Disposition and Pharmacokinetics of Isopropanol in F-344 Rats and B6C3F1 Mice

SLAUTER, R. W.; Coleman, Donna P.; Gaudette, Norman F.; McKee, Richard H.; MASTEN, L. W.; GARDINER, T. H.; STROTHER, D. E.; TYLER, T. R.; Jeffcoat, A

doi:10.1093/toxsci/23.3.407

Cited by 4 publications

(9 citation statements)

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“…The experimental data of the alcohols isopropanol (Slauter et al, 1994) and ethanol (Pastino et al, 1997) were predicted well during and post exposure in rat by the model for two different concentrations. Similarly to the PBPK model for ethanol by Pastino et al (1997), alveolar ventilation was decreased to 60% to account for the fraction of ethanol absorbed by the airway and to obtain a better fit.…”

Section: Other Common Volatile Chemicals Found In the Environmentmentioning

confidence: 87%

“…Halothane data were obtained from Stern et al (1990) and Williams et al (1996), and sevoflurane data from Stern et al (1990). Slauter et al (1994); ethanol data from Pastino et al (1997); acetone data from DiVincenzo et al (1973) (human) and Haggard et al (1944) (rat); ethylene oxide data from Brown et al (1996); and styrene data from Ramsey and Young (1978) (human), Ramsey et al (1980) (human), and Young et al (1979) (rat). (b) to changes in ventilation caused by fire gases.…”

Section: Fire Environment and Halon 1301mentioning

confidence: 99%

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Incorporation of Acute Dynamic Ventilation Changes into a Standardized Physiologically Based Pharmacokinetic Model

Stuhmiller

2007

Inhalation Toxicology

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A seven-compartment physiologically based pharmacokinetic (PBPK) model incorporating a dynamic ventilation response has been developed to predict normalized internal dose from inhalation exposure to a large range of volatile gases. The model uses a common set of physiologic parameters, including standardized ventilation rates and cardiac outputs for rat and human. This standardized model is validated against experimentally measured blood and tissue concentrations for 21 gases. For each of these gases, body-mass-normalized critical internal dose (blood concentration) is established, as calculated using exposure concentration and time duration specified by the lowest observed adverse effect level (LOAEL) or the acute exposure guideline level (AEGL). The dynamic ventilation changes are obtained by combining the standardized PBPK model with the Toxic Gas Assessment Software 2.0 (TGAS-2), a validated acute ventilation response model. The combined TGAS-2P model provides a coupled, transient ventilation and pharmacokinetic response that predicts body mass normalized internal dose that is correlated with deleterious outcomes. The importance of ventilation in pharmacokinetics is illustrated in a simulation of the introduction of Halon 1301 into an environment of fire gases.

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Section: Other Common Volatile Chemicals Found In the Environmentmentioning

confidence: 87%

Section: Fire Environment and Halon 1301mentioning

confidence: 99%

Incorporation of Acute Dynamic Ventilation Changes into a Standardized Physiologically Based Pharmacokinetic Model

Stuhmiller

2007

Inhalation Toxicology

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“…1 The increases in motor activity previously observed for female rats exposed to isopropanol vapor were reproduced in this study with increases in motor activity observed at all of the evaluation time points during the exposure regimen. 1 Due to the reproducibility of these effects in females, as well as the reported similarity in metabolism of isopropanol between male and female rats, 11 the reason for the lack of observed motor activity effects for male animals in the previous subchronic neurotoxicity study is unclear. One possible explanation for the lack of effects is that motor activity evaluations for male rats occurred several hours later than for female rats.…”

Section: Discussionmentioning

confidence: 99%

Motor activity effects in female Fischer 344 rats exposed to isopropanol for 90 days

Burleigh-Flayer¹,

Gill²,

Hurley³

et al. 1998

J. Appl. Toxicol.

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In a previous subchronic neurotoxicity study, increases in motor activity were observed for female rats after 9 and 13 weeks of exposure to 5000 ppm of isopropanol vapor.1 The present study was conducted to evaluate the reproducibility of these effects and, if reproducible, to assess the potential for reversibility following cessation of exposure. Two groups, each containing 30 female Fischer 344 rats, were exposed to concentrations of zero (control) and 5000 ppm of isopropanol vapor for 6 h per day, 5 days per week. Fifteen of the animals in the control and 5000 ppm groups were exposed for 9 weeks (designated as the 9‐week subgroup), while the other 15 animals in each group were exposed for 13 weeks (designated as the 13‐week subgroup). Motor activity was assessed for both subgroups prior to exposure and following 4, 7 and 9 weeks of exposure. Motor activity was also measured for rats in the 13‐week subgroup following 11 and 13 weeks of exposure. These motor activity measurements were made 18–20 h following the end of the last exposure for that week. In addition, to evaluate the reversibility of motor activity effects, measurements were made on three occasions during the week following the final exposure for rats in both the 9‐week and 13‐week subgroups and weekly thereafter for five additional weeks for rats in the 13‐week subgroup. Increases in cumulative test session motor activity counts were observed following 4, 7 and 9 weeks of exposure for rats in the 9‐week subgroup. Increases in cumulative test session motor activity counts were also observed following 4, 7, 9, 11 and 13 weeks of exposure for rats in the 13‐week subgroup. Reversibility of this effect was observed for rats in the 9‐week subgroup within 2 days following the last exposure. Reversibility was also noted for rats in the 13‐week subgroup but not until Study Week 15 (2 weeks following the last exposure). Minor changes were observed in the shape of the motor activity habituation curves for isopropanol‐exposed animals in the 9‐week and 13‐week subgroups at ca. 50% of the measurement intervals beginning at Study Week 4. While most of these statistical changes were observed in conjunction with increases in cumulative test session motor activity, some were observed following time points where recovery of the cumulative test session motor activity counts had occurred. No change in the shape of the motor activity habituation curve was observed at 42 days following the last exposure, indicating that complete recovery of motor activity effects had occurred. Thus, repeated exposure of female rats to 5000 ppm of isopropanol produced reversible increases in motor activity. © 1998 John Wiley & Sons, Ltd.

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“…Elimination from the blood follows first-order kinetics. Approximately 80 % of an intravenous dose is oxidised to acetone in rats and mice (Slauter et al, 1994). Excretion occurs mainly through the expired air either as unchanged isopropanol or as acetone.…”

Section: Absorption Distribution Metabolism and Excretion (Adme) Anmentioning

confidence: 99%

Safety and efficacy of saturated and unsaturated aliphatic secondary alcohols, ketones and esters with esters containing secondary alcohols belonging to chemical group 5 when used as flavourings for all animal species

Aquilina¹,

Bampidis²,

Bastos³

et al. 2015

EFS2

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This opinion considers the safety and efficacy of 17 compounds belonging to chemical group 5 when used as feed flavourings for all animal species. Isopropanol and isopropyl tetradecanoate are safe at a maximum dose level of 25 mg and 5 mg/kg feed, respectively, based on comparable levels of exposure of humans and animals to isopropanol. From toxicological data, heptan-2-one and pentan-2one are safe at the proposed maximum dose level (5 mg/kg) for all species except piglets (4 mg/kg), chickens for fattening and laying hens (3 mg/kg) and cats (2 mg/kg). Since no acceptable toxicological data are available for the remaining compounds, the threshold of toxicological concern approach was used to calculate maximum safe concentrations in feed. For octan-2-ol, pentan-2-ol, octan-3-ol and butan-2-one the safe level is 1.5 mg/kg feed for cattle, salmonids and non-foodproducing animals and 1 mg/kg feed for pigs and poultry. For 6-methylhept-5-en-2-one, undecan-2one, octan-2-one, nonan-2-one, octan-3-one, 6-methylhepta-3,5-dien-2-one, tridecan-2-one, nonan-3one and decan-2-one, the corresponding values are 0.5 mg/kg (cattle, salmonids and non-foodproducing animals) and 0.3 mg/kg (pigs and poultry). Mammals, birds and fish share a similar capacity to metabolise secondary alcohols, ketones and esters to innocuous substances. Consequently, no safety concern would arise for consumers from the use of these compounds as proposed in feeds. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) considers all the compounds under assessment as irritants to skin, eyes and respiratory tract, and as skin sensitisers. Use of the compounds in animal feed at the maximum safe level is considered safe for the environment, except for nonan-3-one in sea cages, where only 0.047 mg/kg is safe. Since all of the compounds are used in food as flavourings and their function in feed is essentially the same as that in food no demonstration of efficacy is necessary. Feed), 2015. Scientific opinion on the safety and efficacy of saturated and unsaturated aliphatic secondary alcohols, ketones and esters with esters containing secondary alcohols belonging chemical group 5 when used as flavourings for all animal species.

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Disposition and Pharmacokinetics of Isopropanol in F-344 Rats and B6C3F1 Mice

Cited by 4 publications

References 0 publications

Incorporation of Acute Dynamic Ventilation Changes into a Standardized Physiologically Based Pharmacokinetic Model

Incorporation of Acute Dynamic Ventilation Changes into a Standardized Physiologically Based Pharmacokinetic Model

Motor activity effects in female Fischer 344 rats exposed to isopropanol for 90 days

Safety and efficacy of saturated and unsaturated aliphatic secondary alcohols, ketones and esters with esters containing secondary alcohols belonging to chemical group 5 when used as flavourings for all animal species

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