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46240802.der.pdf
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46240802
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Terbufos
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13071-79-9
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105001
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Schneider, S.; Deckardt, K.; Van Ravenzwaay, B. (2004) BAS 316 I (Terbufos) - Range Finding Developmental Neurotoxicity Study in Wistar Rats Oral Administration to the Dams and Pups (Gavage). Project Number: 29R0090/02006, 2004/1010807, 08B0090/026005. Unpublished study prepared by BASF Aktiengesellschaft. 228 p.
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2004.0
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Terbufos: In a range-finding study (MRID 46240802) to determine dose level selection for a subsequent developmental neurotoxicity study, BAS 316 I (terbufos; Batch No. AC 12251-100; 88.8% a.i.) was administered to 20 presumed pregnant female Wistar (CrlGlxBrlHan:WI) rats/dose via gavage at dose levels of 0 (corn oil), 0.03, 0.1, or 0.3/0.2 mg a.i./kg/day. Due to marked toxicity in the high-dose group, the high dose was reduced to 0.2 mg/kg/day on GD 15. Eight of the dams in each group were dosed from gestation day (GD) 6 through GD 20, and these dams and their offspring were sacrificed on GD 20 (2-3 hours post dose) for blood (serum and red blood cell) and brain cholinesterase activity assessment. The remaining 12 dams in each group were dosed from GD 6 through postnatal day (PND) 10. These dams were allowed to litter and rear their pups until PND 4 (litters culled to 4/sex), PND 11, or PND 21. The test material was administered directly to the pups orally (via gavage) at their dam¿s dose levels [0 (corn oil), 0.03, 0.1, or 0.2 mg a.i./kg/day] from PND 11 through PND 21. Blood and brain cholinesterase activity was assessed in male and female offspring on PNDs 4 (culled pups), 11, and 21 and pups from each group on PNDs 11 and 21 (approximately 2 hours post dose) and in surviving dams on PND 21. However, times of cholinesterase activity assessment after dosing were not clearly identified for fetuses of each group on gestation day 20, culled pups from each group on PND 4, and surviving dams on PND 21.
Maternal toxicity was observed at the 0.3 mg/kg dose level, as evidenced by the deaths of seven dams during gestation days 14-15 and 18-21, and the death of another high-dose dam on GD 22 due to an inability to deliver her litter. The high-dose level was reduced to 0.2 mg/kg/day on gestation day 15. Clinical signs (unsteady gait, tremor, salivation, piloerection, accelerated/labored breathing, lacrimation, and diarrhea) consistent with cholinesterase inhibition were observed during the dosing period, mainly at the high-dose level. One mid-dose dam was found dead on gestation day 14, and clinical signs consistent with cholinesterase inhibition (salivation, lacrimation, piloerection, accelerated breathing) were observed in a few mid-dose dams. Decreased body-weight gain (13%) and food consumption were observed in the high-dose dams following the first week of dosing. There was a reduction in the number of liveborn pups and an increase in the number of stillborn and dead pups at the high dose only. Live birth, viability, and lactation indices were reduced at the high-dose level also.
Decreased cholinesterase activity was observed in all three compartments in the high-dose dams on gestation day 20 (serum 91%**; RBC 89%**; brain 77%**) and in the RBC (39%*) and brain (32%) compartments of high-dose dams on postnatal day 21 (11 days after cessation of dosing). Decreased cholinesterase activity was observed in all three compartments in the mid-dose dams on gestation day 20 (serum 69%**; RBC 66%**; brain 35%*) and in the RBC (31%**) compartment of dams on postnatal day 21 (11 days after cessation of dosing).
GD 20 fetuses displayed a dose-related decrease in cholinesterase activity in the serum (males 24%** and 52%**/females 29% and 53%), RBC (males 66%** and 89%**/females 54%** and 59%**), and brain (males 19%** and 39%**/females 6% and 32%**) compartments at the mid- and high-dose levels, respectively.
There were no clinical signs in the offspring during lactation, but there was a decrease in pup viability during early lactation (PND 0-4) at the high-dose level. Pup body weight/body-weight gains were reduced at the high-dose level during the initial days of lactation (PND 0-10) when the dams were being dosed. Pup body-weight gain was not affected during PNDs 11-21 when the pups were dosed directly.
PND 4 pups displayed a dose-related (slight) decrease in cholinesterase activity in the RBC compartment only (males 36%** and 48%/females 26% and 47% at the mid- and high-dose, respectively). Cholinesterase activity was inhibited in all three compartments in pups of both sexes on PND 11 at the high-dose level after one direct dose (serum: males 47%**/females 57%**; RBC: females 25%*; brain: males 23%/females 27%) and on PND 21 at the mid- (serum: males 56%**/females 58%**; RBC: males 42%**/females 40%**; brain: males 38%**/females 42%**) and high-dose (serum: males 74%**/females 84%**; RBC: males 72%*/females 83%*; brain: males 50%*/females 69%*) levels following direct dosing for 11 days.
Under the conditions of this range-finding study, the LOAEL is 0.1 mg/kg/day, based on clinical signs (salivation, lacrimation, piloerection, accelerated breathing) in the maternal animals, and inhibition of serum, erythrocyte (RBC), and/or brain cholinesterase activity in GD 20 dams and PND 21 dams, GD 20 fetuses, and PND 4 (RBC only), 11, and 21 pups. The NOAEL is 0.03 mg/kg/day.
Based on these results, the study authors recommended dose levels of 0.01, 0.08, and 0.15 mg/kg/day for the definitive developmental neurotoxicity study in rats. Direct dosing of the pups via gavage was recommended also.
This range-finding study is classified Acceptable/Nonguideline and was not intended to satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft).
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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; range-finding study
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52717.0
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2008-03-19
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2008-04-14
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Added by
Madison Feshuk
on Apr 25, 2022
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