Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 2 (2007) / Chapter Skim
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Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine
Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine
Pages 96-153
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From page 96... ...
. 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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TABLE 4-1 Physical and Chemical Properties of the Alkylamines Vapor CAS Boiling Pressure Registry Point Al- Molecular Melting (torr at Density kylamine No.
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98 TABLE 4-1 Continued Vapor CAS Pressure Alkylamine Registry Molecular Boiling Melting (torr at Density No.
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From page 99... ...
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 2-4week (wk)
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Monoamine oxidases (MAOs) , flavin-containing monooxygenases (FMOs)
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Available data on the metabolism of alkylamines relevant to spacecraft water exposure guidelines (SWEGs) are presented below.
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The formation of aliphatic N-oxide is representative of FMO metabolism of xenobiotic amines. The semicarbazide-sensitive amine oxidase (SSAO)
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. 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)
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. Abbreviations: DMA, dimethylamine; FMO3, flavin-containing monooxygenase isomer 3; MA, methylamine; SSAO, semicarbazide-sensitive amine oxidase; TMA, trimethylamine.
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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.
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. Four healthy men received single oral doses of TMA by gelatin capsule at 300 and 600 mg per capsule (Al-waiz et al.
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(1987c) conducted an experiment to examine the genetic derivation of trimethylaminuria by measuring urinary excretion of TMA and TMAO in two families that each had one member affected by fish-odor syndrome.
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Role of Bacteria in the Production of Endogenous Amines TMA urinary excretions in male Sprague-Dawley rats (125 g body weight) fed a choline-deficient diet for 1 wk decreased only slightly compared with those of animals fed choline-supplemented diets (control)
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Distribution The apparent volume of distribution (during the terminal elimination phase) following a single oral dose of TEA at 25 mg in four male human volunteers was calculated to be 196 L assuming 100% bioavailability (Akesson et al.
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TMA excretion in urine following the fish diet was nine times greater than urinary excretion following the control diet (1.6 μmol per 24 h per kilogram of body weight versus 0.17μmol per 24 h per kilogram of body weight)
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Each rat received a single orogastric dose of either choline chloride or lecithin; each dose delivered 200 mg of free choline base per kilogram of body weight. TMA urinary excretion in dosed animals was more than 200% of that in controls.
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From page 112... ...
Other responses include reproductive or developmental toxicity, statistically significant variations in hepatic enzymes, and amine-induced leucopenia. It is difficult to interpret results of studies that are poorly presented or that reveal adverse health conditions or husbandry of test animals.
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Single dose Rat Smyth et al.
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Single dose Guinea pig Le Din Min 1976 LD50 0.25-4 mL/kg (PA) Single dose Wistar rat, male, 3- No observed effects at 0.25-0.5 mL/kg; Union Carbide 1977 to 4-wk-old death at 1-4 mL/kg; piloerection, eye opacity, fur discoloration, emaciation for one survivor of five dosed at 1 mL/kg 290-300 mg/kg (DBA)
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; transient ataxia and tremors at 150 and intraperitoneal injection 295 mg/kg; TMA at 295 mg/kg increased dead fetuses, caused death in 5 of 11 mice 443 mg/kg (TMA) , Daily for 10 d CD-1 mouse Decreased progeny brain DNA; Guest and Varma intraperitoneal injection (n = 5)
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TABLE 4-2 Continued 116 Treatment Dose of Alkylamine Time Species Toxic Effects Reference In Vitro Studies Culture at 0-2 mM (MA, 48 h CD-1 mouse Decreased yolk-sac diameter, head and Guest and DMA, and TMA) embryos crown rump length, embryonic DNA, Varma 1991 RNA, protein content; decreased fetal survival Culture at 0.75 mM 42 h CD-1 mouse Embryonic growth inhibition (70% of Guest and (TMA)
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. Human urinary excretion of nitrates is rapid and first-order; renal clearance occurs within 24 h of ingestion (Green et al.
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When subjects consumed frozen fish, which contained a quantity of DMA 50-fold higher than that in fresh fish, urinary concentrations of 3-MeAde ranged from 3 to 4 nmol/d. When subjects consumed frozen fish and 325 mg of NaNO3, urinary concentrations of 3MeAde ranged from 2 to 3 nmol/d.
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1982) performed with human volunteers fed test meals containing nitrate and fish concluded that nitrosamine concentrations in urine, blood, and gastric juices were not significantly affected by ingestion of nitrosamine precursors.
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. Amine Induction of Cytosolic Alterations Tertiary amines have been observed to induce cytoplasmic vacuoles in cultured rat urinary carcinoma or rabbit aorta muscle cells (Rorig et al.
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Propylamine (PA) In toxicity studies conducted by the Union Carbide Corporation in 1977, PA was delivered intragastrically to 3- to 4-wk-old male Wistar rats (Union Carbide 1977)
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Five of 15 examined mice developed hepatic nodules; three adenomatous and two trabecular lesions were observed. Two of 17 control mice (treated with distilled water)
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White blood cell counts in MA-dosed animals decreased by 27%, 60%, and 55%, respectively, compared with control animals. All decreases were statistically significant.
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Short-Term Toxicity (6-30 d) CNS Toxicity Trimethylamine TMA administered to CD-1 mice intraperitoneally at 150 or 295 mg/kg once per day from day 1 to day 17 of gestation caused ataxia, shallow and rapid breathing, nasal discharge, and tremors (Guest and Varma 1991)
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From page 125... ...
Female rats receiving TEA at 172 mg/kg were observed to have red blood cell counts at 63% of those in controls. Treated groups of rats averaged 9% lower red blood cell counts than controls.
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Free activity of both enzymes increased significantly, by 60%, when measured as a fraction of total activity. Enzyme Alterations Rabbits and rats orally administered TBA at 6.1 and 4.5 mg/kg, respectively, for 6 mo were observed to have significantly decreased hepatic diamine oxidase activity when compared with control animals (Le Din Min 1976)
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were given a single oral gavage dose of DBA at 100, 160, 250, 400, or 500 mg/kg dissolved in 20 mL corn oil (Putnam et al.
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TABLE 4-3 Summary of Amine Genotoxicity Studies 128 Cytotoxicty Concentration Genotoxicity Exposure Test and Test Metabolic Activation (Mutation Frequency) a Reference Duration Lethal Dose Evaluation Methylamine L5178Y None Distilled water (38)
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Salmonella None and 10% RLI or 0 (water as solvent) , 100, 333, 48 h No toxicity Negative Mortelmans mutagenicity 10% HRL 1,000, 3,333, 10,000 μg/plate et al.
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TABLE 4-3 Continued 130 Cytotoxicty Concentration Genotoxicity Exposure Test and Metabolic Activation (Mutation Frequency) a Reference Test Duration Lethal Dose Evaluation Dimethylamine Saccharomyces None and S9 rat 0 (1.03 convertants/105; 0.40/106 2 h Cell survival S9, negative Galli et al.
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1980 (TA 98, 100) ; Bacillus subtilis; hamster lung fibroblast and rat bone marrow ABS/SCE; silkworm mutation (Continued)
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TABLE 4-3 Continued 132 Cytotoxicty Concentration Genotoxicity Exposure Test and Metabolic Activation (Mutation Frequency) a Reference Test Duration Lethal Dose Evaluation Salmonella None or 10% RLI or 0 (water as solvent)
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Abbreviations: ABS, aberrations; DMSO, dimethylsulfoxide; HLI, hamster liver induced; MLA, mouse lymphoma forward mutation assay; RHI, rat liver induced; SCE, sister chromatid exchange.
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Derived exposures guidelines for target alkylamines should protect against potential genotoxicity resulting from alkylamine ingestion during spaceflight. Developmental Toxicity Methylamine and Trimethylamine MA and TMA were administered to CD-1 mice by ip injection once per day from day 1 to day 7 of gestation (day 0 = day of mating)
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. In male offspring, these decreases persisted through 8 wk after birth; treated animals had 636 μg total brain DNA and 32 mg total brain protein compared with 748 μg total brain DNA and 35 mg total brain protein in controls.
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Human fibroblasts incubated in either 1% or 10% serum without MA or with MA at concentrations up to 20 mM for 23 h demonstrated a 50% decrease in DNA synthesis at 10 mM. Trimethylamine Embryos of CD-1 mice treated with TMA at 0.75 mM exhibited decreased macromolecular synthesis (Guest and Varma 1992)
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The author notes that the tertiary amines with three to four carbons had greater effect on sulfotransferase activity than did the primary or secondary amines, with the exception of DBA. There are currently no data on whether TEA can inhibit human androgen sulfotransferase activity.
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Odor and taste perceptibility are primary concerns for potable water consumed by the space crew. Aversion to odor or taste of drinking water supplies can result in or exaggerate crew dehydration and, consequently, may contribute to diminished crew performance in spaceflight.
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Water-dilution odor thresholds represent the concentrations in water that generate odor thresholds in headspace vapors. Water odor and taste perceptibility thresholds for amines offered by other investigators are included in the table.
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, water-dilution odor thresholds were the preferred chemosensory stimuli used to establish the SWEG values for the alkylamines. Odor perception is presented as a nontoxic chemosensory end point that will prevent or minimize flight-crew dehydration.
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ACs for alkylamine groups were based on odor perception, because developmental toxicity is not considered relevant for space crew. Odor thresholds (Table 4-4)
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Exposure SpaceEnd Point Exposure Data Species and Reference To NOAEL Interspecies Time flight 1 d 10 d 100 d 1,000 d Reproductive NOAEL = 54 Amoore et al. 1978 1 10 1.1 1 -- -- 120 -- toxicity mg/kg Odor Water dilution Humans (Amoore and perception odor threshold Hautala 1983; Trubko 1975; Le Din Min 1976; Baker 1963)
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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)
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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)
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, and Le Din Min (1976) reported water-dilution odor threshold concentrations for monoalkylamines, dialkylamines, and trialkylamines.
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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.
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1982. The acute oral toxicity of isomeric monobutylamines in the adult male and female rat.
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1992. Terotogenic and macromolecular synthesis inhibitory effects of trimethylamine on mouse embryos in culture.
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Le Din Min.
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2000. Methods for Developing Spacecraft Water Exposure Guidelines.
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1951. Range finding toxicity data: List IV.
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: Range Finding Toxicity Studies. TSCA Compliance Audit Program.
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1986. Increase in human exposure to methyl amine precursors of N-nitrosamines after eating fish.
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