Propan-1-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

publication

Title:

Linking internal dosimetries of the propyl metabolic series in rats and humans using physiologically based pharmacokinetic (PBPK) modeling

Author:

Jordan N. Smith,Kimberly J. Tyrrell, Jeremy P. Smith, Karl K. Weitz, Willem Faber

Year:

2020

Bibliographic source:

Regulatory Toxicology and Pharmacology 110 (2020) 104507

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Development of a physiologically based pharmacokinetic (PBPK) model in rats and humans for the propyl metabolic series including propyl acetate, 1-propanol, propionaldehyde, and propionic acid. To develop the PBPK model, in vitro metabolism of propyl acetate in blood and liver S9 fractions was measured. Additionally concentrations of propyl compounds in blood following intravenous (iv) infusion of 13C-propanol or 13C-propionic acid and closed chamber inhalation exposures to propyl acetate or propanol in rats were measured.
Using these studies and other published data, an existing PBPK model for the butyl metabolic series was modified to simulate time course concentrations of propyl compounds in rats and humans.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Propan-1-ol

EC Number:

200-746-9

EC Name:

Propan-1-ol

Cas Number:

71-23-8

Molecular formula:

C3H8O

IUPAC Name:

propan-1-ol

Radiolabelling:

not specified

Test animals

Species:

other: rats and humans

Strain:

other: see "any other information on materials and methods"

Details on species / strain selection:

see "any other information on materials and methods"

Sex:

male/female

Details on test animals or test system and environmental conditions:

see "any other information on materials and methods"

Administration / exposure

Route of administration:

other: intravenous step-up infusion and a restrained whole-body inhalation

Vehicle:

not specified

Details on exposure:

see "any other information on materials and methods"

Duration and frequency of treatment / exposure:

see "any other information on materials and methods"

Doses / concentrations

Doses / concentrations 1

Remarks:

see "any other information on materials and methods"

Doses / concentrations 2

Dose / conc.:

2 000 ppm

Remarks:

propanol for inhalation experiment

No. of animals per sex per dose / concentration:

see "any other information on materials and methods"

Details on study design:

see "any other information on materials and methods"

Details on dosing and sampling:

see "any other information on materials and methods"

Statistics:

see "any other information on materials and methods"

Results and discussion

Main ADME results

Main ADME results 1

Type:

distribution

Results:

Following inhalation exposures to propanol, propanol concentrations in blood peaked (136 μM) 10 min following exposure.

Main ADME results 2

Type:

metabolism

Results:

Sensitivity analyses identified 13C-propionic acid concentrations in blood following iv exposures to isotopic propanol as more dependent on propionic acid clearance in liver compared to other tissues.

Main ADME results 3

Type:

distribution

Results:

Following isotopic propanol infusions, 13C-propanol was detected in blood in 3 min and remained above detection limits at the last time point sampled (42 min).

Main ADME results 4

Type:

metabolism

Results:

in vitro: disappearance of isotopic propionic acid in S9 liver fractions from rats and humans was not observed, suggesting that enzymes present in S9 fractions do not have metabolic capability to oxidize this compound.

Main ADME results 5

Type:

metabolism

Results:

in vivo rat: In general, measured concentrations of propyl compounds in blood did not vary by gender following either compound exposure (propanol or propionic acid).

Main ADME results 6

Type:

metabolism

Results:

in vivo: humans have a 3-fold higher propanol oxidation clearance in other tissues (than blood) compared to rats

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

propanol, propionaldehyde and propionic acid

Any other information on results incl. tables

A PBPK model for the propyl metabolic series in rats and humans was developed. To aid in model development, in vitro metabolism of propyl acetate in blood and liver S9 fractions in rats and humans was measured. In vivo studies administering isotopically labeled propanol and propionic acid intravenously to rats and closed chamber inhalation studies with propyl acetate and propanol were conducted. Concentrations of propyl compounds in blood and in air of closed inhalation chambers were measured and used to optimize and validate the model.

Esterases rapidly hydrolyzed absorbed propyl acetate, leading to limited propyl acetate levels and residence time in blood following propyl acetate exposures. Rapid hydrolysis of propyl acetate in blood and liver S9 fractions from rats and humans in vitro was observed, and higher propanol concentrations in blood than propyl acetate concentrations in blood following inhalation exposures to propyl acetate in rats but not in humans. In rats, measured propyl acetate hydrolysis in liver was between metabolic rates used for modeling ethyl acetate and butyl acetate (11.0 vs. 0.6 and 38.7 L/hr/kg0.75, respectively) but lower than both compounds in blood (0.27 vs. 8.1 and 6 L/hr/kg0.75, respectively) and other tissues (28.6 vs. 49 and 60 L/hr/kg0.75, respectively) (Barton et al., 2000; Crowell et al., 2014; Teeguarden et al., 2005). This suggests variable substrate affinities for different esterases found at varying concentrations among tissues. Overall, based on these rates of hydrolysis, propyl acetate is not ecpected to persist in vivo.

The propyl metabolic series is an example of “non-linear” species extrapolations, where higher concentrations of propanol in blood from propyl acetate inhalation exposures compared to propanol inhalation exposures were observed in rats but are predicted not to occur in humans.

The model predicts lower propanol concentrations in blood compared to predicted propanol concentrations from NOAEL exposures in rats. This observation suggests current TLVs are protective based on an internal dose metric, which presumably would protect against central nervous system intoxication or other systemic toxicity endpoints.

A PBPK model for the propyl metabolic series in rats and humans was developed for application to risk assessment. The model predicts rapid clearance of propyl acetate, higher levels of propanol from propyl acetate inhalation compared to propanol inhalation in rats but not humans, and low concentrations of propionic acid in blood following exposures to propyl acetate or propanol. Regulators can use this model for risk assessment of propyl compounds by linking internal dosimetries under various scenarios of exposure to propyl compounds.

Applicant's summary and conclusion

Conclusions:

Consistent with measured in vitro and in vivo data, the optimized propyl series model predicts rapid clearance of propyl acetate, higher concentrations of propanol in blood from propyl acetate inhalation compared to propanol inhalation in rats but not in humans, and low concentrations of propionic acid in blood from exposures to propyl acetate or propanol.