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EC number: 213-103-2 | CAS number: 924-42-5
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1983
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Well documented report of a guideline study conducted to GLP.
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: NTP 90-day rodent gavage
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- N-(hydroxymethyl)acrylamide
- EC Number:
- 213-103-2
- EC Name:
- N-(hydroxymethyl)acrylamide
- Cas Number:
- 924-42-5
- Molecular formula:
- C4H7NO2
- IUPAC Name:
- N-(hydroxymethyl)acrylamide
- Details on test material:
- - Name of test material (as cited in study report): N-Methylolacrylamide
- Substance type: Non-volatile, organic
- Physical state: Solid
- Analytical purity: approximately >98%
- Impurities (identity and concentrations): unkown but evidence indicates that 1% may have been a polymer of Nmethylolacrylamide,
which would not have been detected by the analytical methods used
- Composition of test material, percentage of components: 100%
- Isomers composition: not applicable
- Purity test date: no data
- Lot/batch No.: 1-45-000
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable
- Storage condition of test material: storage at 5°C
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 7 weeks
- Weight at study initiation: Males: 135±3 - 145±3; Females: 113±2 - 117±1
- Fasting period before study: No
- Housing: 5 animals per cage
- Diet: NIH 07 Rat and Mouse Ration available ad libitum
- Water: available ad libitum by automatic watering system
- Acclimation period: 19-20 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 14/07/1981To: 12/10/1981
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Weighed amounts of N-methylolacrylamide and deionised water were mixed to give the desired concentrations). The stability of N-methylolacrylamide in water was determined by the gas chromatographic system previously described after dilution with methanol containing decyl alcohol as an internal standard; 1% solutions were stable when stored for 2 weeks at room temperature in the dark or when exposed for 3 hours to light and air. During the studies, N-methylolacrylamide/deionised water mixtures were stored at 23" C for up to 2 weeks. Subsequent stability studies specifically designed to evaluate possible formaldehyde formation during storage indicated a slow production of formaldehyde, with a maximum concentration of approximately 25 ppm in the high concentration mixture at the end of 2 weeks. f'eriodic analysis of formulated N-methylolacrylamide/deionised water dose mixtures was conducted at the study laboratory and the analytical chemistry laboratory. Dose mixtures were diluted with methanol containing decyl alcohol as an internal standard and analyzed by gas chromatography with a 10% Carbowax 20MTPA column. Dose mixtures were analyzed once before the 13-week studies began and once during the 13-week studies; the concentration of one sample differed from the target concentration by more than 10%.
- Duration of treatment / exposure:
- 90 days
- Frequency of treatment:
- 5 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
12.5, 25, 50, 100 and 200 mg/kg;
Basis:
nominal in water
- No. of animals per sex per dose:
- 10 male and 10 female
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: doses were 50% of the preliminary 16 day gavage study
- Rationale for animal assignment: assigned to weight classes, and distributed to cages according to a table of random numbers. Cages were assigned to groups according to another table of random numbers.
- Post-exposure recovery period: none - Positive control:
- No
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2 times per day
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: initially and the once a week
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION:
- Time schedule for examinations: weeks 6 and 13
- Dose groups that were examined: all animals
- Battery of functions tested: motor activity, forelimb/hind limb grip strength, acoustic startle reflex measurement, and landing foot spread. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Statistics:
- Dunnett's test
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- hindlimb ataxia
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- hindlimb ataxia
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Lower values than controls at 100 and 200 mg/kg.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly incr
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses.
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
MORTALITY: There was 100% mortality in both sexes of the 200 mg/kg group before the 6th study week. No other test substance related mortality occurred.
CLINICAL OBSERVATIONS:
At 200 mg/kg, the male and female rats showed a generalised irritability to handling during the first study week. Most animals exhibited decreased cage activity. Only those animals in the 200 mg/kg dose group which survived until the third week of dosing had a hind limb ATAXIA which then progressed to a hind limb paralysis. Weak appearance and rough hair coats were additional observations recorded from many of these animals until death.
At 100 mg/kg, hind limb ataxia, beginning in the third week of dosing, did not progress to hind limb paralysis in the males until the 6th or 7th week. All male rats exhibited burrowing behaviour after gavage beginning the 4th study week. In many animals of this dose group a weakened condition, thin appearance and rough hair coats were observed.
At 50 mg/kg, all appeared to be ataxic in the hind limbs during the 8th week which progressed to hind limbs paresis during the 11th week of the study. No significant clinical observations were noted in the lower dose groups or control groups of either sex.
BODY WEIGHT AND WEIGHT GAIN
There was a dose response relationship with respect to depression of body weight gain during the study in both sexes of rats. In the 50 mg/kg dose group, males were 30.5% and females 20.6% less in weight gain than the controls. In the 25 mg/kg dose group, these figures were -15.3% (males) and -12.2 % (females).
NEUROBEHAVIOUR
Behavioural tests performed after 6 and 13 weeks of treatment showed dose-related (one-way analysis of variance) decreases in forelimb and hind limb. GRIP STRENGTH in week 13 was significantly different from controls (Dunnett's test) at doses down to 25 mg/kg/day in males and down to 50 mg/kg/day in females. MOTOR ACTIVITY was not significantly different at any dose group. At 13 weeks, female animals of the 50 mg/kg dose group exhibited significantly lower STARTLE RESPONSE SCORES as compared with control animals. LANDING FOOT SPREAD was increased at 6 weeks only for female rats receiving 50 mg/kg/day (not tested at 13 weeks since hind limb paresis was present in both sexes). No other group showed effects on landing foot spread. These findings are consistent with the development of peripheral neuropathy.
ORGAN WEIGHTS
No differences between any of the organ to body weight rations of any of the dose groups and the control groups of either sex except for the testicle weight in the 50 mg/kg dose group. The respective mean ratio was approx. 20% greater than the control's mean ratio. However, this difference could be explained by the lower body weights in this dose group
HISTOPATHOLOGY: NON-NEOPLASTIC
Degeneration in the CNS and in peripheral nerves was observed at doses of 25 mg/kg/day and higher. No compound-related lesions were observed in the lowest dose level, 12.5 mg/kg.
Effect levels
- Dose descriptor:
- LOAEL
- Effect level:
- 12.5 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- In this study, the No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of N-methylolacrylamide (NMA) administered by gavage to male and female rats for 13 weeks were 12.5 and 25 mg/kg bw respectively based on degeneration of peripheral nerves and decreased bodyweight.
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