Propan-2-ol

Endpoint summary

Description of key information

The pharmacokinetics of iso-propyl alcohol (IPA) following inhalation, oral, and intravenous administration was investigated in rats in a GLP-compliant study.  In addition, a GLP-compliant study was conducted to investigate the dermal absorption of IPA in rats. No bioaccumulation potential for IPA was reported following any of the routes of exposure investigated.

The following absorption data have been taken into account for DNEL derivation: Oral absorption is nearly 100% as evidenced by the nearly complete lack of radiolabel in feces for up to 168 hours following gavage administration of radiolabeled IPA (see toxicokinetic statement). IPA has a molecular weight of <500 g/mol and a log Kow between 0 and 4; therefore, it is assumed to be well absorbed equivalently by the oral and inhalation route; therefore, inhalation absorption assumed to be 100%. Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose wasabsorbed systemically (see toxicokinetic statement) and absorption was conservatively assumed to be 8%. Compared to oral and dermal routes, the inhalation route of exposure was the least effective with regard to absorption of IPA.

Additional information

The low molecular weight (60 g/mol) and log Pow value (0.05) of IPA favour its absorption via various routes of exposure. Studies in rats that have profiled the toxicokinetics of IPA following inhalation, oral, intravenous, and dermal exposure indicate that the likely routes of significant systemic exposure are inhalation and oral. In all cases IPA is absorbed rapidly and detected in the blood along with its primary metabolite, acetone. Inhalation exposure for 6 hours results in blood concentrations that increase over the course of the exposure and that decrease rapidly upon cessation. Oral absorption is nearly 100% as evidenced by the nearly complete lack of radiolabel in feces for up to 168 hours following gavage administration of radiolabeled IPA. Dermal absorption of IPA is rapid but limited. Following a 4-hour occlusive application 84 to 86% of the applied dose was recovered from the skin and 8 to 9% was lost (presumably to volatilization); thus, approximately 5 to 8% of the applied dose was absorbed systemically. By all routes of exposure the blood half life of IPA is short (on the order of 1 or 2 hours) and tissue accumulation is minimal. Tissue distribution is broad, but clearance from the tissue compartment appears to be uniform and nearly complete. In general, greater than 60% of an administered dose of IPA is excreted within 24 hours and greater than 90% is excreted within 72 hours. The major route of excretion for all routes of administration is the exhaled air, primarily in the form carbon dioxide and volatile organic compounds (including IPA and acetone). Urine and feces account for excretion of less than 10% of an administered dose, with the vast majority of this amount contributed by urine. Based on the available data and taking into consideration its low molecular weight, log Pow value, and considerable water solubility, IPA is not expected to bioaccumulate.

 References 

[1] O’Neil MJ (2006) The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals (14th Edition), Merck & Co., Inc.;,,.
(2000) CRC Handbook of Chemistry and Physics (81st Ed), CRC Press; Taylor & Francis Group,,,.

[3] Slauter RW (1991) Disposition and pharmacokinetics of isopropyl alcohol in F-344 rats after intravenous or oral administration or nose only inhalation. Report number: RTI/4444-01F.

[4] Boatman RJ et al. (1995) Dermal absorption and pharmacokinetics of isopropanol in the male and female F-344 rat. Report number: 066094.

[5] Gill MW (1991) Isopropanol Single Exposure Vapor Inhalation Neurotoxicity Study in Rats. Report number: HSE-91-0010.

[6] Burleigh-Flayer et al. (1991) Isopropanol fourteen-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats. Report number: 53-589.

[7] Burleigh-Flayer HD and Benson CL (1994) Isopropanol vapor inhalation oncogenicity study in Fischer 344 rats. Report number: 91N0133.

[8] Burleigh-Flayer HD and Wagner CL (1993) Isopropanol vapor inhalation oncogenicity study in CD-1 mice. Report number: 91N0132.

[9] Tyl RW et al. (1990) Developmental toxicity evaluation of isopropanol administered by gavage to CD (Sprague-Dawley) rats. Report number: 311C-4557.

[10] Tyl RW et al. (1990) Developmental toxicity evaluation of isopropanol administered by gavage to NewWhite rabbits. Report number: 311C-4557.

[11] Martinez, T. T., Jaeger, R. W., deCastro, F. J., Thompson, M. W., & Hamilton, M. F. (1986). A comparison of the absorption and metabolism of isopropyl alcohol by oral, dermal and inhalation routes. Vet Hum Toxicol, 28(3), 233-236.

Basic toxicokinetics

Slauter (1991) investigated the absorption, distribution, metabolism, and excretion of IPA in male and female Fischer 344 rats following inhalation, oral, and intravenous exposure. It should be noted that inhalation is the expected route of exposure for IPA. In the inhalation study, male and female rats were exposed for 6 hours to radiolabeled IPA vapour by nose-only inhalation at nominal concentrations of 500 (low dose) and 5000 ppm (high dose). The concentration of radiolabel and of IPA in the blood increased rapidly following the initiation of inhalation exposure at either concentration. The half-life of IPA was reported to be approximately 0.8 hours in males and 0.9 hours in females at the low dose, and 2.1 hour in males and 1.8 hours in females at the high dose. The mean maximum plasma concentration (C_max) at 6 hours was reported to be 116 μg-eq/g in males and 125 μg-eq/g in females of the low-dose group, and 1258 μg-eq/g in males and 1449 μg/g in females of the high dose group.

IPA and its radiolabeled metabolites were widely distributed among body tissues, with higher levels occuring in the adipose tissue, kidney, liver, and ovarian tissue relative to blood levels. Clearance from the tissue compartment was uniform and nearly complete and no evidence was observed to indicate that IPA or its radiolabeled metabolites accumulated in any tissue; no single tissue contained greater than 1.6% of the recovered dose in either sex, and carcasses contained an average of 5% of the dose. The excretion of the absorbed dose was rapid, with greater than 90% of the absorbed radiolabel being excreted from the breath, urine, and feces within 72 h of the beginning of the inhalation exposure. The breath was the predominant route of excretion of radiolabel by both sexes, with greater than 80% of the absorbed dose excreted via this route.  Urine and feces accounted for excretion of approximately 7% and 2% of the absorbed dose, respectively. Following exposure to 500 ppm males and females exhaled an average of 49% of the absorbed radiolabel as carbon dioxide in the breath. Following exposure to 5000 ppm, only 22% of the radiolabel present in the exhaled breath was found to be carbon dioxide. Following exposure to 500 ppm IPA, nearly all of the radiolabel present as volatile organic compounds in the exhaled breath was accounted for by acetone. Following exposure to 5000 ppm IPA, an average of approximately 80% of the radiolabeled volatile organic compounds in the breath was identified as acetone with the balance being accounted for by IPA. A third radiolabeled metabolite (accounting for less than 5% of the total dose) was detected in the urine; however, the identity of this metabolite was not determined. Based on the results of this study, no bioaccumulation potential for IPA was reported following inhalation exposure. 

In the oral study, male and female Fischer 344 rats received a single gavage dose of 300 or 3000 mg/kg body weight of IPA or were exposed to 300 mg/kg body weight/day of IPA by gavage for 8 consecutive days (Slauter, 1991). In the intravenous study, male and female Fischer 344 rats received a single intravenous injection of 300 mg/kg body weight of IPA (Slauter, 1991). Similar results as in the inhalation study were reported following both oral and intravenous routes of exposure. The radiolabel and IPA were absorbed and appeared in the blood rapidly following oral administration. Following both oral and intravenous administration, IPA and its radiolabeled metabolites were widely distributed among the tissues. The major route of elimination for both sexes was the exhaled breath, accounting for at least 70% of the dose administered following oral (single dose) and intravenous administration. Volatile organic compounds were the major metabolites identified in the exhaled breath and accounted for 55% of the administered radiolabel following both oral (single dose) and intravenous administration. Acetone was identified as the major radiolabeled volatile oraganic compound excreted in exhaled breath; IPA also was identified following high oral dose exposure and intravenous administration. Carbon dioxide was also excreted in the exhaled breath and acounted for at least 15% of the administered radiolabel. Small amounts of the radiolabel (<10% of the dose) was excreted in urine, with 3 metabolites identified as acetone, IPA, and an unknown metabolite. Less than 2% of the administered radiolabel was excreted in feces. No tissue was observed to retain more than 2.4% of the dose, and the carcass contained approximately 4% of the dose. Based on the results of these studies, no bioaccumulation potential for IPA was reported following oral or intravenous routes of exposure. 

Boatman et al. (1995) investigated the dermal absorption of IPA in male and female Fischer 344 rats exposed to a single dose of IPA (70% in water, under occlusion) for 4 hours. Maximum blood concentrations of IPA of approximately 0.2 μmoles/g of blood for both males and females were attained at 4 hours. Acetone blood levels rose steadily during the 4-hour exposure and continued to rise following removal of the test material at 4 hours, reaching peak blood levels of 0.79 and 1.17 μmoles/g in male and female rats, respectively. First-order elimination half-lives for IPA and acetone were similar for male and female rats, with mean values of approximately 0.8 hours for IPA and 2.6 hours for acetone. Dermal absorption rates were calculated to be 0.78 and 0.85 mg/cm²/hour for males and 0.77 and 0.78 mg/cm²/hour for females, using two independent methods. Calculated permeability coefficients of 1.37 to 1.50 x 10^-3cm/hour for males and 1.35 to 1.38 x 10^-3cm/hour for females indicate that IPA is rapidly absorbed dermally. Of the applied radioactivity dose, 84 to 86% was recovered from the skin at the end of the 4-hour exposure and 8 to 9% was lost (presumably to volatilization). Thus, approximately 5 to 8% of the applied dose was absorbed systemically over the course of the 4-hour exposure.  Expired CO₂and volatiles accounted for 4.1 and 2.1%, respectively, of the recovered dose in male rats and 3.7 and 2.1%, respectively, in female rats. Urine, cage wash, and feces contained approximately 0.5% of the remaining radioactivity with the majority of this present in the urine. Under the conditions of this study, the authors concluded that IPA was rapidly absorbed in vivo through rat skin. Cumulatively, these data indicate that IPA does not have bioaccumulation potential following dermal exposure.

Martinez et al., (1986) evaluated the disposition of IPA in rabbits exposed through different routes of exposure. In the oral study, six male rabbits (2.0-2.6 kg body weight) were divided into two dose groups (3 rabbits/group) and administered 2 or 4 ml/kg (1.572 or 3.144 mg/kg bw) of absolute IPA in a 35% IPA/water dilution by gavage. The 2 ml/kg oral dose resulted in peak IPA blood levels of 147 mg/dl at 1-hour, which then fell steadily to 114 mg/dl after 4 hours. 3 ml blood samples were drawn immediately after administration, and then 1, 2, 3 and 4 hours post-exposure. Samples were then assayed for average IPA/acetone blood levels. In the 4 ml/kg rabbits, blood IPA levels plateaued at between 262 and 281 mg/dl over the 4-hour exposure period. The 2 and 4 ml/kg oral doses produced acetone blood levels that rose steadily throughout the experiment to peaks of 74 and 73 mg/dl, respectively, at 4 hours. Elevations in IPA and acetone blood levels were highly significant ( p <0.01) at all time periods relative to unexposed controls.

For the inhalation/dermal exposure study, a third group of rabbits (3/group) was placed in an inhalation chamber with a towel soaked with 70% IPA applied to the chest. Towels soaked with IPA were then placed on the floor of the chamber to ensure a saturated vapor concentration was achieved. Towels were re-soaked in IPA every half-hour for the 4-hour duration of the study. Blood IPA/acetone levels were monitored as described for the oral study. IPA blood levels rose from 0 to 112 mg/dl over the 4-hour period, while acetone blood levels rose steadily from 7-19 mg/dl over the 4-hour period. While IPA blood levels were significant (p <0/01) at all times tested, only the 4-hour blood acetone levels were significantly different (p <0.05) compared to baseline levels.

For the inhalation-only study, a fourth group of rabbits (3/group) were treated identical to rabbits in the inhalation/dermal study except a plastic layer was placed between the towel and the animal to preclude skin contact. IPA/acetone blood monitoring was performed as described for the oral study. Minimal increases in IPA and acetone blood content were observed, rising to 6 and 8 mg/dl respectively at 4 hours. These blood levels were not statistically significant at any time period, compared to baseline levels. Similar to the reports in the Slauter (1991) studies, the half-life of IPA (although not precisely calculated) appeared short and there was no indication that bioaccumulation occurred in these studies, irrespective of exposure route. Overall, IPA was substantially better absorbed through the oral and dermal routes than the inhalation routes, although significant absorption through the dermal route was only achieved with prolonged exposure. The authors concluded that the respiratory route of exposure, even at levels of saturated vapor concentration, led to minimal absorption of IPA, compared to other routes of exposure.