Development of a physiologically based pharmacokinetic model for propylene glycol monomethyl ether and its acetate in rats and humans

Corley, Rick A.; Gies, Richard A.; Wu, Hong; Weitz, Karl K.

doi:10.1016/j.toxlet.2003.12.078

Cited by 17 publications

(8 citation statements)

References 49 publications

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“…PGMEA has a very short half‐life (hydrolyzed to PGME) in humans (∼36 minutes in blood and liver homogenates) and even shorter in rats (∼15 minutes in blood and 30 minutes in liver homogenates). The in vivo half‐life for PGMEA is less than 4 minutes due to the contribution of esterase activity in blood and tissues together (Corley et al , 2004). Thus, very little PGMEA is found in tissues following exposure.…”

Section: Resultsmentioning

confidence: 99%

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Using Physiologically‐Based Pharmacokinetic Modeling to Address Nonlinear Kinetics and Changes in Rodent Physiology and Metabolism Due to Aging and Adaptation in Deriving Reference Values for Propylene Glycol Methyl Ether and Propylene Glycol Methyl Ether Acetate

Kirman¹,

Sweeney²,

Corley³

et al. 2005

Risk Analysis

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Reference values, including an oral reference dose (RfD) and an inhalation reference concentration (RfC), were derived for propylene glycol methyl ether (PGME), and an oral RfD was derived for its acetate (PGMEA). These values were based on transient sedation observed in F344 rats and B6C3F1 mice during a two-year inhalation study. The dose-response relationship for sedation was characterized using internal dose measures as predicted by a physiologically-based pharmacokinetic (PBPK) model for PGME and its acetate. PBPK modeling was used to account for changes in rodent physiology and metabolism due to aging and adaptation, based on data collected during Weeks 1, 2, 26, 52, and 78 of a chronic inhalation study. The peak concentration of PGME in richly perfused tissues (i.e., brain) was selected as the most appropriate internal dose measure based on a consideration of the mode of action for sedation and similarities in tissue partitioning between brain and other richly perfused tissues. Internal doses (peak tissue concentrations of PGME) were designated as either no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) based on the presence or the absence of sedation at each time point, species, and sex in the two-year study. Distributions of the NOAEL and LOAEL values expressed in terms of internal dose were characterized using an arithmetic mean and standard deviation, with the mean internal NOAEL serving as the basis for the reference values, which was then divided by appropriate uncertainty factors. Where data were permitting, chemical-specific adjustment factors were derived to replace default uncertainty factor values of 10. Nonlinear kinetics, which was predicted by the model in all species at PGME concentrations exceeding 100 ppm, complicate interspecies, and low-dose extrapolations. To address this complication, reference values were derived using two approaches that differ with respect to the order in which these extrapolations were performed: (1) default approach of interspecies extrapolation to determine the human equivalent concentration (PBPK modeling) followed by uncertainty factor application, and (2) uncertainty factor application followed by interspecies extrapolation (PBPK modeling). The resulting reference values for these two approaches are substantially different, with values from the latter approach being seven-fold higher than those from the former approach. Such a striking difference between the two approaches reveals an underlying issue that has received little attention in the literature regarding the application of uncertainty factors and interspecies extrapolations to compounds where saturable kinetics occur in the range of the NOAEL. Until such discussions have taken place, reference values based on the former approach are recommended for risk assessments involving human exposures to PGME and PGMEA.

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Section: Resultsmentioning

confidence: 99%

“…A PBPK model was recently developed for PGME and PGMEA (Corley et al , 2004). The structure of the model is depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Using Physiologically‐Based Pharmacokinetic Modeling to Address Nonlinear Kinetics and Changes in Rodent Physiology and Metabolism Due to Aging and Adaptation in Deriving Reference Values for Propylene Glycol Methyl Ether and Propylene Glycol Methyl Ether Acetate

Kirman¹,

Sweeney²,

Corley³

et al. 2005

Risk Analysis

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“…The weak band at around 1640 cm -1 was observed, but the shoulder in the region disappeared for the LDO Mg/Al 0.25, 0.5 and 1.0 (B1.0). The band appeared at around 1390 cm -1 (t 3 ) which was about 20 cm -1 higher than that of the LDHs, and no splitting was found for all the LDO samples. …”

Section: Ft-ir Spectramentioning

confidence: 87%

“…Propylene glycol monomethyl ether (PM) is a member of the family of glycol ether with a wide variety of consumer products and industrial applications. PM is used in the chemical, agricultural, automotive, paint, lacquer, and varnish industry [3]. Its predominant use is as a solvent in various manufacturing processes and as a chemical building block for the manufacture of propylene glycol methyl ether acetate.…”

Section: Introductionmentioning

confidence: 99%

“…Among the products, PPM has a lower toxicity than 2-methoxy-1-propanol, so high selectivity is required for the reaction [2]. Acid catalysts, such as BF 3 , heteropolyacids and solid acids, can be used for the reaction and appear to exhibit good catalytic activity, but they inevitably produce undesirable 2-methoxy-1-propanol and other byproducts. The epoxy ring of PO may preferentially open at the least sterically hindered position over the basic catalyst and lead to most secondary alcohol PPM [2,[4][5][6].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Propylene Glycol Monomethyl Ether Over Mg/Al Hydrotalcite Catalyst

et al. 2010

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Mg-Al hydrotalcites with different Mg/Al molar ratios were prepared and characterized by XRD, FT-IR, SEM and BET analyses. The calcined hydrotalcite with Mg/Al molar ratio of 4.0 (LDO Mg/Al 4.0) exhibited the highest catalytic activity in the synthesis of propylene glycol methyl ether (PM). The catalytic activity relating to the amount of the basic sites and crystallinity depended on the Mg/Al molar ratio. The optimal equilibrium of acidbase property and high crystallinity made the LDO Mg/Al 4.0 an excellent catalyst in the reaction. Etherification of propylene oxide (PO) with methanol over the LDO Mg/Al 4.0 was researched. The optimized reaction conditions were as follows: 140°C, catalyst amount 0.9 wt%, methanol/PO molar ratio 4.0 and 6 h. The PO conversion and PM selectivity were 93.2 and 97.4%, respectively. Above all, almost all the PM was 1-methoxy-2-propanol, for no 2-methoxy-1-propanol was detected by GC analysis in the reaction products, and the catalyst could be reused for five times.

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Physiologically Based Pharmacokinetic Modelling

Leung

2009

General, Applied and Systems Toxicology

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This chapter presents the readers with a primer on the subject of physiologically based pharmacokinetic (PBPK) modelling. It discusses the theory and principles of PBPK modelling, and compares and contrasts it with classical pharmacokinetic modelling. It describes the multiple steps involved in developing PBPK models, and includes a compilation, with complete referencing, of published PBPK models for environmental chemicals that have been developed to date. The many applications of PBPK modelling to address issues in toxicology and health risk assessment are discussed with relevant examples. It concludes with some discussion of the problems and limitations in PBPK modelling, and offers some observations about future directions for this rapidly emerging field.

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Development of a physiologically based pharmacokinetic model for propylene glycol monomethyl ether and its acetate in rats and humans

Cited by 17 publications

References 49 publications

Using Physiologically‐Based Pharmacokinetic Modeling to Address Nonlinear Kinetics and Changes in Rodent Physiology and Metabolism Due to Aging and Adaptation in Deriving Reference Values for Propylene Glycol Methyl Ether and Propylene Glycol Methyl Ether Acetate

Using Physiologically‐Based Pharmacokinetic Modeling to Address Nonlinear Kinetics and Changes in Rodent Physiology and Metabolism Due to Aging and Adaptation in Deriving Reference Values for Propylene Glycol Methyl Ether and Propylene Glycol Methyl Ether Acetate

Synthesis of Propylene Glycol Monomethyl Ether Over Mg/Al Hydrotalcite Catalyst

Physiologically Based Pharmacokinetic Modelling

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