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HYDROQUINONE-QUINONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hydroquinone is 1,4-bihydroxybenzene or p-hydroxyphenol compound. It is a strong reducing agent and is easily oxidized to form quinone. Quinone, also called p-benzoquinone, is the dione of cyclohexadiene.

Specific Substances

    A) HYDROQUINONE
    1) 1,4-benzenediol
    2) 1,4-dihydroxy-benzeen (Dutch)
    3) 1,4-dihydroxy-benzol (German)
    4) 1,4-dihydroxybenzen (Czech)
    5) 1,4-dihydroxybenzene
    6) 1,4-diidrobenzene (Italian)
    7) 4-hydroxyphenol
    8) alpha-hydroquinone
    9) Arctuvin
    10) Benzene, p-dihydroxy-
    11) Benzohydroquinone
    12) Benzoquinol
    13) beta-quinol
    14) Black and white bleaching cream
    15) DIAK 5
    16) Dihydroxybenzene
    17) Dihydroxybenzene (OSHA)
    18) Eldopaque
    19) Eldoquin
    20) HE 5
    21) Hydrochinon (Czech, Polish)
    22) Hydrochinone
    23) Hydroquinol
    24) Hydroquinole
    25) Idrochinone (Italian)
    26) p-benzenediol
    27) p-dihydroxybenzene
    28) p-dioxobenzene
    29) p-dioxybenzene
    30) p-hydroquinone
    31) p-hydroxyphenol
    32) Phiaquin
    33) Pyrogentistic acid
    34) Quinol
    35) Tecquinol
    36) Tenox HQ
    37) Tequinol
    38) CAS 123-31-9
    QUINONE
    1) 1,4-benzoquine
    2) 1,4-benzoquinone
    3) 1,4-cyclohexadiene dioxide
    4) 1,4-cyclohexadienedione
    5) 1,4-diossibenzene (Italian)
    6) 1,4-dioxy-benzol (German)
    7) 1,4-dioxybenzene
    8) 2,5-cyclohexadiene-1,4-dione
    9) Benzo-chinon (German)
    10) Benzoquinone
    11) Chinon (Dutch, German)
    12) Chinone
    13) Cyclohexadienedione
    14) p-benzoquinone (OSHA)
    15) p-quinone
    16) Steara PBQ
    17) CAS 106-51-4

    1.2.1) MOLECULAR FORMULA
    1) C6-H6-O2 (Hydroquinone) C6-H4-O2 (Quinone)

Available Forms Sources

    A) FORMS
    1) Hydroquinone is available as 2% and 4% cream, 3% solution, 4% emulsion, and 4% gel/jelly (Prod Info ALERA(TM) topical emulsion, 2006; Prod Info ACLARO(R) emulsion, 2005; Prod Info EPIQUIN(TM) MICRO topical cream, 2003; Prod Info SOLAQUIN FORTE(R) cream, gel, 1998).
    2) Hydroquinone 4% is available in combination with fluocinolone acetonide 0.01%, and tretinoin 0.05% as topical cream (Prod Info TRI-LUMA(R) topical cream, 2013).
    B) SOURCES
    1) Some herbal health teas made from leaves of plants such as bearberry, blueberry, whortleberry, and cranberry may contain sufficient hydroquinone derivatives so that ingestion of large quantities may cause hydroquinone toxicity (Deichmann & Keplinger, 1981).
    2) Hydroquinone occurs naturally in Xanthium pungens (Noogoora burr) in Africa and Australia, at concentrations high enough to poison pigs and cattle (HSDB , 1999).
    3) Quinone occurs in cigarette smoke and in several arthropods (HSDB , 1999).
    C) USES
    1) MEDICINAL
    a) Hydroquinone emulsion is indicated for the gradual treatment of ultraviolet-induced dyschromia and skin discoloration caused by the use of oral contraceptives, hormone replacement therapy, skin trauma, or pregnancy (Prod Info ACLARO(R) emulsion, 2005)
    b) Hydroquinone cream and gel formulations (with or without sunblock or sunscreens) are indicated for lightening hyperpigmented areas of the skin associated with chloasma, melasma, freckles, senile lentigines, and other forms of melanin hyperpigmentation (Prod Info ELDOQUIN FORTE(R) cream, 1998; Prod Info SOLAQUIN FORTE(R) cream, gel, 1998; Prod Info ELDOPAQUE FORTE(R) cream, 1998).
    c) Fluocinolone acetonide 0.01%/hydroquinone 4%/tretinoin 0.05% cream is indicated for short-term (ie, up to 8 weeks) treatment of moderate to severe melasma of the face when used in conjunction with sun avoidance measures, including sunscreens (Prod Info TRI-LUMA(R) topical cream, 2013).
    d) HERBAL: UVA URSI: Uva Ursi, an inhibitor of melanin synthesis, is extracted from the dried leaves of the bearberry plant. It has been used to treat or prevent cystitis. It is prepared as a tea by extraction of 3 grams of leaf in 150 mL of hot water. Approximately 100 to 220 mg of arbutoside is ingested with each dose. Uva ursi contains arbutin; hydroquinone is formed following the cleavage and conjugation of arbutin (Wang & Del Priore, 2004).
    e) Hydroquinone is used as an active ingredient in skin lightening creams and soaps (EPA, 1985; IPCS, 1994) .
    1) Of 41 different British brands analyzed, 8 contained more than 2% hydroquinone (Boyle & Kennedy, 1986).
    2) INDUSTRIAL
    a) Hydroquinone and quinone are used as photographic reducers and developers, antioxidants, stabilizer in paints, oils, and motor fuels, an antioxidant in fats and oils, and as a chemical intermediate and reagent, and dipigmentators (HSDB , 1999; EPA, 1985; IPCS, 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: MEDICINAL: Hydroquinone is used in topical skin lightening preparations. Topical hydroquinone is also available in combination with fluocinolone acetonide and tretinoin to treat moderate to severe melasma of the face. INDUSTRIAL: Hydroquinone and quinone are used as photographic reducers and developers, antioxidants, stabilizer in paints, oils, and motor fuels, an antioxidant in fats and oils, and as a chemical intermediate and reagent.
    B) PHARMACOLOGY: Hydroquinone is a strong reducing agent and is easily oxidized to form quinone. Hydroquinone inhibits the enzymatic oxidation of tyrosine to 3-(3,4-dihydroxyphenyl) alanine (dopa) and suppresses metabolic processes of melanocytes, thus producing depigmentation of the skin which is reversible.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) DERMAL: Localized contact dermatitis, pruritus, dry skin, burning, desquamation, erythema, brown or orange-brown nail discoloration, paradoxical ochronosis-like hyperpigmentation of the skin, and hypersensitivity reactions.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: ORAL EXPOSURE: Nausea, vomiting, headache, dizziness, delirium, tinnitus, green or brownish urine, elevated liver enzymes, muscle twitching, and dyspnea. DERMAL EXPOSURE: Skin irritation, allergic contact dermatitis, and hypomelanosis of the skin. OCULAR EXPOSURE: Eye irritation, corneal ulceration, and keratitis.
    2) SEVERE TOXICITY: ORAL EXPOSURE: Seizures, metabolic acidosis, cyanosis, methemoglobinemia, albuminuria, hematuria, liver damage, marked cachexia, respiratory failure, coma, and cardiovascular collapse.
    0.2.20) REPRODUCTIVE
    A) Hydroquinone and Fluocinolone acetonide/hydroquinone/tretinoin combination are classified as US Food and Drug Administration (FDA) pregnancy category C. Safety has not been established for the use of topical hydroquinone in pregnant women. Exposure to hydroquinone produced skeletal malformations in animal studies. In rat studies, maternal toxic effects from exposure to hydroquinone included changes in the ovaries, fallopian tubes, and menstrual cycle. Post-implantation mortality was also observed in rat studies.
    B) Observed paternal toxic effects from exposure to hydroquinone included changes in the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowper's gland, accessory glands, and male fertility index.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia.
    F) Monitor pulse oximetry or arterial blood gases and obtain a chest x-ray in any patient with respiratory symptoms.
    G) A urine screen which detects hydroquinone is indicative of exposure. Hydroquinone is not found naturally in the body. Green or brown-green colored urine may be found in patients with hydroquinone exposure.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with benzodiazepines; add barbiturates or propofol, if seizures persist. Treat symptomatic methemoglobinemia with methylene blue.
    C) DECONTAMINATION
    1) PREHOSPITAL: Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds. SKIN: Wash with soap and water. OCULAR: Immediately flush eye with water for at least 15 minutes.
    2) HOSPITAL: Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds. Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is able to maintain airway. OCULAR: Immediately flush eye with water for at least 15 minutes.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe respiratory symptoms, upper airway injury, CNS depression or persistent seizures.
    E) ANTIDOTE
    1) None.
    F) METHEMOGLOBINEMIA
    1) Initiate oxygen therapy. Treat with methylene blue if patient is symptomatic (usually at methemoglobin concentrations greater than 20% to 30% or at lower concentrations in patients with anemia, underlying pulmonary or cardiovascular disease). METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    G) ENHANCED ELIMINATION
    1) Hemodialysis has not been shown to be of value in the removal of these compounds.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for observation until they are clearly improving and clinically stable. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with worsening symptoms or severe systemic symptoms should be admitted to the hospital for further evaluation.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    I) PITFALLS
    1) Missing an ingestion of another chemical or other possible etiologies for a patient’s symptoms. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Hydroquinone readily penetrates the skin. It is metabolized to quinone and partially excreted as hydroquinone, quinone, and conjugates of hexuronic, sulfuric and other acids.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other irritants that can cause respiratory irritation or other drug substances that can cause methemoglobinemia.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: Ingestions of hydroquinone up to 500 mg/day for 5 months produced no symptoms. Ingestion of 1 gram of hydroquinone by an adult has caused symptoms, and death has occurred in adults ingesting 3 to 12 grams.

Clinical Effects

Summary Of Exposure

    A) USES: MEDICINAL: Hydroquinone is used in topical skin lightening preparations. Topical hydroquinone is also available in combination with fluocinolone acetonide and tretinoin to treat moderate to severe melasma of the face. INDUSTRIAL: Hydroquinone and quinone are used as photographic reducers and developers, antioxidants, stabilizer in paints, oils, and motor fuels, an antioxidant in fats and oils, and as a chemical intermediate and reagent.
    B) PHARMACOLOGY: Hydroquinone is a strong reducing agent and is easily oxidized to form quinone. Hydroquinone inhibits the enzymatic oxidation of tyrosine to 3-(3,4-dihydroxyphenyl) alanine (dopa) and suppresses metabolic processes of melanocytes, thus producing depigmentation of the skin which is reversible.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) DERMAL: Localized contact dermatitis, pruritus, dry skin, burning, desquamation, erythema, brown or orange-brown nail discoloration, paradoxical ochronosis-like hyperpigmentation of the skin, and hypersensitivity reactions.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: ORAL EXPOSURE: Nausea, vomiting, headache, dizziness, delirium, tinnitus, green or brownish urine, elevated liver enzymes, muscle twitching, and dyspnea. DERMAL EXPOSURE: Skin irritation, allergic contact dermatitis, and hypomelanosis of the skin. OCULAR EXPOSURE: Eye irritation, corneal ulceration, and keratitis.
    2) SEVERE TOXICITY: ORAL EXPOSURE: Seizures, metabolic acidosis, cyanosis, methemoglobinemia, albuminuria, hematuria, liver damage, marked cachexia, respiratory failure, coma, and cardiovascular collapse.

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) RED HAIR: Workers exposed chronically to these compounds may develop a reddish discoloration of the hair (Arndt & Fitzpatrick, 1965).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) IRRITATION: Both hydroquinone and quinone are known to cause eye irritation with chronic (greater than 5 years) dust or vapor exposure (Deichmann & Keplinger, 1981).
    2) CORNEAL ULCERATION: Corneal ulceration has occurred with accidental eye contamination with hydroquinone particles (Sterner et al, 1947). Acute exposure to high concentrations of hydroquinone vapor may cause irritation, photophobia, lacrimation, corneal epithelium injury, and corneal ulceration without discoloration of the eye (Grant, 1993).
    3) KERATITIS: Discoloration of the conjunctiva and corneal changes (alteration of the curvature) have been reported (Anderson, 1947; Hathaway et al, 1996; HSDB , 1999).
    4) CORNEA: Quinone may injure the conjunctiva causing deposition of pigment (diffuse brown or brown-black globules) in the cornea. All layers of the cornea are involved. Corneal alterations may occur even after the pigment disappears. Discontinuing exposure to hydroquinones may slowly decrease the amount of staining, but the corneal opacities and lost vision may not resolve (Anderson & Olgesby, 1958).
    5) CORNEAL OPACITY: Workers exposed chronically to hydroquinone have developed corneal discoloration, hypesthesia, astigmatism, flattening, and irregularity (Grant, 1993).
    6) BULL'S-EYE MACULOPATHY: After ingesting uva ursi tea for 3 years as a prophylaxis against recurrent urinary tract infection, a 56-year-old woman developed a bull's-eye maculopathy, paracentral scotomas with a decrease in sensitivity, reduction in electroretinography (ERG) amplitude, and retinal thinning on optical coherence tomography. Uva ursi is prepared as a tea by extraction of 3 grams of leaf in 150 mL of hot water. Approximately 100 mg to 220 mg of arbutoside is ingested with each dose. Arbutin is metabolized to hydroquinones, which inhibit melanin synthesis. The authors suspected the maculopathy in this patient resulted from inhibition of melanin synthesis (Wang & Del Priore, 2004).
    3.4.4) EARS
    A) WITH POISONING/EXPOSURE
    1) TINNITUS: Tinnitus has been observed in hydroquinone poisoning (Clayton & Clayton, 1993; Hathaway et al, 1996).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Cyanosis may occur (Deichmann & Keplinger, 1981; Plunkett, 1976; Sittig, 1991).
    B) CARDIOVASCULAR FINDING
    1) WITH POISONING/EXPOSURE
    a) Cardiovascular collapse was reported (Deichmann & Keplinger, 1981).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) Bronchopneumonia has been reported (HSDB , 1999; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; Plunkett, 1976).
    B) INJURY DUE TO ASPHYXIATION
    1) WITH POISONING/EXPOSURE
    a) Quinone has caused asphyxia and pulmonary damage (HSDB , 1999; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; Plunkett, 1976).
    C) APNEA
    1) WITH POISONING/EXPOSURE
    a) Ingestion has caused dyspnea, anoxia, respiratory failure, cyanosis, and death (HSDB , 1999; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; Plunkett, 1976).
    D) CYANOSIS
    1) WITH POISONING/EXPOSURE
    a) Dyspnea and cyanosis may occur with hydroquinone poisoning (HSDB , 1999; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; Plunkett, 1976).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported (HSDB , 1999; Hathaway et al, 1996; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; NIOSH, 1978; Plunkett, 1976).
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness has been reported following hydroquinone exposure (HSDB , 1999; Hathaway et al, 1996; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; NIOSH, 1978; Plunkett, 1976).
    C) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) Delirium has been reported following hydroquinone exposure (HSDB , 1999; Hathaway et al, 1996; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; NIOSH, 1978; Plunkett, 1976).
    D) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Both quinone and hydroquinone may cause seizures (HSDB , 1999; Hathaway et al, 1996; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; NIOSH, 1978; Plunkett, 1976).
    b) CASE REPORT: A 19-month-old boy (weight: 14.5 kg) developed tremors, left gaze deviation, and tonic-clonic seizures within 15 minutes of drinking an unknown amount of a skin-lightening lotion from a 500-mL bottle containing hydroquinone 2%. On presentation, he had seizures and a respiratory rate of 80 breaths/min. He required endotracheal intubation and received 2.5 mg diazepam, 0.1 mg/kg lorazepam, fosphenytoin 20 phenytoin equivalents/kg, another 1.5 mg lorazepam and phenobarbital 20 mg/kg IV before seizures were controlled. Laboratory results revealed metabolic acidosis and mild transaminitis. Following supportive care, his symptoms gradually resolved. He was discharged on day 4 with some residual incoordination and ataxia. On follow-up visit 2 weeks later, he didn't have any symptoms (Burns et al, 2013).
    E) COMA
    1) Quinone has caused paralysis of the medullary centers and coma (HSDB , 1999; Hathaway et al, 1996; Clayton & Clayton, 1993; Sittig, 1991; Deichmann & Keplinger, 1981; NIOSH, 1978; Plunkett, 1976).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting, and irritation of the intestinal mucosa have been seen (Lewis, 1996; Deichmann & Keplinger, 1981; Plunkett, 1976; HSDB , 1999).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) JAUNDICE
    1) WITH POISONING/EXPOSURE
    a) Nonspecific liver changes and jaundice have been reported (Sittig, 1991; Deichmann & Keplinger, 1981; Plunkett, 1976).
    B) INCREASED LIVER ENZYMES
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-month-old boy (weight: 14.5 kg) developed tremors, left gaze deviation, and tonic-clonic seizures within 15 minutes of drinking an unknown amount of a skin-lightening lotion from a 500-mL bottle containing hydroquinone 2%. On presentation, he had seizures and a respiratory rate of 80 breaths/min. Laboratory results revealed metabolic acidosis and mild transaminitis (AST: 81 Units/L [normal 15 to 46 Units/L]; ALT: 52 Units/L [normal: 8 to 36 Units/L]). He required endotracheal intubation and received 2.5 mg diazepam, 0.1 mg/kg lorazepam, fosphenytoin 20 phenytoin equivalents/kg, another 1.5 mg lorazepam and phenobarbital 20 mg/kg IV before seizures were controlled. Following supportive care, his symptoms gradually resolved. He was discharged on day 4 with some residual incoordination and ataxia. On follow-up visit 2 weeks later, he didn't have any symptoms (Burns et al, 2013).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ALBUMINURIA
    1) WITH POISONING/EXPOSURE
    a) Albuminuria and hematuria may occur (Plunkett, 1976).
    B) ABNORMAL COLOR
    1) WITH POISONING/EXPOSURE
    a) GREEN URINE: Ingestion of hydroquinone may cause the urine to turn a green or brownish green color which color darkens on standing (Deichmann & Keplinger, 1981; HSDB , 1999).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Quinone-poisoned experimental animals may develop proteinuria, hematuria, and urinary casts (HSDB , 1999).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 19-month-old boy (weight: 14.5 kg) developed tremors, left gaze deviation, and tonic-clonic seizures within 15 minutes of drinking an unknown amount of a skin-lightening lotion from a 500-mL bottle containing hydroquinone 2%. On presentation, he had seizures and a respiratory rate of 80 breaths/min. Laboratory results revealed metabolic acidosis (pH 7.33, PCO2 30 mmHg, PaO2 69 mmHg, bicarbonate 16 mmol/L, base excess -10 mmol/L) and mild transaminitis. Following supportive care, his symptoms gradually resolved. He was discharged on day 4 with some residual incoordination and ataxia. On follow-up visit 2 weeks later, he didn't have any symptoms (Burns et al, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) Markedly elevated methemoglobin levels may occur following hydroquinone exposure (Clayton & Clayton, 1993).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANEMIA HEMOLYTIC
    a) In experimental animal studies with hydroquinone, methemoglobinemia, hemolytic icterus, anemia, leukocytosis, reticulocytosis and increased cell fragility were seen (Deichmann & Keplinger, 1981). Hemolytic anemia may occur (NIOSH, 1978). Quinone has a nonspecific effect on hemoglobin in animals, which has not yet been seen in man (Deichmann & Keplinger, 1981).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Localized contact dermatitis has been reported with topical hydroquinone use (Prod Info ALERA(TM) topical emulsion, 2006; Prod Info ACLARO(R) emulsion, 2005; Prod Info EPIQUIN(TM) MICRO topical cream, 2003; Prod Info SOLAQUIN FORTE(R) cream, gel, 1998; Prod Info ELDOQUIN FORTE(R) cream, 1998).
    2) WITH POISONING/EXPOSURE
    a) Allergic contact dermatitis can occur with the use of hydroquinone-containing skin lightening creams; the incidence increases as the hydroquinone concentration in the cream increases (Engasser & Maibach, 1981).
    B) VITILIGO
    1) Hypomelanosis of the skin has occurred. Depigmentation may occur even in black patients (Jimbow et al, 1974). Leukoderma has been seen and is slowly reversible (Oliver et al, 1939).
    2) A severe form of confetti-like depigmentation called leukomelanoderma has occurred from the use of skin creams containing hydroquinone (Markey et al, 1989).
    3) The monomethyl ether of hydroquinone appears to be more active than the parent compound in inducing confetti-like hypopigmentation (Boyle & Kennedy, 1985).
    4) The monobenzyl ether of hydroquinone has also appeared to cause the confetti-like pattern of depigmentation on the arms. This depigmentation can occur at sites distant from dermal application and may be permanent (Catona & Lanzer, 1987).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus, generally mild to moderate in intensity, occurred in 11% of patients with 8 weeks of once-daily fluocinolone acetonide/hydroquinone/tretinoin topical treatment in controlled clinical trials (n=161) (Prod Info TRI-LUMA(R) topical cream, 2013).
    D) DRY SKIN
    1) WITH THERAPEUTIC USE
    a) Dryness, generally mild to moderate in intensity, occurred in 14% of patients with 8 weeks of once-daily fluocinolone acetonide/hydroquinone/tretinoin topical treatment in controlled clinical trials (n=161) (Prod Info TRI-LUMA(R) topical cream, 2013).
    E) BURNING SENSATION
    1) WITH THERAPEUTIC USE
    a) Burning at the application site, generally mild to moderate in intensity, occurred in 18% of patients with 8 weeks of once-daily fluocinolone acetonide/hydroquinone/tretinoin topical treatment in controlled clinical trials (n=161) (Prod Info TRI-LUMA(R) topical cream, 2013).
    b) A mild burning sensation may occur following the use of hydroquinone emulsion (Prod Info ACLARO(R) emulsion, 2005).
    F) PEELING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Desquamation, generally mild to moderate in severity, occurred in 38% of patients with 8 weeks of once-daily fluocinolone acetonide/hydroquinone/tretinoin topical treatment in controlled clinical trials (n=161) (Prod Info TRI-LUMA(R) topical cream, 2013).
    G) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) Erythema, generally mild to moderate in intensity, occurred in 41% of patients with 8 weeks of once-daily fluocinolone acetonide/hydroquinone/tretinoin topical treatment in controlled clinical trials (n=161) (Prod Info TRI-LUMA(R) topical cream, 2013).
    H) NAIL FINDING
    1) Brown or orange-brown nail discoloration has been reported with the use of hydroquinone containing creams. The condition is aggravated by light (Mann & Harman, 1983).
    I) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Paradoxical ochronosis-like hyperpigmentation of the skin has occurred with the use of skin lightening creams containing higher concentrations of hydroquinone or with prolonged use of 2% to 8% creams (Prod Info TRI-LUMA(R) topical cream, 2013; Kasilo OJ, Maponga C & Nhachi CFB et al, 1990). The diagnosis is localized exogenous ochronosis (Connor & Braunstein, 1987).
    b) Generally, over-the-counter bleaching creams which contain 2% hydroquinone or less do not cause the ochonosis-like pigmentation seen with the use of creams containing higher concentrations (Brauer, 1985). However, concentrations of even 1% to 2% have produced this condition (Lawrence et al, 1988; Hull & Procter, 1990).
    J) SKIN IRRITATION
    1) WITH POISONING/EXPOSURE
    a) Hydroquinone induced mild to severe skin irritation in the Standard Draize Test (RTECS , 1999).
    b) Quinone is a skin irritant which may cause redness, swelling and necrosis (Deichmann & Keplinger, 1981; ACGIH, 1991; HSDB , 1999; Lewis, 1996).
    K) FIXED DRUG ERUPTION
    1) Nonpruritic papular granulomatous eruptions known as carcoid-like ochronosis have occurred from the use of hydroquinone-containing bleaching creams (Fisher, 1988).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) SPASMODIC MOVEMENT
    1) WITH POISONING/EXPOSURE
    a) Muscle twitching is a rare finding (Deichmann & Keplinger, 1981).

Endocrine

    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) In subacute exposure experimental animal studies, hypoglycemia was seen.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) Occasional hypersensitivity reactions have occurred following hydroquinone use (Prod Info ALERA(TM) topical emulsion, 2006; Prod Info ACLARO(R) emulsion, 2005; Prod Info EPIQUIN(TM) MICRO topical cream, 2003; Prod Info SOLAQUIN FORTE(R) cream, gel, 1998; Prod Info ELDOQUIN FORTE(R) cream, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Hydroquinone and Fluocinolone acetonide/hydroquinone/tretinoin combination are classified as US Food and Drug Administration (FDA) pregnancy category C. Safety has not been established for the use of topical hydroquinone in pregnant women. Exposure to hydroquinone produced skeletal malformations in animal studies. In rat studies, maternal toxic effects from exposure to hydroquinone included changes in the ovaries, fallopian tubes, and menstrual cycle. Post-implantation mortality was also observed in rat studies.
    B) Observed paternal toxic effects from exposure to hydroquinone included changes in the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowper's gland, accessory glands, and male fertility index.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) HYDROQUINONE
    a) CHICKENS: Curled claws, defective beaks, everted viscera, exencephaly, and monophthalmia were induced with hydroquinone in chicks in vivo, but the incidence was not statistically significant when compared to untreated controls (Burgaz et al, 1994).
    b) RABBITS: Hydroquinone at a dose of 150 mg/kg/day by gavage on gestation days 6 to 18 produced a slight, statistically insignificant, increase in the incidences of ocular and minor skeletal malformations (HSDB , 1999a).
    c) RATS: Hydroquinone was not teratogenic when given orally to pregnant rats at 30, 100, or 300 mg/kg on days 6 to 15 of gestation (HSDB , 1999a).
    2) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN
    a) RATS: Teratogenic effects, including cleft palate, protruding tongue, open eyes, umbilical hernia, and retinal folding or dysplasia, were observed in rats administered dermal hydroquinone/fluocinolone acetate/tretinoin during organogenesis (Prod Info TRI-LUMA(R) topical cream, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Hydroquinone and Fluocinolone acetonide/hydroquinone/tretinoin combination are classified as US Food and Drug Administration (FDA) pregnancy category C (Prod Info hydroquinone 4% topical cream, 2014; Prod Info Aclaro(R) topical emulsion, 2011; Prod Info TRI-LUMA(R) topical cream, 2014).
    2) Hydroquinone should only be used during pregnancy if clearly needed (Prod Info hydroquinone 4% topical cream, 2014; Prod Info Aclaro(R) topical emulsion, 2011) and if the potential maternal benefit outweighs the potential fetal risk (Prod Info TRI-LUMA(R) topical cream, 2014).
    B) MISCARRIAGE
    1) Thirteen women became pregnant during treatment with topical fluocinolone acetonide/hydroquinone/tretinoin cream in clinical trials. Outcomes included births of 3 apparently healthy babies, 1 pregnancy termination, and 1 miscarriage. The remaining outcomes were unknown. Epidemiologic studies of topical tretinoin do not show an increased incidence of birth defects, though neurologic or cognitive impairments may not be detected (Prod Info TRI-LUMA(R) topical cream, 2013).
    C) ANIMAL STUDIES
    1) HYDROQUINONE
    a) RATS: Maternal toxic effects (eg, changes in the ovaries, fallopian tubes, and the menstrual cycle) and post implantation mortality were observed in rats exposed to hydroquinone (RTECS , 1999).
    2) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN
    a) RABBITS: An increased number of in utero deaths and decreased fetal weights were observed with dermal application of hydroquinone/fluocinolone acetonide/tretinoin diluted 10-fold, mostly observed in litters at postnatal day 22 and in all litters at 5 weeks (Prod Info TRI-LUMA(R) topical cream, 2014).
    b) RATS: An increase in the number of stillborn pups, lower pup body weights, and delay in preputial separation were observed in rats administered dermal hydroquinone/fluocinolone acetate/tretinoin during organogenesis (Prod Info TRI-LUMA(R) topical cream, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) HYDROQUINONE: Exercise caution when administering hydroquinone to a woman who is breastfeeding (Prod Info hydroquinone 4% topical cream, 2014; Prod Info Aclaro(R) topical emulsion, 2011).
    2) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN: Corticosteroids are excreted in human milk when administered systemically. It is not known if fluocinolone acetonide/hydroquinone/tretinoin is present in human milk following topical therapy, and the potential for adverse effects in the nursing infant from exposure to this drug is unknown. Until additional data are available, use caution with its use in women who are nursing. Avoid contact of fluocinolone acetonide/hydroquinone/tretinoin with the nursing infant (Prod Info TRI-LUMA(R) topical cream, 2013).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) HYDROQUINONE
    a) RATS: Paternal toxic effects (eg changes in the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowper's gland, accessory glands, and male fertility index) were observed in rats exposed to hydroquinone (RTECS , 1999).
    2) FLUOCINOLONE ACETONIDE/HYDROQUINONE/TRETINOIN
    a) RATS, MINIPIGS: Topical therapy with a 10-fold dilution of fluocinolone acetonide/hydroquinone/tretinoin cream in pregnant rats revealed no effects on the traditional parameters used to assess fertility. However, topical treatment of male minipigs with the full-strength of fluocinolone acetonide/hydroquinone/tretinoin for 6 months caused small testes and severe hypospermia (Prod Info TRI-LUMA(R) topical cream, 2013).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS123-31-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Hydroquinone
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    B) IARC Carcinogenicity Ratings for CAS106-51-4 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: para-Quinone
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.4) ANIMAL STUDIES
    A) FLUOCINOLONE/HYDROQUINONE/TRETINOIN
    1) Topical application of fluocinolone/hydroquinone/tretinoin in fixed combinations equivalent to 10%, 25%, 50%, and 100% in male and female SD rats for a duration of 24 months at dosages that approximated 10, 4000 and 50 mcg/kg/day (corresponding to dosages of 60, 24,000 and 300 mcg/m(2) day, respectively) resulted in statistically significant increases in the incidences of islet cell adenomas, combined islet cell adenomas and carcinomas of the pancreas in both males and females (Prod Info TRI-LUMA(R) topical cream, 2013).
    2) Hydroquinone studies in animals have demonstrated evidence of carcinogenicity (Prod Info TRI-LUMA(R) topical cream, 2013).
    B) RENAL CARCINOMA
    1) Hydroquinone can induce renal tubule adenomas in male but not in female Fischer 344 rats; B6C3F1 mice and Sprague-Dawley rats are also resistant to this effect (English et al, 1994a).
    C) HYDROQUINONE
    1) RENAL CARCINOMA
    a) The mechanism apparently involves increased cell proliferation in response to cellular toxicity rather than a primary genetic effect (English, 1994a, 1994b).
    b) An increased incidence of bladder carcinomas has been noted in mice (ACGIH, 1991).
    2) LEUKEMIA
    a) Mononuclear cell leukemia has occurred in female rats (ACGIH, 1991).
    3) HEPATIC CARCINOMA
    a) Heptatocellular neoplasms, primarily adenomas, have been observed in rats (ACGIH, 1991).
    D) QUINONE
    1) LACK OF EFFECT
    a) There was insufficient evidence for carcinogenicity in mice and rats exposed by inhalation, skin application, and subcutaneous injection (ACGIH, 1991).
    2) PULMONARY CARCINOMA
    a) Lung adenocarcinomas were observed in mice following inhalation exposure (HSDB, 1999).
    E) LACK OF EFFECT
    1) FLUOCINOLONE/HYDROQUINONE/TRETINOIN
    a) Topical application of fluocinolone/hydroquinone/tretinoin in fixed combinations equivalent to 10%, 50%, 100% and 150% of the clinical concentrations on male and female CD-1 mice did not result in significant changes in tumor incidence after 24 months (Prod Info TRI-LUMA(R) topical cream, 2013).

Genotoxicity

    A) Exposure to hydroquinone has resulted in DNA damage, unscheduled DNA synthesis, DNA inhibition, DNA adducts, mutations in microorganisms, mutations in mammalian somatic cells, and sister chromatid exchanges. It also produced morphological transformation and sex chromosome loss/nondisjunction and was positive on cytogenic analysis, in the micronucleus test, and for gene conversion/mitotic recombination.
    B) Exposure to quinone has resulted in DNA damage, DNA inhibition, DNA adducts, mutations in microorganisms, mutations in mammalian somatic cells, and sister chromatid exchanges. It also produced morphological transformation and was positive in the micronucleus test.

Laboratory Monitoring

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Quinone can be measured in urine by a colorimetric method. The complex with p-dimethylaminobenzaldehyde is measured by absorption at 410 nm (HSDB , 1999).
    2) A gas chromatography-mass spectrometry method has been described for quantitating hydroquinone in human tissue samples (Saito et al, 1994).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia.
    F) Monitor pulse oximetry or arterial blood gases and obtain a chest x-ray in any patient with respiratory symptoms.
    G) A urine screen which detects hydroquinone is indicative of exposure. Hydroquinone is not found naturally in the body. Green or brown-green colored urine may be found in patients with hydroquinone exposure.
    4.1.2) SERUM/BLOOD
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    D) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Hydroquinone is not naturally found in the body. A urine screen which detects hydroquinone is indicative of exposure. High performance liquid chromatography with fluorometric detection for determination of hydroquinone in urine is specific and reliable (Plunkett, 1976; Lee et al, 1993).
    2) Green or brownish green colored urine may be found in patients with hydroquinone exposure (Deichmann & Keplinger, 1981; Budavari, 1996).
    3) Urine level in a fatal case was 3.4 mcg/mL (Saito et al, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with worsening symptoms or severe systemic symptoms should be admitted to the hospital for further evaluation.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for observation until they are clearly improving and clinically stable. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with significant vomiting.
    C) Monitor vital signs and mental status in symptomatic patients.
    D) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    E) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia.
    F) Monitor pulse oximetry or arterial blood gases and obtain a chest x-ray in any patient with respiratory symptoms.
    G) A urine screen which detects hydroquinone is indicative of exposure. Hydroquinone is not found naturally in the body. Green or brown-green colored urine may be found in patients with hydroquinone exposure.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) DILUTION
    1) Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) SKIN: Wash with soap and water. OCULAR: Immediately flush eye with water for at least 15 minutes.
    6.5.2) PREVENTION OF ABSORPTION
    A) DILUTION
    1) Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds.
    2) DILUTION: If no respiratory compromise is present, administer milk or water as soon as possible after ingestion. Dilution may only be helpful if performed in the first seconds to minutes after ingestion. The ideal amount is unknown; no more than 8 ounces (240 mL) in adults and 4 ounces (120 mL) in children is recommended to minimize the risk of vomiting (Caravati, 2004).
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Although not as irritating as phenol, dilution with water or milk is indicated with hydroquinone-quinone ingestions. This may prevent damage due to the irritant nature of these compounds.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with benzodiazepines; add barbiturates or propofol, if seizures persist. Treat symptomatic methemoglobinemia with methylene blue.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor serum electrolytes in patients with significant vomiting.
    3) Monitor vital signs and mental status in symptomatic patients.
    4) Monitor CBC, renal function, and liver enzymes in symptomatic patients.
    5) Obtain methemoglobin concentrations in all cyanotic patients and patients demonstrating dyspnea or other signs of hypoxia.
    6) Monitor pulse oximetry or arterial blood gases, and obtain a chest x-ray in any patient with respiratory symptoms.
    7) Hydroquinone is not found naturally in the body. Green or brown-green colored urine may be found in patients with hydroquinone exposure.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) GENERAL TREATMENT
    1) Chronically exposed eyes should be examined to determine the extent of pigmentation of the conjunctiva and corneal layers. The eyes also need to be evaluated for corneal opacities and ulceration.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.9.2) TREATMENT
    A) ERUPTION
    1) Sarcoid-like ochronosis, a granulomatous papular eruption caused by hydroquinone-containing bleaching cream, was successfully treated with tetracycline at a dose of 500 mg daily for 3 months (Fisher, 1988).
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis has not been shown to be of value in the removal of these compounds.

Abstracts

Case Reports

    A) ADULT
    1) CHRONIC EFFECTS
    a) DERMAL: A 72-year-old black woman experienced progressive darkening of her face. She had been using hydroquinone-containing skin lightening cream since childhood. The pigmentation was in the form of confluent, blue-black macules and patches on the forehead and temporal and malar regions (Connor & Braunstein, 1987).

Range Of Toxicity

Summary

    A) TOXICITY: Ingestions of hydroquinone up to 500 mg/day for 5 months produced no symptoms. Ingestion of 1 gram of hydroquinone by an adult has caused symptoms, and death has occurred in adults ingesting 3 to 12 grams.

Minimum Lethal Exposure

    A) ACUTE
    1) Ingestions of hydroquinone up to 500 mg/day for 5 months produced no symptoms (Merck Index, 1984). Ingestion of 1 gram of hydroquinone by an adult has caused symptoms, and death has occurred in adults ingesting 3 to 12 grams (Deichmann & Keplinger, 1981; IPCS, 1994).

Maximum Tolerated Exposure

    A) ACUTE
    1) TOXIC DOSE
    a) Because of the limited number of cases, a toxic dose is difficult to establish.
    b) Eye exposure 10 to 30 mg/m(3) (vapor or dust) has caused keratitis (Deichmann & Keplinger, 1981).
    c) Quinone is moderately irritating to the eyes at 0.5 ppm, and definitely so at 3 ppm (Sollman, 1957).
    2) NON-TOXIC EXPOSURES
    a) Ingestion of hydroquinone up to 500 mg/day for 5 months produced no symptoms (Sollman, 1957).

Workplace Standards

    A) ACGIH TLV Values for CAS123-31-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Hydroquinone
    a) TLV:
    1) TLV-TWA: 1 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: SEN
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) SEN: The designation SEN refers to the potential for an agent to produce sensitization, as confirmed by human or animal data. The notation does not imply that this is the critical effect or that this is the sole basis for the TLV. Although, for those TLVs that are based on sensitization, the TLV is meant to protect workers from induction of this effect, but cannot protect workers who have already become sensitized. The notation should be used to assist in identifying sensitization hazards and reducing respiratory, dermal, and conjunctival exposures to sensitizing agents in the workplace. Please see "Definitions and Notations" (in TLV booklet) for full definition.
    c) TLV Basis - Critical Effect(s): Eye irr; eye dam
    d) Molecular Weight: 110.11
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) ACGIH TLV Values for CAS106-51-4 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Quinone
    a) TLV:
    1) TLV-TWA: 0.1 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: Not Listed
    2) Codes: Not Listed
    3) Definitions: Not Listed
    c) TLV Basis - Critical Effect(s): Eye irr; skin dam
    d) Molecular Weight: 108.09
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    C) NIOSH REL and IDLH Values for CAS123-31-9 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Hydroquinone
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling: 2 mg/m(3) [15-minute]
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 50 mg/m3
    b) Note(s): Not Listed

    D) NIOSH REL and IDLH Values for CAS106-51-4 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Quinone
    2) REL:
    a) TWA: 0.4 mg/m(3) (0.1 ppm)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s):
    3) IDLH:
    a) IDLH: 100 mg/m3
    b) Note(s): Not Listed

    E) Carcinogenicity Ratings for CAS123-31-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Hydroquinone
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Hydroquinone
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Hydroquinone
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Hydroquinone
    5) MAK (DFG, 2002): Category 2 ; Listed as: Hydroquinone
    a) Category 2 : Substances that are considered to be carcinogenic for man because sufficient data from long-term animal studies or limited evidence from animal studies substantiated by evidence from epidemiological studies indicate that they can make a significant contribution to cancer risk. Limited data from animal studies can be supported by evidence that the substance causes cancer by a mode of action that is relevant to man and by results of in vitro tests and short-term animal studies.
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS106-51-4 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed ; Listed as: Quinone
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Assessed under the IRIS program. ; Listed as: Quinone
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: para-Quinone
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Quinone
    5) MAK (DFG, 2002): Category 3B ; Listed as: Quinone
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS123-31-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Hydroquinone
    2) Table Z-1 for Hydroquinone:
    a) 8-hour TWA:
    1) ppm:
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 2
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

    H) OSHA PEL Values for CAS106-51-4 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Quinone
    2) Table Z-1 for Quinone:
    a) 8-hour TWA:
    1) ppm: 0.1
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 0.4
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) Hydroquinone
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 100 mg/kg (RTECS , 1999a)
    2) LD50- (ORAL)MOUSE:
    a) 245 mg/kg (RTECS , 1999a)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 182 mg/kg (RTECS , 1999a)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 170 mg/kg (RTECS , 1999a)
    5) LD50- (ORAL)RAT:
    a) 320 mg/kg (RTECS , 1999a)
    B) Quinone
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 8500 mcg/kg (RTECS , 1999a)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 93,800 mcg/kg (RTECS , 1999a)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 30 mg/kg (RTECS , 1999a)
    4) LD50- (ORAL)RAT:
    a) 130 mg/kg (RTECS , 1999a)

Pharmacology Toxicology

Toxicologic Mechanism

    A) Quinone appears to act directly on the medulla and oxygen carrying capabilities of the blood (Deichmann & Keplinger, 1981).
    B) Hydroquinone appears to be oxidized to quinone prior to biologic action (Deichmann & Keplinger, 1981). Hydroquinone causes depigmentation in all races by interfering with the tyrosine-tyrosinase-melanin system (Arndt & Fitzpatrick, 1965).
    1) Hydroquinone inhibits the synthesis of new melanin (HSDB, 1999).
    C) Quinones may be cytotoxic via various mechanisms including arylation, intercalation, induction of DNA strand breaks, redox cycling, generation of site-specific free radicals, and interference with mitochondrial respiration (Monks et al, 1992).

Physicochemical

Physical Characteristics

    A) Hydroquinone occurs as colorless or white to light tan or gray odorless crystals with a sweet taste (EPA, 1985) CHRIS, 1999; (Deichmann & Keplinger, 1981).
    B) Quinone exists as yellow monoclinic prisms or a greenish-yellowish solid with a penetrating, chlorine-like odor (HSDB, 1999).
    1) Quinone has a strong odor; irritating enough to cause sneezing (Deichmann & Keplinger, 1981).

Molecular Weight

    A) HYDROQUINONE: 110.11 (Budavari, 1996)
    B) QUINONE: 108.10 (Budavari, 1996)

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