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Repeated dose toxicity: oral

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Administrative data

short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: test guideline is not identified but according to OECD407. Study was not performed to GLP and no FOB was undertaken.

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guideline
equivalent or similar to
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
test period: 5 days 6 weeks
Principles of method if other than guideline:
exposure period: 30 days instead of 14 or 28 days defined by OECD 407
GLP compliance:
Limit test:

Test material

Details on test material:
purity: >99.9%

Test animals


Administration / exposure

Route of administration:
oral: gavage
other: arabic gum
Details on oral exposure:
test substance was suspended in 5% (w/v) arabic gum water solution
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
30 days
Frequency of treatment:
Doses / concentrations
Doses / Concentrations:
0, 3.5, 11.0, 35.0 mg/kg/day
actual ingested
No. of animals per sex per dose:
Control animals:
other: concurrent no treatment and concurrent vehicle
Details on study design:
Post-exposure period: none


Observations and examinations performed and frequency:
General symptoms and measurement of BW: observed everyday and measured 3 times a week.
Food and water intakes: measured once a week.
Urinalysis: animals were fasted for 10 and several hours after the final administration.
Hematological examination: same as above.
weights of organs and histopathological examination: all rats were autopsied after blood collection.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
1. Depressed weight gain observed in both sexes of 35 mg/kg group is attributed to loss of appetite due to marked injury in the stomach mucous membrane in comparison with other drug-treated groups.
Depressed appetite reduced food intake and induced emaciation as a general symptom.
Water intake of this group fluctuated more largely than those for other groups.
This fluctuation is attributable to secretion of gastric juice and nausea resulting from changes in the stomach.
2. Hematological examination revealed reduced hemoglobin level indicating hypochromic blood in 35 and 11 mg/kg groups.
Leucocyte count was increased or tended to be increased in the groups.
This change is thought to be an inflammatory reaction due to gastritis.
In particular, increased neutrophil count in 35 mg/kg group is compatible with histopathological findings.
3. Of results of blood chemical examination, the rise of GOT value in 35 and 11 mg/kg groups is remarkable.
This elevation is attributable to inflammatory reaction due to gastritis.
The elevating tendancy of potassium level in the 2 groups are thought to result from destruction of tissues relationg to gastritis.
In particular, the level was slightly elevated in 35 mg/kg group in which marked changes were observed in the forestomach and glandular stomach.
The chrolide level was higher in 35 mg/kg groupshowing serious injury in the glandular stomach than in other drug-related groups.
It is presumed that there is some relationship between this elevation and secretion of gastric juice.
The change in the creatinine level varied between males and females.
The relation between this finding and test material was unclear.
The levels of total protein and glucose were markedly fell in both sexes of 35 mg/kg group.
These low levels are attributable to decreased food intake resulting from symptoms of gastritis which were revealed by histopathogical examination.
The change in A:G ratio is also a result of aggravated nutrition and biological response.
4. As to weights of organs, absolute weights in males of 35 mg/kg group were reduced due to aggravated nutrition.
The increase in relative weights is explained by that aggravated nutrition affected the fatty tissue of the body more greatly than organs.
In females, while absolute weights were unchanged, relative weights were increased.
The increase is attributed to weight loss due to decreased food intake.
5. Of histopathological findings, changes in the atomach mucous membrane were remarkable.
As described above the changes were very severe in 35 mg/kg group and relatively slight in 11 mg/kggroups.
In 3.5 mg/kg group, slight simptoms of gastritis were found in half of males, and the changes tended to be improved in some rats.
In females no changes were observed.
These results of various examinations are correlated one another and indicate changes caused by administration of the test material.
On the basis of these resuls, the test material is thought to be irritative to the mucous membrane in the body.
The maximum non-effective dose is presumed to be about 3.5 mg/kg for both sexes.

Effect levels

Dose descriptor:
Effect level:
3.5 other: mg/kg
Based on:
test mat.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

It is concluded from the resuls of the present study that the test material, N-phenyl maleimide, induces toxic changes due to irritation.
The maximum non-effective dose is presumed to be 3.5 mg/kg in oral administration.
It is thought that safety can be assured by preventing the test material from entering into the body.
Executive summary:

In a subchronic toxicity study.PMI provided byNIPPON SHOKUBAI on 1984.08.20 was administered to SPF SD rats four weeks /male and female/dose in susupendid 5 (w/v) % aranbic gum water solution, by gavage at dose levels of 0, 3.5, 11.0, 35.0 mg/kg bw/day.

PMI induces toxic changes due to irritation.

The NOAEL is 3.5 mg/kg/day based on irritative property in Rats by the 30 days oral administration.


There is another screening study by OECD 422, this sudy's result shows irritative property of this substance causes local effects but absence of systemic effects. On the view point of the endpoint on repeat toxicity consideration, male' adverse effect during 51 days exposure is effective but female's adverse effect during this exposure period is not reliable due to maternal toxicity in this combined repeat dose and reproductive/developmental toxicity screening study.

The NOEL and LOAEL for oral repeat dose in male is 2.5 mg/kg/day by using OECD 422 test method