Name: Methylparaben
CAS No: Methyl-4-hydroxybenzoate [99-76-3]
BP: Methyl Hydroxybenzoate JP: Methyl Parahydroxybenzoate PhEur: Methyl Parahydroxybenzoate USP-NF: Methylparaben
Aseptoform M; CoSept M; E218; 4-hydroxybenzoic acid methyl ester; metagin; Methyl Chemosept; methylis parahydroxybenzoas; methyl p-hydroxybenzoate; Methyl Parasept; Nipagin M; Solbrol M; Tegosept M; Uniphen P-23.
Methyl-4-hydroxybenzoate [99-76-3]
C8H8O3 152.15
Methylparaben is widely used as an antimicrobial preservative in cosmetics, food products, and pharmaceutical formulations; see Table I. It may be used either alone or in combination with other parabens or with other antimicrobial agents. In cosmetics, methylparaben is the most frequently used antimicrobial preservative.(1) The parabens are effective over a wide pH range and have a broad spectrum of antimicrobial activity, although they are most effective against yeasts and molds. Antimicrobial activity increases as the chain length of the alkyl moiety is increased, but aqueous solubility decreases; therefore a mixture of parabens is frequently used to provide effective preservation. Preservative efficacy is also improved by the addition of propylene glycol (2–5%), or by using parabens in combination with other antimicrobial agents such as imidurea; see Section 10. Owing to the poor solubility of the parabens, paraben salts (particularly the sodium salt) are more frequently used in formulations. However, this raises the pH of poorly buffered formulations. Methylparaben (0.18%) together with propylparaben (0.02%) has been used for the preservation of various parenteral pharmaceutical formulations; z
Methylparaben occurs as colorless crystals or a white crystalline powder. It is odorless or almost odorless and has a slight burning taste.
See Table II
Antimicrobial activity see Table III. Methylparaben exhibits antimicrobial activity of pH 4–8. Preservative efficacy decreases with increasing pH owing to the formation of the phenolate anion. Parabens are more active against yeasts and molds than against bacteria. They are also more active against Grampositive bacteria than against Gram-negative bacteria. Methylparaben is the least active of the parabens; antimicrobial activity increases with increasing chain length of the alkyl moiety. Activity may be improved by using combinations of parabens as synergistic effects occur. Therefore, combinations of methyl-, ethyl-, propyl-, and butylparaben are often used together. Activity has also been reported to be enhanced by the addition of other excipients such as: propylene glycol (2–5%);(2) phenylethyl alcohol;(3) and edetic acid.(4) Activity may also be enhanced owing to synergistic effects by using combinations of parabens with other antimicrobial preservatives such as imidurea.(5) The hydrolysis product p-hydroxybenzoic acid has practically no antimicrobial activity Density (true) 1.352 g/cm3 Dissociation constant pKa = 8.4 at 228C Melting point 125–1288C NIR spectra see Figure 1. Partition coefficients Values for different vegetable oils vary considerably and are affected by the purity of the oil; see Table IV. Solubility
Aqueous solutions of methylparaben at pH 3–6 may be sterilized by autoclaving at 1208C for 20 minutes, without decomposition.(8) Aqueous solutions at pH 3–6 are stable (less than 10% decomposition) for up to about 4 years at room temperature, while aqueous solutions at pH 8 or above are subject to rapid hydrolysis (10% or more after about 60 days storage at room temperature) Methylparaben should be stored in a well-closed container in a cool, dry place.
The antimicrobial activity of methylparaben and other parabens is considerably reduced in the presence of nonionic surfactants, such as polysorbate 80, as a result of micellization.(10,11) However, propylene glycol (10%) has been shown to potentiate the antimicrobial activity of the parabens in the presence of nonionic surfactants and prevents the interaction between methylparaben and polysorbate 80.(12) Incompatibilities with other substances, such as bentonite,(13) magnesium trisilicate,(14) talc, tragacanth,(15) sodium alginate,(16) essential oils,(17) sorbitol,(18) and atropine,(19) have been reported. It also reacts with various sugars and related sugar alcohols.(20) Absorption of methylparaben by plastics has also been reported; the amount absorbed is dependent upon the type of plastic and the vehicle. It has been claimed that low-density and high-density polyethylene bottles do not absorb methylparaben.(21) Methylparaben is discolored in the presence of iron and is subject to hydrolysis by weak alkalis and strong acids.
Methylparaben is prepared by the esterification of p-hydroxybenzoic acid with methanol.
Methylparaben and other parabens are widely used as antimicrobial preservatives in cosmetics and oral and topical pharmaceutical formulations. Although parabens have also been used as preservatives in injections and ophthalmic preparations, they are now generally regarded as being unsuitable for these types of formulations owing to the irritant potential of the parabens. These experiences may depend on immune responses to enzymatically formed metabolites of the parabens in the skin. Parabens are nonmutagenic, nonteratogenic, and noncarcinogenic. Sensitization to the parabens is rare, and these compounds do not exhibit significant levels of photocontact sensitization or phototoxicity. Hypersensitivity reactions to parabens, generally of the delayed type and appearing as contact dermatitis, have been reported. However, given the widespread use of parabens as preservatives, such reactions are relatively uncommon; the classification of parabens in some sources as high-rate sensitizers may be overstated.(22) Immediate hypersensitivity reactions following injection of preparations containing parabens have also been reported.(23–25) Delayed-contact dermatitis occurs more frequently when parabens are used topically, but has also been reported to occur after oral administration.(26–28) Unexpectedly, preparations containing parabens may be used by patients who have reacted previously with contact dermatitis provided they are applied to another, unaffected, site. This has been termed the paraben paradox.(29) Concern has been expressed over the use of methylparaben in infant parenteral products because bilirubin binding may be affected, which is potentially hazardous in hyperbilirubinemic neonates.(30) The WHO has set an estimated total acceptable daily intake for methyl-, ethyl-, and propylparabens at up to 10 mg/kg bodyweight.(31) LD50 (dog, oral): 3.0 g/kg(32) LD50 (mouse, IP): 0.96 g/kg LD50 (mouse, SC): 1.20 g/kg
Observe normal precautions appropriate to the circumstances and quantity of material handled. Methylparaben may be irritant to the skin, eyes, and mucous membranes, and should be handled in a well-ventilated environment. Eye protection, gloves, and a dust mask or respirator are recommended.
Methylparaben and propylparaben are affirmed GRAS Direct Food Substances in the USA at levels up to 0.1%. All esters except the benzyl ester are allowed for injection in Japan. In cosmetics, the EU and Brazil allow use of each paraben at 0.4%, but the total of all parabens may not exceed 0.8%. The upper limit in Japan is 1.0%. Accepted for use as a food additive in Europe. Included in the FDA Inactive Ingredients Database (IM, IV, and SC injections; inhalation preparations; ophthalmic preparations; oral capsules, tablets, solutions and suspensions; otic, rectal, topical, and vaginal preparations). Included in medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.
Butylparaben; ethylparaben; methylparaben potassium; methylparaben sodium; propylparaben. Methylparaben potassium Empirical formula C8H7KO3 Molecular weight 190.25 CAS number [26112-07-2] Synonyms Methyl 4-hydroxybenzoate potassium salt; potassium methyl hydroxybenzoate. Comments Methylparaben potassium may be used instead of methylparaben because of its greater aqueous solubility. Methylparaben sodium Empirical formula C8H7NaO3 Molecular weight 174.14 CAS number [5026-62-0] Synonyms E219; methyl 4-hydroxybenzoate sodium salt; sodium methyl hydroxybenzoate; soluble methyl hydroxybenzoate. Appearance A white, odorless or almost odorless, hygroscopic crystalline powder. Acidity/alkalinity pH = 9.5–10.5 (0.1% w/v aqueous solution) Solubility 1 in 50 of ethanol (95%); 1 in 2 of water; practically insoluble in fixed oils. Comments Methylparaben sodium may be used instead of methylparaben because of its greater aqueous solubility. However, it may cause the pH of a formulation to become more alkaline.
Methylparaben is one of the materials that have been selected for harmonization by the Pharmacopeial Discussion Group. For further information see the General Information Chapter <1196> in the USP32–NF27, the General Chapter 5.8 in PhEur 6.0, along with the ‘State of Work’ document on the PhEur EDQM website, and also the General Information Chapter 8 in the JP XV. The BP 2009, Ph Eur 6.0 and USP32–NF27 also list Methylparaben Sodium as a separate monograph. The EINECS number for methylparaben is 202-785-7. In addition to the most commonly used paraben esters, some other less-common esters have also been used; see Table VIII. A specification for methylparaben is contained in the Food Chemicals Codex (FCC).(33) The PubChem Compound ID (CID) for methylparaben is 7456.