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45646401.DER.pdf
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45646401
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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 Developmental Neurotoxicity Study in the CD Rat by Oral Gavage Administration: Lab Project Number: CHV006/013331: CHV/066. Unpublished study prepared by Huntingdon Life Sciences Ltd. 1455 p. Relates to L0000813. {OPPTS 870.6300}
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2002.0
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In a developmental neurotoxicity study (MRID 45646401), malathion (96% a.i., batch # 9010501) was administered to 24 parental female Crl:CD®BR rats per dose by gavage at dose levels of 0, 5.0, 50, or 150 mg/kg bw/day in corn oil from gestation day 6 through postnatal day 10, and to the offspring from postnatal day 11 to postnatal day 21 inclusive. A Functional Observational Battery was performed on 10 dams/dose on gestation days 12 and 18 and lactation days 4 and 10. Offspring were evaluated as follows: age-appropriate functional observation battery on days 4, 11, 21, 35, 45, and 60, automated motor activity on days 13, 17, 22, and 60; assessment of auditory startle response on days 23/24 and 60/61, assessment of learning and memory (Morris Water Maze) at postnatal days 23/24, and at postnatal day 61/62 (separate groups), brain weights on days 11, 21, and 65, and brain histopathology and morphometrics on days 21 and 65-. Pup physical development was assessed by body weight. Sexual maturation of females was assessed by age of vaginal opening, and sexual maturation of males was assessed by age at completion of balano-preputial separation.
There were no treatment-related maternal deaths before scheduled termination. Clinical signs were limited to transient post-dosing salivation (5/24 control, 4/24 at 5 mg/kg/day, 3/24 at 50 mg/kg/day, and 20/24 at 150 mg/kg/day). There were no other treatment-related effects on cholinergic signs, and there were no effects on maternal body weight, food consumption, or reproductive indices. The maternal LOAEL for malathion in rats is 150 mg/kg/day based on an increased incidence of post-dosing salivation. The maternal NOAEL is 50 mg/kg/day.
The offspring NOAEL is <5 mg/kg/day (the lowest dose tested). The offspring LOAEL is 5 mg/kg/day, based upon increased auditory startle reflex peak amplitude in PND 23/24 male and female offspring and decreased habituation in PND 60/61 females. At 50 mg/kg/day, there was an increased incidence of slightly flattened gait in PND 60 males, and motor activity counts (rearing and ambulatory) were decreased in female pups at PND 17 and 22. At 150 mg/kg/day, additional treatment-related findings included post-dosing clinical observations on PND 17 and 18 (whole body tremors, hypoactivity, prostrate posture, partially closed eyelids, and/or abnormal gait), delayed surface righting reflex in PND 11 female pups, increased incidences of slightly flattened gait in PND 60 males, and increased thickness of the corpus callosum in PND 63-67 males and females.
In a companion cholinesterase inhibition study (MRID 45566201), acute or repeated exposure to malathion resulted in statistically and biologically significant decreases in cholinesterase activity in the blood and/or brain in dams, fetuses, weanling pups, and adult male and female rats. In pups, effects on RBC cholinesterase were noted at 5 mg/kg in males and 50 mg/kg in females following single dose acute exposures on PND 11, and at 5 mg/kg/day in both sexes on PND 21 after 11 repeated exposures. Following a single dose to young adults, effects on RBC cholinesterase were observed at 450 mg/kg, while after 11 or 14 doses, effects were observed at 50 mg/kg/day in young adults and pregnant dams. In pups, brain cholinesterase was inhibited 44-48% and 81-85% at 150 and 450 mg/kg, respectively, following a single (acute) dose administered on PND 11. Single doses at these levels yielded no brain cholinesterase inhibition in young adult rats. After 11 days of dosing during PND 11-21, brain cholinesterase was inhibited 16% in pups (both sexes) at 150 mg/kg/day. No inhibition of the brain enzyme was observed in young adults following 11 days of dosing. Based upon the results of the cholinesterase study, it is evident that all behavioral and neuropathological effects of treatment observed in the dams and offspring in the developmental neurotoxicity study occurred at doses at which cholinesterase was, or had been, inhibited. For acute and repeated exposures the overall LOAEL for cholinesterase inhibition was 5 mg/kg/day, based on RBC cholinesterase inhibition in PND 11 and 21 pups. The NOAEL was not determined.
This study is classified Acceptable/Guideline and satisfies 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 [83-6, Developmental Neurotoxicity]
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Oral
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No Duration Period; Dams: GD 6- PND 10; offspring PND 11- 21
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50550.0
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2002-08-22
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2006-09-22
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Added by
Madison Feshuk
on Apr 25, 2022
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