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Nitromethane: Assessment of Toxicokinetic Properties

 

CAS number

75-52-5

Chemical name

Nitromethane; nitrocarbol; methane, nitro-; nitroalkane; nitrocarbol; nitroparaffin; nitro fuel

Molecular structure

Molecular formula

CH3NO2

Molecular weight

61.04

Water solubility

1.11 x 105mg/L at 25oC (~11% at 25°C) [1]

Vapour pressure

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

Log Kow

-0.35 [2]

Log Koa

32.53 (estimated by KOAWIN version 1.67)

Absorption

Nitromethane is a clear and colourless liquid at room temperature. It is primarily used as a chemical intermediate in the synthesis of biocides, chemicals, and agricultural products. A small amount is used as an industrial solvent. Nitromethane is also used as a fuel or fuel additive with methanol in hobby cars, boats and model engines. The oral LD50 of nitromethane in rats has been reported to be 1.2 ± 0.3 g/kg bw [3]. The estimated rate constant of oral absorption of nitromethane through human gastrointestinal tract (jejunum) is 0.069 min-1 by ACD/ADME Suite version 5.0 (Advanced Chemistry development, Toronto, ON, Canada). This moderate to high oral absorption is consistent with the pKa of the compound (pKa = 10.10). Most of nitromethane will remain non-ionized in human jejunum which has the pH of 6.5, facilitating oral absorption, affording an estimated 98% oral bioavailability (ACD/ADME Suite). It has also been estimated to have a moderate volume of distribution of 1.1 L/kg in human. Similarly, plasma protein binding of nitromethane is estimated to be ~24% in humans by ACD/ADME Suite. The low oral LD50of nitromethane in rat [3], in conjunction with predicted high oral bioavailability, indicates its low systemic toxicity.

The steady-state dermal permeability coefficient of nitromethane through human epidermis has been estimated to be 4.17 x 104cm/h by Dermwin version 2.00 (EPI Suite version 4.0), which is consistent with its low dermal toxicity in rabbit (LD50>2000 mg/kg) [ANGUS Chemical Company, unpublished data]. Similarly, negligible penetration (0.082% of the dose in 72 hours after 12 hour of application) of dermally applied nitromethane has been reported in rhesus monkeys [4].

Inhalation of nitromethane is likely due to relatively high vapour pressure (35.8 mm Hg at 25oC) and moderate octanol:air partitioning (Koa= 32.53; EPI Suite version 4.0). Even with its expected high absorption upon inhalation, acute (1 h) inhalation toxicity to rats is low (LD50>5113 ppm) [5].

Distribution

Due to its neutral nature (pH = 6.4 at 0.1 M solution [3]), non-lipophilicity (log Kow= -0.35) and low plasma protein binding (~24%), a moderate volume of distribution (1.1 L/kg) is estimated for nitromethane in humans by ACD/ADME Suite. After intra-peritoneal injection (2400 mg/kg) or inhalation exposure (13000 ppm for 6 hours) of nitromethane to rats, no parent compound was detected in any of the tissues (only nitrite was detected in low concentrations in heart, lungs, kidneys, spleen but not in liver) suggesting rapid metabolism/ elimination of the absorbed dose [6].

Accumulation

Due to low plasma protein binding, moderate volume of distribution, rapid metabolism (no parent nitromethane was detected in tissues after inhalation or intraperitoneal injection) [6], nitromethame is expected to have very low bioaccumulation potential.

Metabolism

Nitromethane is oxidized in vitro to formaldehyde, nitrite, and hydrogen peroxide by D-amino acid oxidase prepared from hog kidney [7]. Metabolism of nitromethane by liver microsomes from Fischer 344 rats resulted in formation of only trace amounts of formaldehyde

[7]. Administered nitrometane to Wistar rats by intraperitoneal injection (2400 mg/kg) or inhalation (13.000 ppm for 6 hours) resulted in low concentrations of nitrite metabolite in heart, lungs, kidney, and spleen, but not in the liver [6]. 

No complete in vivo metabolism of nitromethane has been reported. However,based on the structure of nitromethane, it will be expected that the nitro group of nitromethane could be reduced by intestinal microflora [8] to form the corresponding amine, which could be further deaminated by rat liver monoamine oxidase [9] to form formaldehyde. This formed aldehyde could be further metabolized to formic acid by aldehyde dehydrogenase, and subsequently to carbon dioxide [10]

Excretion

The formed formic acid metabolite or nitrite would be much more water-soluble than the parent compound, therefore expected to be rapidly excreted, primarily in urine

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. MSDS for Nitromethane available at:http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0034/0901b80380034ccb.pdf?filepath=angus/pdfs/noreg/319-00011.pdf&fromPage=GetDoc

4.  EPA 1990. Skin Absorption and Metabolism/Toxicokinetic Study of 14C Nitromethane in Female Rhesus Monkeys with Cover Letter Dated 4/23/90

5.  Dequidt J, Vasseur P and Potencier (1973). Experimental toxicological study of some nitroparaffins. 4. Nitromethane.Bull Soc Pharm, 1, 29–35.

6.  Department of Health and Human Services (2002). Report on Carcinogens Background Document for Nitromethane.Department of Health and Human Services, National Toxicology Program,,.

7.  Porter DJT, VoetJGand Bright HJ (1972).Nitromethane. A novel substrate 'for D-amino acid oxidase.J Biol Chem247,1951-1953.

8.  Wheeler LA, Soderberg FB and Goldman P (1975) The relationship between nitro group reduction and the intestinal microflora.J pharmacol Exper Therap194, 135-144.

9.  Yu PH (1989) Deamination of aliphatic amines of different chain lengths by rat liver monoamine oxidase A and B.J Pharmacy pharmacol41, 205-208.

10.Liesivuori J and Savolainen H (1991). Methanol and formic acid toxicity: biochemical mechanisms.Pharmacol Toxicol69, 157-63.