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45627001.DER.pdf
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45627001
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Malathion
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121-75-5
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057701
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Fulcher, S. (2002) Malathion: Dose Finding Study in CD Rats by Oral Gavage Administration Preliminary to Developmental Neurotoxicity Study: Lab Project Number: CHV/062. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 450 p. Relates to L0000581, L0000598, L0000617, and L0000634.
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2002.0
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A preliminary dose range-finding developmental neurotoxicity study (MRID 45627001) with malathion (96% a.i., batch/lot 9010501) was conducted in two phases. In Phase 1, malathion was administered by gavage to 15 female Crl:CD® BR rats per dose at dose levels of 0, 7.5, 750 or 1250 mg/kg bw/day. Ten maternal animals/group were administered the test substance from gestation day (GD) 6 through postnatal day (PND) 10; an additional five dams/group were dosed on GD 6-20. Following mortalities at 1250 mg/kg/day during the first four days of treatment, the dose for this group was reduced to 1000 mg/kg/day. In Phase 2, 10 maternal animals/group were administered the test substance from GD 6 through PND 10; an additional five dams/group were dosed on GD 6-20, at doses of 0, 7.5, 35, 75, or 150 mg/kg/day. In both phases, two male and two female pups/litter were treated from PND 11 to 21. For Phase 1, an additional 2 male and 2 female pups/litter (from dams treated at 0 or 7.5 mg/kg/day) were also dosed from PND 11 to 21 at 200 or 450 mg/kg/day. The females treated up to GD 20 were killed three hours after dosing on that day; litter data were assessed and cholinesterase activity determined in maternal and fetal plasma, RBC, and brain. Treated offspring were killed two hours after dosing on postnatal day 21 and cholinesterase activities determined.
Under the conditions of this study, no adverse effects of treatment were observed in maternal animals at 7.5 or 35 mg/kg/day. Transient post-dosing salivation was seen in the majority of dams at 75 and 150 mg/kg/day. Signs of severe toxicity were observed at 750 and 1250/1000 mg/kg/day, and included tremors, prostrate posture, abnormal gait, decreased body weight and food consumption, moribundity, and mortality; dosing was stopped for these groups and survivors were sacrificed on GD 20. At GD 20, RBC cholinesterase inhibition was observed in dams at 75 mg/kg/day and above; plasma and brain cholineserase inhibition were observed at 750 mg/kg/day and above.
In offspring that were dosed directly, overt clinical signs of toxicity (body tremors and moribundity) were observed at doses of 200 and 450 mg/kg/day; due to the excessive toxicity dosing was terminated and pups sacrificed before reaching weaning. RBC cholinesterase inhibition was observed at all doses tested (i.e., 7.5 mg/kg/day and above) in PND 21 pups. Brain cholinesterase inhibition was seen at 75 mg/kg/day and above, and plasma cholinesterase was inhibited at 150 mg/kg/day and above. For GD 20 fetuses, RBC cholinesterase was inhibited at 750 mg/kg/day and above.
The results from this study were used to select the doses used in the definitive developmental neurotoxicity study (MRID 45646401). The highest dose tested in that study was set at 150 mg/kg/day, based upon the severity of clinical signs noted at 200 mg/kg/day in directly dosed pups on this dose range-finding study.
This study is classified Acceptable/Nonguideline as a dose range-finding study and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6).
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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; Dams: GD 6 to PND 10; pups: PND 11 to PND 21
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50550.0
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2002-08-22
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2006-09-21
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Added by
Madison Feshuk
on Apr 25, 2022
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