Registration Dossier
Registration Dossier
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 203-550-1 | CAS number: 108-10-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2004
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP Guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 004
- Report date:
- 2004
- Reference Type:
- publication
- Title:
- Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl ketone in male rats
- Author:
- Gingell R, Régnier JF, Wilson DM, Guillaumat PO & Appelqvist T
- Year:
- 2 003
- Bibliographic source:
- Toxicology Letters 136 (2003) 199-204
Materials and methods
- Objective of study:
- absorption
- metabolism
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Deviations:
- yes
- Remarks:
- only 1 dose level tested
- GLP compliance:
- yes
Test material
- Reference substance name:
- 4-methylpentan-2-one
- EC Number:
- 203-550-1
- EC Name:
- 4-methylpentan-2-one
- Cas Number:
- 108-10-1
- Molecular formula:
- C6H12O
- IUPAC Name:
- 4-methylpentan-2-one
- Details on test material:
- - Name of test material (as cited in study report): Methyl isobutyl ketone (MIBK)
- Physical state: colorless liquid
- Analytical purity: 99.874/99.903
- Lot/batch No.: 99010101 and 40010101
- Expiration date of the lot/batch: December 2001 (batch no. 990101010)
- Stability under test conditions: Not reported
- Storage condition of test material: at room temperature and protected from light
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS:
- Source: Charles River Laboratories, L'Arbresle, France
- Age at study initiation: 7 to 8 weeks old
- Weight at study initiation: mean body weight of 237 g (range: 226 to 250 g; first arrival) and mean body weight of 205 g (range: 199 to 214 g; second arrival).
- Fasting period before study: fasted for an overnight period of at least 14 hours
- Housing: 3 rats of the same group were housed in a suspended wire-mesh cage
- Individual metabolism cages: no
- Diet (e.g. ad libitum): A04 C pelleted maintenance diet, batch no. 00622 (UAR, Villemoisson, Epinay-sur-Orge, France), ad libitum
- Water (e.g. ad libitum): tap water (filtered with a 0.22 µm filter), ad libitum
- Acclimation period: 7 to 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hr of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Each test item was administered as a solution in the vehicle. Each test item was mixed with the required quantity of vehicle in order to achieve a concentration of 2.5 mmol/mL and then homogenized using a magnetic stirrer. The quantities of test items used for the dosage forms were calculated taking into consideration their respective molecular weight.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Not provided
- Concentration in vehicle: 2.5 mmol/mL
- Amount of vehicle (if gavage): Not reported
- Lot/batch no. (if required): batch no. 89H0149 and 70K0127
- Purity: Not reported
HOMOGENEITY AND STABILITY OF TEST MATERIAL: Not reported - Duration and frequency of treatment / exposure:
- Single dose exposure
Doses / concentrations
- Remarks:
- Doses / Concentrations:
501 mg/kg body weight (5 mmol/kg body weight; 2.5 mmol/mL)
- No. of animals per sex per dose / concentration:
- Test 1: 9 males
Test 2: 3 males - Control animals:
- no
- Positive control reference chemical:
- None used.
- Details on study design:
- - Dose selection rationale: The 5 mmol/kg (500 mg/kg) dose was selected for this study because it is in the range of doses (1.5/6 mmol/kg) used in
previous rat oral MIBK metabolism studies (Duguay and Plaa, 1995), and approaches the limit dose (1000 mg/kg) that would be used in any OECD guideline toxicity studies for MIBC.
- Rationale for animal assignment (if not random): The required number of animals was selected according to body weight and clinical condition and allocated to the groups, according to a computerized stratification procedure, so that the average body weight of each group was similar. - Details on dosing and sampling:
- Test 1 (Study No. 20991 PAR):
PHARMACOKINETIC STUDY (Absorption and metabolism)
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling:
Blood samples from the first 3 animals/group were sampled at 0.125, 0.75, and 3 hours post-dosing
Blood samples from the second 3 animals/group were sampled at 0.25, 1, and 4.5 hours post-dosing.
Blood samples from the third 3 animals/group were sampled at 0.5, 1.5, and 6 hours post-dosing.
Test 2 (Study No. 22776 PAR):
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: blood, plasma
- Time and frequency of sampling: Sampled at 9 and 12 hours post-dosing
- From how many animals: 3 animals
- Method type(s) for identification: GC-MS
- Limits of detection and quantification: >0.005 mmol/L
- Other: Blood samples (1 mL per sampling) were taken into tubes containing lithium heparinate, from the orbital sinus of the animals. For the blood sampling, the animals were lightly anesthetized by isoflurane. The blood samples were kept on ice (+4 °C) until centrifugation to obtain plasma (4000 rpm for 10 min at +4°C). The plasma was stored frozen in individual tubes at -20 °C until analyzed for MIBK, methyl isobutyl carbinol (MIBC), and the common metabolite, 4-hydroxy-4-methyl-2-pentanone (HMP, which is also known as DAA). - Statistics:
- Statistical analysis was not performed (not required).
Results and discussion
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- Following oral administration of MIBK at a nominal dose-level of 5 mmol/kg to male rats, the mean (±SD) plasma parent material levels increased quickly from the first quantifiable time-point at 0.125 hours post-gavage to reach a Cmax (0.644 ± 0.221 mmol/L) at 0.25 hours, post-gavage. Thereafter, the plasma levels fell slowly to time-point 9 hours (0.0584 ± 0.0396 mmol/L) post-gavage, after passing through a second peak at time-point 3.0 hours post-gavage (0.550 ± 0.167 mmol/L).
Toxicokinetic parametersopen allclose all
- Toxicokinetic parameters:
- AUC: 3.558 mmol*h/L (MIBK)
- Toxicokinetic parameters:
- AUC: 13.756 mmol*h/L (HMP)
- Toxicokinetic parameters:
- AUC: 0.089 mmol*h/L (MIBC)
- Toxicokinetic parameters:
- Cmax: 0.644 mmol/L at 0.25 h (MIBK)
- Toxicokinetic parameters:
- Cmax: 2.030 mmol/L at 9.0 h (HPM)
- Toxicokinetic parameters:
- Cmax: 0.014 mmol/L (MIBC)
- Toxicokinetic parameters:
- half-life 1st: 2.529 h (MIBK)
- Toxicokinetic parameters:
- half-life 1st: 4.831 h (HMP)
- Toxicokinetic parameters:
- half-life 1st: 4.657 h (MIBC)
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- methyl isobutyl carbinol (MIBC)
4-hydroxy-4-methyl-2-pentanone (HMP)
Any other information on results incl. tables
No mortality or morbidity was noted. No clinical signs were observed.
After administration of MIBK, the plasma primary metabolite (MIBC) levels rose slowly after gavage to a Cmax at time-point 1.0 hours (0.0118 ± 0.0046 mmol/L) and then declined slowly to time-point 9 hours (0.00610 ± 0.00043 mmol/L) post-dosing; again a secondary peak was noted at time-point 3.0 hours post-gavage (0.0143 ± 0.0001 mmol/L). The Cmax of parent MIBK (0.64 mmol/L) was reached at 0.25 hours, and levels were maintained until 3 hours then decreased with a half life of 2.5 hour. MIBK and its metabolite were no longer detected at the time-point 12 hours after dosing. The plasma secondary metabolite (HMP) levels, increased slowly after gavage to reach a Cmax at 9 hours (2.03 ± 0.07 mmol/L) post-dosing and then decline at the last time-point 12 hours after dosing (1.32 ± 0.45 mmol/L) with a half life of 3.8 hours. MIBK, as well as MIBC and HMP plasma levels showed a slight to considerable inter-animal variability. The area under the curve (AUC)(0 to12 h) for MIBK was 3.56, for MIBC was 0.09 and for HMP was 13.76 mmol*h/L. No other metabolites were present in the blood.
Table 1: Selected Pharmacokinetic Parameters after Oral Administration of MIBK
Test Substance |
Analyte |
Cmax [mmole/L] |
Time of Cmax[hr] |
Half Life [hr] |
AUC0-12hr [mmole*hr/L] |
% Total AUC |
MIBK Total AUC |
MIBC |
0.014 |
NA |
4.657 |
0.089 |
0.05 |
MIBK |
0.644 |
0.25 |
2.529 |
3.558 |
20 |
|
HMP |
2.030 |
9 |
4.831 |
13.756 |
79 |
|
17.436 |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): no bioaccumulation potential based on study results
MIBK is rapidly absorbed into the blood, and is metabolized to HMP, which is the major material in blood after 3 hours; metabolism of MIBK to MIBC is negligible. - Executive summary:
The absorption and metabolism of MIBK was studied in male Sprague-Dawley rats orally administered a single dose of 5 mmol/kg body weight of MIBK in corn oil, equivalent to 501 mg/kg body weight, by gavage. MIBK was rapidly absorbed into the systemic circulation following oral exposure, with a mean maximum plasma concentration (Cmax) of 0.644 mmol/L occurring at 0.25 hours [(time to maximum plasma concentration (tmax)] post-administration. MIBK was detected at very low levels (0.006 mmol/L) at 9 hours post-administration. The plasma levels of methyl isobutyl carbinol (MIBC) were very low (<0.012 mmol/L) all over the study. The major material in the blood was 4-hydroxymethyl-4-methyl-2-pentanone (referred to as HMP based on the chemical name) [i.e., diacetone alcohol (DAA], with a Cmax of 2.03 mmol/L at 9 hours and remained detectable at 12 hours post-dosing. Neither MIBK nor MIBC were detectable in 12-hour samples. No compounds other than HMP and MIBK were detected in the blood. The 12-hour area under the plasma concentration time curve (AUC0-12 h) for MIBK, MIBC and HMP were 0.089, 3.558 and 17, 436mmol·hour/L, respectively. HMP and MIBK represented 79% and 20% of the total AUC, respectively. The plasma elimination half-life (t1/2) of MIBK and HMP were 2.529 and4.831hours, respectively. Based on the results of this study, MIBK is rapidly absorbed into the blood in rats following oral exposure and is rapidly and extensively metabolized to HMP (the major metabolite in blood after 3 hours).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
