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EC number: 237-857-7 | CAS number: 14024-56-7
- 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
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- genetic toxicity in vivo, other
- Remarks:
- In vivo mammalian erythrocytes micronucleus test combined to in vivo mammalian alkaline comet assay on lung and liver
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2019
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 489 (In vivo Mammalian Alkaline Comet Assay)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- other: combined mammalian comet assay and mammalian erythrocyte micronucleus test
Test material
- Reference substance name:
- Bis(pentane-2,4-dionato-O,O')magnesium
- EC Number:
- 237-857-7
- EC Name:
- Bis(pentane-2,4-dionato-O,O')magnesium
- Cas Number:
- 14024-56-7
- Molecular formula:
- C10H14MgO4
- IUPAC Name:
- magnesium;4-oxopent-2-en-2-olate
- Test material form:
- solid: particulate/powder
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- As the search for systemic exposure through the determination of the ratio PCE/NCE as done in the
confirmatory toxicity assay demonstrated a statistically significant decrease exclusively in female rats , the main assay was performed only in female rats that demonstrated a higher sensitivity to the test
item
Administration / exposure
- Route of administration:
- intratracheal
- Vehicle:
- Sterile water.
- Details on exposure:
- Treatment took the form of 3 successive administrations at 24-hour intervals by endotracheal. Samples
were taken 2 to 3 hours after the last treatment. - Duration of treatment / exposure:
- 3 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 7.5 mg/kg bw/day
- Dose / conc.:
- 3.75 mg/kg bw/day
- Dose / conc.:
- 1.875 mg/kg bw/day
- No. of animals per sex per dose:
- 7 females for the higher dose, 5 females for the other doses
- Positive control(s):
- 5 females exposed to positive controle (cyclophosphamide 25 mg/kg IP
5 females exposed to Methylmethane sulfonate 100 mg/kg/day (x2) +70 mg/kg/day PO (x1)
Examinations
- Tissues and cell types examined:
- bone marrow lung and liver.
- Details of tissue and slide preparation:
- The femurs were removed, and the bone marrow was extracted with foetal calf serum (1 mL per animal).
The cell suspensions were centrifuged for 5 minutes at 1000 rpm. The supernatants were removed. After
homogenisation, the centrifugate was spread on slides. The smears were stained using a technique,
derived from the May Grunwald Giemsa technique (Schmid, 1975) (see also § 12.1), which makes it
possible to distinguish between polychromatic (PCE) and normochromatic erythrocytes (NCE): PCE are
purple whereas NCE are red.
After blind coding of slides by a person not involved in the reading, two slides per animal were scored by
two independent operators; for each animal, the number of polychromatic erythrocytes having one or more
Howell-Jolly bodies (micronuclei) was determined from the microscopic examination of 4000 polychromatic
erythrocytes.
The proportion of immature among total (immature and mature) erythrocytes was determined for each
animal. The polychromatic/normochromatic erythrocyte ratio was determined from the microscopic
examination of 1000 erythrocytes per animal. When analysing slides, the proportion of immature
erythrocytes among total erythrocytes should not be less than 20% of the control value. - Evaluation criteria:
- The results are reported in the form of tables giving the number of micronucleated cells per 4000
polychromatic erythrocytes for each animal, together with the total and the statistical analysis.
The ratio of polychromatic to normochromatic erythrocytes (PCE/NCE), calculated from 2000 polychromatic
erythrocytes is also established for both treated and control animals.
The statistical comparison for the polychromatic/normochromatic erythrocyte ratio was performed using
Student's t test.
Statistical analysis was performed for micronucleus number using a non-parametric test, the Mann Whitney
U rank test, recommended by UKEMS (Lovell et al., 1989). Statistical analysis for micronucleus number
was conducted.
Results and discussion
Test results
- Key result
- Sex:
- female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Remarks:
- The preliminary toxicity assay performed on male and female rats at the highest dose of 7.5 mg/ kg/ day (x3) by endotracheal route induced neither clinical signs, nor mortality, and was thus retained for the confirmatory toxicity assay.
- Vehicle controls validity:
- valid
- Remarks:
- The sponsor has chosen to perform the check of the concentration of Magnesium acetylacetonate dihydrate in dosing formulations in a GLP-compliant test site. The stability was studied in the validation study CitoxLab No. 46707 VAS.
- Negative controls validity:
- not specified
- Positive controls validity:
- valid
Applicant's summary and conclusion
- Conclusions:
- The test item Magnesium acetylacetonate dihydrate (batch 18030702), was
investigated for genotoxic potential by the means of the in vivo micronucleus test in bone marrow
combined with the in vivo comet assay under alkaline conditions (SCGE) in the Lung and Liver, in
female OFA Sprague-Dawley rats, according to OECD Guidelines (Nos. 474 and 489, 2016). Animals
were treated endotracheally at dose levels of 7.5, 3.75 and 1.875 mg/kg once a day for 3 consecutive
days, 24 hours apart, followed by one sampling time 2-3 hours after the last treatment.
The results of assays for Magnesium acetylacetonate dehydrate in treatment formulations were
conform. No test item was found in the vehicle control. The results were thus satisfactory.
The validity criteria for the results were considered as fulfilled. The study is thus valid.
Under these experimental conditions, the test item did not present DNA strand breaks and/or alkalilabile
sites inducer activities toward the lung and liver from OFA Sprague-Dawley female rats.
Furthermore, Magnesium acetylacetonate dihydrate induced no genotoxic activity in bone marrow
cells.
As a conclusion, Magnesium acetylacetonate dihydrate induced no in vivo genotoxic activity under
these experimental conditions. - Executive summary:
Study initiation date (date Study Director signed Study Plan): 21/06/18
PURPOSE
The potential clastogenic activity of Magnesium acetylacetonate dihydrate provided was tested using both the in vivo micronucleus test in bone marrow and the comet assay in the lung and liver in the rat. The actual treatment was carried out by endotracheal route, using 1 daily treatment for 3 days.
METHOD
Animals ( strain, species) : OFA Sprague Dawley rat
Feedstuff : A04C-10 from SAFE (batch 17318)
Form administered : suspension
Route : endotracheal
Dose volume : 0.75 mL/kg b.w.
Vehicle : sterile water (Fresenius, batch 13MCP211)
Stability in vehicle : unknown at the preparation dates (dosing formulations were thus prepared just prior to use)
Limiting factors for the top dose used in the toxicity assay and the main assay : solubility of the test item in sterile water (i.e. 10 mg/mL) and maximal volume that can be administered endotracheally to the rats (ca. 150 μL/rat, i.e. 0.7 mL/kg)
TOXICITY ASSAY
Preliminary toxicity assay
Number of animals per group : 2 males and 2 females weight: 220 g and 205 g (males) 190 g and 185 g (females)
Doses tested : 7.5 mg/kg/day (x 3)
Treatment schedule : 3 daily treatments at 24-hour intervals
The preliminary toxicity assay performed on male and female rats at the highest dose of 7.5 mg/ kg/ day (x3) by endotracheal route induced neither clinical signs, nor mortality, and was thus retained for the
confirmatory toxicity assay.
Confirmatory toxicity assay
Number of animals per group : 5 males and 5 females per group (i.e. vehicle control and 7.5 mg/kg treated group weight: 183 g to 210 g (males) 185 g to 202 g (females)
Doses tested : 7.5 mg/kg/day (x 3)
Treatment schedule : 3 daily treatments at 24-hour intervals
The confirmatory toxicity assay performed on 5 male and 5 female rats at the highest dose of 7.5 mg/ kg/day (x3) by endotracheal route induced neither clinical signs, nor mortality, and was thus retained for the
main assay. Two inferior doses of 3.75 and 1.875 mg/kg/day (x3) were also tested.
Otherwise, in accordance with the Sponsor, the proportion of immature among total (immature and mature) erythrocytes was determined for each animal used in the confirmatory toxicity assay. To reach this goal,
bone marrow removal, slide preparation and counting were carried out as depicted in §8.1 (the number of polychromatic erythrocytes (immature) having one or more micronuclei was not determined). To assess an
eventual decrease in the ratio PCE/NCE, vehicle control groups of 5 animals of each sex treated with the vehicle only were also included in the confirmatory toxicity assay.
The ratio of polychromatic (PCE) to normochromatic erythrocytes (NCE) was thus established at the highest dose level tested of 7.5 mg/kg/day (x3). A statistically significant decrease in the ratio PCE to NCE was noted in the Magnesium acetylacetonate dihydrate treatment group when compared to the negative control group, only in female rats. The main assay was thus performed in female rats only as they were
considered as the probably the most sensitive gender.
GENOTOXICITY ASSAY
Number of animals per group : 5 females for both the micronucleus and the comet assays
weight: 179 g to 205 g
Doses tested : 7.5 – 3.75 – 1.875 mg/kg/day (x 3)
Treatment schedule : 3 daily treatments at 24-hour intervals
Number of sampling times : one:
for the negative control and the 3 treated groups: 2-3 hours after the third treatment
for the positive control group (cyclophosphamide): 24 hours after
the single treatment (micronucleus test)
for the positive control group (methylmethane sulfonate): 2-3
hours after the third treatment (comet assay)
Positive reference substances : cyclophosphamide (Baxter, batch 5K044J) in NaCl at 0.9% in distilled water (Aguettant, Batch 170 6841), 25 mg/kg, intraperitoneal administration
methylmethane sulfonate (Aldrich, batch MKCD8572) in sterile water (Fresenius, Batch 13MCP211), 100 mg/kg/day (x2) – 70 mg/kg/day (x1), gavage
Micronucleus test in bone marrow
Number of polychromatic
erythrocytes analysed
for each animal : 4000
No statistically significant increase in the number of micronuclei was noted at the doses of 7.5 – 3.75 and 1.875 mg/kg/day (x3) by endotracheal route in female rats.
Comet assay in the Lung
Number of cells observed
per animal : 150
Number of cells observed
per dose : 750
No statistically significant increase in the mean of medians of percentage of DNA in tail per group was observed at the tested doses of 7.5 – 3.75 and 1.875 mg/kg/day (x3) by endotracheal route of Magnesium
acetylacetonate dihydrate in Lung from OFA Sprague-Dawley female rats.Taking into account the overall results, it was concluded that Magnesium acetylacetonate dihydrate is not
genotoxic toward lung cells from OFA Sprague-Dawley female rats as investigated by the in vivo Comet assay.
Comet assay in the Liver
Number of cells observed
per animal : 150
Number of cells observed
per dose : 750
No statistically significant increase in the mean of medians of percentage of tail DNA per group was observed at the tested doses of 7.5 – 3.75 and 1.875 mg/kg/day (x3) of Magnesium acetylacetonate
dihydrate in Liver from OFA Sprague-Dawley female rats. Statistically significant decreases in the mean of medians of percentage of tail DNA per group were
observed at the tested doses of 7.5 and 1.875 mg/kg/day (x3). They are however without any significance in terms of genotoxicity hazard.
Taking into account the overall results, it was concluded that Magnesium acetylacetonate dihydrate is not genotoxic toward hepatocytes from OFA Sprague-Dawley female rats as investigated by the in vivo Comet assay.
The test item Magnesium acetylacetonate dihydrate (batch 18030702), was investigated for genotoxic potential by the means of the in vivo micronucleus test in bone marrow
combined with the in vivo comet assay under alkaline conditions (SCGE) in the Lung and Liver, in female OFA Sprague-Dawley rats, according to OECD Guidelines (Nos. 474 and 489, 2016). Animals
were treated endotracheally at dose levels of 7.5, 3.75 and 1.875 mg/kg once a day for 3 consecutive days, 24 hours apart, followed by one sampling time 2-3 hours after the last treatment.
The results of assays for Magnesium acetylacetonate dehydrate in treatment formulations were conform. No test item was found in the vehicle control. The results were thus satisfactory.
The validity criteria for the results were considered as fulfilled. The study is thus valid. Under these experimental conditions, the test item did not present DNA strand breaks and/or alkalilabile
sites inducer activities toward the lung and liver from OFA Sprague-Dawley female rats.
Furthermore, Magnesium acetylacetonate dihydrate induced no genotoxic activity in bone marrow cells.
As a conclusion, Magnesium acetylacetonate dihydrate induced no in vivo genotoxic activity under these experimental conditions.
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