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EC number: 263-214-5
CAS number: 61792-11-8
Results of Reproductive Performance
The objective of this study was to provide preliminary information on the potential adverse effects of the test substance on male and female reproduction within the scope of a screening study. This encompassed gonadal function, mating behavior, conception, parturition, and lactation of the parental generation and the development of offspring from conception through day 13 of postnatal life.
The study design was as follows: 10 animals/sex/group treated at dose levels of 0, 200 ppm, 400 ppm, 1000 ppm, in an Oral Dietary Study.
Animals were administered the test substance continuously in the diet. Males were exposed for 14 days prior to mating and continuing through the day of euthanasia. Females were exposed for 14 days prior to mating and continuing through Lactation Day 13. The following parameters and end points were evaluated in this study: clinical signs, body weights, body weight gains, food consumption, estrous cycles, reproductive performance, parturition, litter viability and survival, anogenital distance, areolae/nipple anlagen, thyroid hormones, gross necropsy findings, organ weights, and histopathologic examinations.
Mean compound consumption was 13, 25, and 56 mg/kg/day in the 200, 400, and 1000 ppm group F0 males, respectively, during the premating exposure period (Study Days 0–15). Mean compound consumption was 13, 25, and 55 mg/kg/day during the premating period (Study Days 0–15), 14, 28, and 69 mg/kg/day during gestation (Gestation Days 0–20), and 29, 58, and 152 mg/kg/day during lactation (Lactation Days 1–13) in the 200, 400, and 1000 ppm group F0 females, respectively.
All F0 males and females in the control, 200, 400, and 1000 ppm groups survived to the scheduled necropsy. No test substance-related clinical observations were noted at the daily examinations at any exposure level. Test substance-related slightly lower mean body weight gains or mean body weight losses were noted for F0 males in the 1000 ppm group compared to the control group generally throughout the exposure period and when the premating period (Study Days 0–15) and entire exposure period (Study Days 0–29) were evaluated. Corresponding lower mean food consumption was noted for F0 males at 1000 ppm during the premating period. As a result, mean absolute body weights for F0 males at 1000 ppm were up to 9.3% lower than the control group during Study Days 5–29. The magnitude of these effects is due in part to a single male in the control group with a much higher body weight throughout the majority of dosing period compared to the other control group males. The effects on body weight and food consumption for males at 1000 ppm were considered nonadverse based on the low magnitude of change. Mean absolute body weights, body weight gains, and food consumption for F0 males in the 200 and 400 ppm groupwere unaffected by test substance exposure. For F0 females, lower mean body weight gains or mean body weight losses with corresponding lower mean food consumption were noted in the 400 and 1000 ppm groups compared to the control group throughout the premating period (Study Days 0–15) in a dose-responsive manner. As a result, mean absolute body weights that were up to 7.1% and 11.9% lower than the control group on Study Day 15 (end of premating period) in these same respective groups and remained slightly lower (up to 7.1% and 7.9%, respectively) throughout the gestation and lactation periods
with no corresponding effects on food consumption with exception during Gestation Days 2–3 at 1000 ppm. The effects on body weight gains and food consumption for F0 females at 400 and 1000 ppm group were considered test substance-related but nonadverse based on the low magnitude of change and because the food consumption effect did not persist during gestation or lactation. Mean absolute body weights, body weight gains, and food consumption were unaffected by test substance exposure in the 200 ppm group during the premating period and at all exposure levels during the gestation (Gestation Days 0–20) and lactation (Lactation Days 1-13) exposure periods.
F0 reproductive performance (mating, fertility, copulation, and/or conception indices), as well as mean estrous cycle lengths and precoital intervals, were unaffected by test substance exposure at all exposure levels. No test substance-related effects were noted on mean gestation length or parturition at any exposure level. There were no test substance-related effects on T4 concentration for F0 males at any exposure level.
No test substance-related findings were noted in gross observations, organ weights, or in histopathology. The mean number of unaccounted-for sites and former implantation sites was unaffected by test substance exposure at all concentrations. No test substance-related findings were noted in in F1 pup body weights and body weight gains at any dosage. Mean body weight and body weight gains for F1 pups in the control groups were higher than the Charles River Ashland historical control data range. Due to higher values in the controls group, mean absolute body weights for F1 male and female pups at 200, 400 and 1000 ppm were up to 10.7%, 13.4% and 15.6% lower, respectively, than the control group during PND 4–10. However, all values in the treatment group were close to the mean value of the Charles River Ashland historical control data and therefore these changes were not considered as related to test substance.
There were no test substance-related effects on the mean number of pups born, pup survival, live litter size, mean sex ratio, anogenital distance, areolae/nipple anlagen (males), T4 concentration on PND 13, or thyroid gland weight at any exposure level. There were no clinical observations or gross necropsy findings that could be attributed to F0 maternal exposure of the test substance at any concentration. Under the conditions of this screening study, there were no adverse effects indicative of systemic toxicity and no test substance-related effect on reproductive performance for F0 males and females at any exposure level; therefore, a concentration of 1000 ppm was considered to be the no-observed-adverse-effect level (NOAEL) for F0 systemic and reproductive toxicity of Lemonile when administered in the diet to male and female Crl:CD(SD) rats. There were no adverse effects in the F1 generation that could be attributed to F0 parental exposure of the test substance, and therefore the NOAEL for F1 neonatal toxicity was 1000 ppm. The 1000 ppm concentration level corresponded to actual consumption of 56 mg/kg/day for F0 males during the premating period and 55, 69, and 152 mg/kg/day for F0 females during the premating, gestation, and lactation periods, respectively.
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