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1-Nitropropane: Assessment of Toxicokinetic Properties

 

CAS number

108-03-2

Chemical name

1-Nitropropane; 1-Nitropan; 1-nitro-propan; 1-NP; Propane,1-nitro-

Molecular structure

Molecular formula

C3H7NO2

Molecular weight

98.09

Water solubility

15 g/L at 25°C [1]

Vapour pressure

9.5 mm Hg at 25°C (estimated by EPI Suite version 4.0)

Log Kow

0.87 [2]

Log Koa

3.3 (estimated by KOAWIN version 1.67)

Absorption

1-nitropropane (1-NP) is used as a solvent in the manufacture of cellulose acetate, vinyl resins, lacquers, synthetic rubbers, fats, oils, dyes and protective coatings. 1-NP is also used in the manufacture of rocket propellant, organic intermediate for agrochemicals and pharmaceuticals, solvent-extraction processes and fuel additive. The oral LD50of 1-NP in rats and mice has been reported to be 455 and 800 mg/kg bw, respectively [3]. The estimated rate constant of oral absorption of 1-NP through human gastrointestinal tract (jejunum) is 4.5 hr-1by ACD/ADME Suite version 5.0 (Advanced Chemistry development, Toronto, ON, Canada). The moderate to high oral absorption is consistent with the pKa of the compound (pKa = 8.8). Most of 1-NP will remained non-ionized in human jejunum which has the pH of 6.5 facilitating oral absorption, affording 100% oral bioavailability estimation (ACD/ADME Suite). It has also been estimated in human to have moderate volume of distribution of 1.2 L/kg. Similarly, plasma protein binding of 1-NP is estimated to be ~30% in humans by ACD/ADME Suite. The low to moderate oral LD50of 1-NP in rodents [3] is consistent with the estimation of its high absorption from the GI tract. No experimental data are available on the fate of 1-NP after oral administration in animals for confirmation. However, rapid oral absorption is consistent with only ~3-fold higher oral LD50when compared with intraperitoneal LD50(250 mg/kg in mice [4]).

Dermal penetration of 1-NP has been reported to be <1% of the applied dose in rhesus monkeys [5]. The steady-state permeability coefficient of 1-NP through human epidermis has been reported to 1.80 x 10-4cm/hr [6].

Inhalation of 1-NP is likely due to relatively high vapour pressure (9.5 mm Hg at 25oC) and low octanol:air partitioning (Koa= 3.3; EPI Suite version 4.0). 1-NP is expected to rapidly absorb upon inhalation consistent with the inhalation LD50of 3100 ppm for 8 hours in rats [4]. It has also been reported to be more toxic to rabbit and guinea pigs (LD100of 5000 ppm for 3 hours [3]), indicating high inhalation absorption in these species as well. Consistent with expected toxicity of 1-NP by inhalation, appropriate safety measures are recommended to avoid inhalation exposure to workers.

Distribution

Due to its neutral nature, non-lipophilicity (log Kow= 0.87) and low plasma protein binding (30%), a moderate volume of distribution (1.2 L/kg) is estimated for 1-NP in humans by ACD/ADME Suite. A similar moderate volume of distribution of 1-NP can be deduced from an earlier study in rats and chimpanzees [7]. The intra-peritoneal dose given to rats was rapidly exhaled with maximum concentration in exhaled air reaching within 15 minutes after dosing, suggesting rapid elimination of the absorbed dose from the central compartment (blood) prior to distributing to deeper compartments of the body. The remaining absorbed dose was distributed to almost all rat tissues [7] and only about 6-7% of the administered dose remained in carcass after 48 hours with over 73% recovered in exhaled air, ~17% in urine and ~2% in feces [7].

Accumulation

Due to low plasma protein binding of 1-NP, moderate volume of distribution, rapid elimination and low residual levels in tissues of rats after 48 hours of dosing, 1-NP is expected to have very low bioaccumulation potential.

Metabolism

The disposition and metabolism of 1-NP in rats and chimpanzees has been reported by Haas-Jobeliuset al., 1989 [7]. The administered14C-1-NP to rats or chimpanzees was metabolized to at least 5 polar metabolites in addition to exhalation upon metabolism as CO2. Two of the metabolites were identified as 3-hydroxypropionic acid and 2-(methylsulfinyl) ethylpropionic acid amide which was formed by propionic acid and coenzyme A [7]. Those metabolites are possibly formed by reduction of the nitro group of 1-NP in intestinal microflora [8] to form the corresponding amine, which could be further deaminated byrat liver monoamine oxidase [9] to form the corresponding aldehyde. This formed aldehyde could be further metabolized to propionic acid byaldehyde dehydrogenase, The formed propionic acid can either be metabolized to 3-hydroxypropionic acid by cytochrome p450 in the liver or converted to other metabolites such as2-(methylsulfinyl)ethylpropionic acid amide.  

Excretion

1-NP was predominantly excreted as CO2by rats and chimpanzees followed by urine and feces [7]. Low fecal elimination was expected due to its low molecular weight that doesn’t favour biliary elimination. Based on the study conducted by Haas-Jobeliuset al. [7],the rats given intra-peritoneal14C-1-NP excreted at least 95% of the radioactivity within 48 hours, 73% in exhaled air (mostly as CO2) 17% in urine and only <2% in feces.The absorbed 1-NP was rapidly eliminated in the exhaled air, elimination was monophasic. Most of the absorbed dose was quickly eliminated with ~70% and 85% of the dose within 12 and 24 hours, respectively [7]. The half-life of the elimination through exhaled air was ~55 minutes. Elimination of the absorbed dose from plasma and tissues was moderate, with a half-life between 10 and 18 hours [7]. Urinary and fecal elimination of the intravenous dose to chimpanzees was similar to that observed in rats (15% in urine and 1% in feces over 96 hours) [7]. No exhaled air or tissues were collected from chimpanzees to determine the fate of the remaining dose [7]; however, is expected to be similar to that observed in rats due to similar pattern of metabolism between the two species [7].

References

1. Riddick JA, Bunger WB and Sakano TK (1986).Organic Solvents: Physical Properties and Methods of Purification. 4thEdition,,.

2. Hansch C, Leo A and Hoekman D (1995). Exploring QSAR Hydrophobic, Electronic and Steric Constants, ACS,,.

3. CDC (2010). 1-Nitropropane, IDLH Documentation. Available athttp://www.cdc.gov/Niosh/idlh/108032.html. visited on 4/16/2010.

4. MSDS for 1-Nitropropane (108-03-2) available athttp://www.lookchem.com/1-NITROPROPANE. visisted on 4/14/2010. 

5.  Norman S (1990). Skin absorption and metabolism/toxicokinetic study of 14C-1-nitropropane in female rhesus monkeys. Report of the Coulston International, Incorporated.

6.  Tedesco JA (2005). 1-Nitropropane: in vitro dermal absorption rate testing. Report of The Dow Chemical Company,,.

7. Haas-Jobelius M, Korte, F and Coulston F (1989). Disposition and metabolism of 1-Nitropropane in rats and chimpanzees. Biomed Environ Sci 2, 249-264.

8.  Wheeler,, Soderberg, F.B., and Goldman, P. (1975) The relationship between nitro group reduction and the intestinal microflora. The Journal of pharmacology and experimental therapeutics 194, 135-144.

9.  Yu, P.H. (1989) Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B. The Journal of pharmacy and pharmacology 41, 205-208.