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1334980 
Journal Article 
Abstract 
Influence of the physical state of the plasticizer, di(2-ethylhexyl)phthalate (DEHP) on its biological disposition and action 
Rubin, RJ; Schulz, CO 
1974 
1 
Toxicology and Applied Pharmacology
ISSN: 0041-008X
EISSN: 1096-0333 
29 
1 
143 
English 
is part of a larger document 3378179 Abstracts of papers for the Thirteenth Annual Meeting of the Society of Toxicology, Washington, D.C. March 10–14, 1974
There has been considerable recent interest in the toxicology of phthalate ester plasticizers (Env. Health Perspectives 3, 1973). Our laboratory had previously shown that in rats iv DEHP (500 mg/kg) significantly altered reticuloendothelial (RE) clearance. Since DEHP is a highly insoluble oil, administration of large doses required the use of sonicated aqueous emulsions. We have now sought to develop detergent-containing vehicles for the administration of solubilized DEHP. The sonicated aqueous emulsion (DEHP 50 mg/ml) was milky white and completely opaque; it had 19x10^6 droplets/ml with a diam of 1.9-2.6 μ. DEHP (100 mg/ml) in Vehicle E (50% DMSO, 5% Tween 80, and 45% saline) was opalescent and contained 5.4x10^6 droplets/ml, 10.5-42 μ in diam. DEHP (50 mg/ml) in Vehicle A (25% DMSO, 10% Tween 80, and 65% saline) was completely translucent and had no visible droplets. Addition of rat plasma to these preparations resulted in the settling out of additional oil droplets with the first two preparations, but had no effect on the solubility of DEHP in Vehicle A. DEHP (250 mg/kg iv) as a sonicated emulsion resulted in a 75% increase in the half-time for RE clearance in rats. In Vehicle E this same dose caused a 200% increase while in Vehicle A there was no significant effect. These results clearly implicate the particle size and number in the RE effect and indicate no direct inhibitory effect ofDEHP. The solubilized DEHP disappeared from blood logarithmically with a half-time of 21 min. In contrast, the emulsion form displays two distinct decay rates having a half-time of 9 and 22 min, respectively. These results suggest that the emulsified DEHP is rapidly taken up by RE clearance followed by a slower rate of metabolism of the solubilized molecules. With the solubilized dosage form of DEHP, only the latter rate of clearance pertains. In support of this, whereas 50% of the emulsified dose is in the liver after 1 hr and 10% after 24 hr, only 10% of the solubilized dose is found in the liver after 1 hr and 0.2% after 24 hr. The solubilized DEHP is found primarily in the eviscerated carcass, equally distributed among the muscles and bony skeleton. The solubilized dosage form of DEHP produced a marked pulmonary edema at 200 mg/kg. At 300 mg/kg 50% of the rats died of asphyxiation. The vehicle alone or the sonicated emulsion of DEHP did not produce edema. DEHP solubilized in 15% Tween 80 only was equally edematous. These results emphasize the necessity for knowledge of the physical state of DEHP in evaluating its toxicologic potential. 
dimethyl sulfoxide; drug vehicle; phthalic acid bis(2 ethylhexyl) ester; polysorbate 80; sodium chloride; blood; bone; dose response; drug absorption; drug blood level; drug clearance; drug determination; drug distribution; drug half life; drug response; drug solubility; intravenous drug administration; lung; lung edema; muscle; pharmacokinetics; rat; reticuloendothelial system; theoretical study 
Thirteenth Annual Meeting of the Society of Toxicology 
Washington, D.C. 
March 10–14, 1974