99-76-3 Usage
Description
Methylparaben, also known as Methyl 4-hydroxybenzoate, is a methyl ester of p-hydroxybenzoic acid. It is a non-toxic, non-carcinogenic, stable, and non-volatile compound that occurs as colorless crystals or a white crystalline powder. It is odorless or almost odorless and has a slight burning taste. Methylparaben is soluble in alcohol, ether, and slightly soluble in water, benzene, and carbon tetrachloride. It is a widely used antimicrobial preservative in various industries due to its bacteriostatic and fungistatic properties.
Uses
Used in Cosmetic Industry:
Methylparaben is used as a preservative in beauty products such as cream cleansers, moisturizers, primers, and foundations. It provides anti-fungal and antibacterial properties, which help maintain the effectiveness and extend the shelf life of skincare, haircare, and cosmetic products.
Used in Pharmaceutical Industry:
Methylparaben is used as a preservative in pharmaceutical products, including ophthalmic solutions. It acts as an inhibitor of mold growth and to a lesser extent, bacterial growth, ensuring the safety and efficacy of these products.
Used in Food Industry:
Methylparaben is used as a preservative in foods and beverages. It is effective against yeast, molds, and bacteria, helping to maintain the quality and safety of these products over a wide pH range.
Used in Antimicrobial Applications:
Methylparaben is an antimicrobial agent that is active against yeast and molds. It is used in various applications where microbial control is necessary, such as in the production of cloudberry, yellow passion fruit juice, white wine, botrytised wine, and Bourbon vanilla.
General Description:
Methylparaben is a white free-flowing powder that is readily absorbed through the skin and gastrointestinal tract. Upon hydrolysis, it is hydrolyzed to p-hydroxybenzoic acid, and the conjugates formed get rapidly excreted in the urine.
Chemical Properties:
Methylparaben is a colorless crystalline powder that is odorless or has a faint characteristic odor and a slight burning taste. It is slightly soluble in water, easily soluble in ethanol, ether, acetone, and other organic solvents. Its effectiveness as a preservative increases with decreasing pH.
Aroma Threshold Values:
Detection: 2.6 ppm.
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
The drug is esterified with p-hydroxybenzoic acid and methanol. The p-hydroxybenzoic acid was added to excess methanol to dissolve, stirring and adding concentrated sulfuric acid slowly. After heating and refluxing 10h, pour into the water to precipitate crystallization, then washed with water, sodium carbonate solution and water, finally obtain the crude product. Recrystallize from water or 25% ethanol to obtain finished product. The yield was 85%. Raw material consumption (kg/t): p-hydroxybenzoic acid 1200, methanol 1000.
Preparation
Produced by the methanol esterification of p-hydroxybenzoic acid in the presence of sulfuric acid. The materials are
heated for distillation in a glass-lined reactor under reflux. The acid is then neutralized with caustic soda and the product is crystallized by cooling. The crystallized product is centrifuged, washed, dried under vacuum, milled and blended, all in corrosion-resistant
equipment to avoid metallic contamination.
Acute toxicity
Abdomen-mouse LD50: 960 mg/kg
Flammability hazard characteristics
Combustible, excretes spicy smoke from fireground
Storage
Ventilated , low temperature and dry warehouse.
Production Methods
Methylparaben is prepared by the esterification of p-hydroxybenzoic
acid with methanol.
Hazard
Toxic. Use in foods restricted to 0.1%.
Flammability and Explosibility
Nonflammable
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;
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.
Check Digit Verification of cas no
The CAS Registry Mumber 99-76-3 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 9 and 9 respectively; the second part has 2 digits, 7 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 99-76:
(4*9)+(3*9)+(2*7)+(1*6)=83
83 % 10 = 3
So 99-76-3 is a valid CAS Registry Number.
InChI:InChI=1/C8H8O3/c1-5-4-6(9)2-3-7(5)8(10)11/h2-4,9H,1H3,(H,10,11)/p-1
99-76-3Relevant articles and documents
Carboxyl Methyltransferase Catalysed Formation of Mono- and Dimethyl Esters under Aqueous Conditions: Application in Cascade Biocatalysis
Ashbrook, Chloe,Carnell, Andrew J.,Goulding, Ellie,Hatton, Harry,Johnson, James R.,Kershaw, Neil M.,McCue, Hannah V.,Rigden, Daniel J.,Ward, Lucy C.
supporting information, (2022/02/21)
Carboxyl methyltransferase (CMT) enzymes catalyse the biomethylation of carboxylic acids under aqueous conditions and have potential for use in synthetic enzyme cascades. Herein we report that the enzyme FtpM from Aspergillus fumigatus can methylate a broad range of aromatic mono- and dicarboxylic acids in good to excellent conversions. The enzyme shows high regioselectivity on its natural substrate fumaryl-l-tyrosine, trans, trans-muconic acid and a number of the dicarboxylic acids tested. Dicarboxylic acids are generally better substrates than monocarboxylic acids, although some substituents are able to compensate for the absence of a second acid group. For dicarboxylic acids, the second methylation shows strong pH dependency with an optimum at pH 5.5–6. Potential for application in industrial biotechnology was demonstrated in a cascade for the production of a bioplastics precursor (FDME) from bioderived 5-hydroxymethylfurfural (HMF).
Beyond Basicity: Discovery of Nonbasic DENV-2 Protease Inhibitors with Potent Activity in Cell Culture
Kühl, Nikos,Leuthold, Mila M.,Behnam, Mira A. M.,Klein, Christian D.
, p. 4567 - 4587 (2021/05/06)
The viral serine protease NS2B-NS3 is one of the promising targets for drug discovery against dengue virus and other flaviviruses. The molecular recognition preferences of the protease favor basic, positively charged moieties as substrates and inhibitors, which leads to pharmacokinetic liabilities and off-target interactions with host proteases such as thrombin. We here present the results of efforts that were aimed specifically at the discovery and development of noncharged, small-molecular inhibitors of the flaviviral proteases. A key factor in the discovery of these compounds was a cellular reporter gene assay for the dengue protease, the DENV2proHeLa system. Extensive structure-activity relationship explorations resulted in novel benzamide derivatives with submicromolar activities in viral replication assays (EC50 0.24 μM), selectivity against off-target proteases, and negligible cytotoxicity. This structural class has increased drug-likeness compared to most of the previously published active-site-directed flaviviral protease inhibitors and includes promising candidates for further preclinical development.
Hydroxyl radical-mediated oxidative cleavage of CC bonds and further esterification reaction by heterogeneous semiconductor photocatalysis
Hong, Mei,Jia, Rui,Miao, Hongyan,Ni, Bangqing,Niu, Tengfei,Wang, Hui
, p. 6591 - 6597 (2021/09/10)
A hydroxyl radical-mediated aerobic cleavage of alkenes and further sequence esterification reaction for the preparation of carbonyl compounds have been developed by using tubular carbon nitride (TCN) as a general heterogeneous photocatalyst under an oxygen atmosphere with visible light irradiation. This protocol has an excellent substrate scope and gives the desired aldehydes, ketones and esters in moderate to high yields. Importantly, this metal-free procedure employed photogenerated hydroxyl radicals in situ as green oxidation active species, avoiding the present additional initiators. The reaction could be carried out under solar light irradiation and was applicable to large-scale reactions. Furthermore, the recyclable TCN catalyst could be used several times without a significant loss of activities.