B4 2-Ethoxyethanol

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Physical and Chemical Properties

2-Ethoxyethanol is a colorless liquid with a slightly sweet odor (ACGIH, 1986). Without giving concentrations, Waite et al. (1930) reported that the odor of 2-ethoxyethanol is mild and agreeable in low concentrations and disagreeable in high concentrations. It is completely miscible with water and with many organic solvents.

Synonyms:

Ethylene glycol monoethyl ether; Cellosolve

Formula:

CH3CH2OCH2CH2OH

CAS number:

110-80-5

Molecular weight:

90.1

Boiling point:

135.6°C

Melting point:

-70°C

Vapor pressure:

3.7 mm Hg at 20°C

Conversion factors at 25°C, 1 atm:

1 ppm = 3.68 mg/m3

1 mg/m3 = 0.27 ppm

Occurrence and Use

2-Ethoxyethanol is used as a solvent in synthetic resins and nitrocellulose manufacturing and in varnish removers, cleaning solutions, and lacquers (ACGIH, 1986). There is no known use of 2-ethoxyethanol in the spacecraft, but it has been found in the cabin atmosphere during two



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--> B4 2-Ethoxyethanol King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas Physical and Chemical Properties 2-Ethoxyethanol is a colorless liquid with a slightly sweet odor (ACGIH, 1986). Without giving concentrations, Waite et al. (1930) reported that the odor of 2-ethoxyethanol is mild and agreeable in low concentrations and disagreeable in high concentrations. It is completely miscible with water and with many organic solvents. Synonyms: Ethylene glycol monoethyl ether; Cellosolve Formula: CH3CH2OCH2CH2OH CAS number: 110-80-5 Molecular weight: 90.1 Boiling point: 135.6°C Melting point: -70°C Vapor pressure: 3.7 mm Hg at 20°C Conversion factors at 25°C, 1 atm: 1 ppm = 3.68 mg/m3 1 mg/m3 = 0.27 ppm Occurrence and Use 2-Ethoxyethanol is used as a solvent in synthetic resins and nitrocellulose manufacturing and in varnish removers, cleaning solutions, and lacquers (ACGIH, 1986). There is no known use of 2-ethoxyethanol in the spacecraft, but it has been found in the cabin atmosphere during two

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--> missions (NASA, 1989-1990). The concentrations of 2-ethoxyethanol detected in these missions varied from 0.8 to 3.0 ppb (NASA, 1989-1990), and off-gassing is probably the source of it. Based on the off-gassing data in the Spacelab, it was estimated that 2-ethoxyethanol will also be generated in the space station (Leban and Wagner, 1989). A possible source is the off-gassing from paint because 2-ethoxyethanol has been detected at a geometric mean air concentration of 2.6 ppm during painting operations in two Belgian shops (Veulemans et al., 1987). Pharmacokinetics and Metabolism Absorption In general, about 60% of 2-ethoxyethanol vapor inhaled by human subjects are absorbed. Groeseneken et al. (1986a) found that in 10 resting men exposed for 4 h to 2-ethoxyethanol vapor at 10, 20, or 40 mg/m3 (2.7, 5.4, or 11 ppm), the exhaled concentration was 59-65% lower than the inspired concentration starting at 10 min into the exposure and remained constant throughout the 4-h exposure. Groeseneken et al. also found that the degree of respiratory absorption of 2-ethoxyethanol was not substantially affected by light exercise in the subjects. Metabolism and Excretion In human volunteers, 2-ethoxyethanol was oxidized to ethoxyacetic acid (Groeseneken et al., 1986b). Of the 2-ethoxyethanol absorbed by the human respiratory tract during a 4-h exposure at 2.7, 5.4, or 11 ppm, 7-8% or 22-24% were excreted as ethoxyacetic acid within 12 or 48 h, respectively (Groeseneken et al., 1986b). After the termination of the 4-h inhalation exposure in men, the exhaled concentration of 2-ethoxyethanol declined with time bi-exponentially in 4 h (Groeseneken et al., 1986a). The first phase happened very rapidly, since the exhaled 2-ethoxyethanol concentration declined more than 98% in 7.5 min after exposure (Groeseneken et al., 1986a). The half-life of the second phase was calculated to be 102 min. Integration of the exhaled concentration curve with time showed that less than 0.4% of the amount

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--> of 2-ethoxyethanol absorbed by the human respiratory tract was exhaled unchanged 4 h after exposure (Groeseneken et al., 1986a). From these data in humans, the exhalation rate of 2-ethoxyethanol after exposure is calculated to be 0.1 % of the dose per hour, and the elimination rate of 2-ethoxyethanol as ethoxyacetic acid in urine is 0.6% of the dose per hour. Therefore, it can be concluded that exhalation is less important than metabolism for 2-ethoxyethanol elimination in humans. The formation of ethoxyacetic acid is important because it was postulated by Foster et al. (1983) to be the active metabolite of 2-ethoxyethanol. Foster et al. found that an equimolar oral dose of ethoxyacetic acid was as toxic as 2-ethoxyethanol to the testis of rats. There are some species differences in the way ethoxyacetic acid is excreted in the urine. Groeseneken et al. (1986b) discovered that in resting men exposed for 4 h to 2-ethoxyethanol vapor at 10, 20, or 40 mg/m3 (equivalent to a dose of 0.25, 0.5, or 1.0 mg/kg), ethoxyacetic acid was excreted in the urine entirely in its free form. In rats, 2-ethoxyethanol is also oxidized to ethoxyacetic acid, but, unlike in humans, a part of this metabolite might be first conjugated with glycine before being excreted in the urine (Groeseneken et al., 1986b). Groeseneken et al. (1986b) showed that there were significant amounts of glycine-conjugated ethoxyacetic acid, in addition to the free form, in the urine of rats after an oral dose of 2-ethoxyethanol at 0.5-100 mg/kg. However, Medinsky et al. (1990) failed to find the glycine conjugate of ethoxyacetic acid in the urine of rats exposed to 2-ethoxyethanol in drinking water for 24 h at a dose of 94, 210, or 1216 µg/kg (equivalent to 8.5, 19, or 110 mg/kg). The elimination half-life of ethoxyacetic acid in the urine was 42.0 h in humans and 7.2 h in rats (Groeseneken et al., 1986b). Ethoxyacetic acid is not the only metabolite of 2-ethoxyethanol in rats. Medinsky et al. (1990) reported that in rats given 2-ethoxyethanol at 8.5, 19, or 110 mg/kg in drinking water for 24 h, 2-ethoxyethanol was metabolized by two competing pathways to either ethoxyacetic acid or ethylene glycol. Parts of the ethoxyacetic acid and ethylene glycol formed were further metabolized to carbon dioxide. Of the absorbed 2-ethoxyethanol, about 18% was excreted as ethylene glycol regardless of the dose. However, the elimination of 2-ethoxyethanol as ethoxyacetic acid in the urine and as exhaled CO2 depended on the dose. The fractions of 2-ethoxyethanol excreted as CO2 decreased with the doses: 27%, 22%, and 9% in those given 8.5, 19, or 110 mg/kg, respectively

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--> (Medinsky et al., 1990). In contrast, the fractions of 2-ethoxyethanol excreted as ethoxyacetic acid, the putative active metabolite of 2-ethoxyethanol for testicular toxicity, increased with the doses: 26%, 30%, and 37% in those given 8.5, 19, or 110 mg/kg, respectively (Medinsky et al., 1990). Assuming that the 11-12-week-old male rats used in the study of Medinsky et al. weighed about 240 g, the ventilation of these rats is estimated to be 177 mL/min, according to the data of Leong et al. (1964). It can be calculated that the oral doses of 8.5, 19, or 110 mg/kg used by Medinsky et al. are equivalent to a 6-h inhalation exposure of the 240-g rats to 2-ethoxyethanol at 8.6, 19, or 112 ppm. This calculation allows us to determine if an inhalation study was conducted with high concentrations that overly favored the metabolism of 2-ethoxyethanol to ethoxyacetic acid, the putative active metabolite for testicular toxicity. A question of practical importance in evaluating the pharmacokinetic and metabolic data is whether 2-ethoxyethanol accumulates in the body during repetitive inhalation exposures. There are no pharmacokinetic and metabolism data on repetitive exposures to 2-ethoxyethanol. However, the data from acute exposures seem to indicate that 2-ethoxyethanol is not likely to accumulate during repetitive exposures. As mentioned above, the exhaled concentration of 2-ethoxyethanol declines in a bi-exponential fashion after an acute inhalation exposure in humans, with the half-lives of 7.5 and 102 min, respectively (Groeseneken et al., 1986a). Since the exhaled concentration correlates with the blood concentration of organic compounds, such as trichloroethylene, benzene, and toluene (Stewart et al., 1962; Sato et al., 1974), the exhaled concentration data on 2-ethoxyethanol suggest that the blood concentration of 2-ethoxyethanol declines with time rather rapidly after an inhalation exposure in humans. In other words, there is little accumulation of 2-ethoxyethanol. The data from the rat study of Medinsky et al. (1990) tend to support this conclusion. Comparing the amount of 2-ethoxyethanol absorbed with the sum of the amounts of it and its metabolites excreted in 48 h after the oral exposure, it appears that the amount absorbed was almost totally eliminated from the body in 48 h (Medinsky et al., 1990). Finally, it should be noted that, in addition to inhalation, cutaneous absorption is another possible exposure route for 2-ethoxyethanol. There are data showing that 2-ethoxyethanol is absorbed upon dermal application in rats (Sabourin et al., 1990).

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--> Toxicity Summary Acute and Short-Term Toxicity An acute exposure to 2-ethoxyethanol has been known to produce mucosal irritation, lung congestion, lung edema, and death. Inhalation exposure of human subjects to 2-ethoxyethanol at 6000 ppm for a few seconds resulted in moderate eye irritation and a very disagreeable odor, causing a desire to avoid similar exposures (Waite et al., 1930). A 24-h exposure at 1000 ppm killed one out of six guinea pigs, and it caused acute lung congestion and edema, as well as kidney congestion, but a 16-h exposure at 500 ppm failed to produce any gross pathology or death (Waite et al., 1930). Based on the mortality of guinea pigs exposed for 24 h, the LC50 was estimated to be about 1400 ppm. In a study by Werner et al. (1943a), the 7-h LC50 of 2-ethoxyethanol in mice was 1830 ppm, which resulted in dyspnea, weakness, moderate-to-marked follicular phagocytosis in the spleen and marked congestion of the cavernous veins of the spleen. Carpenter et al. (1956) showed that a 4-h exposure at 4000 ppm or an 8-h exposure at 2000 ppm killed one-half of the rats. Foster et al. (1983) showed that oral administration of 2-ethoxyethanol to rats at concentrations of 250-1000 mg/kg failed to change the weight of the testis, prostate, and seminal vesicles, and it also did not cause any testicular injury in 24 h. However, because 2-ethoxyethanol is known to be toxic to the male reproductive system in subchronic exposure, the finding of Foster et al. cannot rule out the possibility that 2-ethoxyethanol is toxic to the testis after acute exposures. It might take more than 24 h for the testicular toxicity of 2-ethoxyethanol to appear. Subchronic and Chronic Toxicity Testicular Toxicity Subchronic exposures to 2-ethoxyethanol is known to affect the male reproductive system. In a cross-sectional study, Ratcliffe et al. (1987) showed that 80 workers exposed to 2-ethoxyethanol in casting operations had a lower average sperm count per ejaculation than the unexposed controls. The concentration of 2-ethoxyethanol in the breathing

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--> zone during a full work shift ranged from not detectable to 23.8 ppm (Ratcliffe et al., 1987). Welch et al. (1988) conducted a cross-sectional study of 94 shipyard painters exposed to 2-ethoxyethanol and 2-methoxyethanol and 55 unexposed workers. They showed an increased incidence of oligospermia, which was defined as less than 100 million sperm per ejaculate, in the exposed painters who did not smoke compared with the unexposed nonsmokers (36% of 33 exposed nonsmokers had oligospermia versus 16% of 32 unexposed nonsmokers). There was no statistically significant difference in the average sperm count, however, between the exposed and unexposed smokers. There were also no statistically significant differences in sperm morphology, sperm motility, and testicular size. Due to no differences in the levels of luteinizing hormone, follicle-stimulating hormone, and testosterone in the semen of the exposed and the control groups, Welch et al. concluded that the oligospermia was probably not due to any perturbation of the hypothalamic-pituitary axis. The painters had been employed at that site for an average of 8 y (a standard deviation of 7 y and a range of 0.5 to 33 y) (Welch et al., 1988). The 8-h time-weighted average (TWA) concentrations of 2-ethoxyethanol and 2-methoxyethanol, measured during the study, were 2.6 ppm (standard deviation (SD), 4.2 ppm) and 0.8 ppm (SD, 1.0 ppm), respectively. Welch et al. admitted that the measured exposure concentrations might underestimate the concentrations of 2-ethoxyethanol in previous exposures. The exposure concentrations in the Welch et al. study were measured with personal samplers, representing concentrations in the breathing zone of the painters (Sparer et al., 1988). The painters wore respirators less than 25 % of the time. There were minimal cutaneous exposures of the painters to 2-ethoxyethanol and 2-methoxyethanol, since 94% of the painters had no or only a little paint on them (Sparer et al., 1988). Because these painters had been rotated from job to job involving exposures to either or both of the ethanol ethers, it was impossible to separate the effects of the two in this study. In the shipyard study of Welch et al. (1988), the painters potentially were exposed to many chemicals: ammonia, carbon black, coal-tar-pitch volatiles, epichlorohydrin, ethyl silicate, formic acid, phosphoric acid, silica, toluene diisocyanate, 38 organic solvents, and 14 metals. Among these chemicals, only lead and epichlorohydrin are known to affect the male reproductive system in humans, but actual sampling and

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--> analyses demonstrated that the painters were not exposed to these two reproductive toxicants to any significant extent (Welch et al., 1988). It thus appears that the male reproductive effects detected in the shipyard study might be related to exposure to 2-ethoxyethanol, 2-methoxyethanol, or both (Welch et al., 1988). Both chemicals have been shown to be reproductive toxicants in male animals. Seminiferous tubule degeneration was detected in rabbits but not in rats exposed to 2-ethoxyethanol at 400 ppm for 6 h/d, 5 d/w, for 13 w (Barbee et al., 1984). Rats exposed to 2-methoxyethanol at 300 ppm for 6 h/d for 3 d showed degenerative changes in spermatocytes of pachytene and meiotic division at spermatogenic stage XIV (Lee and Kinney, 1989). By comparing the results of exposures to 2-ethoxyethanol at 400 ppm and exposures to 2-methoxyethanol at 300 ppm, it appears that, in the rat, 2-ethoxyethanol is less toxic to the testes than 2-methoxyethanol (Barbee et al., 1984; Lee and Kinney, 1989). Such a conclusion was confirmed by Foster et al. (1983) who showed that oral administration of 2-ethoxyethanol to rats at 250 mg/kg/d for 11 d did not affect the testes, and it took an oral dose of 500 mg/kg/d to produce spermatocyte degeneration of similar severity to that seen with administration of 2-methoxyethanol at 100 mg/kg/d. The adverse effects of 2-ethoxyethanol on the testis do not appear to be permanent. Oudiz et al. (1984) showed that five daily oral intubations of 936, 1872, or 2808 mg/d in rats resulted in sperm-count decreases (starting in the second week after exposure for the highest dose group), with most of the rats exposed to the two highest doses becoming azoospermic by week 7 after exposure. However, partial or complete recovery was seen in the sperm counts and sperm morphology by week 14 and in histological assessment of the testis and epididymis by week 16 (Oudiz et al., 1984). Among the spermatogenesis stages, Oudiz et al. showed that in rats the early-spermatid-late-spermatocyte stages were most sensitive to 2-ethoxyethanol. Foster et al. (1983) showed that in rats, daily oral administration of 2-ethoxyethanol at 1000 mg/kg/d for 7 or 11 d led to degeneration of only the late primary spermatocytes and secondary spermatocytes, with other testicular cell types unaffected. Finally, it should be noted that the reproductive toxicity of 2-ethoxyethanol is confined to males. 2-Ethoxyethanol given in drinking water at 0.5-2% resulted in testicular atrophy and decreased sperm motility in male CD-1 mice, but no reproductive abnormalities were detected in female mice (Lamb et al., 1984).

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--> Hematological Toxicity Other than testicular toxicity, subchronic or chronic exposures to 2-ethoxyethanol also could affect the blood cells. In the cross-sectional study conducted by Welch et al. (1988), anemia, which was defined as a condition with the blood hemoglobin concentration below 14.0 g/dL, was detected in 9 of 94 exposed shipyard male painters, and anemia was not detected in 55 unexposed subjects in the control group (p concentrations in the shipyard painters with anemia ranged from 12.3 to 13.5 g/dL). The shipyard painters with anemia, however, had normal values for mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration (Welch and Cullen, 1988). In addition, the mean blood hemoglobin concentrations in the exposed painters and unexposed controls did not differ statistically (Welch and Cullen, 1988). Therefore, the anemic condition detected in the shipyard painters was relatively mild. Among the chemicals the painters were potentially exposed to, benzene and lead can produce hematological effects, but there were no significant exposures of the shipyard painters to benzene or lead, based on actual sampling and analyses (Welch and Cullen, 1988). The anemia in the painters, therefore, might be related to occupational exposures to 2-ethoxyethanol, 2-methoxyethanol, or both, because both chemicals have been shown to produce hematological abnormalities in laboratory animals. An exposure to 2-ethoxyethanol at 400 ppm for 6 h/d, 5 d/w, for 13 w reduced the leukocyte count in female rats, and it reduced the erythrocyte count in rabbits (Barbee et al., 1984). Exposure of rats to 2-methoxyethanol at 300 ppm for 6 h/d for 9 d resulted in pancytopenia and bone-marrow hypoplasia (Miller et al., 1981). A study of lithographers by Cullen et al. (1983) also showed that occupational exposures to 2-ethoxyethanol might be related to bone-marrow injury. Myeloid hypoplasia with or without stromal injury was observed in the bone marrow of six of seven workers who had worked for 1-6 y with a five-color press, which used solutions containing, among other chemicals, 2-ethoxyethanol. However, blood counts were normal for these workers. They were exposed, via inhalation and direct skin contacts, to 2-ethoxyethanol, dipropylene glycol monomethyl ether, insoluble pigments, acrylic and epoxy resins, C4 and C3 substituted benzene, dichloromethane, 1,2-dichloroethylene, dichloroethane,

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--> 1,1,1-trichloroethane, 2-butanone, glycerol triacetate, and n-propanol (Cullen et al., 1983). The airborne concentration of dipropylene glycol monomethyl ether ranged from 0.6 to 6.4 ppm, but the exposure concentration of 2-ethoxyethanol was not measured (Cullen et al., 1983). There is also evidence of the bone-marrow toxicity of 2-ethoxyethanol in laboratory animals. An exposure of rats at a concentration of 370 ppm for 7 h/d, 5 d/w, for 5 w resulted in fat replacement of cells in the bone marrow and a decrease in myeloid cells in the spleen (Werner et al., 1943b). There was also increased hemosiderosis in the spleen, indicating increased red-blood-cell (RBC) destruction, but the 2-ethoxyethanol exposure had no effects on RBC and reticulocyte counts, hemoglobin concentration, total white-blood-cell counts, and the differential counts of granulocytes, lymphocytes, and monocytes (Werner et al., 1943b). Carcinogenicity No results of carcinogenicity testing with 2-ethoxyethanol were found in the literature. Genotoxicity 2-Ethoxyethanol did not cause mutation in four strains of Salmonella typhimurium (NIOSH, 1983). Developmental Toxicity 2-Ethoxyethanol is known to affect the embryo and fetus in laboratory animals. Exposure of pregnant rats at a concentration of 10 ppm for 6 h/d on days 6-15 of gestation led to an increased incidence of limb malrotation in the fetuses, and a similar exposure at 50 ppm reduced the litter size (Doe, 1984). No adverse effects were detected in the mothers in the 10-ppm and 50-ppm groups. An intrauterine exposure of rats at 250 ppm, however, produced late intrauterine death; reduction of the mean fetal weight; increased incidence of minor skeletal

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--> defects, including partial or nonossification of the skull, the thoracic centra, the lumbar centra, the lumbar vertebrae, and sternebrae; and increased incidence of 27 presacral vertebrae and sternebrae abnormalities (Doe, 1984). Exposure of the rats at 250 ppm reduced the mean corpuscular volume, hematocrit, and hemoglobin level in the mothers. Exposure of pregnant rabbits to 2-ethoxyethanol at 175 ppm for 6 h/d on days 6-18 of gestation also resulted in an increased incidence of minor skeletal defects in the fetuses and no maternal toxicity (Doe, 1984). Exposure of pregnant rats to 2-ethoxyethanol at 100 ppm for 7 h/d on days 7-13 of gestation resulted in the following conditions in newborns: decreased rotorod performance; increased acetylcholine, dopamine, and norepinephrine in the cerebrum; increased acetylcholine, norepinephrine, and protein in midbrain; increased acetylcholine in the cerebellum; and increased norepinephrine in the brainstem (Nelson et al., 1984). Because SMACs generally are not set on the basis of developmental toxicity, these data on the toxicity of 2-ethoxyethanol in the first trimester are not used here. Interaction with Other Chemicals No data on the interaction of 2-ethoxyethanol with other chemicals have been found in the TOXLINE or MEDLINE data bases of the National Library of Medicine (Bethesda, Md.).

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--> TABLE 4-1 Toxicity Summary Concentration, ppm Exposure Duration Species Effects Reference 6000 A few s Human Moderate eye irritation and very disagreeable odor causing desire to avoid similar exposure Waite et al., 1930 10 6 h/d on gestation d 6-15 (rat) or d 6-18 (rabbit) Rabbit, rat In rabbits, no adverse effects in mother or fetus; in rats, limb malrotation without maternal toxicity Doe, 1984 25 6 h/d, 5 d/w for 13 w Rabbit, rat Lacrimation and mucoid nasal discharge from w 2-10; no histopathology; in rabbits, 5-11% decrease in body-weight gain; in rats, 12% reduction in spleen weight in females Barbee et al., 1984 50 6 h/d on gestation d 6-15 (rat) or d 6-18 (rabbit) Rabbit, rat In rabbits, no adverse effects in mother or fetus; in rats, reduced litter size without maternal toxicity Doe, 1984 100 7 h/d on gestation d 7-13 Rat In behavioral tests of pups, decreased rotorod performance at age d 21-29; increased latency of leaving the central area of an open field at age 16-60 d; no effects on activity wheel running, avoidance conditioning, and operant conditioning; in neurochemical tests of pups at age of 21 d, increased acetylcholine, dopamine, and norepinephrine in cerebrum; increased acetylcholine, norepinephrine, and protein in midbrain; increased acetylcholine in cerebellum; increased norepinephrine in brainstem Nelson et al., 1984 100 7 h/d on gestation d 14-20 Rat In behavioral tests of pups, decreased activity wheel running at age 32-33 d; in neurochemical tests of pups at age 21 d, increased acetylcholine, serotonin, and dopamine in cerebrum Nelson et al., 1984

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--> Concentration, ppm Exposure Duration Species Effects Reference 3000 24 h Guinea pig 5/6 died during exposure; inactivity, weakness, and dyspnea; 1 died 3 d after exposure; lung congestion and edema; hyperemia of the kidneys Waite et al., 1930 4000 4 h Rat 3/6 died Carpenter et al., 1956 4000 8 h Rat 6/6 died Carpenter et al., 1956 5000 4 h Rat 1/12 died Carpenter et al., 1956 5000 8 h Rat 10/12 died; hemoglobinuria Carpenter et al., 1956 6000 1 h Guinea pig No deaths, weakness, dyspnea, inactivity, or gross pathology Waite et al., 1930 6000 4 h Guinea pig No deaths, weakness, dyspnea, or inactivity; parenchymatous change in the kidney 4 d after exposure; no gross pathology 8 d after exposure Waite et al., 1930 6000 24 h Guinea pig 4/6 died during exposure; 1 died 3 h after exposure; last one was necropsied immediately after exposure; lung congestion and edema; kidney congestion; petechial hemorrhages of stomach mucosa; inactivity, weakness, and dyspnea during exposure Waite et al., 1930

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--> TABLE 4-2 Exposure Limits Set by Other Organizations Organization Concentration, ppm ACGIH's TLV 5 (TWA) OSHA's PEL 200 (TWA) NIOSH's IDLH 6000 TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. IDLH = immediately dangerous to life and health. TABLE 4-3 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity 1 h 10 40 Hematological toxicity 24 h 10 40 Hematological toxicity 7 da 0.8 3 Hematological toxicity 30 d 0.5 2 Hematological toxicity 180 d 0.07 0.3 Hematological toxicity a There is no official 7-d SMAC. The current official 7-d SMAC for 2-ethoxyethyl acetate is 30 ppm. Rationale for Acceptable Concentrations Although 2-ethoxyethanol is known to cause fetal toxicity and minor teratogenic changes in rats and rabbits (Doe, 1984), SMACs for 2-ethoxyethanol are not established according to its developmental toxicity because pregnant astronauts will not be allowed in space. The major targets of subchronic toxicity of 2-ethoxyethanol are the testes and the hematological system, but very little is known about its acute toxicity. Mucosal Irritation Moderate eye irritation was noted by Waite et al. (1930) in human subjects exposed for a few seconds to 2-ethoxyethanol at a concentration of 6000 ppm. However, these data are not relied on in setting the short-term SMACs because the exposure lasted for only several sec-

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--> onds. In a 13-w study conducted by Barbee et al. (1984), increased incidences of lacrimation and mucoid nasal discharge were observed in rabbits and rats after 2-10 w of exposure to 2-ethoxyethanol at 25, 100, or 400 ppm, as compared with the controls. Barbee et al. reported that the lacrimation and nasal discharge failed to show a concentration-response relationship. Nevertheless, the data indicate that 2-ethoxyethanol vapor at 25 ppm could be irritating to the mucous membranes in animals. Because Groeseneken et al. (1986c) did not report any mucosal irritation in 10 human volunteers exposed to 2-ethoxyethanol at up to 10 ppm for 4 h, the nonirritating concentration appears to be 10 ppm in humans. Because the astronauts are expected to be able to tolerate mild mucosal irritation during 1-h or 24-h contingencies, the acceptable concentration (AC), based on irritation, for 1 and 24 h is 25 ppm. 1-h and 24-h ACs based on irritation = 25 ppm. 7-d, 30-d, and 180-d ACs based on irritation = 4-h NOAEL x 1/safety factor for small n = 10 ppm x (square root of n)/10 = 10 ppm x (square root of 10)/10 = 3 ppm. The 7-d, 30-d, and 180-d ACs are set at the same concentration because mucosal irritation is not expected to increase with time after the first hour of exposure. Testicular Toxicity Although Welch and co-workers (1988) showed that occupational exposures to 2-ethoxyethanol at about 2.6 ppm could result in lower sperm count and mild anemia, the SMACs for testicular toxicity should not be set relying solely on the data of Welch and co-workers for three reasons. First, the exact exposure concentrations of 2-ethoxyethanol were not known in that study. The painters were exposed, several years before the study began, to 2-ethoxyethanol at concentrations

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--> potentially higher than 2.6 ppm (Sparer et al., 1988; Welch and Cullen, 1988; Welch et al., 1988). Second, in addition to 2-ethoxyethanol, the painters were exposed to 2-methoxyethanol at a concentration of 0.8 ppm, which is also known to produce testicular and hematological toxicity (Miller et al., 1981; Welch and Cullen, 1988; Welch et al., 1988; Lee and Kinney, 1989). Third, the painters were potentially exposed to 59 chemicals other than 2-ethoxyethanol and 2-methoxyethanol (Welch and Cullen, 1988; Welch et al., 1988). Although the investigators did determine the airborne concentrations of the testicular or hematological toxicants among those 59 chemicals to reasonably rule them out, it is possible that some of the chemicals can potentiate the toxicity of 2-ethoxyethanol. For these reasons, the SMACs are not derived entirely from the data on the shipyard painters. Rather, the painter data are used only to check the validity of setting SMACs on the basis of animal data. The animal data of Barbee et al. (1984) appeared to be suitable for the derivation of SMACs for 2-ethoxyethanol. In their 13-w study, Barbee et al. showed that rabbits were more sensitive than rats to the testicular and hematological toxicity of 2-ethoxyethanol; therefore, the SMACs are established using the rabbit data. A 13-w exposure at 400 ppm for 6 h/d, 5 d/w resulted in testicular damage and decreases in testicular weight in rabbits but not in rats. A similar exposure at 100 ppm failed to cause any changes in the testis in rabbits; thus, the subchronic toxicity study of Barbee et al. (1984) indicates that 100 ppm is the 13-w no-observed-adverse-effect level (NOAEL) in animals. Applying the traditional interspecies extrapolation factor of 10 to the 13-w NOAEL of 100 ppm, it appears that a 13-w occupational exposure to 2-ethoxyethanol at 10 ppm should be devoid of testicular toxicity in humans. However, compared with the study of Welch et al. (1988) in which an 8-y occupational exposure to a mixture of 2-ethoxyethanol (TWA, 2.6 ppm; SD, 4.2 ppm) and 2-methoxyethanol (TWA, 0.8 ppm; SD, 1.0 ppm) could result in lower sperm counts, the 13-w exposure concentration at 10 ppm, predicted to be safe using the 13-w NOAEL of 100 ppm, does not appear to have any margin of safety. It appears that humans are even more sensitive than rabbits to the testicular toxicity of 2-ethoxyethanol. Although it can be contended that the painter study of Welch et al. had flaws enumerated above, prudence dictates that a 13-w NOAEL lower than 100 ppm should be used to derive the

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--> SMACs. Consequently, the lower 13-w NOAEL of 25 ppm was chosen (Barbee et al., 1984). Even though 25 ppm lowered the body weights of rabbits after a 13-w exposure, 25 ppm is still considered a NOAEL because the higher concentration of 100 ppm did not lower the body weights of rabbits in the same study (Barbee et al., 1984). 7-d AC for testicular toxicity = 13-w NOAEL x 1/species factor =25 ppm x 1/10 = 2.5 ppm. Haber's rule is used to derive the 30-d AC on the basis of testicular toxicity because it is uncertain whether the testicular injury is reparable. For prudence sake, the testicular injury caused by 2-ethoxyethanol is assumed to be irreparable. 30-d AC = 13-w NOAEL x time adjustment x 1/species factor = 25 ppm x (6 h/d x 5 d/w x 13 w)/(24 h/d x 30 d) x 1/10 = 25 ppm x 390 h/720 h x 1/10 = 25 ppm x 0.54 x 1/10 = 1.4 ppm. Because the testicular toxicity in a 180-d exposure is not expected to differ significantly from that in a 30-d exposure, the 180-d AC is set equal to the 30-d AC. Because an oral administration of 2-ethoxyethanol at a dose of 1000 mg/kg failed to cause any male reproductive toxicity in rats (Foster et al., 1983), testicular toxicity is not a consideration in setting the short-term SMACs. Hematological Toxicity A subchronic exposure of rabbits to 2-ethoxyethanol at 400 ppm for 6 h/d, 5 d/w, for 13 w reduced the RBC count (Barbee et al., 1984). No change in the count was observed in rats. In the female rats, there were lower leukocyte counts and a 15% decrease in the spleen weight. A similar exposure at 100 or 25 ppm failed to produce any hematological changes in either rabbits or rats. However, a 12% decrease in

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--> spleen weight was detected in female rats after the 13-w exposure at 100 or 25 ppm (Barbee et al., 1984). Because there were no hematological and histological changes in female rats exposed to 2-ethoxyethanol at 100 or 25 ppm, the toxicological meaning of the decreases in spleen weight is uncertain. The meaning of the decreases in spleen weight in female rats exposed at 100 ppm is further obscured by the fact that the spleen/body-weight ratio showed no change in that group (Barbee et al., 1984). The spleen/body-weight ratio was lowered only in female rats exposed at 400 or 25 ppm, and body weight showed no statistically significant changes in female rats exposed at 400, 100, or 25 ppm. All in all, the data of Barbee et al. (1984) indicate that the NOAEL for a 13-w exposure to 2-ethoxyethanol is 100 ppm for hematological toxicity in rabbits and rats. Similar to the analysis of the NOAEL based on testicular toxicity, the comparison of the subchronic NOAEL of 100 ppm from the animal study with the finding of Welch and co-workers (1988) in human workers indicates that a NOAEL lower than 100 ppm should be used. Welch and co-workers found that workers exposed to a mixture of 2-ethoxyethanol (TWA, 2.6 ppm; S.D., 4.2 ppm) and 2-methoxyethanol (TWA, 0.8 ppm; S.D., 1.0 ppm) developed mild anemia. As a result, the lower NOAEL of 25 ppm from the 13-w study is used in setting the SMACs (Barbee et al., 1984). Microgravity is known to reduce the RBC mass in astronauts (Huntoon et al., 1989). Consequently, a safety factor of 3 is used to account for potential interaction of 2-ethoxyethanol and microgravity on causing anemia. 7-d AC based on hematological toxicity = 13-w NOAEL x 1/species factor x 1/microgravity factor = 25 ppm x 1/10 x 1/3 = 10 ppm. 30-d AC based on hematological toxicity = 13-w NOAEL x 1/species factor x 1/microgravity factor  x time adjustment = 25 ppm x 1/10 x 1/3 x (6 h/d x 5 d/w x 13 w)/(24 h/d  x 30 d) = 0.5 ppm.

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--> 180-d AC based on hematological toxicity = 13-w NOAEL x 1/species factor x 1/microgravity factor  x time adjustment = 25 ppm x 1/10 x 1/3 x (6 h/d x 5 d/w x 13 w)/(24 h/d  x 180 d) = 0.07 ppm. Werner et al. (1943b) found that repetitive exposures of rats to 370 ppm for 7 h/d, 5 d/w, for 1 w did not cause any changes in the RBC count and hemoglobin concentration in blood. The 1-w NOAEL of 370 ppm is used to derive the 1-h and 24-h ACs. 1-h and 24-h ACs based on hematological toxicity = 1-w NOAEL x 1/species factor x 1/microgravity factor = 370 ppm x 1/10 x 1/3 = 10 ppm. Establishment of SMAC Values The ACs for all toxic end points are tabulated below. By choosing the lowest AC for each exposure duration, the 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are set at 10, 10, 0.8, 0.5, and 0.07 ppm, respectively.

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--> TABLE 4-4 End Points and Acceptable Concentrations   Uncertainty Factors Acceptable Concentrations, ppm End Point Exposure Data Species and Reference Time Species Small n 1 h 24 h 7 d 30 d 180 d Mucosal irritation LOAEL at 25 ppm, 6 h/d, 5 d/w, 2-10 w Rabbit and rat (Barbee et al., 1984) — — — 25 25 —a — —   NOAEL at 10 ppm, 4 h Human (n = 10) (Groeseneken et al., 1986c) — — 10/(sq. rt. of 10) — — 3 3 3 Testicular toxicity NOAEL at 25 ppm for 6 h/d, 5 d/w, 13 w Rabbit (Barbee et al., 1984) — 10 — — — 2.5 — —   NOAEL at 25 ppm for 6 h/d, 5 d/w, 13 w Rabbit (Barbee et al., 1984) HRb 10 — — — — 1.4 1.4 Hematotoxicity NOAEL at 370 ppm for 7 h/d, 5 d/w, 1 w Rat (Werner et al., 1943) — 10 — 10 10 — — —   NOAEL at 25 ppm for 6 h/d, 5 d/w, 13 w Rabitt and rat (Barbee et al., 1984) — 10 — — — 0.8 — —   NOAEL at 25 ppm for 6 h/d, 5 d/w, 13 w Rabitt and rat (Barbee et al., 1984) HR 10 — — — — 0.5 0.07 SMAC   10 10 0.8 0.5 0.07 a Extrapolation to these exposure durations produces unacceptable uncertainty in the values. b HR = Haber's rule.

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