With regard to repeat dose toxicity, cecum distension and diffuse hyperplasia of the mucosal epithelium were observed in both sexes of the 60 and 300 mg/kg groups. The NOEL for repeat dose toxicity is considered to be 10 mg/kg/day for both sexes.
In terms of reproductive and developmental toxicity, prolongation of estrous cycle, an increase of the number of irregular estrous cycle, and decreases in the fertility index, number of implantation sites, implantation index, total number of offspring, and number of live offspring were observed in the 300 mg/kg group.
The NOEL for reproductive and developmental toxicity is considered to be 60 mg/kg/day for parental animals and offspring.
| Purity | : | 99.87 % |
| Test species/strain | : | Rats/Crj:CD(SD)IGS |
| Test method | : | OECD Test Guideline 421 |
| Route | : | Oral(gavage) |
| Dosage | : | 0(vehicle), 10, 60, 300 mg/kg/day |
| Number of animals/group | : | Males, 12; females, 12 |
| Vehicle | : | 0.5 % Sodium carboxymethlcellulose with 0.1 % Tween 80 |
| Administration period | : | Males, 45 days Females, from 14 days before mating to day 3 of lactation |
| Terminal kill | : | Males, day 46 Females, day 4 of lactation |
| GLP | : | Yes |
Test results:
Cecum distension was observed in both sexes of the 60 and 300 mg/kg groups. Histopathological examination revealed diffuse hyperplasia of the mucosal epithelium. Body weight gain was suppressed and decrease in food consumption was observed in males and females of the 300 mg/kg group. Relative liver weights were increased in males of the 300 mg/kg group, and histopathological examination revealed hypertrophy of hepatocytes in both sexes of the 300 mg/kg group.
The NOEL for repeat dose toxicity is considered to be 10 mg/kg/day for both sexes.
<Reproductive and developmental toxicity>
Among the dams, prolongation of estrous cycle, an increase in the number of irregular estrous cycles, and decreases in the fertility index, number of implantations, and implantation index were observed in the 300 mg/kg group. No changes attributable to the compound were observed in any other parameters including the mating index, delivery index, gestation index, number of corpora lutea, gestation length, parturition state, or lactation behavior. Total numbers, number of live births and number of live offspring on day 4 of lactation were decreased in the 300 mg/kg group. No changes attributable to the compound were observed in parameters including the sex ratio, the live birth index, sex ratio, body weight, viability index on day 4, anogenital distance, external or necropsy findings.
The NOEL for the reproductive and developmental toxicity is considered to be 60 mg/kg/day for parental animals and offspring.
| 1) | The test was performed by the Mitsubishi Chemical Safety Institute Ltd., Kashima Laboratory, 14 Sunayama, Hasaki-machi, Kashima-gun, Ibaraki, 314-0255, Japan. Tel +81-479-46-2871 Fax +81-479-46-2874 |