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45529701.DER.pdf
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45529701
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Dimethoate
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60-51-5
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035001
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Meyers, D. (2001) Dimethoate Dose Finding Study in CD Rats by Oral Gavage Administration Preliminary to Developmental Neurotoxicity Study: Lab Project Number: CHV/068: 000129. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 239 p.{OPPTS 870.6300}
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2001.0
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In a preliminary developmental neurotoxicity study (MRID 45529701) Dimethoate (99.1% a.i., batch/lot 20522-00) was administered to 15 female Crl:CD® BR rats per dose by gavage at dose levels of 0, 0.2, 3, or 6 mg/kg bw/day. Ten maternal animals/group were administered the test substance from gestation day (GD) 6 through postnatal day 10; an additional five dams/group were dosed on GD 6-20, inclusive. Two male and two female pups/litter were treated from postnatal day 11 to 21, inclusive. The females treated up to GD 20 were killed three hours after dosing on that day; litter data was assessed and cholinesterase activity determined in maternal and fetal plasma, RBC, and brain. For females allowed to litter, the treated offspring were killed two hours after dosing on postnatal day 21 and cholinesterase activities determined. Statistical analyses were performed for gestation body weight and gestation body weight gain data only.
All animals survived to scheduled termination. During gestation, maternal body weight gains after initiation of treatment were slightly decreased in the mid- and high-dose groups (83-88% and 74-88%, respectively, of the control levels). Lower weight gains in the high-dose group resulted in significantly (p<= 0.01; 93-94% of control) lower absolute body weights compared with the controls beginning on GD 10. There were no apparent differences in weight gain among groups during lactation; no effects on body weights or body weight gains were observed in the low-dose group for gestation or lactation. The only effect on food consumption was slightly reduced intake in high-dose dams during the treatment interval (approximately 88-91% of the control levels).
Following sacrifice on GD 20, no differences were observed between the treated and control groups for mean numbers of corpora lutea, implantations, live fetuses, resorptions, fetal body weights, fetal brain weight, or fetal sex ratios. For dams allowed to litter and rear their young, no differences were observed between the treated and control groups for pregnancy rate, mean numbers of implantations, or pup sex ratios. Pup survival was reduced in the high-dose group mainly during lactation days 1-4. Pup body weight gain in the high-dose group was also decreased during early lactation, resulting in lower absolute body weights throughout lactation. From postnatal day 11-21, body weight gains by the high-dose pups (treated and untreated) were similar to the control levels.
No treatment-related gross lesions were observed in dams killed on GD 20 or in dams and pups killed on lactation day 21. Brain weights for fetuses and 21-day old pups were not affected by treatment.
For animals tested on GD 20, plasma cholinesterase activity was decreased 25 and 57% in mid- and high-dose dams, respectively, and 66-79% in mid- and high-dose fetuses; RBC cholinesterase activity was inhibited by 70-96% in mid- and high-dose dams and fetuses; and brain cholinesterase activity was inhibited by 75 and 88% in mid- and high-dose dams, respectively. In addition, brain cholinesterase activity was inhibited by 22-24% and 35-42% in mid and high dose fetuses, respectively. On lactation day 21 male and female pups had approximately 40%, 60-65%, and 42-45% inhibition of plasma, RBC, and brain cholinesterase activities at the mid dose, 60%, 70-80%, and 55-66% inhibition of plasma, RBC, and brain cholinesterase activities at the high dose. Data were not statistically analyzed, and sample sizes were small for some groups, precluding conclusions about relative sensitivity among age groups.
This study is classified Acceptable/Non-guideline as a range-finding study and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); it has provided adequate support for the doses chosen for use in the main developmental neurotoxicity study. These results must be evaluated in context of the developmental neurotoxicity study (MRID 45529703) and the cholinesterase study (MRID 45529702).
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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; Dams: GD 6 - PND 10; Pups: PND 11-21.
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50139.0
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2002-03-27
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2006-09-22
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Added by
Madison Feshuk
on Apr 25, 2022
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