Absorption, Distribution and Excretion
Unlabeled triazolone (97.6% purity), [phenyl-UL-14C]triazolone (15.78 Ci/mmol, radioactivity purity 99.3%); single dose (5 or 50 mg/kg, 5 rats per sex per dose) and multiple oral administrations (5 mg/kg, 10 rats per sex pretreated with unlabeled triazolone before a single 14C-triazolone pulse, once daily for 14 days); rapid absorption, metabolism, and excretion of triazolone; <1% of radioactivity is excreted as CO or other volatile organic compounds; excretion of triazolone residues in urine and feces is sex-dependent; in male rats, 24-28% of the administered dose is excreted in urine and 63-66% in feces. Within 96 hours; in female animals, 57-67% of the administered radioactive material was excreted in urine and 32-41% in feces within 96 hours; female animals excreted the administered radioactive material more rapidly: nearly 95% of the dose was excreted by female animals within 72 hours, while male animals required 96 hours to reach a 90% excretion rate; no evidence of bioaccumulation was found after multiple administrations; the highest concentrations of radioactive residues were found in the liver and kidneys…
The drug can be absorbed by roots and leaves and is rapidly transported to young growing tissues, but transport is slower in older woody tissues.
In mammals, after oral administration, 83-96% of the drug is excreted unchanged in urine and feces within 2 to 3 days.
The absorption of (14)C phenoxy ring-labeled triazolone by dermal absorption in adult and juvenile male and female animals was studied. Sprague Dawley rats were used in this study. Triadimefon (41.1 to 46.4 μg/cm²) was dissolved in 0.2 mL of acetone and applied to an area covering 3% (7.0 to 14.5 cm²) of the body surface. At the start of each study, 36 animals were treated. Subsequently, three animals from each group were sacrificed at 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, and 192 hours post-treatment. Scintillation counting was used to analyze the 14C content in the treated skin, blood, heart, liver, kidneys, remaining carcasses, urine, and feces. Based on the 14C count results, triadimefon was cleared more rapidly from the skin of young mice (half-life 20 to 25 hours) than from the skin of adult mice (half-life 29 to 53 hours). Recovery studies showed that adult males, adult females, juvenile males, and juvenile females absorbed 53%, 82%, 57%, and 52% of the dose, respectively. Based on mass balance, the remaining dose may be lost through evaporation. Approximately 2.5% to 3.9% of the dose penetrates the skin and becomes available for absorption within 1 hour. The rate of triadimefon entry into the bloodstream of juvenile animals is 2 to 2.5 times faster than in adult animals. The rate of triadimefon clearance from the bloodstream of juvenile animals is also faster. The rates of transdermal absorption of triadimefon in adult males, adult females, juvenile males, and juvenile female rats were 0.20, 0.50, 0.58, and 0.48 μg/h/cm² of skin, respectively.
For more complete data on the absorption, distribution, and excretion of triadimefon, please refer to (8 entries in total) on the HSDB record page.

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Metabolism/Metabolites
This study investigated the metabolism of two triazole-containing antifungal azoles using expressed human and mouse cytochrome P450 (CYP) and liver microsomes. Due to the diverse metabolites produced by tebuconazole and triadimefon, a substrate consumption method was employed. Tebuconazole was metabolized faster than triadimefon, consistent with the metabolism of the n-butyl side chain in tebuconazole and the tert-butyl side chain in triadimefon. Human and mouse CYP2C and CYP3A enzyme activities were highest. Metabolism in liver microsomes was similar in the control and low-dose groups. In the high-dose groups (triadimefon 115 mg/kg/day or tebuconazole 150 mg/kg/day), liver weight increased, total CYP activity was enhanced, and the metabolism of both triazoles increased accordingly, but the apparent Km value appeared unchanged relative to the control group. These data suggest that CYP enzymes are crucial for the metabolism of these two triazoles. Estimated liver clearance suggests that CYP induction may have limited effects in vivo.

/After/ Unlabeled triazolone (purity 97.6%, [phenyl-UL-14C]triazolone (15.78 Ci/mmol, radioactivity purity 99.3%); single dose (5 or 50 mg/kg, 5 rats/sex/dose per group) and multiple oral administrations (5 mg/kg, 10 rats/sex pretreated with unlabeled triazolone daily for 14 days prior to a single 14C-triazolone pulse); ... four major metabolites, KWG 0519 acid, KWG 1323-glucoside, DeMe-KWG-1342-gluc and HO-DeMe-KWG were identified in urine. 1342, five major metabolites were detected in feces, including KWG-0519 acid, KWG-1323, KWG-1342 and KWG-1323-gluc; unmetabolized maternal triadimefon was detected only in male rat feces, and at very low levels (<1%).
Triadimefon has been used in cucumber, tomato, legume and wheat plants. The differences are mainly in quantity. In all cases, the 2-butenol analog triadimefon was generated.
In plants, the carbonyl group is reduced to the hydroxyl group to generate triadimefon.
For more complete data on the metabolism/metabolites of triadimefon (6 in total), please visit the HSDB record page.

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Biological half-life
The half-life in plasma is approximately 2.5 hours.
Twelve Sprague rats were given a single gavage dose of 24.5-25.0 mg/kg of [(14)C]triadimefon dissolved in 50% ethanol aqueous solution. Dawley rats (half male and half female)... Plasma radioactivity levels were highest 1-2 hours after administration (2.5-3.2 ppm), with a half-life of approximately 4 hours. ... Triadimefon is cleared from the skin of juvenile animals (half-life 20-25 hours) more rapidly than from the skin of adult animals (half-life 29-53 hours).

Toxicity Data
LC50 (Rat) = 2,450 mg/m³ 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 hours (Dust) LD50 (Rabbit, Oral) 250-500 mg/kg For more complete non-human toxicity data (out of 10) for TRIADIMEFON, please visit the HSDB records page.

According to the U.S. Environmental Protection Agency (EPA), triadimefon can cause developmental toxicity, female reproductive toxicity, and male reproductive toxicity. 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)but-2-one belongs to the triazole class of compounds. Its structure is similar to 1-hydroxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)but-2-one, except that the hydrogen atom on the hydroxyl group is replaced by a 4-chlorophenyl group. It belongs to the triazole, monochlorobenzene, aromatic ether, ketone, and hemiacetal ether classes of compounds. Triadimefon has been reported to have been detected in Colletotrichum gloeosporioides, and relevant data are available. Triadimefon is a fungicide used to control powdery mildew, rust, and other diseases in various crops. It is also a pesticide transdermal product. Its mechanism of action is systemic, exhibiting protective, curative, and eradicative effects. It works by disrupting cell membrane function. As a seed treatment agent, it can be used on barley, corn, cotton, oats, rye, sorghum, and wheat. In fruits, it can be used on pineapples and bananas. Non-food uses include pine seedlings, Christmas trees, lawns, ornamental plants, and landscaping.

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Mechanism of Action
This study linked the toxicological effects of azole compounds to alterations in gene and pathway transcription and identified potential tumorigenic modes of action… Differentially expressed genes and pathways were identified using Affymetrix gene chips. Gene-pathway association information was obtained from the Kyoto Encyclopedia of Genes and Genomes (KEGG), Biocarta, and MetaCore databases. The pathway profiles of each azole compound differed at each time point. Overall, the number of alterations in metabolic, signal transduction, and growth pathways increased with increasing time and dose, with propiconazole showing the most significant alterations. All azole compounds affect nuclear receptors, manifested as increased expression of a range of related cytochrome P450 (CYP) enzymes and increased enzyme activity. Partially altered genes and pathways distinguish these three azole compounds. Triadimefon and propiconazole both altered apoptosis, cell cycle, adhesion junctions, calcium signaling, and EGFR signaling pathways. Triadimefon had a greater impact on genes involved in cholesterol biosynthesis and retinoic acid metabolism, as well as specific signaling pathways. Propiconazole had a greater impact on genes involved in oxidative stress response, as well as the IGF/PI3K/AKt/PTEN/mTOR and Wnt-β-catenin pathways. In summary, although triadimefon, propiconazole, and cyazofamid had similar effects on hepatomegaly, histology, CYP activity, cell proliferation, and serum cholesterol in mouse liver, genomic analysis revealed significant differences in their gene expression profiles. This study employed toxicogenomics techniques to investigate four triazole fungicides to identify their potential mechanisms of action. Adult male Sprague-Dawley rats were administered fluconazole, tebuconazole, propiconazole, or triadimefon by gavage for 14 consecutive days. Following administration, serum hormone levels were measured, and liver and testicular tissues were collected for histological, enzyme biochemical, and gene expression profiling analyses. Body weight and testicular weight were not affected, but all four triazole drugs significantly increased liver weight, and centrilobular hypertrophy of hepatocytes was observed. Tebuconazole treatment increased serum testosterone levels and decreased sperm motility, but no drug-related histopathological changes in testicular tissue were observed. The study hypothesized that gene expression profiling could reveal potential toxic mechanisms and used DNA microarray and quantitative real-time PCR (qPCR) techniques to generate gene expression profiles. Triazole fungicides are designed to inhibit fungal cytochrome P450 (CYP) 51 enzymes, but they can also regulate the expression and function of mammalian CYP genes and enzymes. Triazole drugs affect the expression of multiple CYP genes in rat liver and testes, including multiple Cyp2c and Cyp3a isoenzymes, as well as other xenobiotic metabolic enzymes (XMEs) and transporter genes. For certain genes, such as Ces2 and Udpgtr2, all four triazole drugs showed similar effects on their expression, suggesting a possible common mechanism of action. Many CYP, XME, and transporter genes are regulated by xenobiotic-sensing nuclear receptors. Hierarchical clustering analysis of CAR/PXR-regulated genes showed that the toxic genomic responses of all four triazole drugs were similar in the liver and testes for tebuconazole and triadimefon. Triazole drugs also affect the expression of multiple genes involved in steroid hormone metabolism in both tissues. Therefore, gene expression profiling helps identify the possible toxicological mechanisms of triazole fungicides.
The triazole derivative triadimefon (FON) is a systemic fungicide used to control powdery mildew, rust, and other fungal diseases. Some data have reported teratogenic activity of this compound: craniofacial malformations have been found in mouse, rat, and Xenopus embryos exposed to FON. These malformations are associated with defects in gill arch development, possibly due to abnormal migration of neural crest cells (NCCs) to the gill arch mesenchyme. Since NCC migration is controlled by the HOX gene and the anteroposterior retinoic acid (RA) gradient, we analyzed the expression of CYP26, a key RA metabolism enzyme, after FON exposure. Increased expression of this gene, along with the ability of citral (a RA inhibitor) to reduce the teratogenic effects of bactericides, supports the view that endogenous RA is involved in the mechanism of FON action. Furthermore, we investigated the effects of gastrulation-stage FON exposure on the expression of several genes involved in craniofacial development, hindbrain pattern formation, and neural crest cell (NCC) migration using in situ hybridization. We observed aberrant localization of xCRABP, Hoxa2, and Xbap signaling in migrating NCC regions, while in the hindbrain, we found no alterations in Krox20 and Hoxa2 expression. Triazole derivatives alter pharyngeal morphogenesis in cultured rodent embryos. In vitro fluconazole exposure alters hindbrain segmentation and rhomboid neural crest cell (NCC) migration. This study aims to determine whether other molecules of this class of compounds also share common pathogenic pathways. Rat embryos at 9.5 days post-fertilization (dpc) were exposed in vitro to teratogenic concentrations of flusilazole, triadimefon, and triazol, and cultured for 24, 48, or 60 hours, respectively. After 24 hours of culture, the expression and localization of Hox-b1 and Krox-20 proteins (used as markers for hindbrain segments) were assessed. After 24, 30, and 48 hours of culture, the localization and distribution of neural crest cells (NCCs) were assessed. Embryonic morphology was analyzed after 48 hours of culture, and branchial arch neural structures were assessed after 60 hours of culture. The results showed that exposure to the test molecules altered hindbrain segment and neural crest cell migration, and abnormalities were also observed in the pharyngeal arches and cranial nerves. Test molecules of this class of chemicals have been found to possess a common and severe intrinsic teratogenic property, with the mechanism of action being through alteration of normal hindbrain developmental patterns.
For more complete data on the mechanisms of action of TRIADIMEFON (10 in 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.)