B4 Diacetone Alcohol

John T. James, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Synonyms:

Diketone alcohol, 4-hydroxy-4-methyl-2-pentanone

Formula:

(CH3)2C(OH)CH2COCH3

CAS number:

123-42-2

Form:

Colorless, flammable liquid with pleasant odor

Molecular weight:

116.16

Boiling point:

168°C

Melting point:

-43°C

Specific gravity:

0.94

Vapor pressure:

1.2 mmHg at 25°C

Solubility:

Miscible in water

Conversion factors:

1 ppm = 4.76 mg/m3 1 mg/m3 = 0.21 ppm

OCCURRENCE AND USE

Diacetone alcohol (DAA) is used as an industrial solvent for nitrocellulose, cellulose acetate, celluloid, pigments, waxes, fats, and oils, and in antifreeze and brake fluid (ACGIH, 1991). The odor threshold has been reported to be near 0.3 ppm (Amoore and Hautala, 1983). Concentrations in the space shuttle are typically below 1 mg/m3; how-



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B4 Diacetone Alcohol John T. James, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Synonyms: Diketone alcohol, 4-hydroxy-4-methyl-2-pentanone Formula: (CH3)2C(OH)CH2COCH3 CAS number: 123-42-2 Form: Colorless, flammable liquid with pleasant odor Molecular weight: 116.16 Boiling point: 168°C Melting point: -43°C Specific gravity: 0.94 Vapor pressure: 1.2 mmHg at 25°C Solubility: Miscible in water Conversion factors: 1 ppm = 4.76 mg/m3 1 mg/m3 = 0.21 ppm OCCURRENCE AND USE Diacetone alcohol (DAA) is used as an industrial solvent for nitrocellulose, cellulose acetate, celluloid, pigments, waxes, fats, and oils, and in antifreeze and brake fluid (ACGIH, 1991). The odor threshold has been reported to be near 0.3 ppm (Amoore and Hautala, 1983). Concentrations in the space shuttle are typically below 1 mg/m3; how-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 ever, approximately 10% of the time, DAA concentrations above 1 mg/m 3 were found (James et al., 1994). The source of DAA is probably off-gassing from paint that has not totally cured and possibly off-gassing from hardware. TOXICOKINETICS AND METABOLISM Absorption No data were found on the absorption of DAA. Distribution Complete distribution studies are not available on DAA; however, its blood/brain partitioning has been studied because DAA is a metabolite of methyl isobutyl ketone (Granvil et al., 1994). From 15 to 90 min after direct intraperitoneal (ip) administration to mice of DAA at 2.5 mmol/kg of body weight, the concentrations of DAA in blood and brain were comparable. Distribution into other tissues has not been reported. Elimination Granvil et al. (1994) showed that the concentrations of DAA in blood in mice declined from about 430 µg/mL 15 min after injection to about 70 µg/mL 90 min after injection. The dose was administered ip at a concentration of 2.5 mmol/kg. Metabolism No specific data were found on the metabolism of DAA. Granvil et al. (1994) reported that they did not find any biotransformation products after ip administration of DAA to mice; however, they did not make it clear exactly which possible metabolites could be detected with their analytical procedures.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TOXICITY SUMMARY Few inhalation toxicity data were available on DAA; however, sufficient reports were found to suggest several target organs for this solvent. The data will be divided into acute and short-term exposure studies (less than 4 w duration) and subchronic and chronic exposure studies (more than 4 w duration). Acute and Short-Term Exposures A summary of early studies using various nonhuman species and various routes of administration of DAA suggests that DAA is narcotic and can cause injury to the liver, kidney, or red blood cells (von Oettingen, 1943). Lehman and Flury (1938) were quoted as stating that restlessness, irritation of the mucous membranes, excitement and later somnolence were seen in mice, rats, rabbits, and cats exposed to DAA at 10 mg/L (2100 ppm). That concentration exceeds the saturation concentration of 1600 ppm at 25°C (DHHS, 1988). Smyth and Carpenter (1948) reported that none of the rats (number not specified) died that were exposed to saturated DAA vapor for 8 h. Human exposures have been conducted with the goal of setting industrial hygiene limits (Silverman et al., 1946). Apparently, about 12 subjects were exposed for 15 min to DAA at various concentrations and asked their opinion on the suitability of 8-h exposures. A majority of the test subjects indicated that they could work an 8-h day even when exposed at 100 ppm (table 2 in the paper says 50 ppm), even though irritation of the eyes and throat occurred in the majority of subjects exposed at 100 ppm. Silverman et al. (1946) considered 50 ppm a more suitable worker exposure concentration. They did not explicitly state that the 50-ppm concentration was a no-effect level. Subchronic and Chronic Exposures Only one study could be found on ''long-term'' toxic effects of DAA, and the duration of exposure of that study was only 6 w (Butterworth et al., 1980). Groups of 12 male and 12 female rats were exposed 6 h/d,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 5 d/w for 6 w to DAA concentrations of 0, 230, 1040, and 4500 mg/m 3. The corresponding concentrations of DAA in parts per million were 48, 220, and 950 ppm. The rats were exposed in 1-m3 chambers with a flow rate of about 0.45 m3/min. The DAA concentrations were monitored continuously with total hydrocarbon analyzers, and periodic monitoring of acetone, a decomposition product, was done by gas chromatography. Acetone comprised about 4% of the highest exposure and less than 1% of the other exposures. Observations were made in the following categories: daily clinical signs, weekly body weights, terminal urinalysis, terminal hematology, terminal clinical chemistry, gross pathology, organ weights, and histopathology. The following effects of exposure to DAA were noted: Clinical signs: After 6-h exposures in the last 2 w of the study, the rats receiving the high dose were slightly lethargic for a few hours. Clinical chemistry: A 50% increase over controls was noted in levels of plasma lactate dehydrogenase (LDH) measured in females in the high-dose group; however, levels of two enzymes more specific for liver injury were not increased in the exposed groups. Various minor differences in plasma electrolytes were noted, but there was not a dose-effect relationship. Hematology: The hemoglobin values in high-dose females were 6% above the control values. Organ weights: Relative to body weights, the livers of males in the mid-and high-dose groups were increased 13% and 24%, respectively. Likewise, the liver weights of females in the mid-and high-dose groups were increased 9% and 12%, respectively. The kidney weights of males and females in the high-dose groups were increased 17% and 7%, respectively. Histopathology: Eosinophilic hyaline droplets were found in the kidneys of all but one male in the high-dose group. The droplets were not observed in any of the female groups or in the mid-and low-dose groups of males. This study appears to be a high-quality study with attention paid to randomization of animals, compound purity (99.44%), appropriate air flows and environmental conditions, recovery of test material in the

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 chambers, thorough statistical analysis, and complete assessments of toxic end points. Carcinogenicity No data were found pertaining to the carcinogenic potential of DAA. Genotoxicity During an evaluation of several hydrocarbon solvents for genotoxicity, DAA was the only test material to exhibit any sort of positive response. The solvents were tested in bacterial mutation assays, a yeast mitotic conversion assay, and a chromosome assay in rat liver cells in vitro in concentrations of 2000 to 4000 µg/mL (Brooks et al., 1988). None of the solvents, including DAA, induced reverse gene mutations in bacteria or mitotic gene conversion in yeast. DAA caused a small, but insignificant, increase in chromatid damage in the rat liver chromosome assay. The change was not quantitatively related to dose. The damage consisted of a few chromatid exchanges, breaks, and acentric fragments. Brooks et al. (1988) speculated that the apparent clastogenic activity was likely due to the physical action of the solvent or the detergent-like properties of DAA rather than to its ability to interact directly with DNA. That conclusion is supported by the data of Shehab (1980), who found that a 3-h exposure of plant root tips to DAA (1% by weight) caused some chromosomal stickiness, which can result from random chromosomal breakage. Thus, no convincing data exist to support the possibility of genotoxic activity for DAA. Reproductive Toxicity No data were found on the reproductive toxicity of DAA. Developmental Toxicity No data were found on the developmental toxicity of DAA.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Interactions with Other Chemicals DAA has been shown to potentiate the hepatotoxicity of chloroform in rats (Vezina et al., 1989). Their test procedure was to administer DAA orally at 0, 3.75, 5.6, or 7.5 mmol/kg and 24 h later give an ip injection of chloroform (0.5 mL/kg) to groups of six rats. The chloroform dose alone caused no apparent liver injury. DAA-potentiated liver damage was assessed by the activity of two transferases in plasma, plasma bilirubin concentrations, liver weights, and histopathological examination. Each of the end points showed a clear dose-response relationship for DAA potentiation of chloroform-induced liver injury. Vezina et al. (1989) concluded that DAA might induce one or more of the microsomal cytochrome P450 systems that lead to increased production of reactive intermediates from chloroform. TABLE 4-1 Exposure Limits Set or Recommended by Other Organizations Agency or Organization Exposure Limit, ppm Reference ACGIH's TLV 50 (TWA) ACGIH, 1991 OSHA's PEL 50 (TWA) U.S. Dept. of Labor, 1995 NIOSH's REL 50 (TWA) U.S. Dept. of Labor, 1995 TLV, Threshold Limit Value; TWA, time-weighted average; PEL, permissible exposure limit; REL, recommended exposure limit.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 4-2 Spacecraft Maximum Allowable Concentrations Exposure Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 50 250 Mucosal irritation, CNS depression 24 h 50 250 Mucosal irritation, CNS depression 7 d 20 100 Mucosal irritation, CNS depression 30 d 6 30 Mucosal irritation, potential liver injury, CNS depression 180 d 4 20 Mucosal irritation, potential liver injury, CNS depression RATIONALE FOR ACCEPTABLE CONCENTRATIONS Even though the toxicity data base is limited, several adverse effects of DAA exposure have been clearly demonstrated by the inhalation route. Central-nervous-system (CNS) depression was noted in some of the acute exposure rodent studies and late in the 6-w rat inhalation study (Butterworth et al., 1980). Irritation of the throat, eyes, and nose has been demonstrated in humans (Silverman et al., 1946), and potential liver injury has been found in rats (Butterworth et al., 1980). The kidney injury observed in the high-dose group of male rats by Butterworth and co-workers is similar to a common finding of high concentrations of α2u-globulin present in male rats after prolonged exposure to hydrocarbons. This lesion has not been considered relevant to human risk assessment, because humans have much lower concentrations of α2u-globulin than male rats (Swenberg et al., 1989). The guidelines from the National Research Council were used to develop the rationale for DAA SMACs (NRC, 1992).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 CNS Depression There were no acute inhalation studies suitable for human risk assessment; however, Butterworth et al. (1980) noted that their high-dose group of rats did not exhibit postexposure lethargy until week 5 of the 6-w intermittent 6-h/d exposures. Hence, their highest exposure concentration (950 ppm) was considered a no-observed-adverse-effect level (NOAEL) for CNS effects from short-term exposures. The short-term acceptable concentrations (ACs) were as follows: 1- or 24-h AC = 950 ppm × 1/10 (species) = 95 ppm. The fact that "lethargy" developed late in the 6-w exposure at the highest concentration suggests that lower limits might be needed for long-term exposure. The mid-dose group (220 ppm) never exhibited any obvious CNS effects during the 6-w exposure (180-h cumulative), so 220 ppm is a logical choice for a NOAEL in rats. The long-term ACs for CNS effects were calculated as follows: 7-d AC = 220 ppm × 1/10 (species) = 22 ppm. 30-d AC = 220 ppm × 1/10 (species) × (180 h/720 h) = 6 ppm. Although there is some concern that the lethargy observed late in the exposures was not the traditional type of solvent-induced CNS depression, the 6-ppm limit should be a threshold below which no CNS effects can occur no matter how long the exposure lasts. Hence, the 180-d AC was also set at 6 ppm. Irritation of Eyes and Throat The human exposure study reported by Silverman et al. (1946) indicated that in the 12 (presumably) test subjects, 50 ppm would be an acceptable industrial concentration to avoid irritation; therefore, that concentration was selected as a NOAEL for irritation. The majority of subjects reported an unspecified degree of irritation at 100 ppm. The exposures were for only 15 min, but that time should have been long

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 enough to elicit a maximal irritation response in the subjects. Even though slight irritation would be permitted in short-term ACs, 50 ppm was selected as the limit for accidental astronaut exposures (1 and 24 h ACs). For long-term ACs, the risk of irritation must be kept very low, and, because only 12 subjects were tested, the limit must be reduced using an uncertainty factor for the small n as follows: This limit should preclude DAA induced irritation from occurring in any large group of astronauts exposed to DAA. Potential Liver Injury The hepatomegaly reported in rats exposed at concentrations of 220 or 950 ppm for 6 w (Butterworth et al., 1980) and the ability of DAA to enhance the hepatotoxicity of chloroform suggest that DAA can be a potential hepatotoxicant. Because histopathological changes were not detected in the livers of rats exposed at 950 ppm for 180 h (cumulative), that concentration becomes the NOAEL. No data suggested an approach less conservative than Haber's rule to protect against potential liver injury; therefore, the ACs to avoid liver injury were set as follows: 7-d AC = 950 ppm × 1/10 (species) = 95 ppm. 30-d AC = 950 ppm × 1/10 (species) × (180 h/720 h) = 24 ppm. 180-d AC = 950 ppm × 1/10 (species) × (180 h/4320 h) = 4 ppm. The liver is a remarkably adaptive organ, and it is unlikely that exposures need to be kept this low to prevent liver injury; however, specific data on DAA were not available to predict the effects of variations in exposure times.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 4-3 Acceptable Concentrations   Uncertainty Factors Acceptable Concentrations, ppm Effect, Data, Reference Species Species Time Small n 1 h 24 h 7 d 30 d 180 d CNS effects   NOAEL, 950 ppm, 6 h/d (Butterworth et al., 1980) Rat 10 1 1 95 95 - - - NOAEL, 220 ppm, 6 h/d, 5 d/w, 6 w (Butterworth et al., 1980) Rat 10 1 1 - - 22 6 6 Irritation   NOAEL, 50 ppm, 15 min, 12 subjects (Silverman et al., 1946) Human 1 1 √12 50 50 17 17 17 Potential liver injury   NOAEL, 950 ppm, 120 h cumulative (Butterworth et al., 1980) Rat 10 HR 1 - - 95 24 4 SMACs         50 50 20 6 4 —, Data not considered applicable to the exposure time; HR, Haber's rule.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 RECOMMENDATIONS Given the fairly widespread use of DAA, it is surprising that at least a subchronic inhalation study has not been reported. This type of study would determine whether the risk of liver injury increases with exposure time (Haber's rule) or is negligible below some threshold concentration. Acute inhalation exposures in animals with performance assessments would determine if CNS effects occur that have not been reported. Metabolism studies would be useful to define the metabolites of DAA and to measure the rates of uptake and elimination. On the other hand, astronaut exposures to this chemical will be rare, and an accidental release is unlikely to involve significant exposures to DAA. REFERENCES ACGIH. 1991. Pp. 386-388 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. 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 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. Brooks, T. M., A. L. Meyer, and D. H. Huston. 1988. The genetic toxicology of some hydrocarbon and oxygenated solvents. Mutagenesis 3:227-232. Butterworth, S. T. G., D. G. Clark, and H. R. Roderick. 1980. The inhalation toxicity of diacetone alcohol following six week's exposure to rats . Group Research Report TLGR.80.029, Shell Research Limited, London. Granvil, C. P., M. Sharkawi, and G. L. Plaa. 1994. Metabolic fate of methyl n-butyl ketone, methyl isobutyl ketone and their metabolites in mice. Toxicol. Lett. 70:263-267. James, J. T., T. F. Limero, H. J. Leano, J. F. Boyd, and P. A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the space shuttle: STS-26 to STS-55. Aviat. Space Environ. Med. 65:851-857. Lehmann, B., and F. Flury. 1938. Toxikologie und Hygiene der Technischen Losungsmittel. Berlin: Springer.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. Shehab, A. S. 1980. Comparative cytological studies of the effect of some aliphatic alcohols and the fatty alcohols from Euphorbia granulata and Pulicaria crispa on mitosis of Allium cepa. Cytologia 45:507-513. Silverman, L., H. F. Schulte, and M. W. First. 1946. Further studies on sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 28:262-266. Smyth, H. F., Jr., and C. P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30:63-68. Swenberg, J. A., B. Short, J. Borghoff, J. Strasser, and M. Charbonneau. 1989. The comparative pathobiology of alpha-2-microglobulin nephropathy. Toxicol. Appl. Pharmacol. 97:35-46. U.S. Department of Labor. 1995. Air Contaminants-Permissible Exposure Limits. Title 29, Code of Federal Regulations, Part 1910, Section 1910.1000. Washington, D.C.: U.S. Government Printing Office. Vezina, M, A. B. Kobusch, P. du Souich, E. Greslin, and G. L. Plaa. 1989. Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites. Can. J. Physiol. Pharmacol. 68:1055-1061. von Oettingen, W. F. 1943. The Aliphatic Alcohols: Their Toxicity and Potential Dangers in Relation to Their Chemical Constitution and Their Fate in Metabolism. U.S. Public Health Service, Public Health Bulletin No. 281. Washington, D.C.: U.S. Government Printing Office.