Sodium Benzoate

(BAN, rINN)

💊 Chemical information

Benzoan sodný; Benzoato sódico; E211; Natrii benzoas; Natrio benzoatas; Natrium Benzoicum; Natriumbensoat; Natriumbentsoaatti; Nátrium-benzoát; Sodii Benzoas; Sodium, benzoate de; Sodu benzoesan; Sodyum Benzoat.
Chemical formula: C6H5.CO2Na = 144.1.
CAS — 532-32-1.

Pharmacopoeias.

In Chin., Eur., Jpn, and Viet. Also in USNF.

Ph. Eur. 6.2

(Sodium Benzoate). A white or almost white, slightly hygroscopic, crystalline or granular powder or flakes. Freely soluble in water; sparingly soluble in alcohol (90% v/v).

USNF 26

(Sodium Benzoate). A white, odourless or practically odourless, granular or crystalline powder. Soluble 1 in 2 of water, 1 in 75 of alcohol, and 1 in 50 of alcohol 90%.

Incompatibility.

Benzoic acid and its salts are incompatible with quaternary compounds, calcium salts, ferric salts, and salts of heavy metals. Their activity is also diminished by nonionic surfactants or due to absorption by kaolin. They are relatively inactive above a pH of about 5.

💊 Adverse Effects and Precautions

The benzoates can cause hypersensitivity reactions, but there have also been reports of non-immunological contact urticaria. The acid can be irritant to skin, eyes, and mucous membranes. Infants given large doses of sodium benzoate have suffered vomiting. Symptoms of overdosage reported in this group have included vomiting, irritability and, in more severe cases, renal tubular dysfunction, hypokalaemia, hypocalcaemia, and metabolic acidosis. Premature infants have been reported to be at risk of metabolic acidosis and kernicterus.

Hypersensitivity.

Respiratory reactions to benzoates may occur, especially in patients susceptible to aspirin-induced asthma.1,2 Urticarial reactions have also been associated with these compounds,3,4 though at a lower incidence5 and they can be nonimmunological.6 However, these reports have to be balanced against a controlled study7 that showed no difference in the incidence of urticaria or atopic symptoms between patients given benzoic acid and those given lactose placebo. A retrospective study8 of 47 patients who had previously shown a hypersensitivity reaction after ingesting food or products containing benzoate sodium found that the incidence of a repeat episode of acute urticaria or angioedema on re-challenge was very low (2%). Anaphylactoid reactions have been reported in 2 patients.9,10 Erythema multiforme has been observed in several patients.11
1. Rosenhall L. Evaluation of intolerance to analgesics, preservatives and food colorants with challenge tests. Eur J Respir Dis 1982; 63: 410–19
2. Settipane GA. Aspirin and allergic diseases: a review. Am J Med 1983; 74 (suppl): 102–9
3. Michaëlsson G, Juhlin L. Urticaria induced by preservatives and dye additives in food and drugs. Br J Dermatol 1973; 88: 525–32
4. Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J Dermatol 1976; 94: 401–6
5. Wüthrich B, Fabro L. Acetysalicylsäure-und lebensmitteladditiva-intoleranz bei urtikaria, asthma bronchiale und chronischer rhinopathie. Schweiz Med Wochenschr 1981; III: 1445–50
6. Nethercott JR, et al. Airborne contact urticaria due to sodium benzoate in a pharmaceutical manufacturing plant. J Occup Med 1984; 26: 734–6
7. Lahti A, Hannuksela M. Is Benzoic acid really harmful in cases of atopy and urticaria? Lancet 1981; ii: 1055
8. Nettis E, et al. Sodium benzoate-induced repeated episodes of acute urticaria/angio-oedema: randomized controlled trial. Br J Dermatol 2004; 151: 898–902
9. Moneret-Vautrin DA, et al. Anaphylactoid reaction to general anaesthesia: a case of intolerance to sodium benzoate. Anaesth Intensive Care 1982; 10: 156–7
10. Michils A, et al. Anaphylaxis with sodium benzoate. Lancet 1991; 337: 1424–5
11. Lewis MAO, et al. Recurrent erythema multiforme: a possible role of foodstuffs. Br Dent J 1989; 166: 371–3.

Neonates.

Serious metabolic disturbances in premature neonates given intravenous fluids with benzyl alcohol as a preservative have been attributed to the accumulation of benzoic acid, a metabolite of benzyl alcohol. This risk led to the recommendation that Caffeine and Sodium Benzoate Injection (USP), which has been given as a respiratory stimulant, should not be used in neonates.1 Sodium benzoate has been tried in the treatment of some neonatal metabolic disorders (see Uses and Administration, below). However, benzoates can also displace bound bilirubin from albumin putting neonates at risk of kernicterus.2 Three cases of toxicity have been reported after accidental high doses of intravenous sodium benzoate and sodium phenylacetate were given to children with hyperammonaemia.3 All the children initially became agitated and confused, had Kussmaul respiration (rapid, deep breathing) and developed a partial metabolic acidosis with an increased anion gap. Two patients subsequently developed cerebral oedema and hypotension and died while the third survived after haemodialysis.
1. Edwards RC, Voegeli CJ. Inadvisability of using caffeine and sodium benzoate in neonates. Am J Hosp Pharm 1984; 41: 658
2. Schiff D, et al. Fixed drug combinations and the displacement of bilirubin from albumin. Pediatrics 1971: 48: 139–41
3. Praphanphoj V, et al. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia. J Inherit Metab Dis 2000; 23: 129–36.

💊 Pharmacokinetics

The benzoates are absorbed from the gastrointestinal tract and conjugated with glycine in the liver to form hippuric acid, which is rapidly excreted in the urine.

Neonates.

References.
1. Green TP, et al. Disposition of sodium benzoate in newborn infants with hyperammonemia. J Pediatr 1983; 102: 785–90.

💊 Uses and Administration

Benzoates have antibacterial and antifungal properties. Their antimicrobial activity is due to the undissociated benzoic acid and is therefore pH-dependent. They are relatively inactive above a pH of about 5. Benzoates are used as preservatives in pharmaceutical formulations including oral preparations; benzoic acid and sodium benzoate are typically used in concentrations of up to 0.2% and 0.5%, respectively. They are used as preservatives in foods, (and are also present naturally in some foods), and at similar concentrations in cosmetics. Benzoic acid 6% with salicylic acid 3%, as Compound Benzoic Acid Ointment (BP 2008) (Whitfield’s Ointment) has a long history of use as an antifungal. Benzoic acid has also been used in desloughing preparations and has been given as a urinary antiseptic. An injection of caffeine and sodium benzoate has been used as a CNS stimulant, but see Neonates, under Adverse Effects and Precautions, above for a caution against its use in neonates. Sodium benzoate is used as part of the treatment of hyperammonaemia that occurs in inborn errors of the urea cycle. It has also been reported to be effective in reducing plasma-glycine concentrations in nonketotic hyperglycinaemia, although it may not be effective in preventing mental retardation. Sodium benzoate is a common ingredient of cough preparations.

Hyperammonaemia.

Sodium benzoate is used for treatment of hyperammonaemia.1-3 It is given with sodium phenylacetate and a combined preparation is available in some countries.
1. Maestri NE, et al. Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 1995; 127: 929–35
2. Maestri NE, et al. Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 1996; 335: 855–9
3. Zammarchi E, et al. Neonatal onset of hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with favorable outcome. J Pediatr 1997; 131: 440–3.

💊 Preparations

BP 2008: Benzoic Acid Solution; Compound Benzoic Acid Ointment; Toluflavour Solution; USP 31: Benzoic and Salicylic Acids Ointment; Caffeine and Sodium Benzoate Injection.

Proprietary Preparations

Indon.: To pi x ; Yo d s a b e n ; Mex.: Colufase†. Multi-ingredient: Arg.: Expectosan Hierbas y Miel; Fungicida†; Ixana; No-Tos Adultos; No-Tos Infantil; Pectobron; Refenax Jarabe; Solvex Liquido Fungicida†; Torfan H†; Austral.: Whitfields (Benzoic Acid Compound) Ointment; Austria: Acerbine; Mycopol; Belg.: Colimax†; Kamfeine†; Pholco-Mereprine; Toplexil; Tux†; Braz.: ABC Solucao†; Antimicon†; Benzomel†; Bronquidex; Bronquiogem; Cessatosse†; Dermicon; Dermycose†; Eaca Balsamico; Egotussano†; Expec; Expectobron†; Frenotosse; Fungolab; Gotas Nican†; Iodesin; Iodeto de Potassio†; Iodopulmin†; Iol†; Ipecol†; KIExpectorante; Limao Bravo†; Micotiazol; Micotox†; Micoz†; Peitoral Angico Pelotense†; Penetro; Po Antisseptico; Pulmoforte†; Pulmoverina†; Rhum Creosotado; Tiratosse†; Toplexil; Tossanil†; Tussodina†; Tussol†; Tussucalman†; Xarope de Caraguata†; Xarope Peitoral de Ameixa Composto†; Xarope Sao Joao†; Xpe SPC†; Canad.: Bronco Asmol; MRX†; Plax; Chile: Broncodeina; Caristop; Gotas Nican†; Gruben; Listerine; Pectoral Pasteur; Pectoserum†; Pulmagol; Summer’s Eve Hierbas†; Summer’s Eve Vinagre y Agua†; Denm.: Pectyl; Fr.: Broncalene; Broncalene Nourisson; Codotussyl Maux de Gorge; Dermacide; Dimetane Expectorant Enfant†; Dinacode avec codeine†; Dinacode†; Ephydion; Fluocaril blancheur; Germose†; Listerine; Neo-Codion; Ozothine; Paregorique; Passedyl; Pulmofluide Simple; Quintopan†; Rhinamide; Silomat†; Ger.: Sagrosept†; Hong Kong: Fungifax†; Gly Thymol; Listerine; Listerine Tartar Control; Listerine Teeth and Gum Defence; Hung.: Glycosept; India: Keralin; Mycoderm; Pragmatar; Zoderm; Indon.: Kalpanax; Kopamex; Listerine Coolmint; Mikorex; Sapona; Israel: Oxacatin; Pertussol; Phytoderm Compositum; Pitrisan; Shiulon; Spirit Whitfield; Toplexil; Tussophedrine New Formula; Ital.: Borocaina; Dentinale; Neo Borocillina; Paracodina; Sedocalcio; Tiocosol; Tionamil†; Malaysia: Nixoderm; Mex.: Pulmovital; NZ: Egomycol†; Listerine; Listerine Tartar Control; Philipp.: Dermalin; Listerine Coolmint; Listerine Freshburst; Listerine Original; Listerine Teeth & Gum Defense; United Home Whitfield’s Ointment; Port.: Broncodiazina; Bronquiasmol†; Calmarum†; Codol; Drenoflux; Micaveen; Rus.: Neo-Codion Babies (Нео-Кодион Для Младенцев); S.Afr.: Aserbine; Dry & Clear Medicated Skin Cleanser; Singapore: Listerine; Listerine Cool Mint; Listerine Fresh Burst; Listerine Tartar Control; Whitfield†; Spain: Acerbiol; Broncoformo Muco Dexa; Broncovital†; Bronquidiazina CR; Bronquimar; Etermol Antitusivo; Neumopectolina†; Pastillas Pectoral Kely; Pazbronquial; Pulmo Menal†; Pulmofasa; Tos Mai; Switz.: Acerbine†; Dinacode N†; Foral†; Gem; Nasobol†; Neo-DP†; Nican; Onguent aux herbes Keller; Phol-Tussil; Phol-Tux; Saintbois; Toplexil; Turk.: Artu; Gayabeksin; Latusin; Nesgarin; UK: Aserbine†; Eczema Ointment; Hemocane; Potters Gees Linctus; Sanderson’s Throat Specific; Toepedo; USA: Ammonul; Atrosept; Bensal HP; Cystex; Dolsed†; MHP-A; Prosed/DS; Trac Tabs 2X†; UAA; Ucephan; Uridon Modified†; Urised; Uriseptic; Uritact; Venez.: Acetoben; Amodion; Boramint†; Corsaben†; Dromil Sauco; Fedratal†; Isacol†; Kantol†; Metilfedrin†; Niosilin; Photoderm AKN; Pi-Fedrin; Tabonuco; Yerba Santa; Yodalmina†.
Published November 06, 2018.