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EC number: - | CAS number: -
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- no data
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study performed in compliance with the GLP and similarly to the OECD 407 guideline.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid
- IUPAC Name:
- Reaction mass of N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and methacrylic acid
- Test material form:
- other: brown liquid
- Details on test material:
- - Name of test material (as cited in study report): N-[2-(2-Oxo-1-imidazolidinyl)ethyl] methacrylamide and methacrylic acid combination, other name: WAM II
- Stability under test conditions: The current committee verified that there was stability during the administration period while the test substance stability test was conducted
- Storage condition of test material: Must be stored in a cool environment
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Japan Co. LTD
- Age at study initiation: 5-week old
- Weight at study initiation: males: 147.9-166.4g; females: 122.4-138.8g
- Fasting period before study: not applicable
- Housing: individually housed in a stainless steel metal wire cage (Tokiwa Scientific Equipment Corporation, Ltd., 165W x 300D x 150 H mm) in a room where a barrier system was created (with controlled environmental conditions)
- Diet (e.g. ad libitum): MF solid feed (Oriental Processing Manufacturing Corporation)
- Water (e.g. ad libitum): filtered drinking water from the Hida City tap water were provided
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2°C
- Humidity (%): 55 ±10%
- Air changes (per hr): 10 - 15 times/hour
- Photoperiod (hrs dark / hrs light): 12h/12h
IN-LIFE DATES: From: To: no data
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Since the actual purity of the test substance was 48.61 % w/w (based on the concentration of N-[2-(2-Oxo-1-imidazolidinyl)ethyl] methacrylamide), agitation was conducted by adding distilled water (Takamatsu Pharmaceutical Corporation) to the properly weighing test substance and the density was calculated adjusting it to 10.0 % w/v. Both the 2.0 and 0.4 % w/v were diluted from the 10.0 % w/v preparation using distilled water. These types of preparation were conducted once a week.
DIET PREPARATION
not applicable
VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 3 dosing preparations: 10% , 2% and 0.4% w/v
- Amount of vehicle (if gavage): 10mL/kg bw
- Lot/batch no. (if required): no data
- Purity: no data - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability and homogeneity test were conducted on the test substance solutions by the Chemical Inspection and Testing Institute and formulations were confirmed to be stable and homogeneous for seven days in the range of 0.1 - 10 % w/v.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
40; 200 and 1000 mg/kg bw/d
Basis:
other: based on N-[2-(2-Oxo-1-imidazolidinyl)ethyl] methacrylamide content
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The range-finding study was conducted using 3 separate doses: 50, 250 and 1000 mg/kg bw/d, during a 14-day period. As a result, lesions were observed in the 1000 mg/kg bw/d group during the histopathological examination. Therefore, the revised 3 doses for the main study were set to <200 and 40mg/kg bw/d with 1000mg/kg bw/d being the highest dose. Furthermore, concurrent control recovery groups were set up for the vehicle control group and 1000mg/kg bw/d group.
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: concurrent control recovery groups were set up for the vehicle control group and 1000 mg/kg bw/d group.
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale (if not random): no data - Positive control:
- not required
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day
BODY WEIGHT: Yes
- Time schedule for examinations: day -2 prior to the injections, on day 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 and 28. During the recovery period on day 1, 3, 5, 8, 10, 12 and 14. In addition, one weight measure was taken prior to the autopsy so as to have the relative organ weight.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes. The food consumption was measured twice a week during the exposure and the recovery periods.
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: no
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the 28 day exposure and after the end of the recovery period.
- Anaesthetic used for blood collection: Yes (identity not precised)
- Animals fasted: Yes
- How many animals: all rats excluded those that died before the end
- Parameters checked in table 7.5.1/1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the 28 day exposure and after the end of the recovery period.
- Animals fasted: Yes
- How many animals: all rats excluded those that died before the end
- Parameters checked in table 7.5.1/1 were examined.
URINALYSIS: Yes
- Time schedule for collection of urine: at the end of the 28 day exposure and after the end of the recovery period.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table 7.5.1/1 were examined.
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 7.5.1/2)
HISTOPATHOLOGY: Yes (see table 7.5.1/2) - Other examinations:
- no other examinations
- Statistics:
- With regards to the blood chemistry test, urine volume, hematology test, and the absolute organ weight of all subjects (excluding the Deceased Rats, amount of feed, and weight) the Bartlett method is utilized to officially check the equal dispersion homogeneity of variance. When it was significant at 5%, an analysis for monotonicity trend was conducted. When the analysis significance has been verified, both groups’ example numbers are equal by the Dunnett method between the control group and each treated group. If it has not been verified then it is determined using the Scheffe method.
When the homogeneity of variance cannot be verified, utilize the Kruskal-Wallis test, both groups’ parameters are equal by the non-parametric Dunnett method between the control group and each treated group. If it has not been verified then it is determined using the non-parametric Scheffe method.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- 2/10 males and 1/10 female died in the highest dose group. Decrease in salivation, abnormal breathing sounds, decrease respiratory rate at the top dose.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- 2/10 males and 1/10 female died in the highest dose group. Decrease in salivation, abnormal breathing sounds, decrease respiratory rate at the top dose.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- On day 5 and 8 there was a slight decrease in weight observed in males within the 1000 mg/kg bw group which was found to be related to the death of two subjects which exhibited a decrease in weight. There were no changes in females.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- On day 4 there was a decrease in consumption observed in the 1000 mg/kg group which was found to be related to the death of two subjects who had exhibited a decrease in consumption. There were no changes in females.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant increase in the eosinophile percentage in white blood cell count of the 1000 mg/kg female group. During the recovery period, significant increase in the mean red cell hemoglobin concentration in the top dose female group. No changes in males.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant decrease in Chloride in the top dose female group during the admistration period. During the recovery period, significant decrease in serum glucose in the top dose female group. No changes in males.
- Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant increase in the urine volume in the females during the recovery period.
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Significant increase in relative kidney weight in the top dose female group. No changes in males. No changes in either males or females at the end of the recovery period.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- See details below
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- See details below
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- GROSS PATHOLOGY:
In the 1000 mg/kg male group the following was observed: whitening of the testes (1/4 animals) and elevation of mucosa on the forestomach (limiting lidge) (3/4); within the 200 mg/kg group the following was observed: adherence of liver and kidney (1/6); hair loss was observed in the cervical region in the 40 mg/kg group (1/6). In the 1000 mg/kg female group, animals experienced an elevation of mucosa on the forestomach (limiting lidge) (6/6). At the end of the recovery period, there were no changes in the males whereas blackish mucosa regions were observed in the glandular stomach (1/6) in the female control group. In animals who died during the administration period, dark reddish lesions on the lungs (1/2), gas buildup in the stomach (1/2), gas buildup in the small intestine (2/2) and gas buildup in the colon (1/2) were observed in the 1000 mg/kg male groupwhereas map-like dark redness on the lungs (1/1) and stomach buildup in the colon (1/1) were observed in the 1000 mg/kg female group.
HISTOPATHOLOGY: NON-NEOPLASTIC
Increase in eosinophilic bodies in the kidney (+: 1/4), hyperkeratosis of the forestomach (+: 3/4), decrease in sperm formation (+++:1/4) and sperm granuloma (+; ¼) were observed in the 1000 mg/kg male group; a slight necrosis of the adhered region in macroscopic findings (1/1) with calcium deposition in the kidney, and a slight necrosis of the adhered region in macroscopic findings (1/6) in the liver were observed in the 200 mg/kg male group; basophilic change of tubular epithelium with cell reaction was observed in the kidney (+; 1/6) in the control male group. Hyperkeratosis was observed in the forestomach in the 1000 mg/kg female group (+; 6/6). At the end of the recovery period, there were no changes in males whereas necrosis of the mucous membrane of the glandular stomach was observed in the control female group (+; 1/6). In animals who died during the administration period, atrophy of the Spleen (++;1/2), congestion in the lung (+;1/2, ++;1/2), lung edema (++;1/2) and hyperkeratosis of the forestomach (+; 1/1) were observed in the 1000 mg/kg male group while congestion in the lung (+;1/2, ++;1/2), lung edema (++; 1/2), and hyperkeratosis of the forestomach (+; 1/1) were observed in the 1000 mg/kg female group.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 200 mg/kg bw/day (actual dose received)
- Based on:
- other: dose adjusted for content of the main constituent N-[2-(2-oxo-1-imidazolidinyl)ethyl]methacrylamide (48.61%)
- Sex:
- male/female
- Basis for effect level:
- other: Mortality, effect on the digestive system (forestomach, stomach, small intestine, colon), respiratory system and testes
- Dose descriptor:
- NOAEL
- Effect level:
- 411 mg/kg bw/day (actual dose received)
- Based on:
- other: Dose for the substance as registered (including impurities and residual water necessary for the stability)
- Sex:
- male/female
- Basis for effect level:
- other: Mortality, effect on the digestive system (forestomach, stomach, small intestine, colon), respiratory system and testes
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
No other information
Applicant's summary and conclusion
- Conclusions:
- Under the test conditions, Reaction mass of methacrylic acid and N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide induced mortality in the highest tested dose groups (1000 mg/kg bw/d), alterations in the respiratory and digestive system and also in testes in males. The NOAEL was determined to be of 200 mg/kg bw/d when expressed as the amount of N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide and as 411 mg/kg bw/d when considering the substance as registered (including impurities and residual water necessary for stability).
- Executive summary:
In a subacute oral repeated dose toxicity study performed in compliance with the GLP and similarly to the OECD 407 guideline, Reaction mass of methacrylic acid and N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide diluted in water was administered by gavage to Sprague Dawley rats (10 animals/sex/dose) at doses of 40; 200 and 1000 mg/kg bw/d (based on N-[2-(2-oxoimidazolidin-1-yl)ethyl]methacrylamide content i.e. 82, 411 and 2057 mg/kg bw/d in terms of registered substance).The exposure period was of 28 days, and a recovery period of 14 days was performed for the vehicle control and the highest dose groups.
Mortality was observed in the highest tested dose groups where 2/10 males died on day 8 and 1/10 died on day 14. During an autopsy to determine the cause of death, the lungs were either darkened in a reddish color or exhibited a slight darkening, and the stomach and/or the intestines were filled with gas. The histopathological examination revealed hyperkeratinosis of the forestomach, decrease in the size of the spleen, and a congestion and edema in the lung, thus, related to alterations in the respiratory system and digestive system leading to death. In the surviving animals, the test item induced an increased thickness of the mucous membrane of the forestomach, correlated histopathologically with hyperkeratosis of the forestomach, in both males and females given 1000 mg/kg bw/day. One male of the 1000 mg/kg bw/d group exhibited whitening of the left testis associated by microscopic observation of decrease in sperm formation, and sperm granuloma. Although noted in only one animal, the testes finding is believed to be related to the test substance. In addition, an increase in eosinophilic bodies in the kidneys of the 1000 mg/kg bw/d males was believed to be related to the test substance. During the recovery period, there was no effect related to the test item.
Based on the results of this study, 411 mg/kg bw/d of test item was established as the no-observed-adverse effect-level (NOAEL) in males and females when considering the substance as registered.
Therefore, the registered substance is not classified for repeated dose toxicity according to the classification criteria of the Regulation (EC) 1272/2008 (CLP) and of the Directive 67/548/EEC. This study is considered as acceptable as it satisfied the criteria of the OECD Guideline No. 407.
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