4-Methoxyphenol

log Kow = 1.41 at 25 °C

1.58

1.58

1.57

1.55 at 68 °F (NTP, 1992) - Denser than water; will sink

1.55 at 20 °C/20 °C

1.6 g/cm³

1.55

1.55 @ 20°C

1.55

Plates

White waxy solid

White to tan, flaky, crystalline substance

Colorless to white, waxy solid

Soluble (NTP, 1992)

In water, 19,500 mg/L at 25 °C

In water, 40,000 mg/L at 25 °C

Soluble in benzene, carbon tetrachloride; very soluble in ethanol, ether

Readily soluble in acetone and ethyl acetate.

40 mg/mL at 25 °C

269.6 °F (NTP, 1992)

132 °C

270 °F (132 °C) (Open Cup)

132 °C o.c.

270 °F (open cup)

(oc) 270 °F

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P272, P280, P301+P317, P302+P352, P305+P351+P338, P321, P330, P333+P317, P337+P317, P362+P364, and P501 (click each P-code to see the statement)

This chemical does not meet GHS hazard criteria for 0.2% (11 of 4411) of reports.

Warning

H302 (99.8%): Harmful if swallowed [Warning Acute toxicity, oral]

Chemical: Phenol, 4-methoxy-

Commission Regulation (EC) No 1565/2000 (Repealed by Com. Implementing Reg. (EU) No 872/2012)

Phenol, 4-methoxy- is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of Phenol, 4-methoxy- are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 09-04-2020 https://echa.europa.eu/registration-dossier/-/registered-dossier/16005

4-Methoxyphenol: Does not have an individual approval but may be used under an appropriate group standard

Combustible (NTP, 1992)

Combustible. Finely dispersed particles form explosive mixtures in air.

Can cause leukoderma (depigmentation of skin); [LaDou, p. 328] Symptoms: Irritation eyes, skin, nose, throat, upper respiratory system; eye, skin burns; central nervous system depression; [CAMEO] A skin and eye irritant and can cause depigmentation of the skin; A potential skin sensitizer; [ICSC]

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. Effective date: 3/11/94; Reporting date: 5/10/94.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Methoxyphenol is included on this list. Effective date 3/11/94; Sunset date: 6/30/98.

Excerpt from ERG Guide 171 [Substances (Low to Moderate Hazard)]:

Use water spray, powder, alcohol-resistant foam, carbon dioxide.

Fresh air, rest.

Remove contaminated clothes. Rinse and then wash skin with water and soap.

First rinse with plenty of water for several minutes (remove contact lenses if easily possible), then refer for medical attention.

Rinse mouth. Give one or two glasses of water to drink. Refer for medical attention .

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

(General first aid procedures)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for fire fighters: Wear self contained breathing apparatus for fire fighting if necessary.

Water or foam may cause frothing.

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place.

... Commercially available mequinol and tretinoin topical solution should be protected from light and stored at room temperature, preferably in the manufacturer's carton. /Solage/

Store at 25 °C (77 °F): excursions permitted to 15-30 °C (59-86 °F).

Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust.

Enviornomental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.

Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. keep in suitable, closed containers for disposal.

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, you should dampen the solid spill material with alcohol, then transfer the dampened material to a suitable container. Use absorbent paper dampened with alcohol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with alcohol followed by washing with a strong soap and water solution. Do not reenter the contaminate area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

Personal protection: particulate filter respirator adapted to the airborne concentration of the substance. Sweep spilled substance into covered sealable containers. Carefully collect remainder. Then store and dispose of according to local regulations.

SRP: The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

The worker should immediately wash the skin when it becomes contaminated.

Work clothing that becomes wet or significantly contaminated should be removed and replaced.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.

For more Preventive Measures (Complete) data for 4-METHOXYPHENOL (6 total), please visit the HSDB record page.

Tests were carried out in cultured Chinese hamster ovary (CHO) cells (line CHO-AA8-4) and in X-irradiated Syrian hamster embryo cells (SHE) to investigate the effects of butylated-hydroxyanisole (BHA) on the metabolism and mutagenic activity of benzo(a)pyrene (BaP) and to compare them with those induced by butylated-hydroxytoluene (BHT) and p-methoxyphenol (PMO). Feeder Syrian hamster embryo cells were cocultured with target Chinese hamster ovary cells to provide metabolic transformation of benzo(a)pyrene. The mutagenicity of benzo(a)pyrene in target Chinese hamster ovary cells was reduced by up to 60% by pretreatment with p-methoxyphenol, butylated-hydroxyanisole, or butylated-hydroxytoluene. In Syrian hamster ovary cells, the antioxidants tested inhibited metabolism with reduction in levels of water soluble benzo(a)pyrene glucuronide conjugates in the extracellular medium and apparent increase in levels of intracellular monophenols. As a result of the antioxidant inhibited formation of reactive, electrophilic benzo(a)pyrene metabolites, there was reduction in the binding of benzo(a)pyrene to nuclear macromolecules, especially to DNA.

The modifying effects of para-methoxyphenol second stage treatment on N-methyl-N'-nitro-N-nitrosoguanidine initiated rat forestomach carcinogenesis were investigated. Groups of 15 6 week old male F344 rats were given a single intragastric administration of 150 mg/kg body wt N-methyl-N'-nitro-N-nitrosoguanidine and starting 1 week later were administered powdered diet containing 2.0, 1.0, 0.5, 0.25 or 0% para-methoxyphenol until week 52. para-methoxyphenol caused epithelial damage and hyperplasia in a dose-dependent manner in the forestomach epithelium but nevertheless was not associated with any increase in the incidence of either papillomas or squamous cell carcinomas. Stimulation of cell proliferation does not necessarily correlate with promotion in the second stage of two-stage forestomach carcinogenesis.

The modifying effects of five phenolic antioxidants on N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-initlated forestomach and glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 20 rats were given an intragastric dose of 150 mg/kg body weight N-methyl-N-nitro-N-nitrosoguanine and starting from 1 week later received diet supplemented with 0.8% catechol, 1.0% 2-tert-butyl-4-methylphenol, 1.5% p-tert-butylphenol, 1.5% methylhydroquinone, 1.5% 4-methoxyphenol, or basal diet alone for 51 wk. Further groups of 10-15 rats were maintained as controls without prior treatment with N-methyl-N-nitro-N-nitrosoguanine. The incidences of squamous cell carcinoma of the forestomach in N-methyl-N-nitro-N-nitrosoguanine-treated animals were significantly elevated by the diets containlng catechol (P less than 0.001), 2-tert-butyl-4-methylphenol (P less than 0.001), or p-tert-butylphenol (P less than 0.01), while the development of carcinoma in situ was inhibited by 4-methoxyphenol (P less than 0.01). Treatment with catechol, 2-tert-butyl-4-methylphenol, p-tert-butylphenol, or 4-methoxyphenol alone induced forestomach hyperplasia at incidences of 86.7, 40, 93.3, and 100%, respectively. In the pyloric region of the glandular stomach, the development of adenomatous hyperplasia and adenocarcinoma after N-methyl-N-nitro-N-nitrosoguanine treatment was significantly enhanced by diet containing catechol (P less than 0.001). Moreover, treatment with catechol alone induced 100% adenomatous hyperplasia and induced adenocarcinoma in 20% of animals. ... While antioxidants causing proliferation in forestomach epithelium can markedly enhance carcinogenesis in this tissue, others displaying the same or greater potential for generating a hyperplastic response, like 4-methoxyphenol can exert an inhibitory effect. In addition, it was shown that catechol is an unequivocal glandular stomach carcinogen also possessing strong enhancing activity for N-methyl-N-nitro-N-nitrosoguanine-induced lesion development.

The chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of ascorbylpalmitate (AP), carbenoxolone (CBX), dimethylfumarate (DMF) and p-methoxyphenol (p-MP) administrated in the diet before and during initiation and postinitiation phases of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD levels of AP, CBX, DMF and p-MP were determined in male F344 rats and found to be 5000, 1500, 1000 and 1000 ppm, respectively, in modified AIN-76A diet. Based on these MTD values, 40 and 80% MTD levels of each agent was tested for their efficacy in colon carcinogenesis. At 5 weeks of age, groups of animals were fed the control (modified AIN-76A diet or diets containing 40 and 80% MTD levels of each AP, CBX, DMF and p-MP. At 7 weeks of age, all animals, except those in the vehicle (normal saline) treated groups, were given two weekly s.c. injections of AOM at a dose rate of 15 mg/kg body weight/week. All groups were continued on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. The results indicate that dietary administration of 40% MTD of AP significantly inhibited multiplicities (tumor/animal) of noninvasive and total (invasive plus noninvasive) adenocarcinoma of the colon (P < 0.05) and 80% MTD of AP significantly inhibited the incidence (% animals with tumors) and the multiplicities of invasive and total adenocarcinomas of the colon (P < 0.01). Dietary CBX at 40 and 80% MTD levels suppressed the incidence and multiplicities of invasive and total adenocarcinomas (P < 0.05 to 0.001) whereas 40 and 80% MTD of DMF and p-MP had significantly inhibited invasive adenocarcinoma incidence and multiplicity (P < 0.05 to 0.001). However, DMF and p-MP had no significant effect on noninvasive and total adenocarcinoma incidence and multiplicity (P > 0.05). These results suggest that AP and CBX possess potential chemopreventive properties against colon cancer.

For more Interactions (Complete) data for 4-METHOXYPHENOL (11 total), please visit the HSDB record page.

EC50; Species: Daphnia magna (Water flea); Conditions: freshwater, static, 19-20 °C, pH 7.4-7.8, dissolved oxygen 7.7-8.6 at test start and 5.5-6.1 at test end; Concentration: 2.2 mg/L for 48 hr; Effect: immobilization

LC50; Species: Daphnia magna (Water flea) age < or =24 hr; Conditions: freshwater, static, 20-22 °C, pH 7.6-7.7; Concentration: 19000 ug/L for 24 hr /formulated product/

LC50; Species: Pimephales promelas (Fathead minnow); Conditions: freshwater, static, 19-20 °C, pH 7.4-7.8; Concentration: 55 mg/L for 96 hr

LC50; Species: Pimephales promelas (Fathead minnow) juvenile, age 26-34 days; Conditions: freshwater, flow through, 25 °C, pH 7.8, hardness 45 mg/L CaCO3, alkalinity 42 mg/L CaCO3; Concentration: 84300 ug/L for 96 hr /> or = 95% purity/

For more Ecotoxicity Values (Complete) data for 4-METHOXYPHENOL (9 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), experimentally derived Koc values of 55.7(2) and 90(3), indicates that 4-methoxyphenol is expected to have high mobility in soil(SRC). Volatilization of 4-methoxyphenol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.7X10-8 atm-cu m/mole(SRC), based upon its vapor pressure, 6.73X10-3 mm Hg(4), and water solubility, 1.95X10+4 mg/L(5). 4-Methoxyphenol is not expected to volatilize from dry soil surfaces(SRC) based upon an its vapor pressure(4). An 86% of theoretical BOD using activated sludge in the Japanese MITI test indicates that 4-methoxyphenol is readily biodegradable(6). Complete biodegradation of 4-methoxyphenol under aerobic conditions within 8 days using a soil inoculum(7) suggests that biodegradation may be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), Koc values of 55.7(2) and 90(3), indicates that 4-methoxyphenol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 5.7X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 6.75X10-3 mm Hg(5), and water solubility, 1.95X10+4 mg/L(6). According to a classification scheme(7), an estimated BCF of 4(SRC), from its log Kow of 1.41(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low. 4-Methoxyphenol is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). In general, phenols in surface waters exposed to sunlight react with photo-oxidants (such as hydroxyl radicals, peroxy radicals and singlet oxygen) with a half-life on the order of 13 days(10). The indirect photolysis of 4-methoxyphenol in natural water has been demonstrated(5,11). An 86% of theoretical BOD using activated sludge in the Japanese MITI test indicates that 4-methoxyphenol is readily biodegradable(12). River die-away tests have determined half-lives of 22.5 hours to about 5-6 days(13,14).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-methoxyphenol, which has a vapor pressure of 6.75X10-3 mm Hg at 20 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-methoxyphenol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 4 hours(SRC), calculated from its rate constant of 9.5X10-11 cu cm/molecule-sec at 21 °C(3). Phenol absorbs at wavelengths >290 nm(4) and therefore, by analogy, 4-methoxyphenol may be susceptible to direct photolysis by sunlight(SRC). 4-Methoxyphenol has been observed to photodegrade in pure water exposed to sunlight(5).

The substance can be absorbed into the body by ingestion.

inhalation, skin absorption, ingestion, skin and/or eye contact

The CIR Expert Panel concluded that p-Hydroxyanisole is safe for use in nail adhesives and in artificial nail coatings, as a polymerization inhibitor, that are cured by LED light; and unsafe for use in all other cosmetics due to dermal depigmentation potential.

Safe for use in cosmetics, with qualifications

IDENTIFICATION AND USE: 4-Methoxyphenol (4-MP) is available as a colorless to white, waxy solid or white to tan, flaky, crystalline substance with the odor of caramel and phenol. It is used as an inhibitor for acrylic monomers and acrylonitirles, as a stabilizer for chlorinated hydrocarbons and ethyl cellulose, as an ultraviolet inhibitor, as a chemical intermediate in the manufacture of antioxidants, pharmaceuticals, plasticizers, and dyestuffs. It is also used as a medication for dyschromias, especially hyperpigmentation often in combination with Tretinoin (Solage). HUMAN EXPOSURE AND TOXICITY: In 11 of the 16 patients (69%; 95% confidence interval [CI], 41%-89%) total depigmentation was achieved using the 4-MP cream. Onset of depigmentation was between 4 and 12 months. Mild burning or itching was reported with the cream in 4 cases (25%). Of the 11 patients who responded to the 4-MP cream, 4 had recurrence of pigmentation (relapse rate of 36%; 95% CI, 11%-69%) after a treatment-free period of 2 to 36 months. Excessive application of 4-MP, can result in marked redness, peeling, discomfort, or hypopigmentation. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of vitamin A (hypervitaminosis A). In a vinylidene chloride plant 2 out of 8 process workers handling hydroquinone monomethyl ether developed depigmentation (occupational leukoderma) of skin of forearms and in 1 of them depigmentation of skin of forehead. Report of the follow-up of 2 cases of leukodermia (vitiligo) following exposure to 4-MP described 8 years previously and survey of 169 men exposed to 4-MP or paratertiary-amyl-phenol or both revealed that repigmentation of a significant degree was found in one man and of a limited degree in the other. Screening by means of the Wood's light technique (an ultra-violet light which is absorbed by normally pigmented skin and reflected by non-pigmented skin) of the 169 men surveyed in the same plant revealed no cases of leukoderma attributed to exposure to 4-MP in 148 men tested or in the 129 men exposed to paratertiary-amyl-phenol. In regards to possible genotoxicity, results from cytogenetic analysis show that the salt of 4-MP (p-methoxyphenol phosphate) induced the decrease of numerical and structural chromosome aberration after the first passage of the treated cells. In terms of the results obtained by cytogenetic analysis the reduction of genetic instability seems to remain constant from the first to the sixth passage in the cell cultures treated with p-methoxyphenol phosphate associated to benzo(a)pyrene. ANIMAL STUDIES: Rabbit studies with 4-MP have shown that it can cause considerable necrosis if exposure is not limited to 1 day. Prolonged contact can cause a severe burn. There is also indication that the material is absorbed in toxic amounts when in solution, especially through abraded skin. Acute parenteral poisoning in rabbits included paralysis and anoxia at lower doses and CNS depression at high doses. 4-MP caused depigmentation of the skin when applied topically to guinea pigs (within 5 to 10 days of treatment) and miniature pigs. In a dermal teratology study in rabbits, there were no statistically significant differences in fetal malformation data; however marked hydrocephaly with visible doming of the head was observed in one mid-dose litter (12 and 0.06 mg/kg or 132 and 0.66 mg/sq m of 4-MP and tretinoin, respectively. 4-MP does not appear to be carcinogenic when applied topically. In studies with 5% or 10% 4-MP (0.02 mL) twice a week between the shoulder blades of mice (for 93 weeks) or interior ears of rabbits, there was no significant decrease in survival rates, or tumor incidence compared to controls. Tumors were evident when 4-MP was administered in the diet of F344 rats (30 male and 30 females) administered diets of 2% 4-MP for 104 weeks. Histopathological findings in the 4-MP case included atypical hyperplasias (male, 67%, female, 37%), papillomas (50%, 23%) and squamous-cell carcinomas (77%, 20%) in the forestomach. 4-MC induced forestomach papillomas (70%, 93%) and squamous-cell carcinomas (53%, 37%), also glandular stomach submucosal hyperplasias (90%, 93%), adenomas (100%, 100%) and adenocarcinomas (57%, 47%), with ulceration or erosion. No genotoxic effects were observed when 4-MP was tested in Salmonella typhimurium TA98, TA100, TA1535, and TA1537 or in rats exposed dermally for 6 months.

Redness. Burning sensation. Pain.

Redness. Pain.

irritation eyes, skin, nose, throat, upper respiratory system; eye, skin burns; central nervous system depression

EPA has released the first beta version (version 0.5) of the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The beta version of the iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays; Click on the "Chemical Explorer" button on the tool bar to see the data./[USEPA; ICSS Dashboard Application; Available from, as of December 8, 2014: http://actor.epa.gov/dashboard/]

4-Methoxyphenol was detected in one occurrence from wastewater from the pulp and paper industry(1). An unknown amount of 4-methoxyphenol was accidentally released into an unspecified river with p-nitrochlorobenzene causing extensive fish kills(2). 4-Methoxyphenol was detected in the particle emissions from a wood heater at concentrations of 0.38-3.04 mg/kg dry wood burned(3).

An experimental Koc of 55.7 was determined for adsorption to Brookston clay loam (pH 5.7, 8.8% organic content, 22.22 cation exchange capacity)(1). Using a Lucera-clay sample (0.5% organic carbon, 11 meq/100 g cation exchange capacity), a K value of 0.45 was measured(2) which corresponds to a Koc value of 90(3). According to a classification scheme(4), these Koc values suggest that 4-methoxyphenol is expected to have high mobility in soil(SRC).

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. Effective date: 3/11/94; Reporting date: 5/10/94.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Methoxyphenol is included on this list. Effective date 3/11/94; Sunset date: 6/30/98.

D - Dermatologicals

QD - Dermatologicals

Mequinol is in fact considered a melanocytotoxic chemical which when oxidized in melanocytes results in the formation of toxic entities like quinones. Such cytotoxic compounds subsequently have the potential to damage and destroy pigment cells, therefore causing skin depigmentation. In response, skin cells are naturally capable of protecting themselves against such cytotoxic agents with the help of endogenous intracellular glutathione and the detoxification action of glutathione S-transferase on the cytotoxic compounds. Regardless, it is consequently by way of this seemingly negative and damaging pharmacodynamic profile by which the mechanism of action of mequinol is sometimes described.

Solar lentigines and related hyperpigmented lesions are localized, pigmented, macular lesions of the skin, usually on the areas of the body which have been chronically exposed to sunlight. These lesions are characterized by increased numbers of active melanocytes and increased melanin production. Although the mechanism of action of mequinol is not fully elucidated, when employed as an active ingredient in combination with other agents like tretinoin in skin depigmentation products, a synergy between a number of potential mechanisms is proposed. Firstly, mequinol is in fact considered a melanocytotoxic chemical which when oxidized in melanocytes results in the formation of toxic compounds like quinones. Such cytotoxic agents are subsequently capable of damaging and destroying pigment cells, which results in skin depigmentation of solar lentigines or other related hyperpigmented lesions. Nevertheless, skin cells are naturally capable of protecting themselves against such cytotoxic entities by endogenous intracellular glutathione (GSH). This protection is elicited through the enzymatic action of glutathione S-transferase (GST), which is responsible for the conjugation of agents toxic to glutathione. Conversely, tretinoin has been observed to serve as a potent inhibitor of mammalian GSTs and to be capable of reducing the level of intracellular GSH in various cells. As a result, the combination of mequinol with tretinoin seemingly allows for a synergistic enhancement of a melanocytotoxic effect that involves the inhibition and impairment of GSH and GST cytoprotection. Secondly, even though mequinol is a substrate for the enzyme tyrosinase and therefore acts as a competitive inhibitor of the formation of melanin precursors by way of tyrosinase facilitated reactions, the clinical significance of this action is unknown.

We examined changes in the levels of chaperone proteins to evaluate the toxic effects of environmental chemicals in human cells in vitro. Some chaperones are up-regulated by estrogenic chemicals, but the effect is not necessarily dependent on the receptor. Thus we also investigated whether a chemical-induced change in chaperone protein expression is human estrogen receptor (hER)-dependent or not, using cultured human cell lines transfected with hERalpha cDNA or an empty vector. In the hERalpha-expressed cells, the protein levels of the heat shock protein 27 (HSP27), the glucose-regulated protein 78 (GRP78/BiP), and GRP94 increased after exposure to beta-estradiol (E(2)) (from 10(-9)M to 10(-6)M) and bisphenol A (BPA) (from 10(-6)M to 10(-5)M). On the other hand, the increase was not observed in the cells without hERalpha expression. These results suggest that the E(2)- and BPA-induced increase in the protein levels were hERalpha dependent. We next examined the effect of four phenolic chemicals similar in structure to BPA, and found that among them, 4-methoxyphenol (from 10(-6)M to 10(-5)M) increased the levels of the chaperone proteins with hERalpha dependency. Thus the human cultured cells would be suitable for evaluating whether an increase in chaperone proteins occurs upon exposure to environmental chemicals and whether the effect is ER-dependent.

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.

Mequinol, the monomethyl ether of hydroquinone, is a substrate for the enzyme tyrosinase and acts as a competitive inhibitor of the formation of melanin precursors. The precise mechanism of action of mequinol is not known. /Solage/

Urine samples from melanoma patients treated with mequinol were analyzed and various mequinol metabolites were identified, including 3,4-dihydroxyanisole, the two o-methyl derivatives 3-hydroxy-4-methoxyanisole and 4-hydroxy-3-methoxyanisole, and even hydroquinone which may have originated at least partly from mequinol. All these identified metabolites were excreted predominantly as sulphates and glucuronides - only a small portion of the substances were present in urine in an unconjugated form. Ultimately, the 3,4-dihydroxyanisole is considered the most important metabolite of mequinol.

A tyrosinase-directed therapeutic approach for treating malignant melanoma uses depigmenting phenolic prodrugs such as 4-hydroxyanisole (4-HA) for oxidation by melanoma tyrosinase to form cytotoxic o-quinones. However, in a recent clinical trial, both renal and hepatic toxicity were reported as side effects of 4-HA therapy. In the following, 4-HA (200 mg/kg i.p.) administered to mice caused a 7-fold increase in plasma transaminase toxicity, an indication of liver toxicity. Furthermore, 4-HA induced-cytotoxicity toward isolated hepatocytes was preceded by glutathione (GSH) depletion, which was prevented by cytochrome p450 inhibitors that also partly prevented cytotoxicity. The 4-HA metabolite formed by NADPH/microsomes and GSH was identified as a hydroquinone mono-glutathione conjugate. GSH-depleted hepatocytes were much more prone to cytotoxicity induced by 4-HA or its reactive metabolite hydroquinone (HQ). Dicumarol (an NAD(P)H/quinone oxidoreductase inhibitor) also potentiated 4-HA- or HQ-induced toxicity whereas sorbitol, an NADH-generating nutrient, prevented the cytotoxicity. Ethylenediamine (an o-quinone trap) did not prevent 4-HA-induced cytotoxicity, which suggests that the cytotoxicity was not caused by o-quinone as a result of 4-HA ring hydroxylation. Deferoxamine and the antioxidant pyrogallol/4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL) did not prevent 4-HA-induced cytotoxicity, therefore excluding oxidative stress as a cytotoxic mechanism for 4-HA. A negligible amount of formaldehyde was formed when 4-HA was incubated with rat microsomal/NADPH. These results suggest that the 4-HA cytotoxic mechanism involves alkylation of cellular proteins by 4-HA epoxide or p-quinone rather than involving oxidative stress.

Many of the well-known depigmenting agents such as hydroquinone and 4-hydroxyanisole are, in fact, melanocytotoxic chemicals which are oxidized in melanocytes to produce highly toxic compounds such as quinones. These cytotoxic compounds are responsible for the destruction of pigment cells, which results in skin depigmentation. However, cells are capable of protecting themselves against cytotoxic agents by intracellular glutathione (GSH). This protection takes place under the enzymatic action of the detoxification enzyme glutathione S-transferase (GST), which is responsible for the conjugation of toxic species to GSH. The depigmenting effect of hydroquinone is shown to be potentiated by buthionine sulfoximine (BSO) and cystamine as the result of the reduction of intracellular levels of GSH by these two agents. Additionally, BSO and cystamine are shown to inhibit the activity of GST. The combination of all-trans-retinoic acid (tretinoin, TRA) with hydroquinone or 4-hydroxyanisole is also known to produce synergetic skin depigmentation. TRA serves as a potent inhibitor of mammalian GSTs and is known to make cells more susceptible to the cytotoxic effect of chemicals by inhibiting the activity of this enzyme. This agent is also shown to reduce the level of intracellular GSH in certain cells. We have proposed that the mechanism of action of TRA to synergistically enhance the melanocytotoxic effect of chemicals involves the inhibition of GST and the impairment of glutathione-dependent cytoprotection against melanocytotoxic agents.

Yields 1,4-dimethoxybenzene in guinea pig, rat, rabbit, mouse. Yields 4-methoxycatechol, p-methoxyphenyl-beta-d-glucuronide, & p-methoxyphenyl sulfate in rabbit. /From Table/

4-Methoxyphenol has known human metabolites that include (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-(4-methoxyphenoxy)oxane-2-carboxylic acid.

6HT8U7K3AM

MEQUINOL

Physiologic Effects [PE] - Depigmenting Activity

Mechanisms of Action [MoA] - Melanin Synthesis Inhibitors

Established Pharmacologic Class [EPC] - Skin Lightening Agent

Mequinol is a Skin Lightening Agent. The mechanism of action of mequinol is as a Melanin Synthesis Inhibitor. The physiologic effect of mequinol is by means of Depigmenting Activity.

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Naturally occurring or synthetic substances that inhibit or retard oxidation reactions. They counteract the damaging effects of oxidation in animal tissues.

The systemic exposure to mequinol was assessed in eight healthy subjects following two weeks of twice-daily topical treatment of a tretinoin and mequinol combination product. About dose of the product corresponding to about 37.3 ug/cm^2 of mequinol was applied to the subjects' backs. The mean Cmax for mequinol was 9.92 ng/mL (range between 4.22 and 23.62 ng/mL) and the Tmax was 2 hours (range between 1 to 2 hours). The safety of mequinol in this combination formulation is supported by the low systemic exposures of the agent in the subjects.

Mequinol is predominantly renally eliminated as its metabolites.

The volume of distribution is one that suggests mequinol is distributed throughout the total body water, and intracellular concentrations are not expected to vary greatly from gross measurements.

Readily accessible data regarding the clearance of mequinol is not available. The use of mequinol containing products is typically indicated for topical use.

Solage is a combination product composed of 2% mequinol (4-hydroxyanisole) and 0.01% tretinoin (all-trans-retinoic acid) in an ethanolic solution ... The purpose of this study was to evaluate the extent of percutaneous absorption of [(3)H]tretinoin and to estimate the systemic exposure to mequinol from this combination product when topically applied to the backs of healthy subjects. Eight subjects received bid /twice per day/ topical applications of nonradiolabelled 2% mequinol/0.01% tretinoin solution on a 400 sq cm area of the back for 14 days. The subjects then received a single topical application of 2% mequinol/0.01% ((3)H)tretinoin solution. After 12 hr, the radiolabelled dose was removed and bid /twice per day/ treatment with nonradiolabelled 2% mequinol/0.01% tretinoin solution was continued for 7 days. Plasma, urine and faecal samples were analysed for total radioactivity and plasma was analysed for both mequinol and tretinoin by GC/MS procedure. Mean percutaneous absorption of [(3)H]tretinoin based on the cumulative recoveries of radioactivity in the urine and faeces was about 4.5% (median 2.18%). Tretinoin concentrations in plasma did not increase above endogenous levels. This was consistent with the concentrations of radioactivity in plasma, which showed an average Cmax of 91 pg-eq/mL (median 26 ng/mL). Average Cmax and AUC(0-12 hr) values for mequinol were 10 ng/mL and 33 ng h/mL, respectively. Based on the results of this study, systemic toxicity from topical application of tretinoin in this formulation is unlikely, because percutaneous absorption of tretinoin is minimal and because endogenous levels of tretinoin are not increased following bid /twice per day/ dosing with this combination formulation. The safety of mequinol in this combination formulation is supported by the low systemic exposures of the subjects in this study compared with the systemic exposures at the highest doses in the dermal toxicity studies in mice (16.6-fold) and rats (34.6-fold).

In one study in healthy individuals, following topical application of 0.8 mL of the combination preparation containing mequinol 2% and tretinoin 0.01% on a 400-sq cm back skin area twice daily for 14 days, approximately 4.5% of a radiolabeled dose was recovered as tretinoin in urine and feces. In this study, plasma tretinoin concentrations did not increase above endogenous plasma concentrations and average peak plasma mequinol concentrations were about 10 ng/mL. /Solage/

CIR ingredient: p-Hydroxyanisole

Used as an inhibitor of acrylic monomers, a stabilizer of organic solvents, an ultraviolet inhibitor, and a chemical intermediate; [ACGIH]

Plastic Composites Manufacturing [Category: Industry]

4-Methoxyphenol is employed as an inhibitor for acrylic monomers, as a stabilizer for chlorinated hydrocarbons and ethyl cellulose, as an ultraviolet inhibitor, and as a chemical intermediate.

Manufacture of antioxidants, pharmaceuticals, plasticizers, dyestuffs; stabilizer for chlorinated hydrocarbons and ethyl cellulose; inhibitor for acrylic monomers and acrylonitriles, UV inhibitor.

Stabilizing agent in textile lubricating oils, chemical intermediate.

2023: 700,000 - <850,000 lb

(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS

(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS

Production volumes for non-confidential chemicals reported under the Inventory Update Rule. [Table#4893]

Phenol, 4-methoxy- is listed as a High Production Volume (HPV) chemical (65FR81686). Chemicals listed as HPV were produced in or imported into the U.S. in >1 million pounds in 1990 and/or 1994. The HPV list is based on the 1990 Inventory Update Rule. (IUR) (40 CFR part 710 subpart B; 51FR21438).

For more U.S. Production (Complete) data for 4-METHOXYPHENOL (6 total), please visit the HSDB record page.

Hydroquinone monomethyl ether

4-Hydroxyanisole; p-Hydroxyanisole; 4-Methoxyphenol; p-Methoxyphenol; Phenol, p-methoxy-

IFRA_STD_153.pdf

40

IFRA 51st Amendment - Guidance for the use of IFRA Standards

Prohibition: This material should not be used as a fragrance ingredient

REACTION OF HYDROQUINONE WITH DIMETHYL ETHER OVER A MIXTURE OF SILICA AND ALUMINA AT 250-300 C

Hydroquinone and dimethyl sulphate (methylation).

Miscellaneous Manufacturing

Phenol, 4-methoxy-: ACTIVE

Derivatives: Acid Brown 20; t-butylhydroxyanisole; difenoxuron.

The anti-oxidant BHA is prepared from 4-methoxyphenol and t-butyl alcohol.

Inert pesticide ingredient, Approved for Nonfood Use Only