Absorption, Distribution and Excretion
Rat skin absorption rate: 13% after 10 hours. Cyproheptadine appears to be rapidly absorbed through the skin in an inversely proportional manner to the dose. After skin absorption, the drug is slowly released into the body. The primary route of excretion is apparently urine. There is no evidence that the compound remains in the skin. Based on blood, urine/fecal excretion, and cadaver analysis, the mean absorption rate for animals euthanized at the end of the exposure period was 0.6% to 7%. For animals exposed for 10 and 24 hours and followed up for 48 hours post-exposure, the mean absorption rate was 8% to 14.5%. Total radioactive absorption generally decreased with increasing dose, indicating that absorption saturates with increasing dose. At the end of the experiment, the residual radioactive material on the skin ranged from 4.5% (10 mg dose/2-hour exposure) to 24% (0.1 mg dose/24-hour exposure). Most of the absorbed radioactive material was present in urine and cadaver. Most of the unabsorbed radioactive material was present in the skin flushing solution at each dose/duration. In another part of the same study (rats), the absorption rate at 10 hours was 10%. The mean total radioactive material recovery rate across all dose groups ranged from 85% to 101%. The mean absorption rate based on blood, urine/fecal excretion, and cadaveric excretion ranged from 2% to 11%. Total absorbed radioactive material generally increased with increasing exposure time but decreased with increasing dose, indicating that penetration reached saturation with increasing dose. Most of the absorbed radioactive material was found in urine and cadaveric excretion. Most of the unabsorbed radioactive material was found in the skin flushing solution at each dose/duration (35-90%). However, based on measurements of skin absorption rate, the skin itself also contained a considerable amount of radioactive dose (9-40%). If the radioactivity dissolved in the skin is also taken into account, the mean absorption rate ranged from 10% to 45%. The ratio of the radioactive dose in the skin flushing solution to the radioactivity in the skin itself decreased over time, indicating that the radioactive material gradually penetrated into the subsurface layer of the skin after treatment.
After oral administration of ciprozin, rats absorbed it well. At the low-dose group (3 mg/kg), drug excretion was rapid, but at the high-dose group (300 mg/kg), excretion was significantly delayed. Except for male rats in the high-dose group, fecal excretion was comparable across all dose groups, with a higher proportion of fecal excretion in male rats in the high-dose group. Radioactive material in the feces was primarily excreted via bile. Residual radioactive material in tissues was extremely low in all dose groups. Urinary and fecal metabolites of 14C-cyclopromethazine were separated and identified using thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC/MS). The major compounds were the N-dealkylated product melamine, hydroxycyclopromethazine, and unmetabolized cyclopromethazine. Two male and one female Charles River rat (not further identified) were orally administered a single dose of 0.5 mg/kg body weight of 14C-cyclopromethazine (uniformly triazine ring labeled). Seventy-two hours after administration, 95% of the administered dose was excreted in the urine, almost entirely within the first 24 hours. Approximately 3% was excreted in the feces, also primarily within the first 24 hours. In two male and one female rats given the same dose, the amount excreted as volatiles or carbon dioxide was negligible. Tissue residues, except in the liver, were below the detection limit. However, the radioactive content in the liver was too low to be accurately quantified (approximately 0.007 ppm). Two chickens (strain unspecified) were orally administered 0.75 mg/bird/day of 14C-cyclopromethazine (uniformly triazine ring labeled) for seven consecutive days. Twenty-four hours after the last administration, 99.1% of the radioactive material was recovered in the feces, with almost no radioactivity in the volatiles and carbon dioxide. The radioactive content in egg white and yolk remained consistently at approximately 0.12–0.15 ppm. The radioactive material concentrations in the tissues were as follows: byproducts (i.e., head and paws) 0.047 ppm (based on test equivalents); reproductive tract 0.047 ppm; liver 0.032 ppm; and all other tissues 0.008–0.019 ppm. For more complete data on the absorption, distribution, and excretion of cyclopromethazine (10 items in total), please visit the HSDB record page. Metabolites/Metabolites: Cyclopromethazine was well absorbed in rats after oral administration. …Urinary and fecal metabolites of 14C-cyclopromethazine were separated and identified using thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC/MS). The major compounds were the N-dealkylated product melamine, hydroxycyclopromethazine, and unmetabolized cyclopromethazine.
The urine of female rats who received a single oral dose of 0.5 mg/kg body weight of 14C-cycloprozine (uniformly labeled with a triazine ring) was analyzed using thin-layer chromatography and cation exchange column chromatography. Both systems detected that most of the radioactive material in the urine was present as the unchanged parent compound. The unchanged parent compound in the urine accounted for approximately 80% of the administered dose. Three metabolites, presumed to be the same compound, were detected in both systems. These metabolites accounted for 2.2–3.2%, 3.0–5.5%, and 4.6–5.3% of the administered dose, respectively, but were not identified. In fecal samples from male rats given the same dose as the female rats, the content of the unchanged parent compound was extremely low: <0.1% of the administered dose. The same three metabolites as in the urine were also found in the fecal samples, accounting for 0.1%, 0.1%, and 4.1% of the administered dose, respectively. A male and a female albino Sprague-Dawley rat were fed a diet containing 3000 ppm of 14C-cyclopromethazine for 10 consecutive days. In the male rhesus monkey, the liver contained 31.3 ppm of cyclopromethazine and 0.96 ppm of melamine; the kidney contained 62.4 ppm of cyclopromethazine and 1.3 ppm of melamine. In the female rhesus monkey, the residual amounts of cyclopromethazine and melamine in the liver were 13.2 ppm and 0.51 ppm, respectively, and in the kidney were 22.2 ppm and 0.68 ppm, respectively. This study indicates that cyclopromethazine is converted into melamine in vivo. Following a single oral administration of 0.05 or 0.5 mg/kg body weight of 14C-cyclopromethazine (uniformly triazine ring-labeled) capsules to male and female macaques (Macaca fasicicula), most of the radioactive material in the urine was found to be present in the form of the unmodified parent compound. Regardless of dose, 93.6–96.1% of the urinary radioactive material was present as unmetabolized cyclopromethazine. Furthermore, 2.9–6.4% of the radioactive material was identified as melamine… In another study using monkeys of the same strain and administered the same dose level, 95–100% of the recovered radioactive material in urine collected within 24 hours after administration was present as unmetabolized cyclopromethazine. In one male monkey receiving a dose of 0.05 mg/kg body weight, melamine was not detected in the urine. In a female monkey receiving a dose of 0.05 mg/kg body weight and in a male and female monkey receiving a dose of 0.5 mg/kg body weight, 3.0–3.9% of the urinary radioactive material was present in the form of melamine. For more complete metabolite/metabolite data on cycloprozine (9 metabolites in total), please visit the HSDB record page.

Toxicity Data
LC50 (Rats) > 3,600 mg/m³/4 hours Non-human Toxicity Values LD50 Mice (Male, Female) Oral 2029 mg/kg LD50 Rabbits (Male, Female) Oral 1467 mg/kg LD50 Rat Oral 3387 mg/kg /Technical Grade Ciprozine/ LC50 Rat Inhalation > 2.720 mg/L Air/4 hours LD50 Rat Dermal > 3100 mg/kg

[1]. Survival advantage of cyromazine-resistant sheep blowfly larvae on dicyclanil- and cyromazine-treated Merinos. Aust Vet J. 2014 Nov;92(11):421-6.

[2]. Cyromazine Effects the Reproduction of Drosophila by Decreasing the Number of Germ Cells in the Female Adult Ovary. Insects. 2022 Apr 27;13(5):414.

[3]. Cyromazine and Chlorpyrifos Induced Renal Toxicity in Rats: The Ameliorated Effects of Green Tea Extract. Journal of Environmental and Analytical Toxicology. 2012 June 9; 2(5): 1000146.

[4]. Cyromazine affects the ovarian germ cells of Drosophila via the ecdysone signaling pathway. Front Physiol. 2022 Sep 29;13:992306.

[5]. The ameliorating effects of green tea extract against cyromazine and chlorpyrifos induced liver toxicity in male rats. Asian Journal of Pharmaceutical and Clinical Research. 2013 January; 6(1):47-55.

Cyromazine is a triamino-1,3,5-triazine compound. It is a triazine insecticide and a metabolite in mice.
Exoparasite killer. Insect growth regulator. Specific activity against dipteran larvae. Cyromazine has been approved by the U.S. Food and Drug Administration (FDA) for use in livestock. Cyromazine belongs to the aminotriazine class of compounds. These organic compounds contain an amino group linked to a triazine ring.
See also: Vitazine (note moved here).

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Mechanism of Action
A contact insect growth regulator that interferes with molting and pupation. When used on plants, it acts systemically.
Cyromazine is an effective insecticide for controlling dipteran insects. Its exact mechanism of action remains to be determined, but studies suggest it may interfere with hormone systems, epidermal hardening, or nucleic acid metabolism. To understand the mechanism of action of Cyromazine, the authors located and cloned a Cyromazine resistance gene from Drosophila. Previously, six cycloprozin resistance alleles had been generated by treatment with ethyl methanesulfonate. Two of these alleles were not complementary, and the authors identified independent nonsense mutations in the CG32743 gene. CG32743 is an ortholog of Smg1 in nematodes and mammals, encoding a phosphatidylinositol kinase-like kinase (PIKK). RNAi experiments confirmed that knocking down the CG32743 gene resulted in cycloprozin resistance. These are the first cycloprozin resistance mutations identified at the nucleotide level. In mammals, Smg1 phosphorylates p53 after DNA damage. This finding supports the hypothesis that cycloprozin interferes with nucleic acid metabolism.

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Therapeutic Use
Drug (Veterinary): Ectoplasmic parasite killer
Drug (Veterinary): Cyromazine is a triazine derivative effective against blowfly larvae and other dipteran insects (such as houseflies and mosquitoes) in sheep and lambs. At recommended doses, cycloprozin has limited efficacy against existing infestations and therefore must be used prophylactically. Blowflies typically lay their eggs on the damp wool of treated sheep. Although the larvae can hatch, they immediately come into contact with cycloprothiazide, preventing them from molting and entering the second instar larval stage. The efficacy of topical cycloprothiazide preparations is not affected by weather, wool length, or wool moisture. A single application can maintain efficacy for up to 13 weeks; if applied by soaking or spraying, the efficacy can last even longer.

C6H10N6

166.19

166.096

66215-27-8

Cyromazine-d4;1219804-19-9;Cyromazine-13C3;1808990-94-4

47866

White to off-white solid powder

1.6±0.1 g/cm3

480.6±28.0 °C at 760 mmHg

223-227 °C(lit.)

244.5±24.0 °C

0.0±1.2 mmHg at 25°C

1.851

-0.04

3

6

2

12

148

0

LVQDKIWDGQRHTE-UHFFFAOYSA-N

InChI=1S/C6H10N6/c7-4-10-5(8)12-6(11-4)9-3-1-2-3/h3H,1-2H2,(H5,7,8,9,10,11,12)

2-N-cyclopropyl-1,3,5-triazine-2,4,6-triamine

HSDB-6602; HSDB 6602; Cyromazine

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 : ≥ 1.8 mg/mL (~10.83 mM)

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.)