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EC number: 257-827-7 | CAS number: 52301-70-9
The test item was tested for effects on reproduction and subacute toxicity using the OECD Test Guideline No. 422
Before the start of study with laboratory animals the stability and homogeneity of application form were determined at the test facility. A dose-range finding experimentwas performed to determine the dose levels for the main study.
Wistar rats (SPF quality) were used for testing. The test item was administered in the form of a solution in water for injection. Oral application by stomach tube was performed daily. The animals were without feed two hours before application and two hours after application of the test item. The main study includes four main groups -3 treated groups (doses 150, 300, 600 mg/kg/day) and one control group (vehicle only) and two satellite groups of animals (one control group (vehicle only) and one treated group (600 mg/kg/day). Each main group consisted of 12 males and 12 females; each satellite group consisted of 6 males and 6 females.
The first six males and six mothers who delivered pups per group and a satellite groups of animals (control and treated) are part of therepeated dose toxicity studyand examined with respect to toxicity of the test item. Satellite animals were used for observation of reversibility, persistence or delayed occurrence of systemic toxicity effects up to 14 days post treatment. All twelve males and females per group are a part of thereproduction studyand examined with respect to reproduction parameters.
The treated groups were administered daily. During the study, clinical observation and health status controls were performed daily. The body weight and food consumption were measured weekly or at the specified time intervals. Detailed clinical observation was carried out weekly. Functional observations were performed at the end of the application and observation periods. Vaginal smears were prepared daily, 2 weeks before start of the administration period (oestrous cycle monitoring), during the mating period (until the presence of spermatozoa) and at necropsy. Reproduction parameters relevant to pups (number of pups, weight of litters and weight of pups, sex and vitality of pups, measurement of anogenital distance, nipple retention, serum levels of thyroid hormones (T4 and TSH in pups) were also recorded. The study was completed with urinalysis, haematological and biochemical analysis and gross necropsy of animals. In all males of the main groups, the sperm parameters, sperm motility and sperm morphology were examined. Selected organs from adult animals and pups were removed for weighing and histopathological examination.
Repeated oral administration of the test item did not cause the death of animals except one female from the dose level 150 mg/kg/day/day, who was found dead on day 25 of application; the cause of death was not determined due to partial autolysis of organs. This death was accidental and not treatment-related.
Test item treatment did not produce clinical changes in health status of animals, did not affect the normal growth of males and females.
Repeated Dose Toxicity part of study
The haematological examination did not reveal toxic effect of the test item on administered animals.
The biochemical examination of treated animals showed a toxicologically significant effect of the test item on the treated animals. Changes of Creatinine concentration in serum (irreversibly increased values in males and females) and increased concentration of chloride ions in satellite animals can be associated with the findings reported during the histological examination of kidneys.
The examination of urine parameters showed the presence of blood and leucocytes in urine of animals from middle and highest dose level.
The test item had toxicology significant effect on weight of organs of treated animals. The weight of kidneys (absolute and relative) was significantly increased in all dose groups of females and this increase was irreversible. Insignificant increase of relative weight of kidneys was also reported in males. This was confirmed by pathological and histopathological examination, where the findings would indicate a toxic effect of the test item on kidneys of dosed animals.
During the macroscopic examination, findings related to the test item treatment were found out. Changed colour of kidneys in the mid and high dose groups.
Histological examinationrevealedminimal to marked signs of tubular necrosis in kidneys of rats administered by highest dose of test item (600 mg/kg).Thislesion was subsequently revealed in some rats from the middle and low dose groups (300, respective 150 mg/kg). This lesion was irreversible during recovery period. All recovered high dose males and females showed also this lesion.
Reproduction Toxicity part of study
Test item treatmentdid not affect male ability to produce sperm that can fertilise eggs and ability of females to become pregnant.
No adverse effect of the test item treatment was observed during examination of thyroxine and rat thyroid stimulating hormone blood concentration in males. Decreased concentration of T4 hormone in males at the dose level 150 mg/kg was considered toxicologically insignificant.
Evaluation of the absolute and relative weight of reproductive organs of male and female, as well as the weight of pituitary and thyroid gland revealed only sporadic findings. The absolute weight of testes and epididymis was significantly decreased in males at the dose level 600 mg/kg/day (also reduced absolute weight of testes was noted in males at the dose level 150 mg/kg/day). Evaluation of relative weight of reproductive organs in males, absolute and relative weights of reproductive organs in treated females did not reveal any statistically significant differences compared to control.
Histological examination did not reveal negative effect of the test item on collected reproductive organs, pituitary and thyroid glands.
Spermatogenesis in the testes of the high dose administered males was without any pathological findings. Epididymides of both control and high dose males were without any pathological findings. Sporadic findings were of spontaneous origin.
Examination of sperm motility and morphology in treated parental males did not show any differences in comparison with the control males.
The number of implantations was comparable between treated and control groups.
The calculated parameters (mating and fertility indexes) were similar in all treated groups in comparison with the control groups. Fertility indexes were slightly lower in high dosed groups in comparison with the control group due to one non-pregnant female. Gestation indexes in treated groups were identical with the control group. The viability index was the best in the highest dosed group of females.
The test item did not affect the number of pups and their development.
The total number of pups,mean number of pups per litter and mean litter weight at first litter check after parturition and during the next intervals were similar or higher in treated groups of mothers compared to control group. The mean pup body weights at all checking intervals was slightly lower in all treated groups compared to control group due to higher number of pups per group of treated females. Macroscopical examinationof pups did not show negative effect of the test item administration on development of pups.
No adverse effect of the test item treatment was observed during examination of thyroxine and rat thyroid stimulating hormone blood concentration in pups. Male nipple retention at day 13 was not recorded in any male pup.Corrected anogenital distance in treated pups was comparable to the control pups.
According to the study results the NOAEL (No Observed Adverse Effect Level) value for REPEATED DOSE TOXICITY in MALES was established as 150mg/kg/day and in FEMALES was established to be less than 150 mg/kg/day.
This value is based on toxicologically significant changes recorded in treated males and females. Damage of kidneysconfirmed by the histological examination, evaluation of biochemical parameters and biometry of organs was observed. Histopathological finding -tubular necrosis in the kidneys –was reported in a middle and high dose level in males and in all dose levels of females. This finding was irreversible. All satellite high dose males and females showed also this lesion at the end of recovery period.
According to the study results the NOAEL(No Observed Adverse Effect Level) value for REPRODUCTION and DEVELOPMENT was established as 600 mg/kg/day body weight/day.No biologically significant changes relevant to reproduction and development were observed.
Before the start of study with laboratory animals thestability and homogeneityof application form were determined at the test facility. A dose-range finding experiment was performed to determine the dose levels for the main study.
Wistar rats (SPF quality) were used for testing. The test item was administered in the form of a solution in water for injection. Oral application by stomach tube was performed daily.The animals were without feed two hours before application and two hours after application of the test item. The main study includes four main groups -3 treated groups (doses 150, 300, 600 mg/kg/day) and one control group (vehicle only) and two satellite groups of animals (one control group (vehicle only) and one treated group (600 mg/kg/day). Each main group consisted of 12 males and 12 females; each satellite group consisted of 6 males and 6 females.
Evaluation of the absolute and relative weight of reproductive organs of female, as well as the weight of pituitary and thyroid gland revealed only sporadic findings. Evaluation of relative weights of reproductive organs in treated females did not reveal any statistically significant differences compared to control.
Gestation indexes in treated groups were identical with the control group. The viability index was the best in the highest dosed group of females.
According to the study results the NOAEL(No Observed Adverse Effect Level) value for DEVELOPMENT was established as 600 mg/kg/day body weight/day. No biologically significant changes relevant to reproduction and development were observed.
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