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OCR for page 248
7
Phenol
Chiu-Wing Lam, Ph.D.
NASA-Johnson Space Center Toxicology Group
Habitability ancI Environmental Factors Branch
Houston, Texas
PHYSICAL AND CHEMICAL PROPERTIES
Phenol is a colorless to white solid when pure; it is hydroscopic. Phenol
has a sickening-sweet and tarry characteristic odor. Humans can detect
phenol at about 40 parts per billion (ppb) in the air and ~ milligrams per
liter (mg/L) in water (Amoore and Hautala 1983~. The physicochemical
properties of pure phenol are listed in Table 7-1 (ACGIH 1991~.
OCCURRENCE AND USE
Phenol is used mainly in the manufacture of phenolic resins and a vari-
ety of chemicals and drugs (ACGIH 1991~. It is also used as a disinfectant,
slimicide, deodorant, and sanitizer. Dilute solutions of phenol (1-2%) are
used medicinally in antipruritic skin preparations (Remington 1985, p.
1315~. Phenol has been identified in automobile exhaust and in cigarette
smoke (ATSDR 1998~. In the International Space Station (ISS), phenol was
detected at 15 micrograms (~g)/L in a regenerated potable water sample
(SVO-ZV) collected aboard on Jan 10,2001, during Expedition 1 (ISS-5A);
phenol was not detected (<4 vigil) in the samples collected at various times
(September 2001 to November 2002) during Expeditions 2-5 (Plumiee et
al. 2002, 2003~.
248
OCR for page 249
Phenol
TABLE 7-1 Physical and Chemical Properties of Phenol
249
Formula
CAS registry no.
Synonyms
Molecular weight
Boiling point
Melting point
Vapor pressure
Solubility in water
plea
C6H5OH
108-95-2
Carbolic acid, phonic acid, phenylic acid, phenyl
hydroxide, hydroxybenzene, oxybenzene
94.11
1 82°C
43°C
0.35 mmHg at 25°C
1 g/15 mL
10 at 25°C
PHARMACOKINETICS AND METABOLISM
Absorption and Distribution
Phenol is rapidly absorbed by all routes of exposure (Deichmann and
Keplinger 1981), as illustrated by the observations that symptoms of acute
toxicity occurred within minutes after phenol administration (Pullin et al.
1978) and that a man died 10 minutes (min) after he spilled phenol over his
body (Gottlieb and Storey 1936, as cited inNIOSH 1976~. Humphrey et al.
(1980) reported the half-life of absorption to be 5.5 min in rats that were
injected with doses of phenol (2.5 mg per kilogram ~kg] or 25 mg/kg la-
beled with a radiotracer) directly into the small intestines. A similar study
by Kao et al. (1979) showed that 2 hours (h) after injection into the small
intestine, about 77% of the dose was recovered in the urine. When
radiolabeleUpheno! (0.01 mg/kg) was given to three human subjects in food
or drink, about 90°/O of the radioactivity was recovered in the urine, which
was collected for 24 h (Caper et al. 1972~.
When rats were each given a large oral dose of phenol (207 mg/kg,
one-half an LD50 Close lethal to 50% of subjects]) containing a radiotracer,
liver was found to have the highest specific radioactivity of all the tissues
examined at every sampling time interval (0.5-16 h post-treatment), and it
accounted for about 42% (range 29-56%) of the dose (Liao and Oehme
1981~. Only 0.3% ofthe administered dose remained in tissues 16 h after
dosing. Diechmann and Witherup (1944) showed that in rabbits that died
15 min after an oral phenol dose (500 mg/kg), the total phenol concentration
OCR for page 250
250
Spacecraft Water Exposure Guidelines
in liver was twice that in the blood. For those that died or were killed after
82 min. the concentrations in the liver were less than those in the blood.
These observations indicate that the liver takes up a large fraction of phenol
when the compound is administered in large doses.
When small doses of phenol are given to animals, the liver does not
take up more phenol (per unit tissue) or contain more phenol metabolites
than other tissues. Power et al. (1974) reported that in rats treated with
radiolabeled phenol (10 loci orally or peritoneally), whole-body auto-
radiograms showed that radioisotope levels in the liver did not, at any time,
exceed those in the blood. The authors further showed that neither phenol
nor its metabolites were concentrated in the liver (see "Metabolism" section
below for more information).
In an inhalation study in which human test subjects were exposed to
phenol at 6-20 mg per cubic meter (m3) through a gas mask, the lung uptake
of phenol was 60-80%, as determined by concentration differences between
inhaled and expired air (Piotrowski 1971~.
Metabolism
The metabolic fate of phenol was studied in three human test subjects,
each of whom was given a single oral dose (radiolabeled phenol at 0.01
mg/kg); 77°/O ofthe radioactivity was recovered in the urine as phony! sul-
fate and 16% was recovered in the urine as phony! glucuronide. A total of
about 1°/O was identified es quino! (1,4-dihydroxybenzene) sulfate orglucu-
ronide (Caper et al.1972~. In the same report, Capel et al. also documented
that phenol conjugates were the major metabolic products in 18 animal
species treated with phenol orally or intraperitoneally (25 mg/kg). Using
liver preparations, Campbell and Van Loon (1987) and Bock et al. (1988)
showed that phenol was conjugated with sulfate by cytosolic phenol
sulfotransferases or with glucuronic acid by glucurony~transferases. These
results revealed that, if glucuronic acid and sulfate are not depleted, and the
conjugating enzymes are not saturated, little phenol is metabolized to quino!
or other P-450 metabolic products.
When isolated mouse livers were perfused with phenol, hepatic effluent
was found to contain phenol, phony! glucuronide, phony! sulfate, hydro-
quinone, and hydroquinone glucuronide (Hof~nann et al. 1999~. When
mouse liver microsomal preparation (free of phase II conjugation enzymes)
was used, phenol was found to be metabolized, presumably by P-450, to
hydroquinone (87.5°/O), catecho! (WHO), and trihydroxybenzene (1.2%)
(Scholosser et al.1993~. The same authors also found that liver microsomal
OCR for page 251
Phenol
251
preparations from mice metabolized about twice as much phenol (chiefly
to hydroquinone) as those from rats.
Like phenol, dihydroxybenzenes (catechols), which potentially are P-
450 metabolic products of phenol, are conjugated by sulfotransferases or
glucurony~transferases. The processes of conjugating phenol and dihydr-
oxybenzenes with sulfate or glucuronic acid are metabolically competitive.
The relative amounts of sulfate and glucuronide conjugates depend on the
abundance of sulfate, glucuronic acid, and the conjugation enzymes as well
as the kinetic parameters ofthe two in a given animal species. Because the
conjugates are much more water-soluble than the parent compound, conju-
gation by either pathway enhances the elimination and excretion of phenol.
The role of liver in phenol metabolism in animals given low levels of
phenol was investigated. Using isolated and washed rat gut preparations
(free of debris), Powell et al. (1974) perfused the gut with physiologic
buffer containing 10 loci of ~4C-labeled phenol with or without 10 mg of
unlabeled phenol. After 2 h of perfusion, 50-78°/0 ofthe phenol was recov-
ered in the serosal medium. At the end ofthe experiment, all phenol recov-
ered from both serosal and mucosal media essentially was in the form of
conjugates (5°/0 phony! sulfate and 95°/0 phony! glucuronide). No unchanged
phenol was detected. These results showed that the gut was capable of
metabolizing phenol and that all of the phenol was conjugated.
The role of the gut in phenol metabolism was further investigated.
Powell demonstrated that only phenol conjugates were found in the plasma
of blood collected from the portal vein of rats whose intestines were per-
fused in situ with phenol. Their postulation that the liver does not play a
major role in metabolism of low doses of phenol was further supported by
examination of the extent of phenol conjugation in hepatectomized rats.
Radiolabeled phenol (5 mg/kg or 10 mg/kg) was given by intravenous
injection to intact control rats and to test rats whose livers, spleens, and
intestines were removed. Recovery of radioactivity from the urine of test
and control animals over 3 h was essentially the same. Urine samples from
both groups of rats contained phenol conjugates; the test rats had a higher
proportion of phenol glucuronide in their urine than did control rats. From
the results of these three experiments, Powell et al. (1974) concluded that
liver is not essential in phenol detoxification and that phenol ingested in the
diet is absorbed into the bloodstream from the gut essentially as phenol
conjugates. This observation is consistent with the findings of Casidy and
Houston (1984), who studied invivo capacity of hepatic- and extrahepatic-
enzyme phenol conjugation over a 35-fold dose range; the capacity of the
intestinal conjugating enzymes was found to be remarkably high, whereas
that of hepatic enzymes was readily saturable. At low doses of phenol (less
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252
Spacecraft Water Exposure Guidelines
than 1 mg/kg), the capacity of intestinal and hepatic conjugation was com-
parable, but et higher doses (greater then 5 mg/kg), the capacity of intestinal
enzymes far exceeded that of enzymes in the liver.
Elimination
In a study of three human subjects who ingested single doses of
~4C-labeled phenol, phenyl sulfate and glucuronide accounted for a total of
90°/O of the urinary radioactivity. A trace amount (<1 %) of ~4C was elimi-
nated as sulfate or glucuronide conjugates of 1,4-dihydroxybenzene (Caper
et al. 1972). Similar results were observed in two female rhesus monkeys
given single oral doses of ~4C-labeled phenol (50 mg/kg, 10 loci per ani-
mal); the recovery of radioactivity in urinary phenyl sulfate and phenyl
glucuronide was approximately 65% and 35°/O, respectively. In contrast,
squirrel and capuchin monkeys eliminated phenol mostly as phenyl glucu-
ronide, with phenyl sulfate as a minor metabolite (Caper et al. 1972). When
~4C-labeled phenol (63 .5 nanomoles tnmol]) was administered orally to rats,
Hughes and Hall (1995) observed that less than 1% of the radioactivity
remained in the body 72 h after the administration; the amounts in the liver,
muscle, skin, fat, and blood were 0.2%, 0.08°/O, 0.07°/O, 0.02%, and 0.02%
of the administered dose, respectively. Phenyl sulfate was found to be the
major metabolite in urine.
In an inhalation exposure study, eight human subjects were exposed
(through a face mask) to phenol at 6-20 mg/m3 for ~ h (including two 0.5-h
breaks), and the total pulmonary absorption of phenol was estimated from
inspired and expired air (Piotrowski 1971). The recovery of phenol (phenol
end metabolites) in urine collected for24 h averaged 100% (84°/O to 114%).
The concentrations of phenol in the urine samples reached a peak value 0.5
h after the exposure ended. The concentration then decayed exponentially,
and urinary phenol concentrations returned to pre-exposure levels within 16
h after the exposure ended. Excretion followed f~rst-order kinetics with an
elimination half-life of 3.5 h.
TOXICITY SUMMARY
Phenol is rapidly absorbed into the body by all routes of exposure. It
is moderately toxic at high bolus doses, but is low in toxicity when doses
are administered gradually and do not overwhelm detoxification by conju-
OCR for page 253
Phenol
253
gation. When phenol is ingested in drinking water, a route that allows
gradual and steady intake of phenol and, subsequently, detoxification in the
gut, the toxicity is relatively low. When a large oral dose of phenol is in-
gested, some of the absorbed phenol presumably enters the blood without
being conjugated in the gut. Casidy and Houston (1984) showed that
hepatic conjugating enzymes were readily saturable. Phenol, if not conju-
gated, could cause a spectrum of neurologic symptoms, such as twitching,
tremors, lethargy, and convulsions, and histopathologic changes in liver,
kidneys, spleen, thymus, and other organs. The histopathology is likely to
due to the P-450 metabolites of phenol (such as hydroquinone).
Acute (<1 d) and Short-Term Exposures (2-10 d)
Human Studies
Ingestion of phenol has been documented in numerous reports of sui-
cide or attempted suicide. Staj~ubar-Caric (1968) reported that a woman
died within an hour after ingesting 10-20 g of phenol. On the basis ofthis
information, and assuming that 10 g of phenol was ingested and the woman
weighed 70 kg, Bruce et al. (1987) estimated that the dose ingested was 140
mg/kg.
Gottlieb and Storey (1936, as cited in NIOSH 1976) reported a case of
a 32-year-old man who spilled a solution of phenol over his scalp, face,
neck, shoulders, and back; the victim died in 10 min. The phenol caused
coagulation necrosis of the skin and congestion of the lungs, liver, spleen,
and kidneys.
Cardiac arrhythmias were reported in 39°/O (21/54) of patients who
underwent chemical exfoliation ofthe face end neck simultaneously and in
22% (22/100) of patients who had their faces and necks treated 24 h apart;
the preparation contained approximately 50°/O phenol (Gross 1984~. Infor-
mation about the total amount of phenol applied to each patient was not
provided. Phenol concentrations in serum of blood collected at unspecified
times after application ofthe exfoliator ranged from 4.4 mg/L to 323 mg/L.
If one is to assume that the average concentration of phenol in whole-body
tissue (whole-body - bone = 70 kg - 12.3 kg = 57.7 kg) was the same as that
in the serum, the patients received a dose of 3.6-266 mg/kg per application.
When small doses of phenol are applied to skin, no overt toxicity is
observed. Ruedeman and Dechmann ( 1953) observed no clinical symptoms
in 20 adult humans who received one to four applications, each containing
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254
Spacecraft Water Exposure Guidelines
1 g of phenol in 50 g calamine lotion or in 21 g camphor-Liquid petrolatum.
The applications, covering over 75°/O ofthe skin, were separated by periods
as short as 90 min or as long as 3 weeks (wk). Thus, a subject weighing 70
kg would receive 14.3 mg/kg per application, assuming total absorption.
A retrospective cohort study was conducted in 1,352 Korean house-
holds exposed to phenol in drinking water from a contaminated reservoir.
On March 13,1991, an industrial plant spilled 30 tons of phenol, contami-
nating a river that fed water to a reservoir. Significantly more phenol-asso-
ciated symptoms were reported by the exposed individuals compared with
symptoms reported by the residents of a nearby unexposed area (39.6% vs
9.4°/O) (Kim et al. 1994~. The symptoms were sore throat, gastrointestinal
illness (such as nausea, vomiting, diarrhea, or abdominal pain), dark urine,
and skin rash. During the accident, more people in the exposed group also
experienced a peculiar taste or odor (92% vs 34.3°/O in the control group).
The accident was not reported to the local government, and the Korean
water authorities continued water chlorination until consumers reported that
their water had a bad taste. Analysis of water samples collected on March
16,17, and 18 showed that the samples had phenol concentrations of 0.05,
0.05, and <0.01 mg/L, respectively. On March 19, the concentration of
chlorophenols in tap water was 0.085 mg/L. The authors presumed that by
the time phenol concentrations in the water were measured, the peak phenol
concentration had already passed. The authors pointed out that to humans,
the tastes and odors of some chlorophenols are 100 to 1,000 times stronger
than those of phenol.
Phenol is the active ingredient in Cepastat lozenges. Regular and ex-
tra-strength Cepastats contain 14.5 mg and 29 mg per lozenge, respectively
(PDR 1997~. Cepastat lozenges can be taken once every 2 h, not to exceed
300 mg or 10 lozenges per day, according to SmithKline Beecham (Pitts-
burgh, PA). Thus, an adult taking the maximum allowable number of
Cepastat lozenges would consume about 145-290 mg of phenol a day.
Animal Studies
Flickinger (1976) estimated that for rats, the oral LD50 of phenol would
be 650 mg/kg. Deichmann and Witherup (1944) reported an LD50 of 530-
540 mg/kg for Wistar rats that were given an aqueous solution with phenol
at 10% or less; when a 20% solution was given, the LD50 was 340 mg/kg.
The acute and subacute toxicities of phenol were evaluated in groups
of F-344 rats (eight rats per group). The rats were given phenol orally in
OCR for page 255
Phenol
255
single doses at 0, 12, 40, 120, or 224 mg/kg or in doses of 0, 4, 12, 40, or
120 mg/kg daily for 14 consecutive days (Berman et al. 1995~. In the 1-d
study, two rats of the 224-mg/kg group died, and four of the remaining
animals had necrosis or atrophy of the spleen, thymus, or kidneys. The
incidences of hepatic necrosis in the 0-, 12-, 40-, and 120-mg/kg groups
were 0/8, 0/8, 1/7, and 2/6, respectively. In the 14-d study, all eight rats in
the 120-mg/kg group died. The incidences of necrosis or atrophy of spleen
or thymus in the 0-, 4-, 12-, and 40-mg/kg groups were 0/8, 0/8, 1/8, and
2/8, respectively. Renal lesions were seen in three rats in the 40-mg/kg
group, whereas controls had no renal lesions.
At sublethal toxic doses, phenol given intraperitoneally produced
myoclonus or myoclonic convulsions characterized by short-last muscular
jerks with no evidence of prolonged tetanic activation ofthe muscles (Angel
and Rogers 1972~. The time to the start of the response was 2 min. The
temporal course of the convulsive effect was exponential decay. The CD50
(convulsive dose) of phenol in mice was 1.04 millimoles (mmol)/kg (97.9
mg/kg). The CD50s for some of the possible metabolites of phenol were
also determined. For catechol, resorcinol, and quino! (1,2-, 1,3-, and
1,4-dihydroxybenzene), the CD50s were found to be 0.92, 0.90, and 0.38
mmol/kg, respectively. Liao and Oehme (1981) also observed tremors of
muscles around the eyes, followed by convulsion and coma, in rats dosed
with phenol at 207 mg/kg (half of the oral LD50 dose).
Central nervous system (CNS) symptoms were also seen after dermal
application of molten (pure) phenol at 500 mg/kg to 35°/O to 40°/O of the
body surface of three pigs (Pullin et al. l 978~. Within 5 min after the phe-
no! application, excessive salivation, nasal discharge, respiratory distress,
twitching, and tremors were observed. These signs were immediately fol-
lowed by lethargy, cyanosis, convulsion, and coma; death (two pigs) oc-
curred about 95 min after the exposure.
Subchronic (11-100 d) and Chronic Exposures (>100 d)
Human Studies
An accidental spill of 37,900 L of phenol (100%) from a rail car oc-
curred in a rural area of southern Wisconsin on July 16,1974. The incident
subjected the nearby residents to phenol exposure from contaminated well-
water (Baker et al. 197S, as cited in ACGIH 1991~. Phenol concentrations
in water samples collected 7 ~ after the spill from the two nearest wells (on
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Spacecraft Water Exposure Guidelines
either side of the railroad track) were 0.2 mg/L and 3.2 mg/L. Tests of
water samples collected from the six nearest wells during the last week of
July and all of August showed phenol concentrations ranging from 15 mg/L
to 126 mg/L. Most families continued to drink their well-water for several
weeks after the spill, until an unusual taste or odor developed. On Novem-
ber 26, 1974, EPA proposed an emergency phenol standard of 0.1 mg/L as
temporarily acceptable for human consumption. Several persons living near
the spill site had mouth sores, skin rash, nausea, and diarrhea in late July.
In late October, physical examination and clinical chemistry analysis of
several local families revealed no significant abnormalities.
A retrospective study was conducted by investigators from the Centers
for Disease Control and Prevention, the EPA Water Supply Research Labo-
ratory, end the Wisconsin State Depa~mentofHealth and State Laboratory.
The study, including evaluation of medical records, water-intake history,
and blood and urine chemistry analyses, was conducted 7 months (mo) after
the spill (Baker et al. 1978, as cited in ACGIH 1991~. Study subjects were
divided into three groups on the basis of phenol concentrations in the wells
and distances from the spill site: groups 1 (>0.1 mg/L), 2 (0.1 to 0.001
mg/L), and 3 (no phenol; 1.9 kilometers ~km] away) consisted of 39, 61,
and 58 subjects, respectively. Significantly more people in group 1 com-
plained of diarrhea, mouth sores, dark urine, and burning mouth than in
groups 2 and 3. The authors defined phenol-related illness as having two
of these four symptoms between July 1, 1974, and February 23, 1975.
Groups 1, 2, and 3 reported 17, 5, and 2 cases of illness, respectively. The
average duration of illness was 2 wk. Symptoms in members of group 1
occurred primarily in July and August; those in members of groups 2 and
3 occurred randomly throughout the 8-mo period. The difference in symp-
toms between groups 2 and 3 was not statistically significant, so those two
groups were combined as the control group. Members of group 1 had sig-
nificantly more frequent complaints of bad-tasting or bad-smelling water
during July and August than did their neighbors. Members of all groups
were given a physical examination ~ mo after the spill. Results ofthe blood
test (for liver enzymes, etc.) and urinalysis revealed no statistically signifi-
cant difference among the test groups. The authors concluded that "the
illness appears to have had no long-term sequelae and to have occurred only
in those exposed to more than 0.1 mg/L of phenol in water" (Baker et al.
1 97 8, as cited in ACGIH 1 99 1 ). The symptoms reported by subj ects ex-
posed to <0.1 mg/L and by the control group are shown in Table 7-2. The
symptoms that were related significantly to phenol in drinking water
OCR for page 257
Phenol
TABLE 7-2 Symptom Distribution (°/0) in Subjects Exposed to Phenol
in Contaminated Water
257
Symptoms Group 1a Groups 2 and 3b
Vomiting 15.4 13.9
Diarrhea 41.0C 13.5
Headache 23.1 16.1
Skin rash 35.9 22.6
Mouth sores 48.7c 12.6
Parethesia or numbness 13.2 8.4
Abdominal pain 23.1 11.8
Dizziness 21.1 9.3
Dark urine 17.9 3.4
Fever 15.4 10.9
Back pain 20.5 11.0
Burning mouth 23.1C 6.8
Shortness of breath 10.3 6.7
aPhenol concentration >0.1 mg/L; n = 39.
bPhenol concentration <0.1 mg/L; n = 61 for group 2; n = 58 for group 3.
CSignificantly greater than controls,p < 0.01, Fisher's exact test.
Source: Baker et al. 1978, as cited in ACGIH 1991.
were those produced by phenol in the alimentary tract. Those observations
indicate that at those low concentrations guts that have normal activity of
conjugating enzymes allow no free phenol to enter the bloodstream.
Animal Studies
The subchronic toxicity of phenol was determined in groups of 10
B6C3F, mice and 10 F-344 rats of each gender exposed to drinking water
containing phenol at 0, 100, 300, 1,000, 3,000, or 10,000 parts per million
(ppm) for 13 wk (NCI 1980~. Gross and microscopic histopathologic exam-
ination of tissues or organs showed no changes attributable to the phenol
consumption. Unfortunately, the amounts of phenol consumed by these
animals were not reported. For risk assessment, one would need to know
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Spacecraft Water Exposure Guidelines
how much phenol was consumed daily (mg/kg/~) by the animals; to calcu-
late phenol consumption, one would need to know the amount of water
consumed daily and the body weights of the animals.
The National Cancer Institute (NCI) report documents that water con-
sumption by mice in the 3,000-ppm and 10,000-ppm groups was only 60%
and 20%, respectively, of that of the controls. Male and female rats of the
10,000-ppm group consumed 50°/O and 33°/O less than controls (NCI 1980~.
The decrease in water consumption by these high-dose animals likely was
due to the unpleasant taste of phenol. The amounts of water consumed by
the animals (including controls) in this study were measured, but they were
not reported. Fortunately, wafer consumption by control (untreated) rodents
of the same species and age were reported in several 13-wk subchronic
toxicity studies and 2-y carcinogenesis studies conducted by the National
Toxicology Program (NTP). Table 7-3 shows the 13-wk average daily
water consumption by rats and mice of either gender from the NTP studies.
If we assume that in the 13-wk NCI phenol study the control animals
and the animals whose water consumption was not affected by the phenol
treatment consumed the same amount of water as the control animals in the
NTP 13-wk studies listed in Table 7-3, and if we also take into account the
reduction of water consumption in the high-dose groups, then it is possible
to estimate the 13-wk average amounts of daily water consumption in all the
phenol-treated groups, which is shown in Tables 7-4 and 7-5. The NCI
13-wk phenol study reported the body weights of all groups; that informa-
tion is needed for dose estimation. In the control groups, the initial mean
body weights (10 per group) were 109 (male rats), 91 (female rats), 21
(male mice), and 1 ~ g (female mice); the final mean body weights were 323,
182, 27, and 22 g, respectively. If we assume the 13-wk average body
weight equals the initial body weight plus the final body weight less the
initial body weight divided by two, then the 13-wk average body weights
of the phenol-treated groups can be calculated and are shown in Tables 7-4
and 7-5. Phenol treatment did not significantly (<5°/O) affect the body
weights, except those of the 10,000-ppm groups.
The concentrations of phenol in the drinking water of the NCI rat and
mouse studies were 0,100,300,1,000,3,000, or 10,000 ppm (NCI 1980~.
Using the estimated 13-wk average water consumption and 13-wk average
body weights (Tables 7-4 and 7-5) described above, one can calculate the
average daily phenol consumption in the NCI study. The highest-dosed
male and female rats are estimated by NASA to have consumed 532 ma/
kg/d and 908 mg/kg/d, respectively (Table 7-4~; the corresponding values
OCR for page 279
Phenol
TABLE 7-12 Genotoxicity of Phenol In Vivo
279
Dose (mg/kg)
and Route Species End Point Result Reference
40, 80, 120; Mouse Micronuclei Negative Marrazzini etal.
intraperitoneal (bone marrow) 1994
40, 80, 160; Mouse Micronuclei Negative Barale et al. 1990
intraperitoneal (bone marrow)
265, Mouse Micronuclei Positive Ciranni et al. 1988
intraperitoneal (Bone marrow)
265, Mouse Micronuclei Positive Ciranni et al. 1988
intraperitoneal (fetal liver)
by intraperitoneal administration at doses up to 160 mg/kg did not produce
micronuclei in mice. However, when the dose was 265 mg/kg, the same
laboratory showed that phenol produced micronuclei (Table 7-12~. These
high doses, which overwhelmed the detoxification mechanism, have little
value for assessing the genotoxicity of phenol ingested in drinking water.
The results of in vitro mutagenicity tests will not be discussed here, because
in vitro test systems do not model the detoxification role (conjugation) of
the gut or other organs. Interested readers can find the in vitro data summa-
rized in the ATSDR Toxicological Profile for phenol (ATSDR 1998~.
Interaction of Phenol with Iodine
On the space station, reclaimed water will be treated with iodine. Phe-
no! in water is known to react with chlorine to form 2-chioropheno! (2-CP),
4-CP,2,4-di-CP,2,6-di-CP, and 2,4,6-tri-CP (Kim et al.1994~. Phenol can
also react with bromine in water to form ortho- and/or para-brominated
phenol (Morrison and Boyd 1974, p. 502~. It also can be iodinated in an
anhydrous solvent yielding 2,4,6-triiodopheno! (Fieser and Fieser 1976, p.
503~. However, information about possible reactions between phenol and
iodine in water could not be found.
RATIONALE
The SWEGs for 1 4, 10 4, 100 4, and 1,000 ~ are listed in Table 7-13.
The rationales for those values are presented in this section. An astronaut
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Spacecraft Water Exposure Guidelines
TABLE 7-13 Spacecraft Water Exposure Guidelines for Phenol
Duration Concentration (mg/L)
1 d 80
8
Target Toxicity
Local gastrointestinal effects
Local gastrointestinal effects and
taste
Local gastrointestinal effects and
taste
Local gastronintestinal effects and
taste
10 d
100 d
4
1,000 d 4
consuming 2.8 L of water (in drink and in food) containing phenol at the
1-d SWEG of 80 mg/L would consume 224 mg of the compound per day.
As discussed above, the extra-strength Cepastat lozenge, an over-the-coun-
ter sore-throat medication, contains 29 mg phenol per lozenge; a patient
taking the maximum allowable 10 lozenges daily would ingest 290 mg of
phenol. Phenol at 80 mg/L will make water unpalatable, but will not pose
a toxicologic concern. Phenol has a detectable smell at ~ mg/L (Amoore
and Hautala 1983~; NASA would allow crew to consume water that had a
detectable smell of phenol at ~ mg/L for 10 days, but no longer. Thus, the
SWEGs for 100 ~ and 1,000 ~ are set at 4 mg/L. Standards set by other
organizations are listed in Table 7-14. EPA set 1-d, 10-d, long-term, and
lifetime health advisories (HAs) at 6, 6, 4, and 4 mg/L, respectively. To set
those HAs, EPA used the findings that no maternal or fetal toxicity occurred
in CD-1 mice given phenol in bolus doses at 60 mg/kg/d by gavage on
gestation days 6 to 15 (Jones-Price et al. 1983~. NASA wonders why the
results from the more relevant NCI studies and the multi-generation study
in which phenol was ingested in drinking water were not used for setting
exposure limit of phenol in drinking water. EPA used safety factors differ-
ent from those used by NASA. The NASA spacecraft water exposure
guidelines (SWEGs) for phenol were derived in accordance with guidance
developed by the National Research Council (NRC 1998~. The SWEGs are
set by choosing the lowest values among the acceptable concentrations
(ACs) identified in the literature.
In the section "Comparative Toxicity of Phenol by Different Means of
Administration, Routes of Dosing, and Durations of Exposure," it is pointed
out that when administered in drinking water, phenol is much less toxic than
it is when given in a bolus dose by gavage or by any other route. Data are
available from several good studies in which rodents consumed phenol in
OCR for page 281
281
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OCR for page 282
282
Spacecraft Water Exposure Guidelines
drinking water. Therefore, phenol exposure by other routes or by bolus oral
doses will not be considered in setting phenol exposure limits in spacecraft
drinking water.
When groups of CD- 1 mice (five per group) were exposed to drinking
water containing phenol at 0, 4.7, 19.5, and 95.2 mg/L for 4 wk. Hsieh et
al. (1992) observed that the highest-dose group had significantly fewer
spleenic IgM antibody-producing cells (plaque-forming cells) and circulat-
ing IgM antibodies specific to sheep erythrocytes. When mitogens were
incubated with spleenic lymphocytes isolated from the mice, the
proliferative response to three of four mitogens (assayed by incorporation
of tritiated thymidine) of lymphocytes from the highest-dose group was
significantly lower than the response of lymphocytes isolated from control
animals. However, white blood cell and differential white blood cell counts
and spleen cellularity were not affected by the phenol treatment. NCI
(1980) also did not find any effects on bone marrow, spleen, lymph nodes,
or thymus in 200 F-344 rats and 200 B6C3F~ mice treated with phenol in
drinking water at concentrations of 2,500 ppm or 5,000 ppm for 2 y. In the
NCI study, rats and mice were exposed for their lifetime to phenol in drink-
ing water at daily doses 50 times higher than the highest-dose level in Hsieh
et al. 's study. Survival rate and life-span were not affected by phenol treat-
ment. The effects seen by Hsieh et al. will not be considered for setting
SWEGs.
ACs Based on Data From Humans
As discussed above, the phenol spillage incident in Wisconsin resulted
in phenol concentrations in the six nearest wells at 15-126 mg/L (average
80 mg/L). Most families continued to drink their well-water for several
weeks after the spill until an unusual taste or odor developed. Some ofthe
residents had mouth sores, nausea, and diarrhea. Those are local irritating
effects of phenol in the alimentary canal. If we accept that these symptoms
are relatively mild, the concentration of 80 mg/L could be used as AC for
1 d. An astronaut consuming 2.S L water (in drink and in food) containing
80 mg/L phenol would consume 224 mg of the compound. As discussed
above, the extra-strength Cepastat lozenge, an over-the-counter sore-throat
medication, contains 29 mg of phenol per lozenge; a patient taking the
maximum allowable 10 lozenges per day would ingest 290 mg of phenol.
A 1-d SWEG of 224 mg of phenol would be less than the amount in 10
lozenges.
OCR for page 283
Phenol
283
The AC for 10 ~ was set by applying a safety factor of 10 (from
LOAEL tIowest-observed-adverse-effect level] to NOAEL) to the average
concentration of 80 mg/L of phenol found in the wells; therefore, the AC is
set at ~ mg/L. Because humans can detect phenol at ~ mg/L water (Amoore
and Hautala 1983), the ACs for 100 or 1,000 ~ are further reduced to 4
mg/L. This concentration is the same as EPA's lifetime health advisory
limit on phenol in water (4 mg/L).
ACs Based on Data from NCI Rodent Studies
When rats and mice were given drinking water containing phenol at
1,000 ppm for 13 wk. tissues and organs showed no gross or microscopic
histopathologic effects attributable to the phenol consumption. In this
study, the male and female rats consumed 101 mg/kg/d and 144 mg/kg/d,
respectively; the corresponding values for mice were 196 mg/kg/d and 302
mg/kg/~. The exposure level of 101 mg/kg/d is considered to be the
NOAEL. As pointed out above in the section on phenol metabolism, if
cellular sulfate or glucuronic acid is not depleted and the phenol conjuga-
tion enzymes are not saturated, the amount of time that humans or animals
drink phenol-contaminated water is not likely to influence the outcome of
toxicity. Therefore, an AC was set for all exposure durations. A spe-
cies-extrapolation factor of 10 was applied to obtain a human NOAEL; the
calculation assumes a 70-kg person ingesting 2.S L of water per day. The
AC was calculated as follows:
AC = 101 mg/kg x 70 kg 10 x 2.S L = 253 mg/L.
NCI (1980) also conducted a 2-y study in which groups of 50 B6C3F~
mice and 50 F-344 rats of each gender were provided drinking water con-
taining phenol at 2,500 or 5,000 ppm. No clinical signs or histopathologic
lesions attributed to phenol consumption were observed in either species.
A statistically significant increase in the incidence of leukemia or lym-
phoma was observed only in male rats ofthe low-dose group. NCI does not
consider phenol to be a carcinogen. All groups of mice and rats ingesting
phenol had lower water consumption rates than controls.
After adjusting for the decrease in water consumption, phenol con-
sumption in the 2,500-ppm groups was found to be 135 mg/kg/d and 146
mg/kg/d for male and female rats and 289 mg/kg/d and 296 mg/kg/d for
male and female mice. As discussed previously, bad-tasting water is con-
OCR for page 284
284
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OCR for page 285
Phenol
285
sidered undesirable for long-term consumption. Therefore, 135 mg/kg is
considered a LOAEL. A factor of 10 was used to extrapolate LOAEL to
NOAEL, and a species-extrapolation factor of 10 was applied to obtain a
NOAEL for humans of 34 mg/L. The 1,000-d AC was calculated as fol-
lows:
1,000-d AC = 135 mg/kg x 70 kg 10 x 10 x 2.8 L = 34 mg/L.
AC Summary Table and SWEGs
The ACs derived from various toxicity end points are summarized in
Table 7-15 (above). The SWEGs are set by choosing the lowest values
among those ACs.
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Representative terms from entire chapter:
technical report
