EPA/600/8-86/003F
Jan. 1986
Summary Review of the Health Effects
Associated with Phenol:
Health Issue Assessment
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, DC 20460
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation
for use.
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CONTENTS
Page
... iv
List of Figures
List of Tables
I. Introduction 1
II. Air Quality: Sources, Distribution, Fate, and Ambient Levels 4
III. Health Effects 6
Pharmacokinetics ' g
Absorption and Distribution 6
Metabolism "^ Q
Excretion 14
Acute, Subchronic, and Chronic Toxicity 14
Teratogenicity and Reproductive Toxicity 22
Mutagenicity 23
Carcinogenicity ' 24
IV. Summary and Conclusions 28
V. References 32
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LIST OF FIGURES
1. Fate of a sublethal oral dose of phenol analyzed over
24 hours
Page
.... 9
2. Concentrations and excretion rates of phenol in urine in a
human subject exposed to phenol vapor in a concentration of
18.3 mg/m3 by inhalation for 6 hr
10
3. Fate of a lethal oral dose of phenol analyzed over 5 hours 11
4. Excretion rate of "excess" phenol in relation to absorption in
human subjects during and after 6 hr. inhalation exposures 15
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LIST OF TABLES
Page
1. U.S. Companies Producing Phenol as of January 1984 4
2. Distribution of Phenol in the Organs of Rabbits After an
Oral Dose of 0.5 g/kg 7
3. Species Variation in the Conjugation of Phenol 12
4. Human Responses to Phenol at Various Durations and Airborne
Concentrations -j g
5. Oral Toxicity of Phenol in Humans 19
6. The Acute Toxicity of Phenol to Nonhuman Mammals 19
7. Subchronic Inhalation Toxicity of Phenol 20
8. Tumor Incidence in Rats and Mice Exposed to Phenol Via
Drinking Water 26
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I. INTRODUCTION
The purpose of this overview is to provide a brief summary of the data base
available concerning health effects associated with exposure to phenol
[monohydroxybenzene; carbolic acid]. Emphasis is placed on determining
whether or not evidence exists which suggests that phenol exerts effects on
human health at concentrations commonly encountered by the general public
under ambient air exposure conditions. Both acute and chronic health effects
are addressed, including general toxicity, reproductive toxicity, teratogenicity,
mutagenicity, and carcinogenicity. This report also reviews certain air quality
aspects of phenol in the United States, including sources, distribution, fate, and
concentrations associated with rural, urban, and point source areas as
background for placing the health effects discussion in perspective.
Phenol [CAS no. 108-85-2], sometimes referred to as carbolic acid, is a
monohydroxy derivative of benzene which is a.clear, colorless (light pink in the
presence of impurities), hygroscopic, deliquescent, crystalline solid at 25°C. It
has a molecular formula of C6HSOH and a molecular weight of 94.1. At 25°C,
the specific gravity is 1.071 and the vapor pressure is 0.35 mm Hg. Pure solid
phenol has a melting point of 43°C and a boiling point of 182°C at standard
pressure. It has a very sweet tarry odor which is detectable at a recognition
threshold (100% response) of —0.05 ppm. Phenol has a water solubility of 6.7
g/100ml at 16°C; its solubility, however, is variable between 0-65°C. Above
65.3°C, phenol and water are miscible in all proportions. Phenol is very soluble
in most organic solvents: ethyl ether, methyl alcohol, ethyl alcohol, carbon
tetrachloride, acetic acid, glycerol, liquid sulfur dioxide, and benzene.
Monohydroxybenzene, generically known as phenol, is the simplest member
of a class of organic compounds known collectively as phenols. Members of
this class contain one or more hydroxyl groups attached to an aromatic ring.
This latter attachment causes delocalization of the oxygen electron pair into the
benzene ring due to the electronegativity. This so-called "resonance"
phenomenon of phenol(s) is responsible for their acidity and in this respect they
also differ from alcohols. Phenol is slightly acidic with pKa of 9.9 in aqueous
solutions at 25°C (Ka = 1.3 x 10"10). With the exception of phenol [mono-
hydroxybenzene], most phenols are not soluble in water; however, they readily
ionize in strong bases to form salts collectively referred to as phenoxides,
phenolates, and phenates. Many of these phenoxides, especially those
produced from the alkali earth metals, are soluble in water.
Aside from acidity, the most striking chemical property of phenol(s) is the
extremely high reactivity of the aromatic ring towards electrophilic substitution,
especially the hydrogen atoms that are ortho and para to the hydroxyl group.
This property, like acidity, is due to the electronic interaction between the
hydroxyl and phenyl groups. Phenols undergo not only electrophilic substitu-
tion reactions that are typical of most aromatic compounds, but also react in
ways that are uniquely due to the presence of the hydroxyl group. Some of the
more important reactions are the'formation of salts, ethers and esters, and ring
substitution. The latter encompasses nitration, sulfonation, halogenation,
alkylation, acylation, nitrosation, coupling with diazonium salts, aldehyde
formation, and reaction with formaldehyde. The most important commercial
reaction of phenol is its condensation with formaldehyde to produce phenolic
resins. This reaction accounts for approximately 40 percent of U.S. phenol
usage.
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Phenol was first isolated from coal tar in 1934. The first synthetic method
developed just prior to World War II involved the sulfonation of benzene and
subsequent hydrolysis. Today, the majority of phenol is produced synthetically
and very little (1 -2 percent) is recovered by the fractional distillation of coal tar.
The two most widely used synthetic processes for phenol production are
cumene hydroperoxidation and toluene oxidation. Among the top fifty
chemicals listed in terms of production for 1983, phenol ranked thirty-fourth;
this ranking did not include data from coke and gas retort ovens (Anonymous,
1984a).
As a result of large production volume and natural sources,, occupational and
environmental exposure to phenol is likely; however, the inhalation of phenol
vapors appears to be largely restricted to the occupational environment and/or
populations living in the immediate vicinity of point sources. The National
Institute for Occupational Safety and Health (NIOSH) estimated that as many as
10,000 workers are potentially exposed to phenol. This figure encompasses
people who are employed in the production of phenol, its formulation into
products, and the distribution of concentrated phenol products (National
Institute for Occupational Safety and Health, 1976).
The American Conference of Governmental Industrial Hygienists (1952)
recommended as early as 1952 that air concentrations of phenol vapor in the
workplace be limited to 5 ppm (19 mg/m3). Due in part to its low volatility,
phenol does not frequently constitute a serious respiratory hazard in industry
(Elkins, 1959). A skin notation was added in 1961, and there has been no
change in the TLV (5 ppm) through 1985 by ACGIH (American Conference of
Governmental Industrial Hygienists, 1961, 1984). According to Thomas and
Back (1964), the TLV of 5 ppm provides a sufficiently large safety factor to
prevent systemic poisoning if skin absorption is avoided. The present short-
term exposure limit (STEL) for phenol is 10 ppm (38 mg/m3). Compared to the
TLV, the general ambient levels of phenol, based on monitoring data, are
extremely low, with the possible exception of concentrations in the immediate
vicinity of phenol manufacturing and/or processing plants. Although data on
phenol in soil and water are plentiful, information on the fate of phenol once it
is released into the ambient air is limited. Estimates of reaction rates, based on
data derived from structure-activity relationships, suggest that reactions with
atmospheric radicals are the dominant removal processes. As a result, the
half-life of atmospheric phenol is less than one day.
Phenol is known to be absorbed readily by animals and man after oral,
inhalation, or dermal exposure. The disposition of phenol by the body is
primarily by Phase II conjugation reactions, secondarily by Phase I oxidative
reactions to dihydroxy products, and thirdly by urinary excretion of unchanged
phenol. The relative importance of these elimination processes, and in
particular the nature of the conjugates (predominantly sulfates and glucuro-
nides), differs across species. The conjugation and oxidative products are in
general less toxic than phenol and are excreted into the urine.
Regardless of the route of exposure, the signs and symptoms of acute toxicity
in man and experimental animals are similar. Muscle weakness, convulsions,
and coma are the predominant symptoms associated with exposure to lethal
concentrations of phenol. Dermal and oral LD5o values are reported in the
literature, most falling within one order of magnitude according to the
sensitivity of the species. Although LC5o values are not available in the
literature, rats exposed to 236 ppm (900 mg/m3) phenol vaporfor 8 hr exhibited
signs of irritation, loss of coordination, tremors, and prostration. Subchronic
inhalation studies in animals have demonstrated species-to-species variation
in sensitivity to phenol, with the guinea pig appearing to be most sensitive and
the rat most resistant.
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No chronic inhalation studies were found in the available literature on
phenol; however, there are two chronic oral studies described. If these data are
utilized along with some of the subchronic data, various effect levels (e.g.,
no-observed-adverse-effect level, NOAEL) can be derived for phenol. Terato-
genic effects have not been associated with exposure to phenol by either the
inhalation or oral route, although high doses of phenol are fetotoxic. Although a
clear carcinogenic response is not available from long-term bioassay data,
there were non-dose-related increases in the incidence of some tumor types.
In addition, phenol has been shown to have tumor-promoting activity when
large concentrations of phenol solution were painted on the skins of "S" strain
albino mice.
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II. AIR QUALITY: SOURCES, DISTRIBUTION,
FATE, AND AMBIENT LEVELS
Sources of naturally occurring phenol are animal waste and decomposition
of organic wastes (U.S. Environmental Protection Agency, 1983). Manmade
sources of phenol include the fractional distillation of coal tar (Thurman, 1982),
effluents from the conversion of coal (Parkhurst et al., 1979), and wastewater
from manufacturing of resins, plastics, fibers, adhesives, iron and steel,
aluminum, leather, and rubbers (U.S. Environmental Protection Agency,
1983). Other sources of environmental phenol for all media (air, water, soil)
include spills during transport, storage, and use, and emissions during
manufacturing processes (Delaney and Hughes, 1979). Based on emission
factors for air, provided by Delaney and Hughes (1979), emission of phenol
from its manufacture by the common oxidative process alone is estimated at
0.181 x 103 MT (0.4 x 106 Ibs) for 1983.
Today, the two most widely used processes for phenol production utilize
cumene hydroperoxidation and toluene oxidation (Thurman, 1982). According
to SRI International (1984), the companies in the United States shown in Table
1 are the principal producers of phenol as of January 1984. The Monsanto
Company stopped production of phenol atthe Alvin, TX facility, reducing 1983
production capacity by 500 x 106 pounds (Greek, 1984). Including production
from coke ovens and gas retort ovens, the 1983 production volume for phenol
was 2638 million pounds (U.S. International Trade Commission, 1984).
Table 1. U.S. Companies Producing Phenol as of January 1984
Company
Annual Capacity
(Millions of Pounds)
A/tied Corp., Frankford, PA
Clark Chem. Corp., Blue Island, IL
Diamond Shamrock Corp., Tuscaloosa, AL
Dow Chem., Oyster Creek, TX
Ferro Corp., Sante Fe Springs, CA
General Electric Co., Mount Vernon, IN
Georgia-Pacific Corp., Bound Brook, NJ
Plaquemine, LA
Getty Oil Co., El Dorado, KS
Kalama Chem., Inc., Kalama, WA
Koppers Co., Inc., Follansbee, WV
Merichem. Co., Houston, TX
Shell Oil Co., Deer Park, TX
Stimson Lumber Co., Anacortes, WA
U.S. Steel Corp., Haverhill, OH
Total
500
88
10
465
8
400
157
330
95
75
8
20
500
2
520
3178
Source: SRI International (1984).
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Of the total phenol produced, the consumption pattern is as follows: phenolic
resins, 45 percent; bisphenol-A [2,2-bis-(4-hydroxyphenol) propane], 20
percent; caprolactam, 13 percent; alkyl-phenols, 57 percent; cresols and
xylenols, 5 percent; aniline, 3 percent; miscellaneous usage, 5 percent; and
export, 4 percent (Anonymous, 1984b).
In addition to natural and anthropogenic sources, phenol is also produced
indirectly from other atmospheric chemicals via photochemical reactions. As a
secondary source of pollution, phenol from these reactions appears to have
minimal impact on the ambient budget, compared to that from primary sources.
Based on limited available data, the median ambient atmospheric levels of
phenol (based on estimated 24-hour averages) are 30 ppt (120 ng/m3) for
urban/suburban areas and 5000 ppt (19,000 ng/m3) for source-dominated
areas (Brodzinsky and Singh, 1982).
Relative to other environmental media (water, soil), the data base regarding
the fate of phenol in the atmosphere is somewhat limited. The initial half-life of
phenol in the atmosphere, based on estimated data derived from structure
activity relationships, was 0.5 day (Hendry and Kenley, 1979). In polluted
atmospheres, reactions with NO3 radicals may dominate and the half-life of
phenol would be less than one minute (Carter et al., 1981). The anticipated
products formed from phenol in the atmosphere via photochemical reactions
are dihydroxybenzenes, nitrophenols, and ring cleavage products. Most
recently, Battelle Columbus Laboratories, under contract to EPA, have
determined major reaction products (2-nitrophenol, 4-nitrophenol) and have
experimentally estimatedthe half-life of phenol to be ~4 to 5 hr (disappearance
rate of phenol 0.113 hr~1 corrected for dilution) under photochemically reactive
conditions (1 ppm phenol; 1.0 ppm propylene, 3.0 ppm butane, and 0.5 ppm
NO2) using a smog chamber (Spicer et al., 1985). As for atmospheric removal
mechanisms, Callahan et al. (1 979) have speculated that phenol will undergo
photodecomposition in the atmosphere and some phenol may be removed by
wet deposition. Although atmospheric oxidation via the hydroxyl and nitrate
radicals appears to be the dominant fate-determining pathway for atmospheric
phenol, most recent data (Leuenberger et al., 1985) do indicate that with
respect to wet deposition, gas scavenging is much more important than particle
scavenging for phenols since the latter in air are virtually exclusively present in
the gas phase. The efficiency of this removal process is clearly reflected in the
high concentrations of phenol in rain water.
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III. HEALTH EFFECTS
Pharmacokinetics
Absorption and Distribution
Phenol is readily absorbed upon contact with intact or abraded skin, and from
the gastrointestinal tract and lungs of animals and man (Deichmann and
Keplinger, 1981; Babich and Davis, 1981). Regardless of the route of exposure,
absorption is rapid, as illustrated by the fact that acute doses of phenol can
produce symptoms of toxicity within minutes of administration.
Reports of occupational exposure and controlled human exposure studies
showed that phenol can enter the human body by inhalation and through the
skin by adsorption, and is rapidly detoxified and eliminated by conjugation and
excreted in the urine. Studies by Piotrowski (1971) in which dermal absorption
was precluded (facemask) have demonstrated that phenol in air (6-20 mg/m )
is rapidly absorbed and efficiently (60-88 percent) retained in the lungs of
human volunteers. Phenol vapor readily penetrates the skin with an absorption
rate somewhat lower than that of inhalation but approximately proportional to
the vapor concentration in the air (Piotrowski, 1971). The predominant route of
elimination is through the urine; however, small amounts are excreted in the
fecesor in exhaled air. Ohtsuji and Ikeda (1972} demonstrated that the urinary
concentration of total phenol (free plus conjugated) in Bakelite® factory
workers was a good index of exposure to atmospheric levels of phenol. This
linearity between environmental phenol concentrations and total urinary
phenol is attributable to changes in concentrations of conjugated phenol since
the levels of free phenol remained essentially unchanged regardless of
exposure. The concentration of conjugated phenol increased during the
working shift, but decreased to pre-exposure levels the following morning,
suggesting that these employees readily conjugated and eliminated the phenol
absorbed as a result of their combined inhalation and skin exposure. These
results are in agreement with and appear to support similar conclusions made
by Piotrowski (1971), who separately investigated the inhalation and skin
absorption of phenol vapor. As in adults, phenol was detected in the urine of
infants (2-5 months) when they were skin-painted twice daily for 48 hours with
Magenta Paint BPC (4 percent phenol, w/v) for treatment of seborrhoeic
eczema (Rogers et al., 1978).
In vitro studies of phenol absorption through human abdominal skin obtained
from autopsy demonstrated that 10.9 percent of the applied dose was absorbed
(Franz, 1975). In vitro studies by Hogg et al. (1981) using 14C-phenol, excised
trachea-lung preparations, and isolated perfused lung from rats support the
observation from in vivo human studies that phenol is rapidly and efficiently
absorbed through the lungs.
Once absorbed, phenol is rapidly distributed to all tissues in animals. In
rabbits, after 15 minutes of an oral dose of 0.5 g/kg body weight, the highest
concentrations were found in the liver, followed by the heart, kidneys, lungs,
blood, and muscle (Deichmann, 1944; Table 2). Additional studies on rats
demonstrated that the liver, spleen, kidney, and adrenal gland consistently
exhibited phenol concentrations greater than that observed in plasma (Liao and
Oehme, 1981). Elevated levels of 14C-phenol (phenol plus metabolites) were
also found in the thyroid glands and the lungs compared to the plasma. The
majority of the radioactivity (65-85 percent) detected in the whole blood of rats
was found in the plasma as phenol and phenol conjugates. Even though phenol
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is very soluble in organic solvents and fats (Deichmann and Keplinger, 1981),
its uptake by tissues high in lipids (fat, testes, brain) was very low, based on
total radioactivity.
The kinetics of phenol distribution were studied by Oehme (1969) in a
number of species and in the desert rodent Notomys alexis by Wheldrake et al.
(1978). Intravenously injected 14C-phenol disappeared most rapidly in goats
and most slowly in cats. The half-life of the disappearance of 14C-phenol
(phenol plus metabolites) from the blood of the desert rodent N. a/exiswas 14.1
min (5 mg/kg) and 19.4 min at 100 mg/kg. Within 30 minutes after injection, a
minimum of 95 percent of the 14C-phenol had been metabolized. In rabbits
(Deichmann, 1944) roughly 77 percent of the administered dose was excreted
in the urine during the first 24 hours, and approximately 20 percent was
completely metabolized to CO2 and water plus other trace substances (Figure
Even though the study by Piotrowski (1971) does not provide distributional
data for various organs, it does indicate a rapid rate of clearance of phenol in
man in inhalation experiments (6-20 mg/m3) near the TLV (Figure 2).
Figure 1. Fate of a sublethal oral dose of phenol analyzed over 24 hours.
Source: Deichmann and Keplinger (1981).
Rabbit
Oral Dose
0.3 g/kg
23%
Oxidized in
Body to COz
and Water
Plus Traces of
1,4-Dihydroxy-
benzene and
Orthodihydroxy-
benzene
Excreted
in Urine
Remaining
in Carcass
Exhaled
in Air
Excreted
in Feces
48%
Excreted as
Free Phenol
52%
Excreted as
Conjugated Phenol
50%
Conjugated
With
Suit'uric Acid
30%
Conjugated
With
Glucuronic Acid
20%
Conjugated
With
Other Acids
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Figure 2. Concentrations and excretion rates of phenol in urine in a human
subject exposed to phenol vapor in a concentration of 18.3 mg/m3 by
inhalation for 6 hr.
Source: Piotrowski (1971).
Exposure to
Phenol Vapor
r-720
16 20 24 4 8 12 16 20 24 4
Time of Day (h)
Metabolism
It is well known that man and mammalian species, even with no known
exposure to phenol or its metabolic precursors, excrete phenolic compounds
into urine (Williams, 1959,1964). These phenolic compounds may be derived
from dietary aromatic amino acids or food components (Van Haaften and Sie,
1965). The normal range reported for phenol levels in human blood differs
markedly among various investigators, principally because of analytical
methodology (Ikeda and Ohtsuji, 1969; Adlard et al., 1981) and the amount of
dietary protein, which increases urinary phenol excretions (Folin and Denis,
1915).
Exogenous sources of urinary phenol include environmental chemicals (e.g.,
benzene) and medicines containing phenylsalicylate (Kociba et al., 1976) such
as Pepto-Bismol® and Chloraseptic® lozenges. Although phenol is a well-
known metabolite of the leiikemogen benzene, phenolperse fails to exhibit any
potential for myeloclastogenicity compared to benzene or the mildly clastogenic
benzene metabolite hydroquinone (Gad-EI-Karim et al., 1985). The metabolism
of exogenous phenol has been extensively studied qualitatively and quantita-
tively by Deichmann and Keplinger (1981) in rabbits at lethal and sublethal oral
doses. Results from these studies are summarized in Figures 1 and 3. A
10
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Figure 3. Fate of a lethal oral dose of phenol analyzed o ver 5 hours.
Source: Deichmann and Keplinger (1981).
Rabbit
Oral Dose
0.5g/kg
47%
Oxidized in
Body to COz
and Water
Plus Traces of
1,4-Dihydroxy-
benzene and
Orthodihydroxy-
benzene
Excreted
in Urine
Remaining
in Carcass
Exhaled
in Air
Trace
Excreted
in Feces
37%
Excreted as
Free Phenol
63%
Excreted as
Conjugated Phenol
detailed review of the metabolic fate of phenol is provided by Williams (1964),
and a systematic study of phenol metabolism in various animal species and
man has been described by Capel et al. (1972a,b). In the majority of mammals,
including man, four major metabolites of phenol have been reported, namely
phenyl sulfate, phenyl glucuronide, quinol (or 1,4 benzenediol) sulfate, and
quinol glucuronide (Table 3). Their relative importance, however, depends on
the species and dose level being considered. Urine analysis by paper
chromatography showed that eight of the treated species excreted all four
metabolites, six species excreted only three metabolites, four species excreted
two, and one species excreted only one. In the majority of these animals,
phenyl glucuronide and phenyl sulfate were the principal end products of
metabolism. However, there are certain species such as the cat, pig, and
brush-tailed opossum that give rise to interesting quantitative differences in
metabolic end products. The pig was found to be virtually unable to use the
sulfate conjugation mechanisms. Similarly, the cat was found to produce only
small amounts of the glucuronide conjugate.
Results comparable to Capel et al. (1972a,b) on the metabolism of phenol and
recovery of radioactivity in urine were also obtained by other investigators for
the rat, pig, and cat. Kao et al. (1979) reported that phenyl glucuronide and
phenyl sulfate were the major metabolites for the rat and sheep, with sulfate
and glucuronide conjugates of quinol as the minor constituents. Unlike
rodents, sheep were found to excrete phenyl and quinol phosphates. In the pig,
phenyl glucuronide was the major metabolite (83 percent), compared to 1
11
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Table 3. Species Variation in the Conjugation of Phenol. Dose of 14C-
Phenol = 25 mg/kg Orally (in Man 1 mg/Person or 17 fjg/kg)
4C Excreted in 24 hrs as the
Species
Pig*
Indian
fruit bat
Rhesus
monkey
Cat*
No. of
Metabolites
1
2
2
2
Glucuronide
of
Phenol Quinol
1OO
90
35
0
0
0
O
0
Sulfate of
Phenol
0
10
65
87
Quinol
0
0
O
13
Remarks
no
sulfate
no
Man
23
71
glucuronide
O
Squirrel
monkey
Ring tail
monkey
Guinea pig
Hamster
Rat
Ferret
Rabbit
Gerbil
Hedgehog
Lemming
Mouse
Jerboa
*The sulfate
conjugation
(1972a,b).
3
3
3
3
3
3
3
3
3
4
4
4
70
65
78
50
25
41
46
15
15
38
33
26
19
21
5
25
7
0
0
0
0
15
14
4
10
11
17
25
68
32
45
69
75
35
43
61
0
0
0
0
0
28
9
15
1O
12
5
12
two
glucuronides
and one
sulfate
two sulfates
and one
glucuronide
conjugation of phenol in the pig and the glucuronic acid
of phenol in the cat are very small (about 2%). From Cape/ et al.
percent for the phenyl sulfate conjugate. It should be noted that this sulfate
conjugation deficiency is not common to all phenols, since the pig is capable of
conjugating 1-naphthol with sulfate to an appreciable extent {Capel et al.,
1974). Miller et al. (1973,1976) confirmed previous findings that the cat lacks
the ability to conjugate phenol as glucuronide. Phenyl sulfate and quinol
sulfate were detected as the major metabolites. Even the desert-adapted
rodent N. alexis, like the jerboa and gerbil (Capel et al., 1972a,b), is similar to
hamsters and laboratory rats and mice. N. alexis also fails to diverge from the
typical pattern of four phenolic metabolites. Therefore, the metabolism of
12
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compounds such as phenol, which are rapidly conjugated to soluble form, are
the same and independent of low water turnover (Wheldrake et al., 1978).
When phenol conjugation was studied in vitro using liver preparations from
N. alexis, the formation of phenyl sulfate was found to predominate over
formation of phenyl glucuronide at low phenol concentrations (Ramili and
Wheldrake, 1 981), an observation also recorded in intact animals (Wheldrake
et al., 1978). The preferential formation of phenyl sulfate over phenyl
glucuronide at low phenol dose levels is suggested by the authors to be due to a
higher affinity, for phenol, of sulfotransferase (Km = 1.9x10~5M) compared to
glucuronyl transferase (Km = 6.4 x 10~4M). The reduction of phenyl sulfate
formation seen at high phenol concentrations is due to the depletion of a
cosubstrate in the reaction, 3'-phosphoadenosine-5'-phosphosulfate (PAPS).
The formation of PAPS becomes rate-limiting at high phenol concentrations.
When the phenol dose was increased, a similar decrease in the ratio of
formation, of sulfate to glucuronide was observed by Weltering et al. (1979) as
they studied the incorporation of 3SS-sulfate into phenyl sulfate in male Wistar
rats. No significant depletion of the inorganic sulfate pool was observed.
Even though hepatic metabolism continues to be accepted as quantitatively
the most important route of elimination for drugs and other xenobiotics, the
role of extrahepatic biotransformation in the disposition and toxicity of foreign
compounds is receiving increasing attention. Several in vitro studies utilizing
the intestines and lung as semipurified tissue homogenates, isolated cells, and
isolated perfused organs have been used to indicate potential extrahepatic sites
of phenol metabolism (Cassidy and Houston, 1984). In the rat trachea-lung
preparation, the amount of conjugation was inversely dose-dependent, ranging
from 83 percent at the lowest dose to 65 percent at the highest dose. Phenyl
glucuronide and phenyl sulfate were present in approximately equal propor-
tions, with small amounts of quinol sulfate detected. A similar degree of
conjugation (85 percent) was found for the isolated perfused rat lung. Isolated,
perfused segments of small intestine from the rat were able to convert 14C-
phenol to phenyl sulfate (5 percent) and phenyl glucuronide (95 percent).
Similar results were found in rat gut segments perfused in situ; the radioactivity
that appeared in the portal blood was all associated with 14C-phenol conjugates.
No free phenol was detected.
Additional knowledge concerning the intestine as a major site of phenol
detoxification derives from in vivo studies by Powell et al. (1974). Whole-body
autoradiography of young rats given 14C-phenol either orally or intraperi-
toneally did not indicate any accumulation of phenol in the liver relative to
blood levels. These results strongly support the view that free phenol is not
transported as such from the intestinal lumen but in conjugated form. It
therefore follows that the role of the liver is minimal in the detoxication of orally
ingested phenol. Extensive intestinal metabolism, as suggested by the
observation that isolated, perfused segments of rat small intestine were able to
convert 14C-phenol to phenyl sulfate (5 percent) and phenyl glucuronide (95
percent), may explain the results obtained by oral administration but not by
intraperitoneal injection. When the gastrointestinal tract is bypassed by i.p.
administration of free phenol, however, conjugation with sulfate and glucu-
ronide and subsequent excretion of these conjugates in the urine nevertheless
take place (Capel et al., 1972a,b).
Using whole-animal evaluations, Cassidy and Houston (1984) developed a
procedure to assess the relative in vivo capacity of hepatic and extrahepatic
tissues (intestinal mucosa, lung) to metabolize xenobiotics. Phenol, because of
its high metabolic clearance in the rat and its extensive first pass metabolism,
was chosen as the model compound. The ability of intestinal mucosa, liver, and
lung to conjugate phenol was investigated over a 35-fold dose range by
employing a judicious choice of route of administration. Comparison of blood
13
-------
phenol concentration-time profiles, following intravenous administration into
the jugular and the hepatic portal veins, indicates extensive hepatic conjuga-
tion of phenol at low doses. The relatively poor capacity of the liver to conjugate
phenol was confirmed using isolated perfused livers over a similar dose range.
Comparison of blood phenol concentration time profiles, following vascular
administration into the carotid artery and the jugular vein, indicates substantial
pulmonary conjugation of phenol. Although the extent of pulmonary conju-
gation is less than the hepatic contribution, pulmonary conjugation is evident
over a wider dose range. Intestinal conjugation of phenol is assessed by
comparison of data from intraduodenal and hepatic portal venous administra-
tion. At low doses of phenol {<1 mg/kg), capacities of intestinal and hepatic
enzymes to conjugate phenol were comparable; however, as dose increased,
the intestine, unlike the lung and liver, maintained efficient conjugation over a
wide dose range. At large doses (>5 mg/kg), intestinal conjugation far exceeds
the contribution of the hepatic and pulmonary enzymes. The relative capacity
of the three organs to conjugate phenol may be related to the relative need for
physiological mechanisms to cope with different routes of environmental
exposure to phenolic compounds. Efficient conjugation in intestinal mucosa
over a wide dose range drastically reduces amounts of ingested phenol
reaching the circulatory system. Similarly, an effective array of enzymes in the
lung, another portal of entry for the volatile phenols, provides the body with a
defense barrier. Consequently, amounts of phenols penetrating enzymic
barriers at the portals of entry are minimized. The main source of phenols in the
liver is of endogenous origin, because of mixed function oxidase activity. The
slow rate of phenol production by these oxidative enzymes (MFO) does not
exceed the capacity of the liver to detoxify phenol via conjugation as the
glucuronide and/or sulfate.
Excretion
The contribution of the lungs, intestines, and liver to the conjugation of
phenol(s)/h vivo has been well established. In man and all other mammals that
have been tested, nearly all of the phenol and its metabolites are excreted in the
urine. The amounts excreted in feces and exhaled air are very minimal
(Deichmann and Keplinger, 1981). Twenty-four hours after administering 300
mg phenol/kg body weight orally to rabbits, Deichmann (1944) reported
finding less than 1 percent of the administered dose in the feces. Kinetic results
from controlled human exposure studies by Piotrowski (1971) via inhalation
and skin absorption showed that phenol is quickly excreted from the human
body and that this process may be described with sufficient exactness by a
simple one-compartment open model with an excretion rate constant, K, of 0.2
hr~1. This rate corresponds to a half-life of approximately 3.5 hours (Figures 2
and 4).
Acute, Subchronic, and Chronic Toxicity
Sudden collapse and unconsciousness in humans exposed to phenol are
generally associated with the impact of this agent on the central nervous
system. Human responses to phenol at various airborne concentrations and
durations are listed in Table 4. Based on unpublished data submitted to
American Conference of Governmental Industrial Hygienists in 1971 by the
Connecticut Bureau of Industrial Hygiene, intermittent industrial exposure
(5 to 10 minutes per hour, 8 hr per day) inside a conditioning room for phenol-
impregnated asbestos resulted in marked irritation of the nose, throat, and
eyes. The average phenol concentration in the room was 48 ppm, although
formaldehyde (8 ppm) also was found. This level of formaldehyde alone has
14
-------
Figure 4. Excretion rate of "excess" phenol in relation to absorption in human
subjects during and after 6 hr. inhalation exposures. Means ± S.D.
Dotted Line — theoretical curve for K = 0.2 Hour~\
Source: Piotrowski (1971).
1.2-
6 8 10 12 14 16 18 20 22 24
Hours from Start of Exposure
been shown to cause such irritation {National Institute for Occupational Safety
and Health, 1 976). Workers at the same plant continuously exposed to an
average concentration of 4 ppm during winding operations experienced no
respiratory irritation, although the odor of phenol was noticeable. Under
controlled human exposure conditions (1.5-5.2 ppm for 8 hr with two 30-min
breaks), Piotrowski (1971) described no adverse effects upon inhalation and/or
skin absorption of phenol at the present TLV of 5 ppm. Under both exposure
conditions, urinary phenol concentrations returned to normal within 16 hours
after termination of exposure. Petrov (1 963) reported 29 poisonings during a
three-year period in a group of employees in Russia who quenched coke with
waste water containing 0.3 to 0.8 mg of phenol per liter. Air samples in the
work area indicated phenol vapor concentrations of the order of 2 to 3 ppm.
Although these levels could possibly have been associated with the intoxica-
tions, the observed conditions were most likely produced by some substance
in the effluents from either the waste water or the coking process. Thus, it is
inappropriate to assume that these conditions were produced by phenolperse.
Additional studies of human responses were carried out by Mukhitov(1964).
Six 5-minute inhalation exposures to phenol at 0.004 ppm produced an
increased sensitivity to light in each of three dark-adapted subjects. Further
tests revealed that 15-second exposures to phenol (0.006 ppm) elicited the
15
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formation of conditioned electrocortical reflexes in 4 subjects. In animals,
these effects are generally preceded by muscular twitchings and severe clonic
convulsions due to the action of phenol on the central nervous system motor
mechanism. Regardless of route of exposure, the signs and/or symptoms
(physiological responses) induced by phenol in man and animals are similar.
Subsequent to absorption of an acutely toxic dose, heart rate first increases,
then becomes slow and irregular and, after an initial rise, blood pressure
rapidly declines. Salivation and labored breathing may be evident along with a
decline in body temperature. Death may occur within minutes of an acute
exposure and is usually due to respiratory failure (Deichmann and Keplinger,
1981; Sollmann, 1957).
With respect to odor threshold, Leonardos etal. (1969) reported an average
value for 100 percent recognition at 0.047 ppm, which agrees well with the
upper limit of the range reported by Mukhitov (1964). However, in some
sensitive individuals odor recognition has been reported as low as 0.006 ppm
(Mukhitov, 1964; Makhinya, 1972). Such studies certainly demonstrate that
phenol has warning properties by odor at concentrations far below the
concentrations at which toxic effects occur.
Only limited information exists by which to estimate lethal phenol exposure
levelsfor humans. Even though phenol has long been used in suicide attempts,
a lack of accurate documentation makes it difficult to estimate the LDsofor oral
exposure to man. Assuming a standard 70-kg body weight and using reported
oral toxicity data, estimated ingestion doses for phenol associated with lethal
or near-lethal outcomes can be calculated (Table 5). The human lowest lethal
dose (LDU) for phenol is estimated to be 140 mg/kg. No published information
was found concerning lethal exposure levels for humans via the inhalation
route.
The acute toxicity of phenol in terms of a lethal dose necessary to kill 50
percent of test animals (LD5o) has been evaluated for various species and
various routes of exposure (Table 6). The majority of the LDso values fall within
one order of magnitude, with the cat being most sensitive and the guinea pig
most resistant. No LC50 values associated with acute exposure were found in
the available literature for animal inhalation studies; however, Flickinger
(1976) did report that rats exposed to 236 ppm phenol vapor (900 mg/m3) for 8
hours developed ocular and nasal irritation, loss of coordination, tremors, and
prostration. Also, subsequent to dermal application of reagent grade phenol,
rats developed severe skin lesions, with edema followed by necrosis (Conning
and Hayes, 1970).
Prolonged administration of phenol to animals can lead to pathological
changes in the skin, mucous membranes, esophagus, lungs, liver, kidney,
heart, and genitourinary tract. Subchronic inhalation studies (Table 7) for
various species of animals were reported at 25-52 ppm, 5 ppm, and 1 ppm by
Deichmann et al. (1944), Sandage (1961) and Mukhitov (1964), respectively.
Deichmann et al. (1944) exposed guinea pigs, rabbits, and rats to phenol at 25
ppm (100 mg/m3) for 7 hours per day, 5 days per we.ek. Extensive mortality (42
percent) occurred for guinea pigs after 28 days of exposure. Rabbits, however,
(exposed for 88 days) showed no external signs of toxicity but pathological
changes were noted in the lungs, liver, and kidney. Rats were most resistant,
with no internal or external signs of toxicity with 74 days of exposure.
Sandage (1961) did not find any significant adverse toxic effects when
various animal species (rats, mice, monkeys) were exposed to 5 ppm (19
mg/m3) phenol, 8 hr/day, 5 days/wk, for 90 days (this corresponds to the
presentTWA-TLV recommended by the American Conference of Governmental
Industrial Hygienists, 1984). Also, Mukhitov (1964) reported changes in blood
enzyme (cholinesterase) activity, time for excitation of extensor muscles
(—0.02 ppm and 1 ppm), and decreased rate of weight gain (1 ppm) for rats
18
-------
Table 5. Oral Toxicity of Phenol in Humans
Total Dose
(a)
5
10-20
15
15
25-30
50
53
Estimated*
to/kg)
0.07
0.14-O.29
0.21
0.21
0.36-0.43
0.71
0.75
Effect
Survived
Died
Survived
Died
Died
Survived
Survived
Reference
Willhard, 1886
Stajduhar-Caric,
Model. 1889
Kronlein, 1873
Geill, 1888
Geill, 1888
1968
Bennett et al., 1950
* Assuming a standard 70-kg body weight.
Source: U.S. Environmental Protection Agency (1980).
Table 6. The Acute Toxicity of Phenol* to Nonhuman Mammals
Species
Cat
Cat
Dog
Guinea
pig
Mouse
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rat
Rat
Rat
Rat
Rat
Rat
Route
Sub cut.
Oral
Oral
Subcut.
Subcut.
I.V.
Subcut.
Oral
Oral
I.P.
Subcut.
Oral
Oral
I.P.
Dermal
Dermal
LD50
(a/kg)
O.09
O.I
0.5
0.68
0.3
0.18
0.5-0.6
0.6
0.4-0.6
0.5-0.6
0.45
0.53
0.34 (20% emuls.)
O.25 (In olive oil)
2.5
0.67
Reference
To liens, 1905
Macht, 1915
Macht, 1915
Duplay and Cazin, 1891
To liens, 1905
Deichmann & Witherup, 1944
Tauber, 1895; To/lens, 1905
Clarke & Brown, 1906
Deichmann & Witherup, 1944
Deichmann & Witherup, 1944
Deichmann & Witherup, 1944
Deichmann & Witherup, 1944
Deichmann & Witherup, 1944
Farquharson et al., 1958
Deichmann & Witherup, 1944
Conning & Hayes, 197O
In dilute aqueous solution, unless noted otherwise.
Source: U.S. Environmental Protection Agency (198O).
19
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kidney function, rate of weight
gain, pathological examination).
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exposed to phenol vapors continuously for 2 months. However, insufficient
details were produced by which to evaluate the validity of the reported findings.
Effects of repeated oral exposure of humans to phenol were reported after an
accidental spill of phenol in 1974 caused groundwater contamination, which
resulted in consumption by 17 people of amounts of phenol estimated at
10-240 mg/day for about one month (Baker et al., 1978). Several symptoms
were reported, the most significant (p <0.01) compared to controls being
diarrhea, mouth sores, and dark urine. No long-term sequelae were observed
six months after exposure.
The only subchronic oral study in animals found in the available literature is
an unpublished study conducted by Dow Chemical Company in 1944 and
mentioned in a 1976 review {Dow Chemical Company, 1976). Phenol was
administered to rats by gavage over a six-month period (135 doses; 50 or 100
mg/kg/day). Slight liver changes and slight to moderate kidney damage was
observed in high-dose animals. Low-dose animals (50 mg/kg/day) exhibited
slight kidney damage. No effects were noted on the growth rate of treated rats.
No inhalation studies for chronic toxicity were found in the available
literature Only two chronic oral studies are available (Heller and Pursell, 1938;
National Cancer Institute, 1980). Heller and Pursell (1938) administered
phenol to rats via drinking water at levels ranging from 0-12,000 ppm for
periods lasting up to 5 generations, although the exact duration of exposure
was not reported. Variables observed included growth, fecundity, and general
condition. All were normal at exposures of 100-1,000 ppm for 5 generations or
3,000 or 5,000 ppm for 3 generations. At >8,000 ppm, many offspring died due
to maternal behavioral disturbances, and at 12,000 ppm no reproduction
occurred. The National Cancer Institute (1980) bioassay study is described m
more detail in the section on carcinogenicity. The only effect observed was a
dose-related decrease in weight gain in the group exposed to 10,000 ppm,
thought to be associated with decreased water consumption.
Teratogenicity and Reproductive Toxicity
The only available pertinent data concerning teratogenicity or reproductive
toxicity associated with inhalation exposure to phenol was found in an abstract
in the Russian literature (Korshunov, 1974). In this study, an increased
incidence of preimplantation loss and early postnatal death was observed
among the offspring of rats exposed (exposure regimen not reported)
throughout pregnancy to air containing ~1.3 ppm and 0.13 ppm phenol.
The work of Heller and Pursell (1938) demonstrated adverse effects on
reproduction when phenol was administered in the drinking water of rats at
levels of >5,000 ppm; but the credibility of these results has been questioned
given inadequacies in design as a teratogenicity study. More recent gavage
studies by Jones-Price et al. (1983a,b) on CD rats and CD-1 mice yielded similar
results. CD rats (23/group) given phenol in water at doses of 0, 30, 60 or 120
mg/kg/day on days 6-15 of gestation exhibited dose-related signs of fetal
toxicity (average fetal body weight per litter showed a significant dose-related
[p <0 001 ] decrease; the difference between the high-dose group and controls
was significant [p <0.01 ]), even at dosages below the maternally toxic range,
but failed to significantly increase the incidence of structural malformations. In
addition there was no evidence of maternal toxicity in these rats. These results
appear to coincide with those of Minor and Bechard (1971) which revealed fetal
toxicity, but no teratogenic effect following exposure of Sprague-Dawley rats to
phenol (20, 63, or 200 mg/kg/day, i.p.) on days 9-11 or 12-14 of gestation^
More recently, CD-1 mice given phenol orally at doses of 0, 70, 140 and 280
mg/kg/day on days 6-15 of gestation revealed no teratogenic effects;
however, signs of maternal and fetal toxicity were observed. Although no
22
-------
statistically significant evidence for a teratogenic effect of phenol in CD-I mice
was observed under the conditions of the present study, data from the
preliminary investigation suggest that increased malformations (primarily cleft
palate) may occur with high dose exposure (i.e., >200 mg/kg/day) to phenol in
conjunction with compromised maternal status.
In vitro studies on the ability of lipophilic acids to inhibit growth in Bacillus
subtilis cultures and on several mammalian tissue culture lines have shown
phenol to be strongly inhibitory (Freese et al., 1 979). The authors hypothesized
that the inhibitory potency of a compound may provide an indication of its
potential teratogenicity. Based on their data, the authors suggest that phenol
could be teratogenic if it can reach the embryo.
A proposed in vitro assay system presently under development is designed to
be predictive for teratogenicity based upon the ability of a chemical to inhibit
the attachment of ascites tumor cells to plastic surfaces coated with
concanavalin A (Braun et al., 1 982). The authors tested 102 chemicals and
found that the tumor-cell attachment assay correctly determined the
teratogenic potential of 79 percent of the compounds. The relationship
between the lowest reported in vivo teratogenic dose of a compound and the
concentration of that compound in the in vitro assay which reduced cell
attachment by 50 percent was found to have a correlation coefficient of 0.69. In
this assay, phenol gavea positive response even though the compound has not
been found to be teratogenic in vivo.
Mutagenicity
Demerec et al. (1951) reported that phenol produced reverse-mutations in E.
co//, B/Sd-4 from streptomycin dependence to non-dependence. Significant
reverse mutations occurred from 0.1 to 0.2 percent phenol; however, at these
concentrations, the mortality of bacteria was 95-98 percent. Phenol did not
induce filamentation in a Ion" mutant of £. coli (Nagel et al., 1982). More
recently, the standard Ames test, employing four tester strains of Salmonella
typhimurium with or without metabolic activation, indicated that phenol was
not mutagenic (Florin et al., 1980; Pool and Lin, 1982; Haworth et al., 1983). In
another study, however, phenol showed mutagenic effects after metabolic
activation with S-9 preparations in Salmonella tester strains sensitive to
, frame-shift mutations, specifically strain TA 98 (Gocke et al., 1981). In the
same study, Gocke et al. (1981) performed a sex-linked recessive lethal test in
Drosophila and the micronucleus test on mouse bone marrow, both of which
gave negative results.
In testing the mutagenicity of phenol toward the HGPRT locus of the V79
Chinese hamster fibroblast cell line, phenol was found (analyzed by Student
t-test) to significantly increase the frequency of 8-azaguanine-resistant
mutants at concentrations of 250-500 ,ug/ml (Paschin and Bahitova, 1982). In
a chromosomal study, Morimota et al. (1983) observed an increase in the
frequency of sister-chromatid exchange (SCE) when human lymphocyte
cultures were exposed to phenol. Without metabolic activation, a 3 mM
solution of phenol gave a small but significant increase (P <0.01) in SCE.
Metabolic activation with S-9 mix (from Aroclor-1254 induced rats) produced
an even greater increase in SCE (p <0.001).
Other tests indicative of genetic damage and applied to phenol include
inhibition of DNA synthesis in Helen Lake (HeLa) cells, inhibition of DNA
replication synthesis and DNA repair synthesis in cultured human diploid
fibroblast. The inhibition of DNA synthesis in HeLa cells was produced by a 2
mM solution of phenol upon addition of an S-9 mix from Aroclor-induced rats
(Painter and Howard, 1982). DNA replication synthesis was inhibited (>50%)
by a 1.0 mM solution of phenol, and DNA repair synthesis was inhibited by a 10
23
-------
mM solution of phenol subsequent to damage of cultured human diploid
fibroblast cells with N-acetoxy-2-acetylaminofluorene (Poirier et al., 1975).
Levan andTjio (1948) reported C-mitotic effects in the root tips otAllium cepa
when exposed to phenol. Chromosome fragmentation was very rare.
Carcinogenicity
In a tumor promotion study involving many different phenolic compounds,
various strains (Sutler, Holtzman, CAP, and CHS) of mice were pretreated with
a single dermal application of 7,12-dimethylbenz(a)anthracene (DMBA; 75
mg/kg) and subsequently given repeated dermal applications of selected
phenols (Boutwell and Bosch, 1959). In one experiment of this series, Sutler
strain mice (specially inbred for three generations for susceplibilily to
development of tumors after a single application of DMBA followed by croton
oil) received a single applicalion of 75 mg/kg DMBA via skin painling. After one
week, these sensitive mice were treated Iwice weekly wilh dermal applications
of phenol (as a 10 percent solution in benzene) for 42 conseculive weeks;
severe skin damage, decreased body weighl, and increased mortality were
observed in Ihe mice. Also, the mice developed papillomas (95 percent of the
animals by the thirteenth week of treatment) and carcinomas (73 percent by 42
weeks) at a much higher incidence than mice receiving either DMBA alone (14
percent had papillomas at 42 weeks; no carcinomas) or phenol alone (36
percent had papillomas at 52 weeks; no carcinomas). However, after 72 weeks
of skin painling wilh phenol alone, onefibrosarcoma was observed. Slrains of
mice olher lhan Rusch's special breed of Suller mice also developed papillomas
after prelreatment wilh a 10percenl phenol solulion (w/v), bullhe incidence
was lower. Even Ihe incidence for papillomas and carcinomas decreased in Ihe
Suiter strain upon diluling Ihe 10 percenl solulion lo half slrenglh. No
carcinomas occurred in slandard breeds of mice exposed lo phenol (10 percent,
w/v) withoul prelreatment with the polycyclic aromalic hydrocarbon DMBA.
However, when Ihe phenol concenlralion was increased to 20 percent (5 mg
phenol in benzene), many animals died due lo syslemic loxicily.
Similar experimenls by Salaman and Glendenning (1957) demonslraledlhal
phenol exhibiled a weak carcinogenic and strong lumor-promoting activily in
"S" slrain albino mice after repealed skin painling with a high, skin-ulcerative
concenlralion (20% w/v in acelone) of phenol. The polycyclic aromalic
hydrocarbon DMBA (0.3 mg) was used as the tumor inilialor in the tumor
promolion sludies. A lesser, non-ulceralive concentration of 5% phenol was
found to have moderate promoting bul no carcinogenic activily.
Unlike Boutwell and Bosch (1959) and Salaman and Glendenning (1957),
Van Duuren and colleagues (1968, 1971) ulilized a differenl polycyclic
aromatic hydrocarbon, benzo(a)pyrene, in Iheir iwo-slage (lumor-promoting)
and cocarcinogenesis studies on phenol.
In their tumor-promotion studies (Van Duuren el al., 1968), 20 female
ICR/Ha Swiss mice were ireated first wilh 100 fjg of benzo(a)pyrene, single
dose, followed by applicalions of 3 mg phenol in acelone, ihree limes weekly
for one year. Four animals bore papillomas and one a squamous carcinoma.
There were no lumors in Ihe conlrol groups which received inilialor alone,
phenol alone (bolh al same doses as above), acelone alone, or no-lrealmeni
control groups. Because of Ihe negalive resulls obtained in the same study with
17 other phenols and the clearly positive resulls oblained in Ihe same sludy
wilh Ihe phorbol esters of croton oil, il can be concl uded lhal phenol in Ihis test
is a weak promoting agent.
In subsequenl experimenls on cocarcinogenesis, 20 female ICR/Ha Swiss
mice were trealed wilh 5 /ug benzo(a)pyrene and 3 mg of phenol, applied in Ihe
same acelone solulion, ihree limes weekly for Ihe duralion of Ihe lest, which
24
-------
lasted 46O days. At the conclusion of the test, there were three mice with
papillomas and one with carcinoma. There were no tumors in the group
receiving phenol alone. Benzo(a)pyrene alone resulted in eight mice with
papillomas and one with squamous carcinoma. From this it was concluded that
phenol was not a cocarcinogen but that at the dose used it showed an inhibitory
effect on the mouse skin carcinogenicity of benzo(a)pyrene (Van Duuren et al.,
1971). This partial inhibitory effect of phenol was subsequently confirmed by
Van Duuren and Goldschmidt (1976) and Van Duuren et al. (1973) using a
larger group of 50 mice.
The most recent chronic study on phenol was that performed by the National
Cancer Institute in 1980. Fischer-344 rats and B6C3F1 mice (50 rats, 50 mice)
of each sex were given drinking water containing 2,500 and 5,000 ppm phenol
for 103 weeks. Matched controls (50 rats, 50 mice) received tap water.
Statistically significant increases in pheochromocytomas of the adrenal
medulla and leukemias or lymphomas were observed in low-dose male rats,
compared to controls, and may have been associated with exposure to phenol;
however, the incidences were not significantly different between high-dose
males and the matched controls (Table 8). Therefore, because of the high
spontaneous tumor rate observed in the matched controls (36%) compared to
previous 103 to 104-week bioassays conducted by the NCI testing program and
the lack of an association between increasing dose and the incidence of tumor
development, phenol does not appear to be carcinogenic for male and female
Fischer-344 rats or male and female B6C3F1 mice when administered via
gavage in drinking water.
25
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IV. SUMMARY AND CONCLUSIONS
Phenol is one of many aromatic compounds present in the atmosphere. In
addition to natural and anthropogenic sources, phenol is also produced
indirectly as a secondary pollutant from atmospheric photochemical reactions.
However, as a secondary pollutant, it appears to have minimal impact on the
ambient budget, compared to primary sources. As a result of large volume
production and natural sources, occupational and environmental exposure to
phenol is likely; however, the inhalation of phenol vapors appears to be largely
restricted to the occupational environment and/or to populations living in the
immediate vicinity of point sources. Compared to the threshold limit value (TLV,
5 ppm, 19 mg/m3) as recommended by the American Conference of
Governmental Industrial Hygienists (1984) for occupational settings, the
general ambient levels of phenol are extremely low. The odor recognition
threshold (100% response) of phenol is —0.05 ppm, a concentration far below
the levels where toxic effects have been reported. The median ambient
atmospheric level of phenol, based on an estimated 24-hour average, is 30 ppt
(120 ng/m3) for urban/suburban areas. However, concentrations in source-
dominated areas near phenol manufacturing and/or processing plants have
been estimated from 24-hour average monitoring data to be on the order of
5,000 ppt (19,000 ng/m3) as a median level. Estimates of rates of reactions
with atmospheric radicals, based on data derived from structure-activity
relationships, suggests that these reactions are the dominant removal process,
resulting in a half-life of less than one day. In polluted atmospheres, reactions
with nitrate radicals may dominate, and the half-life of phenol would be less
than one minute. The anticipated products formed from phenol in the
atmosphere via photochemical reactions are dihydroxybenzenes, nitrophenols,
and ring cleavage products. Most recently, Battelle Columbus Laboratories,
under contract to EPA, have determined major reaction products (2-nitro-
phenol, 4-nitrophenol) and have experimentally estimated the half-life of
phenol to be ~4 to 5 hr under photochemically reactive conditions.
Phenol poisoning can occur by skin absorption, vapor inhalation, or ingestion.
The primary route of entry is typically the skin, for vapors readily penetrate the
skin surface with an absorption efficiency close to that for inhalation.
Absorption of phenol from sol utions in contact with the skin may be very rapid,
and death can resultf rom collapse within 30 minutes to several hours. In those
cases where death is delayed, damage to the kidneys, liver, pancreas, and
spleen, and edema of the lungs may result. Phenol vapors are also well
absorbed by the lungs. Inhalation causes dyspnea, cough, cyanosis and
pulmonary edema. Ingestion of even small amounts of phenol causes severe
burns of the mouth and esophagus, as well as abdominal pain.
The human body behaves almost like a single compartment with respect to
phenol absorption and clearance, with an excretion rate constant of 0.2 hr" ,
which corresponds to a half-life of approximately 3.5 hr. After absorption,
exogenous phenol is extensively metabolized, principally by the liver but also at
portals of entry such as the intestinal mucosa and lung. In man and all
mammals that have been tested, virtually all of the phenol and/or its
metabolites are excreted into the urine; the amounts excreted in the feces and
exhaled air are very minimal. Depending upon exposure dose and species, the
urine may contain free phenol, conjugates of phenol (primarily glucuronide
and/orsulfate), and hydroxy derivatives (such as quinol and catechol)andtheir
conjugates. With very high exposure doses, the conjugation reactions resulting
28
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in conjugation of phenol with glucuronide and sulfate, the principal metabolic
process, may become saturated and rate-limited by availability of endogenous
glucuronic acid and/or active sulfate. With low exposure levels in man, the
kinetics of phenol metabolism and renal excretion can be adequately described
by a first-order single compartment model with a biological half-life of about
3.5 hr.
Sudden collapse and unconsciousness of humans exposed to phenol is
generally associated with the impact this agent has on the central nervous
system. In animals, these effects are generally preceded by muscular
twitchings and severe clonic convulsions due to the action of phenol on the
central nervous system motor mechanisms. Regardless of the route of
administration, the signs and/or symptoms induced by phenol in man and
animals are similar. With respect to humans, no acute or chronic inhalation
data were available in the literature. No epidemiologic study of an employee
population exposed to phenol by inhalation has been reported. Based on a
standard 70-kg-man body weight and reported oral toxicity data, a human oral
LDL0 (140 mg/kg) has been estimated for phenol.
With respect to animals, the acute toxicity of phenol in terms of lethal dose
necessary to kill 50 percent of the test animals (LD50) has been evaluated for
various species and routes of exposure. The majority of observed LD50 values
fall within one order of magnitude, with the cat the most sensitive and the
guinea pig most resistant. Although no LCso values were found for animal
inhalation studies, exposure of rats to phenol at 236 ppm for 8 hours resulted in
ocular and nasal irritation, loss of coordination, tremors, and prostration.
Subsequent to dermal application of phenol, rats developed severe skin
lesions, with edema followed by necrosis.
Several subchronic toxicity studies via inhalation and the oral route have
been reported for various species of animals. With respect to inhalation, a
frank-effect-level based on the sensitivity of the guinea pig (42 percent
mortality) can be established at 25 ppm. Additional inhalation studies on rats,
mice, and monkeys demonstrated a no-observed-adverse-effect level (NOAEL)
at 5 ppm, i.e., no significant adverse toxic effects were observed at 5 ppm (a
level corresponding to the present phenol TWA-TLV recommended by the
ACGIH for occupational settings) (American Conference of Governmental
Industrial Hygienists, 1984). One abstract in the Russian literature reported
changes in blood enzyme activity, excitation of extensor muscles, and
decreased body weight at low concentrations (0.02 to 1 ppm) when rats were
exposed to phenol vapor. Additional Russian studies attempted to associate the
toxicity observed among employees with the phenol present in the work
environment at 2.3 ppm as a result of quenching coke with phenol-contami-
nated waste water. These studies, as with most of the Russian studies cited in
this report, are not well documented and the results are not consistent with
other, better known studies at similar exposure levels. Studies by the Dow
Chemical Company in 1944 (Dow Chemical Company, 1976) demonstrated
slight kidney damage at 50 mg/kg, which can be used to establish an oral
exposure LOAEL (lowest-observed-adverse-effect level). No effects were noted
on the growth rate of treated rats.
No inhalation studies for chronic toxicity were found in the available
literature. The only chronic oral studies were those reported by Heller and
Pursell (1938) and the National Cancer Institute (1980). The drinking water
study by Heller and Pursell (1938) demonstrated that growth, fecundity, and
general condition were normal for rats up to 5,000 ppm, the NOAEL. Above
5,000 ppm, the growth of the rats was affected, and at 12,000 ppm there was
no reproduction. The only effect observed in the National Cancer Institute
(1980) study was a dose-related decrease in weight gain, thought to be
associated with decreased water consumption.
29
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The present data base concerning the genotoxicity of phenol indicates no
evidence of maternal toxicity or structural teratogenicity in rats exposed via
gavage from 30 to 120 mg/kg/day of phenol on days 6-15 of gestation
compared to controls. With increasing doses, average fetal body weight/litter
decreased (p <0.001). Although no teratogenic effects were noted, 30
mg/kg/day could be regarded as a LOAELfor fetotoxic effects. Adverse effects
on reproduction were demonstrated for rats only when the phenol concentra-
tion in the drinking water exceeded 5,000 ppm. The only available inhalation
study (Russian literature) demonstrated increased incidence of preimplantation
loss and early postnatal death in the offspring of rats exposed to phenol
concentrations in air of 0.13 and 1.3 ppm throughout pregnancy. Similar
results were obtained for mice exposed via gavage to phenol at doses of 70,
140 and 280 mg/kg/day on days 6-15 of gestation. Like the rats, the mice
revealed signs of fetal toxicity with no evidence of teratogenic effects. Unlike
the rats, the mice in the high-dose group exhibited statistically significant signs
of maternal toxicity (i.e., reduced maternal body weight and reduced weight
gain), increased maternal mortality and clinical signs, including tremors and
ataxia, during phenol treatment.
Phenol has been evaluated in a variety of test systems for its ability to induce
gene mutations, chromosomal aberrations, sister chromatid exchanges (SCE),
and inhibition of DNA replication and repair synthesis. In the Salmonella/
microsome assay both negative and positive results have been reported. In E.
co//, phenol induced mutations involving filamentation, but not reverse
mutation for streptomycin non-dependence. Positive results in mammalian in
vitro test systems were reported for gene mutation in Chinese hamster
f ibroblast (V79) cells, for SCE in human lymphocytes, and for inhibition of DNA
replication and repair synthesis in human fibroblasts. Negative results were
reported for the Drosophila sex-linked recessive lethal test and the mouse
micronucleustest. Because of the positive findings in mammalian in vitro tests
and in certain bacterial tests, phenol may have mutagenic potential.
Phenol may be a promoter and/or weak skin carcinogen in specially inbred
sensitive strains of mice. Studies by Boutwell and Bosch (1959) and Salaman
and Glendenning (1957) demonstrated strong tumor-promoting activity of
phenol in Sutler strain mice and "S" strain albino mice after pretreatment with
the polycyclic organic DMBA, followed by repeated skin applications of 20
percent phenol in various solvents including acetone, ethanol in acetone,
benzene, and dioxnea. A lesser concentration of phenol (5 percent) was found
to have a moderate promoting action, but no carcinogenic action. Van Duuren
et al. (1968), utilizing ICR/Ha Swiss mice, demonstrated that phenol is at best a
weak promoting agent on mouse skin. With respect to cocarcinogenesis
experiments. Van Duuren et al. (1971), using the same strain of Swiss mice,
demonstrated that the tumorigenic response normally exhibited by benzo(a)-
pyrene (BaP) is slightly inhibited by phenol. This partial inhibitory effect that
phenol has on the carcinogenic activity of BaP was also confirmed by Van
Duuren and Goldschmidt (1976) and Van Duuren et al. (1973). However, all of
these studies did not provide for evaluation of effects produced by the solvents
used and, in some cases, for the pretreatment of the albino mice with a known
carcinogen, either DMBA or BaP. These mice studies suggest that phenol may
function primarily as a nonspecific irritant and may be capable of promoting
tumors. It should be pointed out here that tumor promotion represents a special
case of cocarcinogenesis (Berenblum, 1985). The latter corresponds more
closely to the environmental situation, i.e., humans are not ordinarily exposed
sequentially to chemicals, but simultaneously and for prolonged periods of
time to mixtures of large numbers of chemicals, some of which may be
carcinogens and other cocarcinogens.
30
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The most recent gavage study by the National Cancer Institute (1980)
demonstrated an increased incidence of some types of tumors (leukemia,
lymphomia, interstitial cell of the testes) in male rats in a low dose group, but
there was no clear dose-response association between carcinogenicity and the
administration of phenol under the conditions of the bioassay in that tumor
incidence was not significantly elevated in the high-dose group. Therefore,
based on the skin-painting studies of mice and the gavage studies on mice and
rats by the National Cancer Institute, there is no clear evidence that phenol acts
as a complete carcinogen—particularly at low exposure concentrations.
Accordingly, phenol is classified as a Group D compound using the new EPA
weight-of-evidence criteria for cancer data (F.R., 1984). Group D means that
the data are inadequate for evaluating the carcinogenic potential.
In conclusion, the available toxicity data are rather limited, making it difficult
to characterize fully the toxic potential of phenol to humans, especially in
regard to inhalation exposure effects. The weight of evidence for phenol's
carcinogenicity is inadequate in humans; however, the fact that the National
Cancer Institute study did not demonstrate a\clear association between the
incidence of cancer in phenol-exposed animals* compared to controls does not
necessarily imply that phenol is not a carcinogen, inasmuch as the experiments
were conducted under a limited set of conditions (i.e., drinking water). Also,
given evidence suggesting that phenol may be a tumor promoter, it would be
prudent to carry out additional evaluations of the carcinogenic potential of
phenol. It is recommended, therefore, that a long-term bioassay study for
phenol via the inhalation route be nominated for inclusion in the National
Toxicology Program (NTP) or a similar testing program.
In addition, it seems appropriate to further evaluate the reproductive toxicity
and teratogenicity associated with exposure to air containing phenol in view of
the effects reported in the offspring of rats at low levels by the Russians and in
view of the dose-related signs of fetal toxicity exhibited by mice at dosages
below the maternal toxic level.
31
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