Why are many skin depigmenting agents toxic to the body?

Why are many skin depigmenting agents toxic to the body?

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Coming from a developing country, I know many people who regularly use these creams to lighten their skin and some of them have developed liver and kidney problems as a result.

I know that many contain hydroquinone which is said to cause cancer and mercury which can cause neurological issues. Are these the two main problematic skin lightening ingredients or are there any else?


It is estimated that more than 13 million workers in the United States are potentially exposed to chemicals that can be absorbed through the skin. Dermal exposure to hazardous agents can result in a variety of occupational diseases and disorders, including occupational skin diseases (OSD) and systemic toxicity. Historically, efforts to control workplace exposures to hazardous agents have focused on inhalation rather than skin exposures. As a result, assessment strategies and methods are well developed for evaluating inhalation exposures in the workplace standardized methods are currently lacking for measuring and assessing skin exposures.

NIOSH has developed a strategy for assigning multiple skin notations (SK) capable of delineating between the systemic, direct and immune-mediated effects caused by dermal contact with chemicals.

OSD are the second most common type of occupational disease and can occur in several different forms including:

  • Irritant contact dermatitis,
  • Allergic contact dermatitis,
  • Skin cancers,
  • Skin infections,
  • Skin injuries, and
  • Other miscellaneous skin diseases.

Contact dermatitis is one of the most common types of occupational illness, with estimated annual costs exceeding $1 billion.

Occupations at Risk

Workers at risk of potentially harmful exposures of the skin include, but are not limited to, those working in the following industries and sectors:

  • Food service
  • Cosmetology
  • Health care
  • Agriculture
  • Cleaning
  • Painting
  • Mechanics
  • Printing/lithography
  • Construction

Anatomy and Functions of the Skin

The skin is the body&rsquos largest organ, accounting for more than 10 percent of body mass. The skin provides a number of functions including:

  • protection,
  • water preservation,
  • shock absorption,
  • tactile sensation,
  • calorie reservation,
  • vitamin D synthesis,
  • temperature control, and
  • lubrication and waterproofing.

Skin Hazards

Causes of OSD include chemical agents, mechanical trauma, physical agents, and biological agents.

  • Chemical agents are the main cause of occupational skin diseases and disorders. These agents are divided into two types: primary irritants and sensitizers. Primary or direct irritants act directly on the skin though chemical reactions. Sensitizers may not cause immediate skin reactions, but repeated exposure can result in allergic reactions.
    • A worker&rsquos skin may be exposed to hazardous chemicals through:
      • direct contact with contaminated surfaces,
      • deposition of aerosols,
      • immersion, or
      • splashes.

      Dermal Absorption

      Dermal absorption is the transport of a chemical from the outer surface of the skin both into the skin and into the body. Studies show that absorption of chemicals through the skin can occur without being noticed by the worker, and in some cases, may represent the most significant exposure pathway. Many commonly used chemicals in the workplace could potentially result in systemic toxicity if they penetrate through the skin (i.e. pesticides, organic solvents). These chemicals enter the blood stream and cause health problems away from the site of entry.

      The rate of dermal absorption depends largely on the outer layer of the skin called the stratum corneum (SC). The SC serves an important barrier function by keeping molecules from passing into and out of the skin, thus protecting the lower layers of skin. The extent of absorption is dependent on the following factors:

      • Skin integrity (damaged vs. intact)
      • Location of exposure (thickness and water content of stratum corneum skin temperature)
      • Physical and chemical properties of the hazardous substance
      • Concentration of a chemical on the skin surface
      • Duration of exposure
      • The surface area of skin exposed to a hazardous substance

      Research has revealed that skin absorption occurs via diffusion, the process whereby molecules spread from areas of high concentration to areas of low concentration. Three mechanisms by which chemicals diffuse into the skin have been proposed:

      1. Intercellular lipid pathway (Figure 1)
      2. Transcellular permeation (Figure 2)
      3. Through the appendages (Figure 3)

      Figure 1: Intercellular lipid pathway

      As shown in Figure 1, the stratum corneum consists of cells known as corneocytes. The spaces between the corneocytes are filled with substances such as fats, oils, or waxes known as lipids. Some chemicals can penetrate through these lipid-filled intercellular spaces through diffusion.

      Figure 2: Transcellular permeation

      As shown in Figure 2, another pathway for chemicals to be absorbed into and through the skin is transcellular, or cell-to-cell, permeation whereby molecules diffuse directly through the corneocytes.

      Figure 3: Through the appendages (hair follicles, glands)

      As shown in Figure 3, the third pathway for diffusion of chemicals into and through the skin is skin appendages (i.e., hair follicles and glands). This pathway is usually insignificant because the surface area of the appendages is very small compared to the total skin area. However, very slowly permeating chemicals may employ this pathway during the initial stage of absorption.

      Contact Dermatitis

      Contact dermatitis, also called eczema, is defined as an inflammation of the skin resulting from exposure to a hazardous agent. It is the most common form of reported OSD, and represents an overwhelming burden for workers in developed nations. Epidemiological data indicate that contact dermatitis constitutes approximately 90-95% of all cases of OSD in the United States. Common symptoms of dermatitis include:

      Nanoparticles in skin care: The risks may trump the rewards

      Nanotechnology is one of mankind's biggest hopes for technological progress in the 21-st century. It promises to revolutionize manufacturing, materials science, computers, medical devices and much more. Skin care is among the fields where nanotechnology is being enthusiastically introduced.

      While scientific progress should generally be welcomed in all industries, introduction of nanotechnology in skin care and cosmetics may require a special degree of caution. Notably, skin care is not regulated by the FDA, partly because skin care products are topical and their systemic effects tend to be small, if any. Hence the FDA does not consider the health risks of skin care to be significant enough to bother to regulate it. This may be sensible considering the FDA's limited budget and its many other responsibilities. However, nanotechnology, particularly nanoparticles, may throw such logic to the wind.

      Let me explain. When skin care formulas are applied to the skin, each ingredient usually ends up following one of three scenarios (or a combination thereof):

        It stays on the surface of the skin without penetrating it. Eventually it is washed off.

      The situation with nanoparticles is potentially quite different. First, a few details. Nanoparticles are exceedingly small clumps/crystals of some substance with size ranging from 1 to 100 nanometers. For reference, one nanometer (one thousandth of a millimeter) is about the width of human DNA whereas 75,000 nanometers is the width of an average human hair. The ultra-small size of nanoparticles has two important consequences.

      First, many chemicals behave differently when packaged into nanoparticles. For example, normally inert substances, when turned into nanoparticles, can trigger potentially harmful chemical reactions. An imperfect but well known analogy is asbestos: inert silica is harmless in its common forms but hazardous when converted into asbestos crystals.

      Second, many experts believe that some nanoparticles might be able to penetrate the skin and enter systemic circulation under certain conditions. What's worse, commonly used nanoparticles do not dissolve in either water or oil, and, once absorbed, are very difficult for the body to eliminate, which may dramatically increase their long-term risks.

      In view of the above, an ingredient proven safe in ordinary form, may still be hazarous in nanoparticles. A case in point is a recent study of the effects of titanium dioxide nanoparticles in mice. (Titanium dioxide is a popular sun-blocking and makeup ingredient whose ordinary formulations are non-toxic.) A team researchers from UCLA led by Dr Schiestl found that mice exposed to titanium dioxide nanoparticles via drinking water started showing genetic damage within five days. The researchers reported that titanium dioxide nanoparticles induced single- and double-strand DNA breaks and also caused chromosomal damage as well as inflammation, all of which increase the risk for cancer.

      Dr Schiestl believes that titanium dioxide nanoparticles do not penetrate intact skin and, therefore, should probably be safe in sunscreen lotions while posing risk in sunscreen sprays (due to inadvertent inhalation). However, very little research has been done on the ability of nanoparticles to penetrate human skin in real-life use. The risk of penetration may be greater than commonly thought for a number of reasons. First, nanoparticle range in size from from 1 to 100 nm. The smallest ones may penetrate much more easily than the larger ones. Penetration may be affected by the condition of the skin, including inflammation, lesions, dryness, recent exfoliation, concurrently used products, mechanical stress (e.g. rubbing or scratching) and numerous other factors. Until the penetration of a wide variety of nanoparticles under a variety of real-life conditions has been studied, it is premature to rule out the risks of their topical use. Also, even if only a small fraction of topically applied nanoparticles penetrate the skin, they may pose disproportionately high risk due to their ability to accumulate in the body over time.

      So far, only titanium dioxide nanoparticles consumed orally were shown to produce genetic damage. The question of the risks posed by other common types of nanoparticles (e.g. zinc oxide nanoparticles) remains open. It is also unclear whether and under what conditions topical use of nanoparticles might be hazardous. In my view, considering the uncertainly and nascent state of research in this area, it may be prudent to avoid all skin care products with nanoparticles until more studies are available to better estimate the long-term risks.

      Bottom line

      There is evidence that a normally inert and non-toxic skin care ingredient, titanium dioxide, may produce genetic damage if it enters the body in the form of nanoparticles. Other common substances may pose similar risks when converted to nanoparticles. Some experts believe that nanoparticles do not penetrate into the body when applied topically. However, there is not enough data to rule out some penetration, especially of smaller nanoparticles under predisposing conditions. Considering potential risk of the nanoparticle accumulation in the body, it would be prudent to avoid skin care products with nanoparticles until more studies are available to better estimate the long-term risks.

      METHANOL : Systemic Agent

      De Paula PP, Santos E, De Freitas FT, De Andrade JB [1999]. Determination of methanol and ethanol by gas chromatography following air sampling onto florisil cartridges and their concentrations at urban sites in the three largest cities in Brazil. Talanta 49(2):245-252.

      Leibrock E, Slemr J [1997]. Method for measurement of volatile oxygenated hydrocarbons in ambient air. Atmos Environ 31(20):3329-3339.

      Marley NA, Gaffney JS [1998]. A comparison of flame ionization and ozone chemiluminescence for the determination of atmospheric hydrocarbons. Atmos Environ 32(8):1435-1444.

      NIOSH [1994]. NMAM Method 2000 Methanol. In: NIOSH Manual of analytical methods. 4th ed. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication 94-113.

      OSHA [1980]. Methyl Alcohol Method 91. Salt Lake City, UT. U.S. Department of Labor, Organic Methods Evaluation Branch, OSHA Salt Lake Technical Center.

      Qin T, Xu X, Polak T, Pacakova V, Stulik K, Jech L [1997]. A simple method for the trace determination of methanol, ethanol, acetone, and pentane in human breath and in the ambient air by preconcentration on solid sorbents followed by gas chromatography. Talanta 44(9):1683-1690.

      Reichert J, Coerdt W, Ache HJ [1993]. Development of a surface acoustic wave sensor array for the detection of methanol in fuel vapours. Sens Actuators B: Chem 13(1-3):293-296.

      Tyras H [1989]. Spectrophotometric determination of methyl alcohol in the atmosphere. Z Gesamte Hyg 35(2):96-97.

      Martinezsegura G, Rivera MI, Garcia LA [1985]. Methanol analysis by gas-chromatography&ndashcomparative-study using 3 different columns. J Agric Univ Puerto Rico 69(2):135-144.

      Pettersson J, Roeraade J [2003]. Quantitative accuracy in the gas chromatographic analysis of solvent mixtures. J Chromatogr A 985(1-2):21-27.

      Wilson LA, Ding JH, Woods AE [1991]. Gas-chromatographic determination and pattern-recognition analysis of methanol and fusel oil concentrations in whiskeys. J
      Assoc Off Anal Chem 74(2):248-256.


      • TIME COURSE: Adverse health effects from methanol poisoning may not become apparent until after an asymptomatic period of 1 to 72 hours.
      • EFFECTS OF SHORT-TERM (LESS THAN 8-HOURS) EXPOSURE: Methanol&rsquos toxicity is due to its metabolic products. The by-products of methanol metabolism cause an accumulation of acid in the blood (metabolic acidosis), blindness, and death. Initial adverse health effects due to methanol poisoning include drowsiness, a reduced level of consciousness (CNS depression), confusion, headache, dizziness, and the inability to coordinate muscle movement (ataxia). Other adverse health effects may include nausea, vomiting (emesis), and heart and respiratory (cardiopulmonary) failure. Prognosis is poor in patient/victims with coma or seizure and severe metabolic acidosis (pH <7). Early on after methanol exposure, there may be a relative absence of adverse health effects. This does not imply insignificant toxicity. Methanol toxicity worsens as the degree of metabolic acidosis increases, and thus, becomes more severe as the time between exposure and treatment increases.
        • Irritation, redness, and pain.
        • Ingestion of methanol may cause a wide range of adverse health effects:
          • Neurological: headache, dizziness, agitation, acute mania, amnesia, decreased level of consciousness including coma, and seizure.
          • Gastrointestinal: Nausea, vomiting, lack of an appetite (anorexia), severe abdominal pain, gastrointestinal bleeding (hemorrhage), diarrhea, liver function abnormalities, and inflammation of the pancreas (pancreatitis).
          • Ophthalmologic: visual disturbances, blurred vision, sensitivity to light (photophobia), visual hallucinations (misty vision, skin over the eyes, snowstorm, dancing spots, flashes), partial to total loss of vision, and rarely eye pain. Visual examination may reveal abnormal findings. Fixed dilated pupils are a sign of severe exposure to methanol.
          • Other: Electrolyte imbalances. Kidney failure, blood in the urine (hematuria), and muscle death at the cellular level (rhabdomyolysis) have been reported in severe poisonings. Fatal cases often present with fast heart rate (tachycardia) or slow heart rate (bradycardia) and an increased rate of respiration. Low blood pressure (hypotension) and respiratory arrest occur when death is imminent.
          • See Ingestion Exposure.
          • Irritation.
          • See Ingestion Exposure.


          • INTRODUCTION: The purpose of decontamination is to make an individual and/or their equipment safe by physically removing toxic substances quickly and effectively. Care should be taken during decontamination, because absorbed agent can be released from clothing and skin as a gas. Your Incident Commander will provide you with decontaminants specific for the agent released or the agent believed to have been released.
          • DECONTAMINATION CORRIDOR: The following are recommendations to protect the first responders from the release area:
            • Position the decontamination corridor upwind and uphill of the hot zone. The warm zone should include two decontamination corridors. One decontamination corridor is used to enter the warm zone and the other for exiting the warm zone into the cold zone. The decontamination zone for exiting should be upwind and uphill from the zone used to enter.
            • Decontamination area workers should wear appropriate PPE. See the PPE section of this card for detailed information.
            • A solution of detergent and water (which should have a pH value of at least 8 but should not exceed a pH value of 10.5) should be available for use in decontamination procedures. Soft brushes should be available to remove contamination from the PPE. Labeled, durable 6-mil polyethylene bags should be available for disposal of contaminated PPE.
            • Decontamination of First Responder:
              • Begin washing PPE of the first responder using soap and water solution and a soft brush. Always move in a downward motion (from head to toe). Make sure to get into all areas, especially folds in the clothing. Wash and rinse (using cold or warm water) until the contaminant is thoroughly removed.
              • Remove PPE by rolling downward (from head to toe) and avoid pulling PPE off over the head. Remove the SCBA after other PPE has been removed.
              • Place all PPE in labeled durable 6-mil polyethylene bags.
              • Remove the patient/victim from the contaminated area and into the decontamination corridor.
              • Remove all clothing (at least down to their undergarments) and place the clothing in a labeled durable 6-mil polyethylene bag.
              • Thoroughly wash and rinse (using cold or warm water) the contaminated skin of the patient/victim using a soap and water solution. Be careful not to break the patient/victim&rsquos skin during the decontamination process, and cover all open wounds.
              • Cover the patient/victim to prevent shock and loss of body heat.
              • Move the patient/victim to an area where emergency medical treatment can be provided.

              First Aid

              • GENERAL INFORMATION: Initial treatment is primarily supportive of respiratory and cardiovascular function. The goal of treatment is to either prevent the conversion of methanol to toxic metabolites or to rapidly remove the toxic metabolites and correct metabolic and fluid abnormalities.
              • ANTIDOTE: Fomepizole and ethanol are effective antidotes against methanol toxicity. Fomepizole or ethanol should be administered as soon as possible once the patient/victim has been admitted to a medical care facility. See Long Term Implications: Medical Treatment for further instruction.
              • EYE:
                • Immediately remove the patient/victim from the source of exposure.
                • Immediately wash eyes with large amounts of tepid water for at least 15 minutes.
                • Seek medical attention immediately.
                • Immediately remove the patient/victim from the source of exposure.
                • Ensure that the patient/victim has an unobstructed airway.
                • Do not induce vomiting (emesis).
                • Seek medical attention immediately.
                • Immediately remove the patient/victim from the source of exposure.
                • Evaluate respiratory function and pulse.
                • Ensure that the patient/victim has an unobstructed airway.
                • If shortness of breath occurs or breathing is difficult (dyspnea), administer oxygen.
                • Assist ventilation as required. Always use a barrier or bag-valve-mask device.
                • If breathing has ceased (apnea), provide artificial respiration.
                • Seek medical attention immediately.
                • Immediately remove the patient/victim from the source of exposure.
                • See the Decontamination section for patient/victim decontamination procedures.
                • Seek medical attention immediately.

                Long-Term Implications

                • MEDICAL TREATMENT: Antidotes fomepizole or ethanol should be administered intravenously as soon as possible to block the conversion of methanol to formic acid and prevent acidosis. Fomepizole is preferred as its efficacy and safety have been demonstrated, and its therapeutic dose is more easily maintained. Once the patient/victim has become acidotic, administration of fomepizole or ethanol may not provide much benefit, but they may be administered at the discretion of the physician in charge. Hemodialysis is the most effective form of treatment for an acidotic patient/victim. Folinic acid (leucovorin) should also be administered intravenously to increase the rate at which formate is metabolized into less toxic chemicals.
                • DELAYED EFFECTS OF EXPOSURE: The most common permanent adverse health effects following severe methanol poisoning are damage to or death of the nerve leading from the eye to the brain (optic neuropathy or atrophy), resulting in blindness disease caused by damage to a particular region of the brain, resulting in difficulty walking and moving properly (Parkinsonism) damage to the brain caused by exposure to toxins, resulting in abnormal thought (encephalopathy) and damage to the peripheral nervous system.
                • EFFECTS OF CHRONIC OR REPEATED EXPOSURE: Methanol is not suspected to be a carcinogen. Chronic or repeated exposure to methanol is suspected to be a developmental toxicity risk. It is unknown whether chronic or repeated exposure to methanol is a reproductive toxicity risk. Methanol may cause birth defects of the central nervous system in humans. Chronic poisoning from repeated exposure to methanol vapor may produce inflammation of the eye (conjunctivitis), recurrent headaches, giddiness, insomnia, stomach disturbances, and visual failure. The most noted health consequences of longer-term exposure to lower levels of methanol are a broad range of effects on the eye. Inflammatory changes and irritation of the skin (dermatitis), occurs with chronic or repeated exposure to methanol.

                On-Site Fatalities

                • INCIDENT SITE:
                  • Consult with the Incident Commander regarding the agent dispersed, dissemination method, level of PPE required, location, geographic complications (if any), and the approximate number of remains.
                  • Coordinate responsibilities and prepare to enter the scene as part of the evaluation team along with the FBI HazMat Technician, local law enforcement evidence technician, and other relevant personnel.
                  • Begin tracking remains using waterproof tags.
                  • Wear PPE until all remains are deemed free of contamination.
                  • Establish a preliminary (holding) morgue.
                  • Gather evidence, and place it in a clearly labeled impervious container. Hand any evidence over to the FBI.
                  • Remove and tag personal effects.
                  • Perform a thorough external evaluation and a preliminary identification check.
                  • See the Decontamination section for decontamination procedures.
                  • Decontaminate remains before they are removed from the incident site.

                  Occupational Exposure Limits

                  • NIOSH REL:
                    • STEL (skin): 250 ppm (325 mg/m 3 )
                    • TWA (skin): 200 ppm (260 mg/m 3 )
                    • TWA (8-hour): 200 ppm (260 mg/m 3 )
                    • STEL (skin): 250 ppm
                    • TLV (skin): 200 ppm
                    • TEEL-0: 250 mg/m 3
                    • TEEL-1: 694 mg/m 3
                    • TEEL-2: 2,750 mg/m 3
                    • TEEL-3: 9,300 mg/m 3
                    • ERPG-1: 200 ppm
                    • ERPG-2: 1,000 ppm
                    • ERPG-3: 5,000 ppm

                    Acute Exposure Guidelines [Interim]

                    10 min 30 min 60 min 4 hr 8 hr
                    AEGL 1
                    (discomfort, non-disabling) &ndash ppm
                    670 ppm 670 ppm 530 ppm 340 ppm 270 ppm
                    AEGL 2
                    (irreversible or other serious, long-lasting effects or impaired ability to escape) &ndash ppm
                    11,000 ppm* 4,000 ppm 2,100 ppm 730 ppm 520 ppm
                    AEGL 3
                    (life-threatening effects or death) &ndash ppm
                    ** 14,000 ppm* 7,200 ppm* 2,400 ppm 1,600 ppm

                    Lower Explosion Limit (LEL) = 55,000 ppm
                    * = > 10% LEL ** = > 50% LEL
                    AEGL 3 &ndash 10 min = ** 40,000 ppm
                    For values denoted as * safety consideration against the hazard(s) of explosion(s) must be taken into account
                    For values denoted as ** extreme safey considerations against the hazard(s) of explosion(s) must be taken into account
                    Level of Distinct Order Awareness (LOA) = 8.9 ppm

                    IMPORTANT NOTE: Interim AEGLs are established following review and consideration by the National Advisory Committee for AEGLs (NAC/AEGL) of public comments on Proposed AEGLs. Interim AEGLs are available for use by organizations while awaiting NRC/NAS peer review and publication of Final AEGLs. Changes to Interim values and Technical Support Documents may occur prior to publication of Final AEGL values. In some cases, revised Interim values may be posted on this Web site, but the revised Interim Technical Support Document for the chemical may be subject to change. (Further information is available through AEGL Process external icon ).

                    Decontamination (Environment and Equipment)

                    • ENVIRONMENT/SPILLAGE DISPOSAL: The following methods can be used to decontaminate the environment/spillage disposal:
                      • Do not touch or walk through the spilled agent if at all possible. However, if you must, personnel should wear the appropriate PPE during environmental decontamination. See the PPE section of this card for detailed information.
                      • Keep combustibles (e.g., wood, paper, and oil) away from the spilled agent. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact the spilled agent.
                      • Do not direct water at the spill or the source of the leak.
                      • Stop the leak if it is possible to do so without risk to personnel, and turn leaking containers so that gas rather than liquid escapes.
                      • Prevent entry into waterways, sewers, basements, or confined areas.
                      • Isolate the area until gas has dispersed.
                      • Ventilate the area.
                      • Not established/determined

                      Agent Properties

                      • Chemical Formula:
                      • Aqueous solubility:
                      • Boiling Point:
                        148.5°F (64.7°C)
                      • Density:
                        Liquid: 0.79 g/cm 3 at 68°F/39°F (20°C/4°C)
                        Vapor: 1.11 (air = 1)
                      • Flammability:
                        Highly flammable
                      • Flashpoint:
                        54°F (12°C)
                      • Ionization potential:
                        10.84 eV
                      • Log Kbenzene-water:
                        Not established/determined
                      • Log Kow (estimated):
                      • Melting Point:
                        -144°F (-97.8°C)
                      • Molecular Mass:
                      • Soluble In:
                        Miscible with most organic solvents.
                      • Specific Gravity:
                      • Vapor Pressure:
                        96 mm Hg at 68°F (20°C)
                        127 mm Hg at 77°F (25°C)
                      • Volatility:
                        Not established/determined

                      Hazardous Materials Warning Labels/Placards

                      • Shipping Name:
                      • Identification Number:
                        1230 (Guide 131)
                      • Hazardous Class or Division:
                      • Subsidiary Hazardous Class or Division:
                      • Label:
                        Flammable Liquid
                        Poison (Toxic)
                      • Placard Image:

                      Trade Names and Other Synonyms

                      • Alcohol, methyl
                      • Alcool methylique (French)
                      • Alcool metilico (Italian)
                      • Bieleski&rsquos solution
                      • Coat-B1400
                      • Colonial spirit(s)
                      • Columbian spirit(s)
                      • Eureka Products Criosine Disinfectant
                      • Eureka Products, Criosine
                      • Freers Elm Arrester
                      • Ideal Concentrated Wood Preservative
                      • Metanol (Spanish)
                      • Metanolo (Italian)
                      • Methyl hydrate
                      • Methyl hydroxide
                      • Methylalkohol (German)
                      • Methylol
                      • Metylowy alkohol (Polish)
                      • Monohydroxymethane
                      • Pyroligneous spirit
                      • Pyroxylic spirit(s)
                      • Surflo-B17
                      • Wilbur-Ellis Smut-Guard
                      • Wood naphtha
                      • Wood spirit
                      • X-Cide 402 Industrial Bactericide

                      Who to Contact in an Emergency

                      In the event of a poison emergency, call the poison center immediately at 1-800-222-1222. If the person who is poisoned cannot wake up, has a hard time breathing, or has convulsions, call 911 emergency services.

                      For information on who to contact in an emergency, see the CDC website at or call the CDC public response hotline at (888) 246-2675 (English), (888) 246-2857 (Español), or (866) 874-2646 (TTY).

                      Important Notice

                      The user should verify compliance of the cards with the relevant STATE or TERRITORY legislation before use. NIOSH, CDC 2003.

                      The controversy surrounding absorption of oral glutathione and adverse effects of IV glutathione and statutory status

                      Glutathione-based oral dietary supplements have been accorded the status of “Generally Recognized as Safe (GRAS)” consistent with Section 201(s) of the Federal Food, Drug, and Cosmetic Act of the United States Food and Drug Administration (US-FDA) [16]. There is no restriction on its availability in this form in the US, Philippines and Japan. Oral GSH is also easily available over-the-counter (OTC) in India and many other Asian countries. Since oral GSH is known to have a low bioavailability in humans [9], manufacturers of IV injections of GSH “recommend” this route of administration to achieve desired therapeutic levels in the blood and skin rapidly to produce “instant” skin whitening results. However, as emphasized above, the literature evaluating the efficacy of IV GSH is still lacking. Furthermore, the duration of therapy and long-term efficacy is yet to be established. Despite the lack of evidence, manufacturers of IV GSH have been “recommending” a dose of 600� mg, to be injected weekly or twice a week, with no specified net duration of the therapy [8].

                      Although the overall safety of IV GSH, extrapolated from studies evaluating its use for male infertility and liver disorders seems to be convincing [18,19], several adverse effects of IV GSH have been documented in the Philippines ( Figure 2 ), detailed in the position paper by the FDA, Department of Health, Republic of the Philippines [5] with a warning for the public on the subject of the safety of the off-label use of glutathione solution for injection ( Figure 3 ). The reported adverse effects include adverse cutaneous eruptions including potentially fatal Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe abdominal pain, thyroid dysfunction, renal dysfunction, and lethal complications such as air embolism, or potentially fatal sepsis due to incorrect/unsterile method of IV administration and use of counterfeit GSH [5,9]. Apart from the lack of evidence favoring IV GSH for skin lightening, the extremely high cost of injection vials constitutes another compelling deterrent to its use. The important limitations of IV GSH have been enumerated in Figure 4 .

                      Adverse effects reported with intravenous glutathione injections by the Food and Drug Administration, Department of Health, Republic of the Philippines [5] and the intravenous GSH trial by Zubair et al. [15] [Copyright: � Sonthalia et al.]

                      Topical corticosteroids

                      Steroid creams used for bleaching skin colour

                      Topical corticosteroids lighten the skin by the following mechanisms.

                      • Initial blanching due to vasoconstriction
                      • Slowing down skin cell turnover so reducing the number and activity of melanocytes (pigment cells)
                      • Reducing production of precursor steroid hormones thus reducing production of melanocyte stimulating hormone ( MSH ).

                      In New Zealand and many other countries, stronger topical corticosteroids are regulated and can only be obtained with a doctor's prescription. Products containing betamethasone valerate, fluocinonide and clobetasol propionate can be purchased over the counter from a pharmacy or from drug vendors in a marketplace in other countries.

                      Potent topical steroids have a wide range of local side effects including skin thinning and atypical fungal infections (tinea incognita). When used over large areas for prolonged periods, they may risk serious internal disease from hypopituitarism. Steroid addiction syndrome results in folliculitis and steroid rosacea.

                      Steroid side effects after using bleaching cream

                      Depigmenting Effect of Kojic Acid Esters in Hyperpigmented B16F1 Melanoma Cells

                      The depigmenting effect of kojic acid esters synthesized by the esterification of kojic acid using Rhizomucor miehei immobilized lipase was investigated in B16F1 melanoma cells. The depigmenting effect of kojic acid and kojic acid esters was evaluated by the inhibitory effect of melanin formation and tyrosinase activity on alpha-stimulating hormone- (α-MSH-) induced melanin synthesis in B16F1 melanoma cells. The cellular tyrosinase inhibitory effect of kojic acid monooleate, kojic acid monolaurate, and kojic acid monopalmitate was found similar to kojic acid at nontoxic doses ranging from 1.95 to 62.5 μg/mL. However, kojic acid monopalmitate gave slightly higher inhibition to melanin formation compared to other inhibitors at doses ranging from 15.63 to 62.5 μg/mL. Kojic acid and kojic acid esters also show antioxidant activity that will enhance the depigmenting effect. The cytotoxicity of kojic acid esters in B16F1 melanoma cells was significantly lower than kojic acid at high doses, ranging from 125 and 500 μg/mL. Since kojic acid esters have lower cytotoxic effect than kojic acid, it is suggested that kojic acid esters can be used as alternatives for a safe skin whitening agent and potential depigmenting agents to treat hyperpigmentation.

                      1. Introduction

                      Melanin is synthesized via melanogenesis process to give pigment of skin, brain, eye, and hair [1–3]. Tyrosinase is a key enzyme that is responsible for melanogenesis in melanoma and melanocytes [4, 5]. The inhibition of tyrosinase will greatly affect the melanogenesis process and melanin production. The occurrence of abnormal melanin production is the cause for many hyperpigmentation, postinflammatory pigmentation, melasma, and skin-aging process [6–8]. Kojic acid is a well-known antityrosinase agent, efficiently used for skin lightening cosmetic products and widely used to treat hyperpigmentation, melasma, and wrinkle [5, 9–11]. However, most of the kojic acid and its derivatives are not oil soluble and unstable at high temperature for long term storage, prohibiting them to be directly incorporated in oil base cosmetic and skin-care products. Therefore, a few attempts had been made to improve the physical properties and biological activities of kojic acid (KA) via esterification with fatty acids aimed at better industrial application [12–14].

                      The physical properties of kojic acid esters (KA esters) are important factor for inhibition of melanin synthesis where it must penetrate into the cell membrane to inhibit cellular tyrosinase and melanin synthesis. Thus, appropriate hydrophobic and hydrophilic balance of the derivatives is important for the inhibition of melanin synthesis [15]. The improvements of the characteristics of depigmenting agents are very important to enhance their applications in cosmetic and skin-health industries. Reports on the antimelanin and tyrosinase inhibitory of KA esters in cell system are not available in the literature.

                      The objective of this study was to analyze the cytotoxicity and depigmenting activities of KA and KA esters such as KA monooleate (KAMO), KA monolaurate (KAML), and KA monopalmitate (KAMP) in B16F1 melanoma cells. KA was produced by the fermentation employing Aspergillus flavus link and KA esters were produced by the esterification of purified KA with various fatty acids using immobilized lipase.

                      2. Materials and Methods

                      2.1. Materials

                      Immobilized lipase from Rhizomucor miehei (RMIM) was purchased from Novo-Nordisk (Denmark). Dulbecco’s modified Eagle’s medium (DMEM), fetal bovine serum (FBS) penicillin, and streptomycin were purchased from Invitrogen (Grand Island, NY, USA). Glycerol tributyrate, L-dihydroxyphenylalanine (L-DOPA), L-tyrosine, mushroom tyrosinase, phenylmethanesulfonyl fluoride (PMSF), L-ascorbic acid, and alpha-melanocyte stimulating hormone (α-MSH) were purchased from Sigma-Aldrich (Steheim, UK). All other chemicals and solvents used in this study were the analytical grade.

                      2.2. Production of Kojic Acid

                      KA was produced through the fermentation by Aspergillus flavus link 44–1 according to the method as described by Mohamad and Ariff [16]. In this method, the fermentation medium consisted of glucose (100 g/L), yeast extract (5 g/L), potassium dihydrogen phosphate (1 g/L), magnesium sulphate (0.5 g/L), and methanol (10 mL/L). The fungal spores suspension (1 × 10 5 spores/mL) was inoculated into 100 mL medium in 250 mL shake-flasks. The flasks were incubated at 30°C and agitated at 250 rpm for 5 days. The mycelia were filtered, washed, and transferred into 200 mL medium containing 100 g/L glucose in 500 mL shake flasks. The flasks were incubated in an orbital shaker at 30°C and agitated at 250 rpm for 30 days for the conversion of glucose into KA by the actions of cell-bound enzymes in nongrowing mycelia.

                      Cell mycelia were separated from the broth by centrifugation at 10 000 g (GRX-250, Tomy Seiko Co., Ltd. Japan). The supernatant containing KA was concentrated to get a final KA concentration of above 80 g/L using rotary evaporator (BUCHI model R-220, Germany). The concentrated KA solution was kept at 30°C for 24 h for crystallization. The KA crystals were separated by centrifugation and redisolved in methanol for the subsequent crystallization process to remove further pigments and impurities. High-purity KA (99.8%) was obtained after recrystallization with methanol for three times.

                      2.3. Enzymatic Synthesis of Kojic Acid Esters

                      The esterification of KA to KA esters (KAMO, KAML, and KAMP) was performed according to the method previously described [12, 17]. The reaction mixture for esterification process consisted of fatty acids (oleic acid, lauric acid, and palmitic acid), KA, and immobilized lipase in acetonitrile. The flasks containing the reaction mixture were incubated in a horizontal water bath shaker at 50°C, agitated at 180 rpm for 42 h. The reaction was terminated, by removing the enzyme from the mixture through filtration using filter paper. KA esters were purified using crystallization method similar to that used for KA.

                      KA esters were examined by thin layer chromatography (TLC) on precoated silica gel plate (60F254) and developed in hexane/ethyl acetate (70 : 30, v/v). The developed bands were visualized using UV light. Then, the products were analyzed on Agilent gas chromatograph after being silylated to TMS derivatives using a nonpolar column ZB-5HT Inferno (15 m × 0.53 mm × 0.15 μm) with nitrogen as carrier gas. The oven temperature was programmed to rise from 100°C to 225°C at 15°C min −1 , and to 280°C at 30°C min −1 for 1 min. The injector and flame ionization detectors were set at 340°C, and 350°C respectively. The composition of product was quantified by an integrator with 1,2,3-tributyrylglycerol as internal standard.

                      2.4. Characterization of KA Esters

                      The GC-mass spectrometry (GC-MS) analysis of the product isolated using preparative column chromatography was performed on a Perkin Elmer Instrument model Clarus 600 MS spectrometer. The GC was equipped with a non-polar column, ZB-5HT (30 m × 0.32 mm × 0.25 μm). The carrier gas was helium at a flow rate of 1.5 mL min −1 . Proton NMR (1H-NMR) and carbon NMR (13C-NMR) spectra were obtained using Varian NMR Unity Inova 500 MHz with Pulsed Field Gradient. The samples were dissolved in deuterated chloroform with tetramethylsilane as internal standard. On the other hand, FTIR spectra were recorded on a Perkin Elmer 100-series FTIR spectrophotometer using Universal Attenuated Total Reflectance (UATR). The IR spectra were used to identify the possible molecular structures for the pure components and also used to determine the chemical changes during the reaction.

                      2.5. Cell Culture

                      B16F1 melanoma cells were purchased from American Type Culture Collection (ATCC). The cells were cultured in DMEM with 10% w/v fetal bovine serum and 1% w/v penicillin/streptomycin (100 IU/50 μg/mL) in humidified atmosphere containing 5% CO2 in air at 37°C. B16 cells were cultured in 96-well plates and 24-wells plates for different assays. All the experiments were repeated at least in triplicates.

                      2.6. Determination of Cell Viability

                      Cell viability was assessed by the standard MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay with a slight modification [18]. B16F1 melanoma cells (1 × 10 5 cells/well) were seeded in a 96-well microtiter plate and allowed to adhere completely to the plate overnight [19]. On the next day, the medium was removed and a new medium containing test compounds with doses ranging from 1.9 to 500 μg/mL was added to the plate and then incubated at 37°C in CO2 incubator. After a total of 72 h incubation, medium was removed and 50 μL of MTT solutions (1.0 mg/mL) was added to each well and the incubation was continued for 4 h. Then, formazon was solubilized in dimethyl sulfoxide (DMSO) and the absorbance was measured at 450 nm (reference at 630 nm) using MR-96A microplate reader. DMSO at a toxic concentration of 5% v/v was used as a negative control [20].

                      2.7. Determination of Melanin Content

                      The release of extra-cellular melanin was measured according to the method described elsewhere [21]. In brief, B16F1 melanoma cells were seeded into 24-wells tissue culture plates at 1 × 10 4 cells/mL and incubated for 24 h. Then, alpha-MSH (0.1 μM) was added and cells were treated with increasing doses of KA and KA esters for a total of 72 h incubation. After washing twice with phosphate buffered saline, cells were dissolved in 1 mL of 1 N NaOH. For measurement of melanin content, 100 μL aliquots of solution were then placed in 96-well plates and the absorbance was measured at 450 nm using microplate reader. Antimelanin activity was expressed by the percentage of melanin content in KA and KA esters to that of untreated melanoma cells. L-ascorbic acid, a widely used whitening agent, was used as a reference [22].

                      2.8. Determination of Cellular Tyrosinase Activity

                      Cellular tyrosinase activity was determined according to the method described by Shin et al. [23]. In this method, B16F1 melanoma cells were treated with α-MSH alone and α-MSH with the addition of KA and KA esters at various doses for a total of 72 h incubation. The cells were washed with ice-cold PBS then lysed with 100 μL phosphate buffer (pH 6.8) containing 1% Triton X-100 and 0.1 mM phenylmethylsulfonyl fluoride (PMSF). Then, lysate was clarified by centrifugation at 800 rpm for 5 min. The supernatant (100 μL) was added into 50 μL of L-DOPA (1 mM) and 50 uL of L-Tyrosine (2 mM) and the mixtures were placed in a 96-well plate. During the incubation at 37°C, the absorbance was read at 492 nm at every 30 min for 3 h using a microplate reader. L-ascorbic acid was used as a reference.

                      2.9. Determination of Mushroom Tyrosinase Activity

                      KA and KA esters at various doses were dissolved in DMSO, 50 μL of L-DOPA (1 mM) and 50 μL of L-tyrosine (2 mM), dissolved in 20 mM phosphate buffer (pH 6.8). DMSO or test sample (50 μL) was added into these mixtures in a 96-well microplate, followed by mixing with 50 μL of mushroom tyrosinase solution (480 units/mL). After incubation at 25°C for 10 min, the amount of dopachrome in the reaction mixture was determined. The inhibitory activity of the sample was expressed as percentage to control based on the absorbance measured at 492 nm [6].

                      2.10. Determination of Free Radical Scavenging Activity

                      The effect of KA and KA esters on the free radical scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) activities was estimated on a 96-well plate [18]. Test compounds (100 μL) dissolved in dimethyl sulfoxide solutions were added into 100 μL of 0.2 mM DPPH in ethanol. 100 μL of dimethyl sulfoxide solution alone was added into 100 μL of 0.2 mM DPPH in ethanol as blank. The plates were incubated at 25°C for 30 min and the absorbance was read at 492 nm. The percentage of antioxidative activity was calculated according to (1),

                      =  P e r c e n t a g e o f a n t i o x i d a t i v e a c t i v i t y a b s o r b a n c e o f c o n t r o l − a b s o r b a n c e o f t e s t c o m p o u n d

                       a b s o r b a n c e o f c o n t r o l × 1 0 0 . ( 1 )

                      DPPH is a stable free radical with violet colour. It turns to yellow in the presence of antioxidant and scavenging agents.

                      2.11. Statistical Analysis

                      Data were collected as mean ± standard error (S.E.M) of at least three determinations. Statistical analysis was performed using Microsoft Excel 2007 (Microsoft, WA, USA). The evaluation of statistical significance was performed by Student

                      was considered statistically significant,

                      3. Results

                      3.1. Production of Kojic Acid Esters

                      The maximum yield of KA esters synthesized by enzymatic esterification using immobilized lipase is shown in Table 1. The structure of KAMO has been identified and characterized in our previous study [12, 17]. The yield for KAMO, KAML, and KAMP was 32.86%, 34.89%, and 29.30%, respectively. The time taken to reach a maximum KAMO, KAML, and KAMP concentration was 42 h, 15 h, and 12 h, respectively. Meanwhile, KAML and KAMP were identified using GC-MS where the purified samples were fragmented to simple ions. The MS data for the esterification of KA and palmitic acid showed that ions at

                      141 and 365 arise from path a and b cleavage. The

                      363 is the expected rearrangement ion resulting path c cleavage with loss of OH (

                      480–17). The fragmentation at

                      255 and 125 confirm path d and e cleavage. The product of the esterification, KAMP, is shown at

                      380. Meanwhile, the MS data for the esterification of KA and lauric acid showed that ions at

                      141 and 309 arise from path a and b cleavage. The

                      307 is the expected rearrangement of ion resulting to path c cleavage with loss of OH (

                      480–17). The fragmentation at

                      199 and 125 confirm path d and e cleavage. The fragmentation at

                      197 is the expected ion from path f cleavage. The data for esterification reaction of KA also showed that ions at

                      142. The esterification product, KAML, is shown at

                      time of enzymatic esterification to achieve maximum concentration of KA esters.
                      Percentage yield was calculated using following equation:
                      Yield (%) = (

                      comp/mole of KA) × dilution factor × 100

                      comp: area for each component

                      IS: area for internal standard

                      IS: concentration for internal standard

                      Chemical structure of kojic acid (KA), kojic acid monoeolate (KAMO), kojic acid monopalmitate (KAMP) and kojic acid monolaurate (KAML).

                      The 1H-NMR spectrum of the KAMP and KAML gave 3-hydrogen triplet at

                      0.88, indicating a terminal methyl group. Two hydrogen methylene signals are observed at H3′–H15′ and H3′–H11′ of KAMP and KAML, respectively. The downfield methylene signal at

                      2.40 was due to the present of CH2 group, next to the ester linkage. The fatty acid chain was thus established to be present in the product. The KA portion of the molecule was confirmed by the presence of two singlet signals at δ 6.49 and δ 7.85 which were assigned to H-3 and H-6. H-7 gave a singlet signal at δ 4.93. The 13C-NMR spectrum gave a total carbon count for KAMP and KAML of 22 and 18, respectively. The C-1′ (ester group) peak appeared at 163. Very low field signals were observed at δ 172 and δ 173 which were due to C-2 and C-4 of the pyrone ring. The other carbon assignments are also shown in Table 2.

                      The product formation and reactant disappearance were monitored by IR spectroscopy. The infrared spectrum of the KAMP showed the stretching of CH2 and CH3 which gave absorption peaks at 2848 cm −1 and 2914 cm −1 , respectively. The C=O stretching for the expected ester carbonyl gave an absorption peak at 1695 cm −1 . The present of aromatic ring gave absorption at 1619 cm −1 . The CH2 and CH3 bends showed absorptions at 1458 cm −1 and 1290 cm −1 . Meanwhile, O=C–O stretching absorbed at 1109 cm −1 . On the other hand, the infrared spectrum of the KAML showed the stretching of CH2 and CH3 which gave absorption peaks at 2849 cm −1 and 2915 cm −1 , respectively. The C=O stretching for the expected ester carbonyl gave an absorption peak at 1693 cm −1 . The present of aromatic ring gave absorption at 1616 cm −1 . The CH2 and CH3 bends showed absorptions at 1427 cm −1 and 1292 cm −1 , respectively. Meanwhile, O=C–O stretching absorbed at 1138–11073 cm −1 .

                      3.2. Cytotoxicity Effect of KA and KA Esters

                      The results of cell viability assay using MTT in B16F1 melanoma cells are shown in Figure 2. There was no significant reduction of cell viability after incubation of pigmented B16F1 melanoma cells with KAMO, KAML, KAMP and KA at doses ranging from 7.81 μg/mL to 31.25 μg/mL. However, the number of viable cells was significantly reduced to below 60% at KA concentration of 125 μg/mL and 500 μg/mL. On the other hand, even at very high dosages of KAMO and KAMP ranging from 125 to 500 μg/mL, more than 90% of B16F1 melanoma cells were still viable. Meanwhile, it was also noted that the number of viable cells was significantly reduced at 5% of DMSO which was used as a negative control.

                      The effects of KAMO, KAML, KAMP, and KA on the viability of B16F1 melanoma cells. DMSO (5%) was used as a negative control. Cells were treated with various doses of KAMO, KAML, KAMP, and KA (7.81–500 μg/mL) for a total of 72 h incubation and were examined by MTT assay. Denotes *

                      compared to untreated control. Data are presented as means ± S.E.M and expressed as % of control,

                      3.3. Inhibitory Effect of KA and KA Esters on Melanin Content

                      The inhibitory effect of KA and KA esters on melanin formation in B16F1 melanoma cells treated with α-MSH is summarized in Figure 3. The inhibitory effect of KAMO, KAML, KAMP, and KA was evaluated at nontoxic doses ranging from 1.95 to 62.5 μg/mL. The melanin content was significantly reduced at KA and KA esters concentration ranging from 31.3 to 62.5 μg/mL. KA and KA esters showed similar melanin inhibitory effect at the lowest dose tested in this study (1.95 μg/mL). Even at the highest dose tested, KAML was found to have similar melanin inhibitory effect to KA. However, KAMP have slightly higher inhibitory effect than other compounds tested at doses ranging from 15.63 μg/mL to 62.5 μg/mL.

                      compared to α-MSH treated control. Data are presented as means ± S.E.M, and expressed as % of control. 31.25 μg/mL ascorbic acid was used as reference.

                      3.4. Inhibitory Effect of KA and KA Esters on Cellular and Mushroom Tyrosinase Activity

                      The inhibitory effect of KA and KA esters in B16F1 melanoma cells is summarized in Figure 4. The inhibitory effect of KA and KA esters was evaluated at nontoxic doses, ranging from 1.95 to 62.5 μg/mL. Incubation of pigmented melanoma B16F1 melanoma cells with KA and KA esters at doses ranging from 31.25 μg/mL to 62.5 μg/mL showed significant reduction in cellular tyrosinase activity. At very low doses of KA and KA esters, ranging from 1.95 to 15.25 μg/mL, only a slight reduction in cellular tyrosinase activity was observed. The inhibitory effect of KA and KA esters on cellular tyrosinase activity at doses ranging from 31.25 to 62.5 μg/mL was not significantly different. At the same dose (15.63 μg/mL), KAML and KAMP reduced cellular tyrosinase activity at a greater extent than KAMO.

                      The results of the inhibition of tyrosinase activity by KAMO, KAML, KAMP, and KA in B16F1 melanoma cells. Denotes *

                      compared to α-MSH treated control. Data are presented as means ± S.E.M, and expressed as % of control. 31.25 μg/mL ascorbic acid was used as reference.

                      Inhibitory effect of KA and KA esters on mushroom tyrosinase activity is illustrated in Figure 5. The inhibitory effect of KA and KA esters was evaluated at doses ranging from 3.91 to 250 μg/mL. In this study, mushroom tyrosinase inhibitory was found to be in dose-dependent manner. Among KA esters, KAMO significantly inhibited mushroom tyrosinase superior than KAML and KAMP. The inhibitory effect of mushroom tyrosinase activity of KAMO was not significantly different to KA at doses ranging from 62.5 to 250 μg/mL.

                      compared to α-MSH treated control. Data are presented as means ± S.E.M, and expressed as % of control. 62.5 μg/mL ascorbic acid was used as reference.

                      3.5. The Antioxidant Activity of KA and KA Esters

                      The correlation between antimelanogenic activity with oxidative properties of KA and KA esters was also investigated. KA and KA esters showed mild free radical scavenging activity at concentrations ranging from 1.95 to 1000 μg/mL (Table 3). 2,2-diphenyl-1-picrylhydrazyl (DPPH) generation was inhibited by KA and KA esters in dose dependent manner. Among them, KA and KAMO showed slightly better antioxidant activity at higher doses (1000 μg/mL) as compared to KAML and KAMP. L-ascorbic acid, a well-known antimelanogenic vitamin and antioxidant, exerted more scavenging activity than KA and KA esters at 62.5 μg/mL.

                      compared to untreated control. Data are presented as means ± S.E.M, and expressed as % of control,

                      4. Discussion

                      B16F1 melanoma cells is a widely used model to evaluate depigmentation activity with high level of tyrosinase and melanin content as compared to B16F10, due to high level of msg1 (melanocyte-specific gene) [22, 24, 28–33]. In melanogenesis, tyrosinase-related protein-2 and tyrosinase-related protein-1 catalyzes conversion of DOPachrome to DHICA and oxidation of DHICA, respectively, to form melanin [34]. In the presence of alpha-melanocyte stimulating hormone (α-MSH), and isobutylmethylxanthine (IBMX), B16 melanoma cells expressed great amount of tyrosinase and melanin synthesis [10, 31]. α-MSH binds to melanocortin receptor (MC1R), resulting in the activation of stimulatory GTP-binding protein (Gs), which in turn, stimulates adenylate cyclase to generate cAMP. cAMP increases melanin synthesis via activation of cAMP-dependent protein kinase (PKA) and microphthalmia-associated transcription factor (MITF), a melanocyte-specific transcription factor, leading to induction of tyrosinase expression [35–38]. Hyperpigmentation and melasma are the result from the accumulation of tyrosinase and melanin in cells. Therefore, the ability of KAMO, KAML, and KAMP to inhibit tyrosinase activity and melanin content in alpha-MSH induced B16F1 melanoma cells showed their potential as depigmenting agent and to treat hyperpigmentation in vitro.

                      Melanin synthesis can also be induced by the presence of free radicals and reactive species. Excessive explore of ultraviolet radiation, metal ions, free radicals, and reactive species have significantly stimulate transcription of tyrosinase gene and contribute to hyperpigmentation [4, 39]. The presence of metal ions, free radical, and reactive species caused oxidation in melanogenesis pathway that will result in high melanin synthesis [8]. Antioxidant such as vitamin C and multivitamin were known to scavenge free radicals and inhibit tyrosinase activity [40]. The stable DPPH free radicals are a commonly use model and technique to evaluate antioxidant activities. The effect of antioxidants on DPPH free radicals was due to their hydrogen donating ability. DPPH free radicals accept electron or hydrogen radicals to become stable diamagnetic molecules. The decrease in absorbance of DPPH radical caused by antioxidants, because of the reaction between antioxidant molecules and radical progresses, which results in the scavenging of the radical by hydrogen donation [41]. Therefore, the potency of hydroxyl group (OH) at C-7 of KA esters to stabilize free radicals and chelate metal ions [9] may help to reduce melanogenesis process and downregulate hyperpigmentation. In this study, KA esters synthesized using RMIM have slightly greater scavenging activity than other KA esters that were previously reported in the literature [14]. Tyrosinase is known as copper-containing enzyme, thus the capability of KA and KA esters to chelate metal ions may chelate cooper in tyrosinase, changing its three-dimensional conformation to inhibit its enzymatic activity [11].

                      The cytotoxicity of KA and KA esters was investigated in this study. It was previously suggested that inhibition of upregulated tyrosinase enzyme in melanoma cells might inhibit cell proliferation of melanoma cells [42, 43]. This is due to the correlation of microphthalmia-associated transcription factor (MITF) and extracellular signal-regulated kinase (ERK) in the pigmentation, proliferation, and survival of melanocytes and melanoma [23, 26, 35]. Due to this reason, it was expected that the inhibition of MITF expression may also inhibit melanoma cells proliferation. However, KA and KA esters were only known to inhibit melanogenesis by direct inhibition to tyrosinase and do not inhibit the expression of the transcription factor [5]. Therefore, the melanoma cells can still proliferate but the tyrosinase produced are not functional due to inhibition of KA and KA esters. In another study, α-melanocyte-stimulating hormone (MSH) decreased a critical mediator in the tumorigenesis (syndecan-2 expression), melanoma cell migration, and invasion in a melanin synthesis-independent manner [44]. Other depigmenting compound like hydroquinone, is a strong tyrosinase inhibitor with bleaching effect and exerted very high cytotoxicity at high concentrations [45]. Besides that, vitamin C and multivitamin showed satisfactory inhibitory effect in melanin content and tyrosinase activity at low concentrations, though it could be toxic at high concentrations [40]. KA was claimed to be nontoxic at doses below 100 μg/mL [18, 27, 46]. KA esters derived in this study have very low cytotoxicity, even at very high doses (up to 500 μg/L). In summary, results from this study indicated that KA and KA esters are potential depigmenting agents with low cytotoxicity for application in cosmetic and skin-care products.

                      5. Conclusion

                      KA esters derived from esterification of KA and palm oil based fatty acid have been demonstrated as a safe and nontoxic depigmenting agents with a satisfactory inhibitory effect on melanin formation and tyrosinase activity as determined on α-MSH induced B16F1 melanoma cells. Thus, it can be suggested that these depigmenting compounds have potential to be used in cosmetic formulations and to treat hyperpigmentation.


                      This paper was financially supported by CRDF-MTDC Grant from Malaysian Technology Development Corporation. A. F. B. Lajis is a postgraduate student funded by Graduate Research Fund (GRF) of Universiti Putra Malaysia and Mybrain15 from Ministry of Higher Education of Malaysia.


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                      Copyright © 2012 Ahmad Firdaus B. Lajis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                      The Dark Side of Skin Whitening

                      A desire for lighter skin tones is deeply entrenched in many parts of the world, but it comes with equally deep risks to health and society.

                      A 22-year-old call center agent from the Philippines, J.R.,* tells me that he takes whitening capsules and uses a soap and facial cream that both claim to have whitening effects. Being lighter, he says, will make him more “noticeable,” boosting his chances for promotion or better employment. When I point out that the US$1 a day he spends on the whitening products makes up a large chunk of the US$12 he earns daily, he replies: “It’s an investment.”

                      J .R. is part of the growing market for skin whitening products around the world. Shopping malls, cosmetics shops, and online retailers sell a vast number of different soaps, lotions, creams, and more, catering to women and men. Some of them target particular body parts: the face, the hands, the underarm, or even the vagina. From Manila to Mumbai and Jakarta to Johannesburg, celebrities endorse skin lightening or bleaching products in larger-than-life billboards, promising “whiter skin from within” or offering to make users “fair and handsome.” In the Philippines, where I live and work as a medical anthropologist, even the national basketball league has an official skin whitening product.

                      T his trend isn’t harmless. People who are already socially or financially marginalized may end up spending significant amounts of money on products they can ill afford. The whole notion of desiring paler skin relies upon and emphasizes toxic ideas of white superiority. And many skin whiteners are associated with proven skin damage or other health risks. Inorganic mercury, for example, described by the World Health Organization as a “common ingredient found in skin lightening soaps and creams” often used in Africa and Asia, can cause kidney damage. Hydroquinone, found in skin exfoliants, including J.R.’s facial lotion, has been flagged by regulatory agencies around the world due to safety concerns.

                      S ome countries, such as Ghana and Rwanda, have banned skin whitening products altogether . Yet whitening remains popular—and is big business. According to industry estimates , the global skin whitening industry is expected to reach US$31.2 billion by 2024.

                      A s both a physician and a medical anthropologist, I recently dove into this issue as part of the Chemical Youth Project : a multi-country study that looks at the roles of chemicals (from energy drinks to perfumes and vitamins) in the everyday lives of young people seeking to “boost pleasure, moods, sexual performance, appearance, and health.” From 2012 to 2015, our team, led by medical anthropologist Anita Hardon of the University of Amsterdam, interviewed over 400 young men and women in different parts of the Philippines—including students, young professionals, tour guides, pedicab drivers, and construction workers. Whitening products were very popular among our informants, with more than half reporting that they had used them at least once in their life. I decided to explore the topic more, carrying out 10 focus group discussions specifically about whitening. Where does the desire to whiten skin come from, I wanted to know, and is it changing?

                      (RE)THINK HUMAN

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                      T he idea of altering skin tone has been around since ancient times. In imperial Rome, people idealized “a pale, smooth complexion” and used various substances as skin whiteners—from lead shavings to crocodile dung—many of which were toxic or poisonous. In Medieval Japan, literary works like the Tale of Genji celebrated white beauty, and Japanese women and men applied various products—from rice powder to white lead—in pursuit of a skin tone that was “not milky white but translucent, like a polished stone.”

                      Fair skin has long been idealized in some folklore and art, as in this Japanese woodcut of the Tale of Genji story. Library of Congress/Flickr

                      I n these and other cultures, whiteness signified purity, beauty, and high status. American anthropologist Nina Jablonski writes that “untanned skin was a symbol of the privileged class that was spared from outdoor labor. … Dark-skinned people were deprecated because they were of the laboring class that worked out in the sun.” While this explanation is plausible, it probably doesn’t explain the trend in its entirety the extent to which, and the reasons why, skin whiteness has been valued has varied across place and time.

                      A rguably, it was during the height of colonialism and the rise of “scientific racism” (the pseudoscientific idea that empirical evidence supports notions of racial superiority and inferiority) from the 18th to the 19th century that white skin became even more desired. Whiteness came to signify not just personal privilege but also belonging to a privileged group dark(er) skin, meanwhile, was linked to racial inferiority and slavery. Whether in apartheid South Africa, the segregationist U.S., or the U.S. colonial Philippines (where Americans called Filipinos “little brown brothers”), whiteness, in the words of critical race scholar and law professor Cheryl Harris , “became the quintessential property for personhood.”

                      T he desire for tanned skin among white-skinned people might seem like a contradictory, opposite trend. But it is not. Tanning has its own complicated history , linked in part to the ability of richer Europeans and Americans to vacation in sunnier climates, and to early 20th-century notions of the health benefits of ultraviolet light. Importantly, the desire for a temporary color change as a signifier of health or prosperity is fundamentally different than the more deeply ingrained quest for more permanent alteration. While ads for whitening often have racist undertones, those for tanning do not deprecate “whiteness” or celebrate “brownness” or “blackness.”

                      This ad campaign for a skin lightening product incorporates positive messaging about diversity while still promoting whitening. Gideon Lasco

                      T oday, over a century after the zenith of scientific racism, the aesthetic standard of “lighter is better” has persisted, particularly in the “global south.” L. Ayu Saraswati, a scholar of Indonesian society, calls the modern trend a search for “cosmopolitan whiteness”—a fairness of skin that opens the door to international social mobility. “Colorism,” as sociologist Margaret Hunter calls it , “privileges light-skinned people of color over dark in areas such as income, education, housing, and the marriage market.” The Chilean anthropologist Alexander Lipschütz described this situation as a “pigmentocracy .”

                      T he value of paler skin—both perceived and real—has been documented in various ways around the world. In a 2006 study , economist Arthur Goldsmith and colleagues found that across several U.S. cities “mean hourly wages … rise as skin tone lightens, moving from US$11.72 for dark-skinned blacks to US$13.23 for blacks with medium skin shade” to US$14.72 for “light-skinned blacks” and US$15.94 for the “average white respondent.” Based on her research in Brazil, anthropologist Kia Caldwell describes in her 2006 book how the phrase boa aparência (good appearance) in job requirements was often a code for women with lighter skin and served as an exclusionary criteria for Afro-Brazilian women, many of whom no longer bothered to apply for such jobs.

                      A ll of this meshes with the views of the people I spoke to in the Philippines. They often used the word “investment” in explaining their skin whitening practices and saw whiteness as an enabler of better opportunities. Troy, for example, a 19-year-old engineering student, noted that one particular classmate’s white skin seemed to give him an advantage. “Three of us were in the same on-the-job training in a factory,” he told me. “We came from the same class, but my friend, he’s the first to get noticed because he had a different skin tone. He’s always the first to get called … and that’s because he has lighter skin.” Troy told me that he uses a whitening soap made of papaya and an umbrella against sunlight. When he plays basketball, he only plays in indoor courts: a preference shared by many of his peers.

                      Similarly, Laarni, a 20-year-old tourism student in Puerto Princesa, the Philippines, credited her lighter skin for her recent victory in a local beauty pageant and hopes it will be the ticket to her dream job of flight attendant. “Of course, [to be a flight attendant] you need to meet the height requirement and a college degree,” she said. “But when they look at you and you have fair, beautiful skin, you already have a big advantage.”

                      T he perceived attractiveness of whiter skin carries a strong appeal. In a qualitative survey in Tanzania by psychologist Kelly Lewis and colleagues, a 40-year-old teacher offers a simple reason for lightening her skin: “I use skin bleaching creams to avoid my husband from being attracted by other girls. … After my marriage, I intended to maintain my beauty to make my husband proceed loving me.” In a 2017 study of Nepali men , Matthew Maycock describes how the word tājā (fresh) is evolving to describe whiter skin as part of a new form of desirable masculinity.

                      M y own informants in the Philippines also saw fairer skin as adding to their physical attractiveness, but the men were shy about their skin whitening practices. Unlike the Nepali men, they perceived caring too much for their skin as “unmanly.” One of my interviewees recalled his college dormmates discreetly applying whitening lotions in the common shower room late at night when no one was watching.

                      Skin whitening products are commonly sold in stores in the Philippines. Gideon Lasco

                      O thers were openly proud of their whitening achievements, not just of themselves but also of their family members. A pediatric surgeon in Manila told me about the relatively affluent parents of a 1-year-old baby who came to his clinic and greeted him with this question: “Look doctor, don’t you notice how whiter our baby is?” It turned out that the baby underwent an infusion of intravenous glutathione so that he would look “cuter” and more “presentable.” This sort of treatment is now spreading in the U.S., costing US$150–400 dollars per session—and raising questions in both countries as to its safety and efficacy.

                      S till others I met used whitening products but claimed they were not for the whiteness per se but for cleanliness or smoothness. Others said they were striving for “normal” or “natural” skin. Fraink White, a video blogger, was similarly quoted in an article in The Guardian as saying : “Just because I lighten my skin, does not mean I want to be white. I still look African American by my features I’m not trying to change that. I just want to return my skin to the color and texture of the skin usually covered by clothing, which is less exposed to the sun. That’s my natural color.” These explanations gloss over the fact that people implicitly consider whiter, paler skin to be cleaner, smoother, and more “natural,” speaking to how the desire for whiteness itself has become naturalized.

                      W hen I asked Jenna, a 24-year-old mall worker from Puerto Princesa, about the possibility that many of the products she uses don’t actually work, she said that there’s “nothing to lose” in trying them anyway. But, of course, this is not true. Aside from the economic costs and health risks related to these products, the market for them implicitly preaches the virtues of whiteness, adding another layer of inequality for people whose gender, class, or ethnicity already places them in a position of marginality.

                      F ortunately, globalization is also spreading ideas and sensibilities that interrogate the value of whiteness. As Euan, one of my informants who now works in Dubai, told me: “Whitening creams are a product of colonial mentality, which is why I’m against them.” Curiously, nationalist pride and globalized liberation come together in these views. I n a widely shared blog post , DePaul University student and black rights activist Charlene Haparimwi wrote: “I’m starting to see myself and people with my dark skin tone in makeup ads, on the runway, in commercials, in beauty campaigns, and more. … My black is beautiful. … I am an African Queen, a dark-skinned goddess, a melanin princess.”

                      P erhaps an increasing awareness of internalized ideas about whiteness and their origins in the history of racism, combined with the modern push against discrimination based on skin color, will increase acceptance of all skin tones around the world.

                      But there is a long way to go to overturn this long-running chromatic hierarchy and to change ideas that run so deep many people aren’t even conscious of holding them. While I was doing a focus group discussion among students at an elite private university in Manila, one of them showed his tan lines. “I just went surfing last weekend,” he proudly explained. His sunscreen, it turned out, also had a whitening effect—a feature he claimed not to know about. “I don’t care really about my skin color,” he insisted. “But,” he added later, “I also don’t want to be too dark.”

                      * All names of interviewees have been changed to protect people’s privacy.

                      This popular preservative is an extremely toxic skin irritant that can cause headaches, dangerously low blood pressure, and even heart failure. Sadly, its toxicity and ready availability in labs have made it a method of suicide for researchers ( Another word of caution: don’t pour sodium azide down the sink where it can react with copper and lead pipes, forming highly explosive substances!

                      Disturbingly, it’s better to be splashed in the eye with concentrated acid than sodium hydroxide. Acids precipitate proteins, which form a protective “scab” over unharmed tissue, but strong bases like sodium hydroxide saponify fatty acids and destroy cell membranes. The “scab” never forms, so the base can just keep burning its way through. Wear your goggles!


                      The most important thing before beginning any treatment plan is to find the cause of imbalance. Once the root cause has been identified individualized naturopathic care can follow which addresses an individual’s unique needs.

                      • Colon support: colonics, fibre and hydrotherapy
                      • Skin support: sweating, dry skin brushing, rebounding and poultices.
                      • Lung support: steam inhalations, deep breathing and poultices over the lungs.
                      • Urinary support: Can be achieved with increased hydration, acupuncture and teas.
                      • Avoidance: Avoid exposure to all known toxins. Chemical, environmental, alcohol, tobacco can all unnecessarily add toxins to the system.
                      • Nutrition: Eating a whole foods diet can help decrease toxin exposure to the system. Avoid processed foods which contain unnecessary toxins. Also, eating a diet which is more alkalizing in nature can help decrease acid production in the system, decrease toxin load in the body.
                      • Exercise: is essential for adequate elimination. Sweating, lymphatic movement and increased metabolism all facilitate toxin removal.
                      • Rest: relaxation and adequate sleep are essential for proper organ function which is necessary for adequate removal of toxins.

                      Talk to your Naturopathic Doctor about which personalized toxin elimination plan would be best for you. Laboratory tests can be run to determine exactly which toxin is burdening your system, followed by an individualized plan to aid elimination.