1-bromopropane

Endpoint summary

Additional information

A key study (Garner et al., 2006) evaluating the disposition and metabolism of 1-bromopropane and the factors influencing them in male F344/N rats and B6C3F1 mice following inhalation exposure (800 ppm) or intravenous administration (5, 20, or 100 mg/kg) is available. [13C3]-1-bromopropane and [14C]-1-bromopropane were co-administered to enable characterization of urinary metabolites using nuclear magnetic resonance spectroscopy and liquid chromatography coupled with either tandem mass spectrometry or radiochromatography. By 4 hours following intravenous administration, rats and mice exhaled a majority of the administered [14C]-1-bromopropane dose as either volatile organic compounds (VOC) (rats, 50% to 71%; mice, 39% to 48%) or carbon dioxide (rats, 10% to 30%; mice, 19% to 26%). The radioactivity was also excreted in urine (rats, 13% to 19%; mice, 13% to 23%) and faeces (rats, < 2 %; mice, 4%) or retained in tissues and carcass (rats, ≤ 6%; mice, < 4%). The urinary metabolites characterized in rats and mice following both inhalation exposure and intravenous administration were N-acetyl-S-propylcysteine, N-acetyl-S-(2-hydroxypropyl) cysteine, N-acetyl-3-(propylsulfinyl) alanine, 1-bromo-2-hydroxypropane-O-glucuronide, N-acetyl-S-(2-oxopropyl) cysteine, and N-acetyl-3-[(2-oxopropyl) sulfinyl]alanine. In rats, but not in mice, the route of elimination and the metabolite distribution changed significantly as the dose increased, with the percentage of dose excreted as volatile organic compounds increasing significantly between the mid- and high-dose groups. Concomitantly, the percentage of the dose exhaled as carbon dioxide decreased. An investigation of the molar ratio of exhaled carbon dioxide to the total released bromide showed that the proportion of 1-bromopropane metabolized via oxidation to pathways dependent on glutathione conjugation with bromine replacement decreased with increasing dose in rats. As the dose increased, the relative proportion of N-acetyl-S-propylcysteine and N-acetyl-S-(2-hydroxypropyl) cysteine shifted such that the N-acetyl-S-propylcysteine peak predominated at 100 mg/kg accounting for more than 80% of the urinary radioactivity and indicating saturation of oxidation pathways. Rats pretreated with 1-aminobenzotriazole, a potent inhibitor of cytochrome P450, had decreased total radioactivity excreted in urine, exhaled as carbon dioxide, or retained in liver with a concomitant increase in radioactivity in expired volatile organic compounds. The number of urinary metabolites was reduced from 10 to one with N-acetyl-S-propylcysteine accounting for more than 90% of the total urinary radioactivity in the pretreated rats. These data demonstrate a role for P450 and glutathione in the dose-dependent metabolism and disposition of 1-bromopropane in the rat. Based on these results, a metabolic pathway in rodents was proposed.

The same author (Garneret al., 2007) also investigated the contribution of cytochrome P450 2E1 (CYP2E1) to 1-bromopropane metabolism using CYP2E1 knockout and wild type mice. The mercapturic acid of 1-bromo-2-hydroxypropane, N-acetyl-S-(2-hydroxypropyl) cysteine, was observed as the major urinary metabolite in wild type mice; the products of direct conjugation of 1-bromopropane with glutathione were reportedly insignificant. The ratio of glutathione conjugation to 2-hydroxylation was increased fivefold in the CYP2E1 knockout mice relative to wild type mice.

Moon (1998) also suggested that n-propyl bromide is metabolised by the CYPB1/CYPB2 and CYPE1 isozymes, but Kaneko (1997) suggests that hepatic microsomes metabolize n-propyl bromide poorly. The main difference between these studies is that Moon used microsomes obtained from rats exposed by inhalation to n-propyl bromide for 8 weeks whereas Kaneko used microsomes prepared from untreated rats.

Additional information is available from existing dossier studies to infer toxicokinetic properties.

Systemic availability of n-propyl bromide is dependent on absorption across body surfaces, which is increased by lipophilicity and small molecular weight. The partition coefficient for n-propyl bromide in three studies, given as log Pow, is 2.1 to 2.16; lipophilicity is generally regarded as a log Pow of greater than 3.0, so n-propyl bromide is neither strongly lipophilic nor strongly hydrophilic, but close to the transition point that would allow presence in either medium. Water solubility ranged from 2371 to 2500 mg/L, which is within the range defined as water soluble. The molecular weight of n-propyl bromide is 123, well below the size for exclusion by skin (about 500). Based on its known physical properties, n-propyl bromide would be expected to cross all body surfaces, although the proportion of the dose that penetrates the skin may be affected by time of contact and occlusion. Light contamination of bare skin for example is unlikely to remain long given the high vapour pressure (14.772 kPa). Rapid volatilisation is likely to occur before significant absorption can occur.

Examination of the acute studies indicates important toxicokinetic properties of n-propyl bromide. The key acute oral rat study by Clauzeau (1993) used a limit dose of 2000 mg/kg and reported clinical signs suggesting effects on the central nervous system (CNS) on day 1, but no effects on day two, and no macropathology. Other acute studies reported clinical signs consistent with CNS disturbance (Paster 1978a oral; Schorsch 1997 inhalation; Moon 1998 inhalation; Labbe 1997 inhalation) which indicate effects in a lipophilic tissue at a distance from the site of exposure. Therefore, based on effects on the CNS, n-propyl bromide most likely passes through the gastrointestinal (GI) tract and the alveoli of the lungs to produce systemic exposure. However, the CNS effects were limited to the immediate post-dosing period, indicating that n-propyl bromide did not accumulate, consistent with its properties of water solubility. CNS effects were not explicitly reported in a key OECD 402 dermal study by de Jouffrey (1995) at the same limit dose of 2000 mg/kg, indicating that the skin is likely to provide a greater barrier to absorption of n-propyl bromide than the GI tract or lung.

The irritant properties of n-propyl bromide are evident in high dose inhalation and dermal studies in which the organ providing the body surface for absorption is affected by n-propyl bromide at high concentration, providing an inflammatory response that might increase passage of n-propyl bromide across the local surface. A high dose dermal study in rabbits by Paster (1979) indicates skin ulceration and necrosis at all doses (range 2.5 – 10 mL/kg, approximately 3375 – 13,500 mg/kg).

The lung appears to be a target organ for both local and systemic effects as evidenced by both inhalation and oral reports indicating lung toxicity. An acute inhalation study by Schorsch (1997) dosed rats at 30 to 42 g/m³and reported inflammation and oedema in lung, although two other inhalation studies did not explicitly report lung toxicity [Moon (1998) – LC50 14,374 ppm and no reported organ pathology; Labbe (1997) – LC50 25-35 mg/L and inconsistent organ toxicity across doses]. An acute oral rat study by Paster (1979a), with high doses that ranged from 850 to 8500 mg/kg reported pulmonary inflammation in animals that survived two weeks. An acute oral study in rabbits by Paster (1978b) also reported pneumonic signs in the lung at doses above the LD50, but no toxic effects at doses below the LD50. Therefore, data from high doses may show increased relative absorption and change the target organ profile compared to low doses.

While the above acute studies are relevant to the toxicokinetic profile, the key repeat dose inhalation study (Adamo-Trigiani 1997, 3 mg/L for 13 weeks) does not report any clinical signs or effect on the functional observational battery, motor activity, or histopathology that would be consistent with CNS or lung effects. The only pathology reported was vacuolization of centrilobular hepatocytes, again indicating a role for the liver in the metabolism of n-propyl bromide.