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
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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:
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.
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.
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].
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.
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).
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.
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).
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
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.
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