TLV-TWA 10 ppm (～40 mg/m3) (ACGIH),
1 ppm (NIOSH), 50 ppm (MSHA and
OSHA); ceiling 2 ppm/15 min (NIOSH);
carcinogenicity: Animal Sufficient Evidence,
Human Limited Evidence (IARC).
LogP：
1.45 at 20℃
物理描述：
Ethylene dichloride appears as a clear colorless liquid with a chloroform-like odor. Flash point 56°F. Denser than water and insoluble in water. Vapors are heavier than air. Density 10.4 lb / gal.
颜色/状态：
Heavy liquid
气味：
Pleasant, chloroform-like
味道：
Sweet taste
蒸汽密度：
3.4 (NTP, 1992) (Relative to Air)
蒸汽压力：
78.9 mm Hg at 25 °C
水溶性：
-1.06
亨利常数：
Henry's Law constant = 1.18X10-3 atm-cu m/mole at 25 °C
大气OH速率常数：
2.48e-13 cm3/molecule*sec
稳定性/保质期：
Stable under recommended storage conditions.
自燃温度：
775 °F (413 °C)
分解：
Decomposes to vinyl chloride and HCl anove 600 °C.
粘度：
0.84 cP at 20 °C
腐蚀性：
Corrodes iron and other metals at elevated temperatures when in contact with water.
In rats, radiolabeled ethylene dichloride was excreted primarily in the urine, and the major urinary metabolites were chloroacetic acid, 5-carboxymethyl cysteine, and thiodiacetic acid.
The metabolism and binding of (14)C-labelled 1,2-dichloroethane in female C57BL mice were studied. As shown by whole-body autoradiography of iv injected mice, a selective localization of non-volatile and bound 1,2-dichloroethane metabolites occurred in the nasal olfactory mucosa and the tracheo-bronchial epithelium. Low levels of metabolites were also present in the epithelia of the upper alimentary tract, vagina and eyelid, and in the liver and kidney. A decreased mucosal and epithelial binding was observed after pretreatment with metyrapone, indicating that the binding might be due to an oxidative metab of 1,2-dichloroethane. The levels of in vivo binding were considerably lower in mice injected ip with 1,2-dichloroethane as compared to mice given equimolar doses of (14)C-labelled 1,2-dibromoethane. In vitro experiments with 1000 g supernatants from various tissues showed that nasal mucosa has a marked ability to activate 1,2-dichloroethane into products that become irreversibly bound to the tissue. The nasal olfactory mucosa is a target tissue for toxicity of 1,2-dichloroethane.
... Using isolated rat hepatocytes as a model system, and electron spin resonance spectroscopy coupled to the spin trapping technique as a detection technique, the formation of free radical derivatives was demonstrated, both under normoxic as well as under hypoxic conditions from carbon tetrachloride (CCl4), chloroform (CHCl3), 1,1,1-tetrachloroethane, and 1,1,2,2-tetrachloroethane. In contrast, free radical production was only detectable under hypoxic conditions when 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethane, and 1,1,2-trichloroethane were added to the hepatocyte suspensions....
Chlorinated hydrocarbons found in a bioassay to be carcinogenic to both B6C3F1 mice and Osborne-Mendel rats (1,2-dichloroethane), carcinogenic only to mice (1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, hexachloroethane, trichloroethylene, and tetrachloroethylene), and noncarcinogenic to either species (1,1-dichloroethane and 1,1,1-trichloroethane) were used to investigate the biochemical bases for tumorigenesis. Studies were conducted after chronic oral dosing of adult mice and rats with the MTD and 1/4 MTD of each compound. The extent to which the compounds were metabolized in 48 hr, hepatic protein binding, and urinary metabolite patterns were examined. Metabolism of the compounds (mmoles per kg body weight) was 1.7 to 10 times greater in mice than in rats. Hepatic protein binding (nanomole equivalents bound to 1 mg of liver protein) was 1.2 to 8.3 times higher in mice than in rats except for 1,2-dichloroethane and 1,1,1-trichloroethane. The noncarcinogens 1,1-dichloroethane and 1,1,1-trichloroethane exhibited 2 to 18 times more binding in mice than did the carcinogens 1,2-dichloroethane and 1,1,2-trichloroethane. Urinary metabolite patterns of the compounds were similar in both species. The biochemical parameters measured provided no clue to differentiate the carcinogens from the noncarcinogens.
Due to its physical properties such as its lipophilicity, 1,2-dichloroethane is likely to be absorbed across the alveolar membranes of the lung, mucosal membranes of the gastrointestinal tract, and the skin by passive diffusion. Once in the body, it is widely distributed, with the greatest amounts accumulating in the more lipophilic tissues. The primary route of biotransformation involves conjugation with glutathione to yield nonvolatile urinary metabolites. The other route, a cytocrome P-450-mediated oxidation is responsible for the formation of chloroacetaldehyde. Metabolic saturation appears to occur sooner after oral (gavage) administration than after inhalation exposure. Following inhalation or oral exposure, elimination of 1,2-dichloroethane occurs primarily via excretion of soluble metabolites in the urine and excretion of unchanged parent compound and carbon dioxide in the expired air. (L156)
IDENTIFICATION AND USE: 1,2-Dichloroethane is a colorless, oily liquid. It is used in production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane. It is also used as lead scavenger in antiknock gasoline, paint, varnish, and finish removers, metal degreasing, soaps and scouring compounds, wetting and penetrating agents, ore flotation, and as a solvent. HUMAN STUDIES: Acute incidental exposure to 1,2-dichloroethane by inhalation or ingestion has resulted in a variety of effects in humans, including effects on the central nervous system, liver, kidney, lung and cardiovascular system. The respiratory effects exhibited by individuals who died following acute oral exposure to 1,2-dichloroethane included congestion, pulmonary edema (at 570 mg/kg/day) and bronchitis. Ingestion of >/= 570 mg/kg/day of 1,2-dichloroethane resulted in severe hepatocellular damage and liver atrophy and necrosis. The potential carcinogenicity of 1,2-dichloroethane in exposed human populations has not been extensively investigated. It induced unscheduled DNA synthesis in primary cultures of human cells and gene mutation in several cell lines. Mutation frequency in human cell lines has been correlated with differences in glutathione-S-transferase activity. ANIMAL STUDIES: The acute toxicity of 1,2-dichloroethane is low in experimental animals. The results of short-term and subchronic studies in several species of experimental animals indicate that the liver and kidneys are the target organs. Morphological changes in the liver were observed in several species following subchronic exposure to airborne concentrations. Increases in the relative liver weight have been observed in rats following subchronic oral administration. The carcinogenicity of 1,2-dichloroethane has been investigated in a bioassays on experimental animals and significant increases were not reported in the incidence of any type of tumor in rats or mice exposed by by inhalation. There was a non-significant increase in the incidence of mammary gland adenomas and fibroadenomas in female rats exposed by inhalation. In contrast, there was convincing evidence of increases in tumor incidence in two species following ingestion. Significant increases in the incidence of tumors at several sites (including squamous cell carcinomas of the stomach (males), hemangiosarcomas (males and females), fibromas of the subcutaneous tissue (males), adenocarcinomas and fibroadenomas of the mammary gland (females)) were observed in rats administered daily doses by gavage. Similar increases in the incidences of tumors at multiple sites (including alveolar/bronchiolar adenomas (males and females), mammary gland adenocarcinomas (females) and endometrial stromal polyp or endometrial stromal sarcoma combined (females) and hepatocellular carcinomas (males)) occurred in mice administered daily doses by gavage. The incidence of lung tumors (benign papillomas) was significantly increased in female mice following repeated dermal application of 1,2-dichloroethane. Concomitant exposure to inhaled 1,2-dichloroethane and disulfiram in the diet resulted in an increased incidence of intrahepatic bile duct cholangiomas and cysts, subcutaneous fibromas, hepatic neoplastic nodules, interstitial cell tumors in the testes and mammary adenocarcinomas in rats, compared to rats administered either compound alone or untreated controls. No potential to initiate or promote tumor development was evident. In in vitro assays, 1,2-dichloroethane has been consistently positive in mutagenicity bioassays in Salmonella typhimurium. In cultured mammalian cells, 1,2-dichloroethane forms adducts with DNA. It also induces unscheduled DNA synthesis in primary cultures of rodent cells and gene mutation in several cell lines. There is no evidence that 1,2-dichloroethane is teratogenic in experimental animals. ECOTOXICITY STUDIES: In Chlorella pyrenoidosa the content of malondialdehyde (MDA) increased with the increasing concentration of 1,2-dichloroethane. An increase in mutation frequency was reported in barley (Hordeum vuigare) when kernels were treated for 24 hrs at 20 °C with 30.3 mM 1,2-dichloroethane.
1,2-Dichloroethane is metabolized to 2-chloroacetaldehyde, S-(2-chloroethyl)glutathione by conjugation with glutathione, and to other putative reactive intermediates capable of binding covalently to cellular macromolecules in the liver, kidney, and other tissues. The conjugation of 1,2-dichloroethane with glutathione is catalyzed primarily by glutathione S-transferases. 1,2-Dichloroethane appears to be activated to mutagenic species to a lesser extent by the hepatic microsomal cytochrome P-450 enzyme system. Reactive metabolites of 1,2-dichloroethane produced by hepatic microsomal cytochrome P-450 can bind to cellular proteins and DNA. It has been suggested that 1,2-dichloroethane-induced toxicity occurs when the biotransformation processes are saturated, thereby allowing higher levels of 1,2-dichloroethane to circulate throughout the body and conjugate with glutathione instead of being detoxified and eliminated. (L156, A113)
Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,2-dichloroethane. There is sufficient evidence in experimental animals for the carcinogenicity of 1,2-dichloroethane. Overall evaluation: 1,2-Dichloroethane is possibly carcinogenic to humans (Group 2B).
CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on the induction of several tumor types in rats and mice treated by gavage and lung papillomas in mice after topical application. HUMAN CARCINOGENICITY DATA: None.
The compound 1,2-dichloroethane (DCE) is a ubiquitous environmental contaminant. The primary route of exposure of humans to DCE is inhalation of its vapor. The present investigation was undertaken to determine the distribution and accumulation of DCE in the blood, lung, liver, brain, kidney and abdominal fat of rats during and after inhalation exposure. Male rats were exposed to 160 ppm (v/v) of DCE vapor for 360 min and the concentrations of DCE in the blood and tissues during the inhalation exposure period and after the end of the exposure period were measured. DCE accumulation in the abdominal fat was much greater than that in the blood and other tissues. The information we obtained in this study is useful basic data pertaining to the pharmacokinetics of DCE and DCE-mediated carcinogenicity: Our results suggest that one of the factors involved in the induction of peritoneal tumors in rats exposed to DCE vapor by inhalation is DCE accumulation in the abdominal fat.
The effect of the pretreatment of male Sprague-Dawley rats with phenobarbital (PB), butylated hydroxyanisole (BHA) and disulfiram (DSF) on the inhalation kinetics of 1,2-dichloroethane [ethylene dichloride (EDC)] was studied by the gas uptake method. A closed recirculating system was constructed and characterized. The rate curves in all the pretreatment regimens showed saturable dependence on EDC concentration. These saturable dependencies (Michaelis-Menten) appeared to be associated with enzymatic metabolism. In general, a two-compartment, steady-state pharmacokinetic model described the uptake data. Data were transformed by Hanes plots to calculate the inhalational Km, the ambient EDC concentration at which uptake proceeded at half maximum rate, and Vmax, the maximum rate of uptake (i.e., maximum rate of metabolism). Although PB and BHA pretreatments did not affect the Km of EDC, PB pretreatment increased the Vmax while DSF pretreatment decreased both the Km and Vmax.
The levels of 1,2-dichloroethane (1,2-EDC), and its metabolites 2-chloroethanol, monochloroacetic acid, and 2-chloroacetaldehyde were determined by gas chromatography in the organs of human cadavers in cases of acute poisoning. The highest 1,2-dichloroethane levels were observed in the stomach and omentum; lower levels in the kidney, spleen, brain, heart, large and small intestines, and blood, and no detectable amounts in the liver. 2-Chloroethanol and monochloroacetic acid, minor metabolites of 1,2-dichloroethane, were detected in small amounts in the myocardium, brain, stomach, and small intestine. 2-Chloroacetaldehyde, because it is a reactive intermediate in the biotransformation of 1,2-dichloroethane was not detectable in the organs. The administration of acetylcysteine to acutely intoxicated humans showed no positive clinical effect. ...
Urinary excretion of thiodiglycolic acid and thioethers after 1,2-dichloroethane dosing was studied in rats. Male Sprague-Dawley rats were administered 0, 0.12, 0.25, 0.50, 1.01, 2.02, 4.04 or 8.08 umol/kg (14)C labeled 1,2-dichloroethane orally. Urine samples were collected for 24 hours and analyzed for thiodiglycolic acid and thioethers before and after alkaline hydrolysis by gas chromatography and the Ellman reagent/absorption spectrophotometry (thioether assay), respectively. The amounts of 1,2-dichloroethane derived radioactivity excreted decreased as a logarithmic function of increasing 1,2-dichloroethane dose ranging from 62.1% of the dose for 0.12 and 0.25 umol/kg 1,2-dichloroethane to 7.4% of the 8.08 umol/kg dose. The concentrations of urinary thiodiglycolic acid were well correlated with 1,2-dichloroethane dose up to 2.02 umol/kg. When expressed as a percentage of the dose urinary excretion of thiodiglycolic acid was not dependent on the dose over the range 0.12 to 1.01 umol/kg 1,2-dichloroethane and amounted to 21.8% of the dose. Before alkaline hydrolysis no thioethers could be detected. After alkaline hydrolysis, urinary excretion of thioethers by rats dosed with 0.12 and 0.25 umol/kg did not differ significantly from the control value. Between 0.25 and 4.04 umol/kg 1,2-dichloroethane, thioether excretion increased linearly with dose. The highest thioether/thiodiglycolic ratio 0.17 occurred in rats given 8.08 umol/kg 1,2-dichloroethane. Urinary thiodiglycolic acid concentrations were not altered by alkaline hydrolysis. The /results suggest/ that urinary thiodiglycolic acid excretion correlates well with the oral dose of 1,2-dichloroethane in rats. Urinary thiodiglycolic acid excretion may be a useful marker of 1,2-dichloroethane exposure. Thiodiglycolic acid is hydrolyzed under alkaline conditions. The thioether assay is not appropriate for estimating urinary thiodiglycolic acid excretion.
[EN] BCR-ABL TYROSINE-KINASE LIGANDS CAPABLE OF DIMERIZING IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME<br/>[FR] LIGANDS DE TYROSINE-KINASE BCR-ABL CAPABLES DE SE DIMÉRISER DANS UNE SOLUTION AQUEUSE, ET PROCÉDÉS D'UTILISATION DE CEUX-CI
申请人：COFERON INC
公开号：WO2015106292A1
公开（公告）日：2015-07-16
Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. invivo) to form a multimer (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding sites on a Bcr-Abl tyrosine kinase.
DIHYDROPYRIDAZINE-3,5-DIONE DERIVATIVE AND PHARMACEUTICALS CONTAINING THE SAME
申请人：CHUGAI SEIYAKU KABUSHIKI KAISHA
公开号：US20160002251A1
公开（公告）日：2016-01-07
The present invention provides a dihydropyridazine-3,5-dione derivative or a salt thereof, or a solvate of the compound or the salt, a pharmaceutical drug, a pharmaceutical composition, a sodium-dependent phosphate transporter inhibitor, and a preventive and/or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, chronic renal failure, chronic kidney disease, and arteriosclerosis associated with vascular calcification comprising the compound as an active ingredient, and a method for prevention and/or treatment.
The present invention is new excitatory amino acid antagonists (herein referred to as compounds of formula (1)): below: ##STR1## These new antagonists are useful as NMDA (N-methyl-D-aspartate) antagonists.
Phenylacetic acid derivatives of the formula ##STR1## wherein n is an integer of 2 to 5; ##STR2## R.sub.1 is hydrogen, halogen, trifluoromethyl, nitro or amino; R.sub.2 and R.sub.3 each independently is hydrogen or lower alkyl; or together form an ethylene group; X.sub.1 represents two hydrogen atoms or an oxo group; and Y.sub.1 is cyano, hydroxyamidocarbonyl, carbamoyl, 5-tetrazolyl or carboxyl; and for derivatives wherein Y is carboxyl, salts thereof with physiologically compatible bases, esters thereof from physiologically acceptable alcohols and amides thereof from physiologically acceptable amines have valuable pharmacological activity, e.g., as antiinflammatory agents.
[EN] SELF-IMMOLATIVE LINKERS CONTAINING MANDELIC ACID DERIVATIVES, DRUG-LIGAND CONJUGATES FOR TARGETED THERAPIES AND USES THEREOF<br/>[FR] LIEURS AUTO-IMMOLABLES CONTENANT DES DÉRIVÉS D'ACIDE MANDÉLIQUE, CONJUGUÉS MÉDICAMENT-LIGAND POUR THÉRAPIES CIBLÉES, ET LEURS UTILISATIONS
申请人：ASANA BIOSCIENCES LLC
公开号：WO2015038426A1
公开（公告）日：2015-03-19
The invention provides a therapeutic drug and targeting conjugate, pharmaceutical compositions containing these conjugates in pharmaceutical composition, and uses of these conjugates in anti-neoplastic and other therapeutic regimens. Also provided are novel intermediates thereof. The conjugates provide a therapeutic drug fragment or prodrug fragment bound to a targeting moiety via a linker which comprises a substrate cleavable by a protease such as Cathepsin B. The targeting moiety is a ligand which targets a cell surface molecule, such as a cell surface receptor on an anti-neoplastic cell. The ligand may function solely as a targeting moiety or may itself have a therapeutic effect. Following administration of the therapeutic drug and targeting conjugate of formula I and exposure of the conjugate to the protease specific for the substrate, the linker is cleaved and the targeting moiety is separated from the conjugate, which causes the drug fragment or prodrug fragment to convert to the drug or prodrug. The recited conjugates are useful in anti-neoplastic therapies. Also provided are methods of making the therapeutic drug and targeting conjugates and intermediates thereof, and kits comprising the therapeutic drug and targeting conjugates.
