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EC number: 947-217-5 | CAS number: -
ANALYSES OF DOSING FORMULATIONS
- Results of the analyses of dosing formulations are summarised in the tables attached.
- The analysed dosing formulations were within Charles River SOP range for suspensions (85 % to 115 %) and were homogeneous. The test substance was not detected in the analysed vehicle formulation that was administered to the control group (Group 1).
The objectives of the study were to investigate the potential toxic effects of the test substance when administered to rats for a minimum of 28 days and to evaluate the potential of the test substance to affect male and female reproductive performance such as gonadal function, mating behaviour, and conception through day 13 of postnatal life. The protocol was designed in general accordance with the OECD Guideline for Testing of Chemicals, Guideline 422, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, 29 Jul 2016.
The test substance, in the vehicle (corn oil), was administered orally by gavage once daily to 4 groups of Crl:CD(SD) rats. The low- and mid-dose groups (Groups 2–4) each consisted of 10 rats/sex and the high-dose group (Group 5) consisted of 15 rats/sex. Dosage levels were 350, 500, 750, and 1000 mg/kg/day. A concurrent control group of 15 rats/sex received the vehicle on a comparable regimen. The dose volume was 5 mL/kg for all groups. Males and females were approximately 10 weeks of age at the beginning of test substance administration. Males received 14 daily doses prior to mating. Males were dosed throughout the mating period through 1 day prior to euthanasia for a total of 28 doses. Females received 14 daily doses prior to pairing and were dosed through Lactation Day 13 for a total of 49–63 doses; females with no evidence of mating or that failed to deliver were dosed through the day prior to euthanasia (Post-cohabitation Day 25 or Post-mating Day 25, respectively) for a total of 41 or 52 doses. The extra 5 males and 5 females in the control and high-dose groups that were not used for mating were treated beginning on Study Day 0; following 28 doses for males and 49 doses for females, these animals were assigned to a 15-day non-dosing recovery period.
All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at appropriate intervals. FOB and motor activity data were recorded for 5 males/group during the last week of dose administration (Study Day 27) and for 5 females/group on Lactation Day 13. All F0 females selected for pairing were allowed to deliver and rear their pups until Lactation Day 13. F1 clinical observations, body weights, and sexes were recorded at appropriate intervals and anogenital distance was recorded on PND 1. To reduce variability among the litters, 8 pups/litter, 4 pups/sex when possible, were randomly selected on PND 4; blood samples for possible thyroid hormone analysis were collected from the culled pups (at least 2/litter). All F1 male pups were evaluated for areolae/nipple anlagen on PND 13. Remaining F1 pups were euthanised on PND 13; blood samples for thyroid hormone analysis were collected from 1 pup/sex/litter. Clinical pathology evaluations (haematology, coagulation, and serum chemistry) were performed on 5 F0 animals/sex/group at the primary necropsy and 5 animals/sex in the control and high-dose groups at the recovery necropsy. Blood samples for thyroid hormone analysis were collected from F0 males at the primary and recovery necropsies and from F0 females on the day of the last dose (Lactation Day 13); only male samples collected at the primary necropsy were analysed.
F0 males were euthanised following completion of the mating period or 15-day recovery period and F0 females were euthanised on Lactation Day 13 for females that delivered, Post-cohabitation or Post-mating Day 25 for females that failed to deliver, or following the 15-day recovery period. Complete necropsies were conducted on all F0 animals, and selected organs were weighed. Selected tissues were examined microscopically from all F0 animals in the control and high-dose groups at the primary necropsy.
There were no effects on survival. Non-adverse findings (clear and/or red material around the nose and/or mouth) were noted throughout the treatment period approximately 1 hour after dose administration, and to a lesser extent at the weekly detailed physical examinations, in the 500, 750, and/or 1000 mg/kg/day group males and/or the 750 and 1000 mg/kg/day group females. No other noteworthy clinical observations were noted at the daily examinations, detailed physical examinations, or approximately 1 hour after dose administration at any dosage level. No effects on F0 body weight and food consumption parameters were noted for males and females at any dosage level. No effects were noted during the FOB or motor activity evaluations at any dosage level in the F0 generation. No effects were noted for F0 gestation length, oestrous cycle length, reproductive performance (mating, fertility, and copulation/conception indices), and the process of parturition at any dosage level. There were no effects on organ weights, or noteworthy macroscopic and microscopic findings for F0 males and females at any dosage level at the primary and/or recovery necropsies.
Non-adverse higher mean ALT levels in the 1000 mg/kg/day group males, a higher mean percentage of neutrophils and a lower mean percentage of lymphocytes in the 750 and 1000 mg/kg/day group males, and higher mean absolute neutrophil counts in the 1000 mg/kg/day group males were noted compared to the control group. There were no other noteworthy alterations in serum chemistry, haematology, and coagulation parameters for the males during the dosing or recovery periods or females during the dosing period. Thyroid hormone (T4) levels in F0 males were unaffected.
There were no effects on mean numbers of F1 pups born, live litter size, percentage of males at birth, postnatal survival, the general physical condition of the F1 pups, and pup body weights and
body weight gains at any dosage level. There were no effects noted on F1 anogenital distance or areolae/nipple anlagen (males only) in the 350, 500, 750, and 1000 mg/kg/day groups. No
necropsy findings were noted for F1 pups that were euthanised on PND 13. There were no remarkable changes in mean serum T4 levels in F1 males or females on PND 13.
Under the conditions of this screening study, based on the lack of adverse effects at any dosage level, a dosage level of 1000 mg/kg/day (the highest dosage level evaluated) was considered to be the no-observed-adverse-effect level (NOAEL) for F0 reproductive toxicity, F0 systemic toxicity, and F1 neonatal toxicity of test item when administered orally by gavage to Crl:CD(SD) rats.
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