Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Japanese government peer-reviewed the documents, audited selected studies. Only data availavle from OECD SIDS
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Japanese government peer-reviewed the documents, audited selected studies. Only data availavle from OECD SIDS
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Supplier:Mitsui chemicals, Inc.,
Lot No: .710130
Purity: 99.5%
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: 5 weeks old
- Weight at study initiation: 152 - 183 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Administration: Vehicle: Purified water
Total volume applied: 5 mL/kg
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days/week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
7 per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 days
Statistics:
STATISTICAL ANALYSIS
For comparison of grip strength of forelimb or hindlimb, splay of hindlimb, locomotor activity counts, body weights, food consumption, urinary quantitative analysis, hematology, blood chemistry and absolute or relative organ weights, Bartlett’s test for homogeneity of variance was first performed. When variance was homogeneous, one-way ANOVA was used.
If significant differences were observed, the differences between treated group and control group were examined by Dunnett’s multiple comparison test. On the other hand, when variance was not homogeneous, Kruskal-Wallis’s test was used. If significant differences were observed, the differences were examined by Mann-Whitney’s U-test.
For comparison of functional observation scores and urinary qualitative analysis, Kruskal-Wallis’s test was first performed. If significant differences were observed, the differences between treated group and control group were examined by Mann-Whitney’s U-test.
Differences from control group were considered to be significant at p<0.05.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see neuropathological findings
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day: decrease in body weight (p<0.01), body weight gain (p<0.01)
-At the end of recovery period. decrease in body weight (p<0.01)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day: decrease in food consumption (p<0.01)
-At the end of recovery period: recovery after 14 d
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day: non-significant decrease in water consumption
-At the end of recovery period: complete recovery
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
- 30 mg/kg/day; decrease in mean corpuscular volume (p<0.05).
- 100 mg/kg/day; decrease in mean corpuscular volume and mean corpuscular hemoglobin (p<0.05).
- 300 mg/kg/day; decrease in hematokrit (p<0.05), decrease in mean corpuscular volume and mean corpuscular hemoglobin (p<0.01).
- At the end of recovery period; no effects at 30 and 100 mg/kg/d, respectively. At 300 mg/kg/day, increase in platelet count (p<0.01)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
- 100 mg/kg/day; decrease in total protein (p<0.05) - no dose related effect, not observed after recovery
- 300 mg/kg/day; increase in albumin (p<0.05), decrease in alpha2-globulin (p<0.05) and ALP (p<0.05); non-significant decrease in decrease in alpha1-globulin
- At the end of recovery period; increase in albumin (p<0.05), A/G ratio (p<0.05), potassium (p<0.05) and inorganic phosphorous (p<0.05), decrease of total protein (p<0.05), glucose (p<0.01) and triglyceride (p<0.05).
Urinalysis findings:
no effects observed
Description (incidence and severity):
- treatment period: no effects observed
-At the end of recovery period; no eefcts observed
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
–100 mg/kg/day; Increase in relative organ weight of the kidneys (p<0.01).
–300 mg/kg/day; decrease in absolute organ weight of the brain, lungs, heart, liver, and adrenals (p<0.05), spleen and pituitary gland (p<0.01). Increase in relative organ weight of the brain, lungs, heart, liver, kidneys, thyroids, testes and epididymides (p<0.01).
-At the end of recovery period; decrease in absolute organ weight of the heart and liver (p<0.05), increase in testes and epididymides (p<0.05). Increase in relative organ weight of the brain, lungs,kidneys and testes (p<0.01) spleen, adrenals and epididymides (p<0.05).
Gross pathological findings:
not specified
Description (incidence and severity):
Pathology (number of animals):
-300 mg/kg/day; dilation of lumen in bladder (3), dark redness of light lobus anterior (1) and dark red maculae of left anterior (1) in lungs.
-At the end of recovery period; white maculae of light middle and left anterior in lungs (1).
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day; staggering gait, ataxia, decrease in muscle tone, grip strength of forelimb (p<0.01).
-100 mg/kg/day or more; decrease in locomotor activity counts(100mg/kg; p<0.05, 300mg/kg; p<0.01).
-At the end of recovery period; staggering gait, ataxia, decrease in muscle tone, locomotor activity counts (p<0.01), grip strength of hindlimb (p<0.01), splay of hindlimb (p<0.05).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathology (number of animals):
-300 mg kg/day; slight swelling of axonal in the cerebellar peduncle (1), slight degeneration of sciatic nerve fibers (7), moderate cellular infiltration of neutrophil (2) and granuroma (1) in the lungs, slight cellular infiltration of neutrophil at lamina propria in the trachea (1) and slight
hyperplasia of tubular pars nervosa in the pituitary gland (1).
-At the end of recovery period; slight swelling of axonal in the cerebellar peduncle (3), slight (4) or moderate (3) degeneration of sciatic nerve fibers, slight (1) or moderate (1) granuroma in the lungs, retention of step19 spermatids at stage IX and X in testis (1)
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
neuropathology
organ weights and organ / body weight ratios
Critical effects observed:
not specified
Conclusions:
The NOAEL was considered to be 30 mg/kg/day for male rats.
Executive summary:

In a subacute oral  toxicity study (OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents Methacrylamide (99.5%) was administered to 7 rats per dose group (male Crj: CD(SD, 5 week old) in water by gavage at dose levels of 0, 30, 100 and 300 mg/kg bw/day.

Adverse effects observed in any test group: clinical signs; body weight and weight gain; haematology; organ weights. 

The NOAEL is  30 mg/kg bw  based on decrease in locomotor activity.

 This subacute toxicity study in the rats is acceptable and satisfies the guideline requirement for a subacute oral study OECD 407 in rodents. 

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methacrylamide
EC Number:
201-202-3
EC Name:
Methacrylamide
Cas Number:
79-39-0
Molecular formula:
C4H7NO
IUPAC Name:
methacrylamide
Test material form:
solid
Details on test material:
Batch (Lot) Number: 11110320
Specific details on test material used for the study:
Supplier:Mitsui chemicals, Inc.,
Lot No: .710130
Purity: 99.5%

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: 5 weeks old
- Weight at study initiation: 128 - 154 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
Administration: Vehicle; Purified water
Total volume applied: 5 mL/kg
Duration of treatment / exposure:
28 days
Frequency of treatment:
7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
7 animals per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 days

Examinations

Statistics:
STATISTICAL ANALYSIS
For comparison of grip strength of forelimb or hindlimb, splay of hindlimb,
locomotor activity counts, body weights, food consumption, urinary
quantitative analysis, hematology, blood chemistry and absolute or relative
organ weights, Bartlett’s test for homogeneity of variance was first
performed. When variance was homogeneous, one-way ANOVA was used.
If significant differences were observed, the differences between treated
group and control group were examined by Dunnett’s multiple comparison
test. On the other hand, when variance was not homogeneous, Kruskal-
Wallis’s test was used. If significant differences were observed, the
differences were examined by Mann-Whitney’s U-test.
For comparison of functional observation scores and urinary qualitative
analysis, Kruskal-Wallis’s test was first performed. If significant differences
were observed, the differences between treated group and control group
were examined by Mann-Whitney’s U-test.
Differences from control group were considered to be significant at p<0.05.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see neuropathological findings
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
–100 mg/kg/day or more; decrease in body weight gain.
-At the end of recovery period: decrease in body weight (p<0.01)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day: decrease in food consumption (p<0.01)
-At the end of recovery period: recovery after 7 days
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day: decrease in water consumption (p<0.05)
-At the end of recovery period: decrease in water consumption (p<0.05)
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day; decrease in hematocrit (p<0.05) and hemoglobin.
-At the end of recovery period; increase in platelet count (p<0.05) and prothrombin time (p<0.05).
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day; increase in triglyceride(p<0.05), urea nitrogen (p<0.05), creatinine (p<0.05); non-significant increase in Albumin, non-significant decrease in alpha1-globulin and ALP.
-At the end of recovery period; increase in ALP (p<0.05), potassium (p<0.01), inorganic phosphorous (p<0.01) and chlorine (p<0.05), decrease of total protein (p<0.01) and glucose (p<0.01).
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
- treatment period: no effects observed
-At the end of recovery period; 300 mg/kg/day with reduced urine specific gravity (p<0.05)
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
see: neuropathological findings
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
–300 mg/kg/day; decrease in absolute organ weight of the brain, lungs, heart, liver, spleen, pituitary gland and thymus (heart; p<0.05, others; p<0.01), increase in relative organ weight of the brain, lungs, heart, liver and kidneys (p<0.01).
- -At the end of recovery period; decrease in absolute organ weight of the brain, liver, pituitary gland and ovaries (p<0.01), increase in relative organ weight of the brain, lungs, heart, kidneys, spleen, adrenals and thymus (thymus; p<0.05, others; p<0.01).
Gross pathological findings:
not specified
Description (incidence and severity):
Pathology (number of animals):
-300 mg/kg/day; dilation of lumen in bladder (1).
-At the end of recovery period; dilation of light renal pelvis in kidneys (1) and cyst in ovaries (1).
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
-300 mg/kg/day; staggering gait, (beginning with d21, p<0.01), ataxia and decrease in muscle tone (beginning with d28).
–30 mg/kg/day or more; decrease in locomotor activity counts (30 and 100mg/kg; p<0.05, 300mg/kg; p<0.01).
-At the end of recovery period; staggering gait (p<0.01), ataxia, decrease in muscle tone, locomotor activity counts (p<0.05) and grip strength of hindlimb (p<0.01).
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
-300 mg kg/day; slight swelling of axonal in the cerebellar peduncle (2), slight degeneration of sciatic nerve fibers (7), slight granulation of muscular layer in the esophagus (1).
-At the end of recovery period; slight swelling of axonal in the cerebellar peduncle (5), slight (5) or moderate (2) degeneration of sciatic nerve fibers, slight dilation of renal pelvis in the kidney (1), slight cyst in the pituitary gland (1) and uterus (1).
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
< 30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
neuropathology

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
System:
peripheral nervous system
Organ:
other: peripheral nervous system
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL was considered to be below 30 mg/kg/day for female rats because neurofunctional effects were observed in the lowest dose and thus the NOAEL for females cannnot be determined in this study.
Executive summary:

In a subacute oral  toxicity study (OECD 407, Repeated Dose 28-day Oral Toxicity Study in Rodents Methacrylamide (99.5%) was administered to 7 rats per dose group (female Crj: CD(SD, 5 week old) in water by gavage at dose levels of 0, 30, 100 and 300 mg/kg bw/day.  

Adverse effects observed in any test group: clinical signs; body weight and weight gain; haematology; organ weights. 

The NOAEL is    < 30 mg/kg bw  based on decrease in locomotor activity.

This subacute toxicity study in the rats is acceptable and satisfies the guideline requirement for a subacute oral study OECD 407 in rodents.