative metabolism and excretion. After dermal application to rats, m-toluidine was dose-dependently detected in the blood. In the case of a single iv injection of 111.1 mg m-toluidine-HCl/kg bw to dogs, the metabolite, m-nitrosotoluene in blood reached to a maximum concentration of 3.5 ug/mL at 30 min and still remained at approx. 1 ug/mL at 5 hrs.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
m-甲苯胺在大鼠经皮肤（尾部）给药后在血浆中被检测到，血浆水平与剂量水平相关。
m-Toluidine was detected in the blood plasma of rats after dermal application (tail). The plasma levels correlated with the dose-level.
Urinary levels in rats of o-, m-, and p-toluidine (20, 100, or 200 mg/kg, intragastric administration) were positively correlated with the toluidine dose; 26, 10, and 10% of the unchanged toluidines, respectively, were excreted after 24 hr. After chronic administration of m-toluidine, excretion rate of the unchanged toluidine increased with duration of the experiment.
series of novel L-homoserine lactone analogs and evaluated their in vitro quorumsensing (QS) inhibitory activity against two biomonitor strains, Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PAO1. Studies of the structure-activity relationships of the set of L-homoserine lactone analogs indicated that phenylurea-containing N-dithiocarbamated homoserine lactones are more potent than (Z)-
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
An enantioselective alkoxycarbonylation-amination cascade process of terminalallenes with CO, methanol, and arylamines has been developed. It proceeds under mild conditions (room temperature, ambient pressure CO) via oxidative Pd(II) catalysis using an aromatic spiroketal-based diphosphine (SKP) as a chiral ligand and a Cu(II) salt as an oxidant and affords a wide range of α-methylene-β-arylamino
Dihydroquinazolines enhance 20S proteasome activity and induce degradation of α-synuclein, an intrinsically disordered protein associated with neurodegeneration
作者：Taylor J. Fiolek、Christina L. Magyar、Tyler J. Wall、Steven B. Davies、Molly V. Campbell、Christopher J. Savich、Jetze J. Tepe、R. Adam Mosey
DOI：10.1016/j.bmcl.2021.127821
日期：2021.3
traditional small molecule drug design and are often referred to as “undruggable”. The 20Sproteasome is the main protease that targets IDPs for degradation and therefore small molecule 20Sproteasome enhancement presents a novel therapeutic strategy by which these undruggable IDPs could be targeted. The concept of 20S activation is still relatively new, with few potent activators having been identified
Novel compounds and compositions as protease inhibitors
申请人：——
公开号：US20020052378A1
公开（公告）日：2002-05-02
The present invention relates to novel cysteine protease inhibitors of Formula I:
1
the pharmaceutically acceptable salts and N-oxide derivatives thereof, their use as therapeutic agents and methods of making them.
