DNOC appears to be metabolized to less toxic metabolites readily eliminated via the urine. Although small quantities of DNOC may be conjugated, most of the dose appears to be reduced to mono amino derivatives and then subsequently conjugated prior to excretion. These relatively harmless metabolites have been found in the urine and kidney of humans and animals exposed to DNOC.
The major metabolic route in the rat and the rabbit following oral administration is by reduction to 6-amino-4-nitro-o-cresol (6-ANOC, 10 - 12% of administered dose) and, to a lesser extent, to 4-amino-6-nitro-o-cresol (4-ANOC), 4-ANOC conjugates and other minor metabolites.
In the rabbit, 5% of DNOC single oral doses of 20 or 30 mg/kg is excreted unchanged and 1% as conjugated DNOC in 2-day urine collection. The main metabolic pathway is the reduction of DNOC to 6-amino-4-nitro-o-cresol (6-ANOC), and to a lesser extent to 4-amino-6-nitro-o-cresol (4-ANOC). Urinary content of 6-ANOC accounted for 11-12% of the administered dose. Small amounts of other metabolites, such as 4-ANOC conjugates and 3-amino-5-nitrosalicylic acid (3-ANSA), which is produced via an oxidative pathway, are also excreted in the urine.
The metabolism of 4,6-dinitro-o-cresol (DNOC) was studied in rats and in the rabbit. Inbred Wistar-rats received labeled and unlabeled DNOC by gavage in doses of 0.4 to 10 mg/kg bw, with urine and feces being collected separately. When labeled DNOC was administered, blood, a number of organs, and the residual carcasses were collected at sacrifice 1 or 3 days after treatment for use in radioactivity measurements. A female albino white-New-Zealand-rabbit received 76 mg of unlabeled DNOC by gavage, with urine being collected via a catheter at regular intervals over the ensuing 24 hr. ...In rats receiving labeled DNOC in a dose of 0.4 mg/kg, radioactivity was eliminated with a half time of 1-1.5 days. Approximately 25% of the introduced dose was still contained in the body at sacrifice 3 days after treatment, with the major portion being concentrated in the residual carcass. Here, the introduced dose had little effect on the overall pattern of DNOC distribution. The metabolites detected in rat urine were identified as 4,6-diacetamido-o-cresol (DAAOC), 3,5-dinitro-2-hydroxybenzylalcohol, 4-acetamido-6-nitro-o-cresol, 6-acetamido-4-nitro-o-cresol, DNOC, and 6-amino-4-nitro-o-cresol, with 4-acetamido-6-nitro-o-cresol, 6-acetamido-4-nitro-o-cresol, 6-amino-4-nitro-o-cresol, and DAAOC also being present as conjugates. The metabolites detected in rabbit urine were identified as DAAOC, amino-nitro-o-cresol, acetamido-nitro-o-cresol, and 6-amino-4-nitro-o-cresol. The authors conclude that nitro group reduction, followed by acetylation or conjugation, constitutes the major pathway of DNOC biotransformation. When DNOC is administered with a methanol extract of wheat leaves, the major biotransformation reaction is methyl group oxidation.
DNOC was rapidly metabolized by rat cecal microorganisms and could /no/ longer be detected after 1 hr. Simultaneously, 6-ANOC (the monoamine derivative of DNOC) was detected in increasing amounts, reaching maximum levels after 1 hr, indicating an 80% DNOC conversion. Thereafter, the 6-ANOC concentration decreased until it represented only 3% of the initial DNOC concentration at 12 hr. DAOC (the diamine derivative) concentrations increased over the entire incubation period and reached maximum levels at 12 hr, when it represented 90% of the DNOC conversion. When incubated alone 6-ANOC concentrations decreased and DAOC concentrations increased in the same time-dependent manner observed in the DNOC experiments. Analogous experiments using DNBP (dinoseb) and 6-ANBP (the monamine derivative of dinoseb) gave similar results. However, the metabolic turnovers were slower. Rat cecal microorganisms metabolize DNOC and DNBP to the corresponding 6-amino compounds, which are in turn reduced to the diamino derivatives. Hematologic effects reported in rats exposed to DNBP may have been induced by amino metabolites formed in the intestine from DNBP metabolism.
IDENTIFICATION: 4,6-Dinitro-ortho-cresol (DNOC) is a yellow crystalline solid. It is partly soluble in water. DNOC was fungicide, herbicide and insecticide that is no longer registered for use in the U.S. HUMAN STUDIES: Symptoms of DNOC toxicity include restlessness, a sensation of heat, flushed skin, sweating, thirst and deep rapid respiration and tachycardia, severe increase in body temperature, cyanosis leading to collapse, coma and death. Effects are enhanced at high temperatures. Cardiovascular effects have been noted secondary to cellular anoxia but do not appear to be consistent cardinal signs of DNOC exposure in humans. Elevated pulse rates, tachycardia, and palpitations were observed in several patients. Negative results were found in human lymphocytes for sister chromatid exchanges and unscheduled DNA synthesis in both the presence and the absence of metabolic activation at doses up to 50 ug/mL. ANIMAL STUDIES: Dietary administration of DNOC for up to 90 days decreased body weight gain in rats, mice and dogs, usually without significant alteration in food consumption. At high doses, the liver is affected , as shown by an increased activity of liver enzymes. Blood urea levels were also increased at high doses. Environmental temperatures influenced the mortality rate among rats orally dosed with DNOC. Six of 12 rats died after receiving 20 mg/kg at 37-40 °C, while only 2 of 12 rats died after receiving twice the dose (40 mg/kg) at 20-22 °C. Application of DNOC to skin of rabbits induced edema. It was a skin sensitizer in the guinea pig and corrosive to the eyes of the rabbit. Diets containing 0.25% DNOC (or 2500 mg/kg feed) were administered for 2 days to 5-day-old white Peking ducklings. Cataracts were produced within 24 hr in all the birds. This concentration induced 56% mortality the first day and 100% the second day. At high doses, DNOC has a slight effect on reproduction in the form of reduction of body weight and litter size. Other reproduction parameters were not affected. DNOC did not induce any teratogenic effects in pregnant rats receiving oral doses from gestation day 6 to day 15. In rabbits treated orally, the high dose was maternally toxic, inducing mortality. At this high dose level, teratogenic effects included microphthalmia and hydroencephaly or microencephaly. Pregnant rabbits exposed to a cutaneous application of DNOC during gestation, induced maternal toxicity at a high dose resulting in some embryotoxicity but not teratogenicity. No evidence of teratogenicity or embryotoxicity were noted in mice treated orally or by ip administration during pregnancy. DNOC has been shown to have mutagenic potential in bacterial mutagenicity systems (strains TA98 and TA100) both in the presence and absence of metabolic activation. The mutagenic response obtained in the Ames test was markedly reduced or abolished when the nitroreductase strains TA98NR and TA100NR were used, indicating involvement of nitroreductase. ECOTOXICITY STUDIES: DNOC has little effect on soil microorganisms. Acute toxicity to aquatic organisms is variable. Fish were the most sensitive species in laboratory tests. DNOC is acutely toxic for birds, mammals and honeybees.
4,6-Dinitro-o-cresol is an uncoupler of oxidative phosphorylation. It is believed to cause an acceleration of metabolic processes that are part of the tricarboxylic acid (TCA) cycle. DNOC produces its accelerative effect by increasing the permeability of the inner mitochondrial membrane to Ca+, altering the proton electrochemical gradient and thus interrupting the phosphate transfer to adenosine diphosphate (ADP) to form ATP. Uncoupling allows electron transport to proceed unchecked even when ATP synthesis is inhibited. As a consequence, more ADP and inorganic phosphate are available to drive the TCA cycle, and most of the energy produced from catabolism of glucose is not stored in high energy phosphate bonds as ATP but is given off as heat. This results in the elevated body temperature and related effects characteristic of DNOC toxicity. (L198)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
接触DNOC可能会导致胃、肾脏和肝脏轻微受损。长期摄入DNOC可能会导致白内障和皮肤皮疹。
Exposure to DNOC may cause mild damage to the stomach, kidneys, and liver. Ingesting DNOC for long periods may cause cataracts and skin rashes. (L198)
来源:Toxin and Toxin Target Database (T3DB)
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)
DNOC is rapidly absorbed following inhalation, ingestion and via skin contact. Skin absorption is more rapid when DNOC is applied in an oily formulation rather than in aqueous solution, peak plasma concentration is higher and occurs earlier, indicative of a solvent effect on skin penetration.
It was shown that the amount of DNOC absorbed from the gastrointestinal tract of the rat, and the resulting blood level, depend on the type of fat administered shortly after dosing with DNOC (olive oil or castor oil). Gastrointestinal uptake of DNOC increases when 0.2 mL of olive oil is given, whereas 1.0 mL has no influence. Castor oil in a non- purgative dose (0.2 mL) inhibits resorption, and then slows down the decrease of DNOC blood level over a period of 48 h. Rapeseed oil, which is more slowly absorbed than olive oil, shows only a slight inhibitory effect on DNOC digestive absorption.
Blood plasma analysis after dinitro-o-cresol dosing of cows showed at least 95% of the absorbed DNOC bound to plasma proteins; the fact that identical doses of DNOC in ruminants give far lower blood concentrations than in rats and rabbits may be explained by the extensive reduction of the compounds in the rumen.
In a reported study, mists of selected synthetic metalworking fluids were generated in laboratory experiments by two processes, nebulization (atomization) and air sparging (bubbling). Short-chain fatty acid species were determined by in situ trimethylsilyl derivatization. Comparison of relative amounts of the short-chain acids collected from mists generated by nebulization with those generated by sparging showed that the sparged mists had significantly higher amounts of neodecanoic, nonanoic, and dodecanedioic acids. Comparison of the amounts of acids collected by the resin cartridges to amounts found on the filters showed that significant losses of octanoic and isononanoic acids occurred over 8 hours of collection and that only dodecanedioic acid was not lost from the filter over a 22-hour sampling period. In another reported metalworking mist study, contaminants of metalworking fluids, e.g., tramp oils, were shown in laboratory experiments to increase the misting potential of water-based metalworking fluids. Significantly, tramp oil contamination caused less misting in synthetic fluids than soluble and semi-synthetic fluids.
[EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE POLYMERASE VIRALE
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2004065367A1
公开（公告）日：2004-08-05
An isomer, enantiomer, diastereoisomer or tautomer of a compound, represented by formula (I): wherein wherein A, B, R2, R3, L, M1, M2, M3, M4, Y1, Y0, Z and Sp are as defined in claim 1, or a salt thereof, as an inhibitor of HCV NS5B polymerase.
Diamine Compound Having Phosphorylcholine Group, Polymer Thereof, and Process for Producing the Polymer
申请人：Nagase Yu
公开号：US20100036081A1
公开（公告）日：2010-02-11
Highly polymerizable diamine compounds having a phosphorylcholine group are disclosed. High-molecular weight polymers are obtained from the highly polymerizable diamine compound having a phosphorylcholine group as a monomer, and the polymers have improved mechanical strength, water resistance and heat resistance while maintaining excellent biocompatibility and processability of MPC polymers. Processes for producing the polymers are disclosed. The diamine compounds having a phosphorylcholine group are represented by Formula (I). The polymers contain at least 1 mol % of a specific structural unit with a phosphorylcholine group represented by Formula (II) and have a number average molecular weight of not less than 5,000. In the processes, the diamine compound is used as a monomer.
NAPHTHALENE-BASED INHIBITORS OF ANTI-APOPTOTIC PROTEINS
申请人：Pellecchia Maurizio
公开号：US20090105319A1
公开（公告）日：2009-04-23
Methods of using apogossypol and its derivatives for treating inflammation is disclosed. Also, there is described a group of compounds having structure A, or a pharmaceutically acceptable salt, hydrate, N-oxide, or solvate thereof are provided:
wherein each R is independently selected from the group consisting of H, C(O)X, C(O)NHX, NH(CO)X, SO
2
NHX, and NHSO
2
X, wherein X is selected from the group consisting of an alkyl, a substituted alkyl, an aryl, a substituted aryl, an alkylaryl, and a heterocycle. Compounds of group A may be used for treating various diseases or disorders, such as cancer.
COMPOUNDS AND COMPOSITIONS FOR MODULATING EGFR MUTANT KINASE ACTIVITIES
申请人：Yuhan Corporation
公开号：US20160102076A1
公开（公告）日：2016-04-14
The present invention provides a new group of protein kinase inhibitors, aminopyrimidine derivatives, and pharmaceutically acceptable salts thereof that are useful for treating cell proliferative disease and disorder such as cancer and immune disease. The present invention provides methods for synthesizing and administering the protein kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the protein kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefore. The invention also provides useful intermediates generated during the syntheses of the aminopyrimidine derivatives.
[EN] FLAVIN DERIVATIVES<br/>[FR] DÉRIVÉS DE LA FLAVINE
申请人：BIORELIX PHARMACEUTICALS INC
公开号：WO2010019208A1
公开（公告）日：2010-02-18
The present invention relates novel flavin derivatives and other flavin derivatives, their use and compositions for use as riboswitch ligands and/or anti-infectives. The invention also provides method of making novel flavin derivatives.
