Prop-2-yn-1-ol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
In a toxicokinetic study in rats and mice, Propargyl alcohol was administered via the intravenous, oral, dermal (rats only) and inhalation routes in order to assess absorption, distribution, metabolism and excretion. Propargyl alcohol was extensively metabolized and rapidly eliminated in both species upon i.v., oral, dermal and inhalation exposure. Biliary excretion of Propargyl alcohol-derived radioactivity was significant, with relatively little faecal excretion, indicating a high degree of enterohepatic circulation. Owing to the volatility of Propargyl alcohol, the risk to humans from dermal exposure is likely to be low unless dermal contact is prolonged.

Additional information

In a key toxicokinetic study Dix et al. (2001) investigated the disposition of Propargyl alcohol in rats and mice following intravenous (i.v.), oral, inhalation and dermal (rat only) exposure. By 72 hours after an i.v. (1 mg/kg bw) or oral (50 mg/kg bw) single dose, 76-90 % of the dose was excreted. Major routes of excretion by rat were urine (50 -62 %), carbon dioxide (19 -26 %) and faeces (6 -14 %). Major routes of excretion by mouse were urine (30-40 %), carbon dioxide (22 -26 %) and faeces (10 -20 %). Less than 6 % of the dose remained in tissues at 72 hours. Biliary excretion of radioactivity by rat (62% in 4 hours) was much greater than elimination in faeces (6 % in 72 hours), indicating that Propargyl alcohol metabolites underwent extensive enterohepatic recycling. The primary routes of occupational exposure to Propargyl alcohol are dermal contact and inhalation. It was demonstrated that at least 75 % of the applied dermal dose volatilized from the surface of the skin and was unavailable for absorption. Approximately 8 -10 % of the dose recovered in traps for volatile organics may have been Propargyl alcohol that was not absorbed and escaped the dermal appliance, making nearly 85 % of the applied dose unavailable for absorption. In the inhalation studies (1, 10 or 100 ppm for 6 hours), 23 -68 % of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23-53 %), and a significant portion was exhaled as volatile organics (15 -30 %). Propargyl alcohol was extensively metabolized by both rats and mice. One metabolite was identified as 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, which is consistent with results of Banijamali et al. (2000).

 

In a metabolism study, Banijamali et al. (2000) investigated the metabolism of Propargyl alcohol in rats and mice by identifying urinary metabolites following oral administration of radiolabelled Propargyl alcohol. In male Sprague-Dawley rats, 56 % of the radioactivity administered was excreted in the urine within 96 hours. The highest concentration was observed in the first 24 -hour urine. The main metabolites were 2-propynoic acid, 3,3-bis[(2-(acetylamino)-2-carboxyethyl)thio]-1-propanol, 3-(carboxymethylthio)-2-propenoic acid, and 3-[[2-(acetylamino)-2- carboxyethyl]sulphinyl]-3-[[2-(acetylamino)-2-carboxyethyl]thio]-1-propanol accounting for 27, 20, 20, and 15 %, respectively, of the total radioactivity excreted in the urine during the first 24 hours post-administration. From the results, Banijamali et al. suggested that the metabolism of Propargyl Alcohol in rats involves oxidation into 2-propynoic acid and multiple glutathione additions to the carbon-carbon triple bond yielding numerous metabolites. In mice, about 60 % of the radiolabel administered was excreted in the urine by 96 hours. The highest concentration was observed in the first 24-hour urine. The main metabolites were (E + Z)-3-[(2-amino-2-carboxyethyl)thio]-2-propenoic acid, 3-[[2-(acetylamino)-2-carboxyethyl]thio]-3-[[2-(amino)-2-carboxyethyl]thio]-1-propanol, 3,3-bis[(2-(amino)-2-carboxyethyl)thio]-1-propanol, and 3-[(2-formylamino-2-carboxyethyl)thio]-2-propenoic acid accounting for 41, 17, 15, and 13 %, respectively, of the total radioactivity excreted in the urine during the first 24 hours post-administration. The data suggested that metabolism of Propargyl alcohol in mice involves glucuronide conjugation to form 2-propyn-1-ol glucuronide as well as oxidation into 2-propynal which undergoes either multiple glutathione additions or oxidation into 2-propynoic acid (only ca. 2 %). Comparison of rat and mice data indicates quantitative and qualitative differences in formation of glucuronide conjugates and of 2-propynoic acid and metabolites derived from glutathione (Banijamali et al., 2000).

 

DeMaster et al. (1994) stated that the oxidative metabolic conversion of Propargyl alcohol into its aldehyde is not likely to occur via alcohol dehydrogenase since Propargyl alcohol appeared to be a poor substrate for this enzyme. Based on in vitro experiments, they hypothesised that catalysis by liver catalase via a hydrogen peroxide supported reaction could be an alternative oxidative pathway and pointed out that the possibility that this type of conversion could also take place via other pathways such as oxidation by hydroxyl radicals and microsomal cytochrome P450 2E1.

From in vitro experiments with rat hepatocytes, Moridani et al. (2001, see section 7.12) concluded that Propargyl alcohol is preferentially oxidised by cytochrome P450 2E1 rather than by catalyse or alcohol dehydrogenase to form propynal that caused hepatocyte lysis as a result of glutathione depletion and lipid peroxidation.

 

In conclusion, dermal absorption of Propargyl alcohol was demonstrated to be minimal in rats due to its inherent volatility. Thus, it is unlikely that humans would receive a significant internal dose of Propargyl alcohol upon dermal exposure unless the skin was in contact with liquid Propargyl alcohol for a prolonged period. It is likely that inhalation has a higher relevance as route of exposure for humans as compared to dermal exposure. Propargyl alcohol was rapidly absorbed, quickly distributed and extensively metabolized following intravenous, oral or inhalation exposure, and was rapidly eliminated over 24 hours. Major routes of excretion were urine, carbon dioxide and faeces. Propargyl alcohol did not accumulate in the investigated species.

Discussion on bioaccumulation potential result:

In a toxicokinetic study, Propargyl alcohol (99 % a.i.; 90 -95 % radiochemical purity; location of [14 -C] label: C2, C3) was administered to groups of 4 -5 male Fischer 344 rats per group or per group and timepoint via the intravenous (1 mg/kg bw), oral (50 mg/kg bw), dermal (5 mg/kg bw) and inhalation (1, 10 or 100 ppm) routes (Dix KJ et al., 2001). By 72 hours following a single intravenous or oral dose, about 90 % of the dose was excreted. Major routes of excretion were urine (50 -62 %), carbon dioxide (19 -26 %) and faeces (6 -14 %). Less than 6 % of the dose remained in tissues at 72 hours. Biliary excretion of radioactivity (62 % in 4 hours) was much greater than elimination in faeces (6 % in 72 hours), indicating that Propargyl alcohol metabolites underwent extensive enterohepatic recycling. Dermal exposure studies demonstrated minimal absorption due to the inherent volatility of Propargyl alcohol. Owing to the volatility of Propargyl alcohol, the risk to humans from dermal exposure is likely to be minimal unless dermal contact is prolonged. In the inhalation studies (1, 10 or 100 ppm for 6 hours), 33.3 -62.1 % of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (38 -53 %), and a significant portion was exhaled as volatile organics (17 -21 %). Propargyl alcohol was extensively metabolised. One metabolite was indentified as 3,3 -bis[2 -(acetylamino)-2 -carboxyethyl)thio]-1 -propanol.

This toxicokinetics study in the rat is classified acceptable and satisfies the guideline requirement for a toxicokinetic study (OECD 417) in rats.

In a toxicokinetic study, Propargyl alcohol (99 % a.i.; 90 -95 % radiochemical purity; location of [14 -C] label: C2, C3) was administered to groups of 4 -5 male B6C3F1 mice per group or per group and timepoint via the intravenous (1 mg/kg bw), oral (50 mg/kg bw), and inhalation (1, 10 or 100 ppm) routes (Dix KJ et al., 2001).

By 72 hours following a single intravenous or oral dose, about 73 -76 % of the dose was excreted. Major routes of excretion were urine (30 -40 %), carbon dioxide (22 -26 %) and faeces (10 -20 %). Less than 4 % of the dose remained in tissues at 72 hours. In the inhalation studies (1, 10 or 100 ppm for 6 hours), 23.1 -68.4 % of the radioactivity to which animals were exposed was absorbed. The primary route of excretion was urine (23 -43 %), and a significant portion was exhaled as volatile organics (15 -30 %). Propargyl alcohol was extensively metabolised. One metabolite was identified as 3,3 -bis[2 -(acetylamino)-2 -carboxyethyl)thio]-1 -propanol.

This toxicokinetics study in the mouse is classified acceptable and satisfies the guideline requirement for a toxicokinetic study (OECD 417) in mice.

DeMaster et al. (1994) stated that the oxidative metabolic conversion of Propargyl alcohol into its aldehyde is not likely to occur via alcohol dehydrogenase since Propargyl alcohol appeared to be a poor substrate for this enzyme. Based on in vitro experiments, they hypothesised that catalysis by liver catalase via a hydrogen peroxide supported reaction could be an alternative oxidative pathway and pointed out that the possibility that this type of conversion could also take place via other pathways such as oxidation by hydroxyl radicals and microsomal cytochrome P450 2E1.