Phthalimide

フタルイミド


[CAS No. 85-41-6]

1,3-Dihydro-1,3-dioxoisoindole/1H-Isoindole-1,3,(2H)-dione

1,3-ジヒドロ-1,3-ジオキソインドール/1H-イソインドール-1,3,(2H)-ジオン

Molecular formula: C8H5NO2 Molecular weight: 147.13

ABSTRACT

Phthalimide was studied for oral toxicity in rats both in a single dose toxicity test at dose of 2000 mg/kg, and in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 250, 500 and 1000 mg/kg/day.

The single oral dose of 2000 mg/kg of phthalimide caused no deaths non any signs of toxicity both sexes up to 2000 mg/kg.

In the repeat dose toxicity test, no effects of phthalimide were detected in terms of general appearance, body weights, food consumption, organ weights, autopsy, gross pathology, urinalysis, hematological or biochemical parameters, or histopathological findings in males. Histopathological examination revealed periportal fatty change in the liver, renal epithelial fatty change, and atrophy in the thymus in one female given 1000 mg/kg. No other effects of phthalimide were detected on general appearance, body weight, food consumption, organ weights, autopsy, gross pathology of females, or histopathological appearance in the other females and in any males given 1000 mg/kg. On the basis of these findings, the NOELs of phthalimide for repeat dose toxicity were considered to be 1000 mg/kg/day for males, and 500 mg/kg/day for females, respectively. As for the reproductive ability of parental animals, no effects were detected in males, but one female given 500 mg/kg did not deliver until day 26 of gestation. Autopsy of the female revealed dilatation of the uterus and vagina, and five implantation sites. Body weights and food consumption were decreased in the female given 1000 mg/kg which demonstrated abnormal findings on histopathological examination, eight of its pups were dead or cannibalized, and the surviving nine pups showed body weight loss. Male and female pups of the 500 and 1000 mg/kg groups showed lower body weights or body weight gain in the lactation period. On the basis of these findings, the NOELs of phthalimide for reproductive/developmental toxicity were considered to be 1000 mg/kg/day for males, 250 mg/kg/day for females, and 250 mg/kg/day for development of pups, respectively.

Phthalimide was not mutagenic in Salmonella typhimurium TA100, TA1535, TA98, TA1537 and Escherichia coli WP2 uvrA, with or without an exogenous metabolic activation system.

Phthalimide induced structural chromosomal aberrations in CHL/IU cells with 6 hr short-term treatment with S9 mix. Polyploid cells were not induced in any treatment group.

SUMMARIZED DATA FROM THE STUDIES

1. Single Dose Oral Toxicity 1)

Purity:99.9 %
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Test Guideline 401
 Route:Oral (gavage)
 Doses:2000 mg/kg
 Number of animals/group:Males, 5; females, 5
 Vehicle:1 % Carboxymethylcellulose sodium
GLP:Yes

 Test results:

No deaths occurred in either males or females. No effects were detected in terms of general appearance, body weights, autopsy gross pathology or histopathological findings.
LD50: Males, > 2000 mg/kg; females, > 2000 mg/kg

2. Repeat Dose and Reproductive/Developmental Toxicity 1)

Purity:99.9 %
Test species/strain:Rat/Crj:CD (SD)
Test method:OECD Combined Repeat Dose and Reproductive/Developmental Toxicity Screening Test
 Route:Oral (gavage)
 Doses:0 (vehicle), 250, 500, 1000 mg/kg/day
 Number of animals/group:Males, 12; females, 12
 Vehicle:1 % Carboxymethylcellulose sodium
 Administration period:Males, 46 days
Females, from 14 days before mating to day 3 of lactation
 Terminal kill:Males, day 47
Females, day 4 of lactation
GLP:Yes

 Test results:

<Repeat dose toxicity>

No effects of phthalimide were detected on general appearance, body weight, food consumption, organ weights, autopsy, gross pathology, urinalysis, hematological or biochemical parameters, or histopathological findings in males. Histopathological examination revealed periportal fatty change in the liver, renal epithelial fatty change, and atrophy in the thymus in one female given 1000 mg/kg. No effects of phthalimide were detected on general appearance, body weight, food consumption, organ weights, autopsy gross pathology of females, or by histopathological examination of the other females.

On the basis of these findings, the NOELs of phthalimide for repeat dose toxicity were considered to be 1000 mg/kg/day for males, and 500 mg/kg/day for females, respectively.

<Reproductive and developmental toxicity>

No effects were detected in males. One female given 500 mg/kg did not deliver until day 26 of gestation. Autopsy of the female revealed dilatation of uterus and vagina, and five implantation sites. Body weights and food consumption were decreased in the female given 1000 mg/kg which demonstrated abnormal findings in histopathological examination, and eight of its pups were dead or cannibalized, and the surviving nine pups showed body weight loss. Male and female pups of the 500 and 1000 mg/kg groups showed lower body weights or body weight gain in the lactation period. On the basis of these findings, the NOELs of phthalimide for reproductive/developmental toxicity were considered to be 1000 mg/kg/day for males, 250 mg/kg/day for females, and 250 mg/kg/day for development of pups, respectively.

3. Genetic Toxicity

3-1. Bacterial test 2)

Purity:99.9 %
Test species/strain:Salmonella typhimurium TA100, TA1535, TA98, TA1537, Escherichia coli WP2 uvrA
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guidelines 471 and 472
 Procedures:Pre-incubation method
 Solvent:DMSO
 Positive controls:-S9 mix; AF-2 (TA100, TA98), Sodium azide (TA1535), ENNG (WP2 uvrA) and 9-Aminoacridine (TA1537)
+S9 mix; 2-Aminoanthracene (all strains)
 Doses:-S9 mix; 313, 625, 1250, 2500 and 5000 μg/plate
+S9 mix; 313, 625, 1250, 2500 and 5000 μg/plate
 S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
 Plates/test:3
 Number of replicates:2
GLP:Yes

 Test results:

This chemical did not induce gene mutations in the S. typhimurium and E. coli strains. No toxicity was observed up to a concentration of 5000 μg/plate, with or without metabolic activation.

Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

Escherichia coli WP2 uvrA
+?-
Without metabolic activation:[ ][ ][*]
With metabolic activation:[ ][ ][*]

3-2. Non-bacterial in vitro test (chromosomal aberration test)2)

Purity:99.9 %
Type of cell used:Chinese hamster CHL/IU cells
Test method:Guidelines for Screening Mutagenicity Testing of Chemicals (Japan) and OECD Test Guideline 473
 Solvent:1 % Carboxymethyl cellulose sodium
 Positive controls:-S9 mix, Mitomycin C
+S9 mix, Benzo[a]pyrene
 Doses:-S9 mix (24 and 48 hr continuous treatment); 0, 625, 1250, 2500, 5000 μg/mL
-S9 mix (6 hr short-term treatment); 0, 313, 625, 1250, 2500, 5000 μg/mL
+S9 mix (6 hr short-term treatment); 0, 625, 1250, 2500, 5000 μg/mL
 S9:Rat liver, induced with phenobarbital and 5,6-benzoflavone
 Plates/test:2
GLP:Yes
 Test results:
Structural chromosomal aberrations including gaps were induced at 2500 and 5000 μg/mL on 6 hr short-term treatment with S9 mix (6.0 and 10.0 %, respectively). Polyploidy was not induced in any treatment group.

Genotoxic effects:
clastogenicitypolyploidy
+?-+?-
Without metabolic activation:[ ][ ][*][ ][ ][*]
With metabolic activation:[*][ ][ ][ ][ ][*]

1)The tests were performed by the Safety Research Institute for Chemical Compounds Co., Ltd., 363-24 Shin-ei, Kiyota-ku, Sapporo, Hokkaido, 004-0839, Japan. Tel +81-11-885-5031 Fax +81-11-885-5313
2)The tests were performed by the Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874