Methylparaben Chemical Properties

Melting point:

125-128 °C (lit.)

Boiling point:

298.6 °C

Density 

1,46g/cm

vapor pressure 

0.000005 hPa (20 °C)

FEMA 

2710 | METHYL P-HYDROXYBENZOATE

refractive index 

1.4447 (estimate)

Flash point:

280°C

storage temp. 

room temp

solubility 

ethanol: soluble0.1M, clear, colorless

pka

pKa 8.15(H2O,t =20.0) (Uncertain)

form 

Crystalline Powder

color 

White to almost white

Odor

odorless or faint char. odor, sl. burning taste

PH

5.8 (H2O, 20°C) (saturated solution)

Water Solubility 

Slightly soluble in water.

FreezingPoint 

131℃

Merck 

14,6107

BRN 

509801

Stability:

Stable. Incompatible with strong oxidizing agents, strong bases.

InChIKey

LXCFILQKKLGQFO-UHFFFAOYSA-N

LogP

1.98 at 20℃

CAS DataBase Reference

99-76-3(CAS DataBase Reference)

NIST Chemistry Reference

Benzoic acid, 4-hydroxy-, methyl ester(99-76-3)

EPA Substance Registry System

Methylparaben (99-76-3)

Safety Information

Hazard Codes 

Xi,Xn

Risk Statements 

36/37/38-20/21/22-36

Safety Statements 

26-36-24/25-39

RIDADR 

UN 2769

WGK Germany 

1

RTECS 

DH2450000

Autoignition Temperature

>600 °C

TSCA 

Yes

HS Code 

29182930

Hazardous Substances Data

99-76-3(Hazardous Substances Data)

Toxicity

LD50 orally in Rabbit: 2100 mg/kg

MSDS

• Language:English Provider:4-Hydroxybenzoic acid methyl ester
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS
• Language:English Provider:ALFA

Methylparaben Usage And Synthesis

Chemical properties

Methylparaben is a colorless crystalline powder with a faint characteristic odor and a slight burning taste. It is slightly soluble in water but easily dissolves in ethanol, ether, acetone, and other organic solvents. One gram can dissolve in 2.5 ml of ethanol, approximately 4 ml of propylene glycol, or 400 ml of water at 25°C or about 50 ml of water at 80°C. It is commonly used as a fungistat in soft drinks, non-leavened bakery products, and other products, with a permissible level of up to 0.1%. To inhibit Gram-positive bacteria, 1000 to 4000 ppm are required, and its effectiveness increases with decreasing pH, similar to benzoates.

Uses

Methylparaben is the ester of methyl alcohol and p-hydroxybenzoic acid, It is a bacteriostatic agent and preservative that was added to local anesthetic agents without vasoconstrictors before 1984 to prevent bacterial growth. Allergic reactions developed from repeated exposures to parabens led to the removal of this agent from dental anesthetic solutions. Similar products produced by similar production methods, like ethyl p-hydroxybenzoate (paraben B) and propyl p-hydroxybenzoate (Nepalese c), are also disinfectant preservatives. The products are irritating to the skin.

Content analysis

Method one: determinate according to the content analysis method in "butyl p-hydroxybenzoate (07002)". Per mL 1 mol/L sodium hydroxide is equivalent to the product (C8H8O3) 152.2mg.
Method two: Take 0.1 g (accurate to 1 mg) of the sample previously dried on silica gel for 5 h and move into a 300 ml flask with a glass plug. Plus l mol/L sodium hydroxide 10ml, heated in the water bath for 15min. After cooling, add 0.1mol/L potassium bromate 0.00ml, potassium bromide 5.0g and l mol/L hydrochloric acid 30ml. Put 15min in the dark room after sealing. Add potassium iodide 1 g, shake the flask vigorously, with 0.1mol/L sodium thiosulfate titration, with starch test solution (TS-235) as an indicator. Per ml 0.1mol/L potassium bromate is equivalent to the product (C8H8O3) 25.36mg.

Toxicity

ADI 0～10mg/kg(FAO/WHO,2001).
GRAS(FDA,§184．1490，2000).
LD503000mg/kg(Dog, mouth)

Utilization limitation

FAO/WHO (1984): Jam, jelly, 1000mg/kg (single or with benzoate, sorbic acid and potassium sorbate).
EEC(1990,mg/kg): For use in pigment solutions, flavor syrups, coffee extracts, frozen drinks, fruit, glucose and soft drinks, pickled fish, salad, sauce, snack food, concentrated soup and so on, limited to GMP; Beer 70; Snack cereals and soup concentrate 175, the same as "07018 p-hydroxybenzoate".
HACSG is listed as a restricted list.
FDA,§184.1490(2000):0.1%.

Preparation

To prepare the drug, p-hydroxybenzoic acid, and methanol were esterified. First, excess methanol was added to p-hydroxybenzoic acid and stirred to dissolve. Concentrated sulfuric acid was then slowly added while stirring. The mixture was heated and refluxed for 10 hours, before being poured into water to precipitate crystallization. The crude product was then washed with water, sodium carbonate solution, and water, and recrystallized from water or 25% ethanol to obtain the finished product. The yield of the drug was 85%. Raw material consumption for each tonne of product included 1200 kg of p-hydroxybenzoic acid and 1000 kg of methanol.

Chemical Properties

Methylparaben occurs as colorless crystals or a white crystalline powder. It is odorless or almost odorless and has a slight burning taste. Soluble in alcohol,ether; slightly soluble in water, benzene, and carbontetrachloride.

Occurrence

Reported present in cloudberry, yellow passion fruit juice, white wine, botrytised wine and Bourbon vanilla.

Uses

Methyl 4-hydroxybenzoate is used as an anti-fungal agent. It is also used as a preservative in foods, beverages and cosmetics. It acts as an inhibitor of growth of molds and to lesser extent bacteria and as a vehicle for ophthalmic solution.

Uses

Methylparaben is an antimicrobial agent which is a white free-flowing powder. it is active against yeast and molds over a wide ph range. see parabens.

Uses

Methylparaben and propylparaben are the most common of these. parabens is one of the most commonly used group of preservatives in the cosmetic, pharmaceutical, and food industries. Parabens provide bacteriostatic and fungistatic activity against a diverse number of organisms, and are considered safe for use in cosmetics, particularly in light of their low sensitizing potential. An evaluation of preservatives for use in leave-on cosmetic preparations lists parabens among the least sensitizing. The range of concentrations used in cosmetics varies between 0.03 and 0.30 percent, depending on the conditions for use and the product to which the paraben is added.
Methylparaben is one of the most popular preservatives in beauty products and food items. According to the National Library of Medicine, the ingredient occurs naturally in a handful of fruits—like blueberries—though it can also be created synthetically.It's found in everything from cream cleansers and moisturizers to primers and foundations and helps these products maintain their effectiveness. Rabach says that it's chock-full of anti-fungal and antibacterial properties, which work wonders to extend the shelf life of skincare, haircare, and cosmetic products.

Definition

ChEBI: Methylparaben is a 4-hydroxybenzoate ester resulting from the formal condensation of the carboxy group of 4-hydroxybenzoic acid with methanol. It is the most frequently used antimicrobial preservative in cosmetics. It occurs naturally in several fruits, particularly in blueberries. It has a role as a plant metabolite, an antimicrobial food preservative, a neuroprotective agent and an antifungal agent.

Preparation

Methylparaben is produced through the methanol esterification of p-hydroxybenzoic acid in the presence of sulfuric acid. The materials are heated in a glass-lined reactor and distilled under reflux. The resulting acid is neutralized with caustic soda, then crystallized through cooling. The crystallized product is centrifuged, washed, dried under vacuum, milled and blended, all in corrosion-resistant equipment to avoid metallic contamination.

Aroma threshold values

Detection: 2.6 ppm.

General Description

Methyl paraben is basically a methyl ester of p-hydroxybenzoic acid. It is non-toxic, and non-carcinogenic in nature. It is a stable, non-volatile compound and finds application as an anti-microbial preservative in foods, drugs and cosmetics. It is readily absorbed through the skin and gastrointestinal tract. Upon hydrolyzation, it is hydrolyzed to p-hydroxybenzoic acid, and the conjugates formed get rapidly excreted in the urine.

Hazard

Toxic. Use in foods restricted to 0.1%.

Pharmaceutical Applications

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 methylparaben is the most frequently used antimicrobial preservative.
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;
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;

Contact allergens

This substance is one of the parabens family. Parabens are esters formed by p-hydroxybenzoic acid and an alcohol. They are largely used as biocides in cosmetics and toiletries, medicaments, or food. They have synergistic power with other biocides. Parabens can induce allergic contact dermatitis, mainly in chronic dermatitis and wounded skin.

Biochem/physiol Actions

Methyl 4-hydroxybenzoate, also called methyl paraben or nipagin, comprises the ester of p-hydroxybenzoic acid. It is present naturally in cloudberry, white wine and bourbon vanilla. Methyl 4-hydroxybenzoate has antimicrobial and antifungal functionality and is commercially used as a preservative in the food, cosmetic and pharmaceutical industry. Methyl 4-hydroxybenzoate has cytotoxic effects on keratinocytes in the presence of sunlight. Methyl 4-hydroxybenzoate upon solar irradiation mediates DNA damage and modulates esterase metabolism resulting in skin damage and favors cancer progression. Methyl 4-hydroxybenzoate has estrogenic functionality and upregulates estrogen-related genes.

Safety

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 overstated. Immediate hypersensitivity reactions following injection of preparations containing parabens have also been reported.
Delayed-contact dermatitis occurs more frequently when parabens are used topically, but has also been reported to occur after oral administration.
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.
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.
The WHO has set an estimated total acceptable daily intake for methyl-, ethyl-, and propylparabens at up to 10 mg/kg bodyweight.
LD₅₀ (dog, oral): 3.0 g/kg
LD₅₀ (mouse, IP): 0.96 g/kg
LD₅₀ (mouse, SC): 1.20 g/kg

Carcinogenicity

The carcinogenic potential of methyl paraben has been studied in rodents. Several studies are available, but none that expose animals via oral or dermal routes. No evidence of a carcinogenic effect was observed following intravenous or subcutaneous injection .

storage

Aqueous solutions of methylparaben at pH 3–6 may be sterilized by autoclaving at 120°C for 20 minutes, without decomposition. 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.

Purification Methods

Fractionally crystallise the ester from its melt, and recrystallise it from *benzene, then from *benzene/MeOH and dry it over CaCl2 in a vacuum desiccator. [Beilstein 10 IV 360.]

Incompatibilities

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.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.
Incompatibilities with other substances, such as bentonite, magnesium trisilicate,talc,tragacanth,sodium alginate, essential oils,sorbitol,and atropine,have been reported. It also reacts with various sugars and related sugar alcohols. 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.
Methylparaben is discolored in the presence of iron and is subject to hydrolysis by weak alkalis and strong acids.

Regulatory Status

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.

References

The Protective Effect of Rosmarinic Acid against Unfavorable Influence of Methylparaben and Propylparaben on Collagen in Human Skin Fibroblasts DOI:10.3390/nu12051282
https://www.byrdie.com/methylparaben-for-skin-4779820
https://pubchem.ncbi.nlm.nih.gov/compound/Methylparaben
Handa O, et al. (2006). Methylparaben potentiates UV-induced damage of skin keratinocytes. DOI: 10.1016/j.tox.2006.07.018
Parabens in Cosmetics https://www.fda.gov/cosmetics/productsingredients/ingredients/ucm128042.htm
Okamoto T, et al. (2008). Combined activation of methyl paraben by light irradiation and metabolism toward oxidative DNA damage. DOI:10.1021/tx800066u

Methylparaben(99-76-3)Related Product Information

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