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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 157





    HYDROQUINONE




    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    First draft prepared by Dr M. Gillner, Dr G.S. Moore, Dr H. Cederberg 
    and Dr K. Gustafsson, National Chemicals Inspectorate, Solna, Sweden

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization


    World Health Orgnization
    Geneva, 1994

          The International Programme on Chemical Safety (IPCS) is a joint
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    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data

    Hydroquinone.

          Environmental health criteria: 157)

          1. Environmental exposure     2. Hydroquinones - analysis
          3. Hydroquinones - toxicity   I.Series

          ISBN 92 4 157127 8         (NLM Classification QD 341.P5)
          ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR HYDROQUINONE

    1. SUMMARY

         1.1. Identity, physical and chemical properties, analytical
              methods
         1.2. Sources of human and environmental exposure
         1.3. Environmental transport, distribution and transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on laboratory mammals, and  in vitro systems
         1.7. Effects on humans
         1.8. Effects on other organisms in the laboratory and field

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1. Identity
         2.2. Physical and chemical properties
              2.2.1. Reduction-oxidation equilibria
              2.2.2. Oxidation of hydroquinone
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. Sampling  
              2.4.2. Methods of analysis

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production levels and processes
              3.2.2. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

         4.1. Transport and distribution between media
         4.2. Transformation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Bioaccumulation
         4.3. Interaction with other physical, chemical or biological
              factors
         4.4. Ultimate fate following use

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air, soil and water
              5.1.2. Food

         5.2. General population exposure
         5.3. Occupational exposure

    6. KINETICS AND METABOLISM

         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
         6.4. Elimination and excretion
         6.5. Reaction with body components

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO SYSTEMS

         7.1. Single exposure
         7.2. Skin and eye irritation; sensitization
              7.2.1. Skin irritation
              7.2.2. Eye irritation
              7.2.3. Sensitization
         7.3. Short-term exposure
         7.4. Long-term exposure
         7.5. Reproduction, embryotoxicity and teratogenicity
              7.5.1. Effects on male reproduction
              7.5.2. Effects on female reproduction
              7.5.3. Embryotoxicity and teratogenicity
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
              7.7.1. Long-term bioassays
              7.7.2. Carcinogenicity-related studies
                   7.7.2.1   Skin
                   7.7.2.2   Bladder
                   7.7.2.3   Stomach
                   7.7.2.4   Liver
         7.8. Special studies
              7.8.1. Effects on spleen and bone marrow cells;
                        immunotoxicity
              7.8.2. Effects on tumour cells
              7.8.3. Neurotoxicity
              7.8.4. Nephrotoxicity
              7.8.5. Interaction with phenols

    8. EFFECTS ON HUMANS

         8.1. General population exposure
              8.1.1. Acute toxicity - poisoning incidents
              8.1.2. Short-term controlled human studies
              8.1.3. Dermal effects; sensitization
         8.2. Occupational exposure
              8.2.1. Dermal effects
              8.2.2. Ocular effects
              8.2.3. Systemic effects
              8.2.4. Epidemiological studies

                   8.2.4.1   Respiratory effects
                   8.2.4.2   Carcinogenicity studies

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

         10.1. Toxicokinetics
         10.2. Animal and  in vitro studies
         10.3. Evaluation of human health risks
              10.3.1. Exposure
              10.3.2. Human health effects
         10.4. Evaluation of effects on the environment

    11. RECOMMENDATIONS

    12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    APPENDIX

    RESUME

    RESUMEN
    

    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR HYDROQUINONE

     Members

    Dr L. Albert, Program of Health and Environment, Centre for Ecology
         and Development, Xalapa, Veracruz, Mexico  (Chairman)

    Dr H. Cederberg, National Chemicals Inspectorate, Solna, Sweden

    Dr J. Devillers, Centre de Traitement de l'Information Scientifique
         (CTIS), Lyon, France

    Dr D.A. Eastmond, Environmental Toxicology Graduate Program,
         Department of Entomology, University of California, Riverside,
         California, USA

    Dr M. Gillner, Scientific Documentation and Research, National
         Chemicals Inspectorate, Solna, Sweden  (Rapporteur)

    Dr S. Humphreys, Contaminants, Standards, and Monitoring Branch,
         Center for Food Safety and Applied Nutrition, US Food and Drug
         Administration, Washington, DC, USA

    Dr G.A. Moore, Scientific Documentation and Research, National
         Chemicals Inspectorate, Solna, Sweden

    Professor H. Naito, Institute of Clinical Medicine, University of
         Tsukuba, Tsukuba City, Ibaraki, Japan

    Dr C.O. Nwokike, Medical Division, Lever Brothers (Nigeria) PLC,
         Apapa, Lagos, Nigeria

    Dr J. O'Donoghue, Corporate Health and Environment Laboratories,
         Eastman Kodak Company, Rochester, New York, USA

    Professor P.N. Viswanathan, Ecotoxicology Group, Industrial
         Toxicology Research Centre, Lucknow, India

     Observer

    Mr P-G. Pontal, Rhône Poulenc Agro, Lyon, France

     Secretariat

    Dr M. Gilbert, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland  (Secretary)

    Dr J. Wilbourn, Unit of Carcinogen Identification and Evaluation,
         International Agency for Research on Cancer, Lyon, France

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the
    criteria monographs as accurately as possible without unduly
    delaying their publication. In the interest of all users of the
    Environmental Health Criteria monographs, readers are kindly
    requested to communicate any errors that may have occurred to the
    Director of the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland, in order that they may be
    included in corrigenda.

                                  *   *   *

         A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Case
    postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No.
    9799111).

                                  *   *   *

         This publication was made possible by grant number 5 U01
    ES02617-14 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA.

    ENVIRONMENTAL HEALTH CRITERIA FOR HYDROQUINONE

         A WHO Task Group meeting on Environmental Health Criteria for
    Hydroquinone was held at the British Industrial Biological Research
    Association (BIBRA), Carshalton, United Kingdom, from 24 to 28 May
    1993. Dr D. Anderson welcomed the participants on behalf of the host
    institution and Dr M. Gilbert opened the meeting on behalf of the
    three cooperating organizations of the IPCS (ILO/UNEP/WHO). The Task
    Group reviewed and revised the draft criteria monograph and made an
    evaluation of the risks for human health and the environment from
    exposure to hydroquinone.

         The first draft of this monograph was prepared by Dr M.
    Gillner, Dr G.A. Moore, Dr H. Cederberg and Dr K. Gustafsson, 
    National Chemicals Inspectorate, Solna, Sweden. Dr M. Gilbert and 
    Dr P.G. Jenkins, both members of the IPCS Central Unit, were
    responsible for the overall scientific content and editing,
    respectively.

         The efforts of all who helped in the preparation and
    finalization of the monograph are gratefully acknowledged.

    ABBREVIATIONS

    AUC       area under the curve

    BP        benzo [a]pyrene

    BHA       butylated hydroxyanisole

    cAMP      adenosine 3',5'-phosphate

    cGMP      guanine 3',5'-phosphate

    CLV       ceiling value

    HPLC      high-performance liquid chromatography

    HQ        hydroquinone

    IL-1      interleukin-1

    IL-4      interleukin-4

    i.p.      intraperitoneal

    i.v.      intravenous

    MDA       malondialdehyde

    MCL       melanotic cell lines

    NADPH     reduced nicotinamide adenine dinucleotide

    NMCL      nonmelanolic cell lines

    MNNG       N-methyl- N'-nitro- N-nitrosoguanidine

    NOAEL     no-observable-adverse-effect level

    NOEL      no-observed-effect level

    ODC       ornithine decarboxylase

    QSAR      quantitative structure-activity relationship

    s.c.      subcutaneous

    STEL      short-term exposure limit

    TLC       thin-layer chromatography

    TLV       threshold limit value

    TWA       time-weighted average

    1.  SUMMARY

    1.1  Identity, physical and chemical properties, analytical methods

         Hydroquinone (1,4-benzenediol; C6H4(OH)2) is a white
    crystalline substance when pure, with a melting point of 173-174 °C.
    The specific gravity is 1.332 at 15 °C, and the vapour pressure is
    2.4 x 10-3 Pa (1.8 x 10-5 mmHg) at 25 °C. It is highly soluble
    in water (70 g/litre at 25 °C) and the log  n-octanol/water
    partition coefficient is 0.59. With respect to organic solvents, the
    solubility varies from 57% in ethanol to less than 0.1% in benzene. 
    Hydroquinone is combustible when preheated. It is a reducing agent
    which is reversibly oxidized to its semiquinone and quinone.

         Hydroquinone in the air is sampled either by trapping in
    solvent or on a mixed cellulose ester membrane filter.

         Analysis of hydroquinone is carried out by titrimetric,
    spectrophotometric or, most commonly, chromatographic techniques.

    1.2  Sources of human and environmental exposure

         Hydroquinone occurs both in free and conjugated forms in
    bacteria, plants and some animals. Industrially, it is produced in
    several countries. In 1979, the total world capacity for production
    exceeded 40 000 tonnes, while in 1992 it was approximately 35 000
    tonnes. It is extensively used as a reducing agent, as a
    photographic developer, as an antioxidant or stabilizer for certain
    materials that polymerize in the presence of free radicals, and as a
    chemical intermediate for the production of antioxidants,
    antiozonants, agrochemicals and polymers. Hydroquinone is also used
    in cosmetics and medical preparations.

    1.3  Environmental transport, distribution and transformation

         Hydroquinone occurs in the environment as a result of man-made
    processes as well as in natural products from plants and animals.

         Due to its physicochemical properties, hydroquinone will be
    distributed mainly to the water compartment when released into the
    environment. It degrades both as a result of photochemical and
    biological processes; consequently, it does not persist in the
    environment. No bioaccumulation is observed.

    1.4  Environmental levels and human exposure

         No data on hydroquinone concentrations in air, soil or water
    have been found. However, hydroquinone has been measured in
    mainstream smoke from non-filter cigarettes in amounts varying from
    110 to 300 µg per cigarette, and also in sidestream smoke.
    Hydroquinone has been found in plant-derived food products (e.g.,

    wheat germ), in brewed coffee, and in teas prepared from the leaves
    of some berries where the concentration sometimes exceeds 1%.

         Photohobbyists can be exposed to hydroquinone dermally or by
    inhalation. However no data on exposure levels are available. Dermal
    exposure may also result from the use of cosmetic and medical
    products containing hydroquinone, such as skin lighteners. The
    European Community (EC) countries have restricted its use in
    cosmetics to 2% or less. In the USA, the Food and Drug
    Administration has proposed concentrations between 1.5 and 2% in
    skin lighteners. Concentrations up to 4% may be found in
    prescription drugs. In some countries even higher concentrations may
    be found in skin lighteners.

         Few industrial hygiene monitoring data are available for
    hydroquinone. Average concentrations in air during manufacturing and
    processing of hydroquinone have been reported to be in the range of
    0.13 to 0.79 mg/m3. Occupational air exposure limits
    (time-weighted average) in different countries range from 0.5 to 2
    mg/m3.

    1.5  Kinetics and metabolism

         Hydroquinone is rapidly and extensively absorbed from the gut
    and trachea of animals. Absorption via the skin is slower but may be
    more rapid with vehicles such as alcohols. Hydroquinone distributes
    rapidly and widely among tissues. It is metabolized to
     p-benzoquinone and other oxidized products, and is detoxified by
    conjugation to monoglucuronide, monosulfate, and mercapturic
    derivatives. The excretion of hydroquinone and its metabolites is
    rapid, and occurs primarily via the urine.

         Hydroquinone and/or its derivatives react with different
    biological components such as macromolecules and low molecular
    weight molecules, and they have effects on cellular metabolism.

    1.6  Effects on laboratory mammals, and in vitro systems

         Oral LD50 values for several animal species range between 300
    and 1300 mg/kg body weight. However, for the cat LD50 values range
    from 42 to 86 mg/kg body weight. Acute high-level exposure to
    hydroquinone causes severe effects on the central nervous system
    (CNS) including hyperexcitability, tremor, convulsions, coma and
    death. At sublethal doses these effects are reversible. The dermal
    LD50 value has been estimated to be > 3800 mg/kg in rodents.
    Inhalation LC50 values are not available.

         A formulation containing 2% hydroquinone in a single-insult
    patch test in rabbits resulted in an irritation score of 1.22 (on a
    scale of 0 to 4). Daily topical applications for three weeks of 2 or
    5% hydroquinone in an oil-water emulsion on the depilated skin of

    black guinea-pigs caused depigmentation, inflammatory changes and
    thickening of the epidermis. The depigmentation was more marked at
    higher concentrations, and female guinea-pigs were more sensitive
    than males.

         Sensitization tests in guinea-pigs have shown weak to strong
    reactions depending on the methods or vehicles used. The strongest
    reactions were obtained with the guinea-pig maximization test. A
    cross-sensitization of almost 100% between hydroquinone and
     p-methoxyphenol was also seen in guinea-pigs, but only restricted
    evidence of cross-reactions to  p-phenylenediamine, sulfanilic acid
    and  p-benzoquinone was obtained.

         A 6-week oral toxicity study in male F-344 rats resulted in
    nephropathy and renal cell proliferation. Thirteen-week oral gavage
    studies in F-344 rats and in B6C3F1 mice resulted in
    nephrotoxicity in rats at 100 and 200 mg/kg, and tremors and
    convulsions in rats at 200 mg/kg; reduced body weight gain was seen
    in both rats and mice. Dosing at 400 mg/kg was lethal in rats. In
    mice dosed for 13 weeks at 400 mg/kg, tremors, convulsions and
    lesions in the gastric epithelium were reported. Thirteen-week
    hydroquinone exposure of Sprague Dawley rats resulted in decreased
    body weight gain and CNS signs at 200 mg/kg. CNS signs were also
    observed at a dose level of 64 mg/kg body weight but not at 20
    mg/kg.

         Hydroquinone injected subcutaneously reduced fertility in male
    rats, and prolonged the estrus cycle in female rats. However, this
    was not found in oral studies (a dominant lethality study and a
    two-generation study). In a developmental study in rats, oral doses
    of 300 mg/kg body weight caused slight maternal toxicity and reduced
    fetal body weight. In rabbits, the no-observed-effect level (NOEL)
    for maternal toxicity was 25 mg/kg per day, and it was 75 mg/kg per
    day for developmental toxicity. In a two-generation reproduction
    study in rats hydroquinone caused no reproductive effects at oral
    doses of up to 150 mg/kg body weight per day. The no-observed-
    adverse-effect level (NOAEL) for parental toxicity was determined to
    be 15 mg/kg per day, and for reproductive effects through two
    generations it was 150 mg/kg per day.

         Hydroquinone induces micronuclei  in vivo and  in vitro.
    Structural and numerical chromosome aberrations have been observed
     in vitro and after intraperitoneal administration  in vivo.
    Furthermore, the induction of gene mutations, sister-chromatid
    exchange and DNA damage has been demonstrated  in vitro.
    Hydroquinone caused chromosomal aberrations in male mouse germ cells
    at the same order of magnitude as in mouse bone marrow cells after
    intraperitoneal injection. Induction of germ-cell mutations could
    not be established in a dominant lethal test in male rats dosed
    orally.

         In a two-year study, oral administration of hydroquinone caused
    a dose-related incidence of renal tubular cell adenomas in male
    F-344/N rats. The incidence was statistically significant in the
    high-dose group. In the high-dose males, renal tubular cell
    hyperplasia was also found. In female rats a dose-related increased
    incidence of mononuclear cell leukaemia occurred. Female B6C3F1
    mice developed a significantly increased incidence of hepatocellular
    adenomas. In another study, hydroquinone (at a dietary level of
    0.8%) produced a significantly increased incidence of epithelial
    hyperplasia of the renal papilla and a significant increase of renal
    tubular hyperplasia and adenomas in male rats. No increased
    incidence of mononuclear cell leukaemia in female rats was observed.
    In mice, the incidence of squamous cell hyperplasia of the
    forestomach epithelium was significantly increased in both sexes. In
    male mice, there was a significantly increased incidence of
    hepatocellular adenomas and also of renal tubular hyperplasia. A few
    renal cell adenomas were observed.

          In vivo (intraperitoneal injection) and  in vitro studies in
    mice have demonstrated that hydroquinone has a cytotoxic effect by
    reducing the bone marrow and spleen cellularity and also an
    immunosuppressive potential by inhibiting the maturation of
    B-lymphocytes and the natural killer cell activity. Results also
    indicate that bone marrow macrophages may be the primary target for
    hydroquinone myelotoxicity. Myelotoxic effects were not observed in
    a long-term bioassay in rodents.

         In a 90-day study in rats using a functional-observational
    battery, dose levels of 64 and 200 mg hydroquinone/kg produced
    tremors, and 200 mg/kg produced depression of general activity.
    Neuropathological examinations were negative.

    1.7  Effects on humans

         Cases of intoxication have been reported after oral ingestion
    of hydroquinone alone or of photographic developing agents
    containing hydroquinone. The major signs of poisoning included dark
    urine, vomiting, abdominal pain, tachycardia, tremors, convulsions
    and coma. Deaths have been reported after ingestion of photographic
    developing agents containing hydroquinone. In a controlled oral
    study on human volunteers, ingestion of 300-500 mg hydroquinone
    daily for 3-5 months did not produce any observable pathological
    changes in the blood and urine.

         Dermal applications of hydroquinone at concentration levels
    below 3% in different bases caused negligible effects in male
    volunteers from different human races. However, there are case
    reports suggesting that skin lightening creams containing 2%
    hydroquinone have produced leucoderma, as well as ochronosis.
    Hydroquinone (1% aqueous solution or 5% cream) has caused irritation

    (erythema or staining). Allergic contact dermatitis due to
    hydroquinone has been diagnosed.

         Combined exposure to hydroquinone and quinone airborne
    concentrations causes eye irritation, sensitivity to light, injury
    of the corneal epithelium, corneal ulcers and visual disturbances.
    There have been cases of appreciable loss of vision. Irritation has
    occurred at exposure levels of 2.25 mg/m3 or more. Long-term
    exposure causes staining of the conjunctiva and cornea and also
    opacity. Slowly developing inflammation and discoloration of the
    cornea and conjunctiva have resulted after daily hydroquinone
    exposure for at least two years of 0.05-14.4 mg/m3; serious cases
    have not occurred until after five or more years. One report
    described cases of corneal damage occurring several years after the
    exposure to hydroquinone had stopped.

         There are no adequate epidemiological data to assess the
    carcinogenicity of hydroquinone in humans.

    1.8  Effects on other organisms in the laboratory and field

         The ecotoxicological behaviour of hydroquinone has to be
    related to its physicochemical properties, which induce sensitivity
    to light, pH and dissolved oxygen. Its ecotoxicity, which is
    generally high (e.g., < 1 mg/litre for aquatic organisms), varies
    from species to species.

         Algae, yeasts, fungi and plants are less sensitive to
    hydroquinone than the other organisms generally used for toxicity
    testing. However, within the same taxonomic group, the sensitivity
    of different species to hydroquinone may vary by a factor of 1000.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

    Primary constituent

    Chemical formula:        C6 H4 (OH)2

    Chemical structure:

    CHEMICAL STRUCTURE 1

    Relative molecular mass: 110.11

    Common name:             Hydroquinone

    CAS registry number:     123-31-9

    Synonyms:                1,4-benzenediol;  p-benzenediol;
                             benzohydroquinone; benzoquinol; 1,4-
                             dihydroxybenzene;  p-dihydroxybenzene;
                              p-dioxobenzene;  p-dioxybenzene;
                             hydroquinol; hydroquinole; alpha-
                             hydroquinone;  p-hydroquinone;
                              p-hydroxyphenol; quinol; ß-quinol

    Technical product:

    Trade name:              Tecquinol

    Impurities:              none identified

    Isomeric composition:    None

    Additives:               None

    2.2  Physical and chemical properties

    Physical state:          Long needles

    Colour:                  White (analytical grade)

    Odour:                   Odourless

    Taste:                   Not documented

    Melting point:           173-174 °C

    Boiling point:           287 °C

    Flash point:             165 °C (closed cup)

    Flammability:            Combustible when preheated

    Explosion limits:        Slight when exposed to heat.
                             Reactive at high temperature or pressure

    Vapour pressure:         2.4 x 10-3 Pa (1.8 x 10-5 mmHg) at 25 °C
                             0.133 kPa (1 mmHg) at 132.4 °C
                             0.533 kPa (4 mmHg) at 150 °C
                             8.00 kPa (60 mmHg) at 203 °C

    Specific gravity:        1.332 at 15 °C

    Vapour density:          3.81

    Log  n-octanol/water
    partition coefficient:   0.59

    Solubility:     Water:   59 g/litre at 15 °C
                             70 g/litre at 25 °C
                             94 g/litre at 28 °C

         Organic solvents:   Soluble in most polar organic solvents

         ethyl alcohol       57 g/100 grams solvent at 25 °C
         acetone             20 g/100 grams solvent at 25 °C
         methyl isobutyl     27 g/100 grams solvent at 25 °C
          ketone
         2-ethylhexanol      12 g/100 grams solvent at 25 °C

         ethyl acetate  22 g/100 grams solvent at 25 °C

         Virtually insoluble (< 0.1%) in benzene, toluene and carbon
         tetrachloride

    Other properties:   Reducing agent;
         pK1 = 9.9, pK2 = 11.6;
         Redox active (see below)

    2.2.1  Reduction-oxidation equilibria

         Hydroquinone undergoes reversible redox changes which can
    involve a variety of pathways and redox couples (see Fig. 1). Each
    redox couple has an electrochemical potential dependent upon the
    degree of protonation and electron reduction.

    FIGURE 1

         Hydroquinone is a reducing agent with an electrochemical
    potential (E°) of +286 mV for the benzoquinone/hydroquinone
    (Q/H2Q) redox couple at 25 °C and pH 7.0, and under constant
    conditions.

    CHEMICAL STRUCTURE 2

    2.2.2  Oxidation of hydroquinone

         Hydroquinone is oxidized by a variety of oxidants including
    nitric acid, halogens, persulfates and metal salts (NIOSH, 1978). It
    is also oxidized by molecular oxygen in alkaline solutions.

         Hydroquinone reacts with molecular oxygen (autooxidation). In
    an aqueous medium the rate of autooxidation is pH dependent,
    occurring very rapidly at alkaline pH to produce a brown solution,
    but very slowly in acidic medium. This reaction is strongly
    catalysed by copper ions.

         Some of the possible reactions during autooxidation of
    hydroquinone in alkaline medium are outlined in Fig. 2. In alkaline
    solution,  p-benzoquinone can further react to form
    2-hydroxyhydroquinone. In a similar manner to hydroquinone,
    2-hydroxyhydroquinone can be oxidized to 2-hydroxy- p-benzoquinone
    by electron transfer and disproportionation reactions (4a and b).

         In addition, 2-hydroxy- p-benzoquinone (QI) is formed from
    2-hydroxy-hydroquinone (HQI) by sequential mixed-redox reactions
    with  p-benzoquinone involving comproportionation [Eq. 1] and a
    redox equilibrium reaction [Eq. 2].

    CHEMICAL STRUCTURE 3

         Formation of  p-benzoquinone from hydroquinone also occurs in
    a reverse manner by these mixed-redox reactions once
    2-hydroxy- p-benzoquinone is formed. Hydrogen peroxide may be
    generated by the reaction of hydroquinone and oxygen, and can then
    react with  p-benzoquinone forming 2,3-epoxy-hydroquinone. This
    latter product, if reduced, forms 2-hydroxy-hydroquinone. Owing to
    the large number of redox reactions possible between mono-benzo
    products, the possible dimeric combinations, including formation of
    charge transfer complexes between equal molar equivalents of
    hydroquinones and benzoquinones (Q + HQ <-> Q ... HQ), oligomers
    and polymers with various physical chemical properties are numerous
    and, hence, their specific chemical formulae are not shown in Fig.
    2.

         Autooxidation of hydroquinone is not synonymous with
    semiquinone autooxidation, which is also termed quinone redox
    cycling. The latter phenomenon entails redox cycling between a
    semiquinone and quinone in the presence of molecular oxygen,
    generating the superoxide anion radical [Eq. 3]. With
     p-benzosemiquinone and 2-hydroxy- p-benzoquinone, this reaction
    is not marked because the equilibrium constant for the
    disproportionation reaction (Ks) of  p-benzosemiquinone to
    hydroquinone and  p-benzoquinone [Eq. 4] is around two orders of
    magnitude higher than the equilibrium constant (Kc) for
    autooxidation of benzosemiquinone [Eq. 3]. Thus autooxidation of the
    semibenzoquinone does not significantly contribute to oxygen
    depletion as for other hydroquinone/quinone couples. In contrast,
    superoxide anion radical serves to reduce  p-benzoquinone to
     p-benzosemiquinone.

    CHEMICAL STRUCTURE 4

    CHEMICAL STRUCTURE 5

         Confusion over the significance of redox cycling [Eq. 3] has
    arisen from experiments performed in the presence of superoxide
    dismutase (SOD) which catalyses the dismutation of superoxide anion
    radical to H2O2 and O2 [Eq. 5]. Experiments in which addition
    of SOD has been shown to modulate quinone toxicity have often been
    interpreted as indicating that active oxygen species are involved in
    hydroquinone/quinone mechanism of action (oxidative stress). In
    fact, SOD "drives" the autooxidation of  p-benzosemiquinone to
     p-benzoquinone [Eq. 3] by removal of superoxide anion radical [Eq.
    5] (Winterbourn, 1981; Rossi  et al., 1986).

    CHEMICAL STRUCTURE 6

         Dry pure hydroquinone is very stable to oxidation by oxygen,
    darkening slowly upon prolonged exposure to air.

    2.3  Conversion factors

         1 ppm = 4.5 mg/m3 at 25 °C (1 atmosphere pressure)

         1 mg/m3 = 0.222 ppm at 25 °C (1 atmosphere pressure)

    2.4  Analytical methods

         Information about analytical methods for hydroquinone are
    contained in Devillers  et al. (1990) and NIOSH (1978). The
    procedures reported include colorimetry, column-, paper, thin-layer
    and gas chromatography, and HPLC. It should be noted that
    difficulties occur when hydroquinone is analysed by HPLC (Devillers
     et al., 1990). Trace metal impurities, concentration of dissolved
    oxygen in the mobile phase, pH of the solution, age of the water
    sample, and age and history of the guard column may each influence
    the analysis.

    2.4.1  Sampling

         Sampling techniques for air are outlined in Table 1.

    2.4.2  Methods of analysis

         Analytical methods are summarized in Table 2.

    FIGURE 2

    
    Table 1.  Sampling techniques for hydroquinone in air in the occupational setting
                                                                                                                      
    Method                Sample type        Comments                 Technique                       Reference
                                                                                                                      

    Midget                hydroquinone       hydroquinone             sample time =                   Oglesby
    impinger              dust               absorbed in              5-10 min; sample                et al. (1947)
                                             isopropyl alcohol        rate = 2.82 litres/min
                                             in an all-glass
                                             impinger

    Midget                hydroquinone       hydroquinone             air volume= 409-504 litres      Chrostek (1975)
    impinger              mist               collected in             for about 430 min
                                             distilled water;
                                             disadvantage:
                                             sample loss can
                                             occur from spillage

    Mixed cellulose       hydroquinone       filter with 0.8-µm       sample time =                   NIOSH (1976)
    ester                 aerosol            pore size and 37-mm      60 min; sample
    membrane                                 diameter                 rate = 1.5 litres/min
    filter                                   recommended;
                                             collection is >96%
                                                                                                                      

    Table 2.  Analytical methods
                                                                                                                                           
    Method              Sample type    Comments                                             Detection limit         Reference
                                                                                                                                           

    Potentiometric      aqueous        hydroquinone extracted twice with ethyl-             not stated              Stott (1942), 
    titration                          acetate (<99.4% extraction) followed                                         Levenson (1947),
                                       by titration; requires little equipment                                      Stevens (1945)
                                       but is difficult and time consuming

    Oxidiometric        aqueous        ceric sulfate with  o-phenanthrolineferrous          not stated;             Kolthoff & Lee (1946),
    titration                          sulfate complex (ferroin) used as indicator;         accuracy <99.98%        Brunner et al. (1949)
                                       simple and fast with easily discernible
                                       colour change

    Iodometric          aqueous        single methyl acetate extraction involving           not stated;             Baumbach (1946),
    titration                          potentiometric titration of metol (methyl- p-        reproducibility         Shaner & Sparks
                                       amino-phenol sulfate) followed by oxidation          (95.4-97.8%)            (1946)
                                       of both metol and hydroquinone with iodine

    Iodometric          urine          urine hydrolysed at 100 °C for 2 h with conc.        not stated              Baernstein (1945)
    titration                          H2SO4(pH 1.0); pH adjusted to 7.0 with sodium
                                       sulfite followed by extraction of phenols for
                                       4 h in a continuous liquid-liquid extractor;
                                       hydroquinone precipitated with lead acetate
                                       pH 6.5 plus pyridine-acetate buffer; filtrates
                                       acidified, reacted with bromine, and excess
                                       bromine back titrated with 0.2 mol/litre sodium
                                       sulfite after addition of potassium iodide;
                                       alternatively an iodine sensitive electrode can
                                       be used as indicator; disadvantage: ketones
                                       react in a similar manner to hydroquinone

    Colorimetry         aqueous        hydroquinone reacted with phloroglucinol             1-35 mg/m3              Oglesby et al. (1947)
                                       in NaOH; measured at 520 nm

    Colorimetry         aqueous        hydroquinone in styrene reacted with sodium          lower limit             Whettem (1949)
                                       tungstate and sodium carbonate; detected             < 0.01 mg/ml
                                       by visual comparison with standards

    Table 2. (contd).
                                                                                                                                           
    Method              Sample type    Comments                                             Detection limit         Reference
                                                                                                                                           

    Colorimetry         aqueous        reaction with 4-aminoantipyrine;                     0.05 ppm                Jacquemain et al.
                                       disadvantage; reacts with phenols                                            (1975)

    Spectrophotometry   aqueous        absorption wavelength not stated                     not stated              Chrostek (1975)

    Paper               aqueous        uses various solvent systems; separation             qualitative             Borecky (1963)
    chromatography                     of mixtures with hydroquinone is indistinct

    Paper               aqueous        three different solvent systems used;                qualitative             Stom (1975)
    chromatography                     stable derivative formed by reaction with
                                       benzene sulfinic acid

    Paper               aqueous        developed with potassium meta periodate              microgram quantities    Clifford & Wight (1973)
    chromatography

    Chromatography      cigarette      methylether hydroquinone derivative formed           qualitative             Commins & Lindsey,
    and                 smoke          by reactions of dimethyl sulfate and                                         (1956)
    spectrophotometry                  hydroquinone

    Gas                 aqueous        phenols extracted into methyl isobutyl               0.1 mg/litre            Cooper & Wheatstone,
    chromatography                     ketone; trimethylsilyl ethers prepared,                                      (1973)
                                       separated on a Chromosorb W (AW-DCMS)
                                       column coated with 5% tri-2,4-xylenyl
                                       phosphate; detected by flame ionization

    TLC                 aqueous        reaction with feric chloride and                     qualitative             Umpelev et al. (1974)
                                       K3 [Fe (CN)6]

    HPLC                aqueous        hydroquinone absorbed on mixed cellulose             0.84-4.05 mg/m3         NIOSH (1978)
                                       ester filter membrane; filters are extracted
                                       with 1% acetate; samples are injected onto a
                                       Partisil TM 10-ODS column with 1% ethanoic acid
                                       as mobile phase; detected at 290 nm

    Table 2. (contd).
                                                                                                                                           
    Method              Sample type    Comments                                             Detection limit         Reference
                                                                                                                                           

    HPLC                aqueous        separated on Merckogel PGM 2000 column               not stated              Seki (1975)
                                       with 0.05 mol/litre Pi (pH 6) followed by 0.05
                                       mol/litre Pi plus 0.66 mol/litre borate pH 6;
                                       detected at 280 nm

    HPLC                aqueous        separated on µBondapak C18 column with               > 2 µM                  Raghavan (1979)
                                       0.01 mol/litre Pi (pH 7); detected at 280 nm

    HPLC                air            hydroquinone oxidized to  p-benzoquinone             0.005 mg/m3             Levin (1988)
                                       by permanganate impregnated glassfibre               in a 5-litre air
                                       filter;  p-benzoquinone formed is trapped on         sample
                                       XAD-2 adsorbent and desorbed with acetonitrile;
                                       detection at 290 nm
                                                                                                                                           


    
    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

         Hydroquinone occurs in a variety of forms as a natural product
    from plants and animals. It has been found in non-volatile extracts
    of coffee beans (Högl, 1958) and other foods (see section 5.1.2),
    and as Arbutin (a glucoside of hydroquinone) in the leaves of
    blueberry, cranberry, cowberry and bearberry plants (Varagnat,
    1981). Hydroquinone formation from Arbutin in  Pyrus spp. is
    involved in fire blight resistance (Smale & Keil, 1966; Hildebrand
     et al., 1969). Hydroquinone is considered to be the most important
    component of the allelopathic interaction between the perennial weed
    leafy spurge  (Euphorbia esula) and the small everlasting
     (Antennaria microphylla). A differential ability to detoxify
    hydroquinone in the two species was observed in tissue cultures
    (Hogan & Manners, 1990, 1991). Hydroquinones have been isolated from
    marine sponges of  Dysidea sp. (Iguchi  et al., 1990) and from the
    marine colonial tunicate  Aplidium californicum (Howard  et al.,
    1979). Hydroquinone is also found in the bombardier beetle where it
    is involved in defensive biochemistry: the beetle can shoot a hot
    cloud of quinone, formed by the action of hydrogen peroxide,
    hydroquinone and catalase-peroxidase in the explosion chamber of the
    beetle, towards an oncoming enemy (Eisner  et al., 1977).

         The occurrence of hydroquinone in nature can originate from
    metabolic processes. Direct hydroxylation of phenol to form
    hydroquinone has been reported to occur when phenol was used as a
    substrate by cytochrome P-450-enriched extracts of  Streptomyces
     griseus (Trower  et al., 1988). Hydroquinone can also occur as a
    metabolite in the biodegradation of substituted phenols (e.g. Spain
     et al., 1979; Nyholm  et al., 1984). Hydrolytic  p-hydroxylation
    initiates the degradation of many polychlorinated phenolic compounds
    by  Rhodococcus chlorophenolicus with the formation of substituted
    hydroquinones (Häggblom  et al., 1988).

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         In 1979, the world capacity for the production of hydroquinone
    exceeded 40 000 tonnes (Varagnat, 1981). The annual production
    volume of hydroquinone in the USA was estimated to be about 12 000
    tonnes in 1985 (US EPA, 1985). Hydroquinone is manufactured in the
    USA, Japan, France, Italy, and China (IARC, 1977; Varagnat, 1981).
    In 1992, the world production was approximately 35 000 tonnes (USA:
    16 000; Europe: 11 000; Japan: 6000; Central and South America and
    Asian countries other than Japan: 2000) (personal communication from
    H. Naito, University of Tsukuba, to the IPCS in 1993).

         Hydroquinone can be manufactured commercially by several
    processes. In the aniline oxidation process aniline is oxidized with
    manganese dioxide and sulfuric acid to quinone; this is followed by
    reduction of the latter to hydroquinone by an aqueous solution of
    iron or by catalytic hydrogenation (Varagnat, 1981). Hydroquinone is
    also manufactured by hydroxylation of phenol with hydrogen peroxide
    as a hydroxylation agent. The reaction occurs with strong mineral
    acids or ferrous or cobaltous salts as catalysts (Varagnat, 1981). A
    third process to produce hydroquinone is hydroperoxidation of
    diisopropylbenzene. The para isomer is isolated and oxidized with
    oxygen to produce the corresponding dihydroperoxide, which is
    treated with sulfuric acid to produce acetone and hydroquinone (NTP,
    1989).

         Hydroquinone can also be formed, based on Reppe's synthesis, by
    carbonylation of acetylene under pressure. Finally, hydroquinone is
    obtained from the reaction of  p-isopropenylphenol and 30% aqueous
    hydrogen peroxide in acidic conditions, but these syntheses are not
    used for commercial production (Varagnat, 1981).

    3.2.2  Uses

         Hydroquinone has a multitude of used. It is used as a developer
    in black-and-white photography and related graphic arts such as
    lithography, rotogravure, and for medical and industrial X-ray films
    (Varagnat, 1981). It is also widely used in the manufacture of
    rubber antioxidants and antiozonants, monomer inhibitors, and food
    antioxidants to prevent deterioration in many oxidizable products,
    e.g., to stabilize vitamin A in fish oil, vitamins D and E,
    ß-carotene, and antibiotics in feeds, and as a chemical intermediate
    for the production of agrochemicals and performance polymers
    (Varagnat, 1981). Hydroquinone and products containing hydroquinone
    are used in cosmetics and medical skin preparations as a
    depigmenting agent to lighten small areas of hyperpigmented skin. It
    is also used in the treatment of melasma, freckles, senile
    lentigines, and postinflammatory hyperpigmentation (Varagnat, 1981;
    CIR, 1986). It is used as a coupler in oxidative hair dyeing (CIR,
    1986).

         In 1977, the use of hydroquinone in the USA was estimated to be
    as follows: photographic developers, 45%; antioxidants and
    polymerization inhibitors, 50%; other uses, 5%. Corresponding
    figures in western Europe were, respectively, 70%, 15% and 15%
    (Varagnat, 1981), and in Japan 30%, 50% and 20% for 1992 (personal
    communication from H. Naito, University of Tsukuba, to the IPCS in
    1993). In 1981, hydroquinone was an ingredient of 147 hair dyes and
    colour preparations and 23 skin care products, including products
    intended for medical use as skin lighteners in the USA (CIR, 1986).

         Like hydroquinone, many of its derivatives are reducing agents
    and have a wide variety of applications. Hydroquinone derivatives

    that are used as rubber antioxidants and antiozonants include
    dialkylated hydroquinone,  N-alkyl-p-aminophenol and
    diaryl- p-phenylenediamines. The main food antioxidants are
    butylated hydroxyanisole (BHA) and  tert-butylhydroquinone.

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         A calculation of fugacity, according to Mackay's model level I
    (Mackay & Paterson, 1981), shows that hydroquinone will be
    distributed mainly to the water compartment when released in
    the environment. This was also concluded by Devillers  et al.
    (1990).

    4.2  Transformation

    4.2.1  Biodegradation

         Biodegradation of hydroquinone is closely related to many
    variables such as pH, temperature and whether conditions are aerobic
    or anaerobic (Devillers  et al., 1990). It also depends on the
    acclimation level of the microorganisms involved (Tabak  et al.,
    1964; Harbison & Belly, 1982). Harbison & Belly (1982) investigated
    various pure cultures of microorganisms for their ability to utilize
    hydroquinone as sole carbon source. The pure cultures were isolated
    from soil, photographic sludge and laboratory sludge. When incubated
    with 750 mg/litre the isolates gave an average TOC (total organic
    carbon) removal of 97.5% in 5 days. After various incubation
    periods, the possible metabolites and end-products were analysed;
    1,4-benzoquinone, 2-hydroxy-1,4-benzoquinone and ß-ketoadipic acid
    were detected as metabolites. None of the compounds persisted in the
    cultures. Neujahr & Varga (1970) proposed that the first step in the
    degradation of hydroquinone by  Trichosporon cutaneum should be a
    hydroxylating step to hydroquinol. The ring fission should then
    probably result in ß-hydroxymuconate.

         The BOD5 (biological oxygen demand in 5 days)/COD (chemical
    oxygen demand) ratio, which is an indicator of biodegradability, has
    been reported to be 0.37 by Dore  et al. (1975) and 0.53 by Young
     et al. (1968). This indicates that under aerobic conditions
    hydroquinone is readily biodegradable.

         Devillers  et al. (1990) have summarized various metabolic
    pathways (Fig. 3).

    FIGURE 3

         Young & Rivera (1985) studied the methanogenic degradation of
    hydroquinone. When the microbial community from a municipal sewage
    treatment plant digester was acclimated to hydroquinone, the rate of
    metabolism and gas formation increased. The rate of substrate
    metabolism was 23.6 ± 2.0 (n=6) with acclimated microorganisms
    compared to 5.7 ± 1.4 (n=6) mg/litre per day with non-acclimated
    organisms. The rate of gas production (CO2 + CH4) was 9.33 ± 1.7
    and 5.70 ± 1.1 ml/litre culture fluid per day for acclimated and non
    acclimated organisms, respectively. Prior to mineralization
    hydroquinone was metabolized to phenol. The authors have summarized
    various anaerobic degradation steps and proposed the scheme in Fig.
    4.

         Stoichiometrically the anaerobic bioconversion of hydroquinone
    is described as follows:

    C6H6O2 + 3.5 H2O -> 2.75 CO2 + 3.25 CH4

    4.2.2  Abiotic degradation

         The photodegradation of hydroquinone has been discussed by
    Devillers  et al. (1990). Due to its intrinsic properties
    hydroquinone is relatively readily degraded by means of
    photodegradation. Phototransformation may occur from direct
    excitation or from induced or photocatalytic reactions.

         Freitag  et al. (1985) reported that when 62 ng hydroquinone
    adsorbed on silica gel was exposed to ultraviolet light (290 nm) for
    17 h, 57.4% of the hydroquinone was mineralized.

         Tissot  et al. (1985) measured changed toxicity due to
    phototransformation (Table 3). The phototransformation products were
     p-benzoquinone after 0.5 h and hydroxy  p-benzoquinone after 4
    and 22 h.
        Table 3.  Photoirradiation of hydroquinone and toxicity to  Daphnia magna measured as
    inhibition of motility after 24 h (from: Tissot  et al., 1985)
                                                                                            
    Initial          Irradiation    %              EC50 (mg/litre    HPLC analysis at the
    concentration    time           degradation    initial           end of the irradiation
                     (h)                           concentration)    period
                                                                                            

    67.1 mg/litre    0              0              0.15
    (6.1 x 10-4 M)   0.5            15             0.2                p-benzoquinone
                     4              49             0.2               10-4 M hydroxy
                                                                      p-benzoquinone
                     22             80             0.5               1.4 x 10-4 M hydroxy
                                                                      p-benzoquinone
                                                                                            
    
    FIGURE 4

    4.2.3  Bioaccumulation

         With a log  n-octanol/water partition coefficient of 0.59 it
    can be considered that hydroquinone does not bioaccumulate. The
    bioconcentration factors found in the literature for static tests
    are listed in Table 4.

    Table 4.  Bioaccumulation factors (BCF)a
                                                                       

    Species            Test       Hydroquinone   BCF   Comment
                       duration   concentration
                       (days)     (mg/litre)
                                                                       

    Activated sludge   5          0.05           870   dry weight basis

    Algae
     Chlorella fusca   1          0.05           40    wet weight basis

    Fish
     Leuciscus idus
     melanotus         3          0.05           40    wet weight basis
                                                                       

    a  From: Freitag  et al. (1985)

    4.3  Interaction with other physical, chemical or biological factors

         Tratnyek & Macalady (1989) report on direct abiotic reductions
    of nitro groups from nitro aromatic pesticides to amines by
    hydroquinones. In homogeneous solutions of quinone-hydroquinone
    redox couples, which were selected to model the redox-labile
    functional groups in natural organic matter, rapid abiotic reduction
    of nitro aromatic pesticides occurred. The authors proposed that
    hydroquinones contribute to the reduction of pollutants in the
    environment, but their role is likely to be complex.

         The water hyacinth  (Eichhornia crassipes), which is used for
    water treatment, clears more than 98% hydroquinone (50 mg/litre)
    after about 48 h (O'Keeffe  et al., 1987). This property has been
    attributed to enzymatic metabolism by polyphenol oxidases.

    4.4  Ultimate fate following use

         Hydroquinone occurs in photo-processing effluents (Dagon, 1973;
    Harbison & Belly, 1982). However, it is not certain that it reaches
    the water ecosystem, because reliable monitoring data are not
    available.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air, soil and water

         No monitoring data have been found concerning ambient free
    hydroquinone concentrations in air, soil or water. However,
    hydroquinone has been identified in tobacco smoke and measured in
    mainstream smoke from non-filtered cigarettes at amounts ranging
    from 110 to 300 µg per cigarette, with a ratio of the sidestream to
    mainstream concentration of 0.7-0.9 (IARC 1986).

    5.1.2  Food

         Free and conjugated (Arbutin) hydroquinone exist as natural
    components of a variety of plant-derived beverages and food
    products.

         Högl (1958) identified hydroquinone in the non-volatile extract
    of coffee beans. Hydroquinone concentrations in roasted coffee have
    been reported to range between 25 and 40 mg/kg (Maier, 1981). Gold
     et al. (1992) estimated that one cup of coffee would contain
    approximately 100 µg hydroquinone. Teas prepared from leaves of
    blueberry, cowberry, cranberry and bearberry have been reported to
    contain hydroquinone at concentrations sometimes exceeding 1%
    (Deichmann & Keplinger, 1981).

         The concentrations of free and total (free hydroquinone and
    Arbutin) hydroquinone have been measured in a variety of foods and
    beverages by Hill  et al. (1993); results indicate that significant
    exposure to hydroquinone can occur through dietary sources. In most
    of the samples (Table 5) derived from plant sources, the levels of
    Arbutin are considerably higher than those of free hydroquinone.
    However, Arbutin is hydrolysed readily by dilute acids yielding
    hydroquinone and glucose. Therefore, both free hydroquinone and
    Arbutin may contribute to hydroquinone exposure from natural sources
    as well as to the daily intake of dietary antioxidants.

         Adhesives containing trace amounts of hydroquinone are
    permitted as a component of food packaging in the USA (FDA, 1981;
    1991).

    
    Table 5.  Concentrations of free and total hydroquinone in various foods and
              beverages
                                                                                 
    Food sample                                   Concentrations  (mg/kg ± SD)a
                                                    Free HQ        Total HQb
                                                                                 

    Wheat germ, toasted                             0.591          8.352
    Drip-brewed coffee (pre-ground)                 0.293 ± 0.003  0.385 ± 0.016
    Whole wheat bread (100% whole wheat)            0.584 ± 0.202  0.893 ± 0.480
    Whole wheat cereal (commercially available)     0.205 ± 0.019  0.992 ± 0.161
    Processed corn cereal (commercially available)  bkgb           bkg
    Pear skin (D'Anjou, fresh)                      bkg            38.057
    Pear flesh (D'Anjou, fresh)                     bkg            1.301
    Milkfat (2%) homogenized milk                   bkg            bkg
    Yogurt (black cherry)                           bkg            bkg
    Cantaloupe                                      bkg            bkg
    Diet cola                                       0.0362         0.0287
                                                                                 

    a  bkg = background levels comparable to that observed in control blanks
    b  Includes free hydroquinone and hydroquinone released following treatment
       of the samples with ß-glucosidase
        5.2  General population exposure

         Photohobbyists, who develop their own black-and-white films (a
    process which utilizes hydroquinone) may be exposed dermally.
    Exposure to dust is also possible when preparing developer
    solutions. In 1980, the number of photohobbyists was estimated to be
    about 2.2 million in the USA (US EPA, 1985). There are no data on
    exposure levels.

         Dermal exposure to hydroquinone may also occur from products
    intended for cosmetic and medical use. In the USA, hydroquinone has
    been used in cosmetics, and in over-the-counter (OTC or
    non-prescription) and prescription drugs. Both OTC and prescription
    drugs are used to lighten areas of hyperpigmented skin. In
    cosmetics, concentrations of < 0.1% to 5% have been reported
    (CIR, 1986). OTC skin lighteners may contain up to 2% hydroquinone
    and prescription drugs may contain higher concentrations. In the EC
    countries, hydroquinone is restricted for use in cosmetics to 2% or
    less (Boyle & Kennedy, 1985). The US Food and Drug Administration
    has issued a Notice of Proposed Rule-making for the use of
    hydroquinone as a skin lightener in OTC drugs at concentrations
    below 1.5-2.0% (FDA, 1982).

         Skin-lightening creams containing hydroquinone are frequently
    inadequately labelled and the concentration often exceeds the limit

    of 2%; it is likely to be much stronger than 2% (Brauer, 1985;
    Godlee, 1992) and even up to 7% (Boyle & Kennedy, 1986).

         A 2% upper limit on hydroquinone concentration, set by the
    South African government in 1980 and followed by the United Kingdom
    and USA, was based on tests of cutaneous irritancy (Arndt &
    Fitzpatrick, 1965) and contact dermatitis (Bentley-Philips & Bayles,
    1975).

    5.3  Occupational exposure

         Hydroquinone can be encountered in solid form or in solution
    during its production and use (NIOSH, 1978). It has a very low
    vapour pressure, but can be oxidized in the presence of moisture to
    form quinone, which is more volatile. The saturated concentration in
    air for hydroquinone vapour under standard conditions is estimated
    to be 0.108 mg/m3 (approximately 0.024 ppm at 25 °C) (NIOSH,
    1978).

         There are some industrial hygiene monitoring data available for
    hydroquinone. Oglesby  et al. (1947) reported 20-35 mg
    hydroquinone/m3 in a packaging area without exhaust cabinet and
    1-4 mg/m3 in a packaging area with exhaust cabinet in a plant
    manufacturing hydroquinone. However, the analytical methods did not
    distinguish between hydroquinone and quinone. Industrial data,
    provided to the US EPA (1985), indicated worker inhalation exposure
    due to closed production processes within one manufacturing facility
    at an arithmetical average concentration of 0.79 mg/m3 (± 0.52
    standard deviation) and a highest average concentration of 0.2
    mg/m3 in another facility. In the unloading area of a production
    facility the arithmetic average air concentration was reported to be
    0.13 mg/m3 (± 0.15 standard deviation). The concentration of
    hydroquinone was measured in the workroom air in 12 Finnish plants
    (altogether 36 samples) during the period 1950-89 (Rantanen  et
     al., personal communication to the IPCS, 1992). Most samples were
    collected in the printing industry (23 samples from five plants).
    The occupational exposure limit of 2 mg/m3 was exceeded in only
    one measurement: 9.5 mg/m3 during charging of hydroquinone in a
    gas plant in 1962, a short operation carried out once every three
    weeks. Approximately 470 000 workers in the USA are potentially
    exposed to hydroquinone in about 137 occupations (US EPA, 1985).
    Certain occupations in which hydroquinone exposure may occur are
    listed in Table 6. Some of the national occupational air exposure
    limits used in various countries are compiled in Table 7.

    Table 6.  Occupations with potential exposure to hydroquinonea
                                                                       

    Antioxidant makers
    Drug makers
    Hair dressers and cosmetologists
    Hydroquinone manufacturing workers
    Paint makers
    Photo processors
    Organic chemical synthesizers
    Photographic developer makers
    Plastic stabilizer workers
    Rubber coating workers
                                                                       

    a  From: Key  et al. (1977); NIOSH (1978); NIOSH (1990)

    Table 7.  National occupational air exposure limits used in various
              countries (from: IRPTC, 1987; ILO, 1991)
                                                                       

    Country                       TWAa           STELb         
    CLVc
                                  (mg/m3)        (mg/m3)        (mg/m3)
                                                                       

    Australia                     2
    Belgium                       2
    Denmark                                      2
    Finland                                      2              4
    France                                       2
    Germany                       2d
    The Netherlands               2
    Poland                                       2              2
    Romania                       1                             2
    Sweden                        0.5            1.5
    Switzerland                   2              4
    United Kingdom                2              4
    USA: ACGIH                    2
         NIOSH/OSHA               2
    Yugoslavia                    2
                                                                       

    a  TWA = time-weighted average; a maximum mean exposure limit based
       generally over the period of a working day
    b  STEL = short-term exposure limit
    c  CLV = ceiling level value
    d  inhalable dust

    6.  KINETICS AND METABOLISM

         The main results pertinent to this chapter, with the exception
    of section 6.5, have been summarized in Table 8 and will be expanded
    upon only where necessary. Table 8 shows that the majority of
    studies have been performed in Fischer-344 rats.

    6.1  Absorption

         Absorption of orally administered or intratracheally instilled
    hydroquinone is rapid and extensive (Garton & Williams, 1949;
    Divincenzo  et al., 1984; English  et al., 1988). However, the
    rate of hydroquinone absorption through the skin is low. Marty  et
     al. (1981) reported that the  in vitro permeability constants for
    rat and human skin were 28 x 10-6 and 4 x 10-6 cm/h,
    respectively. Based on the data of Bucks  et al. (1988), an  in
     vivo human dermal absorption rate of 3 µg/cm2.h and a
    permeability constant of 2.25 x 10-6 cm/h can be calculated. The
    actual amount of hydroquinone absorbed following dermal exposure
    depends on the exposure concentrations, length of exposure and
    vehicle, as well as other factors. When Bucks  et al. (1988)
    applied 14C-labelled hydroquinone in an alcoholic vehicle to the
    foreheads of human volunteers for 24 h, 57% of the total 14C label
    was excreted in the urine after 5 days. Addition of a sun screen to
    the hydroquinone solution reduced total excretion to 26%.

    6.2  Distribution

         Following the oral administration of radiolabelled hydroquinone
    to F-344 rats, radioactivity was widely distributed throughout the
    animal tissues. The highest activity was localized in the kidney and
    liver (Divincenzo  et al., 1984). However, on a quantitative basis,
    the amount retained within the animal was low, representing < 2%
    of the total dose 48 h after exposure (Divincenzo  et al., 1984;
    English  et al., 1988). Widespread distribution and extensive
    elimination was also observed following intratracheal administration
    of hydroquinone to F-344 rats (Lockhart & Fox, 1985b). However,
    following the intravenous injection of radiolabelled hydroquinone to
    F-344 rats, radioactivity was shown, using whole body
    autoradiographic techniques, to concentrate in the bone marrow,
    thymus and white pulp of the spleen (Greenlee  et al., 1981a).
    Subsequent experiments indicated that significant acid soluble and
    covalently bound radioactivity could be recovered in the thymus,
    bone marrow and white blood cells 24 h after intravenous
    administration (Greenlee  et al., 1981b). These results indicate
    that the route of administration may influence the profile of
    distribution and elimination observed following hydroquinone
    administration.


    
    Table 8.  Summary of toxicokinetic data for hydroquinone (HQ)
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Oral administration

    Species: rabbits                                                                                    less than 1% of the dose     Garton &
    Treatment: 3-6 rabbits                                                                              was excreted unchanged;      Williams
    received 100 or 200 mg/kg                                                                           about 80% of the dose was    (1949)
    HQ as a single dose; urine                                                                          recovered as glucuronide
    metabolites analysed after                                                                          and monosulfate conjugates
    24 h                                                                                                in the urine

    Species: Sprague-Dawley     T1 & T2: rapid and   T1 & T2: for 200 mg/kg      the major radio-       mainly in the urine;         Divincenzo
    rats (m)                    extensive based      0.28-1.25% and              labelled species in    elimination for T1 and       et al.
    Treatment: (T1) 2-4 rats    upon urinary         0.26-0.56% of               the urine were: HQ     T2 was similar; after        (1984)
    per group received 5, 30    excretion            administered radioactivity  monoglucuronide, HQ    48 h around 95% of
    or 200 mg/kg [14C]-HQ as a                       recovered in carcass        monosulfate and HQ     dose had been excreted
    single dose; rats were                           and tissues after 48 h      (T1: 56%, 42% and      in urine (90%), faeces (4%)
    observed for 48 and 96 h                         and 96 h, respectively;     1%; T2: 72%, 23%       and CO2 (0.4%); no
    before sacrifice.                                widely distributedand 1%)                          difference in elimination
    (T2) 4 rats pretreated with                      throughout tissues                                 between single and
    200 mg/kg unlabelled HQ                          with highest concentration                         repeated doses
    once a day for 4 days                            in liver and
    followed by 200 mg/kg                            kidney
    [14C]-HQ on day 5; rats
    observed for 48 h

    Table 8. (contd).
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Species: Fischer-344        T1 & T2: rapid and   T1 & T2: < 1% of            T1 & T2: the major     Excreta                      English
    rats (m,f)                  extensive based      administered                radiolabelled species  T1 & T2: mainly excreted     et al.
    Treatment: (T1) 8 (m,f)     upon peak blood      radioactivity recovered     in the urine were      in the urine; after 48 h     (1988)
    rats per group received 25  concentration        in carcass and              HQ monoglucuronide     around 90% of the
    or 350 mg/kg [14C]-HQ as    within 0.8 h of      tissues for each dose       (44-54%), HQ mono-     administered radioactivity
    a single dose.              dosing and urinary   after 48 h; twice as        sulfate (19-33%),      was recovered as urine
    (T2) 8 rats (m,f)           excretion;           much radioactivity          HQ (0.25-7%), HQ       (approx.78%), cage rinse
    pretreated with 25 mg/kg    no sex               recovered in the            mercapturate           (approx.12%) and faeces
    unlabelled HQ once a day    differences          liver and kidney            (0.16-4.68%) and       (approx.2.2%); dose-related
    for 14 days followed by 25                       of females compared         p-benzoquinone         differences were observed
    mg/kg [14C]-HQ on day 15;                        with males                  (0.24-0.84%); no       at 8 h, 54% (m) and 45% (f)
    after oral administration                                                    sex difference         of the dose was excreted
    4 rats per dose and                                                                                 renally by the high-dose
    sex were designated                                                                                 group compared with 81% (m)
    for blood collection                                                                                and 82% (f) for the low-
    samples (up to 96 h)                                                                                dose group
    and for excreta and
    radiodistribution                                                                                   Blood kinetics
    (up to 7 days)                                                                                      AUC values were increased
                                                                                                        by 17-fold (m) and 26-fold
                                                                                                        (f) for a 13- and 14-fold
                                                                                                        higher mean dose; most of
                                                                                                        radioactivity was excreted
                                                                                                        by 8 h and was associated
                                                                                                        mainly with alpha-
                                                                                                        elimination phase (T´ =
                                                                                                        0.23-1.72 h); accurate ß T´
                                                                                                        could not be determined
                                                                                                        because of the appearance
                                                                                                        of a second peak in the
                                                                                                        blood concentration versus

    Table 8. (contd).
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Species: Fischer-344        rapid and extensive  low distribution,           by 8 h, major          time curve by 24 h,          Lockhart
    rats (m,f)                  absorption as        i.e. less than 1%;          metabolites found      recovery was more than 92%   et al.
    Treatment: a single dose    indicated by marked  no significant              in urinewere HQ        in urine, approx.2% in       (1984);
    of 5, 25 or 50 mg [U-14C]-  recovery of [14C]    differences between         glucuronide            faeces and less than 0.2%    Lockhart
    HQ/kg body weight by        in urine by 24 h     sexes                       (approx.50%),          in CO2                       & Fox
    gavage                                                                       HQ sulfate                                          (1985a)
                                                                                 (approx.30%) and
                                                                                 HQ (approx.2%);
                                                                                 neither dose- nor
                                                                                 sex-dependent

    Species: Fischer-344        rapid and extensive  low distribution:           by 8 h, major          by 24 h, recovery was        Lockhart
    rats (f)                    absorption as        approx. 0.55% in liver and  metabolites found in   approx.92% in urine,         & Fox
    Treatment: 5 rats per dose  indicated by marked  0.64-0.9% in carcass        urine were HQ          approx.2.6% in faeces and    (1985a)
    group 5, 25 or 50 mg        recovery of [14C]                                glucuronide (approx.   approx.0.3% in CO2
    [U-14C]-HQ/kg body weight   in urine by 24 h                                 46%), HQ sulfate
    (single gavage dose)                                                         (approx.29-36%) and
                                                                                 HQ (approx.2.5%)

    Dermal administration
    In vitro: Rat or human      overall absorption                                                                                   Marty et
    skin biopsy; repeated       and permeability                                                                                     al. (1981)
    dosing with 40 mg/cm2 in    constant were low
    water; observed for 24 h    but on average
                                7-fold greater for
                                rat than human skin

    In vivo: Mouse or rat       absorption by        local cutaneous                                    combined urine and faecal
                                mouse was low;       distribution was high                              elimination was low;
                                1.6% after 6 h       in rat                                             approx.10% after 96 h in
                                                                                                        the rat

    Table 8. (contd).
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Species: human              average percutaneous                                                                                 Bucks et
    Treatment: 6 normal adult   taneous absorption                                                                                   al. (1988)
    male volunteers had 2%      estimated from
    (w/w) HQ in ethanol         urinary elimination
    (approx.70%) plus 0.2%      data was 57% after
    ascorbic acid applied to    120 days; sun-
    their foreheads for 24 h;   screens decreased
    single dose = 125 µg/cm2;   absorption but
    observed for up to 120 h    penetration
                                enhancers were
                                without effect

    Species: Fischer-344        skin irritated but                                                      after 1 week, 15-18% HQ      English
    rats (m,f)                  poorly absorbed;                                                        was recovered in urine and   et al.
    Treatment: 8 (m,f) rats     large interanimal                                                       cage rinsings, 1.7-3.7% in   (1988)
    per group were dermally     variation in                                                            the faeces, 2.6 to 12.9%
    exposed for 24 h to 25      disposition; removal                                                    in the body and 0.14 to
    or 150 mg/kg [14C]-HQ       of HQ after skin                                                        2.2% in the excised
    dissolved in distilled      washing with soapy                                                      skin exposure site
    water for 24 h              water was close to
                                100% after 10 min of
                                exposure or around
                                65% after 24 h of
                                exposure

    Table 8. (contd).
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Intravenous administration
    Species: Fischer-344 rat (m)                     whole body                                                                      Greenlee
    Treatment: 1.3 mg/kg                             autoradiography showed                                                          et al.
    [14C]-HQ in saline                               that [14C] concentrated                                                         (1981a)
    administered as a single                         most in the white pulp
    dose; one group of rats                          of the spleen, bone marrow
    was pretreated with                              and thymus; Aroclor 1254
    Aroclor 1254 (250 mg/kg                          pre-treatment decreased
    i.p.)                                            the tissue/blood optical
                                                     density by approx.60% for
                                                     the thymus and bone marrow

    Species: Fischer-344 rat (m)                     acid-insoluble                                                                  Greenlee
    Treatment: rats received                         radioactivity associated                                                        et al.
    14 mg/kg [14C]-HQ as a                           with protein increased                                                          (1981b)
    single administration; one                       with time in the bone
    group of rats was                                marrow > thymus > liver;
    pretreated with Aroclor                          pretreatment with Aroclor
    1254                                             resulted in a significant
                                                     decrease in the
                                                     radioactivity measured in
                                                     the bone marrow

    Intratracheal instillation
    Species: Fischer-344        rapid and extensive  < 0.13% in lung, less       by 8 h, major          by 48 h recovery was         Lockhart
    rats (m)                    absorption as        than 1% to other organs     metabolites recovered  more than 92% in urine,      & Fox
    Treatment: 5 rats per dose  indicated by                                     in the urine were      approx.2% in faeces and      (1985b)
    group: 5, 25 or 50 mg       recovery in urine                                HQ-glucuronide         less than 0.2% in CO2
    [U-14C]-HQ/kg; 2 rats per   within 24 h                                      (approx.50%),
    control group                                                                HQ-sulfate
                                                                                 (approx.30%) and
                                                                                 HQ (approx.2%)

    Table 8. (contd).
                                                                                                                                               
    Species and                 Absorption           Distribution                Metabolic              Elimination and              Reference
    treatment                                                                    transformation         excretion
                                                                                                                                               

    Intraperitoneal administration
    Species: Wistar rat (f)                                                      metabolites recovered  elimination was rapid with   Inoue et
    Treatment: 9 rats received                                                   in urine were 1,2,4-   84% of the metabolites       al.
    a single 50 mg/kg dose                                                       benzenetriol (11%),    recovered within 4 h after   (1989a)
                                                                                 catechol (1%) and      administration; by 24 h,
                                                                                 hydroquinone (87%)     recovery of 1,2,4-
                                                                                                        benzenetriol, catechol and
                                                                                                        hydroquinone in the acid-
                                                                                                        hydrolysed urine comprised
                                                                                                        38% of the administered
                                                                                                        dose

    Species: Japanese white                                                      metabolites recovered  by 24 h, recovery of         Inoue et
    rabbits                                                                      in urine were 1,2,4-   1,2,4,-benzenetriol,         al.
    Treatment: 5 rabbits                                                         benzenehydrotriol      catechol and quinone in      (1989b)
    received a single 50 mg/kg                                                   (12%), catechol (1%)   the acid-hydrolysed urine
    dose                                                                         and hydroquinone       comprised 40% of the
                                                                                 (86%)                  administered dose
                                                                                                                                               


    
    6.3  Metabolic transformation

         Hydroquinone is converted mainly by Phase II metabolism to
    water-soluble conjugates, as shown by the recovery of only little
    parent compound and  p-benzoquinone (0.25-7%) but large amounts of
    hydroquinone-monoglucuronide and hydroquinone-monosulfate (>90%) in
    the urine (Divincenzo  et al. 1984; English  et al. 1988). A small
    percentage of the dose was recovered as the mercapturic acid
    conjugate of hydroquinone, suggesting the intermediate formation of
    a glutathione conjugate of hydroquinone.

         Divincenzo  et al. (1984) demonstrated that repeated dosing
    with 200 mg hydroquinone/kg did not alter the relative or absolute
    rat liver weight or induce the hepatic mixed-function oxidase
    system, nor did hydroquinone undergo Phase I oxidation to other
    metabolites such as 1,2,4-trihydroxybenzene. In addition, the
    formation of 1,2,4-trihydroxybenzene was not observed in the urine
    after oral administration of hydroquinone to rabbits (Garton &
    Williams, 1949). However, following intraperitoneal injection of
    hydroquinone (50 mg/kg) in Wistar rats and Japanese white rabbits,
    1,2,4-trihydroxybenzene represented a significant proportion
    (approximately 12%) of the metabolites recovered in the urine (Inoue
     et al., 1989a,b). This apparent difference in the metabolic
    profile observed when hydroquinone is administered by the
    intraperitoneal route rather than the oral route is probably related
    to the efficient ability of the gastrointestinal system to conjugate
    phenolic compounds absorbed in the intestine, thus reducing the
    amount of free hydroquinone available for Phase I metabolism in the
    liver (Powell  et al., 1974; Cassidy & Houston, 1980a,b; Cassidy &
    Houston, 1984). Fig. 5 shows proposed metabolic pathways for
    hydroquinone biotransformation in Fischer-334 rats.

    FIGURE 5

    6.4  Elimination and excretion

         Hydroquinone is excreted mainly in the form of water soluble
    metabolites via the urine (about 90%). Dose-related differences have
    been observed for rats receiving 25 or 350 mg/kg, which suggests
    that elimination processes are saturated at high-dose levels
    (English  et al., 1988). The area under the curve (AUC) values for
    plasma concentration, which provide an index of bioavailability,
    also showed that saturation of elimination had occurred at high-dose
    levels, particularly for females. The fact that most of the
    radioactivity excreted is associated with the alpha-elimination
    phase suggests that this may be due to conjugation of hydroquinone
    to readily excreted metabolites. The appearance of a double peak in
    the blood concentration versus time curve indicates that
    enterohepatic recycling of hydroquinone may have occurred.

    6.5  Reaction with body components

         The available studies suggest that hydroquinone derivatives are
    responsible for many of the toxicological effects associated with
     in vivo and  in vitro hydroquinone exposure. Hydroquinone itself
    may be responsible for the acute CNS signs (tremors and convulsions)
    that are seen within the first hour following hydroquinone exposure
    (see section 7.8.3), since the signs appear soon after exposure when
    significant metabolism has probably not occurred. However, it is
    possible that derivatives even have a role in inducing CNS effects.

         The derivatives formed from hydroquinone may differ between  in
     vivo and  in vitro studies. Even when the  in vivo situation
    alone is considered, the derivatives may vary qualitatively and
    quantitatively, and the concentrations of derivatives in the various
    body compartments may be different depending on the route of
    exposure. When hydroquinone is administered by expected routes of
    exposure, the primary derivatives should be largely glucuronide and
    sulfate conjugates, which are quickly exported, as well as
    glutathione conjugates, which may represent activated metabolites.
    When hydroquinone is given by intraperitoneal or intravenous routes,
    the primary metabolites are expected to be 1,4-benzoquinone and
    1,2,4-trihydroxybenzene. In most  in vitro systems the primary
    metabolite is expected to be 1,4-benzoquinone. Hydroquinone-and
    oxygen-derived radical species are also likely to be formed both  in
     vivo and  in vitro. The hydroquinone-derived metabolites and
    radical species formed  in vitro will depend on the oxygen content,
    the pH, the ionic strength, the autooxidant and the protein content
    of the culture or reaction medium used in the study, as well as
    other factors including the metabolic capacity of the test system.

         The differences in the potential derivatives and the
    concentrations of the derivatives occurring in the different  in
     vivo and  in vitro exposure systems studied indicate that
    extrapolations from  in vitro to  in vivo systems and between
    routes of exposure need to be made with a great deal of care.

         The main results pertinent to this section have been summarized
    in Table 9, which shows that many of the interactions of
    hydroquinone have been identified  in vitro but not all have been
    demonstrated  in vivo. Hydroquinone reacts with many different
    biological components, including macromolecules such as protein,
    DNA, tubulin, lipids, and low molecular weight molecules such as
    sulfydryls and nucleotides, is toxic to different cell types, has
    affects on cellular metabolism, and modulates enzyme activities.

         Covalent binding and oxidative stress are mechanisms postulated
    to be associated with hydroquinone-induced toxicity. Both oxidized
    hydroquinone species ( p-benzosemiquinone radical and
     p-benzoquinone) and thiol-hydroquinone/quinone conjugates are
    believed to contribute to hydroquinone toxicity.

         Oxidized hydroquinone derivatives can covalently bind cellular
    macromolecules or alkylate low molecular weight nucleophiles, e.g.,
    glutathione (GSH), resulting in enzyme inhibition, alterations in
    nucleic acids and oxidative stress; however, redox cycling is not
    likely to contribute significantly to oxidative stress in contrast
    with other hydroquinones and quinones (see section 2.2; Rossi  et
     al., 1986; O'Brien, 1991). The reaction of benzoquinone with GSH
    results in the formation of GSyl conjugates which can be processed
    to cysteine conjugates. These latter thiol conjugates have been
    speculated to mediate cellular toxicity in the kidney by alkylation
    and/or oxidative stress, possibly involving redox cycling (Lau  et
     al., 1988).


    
    Table 9.  Summary of the reactions of hydroquinone (HQ) with biological componentsa
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Reactions with macromolecules

    Covalent binding to       14 mg/kg [14C]-HQ was administered            acid-insoluble radioactivity associated with      Greenlee et al.
    cell protein              i.v. as a single dose to Fischer-344 rats     protein increased with time in the bone           (1981b)
    (in vivo)                 (m); after 2 and 24 h, acid-insoluble         marrow > thymus > liver; pretreatment with
                              radioactivity associated with proteins        Aroclor resulted in a significant decrease in
                              was determined; one group of rats was         the radioactivity measured in the bone marrow
                              pretreated with Aroclor 1254

    Covalent binding to       25-75 mg/kg [14C]-HQ was incubated            radioactivity associated with protein; the        Eastmond et al.
    boiled rat liver          in the absence or presence of phenol          presence of PhOH enhanced this association        (1987)
    protein (in vitro)        (PhOH) (75 mg/kg) with H2O2-horseradish
                              peroxidase or freshly isolated human
                              polymorphonuclear leucocytes in the
                              presence of boiled rat liver protein

    Covalent binding to       75 mg/kg [14C]-HQ alone or coadministered     after 18 h of administration, acid-insoluble      Subrahmanyam et
    cells (in vivo)           with phenol (PhOH) (75 mg/kg)                 radioactivity was found associated with           al. (1990)
                              was administered i.p. (probably as a          kidney > blood > bone marrow; coadministration
                              single dose) to pathogen-free male            with PhOH significantly (statistically)
                              B6C3F1 mice (5-12); after 4 and 18 h,         increased binding to blood and bone marrow
                              acid-insoluble radioactivity associated       but not kidney or liver
                              with macromolecules was isolated and
                              analysed for covalent binding

    Covalent binding to       isolated liver microsomes from male           radioactivity associated with microsomal          Wallin et al.
    microsomal proteins       S-D rats, either treated or untreated with    proteins; binding was more extensive than         (1985)
    (in vitro)                phenobarbital or 3-methyl cholanthrene,       that of phenol and independent of electron
                              was incorporated with [14C]-HQ, both with     donors
                              and without NADPH

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Covalent binding to       peritoneum macrophages isolated from          [14C]-HQ was activated by macrophages to          Schlosser et
    cells (in vitro)          male C57BL/6 mice were incorporated           metabolites that bind irreversibly to protein;    al. (1989);
                              with [14C]-HQ                                 activation was inhibited by peroxidase inhibitor  Schlosser &
                                                                            aminotriazine and the nucleophile cysteine and    Kalf (1989)
                                                                            enhanced by arachidonic-acid-mediated
                                                                            prostagladin synthesis catalysed reaction

    Covalent binding to       bone marrow macrophages and a fibroblastoid   radioactivity associated with macrophages was     Thomas et al.
    cells (in vitro)          stromal cell (LTF) line obtained              16-fold higher than for LTF cells; DT-            (1989); Ross et
                              from male B6C3F1 mice were incorporated       diaphorase activity [Q -> HQ] was 4 times         al. (1990)
                              with [14C]-HQ                                 higher on LTF cells than in macrophages;
                                                                            slightly decreased (approx.16%) by addition of
                                                                            dicoumarol, an inhibitor of DT-diaphorase,
                                                                            for LTs but not macrophages

    Chromosomal aberration    example: bone marrow cells were isolated      micronuclei induced in polychromatic              Tunek et al.
    (in vivo) (see also       from male NMRI mice (4 per group)             erythrocytes                                      (1982)
    section 7.6)              administered between 20 and 100 mg HQ/kg
                              by subcutaneous injection once a day for
                              6 days

    Mitochondrial DNA         mitoplasts isolated from rabbit bone          covalent adduct formed with guanine               Rushmore et
    (in vitro)                marrow cells were prelabelled with                                                              al. (1984)
                              [3H]-dGTP incorporated with [14C]-HQ and
                              assayed for guanosine adduct formation

    DNA damage (in vitro)     example: calf thymus DNA was incubated        two adducts identified                            Jowa et al.
    (see also section 7.6)    with [14C]-HQ in the presence of Fe3+ at                                                        (1990)
                              pH 7.2

    Microtubulin binding      T1: isolated brain microtubulin from male     T1: HQ inhibited microtubulin polymerization      Irons & Neptun
    (in vitro)                Fischer-344 rats was incubated with between   and bound to high molecular weight tubulin;       (1980)
                              1 and 1.5 x 10-4 mol/litre [14C]-HQ           anaerobic conditions inhibited polymerization

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

                              T2: isolated spleen lymphocytes from rat      T2: HQ suppressed lectin-induced blastogenesis    Pfeifer & Irons
                              were incubated with HQ (10-6-10-4 mol/litre)  and concomitant inhibition of cell                (1983)
                                                                            agglutination

    Lipids (in vivo)          SD rats received a single oral dose of 100    urinary MDA increased in HQ-treated rats          Ekström et
                              or 200 mg HQ/kg; malondialdehyde (MDA),                                                         al. (1988)
                              a lipid peroxidation product, was analysed
                              in the excreted urine for up to 18 h

    Cytochrome c3+            stop- and continuous-flow experiments         HQ reduces cytochrome c3+ via                     Yamazaki & Ohnishi
    reduction (in vitro)                                                    p-benzosemiquinone; reaction accelerated by       (1969); Ohnishi
                                                                            p-benzoquinone                                    et al. (1969)

    Reactions with low molecular weight molecules

    Thiol conjugation         glutathione                                   thiol conjugates formed by reductive addition;    Tunek et al.
    (in vitro)                                                              monothiol HQ conjugate formed by the reaction     (1980)
                                                                            of p-benzoquinone with thiol after oxidation of
                                                                            HQ to the semiquinone or quinone

                              glutathione                                   di, tri and tetra (GSyl)-HQ conjugates are        Eckert et al.
                                                                            formed by reductive addition of the oxidized      (1990)
                                                                            (GSyl)-HQ conjugate, i.e. quinone conjugate with
                                                                            GSH

                              monocysteine-HQ conjugate                     HQ oxidized by prostaglandin H systhetase         Schlosser et
                                                                                                                              al. (1990)

    Nucleotide adduct         [3H]-deoxyguanosine and [14C]-HQ              two doubly labelled products isolated; adduct     Jowa et al.
    (in vitro)                incubated in the presence of Fe3+ at pH 7.2   2: 3-OH benzethano (1, N2) deoxyguanosine         (1990)

    2-Thiobarbituric          glutamate or deoxyribonucleic acid            2-thiobarbituric acid produced; hydroxyl radical  Rao & Pandya
    acid (in vitro)           incorporated with HQ plus Cu2+ at pH 7.4      (OH) formation thought to be involved            (1989)

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Toxicity to cells

    Erythrocytes (in vivo)    polychromatic erythrocytes isolated from      20 mg/kg: no haemotoxic effect; 100 mg/kg:        Tunek et al.
                              male NMRI mice (4 per group)                  haemotoxic effects (suppressed bone marrow        (1982)
                              administered between 20 and 100 mg            cellularity)
                              HQ/kg s.c. once a day for 6 days

    Bone marrow (in vivo)     i.p. administration of HQ (100 mg/kg, twice   transient, mild suppression in bone marrow        Eastmond et
                              daily for 12 days to six male B6C3F1 mice)    cellularity                                       al. (1987)

                              i.p. co-administration of HQ (25-75 mg/kg)    significant decrease in bone marrow cellularity;  Eastmond et
                              and phenol (75 mg/kg) twice daily for         phenol enhanced HQ-induced myelotoxicity          al. (1987)
                              12 days to groups of six male B6C3F1 mice

    Isolated rat spleen       responses of spleen cells from F-344 rats     low concentrations (10-7-10-6) enhanced           Irons & Pfeifer
    and lymphocytes           were assayed after addition of mitogen and    mitogenesis, higher concentrations (10-5)         (1982)
    (in vitro)                phytohaemagglutinin A                         suppressed mitogen response

    Pigment cells (in vitro)  toxic effects of HQ on melanotic cell lines   toxic effects occurred between 0.625 and          HU (1966)
                              (MCL) and non-melanotic cell lines (NMCL)     2.5 µg/ml for MCL and NMCL
                              was studied

    Cell line (in vitro)      lymphoma-derived cell line Raji, erythro-     percentage survival decreased for all cells       Picardo et al.
                              leukaemia cell line K 562 and human           (approx. 65%, low dose) (approx. 20%, high dose)  (1987)
                              melanotic cell lines IRE 1 and IRE 2 were
                              incubated with 0.01 and 0.1 mmol HQ/litre

    Bone marrow cells         bone marrow cells isolated from the femurs    HQ decreased the number of mature surface         King et al.
    (in vitro)                and tibias of male B6C3F1 (C57BL/6J x         IgM+ B cells and adherent cells; HQ may block     (1987)
                              C3h/HeJ) mice were incubated with             final maturation stages of B cell
                              between 10-7 and 10-5 mol HQ/litre            differentiation

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Cell line (in vitro)      bone marrow macrophage and a fibroblastoid    HQ (10-4 mol/litre) decreased viability and       Thomas et al.
                              stromal cell line isolated from male          colonies for macrophages (60% and 70%,            (1989b)
                              B6C3F1 mice were incubated with               respectively) and stromal cells (30% and
                              between 10-8 and 10-4 mol HQ/litre            0%, respectively)

    Cell line (in vitro)      bone marrow stromal cells isolated from       HQ cytotoxicity was greater in stromal cells      Twerdok & Trush
                              male DBA/2 mice and C57BL/6 mice              derived from DBA/2 than C57BL/6 mice; tert-       (1990); Twerdok
                              were incubated with HQ                        butylhydroquinone (tBHQ) or 1,2-dithiole-3-       et al. (1992)
                                                                            thione (DTT) preincubation protected against
                                                                            HQ-induced toxicity; dicoumarol-sensitive
                                                                            quinone reductase activity was increased by
                                                                            tBHQ and DTT, and levels of GSH increased with
                                                                            DTT

    Cell line (in vitro)      human promyelocytic leukaemia cell line,      HQ dose-dependently inhibited TPA- and 1,25-      Oliveira & Kalf
                              which can be induced to differentiate to      dihydroxy vitamin D3-induced (but not             (1992)
                              both monocyte and myeloid cells, was          interleukin (IL)-1) acquisition of
                              incubated with HQ (0.01 µmol/litre to         differentiation characteristics of monocytes
                              10 µmol/litre)                                (adherence, nonspecific esterase activity and
                                                                            phagocytosis), but had no effect on cell
                                                                            proliferation; retinoic-acid- or DMSO-induced
                                                                            differentiation to granuloctyes was not
                                                                            inhibited at the same doses

    Hepatocytes (in vitro)    freshly isolated hepatocytes (106/ml)         time-dependent cell death; complete by 120 min    O'Brien (1991)
                              incubated with 850 µM HQ; % cell viability
                              measured by Trypan blue inclusion

    Effects on cellular metabolism

    Haemoglobin (Hb)          five cats were treated every second day up    15-30% Hb oxidized to ferric form                 Jung & Witt
    (in vivo)                 to 12 times with HQ (40-160 mg/kg)                                                              (1947)

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Reduction of haemoglobin  HQ incubated with Hb in presence of O2        very slow formation of ferrihaemoglobin           Oettel (1936)
    (Hb) (in vitro)

    Iron utilization          female Swiss albino mice administered         inhibition (70%) of erythroid 59Fe utilization    Guy et al.
    (in vivo)                 between 25 and 100 mg HQ/kg 3 times at        occurred only at the highest dose;                (1990, 1991)
                              64, 48 and 40 h prior to administration       coadministration of PhOH or muconaldehyde
                              of 59Fe; coadministration with phenol         enhanced the inhibitory effects of HQ
                              (PhOH) (50 mg/kg)

    Cellular RNA and DNA      the effects of HQ on nucleoside               HQ selectively inhibited the metabolism of MCL    Pennay et al.
    synthesis (in vitro)      incorporation in two melanotic cell lines     cf. NMCL; [3H]-uridine incorporation was de-      (1984)
                              (MCL) and three non-melanotic cell lines      creased approx. 30-fold in MCL cf NMCL; [3H]-
                              (NMCL) was observed                           uridine incorporation was more sensitive to HQ
                                                                            than [3H]-thymidine; DNA and RNA syntheses were
                                                                            decreased by 80 and 50%, respectively, in MCL;
                                                                            HQ may exert depigmenting effect by selective
                                                                            action on MCL metabolism rather than specific
                                                                            effect on melanin synthesis

    Mitochondrial synthesis   mitoplasts isolated from rabbit bone          RNA synthesis inhibited (IC50 = 5.0 x 10-5 mol    Rushmore
                              marrow cells were incorporated with HQ        HQ/litre)                                         et al. (1984)
                              and assayed for RNA synthesis

    Cyclic nucleotides        three different melanomas were treated        cAMP and cGMP were elevated in 3/3 and 2/3        Abramowitz &
    (in vitro)                with HQ and assayed for cAMP and cGMP         tumours, respectively                             Chavin (1980)
                              by radioimmuno assay

    Cytokine synthesis        murine P388D1 macrophages or bone             HQ caused a concentration-dependent inhibition    Renz et al.
                              marrow stromal macrophages were               of the processing of 34-Kd pre-interleukin-1      (1991)
                              incubated with HQ (0.5-10 µmol/litre)         alpha (IL-1alpha) to 71-Kd mature cytokine in
                                                                            both types of macrophages; lipopolysaccharide-
                                                                            induced production of the pre-IL-1alpha
                                                                            precursor or cell viability or DNA and protein
                                                                            synthesis were not inhibited

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Effects on enzymes

    Tyrosine-tyrosinase       radiometric assay                             tyrosinase inhibited by HQ (9 x 10-4 mol/litre);  Usmani et al.
    (tyrosine --> dopa)                                                    suggested that HQ is a competitive inhibitor      (1980); Palumbo
    (required for skin                                                                                                        et al. (1991)
    pigmentation)

    Catalase (in vivo)        male Wistar rats received 5 mg HQ/kg per      5 mg HQ/kg per day inhibits catalase activity in  Vladescu &
                              day p.o. for 10 days and H 18R tumour-        the liver, spleen, blood and H 18R tumour         Apetroae (1983)
                              bearing rats received 5 mg HQ/kg per day
                              p.o. for 7 days; [14C]-HQ was
                              administered i.p.

    Ornithine decarboxylase   SD rats received a single oral dose of 100    ODC activity was increased in a dose-             Ekström et al.
    (ODC)                     or 200 mg HQ/kg; liver ODC activity was       dependent manner                                  (1988)
                              measured after 18 h of exposure

    Horseradish peroxidase    [14C]-phenol incubated with H2O2-HRP in       radioactivity associated with protein             Eastmond et
    (HRP)                     the presence of boiled rat liver protein;     decreased when coincubated with HQ;               al. (1987)
                              coincubated with HQ                           competitive inhibition presumed

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    Reaction of HQ metabolites

    Benzoquinone (BQ)/        numerous: BQ/SQ formed by autooxidation       rate of enzyme-mediated formation of BQ is        Yamazaki et al.
    benzosemiquinone (SQ)     and 1e-mediated enzymic oxidation (e.g.,      much faster than autooxidation; formation of      (1960); Sawada
                              horseradish peroxidase (HRP),                 BQ is enhanced by coincubation of HRP and         et al. (1975);
                              myeloperoxidase (MPO) and prostaglandine      MPO with phenol and other compounds;              O'Brien (1991);
                              H synthase (PHS)) of HQ                       indomethacin partially inhibits H2O2-dependent    Smith et al.
                                                                            HQ oxidation with HRP or MPO or PHS, but          (1989); Hsuanyu
                                                                            substantially inhibits arachidonate-dependent     & Dunford (1992);
                                                                            oxidation mediated by PHS; this latter finding    Eastmond et al.
                                                                            indicates the involvement of cyclooxygenase;      (1987); Thomas
                                                                            both BQ and SQ are electrophiles which readily    et al. (1989);
                                                                            react with low and high molecular weight          Subrahmanyam et
                                                                            nucleophiles; BQ is believed to be the            al. (1991);
                                                                            proximate toxicant responsible for benzene-/      Schlosser
                                                                            hydroquinone-induced myelotoxicity                et al. (1990)

    GSH conjugate (in vivo)   male Sprague-Dawley rats were administered    nephrotoxicity occurred with tris-(GSyl)-HQ >     Lau et al.
                              various (GSyl)-HQ conjugates i.v.;            di-(GSyl)-HQ conjugate; mono and tetra            (1988)
                              nephro- and hepatotoxicity were measured      conjugates were not toxic; toxicity of the tris
                              as increased plasma blood urea nitrogen       conjugate was depressed by AT-125, a gamma
                              (BUN) and serum glutamate pyruvate            glutamyl trans-peptidase (gamma-GT) inhibitor;
                              transaminase (SGPT), respectively             it is suggested that gamma-GT is probably
                                                                            required for the transport of the latent quinone
                                                                            into proximal tubular cells as the corresponding
                                                                            cysteine conjugate; alkylation and/or oxidation
                                                                            are suggested mechanisms of molecular toxicity

    Table 9. (contd).
                                                                                                                                               
    Index studied             Method                                        Result                                            Reference
                                                                                                                                               

    GSH conjugate (in vitro)  O2 consumption measurement of in situ         autooxidation was stimulated by SOD               Brunmark &
                              formed glutathionyl-p-benzoquinone HQ                                                           Cadenas (1988); cf.
                              conjugate in potassium phosphate buffer                                                         Eckert et al.
                              at pH 7.65 in the absence and presence of                                                       (1990)
                              superoxide dismutase (SOD)
                                                                                                                                                

    a  NADPH = reduced nicotinamide adenine dinucleotide
       cAMP  = cyclic adenosine monophosphate
       cGMP  = cyclic guanosine monophosphate


    
    7.  EFFECTS ON LABORATORY MAMMALS AND IN VITRO SYSTEMS

    7.1  Single exposure

         The acute toxicity of hydroquinone has been studied in several
    animal species (Tables 10 and 11). Oral LD50 values for different
    strains of rats range from 720 to 1300 mg/kg body weight (Carlson &
    Brewer, 1953; Mozhaev  et al., 1966). Fasting the animals for 18 h
    previous to the administration of hydroquinone produced a two- to
    three-fold increase in the observed toxicity (Carlson & Brewer,
    1953). The LD50 of unfed rats was 310 mg/kg, in contrast to an
    average of 1064 mg/kg observed in non-fasted animals. Oral LD50
    values range from 340 mg/kg to 400 mg/kg body weights for mice, and
    are 550 mg/kg body weight for guinea-pigs, 540 mg/kg body weight for
    rabbits and 299 mg/kg body weight for dogs. Cats have a greater
    sensitivity (LD50 values of 42-86 mg/kg body weight).

         Signs of hydroquinone intoxication were developed 30-90 min
    after single oral doses and consisted of hyperexcitability, tremors,
    convulsions, dyspnoea and cyanosis. They also included salivation in
    dogs and cats, emesis in dogs and pigeons, swelling of the tissues
    around the eyes, and incoordination of the hind limbs of dogs
    (Woodard 1951; Christian  et al., 1976; Deichmann & Keplinger,
    1981). These signs were followed by complete exhaustion,
    hypothermia, paralysis, loss of reflexes, coma, respiratory failure
    and death. When the dose was sublethal, recovery was complete within
    three days (Christian  et al., 1976).

         Single-dose acute dermal toxicity studies have not been
    reported. However, the acute dermal LD50 can be estimated to be >
    3840 mg/kg for mice and 74 800 mg/kg for rats based on effects
    observed in two-week dermal studies (NTP, 1989). Hydroquinone as a
    2% solution in dimethyl phthalate caused no adverse local or
    systemic effects in rabbits (Draize  et al., 1944).

         In the rat, the LD50 values for intraperitoneal
    administration varied between 160 and 194 mg/kg body weight and the
    LD50 for intravenous administration was 115 mg/kg body weight
    (Woodard, 1951). In rabbits, intravenous injections of hydroquinone
    caused death at doses of 100-150 mg/kg body weight (Delcambre  et
     al., 1962).


    
    Table 10.  Acute oral toxicity of hydroquinone in experimental animals
                                                                                                                                         
    Species               Material tested       LD50 (mg/kg    Comments                                           Reference
                          body weight)
                                                                                                                                         

    Rat                   2% aqueous solution   320            rapid onset of symptoms: twitchings,               Woodard (1951)
     Osborne-Mendel                                            tremors, convulsions, respiratory
                                                               failure and death within a few hours

    Rat
     Priestly             glycerine             1005-1295      unfasted rats; the mean LD50 value                 Carlson & Brewer (1953)
     Sprague-Dawley       propylene-glycol      1090           was 1050 mg/kg
     Sprague-Dawley       distilled water       1182
     Sprague-Dawley       glycerine             1081
     Wistar               propylene-glycol      731

     Sprague-Dawley       propylene-glycol      323            fasted rats; the mean LD50 value                   Carlson & Brewer (1953)
     Wistar                                     298            was 310 mg/kg

    Rat                   water                 743 (m)        when the dose was sufficiently large,              Christian et al. (1976)
                                                627 (f)        death occurred during a severe tonic
                                                               spasm within 2 h; when the dose was
                                                               sublethal, recovery was complete
                                                               within 3 days

    Mouse                 2% aqueous solution   400            the symptoms are similar to those                  Woodard (1951)
     Swiss                                                     in rats

    Guinea-pig            2% aqueous solution   550            the symptoms are similar to those                  Woodard (1951)
                                                               in rats

    Cat                   2% aqueous solution   70             the symptoms are similar to those in               Woodard (1951)
                                                               rats except for salivation and swelling
                                                               of the area around the eye noted in cats

    Cat                   sugar-coated tablets  42-86          Carlson & Brewer (1953)

    Table 10. (contd).
                                                                                                                                         
    Species               Material tested       LD50 (mg/kg    Comments                                           Reference
                          body weight)
                                                                                                                                         

    Dog                   sugar-coated tablets  299            similar symptoms to those of cats                  Carlson & Brewer (1953)

    Dog                   2% aqueous solution   200            hyperexcitability, tremors, convulsions,           Woodard (1951)
                                                               salivation, emesis, incoordination of the
                                                               hind legs, respiratory failure, and death;
                                                               100 mg/kg caused mild to severe swelling
                                                               of the area around the eye, of the nictating
                                                               membrane and of the upper lip

    Rabbit                2% aqueous solution   540            the symptoms are similar to those in rats          Woodard (1951)

    Pigeon                2% aqueous solution   300            the symptoms are similar to those in               Woodard (1951)
                                                               rats, except for emesis noted in pigeons
                                                                                                                                         

    Table 11.  Acute parenteral toxicity of hydroquinone in experimental animals
                                                                                                                                          
    Species                Material           Administration    LD50 (mg/kg body   Comments                        Reference
                           tested             route             weight) (except
                                                                where otherwise
                                                                stated)
                                                                                                                                          

    Rat (Osborne-Mendel)   2 or 3% aqueous    intraperitoneal   160                                                Woodard (1951)
                           solution

    Rat (Wistar)                              intraperitoneal   194                                                Delcambre et al. (1962)

    Rat (Osborne-Mendel)   2 or 3% aqueous    intravenous       115                                                Woodard (1951)
                           solution

    Rabbit                                    intravenous       150a               death                           Delcambre et al. (1962)
                                                                100                tremor, hypotonia, death
                                                                10-20              hypertension, hyperkalaemia

    Mouse                                     subcutaneous      160-170 (LLD)b                                     Busatto (1940)

    Mouse                  1% solution        subcutaneous      182                                                Marquardt et al. (1947)

    Mouse                                     subcutaneous      190                most animals died within 24 h   Nomiyama et al. (1967)
                                                                                                                                          

    a  Single dose
    b  LLD = lowest lethal dose


    
         Single subcutaneous injections of up to 500 mg of
    hydroquinone/kg body weight in white mice caused symptoms in the
    central nervous system: markedly increased motor activity,
    hyperactive reflexes, sensitivity to light and sound, laboured
    breathing and cyanosis, followed by clonic convulsions, complete
    motor exhaustion, paralysis, a nearly complete loss of sensitivity
    and reflexes, semicoma and death (Busatto, 1940). The lowest lethal
    dose was 160-170 mg/kg. The subcutaneous LD50 for hydroquinone has
    been found to be 182-190 mg/kg in mice (Marquardt  et al., 1947;
    Nomiyama  et al., 1967).

         No experimental data on inhalation exposure have been located.

    7.2  Skin and eye irritation; sensitization

    7.2.1  Skin irritation

         Hydroquinone was applied to both epilated and unepilated skin
    of eight black guinea-pigs at concentrations of 1, 3, 5, 7 and 10%
    in three vanishing creams (Bleehen  et al., 1968). The number of
    animals per dose group was not reported. Six animals served as
    controls. The material was applied once daily, five times a week,
    for one month. Hydroquinone was irritating only at concentrations of
    5% or more. Weak to moderate depigmentation occurred in all areas of
    skin to which creams containing 1-10% hydroquinone were applied.

         Hydroquinone (0.001, 0.01 and 0.1% in 0.1 ml water) was not
    found to be a primary irritant when administered intracutaneously in
    18 female guinea-pigs during a period of 10 days (Rajka & Blohm,
    1970).

         Jimbow  et al. (1974) reported depigmentation in the epilated
    skin of 24 black guinea-pigs (both males and females) after topical
    applications of hydroquinone. Creams containing 2 or 5% hydroquinone
    in an oil-water emulsion were applied daily, 6 days a week, for 3
    weeks. The depigmentation was first seen within 8-10 days and was
    greatest between 14 and 20 days. It was more marked at the higher
    concentration. Inflammatory changes and thickening of the epidermis
    were also reported. When hydroquinone was applied topically for
    three weeks, biopsy specimens showed that it had caused a marked
    reduction both in the number of melanized melanosomes in the cells
    and the number of actively functioning melanocytes.

         In a preliminary screening study with eight guinea-pigs, an
    aqueous solution of hydroquinone was slightly irritating at 10% but
    not at 0.5, 1.0 or 5.0% (Springborn Institute for Bioresearch,
    1984).

         The potential of hydroquinone to produce skin depigmentation
    and irritation has also recently been studied in male and female
    black guinea-pigs (Maibach & Patrick, 1989). The study indicated

    that females may be more sensitive than males. Groups of five male
    and five female animals were administered hydroquinone (0.1 ml in a
    hydrophilic ointment) at concentrations of 0.1, 1.0, and 5.0% on an
    epilated area of the back five days a week for 13 weeks. The lowest
    concentration caused marginal irritation without depigmentation,
    while the medium concentration resulted in a slight to marginal
    irritation in 30% of the animals (mainly females) and to weak
    depigmentation in females. Moderate to severe irritation and severe
    ulcerated inflammatory responses occurred with the highest
    concentration. Moderate depigmen-tation was observed in
    approximately 40% of the animals dosed (only females).
    Hyperpigmentation was noticed in 80-100% of the animals in all dose
    groups, but this was not considered to be attributable to the
    treatment.

    7.2.2  Eye irritation

         Powdered hydroquinone (2-5 mg) instilled twice daily (5 days
    per week for 9 weeks) into the eyes of dogs caused immediate but
    transient irritation and lacrimation (Dreyer, 1940). Opacity of the
    cornea, lacrimation and redness of the conjunctiva were produced
    within 4 days, but no ulcers were seen. The eye returned to normal
    within two days after cessation of treatment. In guinea-pigs
    powdered hydroquinone (1-3 mg, twice daily for 9 weeks) also caused
    immediate but transient irritation. During the second day of
    application a slight corneal opacity was observed in some animals
    and on the third day opacity of varying degrees occurred in most of
    the animals. Ulcers appeared in two animals. The eyes had fully
    recovered 3 days after cessation of treatment.

         Following an injection of 0.1 ml of a solution (vehicle not
    specified) of hydroquinone (0.012-0.05 mol/litre) into the cornea of
    rabbits, the resultant reaction was graded 5 out of the possible
    maximum of 100 (Hughes, 1948).

         Finely powdered hydroquinone (amounts not specified) was
    applied daily, from 2-4 months, to the eyes of rabbits in 6 groups,
    which were, respectively, kept in the dark, in sunlight, in normal
    light, irradiated with UV light, or pre-sensitized with
    haematoporphyrin and then kept under either reduced light or
    sunlight. Most rabbits developed pigmentation, first in the
    conjunctiva and then in the cornea. Degenerative alterations of the
    corneal parenchyma were also observed. Pigment formation appeared
    earlier in animals exposed to light. Older animals seemed more prone
    to develop pigment than younger ones. Pigment was deposited in
    albino rabbit eyes as well as in those of rabbits with normal
    pigmentation (Ferraris de Gaspare, 1949).

         Hydroquinone in aqueous solution, e.g., in tears, is oxidized
    by air, forming a brown colour partly due to conversion to
    1,4-benzoquinone (Grant, 1986). No disturbance of the inner parts of

    the eye is known to have been produced by exposure to hydroquinone
    (Grant, 1986).

    7.2.3  Sensitization

         Several sensitization studies have been carried out with
    hydroquinone; methods and results are summarized in Table 12.

         The skin sensitizing potential of hydroquinone for female
    guinea-pigs was investigated by Rajka & Blohm (1970). Hydroquinone
    elicited "weak" sensitivity after sensitization with a 0.001%
    solution injected intracutaneously and challenge with an equipotent
    solution of hydroquinone.

         The ability of guinea-pigs to detect known human contact
    sensitizers was explored by Goodwin  et al. (1981). Sensitization
    induced by hydroquinone was "strong" when assayed by the Magnusson &
    Kligman maximization test, "moderate" by the single injection
    adjuvant test and "weak" by the modified Draize procedure.

         Hydroquinone was found to be a "moderate" sensitizer in female
    guinea-pigs in both the guinea-pig maximization test and Freund's
    complete adjuvant test as performed by Van der Walle  et al.
    (1982a,b). Hydroquinone produced identical sensitization potentials
    in the Freund's complete adjuvant test using induction
    concentrations of 0.5 mol/litre and 0.45 µmol/litre. The study also
    showed almost 100% cross reactivity of hydroquinone and
     p-methoxyphenol. Both substances are used as inhibitors in acrylic
    monomers to prevent unwanted polymerization.

         More recently, Basketter & Goodwin (1988) used three 
    sensitization test methods representing both topical and intradermal
    routes of application. Groups of 10 guinea-pigs were sensitized by
    using the guinea-pig maximization test, a modified single injection
    adjuvant test, and a cumulative contact enhancement test. The
    sensitization potential of hydroquinone was assessed as "strong",
    "weak", and "moderate", respectively, in these three tests.
    Subsequent cross-challenges with  p-phenylenediamine, sulfanilic
    acid, and  p-benzoquinone gave only "restricted evidence" of
    cross-reactions.


    
    Table 12.  Contact allergy predictive tests with hydroquinone in guinea-pigs
                                                                                                                                              
    Test                            Induction dose                   Challenge dose        Sensitization                 Reference
                                                                                           (number positive/number
                                                                                           tested or percentage)
                                                                                                                                              

    Intracutaneous sensitization    0.001% (0.1 ml, injection)       0.001% (injection)    4/18                          Rajka & Blohm (1970)

    Guinea-pig                      2.0% (0.1 ml, injection)         5.0% (patch)          70%, "strong" sensitizer      Goodwin et al. (1981)
    maximization test               10.0% (patch)                    5.0% (patch)          

    Guinea-pig                      0.5 mol/litre (day 0) (patch)    0.125 mol/litre       5/10 (day 21);                Van der Walle
    maximization test               1 mol/litre (day 7) (patch)      0.250 mol/litre       5/10 (day 35)                 et al. (1982a,b)

    Guinea-pig                      2.0% (0.1 ml, injection)         0.5% (patch)          "strong" sensitizer           Basketter &
    maximization test               1.0% (patch)                     0.5% (patch)                                        Goodwin (1988)

    Single injection                2.0% (injection)                 5.0% (patch)          40%, "moderate" sensitizer    Goodwin et al. (1981)
    adjuvant test

    Modified single injection       2.0% (0.1 ml, injection)         10% (patch)           "weak" sensitizer             Basketter &
    adjuvant test                                                                                                        Goodwin (1988)

    Modified Draize test            2.5% (injection)                 1.0% (injection);     0%a, 30%b, "weak"             Goodwin et al. (1981)
                                                                     20% (application)     sensitizer

    Freund's complete               5 x 0.45 µmol/litre              0.115 µmol/litre      3/8 (day 21)                  Van der Walle
    adjuvant test                   (0.1 ml, injection)              (patch)               4/8 (day 35);                 et al. (1982a,b)
                                    5 x 0.5 mol/litre                0.125 mol/litre       4/8 (day 21)
                                    (0.1 ml, injection)              (patch)               4/8 (day 35)

    Cumulative contact              1.0% (patch)                     20% (patch)           "moderate" sensitizer         Basketter &
    enhancement test                                                                                                     Goodwin (1988)
                                                                                                                                              

    a  the proportion of guinea-pigs sensitized after one induction treatment
    b  the proportion of guinea-pigs sensitized after two induction treatments


    
    7.3  Short-term exposure

         The short-term toxicity of hydroquinone has been studied in
    rats and mice. The effects are summarized in Table 13.

         Two groups of rats (14 animals/group, sex and strain not
    reported) were fed a diet containing 0 or 5% HQ for nine weeks
    (Carlson & Brewer, 1953). Findings at the end of the study consisted
    of atrophy of the liver cord cells, adipose tissue, striated muscle
    and lymphoid tissue of the spleen, as well as an average decrease of
    66% in cellularity of the bone marrow (considered as aplastic
    anaemia by the authors). No information was reported on mortality
    but the fact that animal lost 46% of their body weight during the
    course of the study makes the findings difficult to interpret.

         Aqueous solutions of hydroquinone (0, 7.5 or 15 mg/kg, 6 days
    per week) administered by oral gavage to male Wistar rats for 40
    days resulted in haematological changes, including anisocytosis,
    polychromatophilia and acidophilic erythroblasts, at the highest
    dose level (Delcambre  et al., 1962). Administration of 0, 5 or 10
    mg/kg for four months to groups of 15 male Wistar rats resulted in
    mortality in the highest dose group; 5 mg/kg was well tolerated.

         "Mild hyperplastic and hyperkeratotic areas near the
    oesophageal entry" occurred in groups of male and female Wistar rats
    fed powdered diets containing 2% hydroquinone. However, there were
    some deficiencies in the reporting of experimental design (Altmann
     et al., 1985). No other treatment-related changes were found, nor
    were there any sex-related changes concerning forestomach lesions.

         A two-week oral study on Fischer-344 rats and B6C3F1 mice was
    carried out by the National Toxicology Program (NTP, 1989; Kari  et
     al., 1992). The animals were given hydroquinone in corn oil by
    gavage 5 days per week (12 doses over 14 days). Five rats per sex
    and dose group were administered 0, 63, 125, 250, 500 or 1000 mg/kg
    body weight and five mice per sex and dose group 0, 31, 63, 125, 250
    or 500 mg/kg. All rats given 1000 mg/kg died during the dosing
    period; deaths were also reported at the 500 mg/kg dose level.
    Clinical signs of treatment-related toxicity included tremors and
    convulsions at the 500 and 1000 mg/kg dose levels. Tremors,
    convulsions and deaths also occurred in mice during the study period
    at the 250 and 500 mg/kg dose levels.


    
    Table 13.  Effects of short-term exposure to hydroquinone via the oral route
                                                                                                                                         
    Species  Concentration       Means of        Duration     Observation                                           Reference
                                 administration
                                                                                                                                         

    Rat      5%                  diet            9 weeks      reduced weight; aplastic anaemia; decreased           Carlson & Brewer
                                                              bone marrow cellularity; atrophy of liver,(1953)
                                                              spleen, adipose tissue and striated muscle;
                                                              ulceration and haemorrhage of the stomach
                                                              mucosa

    Rat      500, 750, 1000,     stomach tube    12 days      increased mortality                                   Carlson & Brewer
             1250, 1500,                                                                                            (1953)
             1750 mg/kg

    Rat      7.5, 15 mg/kg       intubation      40 days      15 mg/kg: anisocytosis, polychromatophilia,           Delcambre et al.
                                                              acidophilic erythroblasts                             (1962)

    Rat      5, 10 mg/kg         intubation      4 months     10 mg/kg: deaths (7/15)                               Delcambre et al.
                                                                                                                    (1962)

    Rat      2%                  diet            4 weeks;     mild hyperplasia and hyperkeratosis                   Altmann et al.
                                                 8 weeks      of forestomach                                        (1985)

    Rat      20, 64, 200 mg/kg   gavage          90 days      64 mg/kg: tremors, reduced activity;                  Eastman Kodak
                                                              200 mg/kg: tremors, reduced activity, reduced         Company (1988)
                                                              body weight and feed consumption (males)

    Rat      63, 125, 250,       gavage          14 days      1000 mg/kg: tremors, convulsions andNTP (1989);       Kari
             500, 1000 mg/kg                                  death (10/10);                                        et al. (1992)
                                                              500 mg/kg: tremors, convulsions and
                                                              death (1/5 male and 4/5 female)

    Table 13. (contd).
                                                                                                                                         
    Species  Concentration       Means of        Duration     Observation                                           Reference
                                 administration
                                                                                                                                         

    Rat      25, 50, 100, 200,   gavage          13 weeks     25 mg/kg: decreased relative liver weight             NTP (1989)
             400 mg/kg                                        (males); 50 and 100 mg/kg: decreased (males)
                                                              and increased (females) relative liver weight;
                                                              200 mg/kg: lethargy, decreased body weight gain
                                                              and increased relative liver weight; tremors,
                                                              convulsions and deaths (females); nephropathy;
                                                              inflammation and/or epithelial hyperplasia of the
                                                              forestomach; 400 mg/kg: tremors, convulsions
                                                              and deaths

    Rat      2.5, 25, 50 mg/kg   gavage          1,3,6 weeks  50 mg/kg: increased urinary enzyme excretion;         English et al. (1992)
                                                              renal tubular degeneration/regeneration; and
                                                              increased renal tubular cell proliferation in
                                                              male F-344 rats; female F-344 rats and male
                                                              SD rats: no effects

    Mouse    25, 50, 100, 200,   gavage          13 weeks     25 and 50 mg/kg: lethargy (males); increased          NTP (1989)
             400 mg/kg                                        relative liver weight (males); 100 mg/kg: lethargy;
                                                              increased relative liver weight (males); 200 mg/kg:
                                                              lethargy; increased relative liver weight (males);
                                                              tremors (males); lesions in the forestomach (one
                                                              female); deaths (males); 400 mg/kg: lethargy,
                                                              tremors, convulsions, lesions in the
                                                              forestomach, deaths

    Mouse    31, 63, 125, 250,   gavage          14 days      500 mg/kg: tremors, convulsions and death             NTP (1989)
             500 mg/kg                                        (4/5 male and 5/5 female);
                                                              250 mg/kg: tremors, convulsions and death
                                                              (3/5 male)
                                                                                                                                         


    
         Hydroquinone in 95% ethanol was dermally applied (12 doses over
    14 days) to Fischer-344 rats and B6C3F1 mice (NTP, 1989). Rats
    (five per sex and dose group) received 0, 240, 480, 1920 or 3840
    mg/kg and mice (five per sex and dose group) 0, 300, 600, 1200, 2400
    or 4800 mg/kg. The survival rate was not affected. The only findings
    were a 6% lower body weight in male rats administered 3840 mg/kg and
    crystals on the skin and fur of animals at 3840 mg/kg. No
    histopathological examination of the tissues was carried out.

         In a 13-week oral toxicity study, 10 male and 10 female
    CD(SD)BR rats (initially, approximately 7 weeks old) in each of four
    groups were administered hydroquinone (0, 20, 64 or 200 mg/kg per
    day) by gavage on 5 days/week (Eastman Kodak Company, 1988). Brown
    urine was seen in rats of both sexes from all dose groups. Males
    also showed lower feed consumption; however, this was only
    significantly (P < 0.05) reduced during the first week of the
    study. Female body weight gain and food consumption were not
    significantly altered in any dose group during the study. Signs of
    behavioural effects were observed at both the 64 and 200 mg/kg dose
    levels (see section 7.8.3). The animals were sacrificed after the
    exposure period, and six males and six females from each group were
    perfused for neuropathological examination (see section 7.8.3). No
    treatment-related changes were observed at gross necropsy.
    Administration of 200 mg hydroquinone/kg reduced body weight gain in
    male rats so that the final body weight of the treated rats was 7%
    less than the mean weight for the controls.

         Thirteen-week studies in rodents have also been presented by
    the NTP (1989). Groups of 10 males and 10 females of each species
    (F-344/N rats, initially 4 to 5 weeks old, and B6C3F1 mice,
    initially 5 to 6 weeks old) were administered hydroquinone (0, 25,
    50, 100, 200, or 400 mg/kg) in corn oil by gavage, five days per
    week. A dose level of 400 mg/kg was lethal to all rats. Tremors and
    convulsions were observed in most rats at this dose level and in
    several female rats receiving 200 mg/kg. Doses of 100 mg/kg or less
    did not cause signs of central nervous system (CNS) stimulation.
    Rats receiving 200 mg/kg also showed reduced body weight gain,
    nephropathy, and inflammation and/or epithelial hyperplasia of the
    forestomach. The kidney lesions in male rats were judged to be more
    severe than in females.

         In mice, a dose level of 400 mg/kg caused mortality in both
    males (8/l0) and females (8/10). In the 200 mg/kg male group two
    animals died (one due to gavage error). Lethargy was seen in all
    dosed males and in females in the three highest-dose groups of each
    sex. Tremors, often followed by convulsions, were noted in the
    highest-dose group. Liver-to-body weight ratios for all dosed males
    were significantly (P < 0.01) greater than for vehicle controls.
    Ulceration, inflammation or epithelial hyperplasia of the
    forestomach occurred in mice receiving 400 mg/kg (3/10 males and
    2/10 females) and in one female mouse receiving 200 mg/kg.

         Male and female F-344 rats were given hydroquinone (0, 2.5, 25
    or 50 mg/kg) 5 days/week in water by oral gavage for 1, 3 or 6 weeks
    (English  et al., 1992). At each time point, 5 rats per sex and
    dose group were examined for urinalysis changes, renal tubular cell
    proliferation and histopathology. Body and kidney weights were not
    altered by hydroquinone exposure. Increased excretion of urinary
    enzymes was observed in male F-344 rats given 50 mg/kg as early as
    one week into the exposure. The incidence of tubular degeneration
    and regeneration was mild in the 50 mg/kg male group, and cell
    proliferation was increased by 87%, 50% and 34% in the P1, P2 and P3
    tubular segments, respectively. Female rats and males in the lower
    dose level groups were not affected by hydroquinone exposure. Male
    Sprague-Dawley rats given 50 mg/kg for 6 weeks were also not
    affected by hydroquinone exposure.

    7.4  Long-term exposure

         The effects of long-term exposure to hydroquinone in
    experimental animals are shown in Table 14. In addition to the acute
    (see section 7.1) and subacute (see section 7.3) toxicity tests,
    Carlson & Brewer (1953) carried out a "cumulative" toxicity study
    and a series of long-term experiments with rats and dogs. In the
    cumulative toxicity study a group of 16 rats (strain and sex not
    reported) received 500 mg hydroquinone/kg by stomach tube 101 times
    in 151 days. More than 50% of the rats died during the study period.
    However, the survivors grew at the same rate as the controls and
    were autopsied at the end of the experiment. However, no information
    on autopsy findings was reported.

         In the first long-term study, four groups of male and four
    groups of female Sprague-Dawley rats (23 to 24 days old, 10 rats in
    each group) were given a basic diet containing 0, 0.1, 0.5 or 1.0%
    hydroquinone (Carlson & Brewer, 1953). In the second experiment the
    hydroquinone was heated together with the lard in the feed. Eight
    groups of rats (16 to 23 in each group) were fed the basic diet
    containing 0, 0.1, 0.25 or 0.5% hydroquinone. In the third
    experiment eight groups of rats (20 rats in each group) were given a
    basic diet containing 0, 0.1, 0.5 or 1.0% hydroquinone with 0.1%
    citric acid added. The experiments lasted for 103 weeks. During the
    first month of the study the animals given 0.5 or 1.0% hydroquinone
    in their diets gained weight at a slower rate than did control
    animals. A similar reduction was not found in the rats given
    hydroquinone previously heated with lard before feeding. However,
    the final body weights of the dose groups were not significantly
    different from those of the controls. Haematological analysis (red
    blood cell count, % haemoglobin and differential white blood cell
    count) showed no statistically significant deviations from the
    control values. The microscopic examinations (liver, omentum,
    kidney, spleen, heart, lung, bone marrow, stomach wall, pancreas,
    adrenal, subperitoneal and intramuscular abdominal fat) also failed
    to reveal compound-related changes. Some of the males and females

    (number and dose groups not specified) in each experiment were mated
    after six months of dosing to produce two successive litters. The
    average numbers of offspring for the two successive litters showed
    no difference between experimental and control groups. The offspring
    given diets containing 0.1, 0.25 or 0.5% hydroquinone previously
    heated with lard grew at the same rate as the controls.

         Carlson & Brewer (1953) also studied the long-term effects of
    hydroquinone in male and female dogs (four months of age at the
    beginning of the study). One dog was maintained on a diet containing
    16 mg of hydroquinone/kg per day for 80 weeks, while two dogs
    received 1.6 mg of hydroquinone/kg per day for 31 weeks and 40 mg/kg
    per day for the succeeding 49 weeks. The compound was administered
    in sugar-coated tablets mixed with the food. Two dogs served as
    controls. The sex distribution in the different groups was not
    reported. In addition, five adult male dogs were fed 100 mg of
    hydroquinone/kg per day for 26 weeks. Routine blood and urine
    analyses (not specified) were made periodically. After the
    experiment, the dogs were killed and autopsied. The dogs given
    hydroquinone in their diet from four months of age grew at the same
    rate as controls. The adults maintained their body weights.
    Haematological analyses and urinalyses showed no differences between
    exposed rats and controls. No effects on gross pathology or
    histopathology were observed.

         Fifteen-month oral toxicity studies on rats and mice were also
    included in two-year studies presented by the National Toxicology
    Program (NTP, 1989) (see also section 7.). Groups of F-44/N rats and
    B6C3F1 mice (64 or 65 males and 65 females of each species) were
    administered 0, 25 or 50 mg hydroquinone/kg and 0, 50 or 100 mg/kg,
    respectively, in deionized water by gavage 5 days per week. No
    compound-related clinical signs were observed during the study
    period. At 15 months, ten animals from each group were selected for
    haematological and clinical chemical analyses, killed and
    necropsied. In male rats significantly (P < 0.01) higher mean
    relative kidney and liver weights were observed in the high-dose
    group and there was also a compound-related increase in the severity
    of nephropathy. For high-dose female rats, the haematocrit value,
    haemoglobin concentration and erythrocyte counts were decreased. In
    mice the relative liver weights were significantly (P < 0.01)
    higher for high-dose males and females than for vehicle controls. A
    significantly (P < 0.05) higher relative brain weight was noted for
    high-dose female mice and kidney weights were significantly (P <
    0.01) increased for dosed females. In dosed males, but not in
    females, compound-related lesions in the liver were seen, including
    centrilobular fatty changes, cytomegaly and syncytial cells.


    
    Table 14.  Effects of long-term oral administration of hydroquinone in experimental animals
                                                                                                                                   
    Species  Concentration                   Duration       Observation                                               Reference
                                                                                                                                   

    Rat      500 mg/kg body weight           151 days       > 50% died                                                Carlson &
             (by stomach tube)               (101 dosings)                                                            Brewer (1953)

    Rat      0, 0.1, 0.5, 1.0%               103 weeks      decreased weight gain for the first months at 0.5         Carlson &
             (in the diet)                                  and 1.0%; final body weights did not differ               Brewer (1953)

    Rat      0, 0.1, 0.25, 0.5%              103 weeks      no adverse effects                                        Carlson &
             (heated together with                                                                                    Brewer (1953)
             lard in the diet)

    Rat      0, 0.1, 0.5, 1.0% +             103 weeks      no adverse effects                                        Carlson &
             0.1% citric acid (in the diet)                                                                           Brewer (1953)

    Rat      0, 25 or 50 mg/kg in            15 months      significantly higher relative kidney weight in high-dose  NTP (1989)
             deionized water (by gavage)                    males and increased severity of nephropathy in dosed
                                                            males; decreased haematocrit value, haemoglobin
                                                            concentration and erythrocyte count in females

    Mouse    0, 50 or 100 mg/kg in           15 months      significantly higher relative liver weights for high-     NTP (1989)
             deionized water (by gavage)                    dose males and females; liver lesions in males

    Dog      16 mg/kg per day                80 weeks       no adverse effects                                        Carlson &
             (in the diet)                                                                                            Brewer (1953)

    Dog      1.6 mg/kg per day;              31 weeks       no adverse effects during the total experimental          Carlson &
             40 mg/kg per day                49 succeeding  period                                                    Brewer (1953)
             (sugar coated tablets)          weeks
                                                                                                                                   


    
    7.5  Reproduction, embryotoxicity and teratogenicity

    7.5.1  Effects on male reproduction

         In a study by Skalka (1964), hydroquinone was injected
    subcutaneously into 16 male rats (100 mg/kg body weight per day for
    51 days), while 17 male rats served as controls. The average weights
    of the testes, epididymides, seminal vesicles and adrenals were
    decreased after the treatment period. The fertility was reduced by
    33% in the males and the number of pregnancies in mated females was
    reduced by 19% compared with the corresponding results for the
    control animals. Histological examinations indicated a disruption in
    sperm production. Diminished content of DNA in sperm heads was also
    noted.

         In 13-week and two-year oral studies in rats and mice, no
    effects on testicular or epididymal weights or on the histopathology
    of these organs were observed (NTP, 1989). Hydroquinone in corn oil
    was given by gavage to groups of males F-344/N rats and to male
    B6C3F1 mice for 13 weeks. The dose ranged from 0 to 400 mg/kg body
    weight for both animal species. In the two-year studies hydroquinone
    in water was given in doses of 0-50 mg/kg body weight to rats and in
    doses of 0-100 mg/kg to mice.

         In a dominant lethal assay in male rats (CRL:COBS CD (SD) BR)
    (see also section 7.6), the males (25 per dose group) were given
    doses of 0, 30, 100 or 300 mg hydroquinone/kg by gavage 5 days per
    week for ten weeks (Krasavage, 1984b). The controls consisted of two
    groups, one positive and one negative. During the 2 weeks
    immediately following the final treatment, the males were mated
    (1:1) with untreated females. All females were killed on day 14 of
    gestation. In the high-dose group (300 mg/kg) the mean body weight
    and the feed intake of the males were significantly reduced compared
    to the negative controls (P < 0.05). The high-dose males also
    exhibited clinical signs of toxicity such as brown urine,
    sialorrhoea, swollen eyelids, tremors, convulsions and death. No
    compound-related effects were seen on male fertility and no dominant
    lethality was observed. There were no compound-related effects on
    the reproductive parameters studied in the mated females
    (insemination rate, pregnancy rate, mean number of corpora lutea,
    implantation sites, viable implants, early and late deaths, and pre-
    and postimplantation losses).

         In a two-generation study oral administration of hydroquinone
    did not appear to affect the reproduction of Fo and F1 parental
    rats at dose levels up to 150 mg/kg per day (see also section 7.5.3)
    (Bio/dynamics Inc., 1989b). Male fertility indices, mating indices
    and pregnancy rates did not differ significantly between the control
    and the hydroquinone-treated groups.

    7.5.2  Effects on female reproduction

         Hydroquinone was shown to affect the rat estrus cycle when
    given parenterally (Rosen & Millman, 1955). Three rats were given 10
    mg hydroquinone/day subcutaneously for 11 days, and vaginal smears
    were used to indicate estrus or diestrus. Following an induction
    period of about three days, the estrus cycle was interrupted for 5
    days, after which normal cycling was observed.

         Similar results were obtained in a study performed by Racz  et
     al. (1958). One group of rats was given 200 mg hydroquinone/kg
    body weight per day by gavage for 14 days and one group was given
    100 mg hydroquinone plus 100 mg phloridzin/kg per day for 14 days.
    Ten animals were used per group. Some of the rats treated with
    hydroquinone remained in diestrus. In the group treated with both
    hydroquinone and phloridzin no effects on the estrus cycle were
    shown. As the compound caused effects on the central nervous system
    and mortalities occurred after 4-5 days in the 200 mg/kg dose group,
    the dose of hydroquinone was reduced to 50 and 100 mg/kg per day. At
    autopsy no mature Graafian follicles were seen, but some were
    growing.

         Hydroquinone in stock diets (0.003 and 0.3%) fed to female rats
    (10/group) for 10 days prior to insemination had no effect on
    gestation length, maternal mortality or on other reproductive
    parameters studied (fertility index, litter efficiency, mean litter
    size, fetal viability or lactation index (Ames  et al., 1956).
    However, it is not clearly stated if the dosing also included the
    gestation period.

         Hydroquinone did not produce adverse affects on female
    reproduction in a two-generation study in rats (see section 7.5.3)
    after daily oral administration of doses up to 150 mg/kg per day
    (Bio/dynamics Inc., 1989b).

    7.5.3  Embryotoxicity and teratogenicity

         The earliest experimental study of the developmental toxicity
    of hydroquinone and other antioxidants was performed by Telford  et
     al. (1962). They reported that hydroquinone added to the diet
    caused increased resorption rates. Ten Walter Reed-Carworth Farm
    strain rats (first gestation animals), weighing about 200 g at the
    time of breeding, were given 0.5 g hydroquinone in their diet (about
    100 mg/kg body weight per day); however, the treatment period was
    not documented. Based on the number of implantation sites, the
    resorption rate was 26.8% compared to 10.6% for controls (126
    untreated, pregnant rats). The report made no mention of the numbers
    of corpora lutea. Hydroquinone caused no maternal toxicity.

         Burnett  et al. (1976) reported the findings of a teratology
    study on twelve hair dye composite formulations. The study groups

    were tested along with one positive and three negative control
    groups. Mated Charles River CD female rats (20 per group) were
    treated by topical application with 2 ml/kg (0.2% hydroquinone) on
    pregnancy days 1, 4, 7, 10, 13, 16, and 19. No signs of toxicity
    were seen throughout the study. There were no differences between
    untreated controls and the hydroquinone-treated group in any
    reported parameter (maternal toxicity, body weight and food
    consumption, mean number of corpora lutea, implantation sites,
    resorption sites, mean resorptions per pregnancy, live fetuses and
    sex ratio) and no significant soft tissue or skeletal changes.

         Hydroquinone has been found to induce micronuclei
    transplacentally in fetal liver cells (Ciranni  et al., 1988a) (see
    also section 7.6). The compound was given by gastric intubation at a
    dose level of 80 mg/kg to four pregnant Swiss CD-1 mice on the 13th
    day of gestation. Micronuclei were detected from 9 h after the
    administration.

         In a pilot study on developmental toxicity in rats,
    hydroquinone (5% in distilled water) was administered daily by
    gavage to groups of ten pregnant COBSCD(SD)BR rats on gestation days
    6 to 15 at dose levels of 0, 50, 100 or 200 mg/kg (Krasavage,
    1984a). The animals were sacrificed and autopsied on gestation day
    16. No significant maternal toxicity or embryo-toxicity was produced
    in any dose group during the treatment period with the exception of
    slightly reduced weight gain and feed consumption in the
    highest-dose. A dose-dependent brownish discolouration of the urine
    was observed in all treated groups. No other treatment-related
    changes were found.

         In the subsequent developmental toxicity study, hydroquinone
    (5% in distilled water) was administered daily by gavage to groups
    of 30 plug-positive female (COBSCD(SD)BR rats (initially 6 weeks
    old) on gestation days 6 to 15 (0, 30, 100 or 300 mg/kg) (Krasavage
     et al., 1985; Krasavage  et al., 1992). Maternal toxicity,
    manifested as a slight but statistically significant (P < 0.05)
    reduction in body weight gain and feed intake, was observed in those
    dams given 300 mg/kg. A reduction in the fetal body weight was seen
    at 300 mg/kg (statistically significant (P < 0.05) only for the
    females). No compound-related teratogenic effects were recorded.
    Dilated renal pelvis, hydronephrosis and hydroureter were seen more
    frequently in the treated groups than in the controls; however, the
    changes did not appear to be dose-related and were not significantly
    different from the controls. Skeletal variations were seen in
    fetuses from all dose groups and from the control group. The total
    number of fetuses with a vertebral variation was statistically
    increased in the highest dose group compared with the controls, but
    analyses of individual skeletal variations and statistical analyses
    of total number of fetuses with a skeletal variation indicated no
    significant effects. The authors concluded that the
    no-observed-effect level (NOEL) for maternal and developmental

    toxicity in rats was 100 mg/kg body weight, and the
    no-observed-adverse-effect level (NOAEL) for fetal development was
    set at 300 mg/kg (Krasavage  et al., 1992).

         In a pilot study for developmental toxicity in rabbits,
    hydroquinone (0, 50, 100, 200, 300, 400 or 500 mg/kg per day) was
    administered by gavage to mated New Zealand White rabbits (five
    rabbits/group) from days 6 to 18 of gestation (Bio/dynamics Inc.,
    1988). Dose levels of 300, 400 and 500 mg/kg per day caused maternal
    death. At dose levels of 50, 100 and 200 mg/kg per day, dose-related
    reductions in body weight and food consumption were recorded. In the
    200 mg/kg per day dose group, an increased number of resorptions
    were observed, suggesting an embryotoxic effect. Mean fetal weights
    were unaffected at 50 and 100 mg/kg per day, but at 200 mg/kg per
    day they were lower than those of the controls (by 20.7%). No
    fetuses were recovered at the higher dose levels as no females
    survived throughout the study. The fetal external examinations
    showed no treatment-related adverse effects.

         In the subsequent developmental toxicity study, New Zealand
    White rabbits (18 mated females/group) were given hydroquinone by
    gavage at dose levels of 0, 25, 75 or 150 mg/kg per day on gestation
    days 6 to 18 (Bio/dynamics Inc., 1989a; Murphy  et al., 1992). The
    exposure of rabbits to 25 or 75 mg hydroquinone/kg per day had no
    effect on any maternal or fetal parameter. However, there was a
    reduction in mean food consumption during the 11-14 day gestational
    interval at 75 mg/kg per day, but only on days 11 and 12 were these
    differences statistically (P < 0.05) different from control data.
    In the 150 mg/kg per day dose group there were statistically
    significant (P < 0.01) reductions in the body weight and food
    consumption during the dosing period, suggesting maternal toxicity.
    No other parameter (clinical observations, uterine implantations,
    liver or kidney weights or gross pathology) showed any
    treatment-related adverse effect on the females. No embryotoxicity
    was found from uterine implantation data. An increased incidence
    (not statistically significant) of external, visceral and skeletal
    malformations was noticed in the fetuses from the 150 mg/kg per day
    group. The NOEL for maternal toxicity was 25 mg/kg per day and the
    NOEL for developmental toxicity was 75 mg/kg per day.

         The results of a two-generation reproduction study in rats
    revealed no hydroquinone-related reproductive toxicity (Bio/dynamics
    Inc., 1989b). Charles River CD rats (180 Fo and 180 F1) were
    exposed via gavage to hydroquinone at concentrations of 15, 50 or
    150 mg/kg per day (30 rats per sex and group; 120 rats served as
    controls). The two lower dose levels did not affect mortality rates,
    body weight, or feed consumption either in the Fo or the F1
    parental animals. One Fo male given 50 mg/kg per day had tremors
    during the post-dosing period. There were no adverse effects on mean
    litter size, body weight, sex distribution or survival, or in
    postmortem evaluations of pups from females given 15 or 50 mg/kg per

    day. At the highest-dose level, tremors were observed in Fo and
    F1 parental animals of both sexes following dosing. Reproductive
    indices and pregnancy rates for the Fo and F1 parents were not
    considered to have been adversely affected by hydroquinone
    treatment, nor were there any adverse effects of treatment for pups
    from Fo and F1 parental animals. The NOAEL for parental toxicity
    was estimated to be 15 mg/kg per day and for reproductive effects
    through two generations to be 150 mg/kg per day.

         A quantitative approach to relate the physico-chemical
    properties of a series of substituted phenols (including
    hydroquinone) to maternal and developmental toxicity in rats was
    conducted by Kavlock (1990) and by Kavlock  et al. (1991). However,
    due to theoretical and statistical mistakes, no formal conclusions
    can be made on the possibility of modelling these particular
    end-points quantitatively.

         A review of the different reproduction studies is given in
    Table 15.

    7.6  Mutagenicity and related end-points

         The results of genotoxicity studies, with or without S9
    metabolic activation, are indicated in Table 16.

         Hydroquinone has been found to be non-mutagenic in  Salmonella
     typhimurium tester strains TA97, TA98, TA100, TA1535, TA1537 and
    TA1538, with and without metabolic activation, at doses up to 1000
    µg/plate (Bulman & Wampler, 1979; Bulman & Van der Sluis, 1980;
    Florin  et al., 1980; Gocke  et al., 1981; Serva & Bulman, 1981;
    Bulman & Serva, 1982; Haworth  et al., 1983; Sakai  et al., 1985).
    However, in one study hydroquinone was reported to be clearly
    mutagenic without metabolic activation in strain 1535A (a strain
    that the authors suggested might harbour an undefined genetic
    alteration from TA1535 because of differences in length of storage)
    with ZLM minimal medium (a modified minimal medium for  Escherichia
     coli) but not with the standard VB (Vogel-Bonner) minimal medium
    (Gocke  et al., 1981). The concentration of citrate was 3.5 times
    higher in VB medium than in ZLM medium. In a fluctuation test using
    the  Salmonella typhimurium tester strain TA100, hydroquinone was
    shown to be mutagenic at the concentrations 100 and 200 ng/well with
    metabolic activation (Koike  et al., 1988).

         In  Escherichia coli hydroquinone causes differential killing
    of DNA-repair-deficient (Pol A-) and -proficient (Pol A+) strains
    without a supplementary metabolic activation system, indicating
    induction of repairable DNA damage (Bilimoria, 1975; Van der Sluis,
    1980; Wampler, 1980). In  Salmonella typhimurium no SOS-inducing
    activity of hydroquinone (3300 mg/litre liquid medium) could be
    demonstrated (Nakamura  et al., 1987).


    
    Table 15.  Studies on reproductive effects in laboratory animals
                                                                                                                                           
    Species  Route of       Number of    Dosage              Time of              Result                                  Reference
             exposure       animals      treatment
                                                                                                                                           

    Rat      subcutaneous   16 males     100 mg/kg body      51 days              33% reduced fertility, diminished       Skalka (1964)
                                         weight                                   content of DNA in sperm heads; 19%
                                                                                  reduced number of pregnancies in
                                                                                  mated females

    Rat      subcutaneous   3            10 mg/day           11 days              interrupted estrus cycle                Rosen & Millman
                                                                                                                          (1955)

    Rat      oral (gavage)  10/group     200 mg/kg body      14 days              some rats remained in diestrus,         Racz et al.
                                         weight per daya                          CNS effects and death within 5 days     (1958)

    Rat      oral (diet)    10 females/  0.003%              10 days prior to     no effects on gestation and             Ames et al.
                            group        0.3%                insemination         maternal mortality                      (1956)

    Rat      oral (diet)    10           0.5 g               not clearly stated   increased resorption rate               Telford et al.
                                                                                                                          (1962)

    Rat      oral (gavage)  10 females/  0, 50, 100 or 200   gestation days       reduced feed consumption and body       Krasavage (1984a)
                            group        mg/kg body weight   6-15                 weight gain at 200 mg/kg

    Rat      oral (gavage)  25/group     0, 30, 100 or 300   5 days per week      no treatment-related effects on         Krasavage (1984b)
     (male)                              mg/kg body weight   for 10 weeks         reproductive parameters studied

    Rat      oral (gavage)  30/group     0, 30, 100 or 300   gestation days       reduced fetal body weight at            Krasavage et al.
                                         mg/kg               6-15                 300 mg/kg                               (1985)

    Rat      oral (gastric  30/group     0, 15, 50 or 150    two-generation       no effect on reproduction at            Bio/dynamics
                            intubation)  mg/kg body weight   study                150 mg/kg                               Inc. (1989b)

    Table 15. (contd).
                                                                                                                                           
    Species  Route of       Number of    Dosage              Time of              Result                                  Reference
             exposure       animals      treatment
                                                                                                                                           

    Rat      oral           16/group     0, 100, 333, 667    gestation day 11     reduced weight gain at 667 and 1000     Kavlock (1990)
             (intubation)                or 1000 mg/kg                            mg/kg; increased mortality at 1000
                                                                                  mg/kg; malformations of the limbs,
                                                                                  tail and urogenital system

    Rat      embryo                      < 0.5 mmol/litre    from day 10          growth retardation, structural          Kavlock et al.
             culture                                         (approx. 12 somite)  abnormalities of hind limb and tail     (1991)
             system

    Mouse    oral (gastric  4            80 mg/kg body       gestation day 13     micronuclei in fetal liver cells        Ciranni et al.
             intubation)                 weight                                                                           (1988a)

    Rabbit   oral (gastric  5/group      0, 50, 100, 200,    gestation days       increased number of resorptions         Bio/dynamics
             intubation)                 300, 400 or 500     6-18                 and lower fetal weights at 200 mg/kg;   Inc. (1988)
                                         mg/kg body weight                        no females survived 300-500 mg/kg

    Rabbit   oral (gastric  18/group     0, 25, 75 or 150    gestation days       an increased incidence (not             Bio/dynamics Inc.
             intubation)                 mg/kg body weight   6-18                 significant) of malformations at        (1989a); Murphy
                                                                                  150 mg/kg                               et al. (1992)
                                                                                                                                           

    a  Due to high mortality at 200 mg/kg, the dose was reduced for the rest of the 14-day period.


    
         In  Aspergillus nidulans hydroquinone was found to induce
    mitotic segregation at 110-330 mg/litre (Crebelli  et al., 1987)
    and 264-396 mg/litre (Crebelli  et al., 1991) and mitotic
    crossing-over at 250-750 mg/litre (Kappas, 1989) and 264-396
    mg/litre (Crebelli  et al., 1991). The studies were performed
    without a supplementary metabolic activation system.

         Hydroquinone has been shown to induce chromosome aberrations or
    karyotypic alterations in several plant species, e.g.,  Allium cepa
    (Levan & Tjio, 1948a,b),  Allium sativum (Sharma & Chatterjee,
    1964; Valadaud & Izard, 1971),  Callisia fragrans (Roy, 1973),
     Chara zeylanica (Chatterjee & Sharma, 1972),  Nigella sativa
    (Sharma & Chatterjee, 1964),  Trigonella foenum-graecum (Sharma &
    Chatterjee, 1964), and  Vicia faba (Sharma & Chatterjee, 1964;
    Valadaud & Izard, 1971; Valadaud-Barrieu & Izard, 1973).

         Hydroquinone produced an equivocal increase in recessive lethal
    mutations in the X-chromosome of  Drosophila melanogaster after
    feeding adult males with a sucrose solution containing 26.4 or 30.0
    mg hydroquinone/litre (NTP, 1989). No increase in the frequency of
    recessive lethal mutations could be established in similar feeding
    studies with hydroquinone at concentrations of 5500 to 11 000
    mg/litre (Gocke  et al., 1981) and 1000 mg/litre (Serva & Murphy,
    1981), or in a study where males were injected with a dose of 1.5
    mg/litre (NTP, 1989) (see also section 7.5.1).

         At concentrations of 1.25 mg/litre (without a supplementary
    metabolic activation system) and 2.5 mg/litre (with a supplementary
    metabolic activation system), hydroquinone induced forward mutations
     in vitro in the thymidine kinase locus of the mouse lymphoma cell
    line L5178Y (McGregor  et al., 1988a,b).

         Gene mutations to 6-thioguanine resistance were induced  in
     vitro in V79 Chinese hamster cells exposed to hydroquinone at 350
    µg/litre (Glatt  et al., 1989). No supplementary metabolic
    activation system was used.

         Structural chromosome aberrations were induced  in vitro in
    Chinese hamster ovary cells treated with hydroquinone, but only in
    the presence of a supplementary metabolic activation system
    (Galloway  et al., 1987).

        Table 16.  Studies on genotoxicity
                                                                                      
    Genetic end-point                   Resulta         References
                                     +S9       -S9
                                                                                      

    Gene mutations

    Salmonella typhimurium                     -         Bulman & Wampler (1979)
    Salmonella typhimurium           -         -         Bulman & Van der Sluis (1980)
    Salmonella typhimurium           -         -         Florin et al. (1980)
    Salmonella typhimurium           -         -         Gocke et al. (1981)
    Salmonella typhimurium           -         -         Serva & Bulman (1981)
    Salmonella typhimurium           -         -         Bulman & Serva (1982)
    Salmonella typhimurium           -         -         Haworth et al. (1983)
    Salmonella typhimurium           -         -         Sakai et al. (1985)
    Salmonella typhimurium           -         +         Gocke et al. (1981)
    TA1535A, ZLM medium
    Salmonella typhimurium           +         -         Koike et al. (1988)
    TA100, fluctuation test
    Mouse lymphoma cells L5178Y      +         +         McGregor et al. (1988a,b)
    Chinese hamster cells V79        nd        +         Glatt et al. (1989)
    Drosophila melanogaster,             (+)             NTP (1989)
    feeding
    Drosophila melanogaster,                   -         Gocke et al. (1981)
    feeding
    Drosophila melanogaster,                   -         Serva & Murphy (1981)
    feeding
    Drosophila melanogaster,                   -         NTP (1989)
    injection
    Mouse, spot test                           -         Gocke et al. (1983)
    Rat, dominant lethals                      -         Krasavage (1984b)

    Chromosomal aberrations

    Aspergillus nidulans             nd        +         Crebelli et al. (1987, 1991)
    Chinese hamster ovary cells      +         -         Galloway et al. (1987)
    Allium cepa                           +              Levan & Tjio (1948a,b)
    Allium sativum                        +              Sharma & Chatterjee (1964)
    Allium sativum                        +              Valadaud & Izard (1971)
    Callisia fragrans                     +              Roy (1973)
    Chara zeylanica                       +              Chatterjee & Sharma (1972)
    Nigella sativa                        +              Sharma & Chatterjee (1964)
    Trigonella foenum-graecum             +              Sharma & Chatterjee (1964)
    Vicia faba                            +              Sharma & Chatterjee (1964)
    Vicia faba                            +              Valadaud & Izard (1971)
    Vicia faba                            +              Valadaud-Barrieu & Izard (1973)
    Mouse, bone marrow                    +              Xu & Adler (1990)

    Table 16. (contd).
                                                                                      
    Genetic end-point                   Resulta         References
                                     +S9       -S9
                                                                                      

    Mouse, bone marrow                    +              Pacchierotti et al. (1991)
    Mouse, spermatocytes and              +              Ciranni & Adler (1991)
    differentiating spermatogonia
    Rat, dominant lethals                 -              Krasavage (1984b)

    Micronuclei

    Chinese hamster cells V79nd           +              Glatt et al. (1989, 1990)
    Rat intestinal cells             nd        +         Glatt et al. (1990)
    Embryonal human liver cells      nd        +         Glatt et al. (1990)
    Human lymphocytes                nd        +         Yager et al. (1990)
    Human lymphocytes                nd        +         Robertson et al. (1991)
    Chinese hamster embryonicnd           +              Antoccia et al. (1991)
    lung cells
    Mouse, bone marrow                    +              Gocke et al. (1981)
    Mouse, bone marrow                    +              Gad-El-Karim et al. (1985)
    Mouse, bone marrow                    +              Ciranni et al. (1988a,b)
    Mouse, bone marrow                    +              Adler & Kliesch (1990)
    Mouse, bone marrow                    +              Barale et al. (1990)
    Mouse, bone marrow                    +              Adler et al. (1991)
    Mouse, bone marrow                    +              Pachierotti et al. (1991)
    Mouse, fetal liver                    +              Ciranni et al. (1988a)
    Chinese hamster cells V79        nd        +         Glatt et al. (1989)
    Chinese hamster ovary cells      +         +         Galloway et al. (1987)
    Human lymphocytes                nd        +         Erexson et al. (1985)
    Human lymphocytes                nd        +         Morimoto & Wolff (1980)
    Human lymphocytes                nd        ±         Knadle (1985)
    Human lymphocytes                +         nd        Morimoto et al. (1983)
    Mouse, bone marrow                    -              Pacchierotti et al. (1991)

    Mitotic crossing-over

    Aspergillus nidulans             nd        +         Kappas (1989)
    Aspergillus nidulans             nd        +         Crebelli et al. (1991)

    C-mitotic effects

    Mouse, small intestine                +              Parmentier & Dustin (1948)
    Mouse, bone marrow                    +              Miller & Adler (1989)

    DNA damage

    Mouse lymphoma cells L5178YS,    nd        -         Pellack-Walker & Blumer
    breaks                                               (1986)
    Phi X-174 DNA, breaks                 +              Lewis et al. (1988a)

    Table 16. (contd).
                                                                                      
    Genetic end-point                   Resulta         References
                                     +S9       -S9
                                                                                      

    Rat, liver (hepatectomy),             +              Stenius et al. (1989)
    single-strand breaks

    DNA repair

    Escherichia coli                 nd        +         Bilimoria (1975)
    Escherichia coli                 nd        +         Van der Sluis (1980)
    Escherichia coli                 nd        +         Wampler (1980)
    Salmonella typhimurium           nd        +         Nakamura et al. (1987)
    HeLa cells                       +         +         Painter & Howard (1982)
    Mouse lymphoma cells L5178YS     nd        +         Pellack-Walker et al. (1985)

    DNA adducts

    In vitro                              +              Rushmore et al. (1984)
    In vitro                              +              Jowa et al. (1986)
    In vitro                              +              Reddy et al. (1989)
    In vitro                              +              Jowa et al. (1990)
    In vitro                              +              Leanderson & Tagesson (1990)
    In vitro                              +              Reddy et al. (1990)
    In vitro                              +              Levay et al. (1991)
                                                                                      

    a  + = positive; - = negative; (+) = equivocal; ± = induction in some
       cases but not in others; nd = not determined
    
         The induction of sister-chromatid exchanges  in vitro after
    exposure to hydroquinone without the use of a supplementary
    metabolic activation system has been demonstrated in V79 Chinese
    hamster cells at 2.2 mg/litre (Glatt  et al., 1989) and human
    lymphocytes at 0.55-11 mg/litre (Erexson  et al., 1985), 4.4-22
    mg/litre (Morimoto & Wolff, 1980), and 4.4 mg/litre in cells from
    some individuals but not from others (Knadle, 1985), with a
    supplementary metabolic activation system in human lymphocytes at
    110 mg/litre (Morimoto  et al., 1983), and both with and without a
    supplementary metabolic activation system in Chinese hamster ovary
    cells (Galloway  et al., 1987).

         Hydroquinone has been found to induce micronuclei  in vitro in
    V79 Chinese hamster cells (Glatt  et al., 1989, 1990), rat
    intestinal cells IEC-17 and IEC-18, and embryonal human liver cells
    HuFoe-15 (Glatt  et al., 1990). In cultured human lymphocytes an
    11-fold and 3-fold increase in the frequency of micronuclei, was

    reported after exposure to hydroquinone at 13.75 mg/litre (Yager  et
     al., 1990) and 8.25 mg/litre (Robertson  et al., 1991),
    respectively. Hydroquinone induced micronuclei  in vitro in Cl-1
    Chinese hamster embryonic lung cells at concentrations of 1, 3, and
    4.5 mg/litre (Antoccia  et al., 1991). The use of an
    antikinetochore antibody in the three latter studies indicated the
    occurrence of numerical as well as structural chromosome
    aberrations. All studies were performed without a supplementary
    metabolic activation system.

         With the  in vitro porcine brain tubulin assembly assay,
    hydroquinone had no effect with respect to lag-phase, polymerization
    velocity or end absorption at doses up to 2750 mg/litre. The
    disassembly process was stimulated at doses higher than 1100
    mg/litre (Brunner  et al., 1991). In another study, hydroquinone
    exhibited a weak inhibition of microtubule assembly and resulted in
    abnormal microtubule formation at a concentration of 110 mg/litre
    (Wallin & Hartley-Asp, 1993). Although hydroquinone itself appears
    to be a poor inhibitor of microtubule assembly, its oxidation
    products have been shown to bind to both alpha- and beta-tubulin and
    to inhibit microtubule assembly at low concentrations (5 µmol/litre
    or less) (Epe  et al., 1990). In another study it was demonstrated
    that polymerization of tubulin was inhibited by hydroquinone in a
    concentration-dependent manner (Irons  et al., 1981).

         An effect on DNA synthesis, indicating DNA damage, following
     in vitro exposure to hydroquinone has been demonstrated both with
    and without a supplementary metabolic activation system in HeLa
    cells (Painter & Howard, 1982) and without the use of a metabolic
    activation system in the mouse lymphoma cell line L5178YS
    (Pellack-Walker  et al., 1985).

         Female mice (C57BL/6JHan), mated with T-stock males, were
    injected intraperitoneally with hydroquinone (110 mg/kg) on the 10th
    day of pregnancy and subsequently analysed in accordance with the
    mammalian spot test, which detects somatic gene mutations in mouse
    embryos. No substance-related effect on the mutation frequency was
    detected (Gocke  et al., 1983).

         In a study by Xu & Adler (1990), mice [(101/E1 x C3H/E1)F1],
    10-14 weeks old and weighing 25-28 g, were injected
    intraperito-neally with hydroquinone (40, 75 and 100 mg/kg). Bone
    marrow cells, sampled 6 and 24 h later in the case of the two lower
    doses and 6, 12, 18, 24 and 36 h later in the case of the highest
    dose, were analysed for the presence of structural chromosome
    aber-rations. At the highest dose level hydroquinone significantly
    increased the frequency of aberrations 6-24 h after the treatment,
    while at 75 mg/kg such an effect was detectable only 24 h after
    treatment.

         Male mice [(101/E1 x C3H/E1)F1], 10-14 weeks old and weighing
    25-28 g, were injected intraperitoneally with hydroquinone (80, 100
    and 150 mg/kg), and bone marrow cells, sampled 2 h later, were
    analysed for the induction of c-mitotic effects. At dose levels of
    100 and 150 mg/kg hydroquinone significantly increased the frequency
    of metaphases with spread chromosomes (Miller & Adler, 1989).
    Colchicine-like accumulation of metaphases and unusual "three-group
    metaphases" in the small intestine were described in mice injected
    with hydroquinone (125 mg/kg) (Parmentier & Dustin, 1948, 1951).
    Similar results were observed in the intestine and bone marrow cells
    of rats and hamsters following hydroquinone administration
    (Parmentier, 1952, 1953).

         In a study by Pacchierotti  et al. (1991), male mice
    [(C57Bl/Cne x C3H/Cne)F1], 12 weeks old, were injected with
    hydroquinone (40, 80 and 120 mg/kg). Bone marrow cells, sampled 18
    and 24 h later were analysed for the presence of numerical
    chromosome changes, micronuclei and sister-chromatid exchanges. At a
    dose level of 80 mg/kg, hydroquinone significantly increased the
    frequency of hyperploid cells with 41-42 chromosomes after 18 h. At
    all concentrations tested the frequency of micronuclei was
    significantly increased after 24 h, while after 18 h such an effect
    was only detectable at the concentration of 80 mg/kg. An increase in
    sister-chromatid exchange frequencies over control values was not
    detected in any treated animal.

         Mice [(101/E1 x C3H/E1)F1], 10-14 weeks old and weighing
    25-28 g, were injected intraperitoneally with hydroquinone (30, 50,
    75 and 100 mg/kg), and bone marrow cells, sampled 18, 24 and 30 h
    later (75 mg/kg), 6 and 24 h later (50 mg/kg) and 24 h later (30 and
    100 mg/kg), were analysed for the presence of micronuclei. At a dose
    level of 75 mg/kg, hydroquinone significantly increased the
    frequency of micronuclei in cells at all sampling intervals.
    Treatment with hydroquinone at 50 and 100 mg/kg significantly
    increased the frequency of micronuclei after 24 h (Adler & Kliesch,
    1990). The authors also reported results from daily treatments (up
    to 3 days) of male mice of the same strain with hydroquinone (15 or
    75 mg/kg) by the intraperitoneal route of administration. Bone
    marrow cells were sampled 24 h after the first, second and third
    injections, respectively. The frequency of micronuclei increased in
    the case of the lower dose and decreased in the case of the higher
    dose with increasing number of treatments.

         The induction of micronuclei in mouse bone marrow cells after
    intraperitoneal injection of hydroquinone has also been demonstrated
    by Gocke  et al. (1981), Ciranni  et al. (1988a,b), Barale  et al.
    (1990) and Adler  et al. (1991). Oral administration of
    hydroquinone (200 mg/kg) induced an increase in the frequency of
    micronuclei in mice (Gad-El-Karim  et al., 1985). Ciranni  et al.
    (1988b) demonstrated that oral administration of hydroquinone (80
    mg/kg) produced a weak increase in the frequency of micronuclei

    compared to the effect found following intraperitoneal
    administration. In male mice (outbred NMRI) daily subcutaneous
    injections of hydroquinone on six consecutive days induced
    micronuclei in the bone marrow at dose levels of 25 to 100 mg/kg
    (Tunek  et al., 1982).

         When pregnant mice (Swiss CD-1, three months old) were given
    hydroquinone (80 mg/kg) by gastric intubation on the 13th day of
    gestation, micronuclei were induced in fetal liver cells (Ciranni
     et al., 1988a).

         In male rats (Sprague-Dawley), weighing 200 g and subjected to
    70% partial hepatectomy, single-strand breaks were induced in
    hepatic DNA after the rats had received daily hydroquinone doses of
    200 mg/kg, given in a liquid casein-based diet, for 7 weeks (Stenius
     et al., 1989).

         Male mice [(102/ElxC3H/El)F1], 12-14 weeks old and weighing
    25-28 g, were injected intraperitoneally with hydroquinone (40, 80
    and 120 mg/kg). In spermatocytes sampled 12 days after treatment
    (representing cells treated at preleptotene), the frequency of
    chromosomal aberrations excluding gaps was significantly increased
    at 40 and 80 mg/kg but not at 120 mg/kg. In differentiating
    spermatogonia sampled 24 h after treatment, the frequency of
    chromosomal aberrations excluding gaps was significantly increased
    at all dose levels (Ciranni & Adler, 1991).

         No increased frequency of dominant lethal mutations was
    detected in male rats [CRL:COBS"CD"(SD)BR] given repeated doses of
    hydroquinone (30, 100 or 300 mg/kg, 5 days/week for 10 weeks) by
    gavage (Krasavage, 1984b). The induction of sperm-head abnormalities
    could not be demonstrated in male mice after intraperitoneal
    injection of hydroquinone (55-220 mg/kg) (Wild  et al., 1981).

         The ability of hydroquinone to produce adducts with DNA or its
    nucleotides  in vitro has been shown by Rushmore  et al. (1984),
    Jowa  et al. (1986), Reddy  et al. (1989), Jowa  et al. (1990),
    Leanderson & Tagesson (1990), Reddy  et al. (1990) and Levay  et
     al. (1991). There is less evidence for the hydroquinone-induced
    formation of DNA adducts  in vivo. Using the 32P postlabelling
    assay, no treatment-related adducts were detected in the kidneys of
    either male or female F-344 rats following the oral administration
    of hydroquinone at dose levels of up to 50 mg/kg for 6 weeks
    (English  et al., 1992). In additional studies by Reddy  et al.
    (1990), also using the postlabelling assay, no treatment-related DNA
    adducts were detected in the bone marrow, zymbal gland or liver of
    female F-344 rats following the oral co-administration of phenol and
    hydroquinone at either 75 or 150 mg/kg for 4 days (Reddy  et al.,
    1990).

         Hydroquinone has been shown to be capable of producing breaks
    in phi X-174 DNA (Lewis  et al., 1988a). No increase in the
    frequency of breaks was detected in DNA from hydroquinone-treated
    mouse lymphoma cells (L5178YS) at concentrations of up to 11
    mg/litre (Pellack-Walker & Blumer, 1986).

    7.7  Carcinogenicity

         The available studies on the carcinogenicity of hydroquinone
    are summarized in Table 17.

    7.7.1  Long-term bioassays

         In an NTP study (NTP, 1989; Kari  et al., 1992), groups of 65
    F-344/N rats of each sex were given hydroquinone (0, 25 or 50 mg/kg
    body weight) in deionized water by gavage 5 days/week for up to 103
    weeks, and groups of 65 B6C3F1 mice of each sex were administered
    0, 50 or 100 mg/kg body weight according to the same schedule. A
    15-month interim kill of ten animals from each group showed that the
    kidney of male rats was a target organ forthe toxicity (see also
    section 7.4), since there was a compound-related increased severity
    of nephropathy. The lesions were less severe in female rats, in
    which a mild regenerative anaemia was also found (slightly decreased
    haematocrit, haemoglobin and erythrocyte count). After termination
    of the experiment, a dose-related increase in the incidence of renal
    tubular cell adenomas was observed in male rats (controls 0/55, low
    dose 4/55, high dose 8/55; P = 0.003). The incidence of adenomas was
    closely associated with the severity of chronic nephropathy. No
    renal adenomas were observed in animals examined at 15 months, when
    the severity of nephropathy was less severe, or in female rats,
    which developed nephropathy to a lesser degree. In the male rats,
    9/12 adenomas were seen in kidneys with marked nephropathy, two were
    seen in animals with moderate nephropathy, and only one was seen in
    an animal with mild nephropathy. In the high-dose group single
    tubules exhibited tubular cell hyperplasia. No renal tumours were
    seen in females. A dose-related increase in the incidence of
    mononuclear cell leukaemia was found in female rats (controls 9/55,
    low dose 15/55, high dose 22/55) (P < 0.01 in the high-dose group
    versus controls). However, this was not observed in the animals
    killed at 15 months. The incidence in controls was lower than the
    historical control mean incidence but was within the historical
    control group range.


    
    Table 17.  Carcinogenicity studies in animals
                                                                                                                                               
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment
                                                                                                                                               

    Long-term bioassays

    Mouse    oral          64 or 65 of  50 or 100         103 weeks      liver lesions (males),           some evidence of       NTP (1989);
                           each sex     mg/kg                            hepatocellular adenomas          carcinogenic activity  Kari et al.
                           per group    5 days/week                      (females)                        for female mice        (1992)

    Mouse    oral          30 m, 30 f   0.8% in           96 weeks       squamous cell hyperplasia of     potential of           Shibata et al.
                                        the diet                         the forestomach epithelium;      hepatocarcinogenicity  (1991)
                                                                         renal tubular hyperplasia and    in male mice
                                                                         adenomas (males); increased
                                                                         incidence of liver foci and
                                                                         hepatocellular adenomas
                                                                         (males)

    Rat      oral          65 of each   25 or 50          103 weeks      nephropathy (more severe in      some evidence of       NTP (1989);
                           sex per      mg/kg                            males), renal tubular cell       carcinogenic activity  Kari et al.
                           group        5 days/week                      hyperplasia and adenomas         for male and female    (1992)
                                                                         (males), leukaemia (females)     rats

    Rat      oral          30 m, 30 f   0.8% in           104 weeks      renal tubular hyperplasia,       potential of renal     Shibata et al.
                                        the diet                         adenomas and epithelial          carcinogencity in      (1991)
                                                                         hyperplasia of the renal         male rats
                                                                         papilla (males); decreased
                                                                         incidence of liver foci

    Table 17. (contd).
                                                                                                                                               
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment
                                                                                                                                               

    Carcinogenicity-related studies

    Mouse    skin          24 m         0.3 ml of 6.7%    one            skin papilloma (1/24)            no initiating          Roe & Salaman
             application                solution;         application;                                    activity               (1955)
                                        0.3 ml of         then three
                                        0.5% croton       weeks later,
                                        oil               18 weekly
                                                          applications

    Mouse    skin          50 f         5 mg three        368 days       papilloma (7/50), squamous       no co-carcinogenic     van Duuren &
             application   times                                         carcinoma (3/50)                 or tumour-promoting    Goldschmidt
                           weeklya                                       activity; partial                (1976)
                                                                         inhibition of BP
                                                                         carcinogenicity

    Mouse    implantation  not stated   2 mg              25 weeks       carcinomas (6/19)                                       Boyland et al.
             in urinary                                                                                                          (1964)
             bladder

    Rat      oral          20 f         0.8% in           32 weeks       no preneoplastic lesions                                Kurata et al.
                                        basal dietb                      or papillomas of the                                    (1990)
                                                                         urinary bladder

    Rat      oral          15-16 m      0.8% in           51 weeks       no increase in forestomach or                           Hirose et al.
                                        dietc                            glandular stomach neoplasms                             (1989)

    Rat      oral          5 m                            8 weeks        no proliferative changes                                Shibata et al.
                                                                         in forestomach or glandular                             (1990)
                                                                         stomach

    Table 17. (contd).
                                                                                                                                               
    Species  Route of      Number of    Dosage            Time of        Result                           Remarks                Reference
                           exposure     animals           treatment
                                                                                                                                               

    Rat      oral          7-10 m per   100 mg/kg         7 weeks        increased number of liver foci   relatively weak        Stenius et al.
                           group        diet per dayd                    decreased number of liver foci   inducer of enzyme-     (1989)
                                        200 mg/kg                        compared to the 100 mg/kg        altered liver foci
                                        diet per dayd                    dose

    Hamster  oral          15 m         0.5% in basal     20 weeks       no proliferative changes in                             Hirose et al.
                                        diet                             forestomach                                             (1986)
                                                                                                                                               

    a  after initiating dose of benzo[ a] pyrene (BP)
    b  after initiating with  N-butyl-2 N-(4-hydroxybutyl) nitrosamine for four weeks
    c  one week after 150 mg/kg body weight
    d  after partial hepatectomy


    
         In male mice centrilobular fatty changes and cytomegaly were
    found in the animals killed at 15 months, but these findings were
    not seen in mice killed at 2 years. The authors reported that
    hydroquinone dosing stopped two weeks before necropsy and that the
    microscopic lesions were likely to be reversible after cessation of
    treatment. There was a significantly (P=0.0005) increased incidence
    of hepatocellular adenomas in female mice given hydroquinone for 2
    years (controls 2/55, low dose 15/55, high dose 12/55) and the
    incidences of hepatocellular carcinomas were 1/55, 2/55 and 2/55,
    respectively. In males the incidence of adenomas was increased in
    treated mice but the incidence of hepatocellular carcinomas was
    decreased. Preneoplastic changes (anisokaryosis, multinucleated
    hepatocytes, and basophilic foci) were increased in high-dose male
    mice. Treatment-related, but not statistically significant,
    follicular cell hyperplasia of the thyroid gland was observed in
    both male and female mice (NTP, 1989; Kari  et al., 1992).

         The NTP concluded that there was "some evidence of carcinogenic
    activity" of hydroquinone for male F-344/N rats (tubular cell
    adenomas of the kidney) and also for female F-344/N rats
    (mononuclear cell leukaemia). There was "no evidence of carcinogenic
    activity" for male B6C3F1 mice and "some evidence of carcinogenic
    activity" for female B6C3F1 mice (hepatocellular adenomas and
    carcinomas combined).

         Shibata  et al. (1991) administered hydroquinone at dietary
    levels of 0.% or 8 g/kg to groups of 30 Fischer-344 rats and
    B6C3F1 mice of each sex. The rats were dosed for 104 weeks and the
    mice for 96 weeks. Average daily intakes were reported to be 351 and
    368 mg/kg body weight per day in male and female rats, respectively,
    and 1046 and 1486 mg/kg per day in male and female mice,
    respectively. No treatment-related clinical signs and no significant
    differences in mortality were found between treated and control
    animals of either species. The final body weight was significantly
    (P < 0.05) lower in treated female rats than in corresponding
    controls. In male rats the absolute and relative liver and kidney
    weights were significantly (P < 0.01) increased, but in females
    this applied only to the relative kidney weights (P < 0.05).
    Histologically, chronic nephropathy was seen in both control and
    treated groups of male rats. However, treated males were more
    severely affected than the controls, while treated females showed
    only slight nephropathy. The incidence of epithelial hyperplasia of
    the renal papilla was significantly (P < 0.05) increased in treated
    male rats as was the incidence of renal tubular hyperplasia (30/30)
    and renal tubular adenomas (14/30).

         The authors found that renal cell tumour development in male
    rats under the long-term influence of hydroquinone was not
    associated with alpha2u-globulin nephropathy. The incidence of liver
    foci showed a tendency to decrease in treated males. A quantitative

    analysis showed a statistically significant (P < 0.05 in males, P<
    0.01 in females) reduction in both sexes given hydroquinone. The
    authors did not find an increased incidence of mononuclear cell
    leukaemia in female rats (personal communication).

         In mice, the final body weight was significantly (P < 0.05)
    lower in females given hydroquinone; the relative liver and kidney
    weights were significantly (P < 0.05) increased. Histologically,
    the incidence of squamous cell hyperplasia of the forestomach
    epithelium was significantly (P < 0.01) increased in both sexes. A
    significant increase in the incidence of renal tubular hyperplasia
    (P < 0.01) and three renal cell adenomas were seen in 30 males
    given hydroquinone. In treated males the incidence of liver foci and
    hepatocellular adenomas (14/30) was also significantly (P < 0.05)
    increased.

    7.7.2  Carcinogenicity-related studies

    7.7.2.1  Skin

         In a study by Roe & Salaman (1955), stock albino mice (24
    males, "S" strain) were given a single skin application of 0.3 ml of
    a 6.7% solution of hydroquinone in acetone (total dose 20.0 mg).
    Three weeks later the mice received 18 weekly applications of 0.3 ml
    of 0.5% croton oil in acetone as a promoter on the same area of the
    skin. Of the 24 treated animals, two died during the experiment and
    one mouse developed a skin papilloma.

         In a two-stage carcinogenesis test on mouse skin using
    benzo[ a]pyrene (BP) as the initiating agent, no tumour-promoting
    activity was shown (Van Duuren & Goldschmidt, 1976). Hydroquinone (5
    mg) was applied to mouse skin (50 female ICR/Ha Swiss mice/group;
    both positive and negative controls) three times weekly for 368
    days, together with 5 µg BP. Hydroquinone showed no potential as a
    co-carcinogen when applied simultaneously with BP; in fact, it
    partially inhibited BP carcinogenicity.

    7.7.2.2  Bladder

         Implantation of cholesterol pellets containing hydroquinone
    into the urinary bladder of mice (strain and sex unspecified) has
    been studied by Boyland  et al. (1964). The amount of hydroquinone
    was 20% in 10 mg cholesterol pellets (2 mg hydroquinone per mouse).
    Bladder carcinomas were produced in 6 out of 19 mice (32%) surviving
    25 weeks. The incidence of urinary bladder carcinomas in survivors
    of the dosed group was significantly (P=0.03) higher than in
    controls (11.7%) given cholesterol pellets only. However, the number
    of animals surviving the study was low, and the original number of
    animals and their sex distribution were not specified.

         In a study by Kurata  et al. (1990), groups of 20 male
    Fischer-344 rats received 0.05%  N-butyl- N-(4-hydroxybutyl)
    nitrosamine in the drinking-water for four weeks (as initiation)
    followed by 8 g hydroquinone/kg in the basal diet for 32 weeks. No
    increase in the incidence of preneoplastic lesions or
    papillomas/carcinomas of the urinary bladder was observed when
    compared to the incidences in rats given nitrosamine alone.

    7.7.2.3  Stomach

         Hirose  et al. (1989) examined the promotion activity and the
    carcinogenic potential of some dihydroxybenzenes, such as
    hydroquinone, in the glandular stomach and forestomach of F-344
    rats. Groups of 15-16 male rats were given a single intragastric
    dose of 150 mg/kg body weight  N-methyl- N'-nitro- N-
    nitrosoguanidine (MNNG), followed one week later by powdered diet
    containing hydroquinone (8g/kg) or basal diet alone for 51 weeks.
    Further groups of 10 and 15 animals, respectively, were administered
    the basal diet alone or a diet containing hydroquinone (8 g/kg) for
    51 weeks without pretreatment with MNNG. Hydroquinone did not cause
    an increased incidence of forestomach or glandular stomach lesions,
    either with or without pretreatment with MNNG, in comparison with
    the control groups.

         In studies performed by Hirose  et al. (1986), hydroquinone
    did not produce proliferative lesions in the stomach of hamsters.
    Male Syrian golden hamsters (15/group, seven weeks old at the
    beginning of the study) were given basal diet with hydroquinone (5
    g/kg) added or basal diet alone for 20 weeks. The dose was chosen as
    approximately a quarter of the LD50. Tissues from forestomach and
    glandular stomach showed mild to moderate hyperplasia in the group
    given hydroquinone, but at the same incidence as in the controls.
    Similar results were obtained by Shibata  et al. (1990) in an
    8-week oral study using five male F-344 rats. Hydroquinone did not
    induce any proliferative changes in the forestomach or the glandular
    stomach epithelium.

    7.7.2.4  Liver

         Hydroquinone has been shown to be a relatively weak inducer of
    enzyme-altered foci in rat liver when tested for tumour-promoting
    activity in a liver focus test (Stenius  et al., 1989). Male
    Sprague-Dawley rats (7-10/group) given diethylnitrosamine (30 mg/kg
    intraperitoneally) after partial hepatectomy were treated with
    hydroquinone (0, 100 and 200 mg/kg per day) in their diet for 7
    weeks. At 100 mg/kg there was a significantly (P < 0.01) increased
    number of liver foci and an increased focus volume. The 200-mg dose
    caused less foci (0.34 ± 0.16 per cm2) than the 100-mg dose (0.65
    ± 0.25 per cm2), but the incidence was higher than in the control
    group (0.08 ± 0.08 per cm2).

         A study by Kurata  et al. (1990) yielded similar results
    concerning the tumour-promoting potential of hydroquinone in rats.
    Dietary administration of hydroquinone (8g/kg in basal diet) for 32
    weeks, after initiation for four weeks with  N-butyl- N-
    (4-hydroxybutyl) nitrosamine, caused no preneoplastic lesions or
    papillomas of the urinary bladder.

    7.8  Special studies

    7.8.1  Effects on spleen and bone marrow cells; immunotoxicity

         The bone marrow is the target in benzene toxicity; among the
    many metabolites of benzene, hydroquinone has received increased
    scrutiny as one of the possible contributing factors. Intravenous or
    intraperitoneal administration of hydroquinone (100 mg/kg) for three
    consecutive days to male C57BL/6 CRIBR mice significantly (P <
    0.05) reduced the spleen and bone marrow cellularity, with bone
    marrow demonstrating the greatest sensitivity (Wierda & Irons,
    1982). Laskin  et al. (1989) found that after injection in Balb/c
    mice hydroquinone (50 mg/kg) caused a 30-40% decrease in bone marrow
    cellularity.

          In vitro studies have demonstrated direct myelotoxic effects
    of hydroquinone toward mouse bone marrow stromal cells (Gaido &
    Wierda, 1984; Gaido & Wierda 1987). Hydroquinone inhibited stromal
    cell colony growth along with the ability of these cells to support
    granulocyte/monocyte colony formation in co-culture. The bone marrow
    stroma predominantly consists of macrophages and fibroblastoid
    stromal cells which interact to regulate myelopoiesis. Treatment
    with hydroquinone thus results in reduced capacity of the stroma to
    support myelopoiesis.

         In addition to this cytotoxic effect, Wierda & Irons (1982)
    found in  in vivo studies that hydroquinone also affected the
    immune function by reducing the number of progenitor B-lymphocytes
    in the spleen and bone marrow in mice, thus demonstrating an
    immunosuppressive potential. The rapid generation and maturation of
    progenitor B cells renders them highly susceptible to toxic agents
    that affect dividing cells. Evidence has accumulated concerning the
    effect of hydroquinone on the cellular activity of the immune system
     in vitro. Exposure of lymphocytes  in vitro to hydroquinone has
    been shown to result in a dose-dependent inhibition of RNA synthesis
    in the lymphocytes (Post  et al., 1985). A hydroquinone
    concentration of 1-2 x 10-5 mol/litre inhibited the RNA synthesis
    by 50%.

          In vitro exposure (one hour) of mouse bone marrow cells to
    hydroquinone (10-7-10-5 mol/litre) inhibited the maturation of
    B-lymphocytes from pre B-cells after 24 and 48 h in culture (King
     et al., 1987). More recent data have demonstrated that
    hydroquinone-induced inhibition of pre-B cell maturation results

    from toxicity to adherent stromal cells, and that bone marrow
    macrophages may be the primary target for hydroquinone
    myelotoxicity, rather than fibroblastic stromal cells or pre-B cells
    (King  et al., 1989; Thomas  et al., 1989a). Results also indicate
    a dose-related reduction of macrophage interleukin-1 (IL-1)
    secretion in cultures of bone marrow macrophages exposed to
    hydroquinone (King  et al., 1989; Thomas  et al., 1989b). IL-1 is
    necessary for the induction of interleukin-4 (IL-4), which is
    produced by fibroblastic stromal cells and is required for
    maturation of pre-B cells to B cells (King  et al., 1989).

         Fan  et al. (1989) demonstrated that hydroquinone can inhibit
    the natural killer activity of mouse spleen cells  in vitro at low
    concentrations. Concentrations of 1 x 10-5 mol/litre and 1 x
    10-6 mol/litre inhibited 29 and 22% of the activity, respectively.
    Lewis  et al. (1988b) found that hydroquinone had a selective
    effect on macrophage functions important in host defense. At
    concentrations of 3-100 µmol/litre, hydroquinone significantly
    (P < 0.05) inhibited the release of hydrogen peroxide and at 100
    µmol/litre it significantly (P < 0.05) inhibited priming by
    interferon for tumour cell cytolysis. Cheung  et al. (1989) have
    shown a concentration-dependent inhibition of interferon-alpha/ß
    production following exposure to hydroquinone in murine L-929 cell
    cultures.

    7.8.2  Effects on tumour cells

         The cytotoxic activity of hydroquinone has been tested on
    different tumour cells. Chavin  et al. (1980) studied the effect on
    melanoma transplants in female BALB/c mice. The incidence of
    melanoma transplants was reduced and the survival significantly (P
    < 0.0005) increased in mice that received hydroquinone treatment
    (80 mg/kg).

         Vladescu & Apetroae (1983) studied the molecular mechanisms of
    antitumour action and the possibilities of using hydroquinone as a
    toxic agent against cancer cells. In H 18R tumour-bearing male
    Wistar rats treated with hydroquinone (5 mg/kg per day) for seven
    days, the catalase activity was markedly depressed in liver, spleen,
    blood and H 18R tumour.  In vitro studies on tumour and liver
    homogenates from normal and tumour-bearing rats showed a marked
    inhibition of catalase activity in the tumour, which was less
    evident in the liver. The activity was less reduced in normal liver
    homogenates. It was suggested that the mechanism of action of
    hydroquinone as an antitumour agent is achieved mainly via peroxide
    production.

         When tested on cultured rat hepatoma cells hydroquinone showed
    a dose-dependent cytotoxic activity (Assaf  et al. 1987). A dose of
    33 mg/litre (300 µmol/litre) caused cellular mortality of 40% after

    24 h of incubation and 66 mg/litre (600 µmol/litre) resulted in 100%
    cellular mortality.

    7.8.3  Neurotoxicity

         Hydroquinone, given as single oral or subcutaneous lethal
    doses, causes nonspecific effects on the nervous system such as
    hyperexcitability, tremor and convulsions in several experimental
    animal species (see section 7.1). Animals given sublethal oral doses
    recover within a few days.

         These central nervous system stimulation effects were confirmed
    in a 90-day oral study on rats (Eastman Kodak Company, 1988) (see
    also section 7.3). Male and female weanling rats (CD(SD)BR),
    initially seven weeks old, were treated with hydroquinone (20, 64 or
    200 mg/kg per day) dissolved in water at a concentration of 5%.
    Doses were given by gavage 5 days per week. Functional-observational
    battery examinations were performed throughout the study. The
    battery included observations of body position, activity level,
    coordination of movement and gait, behaviour, presence of
    convulsions, tremors, lacrimation, salivation, piloerection,
    pupillary dilatation or constriction, respiration, diarrhoea,
    urination, vocalization, forelimb/hindlimb grip strength and sensory
    function. Tremors and depression of general activity were observed
    in both sexes shortly after dosing with 64 or 200 mg
    hydroquinone/kg. Functional-observational battery examinations did
    not result in any evidence of neurotoxicity as assessed by
    quantitative grip strength measurement, brain weight or
    neuropathological examination. The NOEL was considered to be 20 mg
    hydroquinone/kg body weight.

         Otsuka & Nonomura (1963) reported that hydroquinone reversed
    curare blockage at neuromuscular junctions in frog sciatic nerve -
    sartorius muscle preparations. The authors suggested that this
    effect was due to an increased release of transmitter at the
    neuromuscular junction induced by hydroquinone.

    7.8.4  Nephrotoxicity

         Until recently, exposure to hydroquinone has not been
    associated with nephrotoxicity. Nephrotoxicity has not been reported
    following either occupational exposure to hydroquinone or acute
    exposures in humans. Carlson & Brewer (1953) gave human volunteers
    daily hydroquinone doses of 300 or 500 mg/day for periods of up to
    20 weeks without effects on urinalysis parameters. Exposure of five
    male mixed-breed dogs to 100 mg hydroquinone/kg per day for 26 weeks
    had no effect on urinalysis parameters or renal histopathology
    (Carlson & Brewer, 1953). Christian  et al. (1976) reported that
    exposure of Carworth rats to hydroquinone in the drinking-water at
    concentrations of up to 10 g/litre (6 rats of each sex per group for
    8 weeks) or up to 4 g/litre (20 rats of each sex per group for 15

    weeks) resulted in slight changes in kidney weight but no
    histopathological changes. Carlson & Brewer (1953) also reported no
    evidence of renal histopathological changes in Sprague-Dawley rats
    fed diets containing 10g hydroquinone/kg for 104 weeks.

         NTP (1989) reported that oral gavage of hydroquinone (0, 25,
    50, 100, 200 or 400 mg/kg) in corn oil for 13 weeks resulted in
    toxic nephropathy in F-344 rats at the two highest dose levels (200
    mg/kg: 7/10 males, 6/10 females; 100 mg/kg: 1/10 females). Oral
    gavage of 0, 25 or 50 mg/kg in water for 15 months resulted in an
    increased incidence of chronic nephropathy in male F-344 rats (25
    mg/kg: 5/5 males; 50 mg/kg: 6/10 males). When male F-344 rats were
    dosed at 0, 25 or 50 mg/kg for two years, there was an increased
    severity of chronic progressive nephropathy in 20/55 animals given
    50 mg/kg. At a dosage level of 50 mg/kg for either 15 months or 2
    years, male rats had heavier relative kidney weights.

         Shibata  et al. (1991) also reported that F-344 rats developed
    chronic nephropathy when fed 8g hydroquinone/kg diet for 2 years.
    Male rats showed increased relative and absolute kidney weight, as
    well as an increased severity of chronic nephropathy (14/30
    animals). Female rats showed an increased relative kidney weight,
    but only a minimal increase in severity of chronic nephropathy in
    7/30 animals.

         Boatman  et al. (1992) reported on the urinalysis changes
    observed in male and female F-344 rats and Sprague-Dawley rats given
    single doses of 0, 200 or 400 mg hydroquinone/kg in water by oral
    gavage. B6C3F1 mice were examined after receiving doses of 0 or
    350 mg/kg in a similar fashion. The placement of venous catheters in
    F-344 rats increased their response to hydroquinone. At 400 mg/kg,
    male and female F-344 rats, but not Sprague-Dawley rats, displayed
    pronounced enzymuria and glucosuria, which resolved in 72-96 h. At
    200 mg/kg, enzymuria and glucosuria were present in female F-344
    rats but not males. Epithelial cell counts in the urine were
    statistically significantly increased (P < 0.05) at 400 mg/kg
    (male and female F-344 rats only) and 200 mg/kg (female F-344 rats
    only). Statistically significant (P < 0.05) decreases in
    osmolality were reported at 400 mg/kg for F-344 (both sexes) and
    female Sprague-Dawley rats. Diuresis (ml urine/h) was statistically
    significant (P < 0.005) only for female F-344 rats at 200 mg/kg
    and 400 mg/kg. Although differences were observed in some of the
    urinary parameters measured, mice were generally not responsive to
    hydroquinone.

         To characterize the early development of renal toxicity in
    rats, cell proliferation was quantified within the proximal (P1, P2
    and P3) and distal tubular segments of the kidney in rats given 0,
    2.5, 25 or 50 mg hydroquinone/kg by oral gavage. Male and female
    F-344 rats were treated for 1, 3 or 6 weeks, and male Sprague-Dawley
    rats were treated for 6 weeks. At 6 weeks, an 87% increase in cell

    proliferation was measured in the P1 segment, a 50% increase in the
    P2 segment, and a 34% increase in the P3 segment from kidneys of
    male F-344 rats dosed with 50 mg/kg. Urinalysis indicated increased
    enzymuria in this same dose group, and mild histological changes
    were present in the kidneys. Animals examined at other time points
    or from other dose groups were not affected by hydroquinone.

         The increased incidence of renal adenomas only in male F-344
    rats (NTP, 1989) has led to speculation that the tumours observed
    may be related to alpha2u-globulin-induced nephropathy. This
    mechanism of action for induction of kidney tumours does not appear
    to be relevant for hydroquinone as none of the studies cited above
    has reported finding evidence of hyalin droplet nephropathy
    following subacute, subchronic or chronic hydroquinone exposure.

         Glutathione metabolites, which are at least partially formed in
    the liver and transported to the kidney, are reported to be involved
    in the nephrotoxicity observed. Some of the potential glutathione
    conjugates of hydroquinone have been shown to be more nephrotoxic
    when injected parenterally than the parent chemical (Boatman  et
     al., 1992; Hill  et al., 1992a,b; Kleiner  et al., 1992).
    Administration of hydroquinone by parenteral injection, a route
    which is likely to increase hydroquinone glutathione conjugates,
    induces nephrotoxicity in otherwise non-responsive male
    Sprague-Dawley rats (Hill  et al., 1992a,b; Kleiner  et al.,
    1992). The formation of glutathione metabolites and an increased
    susceptibility of the male F-344 rat to the conjugates appear to be
    mechanistically linked to the nephrotoxicity observed in these rats.

    7.8.5  Interaction with phenols

         Recently there have been a number of studies reporting
    interactive effects between hydroquinone and other phenolic
    compounds. Initially, Eastmond  et al. (1987) showed that the
    co-administration of hydroquinone and phenol (75 mg/kg), when given
    by intraperitoneal injection twice per day, produced a synergistic
    decrease in bone marrow cellularity in B6C3F1 mice that was
    similar to that induced by benzene. This combined treatment was
    significantly more myelotoxic than that observed when either
    hydroquinone or phenol was administered separately. Associated  in
     vitro studies suggested that this interactive effect was due to a
    phenol-induced stimulation of the myeloperoxidase-mediated
    conversion of hydroquinone to 1,4-benzoquinone in the bone marrow
    (Eastmond  et al., 1987; Smith  et al., 1989; Subrahmanyam  et
     al., 1991).

         Subsequent studies have indicated that interactions between
    hydroquinone and other phenolic compounds can result in a variety of
    cytotoxic, immunotoxic and genotoxic effects. Some of the adverse
    interactive effects that have been reported are outlined below:

    a)   Decreased uptake of 59Fe, an indicator of toxicity to the
         bone marrow, has been reported with the combined administration
         of hydroquinone and various phenolic metabolites (Guy  et al., 
         1990, 1991).

    b)   The combined administration of phenol and radiolabelled
         hydroquinone results in increased binding of hydroquinone
         equivalents in the bone marrow (Subrahmanyam  et al., 1990).

    c)   Decreased bone marrow cellularity and increased production of
         reactive oxygen species in phagocytes when stimulated with a
         phorbol ester tumour promoter have been observed following
         hydroquinone and phenol co-administration (Laskin  et al., 
         1989).

    d)   Synergistic increases in the formation of micronuclei have been
         observed in mice and human lymphocytes obtained from one
         individual following exposure to hydroquinone and other
         phenolic metabolites (Barale  et al., 1990; Robertson  et
          al., 1991).

    e)   Three- to six-fold increases in DNA adduct formation (over that
         observed using the sum of the individual metabolites) were
         observed in HL-60 cells treated with the combination of
         hydroquinone and either catechol or 1,2,4-trihydroxybenzene. In
         addition, the combined treatment of hydroquinone and
         1,2,4-trihydroxybenzene produced DNA adducts not detected after
         treatment with either metabolite alone (Levay & Bodell, 1992).

    f)   Co-treatment of phenol and hydroquinone was reported to shift
         the optimal concentration of hydroquinone inducing the maximal
         recombinant granulocyte/macrophage colony-stimulating factor
         response from 1 µmol/litre to 100 pmol/litre (Irons  et al.,
         1992).

    g)   The co-administration of hydroquinone with either phenol or
         catechol  in vivo to B6C3F1 mice increased the formation of
         oxidative DNA damage as measured by the formation of
         8-hydroxy-2'-deoxyguanosine which occurred in the bone marrow
         of B6C3F1 mice (Kolachana  et al., in press).

    8.  EFFECTS ON HUMANS

    8.1  General population exposure

    8.1.1  Acute toxicity - poisoning incidents

         There have been reports of poisoning due to accidental or
    suicidal ingestion of hydroquinone alone (Mitchell & Webster, 1919;
    Rémond & Colombies, 1927) or of photographic developers containing
    hydroquinone (Busatto, 1939; Zeidman & Deutl, 1945; Grudzinski,
    1969; Larcan  et al., 1974). Deaths have been reported after
    ingestion of photographic developers containing hydroquinone in
    amounts of 3-12 g (80-200 mg/kg body weight). The main symptoms of
    intoxication by hydroquinone include tremors, vomiting, abdominal
    pain, headache, tachycardia, convulsions, loss of reflexes, dark
    urine, dyspnoea, cyanosis and coma. No adverse systemic effects have
    been reported after acute inhalation of hydroquinone dust (Anderson,
    1947; Oglesby  et al., 1947; Sterner  et al., 1947).

    8.1.2  Short-term controlled human studies

         In a controlled oral study, ingestion of 500 mg hydroquinone
    daily for 5 months (two males) or 300 mg/day for 3-5 months (17
    volunteers, both males and females) produced no observable
    pathological changes in blood and urine (Carlson & Brewer, 1953). No
    further data were given.

    8.1.3  Dermal effects; sensitization

         Skin lighteners often contain hydroquinone (1.5 to 2%) as the
    bleaching agent, which inhibits the production of melanin. Prolonged
    use (about three years) of strong (>5%) hydroquinone bleaching
    creams has been reported to cause ochronosis and pigmented colloid
    milium in South African black women (Findlay  et al., 1975; Findlay
    & de Beer, 1980). Sporadic skin reactions have also occurred among
    amateurs who develop their own films manually (Fisher, 1986).

         In a study to assess the safety of hydroquinone in cosmetic
    skin-lightening products, 840 male volunteers from different human
    races such as Blacks (Zulu), Asians (Indians), and Coloureds (mixed
    ethnic origins) were treated with various concentrations of
    hydroquinone in different bases (Bentley-Philips & Bayles, 1975).
    They were subjected to open-patch tests, normal usage tests, and
    standard 48 h closed-patch tests. The results of the study showed
    that concentrations of hydroquinone below 3% produced negligible
    adverse effects, irrespective of the base used or the colour of the
    user's skin. In earlier, less extensive studies, Fitzpatrick  et al.
    (1966) found that a 5% cream of hydroquinone caused a high incidence
    of primary irritant reactions such as erythema and tingling at the
    site of application.

         Fisher (1982) reported four cases of leucoderma following the
    use of bleaching creams containing 2% hydroquinone. The leucoderma
    was not preceded by inflammation and the patients had no positive
    patch-test reaction to 1% hydroquinone in petrolatum after 72 h.
    Hypopigmentation produced by 1% hydroquinone occurred in one patient
    (Fisher, 1986). Spencer (1965) found that higher concentrations (5%)
    of hydroquinone might cause sensitization.

         Van Ketel (1984) reported a case of probable sensitization to
    hydroquinone with cross-sensitization to hydroquinone monobenzyl
    ether. Two days after the first application of a cream containing 5%
    hydroquinone monobenzyl ether (after a treatment period of three
    months with 2% hydroquinone in a cream base), an acute dermatitis
    developed. Patch testing was positive for the two substances.
    Sensitization to hydroquinone monobenzyl ether occurs fairly
    frequently (Fisher, 1986), while hydroquinone is regarded as a weak
    sensitizer.

         There have been several cases in Europe and the USA of
    ochronosis in people who have used creams containing 2% hydroquinone
    or less (Connor & Braunstein, 1987; Lawrence  et al., 1988).
    Hardwick  et al. (1989) established a causal link between
    hydroquinone and exogenous ochronosis.

         Hydroquinone, like its monobenzyl ether or monoethyl ether, has
    been reported to cause severe patchy depigmentation disorders in a
    confetti-like pattern in a single black man (Markey  et al., 1989).
    These authors also noted that four other cases had been reported.

         Several cases of brown discoloration of the finger-nails due to
    hydroquinone-containing skin-lightening creams have been reviewed by
    Mann & Harman (1983). The colour change is considered to be due to
    hydroquinone oxidation products resulting from exposure to sunlight.

    8.2  Occupational exposure

    8.2.1  Dermal effects

         There have been case reports of occupational depigmentation of
    the skin where a causal relationship between photographic developers
    containing hydroquinone and depigmentation (leucoderma or vitiligo)
    has been suggested (Frenk & Loi-Zedda, 1980; Kersey & Stevenson,
    1981). In one case a vitiligo-like depigmentation was induced in a
    black man by contact with a dilute hydroquinone solution (0.06%)
    after 8-9 months (Frenk & Loi-Zedda, 1980). The depigmentation
    occurred without any inflammatory skin changes and without itching.
    Biopsy revealed lack of epidermal melanin pigment and melanocytes.
    However, in the upper dermis there were numerous melanin-laden
    macrophages. Developer containing 7% hydroquinone has also caused
    vitiligo in a man wearing protective gloves (Kersey & Stevenson,

    1981). The gloves were considered to have functioned as an occlusive
    bandage.

         Lidén (1989) carried out dermatological examination and patch
    testing on 78 employees exposed to film chemicals at a film
    laboratory. Hydroquinone (1% aqueous solution) was found to cause
    irritation (erythema or staining) in previously non-exposed, healthy
    volunteers. Contact allergy to hydroquinone (1% in water and
    petrolatum) was diagnosed in four out of seven tested employees.

    8.2.2  Ocular effects

         Ocular lesions of various degrees have been observed in workers
    exposed to quinone vapour and hydroquinone dust in the manufacture
    of hydroquinone, and the clinical characteristics are well described
    (Sterner  et al., 1947; Oglesby  et al., 1947; Anderson & Oglesby,
    1958). Airborne concentrations of hydroquinone dust were
    occasionally 20-35 mg/m3 (Oglesby  et al., 1947). In the presence
    of air and moisture hydroquinone is rapidly converted into the more
    volatile quinone. Acute exposure to high (not specified) vapour
    concentrations resulted in irritation, sensitivity to light,
    lacrimation, injury of the corneal epithelium, and corneal
    ulceration. Acute exposure to hydroquinone dust caused eye
    irritation. Chronic exposure to hydroquinone dust led to corneal
    staining (greenish-brown), corneal opacity, and conjunctival
    staining (brownish to brownish-black), with a distribution
    corresponding to the palpebral fissure (Anderson, 1947; Sterner  et
     al., 1947). In some cases, an appreciable loss of vision due to
    permanent fine opacities, astigmatism and irregularity occurred in
    the cornea (Anderson & Oglesby, 1958). Eye irritation occurred
    following exposure to 2.25 mg/m3 (0.5 ppm) and became marked at
    13.5 mg/m3 (3 ppm). Slowly developing inflammation and
    discoloration of the cornea and conjunctiva followed daily exposures
    of 0.05 to 14.4 mg hydroquinone/m3 (0.01 to 3.2 ppm) for two or
    more years (Oglesby  et al. 1947). The degree of eye injury showed
    a positive correlation only with length of employment (Anderson,
    1947; Sterner  et al., 1947; Anderson & Oglesby, 1958). The ocular
    lesions developed gradually over a period of several years of
    exposure; no serious cases were seen until after five or more years
    of exposure. Removal from exposure resulted in considerable
    improvement of the staining, but improvement of the corneal
    opacities was questionable. The relative contribution of quinone
    vapour and hydroquinone dust to eye injury was not assessed.

         Three cases of corneal pigmentation were described among men
    working in a hydroquinone factory (Naumann, 1966). At a later date,
    corneal damage became apparent even though exposure had been
    discontinued, and progressive deterioration of vision was reported.
    Histopathological examinations revealed pigmentary and degenerative
    changes. Two distinct forms of pigment were distinguished. One was
    intraepithelial and contained iron, the other was confined to a

    band-like zone between normal and altered stroma and was considered
    to be quinone.

         An operation nurse repeatedly developed a corneal ulcer while
    mixing bone cement containing methyl methacrylate and hydroquinone
    (Norrelykke Nissen & Corydon, 1985). It was suggested that the eye
    symptoms developed because of a composite effect of methyl
    methacrylate and hydroquinone vapours. However, the presence of
    hydroquinone or quinone vapour in the air was not determined.

    8.2.3  Systemic effects

         Clinical and laboratory evaluation of 88 workers in 1943 and
    101 workers in 1945, who had been exposed to high airborne
    concentrations of both quinone and hydroquinone for periods up to 15
    years, showed no evidence of any systemic toxicity (Sterner  et
     al., 1947).

    8.2.4  Epidemiological studies

    8.2.4.1  Respiratory effects

         In a study on airway responses to hydroquinone (Choudat  et
     al., 1988), 33 workers exposed to hydroquinone, trimethyl-
    hydroquinone, and retinene-hydroquinone were compared to a reference
    group of 55 matched, non-exposed workers regarding the potential
    allergic effect of the exposure. No further information on exposure
    conditions (nature, extent and duration) and possible exposure to
    other chemicals was reported. The prevalence of respiratory symptoms
    was increased in workers exposed to hydroquinone and its
    derivatives. The exposed workers had a significantly (P < 0.01)
    higher prevalence of cough induced by a smoky atmosphere or by cold
    air. The prevalences of eczema and coughing at work were also
    higher. Pulmonary function values were significantly (P < 0.01)
    lower in the exposed than in the non-exposed group. According to the
    results from a bronchodilator test, hydroquinone or its derivatives
    also seemed to induce intermittent dyspnoea and reversible
    obstruction. The exposed workers had higher levels of IgG (P <
    0.002) and IgE (not significant) than the non-exposed workers.
    However, because of the higher chemical reactivity of trimethyl-
    hydroquinone compared with hydroquinone, it is difficult to
    determine the effects of hydroquinone alone (O'Brien, 1991).

    8.2.4.2  Carcinogenicity studies

         Greenwald  et al. (1981) performed a nested case-referent
    study of brain cancer in a group of employees from the Eastman Kodak
    Company. This study was prompted by preliminary data suggesting a
    possible increase of brain cancer incidence in New York state, USA,
    and included a case group of 56 employees who had died with primary
    brain tumours during the period 1956-1975. An elevated relative risk

    was found among photographic processing workers exposed to colour
    developers, but the results were not statistically significant. The
    authors stated that the excess of brain neoplasms noted may have
    resulted from a diagnostic sensitivity bias arising from more
    complete medical evaluation of Kodak employees than of other plant
    employees.

         A cohort study of 478 photographic processors in nine Eastman
    Kodak Color Print and Processing laboratories was undertaken as a
    follow-up study. The primary objectives of the study were to
    evaluate mortality, cancer incidence, and absence due to sickness of
    employees exposed to photographic chemicals. Both industrial and
    general population references were used. There was no significant
    increase in the incidence of the parameters investigated. Two cases
    classified as malignant neoplasms on the brain and CNS were observed
    versus 0.4 expected (Friedlander  et al., 1982), but this
    difference was not statistically significant. Individual exposures
    were not examined, but hydroquinone was identified among the many
    possible exposures. One air sample analysed for hydroquinone
    contained < 0.01 mg/m3.

         Work-related mortality among male employees at Tennessee
    Eastman Company was studied by Pifer  et al. (1986). The exposure
    included hydroquinone among other chemical agents. Cancer mortality
    was lower than that of the general population; the standard
    mortality ratio was 56. No information on levels of hydroquinone
    exposure or total number of workers exposed to hydroquinone was
    reported. However, work is underway to explore the feasibility of
    conducting a mortality and, possibly, a morbidity study of
    hydroquinone workers at this facility (personal communication to the
    IPCS, 1992).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

         Hydroquinone has been shown to be an outlier in numerous QSAR
    (Quantitative Structure-Activity Relationship) studies (e.g.,
    Devillers  et al., 1986, 1987; Hodson  et al., 1988; Nendza &
    Seydel, 1988a,b,c). Due to this fact Devillers  et al. (1990)
    reviewed the environmental and health risks of hydroquinone.
    Ecotoxicity data for hydroquinone are listed in Table 18. From these
    data, it appears that hydroquinone is highly toxic for most of the
    organisms studied. However, a difference in sensitivity exists among
    the taxons. It should be noted that the results need to be analysed
    in relation to the experimental conditions under which they were
    obtained (e.g., pH, light). Thus, numerous studies have been
    performed under static condition. In only a few experiments has the
    concentration of hydroquinone been monitored.


    
    Table 18.  Ecotoxicity data for hydroquinone
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

    Bacteria
     Beneckea harveyi        50% inhibition of luminescence        10 sec        82.6                                            Stom et al.
                             100% inhibition of luminescence       10 sec        550.6                                           (1986)
                             50% inhibition of dehydrogenase       1 h           110
                             activity

     Escherichia coli        toxicity threshold concentration      6 h           50                                              Bringmann &
                             for inhibition of acid production                                                                   Kühn (1959a)
                             from glucose

                             50% inhibition of cell                6-8 h         34.0                                            Devillers et
                             multiplication                                                                                      al. (1990)

     Photobacterium          EC10, luminescence                    30 min        0.022                                           Devillers et
                             phosphoreum                           EC50          0.072                                           al. (1990)
                             EC90                                                0.210

                             EC50, luminescence                    5 min         0.042                                           Ribo & Kaiser
                                                                   10 min        0.038                                           (1983)
                                                                   30 min        0.038

     Pseudomonas             zone of growth inhibition on          24 h          200            the zone of inhibition           Trevors &
                             fluorescens                           agar                         was 14 mm; after exposure        Basaraba
                                                                                                the % survival of resting        (1980)
                                                                                                cells was 0.11

     Pseudomonas putida      toxicity threshold concentration      16 h          58                                              Bringmann &
                             for inhibition of cell                                                                              Kühn (1977a)
                             multiplication

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

    Dinoflagellates
     Crypthecodinium         50% mortality                         40 h          50.0                                            Devillers et
      cohnii                                                                                                                     al. (1990)

     Prorocentrum micans     50% immobilization                    1 h           0.750                                           Devillers et
                             50% immobilization                    2 h           0.300                                           al. (1990)
                             100% immobilization                   18 h          5.00

    Cyanobacteria
    (Blue-green algae)
     Anabaena flos-aque      lowest concentration for no           14 days       39.8           irradiance of 2 W/m2             Wängberg &
                             detectable growth                                                                                   Blanck (1988)

     Anabaena sp.            lowest concentration for no           14 days       10.0           irradiance of 2 W/m2             Wängberg &
                             detectable growth                                                                                   Blanck (1988)

     "LPP sp" 1 PCC6402      lowest concentration for no           14 days       5.01           irradiance of 10 W/m2            Wängberg &
                             detectable growth                                   20.0           irradiance of 2 W/m2             Blanck (1988)

     "LPP sp" 2 PCC73110     lowest concentration for no           14 days       5.01           irradiance of 2 W/m2             Wängberg &
                             detectable growth                                                                                   Blanck (1988)

     Microcystis             toxicity threshold concentration      8 days        1.1                                             Bringmann &
      aeruginosa             for inhibition of cell                                                                              Kühn (1978)
                             multiplication

                             EC100                                 24 h          0.5                                             Fitzgerald et
                                                                                                                                 al. (1952)

     Synechococcus           lowest concentration for no           14 days       10.0           irradiance of 10 W/m2            Wängberg &
      leopoliensis           detectable growth                                   10.0           irradiance of 2 W/m2             Blanck (1988)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

    Algae
     Bumilleriopsis          lowest concentration for no           14 days       10.0           irradiance of 10 W/m2            Wängberg &
      filiformis             detectable growth                                                                                   Blanck (1988)

     Chlamydomonas           lowest concentration for no           14 days       79.4           irradiance of 10 W/m2            Wängberg &
      dysosmos               detectable growth                                                                                   Blanck (1988)

     Chlamydomonas           100% inhibition of motility           15 min        55.1                                            Stom & Roth
                             reinhardii                                                                                          (1981)

     Chlorella emersonii     lowest concentration for no           14 days       79.4           irradiance of 10 W/m2            Wängberg &
                             detectable growth                                                                                   Blanck (1988)

                             slight activation of growth           24 h          10.0                                            Devillers et
                                                                                                                                 al. (1990)

     Dunaliella marina       activation of growth                  24 h          10.0                                            Devillers et
                                                                                                                                 al. (1990)

     Dunaliella salina       100% inhibition of motility           15 min        330.3                                           Stom & Roth
                                                                                                                                 (1981)

     Euglena gracilis        100% inhibition of motility           15 min        7708                                            Stom & Roth
                                                                                                                                 (1981)

     Kirchneriella contorta  lowest concentration for no           14 days       79.4           irradiance of 10 W/m2            Wängberg &
                             detectable growth                                                                                   Blanck (1988)

     Klebsormidium           lowest concentration for no           14 days       20.0           irradiance of 10 W/m2            Wängberg &
      marinum                detectable growth                                                                                   Blanck (1988)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

     Monodus                 lowest concentration for no           14 days       20.0           irradiance of 10 W/m2            Wängberg &
      subterraneus           detectable growth                                                                                   Blanck (1988)

     Monoraphidium           lowest concentration for no           14 days       20.0           irradiance of 10 W/m2            Wängberg &
      pusillum               detectable growth                                   79.4           irradiance of 2 W/m2             Blanck (1988)

     Nitella sp.             100% inhibition of cytoplasmic        15 min        2753                                            Stom & Roth
                             streaming                                                                                           (1981)

     Raphidonema             lowest concentration for no           14 days       0.316          irradiance of 10 W/m2            Wängberg &
      longiseta              detectable growth                                                                                   Blanck (1988)

     Scenedesmus             lowest concentration for no           14 days       39.8           irradiance of 10 W/m2            Wängberg &
      obtusiusculus          detectable growth                                                                                   Blanck (1988)

     Scenedesmus             toxicity threshold concentration for  96 h          4                                               Bringmann &
      quadricauda            inhibition of cell multiplication                                                                   Kühn (1959a)

                             toxicity threshold concentration for  7 days        0.93                                            Bringmann &
                             inhibition of cell multiplication                                                                   Kühn (1978)

     Selenastrum             EC50, growth                          3 days        0.335          irradiance of 17 W/m2            Devillers et
      capricornutum                                                                                                              al. (1990)

                             lowest concentration for no           14 days       79.4           irradiance of 10 W/m2            Wängberg &
                             detectable growth                                                                                   Blanck (1988)

     Tribonema aequale       lowest concentration for no           14 days       2.51           irradiance of 10 W/m2            Wängberg &
                             detectable growth                                                                                   Blanck (1988)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

    Yeasts
     Candida albicans        activation of growth                  24 h          500                                             Devillers et
                             50% inhibition of growth              24 h          3750                                            al. (1990)

     Candida tropicalis R2   100% inhibition of growth             24 h          1000                                            Devillers et
                                                                                                                                 al. (1990)

     Saccharomyces           50% inhibition of growth              24 h          2750                                            Devillers et
                             cerevisiae                                                                                          al. (1990)

     Torulopsis glabrata     50% inhibition of growth              24 h          1000                                            Devillers et
                             100% inhibition of growth                           3000                                            al. (1990)

    Fungi
     Fusarium oxysporum      no significant inhibition of spore                  1000                                            Ismail et al.
      f sp lycopersici       germination                                                                                         (1987)
                             no significant inhibition of length                 1000
                             of germ tube

    Plants
     Elodea canadensis       50% inhibition of growth              9 days        42.9                                            Stom & Roth
                                                                                                                                 (1981)

     Lemna minor             50% inhibition of plant               12 days       7.71                                            Stom & Roth
                             multiplication                                                                                      (1981)

     Vallisneria spiralis    100% inhibition of cytoplasmic        15 min        2753           in leaves                        Stom & Roth
                             streaming                                           275.3          in roots                         (1981)

    Protozoa
     Chilomonas              toxicity threshold concentration for  48 h          22                                              Bringmann &
      paramaecium            inhibition of cell multiplication                                                                   Kühn (1981)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

     Colpidium campylum      EC50, growth                          24 h          73.3                                            Devillers et
                                                                                                                                 al. (1990)

     Entosiphon sulcatum     toxicity threshold concentration for  72 h          11                                              Bringmann
                             inhibition of cell multiplication                                                                   (1978)

     Microregma              toxicity threshold concentration for  28 h          2                                               Bringmann &
                             nutrient uptake                                                                                     Kühn (1959b)

     Tetrahymena             EC50, growth                          60 h          95.0                                            Schultz et al.
      pyriformis                                                                                                                 (1987)

     Uronema parduczi        toxicity threshold concentration for  20 h          21                                              Bringmann &
                             inhibition of cell multiplication                                                                   Kühn (1980)

    Mollusc
     Deroceras reticulatum   0% mortality                          4 days        0.020a                                          Briggs &
                             20% mortality                         4 days        0.200a                                          Henderson
                                                                                                                                 (1987)

    Crustacea
     Artemia salina          LC50                                  2 h           321                                             Devillers et
                                                                   4 h           67.5                                            al. (1990)
                                                                   6 h           57.5
                                                                   24 h          20.7

     Crangon                 LT50                                  84 h          0.83           time to 50% mortality            McLeese et al.
      septemspinosa                                                                                                              (1979)

     Daphnia magna           toxicity threshold concentration for  48 h          0.60                                            Bringmann &
                             inhibition of mobility                                                                              Kühn (1959a)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

     Daphnia magna           LC0                                   24 h          0.04                                            Bringmann &
                             LC50                                                0.09                                            Kühn (1977b)
                             LC100                                               0.31

                             EC0, inhibition of mobility           24 h          0.05                                            Bringmann &
                             EC50                                                0.12                                            Kühn (1982)
                             EC100                                               0.19

                             EC50, inhibition of mobility          24 h          0.137                                           Devillers et
                                                                                                                                 al. (1987)

                             EC0, inhibition of mobility           24 h          0.13                                            Kühn et al.
                             EC50                                                0.32                                            (1989)
                             EC100                                               0.71
                             EC0                                   48 h          0.13                                            Kühn et al.
                             EC50                                                0.29                                            (1989)
                             EC100                                               0.71

                             EC50, inhibition of mobility          24 h          0.15                                            Tissot et al.
                                                                                                                                 (1985)

     Daphnia pulicaria       LC50                                  48 h          0.162                                           DeGraeve et
                                                                                                                                 al. (1980)

     Daphnia pulex           LC100                                 6 min         8809                                            Stom et al.
                                                                                                                                 (1986)

     Gammarus                toxicity threshold concentration                    1.5                                             Bandt (1955)

    Insect
     Apis mellifera          LD50                                  24 h          0.200          concentration in mg per bee      Devillers et
                                                                                                                                 al. (1990)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

    Fish
     Brachydanio rerio       LC50                                  24 h          0.265                                           Devillers et
                                                                                                                                 al. (1988)

                             LC0                                   96 h          0.12                                            Wellens (1982)
                             LC50                                                0.17
                             LC100                                               0.25

     Carassius auratus       100% mortality                        22 h          5                                               US EPA (1987)

                             LC100                                 48 h          0.287                                           Sollmann
                                                                                                                                 (1949)

     Lepomis macrochirus     100% mortality                        22 h          5                                               US EPA (1987)

     Leuciscus idus          LC0                                   48 h          0.1                                             Juhnke &
      melanotus              LC50                                                0.15                                            Lüdemann
                             LC100                                               0.2                                             (1978)
                             LC0                                                 0.1
                             LC50                                                0.16
                             LC100                                               0.25

     Oncorhynchus mykiss     100% mortality                        2 h           7.69                                            Devillers et
                                                                   4 h           4.50                                            al. (1990)

                             LC50                                  96 h          0.097                                           DeGraeve et
                                                                                                                                 al. (1980)
                             LC50                                  96 h          0.639                                           Hodson et al.
                             LD50, intraperitoneal injection                     24.2           concentration in mg per kg       (1984)

    Table 18. (contd).
                                                                                                                                               
    Species                  Effect                                Test          Hydroquinone   Comments                         Reference
                                                                   duration      concentration
                                                                                 (mg/litre)
                                                                                                                                               

     Pimephales promelas     LC50                                  96 h          0.044                                           DeGraeve et
                                                                                                                                 al. (1980)
                             LT50                                  11 h          0.2            time to 50% mortality            Terhaar et al.
                                                                                                                                 (1972)
     Salmo trutta            100% mortality                        22 h          5                                               US EPA (1987)
                                                                                                                                               

    a  Slugs injected with 2 µl of glycerol formal containing 20 or 200 µg of hydroquinone.


    
    10.  EVALUATION OF HUMAN HEALTH RISKS AND ON THE ENVIRONMENT

    10.1  Toxicokinetics

         The property of hydroquinone most pertinent to its toxicity is
    its ability to undergo reversible redox reactions. Autooxidation of
    hydroquinone leads to  p-benzoquinone and/or  p-benzosemiquinone.
    These two strong electrophiles do not redox-cycle under
    physiological conditions to form active oxygen species, but readily
    arylate nucleophiles. They are probably the two major toxic
    metabolites of hydroquinone.

         Toxicokinetic studies with hydroquinone show that although it
    is readily absorbed from the gut of animals it has a low potential
    for bioaccumulation < 2% distributed out of total administered
    dose). Extensive conjugation and rapid excretion, primarily via the
    urine, suggests that hydroquinone is effectively detoxified.
    However, because hydroquinone is oxidized to  p-benzosemiquinone
    and/or  p-benzoquinone, which are able to readily react with
    nucleophilic body components, it represents a potentially harmful
    toxicant. Indeed, hydroquinone and/or its metabolites covalently
    bind to cellular components  in vitro.

         It is, therefore, possible that although the bioaccumulation
    potential of hydroquinone is low critical body components may still
    be adversely affected.

    10.2  Animal and in vitro studies

         Hydroquinone exhibits moderately high acute oral toxicity for
    animals, with LD50 values generally being in the range of 300 to
    1300 mg/kg. However, cats are more sensitive, LD50 values of 40-85
    mg/kg having been reported. The principle toxic effects of a single
    oral lethal dose of hydroquinone are increased motor activity,
    dyspnoea and cyanosis followed by convulsions, paralysis, coma and
    death. Repeated oral dosing has caused tremors and reduced activity
    (> 64 mg/kg), reduced body weight gain (> 200 mg/kg),
    convulsions (> 400 mg/kg) and adverse effects on the liver and
    kidneys (> 200 mg/kg).

         Dermal exposure of black guinea-pigs to hydroquinone (2 or 5%)
    has been found to cause depigmentation, inflammatory changes and
    thickening of the epidermis. Slight skin irritation has been
    recorded following topical application of hydrophillic ointment
    containing 1% hydroquinone. The results also showed that female
    guinea-pigs were more sensitive than males.

         Limited data suggest that powdered hydroquinone causes
    transient eye irritation and corneal opacity in dogs and
    guinea-pigs; in rabbits powdered hydroquinone induced brownish

    pigmentation of conjunctiva and cornea, but only after a period of
    at least 2-4 months.

         Hydroquinone is a skin sensitizer in rabbits. The ability to
    induce sensitization has been found to vary from "weak" to "strong"
    depending on the test procedure and vehicle used. The cross-
    reactivity of hydroquinone and  p-methoxyphenol has been reported
    to be almost 100%.

         Early reproductive studies indicated reduced fertility in male
    rats and a disturbed sexual cycle in female rats when hydro-quinone
    was administered parentally. However, this was not confirmed in more
    recent studies in rats, i.e. a dominant lethality study and a
    two-generation study with oral doses of hydroquinone up to 300 mg/kg
    per day and 150 mg/kg per day, respectively.

         Oral dosing of 100 or 300 mg hydroquinone/kg to pregnant rats
    on days 6-15 of gestation caused maternal toxicity at the higher
    dose level (a statistically significant reduction in body weight
    gain and feed consumption). A reduction in mean fetal body weight
    was correlated with the reduced maternal body weight. No
    compound-related teratogenic effects were produced at this dose
    level; thus, 100 mg/kg was considered the NOEL for maternal and
    developmental toxicity in rats. Findings of increased resorption
    rates in rats given hydroquinone orally at about 100 mg/kg per day
    were not confirmed in this study, and, consequently, the NOAEL for
    maternal reproductive effects and teratogenicity was 300 mg/kg. In
    rabbits, 150 mg/kg caused reductions in body weight and feed intake
    and an increased (but not statistically significant) increase of
    malformations in the fetuses. The malformations may have been
    associated with maternal toxicity. The dose level of 200 mg/kg
    produced an increased number of resorptions, indicating
    embryotoxicity. The NOEL for developmental toxicity in rabbits was
    25 mg/kg per day.

         In a two-generation reproduction study in rats the NOAEL for
    reproductive effects through two generations was 150 mg/kg per day
    (the highest tested dose). In mice, 80 mg hydroquinone/kg given
    orally on the 13th day of gestation transplacentally induced
    micronuclei in fetal liver cells. A single oral dose of 1000 mg/kg
    on gestation day 11 caused maternal toxicity (decreased weight gain)
    and an increased incidence of mortality. Reduced litter size and
    perinatal loss occurred in the treated groups (333, 667 and 1000
    mg/kg), together with dose-related malformations of limbs, tail and
    urogenital system. In a rat embryo culture system, hydroquinone
    (effective concentration < 55 mg/litre, < 0.5 mmol/litre)
    caused growth retardation and an increased incidence of structural
    abnormalities involving tail and hindlimb buds.

         Genotoxicity data indicates that hydroquinone induces
    micronuclei, structural chromosome aberrations, and c-mitotic

    effects  in vivo in mouse bone-marrow cells.  in vitro studies
    with various cell lines showed that hydroquinone was capable of
    inducing gene mutations, structural chromosome aberrations,
    sister-chromatid exchange and DNA damage. Hydroquinone induces
    chromosome aberrations or karyotypic alterations in plant species
    and mitotic crossing-over in fungi. Hydroquinone is not mutagenic in
    the  Salmonella/microsome test, but induces repairable DNA damage
    in  Escherichia coli. It produces adducts with DNA.

         Hydroquinone induces chromosome aberrations in germ cells of
    male mice.

         Cholesterol pellets containing 20% hydroquinone implanted into
    the bladders of mice produced bladder tumours in 6 out of 19 mice
    surviving 25 weeks. However, the study was incompletely reported and
    the method is not generally recognized as a valid measure of
    carcinogenic potential as small pellets of cholesterol are known to
    induce transitional carcinoma of the bladder in both rats and mice.
    There is no support for hydroquinone being a stomach carcinogen in
    experimental animals after oral dosing. Hydroquinone produced an
    increase in the number of liver foci in rats at a dose level of 100
    mg/kg per day for 7 weeks. However, increased dose levels (200 mg/kg
    per day for 7 weeks or 8 g/kg diet for about two years) caused a
    reduction in the number of foci of cellular alteration of the liver.
    In mice, the incidence of liver foci was increased when hydroquinone
    was added to the diet at 8 g/kg.

         Hydroquinone did not show any potential as an initiator or a
    co-carcinogen when dermally applied to mice before application of a
    tumour promoter (croton oil or BP) or following co-exposure with BP.
    Orally administered hydroquinone showed no promotion activity after
    MNNG initiation or carcinogenic potential in the forestomach and
    glandular stomach of rats.

         Most of the earlier carcinogenicity studies on hydroquinone
    lasted for less than one year, which might be considered too short
    for the assessment of carcinogenicity.

         Two-year studies performed recently give support for
    hydroquinone being a carcinogen in F-344 rats and B6C3F1 mice. In
    an NTP study, renal tubular cell adenomas occurred in male rats and
    leukaemia in females, and hepatocellular neoplasms, mainly adenomas,
    in female mice. The NTP concluded that these data indicated "some
    evidence of carcinogenic activity" in male and female rats and in
    female mice. In another study, renal tubular cell adenomas were
    again noted in male rats; hepatocellular adenomas occurred in male
    mice along with a biologically significant increase in the incidence
    of renal tubular cell adenomas.

         Both  in vivo and  in vitro studies have shown that
    hydroquinone causes direct myelotoxic effects in mouse bone marrow

    stromal cells by reducing bone marrow cellularity. In reducing the
    number of progenitor B-lymphocytes in mouse spleen and bone marrow,
    hydroquinone also demonstrates an immunosuppressive potential.
    Moreover, hydroquinone may inhibit the natural killer activity of
    mouse spleen cells  in vitro, and have a selective effect on
    macrophage functions important in host defence.

         Hydroquinone has also demonstrated cytotoxic activity on
    various tumour cells such as cells from melanoma transplants and rat
    hepatoma cells.

         Central nervous system stimulatory effects have been produced
    in animal studies. However, functional-observational battery and
    neuropathological examinations failed to give any evidence of
    neurotoxicity after repeated dosing for 90 days. The NOEL was 20 mg
    hydroquinone/kg per day.

    10.3  Evaluation of human health risks

    10.3.1  Exposure

         Potential exposure of the general population to hydroquinone
    may occur through the consumption of foods that contain hydroquinone
    as a natural component, through smoking or exposure to cigarette
    smoke, or from the use of cosmetics and skin-lightening creams.
    People who use skin lighteners with concentrations of hydroquinone
    exceeding 2%, apply creams over large areas of the body or use
    creams for long time periods represent one group with significant
    and sometimes excessive exposure. Heavy cigarette smokers and those
    living and working in environments contaminated by cigarette smoke
    represent another group that experiences significant exposure to
    hydroquinone. Photohobbyists who develop their film manually may
    also be exposed to hydroquinone solutions through skin contact and
    inhalation.

         Exposure to hydroquinone may occur in a variety of occupations,
    particularly among those involved in its manufacture.

    10.3.2  Human health effects

         Ingestion of large quantities of hydroquinone may produce
    tremors, vomiting, convulsions, dyspnoea, cyanosis and coma. Deaths
    have been reported to occur after ingestion estimated at 3-12 g of
    hydroquinone in developing agents. In studies with human volunteers,
    ingestion of up to 500 mg hydroquinone per day over a 20-week period
    resulted in no observable pathological changes in the blood and
    urine.

         Dermal exposure to hydroquinone causes skin depigmentation;
    cases of ochronosis, patchy depigmentation and brown staining of the
    nails after repeated usage of skin-lightening products have been

    reported. Hydroquinone has shown a sensitizing potential in both
    animals and humans.

         Eye irritation, sensitivity to light, staining of the cornea
    and conjunctiva, corneal opacities and visual disturbances are
    associated with long-term occupational exposure to airborne
    hydroquinone. Isolated cases of corneal ulceration have also been
    described.

         Effects on the central nervous system have been seen in cases
    of acute human poisoning. Similar symptoms have been observed in
    animal studies; these effects were reversible when exposure was
    discontinued.

         Nephrotoxicity has been seen in F-344 rats dosed repeatedly
    with hydroquinone. Male rats are more susceptible to these effects
    than females. Nephrotoxic effects due to hydroquinone have not been
    observed in humans.

         Myelotoxic and immunotoxic effects have been observed in
    animals exposed to hydroquinone. However, the routes of exposure
    differed from those via which humans are normally exposed.

         Studies conducted by routes of exposure similar to those by
    which humans are exposed have not revealed specific reproductive and
    developmental effects.

         Numerous studies using cell culture systems and  in vivo
    rodent experiments have shown that co-exposure to hydroquinone and
    various phenolic compounds can result in toxic effects that are
    substantially greater than the sum of the effects of the individual
    compounds. The relevance of these interactive effects in
    understanding and predicting the toxic effects of human exposure to
    hydroquinone is uncertain. However, since many of the human
    exposures to hydroquinone occur under conditions in which other
    phenolic compounds are present, the possibility that significant
    interactive effects may occur should be considered.

         Several experiments with hydroquinone  in vivo and  in vitro
    have shown mutagenic effects; the relevance of these results to
    human risk is uncertain. The evidence for carcinogenicity in animals
    is limited. Adequate epidemiological studies are lacking, and, at
    present, the experimental data are insufficient to allow a thorough
    assessment of the carcinogenic potential for humans.

    10.4  Evaluation of effects on the environment

         When hydroquinone is released into the environment it is
    distributed mainly to the water compartment due to its
    physicochemical properties. However, hydroquinone can be degraded
    both photochemically and biologically and will therefore not persist

    in the environment. The ecotoxicity of hydroquinone, which can be
    also related to its physicochemical properties, is generally high
    but varies from species to species. Therefore, a battery of tests
    using organisms occupying different trophic levels in the ecosystems
    is required to assess thoroughly the adverse effects of hydroquinone
    in the environment.

    11.  RECOMMENDATIONS

    a)   In view of the widespread inappropriate use of skin-lightening
         creams, it is recommended that over-the-counter sales of creams
         containing hydroquinone be restricted. Health Education
         Programmes should be developed to discourage the use of
         hydroquinone-containing creams for whole body skin lightening.

    b)   Further investigations into the safety of long-term use of
         creams containing 1-2% hydroquinone is needed.

    c)   Hydroquinone in waste water effluent should be allowed
         sufficient time for degradation before reaching recipient
         water.

    d)   Multispecies toxicity testing performed under controlled 
         experimental conditions is required to make a thorough
         assessment of the environmental effects of hydroquinone and its
         derivatives.

    e)   Epidemiological studies, including precise exposure data, would
         assist in an assessment of the occupational hazards from
         hydroquinone. Epidemiological information, including
         reproductive effects, is also required for users of skin
         lighteners, particularly women. More data on human exposure
         from different sources are required, particularly with respect
         to dietary exposure.

    12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         In 1977 the International Agency for Research on Cancer (IARC)
    Working Group concluded that the available data on hydroquinone did
    not allow an evaluation of its carcinogenicity.

         Hydroquinone was evaluated by a Nordic Expert Group for
    Documentation of Occupational Exposure Limits in 1989. It was
    recommended that its genotoxic effects should be given attention and
    also its possible effects on the immune system, bone marrow, skin
    and mucous membranes.

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    APPENDIX 1.
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    RESUME

    1.  Identité, propriétés physiques et chimiques et méthodes
        d'analyse

         L'hydroquinone (1,4-benzènediol; C6H4(OH)2) se présente à
    l'état pur sous la forme d'un solide cristallin blanc dont le point
    de fusion est égal à 173-174°C. Sa densité est de 1,332 à 15°C et sa
    tension de vapeur de 2,4 x 10-3 Pa (1,8 x 10-5 mmHg) à 25°C.
    Elle est extrêmement soluble dans l'eau (70g/litre à 25°C) et le
    logarithme de son coefficient de partage  n-octanol/eau est de
    0,59. Sa solubilité dans les solvants organiques varie de 57% dans
    l'éthanol à moins de 0,1% dans le benzène. L'hydroquinone est
    combustible à condition de subir un chauffage préalable. C'est un
    réducteur qui est oxydé réversiblement en semiquinone correspondante
    et en quinone.

         L'échantillonnage de l'hydroquinone dans l'air s'effectue soit
    par piégeage dans un solvant soit par filtration sur membrane
    d'ester cellulosique mixte.

         Le dosage de l'hydroquinone s'effectue soit par titrimétrie
    soit par spectrophotométrie ou plus couramment par chromatographie.

    2.  Sources d'exposition humaine et environnementale

         L'hydroquinone existe sous forme libre ou conjuguée dans les
    bactéries, les plantes et certains animaux. Plusieurs pays la
    produisent en quantités industrielles. En 1979, la capacité mondiale
    totale de production dépassait 40 000 tonnes et était retombée à
    environ 35 000 tonnes en 1992. L'hydroquinone est très largement
    utilisée comme réducteur, comme développateur en photographie ainsi
    que antioxydant ou comme stabilisant pour certaines substances qui
    se polymérisent en présence de radicaux libres; elle sert encore
    d'intermédiaire dans la production des antioxydants, antiozonants,
    produits agrochimiques et polymères. L'hydroquinone est également
    utilisée pour la fabrication de cosmétiques et de préparations
    médicinales.

    3.  Transport, distribution et transformation dans l'environnement

         L'hydroquinone qui est présente dans l'environnement est le
    produit de l'activité humaine mais elle se trouve également dans des
    substances naturelles d'origine végétale ou animale.

         En raison de ses propriétés physico-chimiques, l'hydroquinone
    se répartit essentiellement dans le compartiment aquatique
    lorsqu'elle est libérée dans l'environnement. Sa décomposition
    résulte principalement de processus photochimiques et biologiques;
    elle n'est donc pas persistante et ne manifeste aucune tendance à la
    bioaccumulation.

    4.  Concentrations dans l'environnement et exposition humaine

         On ne dispose d'aucune données sur la concentration de
    l'hydroquinone dans l'air, le sol ou l'eau. Toutefois le dosage de
    l'hydroquinone dans la fumée de cigarettes (courant principal) sans
    bout-filtre a donné des résultats allant de 110 à 300 ug/cigarette,
    résultats qui valent également pour la fumée du courant latéral. On
    trouve également de l'hydroquinone dans des denrées alimentaires
    d'origine végétale (par exemple le germe de blé), dans le café
    infusé, dans les thés préparés à partir des feuilles de certaines
    baies, avec des concentrations pouvant dépasser quelquefois 1%.

         Les photographes amateurs peuvent être exposés à l'hydroquinone
    par voie percutanée ou respiratoire. Toutefois on ne dispose
    d'aucune donnée sur l'importance de cette exposition. L'exposition
    percutanée peut également résulter de l'utilisation de produits
    cosmétiques ou médicinaux contenant de l'hydroquinone, tels que les
    éclaircissants. Dans les pays de la Communauté européenne, la teneur
    des cosmétiques en hydroquinone est limitée à 2% au maximum. Aux
    Etats-Unis d'Amérique, la Food and Drug Administration a proposé une
    concentration comprise entre 1,5 et 2% pour les éclaircissants
    cutanés. La concentration peut atteindre 4% dans certains
    médicaments délivrés sur ordonnance. Dans certains pays, les
    éclaircissants cutanés peuvent en contenir des quantités encore plus
    importantes.

         Du point de vue hygiène et sécurité, on ne dispose que de peu
    de données concernant la surveillance de l'hydroquinone. On indique
    des concentrations moyennes dans l'air au cours de la fabrication de
    l'hydroquinone et des divers traitements subis par cette substance,
    qui se situeraient dans la gamme de 0,13 à 0,79 mg/m3. Les limites
    d'exposition professionnelles dans l'air (moyenne pondérée par
    rapport au temps) dans les différents pays vont de 0,5 à 2 mg/m3.

    5.  Cinétique et métabolisme

         L'hydroquinone est rapidement et largement résorbée chez
    l'animal au niveau de l'intestin et de la trachée. L'absorption
    percutanée est plus lente mais elle peut s'accélérer en présence de
    véhicules tels que les alcools. L'hydroquinone se répartit
    rapidement et largement dans les différents tissus. Elle est
    métabolisée en  p-benzoquinone et autres produits d'oxydation et sa
    détoxification s'effectue par conjugaison sous forme de
    monoglucuronide, monosulfate et mercapturates. L'excrétion de
    l'hydroquinone et de ses métabolites est rapide et s'effectue
    principalement par la voie urinaire.

         L'hydroquinone et/ou ses dérivés réagissent avec différents
    constituants biologiques tels que les macromolécules et les
    molécules de faible masse moléculaire et ils exercent des effets sur
    la métabolisme cellulaire.

    6.  Effets sur les mammifères de laboratoire et les systèmes
        d'épreuve in vitro

         Les valeurs de la DL50 par voie orale varient de 300 à 1300
    mg/kg de poids corporel pour un certain nombre d'espèces animales.
    Toutefois pour le chat, elle se situe entre 42 et 86 mg/kg de poids
    corporel. Une intoxication aiguë par de fortes concentrations
    d'hydroquinone entraîne de graves effets sur le système nerveux
    central et notamment une hyperexcitabilité, des tremblements, des
    convulsions, le coma et la mort. A des doses sublétales, ces effets
    sont réversibles. Pour les rongeurs, on estime la DL50 par voie
    percutanée à > 3800 mg/kg. On ne dispose d'aucun renseignement sur
    les valeurs de la CL50.

         L'épidermo-réaction effectuée en une seule fois au moyen d'une
    préparation à 2% d'hydroquinone a provoqué une irritation chez le
    lapin notée à 1,22 sur une échelle allant de 0 à 4. Des applications
    topiques quotidiennes effectuées pendant trois semaines avec de
    l'hydroquinone à 2 ou 5% dans une émulsion huile/eau, sur la peau
    rasée de cobayes noirs, a entraîné une dépigmentation, des
    altérations inflammatoires et un épaississement de l'épiderme. La
    dépigmentation était plus marquée à fortes concentrations et les
    femelles se sont révélées plus sensibles que les mâles.

         Les tests de sensibilisation effectués sur des cobayes
    suscitent des réactions faibles à fortes selon la méthode ou le
    véhicule utilisé. Les réactions les plus fortes ont été obtenues
    avec le test de sensibilisation maximale sur le cobaye. On a
    également observé une sensibilisation croisée de presque 100 pour
    cent entre l'hydroquinone et le  p-méthoxyphénol chez le cobaye
    mais les éléments qui pourraient militer en faveur de l'existence de
    réactions analogues avec la  p-phénylénediamine, l'acide
    sulfanilique et la  p-benzoquinone restent limités.

         Une étude de toxicité par voie orale de six semaines chez des
    rats mâles F-344 a permis de mettre en évidence des néphropathies et
    une prolifération des cellules rénales. Après 13 semaines de gavage,
    on a mis en observation des rats F-344 et des souris B6C3F1. Des
    signes de néphrotoxicité se sont manifestés chez les rats aux doses
    respectives de 100 et 200 mg/kg, avec des tremblements et des
    convulsions à cette dernière dose; chez les deux espèces, on a
    observé une diminution du gain de poids. L'administration d'une dose
    de 400 mg/kg a entraîné la mort des rats. Chez les souris qui
    avaient reçu cette même dose pendant 13 semaines, on a relevé des
    tremblements, des convulsions et des lésions affectant l'épithélium
    gastrique. Des rats Sprague Dawley exposés pendant 13 semaines à de
    l'hydroquinone ont présenté une réduction du gain de poids et des
    signes neurologiques témoignant d'une atteinte centrale à 200 mg/kg.
    Ces signes ont également été observés à la dose de 64 mg/kg de poids
    corporel mais ils étaient absents à 20 mg/kg.

         Après injection sous-cutanée d'hydroquinone à des rats, on a
    observé une diminution de la fécondité chez les mâles et un
    allongement du cycle oestral chez les femelles. Toutefois ces effets
    n'ont pas été observés dans les études portant sur une
    administration par voie orale (étude de létalité dominante et étude
    sur deux générations). Une étude portant sur le développement de
    rats ayant reçu par voie orale des doses de 300 mg/kg de poids
    corporel a révélé une légère toxicité pour les femelles gravides et
    une réduction du poids du foetus. Chez le lapin, la dose sans effets
    toxiques observables sur la mère était de 25 mg/kg/jour; la dose
    sans effets toxiques sur le développement était de 75 mg/kg/jour.
    Lors d'une étude de deux générations portant sur la reproduction de
    rats, l'administration d'hydroquinone n'a entraîné aucun effet nocif
    sur la reproduction à des doses orales quotidiennes allant jusqu'à
    150 mg/kg de poids corporel. La dose sans effets toxiques
    observables pour les géniteurs a été fixée par 15 mg/kg/jour; en ce
    qui concerne les effets sur la reproduction observés en l'espace de
    deux générations, on a obtenu une valeur de 150 mg/kg/jour.

         L'hydroquinone provoque la formation de micronoyaux  in vivo
    et  in vitro. Des aberrations portant sur la structure et le nombre
    des chromosomes ont été observées  in vitro ainsi qu'après
    administration intrapéritonéale  in vivo. En outre, on a pu mettre
    en évidence  in vitro des mutations géniques, des échanges entre
    chromatides soeurs et des lésions de l'ADN. Après injection
    intrapéritonéale d'hydroquinone à des souris, on a observé, dans les
    cellules germinales des mâles, de aberrations chromosomiques d'une
    ampleur comparable à celles que l'on observait dans les cellules de
    la moelle osseuse. Une épreuve de létalité dominante effectuée sur
    des rats mâles recevant de l'hydroquinone par voie orale n'a pas
    permis d'établir l'existence de mutations au niveau des cellules
    germinales.

         Lors d'une étude de deux ans, au cours de laquelle on a
    administré à des rats F-344/N de l'hydroquinone par voie orale, on a
    observé, chez les mâles, des adénomes affectant les tubules rénaux
    dont la fréquence était liée à la dose. L'incidence de ces adénomes
    était statistiquement significative dans le groupe qui recevait une
    forte dose. Dans ce même groupe, on a également observé une
    hyperplasie des cellules tubulaires rénales. Chez les femelles, on a
    observé un accroissement de l'incidence, lié à la dose, des
    leucémies à monocytes. Chez des souris B6C3F1, on a observé une
    incidence sensiblement accrue des adénomes hépatocellulaires. Dans
    une autre étude, l'hydroquinone administrée dans la proportion de
    0,8% de la nourriture, a entraîné une augmentation significative de
    l'incidence de l'hyperplasie épithéliale des papilles rénales et une
    augmentation également significative des hyperplasies et des
    adénomes au niveau des tubules rénaux chez les rats mâles. En
    revanche, on n'a pas observé d'augmentation dans l'incidence des
    leucémies à monocytes chez les femelles. Chez les souris,
    l'incidence de l'hyperplasie spinocellulaire affectant l'épithélium

    de la portion cardiaque de l'estomac présentait une augmentation
    significative dans les deux sexes. Chez les mâles, on notait
    également une incidence sensiblement accrue des adénomes
    hépatocellulaires et des hyperplasies tubulaires rénales. Quelques
    adénomes rénaux ont été observés.

         Des études sur des souris, effectuées  in vivo (injection
    intrapéritonéale) et  in vitro montrent que l'hydroquinone a un
    effet cytotoxique, à savoir qu'elle diminue la cellularité
    médullaire et splénique et qu'elle possède également un pouvoir
    immunodépresseur puisqu'elle inhibe la maturation des lymphocytes-B
    et bloque l'activité des cellules tueuses naturelles. Les résultats
    obtenus indiquent également que les macrophages de la moelle osseuse
    pourraient être les principales cibles des effets myélotoxiques
    exercés par l'hydroquinone. Cependant, une étude biologique au long
    cours sur des rongeurs n'a pas révélé l'existence d'effets
    myélotoxiques.

         Une étude de 90 jours sur des rats au cours de laquelle on a
    utilisé une batterie de tests fonctionnels et observationnels, a
    montré qu'à des doses respectives de 64 et 200 mg d'hydroquinone/kg,
    les animaux étaient pris de tremblements et qu'à la dose de 200
    mg/kg, il y avait réduction de l'activité générale. L'examen
    anatomopathologique du système nerveux n'a rien donné.

    7.  Effets sur l'homme

         On a fait état de cas d'intoxication consécutifs à l'ingestion
    d'hydroquinone seule ou de développateurs photographiques contenant
    de l'hydroquinone. Les principaux signes de ces intoxications
    étaient les suivants: urines foncées, vomissements, douleurs
    abdominales, tachycardie, tremblements, convulsions et coma. On a
    également signalé des décès après l'ingestion de développateurs
    photographiques à base d'hydroquinone. Lors d'une étude contrôlée au
    cours de laquelle des volontaires humains ont ingéré quotidiennement
    pendant 3 à 5 mois 300 à 500 mg d'hydroquinone, on n'a pas relevé le
    moindre signe pathologique dans le sang et les urines.

         L'application cutanée d'hydroquinone dans divers excipients à
    des concentrations inférieures à 3% n'a causé que des effets
    négligeables sur des volontaires humains appartenant à diverses
    races. Cependant, on dispose de rapports selon lesquels des crèmes
    destinées à éclaircir la peau et contenant 2% d'hydroquinone ont
    produit une leucodermie ainsi qu'une ochronose. L'hydroquinone
    (solution aqueuse à 1% ou crème à 5%) peut provoquer des irritations
    (érythème ou taches épidermiques). On a également observé des
    dermatites de contact d'origine allergique dues à l'hydroquinone.

         Une double exposition à de l'air chargé d'hydroquinone et de
    quinone entraîne une irritation oculaire, une photophobie, des
    lésions de l'épithélium cornéen, voire des ulcères cornéens et des

    troubles visuels. On connaît des cas où l'acuité visuelle a
    sensiblement baissé. Une irritation peut se manifester à partir de
    2,25 mg/m3. Une exposition de longue durée peut faire apparaître
    des taches sur la conjonctive et la cornée et provoquer
    l'opacification de cette dernière. Après exposition quotidienne
    pendant au moins deux ans à 0,05-14,4 mg d'hydroquinone/m3, on a
    observé une inflammation et une dyschromie de la cornée et de la
    conjonctive; on n'a pas observé de cas graves avant cinq ans au
    moins d'exposition. On dispose d'un rapport qui décrit des cas de
    lésions cornéennes apparues plusieurs années après cessation de
    l'exposition à l'hydroquinone.

         On ne dispose pas de données épidémiologiques suffisantes pour
    évaluer la cancérogénicité de l'hydroquinone chez l'homme.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         Pour expliquer le comportement écotoxicologique de
    l'hydroquinone il faut se rapporter à ses propriétés
    physico-chimiques, et notamment à sa sensibilité à la lumière, au pH
    et à l'oxygène dissous. L'écotoxicité de l'hydroquinone, qui est
    généralement élevée (par exemple < 1 mg/litre pour les organismes
    aquatiques), varie d'une espèce à l'autre.

         Les algues, les levures, les champignons et les plantes en
    général sont moins sensibles à l'hydroquinone que les autres
    organismes habituellement utilisés pour les épreuves toxicologiques.
    Toutefois,au sein d'un même groupe toxonomique, la sensibilité des
    différentes espèces à l'hydroquinone peut varier d'un facteur 1000.

    RESUMEN

    1.  Identidad, propiedades físicas y químicas y métodos analíticos

         La hidroquinona (1,4-bencenodiol; C6H4(OH)2) es una
    sustancia cristalina blanca en estado puro, cuyo punto de fusión es
    de 173-174 °C. Su peso específico es de 1,332 a 15 °C, y su presión
    de vapor, de 2,4 x 10-3Pa (1,8 x 10-5 mmHg) a 25 °C. Es muy
    hidrosoluble (70 g/litro a 25 °C), y el logaritmo de su coeficiente
    de reparto  n-octanol/agua es de 0,59. Por lo que se refiere a los
    disolventes orgánicos, su solubilidad varía entre el 57% para el
    etanol, y menos del 0,1% para el benceno. La hidroquinona es
    combustible si se calienta previamente. Es un agente reductor, que
    se oxida reversiblemente transformándose en semiquinona y quinona.

         Se pueden obtener muestras de la hidroquinona presente en el
    aire capturándola, bien sea en un disolvente o sobre una membrana-
    filtro de éster de celulosa mixto.

         Para analizar los niveles de hidroquinona se utilizan técnicas
    de valorimetría, espectrofotometría o, muy a menudo, cromatografía.

    2.  Fuentes de exposición humana y ambiental

         La hidroquinona está presente en forma tanto libre como
    conjugada en bacterias, plantas y algunos animales. Varios países la
    producen industrialmente. En 1979, la capacidad mundial total de
    producción de esta sustancia superaba las 40 000 toneladas, mientras
    que en 1992 fue de aproximadamente 35 000 toneladas. Es ampliamente
    utilizada como agente reductor, como medio de revelado fotográfico,
    como antioxidante o estabilizador de ciertos materiales que se
    polimerizan en presencia de radicales libres, y como producto
    químico intermedio en la producción de antioxidantes, agentes
    antiozono, productos agroquímicos y polímeros. La hidroquinona se
    emplea también en la elaboración de productos cosméticos y
    preparados médicos.

    3.  Transporte, distribución y transformación en el medio ambiente

         La hidroquinona presente en el medio ambiente procede de la
    actividad del hombre o forma parte de productos naturales de las
    plantas y animales.

         Debido a sus propiedades fisicoquímicas, la hidroquinona
    liberada en el medio penetra sobre todo en los compartimientos de
    agua. Se degrada como resultado de procesos tanto fotoquímicos como
    biológicos, por lo que no persiste en el medio. No se produce
    bioacumulación.

    4.  Niveles ambientales y exposición humana

         No se han hallado datos sobre las concentraciones de
    hidroquinona en la atmósfera, el suelo o el agua. Sin embargo, se ha
    analizado la hidroquinona presente en la corriente principal de humo
    emitida por cigarrillos sin filtro, en la que se han hallado entre
    110 y 300 µg por cigarrillo, así como en el humo lateral. Se ha
    hallado hidroquinona en alimentos derivados de las plantas (por
    ejemplo, el germen de trigo), en el café listo para beber y en los
    tes preparados a partir de las hojas de algunas bayas en que la
    concentración supera a veces el 1%.

         Los aficionados a la fotografía pueden verse expuestos a la
    hidroquinona por vía cutánea o por inhalación; sin embargo, no se
    dispone de datos sobre niveles de exposición. Otra causa de
    exposición cutánea es el uso de productos cosméticos o médicos con
    hidroquinona, como los utilizados para aclarar el color de la piel.
    Los países de la Comunidad Europea (CE) han restringido su empleo en
    los productos cosméticos a un máximo del 2%. En los Estados Unidos,
    la Administración de Alimentos y Medicamentos ha propuesto
    concentraciones de entre 1,5% y 2% para los productos de maquillaje
    decolorante. Algunos medicamentos de venta con receta contienen
    concentraciones de hasta un 4%, y en ciertos países se venden
    cosméticos decolorantes que contienen concentraciones incluso
    mayores.

         Son pocos los datos disponibles sobre la hidroquinona por lo
    que se refiere a la vigilancia de la higiene industrial. Según se ha
    señalado, el valor promedio de las concentraciones que este producto
    alcanza en el aire durante su fabricación y transformación oscila
    entre 0,13 y 0,79 mg/m3. El límite de la exposición atmosférica
    ocupacional (promedio ponderado por el tiempo) oscila entre 0,5 y 2
    mg/m3, según los países.

    5.  Cinética y metabolismo

         La hidroquinona es rápida y ampliamente absorbida en el tubo
    digestivo y la tráquea de los animales. La absorción cutánea es más
    lenta, pero se ve acelerada por vehículos como los alcoholes. La
    hidroquinona se distribuye de forma rápida y generalizada por los
    tejidos. Es metabolizada en  p-benzoquinona y otros productos de
    oxidación, y la detoxificación se produce por conjugación,
    formándose los derivados monoglucurónido, monosulfato y
    mercaptúrico. La excreción de la hidroquinona y de sus metabolitos
    es rápida y se produce principalmente a través de la orina.

         La hidroquinona y/o sus derivados reaccionan con distintos
    componentes biológicos, como macromoléculas o moléculas de bajo peso
    molecular, y tienen efectos sobre el metabolismo celular.

    6.  Efectos en mamíferos de laboratorio y en los sistemas in vitro

         Los valores de la DL50 por vía oral en varias especies
    animales oscilan entre 300 y 1300 mg/kg de peso corporal. En el
    gato, sin embargo, la DL50 varía entre 42 y 86 mg/kg de peso
    corporal. La exposición aguda a altos niveles de hidroquinona tiene
    efectos graves sobre el sistema nervioso central (SNC), que abarcan
    desde la hiperexcitabilidad, pasando por temblores, convulsiones y
    coma, hasta la muerte. A dosis subletales esos efectos son
    reversibles. Se ha calculado que la DL50 por vía cutánea es de >
    3800 mg/kg en roedores. No se dispone de los valores de la CL50
    por inhalación.

         Un preparado de hidroquinona al 2% aplicado a conejos mediante
    una única prueba del parche tuvo unos efectos irritantes de 1,22 (en
    una escala de 0 a 4). La aplicación tópica diaria durante tres
    semanas de hidroquinona al 2% o 5% en una emulsión de aceite/agua
    sobre la piel depilada de cobayos negros provocó despigmentación,
    cambios inflamatorios y espesamiento de la epidermis. La
    despigmentación fue más marcada con las concentraciones mayores, y
    los cobayos hembra se revelaron más sensibles que los machos.

         Las pruebas de sensibilización realizadas en cobayos han
    provocado respuestas de carácter entre débil y fuerte, según los
    métodos o vehículos empleados. Las reacciones más intensas fueron
    las observadas en la prueba de maximización aplicada a cobayos. Se
    observó también en estos animales una sensibilización cruzada de
    casi el 100% entre la hidroquinona y el  p-metoxifenol, pero los
    indicios de reacción cruzada con la  p-fenilendiamina, el ácido
    sulfanílico y la  p-benzoquinona fueron sólo limitados.

         Un estudio de toxicidad oral realizado durante seis semanas con
    ratas macho F-344 reveló la aparición de nefropatía y proliferación
    de las células renales. En estudios de sobrealimentación forzada
    mediante sonda esofágica llevados a cabo durante 13 semanas con
    ratas F-344 y ratones B6C3F1, se observaron en las ratas signos de
    nefrotoxicidad a dosis de 100 y 200 mg/kg, temblores y convulsiones
    a dosis de 200 mg/kg, así como una disminución del aumento del peso
    corporal tanto en las ratas como en los ratones. Las dosis de 400
    mg/kg resultaron letales para las ratas. En los ratones sometidos
    durante 13 semanas a dosis de 400 mg/kg se observaron temblores,
    convulsiones y lesiones del epitelio gástrico. La exposición de
    ratas Sprague Dawley a hidroquinona durante 13 semanas dio lugar a
    una atenuación del aumento del peso corporal y la aparición de
    signos de afección del SNC a la dosis de 200 mg/kg. Estos signos
    neurológicos se observaron también a la dosis de 64 mg/kg de peso
    corporal, pero no así a la de 20 mg/kg.

         La hidroquinona inyectada por vía subcutánea redujo la
    fecundidad de las ratas macho y prolongó el ciclo menstrual de las
    ratas hembra. Esa observación no se reprodujo en cambio en los

    estudios de administración oral (un estudio de dominancia letal y
    otro efectuado con dos generaciones). En un estudio sobre el
    desarrollo de la rata, dosis orales de 300 mg/kg de peso corporal
    tuvieron un ligero efecto tóxico en las madres y provocaron una
    disminución del peso corporal del feto. En el conejo, el nivel sin
    efectos observados (NOEL) por lo que se refiere a la toxicidad
    materna fue de 25 mg/kg al día, y de 75 mg/kg al día en lo que
    respecta a la toxicidad ontogénica. En un estudio de los efectos
    sobre la reproducción realizado con dos generaciones de ratas, la
    hidroquinona no tuvo efecto alguno a dosis orales de hasta 150 mg/kg
    de peso corporal al día. El nivel sin efectos adversos observados
    (NOAEL) fue de 15 mg/kg al día por lo que hace a la toxicidad
    materna, y de 150 mg/kg al día en lo referente a los efectos sobre
    la reproducción observados a lo largo de dos generaciones.

         La hidroquinona tiene un efecto inductor sobre los micronúcleos
     in vivo e  in vitro. Se han observado aberraciones cromosómicas
    estructurales y numéricas  in vitro y tras la administración
    intraperitoneal  in vivo. Se ha demostrado además la inducción de
    mutaciones genéticas, intercambio de cromátides hermanas y lesiones
    del ADN  in vitro. La hidroquinona causó aberraciones cromosómicas
    en las células germinales de ratones macho, del mismo orden de
    magnitud que en las células de médula ósea de esa misma especie tras
    inyección intraperitoneal. En una prueba de dominancia letal llevada
    a cabo con ratas macho tratadas por vía oral no se observó ningún
    efecto de inducción de mutaciones de las células germinales.

         En un estudio de dos años de duración, la administración oral
    de hidroquinona provocó una incidencia dosisdependiente de adenomas
    de las células tubulares renales en ratas macho F-344/N. La
    incidencia fue estadísticamente significativa en el grupo tratado
    con la dosis más alta; en los machos sometidos a esa dosis se halló
    también hiperplasia de las células tubulares renales. En las ratas
    hembra se observó un aumento dosisdependiente de la incidencia de
    leucemia de células mononucleares. En los ratones hembra B6C3F1 se
    observó una incidencia significativamente mayor de adenomas
    hepatocelulares. En otro estudio, la hidroquinona (presente a un
    nivel del 0,8% en la ingesta alimentaria) provocó un aumento
    significativo de la incidencia de hiperplasia epitelial de la papila
    renal y un aumento significativo de la incidencia de adenomas e
    hiperplasia de los túbulos renales en las ratas macho. En las ratas
    hembra no se observó ningún incremento de la incidencia de leucemia
    de células mononucleares. En los ratones, la incidencia de
    hiperplasia de las células escamosas del epitelio del antro cardiaco
    aumentó significativamente en los dos sexos. En los ratones macho se
    observó un aumento significativo de la incidencia de adenomas
    hepatocelulares, así como de hiperplasia tubular renal. Se observó
    también un reducido número de adenomas de células renales.

         Los estudios realizados  in vivo (inyección intraperitoneal) e
     in vitro con ratones han demostrado que el efecto citotóxico de la

    hidroquinona se debe a que reduce la celularidad de la médula ósea y
    del bazo, y a su posible efecto inmunosupresor, mediado por la
    inhibición de la maduración de los linfocitos B y de la actividad
    natural de las células asesinas. Los resultados indican además que
    las células más afectadas por la mielotoxicidad de la hidroquinona
    son quizá los macrófagos de la médula ósea. En una biovaloración
    prolongada realizada con roedores no se observaron esos efectos
    mielotóxicos.

         En un estudio realizado durante 90 días con ratas mediante una
    batería de pruebas funcionales y de observación, se advirtieron
    temblores a dosis de 64 y 200 mg de hidroquinona/kg, dosis esta
    última que además provocó una disminución de la actividad general.
    El resultado de los análisis neuropatológicos fue negativo.

    7.  Efectos en el hombre

         Se han notificado casos de intoxicación tras la ingestión oral
    de hidroquinona sola o de productos de revelado fotográfico que
    contenían dicho producto. Los principales signos de intoxicación
    fueron el oscurecimiento de la orina, vómitos, dolor abdominal,
    taquicardia, temblores, convulsiones y coma. Se han notificado
    muertes provocadas por la ingestión de productos de revelado
    fotográfico que contenían hidroquinona. En un estudio controlado
    realizado con voluntarios, la ingestión de 300-500 mg de
    hidroquinona diarios durante 3-5 meses no produjo cambios
    patológicos observables en la sangre y la orina.

         La aplicación cutánea de distintas bases que contenían
    concentraciones de hidroquinona inferiores al 3% tuvo efectos
    insignificantes en hombres voluntarios de distintas razas. Sin
    embargo, se han notificado algunos casos que llevan a pensar que hay
    cremas cutáneas decolorantes con hidroquinona al 2% que han
    provocado la aparición de leucoderma, así como de ocronosis. Se han
    producido casos de irritación (eritema o coloración) por
    hidroquinona (en solución acuosa al 1% o en forma de crema al 5%).
    También se han diagnosticado casos de dermatitis alérgica de
    contacto por hidroquinona.

         La exposición simultánea a hidroquinona y quinona presentes en
    el aire causa irritación ocular, sensibilidad a la luz, lesiones del
    epitelio corneal, úlceras corneales y trastornos visuales. En
    algunos casos se han producido pérdidas considerables de visión. Se
    han observado efectos irritantes a niveles de exposición de 2,25
    mg/m3 o más. La exposición prolongada provoca coloración de la
    conjuntiva y la córnea, así como opacidad. La exposición diaria
    durante al menos dos años a concentraciones de hidroquinona de 0,05-
    14,4 mg/m3 ha dado lugar al lento desarrollo de inflamación y
    decoloración de la córnea y la conjuntiva; pero no se han observado
    casos graves hasta transcurridos al menos 5 años. En un estudio se

    describieron casos de aparición de lesiones de la córnea al cabo de
    varios años de interrumpida la exposición a la hidroquinona.

         No se dispone de datos epidemiológicos adecuados para evaluar
    la carcinogenicidad de la hidroquinona en el hombre.

    8.  Efectos en otros organismos en el laboratorio y sobre el terreno

         Los efectos ecotoxicológicos de la hidroquinona guardan
    relación con sus propiedades fisicoquímicas, entre ellas su
    sensibilidad a la luz, al pH y al oxígeno disuelto. Su ecotoxicidad,
    que por lo general es alta (por ejemplo, < 1 mg/litro para los
    organismos acuáticos), varía de una especie a otra.

         Las algas, levaduras, hongos y plantas son menos sensibles
    a la hidroquinona que los otros organismos empleados habitualmente
    para evaluar la toxicidad. No obstante, dentro de un mismo grupo
    taxonómico, la sensibilidad de las distintas especies a la
    hidroquinona puede variar de 1 a 1000.


    See Also:
       Toxicological Abbreviations
       Hydroquinone (HSG 101, 1996)
       Hydroquinone (ICSC)
       Hydroquinone  (SIDS)
       Hydroquinone (IARC Summary & Evaluation, Volume 71, 1999)