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45666401.de2.pdf
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45666401
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Methamidophos
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10265-92-6
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101201
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Sheets, L.; Lake, S. (2002) A Developmental Neurotoxicity Screening Study with Technical Grade Methamidophos (MONITOR) in Wistar Rats: Lab Project Number: 00- D72-AI: 110924. Unpublished study prepared by Bayer Corp. 1147 p. Relates to L0000738. {OPPTS 870.6300}
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2002.0
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Methamidophos: In a developmental neurotoxicity study (MRID 45666401) methamidophos (72.3-74.2% a.i., Lot/batch # 803-0182) was administered to 30 female Wistar Crl:W (HAN)BR rats/dose, continuously in the diet, at dose levels of 0, 1, 10, or 30 ppm from gestation day (GD) 0 through lactation day (LD) 21. Average daily intake of the a.i. was 0, 0.1, 0.9 or 2.5 mg/kg/day (gestation) and 0, 0.2, 2.4 or 7.9 mg/kg/day (lactation), respectively. On post-natal day (PND) 4, litters were standardized to 8 pups/litter; excess pups were killed and discarded. Pups were weaned on postnatal day 21, after which time all animals received untreated diet. F1 pups were assigned to subgroups in order to evaluate brain weights, neuropathology, learning and memory, motor activity, and acoustic startle response. In addition, brain, erythrocyte, and plasma cholinesterase (ChE) activity was measured in the dams on LD 21 and the offspring on PNDs 4 and 21.
Maternal mortality, clinical signs, body weights, body weight gains, food consumption, reproductive performance, and abbreviated functional observations (AFO) were unaffected by treatment. However, in the 1 ppm dams, significant (p<=0.05) decrease in brain cholinesterase activity was noted (8% decreased). In the 10- and 30- ppm dams, dose-dependent and significant (p<=0.05) decreases in plasma, erythrocyte, and brain cholinesterase activities were noted (50-84% decreased).
The maternal LOAEL was 1 ppm (0.1 mg/kg/day) based on brain cholinesterase inhibition in the dams. The maternal NOAEL was not established.
Treatment had no adverse effects on offspring survival, food consumption, abbreviated FOB, brain weights, brain morphology, or neuropathology. No treatment-related effects were seen in the body weight or body weight gain of pups at the low and mid dose groups. At the high dose (30 ppm), pre-weaning body weights were decreased (decreased 8-12%; p<=0.01) on PNDs 11, 17, and 21 in the male and female pups. In addition, body weights were decreased (p<=0.05) on PND 4 (precull) in the female pups (decreased 8%). Pre-weaning body weight gains for male and female pups were decreased (p<=0.05) for most measured intervals between PND 0 and PND 21 (decreased 8-19%). Furthermore, body weights were decreased (p<=0.05) throughout most of post-weaning in both sexes (decreased 4-10%). In the 10 ppm pups, post-weaning body weight in the females was decreased (p<=0.05, decreased 4-5%). This decrease is minor and its toxicological importance is considered to be equivocal. A slight but significant (p<=0.01) difference in the time to preputial separation was observed in the high-dose males. It occurred an average of 2.1 days later in the affected males than in the controls.
Treatment-related effects were observed on motor and locomotor activity in both sexes at the mid and high dose on PND 13. The non-statistically significant decreases were 25% in males and 33% in females at the mid dose and 45% in males and 27% in females at the high dose.
A consistent but not dose-dependent decrease in auditory startle reflex was seen in females at all dose levels on PND 22 and PND 38. On Day 22 the decreases were 15%, 15% and 28% at the low, mid and high dose groups, respectively. On Day 38, the decreases were 26%, 42% and 33%, at the low, mid and high dose groups, respectively. Peak startle response amplitude in all females at PND 22 and 38 reached statistical significance in one block at the low dose, two blocks at the mid dose and three blocks at the high dose. Additionally, the magnitude of the response was similar at the low and mid dose groups for PND 22 and PND 38 in females. Therefore, the low dose was determined to be an effect level.
In the passive avoidance test, nonsignificant but marked increases (76, 79 or 97% increased) in the latency to cross were seen at 1, 10 or 30 ppm, respectively. No other adverse effects were seen in the males and females of all dose groups.
Data from the water maze test showed that high-dose males had nonsignificant increases in the number of trials to criterion (15% increased), errors (330% increased), and time to make the correct choice (46% increased) in the first trial of the learning phase of testing. During the memory phase of the water maze testing, high-dose males demonstrated more errors (200% increased) and longer time to achieve the goal (17% increased). More errors (200 and 267% increased) and longer time to achieve the goal (51 and 59% increased) were also observed for the 1- and 10-ppm males during the learning phase. By contrast, there were no adverse effects in the females; females of all dose groups showed fewer errors and less time to make the correct choice compared to the concurrent controls. At 1 ppm, cholinesterase (ChE) activity was comparable to controls for all compartments. At 30 ppm, plasma (decreased 12-40%), erythrocyte (decreased 37-53%), and brain (decreased 14-43%) ChE activities were decreased (p<=0.05) relative to controls on PND 4 and PND 21 for the males and females. At 10 ppm, decreases (p<=0.05) were noted in erythrocyte ChE on PND 4 (decreased 20%, sexes combined); plasma and brain ChE on PND 21 in the males (decreased 22 and 13%, respectively); and a nonsignificant decrease in brain ChE on PND 21 in the females (decreased 17%).
The offspring LOAEL is 1 ppm (0.1 mg/kg/day), the lowest dose tested based on consistent decreases in peak auditory startle reflex response in females on PND 22 and PND 38. An offspring NOAEL was not established.
This study is classified Acceptable/NonGuideline 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 of positive control data.
[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, 11/11/2008]
Comments: The maternal NOAEL/LOAELs have been changed subsequent to a meeting with the DNT Workgroup dated Nov. 23, 2004. In the revised DER, the maternal LOAEL is 0.1 mg/kg/day based on significant (p<=0.05) decrease in brain cholinesterase activity (8% decreased).
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Developmental-Neurotoxicity
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NA [83-6, Developmental Neurotoxicity]
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Oral
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No Duration Period; GD 0 to LD 21
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54922.0
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2008-11-11
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2018-08-30
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Added by
Madison Feshuk
on Apr 25, 2022
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