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45073501.DER.pdf
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45073501;44953901
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Lindane
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58-89-9
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009001
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Lindane has two MRID numbers one in the databse (44953901) and another one in the FOIA database
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4495.0
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In a developmental neurotoxicity study (MRID 45073501), lindane (Batch No. HLS 96/1; 99.78% a.i.) was administered to presumed pregnant Hsd Brl Han:Wist (Han Wistar) rats in the diet at concentrations of 0, 10, 50, or 120 ppm from gestation day (GD) 6 through lactation day 10. These concentrations resulted in F0 maternal doses of 0.8-0.9, 4.2-4.6, and 8.0-10.5 mg/kg/day, respectively, during gestation and 1.2-1.7, 5.6-8.3, and 13.7-19.1 mg/kg/day, respectively, during lactation. The developmental neurotoxicity of lindane was evaluated in the F1 offspring. F1 animals (10/sex) were evaluated for FOB, motor activity, auditory startle response, and learning and memory as well as developmental landmarks such as vaginal perforation and balanopreputial separation, and brain weights and histopathology on days 11 and 65, including morphometrics.
Small differences in absolute maternal body weights (7-8%) were observed between the high dose and control groups during gestation and early lactation (through day 11). Body weight gains by the high-dose dams from GD 6 through GD 20 were 64-79% (p £ 0.01) of the control level. Body weight changes during lactation were similar between the treated and control groups. During gestation, food consumption by the high-dose group was significantly (p £ 0.01; 74-92% of controls) less than the control group for the intervals of GD 10-13, 14-17, and 18-19. Food consumption by the low- and mid-dose groups during gestation and by all treated groups during lactation was similar to the controls.
Absolute body weights of the treated male and female pups in mid and high dose groups during lactation were 12-18% and 16-20% less than controls, respectively on days 4-11 of lactation with recovery to less than 10% by day 21. Body weight gains (p £ 0.05 or 0.01) on lactation days 1-4 and 1-11 were 76% and 84%, respectively, of the control levels for mid-dose males, 79% and 79%, respectively, for mid-dose females, 60% and 73%, respectively for high-dose males, and 63 and 75%, respectively, for high-dose females. Body weight gains by all treated groups were similar to the controls during lactation days 11-21. Except for mid and high dose females, postweaning, body weight gains were similar between the treated and control groups. Body weight differences for high dose dams were 10% less at the beginning of lactation and recovered to 6% less by the end of the study.
The high-dose group had a greater number of stillborn pups as indicated by a live birth index of 77% compared with 99% for the control group. In addition, nine high-dose litters either died or were sacrificed moribund on lactation days 1-4. This resulted in a viability index for the high- dose group of 71% compared with 89% for the controls. Pup mortality in the mid and high-dose groups in litters surviving to weaning was greater before day 4 than in controls [ 3 pups in 2/20 controls; 18 pups in 8/22 litters, mid dose; 14 pups in 4/15 litters, high dose]. Survival was not affected at any time in the low dose group as compared with the control group. No dose- or treatment-related differences were observed between treated and control groups for duration of gestation, number of pups/litter on day 1, or per cent male offspring.
At necropsy, no treatment-related gross abnormalities were observed in the dams or offspring. Absolute and relative liver and kidney weights of the offspring were not affected by treatment.
A few clinical signs were observed in high dose dams and pups; increased reactivity to handling in dams on weeks 2 and 3 of dosing, and slower surface righting in pups on day 4. There were no effects on measures of physical or sexual development.
There was an increase in motor activity at the mid and high dose during lactation in both sexes. Some decrease in habituation of motor activity in females on day 22 was also seen. While there was no effect on auditory startle reflex amplitudes, there was a clear reduction in auditory startle response habituation in both sexes at the high dose on day 28 and on day 60. Slight decreases in absolute, but not relative, brain weights in mid and high dose female pups were observed on postnatal day 11 (9-10%) but narrowed to 3-5% less by day 65. Brain lengths and widths were similar between the treated and control pups. Morphometric brain measurements did not show any significant differences in the sizes of the neocortex, hippocampus, corpus callosum, or cerebellum on days 11 or 65. There were no effects on histopathology of the nervous system.
The maternal toxicity LOAEL is 120 ppm (13.7 mg/kg/day) based on decreased body weight gains, decreased food consumption, and increased reactivity to handling.
The maternal toxicity NOAEL is 50 ppm (5.6 mg/kg/day).
The offspring toxicity LOAEL is 50 ppm (5.6 mg/kg/day) based on reduced pup survival, decreased body weights and body weight gains during lactation, increased motor activity, and decreased motor activity habituation.
The offspring toxicity NOAEL is 10 ppm (1.2 mg/kg/day).
This study is classified as Unacceptable/Guideline [870.6300 (§83-6)] since laboratory validation studies of the neurobehavioral tests were not included, but it may be upgraded and found acceptable if this information is obtained. The number of animals tested at the highest dose is only 6 compared to the required number of 10 animals per dose.
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Developmental-Neurotoxicity
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NA [82-7, Subchronic Neurotoxicity]
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Oral
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Treatment Duration: 5 Gestation Days
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53880.0
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2001-06-14
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2009-01-08
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Added by
Madison Feshuk
on Apr 25, 2022
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