2-butyl-6-(butylamino)-1H-benz[de]isoquinoline-1,3(2H)-dione

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Justification for type of information:

Data is from HPVIS database

Data source

Reference

Reference Type:

secondary source

Title:

Repeated dose toxicity for CAS 550-77-4

Author:

U.S Environmental Protection agency

Year:

2017

Bibliographic source:

High Production Volume Information System (HPVIS)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Repeated dose toxicity study was carried out for substance 2-methyl-1H-isoindole-1,3(2H)-dione on rats.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N-methylphthalimide

EC Number:

208-982-4

EC Name:

N-methylphthalimide

Cas Number:

550-44-7

Molecular formula:

C9H7NO2

IUPAC Name:

2-methyl-1H-isoindole-1,3(2H)-dione

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: basal diet

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

30 days

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 other: mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

250 other: mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

500 other: mg/kg bw/day

Doses / concentrations 4

Dose / conc.:

1 000 other: mg/kg bw/day

No. of animals per sex per dose:

0 rats/sex

Control animals:

yes

Details on study design:

Not specified

Positive control:

Not specified

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data
- Time schedule:
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations:

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: No data
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals:
- Parameters checked in table [No.?] were examined.

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood:
- Animals fasted: No data
- How many animals:
- Parameters checked in table [No.?] were examined.

URINALYSIS: No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

Not specified

Statistics:

The following statistical tests were utilized to evaluate body weight changes, total food consumption and organ weights: Bartlett's test for homogeneity of variance and one-way classification analysis of variance. If the ANOVA was heterogeneous, a log10 transformation was performed, followed by Bartlett's test. If the log10 transformation was ineffective in removing variance heterogeneity, ANOVA of the untransformed data was completed. When the ANOVA indicated homogeneous data, the Scheffe multiple comparison procedure was used to compare the control and treatment group means. When the ANOVA indicated heterogeneous data, Games and Howell's modification of the Tukey-Kramer honestly signific ant difference test was used to compare the group means.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

No significant effects observed.

Mortality:

mortality observed, treatment-related

Description (incidence):

One male rat in the 0.25% group died on Day 26 of the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Statistically significant decreases in body weight of both male and female rats in the 0.5 and 1.0% groups (6% and 18% lower than controls for males and 4% and 11% lower than control for females, respectively) were noted during the fourth week of exposure.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption values of the treated male and female rats were lower than control at some measurement periods, but the food consumption value for the male rats in the 1.0% group during the final week of exposure was the only statistically significant decrease noted. Mean compound consumption for the male rats in the 0.25, 0.50 and 1.0% groups ranged from 146 to 203 mg/kg/day, 330 to 403 mg/kg/day and 685 to 815 mg/kg/day, respectively. The mean compound consumption for the female rats in the 0.25, 0.5 and 1.0% groups range from 197 to 226 mg/kg/day, 409 to 573 mg/kg/day and 921 to 1100 mg/kg/day, respectively.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Mean liver relative to terminal body weight was increased for both sexes and mean kidney weight relative to terminal body weight was increased for males at 1.0%.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

The gross pathology revealed no treatment-related effects in any PI-treated group.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic evaluation revealed compound-related findings of centrilobular to diffuse hepatocellular enlargement in rats of both sexes in the 0.5 and 1.0% treatment groups. In addition, the severity of chronic progressive nephropathy was increased slightly in the male rats in the 1.0% group. There were no compound-related findings present in the tissues examined from the male or female rats in the 0.25% group.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

Dose descriptor:

NOAEL

Effect level:

250 other: mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The No observed adverse effect level (NOAEL) for the substance 2-methyl-1H-isoindole-1,3(2H)-dione is determined to be 250 mg/kg bw/day.

Executive summary:

Groups of 10 rats /sex were fed 2-methyl-1H-isoindole-1,3(2H)-dione at levels of 0, 0.25, 0.5 and 1.0%. All rats were observed for mortality twice each day. Clinical signs and body weights were recorded at initiation and weekly thereafter. Food consumption was recorded weekly. After 30 days of treatment, all surviving rats were fasted overnight and weighed prior to terminal sacrifice and necropsy. At necropsy the liver and kidneys were weighed. The following tissues were saved from all animals: brain, pituitary, thoracic spinal cord, eyes, salivary glands (mandibular), stomach, trachea, thymus esophagus, heart, spleen, adrenals, pancreas, duodenum, jejunum, ileum, colon, cecum, mesenteric lymph node, urinary bladder, testes with epididymides and prostate (males), ovaries and uterus (females), femur, bone marrow (costochondral junction), lungs, liver, kidneys, thyroid (with parathyroids), skeletal muscle, and all gross lesions. Microscopic evaluation was conducted on sections of the lungs, liver, brain and kidneys from rats of all treatment groups. A necropsy also was performed on all rats that were sacrificed in extremis or were found dead during the study. One male rat in the 0.25% group died on Day 26 of the study. Statistically significant decreases in body weight of both male and female rats in the 0.5 and 1.0% groups (6% and 18% lower than controls for males and 4% and 11% lower than control for females, respectively) were noted during the fourth week of exposure. Mean food consumption values of the treated male and female rats were lower than control at some measurement periods, but the food consumption value for the male rats in the 1.0% group during the final week of exposure was the only statistically significant decrease noted. Mean compound consumption for the male rats in the 0.25, 0.50 and 1.0% groups ranged from 146 to 203 mg/kg/day, 330 to 403 mg/kg/day and 685 to 815 mg/kg/day, respectively. The mean compound consumption for the female rats in the 0.25, 0.5 and 1.0% groups range from 197 to 226 mg/kg/day, 409 to 573 mg/kg/day and 921 to 1100 mg/kg/day, respectively. The gross pathology revealed no treatment-related effects in any PI-treated group. Mean liver relative to terminal body weight was increased for both sexes and mean kidney weight relative to terminal body weight was increased for males at 1.0%. Microscopic evaluation revealed compound-related findings of centrilobular to diffuse hepatocellular enlargement in rats of both sexes in the 0.5 and 1.0% treatment groups. In addition, the severity of chronic progressive nephropathy was increased slightly in the male rats in the 1.0% group. There were no compound-related findings present in the tissues examined from the male or female rats in the 0.25% group. 

Thus, the No observed adverse effect level (NOAEL) for the substance2-methyl-1H-isoindole-1,3(2H)-dione is determined to be 250 mg/kg bw/day.