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46455701.DE.pdf
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46455701
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Glufosinate
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77182-82-2
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128850
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Nemec, M. (2004) A Dietary Developmental Neurotoxicity Study of Glufosinate- Ammonium in Rats: Final Report. Project Number: WIL/21202, B004853, WIL/21202A. Unpublished study prepared by WIL Research Laboratories, Inc. 2206 p.
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2004.0
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In a developmental neurotoxicity study (MRID 46455701), Glufosinate-ammonium (50.8% a.i., lot # AAKJ00053) was administered in the diet to 25 mated female Crl:CD®(SD)IGS BR rats/dose at nominal concentrations of 0, 200, 1000 and 4500 ppm from gestation day (GD) 6 through lactation day (LD) 21. Average doses to the animals were 0, 14, 69 and 292 mg/kg/day during gestation and 0, 36, 176 and 756 mg/kg/day during lactation for the 0, 200, 1000 and 4500 ppm groups, respectively. A Functional Operational Battery (FOB) was performed on 25 dams/dose on GDs 6 and 13 and on LDs 10 and 21. On postnatal day (PND) 4, litters were culled to yield five males and five females (as closely as possible). Offspring were allocated for detailed clinical observations (FOB) and assessment of motor activity, auditory startle reflex habituation, learning and memory (watermaze testing), and neuropathology at study termination (PND 72). On PND 21, the whole brain was collected from 10 pups/sex/dose group for micropathologic examination and morphometric analysis. Pup physical development was evaluated at the time of body weight measurements. The age of sexual maturation (vaginal opening in females and preputial separation in males) was assessed.
No parental females died during the study. The only clinical sign was light-colored feces, which occurred primarily between GDs 8 and 13, in dams at 4500 ppm. No treatment-related clinical signs were observed in dams during the FOB. Beginning on GD 7 and continuing throughout gestation, mean body weight in the 4500 ppm group was significantly decreased (4-8%, relative to control). Mean body weight loss was observed in all treated groups at the beginning of treatment (GDs 6-7 and 6-9) but overall (GDs 6-20) weight gain was significantly decreased (27% of control value) only in the 4500 ppm group. A decrease (10% of control value) in overall weight gain at 1000 ppm was also observed. Mean food consumption during gestation was significantly decreased (8-17% of control value) in the 1000 and 4500 ppm groups. Mean body weight was slightly decreased in the 1000 and 4500 ppm groups at the beginning of lactation; however, overall (LD 1-21) mean body weight gain was increased in treated groups relative to control. Mean food consumption was significantly decreased (14% of control value) throughout lactation in the 4500 ppm group. No treatment-related effects were observed in reproductive parameters or at gross necropsy.
The maternal LOAEL for Glufosinate-ammonium in rats is 4500 ppm (292 mg/kg/day during gestation) based on decreased body weight, body weight gain, and food consumption during gestation and lactation. The maternal NOAEL is 1000 ppm (69 mg/kg/day during gestation).
No treatment-related effect on the mean number of pups born, mean live litter size or sex ratio per litter was observed. A significant treatment-related decrease in postnatal survival occurred on PNDs 0-1 and PND 0-4 in the 4500 ppm group, due mostly to total litter losses. The total number of pups found dead during the pre-weaning period was 31, 13, 17 and 60 in the control, 200, 1000 and 4500 ppm groups, respectively. Beginning on PND 4 and continuing throughout the lactation period, mean body weight was decreased in the 1000 (8-11% of control value) and 4500 ppm (13-20% of control value) male and female offspring. Mean body weight gains were decreased in the 4500 ppm male (12-35% of control value) and female (9-36% of control value) offspring and in 1000 ppm males (6-23% of control value) and females (9-23% of control value). Mean post-weaning (PNDs 28-70) body weight was decreased in males (6-9% of control value) and females (7-10% of control value) at 4500 ppm. Post-weaning body weight gain was decreased in males and females at 4500 ppm (6-9% of control value). The average onset of preputial separation in males and vaginal opening in females was not affected by treatment.
Total and ambulatory motor activity counts were increased in males and females at 1000 (1.2-2.5x control value) and 4500 ppm (1.2-2.8x control value) on most of the testing days. Statistically significant increases in several 15-minute interval motor activity counts were observed on PNDs 21 and 61 in all groups of treated males and on PND 21 in females at 1000 and 4500 ppm. No statistically significant differences between treated and control groups were observed in auditory startle response or learning and memory. Brain weight measurements and gross and microscopic necropsy findings were not affected by treatment. For the PND 72 morphometric measurements, decreased mean vertical height between the layers of pyramidal neurons in the hippocampal formation in Level 3 was observed in males at 1000 and 4500 ppm; the values in both groups were outside the historical control range. Females at 4500 ppm had significantly decreased (9% of control value) radial thickness of the cortex in Level 3, which was slightly outside the historical control range. A dose-dependent decrease in mean length of the ventral limb of the dentate hilus (Level 3) was observed in both males (9-15%) and females (12-20%) at >= 200 ppm. Statistical significance was reached in females at 200 ppm.
The offspring LOAEL for Glufosinate-ammonium in rats is 200 ppm (14 mg/kg/day during gestation) based on brain morphometric changes. The offspring NOAEL was not observed.
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 pending review of the positive control data. Additionally, glutamine synthetase measurements in the liver, kidneys, and brain of dams and pups were not measured.
[Note - This classification scheme is applicable only to Developmental Neurotoxicity (DNT) studies. The DNT Work Group determined that this study can be classified as Acceptable. This study does not satisfy the guideline requirements for a developmental neurotoxicity study and is classified as NonGuideline pending review of all available positive control data. J. Rowland, 08/24/2005]
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; GD 6 to LD 21
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53106.0
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2005-08-24
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2005-11-07
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Supplemental #1
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Added by
Madison Feshuk
on Apr 25, 2022
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