Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics in vivo
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented, scientifically acceptable study. Comparable to guideline, with certain restrictions

Data source

No information
NTP Report
Bibliographic source:
CHEM00324, 29-Mar-1995

Materials and methods

Objective of study:
Principles of method if other than guideline:
Method: other
GLP compliance:

Test material

Details on test material:
IUCLID4 Test substance: other TS: Dibutylphthalate, purity: > 99%

Dibutylphthalate, purity: > 99%

Test animals

other: Wistar Rats, Syrian Hamster, B6C3F1 Mice

Administration / exposure

Route of administration:
other: iv or gavage
CMC (carboxymethyl cellulose)
Duration and frequency of treatment / exposure:
7 day(s)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 2nd:
Toxicokinetic parameters:
half-life 1st:
Toxicokinetic parameters:
half-life 3rd:

Any other information on results incl. tables

The toxicokinetic studies were conducted to define the oral bioavailability of DBP when administered as a bolus dose in aqueous methylcellulose and to establish a dose range over which plasma kinetics are linear. Based on the ratios of AUC for iv and oral studies, accounting for relative dose, bioavailability was 0.90 (mice), 0 .62 (rats), and 1 .01 (hamsters) at 83, 50, and 67 mg DBP/kg, respectively . Maximum plasma concentrations at these doses were 77, 21, and 40 µg MBP/ml for mice, rats and hamsters, respectively. Based on examination of plasma concentration vs. time profiles and associated kinetic parameters, the mid and high doses appeared to be associated with nonlinear dispositional processes.

For mice, the Cmax and AUC values for the 166 mg/kg oral dose in the toxicokinetic study were 107% and 89%, respectively. Maximum concentrations obtained in the SD rat toxicokinetic study were approximately 3-fold greater than expected but remained lower than predicted by the prestart WF rat study. Plasma concentrations for hamsters in the toxicokinetic studies were well predicted by those observed in the prestart study. Obviously, the greater number of animals used in the toxicokinetic studies (n=3/timepoint) make this data more reliable than the prestart data (1 animal/timepoint) .

In previous studies with diethylhexylphthalate in rats, it was necessary to administer the dose in a plasma vehicle intraarterially versus intravenously to avoid pulmonary toxicity. The pulmonary toxicity' was attributed to trapping of the iv dose in the lung with resultant hemorrhagic lesions. An analogous sequestration phenomenon may have occurred following iv administration of DBP to mice in the prestart study wherein plasma concentrations began to increase 120 min following iv administration . In fact, in all three species, clinical signs of lethargy were observed for various time periods following iv administration (prestart and toxicokinetic studies) despite efforts to deliver as dilute a dosing solution as possible. In both rats and mice, secondary increases in plasma concentrations were apparent in several of the data sets. DBP and MBP are known to undergo extensive enterohepatic recirculation which could account for the observed plasma kinetics.

Applicant's summary and conclusion