INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 161
PHENOL
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 Ms G.K. Montizaan,
National Institute of Public Health and
Environmental Hygiene, Bilthoven, Netherlands
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 venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
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toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
chemicals.
WHO Library Cataloguing in Publication Data
Phenol.
(Environmental health criteria ; 161)
1.Phenols - standards 2.Environmental exposure
I.Series
ISBN 92 4 157161 6 (NLM Classification: QD 341.P5)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR PHENOL
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 test
systems
1.7. Effects on humans
1.8. Effects on organisms in the environment
1.9. Summary of evaluation
1.9.1. Human health
1.9.2. Environment
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.4.1. Sampling and pre-treatment
2.4.2. Analysis
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural sources
3.2. Anthropogenic sources
3.2.1. Production
3.2.2. Industrial processes
3.2.3. Non-industrial sources
3.3. Endogenous sources
3.4. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Abiotic degradation
4.2.1. Air
4.2.2. Water
4.3. Biodegradation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water and sediment
5.2. Occupational exposure
5.2.1. Production
5.2.2. Application of phenolic resins
5.2.3. Other occupational situations
5.3. General population exposure
5.3.1. Indoor air
5.3.2. Food and drinking-water
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption
6.1.1. Animal uptake studies
6.1.1.1 Pulmonary
6.1.1.2 Dermal
6.1.1.3 Intestinal
6.1.2. Human uptake studies
6.1.2.1 Pulmonary
6.1.2.2 Dermal
6.2. Distribution
6.3. Metabolic transformation
6.3.1. Metabolite identification
6.3.2. Covalent binding to macromolecules
6.3.3. Location
6.4. Elimination and excretion
6.5. Biological monitoring
7. EFFECTS ON LABORATORY MAMMALS, AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. LD50 values
7.1.2. Effects
7.2. Short-term exposure
7.2.1. Oral exposure
7.2.2. Dermal exposure
7.2.3. Inhalation exposure
7.2.4. Subcutaneous exposure
7.2.5. Ear exposure
7.3. Skin and eye irritation; sensitization
7.4. Long-term exposure
7.5. Reproduction, embryotoxicity and teratogenicity
7.5.1. Reproductive toxicity
7.5.2. Embryotoxicity/teratogenicity
7.5.2.1 In vivo studies
7.5.2.2 In vitro studies
7.6. Mutagenicity and related end-points
7.6.1. Mutagenicity studies
7.6.1.1 Bacterial systems
7.6.1.2 Non-mammalian eukaryotic systems
7.6.1.3 Mammalian in vitro systems
7.6.1.4 Mammalian in vivo systems: somatic
cells
7.6.1.5 Mammalian in vivo systems: germ cells
7.7. Carcinogenicity
7.7.1. Oral exposure
7.7.2. Dermal exposure
7.7.3. Inhalation exposure
7.7.4. Two-stage carcinogenicity studies
7.8. Special studies
7.8.1. Neurotoxicity
7.8.2. Myelotoxicity
7.8.3. Immunotoxicology
7.8.4. Biochemical effects
8. EFFECTS ON HUMANS
8.1. General population exposure
8.1.1. Controlled studies
8.1.2. Case reports
8.1.2.1 Dermal exposure
8.1.2.2 Oral exposure
8.1.2.3 Inhalation exposure
8.1.2.4 Exposure by injection
8.2. Occupational exposure
8.3. Organoleptic data
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.2. Aquatic organisms
9.2.1. Freshwater organisms
9.2.1.1 Short-term studies
9.2.1.2 Long-term studies
9.2.2. Marine organisms
9.2.2.1 Short-term studies
9.2.2.2 Long-term studies
9.2.3. Accumulation
9.2.4. Metabolism
9.3. Terrestrial organisms
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.1.1. Exposure
10.1.2. Toxicity
10.1.3. Evaluation
10.2. Evaluation of effects on the environment
10.2.1. Environmental levels
10.2.2. Toxicity
10.2.3. Evaluation
11. FURTHER RESEARCH
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA FOR PHENOL
Members
Dr L.E. Hansen, dk-Teknik, Soeborg, Denmark
Dr R.J. Kavlock, Developmental Toxicology Division, Health Effects
Research Laboratory, US Environmental Protection Agency,
Research Triangle Park, North Carolina, USA
Dr C.J. Price, Neurotoxicology Program Development, Center for Life
Sciences and Toxicology, Research Triangle Institute, Research
Triangle Park, North Carolina, USA
Mr D. Renshaw, Department of Health, Elephant and Castle, London,
United Kingdom
Dr A. Smith, Health and Safety Executive, Toxicology Unit, Bootle,
Merseyside, United Kingdom ( Joint Rapporteur)
Professor J.A. Sokal, Institute of Occupational Medicine and
Environmental Health, Sosnowiec, Poland ( Chairman)
Dr S.H.H. Swierenga, Health and Welfare Canada, Drugs Directorate,
Ottawa, Ontario, Canada ( Joint Rapporteur)
Dr T. Vermeire, National Institute of Public Health and
Environmental Protection, Toxicology Advisory Centre,
Bilthoven, The Netherlands
Secretariat
Professor F. Valic, IPCS Consultant, World Health Organization,
Geneva, Switzerland, also Vice-Rector, University of Zagreb,
Zagreb, Croatia ( Responsible Officer and Secretary)
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 PHENOL
A Task Group on Environmental Health Criteria for Phenol met at
the British Industrial and Biological Research Association (BIBRA)
Toxicology International, Carshalton, United Kingdom from 26 to 30
April 1993. Dr D. Anderson welcomed the participants on behalf of
the host institution, and Professor F. Valic opened the Meeting on
behalf of the three cooperating organizations of the IPCS
(UNEP/ILO/WHO). The Task Group reviewed and revised the draft
monograph and made an evaluation of the risks for human health and
the environment from exposure to phenol.
The first draft of this monograph was prepared by Ms G.K.
Montizaan, National Institute of Public Health and Environmental
Hygiene, Bilthoven, the Netherlands.
Professor F. Valic was responsible for the overall scientific
content of the monograph and for the organization of the meeting,
and Dr P.G. Jenkins, IPCS, was responsible for the technical editing
of the monograph.
The efforts of all who helped in the preparation and
finalization of the monograph are gratefully acknowledged.
ABBREVIATIONS
DMBA dimethylbenzathraline
EEC European Economic Community
LOAEL lowest-observed-adverse-effect level
MATC maximum acceptable tolerance concentration
NOAEL no-observed-adverse-effect level
NOEL no-observed-effect level
NOLC no-observed lethal concentration
PCE polychromatic erythrocytes
TT toxicity threshold
1. SUMMARY
1.1 Identity, physical and chemical properties, analytical methods
Phenol is a white crystalline solid which melts at 43 °C and
liquefies upon contact with water. It has a characteristic acrid
odour and a sharp burning taste. It is soluble in most organic
solvents; its solubility in water is limited at room temperature;
above 68 °C it is entirely water-soluble. Phenol is moderately
volatile at room temperature. It is a weak acid, and in its ionized
form very sensitive to electrophile substitution reactions and
oxidation.
Phenol may be collected from environmental samples by
absorption in NaOH solution or onto solid sorbents. Desorption is
achieved by acidification, steam distillation and ether extraction
(from solutions) or by thermal or liquid desorption (from solid
sorbents). The most important analytical techniques are gas
chromatography in combination with flame ionization/electron capture
detection, and high-performance liquid chromatography in combination
with ultraviolet detection. The lowest reported detection limit for
air is 0.1 µg/m3. Phenol can be measured in blood and urine; in
urine samples a detection limit of 0.5 µg/litre has been reported.
1.2 Sources of human and environmental exposure
Phenol is a constituent of coal tar, and is formed during the
natural decomposition of organic materials. The major part of phenol
present in the environment, however, is of anthropogenic origin.
Production and use of phenol and its products, especially phenolic
resins and caprolactam, exhaust gases, residential wood burning and
cigarette smoke are potential sources. Another potential source is
the atmospheric degradation of benzene under the influence of light,
whereas the presence of phenol in liquid manure may also contribute
considerably to its atmospheric levels. Benzene and phenol
derivatives may, by in vivo conversion, form a source of
endogenous human phenol exposure.
The worldwide production of phenol appeared to be fairly
constant throughout the 1980s, the USA being the most important
producer. Its major use is as a feedstock for phenolic resins,
bisphenol A and caprolactam. Some medical and pharmaceutical
applications are also known.
1.3 Environmental transport, distribution and transformation
The main emissions of phenol occur to air. The major part of
phenol in the atmosphere will be degraded by photochemical reactions
to dihydroxybenzenes, nitrophenols and ring cleavage products, with
an estimated half-life of 4-5 h. A minor part will disappear from
the air by wet deposition (rain). Phenol is expected to be highly
mobile in soil, but transport and reactivity may be affected by pH.
Phenol in water and soil may be degraded by abiotic reactions
as well as microbial activity to a number of compounds, the most
important being carbon dioxide and methane. The proportion of
biodegradation to the overall degradation of phenol is determined by
many factors, such as concentration, acclimation, temperature, and
the presence of other compounds.
1.4 Environmental levels and human exposure
No data are available on atmospheric phenol levels. Background
levels are expected to be less than 1 ng/m3. Urban/suburban levels
vary from 0.1 to 8 µg/m3, while concentrations in source-dominated
areas (industry) were reported to be up to two orders of magnitude
higher. Phenol has been detected in rain, surface water and ground
water, but data are very scarce. Elevated phenol levels have been
reported in sediments and ground waters due to industrial pollution.
Occupational exposure to phenol may occur during the production
of phenol and its products, during the application of phenolic
resins (wood and iron/steel industry) and during a number of other
industrial activities. The highest concentration (up to 88 mg/m3)
was reported for workers in the ex-USSR quenching coke with
phenol-containing waste water. Most other reported concentrations
did not exceed 19 mg/m3.
For the general population, cigarette smoke and smoked food
products are the most important sources of phenol exposure, apart
from the exposure via air. Exposure by way of drinking-water and
inadvertently contaminated food products should be low; phenol has
an objectionable smell and taste, which in most cases leads to
non-acceptance by the consumer.
1.5 Kinetics and metabolism
Phenol is readily absorbed by all routes of exposure. After
absorption, the substance is rapidly distributed to all tissues.
Absorbed phenol mainly conjugates with glucuronic acid and
sulfuric acid and, to a lesser extent, hydroxylates into catechol
and hydroquinone. Phosphate conjugation also occurs. The formation
of reactive metabolites (4,4-biphenol and diphenoquinone) has been
demonstrated in in vitro studies with activated human neutrophils
and leucocytes.
The relative amounts of glucuronide and sulfate conjugates vary
with dose and animal species. A shift from sulfation to
glucuronidation was observed in rats after increasing the phenol
dose.
The liver, the lung, and the gastrointestinal mucosa are the
most important sites of phenol metabolism. The relative role played
by these tissues depends on route of administration and dose.
In vivo and in vitro studies have demonstrated covalent
binding of phenol to tissue and plasma proteins. Some phenol
metabolites also bind to proteins.
Urinary excretion is the major route of phenol elimination in
animals and humans. The rate of urinary excretion varies with dose,
route of administration, and species. A minor part is excreted in
the faeces and expired air.
1.6 Effects on laboratory mammals, and in vitro test systems
Phenol has moderate acute toxicity for mammals. Oral LD50
values in rodents range from 300 to 600 mg phenol/kg body weight.
Dermal LD50 values for rats and rabbits range from 670 to 1400
mg/kg body weight, respectively, and the 8-h LC50 for rats by
inhalation is more than 900 mg phenol/m3. Clinical symptoms after
acute exposure are neuromuscular hyperexcitability and severe
convulsions, necrosis of skin and mucous membranes of the throat,
and effects on lungs, nerve fibres, kidneys, liver, and the pupil
response to light.
Solutions of phenol are corrosive to skin and eyes. Phenol
vapours can irritate the respiratory tract. There is evidence that
phenol is not a skin sensitizer.
The most important effects reported in short-term animal
studies were neurotoxicity, liver and kidney damage, respiratory
effects and growth retardation. Toxic effects in rat kidney have
been reported to occur at oral dose levels of 40 mg/kg per day or
more. Liver toxicity was evident in rats administered at least 100
mg/kg per day. In a limited 14-day study in rats, an oral
no-observed-adverse-effect level (NOAEL) of 12 mg/kg per day was
reported, based on kidney effects. In this experiment miosis (an
iris response to light) was still inhibited at 4 mg/kg per day;
however, the health significance of this finding is not clear. Some
biological changes were reported to occur in the intestinal mucosa
and kidneys of mice at dose levels below 1 mg/kg per day, a finding
of uncertain toxicological significance.
There are no adequate studies on the reproductive toxicity of
phenol. Phenol has been identified as a developmental toxicant in
studies with rats and mice. In two multiple dose rat studies, NOAEL
values of 40 mg/kg per day (the lowest-observed-adverse-effect level
(LOAEL) was 53 mg/kg per day) and 60 mg/kg per day (the LOAEL was
120 mg/kg per day) have been reported. In the mouse, the NOAEL was
140 mg/kg per day (the LOAEL was 280 mg/kg per day).
The majority of bacterial mutagenicity tests have given
negative results. Mutations, chromosomal damage and DNA effects have
been observed in mammalian cells in vitro. Phenol has no effect on
intercellular communication (measured as metabolic cooperation) in
cultured mammalian cells. Induction of micro-nuclei in bone marrow
cells of mice has been observed in some studies. No micronuclei were
observed in mice studies at lower doses.
Two carcinogenicity studies have been conducted with male and
female rats and mice receiving phenol in their drinking-water.
Malignancies (e.g., C-cell thyroid carcinoma, leukaemia) were only
seen in low-dose male rats. No adequate dermal or inhalation
carcinogenicity studies have been conducted. Two-stage
carcinogenicity studies have shown that phenol, applied repeatedly
to mouse skin, has promoting activity.
1.7 Effects on humans
A wide range of adverse effects has been reported following
well-documented human exposure to phenol by the dermal, oral or
intravenous routes. Gastrointestinal irritation has been reported
following ingestion. Local effects following dermal exposure range
from painless blanching or erythema to corrosion and deep necrosis.
Systemic effects include cardiac dysrhythmias, metabolic acidosis,
hyperventilation, respiratory distress, acute renal failure, renal
damage, dark urine, methaemoglobinaemia, neurological effects
(including convulsions), cardiovascular shock, coma and death. The
lowest reported dose resulting in a human death was 4.8 g by
ingestion; death occurred within 10 min.
The potential for poisoning through inhalation of phenol
vapours has long been recognized, but no cases of death following
this route of exposure have been reported. Symptoms associated with
inhalation of phenol included anorexia, weight loss, headache,
vertigo, salivation and dark urine.
Phenol is not a sensitizing agent.
The human odour threshold for phenol has been reported to range
from 0.021 to 20 mg/m3 in air. The odour threshold for phenol in
water has been reported to be 7.9 mg/litre, and the taste threshold
0.3 mg/litre in water.
Adequate human data on the carcinogenicity of phenol are not
available.
1.8 Effects on organisms in the environment
In studies on single bacteria species, the EC50 values found
for growth inhibition varied from 244 to 1600 mg phenol/litre. A
toxicity threshold of 64 mg phenol/litre was found. Values for
protozoa and fungi were of the same order of magnitude as for
bacteria; for algae, they were somewhat lower.
Phenol is toxic to higher freshwater organisms. The lowest
LC50 or EC50 values for crustaceans and fish lie between 3 and 7
mg phenol/litre. The data on the acute toxicity to marine organisms
are comparable with those for freshwater organisms. In long-term
studies on crustacea and fish species, a remarkable difference in
sensitivity has been observed; the LC1 values from embryo-larval
tests on Salmo and Carassius proved to be much lower (0.2 and 2
µg phenol/litre, respectively) than the corresponding values for
other fish species (NOLC 2.2-6.1 mg/litre) and amphibia, or from
reproduction tests on crustacea (NOLC 10 mg phenol/litre). Data from
long-term tests on marine organisms are not available.
The bioconcentration factors of phenol in various types of
aquatic organisms are in general very low (< 1-10), although some
higher values (up to 2200) have also been reported. Phenol,
therefore, is not expected to bioaccumulate significantly.
The available data concerning the fate and effects of phenol in
terrestrial organisms are very scarce. A 120-h EC50 for millet was
found to be 120-170 mg/litre, and in a contact test the LC50 for
earthworm species was 2.4-10.6 µg/cm2.
1.9 Summary of evaluation
1.9.1 Human health
The general population is primarily exposed to phenol by
inhalation. Repeated oral exposure may arise from consumption of
smoked food or drinking-water.
Data are inadequate to determine the degree of exposure of the
general population, but an upper-limit estimate of the daily intake
can be made. On the basis of "the worst case scenario", an estimate
can be made assuming that an individual will be maximally exposed to
phenol through continuous inhalation of heavily contaminated air
with frequent consumption of smoked food items and of drinking-water
containing phenol up to the taste threshold. The estimated maximal
total daily intake of phenol for such a 70-kg individual is
calculated to be 0.1 mg/kg body weight per day.
The lowest NOAEL values identified in animal experiments are
for kidney and developmental effects, and in rats lie within the
range of 12-40 mg/kg body weight per day. Using an uncertainty
factor of 200, a range of 60-200 µg/kg body weight per day is
recommended as the upper limit of the total daily intake (TDI).
Considering the upper-limit estimate of human daily intake of 100
µg/kg body weight per day, it is concluded that the average general
population exposure to phenol from all sources is below this range.
A reason for concern is some evidence that phenol may be
genotoxic and the fact that there is insufficient data to discount
with certainty the possible carcinogenicity of the compound. The
evaluation must be kept under periodic review.
1.9.2 Environment
Phenol is not expected to bioaccumulate significantly. Phenol
is toxic to aquatic organisms; an environmental concern level of
0.02 µg/litre can be determined applying the modified US EPA method.
Adequate data on plants and terrestrial organisms are lacking.
Intercompartmental transport of phenol mainly occurs by wet
deposition and by leaching through soil. Generally, the compound is
not likely to persist in the environment. The scarce exposure data
do not allow the evaluation of the risk from phenol to either
aquatic or terrestrial ecosystems. However, in view of the derived
environmental concern level for water, it is reasonable to assume
that aquatic organisms may be at risk in any surface or sea water
contaminated with phenol.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
Chemical formula: C6H6O
Chemical structure:
Relative molecular mass: 94.11
Common name: phenol
Common synonyms: acidum carbolicum, acidum phenolicum,
acidum phenylicum, benzaphenol, benzene
phenol, benzenol carbolic acid,
hydroxybenzene (IUPAC), oxybenzene,
monohydroxybenzene, monophenol, phenic
acid, phenol alcohol, phenyl hydrate,
phenyl hydroxide, phenylic acid
Common trade names: carbololie (NLD), fenololie (NLD),
kristalliertes Kreosot (GER),
Steinkohlenkreosot (GER),
Steinkohlenteerkreosot (GER), venzénol
(FRA), ENT 1814.
CAS registry number: 108-95-2
CAS chemical name: phenol
2.2 Physical and chemical properties
Some physical and chemical properties of phenol are given in
Table 1.
Table 1. Some physical and chemical properties of phenola
Boiling point (101.3 Pa) 181.75 °C
Melting point 43 °C
40.9 °C (ultrapure material)
Relative density (20 °/4 °)b 1.071
Relative vapour density (air = 1) 3.24
Vapour pressure (20 °C) 0.357 mmHg
(50 °C) 2.48 mmHg
(100 °C) 41.3 mmHg
Saturation concentration in air (20°C) 0.77 g/m3
Solubility in water (16 °C) 67 g/litrec
Log n-octanol/water partition
coefficient (log Pow) 1.46d
Dissociation constant in water
at 20 °C (Ka) 1.28 x 10-10
Flash-point (closed cup) 80 °C
(open cup) 79 °C
85 °Ce
Flammability limits 1.3-9.5%
a From: Kirk-Othmer (1980); RIVM (1986)
b Weast (1987)
c Above 68.4 °C phenol is entirely soluble in water
d The Pow of phenol is very much dependent on pH; pH at log
Pow = 1.46 was not given
e Budavari et al. (1989)
Phenol has a melting point of 43 °C and forms white to
colourless crystals (Budavari et al., 1989). It has also been
described as a colourless to pink solid or thick liquid (NIOSH,
1985a). Phenol has a characteristic acrid smell and a sharp burning
taste. Odour and taste threshold values are reported in section 8.3.
In the molten state, it is a clear, colourless liquid with a low
viscosity. A solution with approximately 10% water is called
phenolum liquefactum, as this mixture is liquid at room temperature.
Phenol is soluble in most organic solvents (aromatic hydrocarbons,
alcohols, ketones, ethers, acids, halogenated hydrocarbons). The
solubility is limited in aliphatic solvents.
The chemical properties of phenol are affected by the resonance
stabilization possibilities of phenol and, in particular, of the
phenolate ion. Because of this, phenol reacts as a mild acid. In the
presence of electrophilic groups (meta-indicators), the acidic
properties are emphasized.
Phenol is sensitive to oxidizing agents. Splitting of the
hydrogen atom from the phenolic hydroxyl group is followed by
resonance stabilization of the resulting phenyloxy radical. The
radical formed can easily be further oxidized. Depending on the
oxidizing agent applied and the reaction conditions, various
products, such as dihydroxy- and trihydroxybenzenes and quinones are
formed. These properties make phenol suitable as an antioxidant,
functioning as a radical trapping agent. Phenol undergoes numerous
electrophilic substitution reactions, such as halogenation and
sulfonation. It also reacts with carbonyl compounds in both acidic
and alkaline media. In the presence of formaldehyde, phenol is
readily hydroxymethylated with subsequent condensation to resins.
2.3 Conversion factors
1 mg/m3 = 0.26 ppm
1 ppm = 3.84 mg/m3
2.4 Analytical methods
Analytical methods for phenol are shown in Table 2.
2.4.1 Sampling and pre-treatment
Phenol in air samples may be collected by absorption in NaOH
solution contained in wash bottles or on filters impregnated with
NaOH solution. Phenol in air, water and solid waste samples may be
collected (directly or after extraction) in tubes containing solid
sorbent (Tenax, silica gel or, less commonly, carbon) (IARC, 1989).
For large air volumes, the NaOH method is usually preferred, whereas
for smaller quantities (personal air sampling, for instance) solid
sorbent tubes have been reported to be more practical (RIVM, 1986).
Release of phenol from aqueous solutions (including NaOH
sorbent, and also urine) is achieved by acidification, steam
distillation and/or ether extraction. After adsorption onto Tenax,
thermal desorption at 250 °C is usually preferred (the whole sample
may be inserted directly into a gas chromatograph), whereas, in the
case of silica gel, liquid desorption with chloroform is generally
applied. There is a small possibility of chemical conversion during
heating, whereas Tenax may react with ozone to form small quantities
of phenol. Only one analysis per sample is possible in the case of
thermal desorption. The use of liquid desorption allows more
analyses per sample, but because of the unavoidable dilution the
detection limit is higher (RIVM, 1986).
Table 2. Methods for the detection of phenol in air
Sampling Volume of air Pre-treatment Analysis Detection limit Reference
(litre) before analysis (µg/m3)
Absorbance in NaOH solution 100 acidification GC and FID 10 µg per NIOSH (1984)
in a wash bottle; 1 litre/min sample
Absorbance in NaOH solution 25 000 acidification and GC and FID 4 Katz (1977)
in an impinger; 20 litre/min steam distillation
Glass fibre filter impregnated with 600 acidification and GC and FID 13 Kifune (1979)
NaOH and glycerol; 120 litre/min extraction with ether
Absorbance in NaOH solution in 1000 acidification and colorimetry with 2 Katz (1977)
an impinger; 28 litre/min steam distillation 4-amino antipyrine
Absorbance in NaOH solution - none colorimetry with 700 Hensehler (1975)
in a wash bottle; 1 litre/min 4-amino antipyrine
Absorbance in NaOH solution in 150 conversion in an HPLC with UV detector 0.2 Kuwata et al.
a sinter wash bottle; 1-2 litre/min azophenol derivate (254 nm) (1980)
Absorbance in Na2CO3 solution; 30 calibration at pH = 10 UV at 235 nm at 2 pH 160 Zavorovskaya &
1 litre/min and pH = 7 values Nekhorosheva (1981)
Absorbance in NaOH solution in 300 calibration at pH = 12 UV at 241 and 295 nm 20 Bergshoeff (1960)
an impinger; 28 litre/min and at pH = 6
Tenax with and without KOH; 5 thermal desorption; GC and FID 0.1 Hoshika & Muto
0.25 litre/min 250 °C (1979)
Tenax; 0.1 litre/min 4 thermal desorption; GC and FID 1 Russell (1975)
260 °C
Tenax; 0.5-1 litre/min 70 thermal desorption; GC and MS 0.3 Hagemann et
250 °C al. (1978)
Table 2 (contd)
Sampling Volume of air Pre-treatment Analysis Detection limit Reference
(litre) before analysis (µg/m3)
Tenax; 0.75 litre/min 90 thermal desorption; IR with 20 m gas 300 Podolak et al.
300 °C cuvette (1981)
Silica gel 25 liquid desorption GC and FID 3 Dimitriev &
with chloroform Mishchikhin (1983)
Silica gel; 0.05-2 litre/min 10 liquid desorption HPLC with UV detector 50 Oomems &
with chloroform (275 nm) Schuurhuis (1983)
Drägen tube gas detection 0.5 none reading of colorisation 19 000 Leichnitz (1982)
2.4.2 Analysis
The most important analytical techniques for the detection of
phenol are gas chromatography (GC) in combination with flame
ionization detection (FID), and high-performance liquid
chromatography (HPLC) in combination with ultraviolet (UV)
detection. The identification of phenol by GC/FID has been improved
by reaction of phenols with bromide or pentafluoro-benzyl bromide,
and the use of electron capture detection (Hoshika & Muto, 1979; US
EPA, 1986a). The identification of phenol using HPLC can be improved
by reaction with, for example, p-nitrobenzene diazonium
tetrafluoroborate to form azo derivatives (Kuwata et al., 1980).
Detection limits of the above techniques for air samples are
given in Table 2. For the GC/FID detection of phenol in water, using
electron capture detection following derivatization with
pentafluorobenzyl bromide, a detection limit of approximately 0.2
µg/litre has been reported (US EPA, 1986a).
GC in combination with mass spectrometry (MS) is more sensitive
than with FID, but is more expensive. This technique, using either
packed or capillary columns, was reported to have practical
quantitative limits of approximately 1 mg phenol/kg wet weight for
soil/sediment samples, 1-200 mg phenol/kg for wastes, and 10
µg/litre for groundwater samples (US EPA, 1986b,c).
Another reported analytical technique is colorimetry after
reaction of phenol with 4-amino antipyrine, in the presence of
potassium ferricyanide, to form an antipyrine dye. The detection
limit of this technique for water samples, after steam distillation,
was reported to be 1 µg/litre (American Public Health Association,
1985). For air samples of 1 m3, the detection limit was reported
to be 2 µg/m3 (see Table 2). The interference by para-substituted
phenols and chlorophenols is low (RIVM, 1986).
Infrared (IR) detection of phenol is a rather insensitive
method, and is highly susceptible to interference by other compounds
such as water vapour. However, it is a rapid and specific method
which allows directly readable continuous measurement. It is
considered to be attractive only at air concentrations of more than
1000 µg/m3, for example in leakage tests and industrial warning
systems (RIVM, 1986). Also directly readable is the Dräger gas
detection tube (see Table 2); however, the detection limit is very
high (> 19 000 µg/m3).
For the GC/FID detection of total phenol in urine samples,
after acidification and ether extraction, a detection limit of 0.5
µg/litre was estimated (NIOSH, 1985b). Colorimetric methods for the
determination of free phenol in both urine and blood are available.
In one method, phenol reacts with p-nitroaniline following
deproteinization and extraction with diethyl ether. Other phenols
will interfere (Müting et al., 1970). In another method, phenol
reacts with ammonia and N-chlorosuccinimide in alkaline media with
sodium nitroprusside as a catalyst. This method was found to be
applicable in the range of 3-24 mg/litre, using spiked samples of
urine (Amlathe et al., 1987). The concentration of total phenol in
urine and plasma can be determined by GC/MS following hydrolysis of
glucuronide and sulfate conjugates with sulfuric acid and
derivatization with propanoic anhydride. The detection limit is
reported to be 10 µg/litre (Pierce & Nerland, 1988).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural sources
Phenol is a constituent of coal tar, and is formed during the
natural decomposition of organic materials. Increased environmental
levels may result from forest fires (Hubble et al., 1981).
Phenol has been detected among the volatile components from
liquid manure at concentrations of 7-55 µg/kg dry weight (Spoelstra,
1978). In the Netherlands, for example, the contribution from this
source to the overall phenol emission into air in 1983 has been
calculated to be 15%, assuming complete volatilization of phenol and
an average phenol concentration in manure of 30 µg/kg dry weight
(RIVM, 1986).
3.2 Anthropogenic sources
3.2.1 Production
The most commonly used production method for phenol, on a
worldwide scale, is from cumene (isopropylbenzene). In the USA, for
example, more than 98% of phenol is produced by this method (IARC,
1989). Phenol is also produced from chlorobenzene and toluene. A
small but steady supply of phenol is recovered as a by-product of
metallurgical coke manufacture (IARC, 1989). The emission factor of
phenol into air during production by the cumene process has been
reported to be 0.16 g phenol emitted per kg phenol produced (UBA,
1981).
In Table 3, information is presented concerning the production
of phenol in various countries in 1981. This information was derived
from the open literature (Chemfacts, 1978-1981; United Nations,
1980; SRI, 1982; CID-TNO, 1984; IARC, 1989) and, where necessary,
was extrapolated to 1981. There have been no major production
changes according to data available up to 1986 (IARC, 1989).
3.2.2 Industrial processes
Phenol is the basic feedstock from which a number of
commercially important materials are made, including phenolic
resins, bisphenol A (2,2-bis-1-hydroxyphenylpropane), capro-lactam,
alkyl phenols, as well as chlorophenols such as pentachlorophenol
(IARC, 1989).
Table 3. Production of phenol in 1981 and 1986 (kilotonne/year)
Country Production Production
in 1981a in 1986b
Brazil 50
Bulgaria 35
Czechoslovakia 44 46
Finland 32
France 150
Germany, Federal
Republic of 247
Italy 223
India 14
Japan 215 260
Mexico 20
The Netherlands 166
Poland 66
Romania 66
Spain 55 70
United Kingdomc 110 53
USA 1350 1413
USSR 497 515
Other countries 34
European Community (total) 920
Total 3374
a Chemfacts (1978-1981); United Nations (1980); SRI (1982); CID-TNO
(1984); IARC (1989)
b From IARC (1989)
c Phenol is no longer produced in the UK
The most important phenol emissions result from the use of
phenolic resins. Phenolic resins are used as a binding material in,
for example, insulation materials, chipboard and triplex, paints and
casting sand foundries. Their contents vary from 2-3% for insulation
material to > 50% for moulds (Bollig & Decker, 1980). Emissions are
approximately proportional to the concentration of free phenol,
which is present as a monomer in these materials (1-5%) (Bollig &
Decker, 1980). In addition, phenol may be released as a result of
thermal decomposition of the resins.
In foundries, phenol emissions develop both during the
production of moulds and kernels and during founding (TNO, 1978).
The content of free phenol may rise by up to 12% (Ryser & Ulmer,
1980). Emission factors reported by RIVM (1986) were 0.35 g phenol
emitted per kg used casting sand, 2-5 g phenol emitted per kg resin
in the production of casting sand, and 10 g phenol emitted per kg
resin during the production of moulds by the "hot-box" procedure.
Other industrial activities in which phenol may be emitted to
the air, as well as some of their reported emission factors, are
listed below:
* production of phenol resins (0-0.5 g phenol emitted per kg
resin produced) (RIVM, 1986)
* production of phenols and phenol derivatives
* production of caprolactam (0.02-0.05 g phenol emitted per kg
cyclohexanone (an intermediate) produced (RIVM, 1986)
* production of cokes
* production of insulation materials
* process emissions
Emissions to water may also result from processing.
3.2.3 Non-industrial sources
Phenol has been detected in the exhaust gases of private cars
at concentrations of 0.3 ppm (approximately 1.2 mg/m3) to 1.4-2.0
ppm (5.4-7.7 mg/m3) (Kuwata et al., 1980; Verschueren, 1983). It
has also been identified in cigarette smoke, in quantities that are
comparable to an average emission of 0.4 mg/cigarette (Groenen,
1978). Emission gases from all material incinerators and home fires,
especially wood-burning, may contain substantial quantities of
phenol (Den Boeft et al., 1984).
Another potential source of phenol is the atmospheric
degradation of benzene under the influence of light (Hoshino &
Akimoto, 1978).
Phenols have been detected in smoked foods (section 5.3.2).
3.3 Endogenous sources
An important additional source of human phenol exposure may be
the in vivo formation from various xenobiotics, e.g., benzene
(Pekari et al., 1992).
3.4 Uses
The largest single use of phenol is the production of phenolic
resins. Next is its use in the production of caprolactam, an
intermediate in the production of nylon 6, and 2,2-bis-1-
hydroxyphenylpropane (bisphenol A), which is mainly used in the
production of phenolic resins (Kirk-Othmer, 1980).
The various applications of phenol as a percentage of total
1981 consumption, in the USA and western Europe, are summarized in
Table 4 (Kirk-Othmer, 1980). The data presented are in close
agreement with the 1986 USA data reported by IARC (1989).
Table 4. Use of phenol in 1981 (% total consumption)a
Production of USA West Europe
Phenolic resins 48 36
Bisphenol A(2,2-bis-1-
hydroxyphenylpropane) 18 17
Caprolactam 15 28
Other products 19 19
Total 100 100
a From: Kirk-Othmer (1980)
Phenol was widely used in the 19th century for wound treatment
and as an antiseptic and local anaesthetic. The medical uses of
phenol today include incorporation into disinfectants, antiseptics,
lotions, salves and ointments (IARC, 1989). Another medical
application of phenol is its use as a neurolytic agent, applied in
order to relieve spasm and chronic pain (Wood, 1978).
In addition to the applications mentioned in section 3.2.2,
phenol is used in the manufacture of paint and varnish removers,
lacquers, paints, rubber, ink, illuminating gases, tanning dyes,
perfumes, soaps and toys (IARC, 1989).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
No data have been found concerning wet and dry deposition of
phenol. Since phenol in air is present almost exclusively in the gas
phase, dry deposition (by particle deposition) is expected to be
negligible. Wet deposition may contribute to the disappearance of
phenol from the atmosphere: when phenol was measured during seven
episodes of rain in Portland, Oregon, USA, relatively high
concentrations were found in the rain water (Leuenberger et al.,
1985).
Based on its relatively high solubility in water and the
relatively low vapour pressure at room temperature, phenol is
expected to end up largely in the water phase upon distribution
between air and water. Consequently, transport from air to soil and
water is likely (RIVM, 1986). Volatilization from dry near-surface
soil should be relatively rapid (Howard, 1989).
Theoretical deposition rates for phenol were estimated assuming
a behaviour similar to SO2, and comparing with the rate of reaction
of phenol with hydroxyl radicals (see below). Based on this
comparison, it was concluded that most phenol in the atmosphere is
degraded chemically, rather than transported (RIVM, 1986).
Partition coefficient (Koc) values of phenol for two silt
loams were reported to be 39 and 91 dm3/kg. Based on these Koc
values, phenol would be expected to be highly mobile in soil, and
therefore may leach to ground water (Howard, 1989). This was
confirmed by Scott et al. (1982) who found low adsorption of
phenol to two sterile silt loams (pH 5.4, organic matter content 1.1
and 3.6, respectively), as shown by Freundlich K values of 0.57 and
1.19, respectively. Based on the pKa (log (1.28 x 10 -10)),
phenol exists in a partially dissociated state in water and moist
soils and, therefore, its transport and reactivity may be affected
by pH (Howard, 1989). Upon measurement of the sorption and
desorption of phenol from water to surface sediment (pH 6.21-6.35;
organic matter content of fine fraction (< 2 µM) was 10.2%), phenol
appeared to bind strongly to the soil. The estimated Koc was 2900
dm3/kg (Isaacson & Frink, 1984). However, no correction was made
for any degradation occurring during the experiments. The adsorption
of phenol onto soil or microbial biomass may be decreased by the
presence of phenol derivatives (Boyd, 1982; Selvakumar & Hsieh,
1988). Phenol has been detected in ground water as a result of
leaching (see section 5.1.2).
4.2 Abiotic degradation
4.2.1 Air
Phenol may react in air with hydroxyl and NO3 radicals, and
undergo other photochemical reactions to form dihydroxy-benzenes,
nitrophenols, and ring cleavage products (Atkinson et al., 1979;
Bruce et al., 1987). The half-life for phenol in air was found to
be 4-5 h under photochemically reactive conditions in a smog chamber
(Spicer et al., 1985); this is in good agreement with the
estimated half-life of phenol in air of 5 h based on its estimated
reaction rate with hydroxyl radicals (RIVM, 1986). Howard (1989)
reported an estimated half-life of 15 h for the reaction of phenol
with hydroxyl radicals in air. The reaction of phenol with nitrate
radicals during the night may be a significant removal process; a
half-life of 15 min has been estimated at an atmospheric
concentration of 2x108 nitrate radicals per cm3 (Howard, 1989).
Phenol absorbs light in the region of 290-330 nm and therefore
could photolyse (Howard, 1989).
4.2.2 Water
Phenols generally react in sunlit natural water via reaction
with photochemically produced hydroxyl and peroxy radicals; typical
half-lives were reported to be 100 and 19.2 h, respectively (Howard,
1989).
Phenol was found to be oxidized to carbon dioxide in water
under experimental conditions (temperature approximately 50 °C), in
the presence of oxygen and sunlight, at a rate of 11% per 24 h
(Knoevenagel & Himmelreich, 1976). It was reported to react with
nitrate ions in dilute aqueous solutions to form dihydroxybenzenes,
nitrophenols, nitrosophenol and nitroquinone, presumably by a
radical mechanism involving hydroxyl and phenoxyl radicals (Niessen
et al., 1988). Phenol has been found to react with nitrous acid in
waste water to form cyanide (Adachi et al., 1987), and to form
chlorophenols in chlorinated drinking-water (Jarvis et al., 1985)
and p-benzoquinone in the presence of chlorine dioxide (Wajon et
al., 1982).
4.3 Biodegradation
Bacteria play a major role in the degradation of phenol in
soil, sediment and water. The number of bacteria capable of
utilizing phenol is usually a small percentage of the total
population present in, for example, a soil sample (Hickman & Novak,
1989). However, repeated phenol exposure may result in acclimation
(the promotion of strains capable of utilizing phenol as food)
(Young & Rivera, 1985; Colvin & Rozich, 1986; Shimp & Pfaender,
1987; Wiggins & Alexander, 1988; Tibbles & Baecker, 1989).
Phenol may be converted by bacteria under aerobic conditions to
carbon dioxide (Southworth et al., 1985; Ursin, 1985; Aelion et
al., 1987; Dobbins et al., 1987; Aquino et al., 1988), and
under anaerobic conditions to carbon dioxide (Bak & Widdell, 1986;
Tschech & Fuchs, 1987) or methane (Healy & Young, 1979; Ehrlich et
al., 1982; Young & Rivera, 1985; Fedorak & Hrudey, 1986; Fedorak
et al., 1986). Benzoate, catechol, cis-cis-muconate,
ß-ketoadipate, succinate and acetate have all been identified as
intermediates in the biodegradation of phenol (Paris et al., 1982;
Krug et al., 1985; Fedorak et al., 1986; Knoll & Winter, 1987).
Some of the carbon derived from the degradation of phenol may be
incorporated into the bacterial biomass (Chesney et al., 1985).
Phenol may be degraded in its free form as well as after
adsorption onto soil or sediment, although the presence of sorbent
reduces the rate of biodegradation (Shimp & Young, 1987; Knezovich
et al., 1988).
When phenol is the only carbon source, it can be degraded in a
biofilm reactor with first-order kinetics at concentrations below
about 20 µg/litre at 10 °C. The first-order rate constants are 3 to
30 times higher than those of easily degraded organic compounds at
100- to 1000-fold higher concentrations (Arvin et al., 1991).
Reported phenol degradation rates suggest rapid aerobic degradation
in sewage (typically > 90% with an 8-h retention time), soil
(typically complete biodegradation in 2-5 days), fresh water
(typically complete biodegradation in < 1 day), and sea water
(typically 50% in 9 days) (Howard, 1989). Anaerobic biodegradation
is slower (Baker & Mayfield, 1980).
The contribution of bacteria to the overall rate of degradation
may be affected by a number of factors such as phenol concentration
(Baker & Mayfield, 1980; Ursin, 1985; Hwang et al., 1989),
temperature (Baker & Mayfield, 1980; Bak & Widdell, 1986; Hwang et
al., 1986; Thornton-Manning et al, 1987; Gurujeyalashmi & Oriel,
1989), sunlight (Hwang et al., 1986), soil depth (Dobbins et
al., 1987; Federle, 1988), the presence of other nutrients
required for bacterial growth (Rubin & Alexander, 1983; Fedorak &
Hrudey, 1986; Rozich & Colvin, 1986; Thorton-Manning et al.,
1987), the presence of other pollutants (Southworth et al., 1985;
Hoffmann & Vogt, 1988; Wang et al., 1988; Namkoong et al., 1989)
and bacterial abundance (Tranvik et al., 1991).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
No data are available for background levels of phenol in air,
away from emission sources. They are expected to be low (< 1 ng
phenol/m3) (RIVM, 1986).
Higher levels of phenol in air may be expected for urban areas,
mainly due to traffic emissions. Urban phenol concentrations have
been reported for Osaka, Japan (1-4 µg phenol/m3; Kuwata et al.,
1980), Nagoya, Japan (0.2-8 µg phenol/m3 with an average of 1.7 µg
phenol/m3; Hoshika & Muto, 1979, 1980), Paris, France (0.7-8 µg
phenol/m3; Hagemann et al., 1978), and Portland, USA (0.22 to
0.42 µg phenol/m3; Leuenberger et al., 1985). Despite
differences in analytical techniques, the first three series of
measurements showed good agreement. The Portland results were lower,
but came from air samples taken during rain periods; phenol was also
detected in rain water (see section 5.1.2).
Ambient air levels of phenol have been extensively monitored in
the highly industrialized and urbanized Upper Silesia region of
Poland (Sanitary Epidemiological Station, Katowice, 1991). Levels
during 1990 ranged from 3.8 to 26.6 µg/m3, the highest values
being in the areas of greatest industrial concentration.
Hoshika & Muto (1979, 1980) reported a phenol level of
approximately 190 µg/m3 "near" a phenolic resin factory (no
details). Kuwata et al. (1980) found phenol levels of 0.8-3.5
mg/m3 in foundry emissions (no details).
Based on limited data, median ambient atmospheric levels of
phenol (based on estimated 24-h averages) were estimated by
Brodzinsky & Singh (1982) to be 0.12 µg/m3 for urban/suburban
areas (7 samples) in the USA (which is lower than reported above for
several cities), and 104 µg/m3 (2-170 µg/m3) for source-
dominated areas (83 samples) in the USA.
5.1.2 Water and sediment
Levels of phenol dissolved in rain water from Portland, USA,
were found to range from 0.08 to 1.2 µg/litre and averaged above
0.28 µg/litre; gas phase concentrations ranged from 220-410 ng/m3
(Leuenberger et al., 1985).
Concentrations reported for surface water in the Netherlands
were 2.5-6.5 µg/litre for two major rivers, 0.3-7 µg/litre for
lakes, and 1.5 µg/litre for coastal waters (the given concentrations
include other phenolic substances) (RIVM, 1986). Industrial rivers
in the USA were reported to contain 0-5 µg/litre, but 3-24 µg/litre
was reported for Lake Huron. Phenol was also detected in 2/100 raw
water supplies in 1977 in the US EPA National Organics Monitoring
Survey (Howard, 1989).
Drinking-water levels of phenol in the USA have been reported
to be around 1 µg/litre or otherwise below the detection limit
(summarized by Howard, 1989). Phenol was detected (no quantitative
data) in drinking-water in the USA from 5 out of 14 drinking-water
plants surveyed and in Great Britain in 2 out of 4 sites (Fielding
et al., 1981). Higher groundwater levels have been reported
following industrial activity (e.g. 6.5-10 000 µg/litre in two
aquifers 15 months after a coal gasification project; summarized by
Howard, 1989). Phenol was detected at a maximum concentration of
1130 mg/litre in nine wells in Wisconsin after a spill, and was
detectable for at least 1.5 years after the spill (Delfino & Dube,
1976).
Phenol was not detected in water samples from three areas in
Japan analysed for an environmental survey; however, levels of
0.03-0.04 mg/litre were detected in 3 out of 9 bottom sediment
samples from the same regions (Fujii, 1978).
Other sediment concentrations reported were 13 000 µg/kg in
samples from Lake Huron, "not detected" in an unspecified industrial
river in the USA, < 1000 µg/kg (dry weight) as the median
concentration in 9% of sediment samples from 318 data points in the
USA, and 10 µg/kg (dry weight) in samples collected 6 km from a
wastewater treatment discharge zone in California (summarized by
Howard, 1989).
Phenol was detected in 63 out of 165 sediments from sampling
areas in the Puget Sound region (Tetra Tech. Inc., 1986). Half the
samples had a concentration of phenol below 40 µg/kg sediment (dry
weight); the maximum level was 1700 µg/kg.
Levels of phenol with means of 0.01-5.7 mg/litre (maximum up to
53 mg/litre) have been reported in effluents from various industrial
sources (summarized by Howard, 1989). Highest levels were associated
with the iron and steel industry. Limited quantitative data from the
VIEW Database (ATSDR, 1989) for ground water at hazardous waste
sites indicated maximum levels of 2.48 to 85 000 µg/litre (average
33 800 µg/litre, 6 data points).
No data have been found indicating the presence of phenol in
soil. Phenol is not likely to persist in soil because of rapid
biodegradation (section 4.3) or transport to ground water or air
(section 4.1).
5.2 Occupational exposure
Occupational exposure to phenol may occur during the production
of phenol and phenol derivatives, during the production of phenolic
resins and other products derived from phenol, during processing of
the latter materials, and during a number of other activities.
5.2.1 Production
Personal air samples of workers involved in the production of
phenol by the cumene process in the ex-USSR contained on average 5.8
mg phenol/m3. For workers occupied in the production of phenol
from chlorobenzene, the mean exposure level was 1.2 mg phenol/m3
(Mogilnicka & Piotrowski, 1974). Values reported in the same
publication for workers in two phenol resin-producing industries
were 0.6-3 mg phenol/m3.
5.2.2 Application of phenolic resins
Occupational exposure during the processing of phenolic resins
appears to be partly determined by the content of free phenol in the
applied resin (Bollig & Decker, 1980; Ryser & Ulmer, 1980).
In the wood industry, indoor phenol concentrations of 0.3 mg
per m3 (Winkler, 1981) and 1.5 mg/m3 (range 0.8-2.6) (Gilli et
al., 1980) have been reported. Concentrations in the breathing
zone of wood workers were 1.3-2.6 mg phenol/m3 (Gspan et al.,
1984). In another study, concentrations of < 0.04 to 1.9 mg
phenol/m3 were found at plywood plants (Kauppinen et al., 1986).
In iron and steel foundries, average hourly phenol
concentrations of 0.4-4.5 mg/m3 were reported in the manufacture
of moulds or kernels (Schütz & Wolf, 1980). Phenol concentrations of
1-4 mg/m3 were measured in a foundry in Osaka, Japan (Kuwata et
al., 1980). Local phenol concentrations were reported to be as
high as 75-420 mg/m3 due to the thermal degradation of the resin.
However, this effect of thermal degradation was not reflected in
hourly concentrations measured during the foundry process: values of
3-16 mg phenol/m3, with an average of 10 mg phenol/m3, were
reported by Schütz & Wolf (1980), and a maximum hourly average of
2.7 mg phenol/m3 was reported by Ryser & Ulmer (1980). (It is not
known whether these results were obtained in personal or area air
samples). Phenol concentrations during the operation of an electric
furnace in a steel factory in Pueblo, Colorado, USA, were 0.04, 0.18
and 0.20 mg/m3 in the vicinity of the furnace. General room air
samples taken during operation of a grey iron foundry were below the
detection limit (Gunter, 1987).
5.2.3 Other occupational situations
Exposure levels of 5-88 mg phenol/m3 have been reported for
employees in the ex-USSR who quenched coke with waste water
containing 0.3-0.8 g/litre phenol (Petrov, 1960).
Measurements at coal gasification and liquefaction plants in
the USA showed relatively low phenol concentrations (< 0.08 mg
per m3) at various sites (Dreibelbis & Hawthorne, 1985).
In a Japanese bakelite factory, area samples contained 0-12.5
mg phenol/m3 (Ohtsuji & Ikeda, 1972).
In a synthetic fibre factory in Japan, concentrations of 19 mg
phenol/m3 were measured, whereas in a USA fibrous glass wool
factory concentrations of 0.05-1.3 mg phenol/m3 were reported
(Dement et al., 1973; Ogata et al., 1986).
The concentrations of phenol in creosote vapour, analysed in
seven creosote impregnation plants in Finland, ranged from < 0.1 to
1.8 mg/m3 air (Heikkilä et al., 1987). The highest exposures
occurred during the cleaning of creosote warming chambers.
During the dissection of cadavers by dental students, phenol
breathing zone concentrations ranged from 5 to 19 mg phenol/m3.
(The high phenol concentrations resulted from the applied embalming
solution, in combination with inadequate ventilation) (Boiano,
1985).
5.3 General population exposure
5.3.1 Indoor air
Borovik & Dmitriev (1981) found a maximal concentration of 0.02
µg phenol/m3 in hospitals in the ex-USSR. It is, however, not
clear from where the phenol originated; it may have been used as a
disinfectant in these hospitals.
No information has been found with regard to phenol
concentrations in residential houses and apartments. Cigarette
smoking must be considered as the most important potential source in
dwellings. A distinction should be made between the main stream (the
smoke inhaled by the smoker) and the side stream (produced by the
smouldering cigarette itself). It was estimated that 0.01-0.22 mg
phenol per cigarette was released in the mainstream, while the
sidestream phenol content was 2.6 times higher. In the case of
various Japanese cigarettes, 0.3-0.4 mg phenol was emitted into air
during burning (Kuwata et al., 1980). For an unventilated room of
50 m3, the smoking of one cigarette would thus result in a phenol
concentration of 6-8 µg/m3.
5.3.2 Food and drinking-water
Phenol is found in smoked meat and fish products. The wood
smoke with which such products are treated contains, among other
ingredients, a wide range of phenols and phenol ethers, which
contribute significantly to the characteristic smoke aroma (smell
and taste) of the product.
Phenol is absorbed into the food products during smoking.
Quantitative data, however, are scarce, since phenols are usually
determined as a group. According to Toth (1982), the total phenol
content of smoked sausage is 70 mg/kg; Bratzler et al. (1969)
found a content of 37 mg/kg in the outer layer of the product, and
lower contents in the inner part. Luten et al. (1979) determined a
number of individual phenols in smoked herring and found a phenol
content, depending on the duration of smoking, of approximately
10-30 mg/kg. Potthast (1976, 1982) measured 2-18 mg/kg in smoked ham
and liver sausage.
If liquid smoke derivates are used in order to give a smoky
flavour to fish and meat products, the end product also contains
phenol. However, with regard to smell and taste aspects, phenol is
not the most important phenolic compound from wood smoke. In this
respect, methoxy and dimethoxy phenols are more important, together
with aliphatic fatty acids and carboxyl compounds.
Phenol may also enter food unintentionally by, for instance,
contamination in transport or from packaging materials, or contact
with other phenol-containing materials. However, these accidental
cases would probably be detected and lead to non-acceptance by the
consumer, owing to the conspicuous phenol smell and taste (see
section 8.3 for odour and taste thresholds).
Phenol has been found in botton pits fish from 5 sites in
Commencement Bay in Tacoma, USA, at a maximum average of 0.14 mg/kg
and an overall maximum of 0.22 mg/kg (Nicola et al., 1987).
Little information is available with respect to the occurrence
of phenol in drinking-water. Surface and ground waters intended for
the production of drinking-water in the Netherlands were reported to
contain 1-9 µg phenol/litre (phenol index, including other phenolic
compounds) (RIVM, 1986). Phenol was found in a domestic water supply
in the USA at a level of 1 µg/litre (Ramanathan, 1984). Cases of
drinking-water pollution with phenol have been reported in the UK
and the USA; the phenol water concentrations were reported to be
5-10 µg and 5-120 mg per litre, respectively (see section 8.1.2.2).
Chlorination of drinking-water may result in the formation of
chlorophenols from phenol, which greatly adds to the objectionable
smell and taste (Jarvis et al., 1985).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
Phenol and conjugated metabolites of phenol occur naturally in
animal and human tissue and can be detected in the urine, faeces,
saliva and sweat. The body's production of phenol depends on the
type of diet: a high protein or meat diet promotes phenol formation.
6.1 Absorption
Phenol is readily absorbed through all routes, such as the
lungs, intact and abraded skin, and the gastrointestinal tract of
both humans and animals (Von Oettingen, 1949; Deichmann & Keplinger,
1963).
6.1.1 Animal uptake studies
6.1.1.1 Pulmonary
There are no in vivo data on absorption of phenol following
inhalation exposure. However, in vitro studies by Hogg et al.
(1981), using 14C-phenol with excised trachea-lung preparations
and isolated perfused rat lung, demonstrated that phenol can be
rapidly and efficiently absorbed in the lungs.
6.1.1.2 Dermal
The extent of absorption of phenol through rabbit skin is more
strongly influenced by the area of the skin exposed than by the
concentration of the applied solution in water (Deichmann &
Witherup, 1944; Liao & Oehme, 1980).
In studies with the hairless mouse, phenol destroyed the
stratum corneum (Behl et al., 1983a). Similar effects were
reported by Huq et al. (1986) and Jetzer et al. (1986).
Absorption of phenol through thermally damaged mouse skin in vitro
was also reported to be greatly enhanced (Behl et al., 1983b). In
contrast, Deichmann et al. (1952) observed that injury of the
rabbit skin caused by phenol appeared to retard the rate of
absorption.
The permeability of mouse skin to phenol from aqueous solution
in vitro increased with increasing temperature of the carrier
solution (from 10 to 37 °C) (Jetzer et al., 1988).
Measurement of the permeation constant of phenol through
hairless mouse skin at 37 °C in vitro yielded a value of 18 800 ±
3000 cm/h (Huq et al., 1986; Jetzer et al., 1986).
6.1.1.3 Intestinal
When a single oral dose of 25 mg/kg body weight was
administered to rats, pigs or sheep, more than 95% was absorbed (Kao
et al., 1979).
In vitro studies showed that aqueous solutions of phenol
placed into ligated sections of the gastrointestinal tract had the
fastest absorption rate in the colon, followed by the ileum. The
absorption rate in the stomach was much slower (Deichmann &
Keplinger, 1963).
6.1.2 Human uptake studies
6.1.2.1 Pulmonary
The retention of phenol in the bodies of eight human volunteers
exposed to 6-20 mg/m3 by inhalation only for 8 h was 70%-80%
during the course of the study (Piotrowski, 1971). Ohtsuji & Ikeda
(1972) reported similar observations.
6.1.2.2 Dermal
Human skin absorption of phenol vapour (5-25 mg/m3) occurs
rapidly (Ruedemann & Deichmann, 1953). Fatal cases reflect the rapid
rate of absorption of phenol through the skin (Turtle & Dolan, 1922;
Duverneuil & Ravier, 1962; Hinkel & Kintzel, 1968; Lewin & Cleary,
1982). The retention in eight human volunteers, exposed to phenol
vapour at concentrations of 6-20 mg/m3, by skin only, for 6 h was
70-80% (Piotrowski, 1971). Piotrowski (1971) proposed the following
formula for calculating the absorption rate of phenol vapour through
the skin:
A = (0.35)C
where A is the amount of phenol absorbed in mg/h per unit area
and C is the phenol air concentration in mg/m3.
Concentrations of between 5 and 10% phenol denature epidermal
protein, and this can partly prevent absorption. The phenol-protein
complex is not stable and by dissociation of phenol the substance
may exert its action over a period of time (Schmidt & Maibach,
1981).
Phenol was detected in the urine of 4 out of 16 infants (2-5
months) with seborrhoeic eczema who were skin-painted twice daily
for 48 h with a commercial paint containing 4% (w/v) phenol and 8%
(w/v) resorcinol (Rogers et al., 1978). In adults, a single
topical application of 4 µg phenol/cm2 on 13 cm2 of the ventral
forearm, reportedly gave an absorption of 4.4% of the administered
dose (Feldman & Maibach, 1970). The period of exposure and the
concentration of phenol are both factors that determine the extent
of absorption (Piotrowski, 1971; Roberts et al., 1977;
Baranowska-Dutkiewicz, 1981).
In vitro studies have also shown that phenol from aqueous
solutions (1% w/v) readily penetrates human skin (Roberts et al.,
1977, 1978). A value of 8200 cm/h was obtained as the permeation
constant of phenol through human skin at 25 °C (Flynn & Yalkowsky,
1972). In an in vitro study with human abdominal skin, 10.9% of
the applied dose was absorbed. This study showed an excellent
qualitative, but a somewhat less accurate quantitative, agreement
between the in vivo and in vitro skin absorption of 12 compounds
(Franz, 1975).
6.2 Distribution
Phenol is rapidly distributed to all tissues in exposed
animals.
In rabbits, 15 min after oral administration of 0.5 g
phenol/kg, chemical analysis indicated that the liver contained the
highest concentration of total phenol followed by the central
nervous system, lungs and blood. After 82 min, phenol was fairly
uniformly distributed over all tissues. The proportion of free to
conjugated phenol changed with time, and, after 360 min, most of the
phenol was conjugated (Deichmann, 1944).
After a single oral administration of 14C-phenol (207 mg/kg)
to rats, the highest concentration ratios between tissue and plasma
were found in liver (42%), followed by spleen, kidney, adrenal,
thyroid and lungs, with a peak tissue level occurring after 0.5 h
(Liao, 1980; Liao & Oehme, 1981a).
Highest tissue residues were found after 2 h in the kidneys and
livers of mice and rats treated intravenously (Gbodi & Oehme, 1978;
Wheldrake et al., 1978; Greenlee et al., 1981).
6.3 Metabolic transformation
6.3.1 Metabolite identification
Studies employing several species have demonstrated that
conjugation with glucuronic acid and sulfate are major metabolic
pathways for phenol. Hydroxylation to hydroquinone and catechol also
occurs (Williams, 1938, 1959; Garton & Williams, 1949; Bray et
al., 1952a,b,c; Parke & Williams, 1953).
In vitro studies have shown the formation of 4, 4'-biphenol
and diphenoquinone by neutrophils, activated leucocytes and by
horseradish peroxidase following addition of phenol (Eastmond et
al., 1986).
Phenol metabolism in rabbits was studied by Deichmann &
Keplinger (1963). During the first 24 h following oral
administration of a sublethal dose of 300 mg phenol/kg body weight,
23% of the administered dose was recovered as exhaled carbon
dioxide. Trace amounts of catechol and hydroquinone were also
detected in the breath. Over the same period, 72% of the dose was
excreted in the urine (48% of which was excreted as free and 52% as
conjugated phenols), 1% was excreted in the faeces, 4% remained in
the carcass, and trace amounts were exhaled.
Oral administration of 14C-phenol (1.2 mg/kg) to rats
resulted in at least 80% excretion in urine within 24 h, with 68% as
phenyl sulfate and 12% as phenyl glucuronate (Edwards et al.,
1986).
A pronounced shift from sulfation to glucuronidation was
observed in rats after increasing the phenol dose (Koster et al.,
1981). This observed shift is apparently due to a saturation of the
overall sulfation process, rather than to a depletion of inorganic
sulfate (Weitering et al., 1979; Koster et al., 1981; Koster,
1982). A limited availability of 3-phosphoadenosine-5-phosphosulfate
may account for the decreased proportion of phenol conjugation to
sulphate at relatively high doses (Ramli & Wheldrake, 1981).
Repeated administration of phenol, however, did not affect
glucuronide synthesis in rats (Takemori & Glowacki, 1962).
The pig has limited ability for phenol sulfation. The domestic
cat lacks the ability for glucuronic acid conjugation of phenol. In
cats, phenyl phosphate has been detected as a metabolite in small
amounts, in addition to sulfate conjugates (Capel et al., 1974;
French et al., 1974).
Following oral administration of 14C-phenol (0.01 mg/kg) to
three men, 90% of the dose was excreted in the urine within 24 h,
mainly as phenyl sulfate (77%) and phenyl glucuronide. Small amounts
of guinol sulfate and guinol glucuronide were also present (Capel
et al., 1972b).
Several investigators have confirmed the above-mentioned
results using in vitro methods (DeMeio & Arnolt, 1944; Capel et
al., 1972b; Shirkey et al., 1979; Hogg et al., 1981; Koster
et al., 1981; Sawahata & Neal, 1983).
6.3.2 Covalent binding to macromolecules
Early pharmacokinetic studies (measuring distribution volumes)
in dogs, pigs and goats suggested that tissue binding occurs (Oehme,
1969). Further animal studies have indicated that phenol and/or its
metabolites bind covalently to tissue protein, mainly in the liver
(Bolt, 1977; Illing & House, 1980; Jergil et al., 1982; Smart &
Zannoni, 1984). Binding to rabbit bone marrow mitochondrial DNA in
studies with isolated cells has also been reported (Rushmore et
al., 1984). in vivo and in vitro studies have demonstrated
covalent binding of radiolabelled phenol to plasma proteins from
humans, dogs, rats and trout (Liao, 1980; Liao & Oehme, 1981a,b;
Judis, 1982; Schmieder & Henry, 1988). Reactive phenol metabolites
formed by peroxidases bind readily to proteins (Eastmond et al.,
1986, 1987a) and DNA (Subrahmanyam & O'Brien, 1985).
6.3.3 Location
Quantitatively, the most important sites of phenol conjugation
are the liver, lung and gastrointestinal mucosa. The relative roles
played by these tissues depend on the route of administration and
the dose.
The liver is an important site of phenol metabolism. After
direct administration of phenol into the hepatic circulation, the
liver showed considerable first-pass metabolism in rats (Cassidy &
Houston, 1980; Houston & Cassidy, 1982). Phenol-metabolizing enzymes
have been detected in rabbit hepatic microsomes (Koop et al.,
1989).
Other tissues, such as lungs, intestines and kidneys, also play
an important role in phenol metabolism (Quebbemann & Anders, 1973;
Powell et al., 1974; Houston & Cassidy, 1982). Phenol
sulfotransferases, which catalyse phenol sulfation, occur in a
variety of human tissues (intestinal wall, lungs, platelets, adrenal
glands, brain, placenta, etc.) (Campbell et al., 1987; Gibb et
al., 1987). After oral uptake of phenol, there is a very large
first-pass metabolism in the intestines. The lungs also show
considerable first-pass metabolism (as was established after direct
administration into the pulmonary circulation of rats) (Cassidy &
Houston, 1980; Houston & Cassidy, 1982). Due to saturation of
hepatic enzymes, extrahepatic tissues play an increasing role in the
conjugation of phenol as the dose of phenol increases; at doses
higher than 5 mg/kg body weight, intestinal conjugation in rats
exceeds the contribution of the hepatic and pulmonary enzymes
(Cassidy & Houston, 1984).
Myeloperoxidases isolated from human neutrophils and
peroxidative enzymes from activated human leucocytes mediate the
formation of reactive phenol metabolites including 4,4'-biphenol and
diphenoquinone. Myeloperoxidase-mediated hydroxylation occurs in
addition to hepatic cytochrome P-450 oxidation. In several species,
myeloperoxidase activity has been reported in bone marrow, where it
may play a role in phenol metabolism and toxicity (Eastmond et
al., 1986, 1987a; Subrahmanyam et al., 1991).
6.4 Elimination and excretion
Urinary excretion is the major route of phenol elimination in
animals and humans. The rate of excretion varies with dose, route of
administration and animal species (Deichmann, 1944; Capel et al.,
1972a,b). Of 18 animal species studied by Capel et al. (1972a,b),
the 24-h urinary excretion of phenol was greatest in the rat (95% of
the 25 mg/kg body weight oral dose) and the lowest in the squirrel
monkey (only 31% of the dose). Liao & Oehme (1981a,b) reported a
half-life of 4 h in rats.
Five days after oral gavage with 14C-phenol (0.1 mg/kg body
weight), only 0.3% of the applied dose was retained in rats (Freitag
et al., 1985).
Only minor amounts of unchanged phenol are excreted in exhaled
air or in faeces (Deichmann & Keplinger, 1963). Less than 1% of an
orally administered dose of 300 mg phenol/kg body weight to rabbits
was found in the faeces after 24 h (Deichmann, 1944).
Phenol conjugates may also be excreted in the bile of rats
(4.6% of a 50 mg/kg dose) (Abou-el-Makarem et al., 1967). It has
been suggested that biliary excretion of phenol plays an important
role when urinary excretion is impeded. Rats, whose kidneys were
ligated, showed a marked increase in biliary excretion of phenol
metabolites (Weitering et al., 1979). Furthermore, it has been
reported that phenol and its metabolites can undergo enterohepatic
circulation in rats (Gbodi & Oehme, 1978).
Urinary excretion of phenol in human volunteers exposed to
phenol vapour via inhalation (chamber studies) or skin, occurred
with an excretion rate constant of k = 0.2/h. For a one-compartment
model, this corresponds to a half-life of approximately 3.5 h
(Piotrowski, 1971).
6.5 Biological monitoring
The US ACGIH has listed a biological exposure index for phenol
of 250 mg/g creatinine for end-of-shift urine samples (ACGIH, 1991).
The excretion of phenol and phenol conjugates in the urine may
be used as an index of exposure, but it should be noted that there
are other causes that may lead to phenol excretion in the urine. One
of these is benzene exposure; other possible significant sources are
food and drugs (Docter & Zielhuis, 1967; Ikeda & Ohtsuji, 1969;
Fishbeck et al., 1975; Paradowski et al., 1981). Elevated
urinary phenol excretion is thus not a specific index of exposure to
phenol. Furthermore, the large range of "normal" urine values
(phenol concentrations have been found to vary from 0.5 to 81.5
mg/litre) (Deichmann & Schafer, 1942; Docter & Zielhuis, 1967;
Piotrowski, 1971; Gspan et al., 1984; Pekari et al., 1992) would
appear to limit the usefulness of urinary phenol excretion as an
accurate index of low occupational exposure levels.
In volunteers, after a single 8-h exposure to phenol vapour
concentrations of up to 6.8 mg/m3, the phenol excretion in urine
increased up to a maximum of 100 mg total phenol/litre (Piotrowski,
1971). In workers occupationally exposed to 10 mg phenol/m3,
concentrations in urine of up to 262 mg/litre were reported
(Ohtsuji & Ikeda, 1972). However, another recent study, using more
specific methods of analysis, showed good correlation (R=0.91) between
exposure levels in the range 5-17 mg/m3 and the total concentration
of phenyl sulfate and phenyl glucuronide in the urine at the end of the
workshift (Ogata et al., 1986).
7. EFFECTS ON LABORATORY MAMMALS, AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 LD50 values
After oral administration of phenol to mice, rats and rabbits,
LD50 values ranged from 300-600 mg phenol/kg body weight. No
LC50 values have been reported in the published literature.
However, after inhalation of 900 mg phenol/m3 by rats for 8 h, no
deaths were observed. The dermal LD50 (by occlusive and
non-occlusive techniques) was 670 mg/kg body weight for rats and
850-1400 mg phenol/kg body weight for rabbits. LD50 values for
intraperitoneal injection were in the range of 127-223 mg phenol/kg
body weight for rats.
A summary of LD50 values is given in Table 5.
7.1.2 Effects
The acute lethality of phenol, associated with exposure to high
concentrations, is generally attributed to a depressing effect on
the central nervous system (see also section 7.8.1). The clinical
effects of phenol poisoning are independent of the route of
administration. Reported symptoms include neuromuscular
hyperexcitability, including twitching and severe convulsions. Heart
rate at first increases, then becomes slow and irregular. Blood
pressure at first increases slightly, then falls markedly.
Salivation, marked dyspnoea and a decrease in body temperature are
also among the effects reported (Deichmann & Witherup, 1944; Von
Oettingen & Sharples, 1946; Farquharson et al., 1958; Ernst et
al., 1961; Deichmann & Keplinger, 1963; Oehme & Davis, 1970;
Pullin et al., 1978; Liao & Oehme, 1980; Reid et al., 1982).
After oral ingestion, the mucous membranes of the throat and
oesophagus showed swelling, corrosion, and necrosis, with
haemorrhages (Deichmann & Keplinger,1963).
In a study by Schlicht et al. (1992), female Fischer-344 rats
were administered 0, 12, 40, 120 or 224 mg phenol/kg body weight by
gavage in a water vehicle. Animals were examined for clinical signs,
and neurotoxicity and systemic (liver, kidney, adrenal and thymus)
effects, 4-20 h after treatment. Tremors were observed 1-2 min after
dosing in the two highest dose groups. The pupil response to light
(miosis) was significantly inhibited at all dose levels at 24 h
after exposure. Locomotor activity was reduced at 224 mg/kg. At this
dose level, 2/6 animals had hepatocyte necrosis, 4/6 had renal
vascular stasis and 4/6 had necrosis of the thymus. At 120 mg/kg,
liver necrosis was present in 1/7 animals, as was necrosis of the
thymus gland.
Table 5. Acute animal toxicity of phenol LD50 values
Species Route of LD50 values Vehicle Reference
administration (mg/kg body
weight)
Mouse oral 300 Von Oettingen &
Sharples (1946)
Mouse oral 427 Kostovetskii &
Zholdakova (1971)
Rat oral 340-530 2-7% in
water Deichmann &
Witherup (1944)
Rat oral 512 Kostovetskii &
Zholdakova (1971)
Rat oral 445-520 water Thompson & Gibson
(1984)
Rat oral 400 water Schlicht et al.
(1992)
Rat dermal 670 undiluted Conning & Hayes
(570-780) (1970); Brown et al.
(1975)
Rat intraperitoneal 127-223 water or Thompson & Gibson
undiluted
(1984)
Rabbit oral 400-600 2-7% in Deichmann &
water Witherup (1944)
Rabbit dermal 850 Flickinger (1976)
(600-1200)
Rabbit dermal 1400 Vernot et al. (1977)
(740-2670)
In various animal species, inhalation of phenol adversely
affected the lungs, causing hyperaemia, infarcts, bronchopneumonia,
purulent bronchitis and hyperplasia of the peribronchial tissues
(Von Oettingen, 1949).
Sensory irritation was measured in mice by the Alarie assay. A
50% decrease in respiratory rate (RD50) was found at 638 mg
phenol/m3 (De Ceaurriz et al., 1981).
Ocular and nasal irritation, tremors and incoordination were
reported in rats exposed via inhalation to 906 mg/m3 for 8 h
(Flickinger, 1976).
Other pathological abnormalities induced by phenol by various
routes of administration included demyelination of nerve fibres (see
also section 7.8.1), myocardial degeneration and necrosis (Deichmann
& Keplinger, 1963; Liao & Oehme, 1980). Kidney damage (vacuolization
and enlargement of cells) and liver damage (e.g., enlargement of
hepatic cells) were also observed (Oehme & Davis, 1970; Coan et
al., 1982). Urine was usually dark or "smoky" in appearance,
probably due to oxidation products of phenol (Solliman, 1957).
7.2 Short-term exposure
7.2.1 Oral exposure
In a study by Schlicht et al. (1992), groups of eight female
Fischer-344 rats received oral doses of phenol in a water vehicle of
0, 4, 12, 40 or 120 mg/kg body weight daily for 14 days. Tremors
were apparent only after the first dose at the highest level.
Exposure to 120 mg/kg per day was lethal to all rats within 11 days.
The pupil response (miosis) was decreased one day after the last
dose for all but the highest surviving dose group (the incidences
were 100%, 50%, 62% and 76% for the 0, 4, 12 and 40 mg/kg groups,
respectively). Locomotor activity was not affected after the 4th,
9th or 14th dose. No hepatic effects were observed at 40 mg/kg per
day, while 3/8 animals had renal vascular stasis. There were no
histological effects at 12 mg/kg per day. At 40 mg/kg per day, the
pathological changes in the kidneys included two animals with
tubular degeneration in the papillar region, and one with protein
casts in the tubules. The pathological report attributed these
findings to decreased vascular perfusion (MacPhail, personal
communication to the IPCS).
Rats were administered, by gavage, 20 daily doses of 10, 50 or
100 mg phenol/kg body weight. At necropsy, slight effects on liver
and kidneys were reported at 100 mg phenol/kg body weight (Dow
Chemical Company, 1976).
Rats receiving 50 or 100 mg phenol/kg body weight, by gavage,
over a 6-month period (135 doses, presumably daily, 5 days/week)
were reported to show slight to moderate kidney damage.
Administration of 100 mg phenol/kg body weight apparently resulted
in slight liver changes (Dow Chemical Company, 1976).
In a range-finding study, carried out prior to a long-term
carcinogenicity study, mice and rats were provided with tap water
containing 0, 100, 300, 1000, 3000 or 10 000 mg phenol/litre for 13
weeks. Mean body weight gain was decreased only in mice and rats
receiving 10 000 mg phenol/litre (NCI, 1980). In these
drinking-water studies, the highest daily doses were calculated to
be approximately 2000 mg phenol/kg body weight for mice and 1000 mg
phenol/kg body weight for rats.
Phenol was provided to rats in drinking-water for 12 months at
0, 800, 1200, 1600, 2000 and 2400 mg phenol/litre. Depressed weight
gain was observed in rats receiving doses > 2000 mg/litre. The
corresponding daily dose was calculated by the authors of the study
to be > 200 mg/kg body weight (Deichmann & Oesper, 1940).
7.2.2 Dermal exposure
In a study by Deichmann et al. (1950), rabbits were exposed
to 1.18-7.12% phenol in water (64-380 mg phenol/kg body weight) for
5 h/day, 5 days/week, for 18 days. Dose-related systemic effects
(tremors, death) were observed in rabbits exposed to > 2.37%
phenol (130 mg phenol/kg body weight), while skin irritation
(hyperaemia, tissue necrosis) occurred at doses of > 3.56% phenol
(190 mg phenol/kg body weight). This effect was particularly
apparent when the application sites were bandaged.
7.2.3 Inhalation exposure
No studies reported or conducted according to contemporary
standards were available.
In a study by Deichmann et al. (1944), rats, rabbits and
guinea-pigs were exposed to concentrations of 100-200 mg phenol
vapour/m3, 7 h/day, for 5 days/week. Rats exposed for a period of
74 days did not show any gross or microscopic evidence of injury.
Rabbits survived a 3-month exposure but, at autopsy, lung and heart
damage and indications of liver and kidney damage were found.
Guinea-pigs were the most susceptible. Five out of twelve died after
12 days of exposure, and the remaining seven were killed after 29
days of exposure. Prior to death, guinea-pigs showed weight loss,
respiratory difficulties, and signs of paralysis. At autopsy, there
was evidence of acute lobular pneumonia, vascular damage, and
hepatic and renal damage; the total (free and conjugated) phenol
content of the blood was 14 mg/litre. The rabbits had similar, but
less severe, symptoms.
Groups of 10 monkeys, 50 rats and 100 mice were exposed to 19
mg phenol/m3, 8 h/day, 5 days/week for 90 days. Concurrent control
groups were exposed to fresh air only. No deaths occurred and there
was no reduction in weight gain of treated animals. There were no
statistically significant adverse effects observed when the animals
were assessed by a stress test involving swimming performance. A
range of clinical chemistry, haematology and urinalysis parameters
were not affected by exposure to phenol. Routine histology was
performed on the liver, lungs, kidneys, brain and heart. The results
of the percentage of animals showing evidence of "pathological
change" indicated effects in the liver and kidneys of exposed
animals. However, the author of the study concluded that no clinical
or pathological changes occurred that were of toxicological
importance. It is not clear if the upper respiratory tract was
examined in this study in order to look for evidence of irritation
(Sandage, 1961).
Continuous exposure to 100 mg phenol/m3 for 15 days
significantly affected the central nervous system of rats, as was
demonstrated by their performance in the "tilted plane" test. Plasma
levels of potassium, magnesium, lactate dehydrogenase, aspartate
aminotransferase (ASAT), alanine aminotransferase (ALAT) and
glutamate dehydrogenase were elevated. Haemoglobin, haematocrit, and
plasma sodium, calcium and chloride levels were unaffected (Dalin &
Kristofferson, 1974).
7.2.4 Subcutaneous exposure
Subcutaneous exposure to phenol was studied principally to
obtain information about neurological or haematopoietic effects (see
sections 7.8.1 and 7.8.2). No other effects were reported.
7.2.5 Ear exposure
Instillation of phenol (form and amount not specified) into the
inner ear round window of Sprague-Dawley rats caused morphological
damage to the organ of Corti in the basal coil. The outer hair cells
appeared to be more sensitive to phenol than the inner hair cells,
which were mostly intact. As a result of the damage, impairment of
inner ear function was noted (as determined by auditory brain stem
recordings) which was regressive for lower sound frequencies, but
appeared to be permanent for higher frequencies (Anniko et al.,
1988).
7.3 Skin and eye irritation; sensitization
Local damage to the skin, following exposure to phenol, was
found to include erythema, inflammation, discoloration, eczema,
papillomas and necrosis (Deichmann, 1949; Deichmann et al., 1950;
Conning & Hayes, 1970; Pullin et al., 1978). For example, in
rabbits, 0.5 g phenol, moistened with physiological saline, produced
necrosis of both the intact and abraded skin (Flickinger, 1976).
Solutions of 10-14% (v/v) phenol in water have been reported to
cause transient delayed erythema (after 0.5-5 h) and acute vascular
permeability, as assessed by exudation of intravenously injected
Evans blue, in guinea-pigs after dermal treatment for 1 min (Steele
& Wilhelm, 1966).
In one study, an increase in ear thickness was used as an index
of skin irritation (inflammation). Maximal responses to phenol were
observed one hour after application of 1-2 mg phenol to the ear of
female ICR mice. Significant thickening could still be detected 6
weeks after exposure (Patrick et al., 1985).
When phenol, in glycerine dilutions down to 10% or 5% aqueous
solutions, was applied to the rabbit eye, severe damage (complete
destruction to opaque corneas) was seen. Immediate water irrigation
was very effective in preventing the opacity. A delay of 10 seconds
reduced this effectiveness (Murphy et al., 1982).
Fourteen days after the application of 0.1 g phenol to the
rabbit eye, all eyes exhibited keratoconus and pannus formation
(Flickinger, 1976).
Phenol gave negative results in a Magnussen and Kligman skin
sensitization test (Itoh, 1982).
7.4 Long-term exposure
No adequate data are available. Studies on carcinogenicity are
presented in section 7.7.
7.5 Reproduction, embryotoxicity and teratogenicity
7.5.1 Reproductive toxicity
No adequate studies conducted according to current protocols
are available.
Heller & Pursell (1938) exposed rats to 100-12 000 mg
phenol/litre drinking-water, corresponding to calculated approximate
daily oral doses of 10-1200 mg phenol/kg body weight. General
appearance, growth and fecundity were normal for rats exposed to
100-1000 mg/litre for five generations and to 3000 or 5000 mg/litre
for three generations. Stunted growth was noted in the offspring of
rats exposed to 7000 mg/litre. Many of the offspring died at levels
of 8000 mg/litre because of maternal neglect. At 10 000 mg/litre,
the offspring died at birth, and at 12 000 mg/litre there was no
reproduction.
7.5.2 Embryotoxicity/teratogenicity
7.5.2.1 In vivo studies
Phenol was evaluated for maternal and developmental toxicity in
timed-pregnant Sprague-Dawley rats (20-22 confirmed pregnancies per
group). Distilled water (vehicle) or phenol (30, 60 or 120 mg/kg per
day) was administered daily by gavage in a volume of 5 ml/kg of body
weight throughout the period of major organogenesis (gestational
days 6-15). Dams were weighed on the day of sperm detection
(gestational day 0), prior to daily dosing, and at termination
(gestational day 20); observations for clinical signs of toxicity
were conducted during the treatment period. At termination
(gestational day 20), maternal liver weight, gravid uterine weight
and status of uterine implantation sites (i.e. number of implants,
resorptions, late fetal deaths and live fetuses) for each dam were
recorded. Each live fetus was weighed, sexed and examined for
external morphological abnormalities. Visceral examination of each
fetus was performed using a fresh tissue dissection method;
approximately one-half of the fetal heads from each litter were
fixed (Bouins' solution) and sectioned free-hand for examination of
internal structures; carcasses (one-half without heads) were cleared
and stained with Alizarin Red S prior to skeletal examination. All
control and phenol-treated dams survived to scheduled sacrifice, and
no distinctive treatment-related signs of toxicity were noted.
Pregnancy rates at termination were high (95-100% per group) and no
litters were totally resorbed, so that a total of 20-22 live litters
per group (268-293 fetus per group) was available for examination.
No significant dose-related changes were noted for the following
end-points: maternal body weight (gestational day 0, 6, 11, 15 or
20), maternal body weight gain (treatment period, gestational period
or gestational period corrected for gravid uterine weight), maternal
liver weight, gravid uterine weight, prenatal mortality, live litter
size or incidence of morphological abnormalities (malformations or
variations). However, average fetal body weight per litter was
significantly reduced at the high-dose (93% of average control
weight) (Jones-Price et al., 1983a).
In a study by Kavlock (1990), phenol was administered by oral
gavage to groups of Sprague-Dawley rats on day 11 of gestation (day
1 : sperm plug) at 0, 100, 333, 667 and 1000 mg phenol/kg body
weight. The vehicle used in this study was a 4:4:1:1 mixture of
water, Tween 20, propylene glycol and ethanol. Maternal toxicity
(decreased weight gain) was seen at the two highest doses. Offspring
viability and growth were not affected up to postnatal day 6,but
hind limb paralysis was observed in some offspring in the two
highest dose groups.
In a screening assay, groups of 17-21 Fischer-344 rats received
0, 40 or 53.3 mg phenol/kg body weight by gavage in water on
gestation days 6-15. There were no significant effects on maternal
body weight gain. One of 15 pregnant females resorbed the entire
litter at 40 mg/kg and 2 of 16 did so at 53.3 mg/kg (there were no
similar effects in 153 control litters in the study). All three
females had severe respiratory syndromes (rales and dyspnoea). One
high-dose female with symptoms of respiratory toxicity delivered a
low weight litter that had poor viability. Kinked tails were present
in 2 of 4 surviving pups in that litter. Litter size on postnatal
days 1 and 6 was significantly reduced at 53.3 mg/kg but not at 40
mg/kg. There were no effects on pup body weights on postnatal days 1
or 6 (Narotsky & Kavlock, 1993).
Phenol was evaluated for maternal and developmental toxicity in
timed-pregnant Swiss albino (CD-1) mice (22-29 confirmed pregnancies
per group). Distilled water (vehicle) or phenol (70, 140 or 280
mg/kg per day) was administered daily by gavage in a volume of 10
ml/kg of body weight throughout the period of major organogenesis
(gestational days 6-15). Dams were weighed on the day of vaginal
plug detection (gestational day 0), prior to daily dosing
(gestational days 6-15), and at termination (gestational day 17);
observations for clinical signs of toxicity were conducted during
the treatment period. Evaluation of maternal and developmental
end-points at termination (gestational day 17) were the same as for
rats (see description from the study by Jones-Price et al., 1983a,
above). Toxicity observed at the high-dose level included 11%
mortality (4/36 treated females), clinical signs (especially tremor
and ataxia), reduced maternal body weight (gestational day 17),
reduced maternal body weight gain (treatment period, gestational
period and gestational period corrected for gravid uterine weight),
and a trend only toward reduced maternal liver weight. Pregnancy
rates at termination ranged from 71 to 84%; no litters were totally
resorbed so that 22-29 live litters (214-308 fetuses) were available
for examination. No dose-related changes were noted for prenatal
mortality, live litter size or incidence of morphological
abnormalities, except for an apparent increase in cleft palate
(8/214 fetuses in the high dose versus 0/308 among controls). (It
should be noted that cleft palate is a malformation to which the
CD-1 mouse is predisposed under conditions of maternal stress).
Average fetal body weight per litter was significantly reduced (82%
of average control weight) in the highest dose group (Jones-Price
et al., 1983b).
In a study by Minor & Becker (1971), groups of Sprague-Dawley
rats were given 20, 63, or 200 mg phenol/kg body weight
intraperitoneally on days 9-11 or 12-14 of gestation. Fetal body
weight was reduced in the highest dose group treated on days 12-14.
No gross anomalies were observed, and intrauterine death was not
increased at any dose level.
7.5.2.2 In vitro studies
In the chick embryotoxicity screening test (CHEST), 130
substances were tested. For each compound, 120 selected White
Leghorn Fowl embryos, aged 1.5, 2, 3 and 4 days of incubation, were
used. Phenol did not exhibit embryotoxic properties in this test up
to 100 µg, and was one of the least embryotoxic compounds tested
(Jelinek et al., 1985).
In a study by Oglesby et al. (1992), phenol was added to
cultures of five rat embryos on gestational day 10 at
concen-trations of 0 to 100 µg/ml. Embryos were examined 42 h later
for viability, growth and morphology. Viability was not affected at
any concentration, but a low incidence of tail defects was observed
at 100 µg/ml, and embryonic growth was decreased at 75 and 100
µg/ml. When hepatocytes isolated from pregnant rats were co-cultured
with the embryos, the toxicity to the embryos was increased. Tail
defects were observed at 25 and 50 µg/ml, and growth was reduced at
these concentrations. Without the presence of hepatocytes, phenol
was the least toxic of 13 para-substituted phenols tested in this
system; however, it was the only one which became more embryotoxic
when hepatocytes were present.
When phenol was added to cultures of human embryonic palatal
mesenchyme cells, cell growth was 50% inhibited at a concentration
(IC50) of 0.8 mM (78 µg/litre) (Pratt & Willis, 1985).
7.6 Mutagenicity and related end-points
Data on mutagenicity and related end-points are summarized in
Tables 6, 7, 8 and 9, respectively.
7.6.1 Mutagenicity studies
7.6.1.1 Bacterial systems
Phenol has been tested for mutagenicity by a number of authors
in various strains of Salmonella typhimurium and was shown to be
reproducibly negative, both with and without metabolic activation
(Epler et al., 1979; Gilbert et al., 1980; Rapson et al.,
1980; Pool & Lin, 1982; Haworth et al., 1983). A positive effect
was observed in strain TA98 in the presence of an exogenous
metabolic activation system in a study employing a modified culture
medium (Wild et al., 1980; Gocke et al., 1981).
A positive effect was reported for phenol in a fluctuation test
with strain TA100 after metabolic activation, but no data were given
on toxicity (Koike et al., 1988; abstract). A positive result was
reported in a mutation test with Escherichia coli B/Sd-4; however,
the applied dose levels were highly toxic (Demerec et al., 1951).
7.6.1.2 Non-mammalian eukaryotic systems
Negative data were obtained in the absence of exogenous
metabolic activation with the eukaryotic microorganism
Saccharomyces cerevisiae. At high doses and in the presence of an
activation system, a positive result was obtained (Cotruvo et al.,
1977). Phenol induced mitotic segregation in Aspergillus nidulans
(Crebelli et al., 1987).
Table 6. Tests for genotoxicity in bacteria
Species Strain Measured end-point Test conditions Metabolic Resultsb Reference
activationa
Escherichia coli Sol-4 reverse mutation 0.1-0.2%; 3-24 h - + Demerec et al.
(survival less than 2%) (1951)
AB1899 nm filamentation 10-500 µg/ml; 3-4 h - Nagel et al.
(1982)
Salmonella TA100 reverse mutation fluctuation test - - Koike et al.
typhimurium 0-500 ng/well + (rat) + (no data (1988)
on toxicity)
TA98 reverse mutation 1000-fold concentration + and - - Epler et al.
TA100 range in DMSOc (1979)
TA1535 reverse mutation 0-100 µg/plate - - Gilbert et al.
(1980)
TA1538 reverse mutation 0-50 µg/plate - -
TA98 reverse mutation 0-333