Disposition of propargyl alcohol in rat and mouse after intravenous, oral, dermal and inhalation exposure

Abstract

1. The disposition of propargyl alcohol (PAL) radiolabelled with carbon-14 ([2,3-14C]PAL) was determined in the F344 rat and B6C3F1 mouse following intravenous (i.v.), oral, inhalation and dermal exposure. 2. By 72h following an i.v. (1 mg kg(-1) or oral (50 mg kg(-1) dose, 76-90% of the dose was excreted. Major routes of excretion by rat were urine (50-62%), CO2 (19-26%) and faeces (6-14%). Major routes of exerection by mouse were urine (30-40%), CO2 (22-26%) and faeces (10-20%). Less than 6% of the dose remained in tissues at 72 h. Biliary exeretion of radioactity by rat (62% in 4 h) was much greater than elimination in faeces (6% in 72 h), indicating that PAL metabolites underwent extensive enterohepatic recycling. 3. Dermal exposure studies demonstrated that dermal absorption of PAL was minimal due to its inherent volatility. 4. In the inhalation studies (1, 10 or 100 ppm for 6 h), 23-68% of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23-53%), and significant portion was exhaled as volatile organics (15-30%). 5. PAL was extensively metabolized by both species. One metabolite was identified as 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, which is consistent with Banijamali et al. (1999).

NIOSH skin notation (SK) profiles: propargyl alcohol [CAS No. 107-19-7].

“…No toxicokinetic data were identified that evaluated the potential of propargyl alcohol to be absorbed through the skin of humans following dermal exposure. Dix et al [2001] investigated the disposition of propargyl alcohol in male rats following dermal exposure.…”

“…The reported results indicated that only 4.3% of the applied dose was absorbed through the skin that up to 85% of the applied dose was unavailable for dermal absorption because of the volatile nature of propargyl alcohol. In addition, Dix et al [2001] indicated that it is unlikely that humans would receive a significant internal dose of propargyl alcohol following dermal exposure unless the skin was in contact with liquid propargyl for a prolonged period. However, Dix et al [2001] did not evaluate the potential of propargyl alcohol to be dermally absorbed under occluded conditions.…”

“…In addition, Dix et al [2001] indicated that it is unlikely that humans would receive a significant internal dose of propargyl alcohol following dermal exposure unless the skin was in contact with liquid propargyl for a prolonged period. However, Dix et al [2001] did not evaluate the potential of propargyl alcohol to be dermally absorbed under occluded conditions. Due to the volatility of the chemical, the amount of propargyl alcohol that was dermally absorbed could have differed compared to the study using non-occluded conditions.…”

“…For example, Vernot et al [1977] measured skin absorption toxicity under occluded conditions, and reported findings that propargyl alcohol was acutely fatal at relatively low doses. Additionally, Dix et al [2001] were using very low concentrations in the dermal absorption studies of propargyl alcohol. At concentrations as low as of 8 mg/kg, Dow Chemical Company [1957] reported no toxicity, but exposures to a 1.58% solution of propargyl alcohol in Dowanol 50B at 15.8 mg/kg or 31.6 mg/kg in rabbits was fatal.…”

A mechanism for the formation of bis‐glutathione conjugates of propargyl alcohol

“…Using a chemical approach, this study was designed to determine the precise pathway involved in the formation of the bis‐glutathione conjugates of propargyl alcohol that had previously been identified in rat and mouse urine 2. 3, 6 For this purpose rats were administered a mixture of [2,3‐ 14 C]propargyl alcohol and [3‐ 2 H 2 ]propargyl alcohol. Mass spectrometry and synthetic standards of the unlabeled material were used to determine the number of deuteriums retained in the isolated bis‐conjugate (Fig 1, metabolite I ), providing the key to understanding mechanism of formation.…”