N-phenylmaleimide

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1985

Reliability:

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

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

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:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-phenylmaleimide

EC Number:

213-382-0

EC Name:

N-phenylmaleimide

Cas Number:

941-69-5

Molecular formula:

C10H7NO2

IUPAC Name:

1-phenyl-2,5-dihydro-1H-pyrrole-2,5-dione

Details on test material:

purity: >99.9%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

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:

no

Duration of treatment / exposure:

30 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 3.5, 11.0, 35.0 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

other: concurrent no treatment and concurrent vehicle

Details on study design:

Post-exposure period: none

Examinations

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.

Statistics:

t-test

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):

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:

NOAEL

Effect level:

3.5 other: mg/kg

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

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