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EC number: 210-519-6 | CAS number: 617-52-7
- 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:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: meets basic scientific principles non-GLP
Data source
Reference
- Reference Type:
- publication
- Title:
- Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis.
- Author:
- Talalay P, De Long MJ, Prochaska HJ.
- Year:
- 1 988
- Bibliographic source:
- Proc Natl Acad Sci U S A. 1988 Nov;85(21):8261-5. PMID: 3141925
Materials and methods
- Objective of study:
- metabolism
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Several chemicals featuring a Michael-System were tested including dimethyl itaconate (DMI) and results summarized in a survey article.
- in vitro experiment: Hepa 1c1c7 murine hepatoma cells treated with various concentrations of the test item in a cell culture system and the concentration needed for doubling of quinone reductase activity (QR) was determined
- in vivo experiment: Female CD1 mice were treated with 25 or 75 µmol of the test items via gavage for 5 days. After sacrifice QR and glutathione-S-transferase (GST) activities were determined in liver, forestomach and glandular stomach. - GLP compliance:
- no
Test material
- Reference substance name:
- Dimethyl itaconate
- EC Number:
- 210-519-6
- EC Name:
- Dimethyl itaconate
- Cas Number:
- 617-52-7
- Molecular formula:
- C7H10O4
- IUPAC Name:
- 1,4-dimethyl 2-methylidenebutanedioate
- Details on test material:
- - Name of test material (as cited in study report): dimethyl itaconate
- Physical state: not reported
- Analytical purity: All compounds were of the highest quality obtainable commercially and were purified when necessary.
- No further details reported in this survey article.
Constituent 1
- Radiolabelling:
- no
Test animals
- Species:
- mouse
- Strain:
- CD-1
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- - in vitro experiment: not applicable
- in vivo experiment:
TEST ANIMALS
- Age at study initiation: 6 wks
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):
IN-LIFE DATES: From: To:
Administration / exposure
- Route of administration:
- other: oral (gavage) in the in vivo experiment
- Vehicle:
- other: in the in vivo experiment: Emulphor EL620P
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
in indicated single daily doses in 0.1 mL of Emulphor EL620P
VEHICLE
- Justification for use and choice of vehicle (if other than water): not given, but Emulphor is an often used vehicle in toxicologic experiments
- Concentration in vehicle: 250 and 750 mMol/L
- Amount of vehicle (if gavage): 0.1 mL
- Purity: not reported - Duration and frequency of treatment / exposure:
- - in vitro experiment: not applicable
- in vivo experiment: once daily (for 5 days)
Doses / concentrations
- Remarks:
- Doses / Concentrations:
- in vitro: concentration above and below 35 µM (details not reported)
- - in vivo experiment: 25 and 75 µMol
- No. of animals per sex per dose / concentration:
- - in vitro experiment: not applicable
- in vivo experiment: 3 - 6 per group - Control animals:
- other: in vivo experiment: yes, concurrent vehicle
- Positive control reference chemical:
- - in vitro experiment: no
- in vivo experiment: BHA, 2(3)-tert-butyl-4-hydroxyanisole - Details on study design:
- - Dose selection rationale: not reported
- Rationale for animal assignment (if not random): not reported - Details on dosing and sampling:
- not applicable
- Statistics:
- no statistics used beyond determination of averages and standard deviations
Results and discussion
- Preliminary studies:
- not applicable
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- not applicable
- Details on distribution in tissues:
- not applicable
- Details on excretion:
- not applicable
Metabolite characterisation studies
- Metabolites identified:
- no
- Details on metabolites:
- not applicable
Any other information on results incl. tables
- Table 1: Concentration (CD) of fumarate, maleate, and itaconate derivatives required to double quinone reductase in Hepa Lc1c7 cells
|
Compound |
CD, µM |
|
No. |
Name |
Structure |
|
33 |
Fumaric acid |
HOOCCH=CHCOOH (trans) |
I |
34 |
Dimethyl fumarate |
CH3OOCCH=CHCOOCH3 (trans) |
22 |
35 |
Diethyl fumarate |
C2H5OOCH=CHCOOC2H5 (trans) |
100 |
36 |
Maleic acid |
HOOCCH=CHCOOH (cis) |
I |
37 |
Dimethyl maleate |
CH3OOCCH=CHCOOCH3 (cis) |
20 |
38 |
Diethyl maleate |
C2H5OOCCH=CHCOOC2H5 (cis) |
40 |
39 |
Dimethyl succinate |
CH3OOCCH2CH 2C 00CH3 |
I |
40 |
Dimethyl itaconate |
CH3OOCC(=CH2)CH2COOCH3 |
35 |
I: inactive; <20% increase in specific activity at 200 µM.
CD: concentration at which QR activity was doubled
Dimethyl itaconate was a moderately potent inducer with a CD value of 35 µM.
- Table 2: Induction patterns of QR and GSTs (the latter measured with CDNB and DCNB) in mouse tissues.
Inducing agent |
Dose, µmol |
Enzyme |
Ratio of specific activities (treated/control) |
||
Liver |
Forestomach |
Glandular stomach |
|||
Dimethyl itaconate |
25 |
QR |
2.37 ± 0.22 |
2.74 ± 0.11 |
2.63 ± 0.13 |
|
25 |
GST (CDNB) |
1.79 ± 0.06 |
3.47 ± 0.06 |
5.07 ± 0.53 |
|
25 |
GST (DCNB) |
0.90 ± 0.06 |
4.34 ± 0.30 |
6.73 ± 0.71 |
|
75 |
QR |
3.30 ± 0.05 |
2.73 ± 0.15 |
2.90 ± 0.07 |
|
75 |
GST (CDNB) |
2.79 ± 0.07 |
4.27 ± 0.28 |
6.71 ± 0.30 |
|
75 |
GST (DCNB) |
1.71 ± 0.08 |
4.90 ± 0.22 |
7.75 ± 0.57 |
Absolute values of vehicle controls (nmol/min/mg of protein ± SEM) |
|||||
Vehicle control |
0 |
QR |
126 ± 3.3 |
1454 ± 88 |
3955 ± 187 |
|
0 |
GST (CDNB) |
1800 ± 30 |
1130 ± 69 |
684 ± 40 |
|
0 |
GST (DCNB) |
37.9 ± 3.9 |
15.6 ± 0.8 |
8.35 ± 1.06 |
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): other: Dimethyl itaconate is a relatively potent inducer of phase II metabolic enzymes
Dimethyl itaconate (DMI) was tested in vitro (in Hepa 1c1c7 murine hepatoma cells) for its potency to induce quinone reductase activity as surrogate for phase II metabolic enzymes. In addition in an in vivo experiment in female CD1 mice treated 5 d via gavage with DMI the induction of QR and glutathione-S-transferase (GST) activity was measured. Both experiments led to the conclusion that DMI is a relatively potent inducer of phase II metabolic enzymes. - Executive summary:
Dimethyl itaconate (DMI) was tested in vitro (in Hepa 1c1c7 murine hepatoma cells) for its potency to induce quinone reductase (QR) activity as surrogate for phase II metabolic enzymes. In addition in an in vivo experiment in female CD1 mice treated 5 d via gavage with DMI the induction of QR and glutathione-S-transferase (GST) activity was measured.
In the in vitro experiment Hepa lc1c7 murine hepatoma cells were grown in microtiter plates and the QR activity measured after incubation with the test item.
In the in vivo experiment the compound was administered in single daily doses in 0.1 ml of Emulphor EL620P for 5 days. Cytosols were prepared from the tissues 24 hr after the last treatment and assayed for enzyme activities (using CDNB (1 -chloro-2,4 -dinitrobenzene) and DCNB (1,2 -dichloro-4 -nitrobenzene) as substrates for GST).
Both experiments led to the conclusion that DMI is a relatively potent inducer of phase II metabolic enzymes.
Dimethyl itaconate was a moderately potent inducer compared to other "Michael acceptor" substances with a CD value (concentration at which the QR activity was doubled) of 35 µM in the invitro experiment.
In the in vivo experiment dimethyl itaconate was more potent and more effective than BHA (2(3)-tert-butyl-4-hydroxyanisole) and tert-butylhydroquinone, know inducers of phase II metabolism. In the glandular stomachof female mice, phase II enzymes are only slightly responsive to BHA and tert-butylhydroquinone, whereas five doses of 25 µmol of dimethyl itaconate raised the enzyme specific activities 2.63- to 6.73-fold.
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