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EC number: 418-140-1 | CAS number: 5117-12-4 ACRYLOYLMORPHOLIN
- 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:
- in vivo mammalian cell study: DNA damage and/or repair
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 19 May to 28 September 2022
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
- Report date:
- 2022
Materials and methods
Test guideline
- 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:
- mammalian comet assay
Test material
- Reference substance name:
- 4-(1-oxo-2-propenyl)-morpholine
- EC Number:
- 418-140-1
- EC Name:
- 4-(1-oxo-2-propenyl)-morpholine
- Cas Number:
- 5117-12-4
- Molecular formula:
- C7H11NO2
- IUPAC Name:
- 1-(morpholin-4-yl)prop-2-en-1-one
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- Lot No.: 0620451-LI
Purity: 99.95%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: The Jackson Laboratory Japan, Inc.
- Age at study initiation: 6 weeks old
- Weight at study initiation: 233.60 g to 261.84 g
- Assigned to test groups randomly: stratified-by-weight randomization method
- Fasting period before study:
- Housing: Rat and mouse room (2124), Polycarbonate cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Actual range: 21.8 to 22.4°C (acceptable range: 19.0 to 25.0°C)
- Humidity (%): Actual range: 49.9 to 60.9% (acceptable range: 35.0 to 75.0%)
- Air changes (per hr): 6 to 20 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours per day (7:00 to 19:00)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- - Vehicle(s)/solvent(s) used: water
- Details on exposure:
- Dose Methods:
A 3-mL disposable syringe attached with a gastric tube for rats was used for administration to each group. The test article formulations were taken into the syringe while being stirred with a magnetic stirrer.
Dose volume: 10 mL/kg - Duration of treatment / exposure:
- 24 hours
- Frequency of treatment:
- Twice (at a 24-hour interval)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 62.5 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 125 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 5 males
- Control animals:
- yes, concurrent vehicle
- Positive control(s):
- Ethyl methanesulfonate
- Route of administration: oral gavage
- Doses / concentrations: 200 mg/kg
Examinations
- Tissues and cell types examined:
- Liver, glandular stomach and duodenum were evaluated for the comet assay.
The liver is the major metabolism organ. The glandular stomach and duodenum are the first organ to be contacted by a test chemical when the animal is administered by oral route. - Details of tissue and slide preparation:
- Preparation of specimens:
All animals were used for the specimen preparation at 3 hours after the final administration as the following procedures.
(1) Each rat was anesthetized with thiopental sodium by intraperitoneal injection. The animal was euthanized by exsanguination from the abdominal aorta.
(2) The liver, stomach and duodenum were removed from each animal and the single cells were isolated from these organs and prepared the comet samples as the following procedures.
(3) A corresponding sheet was made for each organ between the animal numbers and coding ones to prepare the sampling tubes including the cell suspensions coded.
(4) Each sample (40 µL of the cell suspension) was mixed with 0.5 w/v% low melting agarose gel (360 µL), and the mixture (40 µL) was placed onto each well of a comet slide.
(5) Three slides (3 wells/sample/animal) were assigned to each sample.
Preparation of the liver samples:
(1) The removed liver was examined macroscopically.
(2) A portion of the liver, around the central part of the left lateral lobe, was cut into a cube (approximately 5 mm).
(3) The residual parts of the left lateral lobe were fixed with 10% phosphate buffered formalin for the histopathological examinations.
(4) The liver cube was washed with a cold mincing buffer, and was minced with scissors about 100 times to isolate the hepatocytes.
(5) The isolated hepatocytes were suspended in a 3 mL of the cold mincing buffer by gently pipetting about 15 times. The cell suspension was filtered through a cell strainer (pore size: 40 µm).
(6) The filtered cell suspension was prepared at approximately 2.0E+05 cells/mL with the cold mincing buffer and the resultant cell suspension was used as the liver sample for the comet assay.
Preparation of the glandular stomach samples:
(1) The removed stomach was cut open along its greater curvature, washed twice with cold PBS (-) and examined macroscopically.
(2) A half of the stomach was used for the comet assay and another half was fixed with 10% phosphate buffered formalin for the histopathological examinations.
(3) The stomach tissue for the comet assay was washed with the cold mincing buffer and the forestomach was removed away if necessary. The glandular stomach was immersed into the fresh cold mincing buffer for 15 to 19 min actually (as prescribed for 15 to 30 min).
(4) The surface epithelium of the glandular stomach was scraped and exfoliated with a scraper and then washed well away with the cold mincing buffer.
(5) The mucous epithelium of the glandular stomach was scraped 5 times or more with a spatula to release the stomach cells. The cells were suspended in a 3 mL of the cold mincing buffer by gently pipetting about 15 times. The cell suspension was filtered through a cell strainer (pore size: 40 µm).
(6) The filtered cell suspension was prepared at approximately 2.0E+05 cells/mL with the cold mincing buffer and the resultant cell suspension was used as the glandular stomach sample for the comet assay.
6.6.5.2.3 Preparation of the duodenum samples
(1) The small intestine corresponding to the duodenum (proximal side) was cut open in the longitudinal direction along the mesenteric attachment side, this duodenum was used for the comet assay, and washed well with cold PBS(-). The duodenum was examined macroscopically.
(2) Residual duodenum (distal side) was fixed with 10% phosphate buffered formalin for the histopathological examinations.
(3) The duodenum for the comet assay was washed with the cold mincing buffer, and then immersed into the fresh cold mincing buffer for 15 to 21 minutes actually (as prescribed for 15 to 30 minutes).
(4) The mucosal surface of the duodenum was scraped and exfoliated well with a scraper and then washed well away with cold mincing buffer.
(5) The epithelial cells were exfoliated with a spatula to release the cells. The cells were suspended with a 3 mL of the cold mincing buffer by gently pipetting about 15 times. The cell suspension was filtered through a cell strainer (pore size: 40 µm).
(6) The filtered cell suspension was prepared at approximately 2.0E+05 cells/mL with the cold mincing buffer. The resultant cell suspension was used as the duodenum sample for the comet assay. - Evaluation criteria:
- If the % tail DNA statistically increased in the test article group(s), the study result(s) would be evaluated whether the tissue damage and/or cytotoxic effects were related to the significance based on the frequencies of hedgehog cells and histopathological examinations (if those were done). If the test article induced significant increase(s) in the % tail DNA apart from the tissue damage or cytotoxicity, biological relevance should be comprehensively considered for the comet assay on the basis of the laboratory historical data, distribution and variation of individual data and so on. If the % tail DNA increased in the test article group(s) with biological and toxicological significances, the assay results should be judged positive.
- Statistics:
- EXSUS statistical software system (ver. 8.1.0, EPS Corporation) was used for the statistical analyses.
Results and discussion
Test results
- Key result
- Sex:
- male
- Genotoxicity:
- ambiguous
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Remarks on result:
- other: negative in liver and glandular stomach, equivocal in duodenum
- Additional information on results:
- Liver:
The group means (± SD) of the median % tail DNA were 1.69 ± 0.36%, 1.71 ± 0.86%, 1.89 ± 0.32% and 1.72 ± 0.13% at 0 (negative control), 62.5, 125 and 250 mg/kg, respectively. No statistically significant increases in the median % tail DNA were detected in any of the test article groups compared to the negative control group. In contrast, the group mean of the median % tail DNA in the positive control group (24.23 ± 2.22%) was significantly higher than those in the negative control group.
The frequencies (%) of hedgehogs were 2.7% or lower in all the animals and the group mean frequencies were 1.5% or lower in all the groups.
Glandular stomach:
The group means (± SD) of the median % tail DNA were 5.50 ± 1.54%, 3.79 ± 0.41%, 4.74 ± 1.70% and 4.65 ± 1.90% at 0 (negative control), 62.5, 125 and 250 mg/kg, respectively. No statistically significant increases in the median % tail DNA were detected in any of the test article groups compared to the negative control group. In contrast, the group mean of the median % tail DNA in the positive control group (32.34 ± 3.28%) was significantly higher than those in the negative control group.
The frequencies (%) of hedgehogs were 6.7 % or lower in all the animals and the group mean frequencies were 5.5% or lower in all the groups.
Duodenum:
The group means (± SD) of the median % tail DNA were 1.00 ± 0.34%, 1.85 ± 0.23%, 1.98 ± 0.23% and 1.61 ± 0.33% at 0 (negative control), 62.5, 125 and 250 mg/kg, respectively. Statistically significant increases in the median % tail DNA were detected in all of the test article groups compared to the negative control group but there was no dose-dependency. The group mean of the median % tail DNA in the positive control group (17.63 ± 3.03%) was significantly higher than those in the negative control group.
The frequencies (%) of hedgehogs were 8.0 % or lower in all the animals and the group mean frequencies were 6.0% or lower in all the groups.
No abnormal findings were macroscopically observed in either the liver, stomach or duodenum of any animals.
No abnormal findings were observed in all animals.
Applicant's summary and conclusion
- Conclusions:
- Based on the results, ACMO was judged equivocal in the comet assay of the duodenum in rats. Therefore, it could not be completely denied that ACMO had potential to induce DNA damage in the duodenum. It was also concluded that ACMO did not have a potential to induce DNA damage in the liver and glandular stomach under the conditions of this study.
- Executive summary:
A comet assay of ACMO was conducted in rats to assess the in vivo genotoxic potential to induce DNA damage by analyzing the DNA fragmentation of cellular nuclei of the liver, glandular stomach and duodenum in rats, according to OECD Guideline 489.
The test article was suspended in a vehicle (water for injection) and administrated orally by gavage to male Crl:CD(SD) rats (5 animals per group, 7 weeks old at dosing) at dose levels of 0 (vehicle alone; negative control group), 62.5, 125 and 250 mg/kg for two consecutive days at a 24-hour interval. The positive control, ethyl methanesulfonate (EMS), was treated at 200 mg/kg in the same manner with the test article.
As a result, there were no significant increases in the median % tail DNA in the liver or glandular stomach in any of the test article groups compared to the negative control group. In contrast, there were significant increases in the median % tail DNA in the duodenum in all of the test article groups compared to the negative control group but there was no dose-dependency. There was no clear evidence of tissue damage or cytotoxic effect in the scoring of hedgehogs and gross necropsy in all organs, and histopathological examination in the duodenum. In the duodenum, each individual median % tail DNA in the negative control group was lower than the minimum limit of the laboratory historical data, and the median % tail DNA of the test article groups were comparable to the laboratory historical data (mean ± 2SD). Therefore, it would be considered that a statistically increase was detected in all the test article groups due to lower values of the negative control group.
The liver and glandular stomach comet assay were judged to have been conducted under the appropriate conditions based on the results obtained from the control groups. On the other hand, the negative and positive control groups in the duodenum comet assay did not satisfy the acceptance criteria of the study.
Based on the results described above, ACMO was judged equivocal in the comet assay of the duodenum in rats. Therefore, it could not be completely denied that ACMO had potential to induce DNA damage in the duodenum. It was also concluded that ACMO did not have a potential to induce DNA damage in the liver and glandular stomach under the conditions of this study.
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