Comparison of the teratogenic potential of inhaled ethylene glycol monomethyl ether in rats, mice, and rabbits.

Toxicology Research Laboratory, Health and Environmental Science, The Dow Chemical Company, Midland, Michigan 48640 USA
Toxicology and Applied Pharmacology (Impact Factor: 3.63). 10/1984; 75(3):409-22. DOI: 10.1016/0041-008X(84)90178-9
Source: PubMed

ABSTRACT Studies to assess the effects of inhaled ethylene glycol monomethyl ether (EGME) on embryonal and fetal development were conducted on groups of Fischer 344 rats, CF-1 mice, and New Zealand White rabbits. Rabbits and rats were exposed to vapor concentrations of 0, 3, 10, or 50 ppm for 6 hr/day on Days 6 through 18, or Days 6 through 15 of gestation, respectively; mice were exposed to 0, 10, or 50 ppm on Days 6 through 15 of gestation. Exposure of pregnant rabbits to 50 ppm produced significant increases in the incidence of malformations, minor variations, and resorptions, as well as a decrease in fetal body weight. Rats and mice exposed to 50 ppm showed no evidence of a teratogenic effect, although indications of slight fetotoxicity were observed in both species. Transient decreases in maternal body weight gain among rats, mice, and rabbits exposed to 50 ppm were the only consistent signs of maternal effects. No significant treatment-related effects on fetal development were observed in any of the species tested at 10 ppm of EGME or below.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Toxicological Sciences 02/2003; 71(2):217-28. · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.
    Toxicological Sciences 08/2001; 62(1):124-39. DOI:10.1093/toxsci/62.1.124 · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The Threshold of Toxicological Concern (TTC) is a principle that refers to the possibility of establishing a human exposure threshold value for all chemicals below which there is no significant risk to human health. The threshold value is primarily based on carcinogenesis data. For other potentially sensitive endpoints, such as neurotoxicity and developmental toxicity, higher TTC values are applicable, based largely on their chemical structure. The database study documented here was prompted by the question on whether such thresholds would cover irreversible structural developmental (teratogenic) effects, or whether these effects would need an extra safety factor. This would be relevant when teratogenicity occurs at lower doses than general developmental toxicity such as growth retardation and fetal death.The database presented is intended to compare the NOELs of teratogenicity with the NOELs of general developmental toxicity and the NOELs of maternal toxicity of the same compound. The studies tabulated in the database were retrieved from a variety of sources, and original scientific literature was analysed. Only those compounds producing undisputed teratogenic effects were included in the database. The additional safety factor was considered as possibly being necessary if teratogenic effects of compounds were to generally occur at lower doses than other signs of developmental toxicity. For this reason, an Embryotoxicity/Teratogenicity ratio of each compound was determined by dividing the NOEL for embryotoxicity by the NOEL for teratogenicity. Compounds with an E/T ratio greater than 1 would need an additional safety factor. From the database of 38 compounds compiled here, only 8 compounds showed a ratio larger than 1. All these compounds would be excluded from the TTC concept because of their genotoxic properties. This database therefore does not justify an extra safety factor for teratogenic compounds within the TTC concept. The database reflects an initial incomplete inventory, and does not allow for definitive conclusions. It can, however, be used as a starting point for further work by the ILSI Europe Threshold of Toxicological Concern Task Force. Het principe van de Threshold of Toxicological Concern (TTC) verwijst naar de mogelijkheid om voor alle chemische stoffen een humane blootstellinggrens te bepalen, waaronder geen noemenswaardig risico optreedt voor de gezondheid van de mens. Deze grenswaarde is in de eerste plaats gebaseerd op carcinogenese gegevens. Voor andere gevoelige effecten, zoals neurotoxiciteit en ontwikkelingseffecten gelden hogere grenswaarden. Daarbij is met name de chemische structuur bepalend voor de hoogte van de TTC. De vraag is of grenswaarden afgeleid op basis van algemene toxiciteit ook van toepassing kunnen worden beschouwd voor teratogene effecten, danwel of voor deze effecten een extra veiligheidsfactor in rekening gebracht moet worden. Dit zou het geval kunnen zijn indien teratogene effecten bij lagere doseringen gevonden worden dan meer algemene effecten op de ontwikkeling, zoals groeivertraging en foetale sterfte. In dit rapport wordt een database gepresenteerd, waarmee het mogelijk is de NOELs voor teratogeniteit met de NOELs van andere ontwikkelingseffecten en de NOELs van maternale toxiciteit van dezelfde stof te vergelijken. Om bruikbare studies naar ontwikkelingstoxiciteit te vinden van stoffen met teratogene effecten zijn meerdere bronnen geraadpleegd, en zijn de originele wetenschappelijke artikelen geanalyseerd. Alleen stoffen met onomstreden teratogene effecten werden in de database vermeld. Het idee was dat als een teratogeen effect bij een lagere dosering optreedt dan een ander toxisch ontwikkelingseffect, er een extra veiligheidsfactor 10 overwogen zou moeten worden. Om dit te bepalen is voor iedere stof de ratio bepaald van de NOEL voor ontwikkelingseffecten en de NOEL voor teratogene effecten. Stoffen waarvan de ratio groter is dan 1, zouden een extra factor 10 nodig hebben. Uit de hier samengestelde database van 38 chemische stoffen blijkt dat slechts 8 stoffen een ratio opleveren die groter is dan 1. Voor al deze stoffen geldt dat ze vanwege hun genotoxiciteit al in een vroege fase buiten het TTC concept gehouden worden. Deze database geeft daarmee geen aanleiding voor een extra veiligheidsfactor in het TTC concept voor stoffen met een teratogeen effect. De database in dit rapport is echter nog maar een voorlopige inventarisatie en laat geen definitieve conclusies toe. De database dient als basis voor verder onderzoek door de ILSI Europe Threshold of Toxicological Concern Task Force.