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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 in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
- Objective of study:
- toxicokinetics
Test guideline
- Qualifier:
- no guideline followed
- Version / remarks:
- This study is a pilot pharmacokinetic investigation and as such is not designed to follow specific test guidelines.
- Principles of method if other than guideline:
- This study was performed to obtain blood samples from rats at selected time points following a single 6-hour exposure of the test atmosphere of Methyisobutylketone at two different concentration levels of Low (500 ppm) and High (1000 ppm) in order to determine the concentrations and the pharmacokinetics parameters of Diacetone alcohol (DAA), Methyl-isobutyl ketone (MIBK) and Methylisobutylcarbinol (MIBC) from the plasma.
- GLP compliance:
- yes (incl. QA statement)
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
- Test material form:
- liquid
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- SPF colony
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633
- Age at study initiation: 10-11 weeks old
- Weight at study initiation: 387g-468g
- Housing: three animals per cage
- Diet (ad libitum): ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice
- Water (ad libitum): tap water from municipal supply
- Acclimation period: At least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1 - 25.6
- Humidity (%): 40 - 62
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- inhalation: vapour
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TYPE OF INHALATION EXPOSURE: nose only
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose only, past flow, dynamic flow exposure unit, consisted of two, concentric anodised aluminium cylinders, the inner plenum and the outer chamber with 20 circularly arranged exposure ports.
- Method of holding animals in test chamber: tube
- Source and rate of air: no data
- Method of conditioning air: oil-free compressor passed through a suitable filter system prior to introduction to the nebuliser
- System of generating particulates/aerosols: The test item was administered as vapours. The test item was aerosolised using a stainless steel concentric jet nebulisers (TSE Systems GmbH, Bad Homburg, Germany) located at the top of the exposure chambers and a separator glass was installed to remove any liquid particles from the atmosphere prior entering into the inhalation tower. The rate of test item use was controlled by a syringe pump.
- Temperature, humidity in air chamber: 21.0-25.5°C, 3.0-4.5%
- Air Flow In (Inner Plenum) (L/min): 29.6-30.8
- Air Flow Out (Outer Cylinder) (L/min): 23.6-25.7
- Air change rate: no data
- Method of particle size determination: not determined since the test item was evaporated and non-condensing.
- Treatment of exhaust air: no data
TEST ATMOSPHERE
- Brief description of analytical method used: the concentration of the test item during the exposure was measured by gas chromatography (GC/FID). Samples for analytical determination were taken once an hour during the exposure into an impinger containing ethanol as a solvent.
- Samples taken from breathing zone: yes - Duration and frequency of treatment / exposure:
- single 6-hour exposure
Doses / concentrationsopen allclose all
- Dose / conc.:
- 500 other: ppm (target)
- Dose / conc.:
- 531 ppm (analytical)
- Remarks:
- 2.18 mg/L
- Dose / conc.:
- 1 000 other: ppm (target)
- Dose / conc.:
- 1 022 ppm (analytical)
- Remarks:
- 4.19 mg/L
- No. of animals per sex per dose / concentration:
- 9
- Control animals:
- no
- Details on dosing and sampling:
- TOXICOKINETIC STUDY
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 0 (on day -1 or -3), 0.5, 1, 1.5, 3, 4.5, 6, 8, 18 and 24 hours post exposure
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: plasma
- Time and frequency of sampling: 0 (on day -1 or -3), 0.5, 1, 1.5, 3, 4.5, 6, 8, 18 and 24 hours post exposure
- From how many animals: 3
- Method type(s) for identification: Gas Chromatography coupled with MS detection after electron impact ionization (GC-MS)
- Limits of quantification: DAA < 0.5 µg/mL; MIBC < 0.1 µg/mL; MIBK < 0.2 µg/mL
TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): no
Results and discussion
Toxicokinetic / pharmacokinetic studies
Toxicokinetic parametersopen allclose all
- Key result
- Toxicokinetic parameters:
- other: Cmax (µg/mL)/500 ppm: DAA 45.1, MIBC 0.66, MIBK 23.5
- Key result
- Toxicokinetic parameters:
- other: Tmax (h)/500 ppm: DAA 1.5, MIBC 0.5, MIBK 0.5
- Key result
- Toxicokinetic parameters:
- other: t1/2 (h)/500 ppm: DAA 2.4, MIBC nc, MIBK 0.581
- Key result
- Toxicokinetic parameters:
- other: AUC0.5-24h (h*µg/mL)/500 ppm: DAA 266, MIBC 0.499, MIBK 20.1
- Key result
- Toxicokinetic parameters:
- other: Cmax (µg/mL)/1000 ppm: DAA 82.7, MIBC 1.36, MIBK 56.8
- Key result
- Toxicokinetic parameters:
- other: Tmax (h)/1000 ppm: DAA 1.5, MIBC 0.5, MIBK 0.5
- Key result
- Toxicokinetic parameters:
- other: t1/2 (h)/1000 ppm: DAA 4.91, MIBC nc, MIBK nc
- Key result
- Toxicokinetic parameters:
- other: AUC0.5-24h (h*µg/mL)/1000 ppm: DAA 522, MIBC 1.82, MIBK 70.2
Metabolite characterisation studies
- Metabolites identified:
- yes
- Details on metabolites:
- Diacetone alcohol (DAA), Methyl-isobutyl ketone (MIBK) and Methylisobutyl carbinol (MIBC)
Any other information on results incl. tables
Mean plasma concentrations of DAA, MIBK and MIBC after an inhalation exposure to MIBK at 500 and 1000 ppm
Exposure |
Analyte (µg/mL) |
Sampling time |
|||||||||
Pre-dose |
0.5 h |
1 h |
1.5 h |
3 h |
4.5 h |
6 h |
8 h |
18 h |
24 h |
||
500 ppm
|
DAA |
BLQ |
41.7 |
44.3 |
45.1 |
43.1 |
29.0 |
15.8 |
12.9 |
0.559 |
BLQ |
MIBK |
BLQ |
23.5 |
13.7 |
5.18 |
2.32 |
0.15 |
BLQ |
BLQ |
BLQ |
BLQ |
|
MIBC |
BLQ |
0.660 |
0.356 |
0.170 |
BLQ |
BLQ |
BLQ |
BLQ |
BLQ |
BLQ |
|
MIBK
|
DAA |
BLQ |
62.6 |
58.7 |
82.7 |
70.8 |
49.9 |
52.8 |
32.4 |
0.84 |
0.73 |
MIBK |
BLQ |
56.8 |
33.1 |
23.6 |
12.5 |
0.633 |
0.267 |
0.193 |
BLQ |
BLQ |
|
MIBC |
BLQ |
1.36 |
0.852 |
0.698 |
0.280 |
BLQ |
BLQ |
BLQ |
BLQ |
BLQ |
BLQ: Below Limit of Quantification.
Toxicokinetic
parameters of DAA, MIBC and MIBK after a single 6-hour inhalation
exposure of male Sprague-Dawley rats to 500 ppm and 1000 ppm of DAA
Concentration |
Analytes |
r² |
Number of point used to calculatelz |
lz |
t1/2 |
Tmax |
Cmax |
Cmax/ |
AUC0.5-24h |
AUC0.5-24h/ |
Metabolite/ |
|
1/h |
h |
h |
µg/mL |
h*µg/mL |
Cmax |
AUC0.5-24h |
||||||
500 ppm |
DAA |
0.994 |
5 |
0.289 |
2.40 |
1.5 |
45.1 |
22.0 |
266 |
130 |
1.92 |
13.20 |
MIBC |
na |
na |
nc |
nc |
0.5 |
0.66 |
0.322 |
0.499 |
0.243 |
0.0281 |
0.0248 |
|
MIBK |
0.944 |
4 |
1.19 |
0.581 |
0.5 |
23.5 |
11.5 |
20.1 |
9.82 |
na |
na |
|
1000 ppm |
DAA |
0.948 |
6 |
0.248 |
2.79 |
1.5 |
82.7 |
20.2 |
522 |
127 |
1.45 |
7.44 |
MIBC |
0.995 |
3 |
0.569 |
1.22 |
0.5 |
1.36 |
0.331 |
1.82 |
0.445 |
0.0239 |
0.0260 |
|
MIBK |
0.912 |
6 |
0.832 |
0.833 |
0.5 |
56.8 |
13.9 |
70.2 |
17.1 |
na |
na |
na: not applicable.
nc: not calculated as not enough quantifiable points were available.
#:Cmaxand AUC0.5-24hwere divided by the exposure concentrations of DAA (in mg/L).
Applicant's summary and conclusion
- Executive summary:
A study was performed to obtain blood samples from rats at selected time points following a single 6-hour exposure of the test atmosphere of Methylisobutylketone at target concentration levels of 500 and 1000 ppm in order to determine the concentrations and the pharmacokinetics parameters of Diacetone alcohol (DAA), Methyl-isobutyl ketone (MIBK) and Methyl-isobutyl carbinol (MIBC) from the plasma. The animals were exposed to the test atmosphere (in the form of a vapour) using a nose-only exposure system. Analytical concentrations of 531 ppm, 1022 ppm were achieved in the respective groups. No control animals were used in the study. The test atmosphere concentration was monitored based on a validated GC method (by trapping the vapors in an impinger containing ethanol). The results of the test atmosphere characterization were considered suitable for the study purposes. Heighteen male Sprague-Dawley rats were involved in the study, 9 animals in each treatment groups. Plasma samples were prepared from male rats following the end of the exposure at nine time-points (three animals at each sampling occasion) and the plasma level of DAA, MIBK and MIBC was determined. The analytical method consisted of a liquid/liquid extraction of the three analytes from plasma with Methyl tert-Butyl Ether (MtBE) followed by analysis of supernatant by Gas Chromatography coupled with MS detection after electron impact ionization (GC-MS). The toxicokinetic evaluation was performed using non-compartmental analysis on Phoenix WinNonlin software (Pharsight Corporation, Mountain View, California 94040/USA). DAA, MIBC and MIBK toxicokinetic parameters were determined from the mean plasma concentration collected from each animal/group, at each post-exposure time-point. A separate analysis was performed for each dose-level. The following toxicokinetic parameters were calculated t½, ¿z, AUC0.5-24h, Tmaxand Cmax.
The mean actual achieved concentration of the test item were:
Target Concentration
(ppm)* [mg/L]
Achieved Concentration
(ppm)* [mg/L]
Nominal Concentration
mg/L
500 [2.05]
531 [2.18]
3.69
1000 [4.10]
1022 [4.19]
6.17
For the three analytes (DAA, MIBK and MIBC), the standard acceptance criteria for the calibration lines and Quality Control samples were met for a successful analysis of the study samples.
Study samples with concentrations above the calibration ranges were repeated diluted (for DAA principally and MIBK). DAA, MIBC and MIBK were not quantifiable in pre-dose samples in any group.
The mean plasma concentrations of DAA, MIBK and MIBC after an inhalation exposure to MIBK at 500 and 1000 ppm were:
Exposure
Analyte (µg/mL)
Sampling time
Pre-dose
0.5 h
1 h
1.5 h
3 h
4.5 h
6 h
8 h
18 h
24 h
MIBK500 ppm
DAA
BLQ
41.7
44.3
45.1
43.1
29.0
15.8
12.9
0.559
BLQ
MIBK
BLQ
23.5
13.7
5.18
2.32
0.15
BLQ
BLQ
BLQ
BLQ
MIBC
BLQ
0.660
0.356
0.170
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ
MIBK
1000 ppmDAA
BLQ
62.6
58.7
82.7
70.8
49.9
52.8
32.4
0.84
0.73
MIBK
BLQ
56.8
33.1
23.6
12.5
0.633
0.267
0.193
BLQ
BLQ
MIBC
BLQ
1.36
0.852
0.698
0.280
BLQ
BLQ
BLQ
BLQ
BLQ
BLQ: Below Limit of Quantification.
The toxicokinetic parameters of DAA, MIBC and MIBK after a single 6-hour inhalation exposure of male Sprague-Dawley rats to 500 ppm and 1000 ppm of MIBK were:
Concentration
Analytes
r²
Number of point used to calculatelz
lz
t1/2
Tmax
Cmax
Cmax/
concentration#AUC0.5-24h
AUC0.5-24h/
concentration#Metabolite/
Administered compound1/h
h
h
µg/mL
h*µg/mL
Cmax
AUC0.5-24h
500 ppm
(2.38 mg/L)DAA
0.994
5
0.289
2.40
1.5
45.1
22.0
266
130
1.92
13.20
MIBC
na
na
nc
nc
0.5
0.66
0.322
0.499
0.243
0.0281
0.0248
MIBK
0.944
4
1.19
0.581
0.5
23.5
11.5
20.1
9.82
na
na
1000 ppm
(4.75 mg/L)DAA
0.948
6
0.248
2.79
1.5
82.7
20.2
522
127
1.45
7.44
MIBC
0.995
3
0.569
1.22
0.5
1.36
0.331
1.82
0.445
0.0239
0.0260
MIBK
0.912
6
0.832
0.833
0.5
56.8
13.9
70.2
17.1
na
na
na: not applicable.
nc: not calculated as not enough quantifiable points were available.
#:Cmaxand AUC0.5-24hwere divided by the exposure concentrations of DAA (in mg/L).
After a 6-hour inhalation exposure to MIBK:
· MIBK was on average quantifiable from 0.5 to 4.5 h after the end of exposure to 500 ppm and for up to 8 h at 1000 ppm. Maximum concentrations of MIBK were at 0.5 h after the end of exposure for both MIBK concentrations,
· DAA was on average quantifiable from 0.5 to 18 h after the end of exposure to MIBK at 500 ppm and for up to 24 h at 1000 ppm. Maximum concentrations of DAA were at 1.5 h after the end of exposure for both MIBK concentrations,
· MIBC plasma concentrations were very low but nevertheless quantifiable from 0.5 to 1.5 h after the end of exposure to 500 ppm of MIBK and for up to 3 h at 1000 ppm. Maximal plasma concentrations of MIBC were at 0.5 h after the end of exposure for both MIBK concentrations.
· the elimination rates and half-live of DAA and MIBK were not significantly changed between both exposure concentrations, indicating that the excretion pathway was not saturated.
The plasma concentration values of DAA were higher than those of MIBC and MIBK after administration of MIBK, this indicates that DAA may represent a major metabolite of MIBK in rats. MIBC was considered to be a minor metabolite as it represented approximately 2.5% of the plasma MIBK exposure.
Based on AUC0-24hand Cmax(both normalized by exposure concentration), plasma DAA, MIBC and MIBK exposure increased dose proportionally, between 500 and 1000 ppm of MIBK.
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