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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
A Toxicokinetic Study of Inhaled Ethylene Glycol Monomethyl Ether (2-ME) and Validation of a Physiologically Based Pharmacokinetic Model for the Pregnant Rat and Human
Author:
Gargas ML, Tyler TR, Sweeney LM, Corley RA, Weitz KK, Mast TJ, Paustenbach DJ and Hays SM.
Year:
2000
Bibliographic source:
Toxicol Appl Pharmacol 165: 53-62

Materials and methods

Objective of study:
toxicokinetics
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: > 99.8%
- Impurities (identity and concentrations): Water content < 0.02%
- Storage condition of test material: Stored at room temperature under a nitrogen headspace
- Other: Supplied by Union Carbide (Charleston, WV)
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: Sprague-Dawley Crl:CD
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Raleigh, NC)
- Housing: Individually
- Diet: Purina 5002 certified pelleted diet, ad libitum except during exposure
- Water: Municipal tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: Exposure chamber temperature was maintained at approximately 75 degrees F
- Humidity: Exposure chamber relative humidity was maintained at approximately 55%

Administration / exposure

Route of administration:
other: Inhalation: vapor
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: Atmospheres were produced using a Battelle-designed vapor generation system. Concentrations were controlled by adjusting the test material pump rate and dilution airflow.
- Method of holding animals in test chamber: Individually housed in Hazelton 2000 chambers (Hazelton, Aberdeen, MD)
Duration and frequency of treatment / exposure:
Animals were exposed 5 consecutive days (gestation days 11-15). Total daily exposure duration was 6 hr plus the time required to reach 90% of the targeted concentration, which averaged 18 minutes.
Doses / concentrations
Remarks:
Doses / Concentrations:
Target concentrations were 10 and 50 ppm. Average concentrations over the 30 hrs of exposure were 10.7 ppm and 47.2 ppm (range of 34.5 to 59.2 ppm).
Details on study design:
- Dose selection rationale: Target concentrations were selected based on the no observed effect level (NOEL, 10 ppm) and the lowest observed effect level (LOEL, 50 ppm) reported for developmental toxicity in rats.

Exposures were conducted over a 5-day period to allow near steady-state conditions to be achieved, based on a published half-life for 2-MAA in urine on the order of 24 hr in rats (Medinsky et al, 1990)
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: 2-ME and 2-MAA levels were quantified in blood, urine and fetal homogenates
- Time and frequency of sampling:
- Blood – at 1 and 3 hours during the final exposure, immediately post-exposure and at 0.5, 1, 2, 4, 8, 18, 42, 66 and 90 hr postexposure.
- Urine – Each rat scheduled for the 18 hr postexposure blood collection was placed in an individual metabolism cage (Lab Products, Seaford, DE) for 0 – 18 hr postexposure urine collection. Urine samples were collected over dry ice and stored at -70 degrees C until analyzed.
- Fetal homogenates – The uterus was removed from each rat at the time of blood collection. Fetuses were removed, placed as a litter in a single container, weighed and flash frozen. Fetuses collected at 0 and 8 hr postexposure were analyzed.

- Other:
Blood, urine and fetal samples were collected from control animals, spiked with known quantities of 2-ME and 2-MAA, and stored frozen along with samples collected from exposed animals to correct for potential losses of analytes during storage.

Sample analysis was by GC/FID

Results and discussion

Any other information on results incl. tables

Despite minor differences between the rat model predictions and observed data, the authors consider the model predictions to be quite good considering they represent exposures to 2-ME over a 5-day period, and that the parent compound is rapidly eliminated and the key metabolite is significantly more long-lived.

The authors consider the human model described as being only partially validated since there was only a single human data set that could be used for comparison of model predictions, and that data set was used to set one of the model parameters.

Applicant's summary and conclusion

Conclusions:
The human equivalent exposure concentrations that were estimated in this work were 20% higher than the corresponding NOEL and LOEL values established in the rat. This indicates that pregnant women exposed to inhaled concentrations of 2-ME for 8 hr/day, 5 days/week for the duration of pregnancy do not reach blood 2-MAA concentrations that are known to be developmentally toxic to mice and rats until the exposure concentration reaches 60 ppm or higher.
Executive summary:

In a study to expand previous work on a PBPK model for 2 -methoxyethanol (2 -ME), pregnant rats were exposed for 5 days (gestation days 11-15), 6 h/day, to 2-ME vapor at 10 and 50 ppm. Validation consisted of comparing model output to maternal blood and fetal 2-ME and 2-MAA concentrations during and following 5 days of exposure (gestation days 11-15). These concentrations correspond to a known no observed effect level (NOEL) and a lowest observed effect level (LOEL) for developmental effects in rats. The rat PBPK model for 2-ME/2-MAA was scaled to humans and the model (without the pregnancy component) used to predict data collected by other investigators on the kinetics of 2-MAA excretion in urine following exposures to 2-ME in human volunteers. The partially validated human model (with the pregnancy component) was used to predict equivalent human exposure concentrations based on 2-MAA dose measures (maximum blood concentration, C(max), and average daily area under the 2-MAA blood concentration curve, AUC, during pregnancy) that correspond to the concentrations measured at the rat NOEL and LOEL exposure concentrations.

The human equivalent exposure concentrations that were estimated in this work were 20% higher than the corresponding NOEL and LOEL values established in the rat. This indicates that pregnant women exposed to inhaled concentrations of 2-ME for 8 hr/day, 5 days/week for the duration of pregnancy would not reach blood 2-MAA concentrations that are known to be developmentally toxic to mice and rats until the exposure concentration reaches 60 ppm or higher (based on the 12ppm NOAEL in rats).