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Nitroethane: Assessment of Toxicokinetic Properties

 

CAS number

79-24-3

Chemical name

Nitroethane; Nitroetan; UN 2842; NE; Nitroparaffin; 1-Nitroethane

Molecular structure

Molecular formula

C2H5NO2

Molecular weight

75.07

Water solubility

4.7 x 104mg/L at 25oC (~5% at 25°C) [1,2]

Vapour pressure

20.93 mm Hg at 25°C [2]

Log Kow

0.45 (estimated by KOAWIN version 1.68)

Log Koa

2.89 (estimated by KOAWIN version 1.10)

Absorption

Nitroethane is a colourless oily liquid at room temperature with an unpleasant odour. It is mainly used as a chemical intermediate for organic synthesis. It is also an excellent solvent for a wide variety of organic compounds and for resins. Nitroethane is useful in inhibiting the decomposition of halogenated hydrocarbon solvents as well. The oral LD50of nitroethane in rats has been reported to be 1.1 g/kg bw [2]. The estimated rate constant of oral absorption of nitroethane through human gastrointestinal tract (jejunum) is 0.073 min-1by ACD/ADME Suite version 5.0 (Advanced Chemistry development, Toronto, ON, Canada). This low to moderate oral absorption is consistent with the pKa of the compound (pKa = 8.8). Most of nitroethane will remain non-ionized in human jejunum which has a pH of 6.5, facilitating oral absorption, affording an estimated 100% oral bioavailability (ACD/ADME Suite). It has been estimated to have a moderate volume of distribution of 1.1 L/kg in human, consistent with the low log Kow for this compound. Similarly, plasma protein binding of nitroethane is estimated to be ~20% in humans by ACD/ADME Suite. The high oral LD50of nitroethane in rat [2], in conjunction with predicted high oral bioavailability, is consistent with its low systemic toxicity.

The steady-state dermal permeability coefficient of nitroethane through human epidermis has been estimated to be 7.82 x 10-4cm/h by Dermwin version 2.01 (EPIWEB version 4.1), which is consistent with its low dermal toxicity in rabbit (no lethality at 2000 mg/kg) [2].

Inhalation of nitroethane is likely due to relatively high vapour pressure (20.4 mm Hg at 25oC) and low octanol:air partitioning (Koa= 2.89; EPIWEB version 4.1). Consistent with low oral, intraperitoneal (no lethality up to 1.1 g/kg) and dermal toxicity, no lethality was observed in rats exposed through inhalation to air containing 2200 ppm nitroethane [2]. Similarly, inhalation exposure of rats for two years (7 h/day) to 100 and 200 ppm nitroethane did not cause any toxicity [2].

Distribution

Due to its acid nature (pH = 6.0 at 0.01 M solution [2]), non-lipophilicity (log Kow= 0.45) and low plasma protein binding (~20%), a moderate volume of distribution (1.1 L/kg) is estimated for nitroethane in humans by ACD/ADME Suite. After oral administration of nitroethane to rats, parent compound was detected fairly rapidly in exhaled air suggesting rapid absorption, distribution and elimination of nitroethane [2].

Accumulation

Due to low plasma protein binding, moderate volume of distribution, rapid elimination of from tissues [2], nitroethane is expected to have very low bioaccumulation potential.

Metabolism

The parent compound was only detected in liver and exhaled air of rats administered via intraperitoneal injection (1.1 g/kg) of nitroethane and only nitrites were found in heart, lungs, kidney, and spleen and in urine [2]. Similarly, most of the parent compound was rapidly excreted unchanged by the lungs when rabbits were exposed to nitroethane either through oral or intravenous routes [2].

 

Based on the structure of nitroethane, it will be expected that the nitro group of nitroethane will be reduced in intestinal microflora [3] to form the corresponding amine, which could be further deaminated byrat liver monoamine oxidase [4] to form the corresponding aldehyde. This formed aldehyde could be further metabolized to acetic acid byaldehyde dehydrogenase. The formed acetic acid would be the major metabolite of nitroethane. 

Excretion

The unmetabolized nitroethane is rapidly excreted through lungs [2] and the remaining nitroethane will be rapidly metabolized to acetic acid which is much more water-soluble than the parent compound, therefore rapidly excreted, primarily in urine. Similar is true for nitrite which has an average plasma elimination half-life of 21-35 min in humans [5].

References

1. Yalkowsky SH and He Y (2003). Handbook of Aqueous Solubility Data, CRC Press, Boca Raton, FL.

2. ANGUS Chemical Company Technical Data Sheet (1998). Nitroethane (NETM) – TDS21.

3.  Wheeler, L.A., 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.

 

4.  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.

 

5. Hunault, C.C., van Velzen, A.G., Sips, A.J.A.M., Schothorst, R.C., and Meulenbelt, J. (2009). Bioavailability of sodium nitrite from an aqueous solution in healthy adults. Toxicol Letters 190, 48-53.