| Identification | More | [Name]
Chlorhexidine | [CAS]
55-56-1 | [Synonyms]
1,1'-HEXAMETHYLENEBIS[5-(4-CHLOROPHENYL)BIGUANIDE]
1,6-DI(N-P-CHLOROPHENYL-DIGUANIDO) HEXANE
bis(5-(p-chlorophenyl)biguanidinio)hexane
CHLORHEXIDINE
CHLORHEXIDINE BASE
hexamethylenebis(5-(4-chlorophenyl)biguanide)
LABOTEST-BB LT00440966
n,n'-bis(4-chlorophenyl)-3,12-diimino-tetraazatetradecanediimidamide
1,1’-hexamethylenebis(5-(p-chlorophenyl)-biguanid
1,6-bis(5-(p-chlorophenyl)biguandino)hexane
1,6-bis(p-chlorophenyldiguanido)hexane
1,6-di(4’-chlorophenyldiguanido)hexane
2,4,11,13-tetraazatetradecanediimidamide,n,n’’-bis(4-chlorophenyl)-3,12-diim
chlorhexidin
fimeil
hexadol
nolvasan
rotersept
soretol
sterilon | [EINECS(EC#)]
200-238-7 | [Molecular Formula]
C22H30Cl2N10 | [MDL Number]
MFCD00009673 | [Molecular Weight]
505.45 | [MOL File]
55-56-1.mol |
| Chemical Properties | Back Directory | [Appearance]
solid | [Melting point ]
134-136 °C (lit.) | [Boiling point ]
641.45°C (rough estimate) | [density ]
1.1555 (rough estimate) | [refractive index ]
1.6300 (estimate) | [storage temp. ]
2-8°C | [solubility ]
water: soluble0.08% at 20°C | [form ]
neat | [pka]
pKa 10.78 (Uncertain) | [color ]
White to off-white | [Stability:]
Stable. Incompatible with strong oxidizing agents. | [Water Solubility ]
0.08 g/100 mL (20 ºC) | [Merck ]
13,2108 | [BRN ]
2826432 | [InChIKey]
GHXZTYHSJHQHIJ-UHFFFAOYSA-N | [LogP]
0.080 | [Uses]
chlorhexidine is used as a topical antiseptic in liquid cosmetics. It is strongly alkaline and may cause irritation. | [CAS DataBase Reference]
55-56-1(CAS DataBase Reference) | [EPA Substance Registry System]
55-56-1(EPA Substance) |
| Safety Data | Back Directory | [Hazard Codes ]
Xi,N | [Risk Statements ]
R36/37/38:Irritating to eyes, respiratory system and skin .
R43:May cause sensitization by skin contact.
R51/53:Toxic to aquatic organisms, may cause long-term adverse effects in the aquatic environment . | [Safety Statements ]
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36/37:Wear suitable protective clothing and gloves .
S60:This material and/or its container must be disposed of as hazardous waste .
S61:Avoid release to the environment. Refer to special instructions safety data sheet . | [RIDADR ]
UN 3077 9/PG 3
| [WGK Germany ]
3
| [RTECS ]
DU1925000
| [F ]
10-34 | [HazardClass ]
9 | [PackingGroup ]
III | [HS Code ]
29215900 | [Hazardous Substances Data]
55-56-1(Hazardous Substances Data) | [Toxicity]
LD50 orally in Rabbit: 5000 mg/kg |
| Questions and Answers (Q&A) | Back Directory | [Description]
Chlorhexidine is a cationic broad-spectrum antimicrobial agent belonging to the bis(biguanide) family. Its mechanism of action involves destabilization of the outer bacterial membrane. It is effective on both Gram-positive and Gram-negative bacteria, although it is less effective with some Gram-negative bacteria. It has both bactericidal and bacteriostatic mechanisms of action.
Chlorhexidine's antimicrobial effects are associated with the attractions between chlorhexidine (cation) and negatively charged bacterial cells. After chlorhexidine is absorpted onto the organism's cell wall, it disrupts the integrity of the cell membrane and causes the leakage of intracellular components of the organisms.
Aqueous solutions of chlorhexidine are most stable within the pH range of 5-8. Above pH 8.0 chlorhexidine base is precipitated and in more acid conditions there is gradual deterioration of activity because the compound is less stable. Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs. It has a LD-50 orally in mice as a diacetate at 2gm./kg. In digluconate form the LD-50 is 1800 gm./kg.
| [History]
Chlorhexidine (CHX) was the first antimicrobial agent shown to inhibit dental plaque formation and the development of chronic gingivitis (Loe and Schiott 1970).
Chlorhexidine is a cationic chlorophenyl bisbiguanide antiseptic.
Bisbiguanides are the primary second generation antiplaque agents exhibiting considerable substantivity and broad spectrum antibacterial properties.
In dental medicine, CHX was initially used for disinfection of the oral cavity prior to oral surgical procedures and in endodontics. Plaque inhibition by CHX was first investigated in 1969 (Schroeder) but the first controlled clinical study was performed by Loe and Schiott (1970). [16] This study showed that rinsing for 60 sec, twice a day with 10 ml of a 0.2% (20 mg dose) CHX gluconate solution, in the absence of normal tooth cleaning, inhibited plaque regrowth and the development of gingivitis.
CHX is one of the most widely investigated and used antiplaque agents.The advantage of CHX over other cationic agents is that it can bind strongly to many sites in the oral cavity and is released slowly over 7 to 12 hours after rinsing, thus providing considerable substantivity and a sustained antimicrobial effect restricting bacterial proliferation. CHX binds strongly with anionic glycoproteins and phosphoproteins on the oral mucosa and tooth pellicle in addition to its property of binding to the surfaces of bacterial cell membranes affecting the cells ability to adhere. CHX is considered the most potent chemotherapeutic agent currently available.
| [Uses]
Chlorhexidine is an antibacterial used for numerous applications. It is a cationic polybiguanide (bisbiguanide) used primarily as its salts, dihydrochloride, diacetate, and digluconate. Chlorhexidine is one of those drugs which are enlisted/included in the World Health Organization's List of Essential Medicines, a list of the most important drugs needed in a basic health system.
- Chlorhexidine is used as a germicidal compound in teat dips. Also used as navel treatment, udder and eye wash, surgical scrub and sterilization material.
- Chlorhexidine is used primarily as a topical antiseptic/disinfectant in wound healing, at catheterization sites, in various dental applications and in surgical scrubs. it is used as an antibacterial agent in humans to control gingivitis and over all plaque control in preventative dentistry.
- Hydrogenolysis of benzyl-nitrogen bonds.
- Bacteriostatic;Detergent.
|
| Hazard Information | Back Directory | [Chemical Properties]
Chlorhexidine occurs as an odorless, bitter tasting, white crystalline
powder. | [Chemical Properties]
solid | [Originator]
Hibiclens,Stuart,US,1976 | [Application]
Chlorhexidine is an important medical, dental and pharmaceutical antiseptic, disinfectant and preservative. It is bactericida and fungicidalsy but does not kill bacterial spores or mycobacteria, although it inhibits growth. It has a low order of activity against viruses, but high concentrations are effective in killing cysts of Acanthamoeba spp., organisms of potential clinical significance to the wearers of contact lenses. Properties Chlorhexidine is a bisbiguanide which is available as the acetate (diacetate), hydrochloride and gluconate salts. These are stable in solution and can be autoclaved although small amounts of chloroaniline are released.” As a cationic agent, chlorhexidine is incompatible with anionic surfactants and its antimicrobial activity is reduced in the presence of non-ionic surface-active agents. Activity is also reduced or abolished by phospholipids (a factor of significance in neutralizing chlorhexidine activity during the performance of biocidal tests) and by organic matter including serum. Some of these aspects have been well documented in the recent comprehensive paper of Nicoletti et al.” They also point out that the efficacy of chlorhexidine is influenced by formulation components and by the composition of the culture medium in which minimum inhibitory concentrations (MICs) are determined. | [Definition]
ChEBI: A bisbiguanide compound with a structure consisting of two (p-chlorophenyl)guanide units linked by a hexamethylene bridge. | [Indications]
This topical antiseptic product acts rapidly but, like hexachlorophene,
persists on the skin to give a cumulative, continuing antibacterial effect.
Like iodophors and alcohol, it is active against gram-positive and gram-negative
bacteria, including P. aeruginosa, as well as common yeasts and fungi. It does not
lose effectiveness in the presence of whole blood. Many consider it the antiseptic
of choice for skin cleansing and surgical scrubs. Contact allergy is not uncommon.
Chlorhexidine should not be used near the eyes or mucosal surfaces, because it may
cause irritation or even anaphylaxis. | [Production Methods]
Chlorhexidine may be prepared either by condensation of
polymethylene bisdicyandiamide with 4-chloroaniline hydrochloride
or by condensation of 4-chlorophenyl dicyandiamine with
hexamethylenediamine dihydrochloride. Chlorhexidine may also be
synthesized from a series of biguanides. | [Manufacturing Process]
25 parts of hexamethylene bis-dicyandiamide, 35 parts of p-chloroaniline
hydrochloride and 250 parts of beta-ethoxyethanol are stirred together at
130°C to 140°C for 2 hours under reflux. The mixture is then cooled and
filtered and the solid is washed with water and crystallized from 50% aqueous
acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanido-N5,N5')hexane
dihydrochloride is obtained as colorless plates of MP 258°C to 260°C.
The following is an alternative route: 19.4 parts of pchlorophenyldicyandiamide, 9.4 parts of hexamethylene
diaminedihydrochloride and 100 parts of nitrobenzene are stirred together and
heated at 150 C to 160°C for 6 hours. The mixture is cooled, diluted with 200
parts of benzene and filtered. The solid residue is washed with benzene and
crystallized from 50% acetic acid. 1,6-di(N1,N1'-p-chlorophenyldiguanidoN5,N5')hexane dihydrochloride is obtained. | [Therapeutic Function]
Antimicrobial | [General Description]
Effect of the chlorhexidine:hydroxypropyl-β-cyclodextrin inclusion compound on in vitro slabs of bovine dentine has been investigated. | [Pharmaceutical Applications]
Chlorhexidine salts are widely used in pharmaceutical formulations
in Europe and Japan for their antimicrobial properties.
Although mainly used as disinfectants, chlorhexidine salts are also
used as antimicrobial preservatives.
As excipients, chlorhexidine salts are mainly used for the
preservation of eye-drops at a concentration of 0.01% w/v;
generally the acetate or gluconate salt is used for this purpose.
Solutions containing 0.002–0.006% w/v chlorhexidine gluconate
have also been used for the disinfection of hydrophilic contact
lenses.
For skin disinfection, chlorhexidine has been formulated as a
0.5% w/v solution in 70% v/v ethanol and, in conjunction with
detergents, as a 4% w/v surgical scrub. Chlorhexidine salts may also
be used in topical antiseptic creams, mouthwashes, dental gels, and
in urology for catheter sterilization and bladder irrigation.
Chlorhexidine salts have additionally been used as constituents
of medicated dressings, dusting powders, sprays, and creams. | [Clinical Use]
Chlorhexidine is a biguanide topical antiseptic and disinfectant with broad antimicrobial efficacy. It is increasingly being used as an aseptic but it is also gaining use as a biocidal ingredient in shampoos, conditioners, hair dyes, sunscreens, toothpastes, mouthwashes (Corsodyl), wet wipes (also for babies), eye creams, antiwrinkle creams, moisturizers, contact lens solutions, and instillation gels for urinary catheters.Urticaria following application to intact skin or mucosae, in some cases accompanied by dyspnea, angioedema, syncope, or anaphylaxis has been described via the mucosal route at much lower concentration than elsewhere, generally as low as 0.05%. | [Safety Profile]
Poison by intraperitoneal andintravenous routes. Mildly toxic by ingestion.Experimental reproductive effects. A human skin irritant.Mutation data reported. When heated to decomposition itemits very toxic fumes of Cl- and NOx. | [Safety]
Chlorhexidine and its salts are widely used, primarily as topical
disinfectants. As excipients, chlorhexidine salts are mainly used as
antimicrobial preservatives in ophthalmic formulations.
Animal studies suggest that the acute oral toxicity of chlorhexidine
is low, with little or no absorption from the gastrointestinal
tract. However, although humans have consumed up to 2 g of
chlorhexidine daily for 1 week, without untoward symptoms,
chlorhexidine is not generally used as an excipient in orally ingested
formulations.
Reports have suggested that there may be some systemic effects
in humans following oral consumption of chlorhexidine.
Similarly, the topical application of chlorhexidine or its salts
produced evidence of very slight percutaneous absorption of
chlorhexidine, although the concentrations absorbed were insufficient
to produce systemic adverse effects.
Severe hypersensitivity reactions, including anaphylactic shock,
have been reported following the topical administration of
chlorhexidine, although such instances are rare given the
extensive use of chlorhexidine and it salts.
In ophthalmic preparations, irritation of the conjunctiva occurs
with chlorhexidine solutions of concentration stronger than 0.1%
w/v. Accidental eye contact with 4% w/v chlorhexidine gluconate
solution may result in corneal damage.
The aqueous concentration of chlorhexidine normally recommended
for contact with mucous surfaces is 0.05% w/v. At this
concentration, there is no irritant effect on soft tissues, nor is healing
delayed. The gluconate salt (1% w/v) is frequently used in creams,
lotions, and disinfectant solutions.
Direct instillation of chlorhexidine into the middle ear can result
in ototoxicity; when used in dental preparations, staining of
teeth and oral lesions may occur.
Use of chlorhexidine on the brain or meninges is extremely
dangerous.
LD50 (mouse, IP): 0.04 g/kg
LD50 (mouse, oral): 2.52 g/kg
LD50 (rat, IP): 0.06 g/kg
LD50 (rat, IV): 0.02 g/kg
LD50 (rat, oral): 9.2 g/kg | [Veterinary Drugs and Treatments]
A topical antiseptic, chlorhexidine has activity against many bacteria, but apparently not predictably active against Pseudomonas or Serratia
spp. It is available with veterinary labels in many different forms (solutions, shampoos, scrubs, ointments, sprays, etc).
Because it causes less drying and is usually less irritating than benzoyl peroxide, it is sometimes used in patients that cannot tolerate benzoyl
peroxide. It does not have the keratolytic, degreasing or follicular flushing effects of benzoyl peroxide however. Chlorhexidine possesses
some residual effects and can remain active on skin after rinsing.
At usual concentrations, chlorhexidine acts by damaging bacterial cytoplasmic membranes. Antifungal activity can be obtained with
2% or higher concentrations. For wound irrigation, 0.05 – 0.1% dilution in water is recommended. | [storage]
Chlorhexidine and its salts are stable at normal storage temperatures
when in the powdered form. However, chlorhexidine
hydrochloride is hygroscopic, absorbing significant amounts of
moisture at temperatures up to 378℃ and relative humidities up to
80%.
Heating to 1508℃ causes decomposition of chlorhexidine and its
salts, yielding trace amounts of 4-chloroaniline. However, chlorhexidine
hydrochloride is more thermostable than the acetate and
can be heated at 1508℃ for 1 hour without appreciable formation of
4-chloroaniline.
In aqueous solution, chlorhexidine salts may undergo hydrolysis
to form 4-chloroaniline, catalyzed by heating and an alkaline pH.
Following autoclaving of a 0.02% w/v chlorhexidine gluconate
solution at pH 9 for 30 minutes at 1208℃, it was found that 1.56%
w/w of the original chlorhexidine content had been converted into
4-chloroaniline; for solutions at pH 6.3 and 4.7 the 4-chloroaniline
content was 0.27% w/w and 0.13% w/w, respectively, of the
original gluconate content. In buffered 0.05% w/v chlorhexidine
acetate solutions, maximum stability occurs at pH 5.6.
When chlorhexidine solutions were autoclaved at various time
and temperature combinations, the rate of hydrolysis increased
markedly above 1008℃, and as pH increased or decreased from pH
5.6. At a given pH, chlorhexidine gluconate produced more 4-
chloroaniline than the acetate.
It was predicted that in an autoclaved solution containing 0.01%
w/v chlorhexidine, the amount of 4-chloroaniline formed would be
about 0.00003%. At these low concentrations there would be little
likelihood of any toxic hazard as a result of the increase in 4-
chloroaniline content in the autoclaved solution.
Chlorhexidine solutions and aqueous-based products may be
packaged in glass and high-density polyethylene or polypropylene
bottles provided that they are protected from light. If not protected
from light, chlorhexidine solutions containing 4-chloroaniline
discolor owing to polymerization of the 4-chloroaniline.
Cork-based closures or liners should not be used in packaging in
contact with chlorhexidine solutions as chlorhexidine salts are
inactivated by cork.
As a precaution against contamination with Pseudomonas
species resistant to chlorhexidine, stock solutions may be protected
by the inclusion of 7% w/v ethanol or 4% w/v propan-2-ol.
Chlorhexidine salts, and their solutions, should be stored in wellclosed
containers, protected from light, in a cool, dry place. | [Incompatibilities]
Chlorhexidine salts are cationic in solution and are therefore
incompatible with soaps and other anionic materials. Chlorhexidine
salts are compatible with most cationic and nonionic surfactants,
but in high concentrations of surfactant chlorhexidine activity can
be substantially reduced owing to micellar binding.
Chlorhexidine salts of low aqueous solubility are formed and
may precipitate from chlorhexidine solutions of concentration
greater than 0.05% w/v, when in the presence of inorganic acids,
certain organic acids, and salts (e.g. benzoates, bicarbonates,
borates, carbonates, chlorides, citrates, iodides, nitrates, phosphates,
and sulfates). At chlorhexidine concentrations below
0.01% w/v precipitation is less likely to occur.
In hard water, insoluble salts may form owing to interaction with
calcium and magnesium cations. Solubility may be enhanced by the
inclusion of surfactants such as cetrimide.
Other substances incompatible with chlorhexidine salts include
viscous materials such as acacia, sodium alginate, sodium carboxymethylcellulose,
starch, and tragacanth. Also incompatible
are brilliant green, chloramphenicol, copper sulfate, fluorescein
sodium, formaldehyde, silver nitrate, and zinc sulfate.
Interaction has been reported between chlorhexidine gluconate
and the hydrogel poly(2-hydroxyethyl methacrylate), which is a
component of some hydrophilic contact lenses. | [Regulatory Status]
Chlorhexidine salts are included in nonparenteral and parenteral
medicines licensed in the UK. Included in the Canadian List of
Acceptable Non-medicinal Ingredients. |
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