Absorption, Distribution and Excretion
When applied topically, chlorhexidine undergoes virtually no systemic absorption. Oral chlorhexidine, such as that used in dental mouthwash, is absorbed very poorly in the gastrointestinal tract—the peak plasma concentration (Cmax) after oral administration of 300 mg chlorhexidine is 0.206 μg/g, with a time to peak concentration (Tmax) of approximately 30 minutes after ingestion. No chlorhexidine levels were detected in plasma or urine after implantation of four Periodips in 18 adult patients. Chlorhexidine gluconate is almost entirely excreted in feces, with less than 1% of the ingested dose excreted in urine. One study investigated 34 newborns who underwent standard bathing with Hibiscrub to determine whether it was absorbed percutaneously. Low concentrations of chlorhexidine were detected in blood samples from 10 infants collected via heel prick, and also in 5 of the 24 infants who received intravenous blood samples. /Chlorhexidine Gluconate/
The transdermal absorption of the antibacterial agent chlorhexidine (carbon-14 labeled) was studied in rats. Within 5 days, the absorption rate of topically applied chlorhexidine was less than 5%. The absorbed radioactive material was primarily excreted in feces.
The transdermal absorption of chlorhexidine gluconate (chlorhexidine disodium; Hibitane) through the skin (with or without stratum corneum) of hairless rats was studied. In tests conducted on intact skin, drug storage in the skin tissue was more important than diffusion after 48 hours; the opposite was observed for skin with the stratum corneum removed. When the skin was peeled, the absorption increased approximately 100-fold, and the amount stored in the skin increased approximately 10-fold. The difference in chlorhexidine diffusion observed between intact and peeled skin was related to the physicochemical properties of chlorhexidine. /Chlorhexidine Gluconate/
This study aimed to evaluate the elimination kinetics of chlorhexidine in milk when used as an intramammary infusion to stop lactation in dairy cows. …The study was conducted in two phases. Three cows were studied in each phase. All cows received intramammary infusion of chlorhexidine suspension after two milkings 24 hours apart. Foremilk samples (100 mL) were collected from the udders of both the treated and untreated (control) cows. Chlorhexidine was extracted from the raw milk, and residual concentrations were quantitatively analyzed using high-performance liquid chromatography (HPLC). Foremilk samples were analyzed on days 2, 5, and 8 in the first phase; and on days 0, 3, 7, 14, 21, 28, 35, and 42 in the second phase. No quantitative transfer of chlorhexidine to milk was detected in the untreated mammary gland area in either phase. During the 42-day sampling period in the second phase, measurable chlorhexidine residues were detected in the milk from the treated mammary gland area of two cows. The mean elimination half-life of chlorhexidine in milk was estimated to be 11.5 days.
Metabolism/Metabolites
Due to the extremely low absorption rate of chlorhexidine in the gastrointestinal tract, significant metabolic transformation is unlikely.

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Biological Half-Life
This study aimed to evaluate the elimination kinetics of chlorhexidine in milk when used as an intramammary infusion to stop lactation in dairy cows. …The study was conducted in two phases. Three cows were studied in each phase. All cows received chlorhexidine suspension infusion after two milkings 24 hours apart, with the suspension injected into the mammary gland area affected by mastitis. Foremilk samples (100 mL) were collected from the treated and untreated (control) areas of each cow. Chlorhexidine was extracted from the raw milk, and residual concentrations were quantitatively analyzed using high-performance liquid chromatography. In the first phase, foremilk samples were analyzed on days 2, 5, and 8; in the second phase, samples were analyzed on day 0 and on days 3, 7, 14, 21, 28, 35, and 42. In both phases, no quantitative transfer of chlorhexidine to milk was detected in the untreated mammary gland area. During the 42-day sampling period in the second phase, measurable chlorhexidine residues were detected in the milk from the treated mammary gland areas of two cows. The estimated mean elimination half-life of chlorhexidine in breast milk is 11.5 days.

Toxicity Summary
Identification and Uses: Chlorhexidine forms solid crystals. Chlorhexidine diacetate is currently registered for use in the United States, but approved pesticide uses may change periodically, so it is essential to consult federal, state, and local authorities for currently approved uses. Currently, two end products containing 2% chlorhexidine diacetate are registered for use as hard surface treatment disinfectants/viricides. Chlorhexidine is primarily used in its salt forms, such as dihydrochloride, diacetate, and digluconate, for use in disinfectants (skin and hand disinfectants), cosmetics (additives in creams, toothpastes, deodorants, and antiperspirants), and pharmaceuticals (preservatives in eye drops, active ingredients in wound dressings, and mouthwashes). Human Contact and Toxicity: Chlorhexidine diacetate is highly acutely toxic upon contact with the eyes. Skin reaction tests for chlorhexidine acetate and chlorhexidine gluconate were conducted on patients with eczema. In the initial test, 52 out of 1063 subjects (5.4%) showed a positive reaction. Of the 29 subjects who underwent retesting, 21 remained positive. Chlorhexidine-specific IgE was detected only in Japanese individuals who had previously experienced anaphylactic shock, and not in Japanese nurses and patients or a group of British nurses and hospital staff frequently exposed to chlorhexidine. All chromogenic agents, when used in combination with chlorhexidine, rather than chlorhexidine alone, caused some degree of discoloration in hydroxyapatite and human teeth. A 67-year-old male undergoing colectomy for colon cancer accidentally received an intravenous injection of 0.8 mg chlorhexidine gluconate and subsequently developed acute respiratory distress syndrome. There have been two case reports of healthcare workers developing occupational asthma due to exposure to chlorhexidine and alcohol aerosols. Another case report describes six patients experiencing urticaria, dyspnea, and anaphylactic shock after topical application of chlorhexidine gluconate solution. Even highly diluted chlorhexidine solutions can cause significant articular cartilage resorption, leading to severe permanent knee joint damage. Animal studies: Rabbits experienced severe eye irritation after treatment with chlorhexidine acetate. No skin irritation was reported in rabbits within 72 hours of treatment with the investigational drug. In developmental studies, no observable malformations or developmental toxicities were observed at any tested dose. Mutagenicity of chlorhexidine was observed in both positive and negative results in bacterial studies. However, no mutagenic activity was observed in in vivo micronucleus assays or mammalian cytogenetics assays using Chinese hamster ovary cells. No carcinogenic effects were observed in long-term animal studies.

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Interactions
Chlorhexidine enhances the activity of itraconazole against Candida isolates; the itraconazole-chlorhexidine combination showed synergistic activity in culture media.

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Non-human toxicity values
Oral LD50 in rats: 5,000 mg/kg
Oral LD50 in male rats: 1710 mg/kg / chlorhexidine diacetate/
Oral LD50 in female rats: 1180 mg/kg / chlorhexidine diacetate/
Dermal LD50 in rabbits: >2000 mg/kg / chlorhexidine diacetate/
For more complete non-human toxicity data for chlorhexidine (6 types), please visit the HSDB record page.

Chlorhexidine hydrochloride belongs to the guanidine class of compounds. Chlorhexidine is a broad-spectrum antibacterial biguanide compound used as a topical disinfectant and in dentistry to treat inflammatory dental diseases caused by microorganisms. It is one of the most commonly used skin and mucous membrane disinfectants. The molecule itself is a cationic biguanide, consisting of two 4-chlorobenzene rings and two biguanide groups linked by a central hexamethylene chain. Topical chlorhexidine used for disinfection, as well as dental mouthwashes, are active against a variety of pathogens, including bacteria, yeasts, and viruses. Chlorhexidine was developed by Imperial Chemical Industries in the early 1950s and introduced to the United States in the 1970s. Due to numerous reports showing that the use of 0.5% chlorhexidine gluconate tincture caused chemical and thermal burns, the U.S. Food and Drug Administration (FDA) revoked the product's approval. Other formulations of chlorhexidine remain available for use. Chlorhexidine is a biguanide compound used as a disinfectant with topical antibacterial activity. Chlorhexidine carries a positive charge and reacts with the negatively charged surface of microbial cells, thereby disrupting the integrity of the cell membrane. Chlorhexidine then penetrates the cell interior, causing leakage of intracellular components and ultimately cell death. Gram-positive bacteria, being predominantly negatively charged, are more sensitive to this disinfectant. Chlorhexidine is a disinfectant and topical anti-infective agent, and can also be used as a mouthwash to prevent plaque buildup. Drug Indications Chlorhexidine is available as a topical disinfectant for use before surgery and/or medical procedures. It is available without a prescription in various forms (e.g., solution, sponge, cloth, swabs). Dental preparations require a prescription and include mouthwashes for treating gingivitis and sustained-release "chips" implanted in periodontal pockets to reduce pocket depth in adults with periodontitis, as an adjunct to scaling and root planing. FDA Label Mechanism of Action Chlorhexidine's broad-spectrum antibacterial action stems from its ability to disrupt microbial cell membranes. Positively charged chlorhexidine molecules react with negatively charged phosphate groups on the surface of microbial cells—this reaction disrupts cell integrity, leading to leakage of intracellular substances, and allows chlorhexidine to enter the cell, causing precipitation of cytoplasmic components, ultimately resulting in cell death. The specific mechanism of cell death depends on the concentration of chlorhexidine—low concentrations have an antibacterial effect, leading to leakage of intracellular substances such as potassium and phosphorus; while high concentrations have a bactericidal effect, leading to cytoplasmic precipitation.

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Therapeutic Uses
Disinfectant; bactericide. (Veterinary): Disinfectant; bactericide.
Cleanser: Used as a surgical hand sanitizer, skin wound cleaner, general skin cleanser, healthcare worker hand sanitizer, and preoperative skin preparation agent. Chlorhexidine gluconate can significantly reduce the number of microorganisms on the hands and forearms before surgery or patient care. /Chlorhexidine gluconate - Topical/
Exploratory Treatment: Aimed at determining whether chlorhexidine can be used as an intervention to prolong the recurrence time of oral candidiasis. Subjects and Methods: This study was a double-blind, randomized clinical trial involving 75 HIV/AIDS patients with oral candidiasis. All subjects received clotrimazole lozenges and were followed up every 2 weeks until the lesions were completely cleared. Subsequently, subjects were randomized to two groups: a 0.12% chlorhexidine group (n = 37, age 22–52 years, mean age 34 years) and a 0.9% saline group (n = 38, age 22–55 years, mean age 38 years). Follow-up was every 2 weeks until the next recurrence was observed. Results: There was no statistically significant difference in the time to recurrence of oral candidiasis between the chlorhexidine and saline groups (P > 0.05). The following variables were significantly associated with the time to recurrence: frequency of antifungal treatment (P = 0.011), total lymphocyte count (P = 0.017), alcohol consumption (P = 0.043), and gingival candidiasis (P = 0.048). Subjects with lower lymphocyte counts had shorter periods of relapse-free period for oral candidiasis (P = 0.034). Conclusion: Chlorhexidine showed a small but not statistically significant effect in maintaining relapse-free period for oral candidiasis. This lack of significant effect may be due to the small sample size. Further studies should be conducted to better assess the magnitude of the effect or to confirm our findings.
/Experimental Therapy:/ Rats were subcutaneously injected weekly with 10 mg/kg azomethane for 12 weeks to induce colorectal cancer. At week 20, rats with colorectal tumors but without peritoneal implantation or liver metastasis underwent subtotal colectomy. During surgery, the excised tumor portion was placed in the peritoneal cavity for 30 minutes; then, rats were randomly assigned to receive either chlorhexidine or sterile water (control group) for peritoneal lavage. Autopsy was performed 8 weeks postoperatively. At this time, histological evaluation was performed on obvious and suspected recurrent lesions and the anastomotic area. Chlorhexidine showed significant differences compared to water in both the detection of macroscopically visible tumors (P=0.05) and microscopically visible tumors (P<0.05).

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Drug Warnings
For external use only: For external use only. Avoid contact with eyes, ears, and mouth. Chlorhexidine gluconate should not be used for preoperative skin disinfection of the face or head. Misuse of products containing chlorhexidine gluconate, if it gets into the eyes during surgery and remains there, has been reported to cause serious, permanent eye damage. If chlorhexidine gluconate comes into contact with these areas, rinse thoroughly with cold water immediately. Avoid contact with nerves. Do not use on the genital area.
/Chlorhexidine gluconate - External Use/
Hypersensitivity: Contraindicated in patients with known hypersensitivity to chlorhexidine gluconate or any of its components.
Hypersensitivity: Products containing chlorhexidine have been reported to cause irritation, sensitization, and systemic allergic reactions, especially in the genital area. If an adverse reaction occurs and persists for more than 72 hours, discontinue use immediately; if the reaction is severe, contact a healthcare professional.
Deafness: There have been reports of deafness caused by chlorhexidine gluconate instilled into the middle ear through a tympanic membrane perforation. /Chlorhexidine Gluconate - Topical Use/
For more complete data on chlorhexidine (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
Chlorhexidine is a broad-spectrum antibacterial agent that has been shown to be active against Gram-positive and Gram-negative bacteria, yeasts, and viruses. Its antibacterial activity is dose-dependent—chlorhexidine has bacteriostatic activity at low concentrations (0.02%-0.06%) and bactericidal activity at high concentrations (>0.12%). Pharmacokinetic studies of oral chlorhexidine mouthwash have shown that approximately 30% of the active ingredient remains in the oral cavity after rinsing and is subsequently released slowly into the oral fluid. Like tetracycline antibiotics (such as doxycycline), chlorhexidine has the ability to adhere to dentin; this ability, known as "persistence," is a result of the positive charge on chlorhexidine. This persistence likely plays a role in chlorhexidine's antibacterial activity, as it adheres persistently to surfaces such as dentin, thus preventing microbial colonization. Using chlorhexidine mouthwash may cause staining of oral surfaces, such as teeth. This effect is not universal and appears to be more pronounced with long-term treatment (e.g., up to 6 months). However, chlorhexidine mouthwash should be used with caution in patients who cannot tolerate oral staining, and the duration of use should be minimized. Allergic reactions to chlorhexidine may be associated with the occurrence of anaphylactic shock.

C22H32CL4N10

578.3685

576.156

3697-42-5

Chlorhexidine (digluconate);18472-51-0;Chlorhexidine;55-56-1;Chlorhexidine diacetate;56-95-1;Chlorhexidine-d8 dihydrochloride;2012598-75-1

9571016

Crystals from methanol
Solid

699.3ºC at 760mmHg

255-262 ºC

376.7ºC

7.887

8

2

13

36

649

0

ClC1C([H])=C([H])C(=C([H])C=1[H])N([H])/C(/N([H])[H])=N/C(/N([H])[H])=N/C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N=C(\N([H])[H])/N([H])C1C([H])=C([H])C(=C([H])C=1[H])Cl.Cl[H].Cl[H]

WJLVQTJZDCGNJN-UHFFFAOYSA-N

InChI=1S/C22H30Cl2N10.2ClH/c23-15-5-9-17(10-6-15)31-21(27)33-19(25)29-13-3-1-2-4-14-30-20(26)34-22(28)32-18-11-7-16(24)8-12-18;;/h5-12H,1-4,13-14H2,(H5,25,27,29,31,33)(H5,26,28,30,32,34);2*1H

(1E)-2-[6-[[amino-[(E)-[amino-(4-chloroanilino)methylidene]amino]methylidene]amino]hexyl]-1-[amino-(4-chloroanilino)methylidene]guanidine;dihydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~20.83 mg/mL (~36.02 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.60 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 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 (3.60 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 (3.60 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.)