N-(hydroxymethyl)methacrylamide

Repeated dose toxicity: oral

Administrative data

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.

Data source

Reference

Reference Type:

publication

Title:

Chronic effects of methacrylamide - 12 month study of administration in drinking water to rats and mice.

Author:

Aratani J

Year:

1993

Bibliographic source:

Kanazawa Daigaku Juzen Igakkai Zasshi 102(6): 720 - 727; Secondary literature from SIDS

Materials and methods

Principles of method if other than guideline:

Method: no data.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Methacrylamide

EC Number:

201-202-3

EC Name:

Methacrylamide

Cas Number:

79-39-0

Molecular formula:

C4H7NO

IUPAC Name:

methacrylamide

Details on test material:

Purity of the test substance: no data

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: drinking water

Duration of treatment / exposure:

4, 8, and 12 months

Doses / concentrations

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

Examinations

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.

Results and discussion

Results of examinations

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.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

ca. 9.1 mg/kg bw/day (nominal)

Sex:

male

2

Dose descriptor:

LOAEL

Effect level:

ca. 19.5 mg/kg bw/day (nominal)

Sex:

male

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

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