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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

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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 82C 43C 0.35 mmHg at 25C 1 g/15 mL 10 at 25C 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

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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

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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-

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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

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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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256 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

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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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258 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

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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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280 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

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281 an C) A as o . - .~ o so as o D as V] _I _I as o U. as o V as Ct o . ~ Ct o .~ O C) v at ED at U. o O O Do Do at Ct ~ ~ ~ ~ _' 1- 1- 1- 1- c) as as O O O O ~ X X X X _t ~ ~ ~ ~ ~ O 11 11 11 11 ~ ~ ~ ~ ~ ~ ~ ~ c g g g g =^o ~ ~ .l. l- l- l- ~ ~ ~ o Mo Mo Mo Mo ~ o ~ ~ 11 11 11 11 ~ 11 >,~o ~ ~ ~ ~ o ~ ~ ~ z c c c c ~ ~ . . Mo Mo Mo ~ ~ o a~ ~ a~ cd .= ~. ;~e P O ~ 0~ ~ 0 5=c =~ ~ ~0~0 =^ O .~ ~ ~ O ~ ~ -= ~ s- cq, u, a~ ~ O ~ .o O ~ a~ ~ s- ,,0 ~ ~ ~ =' - ~ ~ ~ ,= ~ 9 ~ 5 9 ~ C ~ ~ \0.> o.~ ~ 8 3 ~ ~ V ~ s~- ,= ~ ~ .. (3 ~= ~ ~ o ~ ~ .~ U, ~= ~ r r ~5 ~ a~ U,

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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.

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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-

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284 U. v as U. U. o ~g N_ .: .o ~ Ct Al V as Cal to o ~ o o ~ o ~ 1 ~ ~ 1 Do Io ~ ~ Do o o o U. at C) V) C) U. ~ . - sit C) t V) at o o o to Do V to Do ~ V Ct ~ Al o t^ ~ 3 11 C<, ~ no .~ ~ O ~ ~ O ~ ~ 3 Ct u, a~ oo oo i 3 ~ ~ i Z o

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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. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of the Threshold Limit Values and Biological Exposure Indi- ces, 6th Ed. Cincinnati, OH: ACGIH. Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 indus- trial chemicals in air and water dilution. J. Appl. Toxicol. 3~6~:272-290. Angel, A., and K.J. Rogers. 1972. An analysis ofthe convulsant activity of substi- tuted benzenes in the mouse. Toxicol. Appl. Pharmacol. 21 :214-229. ATSDR (Agency for Toxic Substance and Disease Registry). 1998. Toxicological Profile for Phenol. Agency for Toxic Substance and Disease Registry, U.S. Department of Health and Human Services, Atlanta, GA. Baker, E.L., P.J. Landritan, P. E. Bertpzzo et al. 1978. Phenol Poisoning due to contaminated drinking water. Arch. Environ. Health 33:89-94. Barale, R., A. Marrazzini, C. Betti, V. Vangelisti, N. Loprieno, and I. Barrai. 1990. Genotoxicity of two metabolites of benzene: phenol and hydroquinone show strong synergistic effects in vivo. Mutat. Res. 244~1~: 15-20. Berman E., M. Schlicht, V.C. Moser, and R. C. MacPhail. 1995. A multidisciplinary approach to toxicological screening. I. Systemic toxicity. J. Toxicol. Environ. Health 45: 127-143. Bock, K.W., G. Schirmer, M.D. Green, and T.R. Tephly. 1988. Properties of 3-methcholanthrene-inducible phenol UDP-glucuronosyltransferase from rat liver. Biochem. Pharmacol. 37:1439-1443. Bruce, R.M., J. Santodonato, and M.W. Neal. 1987. Summary review of health effects associated with phenol. Toxicol. Ind. Health 3:535-568.

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286 Spacecraft Water Exposure Guidelines Campbell, N., J.A. Van Loon, and R.M.Weinshilboum.1987. Human liver phenol sulfotransferase: Assayconditions,biochemicalpropertiesandpartialpurifica- tion of isozymes of the thermostable form. Biochem. Pharmacol. 36:1435- 1446. Capel, I.D., M.R. French, P. Millburn, R.L. Smith, and R.T. Williams. 1972. The fate of [TIC] phenol in various species. Xenobiotica 2:25-34. Casidy, M.K., and J.B. Houston.1984. In vivo capacity of hepatic and extra hepatic enzymes to conjugated phenol. Drug Metab.Dispos. 12:619-624. Ciranni, R., R. Barale, A. Marrazzini, and N. Loprieno. 1988. Benzene and the genotoxicity of its metabolites. I. Transplacental activity in mouse fetuses and in their dams. Mutat. Res. 208~1~:61-7. Clarke, T.W., and E.D. Brown. 1906. The value of alcohol in carbolic acid poison- ing. A clinical and experimental study. JAMA 46:782-790. Deichmann, W.B., and S. Witherup. 1944. Phenol studies. VI. The acute and com- parative toxicity of phenol and o-, m-, end p-creasol for experimental animals. J. Pharmcol. Exp. Ther. 80:233-240. Deichmann, W.B., and M.L. Keplinger. 1981. Phenols and Phenolic Compounds. Chapter 36 in Patty's Industrial Hygiene and Toxicology, 3rd Ed., G.D. Clay- ton and F.E. Clayton, eds. New York, NY: John Wiley and Sons. Deichmann, W.B., K.V. Kitzmiller, and S. Witherup. 1944. Phenol studies. Phe- nol studies VII. Chronic phenol poisoning with special reference to the effects upon experimental animals of the inhalation of phenol vapor. Am. J. Clin. Pathol. 14: 273-277. EPA (U.S. Environmental Protection Agency). 1993. Phenol. Pp. 191-212 in Health Advisories for Drinking Water Contaminants. Office of Water Health Advisories, U.S. Environmental Protection Agency. Boca Raton, FL: Lewis Publishers. Fieser, M., and L.F. Fieser. 1976. Reagents for Organic synthesis, Vol. 5. New York, NY: Wiley-Interscience. Flickinger, C.W. 1976. The benzenediols: Catechol, resorcinol and hydroquinone. A review of the industrial toxicology and current industrial exposure limits. Am. Ind. Hyg. Assoc. J. 37:596-606. Gottlieb, J., and E. Storey. 1936. Death due to phenol absorption through unbro- ken skin. Maine Med. J. 27: 161-164. Gross, B.G. 1984. Cardiac arrhythmias during phenol face peeling. Plast. Reconstr. Surg. 73:590-594. Heller, V. G., and L. Pursell.1938 Phenol-contaminated water and their physiologi- cal action. J. Pharmacol. Exp. Ther. 63:99-107. Hoffmann, M. J., S. Ji, C.C. Hedli, end R. Snyder. 1999. Metabolismoft~4C]phenol in the isolated perfused mouse liver. Toxicol. Sci. 49~1~:40-47. Hsieh, G.C., R.P. Sharma, R.D.R. Parker, and R.A. Coulombe. 1992. Immunolog- ical and neurobiochemical alteration induced by repeated oral exposure of phenol in mice. Eur. J. Pharmacol. 228: 107-114. Hughes, M.F., and L.L. Hall. 1995. Disposition of phenol in rat after oral dermal, intravenous and intratracheal administration. Xenobiotica 25:873-883.

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Phenol 287 Humphrey, M.J., C.W. Filer, D.J. Jeffery, P.F. Langley, and G.A. Wadds. 1980. The availability of carfecillin and its phenol moiety in rat and dog. Xenobiotica 10:771 -778. Jones-Price, C., T.A. Ledoux, J.R. Reed, P.W. Fisher, L. Langhoff-Paschke, and M.C. Marr. 1983. Teratologic evaluation of phenol (CAS No. 105-92-2) in CD rats. Conducted by Research Triangle Institute, Research Triangle Park, NC, for National Institute of Environmental Health Sciences, National Insti- tutes of Health, Bethesda, MD. Kao, J., J.W. Bridges, and J.K. Faulkner. 1979. Metabolism of [TIC] phenol by sheep, pig, rat. Xenobiotica 9:141-147. Kim, D.-H., S.-K. Lee, B.-Y. Lee, D.H. Lee, S.-C. Hong, and B.-K Jang. 1994. Illness associated with contamination of drinking water supplies with phenol. J. Korean Med. Sci. 9:218-223. Liao, T.F., and F.W. Oehme. 1981. Tissue distribution end plasma protein birding of [~4C]phenol in rats. Toxicol. Appl. Pharmacol. 57:220-225. Marrazzini, A, L. Chelotti, I. Barrai, N. Loprieno, and R. Barale. 1994. In vivo genotoxic interactions among three phenolic benzene metabolites. Mutat. Res. 341(1):29-46. Minor, J.L., and B.A. Becker. 1971. A comparison of the teratogenic properties of sodium salicylate, sodium benzoate, and phenol [Abstract]. Toxicol. Appl. Pharmacol. 19:373. Morrison, R.T., and R.N. Boyd. 1974. Organic Chemistry, 3rd Ed. Boston, MA: Allyn and Bacon. NCI (National Cancer Institute).1980. Bioassay of phenol for possible carcinoge- nicity (CAS No 108-95-2~. National Cancer Institute Carcinogenesis Techni- cal Report 203. U.S. Department of Health and Human Services, Public Health Service, Washington, DC, and National Institutes of Health, Bethesda, MD. NIOSH (National Institute for Occupational Safety and Health). 1976. Criteria for a Recommended Standard - Occupational Exposure to Phenol. DHEW Pub. No. 76-196. National Institute for Occupational Safety and Health, U.S. Department of Health and Human Services, Washington, DC. NTP (National Toxicology Program).199la. NTP Technical Report on the Toxi- cology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine dihydrochloride in F344/N Rats (Drinking Water Studies). NTP TR 390 (NIH Publication No. 91-2845~. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP (National Toxicology Program).199lb. NTP Technical Report on the Toxi- cology and Carcinogenesis Studies of C.I. Acid Red 114 in F344/N Rats (Drinking Water Studies). NTP TR 405 (NIH Publication No. 92-3136~. Na- tional Toxicology Program, National Institutes of Health, Bethesda, MD. NTP (National Toxicology Program). 1992a. NTP Technical Report on Toxicity Studies of diethanolamine administered topically and in drinking water to F344/N rats and B6C3F1 mice. NTP TR Series No.20 (NIH Publication No. 92-3343~. National Toxicology Program, National Institutes of Health, Bethesda, MD.

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288 Spacecraft Water Exposure Guidelines NTP (1992b). NTP Technical Report on the Toxicology and Carcinogenesis Stud- ies of Chlorinated Water and Chloraminated Water in F344/N Rats and B6C3F 1 Mice (Drinking Water Studies). NTP TR 392 (NIH Publication No. 92-2847~. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP. 1993a. NTP Technical Report on Toxicity Studies of ethylene glycol ethers 2-methoxyethano,2-ethoxyethanol,2-butoxyethanol administered in drinking water to F344/N rats and B6C3F1 mice. NTP TR Series No.26 (NIH Publica- tionNo.93-3349~. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP.1993a. NTP Technical Report on Toxicity Studies of cupric sulfate adminis- tered in drinking water to F344/N rats and B6C3F1 mice. NTP TR Series No.29 (NIH Publication No.93 -3349~. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP.1996b. NTP Technical Report on Toxicity Studies of Cyclohexanone Oxime administered in drinking water to F344/N rats and B6C3F1 mice. NTP TR Series No.50. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP. 1996b NTP Technical Report on Toxicity Studies of Urethane in Drinking Water and Urethane in 5/O Ethanol administered in drinking water to F344/N rats and B6C3F1 mice. NTP TR Series No.52. National Toxicology Program, National Institutes of Health, Bethesda, MD. NTP (2000~. NTP Technical Report on the Toxicology and Carcinogenesis Stud- ies of Pyridine in F344/N Rats, Wistar Rats, and B6C3F1 Mice (Drinking Water Studies). NTP TR 470 (NIH Publication No.00-3960~. National Toxi- cology Program, National Institutes of Health, Bethesda, MD. NTP (2001~. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Sodium nitrite in F344/N Rats and B6C3F 1 Mice (Drinking Water Studies). NTP TR 495 (NIH Publication No. 01-3954~. National Toxicology Program, National Institutes of Health, Bethesda, MD. PDR (Physcians' Desk Reference). 1997. Physcians' Desk Reference forNonpre- scription Drugs, 18th Ed. Montvale, NJ: Medical Economics Company. Piotrowski, J.K. 1971. Evaluation of exposure to phenol - Absorption of phenol vapor in the lungs and through the skin and excretion of phenol in urine. Br. J. Ind. Med. 28:172-178. Plumlee, D.K., P.D. Mudgett, and J.R. Schultz. 2002. Chemical sampling and analysis of ISS potable water: Expeditions 1-3. SAE Paper. Presented in the 32nd International Conference on Environmental Systems, San Antonio, TX (July). Plumlee, D.K., P.D. Mudgett, and J.R. Schultz. 2003. Chemical sampling and analysis of ISS potable water: 4-5. SAE Paper. Presented in the 33rd Interna- tional Conference on Environmental Systems, Vancouver, BC (July). Powel, G.M., J.J. Miller, and A.H. Olavesen. 1974. Liver as major organ of phe- nol detoxiciation. Nature (London) 252:234-235. Price, C.J., T.A. Ledoux, J.R. Reed, P.W. Fisher, L.L. Paschke, M.C. Marr, and

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Phenol 289 C.A. Kimmel. 1986. Teratological evaluation of phenol in rats and mice. Teratology 33:92C-93C. Pullin, T.G., M.N. Pinkerton, R.V. Johnston, andD.J. Kilian. 1978. Decontamina- tion of the skin of swine following phenol exposure: A comparison of the relative efficacy of water versus polyethylene glycol/industrial methylated spirits. Toxicol. Appl. Pharmacol. 43:199-206. Remington.1985. Remington's Pharmaceutical Sciences, A. Gennaro, ed. Easton, PA: Mack Publishing Co. Ruedeman, R., and W. Dechmann. 1953. Blood phenol level after topical applica- tionofphenol-containingpreparations. JAMA 152:506-509. Scholosser, P.M., J.A. Bond, and M.A. Midinsky. 1993. Benzene and phenol metabolism by mouse and rat liver microsomes. Carcinogenesis 14 :2477-2486. Stajdubar-Caric, Z. 1968. Acute phenol poisoning. Singular findings in a lethal case. J. Forensic Med. 15:41-42.