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Basic toxicokinetics

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basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline, in-vitro and human experimental studies, published in peer reviewed literature, minor restrictions in design and reporting but otherwise acceptable for assessment.

Data source

Reference Type:

Materials and methods

Objective of study:
Test guideline
no guideline followed
Principles of method if other than guideline:
Toxicokinetic parameters for inhaled isoprene were determined in healthy human volunteers. These parameters were used to develop a physiological toxicokinetic model.
GLP compliance:
not specified

Test material

Constituent 1
Details on test material:
in-vitro studies - Isoprene, 99% was supplied by Aldrich, Steinheim, Germany.
in-vivo animal studies - see Basic toxicokinetics, Supporting study, Peter et al, 1987.
Human study- Isoprene, 99.5% was supplied by Chemie AG, Buchs, Switzerland.

Test animals

other: human, rat and mice
other: healthy human volunteers, Sprague-Dawley rats and NMRI mice
Details on test animals or test system and environmental conditions:
In-vitro animal studies: male Sprague-Dawley rats and male NMRI were supplied by GSF, Neuherberg, Germany and Charles River, Sulzfeld, Germany respectively; blood and tissues were used for determination of partition coefficients.

In-vivo animal studies used male Wistar rats and male B6C3F1 mice; see Supporting study, Peter et. al., 1987 for details.

Human studies involving exposure by inhalation to isoprene: 4 male and 1 female healthy volunteers, 54-91kg body weight, 28-41 years.

Human studies involving measurement of endogenous production of isoprene: 3 male and 1 female healthy volunteers, 54-75kg body weight, 19-34 years.

Administration / exposure

Route of administration:
other: air
Details on exposure:
Human volunteers were exposed to isoprene using a modified spirometer system; the system was flushed and filled with synthetic air prior to exposures. Oxygen consumed during exposure was replaced.
Duration and frequency of treatment / exposure:
up to 2.5 hours
Doses / concentrations
Doses / Concentrations:
approximately 8 and 40 ppm
Details on dosing and sampling:
Isoprene concentrations in head space (in-vitro measurements) and inhaled atmospheres were determined by GC.
Toxicokinetic parameters were determined using Solvekin. A physiological toxicokinetic model for isoprene was developed using ACSL 9C1, Mitchell & Gauthier Associates, 1990, USA. The production of endogenous isoprene was determined using SimuSolv version 2.1, Dow Chemical Co., 1990, USA.

Results and discussion

Preliminary studies:
Tissue:air and tissue:blood partition coefficients for isoprene were determined in mouse, rat and human.

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: Endogenous production of isoprene was 23.8 µmol/h for a 70kg man (0.34 µmol/h/kg).
Toxicokinetic parameters:
other: The rate of metabolism of endogenous isoprene in humans was 0.31 µmol/h/kg.
Toxicokinetic parameters:
other: Predicted blood concentration of isoprene in humans resulting from endogenous production are 9.5 nmol/L.
Toxicokinetic parameters:
other: Rates of metabolism of isoprene to the monoepoxides were approximately 14x faster in mice and 8x faster in rats than in humans.
Toxicokinetic parameters:
other: The AUC for isoprene in blood following exposure by inhalation to 10 ppm isoprene for 8 h is approximately 4 fold higher than the AUC resulting from 24h exposure to endogenous isoprene.

Applicant's summary and conclusion

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