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.
| 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:
| 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:
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.
| 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:
Genetic effects:
Salmonella typhimurium TA100, TA1535, TA98, TA1537
| + | ? | - | |
| Without metabolic activation: | [ ] | [ ] | [*] |
| With metabolic activation: | [ ] | [ ] | [*] |
Escherichia coli WP2 uvrA
| + | ? | - | |
| Without metabolic activation: | [ ] | [ ] | [*] |
| With metabolic activation: | [ ] | [ ] | [*] |
| 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 |
Genotoxic effects:
| clastogenicity | polyploidy | |||||
| + | ? | - | + | ? | - | |
| 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 |