Fungal[1]

Absorption, Distribution and Excretion
Cymoxanil is rapidly absorbed and maximum concentrations in the blood and plasma is reached within 4 hours after dosing. Rapid and almost complete elimination of the administered radioactive dose was observed in urine and feces within 48 hours. Excretion is primarily by urine (64 - 75%), fecal (16 - 24%) and expired air (< 5%) of the administered dose. There is no significant difference in residue profiles or elimination rates between sexes, dose levels, or single or multiple dosing. No evidence of bioaccumulation was detected. DPX-T3217 is metabolized extensively and only trace level of the administered (14)C-cymoxanil was detected in the urine and feces. ...
Five SD rats/sex with cannulated bile ducts were dosed orally with 2.5 mg/kg of (14)C-Cymoxanil (radiochemical purity = 98%; 14.09 uCi/mg) as a corn oil suspension. Urine, feces, and bile were collected over a 48 h period, after which the animals were terminated and whole blood, liver, kidneys, and residual carcass were collected for measurement of radiolabel. ...More than 85% of the test compound was eliminated in urine ( approximately 65%), feces (approximately 14%), and bile (approximately 7%) within 48 hr in both sexes, with most elimination occurring with the first 24 hr; polar amino acid conjugates comprised the major class of metabolites found in both urine (approximately 45-50%) and bile (approximately 4-6%); Metabolite A (unknown) and IN-W3595 /(2-cyano-2-methoxyimino acetic acid)/ were found at much lower concentrations (< 10%) in urine. IN-W3595 was found at higher concentrations in the urine of females (7.7%) as compared to males (2.8%); Metabolite A was not found in bile.
/To study the absorption, distribution, metabolism, and excretion of 2-(14)C-DPX-T3217 in rats, doses of/ 2.5 & 120 mg/kg in corn oil /at/ 0.5 & 2 mL/animal, /were administered. Radioactivity amounted to/ ~10 & ~20 uCi/animal, respectively. /High dose/ set by expectation of slight toxicity. /With/ single gavage administration: 3/sex/dose - blood pharmacokinetics, 5/sex/dose - elimination/distribution, 8/sex/dose - tissue distribution; multiple administration (cold dosing at 2.5 mg/kg for 14 days followed by labeled dose): 5/sex; no significant differences between groups in blood/plasma and tissue residue profiles. Max. blood concentrations were attained by 4 hr; with the possible exception of a somewhat decreased relative fecal excretion at the high dose (both sexes) and at the multiple low dose (males only). No significant differences in excretion time or route were seen when comparing sexes, doses, or single vs. multiple dosing regimens. Including all dose groups, 57-65% of the administered dose (AD) recovered in urine & 5-17% in feces by 24 hr, 63-75% in urine & 16-24% in feces by 96 hr; at 96 hr <1% of AD remained in tissues (highest levels found in kidney, liver, & skin).
(14)C-Cymoxanil was applied to either the root system or to the foliage of tomato plants and its uptake, translocation and degradation was followed using autoradiography, combustion and thin-layer chromatographic analyses of water or methanolic extracts. Cymoxanil was taken up by the root system within 1 hr and translocated to cotyledons, stem and leaves within 16 hr. The compound was degraded, mostly to glycine, within 16-44 h, in the root and all parts of the shoot. When applied to the surface of leaf 2 of five-leaf plants, enhanced uptake, translocation and degradation (mainly to glycine) of (14)C-cymoxanil was observed in plants treated with a mixture of oxadixyl and (14)C-cymoxanil, compared with plants treated with (14)C-cymoxanil alone. Root application data confirm that cymoxanil is a systemic compound with a short persistence in tomato plants. Foliage application data suggest that the well-documented synergistic interaction between cymoxanil, oxadixyl and mancozeb in controlling plant diseases caused by Peronosporales does not result from a delayed degradation of cymoxanil in the presence of the other fungicides; the mechanism of synergism has not yet been elucidated.

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Metabolism / Metabolites
... In feces intact (14)C-cymoxanil (< 1%) and IN W3595 was detected, but the majority of radioactivity was (14)C-glycine (about 9 - 13%). Based on the data, the metabolic pathway involves hydrolysis of cymoxanil to IN W3595, which is then degraded to glycine, which in turn is incorporated into natural constituents or further metabolized.
... IN-U3204 (1-ethyl-5,6-di-2,4(1H,3H) pyridinedione) was detected in pooled 0-48 hr urine samples, both sexes, from animals treated with 120 mg/kg DPX-3217 and in pooled 0-24 hr samples, both sexes, from animals treated with 2.5 mg/kg in an ongoing low dose biliary fistula study. The latter group was included to ensure that the presence of IN-U3204 was not an artifact of storage; IN-U3204 was detected in both groups, though at apparently low levels.
/2-(14)C-DPX-T3217/ was administered /to rats/ in corn oil to/ single dose groups: 2.5 & 120 mg/kg, 0.5 & 2 mL/animal (~10 & ~20 uCi/animal, groups D & E, respectively) and a multiple dose group: daily administration at 2.5 mg/kg for 14 days followed by labeled dose at 2.5 mg/kg (group F). /In a/ 5/sex/dose regimen, the primary metabolites detected by HPLC and TLC in excreta were IN-W3595 (2-cyano-2-methoxyimino acetic acid) and polar components (glycine and other amino acid conjugates); In group D males, 24 hr: 58% of /administered dose (AD)/ in urine (8.6% as IN-W3595, 46.5% as polars), 21.9% in feces (14% extractable, <1% IN-W3595, 13.1% polars). In /group D/ females, 64.2% of AD /appeared/ in urine (16.1% IN-W3595, 45.2% polars), 16.3% in feces (10.1% extractable, <1% IN-W3595, 8.7% polars). In group E males, 70.3% of AD /appeared/ in urine (26.3% IN-W3595, 40.3% polars), 16.1% in feces (11.3% extractable, <1% IN-W3595, 8.6% polars). /In group E/ females, 73% of AD in urine (33% IN-W3595, 36.7% polars), 17.1% in feces (11.5% extractable, <1% IN-W3595, 8.5% polars). In group F males, 66.2% of AD /appeared/ in urine (6.5% IN-W3595, 55% polars), 14.5% in feces (9% extractable, <1% IN-W3595, 8.9% polars). In group F females, 63.1% of AD /appeared/ in urine (11.1% IN-W3595, 46.6% polars), 19.4% in feces (12.3% extractable, <1% IN-W3595, 12.2% polars). /IN-W3595 metabolite/
Organic nitriles are converted into cyanide ions through the action of cytochrome P450 enzymes in the liver. Cyanide is rapidly absorbed and distributed throughout the body. Cyanide is mainly metabolized into thiocyanate by either rhodanese or 3-mercaptopyruvate sulfur transferase. Cyanide metabolites are excreted in the urine. (L96)

Toxicity Summary
Organic nitriles decompose into cyanide ions both in vivo and in vitro. Consequently the primary mechanism of toxicity for organic nitriles is their production of toxic cyanide ions or hydrogen cyanide. Cyanide is an inhibitor of cytochrome c oxidase in the fourth complex of the electron transport chain (found in the membrane of the mitochondria of eukaryotic cells). It complexes with the ferric iron atom in this enzyme. The binding of cyanide to this cytochrome prevents transport of electrons from cytochrome c oxidase to oxygen. As a result, the electron transport chain is disrupted and the cell can no longer aerobically produce ATP for energy. Tissues that mainly depend on aerobic respiration, such as the central nervous system and the heart, are particularly affected. Cyanide is also known produce some of its toxic effects by binding to catalase, glutathione peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, succinic dehydrogenase, and Cu/Zn superoxide dismutase. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin. (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 skin >3 g/kg
LD50 Guinea pig oral 1096 mg/kg
LD50 Dog percutaneous >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 member of the class of ureas that is urea in which the two nitrogen atoms are substituted by an ethyl group and a 2-cyano-2-(methoxyimino)acetyl group respectively. A fungicide used to control Peronosporales on a range of crops including vines, hops and potatoes. It has a role as an environmental contaminant, a xenobiotic and an antifungal agrochemical. It is a member of ureas, a nitrile, an oxime O-ether and an aliphatic nitrogen antifungal agent.
Cyomaxinil is a fungicide which was first introduced in 1977. It is an acetimide compound used as both a curative and preventative foliar fungicide. In Europe it is being sold for use on grapes, potatoes, tomatoes, hops, sugarbeets and other vegetable crops. Cymoxanil is currently not registered in the U.S. Cymoxanil's mode of action is as a local systemic. It penetrates rapidly and when inside the plant, it cannot be washed off by rain. It controls diseases during the incubation period and prevents the appearance of damage on the crop. The fungicide is primarily active on fungi belonging to the Peronosporales order: Phytophthora, Plasmopara, and Peronospora. Cymoxanil has 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.)