INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 168
CRESOLS
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
First draft prepared by Dr L. Papa, US Environmental Protection
Agency, Cincinnati, USA
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization
World Health Organization
Geneva, 1995
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 Organization. The main
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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
Cresols
(Environmental health criteria ; 168)
1.Cresols - adverse effects
2. Environmental exposure I.Series
ISBN 92 4 157168 1 (NLM Classification: QV 223)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS
1. SUMMARY
1.1. Identity, properties and analytical methods
1.2. Uses, sources and levels of exposure
1.3. Kinetics and metabolism
1.4. Effects on laboratory mammals; in vitro systems
1.5. Effects on humans
1.6. Effects on other organisms
1.7. Conclusion and recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factorsl
2.4. Analytical methods
2.4.1. Sampling
2.4.2. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels and processes
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Air
4.1.2. Water
4.1.3. Soil
4.2. Transformation
4.2.1. Abiotic transformation
4.2.2. Biodegradation
4.3. Bioaccumulation and biomagnification
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.1.3. Soil
5.1.4. Food and beverages
5.2. General population exposure
5.3. Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption
6.2. Distribution
6.3. Metabolic transformation
6.4. Elimination and excretion
6.5. Endogenous cresols
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Inhalation route
7.1.2. Oral route
7.1.3. Dermal route
7.2. Short-term exposure
7.2.1. Inhalation route
7.2.2. Oral route
7.3. Long-term exposure
7.3.1. Inhalation route
7.3.2. Oral route
7.4. Skin and eye irritation
7.5. Reproductive toxicity, embryotoxicity and teratogenicity
7.5.1. Reproduction
7.5.2. Embryotoxicity and teratogenicity
7.6. Mutagenicity and related end-points
7.7. Carcinogenicity
7.8. Other special studies
7.8.1. Neurological effects
7.8.2. Effects on the skin
7.9. Mechanism of toxicity - mode of action
8. EFFECTS ON HUMANS
8.1. General population exposure
8.1.1. Poisoning incidents
8.1.2. Controlled human studies
8.1.3. Cancer
8.2. Occupational exposure
8.2.1. Poisoning incidents
8.2.2. Epidemiological studies
8.3. Subpopulations at special risk
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.1.1. Aquatic
9.1.1.1 Laboratory studies
9.1.1.2 Field studies
9.1.2. Terrestrial
9.1.2.1 Laboratory studies
9.1.2.2 Field studies
9.2. Plants
9.2.1. Aquatic
9.2.1.1 Laboratory studies
9.2.1.2 Field studies
9.2.2. Terrestrial
9.2.2.1 Laboratory studies
9.2.2.2 Field studies
9.3. Invertebrates
9.3.1. Aquatic
9.3.1.1 Laboratory studies
9.3.1.2 Field investigations
9.3.2. Terrestrial
9.3.2.1 Laboratory studies
9.3.2.2 Field studies
9.4. Vertebrates
9.4.1. Aquatic
9.4.1.1 Laboratory studies
9.4.1.2 Field studies
9.4.2. Terrestrial
9.4.2.1 Laboratory studies
9.4.2.2 Field studies
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Evaluation of environmental risks
10.3. Guidance value
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
11.1. Conclusions
11.2. Recommendations
12. FURTHER RESEARCH
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
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This publication was made possible by grant number
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Sciences, National Institutes of Health, USA, and by financial support
from the European Commission.
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WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS
Members
Dr D. Anderson, British Industrial Biological Research Association
(BIBRA) Toxicology International, Carshalton, Surrey, United
Kingdom
Dr M.R. Elwell, National Institute of Health, National Institute of
Environmental Health Sciences, Research Triangle Park, North
Carolina, USA
Dr A. Meharg, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, United Kingdom
Dr C.-N. Ong, Department of Community, Occupational and Family
Medicine, National University of Singapore, Singapore
(Vice-Chairman)
Dr Y. Pang, Division of Standard Setting, Chinese Academy of
Preventive Medicine, Beijing, China
Dr L. Papa, System Toxicants Assessment Branch, Office of Research and
Development, Environmental Criteria and Assessment Office, US
Environmental Protection Agency, Cincinnati, Ohio, USA
(Rapporteur)
Dr A. Pinter, National Institute of Hygiene, Budapest, Hungary
Dr S. Soliman, Pesticide Chemistry and Toxicology, College of
Agriculture and Veterinary Medicine, Bureidah, Saudi Arabia
Dr F.M. Sullivan, Division of Pharmacology and Toxicology, St Thomas's
Hospital, London, United Kingdom (Chairman)
Secretariat
Dr B.H. Chen, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland (Secretary)
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS
A WHO Task Group on Environmental Health Criteria for Cresols met
at the British Industrial Biological Research Association (BIBRA)
Toxicology International, Carshalton, Surrey, United Kingdom, from 27
June to 1 July 1994. Dr D. Anderson opened the meeting and welcomed
the participants on behalf of the host institution. Dr B.H. Chen,
IPCS, welcomed the participants on behalf of the Director, IPCS, and
the three cooperating organizations (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 cresols.
Drs N.N. Molodkina, L.P. Kuzmina and A.L. Germanova, Centre for
International Projects, Moscow, Russian Federation, prepared a
preliminary draft. The first draft of this monograph was prepared by
Dr L. Papa, US Environmental Protection Agency, Cincinnati, USA. The
second draft was also prepared by Dr L. Papa, incorporating comments
received following the circulation of the first draft to the IPCS
Contact Points for Environmental Health Criteria monographs.
Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content and
technical editing, respectively.
The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.
* * * *
Financial support for this Task Group was provided by the United
Kingdom Department of Health as part of its contributions to the IPCS.
1. SUMMARY
1.1 Identity, properties and analytical methods
Cresols are isomeric substituted phenols with a methyl
substituent at either the ortho, meta or para position relative to
the hydroxyl group. Commercial cresol, also known as cresylic acid,
contains all three isomers with small amounts of phenol and xylenols.
However, commercial products contain up to 30% xylenol and 60%
C9-phenols and are known as "cresylic acids". Physically, cresols
consist either of a white crystalline solid or a yellowish liquid and
have a strong, phenol-like odour. They are highly flammable and are
soluble in water, ethanol, ether, acetone and alkali hydroxides.
Cresols undergo electrophilic substitution reactions at the vacant
ortho or para position relative to the hydroxyl group. They also
undergo condensation reactions with aldehydes, ketones or dienes.
Several methods can be used for determining the presence of
cresols in both environmental and biological media. The most commonly
used methods are gas chromatography with flame ionization detection
(GC-FID), gas chromatography with mass spectrophotometry (GC-MS) and
high-performance liquid chromatography (HPLC). Sampling of cresols in
air can be done by passing air through absorption cells using sodium
hydroxide or solid adsorbents.
1.2 Uses, sources and levels of exposure
Cresols have a wide variety of uses as solvents or disinfectants
or as intermediates in the production of numerous other substances.
These compounds are most commonly used in the production of
fragrances, antioxidants, dyes, pesticides and resins. Ortho- and
para-cresols are used in the production of lubricating oils, motor
fuels and rubber polymers, while meta-cresol is used in the
manufacture of explosives.
Cresols and cresol derivatives occur naturally in oils of various
plants, including Yucca gloriosa flowers, jasmine, Easter lily,
conifers, oaks and sandalwood trees, and are also a product of
combustion from natural fires and volcanic activity. Para-cresol is
found in the urine of animals and humans. Commercially cresols are
produced as by-products in the fractional distillation of crude oil
and coal tars. Small amounts are produced in vehicle exhaust,
municipal waste incinerators and from coal and wood combustion.
Cigarette smoke also contains cresols. The worldwide production of
cresols is unknown; annual production in the USA in 1990 was reported
to be 38 300 tonnes.
Environmental transport of cresols occurs through the vapour
phase of the atmosphere and from the atmosphere to surface water and
soil by rain-scavenging. Due to their volatilization, binding to
sediment and biodegradation, only small amounts of cresols are found
in water. In soils, cresols are slightly to highly mobile depending on
the sorption coefficient (Koc) of the soil. Cresols have been
detected in ground water, and so leaching must occur in soil.
Exposure to cresols can occur through air, water or food. The
median air concentration of o-cresols was 1.59 µg/m3 (0.359 ppb)
for 32 source-dominated sites in the USA. Surface water
concentrations in the USA range from below the detection limit to
77 µg/litre (STORET, 1993). Levels of 204 µg/litre were reported in
Japan in a river polluted by industrial effluents. Concentrations as
high as 2100 µg/litre for o-cresol and 1200 µg/litre for mixed
m- and p-cresols have been detected in waste waters. Rainwater
concentrations range from 240 to 2800 ng/litre for o-cresol and 380
to 2000 ng/litre for p- and m-cresol combined. Cresols have been
detected in foods and beverages. Concentrations in spirit beverages
were found to be within the range of 0.01-0.2 mg/litre. The amount in
tobacco smoke is 75 µg in a nonfilter American cigarette (85 mm). The
general population can be exposed to cresols from air inhalation,
drinking-water, food and beverage ingestion and dermal contact. In
general, the lack of adequate monitoring data makes the quantitative
estimates of daily intakes of cresol from these sources impossible.
Occupational exposure levels as high as 5.0 mg/m3 have been
reported.
1.3 Kinetics and metabolism
Cresols are absorbed across the respiratory and gastrointestinal
tracts and through the skin. The rate and extent of absorption of
cresols has not been studied specifically. However, studies have
shown that gastrointestinal and dermal absorption are rapid and
extensive. Cresols are distributed to all the major organs. The
primary metabolic pathway for cresols is conjugation with glucuronic
acid and inorganic sulfate. Minor metabolic pathways for cresols
include hydroxylation of the benzene ring and side-chain oxidation.
The main route for elimination of cresols from the body is renal
excretion in the form of conjugates.
1.4 Effects on laboratory mammals; in vitro systems
Acute poisoning with cresol vapours is unlikely due to the low
vapour pressure of these compounds. Mean lethal concentrations of
cresols in rats have been reported to be 29 mg/m3 for o- and
p-cresols and 58 mg/m3 for m-cresol. Oral LD50 values in rats
have been reported to be 121, 207 and 242 mg/kg body weight for o-,
p- and m-cresols, respectively. Interspecies comparisons show
that all three isomers are more toxic to mice than to rats and that
toxicity increases with concentration. Systemic toxicity and death
can result from dermal exposure. Dermal LD50 values in rabbits were
890, 2830, 300 and 2000 mg/kg body weight for o-, m-, p-and
mixed cresols, respectively. In rats dermal LD50 values were 620,
1100, 750 and 825 mg/kg body weight for o-, m-, p- and dicresol,
respectively.
Cresols are highly irritating to the skin and eyes of rabbits,
rats and mice.
Short-term exposure to inhaled mixtures of o-cresol aerosol and
vapour resulted in irritation of the respiratory tract, small
haemorrhages in the lung, body weight reduction and degeneration of
heart muscle, liver, kidney and nerve cells. Short-term (28-days)
oral exposure to daily doses of approximately 800 mg/kg body weight or
more resulted in reduced body weights, organ weight changes and
histopathological changes in the respiratory and gastrointestinal
tracts of rats. In mice, similarly exposed at 1500 mg/kg body weight,
more severe effects were reported, and at the highest concentrations
death resulted from exposure to o-, m- and p-cresols but not
from exposures to mixtures of isomers.
Longer-term exposure of rats to vapours of o-, m- or
p-cresol for up to 4 months resulted in weight loss, reduced
locomotor activity, inflammation of nasal membranes and skin, and
changes in the liver. Oral exposures for up to 13 weeks of mice,
rats and hamsters resulted in mortality, tremor, reduced body weights,
haematological effects, increase in organ weight, and hyperplasia of
nasal and forestomach epithelium.
Oral and inhalation exposure to cresol isomers result in
lengthened estrus cycle and histopathological changes in the uterus
and ovaries of rats and mice. No adverse effects on spermatogenesis
were observed in rats or mice. Mild fetotoxic effects have been
reported in rats and rabbits exposed to o- and p-cresols, but only
minor treatment-related developmental effects have been reported.
Some evidence of genotoxicity has been reported to result in vitro
from treatment with o- and p- cresols but not m-cresol. No
positive results were obtained in in vivo studies. However, some
evidence of promotive activities in skin has been reported. No
studies of carcinogenicity have been reported for any cresol isomers.
1.5 Effects on humans
Ingestion of cresols results in burning of the mouth and throat,
abdominal pain and vomiting. The target tissues/organs of ingested
cresols in humans are the blood and kidneys, and effects on the lungs,
liver, heart and central nervous system have also been reported. In
severe cases, coma and death may result. Dermal exposure has been
reported to cause severe skin burns, scarring, systemic toxicity and
death.
Occupational exposure to cresols usually results from dermal
contact. Acute exposures can result in severe burns, anuria, coma and
death. Very few data are available regarding reproductive effects and
there are no data on carcinogenicity in humans.
1.6 Effects on other organisms
Observations on microorganisms, invertebrates and fish have shown
that cresols may represent a risk to non-mammalian organisms at point
sources with high cresol concentration but not in the general
environment.
1.7 Conclusion and recommendations
At concentrations normally found in the environment, cresols do
not pose any significant risk for the general population. However,
the potential for adverse health effects exists in the case of people
with renal insufficiency or specific enzymic deficiency and under
conditions of high exposure.
Cresols may represent a risk to microorganisms, invertebrates and
fish at point sources with high cresol concentrations but not in the
general environment.
No information is available regarding the effects of chronic
exposure to cresols. Therefore, there is inadequate information to
assess the carcinogenic hazard of cresols. Based on the results of
subchronic studies, an NOAEL of 50 mg/kg body weight per day can be
established for all three cresol isomers. An uncertainty factor of
300 was recommended, composed as follows: 10 to account for
interspecies variation; 10 to account for the lack of chronic toxicity
studies and possible genotoxic and promoting activity of cresols, and
3 to account for intraspecies variation based on the rapid and
complete metabolism. Therefore, an acceptable daily intake (ADI) of
0.17 mg/kg body weight per day can be established for cresols.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
Cresols are isomeric substituted phenols with a methyl
substituent at either the ortho, meta or para positions relative to
the hydroxyl group. Commercial cresol, also known as cresylic acid,
contains all three isomers with small amounts of phenol and xylenols
(Deichmann & Keplinger, 1981). Mixtures of m- and p-cresol and of
o-, m- and p-cresol are occasionally called dicresol and
tricresol, respectively (Fiege & Bayer, 1987). Pure and commercial
cresol or cresylic acid is different from the commercial products
called "cresylic acids". The substance "cresylic acids" is a mixture
of phenolic compounds with a typical composition as follows: 0-1% m-
and p-cresol; 0-3% 2,4- and 2,6-xylenols; 10-20% 2,3- and
3,5-xylenols; 20-30% 3,4-xylenol; and 50-60% C9-phenols (Sax & Lewis,
1987). The chemical identity of cresols is shown in Table 1.
Commercial cresols are manufactured in a wide range of
grades and purities to suit the user's requirements. Typically,
technical grade cresol available in the USA contains about 20%
o-cresol, 40% m-cresol, 30% p-cresol, and 10% phenol and
xylenols (Deichmann & Keplinger, 1981). The individual isomers are
available at purity levels as low as 85% and as high as > 99% from
chemical suppliers in the USA.
2.2 Physical and chemical properties
The physical properties of the three individual isomers and the
mixture are given in Table 2.
Chemically, cresols behave similarly to phenol. These compounds
undergo electrophilic substitution reactions at the vacant ortho or
para position relative to the hydroxyl group. Chlorination,
bromination, sulfonation and nitration are examples of such
substitution reactions. Cresols can undergo condensation reactions
with aldehydes, ketones and dienes (Fiege & Bayer, 1987).
2.3 Conversion factors
Air at 25°C: 1 ppm = 4.42 mg/m3
1 mg/m3 = 0.23 ppm
Table 1. Chemical identity of cresols
o-Cresol p-Cresol m-Cresol Mixture
Chemical structure:
Empirical formula: C7H8O C7H8O C7H8O C7H8O
Relative molecular mass: 108.14 108.14 108.14 108.14
Common synonyms: 2-methyl phenol 4-methyl phenol 3-methyl phenol methyl phenol
2-hydroxy toluene 4-hydroxy toluene 3-hydroxy toluene hydroxy toluene
o-cresylic acid p-cresylic acid m-cresylic acid cresylic acid
acide cresylique (French)
cresoli (Italian)
kresolen (Dutch)
krezol (Polish)
kresol (German)
IUPAC name: 2-hydroxy toluene 4-hydroxy toluene 3-hydroxy toluene hydroxy toluene
CAS registry number: 95-48-7 106-44-5 108-39-4
RTECS: G06300000 G06475000 G06125000 G05950000
EEC number: 604-004-00-9 604-004-00-9 604-004-00-9 604-004-00-9
Table 2. Physical and chemical properties of cresolsa
o-Cresol m-Cresol p-Cresol Mixturef
Physical state and colour: white crystalline solid colourless to yellowish crystalline solid or colourless to yellowish
or yellowish liquid liquid yellowish liquid liquid
Odour: phenol-like phenol-like phenol-like phenol-like
Air odour thresholdb: 1.4 mg/m3 0.007 mg/m3 0.004 mg/m3 ND
Melting point (°C): 30.94 12.22 34.74 11-35
Boiling point at 1 atm (°C): 191.0 202.32 201.94 191-203
Flash point, closed cup (°C): 81 86 86 82
Ignition point (°C): 598 558 558 ND
Vapour pressure at 25°C (mmHg): 0.31 0.143 0.13 0.975 (at 38-53°C)g
Relative density at 25°C (g/cm3): 1.135 1.030 1.154 1.03-1.038
Refractive index at 25°C: 1.544 1.540 1.539 ND
Vapour density (air = 1 at 20°C): 3.7 3.72 3.72 NDe
Solubility in water at 25°C
(g/litre)c: 25.95 22.70 21.52 ND
Solubility in other solvents: soluble in ethanol, soluble in ethanol, soluble in ethanol, soluble in ethanol,
ethyl ether, acetone, ethyl ether, acetone, ethyl ether, acetone, glycol, aqueous
benzene, aqueous benzene, aqueous benzene, aqueous alkali hydroxides
alkali hydroxides alkali hydroxides alkali hydroxides
Table 2 (contd).
o-Cresol m-Cresol p-Cresol Mixturef
Sorption coefficient,
Koc (all isomers)d 22-3420
Log n-octanol/water partition
coefficiente (log Ko/w): 1.95 1.96 1.94 ND
pKa (25°C): 10.287 10.09 10.26 ND
Bioconcentration factorsh 14.1 19.9 ND ND
Odour threshold in water
(mg/litre)i,j 1.4 0.8 0.2 ND
Taste threshold concentration
in water (mg/litre)j 0.003 0.002 0.002 ND
Saturation concentration
in air (g/m3)j at 20°C 1.2 0.24 0.24 ND
at 30°C 2.8 0.68 0.74 ND
a Adapted from: Weast et al. (1988); Sax & Lewis (1987); Windholz et al. (1983); Riddick et al. (1986), unless otherwise specified
b Amoore & Hautala (1983)
c Yalkowsky et al. (1987)
d Boyd (1982); Southworth & Keller (1986); Koch & Nagel (1988)
e Hansch & Leo (1985)
f No data
g Parrish (1983)
h Freitag et al., (1982)
i Dietz & Traud (1978)
j Verschuesen (1983)
2.4 Analytical methods
2.4.1 Sampling
As is the case with any other analyte, sample loss and
contamination should be avoided during the collection, storage and
analysis of samples for cresol determination. Glass bottles, vials or
tubes have been used for the collection of environmental samples (US
EPA, 1982). Polyethylene containers are suitable for the collection
of biological samples (US NIOSH, 1989). Environmental aqueous samples
can be stored for a limited time (28 days) by adding sulfuric acid to
a pH < 2 (US EPA, 1982). Thymol has been used as a preservative for
biological samples (US NIOSH, 1989). Environmental and biological
samples that are to be shipped from the collection site to the
laboratory are cooled in ice.
Cresols in air can be sampled by passing air through an
absorption cell containing 0.1 N sodium hydroxide solution (Manita,
1966). More recent methods use solid adsorbents such as XAD-2 or
silica gel for trapping cresols from air (Neiminen & Heikkila, 1986;
US NIOSH, 1989). In a novel system, a miniaturized enrichment unit
has been used to concentrate cresols and other water-soluble analytes
in air by a water mist (Vecera & Janak, 1987). Aqueous samples can be
collected either by manual grab methods or by automated samplers.
Composite samples can be obtained by combining random samples
collected manually or by automated samplers (US EPA, 1982). Several
mechanical devices are available for collecting random or composite
semi-solid and solid samples either by grab or automated methods (US
EPA, 1982, 1986).
2.4.2 Analytical methods
Some of the methods used in measuring cresols in various
environmental and biological media are given in Table 3 along with
their corresponding references. The problem with the determination of
cresols by gas chromatography arises as a result of non-reproducible
elution from the gas chromatography column due to the polar and
volatile nature of cresols. Special columns or derivatization of the
cresols may alleviate the problem. Cresols are present in biological
samples as conjugates, and a hydrolysis method is used to release free
cresols. There is no consensus on the reliability of total hydrolysis
of the cresol conjugates (Balikova & Kohlicek, 1989).
Chudyk et al. (1985) tested a remote fluorescence technique using
ultraviolet laser fibre optics to analyse groundwater contaminants,
including o-cresol, in artificially prepared solutions. No data were
given on the detection limits or on the use of this technique in the
field. However, the authors speculated that the sensitivity is at or
below parts per billion levels at an instrument/analyte distance of
25 m.
Hoshika & Muto (1978) described a simple and rapid
gas-liquid-solid chromatographic (GLSC) method for the determination
of trace concentrations of 11 phenols including all isomers of cresol
in air. This method has been adopted and recommended by many other
investigators for measuring cresols in air samples. To overcome
interference by certain acidic compounds such as lower fatty acids and
mercaptans, the method uses two precolumns, a Tenax-GC and a Tenax-GC
plus alkaline. The gas chromatograph used was equipped with a flame
ionization detector (FID), a digital integrator and a glass analytical
column. With the Tenax-GC plus alkaline precolumn the phenol peaks
disappeared completely in the chromatograms, enabling phenols to be
identified by comparison with the chromatograms from the ordinary
Tanex-GC precolumn. The detection limit for cresols by this method
was reported to be at the ppb level.
Table 3. Sampling and analytical methods for determining cresols in environmental and biological samples
Sample Analytical Sample detection Percentage
matrix Preparation method methodb Isomer limit recovery Reference
Air
Air pump air through adsorbent tube; HPLC/UV o, m, p 0.3 ppt 90-110% Kuwata & Tanaka
desorb with methanol (1988)
Air aerodispersive enrichment into HPLC/ED o no data no data Vecera & Janak
water (1987)
Air pump air through silica gel tube; GC-FID o, m, p no data 98% at US NIOSH (1989)
desorb with acetone 22 mg/m3
Air pump air through mixed cellulose HPLC-UV o, m, p 0.5 ppb 52.4% Risner (1993)
ester membrane connected to silica
Sep-Pak, desorp with 1% acetic
acid in acetonitrile
Auto exhaust vapour collected in fritted bubbler HPLC-UV o, m, p 0.1-0.5 no data Kuwata et al.
and tobacco with aqueous NaOH buffered to pH 11.5; ng/sample (1981)
smoke add p-nitrobenzene-diazonium
tetra-fluoroborate; extract with CCl4
Air and water
Air and water mix NaOH solution from bubbler in case spectrophotometry o, m, p 0.005-0.03 no data Druyan (1974)
of air and distillate of water samples (TLC) µg/sample
in 1 N NaOH solution with
p-nitrophenyl-diazonium at pH 7-9;
extract with ether; spot on TLC plate
Table 3 (contd).
Sample Analytical Sample detection Percentage
matrix Preparation method methodb Isomer limit recovery Reference
Water adjust pH to 11; extract with GC/MS o, p 10 µg/litre no data US EPA (1988)
CH2Cl2; concentrate
Water solvent extraction, liquid GC/MS not no data no data Hites (1979)
chromatography prefractionation specified
Water adjust pH to 8-9; extract with spectrophotometry o, m 4 µg/litre 99-100.1% Hassan et al.
chloroform-ether; back extract (VIS) at 5-120 (1987)
in 0.1 N aqueous NaOH; add NaNO2 µg/litre
and H2SO4; remove excess NO;
add resorcinol
Water direct flow and spectrophotometry o, m 10-30 µg/litre 90-115% Khalaf et al.
stopped-flow injection, then (VIS) (1993)
derivatization with p-aminophenol
Rainwater direct injection onto ion exchange HPLC/CD o, m, p no data no data Hoffman &
column Tanner (1986)
Rainwater acidify; extract with CH2Cl2; GC/MS o, m, p no data > 50% Kawamura &
concentrate, methylate Kaplan (1986)
Soil
Soil, extract sample with CH2Cl2 using GC/MS o, p 330 ppb no data US EPA (1988)
sediment ultrasonic probe
Table 3 (contd).
Sample Analytical Sample detection Percentage
matrix Preparation method methodb Isomer limit recovery Reference
Sediment extract rapidly stirred sediment GC/MS not no data no data Goodley & Gordon
slurry with CH2Cl2 or ether, specified (1976)
concentrate
Biological samples
Expired draw air through XAD-2 adsorbent HPLC/ED o, m, p 8 µg/m3 no data Neiminen &
air tube; acetonitrile desorbtion Heikkila (1986)
Expired collect breath in Teflon bag; GC/MS not no data no data Krotoszynski &
air concentrate on Tenax GC absorbent; specified O'Neill (1982)
thermal desorption
Beef steam distil; extract distillate HRGC/MS o, m, p 0.2 mg/kg 83-98% at Matsumoto et al.
with ether 20-100 µg (1989)
per sample
Urine hydrolyse with sulfuric acid; GC/FID o, m, p no data 78-97% Needham et al.
extract with ethyl acetate (1984)
Urine hydrolyse with HCl and extract with HPLC/UV o, m, p 1 mg/litre 97-102% Yoshikawa et al.
isopropyl ether; remove solvent; (1986)
dissolve residue in water; add
ß-cyclodextrin
Urine acidify; steam distil; extract with GC/MS o no data no data Angerer & Wulf
methylene chloride (1985)
Urine hydrolyse with sulfuric acid; extract HPLC/UV o no data no data DeRosa et al.
with CH2Cl2; concentrate (1987)
Table 3 (contd).
Sample Analytical Sample detection Percentage
matrix Preparation method methodb Isomer limit recovery Reference
Urine hydrolyse with HCl or HClO4; extract GC-FID p 0.5 mg/litre 95% at US NIOSH (1989)
with ether 50 µg/ml
Urine and hydrolyse with H3PO4; extract with GC-FID o, m, p 1 mg/litre 69.4-73.3% Balikova &
serum n-hexane, acetylate extract at 50 Kohlicek (1989)
mg/litre
Faeces and homogenize faeces and hydrolyse HPLC-fluorescence p < 1 µg/kg for 99.4-101.9% Murray & Adams
urine urine buffered to pH 5.5, steam detector faeces; (1988)
distil < 1 µg/litre
for urine
a 0.01 nmol = 1.08 ng
b CD = conductivity detector; ED = electrochemical detector; FID = flame ionization detector; GC = gas chromatography;
HPLC = high-performance liquid chromatography; HRGC = high-resolution gas chromatography; m = meta-cresol; MS = mass spectrometry;
o = ortho-cresol; p = para-cresol; UV = ultraviolet detector
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Cresols and cresol derivatives occur naturally in various plants.
They are present in oils from jasmine, cassia, Easter lily, ylang
ylang, and Yucca gloriosa flowers and in peppermint, eucalyptus and
camphor. Oils from conifers, oaks and sandalwood trees also contain
cresol (Fiege & Bayer, 1987). Mammalian urine and faeces naturally
contain p-cresol (section 6.5). Poultry manure reportedly contains
p-cresol at an average concentration of 11.7 mg/kg (Yasuhara, 1987).
Cresols are frequently produced as metabolic intermediates in the
degradation of bound phenols by soil microorganisms. They are also
products of combustion and can be released to the atmosphere from
natural fires associated with lightning, spontaneous combustion and
volcanic activity (McKnight et al., 1982).
3.2 Anthropogenic sources
Cresols are contained in crude oil and coal tar. Therefore, the
dominant anthropogenic sources of cresols are accidental and process
discharge during the manufacture, use, transport and storage of
cresols or associated products of the coal tar and petroleum
industries. Cresols are also produced during coal gasification
(Giabbai et al., 1985; Neufeld et al., 1985), coal liquefaction
(Fedorak & Hrudey, 1986) and shale oil production (Snider & Manning,
1982; Dobson et al., 1985). Low levels of cresols are present in the
exhaust of vehicles powered with petroleum-based fuels (Hampton et
al., 1982; Johnson et al., 1989), stack emissions from municipal waste
incinerators (Junk & Ford, 1980; James et al., 1984), and emissions
from the incineration of vegetable materials (Liberti et al., 1983).
Cresols are also found in fly ash from coal and wood combustion (Junk
& Ford, 1980; Hawthorne et al., 1988, 1989). Cigarette smoke contains
cresols (Wynder & Hoffmann, 1967). In addition, the atmospheric
reaction of toluene with photochemically generated hydroxyl radicals
(HO*) produces cresols (Leone et al., 1985).
3.2.1 Production levels and processes
The oldest cresol production method used in the USA is fractional
distillation of coal tar. Most cresols in the USA are obtained via
catalytic and thermal cracking of naphtha fractions during petroleum
distillation. Since 1965, quantities of coal tar and petroleum
isolates have been insufficient to meet the rising demand for cresols
in the USA. Consequently, several processes for the manufacture of
the various isomers have been developed. One method of producing
o-cresol is by the methylation of phenol in the presence of
catalysts. Another method uses toluene sulfonation followed by
alkaline hydrolysis to produce p-cresol. Until 1972, cresols were
also produced by the cymene-cresol process, where cymene
( p-isopropyltoluene) is oxidized to cymene hydroperoxide, which
decomposes to cresols and acetone. This method is capable of
producing p- or m-cresol from the corresponding cymene isomer.
Alkaline chlorotoluene hydrolysis is used to produce a cresol mixture
with a high m-cresol content (Fiege & Bayer, 1987). The total
production of cresols in the USA, excluding production from coke oven
and gas-retort ovens, was 34 400 tonnes in 1989 and 38 300 tonnes in
1990 (USITC, 1990, 1991).
According to the Toxic Release Inventory (TRI) database,
maintained by the US EPA, manufacturing and processing industries in
the USA in 1987 released or transferred 52 tonnes of cresols to air,
water and land, 172.5 tonnes to wastewater treatment plants, and 20.45
tonnes to off-site locations for disposal (US EPA, 1989). The TRI
data may have under-estimated the actual release since only certain
types of facilities were required to report.
3.2.2 Uses
A considerable amount of o-cresol is consumed directly as
either a solvent or disinfectant. o-Cresol is also used as a
chemical intermediate for a variety of products, including deodorizing
and odour-enhancing compounds, pharmaceuticals, fragrances,
antioxidants, dye and dye intermediates, pesticides and resins.
Recently, an increasing proportion of o-cresol has been devoted to
the formulation of epoxy- o-cresol novolak resins (sealing materials
for integrated circuits silicon chips). o-Cresol is also used as an
additive to phenol-formaldehyde resins (Windholz et al., 1983; Fiege &
Bayer, 1987; Sax & Lewis, 1987).
p-Cresol is mainly used in the formulation of antioxidants such
as 2,6-di- tert-butyl- p-cresol for lubricating oil and motor fuels,
rubber, polymers, elastomers and food products. It is also used as an
intermediate in the fragrance and dye industries (Windholz et al.,
1983; Fiege & Bayer, 1987; Sax & Lewis, 1987).
m-Cresol, either pure or mixed with p-cresol, is important in
the production of contact herbicides and insecticides. Furthermore,
many flavour and fragrance compounds and several important
antioxidants are produced from m-cresol. It is also used in the
manufacture of explosives (Fiege & Bayer, 1987).
Mixtures of m- and p-cresol are used as disinfectants and
preservatives. Crude cresols are used as wood preservatives.
Tricresyl phosphate and diphenyl cresyl phosphate produced from m-
and p-cresol mixtures are used as flame-retardant plasticizers for
polyvinyl chloride and other plastics, fire-resistant hydraulic
fluids, additives for lubricants and air filter oils. Cresol mixtures
condensed with formaldehyde are important for modifying phenolic
resins. Cresols are also used in paints and textiles. Mixtures of
cresols are used as solvents for synthetic resin coatings such as wire
enamels, metal degreasers, cutting oils and agents to remove carbon
deposits from combustion engines. They are also used in ore
flotation, fibre treatment and photography (Deichmann & Keplinger,
1981; Windholz, 1983; Fiege & Bayer, 1987).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
4.1.1 Air
The levels of cresols in the atmosphere will be regulated by the
physical properties of the compounds, their chemical reactivity and by
prevailing weather conditions (wind speed, precipitation, temperature
inversions, etc.). The vapour pressures of cresols range from 0.13 to
0.31 mmHg (Table 2); compounds with values greater than 0.0001 mmHg
should exist predominantly in the vapour phase (Eisenreich et al.,
1981) as opposed to the particulate-bound phase (Cautreels & van
Cauwenberghe, 1978). Photochemical attack (section 4.2) and rain
scavenging (Leuenberger et al., 1985; Czuczwa et al., 1987) rapidly
remove cresols from the vapour phase, counteracting the tendency of
compounds that exist in the vapour phase to be transported over long
distances.
4.1.2 Water
The processes that control the transport of cresols from water
and their distribution in water are volatility, values for the
sorption coefficient (Koc) to suspended solids and sediment, and
bioaccumulation in aquatic organisms. The bioaccumulation of cresols
in aquatic organisms is discussed in section 4.3. The volatility of a
compound can be qualitatively predicted from its Henry's Law constant
(H). The rate of volatilization from water is high for compounds with
H values ranging from 10-2 to 10-3 atm-m3/mol, and it is very
low for compounds with H values of 10-7 atm-m3/mol or less (Lyman et
al., 1990). Therefore, transport of cresols with H values of 1.26 ×
10-6 to 7.92 × 10-7 atm-m3/mol from water to the atmosphere will
not be significant. Furthermore, the ability of these phenolic
compounds to dissociate and to form hydrogen bonds, leading to binding
with both suspended solids or sediments, will decrease the rate of
volatilization even further. Since the cresols are soluble in water
(see Table 2), the small amounts of cresols typically found in the
aquatic environment will be present mostly in the aqueous phase.
However, transport of cresols from water to bottom sediment is
possible as a result of sorption and subsequent precipitation. For
hydrophobic compounds, the importance of the sorption process can
usually be predicted from the Koc values. Details of Koc levels are
given in section 4.1.3.
4.1.3 Soil
Koc values in soil of between 22 and 3420 have been reported
(Boyd, 1982; Southworth & Keller, 1986; Koch & Nagel, 1988). The
sorption of cresols to several soils correlates well with both pH and
clay mineral content in soil (Artiola-Fortuny & Fuller, 1982), and
several investigators reported that hydrogen bonding plays an
important role in the sorption of cresols to soil (Boyd, 1982;
Southworth & Keller, 1986).
The transport of cresols from soil to the atmosphere will occur
as a result of volatilization. The volatilization of cresols from
soil will be directly proportional to H values and inversely
proportional to Koc. Since the H values for cresols are low and the
Koc in soils capable of hydrogen bonding can be as high as 3420,
volatilization will not be significant in such soils. However, some
volatilization may occur due to the relatively high vapour pressure of
cresols (Table 2) and to the diffusion gradient between the soil and
the atmosphere. Loss of cresols by volatilization has been shown to
occur from highly contaminated soils (Evangelista et al., 1990).
Another process that may transport cresols from soil to ground water
is leaching. The leaching of cresols from soil will depend on the
Koc. This is variable so that with values near 3000, cresols will
be slightly mobile, whereas cresols in soil with Koc values in the
lowest range will be highly mobile (Swann et al., 1983). The
horizontal transport of cresols from one land area to another or to
surface water as a result of run-off will also occur to a certain
extent, dependent among other factors on the soil Koc value.
4.2 Transformation
4.2.1 Abiotic transformation
Two abiotic transformation processes, namely reaction with
hydroxyl HO* and nitrate NO3* radicals, are most important for
determining the fate of cresols in air. The rate constants for the
reaction with HO* are 4.2 × 10-11, 6.4 × 10-11 and 4.7 × 10-11
cm3/molecule-sec for o-, m- and p-cresol, respectively
(Atkinson et al., 1992). It may be estimated from the range of HO*
concentrations in the lower troposphere (from below the limits of
detection at 1 × 106 radicals/cm3 to a maximum of 5 × 106
radicals/cm3) (Atkinson, 1985), that the half-lives for the cresols
during the daytime may range from 3 to 5 h. The major products of the
reactions of HO* with cresols in the presence of nitrogen oxides are
pyruvic acid, acetaldehyde, formaldehyde, peroxyacetylnitrate and
nitrocresols (Atkinson et al., 1980; Grosjean, 1984, 1985). NO3* is
formed in the atmosphere as a result of the reaction of nitrogen oxide
with ozone and is photodecomposed quickly by sunlight (Carter et al.,
1981). Therefore, the reaction of atmospheric pollutants with NO3*
can be significant only during the night. The determined rate
constants for the reaction of NO3* with vapour-phase cresols are
1.37 × 10-11, 9.74 × 10-12 and 1.07 × 10-11 cm3/molecule-sec
for o-, m- and p-cresol, respectively (Carter et al., 1981;
Atkinson et al., 1992). Assuming that the average concentration of
NO3* in a typical night-time urban atmosphere is 2.4 × 108
molecules/cm3, cresols are estimated to be removed from the
atmosphere with half-lives of 5-10 min (Atkinson, 1985).
Abiotic reactions, such as photolysis, hydrolysis and oxidation
by photolytically produced HO* and singlet oxygen, play a minor role
in determining the fate of cresols in water (Smith et al., 1978; Faust
& Hoigné, 1987). However, the photolysis of o- and p-cresol is
accelerated in the presence of fulvic and humic materials present in
water. The estimated half-life for the disappearance of p-cresol in
pure water containing humic acid (9.5 mg/litre) and exposed to April
sunlight at 37.5°N latitude was 3 days (Smith et al., 1978). In a
polluted eutrophic Swiss lake with a dissolved organic matter
concentration of 3.1 mg/litre, the estimated natural half-lives for
p- and o-cresol in the top metre as a result of exposure to June
sunlight were 4.4 and 11 days, respectively (Faust & Hoigné, 1987).
The investigators concluded that photochemically produced organic
peroxide radicals generated from dissolved organic matter controlled
the sensitized photooxidation of cresols in the Swiss lake. In
addition, laboratory experiments have shown that iron (FeOOH) and
manganese (III/IV) oxides (MnOOH and MnO2), commonly found in
surface water particulate and soil, can oxidize cresols in solution
particularly at low pH (< 4) (Stone, 1987). However, oxidation of
cresols occurs more readily in fog and rain water due to the higher
concentration of manganese and iron oxide and low pH of these waters
(Stone, 1987).
Direct attack of cresols by ozone may also occur in water and
follows first-order reaction kinetics: 3 moles of ozone are required
to cause ring-opening of 1 mole of cresol (Zheng et al., 1993a,b). The
overall rate constant for the reaction increases with increasing pH
and temperature. Ozonation may be a possible remediation treatment for
cresol-contaminated waters.
Photochemical reactions will only occur in the upper few
millimetres of the soil surface, and it is unlikely that photochemical
attack will be an important pathway for cresol removal from soil. As
in the case of water, the abiotic hydrolysis of cresols in moist soil
may not be significant since there is no evidence that any soil
component is capable of accelerating this reaction. The oxidation of
cresols by iron(III) and manganese (III/IV) is likely in soils that
have low pH; however, laboratory or field data assessing the
importance of this reaction in determining the fate of cresols in soil
are not available.
4.2.2 Biodegradation
Biotic processes, namely biodegradation, may be more important
than other processes in determining the fate of cresols in water
(Smith et al., 1978). Cresols degraded rapidly in aerobic
biodegradation screening and sewage treatment plant simulation studies
(McKinney et al., 1956; Ludzack & Ettinger, 1960; Malaney, 1960;
Chambers et al., 1963; Tabak et al., 1964; Alexander & Lustigman,
1966; Malaney & McKinney, 1966; Young et al., 1968; Pauli & Franke,
1971; Baird et al., 1974; Pitter, 1976; Singer et al., 1979; Lund &
Rodriguez, 1984; Babeu & Vaishnav, 1987; Brown & Grady, 1990; Klecka
et al., 1990). According to one screening study, the rate of aerobic
biodegradation of the three isomeric cresols increased in the
following order: p- > m- > o-. While no lag time for
biodegradation was observed for m- and p-cresol, o-cresol showed
a lag time of 6 days (Liu & Pacepavicius, 1990). Aerobic
biodegradation in salt water (estuarine and sea water) is slower than
in fresh water, but the decrease in the rate is not enough to preclude
biodegradation as an important removal pathway in salt water (Palumbo
et al., 1988). Mixed and pure culture studies indicate that aerobic
biodegradation of cresols proceeds by initial formation of
hydroxylation products followed by ring-opening reactions (Bayly &
Wigmore, 1973; Masunaga et al., 1983, 1986).
Biodegradation reaction rates are widely variable and depend on a
number of interrelated factors or conditions of the source waters.
Results of several investigations have shown that factors such as
substrate and nutrient concentration, spatial and temporal sampling,
bacterial growth, biofilm formation, pH and temperature all influence
reaction rates. In general, higher nutrient concentrations and
temperatures (summer versus winter) increase the biodegradation of
cresols. However, degradation will decrease with increased humic acid
content (Visser et al., 1977; Smith et al., 1978; Paris et al., 1983,
Spain & van Veld 1983; Rogers et al., 1984; Lewis et al. 1984,1986;
Shimp & Pfaender, 1985a,b; Kollig et al., 1987; Gantzer et al., 1988;
Hwang et al. 1989).
The anaerobic biodegradation potential of cresols in aquatic
media has been observed in the presence of an electron acceptor, as
occurs in nitrate reduction, methanogenesis and sulfate reduction
conditions (Shelton & Tiedje, 1981; Horowitz et al., 1982; Boyd et
al., 1983; Fedorak & Hrudey, 1984; Bak & Widdel, 1986; Roberts et al.,
1987; Battersby & Wilson, 1988, 1989; Wang et al., 1988, 1989).
Cresols biodegrade more slowly under anaerobic conditions than under
aerobic conditions. While several investigators observed a lag period
before the onset of anaerobic biodegradation (Suflita et al., 1988;
Battersby & Wilson, 1989; Liu & Pacepavicius, 1990), Young & Rivera
(1985) observed no significant increase in the rate of p-cresol
metabolism as a result of acclimation. The anaerobic biodegradation
rate for cresols was p- > m- > o- (Suflita et al., 1988; Wang
et al., 1988; Battersby & Wilson, 1989). Other investigators have
reported that o-cresol is more biodegradable under anaerobic
conditions than p-cresol. The m-cresol isomer was found to be
the least biodegradable (Liu & Pacepavicius, 1990). The anaerobic
biodegradation of o- and p-cresol appears to proceed metabolically
by oxidation of the methyl group to produce first the corresponding
hydroxybenzaldehyde and then hydroxy-benzoic acid. The hydroxybenzoic
acid is then decarboxylated or dehydroxylated to produce phenol or
benzaldehyde, respectively (Smolenski & Suflita, 1987; Kühn et al.,
1988; Suflita et al., 1988, 1989). The metabolic pathway for
anaerobic biodegradation of m-cresol may be different from the
pathway for o- and p-cresols (Suflita et al., 1989).
Pseudomonads and other bacteria contain a flavocytochrome enzyme,
p-cresol methylhydroxylase (PCMH), which is capable of oxidizing
p-cresol without the participation of exogenous oxygen (Hopper,
1976, 1978; Hopper & Taylor, 1977; Keat & Hopper, 1978). This enzyme
catalyses the dehydrogenation and hydration of p-cresol and its
homologues to the corresponding alcohols and their further
dehydrogenation to the corresponding aldehydes or ketones. Thus,
p-cresol is oxidized under this condition to p-hydroxybenzyl
alcohol and then to p-hydroxybenzaldehyde. Isolation and then
resolution of the flavocytochrome PCMH into subunits and
reconstitution of the enzyme were studied by Keat & Hopper (1978),
McIntire et al. (1981, 1984, 1985, 1986), McIntire & Singer (1982),
Shamala et al. (1985, 1986) and Koerber et al. (1985).
The biodegradation of cresols in soil under aerobic conditions is
rapid. However, complete metabolism (to CO2 and H2O) of the
intermediate metabolites is slower (Medvedev & Davidov, 1981a,b;
Dobbins & Pfaender, 1988; Namkoong et al., 1988). Biodegradation is
likely to control the fate of cresols in soils. In surface soils from
an uncultivated grassland site, the estimated half-life for the
pseudo-first-order disappearance of the parent compound was 1.6 days
for o-cresol and 0.6 days for m-cresol. It could not be
calculated for p-cresols as the concentration had fallen below the
detection limits at the first sampling, which was 24 h after
initiation of the experiment (Namkoong et al., 1988). The half-lives
for complete metabolism in different soils ranged from 39 days to
about 1 year (Dobbins & Pfaender, 1988; Swindoll et al., 1988).
4.3 Bioaccumulation and biomagnification
The measured bioconcentration factors for o-cresol and
m-cresol in aquatic organisms were 14.1 and 19.9, respectively
(Freitag et al., 1982; Sabljic, 1987). There is no evidence in the
literature to indicate that biotransfer of cresols via the food chain
causes biomagnification of these compounds.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
Ambient air monitoring data for cresols are sparse. These
compounds are short-lived in the air (see section 4.2.1) unless large
amounts are released over a short period of time. According to the
National Ambient Volatile Organic Compounds (VOCs) Data Base, a
compilation of published and unpublished air monitoring data in the
USA from 1970 to 1987, the median air concentration of o-cresol at
source-dominated sites was 1.59 µg/m3 (0.359 ppb) (range from below
detection limit to 10.58 µg/m3, 2.394 ppb) for 32 samples (Shah &
Heyerdahl, 1989). According to the same data base, o-cresol was not
detected in air samples from one urban, one rural and one remote area,
and m-cresol was also not detected in air samples from one urban,
one suburban, and one remote area in the USA. This data base does not
contain any monitoring data for p-cresol. The concentration of
o-cresol in one sample of the ambient air near a phenolic resin
factory in Japan was 179 µg/m3 (40 ppb) (Hoshika & Muto, 1978). In
air samples from rooms with a fireplace, cresol concentrations around
5 mg/m3 have been detected (Risner, 1993).
5.1.2 Water
In general, cresols will degrade in surface waters very rapidly.
The STORET data base, a computerized data base maintained by US EPA,
contains water quality data. According to STORET (1993), the mean,
minimum and maximum concentrations of ocresol in surface water were
10.89, below the detection limit and 68 µg/litre, respectively, out of
315 samples reported; for p- or m-cresol they were 12.5, 3.4 and
25 µg/litre out of 52 samples; and for p-cresol they were 12.45,
below the detection limit and 77 µg/litre out of 285 samples. In
addition, the three isomers of cresol were qualitatively detected in
Spirit Lake, a freshwater lake in the state of Washington, USA.
o-Cresol was also detected in two other freshwater bodies in the
same state. The presence of cresols was attributed to the Mount St.
Helens eruption (McKnight et al., 1982). Whether or not the cresols
originated from woodfires or the actual eruption was not clarified in
this study. p-Cresol was detected at a concentration of
200 µg/litre in water samples from the lower Tennessee River near
Calvert City, Kentucky, USA (Goodley & Gordon, 1976). m-Cresol was
qualitatively detected in St. Joseph River of the Lake Michigan Basin
(Great Lakes Water Quality Board, 1983). Cresols (isomers
unseparated) were not detected in Delaware River water samples taken
between Marcus Hook, Pennsylvania, and Trenton, New Jersey, USA,
during summer months, but were detected at 2 µg/litre in winter
(Sheldon & Hites, 1978). Concentrations of p-cresol as high as
204 µg/litre have been detected in a river in Japan polluted by
effluents from a leather factory (Yasuhara et al., 1981).
Although o-cresol has been qualitatively detected in
drinking-water in the USA (Clark et al., 1986), quantitative data
regarding cresol levels in drinking-water are not available.
Cresols have been qualitatively detected in effluent from sewage
treatment plants in the USA (Ellis et al., 1982). Concentrations of
70-150 µg/litre (isomer unidentified) have been measured in the
wastewater from a chemical manufacturing plant (Jungclaus et al.,
1978), and concentrations as high as 2100 µg/litre for o-cresol and
1200 µg/litre for mixed m- and p-cresol have been measured in
wastewater from a shale oil plant (Hawthorne & Sievers, 1984).
Cresols were detected at 20 µg/litre in the treated secondary effluent
from Philadelphia Northeast Sewage Treatment Plant, but were not
detected in Delaware River water near the discharge point of the
effluents or further downstream (Hites, 1979; Sheldon & Hites, 1979).
Furthermore, cresols have been detected in treated coke oven aqueous
condensates, wastewater from petroleum refineries and wood-preserving
plants, and aqueous effluents from synfuel processing (US EPA, 1982).
Cresols may persist in groundwater due to a lack of
microorganisms. Very little information regarding the concentration
of individual isomers has been reported in the literature.
Cresol concentrations measured in groundwater from hazardous
waste and landfill sites are shown in Table 4. Although the
concentration of p-cresol was below the detection limit
(30 µg/litre), o- and m-cresol concentrations of around
1400 µg/litre have been detected in creosote-contaminated groundwater
in Denmark (Flyvbjerg et al., 1993). According to STORET (1993), the
mean, minimum and maximum levels in groundwater from undefined sources
for o-cresol were 234.3, 0.9 and 100 000 µg per litre out of 1848
samples collected; for m-cresol were 1421.3, below the detection
limit and 100 000 µg/litre out of 712 samples; and for p-cresol were
15.79, 0.09 and 4800 µg/litre out of 1147 samples, respectively.
Rainwater from Portland, Oregon, collected during seven falls of
rain in 1984, contained o-cresol concentrations of 0.24-2.8 µg per
litre (mean of 1.02 µg/litre) and combined p- and m-cresol
concentrations of 0.38-2.0 µg/litre (mean of >1.1 µg/litre)
(Leuenberger et al., 1985). The concentration of o-cresol in
rainwater at a rural site in Switzerland (Greppen) ranged from
undetectable to 1.3 µg/litre. The combined concentration range of
m- and p-cresols in the same rainwater was 0.65-9.3 µg/litre
(Czuczwa et al., 1987).
Table 4. Cresol concentrations in the ground water of hazardous waste sites and landfills in the USA
No. of samples/ Concentration
Type/location Sampling date no. detecteda Isomer (mg/litre) Reference
Hazardous waste, no data 1/1 o 2.3 Weber & Matsumoto (1987)
Buffalo, New York 1/1 p 15.0
Former pine-tar manufacturing, no data 11/10 o 0.002-5.2 McCreary et al. (1983)
Gainesville, Florida 11/10 m and p 0.0004-11.1
Former wood preserving, 1984 19/6 o 0.04-7.1 Goerlitz et al. (1985)
Pensacola, Florida 19/3 p 0.02-6.2
19/4 m 0.05-13.7
Former coal gasification, no data 3/3 o 0.063-6.6 Stuermer et al. (1982)
Hoe Creek, Wyoming 3/3 m and p 0.096-16.0
Municipal landfill, 1982-1983 1/1 p 1.5 Sawhney & Kozloski (1984)
Southington, Connecticut 1982-1983 1/1 m 0.6
Underground solvent 1983 10/1 unseparated 0.04 Oliveira & Sitar (1985)
storage tanks,
Santa Clara, California
Hazardous waste, 1979-1984 4/1 unseparated 0.11 Ram et al. (1985)
Coventry, Rhode Island
a Number of samples compared with number in which cresols were detected
5.1.3 Soil
Cresols have been detected in about 1% of soil samples from 1300
Superfund (hazardous waste sites listed by US EPA in the National
Priority List) sites. The geometric mean concentrations of o- and
p-cresols in these samples were 409 and 677 µg/kg, respectively
(HAZDAT, 1992).
5.1.4 Food and beverages
Cresols have been detected in certain foods and beverages, such
as tomatoes, tomato ketchup, cooked asparagus, various cheeses,
butter, oil, red wine, spirits, raw and roasted coffee, black tea,
smoked foods and tobacco (Fiege & Bayer, 1987). Cresols were
identified as volatile components of fried chicken (Ho et al., 1983).
Quantitative data regarding cresols in food and beverages are limited.
Cresols have been detected in various beverages including Scotch
whisky (0.01-0.20 mg/litre), whiskies made outside of Scotland
(0.01-0.07 mg/litre), brandies including cognac and armagnac (trace to
0.02 mg/litre), and white and dark rums (trace to 0.20 mg/litre)
(Lehtonen, 1983). The total amount of cresols in the smoke from a
nonfilter American cigarette (85 mm) is about 75 µg (Wynder &
Hoffmann, 1967).
5.2 General population exposure
The general population can be exposed to cresols from air
inhalation, drinking-water and food ingestion, and dermal contact with
water or consumer products that contain cresols. Due to the lack of
adequate monitoring data regarding cresol levels in ambient air and
drinking-water, it is not possible to estimate quantitatively the
daily intake of cresols from these sources. Similarly, to estimate
the daily intake of cresol from food for a member of the general
population requires data concerning the level of these compounds in
total diet samples (various categories and quantities of food consumed
daily by a typical individual), and these data are not available.
Dermal contact to cresols may also result from use of certain consumer
products, since cresols may be used as disinfectants in some soap and
as wood preservatives. It is likely that people who live near certain
kinds of emission sources (e.g., heavy vehicular traffic, certain
incinerators, and landfill sites, such as abandoned coal tar or
creosote producer/user sites) will be exposed to higher levels of
cresols than the general population. Since both mainstream and
sidestream smoke of cigarettes contain cresols (Wynder & Hoffmann,
1967), smokers and those who inhale sidestream smoke may be exposed to
a higher level of cresols.
5.3 Occupational exposure
Occupational exposure to cresols is likely among workers
involved in the production of cresols or processes that produce
cresols (coal gasification, shale oil retorting) and those who use
cresols or products containing cresols (such as creosote). Little
information regarding occupational exposure to cresols is available.
The concentration of cresols in the workroom air of a pilot coal
gasification plant in the USA was < 0.44 mg/m3 (< 0.1 ppm)
(Dreibelbis et al., 1985). The extent of worker exposure to cresols
and other pollutants was measured in a facility in Finland that used
creosote for impregnation of wood. The highest observed mean
concentration of cresols in the air was 0.6 mg/m3 during periods in
which the cylinder used for impregnation was opened, followed by a
concentration of 0.2 mg/m3 during periods in which the cylinder was
closed (Heikkila et al., 1987).
All 14 countries listed in ILO Occupational Exposure Limits for
Airborne Toxic Substances (1991) have set an environmental
concentration of 22.1 mg/m3 (5 ppm) for time-weighted average (TWA)
exposure for all isomers of cresol.
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption
Cresols are absorbed across the respiratory and gastrointestinal
linings and through the intact skin. Absorption of cresols through
the lungs has not been studied quantitatively. However, the
occurrence of mortality and other systemic effects in animals exposed
to cresol aerosols and vapours in air shows that absorption through
the lungs does occur (Uzhdavini et al., 1972; Pereima, 1975). The
rate and extent of gastrointestinal absorption of cresols have not
been studied specifically. However, they are suggested by data
showing that rabbits exposed orally to cresols excreted 65-84%
(depending on the isomer) of the administered dose in the urine within
24 h (Bray et al., 1950), indicating that at least that amount was
absorbed within that time period. The occurrence of coma, death and
systemic effects in humans after dermal exposure to cresols (see
section 8) indicates that these compounds can be absorbed through the
skin. In the case of an infant who had coal tar fluid (90% cresols in
water) spilled on his head, unconsciousness occurred within 5 min and
death within 4 h, showing that absorption was rapid (Green, 1975). An
in vitro study of the permeability of human skin to cresols showed
that these substances have permeability coefficients greater than that
of phenol, which is known to be readily absorbed across the human skin
(Roberts et al., 1977). Permeability coefficients (Kp) were estimated
from the steady-state slopes of the relation between the cumulative
amount of cresol isomer per unit area of membrane with time. The
following Kp values were determined: m-cresol = 2.54 × 10-4
cm/minute; o-cresol = 2.6 × 10-4 cm/minute; and p-cresol = 2.92 ×
10-4 cm/minute (Roberts et al., 1977).
In a similar study, Hinz et al. (1991) showed rapid percutaneous
transport of p-cresol across mouse skin in vitro. Approximately
70% of the dose was transported within 6 h.
6.2 Distribution
Very few data are available regarding the distribution of cresols
into various tissues. Oral exposure studies in dogs indicate that
cresols in the body concentrate in the blood, liver and brain
initially, but soon become more widespread, appearing in the lungs,
kidneys and other organs (Gadaskina & Filov, 1971). Cresols were
detected in the blood (120 mg/litre), liver, brain and urine of a
human infant who died 4 h after 20 ml of a cresol derivative was
spilled on his head (Green, 1975).
6.3 Metabolic transformation
The primary metabolic pathway for cresols is conjugation with
glucuronic acid and inorganic sulfate. At physiological pH, the
conjugated metabolites are ionized, thus reducing renal reabsorption
and aiding urinary excretion. After oral administration of cresols to
rabbits, 60-72% of the dose was recovered as ether glucuronide, and an
additional 10-15% was recovered as ethereal sulfate in the urine (Bray
et al., 1950). Similarly, in an earlier study in rabbits, 14.5-23.5%
of orally administered cresols was found to be conjugated with sulfate
in the urine (Williams, 1938). By analogy with other phenols, it may
be expected that the relative amounts of glucuronide and sulfate
conjugates will differ between species and will also vary with dose.
Minor metabolic pathways for cresols include hydroxylation of the
benzene ring (primarily for o- and m-cresols) and side-chain
oxidation (only for p-cresol). In orally dosed rabbits, 3% of the
administered dose was recovered in the urine as conjugated
2,5-dihydroxytoluene for both o- and m-cresols (Bray et al.,
1950). For p-cresol, only a trace amount of 3,4-dihydroxytoluene
was found, but 10% of the dose was recovered as p-hydroxybenzoic
acid. After cresols were administered to rabbits, only 1-2% of the
dose was found as unconjugated free cresol in the urine (Bray et al.,
1950). Thompson et al. (1994) studied the metabolism of
[14C]- p-cresol in rat liver slices and a microsomal fraction.
They found that [14C]- p-cresol is metabolized to a reactive
intermediate which co-valently binds to proteins in the liver slices
and that the binding is inhibited by n-acetylcysteine. In
microsomal incubations and a NADPH-generating system, covalent binding
of [14C]- p-cresol metabolites was also observed. This binding was
inhibited by glutathione (GSH) resulting in the formation of a
glutathione conjugate. In the absence of GSH, p-hydroxybenzyl
alcohol was the major microsomal metabolite formed from p-cresol.
Yashiki et al. (1989) reported the recovery of conjugated cresols in
the biological fluids of a 46-year-old man following the ingestion of
100 ml saponated cresol soap solution (42%). Conjugated and free m-
and p-cresols were measured in both the serum and urine 2 h after
ingestion. Of the total recovered in the serum, 79% p-cresol and
75% m-cresols were in the conjugated form while over 99% of m- and
p-cresols recovered in the urine was conjugated.
6.4 Elimination and excretion
Significant amounts of cresols are excreted in the bile, but most
of the cresols excreted in this manner are reabsorbed from the
intestine following hydrolysis by gut bacteria (Deichmann & Keplinger,
1981). The main route for removing cresols from the body is renal
elimination.
6.5 Endogenous cresols
Healthy humans excrete an average of about 50 mg (range 16-74 mg)
of p-cresol in the urine daily (Bone et al., 1976; Renwick et al.,
1988). Endogenous p-cresol is produced from tyrosine, an amino acid
present in most proteins, by anaerobic bacteria in the intestine (Bone
et al., 1976). Free p-cresol formed in this way is absorbed from
the intestine and eliminated in the urine as conjugates.
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 Inhalation route
Acute poisoning with cresol vapour is unlikely due to the low
vapour pressure of these compounds. However, inhalation of an aerosol
and vapour mixture may cause death. Uzhdavini et al. (1972) conducted
studies into the acute toxicity of o-cresol in mice. The mean lethal
concentration of the vapour/aerosol mixture was 178 mg/m3 (duration of
exposure not specified). Clinical signs of toxicity included
irritation of mucous membranes and neuromuscular excitation that
progressed from twitching of individual muscles to clonic convulsions.
Haematuria was reported at very high concentrations. Microscopic
examination revealed oedematous changes in the lung and necrotic and
degenerative changes in the liver (fatty degeneration, centrilobular
necrosis) and kidneys (oedema, swelling of the glomeruli, degeneration
of the tubular epithelium, and perivascular haemorrhage). Mean lethal
concentrations of cresols in rats were reported to be 29 mg/m3 for
o- and p-cresols and 58 mg/m3 for m-cresol (Pereima, 1975).
7.1.2 Oral route
Oral LD50 values for cresols are shown in Table 5. A
comparison of the LD50 values for all three cresol isomers from
these studies (e.g., Deichmann & Witherup, 1944; Bio-Fax, 1969) shows
that o-cresol is the most toxic isomer, followed by p-cresol and
then m-cresol. Interspecies comparisons reveal that all three
isomers are more toxic to mice than to rats, by this route of
administration, the LD50 values being 3-4 times higher in rats than
in comparably treated mice (Uzhdavini et al., 1972; Pereima, 1975).
The data also show that for all three isomers toxicity increases with
concentration; undiluted cresols were more toxic than cresols
delivered as 10% solutions in oil. In addition, there is some
evidence that the delivery vehicle affects toxicity; the LD50 value
for m-cresol was lower in rats given a 10% solution in water than in
rats given a 10% solution in oil.
Clinical signs of toxicity that preceded death in acute oral
lethality studies of all three cresol isomers were hypoactivity and
lethargy, excess salivation, dyspnoea, haemorrhagic rhinitis
( p-cresol only), incoordination, prostration, muscle twitches and
tremors, convulsions and coma (Deichmann & Witherup, 1944; Mellon
Institute, 1949; Bio-Fax, 1969; Hornshaw et al., 1986). Necropsy of
rats that died revealed gastrointestinal inflammation and haemorrhage,
as well as hyperaemia of the lungs, liver and kidney (Mellon
Institute, 1949; Bio-Fax, 1969). Necropsy of survivors after 14 days
of observation revealed only gastro-intestinal tract inflammation in
rats treated with p-cresol and no gross lesions in rats treated with
o- or m-cresol (Bio-Fax, 1969).
Table 5. Oral LD50 values for cresols
LD50
Cresol Species Vehicle (mg/kg) Reference
o-Cresol Rat 10% in oil 1470 Uzhdavini et al. (1976)
10% in oil 1350 Deichmann & Witherup (1944)
50% in oil 360 FDRL (1975)
Undiluted 121 Bio-Fax (1969)
Mouse 10% in oil 344 Uzhdavini et al. (1976)
Rabbit 10% in oil 940 Uzhdavini et al. (1976)
m-Cresol Rat 10% in oil 2010 Pereima (1975)
10% in oil 2020 Deichmann & Witherup (1944)
10% in water 520 Mellon Institute (1949)
Undiluted 242 Bio-Fax (1969)
Mouse 10% in oil 600 Pereima (1975)
10% in oil 828 Uzhdavini et al. (1976)
p-Cresol Rat 10% in oil 1430 Pereima (1975)
10% in oil 1460 Uzhdavini et al. (1976)
10% in oil 1800 Deichmann & Witherup (1944)
Undiluted 207 Bio-Fax (1969)
Mouse 10% in oil 440 Pereima (1975)
10% in oil 344 Uzhdavini et al. (1976)
Dicresol Rat 10% in oil 1625 Uzhdavini et al. (1976)
Mouse 10% in oil 651 Uzhdavini et al. (1976)
7.1.3 Dermal route
Cresols may cause death when applied to the skin. Dermal LD50
values in rabbits were 890, 2830, 300 and 2000 mg/kg for o-, m-,
p- and mixed cresols, respectively, following 24-h dermal exposure
(Vernot et al., 1977). In rats, the dermal LD50 values were 620,
1100, 750 and 825 mg/kg for o-cresol, m-cresol, p-cresol and
dicresol (a mixture of m- and p-cresols), respectively (Uzhdavini
et al., 1974, 1976).
7.2 Short-term exposure
7.2.1 Inhalation route
Uzhdavini et al. (1972) exposed mice to a mixture of o-cresol
aerosol and vapour 2 h/day, 6 days/week for 1 month; exposure
concentrations varied from 26 to 76 mg/m3, with an average of
50 mg/m3. No mortality was recorded. Clinical signs of toxicity
during the daily exposure periods were limited to signs of
respiratory irritation at the start of the exposure, followed by a
period of hypoactivity lasting until the end of the exposure. The
tails of some animals mummified and fell off after 18-20 days. Body
weight gain was slightly reduced compared to controls. Microscopic
examination revealed signs of irritation in the respiratory tract;
these included oedema, cellular proliferation, and small haemorrhages
in the lung. Other lesions included degeneration of heart muscle,
liver, kidney and nerve cells and glial elements of the central
nervous system.
7.2.2 Oral route
Female B6C3Fl mice (8-10 weeks of age) were exposed to
o-cresol at concentrations of 0, 6.5, 32.5, 65 or 130 mg/kg per day
ad libitum in the drinking water) for 14 days (CIIT, 1983).
Immunotoxicity or altered host resistance was measured as changes in
haematological values, lymphoid organ weights, altered lymphoid cell
morphology and cell or humoral-mediated immune function. No evidence
of immunotoxicity was seen in any of the parameters tested. No
changes in immune functions were reported at any dose level.
Therefore the threshold for immune response in these studies is above
130 mg/kg per day (see Table 6).
US NTP (1992) conducted 28-day studies in which Fischer 344/N
rats and B6C3F1 mice were exposed to o-, m-, p- or
m-/ p-cresol (60:40 mixture of the m- and p-) in the feed. For
each substance, groups of five animals of each sex and each species
were fed ad libitum diets containing 0, 300, 1000, 3000,
10 000 or 30 000 mg/kg. Estimated daily doses (mg/kg body weight per
day) in males and females of each species exposed to each test
substance are shown in Table 7. None of the cresols caused mortality
in rats. All cresols reduced feed consumption during the first week
of the study and body weight gain throughout the study in rats exposed
at the highest level. However, feed consumption of all dosed groups
was comparable to that of controls after the first week. Clinical
signs of toxicity were not observed in rats treated with o- or
m-cresol, but rats exposed to 30 000 mg p-cresol/kg had hunched
posture, rough hair coat and thin appearance. Thin appearance was
also noted in rats exposed to the highest dose of m-/ p-cresol.
Organ weight changes in rats included increases in absolute and
relative liver weight and kidney weight compared to brain weight.
Increases in several other organ weights, relative to body weight were
reported, but as there was a very marked decrease in body weight at
the highest dose levels, only the increased liver and kidney weights,
relative to brain weight, were regarded as being of biological
significance. No gross or microscopic lesions were found in rats
exposed to o-cresol. m-Cresol caused minimal-t o-mild atrophy of
the uterus in females exposed to 30 000 mg/kg. p-Cresol also caused
uterine atrophy in females exposed to 30 000 mg/kg, as well as bone
marrow hypo-cellularity and nasal lesions (atrophy of olfactory
epithelium and hyperplasia and squamous metaplasia of respiratory
epithelium) in rats exposed to > 3000 mg/kg. m-/ p-Cresol caused
hyperplasia of the respiratory epithelium in the nasal cavity at >
1000 mg/kg, increased colloid within thyroid follicles at >
3000 mg/kg, mild hyperplasia and hyperkeratosis of the oesophageal
epithelium and forestomach at > 3000 and > 10 000 mg/kg,
respectively, and mild bone marrow hypocellularity at >
10 000 mg/kg. A no-observed-adverse-effect level (NOAEL) of
3000 mg/kg was established for o, m and m/p cresols and a NOAEL of
1000 mg/kg for p-cresol based on organ weight and body weight
changes at higher doses.
In the mice exposed in this study death was caused by o-,
m-and p-cresol at 30 000 mg/kg and only by m- or p-cresol at
10 000 mg/kg. The m-/ p-mixture was not lethal to mice at any
concentration. For all cresols, high-dose mice that survived exposure
lost weight during the study, and body weight gain was generally
decreased in the 10 000 mg/kg groups as well. Clinical signs of
toxicity seen at > 10 000 mg/kg in mice exposed to m-and
p-cresols and 30 000 mg/kg in mice exposed to o- and
m-/ p-cresols included hunched posture, thin appearance, rough hair
coat, lethargy, hypothermia, rapid breathing and tremors. Organ
weight changes in mice were increased in absolute and relative liver
Table 6. Short-term toxicity of cresolsa
Species/ Number/ Compound Route Dose Length of Effects References
strain sex exposure
Mice/ NR/F (8-10 o-cresol oral 0, 6.5, 32.5, 14 days No effects noted in haematology or CIIT (1983)
B6C3Fl weeks old) (drinking) 65 or 130 immune functions
water mg/kg/day
Mice/ 5/sex f/m o-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg death, (2 males & 1 US NTP
B6C3Fl 1000, 3000, female) tremors, rough hair coat, (1992)
10 000 or ovarian atrophy; > 10 000 mg/kg
30 000 body weight decreased, uterine
mg/kg diet atrophy; > 3000 mg/kg increased
relative liver weight
Mice/ 5/sex f/m m-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg increased brain weight, US NTP
B6C3Fl 1000, 3000, ovarian, uterine and mammary gland (1992)
10 000 or atrophy; 10 000 mg/kg (1 female)
30 000 and 30 000 mg/kg (2 male, 2 female)
mg/kg diet death, decreased body weight, clinical
signs of toxicity; > 3000 mg/kg
increased kidney weight; > 300 mg/kg
increased liver weight
Mice/ 5/sex f/m p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg death all animals; US NTP
B6C3Fl 1000, 3000, 10 000 mg/kg (1 male) death, clinical (1992)
10 000 or signs of toxicity, reduced body
30 000 weight; > 3000 mg/kg increased liver
mg/kg diet weight; > 300 mg/kg nasal respiratory
lesions
Table 6 (cont'd).
Species/ Number/ Compound Route Dose Length of Effects References
strain sex exposure
Mice/ 5/sex f/m m-/p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg clinical toxicity, and US NTP
B6C3Fl (60:40 ratio) 1000, 3000, respiratory metaplasia and atrophy of (1992)
10 000 or nasal epithelium; > 3000 mg/kg
30 000 hyperplasia lungs, oesophagus and
mg/kg diet forestomach, uterine and ovarium
atrophy
Mink 5/sex f/m o-cresol oral (diet) 0, 240, 432, 28 days 2520 mg/kg reduced body weight Hornshaw
178, 1400 gain, increased relative heart weight, et al.,
or 2520 decreased haemoglobin; > 1400 (1986)
mg/kg diet mg/kg decreased RBC count; > 432
mg/kg increase relative liver weight
Ferrets 5/sex f/m o-cresol oral (diet) 0, 432, 778, 28 days 4536 mg/kg decreased RBC count; > Hornshaw
1400, 2520, 1400 mg/kg increased relative liver et al.,
4536 and kidney weight (1986)
mg/kg diet
Rats/ 5/sex f/m o-cresol oral (diet) 0, 300, 28 days > 3000 mg/kg increased relative liver US NTP
Fischer-344 1000, 3000, and kidney weight; 30 000 mg/kg (1992)
10 000, decreased body weight
30 000
mg/kg diet
Rats/ 5/sex f/m m-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg decreased body US NTP
Fischer-344 1000, 3000, weight; increased relative kidney (1992)
10 000, weight; mild atrophy of uterus; >
30 000 10 000 mg/kg increased relative liver
mg/kg diet weight
Table 6 (cont'd).
Species/ Number/ Compound Route Dose Length of Effects References
s