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Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information
ADONA was tested in a custom protocol to evaluate developmental toxicity.  Maternal and developmental NOAELs for ADONA in this study were both 30 mg/kg/d.
Additional information

ADONA was evaluated in a developmental toxicity screening study in Sprague Dawley rats. ADONA (lot 140499 19/10) was diluted in deionized water and administered once daily by oral gavage to groups of 10 presumed-pregnant female rats at doses of 0 (control),10, 30, 90, 270, and 500 mg/kg/d beginning on the first day of presumed gestation (GD 0) and continuing through the day of delivery or GD 24 for rats that did not deliver. The following maternal (F0) evaluations were performed: clinical observations (at least once daily during gestation, throughout parturition, and on postnatal days 1, 4, and 6), body weight and feed consumption (daily), duration of gestation, length of parturition, and necropsy. Pregnancy status, uterine contents and implantation sites were recorded. Litter and pup (F1) evaluations were performed through postnatal day (PND) 6 and included: litter size, pup viability at birth, pup survival and body weight on PND 1, 4, and 6, clinical observations, and necropsy. Homogeneous, continuous data were analyzed by ANOVA followed by Dunnett’s test. Non-homogeneous data were ranked and ANOVA and Dunnett’s test, if appropriate, were performed on the ranks. Frequency data were evaluated using Fisher’s exact test.

The 500 mg/kg/d group was terminated on GD 2 due to two deaths, significant body weight loss, reduced food consumption, and clinical signs. Necropsy findings for these animals were unremarkable. Pregnancy status could not be confirmed due to the early stage of gestation. At 270 mg/kg/d, 4 of 10 females were found dead between GD 3 and 5 and another was euthanized in moribund condition on GD 21. Clinical signs were similar to those observed at 500 mg/kg/d but subsided in surviving animals after approximately 4 to 7 doses. Maternal food consumption and weight gains during gestation were significantly reduced. Necropsy findings were unremarkable except for red areas in various tissues of two of the animals found dead. The animal euthanized on GD 21 had 12 dead fetuses and one early resorption in utero. The pregnancy status of the four early deaths in this group could not be confirmed due to the early stage of gestation. All females in the 90 and 30 mg/kg/d groups survived to scheduled termination. One female in the 10 mg/kg/d group was euthanized on GD 23 due to delivery problems but this event was not considered to be treatment-related since it did not occur at higher doses and because delivery problems are known to occasionally occur in rats. Other than urine-stained abdominal fur in two females in the 90 mg/kg/d group, no significant treatment-related clinical signs were observed at 10, 30 and 90 mg/kg/d. Maternal weight gains were reduced during gestation in the 90 mg/kg/d group but the reductions were not statistically significant. There were no unusual necropsy findings among dams in these groups except for the presence of red gelatinous material in the right uterine horn of the animal in the 10 mg/kg/day dose group that was euthanized on GD 23. This animal had 2 live and 14 dead fetuses in utero. With the exception of the dam in the 10 mg/kg/d group that was euthanized on GD 23, all surviving pregnant dams in the 10, 30, 90 and 270 mg/kg/d groups delivered normally. Duration of gestation and length of parturition were not significantly different from controls for any dose group. One dam in the control group and two dams in the 270 mg/kg/day dose group had all pups die between postnatal days 1 and 4. The mean number of pups per litter, percentage of liveborn pups per litter, and percentage of stillborn pups per litter were not significantly different from controls for any dose group. Pup survival on PND 1, 4 and 6 was significantly reduced in the 270 mg/kg/d group. Mean pup weight per litter was significantly reduced on PND 1, 4 and 6 in the 270 mg/kg/d group and on PND 1 in the 90 mg/kg/d group. Two pups in the 270 mg/kg/d group had body regions that were discolored purple and 10 pups from this group that were found dead had no milk present in their stomachs. Other clinical signs and necropsy findings in pups from treated groups were considered to be incidental and unrelated to treatment. There were no gross malformations noted at necropsy among pups from any group. Maternal and developmental NOAELs for ADONA in this study were both 30 mg/kg/d.

Justification for classification or non-classification

Based on the findings in this study, ADONA does not meet the DSD or CLP criteria for classification as a developmental toxicant.  Adverse developmental effects occurred at 270 mg/kg/d, which was above the maximum tolerated dose, as indicated by a 50% maternal mortality rate. Decreased pup weight on postnatal day 1 was seen at 90 mg/kg/d, a dose that caused a 40% decrease in maternal body weight gain during gestation days 0-3. Decreased pup weight alone is not sufficient for classifying a substance as a developmental toxicant.

Additional information