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99-76-3

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Identification

Name
Methylparaben
CAS
99-76-3
Synonyms
4-(carbomethoxy)phenol
4-HYDROXYBENZOIC ACID METHYL ESTER
4-HYDROXYBENZOIC ACID METYL ESTER
4-(methoxycarbonyl)phenol
AKOS BBS-00004393
FEMA 2710
metaben
methaben
METHYL 4-HYDROXYBENZOATE
methyl butex
METHYLIS PARAHYDROXYBENZOAS
METHYLPARABEN
Methyl parasept
METHYL P-HYDROXYBENZOATE
NIPAGIN
NIPAGIN PLAIN
P-HYDROXYBENZOIC ACID METHYL ESTER
RARECHEM AL BF 0098
4-hydroxy-benzoicacimethylester
Abiol
EINECS(EC#)
202-785-7
Molecular Formula
C8H8O3
MDL Number
MFCD00002352
Molecular Weight
152.15
MOL File
99-76-3.mol

Chemical Properties

Appearance
white crystalline powder
Melting point 
125-128 °C(lit.)

mp 
125-128 °C(lit.)

Boiling point 
298.6 °C
bp 
298.6 °C
density 
1,46g/cm
vapor pressure 
0.000005 hPa (20 °C)
refractive index 
1.4447 (estimate)
FEMA 
2710
Fp 
280°C
storage temp. 
0-6°C
solubility 
ethanol: soluble0.1M, clear, colorless
pka
pKa 8.15(H2O,t =20.0) (Uncertain)
form 
Crystalline Powder
color 
White to almost white
Stability:
Stable. Incompatible with strong oxidizing agents, strong bases.
PH
5.8 (H2O, 20°C) (saturated solution)
Water Solubility 
Slightly soluble in water.
FreezingPoint 
131℃
Merck 
14,6107
BRN 
509801
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.
InChIKey
LXCFILQKKLGQFO-UHFFFAOYSA-N
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
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.
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
99-76-3(EPA Substance)

Hazard Information

Uses
It is used as preservative in foods, beverages and cosmetics.
Uses
As preservative in foods, beverages and cosmetics.
Definition
ChEBI: 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 blu berries.
Hazard
Toxic. Use in foods restricted to 0.1%.
Occurrence
Reported present in cloudberry, yellow passion fruit juice, white wine, botrytised wine and Bourbon vanilla.
Production Methods
Methylparaben is prepared by the esterification of p-hydroxybenzoic acid with methanol.
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.

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 .
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.

Safety Data

Hazard Codes 
Xi,Xn
Risk Statements 
R36/37/38:Irritating to eyes, respiratory system and skin .
R20/21/22:Harmful by inhalation, in contact with skin and if swallowed .
Safety Statements 
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36:Wear suitable protective clothing .
S24/25:Avoid contact with skin and eyes .
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)

Raw materials And Preparation Products

Material Safety Data Sheet(MSDS)

Questions And Answer

Chemical properties
Methylparaben is a colourless crystalline powder that is odourless or has a faint characteristic odour and a slight burning taste. Slightly soluble in water, easily soluble in ethanol, ether, acetone and other organic solvents.One gram dissolves in 2.5 ml ethanol, in about 4 ml of propylene glycol, and in 400 ml of water at 25°C or about 50 ml of water at 80 a C. It is permissible at levels up to 0.1 % in soft drinks, non-leavened bakery products, and other products where it is generally used as a fungistat. From 1000 to 4000 ppm are required to inhibit Gram-positive bacteria. Like the benzoates, its effectiveness increases with decreasing pH.
Methylparaben
Methylparaben can by assayed by placing 2 g in a flask and adding 40.0 ml of I N NaOH (with rinsing of sides of flask with water). With a watch glass cover in place, boil gently for I h and cool. Add five drops of bromthymol blue T.S., and titrate the excess NaOH with 1 N H2S04 to pH 6.5 by matching the colour of pH 6.5 phosphate buffer containing the same proportion of indicator. Each ml of 1 N NaOH = 152.2 mg of methylparaben (National Academy of Sciences, 1963).
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
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.
Category
Toxic Chemicals
Toxic grading
Moderate toxicity
Acute toxicity
Abdomen-mouse LD50: 960 mg/kg
Flammability hazard characteristics
Combustible, excretes spicy smoke from fireground
Storage
Ventilated , low temperature and dry warehouse.
Extinguishing agent
Water, carbon dioxide, dry powder, sand.

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