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EC number: 292-059-6 | CAS number: 90530-20-4
The purpose of this combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was to obtain initial information on the toxic potential of CeTePox® 0214 H and its possible effects on male and female reproductive performance such as gonadal function, mating behavior, conception, pregnancy, parturition as well as development of the F1 offspring from conception to day 13 post-partum when repeatedly administered orally (by gavage) to parental animals at doses of 10 mg/kg bw/day, 30 mg/kg bw/day and 100 mg/kg bw/day compared to control animals.
Four groups of Han:WIST rats (n=12/sex/group) were administered with the test item orally (by gavage) once a day at 0 (vehicle), 10, 30 and 100 mg/kg bw/day doses corresponding to concentrations of 0, 2, 6 and 20 mg/mL. The application volume was 5 mL/kg bw. Control animals received the vehicle, distilled water.
The suitability of the vehicle at the intended concentrations of the test item was analytically verified up front. The concentration of the test item in the dosing formulations was checked two times during the study. CeTePox® 0214 H concentrations in the dosing formulations varied in the acceptable range between 93 % and 109 % of the nominal values confirming the proper dosing.
All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before the necropsy (altogether for 49 days). Females were additionally exposed through the gestation period and up to lactation days 13-17 (altogether for 50-67 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, clinical chemistry, gross necropsy, organ weighing and histopathology.
Blood samples were collected for possible determination of serum levels of thyroid hormones (T4, TSH) from at least two pups per litter (where it was feasible) on post-natal day 4, from all dams and at least two pups per litter at termination on post-partum/post-natal day 13 and from all parent male animals at termination.
All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all adult male animals were determined.
Histopathology examination was performed on reproductive organs (testes, epididymides, uterus and ovaries) in the control and high dose groups and in non-pregnant females and the males these females cohabited with and not mated animals in the low and mid dose groups. Additionally, full histopathology was performed on the organs and tissues of parental animals (male and female) selected for general toxicological examinations in the control and high dose groups.
In addition, kidneys for one male and one female at 30 mg/kg bw/day and uterus for one female at 10 mg/kg bw/day were also processed and examined due to the necropsy observations (pyelectasia, hydrometra).
The results were interpreted comparing treatment groups with respect to controls, which were treated concurrently with vehicle (distilled water) only. Historical control data were also considered.
There was no mortality at 10, 30 or 100 mg/kg bw/day groups during the course of study.
Adverse clinical signs of systemic toxicity related to the test item were not detected at any dose level at the daily or detailed weekly clinical observations or at the terminal functional observations. The behavior and physical condition of animals was not affected by the test item at any dose level (10, 30 or 100 mg/kg bw/day) during the entire observation period.
Body weight and body weight gain
The mean body weight gain and mean body weight were reduced in male and female animals at 100 mg/kg bw/day.
The mean food consumption was lower than in the control group in male and female animals at 100 mg/kg bw/day.
There were no test item related adverse changes in the examined hematological parameters in male or female animals at 10, 30 or 100 mg/kg bw/day.
Elevated activity of aspartate aminotransferase and alkaline phosphatase was detected in male animals at 100 mg/kg bw/day referring to hepatic/hepatobiliary damage or alteration in hepatic function.
Serum thyroid hormones
There were no test item related changes in the serum thyroid hormone (T4, TSH) levels at any dose.
Macroscopic alterations were observed in the liver (pale) in some male animals at 100 mg/kg bw/day with low incidence.
There were no test item related changes in the weights (absolute and relative to body or brain weights) of brain, testes, epididymides and seminal vesicles of male animals at any dose level.
Test item related changes were observed in the weight of liver (higher absolute, relative to body and brain weights) of male animals at 100 mg/kg bw/day coinciding with changes in clinical chemistry parameters, necropsy and histopathology observations.
Histopathological examinations of the investigated sexual organs and accessory sex organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) did not reveal any test item related changes at 100 mg/kg bw/day.
Hepatic lipidosis was detected in the male animals at 100 mg/kg bw/day. Hepatic lipidosis is considered as a slight reversible liver injury in connection with a disturbance of energy metabolism of affected hepatocytes.
Under the conditions of the present study, CeTePox® 0214 H caused reduced body weight and body weight gain, reduced food consumption in parental male and female Han:WIST rats at 100 mg/kg bw/day administered by oral gavage.
In male animals at 100 mg/kg bw/day, test item influence on hepatic function was detected in clinical chemistry parameters, in necropsy findings and histopathological findings (centrilobular vacuolation in the hepatocytes).
There were no test item related changes in male or female animals at 10 or 30 mg/kg bw/day.
Based on these observations the No Observed Adverse Effect Levels (NOAEL) was determined as follows:
NOAEL for systemic toxicity
of male/female rats: 30 mg/kg bw/day
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