4
C1-C4 Mono-, Di-, and Trialkylamines

Jean M. Hampton, Ph.D. NASA Administrator’s Fellowship Program Johnson Space Center Houston, Texas

PROPERTIES AND OCCURRENCE

Background

Alkylamines are colorless, flammable gases or liquids that emit “fishy” or ammonia-like odors. The alkylamines share common properties, including fat solubility, high alkalinity, and, for those amines with boiling points less than 100C (Table 4-1), considerable volatility. These properties account for their irritation to skin and mucous membranes and for their classification as hazardous chemicals in the workplace. Amines are produced endogenously by microbial breakdown of food constituents choline and lecithin (Asatoor and Simenhoff 1965), which are found in many common foods (such as eggs and liver) (Spellacy and Watts 1979). Methylamine is biosynthesized by degradation of muscle sarcosine and creatine (Davis and DeRopp 1961). Methylamine, dimethylamine, and trimethylamine are found in human gastric fluid and in the saliva and blood of humans and other mammalian species, including rats, ferrets, and dogs (Zeisel et al. 1988). Amines are also normal constituents of mammalian wastes, including urine, feces, and exhaled air. Humans excrete approximately 1 millimole (mmol) each of methylamine, dimethylamine, and trimethylamine in urine per day following consumption of a normal diet (Ziesel et al. 1983). Following consumption of 27 mmol of choline chloride, six healthy human subjects excreted 2 mmol of methylamine, 2 mmol of dimethylamine, and >17 mmol of trimethylamine in urine per day.



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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 4 C1-C4 Mono-, Di-, and Trialkylamines Jean M. Hampton, Ph.D. NASA Administrator’s Fellowship Program Johnson Space Center Houston, Texas PROPERTIES AND OCCURRENCE Background Alkylamines are colorless, flammable gases or liquids that emit “fishy” or ammonia-like odors. The alkylamines share common properties, including fat solubility, high alkalinity, and, for those amines with boiling points less than 100C (Table 4-1), considerable volatility. These properties account for their irritation to skin and mucous membranes and for their classification as hazardous chemicals in the workplace. Amines are produced endogenously by microbial breakdown of food constituents choline and lecithin (Asatoor and Simenhoff 1965), which are found in many common foods (such as eggs and liver) (Spellacy and Watts 1979). Methylamine is biosynthesized by degradation of muscle sarcosine and creatine (Davis and DeRopp 1961). Methylamine, dimethylamine, and trimethylamine are found in human gastric fluid and in the saliva and blood of humans and other mammalian species, including rats, ferrets, and dogs (Zeisel et al. 1988). Amines are also normal constituents of mammalian wastes, including urine, feces, and exhaled air. Humans excrete approximately 1 millimole (mmol) each of methylamine, dimethylamine, and trimethylamine in urine per day following consumption of a normal diet (Ziesel et al. 1983). Following consumption of 27 mmol of choline chloride, six healthy human subjects excreted 2 mmol of methylamine, 2 mmol of dimethylamine, and >17 mmol of trimethylamine in urine per day.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 4-1 Physical and Chemical Properties of the Alkylamines Al-kylamine CAS Registry No. Formula Molecular Weight Synonyms Boiling Point (°C) Melting Point (°C) Vapor Pressure (torr at 25°C) Density (°C) Solubility Methyl 74-89-5 CH5N 31.07 Aminomethane 6.3 −93.5 2,650 0.662 (25) Water         Carbinomine         Alcohol         Methanamine         Ether Ethyl 75-04-7 C2H7N 45.1 Ethanamine 16.6 −81.2 1,048 0.689(15) Water         Aminoethane         Alcohol         Monoethylamine         Ether Propyl 107-10-8 C3H9N 59.13 1-Aminopropane 48-49 −83 310 0.719 (20) Water         Propanamine         Alcohol         n-Propylamine         Ether Isopropyl 75-31-0 C3H9N 59.13 2-Aminopropane 33-34 −101 579.6 0.694 Water n-Butyl 109-73-9 C4H11N 73.14 1-Butanamine 78 −50 92.9 0.741 (20) Water         1-Aminobutane         Alcohol         Mono-n-butylamine                   Methanamine         Dimethyl 124-40-3 C2H7N 45.03 N-Methyl-ethanamine 6.8 −92.2 1520 0.684 (0) Water Diethyl 109-89-7 C4H11N 73.14 N-Ethyl-1-butanamine 55.6 −50 237 0.707 (20) Water Di-n-butyl 111-92-2 C8H19N 129.24 n-Butyl- 160 −60 2.59 0.760 (20) Water Alcohol

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Alkylamine CAS Registry No. Formula Molecular Weight Synonyms Boiling Point (°C) Melting Point (°C) Vapor Pressure (torr at 25°C) Density (°C) Solubility Trimethyl 75-50-3 C3H9N 59.13 TMA 2.87 −117 1,610 0.636 (20) Water         N,N-Dimethyl-methanamine         Alcohol         Amine, trimethyl         Ether Triethyl 121-44-8 C6H15N 101.22 (Diethylamino)-ethane 89.5 −115 57.1 0.726 (25) Water         N,N-Diethylethan-amine         Alcohol         TEN         Ether Tripropyl 102-82-9 C9H21N 143.31 N,N-Di-propyl-1-propanamine 156 −93 2.25 0.75 (25) Water         Tri-n-propylamine                   Propyldi-n-propylamine           Tributyl 102-69-2 C12H27N 185.4 Tri-n-butylamine 216-217 <−70 0.29 0.778 (20) Water         Tris-n-butylamine         Alcohol         N,N-dibutyl-1-butanamine         Ether Source: Data from HSDB 2001.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Amines occur naturally in various plants, such as tobacco, algae, and celery, as well as in other consumables, such as cheese, brown breads, boiled beef, rice, wine, and coffee (Benya and Harbison 1994). They are used in industry as solvents, rubber accelerators, ion-exchange resins, and catalysts. Detection in Spacecraft The Water and Food Analytical Laboratory (WAFAL) at Johnson Space Center has evaluated eight alkylamines found to be contaminants in water samples from spacecraft. Those amines—methylamine, ethylamine, propylamine, di-n-butylamine, trimethylamine, triethylamine, tripropylamine, and tributylamine—are illustrated with other target alkylamines in Figure 4-1. Twenty-eight raw humidity-condensate samples, 29 recycled-water samples from the condensate-recovery system galley dispenser, and eight stored-water samples were collected in 2-4-week (wk) intervals during Mir space station missions from 1995 to 1998 (Pierre and Schultz 1999). Mean concentrations of detected amines in raw humidity condensate included methylamine at 0.092 milligrams per liter (mg/L) (8 of 28 samples), di-n-butylamine at 0.003 mg/L (6 of 28 samples), and triethylamine at 0.002 mg/L (6 of 28 samples). Triethylamine, the only alkylamine reported at above the detection limit in recycled galley samples, was detected in 1 of 27 galley samples at 0.012 micrograms per liter (µg/L). Amines were not detected in stored water samples. In-flight galley and low iodine residual system (LIRS [see list of abbreviations used in this chapter]) cartridge effluent samples were collected on Space Transportation System (STS)-95 after a malfunction of the LIRS water reclamation system (Schultz 1998). The crew reported an objectionable taste and smell of galley water, which was later attributed to the presence of amines—specifically trimethylamine, tributylamine, and tripropylamine at 60 mg/L, 176 mg/L, and 793 mg/L, respectively. WAFAL studies determined that the most likely source of the amines in the water samples was the decomposition of iodosorb and microbial check valve resins during normal storage and/or gamma irradiation sterilization. Amines were not detected in samples taken from the STS-95 ACTEX (activated carbon/ion exchange) water reclamation system.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 FIGURE 4-1 Alkylamine groups relevant to spacecraft water exposure guidelines. Source: Adapted from the National Library of Medicine 2006. PHARMACOKINETICS AND METABOLISM In general, amines are well absorbed from the gut and respiratory tract (Benya and Harbison 1994). Lower aliphatic amines are primarily metabolized to corresponding carboxylic acids and urea; aldehydes and ammonia are intermediate compounds. Monoamine oxidases (MAOs), flavin-containing monooxygenases (FMOs), and cytochrome P-450 enzymes are all purportedly involved in amine biotransformation and have

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Abbreviations Used in Text 3-MeAde 3-methyladenine ACTEX activated carbon/ion exchange BA n-butylamine BCPN N-butyl-n-(3-carboxypropyl)nitrosamine BHA butylated hydroxyanisole CCV clear cytoplasmic vacuoles DBA di-n-butylamine DEA diethylamine DMA dimethylamine EA ethylamine FMO3 flavin-containing monooxygenase (isomer 3) IPA isopropylamine LIRS low iodine residual system MA methylamine MDA malondialdehyde NDBA N-nitrosodi-n-butylamine PA propylamine SSAO semicarbazide-sensitive amine oxidase TBA tributylamine TEA triethylamine TEAO triethylamine-N-oxide TMA HCl trimethylamine hydrochloride TMA trimethylamine TMAO trimethylamine-N-oxide TPA tripropylamine overlapping substrate specificities. Biotransformation of amines might involve oxidative deamination or de-alkylation, as well as N-oxidation. Available data on the metabolism of alkylamines relevant to spacecraft water exposure guidelines (SWEGs) are presented below. Amine Biotransformation Enzymes Two classes of flavoproteins, MAOs and FMOs, are implicated in the metabolism of amines. MAO A and MAO B are involved in the deamination of both biogenic and xenobiotic amines (Cashman 1997). MAO A preferentially oxidizes biogenic amines, such as serotonin and epinephrine, whereas MAO B oxidizes noncatecholamines, such as phenylethylamine and benzylamine. MAOs oxidatively deaminate pri-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 mary, secondary, and tertiary amines; however, amine substrates that have a methyl group on the alpha carbon (with respect to the nitrogen atom of the substrate) are resistant to oxidation by MAO (Benedetti and Dostert 1994). Methylamine, ethylamine, and propylamine are established as poor substrates for MAO (Benya and Harbison 1994). FMOs are a family of enzymes that detoxify organic nitrogen- and sulfur-containing nucleophilic xenobiotics by converting the lipophilic heteroatom-containing compounds to polar, oxygenated metabolites that are readily excreted (Cashman 1997). Nucleophilic tertiary amines, sulfides, thiones, and phosphines are converted to their corresponding N-, S-, and P-oxides. Dietary xenobiotics have been demonstrated to influence the expression of rat liver FMO. Ziegler (1984) proposed that FMO is induced by one or more organic nitrogen- or sulfur-containing xenobiotics present in food. A defect in the FMO isomer FMO3 causes the disorder trimethylaminuria. Affected individuals cannot effectively metabolize trimethylamine (TMA) to its N-oxide, TMAO (Ayesh et al. 1993). Missense and nonsense mutations in the FMO3 gene have been identified as causes of the more persistent “primary” trimethylaminuria (Treacy et al. 1998; Dolphin et al. 2000). Several other common genetic polymorphisms have been shown to cause partial attenuation of FMO3 N-oxidation capacity. Genetic polymorphisms distributed in Canadian and Australian white populations have been suggested to modulate the activity of human FMO3 (Cashman et al. 2000). Affected individuals excrete large amounts of unchanged malodorous TMA in their skin, breath, sweat, and urine. These excretions impart a fishy smell to the individual, and the disease is hence referred to as the “fish-odor syndrome.” Normally, healthy individuals excrete 50 mg of TMA per day (Ayesh and Smith 1992). That amount might vary with diet. Greater than 90% of excreted TMA is in the N-oxide form, TMAO. Formation of triethylamine-N-oxide (TEAO) from ingested or inhaled triethylamine (TEA) conceivably is dependent on an FMO (Akesson et al. 1988). As in the case of other aliphatic trialkylamines, TEA purportedly is metabolized by addition of oxygen to its nucleophilic nitrogen (Ziegler 1984). N-oxygenation of trialkylamines is a significant route for the oxidative metabolism of a large number of medicinal amines and naturally occurring alkaloids that have basic side chains. The formation of aliphatic N-oxide is representative of FMO metabolism of xenobiotic amines. The semicarbazide-sensitive amine oxidase (SSAO) is an enzyme (or a family of enzymes) found in vascular smooth muscle cells, in cartilage, and in microvessels of the retina and brain (Yu 1998). This amine

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 oxidase, which is inhibited by semicarbazide and pargylamine, oxidizes various endogenous and exogenous amine substrates (Yu 1990). Methylamine and ethylamine are readily oxidized by male Wistar rat aorta SSAO (Yu 1990). Substrate affinity for SSAO was observed in C1-C18 aliphatic amines, with affinity increasing with carbon-chain length. Aldehydes are products of SSAO deamination of aliphatic amines. Methylamine Methylamine (MA) in humans might be derived from metabolic reactions, including the deamination of adrenaline (Schayer et al. 1952) and the metabolism of sarcosine and creatine (Dar et al. 1985). MA might also be ingested from food and drink or via inhalation of tobacco smoke. Asatoor and Simenhoff (1965) have proposed that methylamine enters one of two metabolic pathways: (1) metabolism to carbon dioxide and ammonia, or (2) transmethylation to dimethylamine (DMA) using methionine as the methyl donor (Figure 4-2). In vivo studies conducted by Dar et al. (1985) concluded that MAO does not play a major role in the metabolism of MA. In vitro studies have shown that MA is deaminated by a SSAO to hydrogen peroxide and formaldehyde (Yu and Zuo 1996). Other in vitro studies have demonstrated oxidative deamination of methylamine by SSAO (Boor et al. 1992; Yu 1998; Yu and Zuo 1996; Yu and Zuo 1993). Formaldehyde was shown to be a metabolic product when rat aortic homogenate supernatant or purified porcine SSAO preparations were incubated with 1 millimolar (mM) of MA (Boor et al. 1992). Formaldehyde was measured by high-performance liquid chromatography (HPLC) detection of 2,4-dinitrophenylhydrazine-formaldehyde adducts. In this same study, formaldehyde production was inhibited by semicarbazide, an SSAO inhibitor, but not by pargyline, an MAO inhibitor, when MA rat aorta homogenates or porcine SSAO were incubated with MA. MA was demonstrated to be an endogenous substrate for SSAO (Precious et al. 1988). MA metabolism by amine oxidase activities was studied in rat aorta and human umbilical artery preparations using 14C radiochemical assays or spectrophotometric determination of hydrogen peroxide (H2O2) formation resulting from MA metabolism. Deamination of MA was completely inhibited by the SSAO-selective inhibitors semicarbazide and propargylamine. Deamination of MA was not inhibited by MAO-selective inhibitors clorgyline and pargylamine.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 FIGURE 4-2 Metabolic pathways of methylamines as proposed by Asatoor and Simenhoff (1965), Boor et al. (1992), Ayesh et al. (1993), and Yu (1998).Abbreviations: DMA, dimethylamine; FMO3, flavin-containing monooxygenase isomer 3; MA, methylamine; SSAO, semicarbazide-sensitive amine oxidase; TMA, trimethylamine.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Lyles and McDougall (1989) proposed that MA is metabolized in vivo by SSAO. When male albino Sprague-Dawley rats were treated with semicarbazide (100 mg per kilogram [kg]), a chemical that irreversibly inhibits SSAOs, urinary excretion of MA increased threefold (24 hours [h]) to sixfold (48 h) for two daily periods following dosing. The authors conclude that the results do not prove that decreased degradation of MA occurs specifically because of semicarbazide; however, the results support the argument that MA is metabolized to formaldehyde via SSAO. In a separate study, when SSAO enzyme preparations from rat aorta were treated with semicarbazide, deamination of MA was completely inhibited (Yu 1990). Trimethylamine Radioactive [14C]-TMA hydrochloride was administered orally in aqueous solution at 15 mg/kg to three female adult rats (150-200 g body weight) of each of seven different strains, Wistar, Lewis, Fischer, A/GUS, PVG, DA, and BN (Al-waiz and Mitchell 1991). There were no statistically significant differences in results among the strains investigated. TMA, its metabolite TMAO, and DMA were detected by thin layer chromatography. Greater than 75% of the administered dose of TMA was excreted in the urine within 24 h after dosing. Amounts up to 9% were detected in the feces. Rats excreted 45% of the administered TMA dose as TMAO, 3% as DMA, and the remaining dose as unchanged TMA. Results from this study suggest N-oxidation as the major metabolic path and demethylation as the secondary path for TMA biotransformation. TMA is a common constituent of urine and is produced by the action of normally present intestinal bacteria on dietary choline. TMA is proposed as an intermediate in the production of endogenous DMA (Asatoor and Simenhoff 1965). Male albino rats (number not given) received 100 mg of TMA hydrochloride by gastric intubation. A second group of rats received 50 mg of intraperitoneally (ip) administered TMA hydrochloride. Urinary excretion of DMA in treated animals was measured prior to dosing. Both groups of rats were observed to have marked increases in urinary excretion of DMA following TMA hydrochloride dosing. Orally dosed rats excreted 40 µg of DMA per milligram of creatinine prior to dosing and 185 µg of DMA per milligram of creatinine after dosing. Rats ip dosed excreted 45.6 µg of DMA per milligram of creatinine prior to dosing and 110 µg of DMA per milligram

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 creatinine after dosing. These results suggest that TMA is physiologically demethylated to DMA. TMA commonly occurs in mammalian urine and is produced by normal digestive and intestinal microbial breakdown of dietary lecithin and choline (Al-waiz et al. 1987a). In humans, the major precursor of TMA is dietary choline (Humbert et al. 1970). TMA is metabolized partly by N-demethylation to form urea and formaldehyde and partly by oxidation to TMAO (Parke 1968). TMA is also reported to be an intermediate in the metabolism of choline to DMA (Asatoor and Simenhoff 1965). Four healthy men received single oral doses of TMA by gelatin capsule at 300 and 600 mg per capsule (Al-waiz et al. 1987a). Analysis of urine prior to TMA administration demonstrated TMA, TMAO, and DMA at concentrations of 10, 311, and 98 micromoles (µmol) per 8-h urine sample, respectively, presumably resulting from normal metabolism of dietary sources. Eight hours following ingestion of the 300 mg (5 mmol) TMA capsule, urinary TMA, TMAO, and DMA increased 11-, 10.2-, and 1.4-fold, respectively. Urinary concentrations of TMA increased 39-fold (390 µmol) and concentrations of TMAO increased 24-fold (7,464 µmol) after ingestion of the 600 mg capsule. A minimal 1.8-fold increase in DMA (175 µmol) was noted. For both doses, TMAO composed 93% of the excreted TMA, suggesting that N-oxidation is a primary metabolic pathway for orally ingested TMA. A fish-like odor was imparted to urine samples after dosing at both concentrations. Trimethylaminuria Trimethylaminuria, also referred to as “fish-odor syndrome,” is marked by the inability of affected individuals to effectively metabolize TMA to its relatively odorless N-oxide metabolite, TMAO (Al-waiz et al. 1987c). This condition is biochemically characterized by excretion of abnormally large amounts of unoxidized TMA, which consequently imparts a fish-like odor to the affected individual. Primary trimethylaminuria is the malodorous phenotypical expression in individuals who are homozygous for the recessive allele that results in impairment of the TMA N-oxidation mechanism. Individuals with primary trimethylaminuria are deficient in hepatic FMO3 activity, which catalyzes the N-oxidation of dietary TMA. However, trimethylaminuria may present as sequelae to other underlying disorders, such as liver cirrhosis or uremia, in which individuals with chronic kidney failure have increased total body burden of TMA as a result of bacterial overgrowth and decreased

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 selected for alkylamines that had multiple reported thresholds, with the exception of that selected for TMA, because the lowest threshold reported for that chemical is presumed to be an experimental outlier. It is reasonable to expect that crew members would tolerate consumption of malodorous water for a short period of time (1 d). One-day ACs were set as the mean water-dilution odor threshold for each amine group. Ten-day ACs were set at the lowest odor threshold for each amine group, as were long term ACs (100- and 1,000-d). 1-d ACs Amoore and Hautala (1983), Baker (1963), Trubko (1975), and Le Din Min (1976) reported water-dilution odor threshold concentrations for monoalkylamines MA, EA, IPA, and BA at 2.4, 4.3, 4.9, and 6.0 mg/L, respectively (Table 4-4). Respective thresholds for dialkylamines DMA, DEA, and DBA were reported at 0.29, 0.47, and 2.0 mg/L. For trialkylamines TEA, TMA, and TBA, water-dilution odor thresholds were reported at 0.42 mg/L, 1.7mg/L, and 0.8 mg/L, respectively. The lowest of the reported odor threshold values for each group of alkylamines, with exception of a presumed outlier value for TMA (0.0002 mg/L) that was not used, was selected as the AC. The 1-d ACs for the alkylamine groups were established as follows: 1-d AC for monoalkylamines = 2 mg/L, 1-d AC for dialkylamines = 0.3 mg/L, 1-d AC for trialkylamines = 0.4 mg/L. 10-d ACs Amoore and Hautala (1983), Baker (1963), Trubko (1975), and Le Din Min (1976) reported water-dilution odor threshold concentrations for monoalkylamines, dialkylamines, and trialkylamines (Table 4-4). The lowest of the reported odor threshold values for each group of alkylamines, with the exception of a presumed outlier value for TMA (0.0002 mg/L) that was not used, was selected as the AC. The 10-d ACs for the alkylamine groups were established as follows: 10-d AC for monoalkylamines = 2mg/L, 10-d AC for dialkylamines = 0.3mg/L, 10-d AC for trialkylamines = 0.4mg/L.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 100-d ACs Reproductive Toxicity Amoore et al. (1978) reported that among rats receiving TMA at 27, 54, 105, and 210 mg/kg daily for 90 d, rats dosed at 210 mg/kg demonstrated a 33-50% reduction in seminal vesicle weight upon examination. No adverse effects were seen in rats receiving 54 mg/kg, and that was considered a NOAEL. The AC calculation assumed a 70 kg body weight and water consumption of 2.8 L/d. A factor of 10 was applied for species extrapolation, and a factor of 1.1 was applied for time extrapolation. The 100-d AC from the data of Amoore et al. (1978) was calculated as follows: This calculated dose, 120 mg/L, approaches or exceeds detected measures of trialkylamines presumed to be responsible for the objectionable odor and taste of in-flight galley water on shuttle flight STS 95. A benchmark dose calculation (by benchmark dose software from the U.S. Environmental Protection Agency NCEA, version 1.3.1) for this study was executed using the above animal dose and physiologic data. A benchmark dose calculation at the 95% confidence interval and at a benchmark response of 1% (BMDL1) resulted in a 223 mg/L AC for reproductive toxicity. This calculated dose, 223 mg/L, approaches or exceeds detected measures of trialkylamines presumed to be responsible for the objectionable odor and taste of in-flight galley water on shuttle flight STS 95. Moreover, because of scanty dose-response data presented in this study, the author elected to forego consideration of derived benchmark dose calculations. Water-Dilution Odor Thresholds Amoore and Hautala (1983), Baker (1963), Trubko (1975), and Le Din Min (1976) reported water-dilution odor threshold concentrations for monoalkylamines, dialkylamines, and trialkylamines. The lowest of the

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 reported odor threshold values for each group of alkylamines, with exception of a presumed outlier value for TMA (0.0002 mg/L) that was not used, was selected as the AC. The 100-d ACs for the alkylamine groups were established as follows: 100-d AC for monoalkylamines = 2mg/L, 100-d AC for dialkylamines = 0.3mg/L, 100-d AC for trialkylamines = 0.4mg/L. 1,000-d ACs Amoore and Hautala (1983), Baker (1963), Trubko (1975), and Le Din Min (1976) reported water-dilution odor threshold concentrations for monoalkylamines, dialkylamines, and trialkylamines. The lowest of the reported odor threshold values for each group of alkylamines, with exception of a presumed outlier value for TMA (0.0002 mg/L) that was not used, was selected as the AC. The 1,000-d ACs for the alkylamine groups were established as follows: 1,000-d AC for monoalkylamines = 2mg/L, 1,000-d AC for dialkylamines = 0.3mg/L, 1,000-d AC for trialkylamines = 0.4mg/L. REFERENCES Abe, S., and M. Sasaki. 1977. Studies on chromosomal aberrations and sister chromatid exchanges induced by chemicals. Proc. Jpn. Acad. 53:46-49. ACGIH (American Conference of Governmental and Industrial Hygienists). 1995. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 1995-1996. American Conference of Governmental and Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental and Industrial Hygienists). 1998. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 1995-1996. American Conference of Governmental and Industrial Hygienists, Cincinnati, OH. Airoldi, L., R. Pastorelli, A. Macri, M. Bonfanti, and R. Fanelli. 1987. Effect of butylated hydroxyanisole on in vitro and in vivo nitrosation of dibutylamine. Toxicology 43:217-225. Akerman B.R., S. Forrest, L. Chow, R. Youil, M. Knight, and E.P. Treacy. 1999a. Two novel mutations of the FMO3 gene in a proband with trimethylaminuria. Hum. Mutat. 13:376-379.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Akerman B.R., H. Lemass, L.M. Chow, D.M. Lambert, C. Greenberg, C. Bibeau, O.A. Mamer, and E.P. Treacy. 1999b. Trimethylaminuria is caused by mutation of the FMO3 gene in a North American cohort. Mol. Genet. Metab. 68(1):24-31. Akesson, B., S. Skerfving, and L. Mattaisson. 1988. Experimental study on the metabolism of triethylamine in man. Br. J. Ind. Med. 45:262-268. Akesson, B., E. Vinge, and S. Skerfving. 1989. Pharmacokinetics of triethylamine and triethylamine-N-oxide in man. Toxicol. Appl. Pharmacol. 100:529-538. Al-waiz, M., S.C. Mitchell, J.R. Idle, and R.L. Smith. 1987a. The relative importance of N-oxidation and N-Demethylation in the metabolism of trimethylamine. Toxicology 43:117-121. Al-waiz, M., S.C. Mitchell, J.R. Idle, and R.L. Smith. 1987b. The metabolism of 14C-labelled trimethylamine and its N-oxide in man. Xenobiotica 17(5): 551-558. Al-waiz, M., R. Ayesh, S.C. Mitchell, J.R. Idle, and R.L. Smith. 1987c. Trimethylaminuria (fish-odor syndrome): An inborn error of oxidative metabolism. Lancet 1(8533):634-635. Al-waiz, M., and S.C. Mitchell. 1991. The fate of trimethylamine in the rat. Drug Metabol. Drug Interact. 9(1):41-48. Amoore, J.E., M.R. Gumbmann, A.N Booth, and D.H. Gould. 1978. Synthetic flavors: Efficiency and safety factors for sweaty and fishy odorants. Chem. Senses Flavor 3(3):307-317. 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. Asatoor, A.M., and M.L. Simenhoff. 1965. The origin of urinary dimethylamine. Biochem. Biophys. Acta 3:384-392. Ayesh, R., and R. Smith. 1992. Genetic polymorphism of trimethylamine N-oxidation. Pp. 315-332 in Pharmacogenetics of Drug Metabolism. New York: Pergamon Press. Ayesh, R., S.C. Mitchell, and A. Zhang. 1993. The fish odor syndrome; Biochemical familial and clinical aspects. Br. Med. J. 307:655-657. Baker, R.A. 1963 . Threshold odors of organic chemicals. J. Am Water Works Assoc. 55:911-916. Basarab, T., G.H. Ashton, H.P. Menage, and J.A. McGrath. 1999. Sequence variations in the flavin-containing monooxygenase 3 gene (FMO3) in fish odor syndrome. Br. J. Dermatol. 140(1):164-167. Benedetti, M.S., and P. Dostert. 1994. Contribution of amine oxidases to the metabolism of xenobiotics. Drug Metabol. Rev. 26:507-535. Benya, T.J., and R.D. Harbison. 1994. Aliphatic and alicyclic amines. Pp. 1087-1175 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. 2, Part B. New York: John Wiley and Sons.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 BIBRA. 1993. Toxicity Profile: Trimethylamine and Its Hydrochloride. Carshalton, Surrey, UK: BIBRA International, Ltd. Boor, P.J., M.B. Trent, G.A. Lyles, M. Tao, and G.A. Ansari. 1992. Methylamine metabolism to formaldehyde by vascular semicarbazide-sensitive amine oxidase. Toxicology 73:251-258. Brewster, M.A., and H. Schedewie. 1983. Trimethylaminuria. Ann. Clin. Lab. Sci. 13:20-24. Brown, N.A., and S. Fabro. 1981. Quantitation of rat embryonic development in vitro: A morphological scoring system. Teratology 24(1):65-78. Burmester, J., K. Handrock, and R. Lullmann-Rauch. 1990. Cultured corneal fibroblasts as a model system for the demonstration of drug-induced mucopolysaccharidosis. Arch. Toxicol. 64:291-298. Cashman, J.R. 1997. Monoamine oxidase and flavin-containing monooxygenases. Pp. 69-96 in Comprehensive Toxicology, Volume 3: Biotransformation, I.G. Spies, C.A. McQueen, and A.J. Gandolfi, eds. New York: Pergamon, Elsevier Science Ltd. Cashman, J.R., B.R. Akerman, S.M. Forrest, and E.P. Treacy. 2000. Population-specific polymorphisms of the human FMO3 gene: Significance for detoxication. Drug Metab. Dispos. 28(2):169-173. Caspary, W.J., and B. Myhr. 1986. Mutagenicity of methylisocyanate and its reaction to cultured mammalian cells. Mutat. Res. 174:285-293. Chang, M.C. 1964. Effects of certain antifertility agents on the development of rabbit ova. Fertil. Steril. 15(1):97-106. Cheever, K.L., D.E. Richards, and H.B. Plotnick. 1982. The acute oral toxicity of isomeric monobutylamines in the adult male and female rat. Toxicol. Appl. Pharmacol. 63:150-152. Dalton, P.N. Doolittle, H. Nagata, and P.A. Breslin. 2000. The merging of the senses: Integration of subthreshold taste and smell. Nat. Neurosci. 3(5): 431-2. Dar, M.S., P.L. Morselli, and E.R. Bowman. 1985. The enzymatic systems involved in the mammalian metabolism of methylamine. Gen. Pharmacol. 16(6):557-560. Darad, R., A.K. De, and A.S. Aiyar. 1983. Toxicity of nitrite and dimethylamine in rats. Toxicol. Lett. 17:125-130. Davis, E.J., and R.S. DeRopp. 1961. Metabolic origin of urinary methylamine in the rat. Nature 190:636-637. Davison, R.R., D.W. Hood, and B. McMullen. 1965. Solvent demineralization final report: Toxicity of triethylamine to albino rats. Texas A&M University System, Department of Oceanography, Project 325. De Duve, C., T. de Barsy, B. Poole, A. Trouet, P. Tulkens, and F. Van Hoof. 1974. Commentary. Lysomotropic agents. Biochem. Pharmacol. 23(18): 2495-2531. Dolphin, C.T., A. Janmohamed, R.L. Smith, E.A. Shephard, and I.R. Phillips. 2000. Compound heterozygosity for missense mutation in the flavin-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Ishidate, M., and S. Odashima. 1977. Chromosome tests with 134 compounds on chinese hamster cells in vitro—A screening for chemical carcinogens. Mutat. Res. 48:337-354. Kagan, G.Z. 1965. The determination of the maximum permissible concentrations of diethylamine and triethylamine in bodies of water. Hyg. Sanit. 30(7-9):351-356. Kaneda, H., K. Maeshima, N. Goto, T. Kobayakawa, S. Ayabe-Kanamura, and S. Saito. 2000. Decline in taste and odor discrimination abilities with age, and relationship between gustation and olfaction. Chem. Senses 25(3): 331-337. Kawachi, T., T. Yahagi, T. Kada, Y. Tazima, M. Ishidate, M. Sasaki, and T. Sugiyama. 1980. Cooperative program on short-term assays for carcinogenicity in Japan. Pp. 323-330 in IARC Scientific Publication 27. Lyon, France: International Agency for Research on Cancer. Keil, D.E., E.L. Padgett, D.B. Barnes, and S.B. Pruett. 1996. Role of decomposition products in sodium methyldithiocarbamate-induced immunotoxicity. J. Toxicol. Environ. Health 47:479-492. Kennedy, G.L., and G.J. Graepal. 1991. Acute toxicity in the rat following either oral or inhalation exposure. Toxicol. Lett. 56:317-326. King, A.C., L.-H. Davis, and P. Cuatrecasas. 1981. Lysosomotropic amines inhibit mitogenesis induced by growth factors. Proc. Natl. Acad. Sci. USA 78(2):717-721. Kinney, L.A., R. Valentine, H.C. Chen, R.M. Everett, and G.L. Kennedy, Jr. 1990. Inhalation toxicology of methylamine. Inhal. Toxicol. 2:29-39. Klaassen, C.D., ed. 1996. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 5th Ed. New York: McGraw-Hill. Langley, W.D. 1929. Metabolism of amines. J. Biol. Chem. 75:561-571. Lakritz, L., R.A. Gates, A.M. Gugger, and A.E. Wasserman. 1982. Nitrosamine levels in human blood, urine and gastric aspirate following ingestion of foods containing potential nitrosamine precursors or preformed nitrosamines. Food Chem. Toxicol. 20:455-459. Le Din Min. 1976. Hygienic standards for tributylamine in reservoir water [in Russian]. Gig. Sanit. (12):36-42. Lewis, R.J., ed. 1996. Hazardous Chemical Desk Reference. Fourth Edition. John Hoboken: Wiley and Sons, Inc. L’hirondel, J.-L. 1999. Are dietary nitrates a threat to human health? Pp. 38-46 in Fearing Food: Risk Health and Environment, J. Morris and R. Bate, eds. Oxford: Butterworth-Heinemann. Lijinsky, W. 1976. Health problems associated with nitrites and nitrosoamines. Ambio 5(2):67-72. Lijinsky, W. 1980. Significance of in vivo formation of N-nitroso compounds. Oncology 37:223-226. Lijinsky, W., and H.W. Taylor. 1977. Feeding tests in rats on mixtures of nitrite with secondary and tertiary amines of environmental importance. Food Cosmet. Toxicol. 15:269-274.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Lyles, G.A., and S.A. McDougall. 1989. The enhanced daily excretion of urinary methylamine in rats treated with semicarbazide or hydralazine may be related to the inhibition of semicarbazide-sensitive amine oxidase activities. J. Pharm. Pharmacol. 41:97-100. Matsui, M., M. Takahashi, and H. Homa. 1993. Inhibition of rat liver hydroxysteroid sulfotransferase activity by alkylamines. Biochem. Pharmacol. 46(3):465-470. Meshram, G.P., R.P. Malini, and K.M. Rao. 1992. Mutagenicity of N,N-dimethylurea and methylamine hydrochloride in the Ames Salmonella/ microsome test: Absence of mutagenic response. Mutat. Res. 279:275-280. Mitchell, S.C., A. Zhang, and R.L. Smith. 1996. Fish odor syndrome and impaired N-oxidation. Biochem. Soc. Trans. 24:96S. Moncrieff, R.W. 1967. The Chemical Senses, 3rd Ed. Cleveland, OH: CRC Press. Monsanto Co. 1992. Toxicological investigation of tributylamine. TSCA Compliance Audit Program. Monsanto Company, St. Louis, MO. Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer, and E. Zeiger. 1986. Salmonella mutagenicity test: II. Results from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl. 7):1-119. National Library of Medicine. 2006. Specialized Information Services ChemIDplus Advanced. [Online]. Available: http://chem.sis.nlm.nih.gov/ chemidplus/. [accessed August 2006]. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1983. NTP Technical Bulletin, Issue No. 9. National Toxicology Program, National Institutes of Health, Research Triangle Park, NC. Parke, D.V. 1944. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press. Patel, V.K., H. Venkatakrishna-Bhatt, N.B. Patel, and M.N. Jindal. 1985. Pharmacology of new glutarimide compounds. Biomed. Biochim. Acta 44(5): 795-803. Pierre, L.M., and J.R. Schultz. 1999. Chemical Analysis of Potable Water and Humidity Condensate: Phase One Final Results and Lessons Learned. SAE #01-2028. Warrendale, PA: Society of Automotive Engineers. Precious, E., C.E. Gunn, and G.A. Lyles. 1988. Deamination of methylamine by semicarbazide-sensitive amine oxidase in human umbilical artery and rat aorta. Biochem. Pharmacol. 37(4):707-713. Putnam, D., R. Gudi, and R.R. Young. 1995. Micronucleus Cytogenic Assay in Mice. Study No. G95AT39.122. Elf Atochemical North America Inc., Philadelphia, PA. Rehman, H.U. 1999. Fish odor syndrome. Postgrad. Med. J. 75:451-452. Rijhsinghani, K.S., C. Abrahams, C. Krakower, M. Swerdlow, and T. Ghose. 1982. Tumor induction in C57BLxC3HF1 mice following single oral ad-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Zeisel, S.H., J.S. Wishnok, and J.K. Blusztajn. 1983. Formation of methylamines from ingested choline and lecithin. J. Pharmacol. Exp. Ther. 225(2):320-324. Zeisel, S.H., and K.A. deCosta. 1986. Increase in human exposure to methylamine precursors of N-nitrosamines after eating fish. Cancer Res. 46: 6136-6138.