Absorption, Distribution and Excretion
Non-radiolabeled triadimefon (97.6% purity, [phenyl-UL-14C] triadimefon (15.78 Ci/mmole, 99.3% radiopurity); single (5 or 50 mg/kg, 5 rats/sex/dose) and multiple oral dosing (5 mg/kg, pretreat 10 rats/sex daily with non-labeled triadimefon for 14 days prior to pulsing with a single dose of 14C-triadimefon; triadimefon is rapidly absorbed, metabolized and excreted; <1% of the radioactivity was expired as CO or other volatile organic products; excretion of triadimefon residues in urine and feces was sex dependent; in males, 24-28% of the administered dose was eliminated in urine, and 63-66% in feces, within 96 hrs; in females, 57-67% of the administered radioactivity was excreted in urine, and 32-41% was excreted in the feces, within 96 hrs; total excretion of the administered radioactivity was faster by females: nearly 95% of the dose was excreted by females within 72 hours, whereas males required 96 hrs to reach 90% excretion; no evidence of bioaccumulation after multiple dosing; radioactive residues were highest in the liver and kidneys...
Absorbed by the roots & leaves, with ready translocation in young growing tissues, but less ready translocation in older, woody tissues.
In mammals, following oral admin, 83-96% is excreted unchanged in the urine & feces within 2 to 3 days.
The percutaneous absorption of (14)C phenoxy ring labeled triadimefon was studied in adult & young male & female Sprague Dawley rats. Triadimefon was applied (41.1 to 46.4 ug/sq cm) in 0.2 mL of acetone to areas comprising 3% of the body surface (7.0 to 14.5 sq cm). Thirty six animals were treated at the initiation of each study.Groups of 3 animals were subsequently killed at 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hr after treatment. Skin from the treated area as well as blood, heart, liver, kidneys, remaining carcass, urine, and feces were analyzed for (14)C by scintillation counting techniques. Based on 14 counts, triadimefon was lost more rapidly from the skin of young animals (half-life, 20 to 25 hr) than from the skin of adult animals (half-life, 29 to 53 hr). Recovery studies indicated that adult males, adult females, young males, and young females, respectively, absorbed 53, 82, 57, and 52% of the dose. The rest of the dose based on material balance was presumably lost by evaporation. Approx 2.5 to 3.9% of the dose penetrated the skin in 1 hr and was available for absorption. The rate of entry triadimefon into blood was 2 to 2.5 times faster for young than that observed in adult animals. Elimination of it from blood was faster in the case of the young animals. Triadimefon was absorbed through the skins of the adult male, adult female, young male, and young female rat, respectively, at rates of 0.20, 0.50, 0.58, and 0.48 ug/hr/sq cm of skin.
For more Absorption, Distribution and Excretion (Complete) data for TRIADIMEFON (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil was metabolized more rapidly than triadimefon, which is consistent with metabolism of the n-butyl side-chain in the former and the t-butyl group in the latter compound. Human and rat CYP2C and CYP3A enzymes were the most active. Metabolism was similar in microsomes prepared from livers of control and low-dose rats. High-dose (115 mg/kg/day of triadimefon or 150 mg/kg/day of myclobutanil) rats showed increased liver weight, induction of total CYP, and increased metabolism of the two triazoles, though the apparent Km appeared unchanged relative to the control. These data identify CYP enzymes important for the metabolization of these two triazoles. Estimated hepatic clearances suggest that CYP induction may have limited impact in vivo.
/After/ non-radiolabeled triadimefon (97.6% purity, [phenyl-UL-14C] triadimefon (15.78 Ci/mmole, 99.3% radio-purity); single (5 or 50 mg/kg, 5 rats/sex/dose) and multiple oral dosing (5 mg/kg, pretreat 10 rats/sex daily with non-labeled triadimefon for 14 days prior to pulsing with a single dose of 14C-triadimefon; ... four major metabolites, KWG 0519 acid, KWG 1323-gluc, DeMe-KWG-1342-gluc and HO-DeMe-KWG 1342, were identified in urine and five major metabolites including KWG-0519 acid, KWG-1323, KWG-1342, KWG-1323-gluc were detected in feces; unmetabolized parent triadimefon was detected only in male rat feces and only in trace amounts (<1%).
Triadimefon was applied to cucumber, tomato, bean and wheat plants. Differences were primarily quantitative. Triadimenol, the 2-butenol analog, was formed in each case.
In plants, the carbonyl group is reduced to a hydroxyl group, with the formation of triadimenol.
For more Metabolism/Metabolites (Complete) data for TRIADIMEFON (6 total), please visit the HSDB record page.

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Biological Half-Life
Half-life in blood plasma is approx 2.5 hr.
[(14)C] triadimefon in 50% aqueous ethanol was administered as a single gavage dose at 24.5-25.0 mg/kg to 12 Sprague Dawley rats/sex ... Plasma levels of radioactivity were highest 1-2 hours post-dose (2.5-3.2 ppm), and the half-life was approximately 4 hours.
...Triadimefon was lost more rapidly from the skin of young animals (half-life, 20 to 25 hr) than from the skin of adult animals (half-life, 29 to 53 hr).

Toxicity Data
LC50 (rat) = 2,450 mg/m3

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Non-Human Toxicity Values
LD50 Rat oral 90 mg/kg
LD50 Rat dermal 310 mg/kg
LC50 Rat inhalation 3.27 mg/L air/4 hr (dust)
LD50 Rabbit oral 250-500 mg/kg
For more Non-Human Toxicity Values (Complete) data for TRIADIMEFON (10 total), please visit the HSDB record page.

Triadimefon can cause developmental toxicity, female reproductive toxicity and male reproductive toxicity according to The Environmental Protection Agency (EPA).
Triadimefon is a colorless to pale yellow crystalline solid with a slight odor. (NTP, 1992)
1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one is a member of the class of triazoles that is 1-hydroxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one in which the hydroxyl hydrogen is replaced by a 4-chlorophenyl group. It is a member of triazoles, a member of monochlorobenzenes, an aromatic ether, a ketone and a hemiaminal ether.
Triadimefon has been reported in Colletotrichum gloeosporioides with data available.
Triadimefon is a fungicide used to control powdery mildew, rusts, and other infections in many crops. It is also a pesticide transformation product. Its mode of action is systemic with protective, curative and eradicant action. It disrupts membrane function. As a seed treatment, it is used on barley, corn, cotton, oats, rye, sorghum, and wheat. In fruit it is used on pineapple and banana. Non-food uses include pine seedlings, Christmas trees, turf, ornamental plants, and landscaping.

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Mechanism of Action
The present study relates the toxicological effects of conazoles to alterations of gene and pathway transcription and identifies potential modes of tumorigenic action ... Differentially expressed genes and pathways were identified using Affymetrix GeneChips. Gene-pathway associations were obtained from the Kyoto Encyclopedia of Genes and Genomes, Biocarta, and MetaCore compendia. The pathway profiles of each conazole were different at each time point. In general, the number of altered metabolism, signaling, and growth pathways increased with time and dose and were greatest with propiconazole. All conazoles had effects on nuclear receptors as evidenced by increased expression and enzymatic activities of a series of related cytochrome P450s (CYP). A subset of altered genes and pathways distinguished the three conazoles from each other. Triadimefon and propiconazole both altered apoptosis, cell cycle, adherens junction, calcium signaling, and EGFR signaling pathways. Triadimefon produced greater changes in cholesterol biosynthesis and retinoic acid metabolism genes and in selected signaling pathways. Propiconazole had greater effects on genes responding to oxidative stress and on the IGF/P13K/AKt/PTEN/mTor and Wnt-beta-catenin pathways. In conclusion, while triadimefon, propiconazole, and myclobutanil had similar effects in mouse liver on hepatomegaly, histology, CYP activities, cell proliferation, and serum cholesterol, genomic analyses revealed major differences in their gene expression profiles.
Four triazole fungicides were studied using toxicogenomic techniques to identify potential mechanisms of action. Adult male Sprague-Dawley rats were dosed for 14 days by gavage with fluconazole, myclobutanil, propiconazole, or triadimefon. Following exposure, serum was collected for hormone measurements, and liver and testes were collected for histology, enzyme biochemistry, or gene expression profiling. Body and testis weights were unaffected, but liver weights were significantly increased by all four triazoles, and hepatocytes exhibited centrilobular hypertrophy. Myclobutanil exposure increased serum testosterone and decreased sperm motility, but no treatment-related testis histopathology was observed. /It was/ hypothesized that gene expression profiles would identify potential mechanisms of toxicity and used DNA microarrays and quantitative real-time PCR (qPCR) to generate profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzyme but can also modulate the expression and function of mammalian CYP genes and enzymes. Triazoles affected the expression of numerous CYP genes in rat liver and testis, including multiple Cyp2c and Cyp3a isoforms as well as other xenobiotic metabolizing enzyme (XME) and transporter genes. For some genes, such as Ces2 and Udpgtr2, all four triazoles had similar effects on expression, suggesting possible common mechanisms of action. Many of these CYP, XME and transporter genes are regulated by xeno-sensing nuclear receptors, and hierarchical clustering of CAR/PXR-regulated genes demonstrated the similarities of toxicogenomic responses in liver between all four triazoles and in testis between myclobutanil and triadimefon. Triazoles also affected expression of multiple genes involved in steroid hormone metabolism in the two tissues. Thus, gene expression profiles helped identify possible toxicological mechanisms of the triazole fungicides.
The triazole derivative Triadimefon (FON) is a systemic fungicide used to control powdery mildews, rusts, and other fungal pests. Some data have already been published about the teratogenic activity of this compound: craniofacial malformations were found in mouse, rat, and Xenopus laevis embryos exposed to FON. These alterations were correlated to defective branchial arch development possibly caused by abnormal neural crest cell (NCC) migration into the branchial mesenchyme. As the migration of NCCs is controlled by the HOX code and by an anteroposterior retinoic acid (RA) gradient, we analyzed the expression of CYP26, a key enzyme in RA metabolism, following FON exposure. The increased expression of this gene and the ability of citral (a RA inhibitor) to reduce the teratogenic effects of the fungicide support the notion that endogenous RA is involved in the mechanism of action of FON. Moreover, by in situ hybridization, we studied the effects of FON exposure at gastrula stage on the expression of some genes involved in craniofacial development, hindbrain patterning, and NCC migration. We observed abnormal localization of xCRABP, Hoxa2 and Xbap signal expression at the level of migrating NCC domains, whereas in the hindbrain, we did not find any alteration in Krox20 and Hoxa2 expression.
Triazole-derivatives alter the pharyngeal apparatus morphogenesis of rodent embryos cultured in vitro. The hindbrain segmentation and the rhombencephalic neural crest cell (NCCs) migration are altered by Fluconazole exposure in vitro. The aim of the present work is to identify if a common pathogenic pathway is detectable also for other molecules of this class of compounds. 9.5 days post coitum (d.p.c.) old rat embryos were exposed in vitro to the teratogenic concentrations of Flusilazole, Triadimefon and Triadimenol and cultured for 24, 48 or 60 hr. The expression and localization of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segmentation) were evaluated after 24 hr of culture. The localization and distribution of NCC was evaluated after 24, 30 and 48 hr of culture. The morphology of the embryos was analyzed after 48 hr, while the branchial nerve structures were evaluated after 60 hr of culture. Hindbrain segmentation and NCC migration alteration as well as pharyngeal arch and cranial nerve abnormalities were detected after exposure of the tested molecules. A common severe teratogenic intrinsic property for the tested molecules of this chemical class has been found, acting through alteration of the normal hindbrain developmental pattern.
For more Mechanism of Action (Complete) data for TRIADIMEFON (10 total), please visit the HSDB record page.

C14H16CLN3O2

293.749

293.093

43121-43-3

39385

Colorless solid

1.2±0.1 g/cm3

441.9±55.0 °C at 760 mmHg

82°C

221.0±31.5 °C

0.0±1.1 mmHg at 25°C

1.580

2.77

0

4

5

20

338

0

CC(C)(C)C(=O)C(N1C=NC=N1)OC2=CC=C(C=C2)Cl

WURBVZBTWMNKQT-UHFFFAOYSA-N

InChI=1S/C14H16ClN3O2/c1-14(2,3)12(19)13(18-9-16-8-17-18)20-11-6-4-10(15)5-7-11/h4-9,13H,1-3H3

1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)butan-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO : ~250 mg/mL (~851.06 mM)

Solubility in Formulation 1: 2.08 mg/mL (7.08 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (7.08 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 20.8 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: ≥ 2.08 mg/mL (7.08 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 20.8 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.)