Fungal[1]

Absorption, Distribution and Excretion
Cyclozolin is rapidly absorbed, reaching peak plasma and blood concentrations within 4 hours of administration. The administered radioactive dose is almost completely excreted in urine and feces within 48 hours. The administered dose is primarily excreted via urine (64-75%), feces (16-24%), and exhaled air (<5%). There were no significant differences in residual distribution or elimination rates between sexes, dose levels, or between single and multiple administrations. No bioaccumulation was detected. DPX-T3217 is extensively metabolized, with only trace amounts of (14)C-cyclozolin detected in urine and feces. ... Five SD rats (half male and half female) were administered 2.5 mg/kg of (14)C-cyclozolin (radiochemical purity = 98%; 14.09 uCi/mg) orally via bile duct cannulation in corn oil suspension. Urine, feces, and bile were collected over 48 hours, after which the animals were euthanized, and whole blood, liver, kidneys, and remaining carcasses were collected for radiolabeling determination. ...Over 85% of the tested compounds in male and female rats were excreted in urine (approximately 65%), feces (approximately 14%), and bile (approximately 7%) within 48 hours, with the majority excreted within the first 24 hours; polar amino acid conjugates were the major class of metabolites found in urine (approximately 45-50%) and bile (approximately 4-6%); metabolites A (unknown) and IN-W3595/(2-cyano-2-methoxyiminoacetic acid)/ were present in urine at much lower concentrations than other substances (< 10%). The concentration of IN-W3595 in female urine (7.7%) was higher than in male urine (2.8%); metabolite A was not detected in bile.
/To investigate the absorption, distribution, metabolism, and excretion of 2-(14)C-DPX-T3217 in rats, rats were given 2.5 and 120 mg/kg of corn oil solution, respectively, with each animal receiving 0.5 and 2 mL. The radioactivity was approximately 10 and 20 uCi per animal, respectively. /The high dose was set based on the expectation of mild toxicity. Single gavage administration: 3 cases/sex/dose-pharmacokinetics, 5 cases/sex/dose-elimination/distribution, 8 cases/sex/dose-tissue distribution; multiple administrations (cold administration for 14 days at a dose of 2.5 mg/kg, followed by the labeled dose): 5 cases/sex; there were no significant differences in blood/plasma and tissue residues among the groups. Peak plasma concentrations were reached within 4 hours; however, fecal excretion may have been slightly reduced in the high-dose group (both males and females) and the multiple low-dose group (males only). No significant differences in excretion time and route were observed when comparing different sexes, doses, or single-dose versus multiple-dose regimens. Within 24 hours, 57-65% of the administered dose (AD) was recovered in urine and 5-17% in feces across all dose groups; within 96 hours, 63-75% was recovered in urine and 16-24% in feces. After 96 hours, less than 1% of AD remained in tissues (highest levels were found in the kidneys, liver, and skin). (14)C-cymoxanil was applied to the roots or leaves of tomato plants, and its absorption, translocation, and degradation were traced using autoradiography, combustion, and thin-layer chromatography analysis of water or methanol extracts. Cymoxanil was absorbed by the roots within 1 hour and translocated to cotyledons, stems, and leaves within 16 hours. The compound degraded in the roots and aboveground parts within 16-44 hours, primarily to glycine. When applied to the surface of the second leaf of plants at the five-leaf stage, the absorption, translocation, and degradation (primarily to glycine) of (14)-cymoxanil were significantly enhanced in plants treated with a mixture of oxadiazon and (14)-cymoxanil compared to plants treated with (14)-cymoxanil alone. Root application data confirmed that cymoxanil is a systemic compound with a short residual time in tomato plants. Foliar application data indicated that the synergistic effect of cymoxanil, oxadiazon, and mancozeb in controlling plant diseases caused by perennial fungi was not due to delayed degradation of cymoxanil caused by the presence of other fungicides. The mechanism of the synergistic effect has not been elucidated.

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Metabolites
...Intact (14)-cymoxanil (< 1%) and IN W3595 were detected in feces, but the majority of the radioactivity was (14)-glycine (approximately 9-13%). According to the data, the metabolic pathway involves the hydrolysis of ciprofloxacin to IN W3595, which is then degraded to glycine, which is subsequently incorporated into the natural components or further metabolized. ...In an ongoing low-dose bile fistula study, IN-U3204 (1-ethyl-5,6-di-2,4(1H,3H)pyridinedione) was detected in mixed 0-48 hour urine samples (both male and female) from animals treated with 120 mg/kg DPX-3217, and also in mixed 0-24 hour urine samples (both male and female) from animals treated with 2.5 mg/kg DPX-3217. The latter group of samples was included to ensure that the presence of IN-U3204 was not an artifact generated during storage; IN-U3204 was detected in both groups, but at seemingly low levels.
/2-(14)C-DPX-T3217/dissolved in corn oil, single-dose groups: 2.5 and 120 mg/kg, 0.5 and 2 mL/animal (~10 and ~20 uCi/animal, respectively, groups D and E), and multiple-dose groups: 2.5 mg/kg daily for 14 consecutive days, followed by a labeled dose of 2.5 mg/kg (group F). In the 5/sex/dosage regimen, the major metabolites detected in excrement by HPLC and TLC were IN-W3595 (2-cyano-2-methoxyiminoacetic acid) and polar components (glycine and other amino acid conjugates). 24 hours after administration to male mice in group D: 58% of the administered dose (AD) was present in the urine (8.6% of which was IN-W3595 and 46.5% was polar substance), and 21.9% was present in the feces (14% of which was extractable, <1% of which was IN-W3595 and 13.1% was polar substance). 24 hours after administration to female mice in group D: 64.2% of the administered dose (AD) was present in the urine (16.1% of which was IN-W3595 and 45.2% was polar substance), and 16.3% was present in the feces (10.1% of which was extractable, <1% of which was IN-W3595 and 8.7% was polar substance). In males of group E, 70.3% of AD was found in urine (26.3% from IN-W3595, 40.3% from polar voles), and 16.1% in feces (11.3% extractable, <1% from IN-W3595, 8.6% from polar voles). In females of group E, 73% of AD was found in urine (33% from IN-W3595, 36.7% from polar voles), and 17.1% in feces (11.5% extractable, <1% from IN-W3595, 8.5% from polar voles). In males of group F, 66.2% of AD was found in urine (6.5% from IN-W3595, 55% from polar voles), and 14.5% in feces (9% extractable, <1% from IN-W3595, 8.9% from polar voles). In female mice of group F, 63.1% of AD was found in urine (11.1% was IN-W3595, 46.6% was a polar compound), and 19.4% was found in feces (12.3% was extractable, <1% was IN-W3595, 12.2% was a polar compound). /IN-W3595 metabolites/
Organic nitriles are converted to cyanide ions in the liver by cytochrome P450 enzymes. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized to thiocyanate by thiocyanate esterase or 3-mercaptopyruvate thiotransferase. Cyanide metabolites are excreted in urine. (L96)

Toxicity Summary
Organic nitriles can decompose into cyanide ions both in vivo and in vitro. Therefore, the main toxic mechanism of organic nitriles is the production of toxic cyanide ions, or hydrogen cyanide. Cyanide ions are inhibitors of cytochrome c oxidase in the fourth electron transport chain complex (located on the mitochondrial membrane of eukaryotic cells). It forms a complex with the ferric atom in this enzyme. The binding of cyanide ions to this cytochrome prevents electrons from being transferred from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted, and the cell can no longer perform aerobic respiration to produce ATP for energy. Tissues that rely primarily on aerobic respiration, such as the central nervous system and the heart, are particularly susceptible to this. Cyanide can also produce some toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydrocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinate dehydrogenase, and copper/zinc superoxide dismutase. Cyanide binds to the iron ions in methemoglobin to form inactive methemoglobin cyanide. (L97)

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Toxicity Data
LCLo (Rat) = 4,980 mg/m3/4h

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Non-human Toxicity Values
LD50 Rat Oral 1100 mg/kg
LD50 Rabbit Dermal >3 g/kg
LD50 Guinea Pig Oral 1096 mg/kg
LD50 Dog Dermal >3000 mg/kg

[1]. Frederique Tellier , et al. Characterization of Metabolites of Fungicidal Cymoxanil in a Sensitive Strain of Botrytis Cinerea. J Agric Food Chem. 2008 Sep 10;56(17):8050-7.

Cymoxanil is a urea compound in which two nitrogen atoms are replaced by ethyl and 2-cyano-2-(methoxyimino)acetyl groups, respectively. It is a fungicide used to control downy mildew on various crops, including grapes, hops, and potatoes. It is both an environmental pollutant and an exogenous substance and antifungal pesticide. Cymoxanil belongs to the urea, nitrile, oxime ether, and aliphatic nitrogen-containing antifungal agents. Cyomaxinil, a fungicide, was first marketed in 1977. It is an acetilimide compound used as a therapeutic and preventative foliar fungicide. In Europe, it is sold for use on grapes, potatoes, tomatoes, hops, sugar beets, and other vegetable crops. Currently, cymoxanil is not registered in the United States. Cymoxanil's mechanism of action is that of a localized systemic fungicide. It penetrates plants rapidly and is not easily washed away by rainwater. It controls diseases during the latent period, preventing crop damage. This fungicide primarily targets fungi in the order Peronomycetes, including those in the genera Phytophthora, Peronospora, and Peronospora. Propamocarb exhibits low acute and chronic toxicity.

C7H10N4O3

198.18

198.075

57966-95-7

Cymoxanil-d3;2140803-92-3

5364079

Colorless crystals

1.3±0.1 g/cm3

160-161ºC

100 °C

1.537

0.67

2

5

3

14

301

0

N#C/C(C(NC(NCC)=O)=O)=N\OC

XERJKGMBORTKEO-VZUCSPMQSA-N

InChI=1S/C7H10N4O3/c1-3-9-7(13)10-6(12)5(4-8)11-14-2/h3H2,1-2H3,(H2,9,10,12,13)/b11-5+

(1E)-2-(ethylcarbamoylamino)-N-methoxy-2-oxoethanimidoyl cyanide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : 100 mg/mL (504.59 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (12.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (12.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (12.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)