Bronopol

Identification

Name
Bronopol
Accession Number
DB13960
Type
Small Molecule
Groups
Approved
Description

Bronopol, or 2-Bromo-2-nitro-1,3-propanediol, is an inorganic compound with wide-spectrum antimicrobial properties. First synthesized in 1897, bronopol was primarily used as a preservative for pharmaceuticals and was registered in the United States in 1984 for use in industrial bactericides, slimicides and preservatives [7]. Bronopol is used as a microbicide or microbiostat in various commercial and industrial applications, including oil field systems, air washer systems, air conditioning or humidifying systems, cooling water systems, papermills, absorbent clays, metal working fluids, printing inks, paints, adhesives and consumer products [7]. Compared to other aliphatic halogen-nitro compounds, bronopol is more stable to hydrolysis in aqueous media under normal conditions [3]. The inhibitory activity against various bacteria, including Pseudomonas aeruginosa, was demonstrated in vitro [3]. Bronopol is approved for use in antibacterial OTC products in Canada.

Structure
Thumb
Synonyms
  • 2-Bromo-2-nitropropane-1,3-diol
  • 2-Nitro-2-bromo-1,3-propanediol
  • beta-Bromo-beta-nitrotrimethyleneglycol
  • Bronopolu
  • Bronopolum
External IDs
AI3-61639 / BRN 1705868 / NSC 141021
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Antiseptic Hand SoapBronopol (0.1 %) + Triclosan (0.6 %)LiquidTopicalDustbane Products Ltd1983-12-31Not applicableCanada
Michaels Antiseptic Hand SoapBronopol (.1 %) + Triclosan (.6 %)SoapTopicalMichael's Equipment (Ottawa) Ltd.1983-12-311999-07-05Canada
T.R.U.E. Test Thin-Layer Rapid Use Patch TestBronopol (203 ug/48h) + 2,2'-Dibenzothiazyl disulfide (20 ug/48h) + 2-mercaptobenzothiazole (61 ug/48h) + 4-(Isopropylamino)diphenylamine (10 ug/48h) + Bacitracin (486 ug/48h) + Balsam of Peru (648 ug/48h) + Benzocaine (378 ug/48h) + Benzylparaben (162 ug/48h) + Bisphenol A diglycidyl ether (32 ug/48h) + Bromothalonil (4 ug/48h) + Budesonide (0.8 ug/48h) + Butylparaben (162 ug/48h) + Chlorquinaldol (77 ug/48h) + Cinchocaine hydrochloride (66 ug/48h) + Cinnamaldehyde (41 ug/48h) + Cinnamyl alcohol (63 ug/48h) + Clioquinol (77 ug/48h) + Cobalt chloride hexahydrate (4 ug/48h) + Diazolidinylurea (446 ug/48h) + Potassium dichromate (15.7 ug/48h) + Dipentamethylenethiuram disulfide (5.5 ug/48h) + Diphenylguanidine (68 ug/48h) + Disperse Blue 106 (41 ug/48h) + Disulfiram (5.5 ug/48h) + Ditiocarb Zinc (68 ug/48h) + Ethyl hydroxybenzoate (162 ug/48h) + Ethylenediamine (18 ug/48h) + Eugenol (41 ug/48h) + Evernia prunastri (81 ug/48h) + Formaldehyde (146 ug/48h) + Geraniol (81 ug/48h) + Hydrocortisone butyrate (16 ug/48h) + Hydroxycitronellal (63 ug/48h) + Imidurea (486 ug/48h) + Isoeugenol (17 ug/48h) + Lanolin alcohols (810 ug/48h) + Methylchloroisothiazolinone (3 ug/48h) + Methylparaben (162 ug/48h) + Morpholinylmercaptobenzothiazole (20 ug/48h) + N,N'-diphenyl-1,4-phenylenediamine (25 ug/48h) + N-Cyclohexyl-N'-phenyl-1,4-phenylenediamine (25 ug/48h) + Neomycin sulfate (486 ug/48h) + Nickel sulfate hexahydrate (36 ug/48h) + P-Tert-Butylphenol-Formaldehyde Resin (Low Molecular Weight) (36 ug/48h) + Parthenolide (2 ug/48h) + Propylparaben (162 ug/48h) + Quaternium-15 (81 ug/48h) + Rosin (972 ug/48h) + Sodium aurotiosulfate (23 ug/48h) + Tetracaine hydrochloride (66 ug/48h) + Tetramethylthiuram monosulfide (5.5 ug/48h) + Thimerosal (6 ug/48h) + Thiohexam (20 ug/48h) + Thiram (5.5 ug/48h) + Tixocortol pivalate (2 ug/48h) + Zinc Dibutyldithiocarbamate (68 ug/48h) + alpha-Amyl cinnamaldehyde (17 ug/48h) + p-Phenylenediamine (65 ug/48h)KitSmartPractice Denmark ApS2012-03-01Not applicableUs
Categories
UNII
6PU1E16C9W
CAS number
52-51-7
Weight
Average: 199.988
Monoisotopic: 198.948020332
Chemical Formula
C3H6BrNO4
InChI Key
LVDKZNITIUWNER-UHFFFAOYSA-N
InChI
InChI=1S/C3H6BrNO4/c4-3(1-6,2-7)5(8)9/h6-7H,1-2H2
IUPAC Name
2-bromo-2-nitropropane-1,3-diol
SMILES
OCC(Br)(CO)[N+]([O-])=O

Pharmacology

Indication

Indicated for use as a over-the-counter, industrial, or commercial antibacterial agent.

Associated Conditions
Pharmacodynamics

At concentrations of 12.5 to 50 μg/mL, bronopol mediated an inhibitory activity against various strains of Gram negative and positive bacteria in vitro [3]. The bactericidal activity is reported to be greater against Gram-negative bacteria than against Gram-positive cocci [3]. Bronopol was also demonstrated to be effective against various fungal species, but the inhibitory action is reported to be minimal compared to that of against bacterial species [3]. The inhibitory activity of bronopol decreases with increasing pH of the media [3, 7]. Bronopol also elicits an anti-protozoal activity, as demonstrated with Ichthyophthirius multifiliis in vitro and in vivo [2]. It is proposed that bronopol affects the survival of all free-living stages of I. multifiliis [2].

Mechanism of action

It is proposed that bronopol generates biocide-induced bacteriostasis followed by a growth at an inhibited rate in bacteria, via two distinct reactions between bronopol and essential thiols within the bacterial cell [1]. Under aerobic conditions, bronopol catalyzes the oxidation of thiol groups, such as cysteine, to disulfides. This reaction is accompanied by rapid consumption of oxygen, where oxygen acts as the final oxidant. During the conversion of cysteine to cystine, radical anion intermediates such as superoxide and peroxide are formed from bronopol to exert a direct bactericidal activity. The oxidation of excess thiols alters the redox state to create anoxic conditions, leading to a second reaction involving the oxidation of intracellular thiols such as glutathione to its disulfide. The resulting effects are inhibition of enzyme function, and reduced growth rate following the bacteriostatic period [1]. Under the anoxic conditions, the reaction between thiol and bronopol decelerates without the involvement of oxygen and the consumption of bronopol predominates. Bronopol is ultimately removed from the reaction via consumption and resumption of bacterial growth occurs [1].

TargetActionsOrganism
AThiol groups
oxidizer
Human
Absorption

Bronopol was rapidly absorbed in animal studies. It may be absorbed via aerosol inhalation, dermal contact, and ingestion [6]. In rats, approximately 40% of the topically applied dose of bronopol was absorbed through the skin within 24 hr [6]. Following oral administration of 1 mg/kg in rats, the peak plasma concentrations of bronopol were reached up to 2 hours post-dosing [5].

Volume of distribution

The highest concentrations of bronopol were detected in the excretory organs of rat such as kidney, liver, and lung [5]. The lowest concentration was in the fat [5].

Protein binding

No data available.

Metabolism

Bronopol undergoes degradation in aqueous medium to form bromonitroethanol from a retroaldol reaction with the liberation of an equimolar amount of formaldehyde [4]. Formaldehyde is a degradation product of bronopol, which may cause sensitization [6]. Bromonitroethanol further decomposes to formaldehyde and bromonitromethane. Bromonitroethanol may also break down to release a nitrite ion and 2-bromoethanol [4].

Route of elimination

Metabolism studies indicate that bronopol is primarily excreted in the urine [7]. In rats, about 19% of dermally-applied bronopol was excreted in the urine, feces and expired air [6]. Following oral administration of 1 mg/kg radiolabelled bronopol in rats, approximately 81% and 6% of the administered radioactivity was recovered in the urine and expired air, respectively, within a period of 24 hours [5]. Following intravenous administration in rat, the recoveries in the urine and expired air were 74% and 9% of the dose, respectively [5].

Half life

The half-life of bronopol in the biological systems is not reported in the literature. The half-life value reported for bronopol reflects the environment fate of the compound. When released into the air as vapours, bronopol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals where the half life for this reaction is approximately 11 days [6]. The photolysis half-life is 24 hours in water but may be up to 2 days under natural sunlight [6].

Clearance

No data available.

Toxicity

Oral LD50, dermal LD50, and inhalation LD50 in rat are 180 mg/kg [MSDS], 64-160 mg/kg [6], and > 5000 mg/m^3 [MSDS] , respectively. In a 90-day dermal toxicity study in rabbits, the NOEL for systemic toxicity was 2 mg/kg/day [7]. In a rat 90-day oral toxicity study, bronopol was associated with a severe gastrointestinal irritation [7]. A chronic feeding or carcinogenicity study with rats resulted in high mortality, stomach lesions, and severe reduction in body weight gain. A reduction in weight gain was also observed in a chronic dermal or carcinogenicity study of mice [7]. Bronopol was not mutagenic in four mutagenicity studies [7].

Affected organisms
  • Yeast and other fungi
  • Gram negative and gram positive bacteria
  • Pseudomonas aeruginosa
  • Streptococcus pyogenes
  • Escherichia coli
  • Staphylococcus aureus
  • Proteus vulgaris
  • Shigella
  • Proteus mirabilis
  • Klebsiella pneumoniae
  • Enterobacter aerogenes
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Shepherd JA, Waigh RD, Gilbert P: Antibacterial action of 2-bromo-2-nitropropane-1,3-diol (bronopol). Antimicrob Agents Chemother. 1988 Nov;32(11):1693-8. [PubMed:3075439]
  2. Shinn AP, Picon-Camacho SM, Bron JE, Conway D, Yoon GH, Guo FC, Taylor NG: The anti-protozoal activity of bronopol on the key life-stages of Ichthyophthirius multifiliis Fouquet, 1876 (Ciliophora). Vet Parasitol. 2012 May 25;186(3-4):229-36. doi: 10.1016/j.vetpar.2011.11.025. Epub 2011 Nov 12. [PubMed:22153260]
  3. CROSHAW B, GROVES MJ, LESSEL B: SOME PROPERTIES OF BRONOPOL, A NEW ANTIMICROBIAL AGENT ACTIVE AGAINST PSEUDOMONAS AERUGINOSA. J Pharm Pharmacol. 1964 Dec;16:SUPPL:127-30T. [PubMed:14265925]
  4. Wang H, Provan GJ, Helliwell K: Determination of bronopol and its degradation products by HPLC. J Pharm Biomed Anal. 2002 Jun 20;29(1-2):387-92. [PubMed:12062701]
  5. Buttar HS, Downie RH: The biotransformation and disposition of bronopol following topical and intravenous administration to rats. Toxicol Lett. 1980 Jul;6(2):101-7. [PubMed:7414618]
  6. BRONOPOL - National Library of Medicine HSDB Database [Link]
  7. United States Environmental Protection Agency (EPA): Bronopol R.E.D. Facts Sheet [File]
  8. The activity and safety of the antimicrobial agent Bronopol (2-bromo-2-nitropropan-1, 3-diol) [File]
External Links
KEGG Drug
D01577
KEGG Compound
C13034
ChemSpider
2356
ChEBI
31306
ChEMBL
CHEMBL1408862
Wikipedia
Bronopol
MSDS
Download (63.7 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidTopical
SoapTopical
Kit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)123-130MSDS
boiling point (°C)130MSDS
water solubility25-25g/100mL at 22°CMSDS
logP-0.6MSDS
Predicted Properties
PropertyValueSource
Water Solubility12.8 mg/mLALOGPS
logP-0.21ALOGPS
logP-0.19ChemAxon
logS-1.2ALOGPS
pKa (Strongest Acidic)12.55ChemAxon
pKa (Strongest Basic)-3.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area83.6 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity31.66 m3·mol-1ChemAxon
Polarizability13.17 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Mass Spectrum (Electron Ionization)MSsplash10-057r-9800000000-96a2fa8203c140ebd484
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Taxonomy

Classification
Not classified

Targets

Kind
Small molecule
Organism
Human
Pharmacological action
Yes
Actions
Oxidizer
Thiol groups are encountered in biological systems in cysteine residues and in cofactors such as lipoamide and lipoic acid. They are also called sulfhydryl and mercapto groups.
References
  1. Shepherd JA, Waigh RD, Gilbert P: Antibacterial action of 2-bromo-2-nitropropane-1,3-diol (bronopol). Antimicrob Agents Chemother. 1988 Nov;32(11):1693-8. [PubMed:3075439]

Drug created on January 17, 2018 10:10 / Updated on November 02, 2018 07:48