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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:
key study
Study period:
1982
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Published study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1982

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The objective of this study was to determine the absorbed “dose” of EDC and to characterize its elimination after exposure by the two routes. This was estimated by administering EDC to the animals, measuring blood levels of EDC at various times, and then constructing a pharmacokinetic model. A second objective was to determine the major routes of elimination after exposure to [14C]EDC by gavage or inhalation. This was done to investigate the possibility that different metabolic pathways might be involved after the two exposures.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
gas under pressure: refrigerated liquefied gas
Details on test material:
Non-labeled EDC was obtained from Dow Chemical USA. This material was assayed by gas chromatography at the beginning and end of the study and tested greater than 99.9% purity in each case. [ ‘%]EDC (uniformly labeled, 3.2 mCi/mmol) was purchased from New England Nuclear (Lot No. 1194-143). The radio chemical purity of this material was checked by GC/ MS analysis and was >99%.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Osborne-Mendel
Sex:
male
Details on test animals and environmental conditions:
The animals weighed 150 to 250 g when received and were acclimated at least 1 week before use. All animals were housed in rooms designed to maintain 22°C, 50% humidity, and a 7 AM to 7 PM light cycle. Food (Purina Laboratory Chow, Ralston Purina Co., St. Louis, MO.) and water were available ad libitum except during exposures or where otherwise indicated.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Animals were exposed to EDC at doses of 150 mg/kg by gavage with a solution of 100 mg/ml EDC in corn oil (1.5 ml/kg body wt). Oral dosing was carried out between 7 AM and 10 AM. Animals were not fasted prior to exposures.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
150 mg/kg by gavage

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Blood levels of EDC were measured after gavage with 150 mg/kg EDC. Absorption was very rapid following gavage. Peak blood levels were reached in less than 15 min and were considerably higher (30 to 44 pg/ml) than observed after inhalation.
Details on excretion:
The elimination of EDC after gavage was complex. Although the elimination was roughly log-linear for the first part of the experiment (with an apparent half-life of ca. 90 min in this portion), the pattern changed considerably during the latter part of the experiment (Fig. 1B). Once the blood levels of EDC fell below 5 to 10 pg/ml, the EDC seemed to be eliminated more rapidly, with a half-life approaching that observed for the beta-phase after inhalation exposure (20 to 30 min).

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

Ethylene dichloride (EDC) induces tumors in rats and mice when administered chronically by gavage. However, chronic inhalation of EDC vapor failed to induce any treatment-related tumors. To help understand the consequences of environmental exposure to EDC by either route, 14C-EDC was administered to male Osborne-Mendel rats by gavage (150 mg/kg in corn oil) or inhalation (150 ppm, 6 hr). EDC was extensively metabolized following either exposure. No significant differences were observed in the route of excretion of nonvolatile metabolites. In each case, -85% of the total metabolites appeared in the urine, with 7 to 8, 4, and 2% found in the CO,, carcass, and feces, respectively. The major urinary metabolites were thiodiacetic acid and thiodiacetic acid sulfoxide, suggesting a role for glutathione in biotransformation of EDC. Gross macromolecular binding (primarily protein binding) was studied after inhalation or gavage. No marked differences were noted between the two routes, or between “target” and “nontarget” tissues, after in vivo administration of EDC. Covalent alkylation of DNA by EDC was studied in Salmonella typhimurium and rats. DNA alkylation in S. typhimurium was directly related to the frequency of mutation in these bacteria. However, when DNA was purified from the organs of rats exposed in vivo to EDC, very little alkylation was observed after either gavage or inhalation (2 to 20 alkylations per million nucleotides). DNA alkylation after gavage was two to five times higher than after inhalation, but no marked differences were noted between target and nontarget organs. Pharmacokinetic studies indicated that peak blood levels of EDC were approximately five times higher after gavage than after inhalation. When pharmacokinetic data were modeled, it appeared that the elimination of EDC may become saturated when high blood levels are produced and that such saturation is more likely to occur when equivalent doses are administered by gavage versus inhalation. Since toxicity often occurs when the normal detoxification pathways are overwhelmed, this toxicity may represent the most reasonable explanation for the apparent differences between the two bioassays.