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4
Phenol1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-1, AEGL-2, and AEGL-3, as appropriate, will be developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population, including infants and children and other individuals who may be sensitive or susceptible. The three AEGLs have been defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m³]) of a substance above which it is
1
This document was prepared by the AEGL Development Team composed of Peter Griem (Forschungs- und Beratungsinstitut Gefahrstoffe GmbH) and Chemical Managers Robert Snyder and Bill Bress (National Advisory Committee [NAC] on Acute Exposure Guideline s for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline s. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including sensitive subpopulations, it is recognized that certain individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
Phenol is a colorless to pink, hygroscopic solid with a characteristic, sweet, tarlike odor. Pure phenol consists of white-to-clear acicular crystals. In the molten state, it is a clear, colorless liquid with a low viscosity.
Human fatalities by phenol have been reported after ingestion and skin contact. Few studies after inhalation of phenol are available: one occupational study reported slight changes in liver and blood parameters (increased serum transaminase activity, increased hemoglobin concentration, increased numbers of basophils and neutrophils, and lower levels of monocytes) after repeated exposure to a mean time-weighted average concentration of 5.4 ppm (Shamy et al. 1994). Piotrowski (1971) did not report symptoms or complaints in a toxicokinetic study, in which subjects were exposed at 6.5 ppm for 8 h. Likewise, Ogata et al. (191986) in a toxicokinetic field study did not mention any effects on workers exposed to mean workshift concentrations of 4.95 ppm. Among persons exposed to phenol at more than 1 mg/liter (L) of contaminated drinking water for several weeks, gastrointestinal symptoms (diarrhea, nausea, and burning pain and sores in the mouth) and skin rashes occurred (Baker et al. 1978). A geometric mean odor detection threshold of 0.060 ppm (range of all critiqued odor thresholds 0.0045-1 ppm) has been reported (AIHA 1989). Don (1986) reported an odor detection threshold of 0.010 ppm in a CEN (2003) comparable study.
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No studies reporting LC50 (concentrations with 50% lethality) values for phenol in animals are available. Oral LD50 values were reported as 420 mg/kg for rabbits, 400-650 mg/kg for rats, and 282-427 mg/kg for mice. In rats, exposure to a phenol aerosol concentration of 900 mg/m³ for 8 h resulted in ocular and nasal irritation, incoordination, and prostration in one of six rats (Flickinger 1976). After 4 h of exposure of phenol vapor at 211 or 156 ppm, a decrease of the number of white blood cells but no signs of toxicity were reported (Brondeau et al. 1990). After vapor exposure of rats at 0.5, 5, or 25 ppm for 6 h/d, 5 d/wk for 2 weeks, no clinical, hematologic, or histopathologic effects were found (Huntingdon Life Sciences 1998; published in Hoffman et al. 2001). Continuous exposure to phenol vapor at 5 ppm for 90 days caused no hematologic or histologic effects in rhesus monkeys, rats, and mice. A vapor concentration of 166 ppm (for 5 min) resulted in a 50% decrease of respiration (RD50) in female Swiss OF1 mice. No teratogenic effects were found in studies using repeated oral gavage and doses of up to 120 mg/kg in CD rats and 140 mg/kg in CD-1 mice. In a two-generation drinking-water study in Sprague-Dawley rats, decreased pup survival linked to decreased maternal body weight was observed at the highest dose of 5,000 ppm; the no-observed-adverse-effect level (NOAEL) was 1,000 ppm (equivalent to 70 mg/kg/d for males and 93 mg/kg/d for females). In an oral carcinogenicity study, B6C3F1 mice and Fischer 344 rats received phenol at 2,500 or 5,000 mg/L of drinking water (corresponding to 281 and 412 mg/kg/d for mice and 270 and 480 mg/kg/d for rats). No increased incidence of tumors was observed in mice and female rats; a significant incidence of tumors (pheochromocytomas of the adrenal gland, leukemia, or lymphoma) occurred in male rats of the high-exposure group. Phenol had tumor promoting activity when applied repeatedly on the skin after induction using benzene. It can cause clastogenic and possibly very weak mutagenic effects. IARC evaluated the findings on carcinogenicity and concluded that there is inadequate evidence in both humans and experimental animals for the carcinogenicity of phenol. Consequently, phenol was found “not classifiable as to its carcinogenicity to humans (Group 3)” (IARC 1999, p.762). EPA concluded that “the data regarding the carcinogenicity of phenol via the oral, inhalation, and dermal exposure routes are inadequate for an assessment of human carcinogenic potential. Phenol was negative in oral carcinogenicity studies in rats and mice, but questions remain regarding increased leukemia in male rats in the bioassay as well as the positive gene mutation data and the positive results in dermal initiation/promotion studies at doses at or above the maximum tolerated dose (MTD). No inhalation studies of an appropriate duration exist. Therefore, no quantitative assessment of carcinogenic potential via any route is possible” (EPA 2002, p. 103). Therefore, carcinogenicity was not an end point in the derivation of AEGL values.
The AEGL-1 was based on a repeat inhalation study of phenol in rats (Huntingdon Life Sciences 1998; Hoffman et al. 2001), which found no clinical, hematologic or histopathologic effects after exposure to phenol at 25 ppm (highest concentration used) for 6 h/d, 5 d/wk for 2 weeks. An uncertainty factor of 1 was applied for interspecies variability: the toxicokinetic component of the un-
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certainty factor was reduced to 1 because toxic effects are mostly caused by phenol itself without requirement for metabolism; moreover, possible local irritation effects depend primarily on the phenol concentration in inhaled air with little influence of toxicokinetic differences between species. The starting point for AEGL derivation was a NOAEL from a repeat exposure study, and thus the effect level was below that defined for AEGL-1. The human experimental and workplace studies (Piotrowski 1971; Ogata et al. 1986) support the derived values. For these reasons, the interspecies factor was reduced to 1. An uncertainty factor of 3 was applied for intraspecies variability because, for local effects, the toxicokinetic differences do not vary considerably within and between species. Therefore the toxicokinetic component of the uncertainty factor was reduced to 1 and the factor of 3 for the toxicodynamic component was retained, reflecting a possible variability of the target-tissue response in the human population. The other exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods and n = 1 for longer exposure periods, because of the lack of suitable experimental data for deriving the concentration exponent. For the 10-min AEGL-1, the 30-min value was applied because the derivation of AEGL values was based on a long experimental exposure period, and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
A level of distinct odor awareness (LOA) for phenol of 0.25 ppm was derived on the basis of the odor detection threshold from the study of Don (1986). The LOA represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity; about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure due to odor perception.
The AEGL-2 was based on a combination of the Flickinger (1976) and Brondeau et al. (1990) studies. Aerosol exposure to phenol at 900 mg/m³ (equivalent to phenol vapor at 234 ppm) for 8 h resulted in ocular and nasal irritation, slight loss of coordination, and spasms of the muscle groups at 4 h into the exposure. After 8 h, additional symptoms (tremor, incoordination, and prostration) were observed in one of the six animals. No deaths occurred. Because the aerosol concentration was below the saturated vapor concentration at room temperature of about 530 ppm, it was assumed that much of the phenol had evaporated from the aerosol and a mixed aerosol and vapor exposure prevailed. This study is supported by the study of Brondeau et al. (1990), who reported only slight effects after exposure to phenol vapor at 211 ppm for 4 h. Although both studies had shortcomings—that is, aerosol exposures, nominal concentrations, and no description of toxic signs in one study—taken together, they had consistent results. The derivation of AEGL-2 values was based on an exposure concentration of 234 ppm for 8 h. An uncertainty factor of 3 was applied for interspecies variability because oral lethal data did not indicate a high variability between species (cf. section 4.4.1.) and because application of a higher uncertainty factor
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would have resulted in AEGL-2 values below levels that humans can stand without adverse effects (Piotrowski 1971; Ogata et al. 1986). An uncertainty factor of 3 was applied for intraspecies variability because the study of Baker et al. (1978) who investigated health effects in members of 45 families (including children and elderly) that were exposed to phenol through contaminated drinking water for several weeks did not indicate that symptom incidence or symptom severity was higher in any specific subpopulation. Moreover, newborns and infants were not considered more susceptible than adults because of their smaller metabolic capacity to form toxic phenol metabolites (cf. section 4.4.2.). Based on the small database and study shortcomings, a modifying factor of 2 was applied. The other exposure duration-specific values were derived by time scaling according to the dose-response regression equation Cn × t = k, using the default of n = 3 for shorter exposure periods, because of the lack of suitable experimental data for deriving the concentration exponent. For the 10-min AEGL-2, the 30-min value was applied because the derivation of AEGL values was based on a long experimental exposure period and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
Although phenol is a high-production-volume chemical, no acute inhalation studies of adequate quality were available for the derivation of the AEGL-3 value. Therefore, due to insufficient data and the uncertainties of a route-to-route extrapolation, AEGL-3 values were not recommended. The calculated values are listed in Table 4-1.
TABLE 4-1 Summary of AEGL Values for Phenola
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (Nondisabling)
19 ppm (73 mg/m³)
19 ppm (73 mg/m³)
15 ppm (58 mg/m³)
9.5 ppm (37 mg/m³)
6.3 ppm (24 mg/m³)
No effects in rats (Huntingdon Life Sciences 1998; Hoffman et al. 2001)
AEGL-2 (Disabling)
29 ppm (110 mg/m³)
29 ppm (110 mg/m³)
23 ppm (90 mg/m³)
15 ppm (57 mg/m³)
12 ppm (45 mg/m³)
Irritation and CNS depression in rats (Flickinger 1976; Brondeau et al. 1990)
AEGL-3 (Lethal)
N.R. b
N.R.
N.R.
N.R.
N.R.
aSkin contact with molten phenol or concentrated phenol solutions should be avoided; dermal penetration is rapid, and fatal intoxications have been observed when a small part of the body surface was involved.
bNot recommended because of insufficient data.
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1.
INTRODUCTION
Phenol is a colorless to pink, hygroscopic solid with a characteristic, sweet, tarlike odor. Pure phenol consists of white-to-clear acicular crystals. In the molten state, it is a clear, colorless liquid with a low viscosity. A solution with approximately 10% water is called phenolum liquefactum, as this mixture is liquid at room temperature (WHO 1994).
Phenol is produced either by oxidation of cumene or toluene, by vaporphase hydrolysis of chlorobenzene, or by distillation from crude petroleum (WHO 1994). Worldwide phenol production has been reported to be about 500,000 to 1,000,000 metric tons per year (IUCLID 1996). Newer data report a production of 1,800,000 metric tons per year in the European Union (ECB 2002) and about 1,500,000 metric tons for 1994 in the United States (HSDB 2003).
Phenol is pumped in molten form (about 50°C) or in liquefied form (containing 10% water) through pipes on industrial sites and is also transported in molten form in tank trucks and rail tank cars between industrial sites. Therefore, inhalation exposure during accidental release cannot be ruled out.
Phenol is principally used in production of various phenolic resins, biphenol A, caprolactam, and a wide variety of other chemicals and drugs. It is also used as a disinfectant and in germicidal paints and slimicides (ACGIH 1996). The TRI database (DHHS 2008) lists 649 sites in the United States where production and use of phenol causes emissions to the air. Chemical and physical data are provided in Table 4-2.
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
No relevant studies documenting lethal effects in humans after inhalation exposure to phenol were identified. During the second half of the nineteenth century, several hundred cases of intoxication occurred from inhalation, oral, or dermal exposure (Lewin 1992). Contemporary reports concerning fatalities after oral or dermal exposure are available; however, for dermal exposures, information about the absorbed dose is often not reported (WHO 1994). Lethality data in humans are summarized in Table 4-3.
2.1.1.
Case Studies
Heuschkel and Felscher (1983) reported on the death of a newborn (weight 3 kg) that was exposed through a contaminated continuous positive airway pressure system of an incubator. Instead of distilled water, the system contained a disinfection fluid, composed of 2% formalin (30% formaldehyde), 1.5% sodium tetraborate, and 0.5% phenol. This solution was removed after 5-6 h.
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TABLE 4-2 Chemical and Physical Data for Phenol
Parameter
Data
Reference
Molecular formula
C6H6O; C6H5OH
WHO 1994
Molecular weight
94.11
WHO 1994
CAS Registry Number
108-95-2
WHO 1994
Physical state
Solid
ACGIH 1996
A solution with approx. 10% water (phenolum liquefactum) is liquid at room temperature
WHO 1994
Color
Colorless
ACGIH 1996
Assumes a pink to red discoloration on exposure to air and light
Synonyms
Carbolic acid; hydroxybenzene; phenyl hydroxide; phenol
ACGIH 1996
Vapor pressure
0.48 hPa at 20°C
IUCLID 1996
0.357 mm Hg at 20°C
WHO 1994
1 mm Hg at 40.1°C
Weast 1984
3.5 hPa at 25°C
IUCLID 1996
2.48 mm Hg at 50°C
WHO 1994
10 mm Hg at 73.8°C
Weast 1984
18.39 hPa at 80.1°C
IUCLID 1996
40 mm Hg at 100.1°C
Weast 1984
100 mm Hg at 121.4°C
Weast 1984
Density
1.0719 g/cm³
ACGIH 1996
Melting point
43°C
Weast 1984
Boiling point
181.75°C
Weast 1984
Solubility
Very soluble in chloroform, alcohol, ether, and aqueous alkali hydroxides; 67 g/L in water at 16°C
ACGIH 1996
WHO 1994
Odor
Sweet, tarlike odor
ACGIH 1996
Sweet and acrid
IARC 1999
Explosive limits in air
1.7% (lower), 8.6% (upper)
ACGIH 1996
Conversion factors
1 ppm = 3.84 mg/m³
WHO 1994
1 mg/m³ = 0.26 ppm
However, exposure was continued since disinfection fluid was also used for filling up the reservoir for humectation of the air. The newborn developed severe symptoms after 20 h of exposure. It showed a gray-pale skin color, edema on the head and legs, and tachypnea and died on the fifth day from pro-
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TABLE 4-3 Summary of Data on Lethal Effects in Humans
Subject information
Exposure Route
Exposure Information
Estimated Dose
Effect
Reference
1-d-old newborn
Inhalation
About 5.2 ppm for 5-6 h, subsequently about 1.3 ppm for 14-15 h
Unknown
Cyanosis, tachypnea, death 4 days later; additional formaldehyde exposure
Heuschkel and Felscher 1983
65-y-old female
Oral
70 mL of 42-52% phenol solution
490-606 mg/kg
Assuming a density of 1 g/mL and a body weight of 60 kg
After 1 h respiratory arrest, coma, survived due to intensive care
Kamijo et al. 1999
50-y-old male
Oral
Approx. 60 mL of an 88% phenol emulsion
754 mg/kg
Assuming a density of 1 g/mL and a body weight of 70 kg
After 45 min stuporous, tachycardia, stertorous breathing, rales in the lungs, survived with medical treatment
Bennett et al. 1950
19-y-old female
Oral
15 mL liquefied phenol
250 mg/kg
Assuming a density of 1 g/mL and a body weight of 60 kg
90 min later nausea, vomiting, diarrhea, cyanosis, stuporous, death after 17.5 h
Bennett et al. 1950
Adult female
Oral
10-20 g phenol
166-333 mg/kg
Assuming a body weight of 60 kg
Coma, absence of reflexes, tachypnea, tachycardia, death after 1 h due to cardiac and respiratory arrest
Stajduhar-Caric 1968
27-y-old male
Oral (+ dermal)
Unknown
106-874 mg/kg,
Based on tissue concentration
Found dead next day; at autopsy tissue phenol concentrations between 106 and 874 mg/kg, 60 mg/kg in blood
Tanaka et al. 1998
1-d-old newborn
Dermal
2% phenol solution in umbilical bandage
125-202 mg/kg
Based on tissue concentration, assuming uniform distribution and no elimination
Cyanosis, death after 11 h, at autopsy tissue phenol concentrations between 125 and 202 mg/kg
Hinkel and Kintzel 1968
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gressive respiratory insufficiency. On experimental reconstitution of the exposure conditions, phenol at about 20 mg/m³ (5.2 ppm) and formaldehyde at about 30 mg/m³ (24.9 ppm) were measured in the incubator after 2 h (lower concentrations of phenol and formaldehyde after 5 h not reported) when disinfection solution was present in the evaporation container, and phenol at about 5 mg/m³ (1.3 ppm), formaldehyde at 50 mg/m³ (41.5 ppm), and methanol at 350 mg/m³ (267 ppm) were found (with decrease of the formaldehyde and methanol concentrations within the first hour) with disinfection fluid in the water reservoir. It should be noted that concentrations in the incubator were measured using simple solid sorbent test tubes. Autopsy revealed hypoxemia-caused organ alterations. The authors contributed these to two causes: (1) central respiratory depression by the intoxication and (2) congenital pulmonary adaptation disorder, expressed in an immature tissue structure of the lung.
A 65-year-old Japanese woman ingested 70 mL of 42-52% phenol in a suicide attempt. Upon hospital admission and about 1 h after ingestion, respiration had arrested, and the patient was comatose. The patient survived due to intensive medical care (Kamijo et al. 1999).
Bennett et al. (1950) reported on two suicide cases. The first case involved a 50-year-old morphine addict who swallowed approximately 60 mL of an 88% aqueous phenol emulsion. Forty-five minutes later, he was stuporous with cold and clammy skin and had a rapid and weak pulse, stertorous breathing with a phenol odor on the breath, constricted pupils that did not react to light (probably due to morphine injection prior to phenol ingestion), and rales in the lungs. An electrocardiogram showed auricular flutter with a variable auriculoventricular block. His urine was greenish with no albumin, but 12 h later there was a marked albuminuria and cylindruria. Albuminuria persisted for 10 days. The patient responded to medical treatment and recovered in 20 days. The second case involved a 19-year-old woman who had ingested 15 mL of liquefied phenol. Ninety minutes later, she complained of severe nausea and burning in the throat and epigastrium. Laryngoscopic examination revealed superficial burns and slight edema of the hypopharynx. Despite gastric lavage with olive oil and intravenous saline administration, she continued to be nauseated. One hour later, she began to vomit blood and to have diarrhea, passing copious amounts of blood with clots. She gradually became cyanotic and stuporous and died 17.5 h after ingestion.
Stajduhar-Caric (1968) described a woman who committed suicide by ingesting 10-20 g of phenol. She became comatose with partial absence of reflexes, pallor of the skin, accelerated respiration, weak and rapid pulse and dilated pupils that did not react to light. Almost 1 h after the ingestion, her heart and respiration stopped and, in spite of repeated attempts at resuscitation for 2 h, she died. Autopsy revealed marked hyperemia of the tracheal and bronchial mucous membranes. Histologic examination revealed pulmonary and liver edema as well as hyperemia of the intestine.
Tanaka et al. (1998) reported on the case of a 27-year-old male student, who died after ingestion of a DNA extraction fluid containing phenol. He was
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found in the laboratory the next day lying on the floor with his trousers soaked. At autopsy on the same day, the body surface was grayish in color; the skin in the large area extending from the right arm to both legs had changed color to dark brown, and some parts of its surroundings were chemically burned. There were also blisters in the skin across the burned area. The lips, oral mucous membranes, and the walls of the orsopharynx, larynx, bronchus, esophagus, and stomach were dark brown and inflamed. Histology revealed inflammatory changes in the lungs, interstitial edema and renal tubular hemorrhage in the kidneys, and interstitial hemorrhage in the pancreas and adrenal glands. Analysis of free phenol was performed by gas chromatography/mass spectroscopy on ethyl acetate extracts of tissues. The following phenol concentrations were found: 60 mg/L in the blood, 208 mg/L in urine, 106 mg/L in the brain, 116 mg/L in the lung, and 874 mg/L in the kidney. Upon skin contact with liquefied phenol or phenol solutions, symptoms can develop rapidly leading to shock, collapse, coma, convulsions, cyanosis and death (NIOSH 1976; Lewin 1992).
Horch et al. (1994) described a healthy 22-year-old male worker who was splashed with aqueous phenol (concentration not reported) over his face, chest, one hand, and both arms (20.5% of the body surface). Extensive water showering and topical treatment with polyethylene glycol was carried out before hospital admission. Affected skin areas were swollen and reddish and looked like partial skin thickness burn wounds. Blood gas analysis revealed that oxygen saturation dropped from 99% on admission to 72% 6 h after exposure. During this period, cardiac arrhythmia and bradycardia were noted. Serum levels of phenol were 11.4 mg/L at 1 h, 17.4 mg/L at 4 h, 6.0 mg/L at 8 h, 0.37 mg/L at 22 h, and 0.07 mg/L at 28 h post-exposure. The man survived and his skin healed completely within 12 days.
Bentur et al. (1998) reported on the case of a 47-year-old male who had 90% phenol spilled over his left foot and shoe (3% of the body surface). After 4.5 h of exposure, with no attempt to remove the phenol, confusion, vertigo, faintness, hypotension, ventricular premature beats, and atrial fibrillation developed and the affected skin area showed swelling and blue-black discoloration and was diagnosed as a second degree burn. Peak serum phenol was 21.6 mg/L and was eliminated with a half-life of 13.9 h.
Lewin and Cleary (1982) described a 24-year-old male who died shortly after being painted with benzyl benzoate as a scrabicide with a brush that had been steeped in 80% phenol and not thoroughly washed before use.
Hinkel and Kintzel (1968) described two newborns having cutaneous contact with phenol-containing disinfectants. A 1-day-old newborn died 11 h after application of an umbilical bandage that was accidentally soaked with 2% phenol instead of saline. After 6 h, the baby developed severe cyanosis and died at 11 h from central respiratory depression. Autopsy revealed edematous swelling of all parenchymal organs. Phenol concentrations of 125 mg/kg in blood, 144 mg/kg in liver and 202 mg/kg in kidney were measured. Another infant, 6 days old, was treated for skin ulcer with Chlumsky’s solution (phenol-camphor complex) and developed life-threatening methemoglobinemia, vomiting, cyanosis,
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muscle twitchings and tremors, central circulatory collapse, mimic rigidity, muscular hypertonia, and tenderness to touch. These symptoms persisted for 3 days. The baby survived following intensive care and blood-exchange transfusion.
Schaper (1981) reported on the case of a 19-year-old woman who was accidentally splashed with molten phenol (80-90°C) on the face, left arm, and left leg (about 35-40% of the body surface). Five minutes later the patient lost consciousness, and upon hospital admission 15 min after the accident she was comatose. The patient developed bradypnea and tachycardia, brownish necrosis of the affected skin and massive intravasal hemolysis. After intensive medical care, the patient regained consciousness after 6 h; cardiac activity normalized after 8 h. No sign of organ damage was observed and the patient was discharged after 33 days. The peak phenol concentration in urine was about 600 mg/L 2 days after the accident; the urinary concentration decreased to 100-150 mg/L during the first week and second weeks.
2.2.
Nonlethal Toxicity
Although some studies describe odor thresholds for phenol, no studies are available reporting adverse health effects after single inhalation exposures.
2.2.1.
Experimental Studies
Piotrowski (1971) published a toxicokinetic study on phenol. Eight healthy volunteers (seven men ages 25-42 and one woman age 30) were exposed by face mask to phenol concentrations between 5 and 25 mg/m³ (1.3-6.5 ppm) for 8 h, with two breaks of 0.5 h, each after 2.5 and 5.5 h. The author did not report any complaints concerning adverse effects of phenol exposure on the subjects, nor did the report explicitly state the absence of any effects.
Don (1986) reported an odor detection threshold of 0.010 ppm for phenol in a study considered equivalent to a CEN (2003) compliant study. The study methodology has been described in TNO (1985). In this study, the odor threshold for the reference chemical n-butanol was determined as 0.026 ppm.
Leonardos et al. (1969) used a combination of a test room and an antechamber, which was held odor-free using an air filter system. A trained panel of four staff members of the Food and Flavor Section of Arthur D. Little, Inc., determined the odor threshold for various compounds. At least five concentrations of phenol were tested. The individual concentrations were not reported. An odor recognition threshold of phenol at 0.047 ppm was determined for all four subjects.
Mukhitov (1964) determined the odor perception threshold in 14 subjects. Each subject was tested from 33 to 43 times over a period of 2-3 days. The odor perception threshold concentration ranged from 0.022 to 0.14 mg/m³ (0.0057-
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Narotsky, M.G., and R.J. Kavlock. 1995. A multidisciplinary approach to toxicological screening: II. Developmental toxicity. J. Toxicol. Environ. Health 45(2):145-171.
NCI (National Cancer Institute). 1980. Bioassay of Phenol for Possible Carcinogenicity. National Cancer Institute Carcinogenesis Technical Report 203. NTP 80-15. NIH 80-1759. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Bethesda, MD.
NIOSH (National Institute of Occupational Safety and Health). 1976. Criteria for a Recommended Standard. Occupational Exposure to Phenol. DHEW (NIOSH) 76-196. U.S. Department of Health, Education and Welfare, Public Health Service, Center for Disease Control, National Institute of Occupational Safety and Health, Cincinnati, OH.
NIOSH (National Institute for Occupational Safety and Health). 1996. Phenol. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95). Centers for Diseases Control and Prevention, National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/idlh/108952.html [accessed Oct. 10, 2008].
NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
Ogata, M., Y. Yamasaki, and T. Kawai. 1986. Significance of urinary phenyl sulfate and phenyl glucuronide as indices of exposure to phenol. Int. Arch. Occup. Environ. Health 58(3):197-202.
Ohtsuji, H., and M. Ikeda. 1972. Quantitative relationship between atmospheric phenol vapour and phenol in the urine of workers in bakelite factories. Br. J. Ind. Med. 29(1):70-73.
Piotrowski, J.K. 1971. Evaluation of exposure to phenol: Absorption of phenol vapour in the lungs and through the skin and excretion of phenol in urine. Br. J. Ind. Med. 28(2):172-178.
Powley, M.W., and G.P. Carlson. 2001. Cytochrome P450 isozymes involved in the metabolism of phenol, a benzene metabolite. Toxicol. Lett. 125(1-3):117-123.
Renwick, A.G. 1998. Toxicokinetics in infants and children in relation to the ADI and TDI. Food Addit. Contam. 15(Suppl.):17-35.
Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151.
Ryan, B.M., R. Selby, R. Gingell, J.M. Waechter Jr., J.H. Butala, S.S. Dimond, B.J. Dunn, R. House, and R. Morrissey. 2001. Two-generation reproduction study and immunotoxicity screen in rats dosed with phenol via the drinking water. Int. J. Toxicol. 20(3):121-142.
Sandage, C. 1961. Tolerance Criteria for Continuous Inhalation Exposure to Toxic Material, Part I. Effects on Animals of 90-Day Exposure to Phenol, CCl4 and a Mixture of Indole, Skatole, H2S and Methyl Mercaptan. Technical Report ADS 61-519. U.S. Air Force Systems Command, Aeronautical Systems Division, Wright-Patterson Air Force Base, OH.
Schaper, K.A. 1981. Acute phenolic intoxication-A report on clinical experience [in German]. Anaesthesiol. Reanimat. 6(2):73-79.
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Shamy, M.Y., R.M. el Gazzar, M.A. el Sayed, and A.M. Attia. 1994. Study of some biochemical changes among workers occupationally exposed to phenol, alone or in combination with other organic solvents. Ind. Health 32(4):207-214.
Shelby, M.D., G.L. Erexson, G.J. Hook, and R.R. Tice. 1993. Evaluation of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ. Mol. Mutagen. 21(2):160-179.
Sittig, M. 1980. Phenol. Pp. 300-304 in Priority Toxic Pollutants: Health Impacts and Allowable Limits. Park Ridge, NJ: Noyes Data Corporation.
Spiller, H.A., D.A. Quadrani-Kushner, and P. Cleveland. 1993. A five year evaluation of acute exposures to phenol disinfectant (26%). J. Toxicol. Clin. Toxicol. 31(2):307-313.
Stajduhar-Caric, Z. 1968. Acute phenol poisoning. J. Forensic Med. 15(1):41-42.
Tanaka, T., K. Kasai, T. Kita, and N. Tanaka. 1998. Distribution of phenol in a fatal poisoning case determined by gas chromatography/mass spectrometry. J. Forensic. Sci. 43(5):1086-1088.
TNO (Dutch Organization for Applied Scientific Research). 1985. Standaardisatie von olfactometers. TNO report No. 85-03661. Dutch Organization for Applied Scientific Research (TNO), Apeldoorn, The Netherlands.
Tsutsui, T., N. Hayashi, H. Maizumi, J. Huff, and J.C. Barrett. 1997. Benzene-, catechol-, hydroquinone- and phenol-induced cell transformation, gene mutations, chromosome aberrations, aneuploidy, sister chromatid exchanges and unscheduled DNA synthesis in Syrian hamster embryo cells. Mutat. Res. 373(1):113-123.
Tunek, A., T. Olofsson, and M. Berlin. 1981. Toxic effects of benzene and benzene metabolites on granulopoietic stem cells and bone marrow cellularity in mice. Toxicol. Appl. Pharmacol. 59(1): 149-156.
Van Doorn, R., M. Ruijten and T. Van Harreveld. 2002. Guidance for the Application of Odor in 22 Chemical Emergency Response. Version 2.1, 29.08.2002
Von Oettingen, W.F., and N.E. Sharples. 1946. The toxicity and toxic manifestation of 2,2-bis-(p-chlorophenyl)-1,1,1-trichloroethane (DDT) as influenced by chemical changes in the molecule. J. Pharmacol. Exp. Ther. 88:400-413 (as cited in WHO 1994).
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Yager, J.W., D.A. Eastmond, M.L. Robertson, W.M. Paradisin, and M.T. Smith. 1990. Characterization of micronuclei induced in human lymphocytes by benzene metabolites. Cancer Res. 50(2):393-399.
Zamponi, G.W., and R.J. French, 1994. Arrhythmias during phenol therapies: A specific action on cardiac sodium channels? Circulation 89(2):914.
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APPENDIX A
TIME-SCALING CALCULATIONS FOR AEGLS
AEGL-1 VALUES
Key study:
Huntingdon Life Sciences 1998; Hoffman et al. 2001
Toxicity end point:
Exposure of rats at 0.5, 5 or 25 ppm for 6 h/d, 5 d/wk for 2 weeks did not cause clinical, hematologic or histopathologic effects. A concentration of 25 ppm for 6 h was used as the basis for derivation of AEGL-1 values.
Scaling:
C³ × t = k for extrapolation to 4 h, 1 h and 30 min
k = 25³ ppm³ × 6 h = 93,750 ppm³-h
C1 × t = k for extrapolation to 8 h
k = 251 ppm × 6 h = 150 ppm-h
The AEGL-1 for 10 min was set at the same concentration as the 30-min value.
Uncertainty factors:
Combined uncertainty factor of 3
1 for interspecies variability
3 for intraspecies variability
Calculations:
10-min AEGL-1
10-min AEGL-1 = 19 ppm (73 mg/m³)
30-min AEGL-1
C³ × 0.5 h = 93,750 ppm³-h
C = 57.24 ppm
30-min AEGL-1 = 57.24 ppm/3 = 19 ppm (73 mg/m³)
1-h AEGL-1
C³ × 1 h = 93,750 ppm³-h
C = 45.43 ppm
1-h AEGL-1 = 45.43 ppm/3 = 15 ppm (58 mg/m³)
4-h AEGL-1
C³ × 4 h = 93,750 ppm³-h
C = 28.62 ppm
4-h AEGL-1 = 28.62 ppm/3 = 9.5 ppm (37 mg/m³)
8-h AEGL-1
C1 × 8 h = 150 ppm-h
C = 18.75 ppm
8-h AEGL-1 = 18.75 ppm/3 = 6.3 ppm (24 mg/m³)
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AEGL-2 VALUES
Key study:
Flickinger 1976; Brondeau et al. 1990
Toxicity end point:
Aerosol exposure to phenol at 900 mg/m³ (equivalent to phenol vapor at 234 ppm) for 8 h resulted in ocular and nasal irritation, slight loss of coordination and spasms of the muscle groups at 4 h into the exposure, after 8 h additional symptoms (tremor, incoordination and prostration) were observed in one of the six animals. No deaths occurred. This study is supported by the study of Brondeau et al. (1990), which reported only slight effects after exposure to phenol vapor at 211 ppm for 4 h. The derivation of AEGL-2 values was based on an exposure concentration of 234 ppm for 8 h.
Scaling:
C³ × t = k for extrapolation to 4 h, 1 h, and 30 min
k = 234³ ppm × 8 h = 1.025 × 108 ppm³-h
The AEGL-2 for 10 min was set at the same concentration as the 30-min value.
Uncertainty/modifying factors:
Combined uncertainty factor: 10
3 for interspecies variability
3 for intraspecies variability
Modifying factor: 2
Calculations:
10-min AEGL-2
10-min AEGL-2 = 29 ppm (110 mg/m³)
30-min AEGL-2
C³ × 0.5 h = 1.025 × 108 ppm³-h
C = 589.64 ppm
30-min AEGL-2 = 589.64 ppm/20 = 29 ppm (110 mg/m³)
1-h AEGL-2
C³ × 1 h = 1.025 × 108 ppm³-h
C = 468.00 ppm
1-h AEGL-2 = 468.00 ppm/20 = 23 ppm (90 mg/m³)
4-h AEGL-2
C³ × 4 h = 1.025 × 108 ppm³-h
C = 294.82 ppm
4-h AEGL-2 = 294.82 ppm/20 = 15 ppm (57 mg/m³)
8-h AEGL-2
8-h AEGL-2 = 234 ppm/20 = 12 ppm (45 mg/m³)
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APPENDIX B
LEVEL OF DISTINCT ODOR AWARENESS
Derivation of the Level of Distinct Odor Awareness (LOA)
The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002).
For derivation of the odor detection threshold (OT50), a study (Don 1986) is available that is considered an equivalent to a CEN (2003) compliant study. The study methodology has been described in TNO (1985). In this study, the odor threshold for the reference chemical n-butanol (odor detection threshold 0.04 ppm) has also been determined (Don 1986):
The concentration (C) leading to an odor intensity (I) of distinct odor detection (I = 3) is derived using the Fechner function:
For the Fechner coefficient, the default of kw = 2.33 will be used because of the lack of chemical-specific data:
The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in every day life factors, such as sex, age, sleep, smoking, upper airway infections, and allergy as well as distraction, increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 seconds), which leads to the perception of concentration peaks. Based on the current knowledge, a factor of 1/3 is applied
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to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4/3 = 1.33.
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APPENDIX C
ACUTE EXPOSURE GUIDELINES FOR PHENOL
Derivation Summary for Phenol
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
19 ppm
19 ppm
15 ppm
9.5 ppm
6.3 ppm
Reference: CMA (Chemical Manufacturers Association). 1998. Two-week (ten day) inhalation toxicity and two-week recovery study of phenol vapor in the rat. Huntingdon Life Sciences Study No. 96-6107, CMA Reference No. PHL-4.0-Inhal-HLS. Chemical Manufacturers Association, Phenol Panel, Arlington, VA; Hoffman, G.M., B.J. Dunn, C.R. Morris, J.H. Butala, S.S. Dimond, R. Gingell, and J.M. Waechter, Jr., 2001. Two-week (ten-day) inhalation toxicity and two-week recovery study of phenol vapor in the rat. International Journal of Toxicology 20:45-52.
Test Species/Strain/Number: Rats/Fischer 344/20/sex/group.
Exposure Route/Concentrations/Durations: Inhalation /0, 0.5, 5 or 25 ppm/6 h/d, 5 d/wk for 2 weeks (half of the animals were killed for analysis at the end of the exposure period and the other half after a 2-week recovery period).
Effects: No differences between controls and phenol-exposed animals for clinical observations, body weights, food consumption, and clinical pathology were found. The authors stated that “scattered observations of chromodacryorrhea and nasal discharge were noted during the 2 weeks of exposure. However, they did not appear in a clearly treatment-related pattern and mostly abated during the 2-week recovery period.” While this was true for chromodacryorrhea, the summary tables of in-life physical observations reported the following incidences of red nasal discharge in the control group and 0.5-ppm, 5-ppm, and 25-ppm groups: 0/20, 0/20, 3/20, and 4/20 males and 0/20, 0/20, 1/20, and 0/20 females in the first week and 0/20, 0/20, 7/20, and 10/20 males and 0/20, 1/20, 3/20, and 0/20 females in the second week. No differences between controls and phenol-exposed animals for organ weights and macroscopic and microscopic postmortem examinations were reported. Complete macroscopic evaluations were conducted on all animals. Microscopic evaluations were conducted on the liver, kidney, respiratory tract tissues (examined organs were nasopharyngeal tissues, larynx, trachea, and lungs), and gross lesions for animals in the control and high-exposure groups at termination and recovery. For histopathology of nasopharyngeal tissues, the skull, after decalcification, was serially sectioned transversely at approximately 3-μm intervals, and routinely, four sections were examined per animal.
End Point/Concentration/Rationale: Although phenol does not seem to be a strong irritant, it causes local tissue damage in the respiratory tract as evidenced by the histopathologic findings after repeated exposure described by Deichmann et al. (1944) for guinea pigs and rabbits. At higher concentrations, phenol causes irritation in rats (Flickinger 1976) and respiratory depression in mice (De Ceaurriz et al. 1981).
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10 min
30 min
1 h
4 h
8 h
19 ppm
19 ppm
15 ppm
9.5 ppm
6.3 ppm
The pharmacokinetic study in humans (Piotrowski 1971) was not used as a key study because it did not report on health effects. The Sandage (1961) study was not used because, apparently, exposure chambers did not allow observation of monkeys during the exposure, and histopathology was performed on the lungs but not on the upper respiratory tract so that possible upper airway irritation was not adequately evaluated. Therefore, the study by Huntingdon Life Sciences 1998 (published as Hoffman et al. 2001) was the only study fulfilling the SOP requirements for a key study and was therefore used for derivation of AEGL-1 values, although it was a repeated exposure study. After exposure of rats for 6 h/d, 5 d/wk for 2 weeks, no histopathologic alterations of the epithelium of the nasal turbinates or other respiratory tract tissues were found. The observation of red nasal discharge in a few male rats of the 5-ppm and 25-ppm groups was not considered a relevant effect, because no clear dose-response relationship was found and because predominantly males, but not females, showed this effect. Moreover, red nasal discharge occurs at the plexus antebrachii, which is very prominent in the rat, and extravasation of red blood cells visible as red nasal discharge is caused easily in the rat not only by locally acting chemicals but also by stress, dry air, or upper respiratory tract infections. The derivation of AEGL-1 values was based on an exposure concentration of 25 ppm for 6 h.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, the toxicokinetic component of the uncertainty factor was reduced to 1 because toxic effects are mostly caused by phenol itself without requirement for metabolism; moreover, possible local irritation effects depend primarily on the phenol concentration in inhaled air with little influence of toxicokinetic differences between species. The starting point for AEGL derivation was a NOAEL from a repeated exposure study and, thus, the effect level was below that defined for AEGL-1. The human experimental and workplace studies (Piotrowski 1971; Ogata et al. 1986) support the derived values. Therefore, the interspecies factor was reduced to 1.
Intraspecies: 3, because for local effects, the toxicokinetic differences do not vary considerably within and between species. Therefore the toxicokinetic component of the uncertainty factor was reduced to 1 and the factor of 3 for the toxicodynamic component was retained, reflecting a possible variability of the target-tissue response in the human population.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
Time Scaling: The equation Cn × t = k was used to derive exposure duration-specific values. Due to lack of a definitive dataset, a default value for n of 3 was used in the exponential function for extrapolation from the experimental period (6 h) to shorter exposure periods and a default value for n of 1 was used for extrapolation to longer exposure times. For the 10-min AEGL-1, the 30-min value was applied because the derivation of AEGL values was based on a long experimental exposure period, and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
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AEGL-1 VALUES Continued
10 min
30 min
1 h
4 h
8 h
19 ppm
19 ppm
15 ppm
9.5 ppm
6.3 ppm
Data Adequacy: No study assessing irritative effects in humans was available. However, in two toxicokinetic studies, no statement was made on the presence or absence of effects in humans exposed experimentally at up to 6.5 ppm for 8 h (with 2 × 30 min breaks) (Piotrowski 1971) or exposed at the workplace to a mean workshift concentration of up to 4.95 ppm (Ogata et al. 1986). The derived AEGL-1 values are supported by the study of Sandage (1961), in which continuous exposure of rhesus monkeys at 5 ppm phenol for 90 days did not result in any signs of toxicity.
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
29 ppm
29 ppm
23 ppm
15 ppm
12 ppm
Reference: Flickinger, C.W. 1976. The benzenediols: catechol, resorcinol, and hydroquinone—a review of the industrial toxicology and current industrial exposure limits. American Industrial Hygiene Association Journal 37:596-606.
Brondeau, M.T., P. Bonnet, J.P. Guenier, P. Simon, and J. de Ceaurriz. 1990. Adrenal-dependent leucopenia after short-term exposure to various airborne irritants in rats. Journal of Applied Toxicology 10:83-86.
Test Species/Strain/Sex/Number: (a) Rat /Wistar /6 females (b) Rat/Sprague-Dawley/not stated.
Exposure Route/Concentrations/Durations:
Inhalation/900 mg phenol/m³ aerosol/8 h
Inhalation/111, 156 or 211 ppm/4 h
Effects: Ocular and nasal irritation were observed, as well as slight loss of coordination with spasms of the muscle groups within 4 h and tremors and prostration (in 1/6 rats) within 8 h. Rats appeared normal the following day and had normal 14-day weight gains. No deaths occurred. No lesions attributable to inhalation of the aerosol were seen at gross autopsy. The total white blood cell count was significantly decreased after exposure to 156 or 211 ppm; no effect was observed at 111 ppm. Other signs of toxicity were not evaluated. The authors interpreted this finding as a result of increased secretion of corticosteroids as a response to sensory irritation.
End Point/Concentration/Rationale: Due to the lack of more adequate studies, a combination of the Flickinger (1976) and Brondeau et al. (1990) studies was used as the basis for derivation of AEGL-2 values. Aerosol exposure at 900 mg/m³ (equivalent to phenol vapor at 234 ppm) for 8 h resulted in ocular and nasal irritation, slight loss of coordination, and spasms of the muscle groups at 4 h into the exposure; after 8 h, additional symptoms (tremor, incoordination, and prostration) were observed in 1/6 animals. No deaths occurred. This study is supported by the study of Brondeau et al. (1990), who reported only slight effects after exposure to phenol vapor at 211 ppm for 4 h. Although both studies had shortcomings, that is, aerosol exposures, nominal concentrations, and no description of toxic signs in one study, taken together, they had
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10 min
30 min
1 h
4 h
8 h
29 ppm
29 ppm
23 ppm
15 ppm
12 ppm
consistent results. It was considered adequate to calculate and use the phenol vapor concentration corresponding to a phenol aerosol concentration of 900 mg/m³. The aerosol concentration of 900 mg/m³ is equivalent to a vapor concentration of 234 ppm. The derivation of AEGL-2 values was based on an exposure concentration of 234 ppm for 8 h.
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3, because oral lethal data did not indicate a high variability between species (cf. section 4.4.1.), and because application of a higher uncertainty factor would have resulted in AEGL-2 values below levels that humans can stand without adverse effects (Piotrowski 1971; Ogata et al. 1986).
Intraspecies: 3, because the study of Baker et al. (1978) who investigated health effects in members of 45 families (including children and elderly) that were exposed to phenol through contaminated drinking water for several weeks did not indicate that symptom incidence or symptom severity was higher in any specific subpopulation. Moreover, newborns and infants were not considered more susceptible than adults because of their smaller metabolic capacity to form toxic phenol metabolites (cf. section 4.4.2.).
Modifying Factor: 2, because of the small data base and study shortcomings.
Animal to Human Dosimetric Adjustment: Not applicable, local irritative effect.
Time Scaling: The equation Cn × t = k was used to derive exposure duration-specific values. Due to lack of a definitive dataset, a default value of n of 3 was used in the exponential function for extrapolation from the experimental period (8 h) to shorter exposure periods. For the 10-min AEGL-2, the 30-min value was applied because the derivation of AEGL values was based on a long experimental exposure period and no supporting studies using short exposure periods were available for characterizing the concentration-time-response relationship.
Data Adequacy: Both studies used for the AEGL-2 derivation had shortcomings, that is, aerosol exposures, nominal concentrations, and no description of toxic signs in one study. Nevertheless, the studies had consistent results, and the derived values are supported by the overall toxicity profile of phenol.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
N.R.
N.R.
N.R.
N.R.
N.R.
Reference: Not applicable.
Test Species/Strain/Sex/Number: Not applicable.
Exposure Route/Concentrations/Durations: Not applicable.
Effects: Not applicable.
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10 min
30 min
1 h
4 h
8 h
N.R.
N.R.
N.R.
N.R.
N.R.
End Point/Concentration/Rationale: The study by Deichmann et al. (1944) was not used as a key study because of the uncertainties in the exposure concentration and because deaths were observed only after repeated exposure. No acceptable vapor or aerosol LC50 studies in experimental animals or suitable reports on lethality after inhalation exposure in humans were available for the derivation of AEGL-3. Therefore, due to insufficient data and the uncertainties of a route-to-route extrapolation, AEGL-3 values were not recommended.
Uncertainty Factors/Rationale: Not applicable.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Insufficient data.
Time Scaling: Not applicable.
Data Adequacy: Adequate animal data relevant for the derivation of AEGL-3 values are not available.