Most of the (14)C collected in the urine of rats following a single oral dose of (14)C-DINP was in the form of phthalic acid or side-chain oxidation products of the monoester (MINP). The relative amount of phthalic acid in the urine decreased at the high dose. The monoester itself, as well as the diester, was present in only trace amounts. In feces, 8 and 41% of the radioactivity was associated with the diester following administration of a low (50 mg/kg) or a high (500 mg/kg) oral dose of (14)C-DINP. This indicates saturation of metabolism at the high dose. The remainder of the fecal radioactivity was associated with the monoester or its side-chain oxidation products. Major metabolites in the liver were the monoester and its side-chain oxidation products. The same metabolites and phthalic acid were in testes. Fat contained the monoester and its oxidation products. Repeated exposures revealed similar metabolites in the tissues. In summary, in the rat, DINP was de-esterfied to the monoester, which was further metabolized by side-chain oxidation of the ester group or by hydrolysis to phthalic acid. Formation of oxidation products appeared to increase following the high dose or repeated dosing, while the hydrolysis to phthalic acid decreased.
来源:Hazardous Substances Data Bank (HSDB)
代谢
(14)C-二异壬基邻苯二甲酸酯(DINP CAS 68515-48-0，纯度97-98%)在给予单次口服剂量50或500 mg/kg的雄性和雌性Fischer 344大鼠中的情况进行了研究。在给药后72小时内，检查了尿和粪便中放射性物质的消除情况... 高效液相色谱分析显示，在给药后0-8小时内从雄性大鼠收集的尿液中，大部分放射性物质（高达28%）对应于邻苯二甲酸，而一小部分（高达7%）在色谱图的起点处洗脱（极性组分4）。回收的大部分放射性物质（58-83%）以比单酯（单异壬基邻苯二甲酸酯，MINP）更极性的宽峰洗脱。这个峰，暂时被识别为MINP的侧链氧化产物（MINPox），在8至24小时收集的尿液中含量较高（回收的邻苯二甲酸（PA）量减少，极性组分的水平相当）。邻苯二甲酸的消除是剂量依赖性的，并且在接受高剂量治疗的大鼠尿液中减少。从雌性大鼠收集的尿液显示出与雄性相似的图谱。在所有尿样中，单酯和二酯要么不存在，要么仅以痕量存在。在粪便中，低剂量和高剂量治疗后与二酯相关的放射性物质分别为8%和41%。其余的放射性物质在MINP和MINPox的区域洗脱；在高剂量中未检测到邻苯二甲酸，或在低剂量中以小量存在。与极性组分相关的放射性物质未检测到。接受低剂量治疗的雌性大鼠的粪便样本与雄性大鼠的样本在数量上存在微小差异，但在接受高剂量治疗后，雌性大鼠的粪便中母化合物含量较高，氧化代谢物含量较低。在胃肠道中观察到了代谢物非常相似的分布，低剂量DINP给药后，83%的放射性物质与MINPox相关（也回收了少量的DINP、MINP和PA）。对于高剂量，在胃肠道中回收了更多的DINP和较少的MINPox。在肝脏中，无论给予的剂量如何，主要的代谢物都是MINP和MINPox。对于低剂量，还回收了少量的PA。从暴露后1小时到72小时，MINP和PA逐渐减少，同时MINPox增加。对于高剂量，在1-4小时的时间间隔内回收了少量的DINP，并且在1小时时仅回收了1%的PA。在接受单次(14)C-DINP剂量的雄性大鼠睾丸中回收的主要代谢物包括单酯、其氧化产物和酸；也发现了少量的极性组分。在接受高剂量的大鼠睾丸中，回收的单酯量略高，酸的量较低。在任何剂量水平下均未检测到母化合物。在接受单次低剂量的脂肪组织中，出现了对应于单酯、其氧化产物和极性组分的微量峰。仅在接收高剂量的脂肪组织中检测到了二酯。... /1,2-苯二甲酸，C8-10支链烷基酯，富含C9/
... (14)C-diisononyl phthalate (DINP CAS 68515-48-0, 97-98% pure) were investigated in male and female Fischer 344 rats treated with a single oral dose of 50 or 500 mg/kg ... . Elimination of radioactivity in urine and feces was examined for up to 72 hours after /dosing/ ... HPLC analyses of urine collected from male rats between 0-8 hours following a single dose of (14)C-DINP showed a major portion of the radioactivity (up to 28%) corresponding to phthalic acid and a minor amount (up to 7%) eluting at the origin of the chromatogram (polar component 4). Most of the radioactivity recovered (58-83%) eluted as a broad peak more polar than the monoester (monoisononyl phthalate, MINP). This peak, tentatively identified as side chain oxidation products of MINP (MINPox), was present in higher amounts in urine collected between 8 and 24 hours (there was a decrease of the amount of phthalic acid (PA) recovered and levels equivalent for polar component). Elimination of phthalic acid was dose-dependent and decreased in urine of rats treated with the high dose. Urine collected from female rats showed similar profiles to those of males. In all urine samples, the monoester and diester were absent or present only in trace amounts. In feces, 8 and 41% of the radioactivity was associated with the diester following treatment with the single low and high dose, respectively. The remainder eluted in the areas of the MINP and MINPox; phthalic acid was absent (high dose) or present in small amounts (low dose). No radioactivity was associated with the polar component. Fecal samples collected from female rats treated with the low dose showed minor quantitative differences from those of male rats, but following the high dose, the feces of female rats showed higher amounts of the parent compound and lower amounts of the oxidative metabolites. A quite similar distribution of the metabolites was observed in the GI tract, 83% of the radioactivity was associated with MINPox following a low dose of DINP administered (small quantities of DINP, MINP and PA were also recovered). For the high dose, more DINP and less MINPox were recovered in the GI tract. In the liver, the major metabolites were MINP and MINPox whichever the dose administered. For the lower dose, a small amount of PA was recovered too. From 1 hour to 72 hours post exposure, progressive decrease of MINP and PA was observed concurrently with an increase of MINPox. For the higher dose, small amounts of DINP were recovered between 1-4 hours interval and only 1% of PA was recovered at 1 hour. The major metabolites recovered in the testes of rats receiving one dose of (14)C-DINP include the monoester, its oxidation products, and the acid; small amounts of the polar component were also present. Slightly higher amounts of the monoester and lower amounts of the acid were recovered in testes of rats receiving the high dose. The parent compound was not detected from either dose level. Fat collected from rats receiving a single low dose showed peaks corresponding to the monoester, its oxidation products, and traces of the polar component. The diester was detected only in fat collected from rats receiving the high dose. ... /1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich/
来源:Hazardous Substances Data Bank (HSDB)
代谢
(14)C-二异壬基邻苯二甲酸酯（DINP CAS 68515-48-0，纯度为97-98%）在雄性大鼠中进行了研究，这些大鼠每天口服50、150和500毫克/千克的剂量，共五天。在最后一次给药后，对尿和粪便中放射性物质的消除进行了长达72小时的检查。... 对DINP在粪便中的代谢轮廓的研究表明，粪便排泄代表未吸收的DINP和通过胆汁排出的代谢物之间的平衡。在尿液中，大部分放射性物质（79至91%）以一个对应于MINPox的宽峰形式洗脱。在0到8小时或8到24小时收集的尿液中，这种代谢物的量是相似的，但在接受高剂量的老鼠的尿液中略高。在尿液中回收了少量的邻苯二甲酸（最多13%）；其排泄在重复给药后显示无剂量依赖性。极性组分在高剂量水平下仅以微量回收，但在低剂量下占尿液放射性的高达6%。二酯和单酯在任何剂量下都缺席或仅以微量存在。粪便中的放射性物质在二酯、单酯和氧化产物之间分配；在高剂量后回收了较高量的二酯。仅以微量回收了邻苯二甲酸和极性组分。在胃肠道中观察到了类似的分布。肝脏含有大量的单酯及其氧化产物。在较晚的牺牲时间，大部分肝脏放射性物质（71至90%）对应于氧化产物。仅检测到少量的邻苯二甲酸和极性组分，而二酯缺席或仅以微量存在。无论剂量如何，肝脏的代谢轮廓是相似的。来自睾丸的轮廓主要显示氧化产物，在高剂量后占放射性的高达89%；回收了少量的单酯和邻苯二甲酸。二酯和极性组分缺席或偶尔出现。经过五次剂量处理的鼠类脂肪含有大量的单酯及其氧化产物，以及少量的二酯；邻苯二甲酸和极性组分只是偶尔检测到。/1,2-苯二甲酸，二-C8-10-支链烷基酯，C9-丰富/
... (14)C-diisononyl phthalate (DINP CAS 68515-48-0, 97-98% pure) were investigated ... in male rats treated with five daily oral doses of 50, 150 and 500 mg/kg. Elimination of radioactivity in urine and feces was examined for up to 72 hours after the last dose. ... Studies on DINP metabolic profiles in feces indicated that fecal excretion represents a balance of unabsorbed DINP and the metabolites eliminated in bile. In the urine, the major portions of radioactivity (79 to 91%) eluted as a broad peak corresponding to MINPox. The quantities of this metabolite in urine collected between 0 and 8 hours, or 8 and 24 hours, were similar, but were slightly higher in urine of rats receiving the high dose. Smaller amounts (up to 13%) of phthalic acid were recovered in urine; its excretion following repeated dosing showed no dose-dependence. The polar component was recovered in trace amounts following the high-dose level but represented up to 6% of urinary radioactivity following the low dose. The diester and the monoester were absent or present only in trace amounts at any dose. The fecal radioactivity was divided between the diester, monoester, and the oxidation products; higher amounts of the diester were recovered following the high dose. Only trace amounts of phthalic acid and the polar component were recovered. A similar distribution was observed in the GI tract. The livers contained major amounts of the monoester and its oxidation products. At later sacrifice times, most liver radioactivity (71 to 90%) corresponded to oxidation products. Only small amounts of phthalic acid and the polar component were detected, while the diester was absent or present only in trace amounts. The metabolic profiles in the liver were similar irrespective of dose. The profiles from testes showed primarily oxidation products present in amounts up to 89% of the radioactivity following the high dose; small amounts of the monoester and phthalic acid were recovered. The diester and the polar component were absent or only occasionally present. Fat from rats treated with five doses contained major amounts of the monoester and its oxidation products, and minor amounts of the diester; phthalic acid and the polar component were only occasionally detected. /1,2-Benzenedicarboxylic acid, di-C8-10-branched alkyl esters, C9-rich/
IDENTIFICATION AND USE: Di-isononyl phthalate (DiNP) is a mixture of phthalates with branched alkyl side chains of varying length (C8, C9, and C10). DiNP is primarily used to produce flexible plastics and has replaced di-2-ethylhexyl phthalate (DEHP) in some plastics, though not in medical products. DiNP is widely used in such products as toys, flooring, gloves, drinking straws, garden hoses, and in sealants used for food packaging. HUMAN EXPOSURE AND TOXICITY: No evidence of clinical sensitization or irritation was observed in human subjects. People exposed to DiNP will excrete small amounts of mono-isononyl phthalate (MiNP) and other secondary oxidative metabolites. These metabolites can be used to monitor occupational exposure to DiNP, as well as in epidemiological studies. ANIMAL STUDIES: The pivotal toxicological effect for DINP is considered to be the hepatic changes seen in various studies. In a two-year chronic toxicity study in rats, there was an increased incidence of spongiosis hepatis, accompanied by increased serum levels of liver enzymes and increases in absolute and relative liver and kidney weights in both sexes. DiNP administered to rodents produced liver and kidney toxicity. DINP is clearly carcinogenic to the rodent, inducing hepatocellular carcinoma in rats and mice of both sexes and mononuclear cell leukemia in male and female rats. There is limited evidence of carcinogenicity based upon renal tubular carcinoma in male rats. The carcinogenic effects in the liver of rodent species are linked to peroxisome proliferation and are no longer considered as relevant to humans. DINP appears to act by an alpha2u-globulin mechanism to cause renal tubular carcinoma, which is considered to be a rodent specific mechanism and unlikely to be relevant to a determination of human risk. In a developmental study in rats at dose levels up to 1000 mg/kg bw/day, visceral variations (dilated renal pelvis and hydroureter) were observed. In another study in rats, skeletal variations (rudimentary cervical and accessory 14th ribs) were observed. In chronic rat studies relative testis weights were statistically significantly increased with or without concurrent increase of absolute testis weights and decrease of body weights at high doses. DNIP produced behavioral changes in developmental studies. DINP is not mutagenic in vitro in bacterial mutation assays or mammalian gene mutation assay (with and without metabolic activation) and is not clastogenic in one cytogenetic assay in vitro on CHO cells and in one in vivo assay on bone marrow cell of rats. This suggests that DINP is not genotoxic in vivo or in vitro. ECOTOXICITY STUDIES: The observed toxicity to daphnids with most of the higher-molecular-weight phthalate esters appeared to be due to surface entrapment or a mode of toxicity that is not due to exposure to the dissolved aqueous-phase chemical. This pattern of observed toxicity with the lower-molecular-weight phthalate esters and not the higher-molecular-weight phthalate esters is consistent with previously reported acute toxicity studies for several aquatic species.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
暴露途径
该物质可以通过吸入其气溶胶被吸收进入人体。
The substance can be absorbed into the body by inhalation of its aerosol.
来源:ILO-WHO International Chemical Safety Cards (ICSCs)
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病例。
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
毒理性
毒性数据
LC50 (大鼠) > 4,400 毫克/立方米/4小时
LC50 (rat) > 4,400 mg/m3/4h
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
Phthalates, widely used in flexible plastics and consumer products, have become ubiquitous contaminants worldwide. This study evaluated the acute toxicity and estrogenic endocrine disrupting activity of butyl benzyl phthalate (BBP), di(n-butyl) phthalate (DBP), bis(2-ethylhexyl) phthalate (DEHP), diisodecyl phthalate (DIDP), diisononyl phthalate (DINP), di-n-octyl phthalate (DNOP) and their mixtures. Using a 72 h zebrafish embryo toxicity test, the LC50 values of BBP, DBP and a mixture of the six phthalates were found to be 0.72, 0.63 and 0.50 ppm, respectively. The other four phthalates did not cause more than 50% exposed embryo mortality even at their highest soluble concentrations. The typical toxicity symptoms caused by phthalates were death, tail curvature, necrosis, cardio edema and no touch response. Using an estrogen-responsive ChgH-EGFP transgenic medaka (Oryzias melastigma) eleutheroembryos based 24 h test, BBP demonstrated estrogenic activity, DBP, DEHP, DINP and the mixture of the six phthalates exhibited enhanced-estrogenic activity and DIDP and DNOP showed no enhanced- or anti-estrogenic activity. These findings highlighted the developmental toxicity of BBP and DBP, and the estrogenic endocrine disrupting activity of BBP, DBP, DEHP and DINP on intact organisms, indicating that the widespread use of these phthalates may cause potential health risks to human beings. /Mixture/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
DINP的皮肤吸收极低。...反复给药不会导致DINP及其代谢物在血液或组织中的积累。
The dermal absorption of DINP is extremely low. ... Repeated dosing does not result in accumulation of DINP and/or its metabolites in blood or tissue.
Dermal absorption of (14)C-DINP was studied in male Fischer 344 rats in both conditioned (pre-treatment with non-labeled DINP) and non-conditioned skin. Following exposure, the dosed area was occluded. Under all conditions, the amount absorbed after 7 days ranged from 2 to 4% of the dose. Approximately 93-99% of the administered radioactivity was recovered at the site of application. Radioactivity in feces and gut of the exposed rats suggested some excretion via the biliary route.
Oral absorption of (14)C-DINP (dose=2,500 mg/kg) was studied in conditioned (pre-treatment with nonlabeled DINP) and non-conditioned male albino rats. The rats were administered 0.5 mL of radiolabeled DINP by gavage and the dose was estimated at approximately 2,500 mg/kg bw by the Expert Panel based on the density of DINP and reported rat body weights. Within 72 hours, 85% of the administered dose was excreted in the feces, most within the first 24 hours. The rest of the dose was excreted in urine (average of 12%) or remained in the tissues (trace amounts). Thus, the oral absorption was approximately 12%. ...Male and female Fischer 344 rats were dosed orally either in a single or in 5 daily doses of 50, 150, or 500 mg/kg. At least 49% of the single low dose was absorbed. Absorption was decreased at the high single dose and at all doses following repeated exposures.
In albino rats receiving 0.5 mL of (14)C-DINP (approximately 2,500 mg/kg bw) after 5 days of dosing with the same amount of unlabeled DINP, no tissue studied had over 0.001% per gram of the administered dose after 3 days. The liver contained the most radioactivity on a total tissue basis. In male and female Fischer 344 rats receiving single or repeated oral doses of (14)C-DINP, radioactivity also cleared from the tissues rapidly, but analysis of tissues soon (within 1 hour) after the exposure indicated that the highest levels were in liver (4.7% of administered dose), kidneys (0.31%), and blood (1.62 %). Fat and testes contained small amounts of metabolites. No bioaccumulation occurred over 72 hours postdosing.
邻苯二甲酸二异壬酯 在
Ru-containing catalyst A or B 氢气 作用下，
80.0~120.0 ℃
、20.0 MPa
条件下，
反应 20.0h，
生成 1,2-环已烷二羧酸二异壬基酯
参考文献：
名称：
[DE] FEINPORIGER KATALYSATOR UND VERFAHREN ZUR HYDRIERUNG VON AROMATISCHEN VERBINDUNGEN [EN] MICROPOROUS CATALYST AND METHOD FOR HYDROGENATING AROMATIC COMPOUNDS [FR] CATALYSEUR A MICROPORES ET PROCEDE D'HYDROGENATION DE COMPOSES AROMATIQUES
[EN] AROMATIC COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF [FR] COMPOSÉ AROMATIQUE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION [ZH] 一种芳香化合物、其制备方法及应用
Process for the preparation of olmesartan medoxomil
申请人：KRKA, tovarna zdravil, d.d., Novo mesto
公开号：EP1816131A1
公开（公告）日：2007-08-08
The present invenion relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
申请人：Zupancic Silvo
公开号：US20090131680A1
公开（公告）日：2009-05-21
The present invention relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
CITRATE-BASED PLASTICIZER AND RESIN COMPOSITION INCLUDING THE SAME
申请人：LG CHEM, LTD.
公开号：US20200270196A1
公开（公告）日：2020-08-27
Provided is a citrate-based plasticizer and a resin composition including the same. The citrate-based plasticizer includes one or more citrates having alkyl groups with 7 carbon atoms. The citrate-based plasticizer can solve limitations on migration and volatile loss inherent in the conventional plasticizer and limitations on characteristics of processing such as plasticizing efficiency and absorption rate.
NITROGEN-CONTAINING COMPOUNDS SUITABLE FOR USE IN THE PRODUCTION OF POLYURETHANES
申请人：Evonik Degussa GmbH
公开号：US20180194889A1
公开（公告）日：2018-07-12
The present invention provides for the use of nitrogen compounds of formula (I) and/or of corresponding quaternized and/or protonated compounds for production of polyurethanes, compositions containing these compounds and polyurethane systems, especially polyurethane foams, which have been obtained using the compounds.
