Registration Dossier
Registration Dossier
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EC number: 201-143-3 | CAS number: 78-79-5
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vitro / ex vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 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
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 996
Materials and methods
- Objective of study:
- toxicokinetics
Test guideline
- Qualifier:
- 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
- Reference substance name:
- Isoprene
- EC Number:
- 201-143-3
- EC Name:
- Isoprene
- Cas Number:
- 78-79-5
- Molecular formula:
- C5H8
- IUPAC Name:
- 2-methylbuta-1,3-diene
- Reference substance name:
- 2-methyl-1,3-butadiene
- IUPAC Name:
- 2-methyl-1,3-butadiene
- 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.
Constituent 1
Constituent 2
- Radiolabelling:
- no
Test animals
- Species:
- other: human, rat and mice
- Strain:
- other: healthy human volunteers, Sprague-Dawley rats and NMRI mice
- Sex:
- male/female
- 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:
- inhalation
- Vehicle:
- 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
- Remarks:
- 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.
- Statistics:
- 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
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
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