Absorption, Distribution and Excretion
A lactating goat was given (propyl-1-(14)C)-critin in an alfalfa diet at a dose of 1.16 mg/kg body weight/day, administered in three equal doses of 14.2 mg daily for three days, followed by a single dose of 14.2 mg on the fourth day, for a total of 10 doses. A female goat served as a control. The treated goats were euthanized 4 hours after the last administration. Critin was rapidly absorbed: peak blood radiocarbon concentration (0.273 ppm) was reached within 1 hour of the first administration. The average amount of radiolabeled material recovered in urine was 56% of the administered dose, and in feces, 34%. The total amount of radiolabeled material detected in milk, blood, and tissues was less than 1% of the administered dose. …The radiolabeled material content in tissues was 0.37% of the administered dose, and in blood, 0.22%. The highest residual tissue concentrations were detected in the liver and kidneys. Eight to ten Leghorn laying hens were divided into groups and administered (cyclohexene-4,6-(14)C)-clethodim at doses of 0, 2.1, or 51.3 mg/kg body weight daily for five consecutive days. The hens were sacrificed approximately four hours after the last administration. Radioactive analysis showed that 78% of the radioactive material in the low-dose group and 85% in the high-dose group was excreted in feces; 1.9% of the radioactive material in the low-dose group and 4.2% in the high-dose group was present in tissues. The distribution concentration of the radiolabeled material in tissues, from highest to lowest, was: gastrointestinal tract > kidney > liver. In eggs, 0.1% of the radioactive material in the low-dose group and 0.3% in the high-dose group were detected. The highest radioactivity level was found in egg white, followed by eggshell, and the lowest in yolk. Male and female Cr1:CD(SD)BR rats were administered a single oral dose of [propyl-1-(14)C]-clethodim (4.4 or 468 mg/kg body weight) or an unlabeled test substance (4.5 mg/kg body weight) daily for 14 consecutive days, followed by a single oral dose of a radiolabeled substance at 4.8 mg/kg body weight. Drug clearance was rapid: 94-98% of the administered dose was eliminated within 48 hours. The primary route of excretion was urine (87-93%), with a small amount (9-17%) excreted in feces. The average amount of radioactive material excreted in exhaled air as carbon dioxide was 0.5-1% of the administered dose. Although clearance patterns were similar across groups, animals given a single dose (4.4 mg/kg body weight) cleared the drug slightly faster than those given a single dose (468 mg/kg body weight) (98% cleared within 50 hours). Clearance rates were not different between male and female animals after repeated administration of low doses of cristatin. After 7 days of treatment, the total amount of radiolabeled material recovered from organs and tissues was less than 1% of the administered dose. The highest residual tissue concentrations were found in the adrenal glands, kidneys, and liver. No significant dose-related or sex-specific differences were found in tissue distribution when expressed as a percentage of the administered dose, and no evidence of bioaccumulation was found.

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Metabolism/Metabolites
……A lactating goat was given (propyl-1-(14)C)-cristatin in an alfalfa diet at a dose of 1.16 mg/kg body weight/day, divided into three equal doses of 14.2 mg daily for three days, followed by a single dose of 14.2 mg on the fourth day, for a total of 10 doses. A female goat served as a control. The test goat was sacrificed 4 hours after the last administration. /……Samples were collected from hind limb and forelimb muscles, peritoneum and subcutaneous fat, liver, kidneys, heart, and blood for metabolite identification. The main metabolite in urine was cristatin sulfoxide, accounting for 67% of the radiocarbon in urine. Other radiolabeled components in urine were identified as clethodim (3-27%), demethyl sulfoxide (12-18%), S-methyl sulfoxide (7-13%), imine sulfoxide (1.5-2.8%), sulfone (1.5-2.2%), and 5-hydroxy sulfoxide (0-3%). In milk, approximately half of the radiocarbon was extractable into organic solvents and was present in clethodim, clethodim sulfoxide, and clethodim demethyl sulfoxide; the other half was water-soluble and was identified as C-lactose. In blood and tissues, extractable radiocarbon residues accounted for 77-95% of the total radiolabeled components and were identified as clethodim, as well as sulfoxide, demethyl sulfoxide, imine sulfoxide, sulfone, and 5-hydroxy sulfone. The metabolic pathways proposed in goats were essentially the same as those in rats. Eight white Leghorn laying hens in two groups were administered (cyclohexene-4,6-(14)C)-criticine capsules at a dose of 2.1 or 51.3 mg/kg body weight daily for five consecutive days. Approximately four hours after the last administration, the hens were sacrificed, and tissues were collected for analysis. Two major metabolites were identified in the tissues and eggs: criticine sulfone and criticine sulfoxide. Criticine sulfone accounted for 57% of the radiolabeled content in the tissues, while criticine sulfoxide accounted for 10-31%. Criticine sulfoxide was the major metabolite in egg white (26-82%) and egg yolk (25-37%); maternal criticine levels were significantly lower in both tissues and eggs. The metabolic pathway in chickens differs from that in rats and goats and is considered simpler because imine, 5-hydroxy, or S-methyl analogs were not detected in chickens. A group of male rats/Crl:CD(SD)BR were administered a single oral dose of 450 mg/kg body weight of the radiolabeled compound to ensure adequate amounts of the labeled metabolites. Urine and feces were collected, and the parent compound and its metabolites were analyzed. Metabolomic profiles were very similar in males and females across all dose groups. Nine urinary metabolites were identified and characterized. The major metabolite was chlorothiazide sulfoxide (65-75% of the administered dose), with minor metabolites including imine sulfoxide (6-13%), sulfones (1-3%), 5-hydroxysulfoxide/sulfones (0.5-1.5%), and oxazolium sulfone (0-5%). Major fecal metabolites (more than 1% of the radiolabeled compound) were identified as chlorothiazide sulfoxide and imine sulfoxide. Minor urinary and fecal metabolites (less than 1% of the administered dose) included oxazolium sulfoxide, demethyl sulfoxide, and aromatic sulfones. Other minor fecal metabolites included chlorothiazide sulfone, trione sulfoxide, and C-olefins. The parent chlorothiazide accounts for approximately 1% of the administered dose. The metabolic pathway of chlorothiazide in rats is presumed as follows: after absorption, chlorothiazide undergoes the following metabolism: oxidation to chlorothiazide sulfoxide (the main metabolic pathway); conversion to S-methyl via a sulfonium cationic intermediate; cleavage at the oxime NO bond to generate an imine; or hydroxylation at the 5-position.

Non-Human Toxicity Values
Rat inhalation LC50: 3.9 mg/L/4 hr
Rabbit dermal LD50: >5000 mg/kg
Female mouse oral LD50: 2430 mg/kg
Male mouse oral LD50: 2570 mg/kg
For more complete (6 data points) non-human toxicity values of Clethodim, please visit the HSDB record page.

Clethodim is an oxime O-ether, prepared by converting the acyclic ketone group of 5-[2-(ethylthio)propyl]-3-hydroxy-2-propionylcyclohex-2-en-1-one into the corresponding oxime, followed by O-alkylation of the oxime group by (E)-3-chloroallyl. It is a selective post-emergence herbicide used to control annual and perennial weeds in a variety of crops, including alfalfa, celery, clover, conifers, cotton, cranberries, garlic, onions, ornamental plants, peanuts, soybeans, strawberries, beets, sunflowers, and vegetables; the (-)-enantiomer has been reported to be more active than the (+)-enantiomer. It is both a herbicide and an EC 6.4.1.2 (acetyl-CoA carboxylase) inhibitor. It is an organosulfur compound, cyclic ketone, organochlorine compound, oxime ether, β-diketone, and enol.

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Mechanism of Action
...Fatty acid synthesis inhibitor.

C17H26CLNO3S

359.9

359.132

99129-21-2

135491728

Clear amber liquid

1.2±0.1 g/cm3

467.3±55.0 °C at 760 mmHg

236.4±31.5 °C

0.0±1.2 mmHg at 25°C

1.531

4.05

1

5

9

23

488

0

CC/C(=N\OC/C=C/Cl)/C1=C(CC(CC(C)SCC)CC1=O)O

SILSDTWXNBZOGF-KUZBFYBWSA-N

InChI=1S/C17H26ClNO3S/c1-4-14(19-22-8-6-7-18)17-15(20)10-13(11-16(17)21)9-12(3)23-5-2/h6-7,12-13,20H,4-5,8-11H2,1-3H3/b7-6+,19-14+

2-[(E)-N-[(E)-3-chloroprop-2-enoxy]-C-ethylcarbonimidoyl]-5-(2-ethylsulfanylpropyl)-3-hydroxycyclohex-2-en-1-one

Prism; Centurion; Clethodim

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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