Glyphosate Trimesium Neurotoxicity Study.pdf

In a developmental neurotoxicity study, Glyphosate trimesium (57.4% a.i.) was administered to 30 female Wistar-derived rats/group by gavage at doses of 0.1, 25, or 100 mg (a.i.) /kg/day from gestation day 7 through postnatal day (PND) 11. Doses were based on the results of two range-finding studies. A Functional Operational Battery (FOB) was performed on all dams on gestation days 10 and 17 and on lactation days 2 and 9. Offspring, from at least 20 litters/dose, were allocated for detailed clinical observations, assessment of motor activity, auditory startle response habituation, and learning and memory. Neural tissues were collected (1/sex/dose) on PND 12 and at study termination (63 days of age). Pup physical development was assessed by body weight and sexual maturation was assessed for females by age at vaginal opening and for males by age at completion of balano-preputial separation. No treatment-related effects were seen in the dams on survival, clinical signs, FOB, or reproductive performances at any dose level. The salivation and the decreases in body weight, body weight gains, or food consumption seen at the high dose (100 mg/kg/day) were not considered to be adverse treatment-related effects. The maternal LOAEL is greater than 100 mg/kg/day; the maternal NOAEL was not established. Overall motor activity was decreased in males and females at the 25 and 100 mg/kg/day dose groups on lactation day 14. Activities were decreased to 72% and 65% for the mid-dose males and females, respectively, and to 70% and 45% for the high-dose males and females, respectively. At day 18, in females activities were reduced 60%, in the mid-dose group but only 34.7% in the high-dose group. At 100 mg/kg/day, there was a decrease (19%) in survival on Day 5 and during Days 1-5, the percentage of pup survival was lower (84.8%) than controls (93.7%). At 100 mg/kg/day, body weight gains for males and females were reduced approximately 10% during lactation days 1-5. The offspring LOAEL is 25 mg/kg/day, based on dose-dependent decreases in motor activity in males and females on PND 14. The offspring NOAEL is 10 mg/kg/day. This study is classified Acceptable/Non Guideline and may be used for regulatory purposes. It does not, however, satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft) due to the inadequacies in the assessment of learning and memory in the offspring and the pending review of the positive control data.