Significance of 2-methoxypropionic acid formed from beta-propylene glycol monomethyl ether: integration of pharmacokinetic and developmental toxicity assessments in rabbits.
Commercial grade propylene glycol monomethyl ether (PGME), which is composed of > 99.5% alpha-isomer and < 0.5% beta-isomer, has been shown in several studies to have a low potential for developmental toxicity. Nonetheless, questions have been raised about potential human developmental toxicity due to beta-PGME, because it can be metabolized to 2-methoxypropionic acid (MPA), a compound bearing structural similarity to the teratogen, methoxyacetic acid (MAA). Accordingly, a series of in vivo developmental toxicity, whole embryo culture, and in vivo pharmacokinetic experiments were conducted in New Zealand White rabbits (highly sensitive to these compounds) to better understand the developmental toxicity potential of MPA and the kinetics of its formation from beta-PGME. For the in vivo developmental toxicity studies, groups of 20 inseminated rabbits were gavaged with 0, 10, 26, or 78 mg/kg/day of MPA on gestation day (GD) 7-19, followed by fetal evaluation on GD 28. Results with MPA were compared with those of rabbits similarly dosed with 0, 2.5, 7.5, or 15 mg/kg/day of MAA. Developmental toxicity no-observable-effect levels (NOEL) were approximately 10-fold higher for MPA (26 mg/kg/day) than for MAA (2.5 mg/kg/day). Also, the severity of effects caused by MPA was less than that of MAA, and unlike MAA, MPA was not selectively toxic to the fetus. This differential toxicity was also seen in whole embryo cultures of GD 9 rabbit embryos, in which there were no adverse effects of MPA (1.0, 5.0 mM) or its parent compound, beta-PGME (0.5, 2.0 mM), but severe dysmorphogenesis in 100% of embryos cultured in 5.0 mM MAA. The pharmacokinetics study showed rapid and complete conversion of beta-PGME to MPA, with a relatively long elimination half-life (33-44 h) for MPA. However, peak and AUC concentrations of MPA in blood associated with the MPA LOEL dose of 78 mg/kg/day were 1.3 mM and 52.9 mM-h/l, respectively, suggesting a relatively high threshold based on internal dosimetry. Taken together, these data indicate a negligible risk of developmental toxicity due to MPA formation from the small amounts of beta-isomer present in commercial PGME.
Carney
E W
EW
Toxicology & Environmental Research and Consulting, 1803 Building, The Dow Chemical Company, Midland, Michigan 48674, USA. ecarney@dow.com
Pottenger
L H
LH
Johnson
K A
KA
Liberacki
A B
AB
Tornesi
B
B
Dryzga
M D
MD
Hansen
S C
SC
Breslin
W J
WJ
D000014:Abnormalities, Drug-Induced; D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D009924:Organ Culture Techniques; D011247:Pregnancy; D011422:Propionates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D011409:Propylene Glycols / Q000493:pharmacokinetics* / Q000633:toxicity*; D011817:Rabbits; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
D000085:Acetates; D011422:Propionates; D011409:Propylene Glycols; D013723:Teratogens; C107446:2-methoxypropanoic acid; C005216:propylene glycol methyl ether; C013598:methoxyacetic acid