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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2 (2007)

Chapter: Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine

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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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-

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

renal clearance. Trimethylaminuria may also occur in cases of vaginitis or cervical cancer (Brewster and Schedewie 1983).

Genetic Predisposition

Al-waiz et al. (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. The two affected family members excreted only 22% and 10%, respectively, of a normal dietary load of TMA as the oxidized metabolite TMAO. Following oral administration of TMA at 300 mg, the affected people excreted only 18% and 5% TMAO, respectively, and were observed to have a prominent fish odor. Healthy individuals given an oral dose of TMA at 600 mg excreted 93% of the dose as TMAO. Parents of the affected family members excreted 95% of a 300 mg TMA dose as TMAO, but when given TMA at 600 mg, TMAO excretion dropped to 79% of the dose and TMA excretion was increased. Urinary excretions of TMAO were normal in other tested family members who did not have the defect but were decreased in a sibling who apparently was also affected.

The occurrence of trimethylaminuria in the general population was investigated in a random population study in which 169 individuals were screened for TMA N-oxidation (Al-waiz et al. 1987c). Two test subjects were observed to be deficient in N-oxidation, and upon challenge with TMA at 600 mg (oral route assumed), those subjects were determined to be carriers of the N-oxidation impairment allele. Based on this evaluation, approximately 1% of the population may be carriers of the genetic defect purportedly associated with trimethylaminuria. Several genetic polymorphisms have been shown to modulate the activity of human FMO3 (Akerman et al. 1999a, b; Cashman et al. 2000). Modulated FMO3 activity might result in less severe symptoms of trimethylaminuria. There is also evidence that heterozygotes are subject to N-oxidation saturation when challenged with increased loads (for example, 600 mg) of TMA (Ayesh and Smith 1992).

Psychosocial Effects

Trimethylaminuria is not harmful, but affected persons might experience serious psychosocial problems as a direct result of the disorder

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

(Al-waiz et al. 1987c). The highly objectionable body odor associated with trimethylaminuria can be destructive to the personal, social, and work life of affected individuals. Those individuals undergo personal distresses, including social isolation, ridicule, and rejection, and medical or psychological misdiagnosis (Ayesh et al. 1993).

Relevance to Crew Operations

Expression of trimethylaminuria should be revealed in the physical and clinical evaluation of potential spacecraft crew. Mild presentations of the anomaly might exist in some crew members but should not adversely impact flight operations or the performance of affected crew, provided that crew health is otherwise adequate. Malodor can be managed by reduction or elimination of foods that contain TMA or its precursors (Ayesh et al. 1993).

Triethylamine

TEA is metabolized into TEAO by N-oxidation resulting from intestinal bacteria activity (Akesson et al. 1989). Akesson et al. (1989) established that humans given oral doses of TEA at 25 mg (248 µmol) produced DEA at less than 0.5% of the dose in urine samples obtained 8-14 h after administration. The authors concluded that DEA was generated via microbial activity within the gastrointestinal (GI) tract, absorbed, and then excreted in the urine. TEAO in urine samples averaged 33% of the orally administered TEA dose.

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) (Ziesel et al. 1985). Urinary excretion of TMA in choline-deficient rats was 2 µmol/kg per 24 h, whereas excretion was 2.5 µmol/kg per 24 h in control rats. MA urinary excretions in choline-deficient animals were comparable to those in choline-supplemented animals. These results suggest that TMA and MA are formed endogenously from sources other

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

than dietary choline. In this same study, rats with no bacterial colonization of the bowel (germ-free) exhibited markedly decreased urinary excretion of TMA and MA in a 24-h collection period compared with control animals. MA urinary excretion decreased from 40 µmol/kg per 24 h (controls) to 16 µmol/kg per 24 h (germ-free animals). TMA excretion decreased from 5 µmol/kg per 24 h (controls) to 0.7 µmol/kg per 24 h. These results suggest that both TMA and MA are formed via action of bacteria within the gut.

Absorption
Triethylamine

Human volunteers who received oral doses of TEA demonstrated absorption of >90% from the GI tract (Akesson et al. 1989). Four men received a single oral dose of TEA at 25 mg (248 µmol) dissolved in 15 milliliters (mL) of 0.1 M hydrochloric acid and adjusted to a pH of 7.0. Greater than 90% (90-97%) of orally administered TEA was recovered as TEA and its metabolite TEAO in the urine. TEAO recovered in the urine corresponded to an average of 33% of the dose.

Trimethylamine

Radioactive [14C]-TMA hydrochloride was administered to female adult rats as a single oral dose at 15 mg/kg (Al-waiz and Mitchell 1991). This study demonstrated GI absorption of orally ingested TMA followed by rapid removal of the dose via urinary excretion. More than 75% of the administered radioactivity was excreted in the urine within 24 h after dosing. Up to 9% of radioactivity was detected in the feces.

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. 1989).

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×
Excretion

Amines are normal constituents of mammalian wastes, including urine, feces, and exhaled air. Sources of normal urinary and fecal aliphatic amine levels include both dietary intake and endogenous production of amines. Aliphatic amines normally excreted in urine include MA, ethylamine (EA), DMA, and TMA; DMA is the major constituent (Asatoor and Simenhoff 1965). Ziesel et al. (1983) report that humans excrete approximately 1 mmol each of MA, DMA, and TMA per day in their urine following consumption of a normal diet; however, amine excretion varies with diet.

Methylamine and Trimethylamine

MA and TMA were excreted in the urine of five healthy subjects (one male, four female), ages 23 to 35, after ingestion of restricted diets containing known amounts of the amines (Zeisel and deCosta 1986). Subjects were given diets without fish for 2 d (control diet), diets containing fish for 1 d, and the control diet for the final day. In urine samples collected in 24-h blocks, excreted MA amounts were comparable throughout the experiment regardless of dietary content. 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). TMA urinary excretion remained elevated at 0.86 µmol per 24 h per kilogram of body weight on the day after the fish was eaten (five times greater than that on control days). Zeisel and deCosta (1986) suggest that TMA in the fish was absorbed from the intestine into the blood and then excreted in urine. TMA was not detected in the diet that did not contain fish.

Rabbits were maintained on a diet of carrots and given TMA hydrochloride dissolved in water intragastrically at unspecified intervals. TMA hydrochloride dosing concentrations were 0.3-0.6 g per rabbit (Langley 1929). Between 4% to 20% of ingested TMA was excreted unchanged, and 80-96% was excreted as other substances, including varying amounts of ammonia and urea and insignificant amounts of DMA.

Three male volunteers were administered a single oral dose of 62 mg of [14C]-TMA hydrochloride dissolved in water (Al-waiz et al. 1987b). Excretion patterns demonstrated rapid absorption. Urine was the

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

primary route of excretion. Within 6 h of treatment, 84% of the administered dose was recovered, and 95% was recovered by 24 h. TMAO was the major metabolite of the administered TMA, accounting for greater than 95% of the given dose in the excreted urine.

[14C]-TMA administered orally in aqueous solution to adult female rats at 15 mg/kg was excreted primarily in the urine (Al-waiz and Mitchell 1991). Over 75% of the dose was excreted in the urine within 24 h of dosing. Up to 9% of the dose was detected in the feces. Approximately 45% of the TMA dose was excreted as TMAO, 3% as DMA, and the remaining dose as unchanged TMA.

Triethylamine

Following an oral dose of TEA at 248 µmol in four healthy male humans, the plasma half-life of TEA ranged from 2.4 to 3.5 h and the urine half-life ranged from 2.5 to 3.0 h (Akesson et al. 1989). The plasma clearance following oral TEA administration ranged from 41.2 to 50.7 L/h. Nonrenal clearance ranged from 23.3 to 31.6 L/h. Renal clearance following oral exposure to TEA averaged 28.6 L/h.

Methylamine, Dimethylamine, and Trimethylamine

Fourteen healthy human subjects were found to excrete approximately 1 mmol each of MA, DMA, and TMA per day after ingesting a normal diet (Zeisel et al. 1983). Following a single oral dose of 27 mmol (3.5 g) of choline chloride (in orange juice), human subjects (n = 6) excreted MA and DMA at 2 mmol/d and TMA at 17 mmol/d. After consumption of 27 mmol (10.2 g) of choline stearate in orange juice, six subjects excreted DMA at 1.2 mmol/d and TMA at 9.3 mmol/d. Five subjects who ingested 27 mmol (20 g) of lecithin excreted DMA at 1.7 mmol/d and TMA at 3.8 mmol/d; There was no increase in MA excretion. In this same study, Sprague-Dawley rats were maintained on choline-free diets. 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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TOXICITY SUMMARY

There are no studies available on human oral toxicity for the targeted group of alkylamines. Limited animal toxicity studies have been conducted with MA, propylamine (PA), n-butylamine (BA), diethylamine (DEA), DMA, di-n-butylamine (DBA), TMA, TEA, and tributylamine (TBA). The studies discussed in this document, some of which were conducted prior to general acceptance of good laboratory practice guidelines, lacked descriptive information on experimental proceedings, such as methods of oral administration and designation of animal strain and physical condition. At least one study that did not achieve peerreviewed publication is included, but it presents an investigation of mammalian toxicity employing the preferred oral route of administration and the targeted compounds. Also, because of the rapid absorption characteristics of alkylamines, studies employing ip amine administration to test subjects are discussed.

On the basis of existing data, mammalian toxicity to alkylamines appears to consists of adverse central nervous system (CNS) effects, including tremors, convulsions, and lethargy. 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. There are no data available on the oral toxicity of ethylamine (EA), isopropylamine (IPA), or tripropylamine (TPA) beyond the LD50s (concentrations lethal to 50% of subjects). A toxicity summary is presented in Table 4-2.

Formation of N-Nitroso Compounds

The in vivo formation of N-nitroso compounds from reaction of amines and nitrite has been investigated relative to the toxicologic importance of nitrosamines in the development of human cancer. In vivo formation of nitrosamines may occur in the stomach or in other parts of the GI tract. Salivary nitrites react with various amines in the stomach (L’hirondel 1999), where favorable acid conditions (pH of 2-4) for the formation of nitrosamines prevail (Klaassen 1996). In vivo formation of nitrosamines is obviously affected by the dietary intake and the pharmacokinetics of both amines and nitrates (or nitrites). Dietary sources of

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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TABLE 4-2 Toxicity Summary

Dose of Alkylamine

Treatment Time

Species

Toxic Effects

Reference

Acute Exposures (1-5 d)

100 mg/kg (MA)

Single dose

Rat

LD50

Kinney et al. 1990

400 mg/kg (EA)

Single dose

Rat

LD50

Smyth et al. 1954

570 mg/kg (PA)

Single dose

Rat

LD50

Smyth et al. 1962

820 mg/kg (IPA)

Single dose

Rat

LD50

Smyth et al. 1951

3,200 mg/kg (IPA)

Single dose

Rabbit

LD50

Lewis 1996

2,700 mg/kg (IPA)

Single dose

Guinea pig

LD50

Lewis 1996

500 mg/kg (BA)

Single dose

Rat

LD50

Smyth and Carpenter 1944

371 mg/kg (BA)

Single dose

SD rat

LD50

Cheever et al. 1982

430 mg/kg (BA)

Single dose

Mouse

LD50

Lewis 1996

430 mg/kg (BA)

Single dose

Guinea pig

LD50

Lewis 1996

698 mg/kg (DMA)

Single dose

Rat

LD50

Dzhanashvili 1967

316 mg/kg (DMA)

Single dose

Mouse

LD50

Dzhanashvili 1967

240 mg/kg (DMA)

Single dose

Guinea pig and rabbit

LD50

Dzhanashvili 1967

540 mg/kg (DEA)

Single dose

Rat

LD50

Smyth et al. 1951

500-600 mg/kg (DEA)

Single dose

Mouse

LD50

Patel et al. 1985

550 mg/kg (DBA)

Single dose

Mouse

LD50

Smyth et al. 1954

290 mg/kg (DBA)

Single dose

Mouse

LD50

Trubko 1975

230 mg/kg (DBA)

Single dose

Guinea pig

LD50

Trubko 1975

500 mg/kg (TMA)

Single dose

Rat

LD50

Kinney et al. 1990

546 mg/kg (TMA)

Single dose

Mouse

LD50

Kinney et al. 1990

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Dose of Alkylamine

Treatment Time

Species

Toxic Effects

Reference

460 mg/kg (TEA)

Single dose

Rat

LD50

Smyth et al. 1951

546 mg/kg (TEA)

Single dose

Mouse

LD50

Kagan 1965

96 mg/kg (TPA)

Single dose

Rat

LD50

Smyth et al. 1969

340 mg/kg (TBA)

Single dose

Rat

LD50

Monsanto Co. 1992

455 mg/kg (TBA)

Single dose

Rat

LD50

Le Din Min 1976

114 mg/kg (TBA)

Single dose

Mouse

LD50

Le Din Min 1976

615 mg/kg (TBA)

Single dose

Rabbit

LD50

Le Din Min 1976

350 mg/kg (TBA)

Single dose

Guinea pig

LD50

Le Din Min 1976

0.25-4 mL/kg (PA)

Single dose

Wistar rat, male, 3-to 4-wk-old

No observed effects at 0.25-0.5 mL/kg; death at 1-4 mL/kg; piloerection, eye opacity, fur discoloration, emaciation for one survivor of five dosed at 1 mL/kg

Union Carbide 1977

290-300 mg/kg (DBA)

Single dose

Mouse and rat

GI fatty infiltration and local irritation

Trubko 1975

230 mg/kg (DBA), intragastric

Single dose

Guinea pig

GI fatty infiltration and local irritation

Trubko 1975

100, 160, 250, 400, or 500 mg/kg (DBA), gavage

Single dose

ICR mouse (five per gender per group)

Lethargy at 100-400 mg/kg; convulsions at 500 mg/kg; death in two of five females at 250 mg/kg, five of five females at 400 and 500 mg/kg, and five of five males at 500 mg/kg

Putnam et al. 1995

0.7-2 cm3/kg (DBA), intragastric

Single dose

Rabbit (n = 6)

Death at 1-2 cc/kg; increased reflex, convulsions at 0.7 cc/kg

Hanzlik 1922

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

10-20 mg (TEA), intragastric

Single dose (1 per day for 3 d)

Rabbit (n = 6), 3.35 kg

Decreased formation of normal blastocysts

Chang 1964

500-600 mg/kg (BA), gavage

Single dose

Sprague-Dawley rat, male and female

Ataxia, convulsions

Cheever et al. 1982

50 mg/kg (DEA), intragastric

Single dose

Mice (n = 15), male

Hepatic nodules in 5 of 15

Rijhsinghani et al. 1982

Short-Term Exposures (6-30 d)

7.8, 31, 78, 155 mg/kg (MA); 15, 59, 150, 295, mg/kg (TMA); intraperitoneal injection

Daily for 17 d

CD-1 mouse (n = 6-11)

Abdominal contractions lasting 3-10 min at maximal doses; TMA induced transient ataxia and tremors at 150 and 295 mg/kg; TMA at 295 mg/kg increased dead fetuses, caused death in 5 of 11 mice

Guest and Varma 1991

443 mg/kg (TMA), intraperitoneal injection

Daily for 10 d

CD-1 mouse (n = 5)

Decreased progeny brain DNA; decreased serum testosterone; adverse male postnatal growth

Guest and Varma 1993

Subchronic Exposures (30-180 d)

54, 105, 210 mg/kg/d (TMA), diet

90 d

Sprague-Dawley rat, (n = 5-6), male, 4-wk-old

33-50% reduction in seminal vesicle weight at highest dose

Amoore et al. 1978

Chronic Exposures (0.5-3 y)

400 mg/kg/d (DMA), diet

9 mo

Wistar rat (n = 30), male

Increased lipid peroxidation as indicated by higher MDA production, 19% over controls; 60% increase in lysosomal enzymes

Darad et al. 1983

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Dose of Alkylamine

Treatment Time

Species

Toxic Effects

Reference

In Vitro Studies

Culture at 0- 2 mM ( MA, DMA, and TMA)

48 h

CD- 1 mouse embryos

Decreased yolk- sac diameter, head and crown rump length, embryonic DNA, RNA, protein content; decreased fetal survival

Guest and Varma 1991

Culture at 0.75 mM ( TMA)

42 h

CD- 1 mouse embryos

Embryonic growth inhibition ( 70% of controls) ; neural tube defects in 73% of embryos; 60% decrease in DNA and RNA content

Guest and Varma 1992

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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nitrates and nitrites include vegetables, drinking water, and cured meats. Nitrates are also produced endogenously when extracellular nitrogen monoxide combines with oxygen to form nitrates, nitrites, and nitrosamines; production is increased by various physiologic and pathologic conditions (L’hirondel 1999). Dietary sources of amines include fish, an array of edible plants, dairy products, boiled beef, and a variety of beverages. Nitrosamines are found in foods such as cured meats and oils (Lijinsky 1976; Lijinsky 1980).

Human urinary excretion of nitrates is rapid and first-order; renal clearance occurs within 24 h of ingestion (Green et al. 1981). Nitrate ions that reach the stomach intact (that is, that escape bacterial conversion to nitrites) are not involved in nitrosamine formation (L’hirondel 1999). It is the nitrite that is the source of the “nitroso” group for nitrosamines formed in vivo from secondary amines (Klaassen 1996). Approximately 5% of ingested nitrate is converted to nitrite (Vermeer et al.1998). Nitrites in saliva arise from the reduction of nitrate in food or water by bacteria in the mouth (Lijinsky 1976; Tenovuo 1986). Salivary nitrites, upon swallowing, react with various amines in the stomach to form nitrosamines (L’hirondel 1999).

Endogenous formation of N-nitrosodi-n-butylamine (NDBA) was studied to examine butylated hydroxyanisole inhibition of DBA nitrosation in rats (Airoldi et al. 1987). Rats given three doses of DBA at 50 mg/kg perorally at 8-h intervals along with one 1.4 mg dose of sodium nitrate (NaNO3) reportedly excreted 0.085 nanomoles (nmol) of the NDBA metabolite N-butyl-n-(3-carboxypropyl)nitrosamine (BCPN) in a 24-h post-dose urine sample. A second set of rats given DBA at 10 µmol and NaNO2 at 20 µmol in 1 mL of DMSO twice at 12-h intervals was observed to excrete 0.213 nmol of BCPN in a 24-h postdose urine sample. Administration of DBA alone did not result in urinary BCPN excretion. Animals in this study are assumed to have received standard dietary feedings in addition to dose chemicals. In vitro nitrosation of DBA was tested utilizing an incubation medium containing DBA at 10 mM and NaNO2 at 20 mM (alone or together with varying concentrations of BHA). The percentage of in vitro nitrosated DBA was 22.5%; in vivo nitrosation of DBA was measured at 0.005% in the animal experiments. The authors concluded that the comparatively smaller amount of DBA nitrosation in the in vivo study might be attributed to the limited period of DBA and/or nitrite in the stomach. The authors also noted that observed nitrosation in dosed animals might have occurred in other parts of the gastric tract.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Relative to amine-induced tumor formation, DEA and TMAO fed to rats in combination with nitrite for 1-2 years (y) did not induce excess tumor formation (Lijinsky 1980; Lijinsky and Taylor 1977). Fifteen male and 15 female Sprague- Dawley rats were given 0.1% amine (average) and 0.2% NaNO2 in 60 mL of water 5 d/wk for 2 y. Results of this study indicate that insufficient nitroso compounds were formed to induce tumors, although it is possible that nitroso formation occurred. To date, there are no studies that suggest that the target alkylamines are carcinogenic by reaction of ingested amines and nitrates or nitrites.

Human volunteers (eight males), ages 22-50, who were nonsmokers and free of medications were evaluated for urinary excretion of 3methyladenine (3-MeAde), a biomarker used to assess endogenous formation of NDBA or other methylating agents that induce genetic damage by alkylation of DNA (Fay et al. 1997). Urinary levels of 3-MeAde varied, ranging from 8 to 150 nmol/d when volunteers consumed freechoice diets. Basal concentrations of 3-MeAde at 2-3 nmol/d were recorded when subjects consumed a controlled liquid diet. Urinary concentrations of 3-MeAde increased slightly when subjects consumed fresh or frozen fish; however, that increase was attributed to preformed 3-MeAde in the fish itself. 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. From these results, the authors suggest that endogenous formation of N-nitrosodimethylamine (NDMA) from DMA is insignificant. The authors concluded that exposure to endogenously formed NDMA from dietary DMA in frozen fish appears negligible when compared with exposure from preformed dietary N-nitroso compounds. The authors also suggested that their findings indicate minimal health risk concerns in humans consuming high concentrations of DMA in various foods.

Acceptable daily intake (ADI) guidelines for nitrate and nitrite have been set by the World Health Organization (WHO) at 3.67 mg/kg and 0.13 mg/kg, respectively (Vermeer et al. 1998). Twenty-five healthy women (nonsmokers and medication free) who had an average weight of 60 kg were evaluated for nitrosamine formation (Vermeer et al. 1998). During control weeks, subjects received low-nitrate diets. During test weeks, subjects received an ADI nitrate load (220 mg/d) combined with meals of fish (high amounts of amines), including cod, salmon, shrimp, and pollack. NDMA and N-nitrosopiperidine (NPIP) were detected in multiple 24-h urine samples. The mean NDMA urinary excretion during

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

control weeks was 287 nanograms (ng) per 24-h sample, and the mean during test weeks was 871 ng per 24-h sample. This study concluded that nitrosamine formation increases during nitrate intake in combination with meals of fish. The authors of this study did not evaluate preformed nitrosamine concentrations in the test meals consumed by the subjects.

A separate study (Lakritz et al. 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. Yamamoto et al. (1980) measured blood nitrosamines in eight human subjects fed a Japanese diet rich in nitrate and amines. There were no observed increases in nitrosamine concentrations in the blood samples of test subjects.

In vivo formation of nitrosamines in humans was observed following subjects’ ingestion of a bacon, lettuce, and tomato sandwich and beer (Fine et al. 1977). NMDA concentrations increased from 2 µg before the meal (in a blood volume of 6 L) to 4.4 µg 35 minutes (min) after the meal. NMDA concentrations in blood prior to the meal indicate the presence of background concentrations of nitrosamines. Fine et al. (1977) also observed that when volunteers maintained diets low in nitrite and nitrate and high in ascorbate for 24 h prior to the meal, NMDA could not be detected in their blood.

L’hirondel (1999) asserts that the amounts of nitrosamines formed in the stomach during the metabolism of nitrates are miniscule and are not capable of increasing the incidence of cancer in humans. There are no studies (in rats or mice) that have proved that sustained intake of nitrates results in an increased incidence of cancer. The author maintains that the amount of nitrosamines formed in the stomach during the metabolism of nitrates is several tens of thousands times smaller than the potential toxic concentration.

Prediction of in vivo formation of nitrosamines is difficult because of affecting factors, including reaction conditions in the stomach, nitrite and amine concentrations, and types of amines available (Lijinsky 1980). However, because formation of nitrosamines has been demonstrated in humans and because it is impossible to establish a “safe” dose for carcinogens (Lijinsky 1976), prudence in dietary consumption of foods containing nitrates or nitrites is recommended for spacecraft crew. On the basis of the above observations and deductions, it can be reasonably argued that there is minimal risk of amine nitrate- or nitrite-induced cancer for astronauts relative to that posed by orally ingested amines. Preformed dietary nitrosamines would be of greater concern, but it has been determined that the concentrations of direct dietary nitrosamine intake in a

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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normal diet is several hundreds of times lower than potentially toxic levels (i.e., the no-observed-adverse-effect concentrations [NOAELs] for ingested nitrosamines in animals) (L’hirondel 1999).

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. 1987). Aliphatic diamines and the bis-tertiary amines were both potent inducers of clear cytoplasmic vacuoles (CCV). The cationic moiety (the highly basic or protonated amine component with hydrophilic properties) of amphiphilic amine drugs and chemicals employed in a study by Ruben et al. (1993) was determined to be responsible for the induction of CCV. Ruben suggests a complimentary link between the basicity of the cationic moiety of amphiphilic amines and the storage of such drugs in cytoplasmic acidic vesicular compartments. Entrapped protonated amines cause an osmotic swelling of lysosomes, resulting in the morphologic manifestation of CCV (De Duve et al. 1974). A moiety of an anti-arrhythmic cationic amphiphilic bis-tertiary amine drug that had pKa’s for each amine of >8.0 was determined to be a highly potent vacuole inducer (Rorig et al. 1987). Most of the target alkylamines of this document have pKa’s of 10 or greater at 25­°C (see Table 4-1). These amines will be positively charged at a pH of less than 10. On the basis of chemical equilibrium considerations, at a physiologic pH of 7.4 there is a fraction of amine that has no charge that can pass through membranes, although the charged species cannot. In principle, alkylamines can employ this equilibrium behavior to distribute between acidic vesicles and areas of the cell that have a higher pH.

Chemical induction of CCV, as in the case of cationic amphiphilic amine drugs, indicates intracellular storage (Ruben 1987; Ruben et al. 1989; Burmester et al. 1990). Vacuolated cells did not show evidence of cell degeneration, such as dysplasia, atrophy, functional impairment, release of lactic dehydrogenase, or other ultra-structural cellular alterations, whether in whole animal or cultured mammalian cells. From these studies, it can be concluded that vacuolar induction is a sign of intracellular storage, is within the physiologic limits of cells, and is not associated with overt toxicity. There are no data describing vacuolar induction or other cellular alterations by the target alkylamines.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Acute Toxicity (1-5 d)
Lethality and General Toxicity

Several independent studies have demonstrated the lethality of intragastrically administered alkylamines.

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). Three of three rats that received a 4 mL/kg dose died within the hour. Five of five rats dosed with 2 mL/kg died within 1 d. One of five rats survived a dose of 1 mL/kg. Exposure symptoms of the survivor included piloerection, bloody urine, emaciation, discoloration of fur, and bilateral lens opacity to complete eye opacity. Pathology of animals receiving lethal doses included petechial to diffuse hemorrhages of the lungs, stomach and intestinal distention, intestinal discoloration, and prominent acini of the liver. Five rats per group dosed with 0.5 mL/kg or 0.25 mL/kg exhibited no symptoms of toxicology, although one death occurred in the 0.5 mL/kg group.

Di-n-butylamine (DBA)

DBA was administered in a single dose by oral gavage to 6- to 8wk-old male and female ICR mice weighing between 24 and 38 g (Putnam et al. 1995). In the toxicity assay of this study, mice received doses ranging from 100 to 500 mg/kg. Mortality, which occurred within 2 d of dosing, was observed in female and male mice receiving 250 mg/kg and in all dosed animals receiving 400 mg/kg or greater. Clinical manifestations included lethargy and, at the highest dose of 500 mg/kg, convulsions in both male and female mice.

Six rabbits received intragastric dosages of DBA at 1-2 cubic centimeters (cm3) per kilogram body weight (Hanzlik 1922). Death occurred in all dosed animals within 6 min of dosing. Clinical symptoms associated with dosing included increased reflex excitability and increased

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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pulse and respirations followed by convulsions, coma, and eventual death.

Hepatotoxicity

Thirty C57BL × C3H F1 male mice were administered a single intragastric dose of DEA at 50 mg/kg dissolved in distilled water to assay induction of hepatic nodules (Rijhsinghani et al. 1982). Mice were sacrificed between 70 and 110 wk after dosing. 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) developed trabecular lesions.

GI Toxicity

Pathomorphologic examination of the internal organs of animals that were administered intragastric doses of DBA at 290-300 mg/kg (mice and rats) and 230 mg/kg (guinea pigs) revealed fatty infiltration, changes indicating local GI irritation, and signs of necrotic liver damage (Trubko 1975). Further experimental methods were not stated.

Reproductive Toxicity

Rabbits (six) were intragastrically fed TEA at 10 or 20 mg 1, 2, and 3 d following artificial insemination to examine the effectiveness of mammalian antifertility agents (Chang 1964). Animals were sacrificed on day 6 of the experiment, and calculation of normal blastocysts was based on the number of corpora lutea. Dosing at 10 and 20 mg produced uterine blastocysts totaling 29% and 12% of corpora lutea. Normal blastocysts in untreated animals were 89% of total corpora lutea. Results indicate that TEA is effective in preventing the development of rabbit ova into normal blastocysts. Chang (1964) suggests that TEA inhibits the normal mechanism of blastocyst implantation into the endometrium; however, data presented in this study do not verify that.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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CNS Toxicity

Di-n-butylamine

Five male and five female ICR mice were dosed with DBA at 100, 160, 250, 400, or 500 mg/kg dissolved in 20 mL corn oil; dosing was by a single oral gavage (Putnam et al. 1995). Lethargy occurred in both male and female mice at 100, 160, 250, and 400 mg/kg. Convulsions were observed in male and female mice at the 500 mg/kg dose. Additional testing to assess the clastogenic potential of DBA by increased incidence of micronucleated polychromatic erythrocytes in bone marrow produced negative results.

n-Butylamine

BA was administered by gavage to male and female weanling Sprague-Dawley rats at 100, 200, 300, 400, 500, and 600 mg/kg in corn oil (Cheever et al. 1982). Animals were observed for mortality and toxicity for 14 d following dosing. Signs of toxicity included sedation, ataxia, nasal discharge, gasping, and salivation. Convulsions and death were observed at higher doses (amount not specified). Further description of toxic response was not presented. An LD50 of 371 mg/kg was calculated for BA.

Other Adverse Acute Effects

Methylamine-Induced Leucopenia

Five B6C3F1 female mice were dosed daily with MA at 122, 489, or 978 mg/kg in Hanks balanced salt solution via intraperitoneal injection for 5 d to assess the immunologic effects of the decomposition products of the agricultural pesticide sodium methyldithiocarbamate (Keil et al. 1996). Suppression of immune parameters in dosed animals was assayed to include decreases in natural killer cell activity, spleen and thymus weight, lymphocytes, and specific thymocytes. White blood cell counts in MA-dosed animals decreased by 27%, 60%, and 55%, respectively, compared with control animals. All decreases were statistically significant. White blood cell differentials revealed no change in proportional

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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leukocyte cell types resulting from this study. No further adverse immunologic effects measured in this study were induced by MA.

Enzyme Alterations

Di-n-butylamine Doses of one-fifth and one-twentieth the LD50 (58 mg/kg and 14.5 mg/kg) administered to white mice caused decreased hepatic diaminoxidase activity (Trubko 1975). The route of administration in this study was not clarified.

Dimethylamine Male Swiss albino CD-1 mice and Sprague-Dawley rats were treated with DMA at 25 or 50 mg/kg by a single ip injection or for 3 consecutive days (Galli et al. 1993). Monooxygenase activities, including ethoxyresorufin O-deethylase (EROD), pentoxyresorufin O-dealkylase (PROD), p-nitrophenol hydroxylase (pNPH), and aminopyrine n-demethylase (APD), were monitored for amine effects on hepatic oxidative enzymes. Significant inhibitory effects were induced by DMA. Reductions in EROD, PROD, and pNPH resulted in levels that ranged from 54% to 86% of controls for the single ip injections at 50 mg/kg. For 3-d repeated dosing, enzyme reductions resulted in levels ranging from 36% to 75% of controls. Single injections at 25 mg/kg induced a 17-47% reduction in activity of the hepatic enzymes PROD, EROD, and pNPH. Multiple injections at 25 mg/kg induced a 28-57% reduction. There were no significant alterations in the expression of ADP enzymes.

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). Those effects persisted for 10 min; complete recovery was observed within 20 min.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Triethylamine

In short-term experiments using white mice perorally administered TEA (doses not given), marked CNS effects were observed (Kagan 1965). Physical signs of CNS toxicity included increased excitability replaced by inhibition, disturbances in the coordination of movements, and clonic spasms. Further experimental details were not presented.

In a non-peer-reviewed study, 3-month (mo)-old albino rats grouped in tens (five male and five female) were administered TEA intragastrically at 0, 5, 15, 30, and 60 mg three times per week for 6 wk (Davison et al. 1965). TEA doses were 14, 43, 86, and 172 mg/kg, respectively. 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. This decrease was attributed to hemorrhaging of the stomach lining, which was revealed upon necropsy. White blood cell count, differential cell counts, and sodium and potassium values were within control levels. At 30 mg (86 mg/kg), rats exhibited convulsions and abnormal balance and tail wringing when disturbed. These symptoms disappeared 6-8 h after dosing. Rats given TEA at 60 mg (172 mg/kg) exhibited marked convulsions. Symptoms included extended periods of hunching, odd posturing, lethargy, violent head shaking, tail wringing, and tremors. Convulsions were most severe in females, and death occurred only in females. An evaluation of the significance of observed changes in dosed rats was not presented. Additional pathology upon examination of lung tissue and kidneys revealed the presence of pneumonia, to which the author attributes the excess animal mortality occurring in the study. The results of this study are difficult to interpret because of the adverse health status of test animals.

Subchronic Toxicity (30-180 d)
Reproductive Toxicity

Groups of five or six male Sprague-Dawley rats were fed daily doses of TMA at 27, 54, 105, or 210 mg/kg for 90 d (Amoore et al. 1978). The maximum concentration of TMA administered in the diet that was not incompatible with normal food consumption and growth was 54 mg/kg. That dose was hence affirmed to be the no-adverse-effect level

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

(NAEL) for TMA for this study. Rats administered the highest dose of 210 mg/kg (four times the NAEL level) were observed to have 33-50% reductions in seminal vesicle weights compared with controls. No data specific to pathologic or physiologic changes were presented for animals that received the 105-mg/kg dose.

Enzyme Alterations

Rabbits dosed with DBA at 7.6 mg/kg for 6 wk exhibited a 47% increase in serum glutamic oxalate and a 36% increase in glutamic pyruvic transaminase (Trubko 1975). The maximal response was observed in week 14 of the experiment; a return to normal enzymatic activity levels was observed by week 21 of observation. The route of administration was not clarified. Other data defining the quality of experimental methods are not presented in the study.

Chronic Toxicity (0.5-3 y)
Hepatotoxicity

In vitro microsomal lipoperoxidation and hepatic lysosomal enzyme activity were studied for toxic response in male Wistar rats administered DMA (Darad et al. 1983). DMA was administered to 30 rats at a concentration of 0.2% in drinking water for 9 mo. The DMA dose per rat was 400 mg/kg/d. Hepatic microsomal lipoperoxidation was assayed by malondialdehyde formation. DMA caused significantly higher peroxidation in rat liver microsomes, eliciting 19% greater malondialdehyde formation than in controls. DMA increased free activities of cathepsin by 32% over controls and of acid phosphatase by 11% over controls. 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). Diamine oxidase activity in dosed animals was measured

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

at 48% of the activity in control animals. In addition, serum amine oxidase activity was observed to decrease to below 30% of the baseline value. Values of other measured parameters, including differential cell counts, were stated as not significantly distinct from those of control animals. It is unclear whether the author conducted this study or results were obtained from other studies.

Genotoxicity

The evaluated alkylamines (MA, EA, PA, IPA, BA, DMA, DEA, DBA, TMA, TEA, TBA) were negative for induction of point mutations with and without hamster or rat Aroclor-induced S9 fraction in Salmonella typhimurium mutagenic assays (Mortelmans et al. 1986; Zeiger et al. 1987). Tested alkylamines were negative in other mutagenicity tests that employed prokaryotic systems (Table 4-3).

DMA was positive for induction of a dose-dependent increase in mitotic gene conversion and point reverse mutation in the mutagenic assay employing the D7 strain of Saccharomyces cerevisiae (Galli et al. 1993). The authors attributed the positive results, which occurred in the presence of S9 fraction to formaldehyde, to the primary DMA metabolite.

Mammalian genotoxicity assays of DBA yielded both positive and negative results. DBA was positive for induction of sister chromatid exchanges in Chinese hamster cells (Abe and Sasaki 1977). Cell type or other experimental data for this study are not presented. When tested for chromosomal aberrations using Chinese hamster lung fibroblasts, DBA was evaluated as negative for mutagenicity, although it was judged “suspicious” in accordance with the authors’ experimental criteria of 5-5.9% greater occurrence of chromosomal aberrations than controls (<3%) (Ishidate and Odashima 1977). In an unpublished study, male and female ICR mice (five per gender per dose) 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. 1995). The results of an assessment of the clastogenic potential of DBA by induction of increased incidence of micronucleated polychromatic erythrocytes in bone marrow were concluded to be negative. DBA was also negative for chromosomal aberrations in human embryo and hamster lung fibroblasts and in rat bone marrow cells in genotoxicity assays conducted in separate studies (Kawachi et al. 1980).

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 4-3 Summary of Amine Genotoxicity Studies

Test

Metabolic Activation

Concentration (Mutation Frequency)a

Exposure Duration

Cytotoxicty Test and Lethal Dose

Genotoxicity Evaluation

Reference

Methylamine

L5178Y MOLY forward mutation assay

None

Distilled water (38) (average of three cultures) 0.65, 1.3, 1.95, 2.6b mM (negative) 3.9 mM (57) 5.2 mM (57)

4 h

3.9 mM

Positive

Caspary and Myhr 1986

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None and 10% RLI or 10% HLI Aroclor 1254 S9 fraction

0 (water as solvent) 33, 100, 333, 1,000, 3,333, 10,000 µg/plate (negative)

48 h

No toxicity

Negative

Mortelmans et al. 1986

Salmonella mutagenicity (TA 98, 100, 104)

(5%, 15%, 30%) S9 fraction Aroclor 1254

0 (DMSO as solvent) 0.0368, 0.368, 0.736, 14.72, 29.44 mg/plate (negative)

48 h

29.4 mg/plate

Negative

Meshram et al. 1992

Ethylamine

Paper-disk E. coli reversion to streptomycin independence

None

0.01-0.025 mL solution or small crystals

Not given

No data

Negative

Syzbalski 1958

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None and 10% RLI or 10% HRL Aroclor 1254 S9 fraction

0 (water as solvent), 100, 333, 1,000, 3,333, 10,000 µg/plate (negative)

48 h

No toxicity

Negative

Mortelmans et al. 1986

Propylamine

Salmonella mutagenicity (TA 98 and 100)

None and Aroclor Hamster S9

10 µL in DMSO per plate (negative)

48 h

No toxicity

Negative

Speck et al. 1982

Isopropylamine

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None and 10% RLI or 10% LHI Aroclor 1254 S9 fraction

0 (water as solvent), 10, 33, 100, 333, 1,000, 3,333, 10,000 µg/plate (negative)

48 h

No toxicity

Negative

Zeiger et al. 1987

n-Butylamine

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None and 10% RLI or 10% HRL Aroclor 1254 S9 fraction

0 (water as solvent), 3.3, 10, 33, 100, 333, 1,000, 3,333 µg/plate (negative)

48 h

No toxicity

Negative

Zeiger et al. 1987

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Test

Metabolic Activation

Concentration (Mutation Frequency)a

Exposure Duration

Cytotoxicty Test and Lethal Dose

Genotoxicity Evaluation

Reference

Dimethylamine

Saccharomyces cerevisiae D7; mitotic genconversion and point reverse mutation

None and S9 rat

0 (1.03 convertants/105; 0.40/106 2 h revertants) 0.5, 1 mM (negative) 2 mMb (3.8-fold increase convertants; 3.5-fold increase revertants) 3 mM (3.8-fold increase convertants; 3.5-fold increase revertants) 4 mM (3.8-fold increase convertants; 3.5-fold increase revertants)

2 h

Cell survival 25% of controls at 4 mM

−S9, negative +S9, positive Genotoxicity results of DMA metabolites

Galli et al. 1993

Salmonella mutagenicity (TA 98, 100, 1535, 1357)

None and 10% RLI 10% HLI Aroclor 1254 S9 fraction

0 (water as solvent) 33, 100, 333, 1,000, 2,000, 3,333, 4,000, 4,500 µg/plate (negative)

48 h

Toxicity at 3,333 µg/plate

Negative

Zeiger et al. 1987

Diethylamine

Salmonella mutagenicity (TA 98, 100, 1535, 1357)

None or 10% RLI 10% HLI Aroclor 1254 S9 fraction

0 (water as solvent) 33, 100, 333, 1,000, 3,333 µg/plate (negative)

48 h

No toxicity

Negative

Zeiger et al. 1987

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Di-n-butylamine

Chinese hamster ABS

None

0 (ethanol) (0.2 breaks per cell) 10−6-10−3 M (in ethanol)

26 h

No data

Negative

Abe and Sasaki 1977

Chinese hamster SCE

None

0 (ethanol) (3.36 SCEs per cell) 10−6-10−3 M (in ethanol) 5 × 10−4 Mb (5.83 SCEs per cell)

26 h

No data

Positive

Abe and Sasaki 1977

Paper-disk E. coli reversion to streptomycin independence

None

0.01-0.025 mL solution or small crystals

Not given

No data

Negative

Syzbalski 1958

Salmonella mutagenicity (TA 98, 100); Bacillus subtilis; hamster lung fibroblast and rat bone marrow ABS/SCE; silkworm mutation

None

Not given

Not given

No data

Negative

Kawachi et al. 1980

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Test

Metabolic Activation

Concentration (Mutation Frequency)a

Exposure Duration

Cytotoxicty Test and Lethal Dose

Genotoxicity Evaluation

Reference

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None or 10% RLI or 10% HLI Aroclor 1254 S9 fraction

0 (water as solvent), 100, 333, 1,000, 3,333, 10,000 µg/plate

48 h

No toxicity

Negative

Mortelmans et al. 1986

Salmonella mutagenicity

−S9/+S9

Not given

Not given

No data

Negative

Sugimura et al. 1977

CHL ABS

None

0.2-15.5 mg/mL in ethanol

48 h

No data

Negative

Ishidate and Odashima 1977

Trimethylamine

Salmonella mutagenicity (TA 98, 199, 1535, 1537)

None or 10% RLI or 10% HLI Aroclor 1254 S9 fraction

0 (water as solvent) 10, 33, 100, 333, 1,000 µg/plate (negative)

48 h

No toxicity

Negative

Mortelmans et al. 1986

Triethylamine

Salmonella mutagenicity (TA 98, 100, 1535, 1357)

None or 10% RLI 10% HLI Aroclor 1254 S9 fraction

0 (ethanol as solvent) 100, 333, 1,000, 3,333, 10,000 µg/plate (negative)

48 h

No toxicity

Negative

Zeiger et al. 1987

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

Tributylamine

Salmonella mutagenicity (TA 98, 100, 1535, 1537)

None 10% RLI or 10% LHI Aroclor 1254 S9 fraction

0 (ethanol as solvent) 33, 100, 333, 1,000, 3,333 µg/plate

48 h

No toxicity

Negative

Zeiger et. al. 1987

aRelative to controls.

bLowest effective dose.

Abbreviations: ABS, aberrations; DMSO, dimethylsulfoxide; HLI, hamster liver induced; MLA, mouse lymphoma forward mutation assay; RHI, rat liver induced; SCE, sister chromatid exchange.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

MA was positive in the mouse lymphoma forward mutation assay employing L5178Y mouse lymphoma cells (Caspary and Myhr 1986). The two highest effective doses, 3.9 and 5.6 mM, produced lethality in the cells. There are no data available on TPA mutagenicity testing and no further data available for other target alkylamines.

The target alkylamines for this document can be considered non-mutagenic on the basis of the results of Ames S. typhimurium mutagenicity assays, although there are limited data from mutagenicity tests that employed eukaryotic or mammalian cell systems that produced positive results for amine-induced genotoxicity. The potential genotoxicity of the target alkylamines is considered negligible when related to the levels of possible ingestion by crew members over designated periods of exposure. 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) (Guest and Varma 1991). The objective of this study was to determine if amines adversely affect fetal development. Amine doses were 7.8, 31, 78, 155 mg/kg, for MA and 15, 59, 150, and 295 mg/kg for TMA. Amines were dissolved in 0.9% saline for injections. TMA at 150 and 295 mg/kg and MA at 155 mg/kg caused abdominal contractions at the injection site that lasted from 3 to 10 min. The same doses of TMA caused ataxia, shallow and rapid breathing, nasal discharge, and tremors. These effects persisted for 10 min; complete recovery was observed within 20 min. The TMA dose of 295 mg/kg (maximum dose) produced death in 5 of 11 pregnant mice and 6 of 6 virgin mice. TMA at the maximum dose adversely affected fetal development by significantly increasing the number of dead fetuses per litter (0.83 dead fetuses per litter for controls and 1.63 dead fetuses per litter for TMA-exposed animals); however, that dose was lethal to almost half the dams.

Both MA and TMA produced concentration-dependent adverse effects in cultured CD-1 mice embryos (Guest and Varma 1991). Mice were killed on day 8 of gestation and embryos were scored for development on the basis of an adaptation of the developmental scoring assess-

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

ment described by Brown and Fabro (1981). Head length was most adversely affected by both MA and TMA at concentrations of 0.5-2 mmol (maximum doses). Decreases in yolk-sac diameter, crown-rump length, and fetal survival were also observed at 0.5-2 mmol. TMA was the more toxic of the amines. TMA and MA induced significantly decreased embryonic DNA and RNA and protein content at 0.25-2 mmol (TMA) and 0.5-2 mmol (MA).

Trimethylamine

Intraperitoneal injections of TMA at 7.5 mmol (443 mg/kg) administered to Swiss CD-1 mice (n = 5) from gestation day 6 to gestation day 15 caused a 15% decrease in brain DNA and a 10% decrease in brain protein in male and female offspring at 3 wk after birth (Guest and Varma 1993). 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. Serum testosterone in 8-wk-old male offspring was 5.6 nmol/L compared with 16 nmol/L in controls, demonstrating a 65% decrease. Other growth-related variables measured in offspring that showed 6-20% decreases compared with controls included body, brain, kidney, and seminal vesicle weights. The authors hypothesize that TMA adversely affected postnatal growth of male offspring by decreasing testosterone production, which consequently reduced brain DNA and protein.

TMA interferes with histiotrophic nutrition in the developing CD-1 mouse embryo by inhibiting receptor-mediated protein uptake by the yolk sac of CD-1 mice (Guest et al. 1994). The authors concluded that this inhibition causes a reduction in macromolecular synthesis in embryos and consequently causes reductions in growth and abnormal development. TMA at a concentration of 0.75 mM inhibited the uptake of [125I]-BSA in 15-d isolated yolk sacs. Uptake in TMA-treated yolk sacs was 75% of the uptake in controls after a 5-h culture period. In this same study, yolk-sac uptake of [3H]-leucine in TMA-treated embryos (28.7 femtomoles [fmol]) was 47% of that in controls (61.2 fmol) in 8-d mouse embryos cultured for 16 h with TMA at 0.75 mM. Incorporation of radioactivity in TMA-treated embryo protein (8.9 fmol) was 44% of that in controls (20.3 fmol).

In an earlier study (Guest and Varma 1992), TMA at 0.75 mM inhibited the growth and morphologic development of treated CD-1 mouse

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

embryos, caused neural-tube defects, and decreased macromolecular synthesis. Treated embryos grew to only 70% of controls. Neural tube defects, characterized by a split-head appearance, occurred in 73% of TMA-treated embryos. Data from this study suggest that TMA-induced developmental inhibition is temporally related to decreased DNA and RNA synthesis, because DNA and RNA embryonic content decreased by as much as 60% in comparison with controls.

Mechanistic Toxicology
Methylamine

MA has been shown to inhibit DNA synthesis stimulated by epidermal growth factor (EGF), insulin, and serum (King et al. 1981). Inhibition of DNA synthesis was determined by cell incorporation of [3H]-thymidine. MA had no effect on resting-level DNA synthesis in cultured human fibroblasts. However, MA inhibited EGF-induced mitogenesis in confluent monolayers of human fibroblasts incubated with MA at 0-20 mM; the maximal inhibition was observed at MA concentrations of 10-20 mM. A 50-75% inhibition of cell incorporation of 3H was demonstrated in 3T3 cells when stimulated by insulin at 5-20 µg/mL in the presence of MA at 10 mM. 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). DNA content of TMA-treated embryos was decreased significantly (10 µg per embryo) compared with that of controls (25 µg per embryo) beginning 16 h into the 42-h culture period. [3H]-thymidine incorporation into DNA in TMA-treated embryos also was significantly decreased when compared with controls beginning 8 h into the culture period. RNA content of TMA-treated embryos was significantly decreased compared with controls at 16 h into the culture period and remained so throughout the experiment. Uptake of [3H]-uridine into TMA-treated embryos was decreased significantly beginning at 8 h into the culture period. TMA decreased the incorporation of [3H]-leucine into embryonic protein during

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

the entirety of a 24-h culture period; the decrease became significant beginning at 8 h into the culture period.

Triethylamine

TEA inhibits rat liver hydrosteroid sulfotransferase activity (Matsui et al. 1993). Hepatic cytosolic fractions obtained from adult male and female Wistar rats were incubated with the biochemically prepared substrate 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and TEA at 100 or 300 µM to assess inhibition of sulfotransferase activity. Under normal physiologic conditions, sulfotransferase catalyzes the transfer of a sulfate group from PAPS to a variety of xenobiotic and endogenous compounds, including androgens. In female rats, sulfotransferase activity toward the androgens androsterone and dehydroepiandrosterone by TEA at 100 µM ranged from 16% to 47% of controls. Sulfotransferase activity toward the androgens by TEA at 300 µM ranged from 15% to 49% of controls. These results indicate that TEA is an inhibitor of hydroxysteroid sulfotransferase. In this same study, multiple amines at 300 µM each were examined for inhibitory actions on sulfotransferase activity toward the androgen dehydroepiandrosterone obtained from male and female hepatic cytosols. DBA, TEA, TPA, and TBA decreased sulfotransferase activity to 40-60% of that of the controls. Other tested amines, MA, EA, PA, and TMA, resulted in 87%, 79%, 96%, and 99% of control sulfotransferase activity. 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.

Odor and Taste Aversion

The chemical senses of taste and smell are critical to nutrition and serve to alert individuals to potentially hazardous exposures. Smell is more sensitive than taste, and only a minute quantity of an airborne stimulating agent is required to elicit olfactory sensation (Moncrieff 1967; Guyton and Hall 2000). Humans have an innate ability to detect bad, aversive smells and to use smell as a warning device. The relationship between taste (gustation) and smell (olfaction) is illustrated during episodes of nasal congestion when the sense of taste becomes dulled. The

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

tastes of foods encountered in daily life are strongly affected by their smell (Kaneda et al. 2000). It is proposed that the flavor of food is ostensibly affected by its aroma. Volatile food molecules reach the nasal cavity prior to ingestion, and other molecules travel via the retronasal route, through the pharynx, to reach olfactory neurons (Freedman 1993).

Olfaction and gustation are closely related. Neuronal inputs from both olfactory and gustatory receptors travel in several common areas of the brain. The olfactory and gustatory neural pathways are known to converge in various parts of the brain, although those pathways have not been fully elucidated. The insular cortex, the orbital-frontal cortex, and the amygdala are candidate sites that might serve as a central point of intermodal convergence that contains neurons responsive to the combined inputs of olfactory and gustatory chemosensation (Dalton et al. 2000). In an investigation of central neural integration of simultaneous chemosensation that used benzaldehyde and saccharin as odor and taste stimuli, respectively, at (individual) sub-threshold levels, Dalton et al. (2000) concluded that benzaldehyde thresholds were 28% lower with saccharin in the mouth than the thresholds obtained with benzaldehyde alone. In effect, sensitivity to benzaldehyde was significantly increased by the presence of subthreshold concentrations of saccharin in the mouth. This finding supports the functional significance of neural response to combinations of odor and taste stimuli (the sense of smell working in conjunction with the sense of taste to create a flavor perception). It also supports the existence of central neural integration loci that respond to commonly conveyed chemosensory events.

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. Alkylamines have a distinctly unpleasant odor characterized as “fishy” or ammoniacal. Amines are nasal irritants; however, symptoms of irritation do not occur from chronic exposure to amine concentrations less than 10 parts per million (ppm) (Benya and Harbison 1994). Aversion to the taste or odor of amine-contaminated water occurred during the operative phase of the LIRS water reclamation assembly wherein concentrations were 60 mg/L, 176 mg/L, and 793 mg/L for TMA, TBA, and TPA, respectively, in a single galley sample.

Geometric means of air and water-dilution odor thresholds are presented for MA, EA, BA, IPA, DMA, DEA, TEA, and TMA in Table 4-4 as compiled by Amoore and Hautala (1983). Thresholds are based on

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 4-4 Water Odor and Taste Perceptibility Thresholds for the Alkylamines

Alkylamine

Water-Dilution Odor Threshold (mg/L)

Taste Perceptibility (water mg/L)

MA

2.4a

NA

 

3.3b

 

EA

4.3a

NA

PA

NA

NA

BA

6.0c

3.5-4.0c

IPA

4.9a

NA

DBA

2.0c

3.5-4.0c

DEA

0.47a

8d

 

10d

 

DMA

0.29a

NA

 

23.2b

 

TMA

0.0002a

NA

 

1.7b

 

TEA

0.42a

3.0d

 

4.0d

 

TPA

NA

NA

TBA

0.8e

NA

aAmoore and Hautala 1983 (presented as geometric means).

bBaker 1963.

cTrubko 1975.

dKagan 1965.

eLe Din Min 1976.

Note: Italicized numbers were used in the calculation of ACs for odor aversion.

Abbreviations: BA, n-butylamine; DBA, dibutylamine; DEA, diethylamine; DMA, dimethylamine; EA, ethylamine; IPA, isopropylamine; MA, methylamine; NA, data not available; PA, propylamine; TBA, tributylamine; TEA, triethylamine; TMA, trimethylamine; TPA, tripropylamine.

human studies conducted to assess odor perception of amines in air or water. 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. There are no data available on thresholds for PA or TPA. Several amines have at least two reported threshold concentrations.

Limited data are available on taste perceptibility of alkylamines in potable water. Taste perceptibility concentrations for BA, DBA, DEA,

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

and TEA were roughly comparable to respective amine water-dilution odor threshold concentrations reported by the same authors (Kagan 1965; Trubko 1975; Amoore and Hautala 1983). In addition, taste perceptibility concentrations for DBA, DEA, and TEA are similar to their respective recommended maximal permissible concentrations. The recommended maximal permissible concentration for TBA (0.3 mg/L reported by Le Din Min [1976]) is comparable to its reported water-dilution odor threshold.

REGULATORY STANDARDS

There are no regulatory standards set for alkylamines in potable water relevant to SWEGs.

RATIONALE

No toxicity studies were found in which humans were orally administered target SWEG alkylamines. Oral toxicity data on EA, IPA, and TPA were not found. Limited oral toxicity data in nonhuman mammalian species were reported for MA, PA, BA, DMA, DEA, DBA, TMA, TEA, and TBA. The majority of those studies do not present findings that reliably indicate amine induction of toxicity, but they present physiologic changes or irregularities that could be biologically significant. One such study, Davison et al. (1965), cannot be effectively interpreted because of adverse health conditions in the majority of the study animals. SWEGs are not set to protect against developmental toxicity. (The SWEGs are presented in Table 4-5.)

Alkylamines are involved in comparable physiologic disposition, including rapid absorption, N-oxidation, and elimination. Chemosensory thresholds for the amines also are comparable. Therefore, the derived SWEG values apply broadly to each alkylamine group (the mono-, di-, and trialkylamines discussed in this document). Because odor perception is a more sensitive end point than taste perception (Moncrieff 1967; Guyton and Hall 2000), 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. It is expected that odor perception would adversely impact crew willingness to drink amine-contaminated potable water supplies. Smell aversion to

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 4-5 Spacecraft Water Exposure Guidelines for the Alkylamine

Groupsa

Duration

Concentration (mg/L)

End Point

Monoalkylamines

1 d

2.0

Odor perception

10 d

2.0

Odor perception

100 d

2.0

Odor perception

1,000 d

2.0

Odor perception

Dialkylamines

1 d

0.3

Odor perception

10 d

0.3

Odor perception

100 d

0.3

Odor perception

1,000 d

0.3

Odor perception

Trialkylamines

1 d

0.4

Odor perception

10 d

0.4

Odor perception

100 d

0.4

Odor perception

1,000 d

0.4

Odor perception

aData from Amoore and Hautala 1983; Le Din Min 1976; Trubko 1975; Baker 1963.

malodorous water supplies could cause or increase the possibility of crew dehydration, which could adversely affect crew performance and could increase both crew health risks and mission flight risks. Therefore, the SWEG values based on odor perception are intended to support optimal flight-crew consumption of potable water supplies, thus minimizing crew dehydration.

Acceptable concentrations (ACs) (see Table 4-6) were established for toxic or adverse health end points—for the alkylamines, those include reproductive toxicity and odor perception. ACs were determined on the basis of guidelines established by the National Research Council (NRC 2000). By convention, each crew member is assumed to ingest 2.8 L of water per day of flight and to have an average body weight of 70 kg. Interspecies and lowest-observed-adverse-effect level (LOAEL)-to-NOAEL factors of 10 each were employed as needed. ACs for alkylamine groups were based on odor perception, because developmental toxicity is not considered relevant for space crew. Odor thresholds (Table 4-4) used to establish ACs were selected on the basis of the most recently conducted experimental assessments and/or on the consistency among alkylamine groups. The lowest of the odor thresholds was

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

TABLE 4-6 Acceptable Concentrations (ACs) for Relevant Mono-, Di-, and Trialkylaminesa

End Point

Exposure Data

Species and Reference

Uncertainty Factors

ACs (mg/L)

To NOAEL

Interspecies

Exposure Time

Spaceflight

1 d

10 d

100 d

1,000 d

Reproductive Toxicity

NOAEL = 54mg/kg

Amoore et al. 1978

1

10

1.1

1

120

Odor perception

Water dilution odor threshold

Humans (Amoore and Hautala 1983; Trubko 1975; Le Din Min 1976; Baker 1963)

 

 

 

 

 

 

 

 

 

Monoalklyamines

 

2

2

2

2

 

Dialkylamines

 

0.3

0.3

0.3

0.3

 

Trialkylamines

 

0.4

0.4

0.4

0.4

SWEGs for monoalkylamines

 

 

 

 

 

2

2

2

2

SWEGs for dialkylamines

 

 

 

 

 

0.3

0.3

0.3

0.3

SWEGs for trialkylamines

 

 

 

 

 

0.4

0.4

0.4

0.4

aIncludes methylamine, ethylamine, propylamine, isopropylamine, n-butylamine, dimethylamine, diethylamine, di-n-butylamine, triethylamine, tripropylamine, and tributylamine.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×
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

Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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.

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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×

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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
×
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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Suggested Citation:"Appendix 4 C1-C4 Mono-, Di-, and Trialkylamine." National Research Council. 2007. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/11778.
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