1-chlorobutane

Endpoint summary

Additional information

There are no studies available in which the toxicokinetic properties of 1-chlorobutane were investigated.

 

1-chlorobutane (molecular weight of 92.57 g/mol) is a clear, colourless, which is moderately soluble in water (measured water solubility: 110 mg/L at 20°C (Study director, 2009)). The log P_O/Wis 2.66 (89 -0514 -DKP), indicating a general lipophilicity of 1-chlorobutane.

 

 

Absorption

In acute oral toxicity studies, rats and mice were administered 1-chlorobutane. Exact levels of the LD₅₀ (2200 mg/kg bw and 5600 mg/kg bw, respectively) were reported; therefore bioavailability of 1-chlorobutane after oral administration is indicated (Rudnev et al., 1979). In a repeated dose toxicity study bioavailability was confirmed via the oral route. Male and female rats were administered 1-chlorobutane by gavage at doses of 0, 190, 380, 750, 1500 and 3000 mg/kg bw/day for 14 days. Mortality and decrease of body weights were observed at the dose of 750 mg/kg bw/day or more, and these findings were considered compound related (NTP, 1986).

In an acute dermal toxicity study, dose levels up to 17600 mg/kg bw 1-chlorobutane were administered to albino rabbits (Smyth et al., 1954). The LD50 level was not attained even with these very high doses, indicating primarily a very low dermal toxicity. QSAR based dermal permeability calculated a moderate dermal absorption of 0.021 mg/cm²/event (Danish (Q)SAR database 2010). 1-chlorobutane has a comparably high vapour pressure of 120.6 hPa at 20°C (see IUCLID chapter 4.6, 2009-0078-DGP); subsequently, the calculated vapour saturation threshold is ca. 458 mg/L at 20 °C. In an aerosol inhalation assay, all rats survived concentrations up to 7.74 mg/L air (1990-0524-FGT). No clinical signs were observed and there were no necropsy findings. In another acute inhalation respiratory study, two of six male rats died within 14 days after 4 hours exposure to the vapour of 1-chlorobutane. The authors determined the LC50 value to be greater than 30.3 mg/L (Smith et al., 1954). Although only a low potential of toxicity of the substance via the inhalative route is indicated, bioavailability can be assumed due to the high vapour pressure and the relatively low molecular weight.

 

Distribution

Some information on the distribution of a chemical compound in the body might be derived from the available physico-chemical and toxicological data. In general, the smaller a molecule, the wider is its distribution throughout the body.

In toxicological studies (compare IUCLID chapter 7.5) hyperactivity and convulsion as well as effects on the spleen were observed following repeated administration of the test material. Thus, distribution throughout the body — at least to some extent — can be assumed.

 

Metabolism

Cytochromes P450 and phase-II-enzymes, such as glutathione-S-transferases are the most important enzymes involved in the bio-activation and clearance of halogenated hydrocarbons (Guengerich et al., 1980; Wheeler et al., 2001 a, b). Cytochrome P-450-catalyzed oxidative dehalogenations yield intermediates that are unstable and rearrange rapidly to give the corresponding aldehydes, which may be oxidized to carboxylic acids or reduced to alcohols. These assumptions are supported by the potential metabolites calculated by OECD toolbox 1.1. Here the metabolism simulator provided n-butyl aldehyde (CAS No. 123-72-8), butyric acid (CAS No. 107-92-6) and 1-butanol (CAS No. 71-36-3). Glutathione S-transferases catalyze the conjugation of glutathione with the alkyl-halides. The resulting conjugates are mainly catabolised to cysteine-conjugates by gamma-glutamyltrans-peptidase and cysteinyl-glycine dipeptidase that are present in liver and kidney. After acetylation of the cysteine moiety via cysteine-S-conjugate N-acetyltransferase, the corresponding mercapturic acids are formed which are predominantly excreted with urine (Voelkel et al., 1998).

 

Excretion

The expected metabolites of 1-chlorobutane (see above) are at least slightly more water soluble than their former and have a molecular weight lower than 500 u.

Taking into consideration the above mentioned, 1 -chlorobutane and its metabolites are expected to be excreted in both expired air and urine. Excretion via feces can be regarded as negligible.

 

References

Guengerich, F. P., Crowford, W. M. Jr., Domoradzki, J. Y., Macdonald, T. L. and Watanabe, P.G. (1980) in vitro activation of 1,2-dichloroethane by microsomal and cytosolic enzymes.Toxicol. Appl. Pharmacol.55, 303-317

Voelkel, W. Friedewald, M., Lederer, E. Paehler, A., Parker, J. and Dekant, W. (1998) Biotransformation of perchloroethene: dose-dependent excretion of trichloroacetic acid, dichloroacetic acid and N-acetyl-S-(trichlorovinyl)-Lcysteine in rats and humans after inhalation.Toxicol. Appl. Pharmacol.153, 20-27

Wheeler, J. B., Stourman, N. V., Thier, R., Dommermuth, A., Vuilleumier, S., Rose, J. A., Armstrong, R. N. and Guengerich, F. P. (2001a) Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and dihalomethanes. Chem. Res. Toxicol. 14, 1118-11127

Wheeler, J. B., Stourman, N. V., Armstrong, R. N. and Guengerich, F. P. (2001b) Conjugation of haloalkanes by bacterial and mammalian glutathione transferases: mono- and vicinal dihaloethanes. Chem. Res. Toxicol. 14, 1107-11017

Danish (Q)SAR database 2010: http://130.226.165.14/index.html