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Description of key information

N-methylol methacrylamide was assessed for repeated dose toxicity in analogy to the structurally closely related methacrylamide. The systemic NOAEL of 9.1 mg/kg/d from a chronic oral study in rats is in good accordance with a NOAEL of approximately 18 mg/kg/d derived  from a subchronic inhalation study. Inhalation is not a relevant pathway for N-methylol methacrylamide which has a very low intrinsic vapour pressure and exists in practice as aqueous solution only.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Japanese reference, only abstract and tables in English available. Japanese government peer-reviewed the documents, audited selected studies.
Principles of method if other than guideline:
Method: no data.
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
male
Route of administration:
oral: drinking water
Duration of treatment / exposure:
4, 8, and 12 months
Remarks:
Doses / Concentrations:
0, 200, 400, 800 and 1200 ppm (equivalent to ca. 0, 4.6, 9.1, 19.5, and 31.6 mg/kd/day)
Basis:
other: The equivalent doses mentioned above are re-calculated because the original doses in the literature by Aritani were apparently incorrect.
No. of animals per sex per dose:
Number of animals in each dose group was 18 to 20
Control animals:
yes
Details on study design:
Post-exposure period: 12 month in the longest case
Statistics:
STATISTICAL ANALYSIS
For comparison of 3 or more groups, the differences between group means were first examined by one-way ANOVA and then by Dunnett’s
multiple comparison test. Differences were considered significant at p<0.05.
For comparison of 2 groups, Fisher’s exact probability test were used.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
Results:
1200 ppm: Body weight gain was slightly but insignificantly suppressed compared to control during the treatment period.
Symptoms of peripheral neuropathy including hindlimb weakness and abnormal gait were detected.
800 and 1200 ppm: Walking performance on a rotating rod decreased significantly.
More than 800 ppm: shrinkage and loss of myelinated fibers of the sciatic nerve and atropy of the gastrocnemius muscle was detected.
Some rats showed a distension of the urinary bladder. Water and food consumption were not different among control and treatment groups during
the treatment period. Hemogram did not change significantly.
Dose-related increases in serum total cholesterol and phospholipid content and y-glutamyl transpeptidase activity were seen after 12 months,
although the increase in the last item was not statistically significant. Rat urine after 12 months did not show any significant biochemical change.
During post-administration period, pigmentation of body fur due to urinary incotinence, and symptoms of neuropathy were advanced,
especially in rats receiving the two higher doses. No significant differences in absolute or relative organ weights were seen among either treatment or post treatment periods.
Dose descriptor:
NOAEL
Effect level:
ca. 9.1 mg/kg bw/day (nominal)
Sex:
male
Dose descriptor:
LOAEL
Effect level:
ca. 19.5 mg/kg bw/day (nominal)
Sex:
male
Critical effects observed:
not specified
Conclusions:
Neurotoxic effects were observed. The NOAEL for male rats in this drinking water study was considered to be ca. 9.1 mg/kg/day (400 ppm).
Executive summary:

In a chronic toxicity study Methacrylamide  was administered to male Wistar rats in drinking water at dose levels of 0, 4.6, 9.1, 19.5 and 31.6 mg/kg bw/day for 4, 8 and 12 month.

Histopathological observations related to neurotoxicity such as shrinkage and loss of myelinated fiber of sciatic nerve were observed at 800 ppm (ca. 19.5 mg/kg/day) and higher.

The NOAEL is 9.1 mg/kg/day

Original study in Japanese. Only abstract in English available

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
9.1 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Study is of sufficient reliability as the Japanese government peer-reviewed the documents, audited selected studies. Study was accepted as key study within OECD SIDS. The systemic NOAEL of 9.1 mg/kg/d from a chronic oral study in rats is in good accordance with a NOAEL of approximately 18 mg/kg/d derived from a subchronic inhalation study.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Inhalation is not a relevant pathway for N-methylol methacrylamide as it has a very low intrinsic vapour pressure and exists in practice as aqueous solution only.

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Inhalation is not a relevant pathway for N-methylol methacrylamide as it has a very low intrinsic vapour pressure and exists in practice as aqueous solution only.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The dermal absorption potential of N-methylol methacrylamide is low (details see toxicokinetics, 7.1.2). There is no evidence for enhanced systemic toxicity of the substance via the dermal route.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The dermal absorption potential of N-methylol methacrylamide is low (details see toxicokinetics, 7.1.2). There is no evidence for local skin effects.

Additional information

N-methylol methacrylamide was assessed for repeated dose toxicity in analogy to the structurally closely related methacrylamide.Neurotoxicity observed in methacrylamide studies and clearly attributed to the methacrylamide structure is considered as the most critical endpoint. Due to the lower molar equivalent of methacrylamide in N-methyl methacrylamide, the results obtained in repeated dose studies on methacrylamide are considered as worst case. Although inhalation was not identified as relevant exposure pathway for N-methyl methacrylamide, the 90 d inhalation study was considered as it was the most current repeated dose study with extensive testing of neurotoxicity parameters.For methacrylamide, the NOAEL in a chronic oral study in rats was 9.1 mg/kg/d. In the 90 day inhalation study with methacrylamide in rats, the NOAEL for systemic effects was the highest administered dose, 62.5 mg/m³, which is equivalent to ca. 18 mg/kg b.w./d. The systemic NOAEL of 9.1 mg/kg/d from the chronic study in rats is in good accordance with a NOAEL of approximately 18 mg/kg/d derived from the subchronic study. Inhalation is not a relevant pathway for N-methylol methacrylamide because it has a very low intrinsic vapour pressure and exists in practice as aqueous solution only.


Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: other

Justification for classification or non-classification

Methacrylamide showed neurotoxicity after single and repeated exposure in a number of animal tests.

Therefore, N-methylol methacrylamide is classified in analogy for STOT SE category 2 and STOT RE category 2.

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