46179301f.der.pdf

• filename: 46179301f.der.pdf
• MRIDs: 46179301f
• CHEMICAL_SUBSTANCE_NAME: Finasteride
• CHEMICAL_CASRN: 98319-26-7
• CHEMICAL_PC_CODE: 129113
• STUDY_CITATION: Hoberman, A. (2003) Positive Control Data to Support the Study "Oral (Gavage) Developmental Neurotoxicity Study of Acephate Technical in Rats. Project Number: VP/23747, 200300367, 012/014. Unpublished study prepared by Argus Research Laboratories, Inc. 2183 p.
• STUDY_YEAR: 2003.0
• EXECUTIVE_SUMMARY: MRID 46179301 contains eight different DNT positive control studies. MRID 46179301a: In a positive control study, presented as a poster that addressed developmental neurotoxicity (MRID 46179301a), lead nitrate (% a.i., batch/lot # not provided) was administered to groups of 25 female Crl:CD®BR VAF/Plus® rats by gavage at dose levels of 0, 5 or 50 mg/kg bw/day from gestation day 6 through day 10 of lactation. Feed consumption and body weight of the dams were monitored, and the dams were observed for clinical signs. Duration of gestation, number of liveborn and stillborn pups, dams with stillborn pups, and pups dying on days 1 to 4 postpartum were monitored. Offspring feed consumption and body weight were observed during the early postweaning period. The following neurobehavioral tests were conducted on the F1 generation: motor activity on days 13, 17, 21 and 60 postpartum, auditory startle habituation on days 22 and 60 postpartum, passive avoidance on days 23 or 24 postpartum, and a water maze on days 58 or 59 postpartum. Brain weight to body weight ratios were measured in selected pups on day 11 and in dams. Sexual maturation was also monitored in pups. F0 females in the high dose groups were examined for neurohistological lesions. Details were provided for only some of the methods and observations. Dose analysis information was not provided. At the high dose, clinical signs of toxicity (ptosis, labored breathing, excess salivation, decreased motor activity, and localized areas of alopecia in 3-4/25 animals; p<0.01) and reduced food consumption were noted in the dams. Single incidences of these signs in the 5 mg/kg/day group were not considered treatment-related. Treatment with lead nitrate had no effect on gestation length, number of litters, or number of liveborn at either dose. Results of the neurohistological evaluations were not provided. Lower pup survival on PNDs 1-4 and decreased pup body weight on PNDs 1-7 were found in the high-dose group. Offspring from high-dose dams also had reduced body weight and feed consumption early in the post-weaning period. Data on sexual maturation were not provided. No effects of maternal treatment were found on motor activity at any age. Habituation was present by PND 21. No differences in response amplitude to noise were noted between the dose groups at each age. Habituation was apparent in PND 60 animals. In the passive avoidance test, no differences in latency, number of trials to criterion, or number of animals that failed to learn were seen between the groups on either testing day. In the water maze, no differences in total trials, errors per trial, or number of animals that failed to learn were seen between the groups on either testing day. Results for these four neurobehavioral tests were consistent with historical control data. This study is classified Unacceptable/Nonguideline. Argus Research Laboratories, Inc. has not demonstrated proficiency in testing the following neurobehavioral functions in the offspring (pre- and postweaning) of Crl:CD®BR VAF/Plus® dams treated with lead nitrate: motor activity, auditory startle, passive avoidance, and learning and memory using the water maze due to major reporting deficiencies. The in life time period was not reported. This positive control study does not satisfy any guideline requirement. ******************** MRID 46179301b: In a Functional Observational Battery (FOB) positive control study (MRID 46179301b), groups of four Sprague-Dawley Crl:CD®(SD)IGS BR VAF/Plus® rats/sex/group were administered one of the following: 0.9% saline (control) intraperitoneally once daily for 10 days; a single oral (gavage) dose of corn oil (control); 30 mg acrylamide/kg/day intraperitoneally once daily for 10 days; 250 mg IDPN/kg/day intraperitoneally once daily for five days; a single oral (gavage) dose of 4 mg d-amphetamine sulfate/kg; a single oral (gavage) dose of 100 mg carbaryl/kg; or a single oral (gavage) dose of 100 mg DDT/kg. Animals were observed for mortality, clinical signs, body weight, body weight gain and food consumption. FOB evaluations were conducted on all animals pre-dosing. A second FOB was conducted on all groups at various times after dosing and a third was performed with acrylamide and IDPN. The animals were sacrificed and subjected to a gross necropsy after the FOB evaluations. Three animals (one male, two females) treated with DDT were either found dead or sacrificed in moribund condition. No treatment-related clinical signs or gross findings were observed in any animal administered any chemical. Body weight, body weight gain and food consumption were adversely affected to difference degrees with all chemicals, except d-amphetamine. FOB evaluations of acrylamide treated animals demonstrated increases in the incidence of the following findings on days 10 and 17: no feces (decreased incidence with normal feces) in females (open field); average landing foot splay in males; whole body tremor/spasm (open field) in combined sexes; ataxia and slight gait abnormality in combined sexes; abnormal respiration in combined sexes; and startle and more energetic reaction to tail pinch in combined sexes; number of rears in treated females (open field); and landing foot splay in males. Also, considered treatment-related was a significant decrease in the number of treated females with normal movement in the home cage on day 17. FOB evaluations of IDPN treated animals demonstrated the following treatment-related increases on days 10 and 17: stereotyped behavior (open field) in combined sexes; mean score for air righting response in combined sexes; landing foot splay in males; unusual behavior (home cage) in males; stereotyped behavior (home cage) and abnormal respiration in combined sexes; increased mean score for air righting reaction in combined sexes; and number of rears in males. Also considered treatment-related was a decreased mean score for auditory reaction in combined sexes. FOB evaluations of d-amphetamine treated animals demonstrated the following treatment-related differences: increased unusual behavior (home cage) in females; increased number of rears in males; decreased landing foot splay in females; decreased incidence of combined sexes with no alterations (home cage); decreased incidence of no alterations (open field) and increased stereotyped behavior in combined sexes; increased unusual behavior (home cage) in males; increased piloerection in combined sexes; increased abnormal respiration in combined sexes; decreased maximum and average forelimb grip strength in combined sexes; increased stereotyped behavior; whole body tremor/spasm (home cage) in the combined sexes; and increased limb twitches/tremor (open field) in combined sexes. FOB evaluations of carbaryl treated animals demonstrated the following treatment-related effects: increase in females with unusual behavior (home cage); and decreased body temperature in males and females. The following increases were observed in combined sexes: whole body tremor/spasm (home cage); mean score for urination (open field); limb twitches/tremor and whole body tremor/spasm (open field); ataxia; mean score for gait abnormality, lacrimation and salivation; abnormal respiration; and piloerection. Also observed when the sexes were combined were decreased mean scores for visual reaction and tail-pinch reaction. FOB evaluations of DDT treated animals demonstrated the following treatment-related differences: increased unusual behavior (home cage) in males and females; increased number of combined sexes with limb twitches/tremor and whole body tremor/spasm (home cage); decreased number of males with no defecations (open field); increased number of combined sexes with limb twitches/tremor (open field); increased auditory reaction mean score in combined sexes; decreased maximum hindlimb grip test in combined sexes; decreased number of rears (open field) in males and females; and decreased tail-pinch reaction in combined sexes. This study is classified Acceptable/Nonguideline. Argus Research Laboratories, Inc., has demonstrated proficiency in this study for detecting neurobehavioural changes (FOB) due to treatment with acrylamide, IDPN, d-amphetamine sulfate, carbaryl and DDT in adult (older than 75 days) Sprague-Dawley Crl:CD®(SD)IGS BR VAF/Plus® rats in the time period around 2000 (in life period of study). This positive control study does not satisfy any guideline requirement. ******************** MRID46179301c: In a motor activity positive control study (MRID46179301c), five adult (assumed) Crl:CD®(SD)IGS BR VAF/Plus® rats/sex/group were treated by intraperitoneal (IP) administration with either a vehicle control (0.9% saline) or 45 mg acrylamide/kg/day once daily for 10 days. Another group of five rats/sex was given 0.75 mg d-amphetamine/kg by IP possibly on days 8, 10 and 13 (dosing schedule is unclear). Mortality, clinical signs of toxicity, body weight, body weight gain and food consumption data were recorded but not analyzed statistically. Motor activity was measured four times: 1) before dosing; 2) as soon as possible after the eighth acrylamide dose and the second (according to the report but probably should say first dose) d-amphetamine dose; 3) on the last day of dosing with acrylamide and after the next dose of d-amphetamine; and 4) three days after the last acrylamide dose and after another dose of d-amphetamine. Rats were sacrificed either the day following the last dose (d-amphetamine) or three or four days after the last day of dosing (vehicle and acrylamide) and gross necropsies were performed. Brain weight was reported for acrylamide-treated animals. Three acrylamide-treated males were found dead or were sacrificed moribund on days 12 and 13. One acrylamide-treated female was sacrificed moribund on day 13. Clinical signs of toxicity observed in acrylamide-treated males and females and not in control animals included the following: ataxia, labored breathing, splayed and/or dragging hindlimbs, red or red-brown urine, convulsions, impaired or lost righting reflex, urine-stained abdominal fur and no feces or soft/liquid feces. No clinical signs were observed in d-amphetamine-treated males and females. Body weight was decreased in acrylamide-treated males (82-93% of control value) and females (89-92% of control value). There was a net body weight loss in acrylamide-treated males and females for days 1-8 and 1-14. Food consumption for days 1-8 was decreased in acrylamide-treated males (72% of control value) and females (52% of control value). Body weight and food consumption in d-amphetamine-treated animals were comparable to the control group. Body weight gain for days 1-8 was decreased in males (25% of control value) and increased in females. No difference between control and treated groups was observed in motor activity testing prior to dosing. With acrylamide, the total number of movements was significantly decreased in sessions 2, 3 and 4 in males (29-60% of control value) and females (31-64% of control value). The total time spent in movement was non-significantly decreased in males in sessions 2 and 3 (41-43% of control value) and significantly decreased in session 4 (22% of control value). The total time spent in movement was significantly decreased in females in sessions 2, 3 and 4 (17-43% of control value). With d-amphetamine, the total number of movements was significantly increased in males (202-229% of control value) and females (171-207% of control value) in all sessions. The total time spent in movement was significantly increased in males (263-310% of control value) and females (297-315% of control value) for all sessions. Terminal mean body weights were decreased in acrylamide-treated males (81% of control value) and females (89% of control value). Mean brain weights in these animals were comparable to the control group; therefore, the relative brain weights were increased in males (125% of control value) and females (112% of control value). This study is classified Acceptable/Nonguideline. Argus Research Laboratories, Inc., has demonstrated proficiency in this study for detecting neurobehavioural changes (MA) due to treatment with acrylamide and d-amphetamine in adult (assumed) Crl:CD®(SD)IGS BR VAF/Plus® rats in the time period around 1996 (in life period of study). This positive control study does not satisfy any guideline requirement. ******************** MRID 46179301d: A motor activity study (MRID 46179301d) was conducted in three phases, as follows: 1) untreated adult mice (11 males, 12 females) and rats (28/sex) were monitored for motor activity for 60 or 90 minutes; 2) 22 untreated rats/sex were monitored for 60 minutes on postnatal days 13, 17, 21 and 58 or 59; and 3) 15 male and 15 female 60 day-old rats were sequentially treated with a control or three dose levels of either d-amphetamine (0.75, 1.5 and 4.0 mg/kg) or chlorpromazine (1.0, 2.0 and 4.0 mg/kg) and monitored for 115 minutes either immediately (d-amphetamine) or 70 minutes (chlorpromazine) thereafter. The study was conducted to demonstrate that an infrared sensor apparatus could adequately measure motor activity in a single session. Only the number of movements was reported, although time spent in movement data were also collected. The study was also conducted to confirm the ability to detect changes due to treatment with d-amphetamine and chlorpromazine. In untreated adult mice and rats, movement decreased in all groups within the test session, reflecting habituation; the changes were more pronounced in rats. In untreated neonate rats [preweaning (days 13-21) and postweaning (days 58/59)], differences between the values across the measurement intervals were significant at all ages (p¿.05) but the pattern on day 17 did not have a significant trend. Neither the differences in the mean values between male and female rats nor the differences in the patterns across measurement intervals were significant. The number of movements increased with age in males and females. Habituation was apparent on days 21 and 58/59. In treated adult rats, differences among the values recorded at each dose of d-amphetamine and chlorpromazine were significant (p¿.001) in male and female rats. In pairwise comparisons, the number of movements detected after the 0.75, 1.5 and 4.0 doses of d-amphetamine in males was significantly increased (p¿.01) compared to the vehicle control. The increase declined at the high dose and was attributed to an increase in stereotypic behavior that may have interfered with movement. In females, the values for the vehicle and the high-dose group of d-amphetamine were not significantly different but significantly more movements were detected at 0.75 and 1.5 mg/kg. With chlorpromazine, the number of movements was decreased in a dose-dependent pattern in males and females. The number of movements with the 2.0 and 4.0 mg/kg doses was significantly (p¿.01) decreased in males and females compared to the vehicle control. This study is classified Unacceptable/Nonguideline. Argus Research Laboratories, Inc. has not demonstrated proficiency in testing for neurobehavioral functions (motor activity) in adult rats (strain unspecified) treated with d-amphetamine and chlorpromazine in the time period around 1991 (in life period). This positive control study does not satisfy any guideline requirement. ******************** MRID 46179301e: In a positive control study (MRID 46179301e) for neuropathology, groups of 3 (4 for female rats treated with MK-801) Crl:CD® BR VAF/Plus® (Sprague -Dawley) rats/sex/group were administered intraperitoneal doses of either 0 mg/kg/day (0.9% sodium chloride vehicle, 10 days plus 2 additional doses) or 45 mg acrylamide/kg/day (10 days), or a single dose of 10 mg MK-801/kg or 8 mg trimethyltin chloride/kg. Nervous system tissues were perfusion fixed with 10% neutral buffered formalin, then further exposed to formalin by immersion. Only the peripheral nervous system tissues (peripheral nerves, spinal nerve roots, and dorsal root ganglia) were examined from the acrylamide-treated rats. Only brains were examined from MK-801 and trimethyltin-treated rats. Both central and peripheral nervous system tissues were examined from control rats. The slices of brain, as well as the spinal nerve roots and dorsal root ganglia, were embedded in paraffin, cut into 6 mm slices, and stained with hematoxylin and eosin (H&E), luxol fast blue/cresyl violet (LFB/CV) and the Bielschowsky¿s technique. Sections of the peripheral nerves were embedded in glycol methacrylate, sectioned into 2 mm slices and stained with H&E, toluidine blue, and the Bielschowsky¿s technique. The brains and/or peripheral nervous system tissues were examined microscopically for neuropathologic lesions. In acrylamide-treated rats, mild chromatolysis was seen in the dorsal root ganglia from all treated rats. Nerve fiber degeneration was found in one or more of the peripheral nerves from all treated rats. Neither lesion was observed in controls. All MK-801-treated rats had degenerative or necrotic neurons within the retrosplenial cortex; this lesion also was seen in the cingulate cortex of one male and one female. The lesion was not found in any controls. All trimethyltin-treated rats had neuron degeneration in several areas of the brain, most notably the hippocampus. The severity was greater in females than in males. Additionally, several animals had vacuolation in the cerebellar cortex or white matter. This study is classified Acceptable/Nonguideline. Argus Research Laboratories, Inc., has demonstrated proficiency in this study for detecting neuropathological changes in the central and peripheral nervous systems due to treatment with acrylamide, MK-801 and trimethyltin chloride in adult (assumed) Crl:CD®(SD)IGS BR VAF/Plus® rats in the time period around 1996 (in life period of study). This positive control study does not satisfy any guideline requirement. ******************** MRID 46179301f: In a developmental toxicity study (MRID 46179301f), finasteride (purity not provided, batch/lot No. L-652.931) was administered by gavage to groups of 19 or 20 pregnant female Sprague-Dawley Crl:CD (SD)BR rats at dose levels of 0, 0.0003, 0.03, or 3 mg/kg bw/day from gestation day (GD) 15 through postpartum day 21 (Study 1). The dams delivered their offspring naturally and selected F1 male offspring were maintained for various times until study termination between postnatal days 114 and 117. In study 2, finasteride at a dose level of 20 mg/kg/bw/day was administered by gavage to 9 or 10 pregnant rats on GD 14-15, 16-17, 18-19, or 20-21; F1 offspring were delivered naturally and the males were maintained until termination between postnatal days 62 and 67. Endpoints evaluated in male offspring included body weight, survival, anogenital distance on postnatal day 1, 22, and 114-117 (Study 1 only) or postnatal days 1 and 62-67 (Study 2 only), nipple formation on postnatal day 12, age at testes descent and age at preputial separation (Study 1 only), weights of ventral prostate and seminal vesicle/coagulating gland between postnatal days 114-117 (Study 1 only), and examination of the penis for hypospadias and cleft prepuce at study termination. No effects were reported for changes in body weight or survival in maternal animals. The only treatment-related maternal effect observed in this study was a 1-day increase in gestation length in pregnant females administered finasteride at 20 mg/kg/bw/day on GD 20-21; offspring effects were not observed in this group. Survival and body weight of offspring were not affected by treatment with any dose of finasteride during gestation. Developmental effects in male offspring included 13 and 27% decreases in anogenital distance at 0.03 and 3 mg/kg/day, respectively, compared with that of controls on postnatal day 1; the effect was completely reversed in the 0.03-mg/kg/day group by postnatal day 22, but remained significantly decreased (-5 to -6%) compared with that of controls on postnatal days 22 and 114-117 in the 3-mg/kg/day group indicating a partial reversal in this group. Nipples were observed on 3% and 29% of male pups from 10% and 53% of litters in the 0.03- and 3-mg/kg/day groups, respectively, on postnatal day 12 compared to none in the control group. The age of testes descent was not affected by treatment with finasteride at any dose, but preputial separation in male offspring without hypospadias was delayed by 5 days at 3 mg/kg/day compared with the age of separation in the control group. Hypospadias with cleft prepuce was observed in 53% of litters and 29% of male offspring in the 3-mg/kg/day group compared with none of the male offspring in the control, 0.0003, or 0.03-mg/kg/day groups. The critical time for disrupting development of male fetuses was GD 16-17. The greatest effect occurred on the decrease in anogenital distance (-25% compared with controls), decease in the absolute and relative ventral prostate weight (¿18% compared with controls), and the number of pups with hypospadias with cleft prepuce (78% of litters and 39% of male offspring) when females were treated with 20 mg/kg/bw/day on GD 16-17 compared with the other 2-day intervals. Nipple formation was observed on 19% of male offspring treated on GD 16-17 and 8% of offspring treated on GD 14-15, but the litter incidence was the same whether treated on GD 16-17 or GD 14-15. This study showed specific effects on the development of male offspring from females administered finasteride at non-maternally toxic doses during gestational and postpartum periods and established the critical time for inducing specific developmental effects in male offspring. The most notable deficiency was lack of purity or stability analysis of the compound. However, the dosing suspension was analyzed for the concentration of test material prior to dosing. This study is classified Acceptable/Nonguideline. Argus Research Laboratories, Inc., has demonstrated proficiency in this study for detecting developmental landmarks (male genitalia) and in determining the critical time for inducing these effects in male offspring due to treatment with finasteride treated female Crl:CD (SD)BR rats. The in life time period was not provided. However it was sometime prior to 1993. ******************** MRID 46179301g: In a published study (MRID 46179301g), 14 mated female Crl:COBS®CD®(SD)BR rats per group were fed a liquid diet containing either 0%, 17.5% or 35% ethanol derived calories (EDC) from gestation day (GD) 5 through 18. A pair feeding procedure was used to control for daily caloric intake. Each dam in the 17.5% and 0% EDC groups was matched to a 35% EDC dam and was fed the amount consumed by the 35% EDC dam on a mL/kg/day basis. Dams in the 35% EDC group had free access to the diet. Dams in the 35% and 17.5% EDC groups consumed an average of 13.85 ± 0.35 g and 6.8 ± 1.0 g ethanol per kg body weight per day, respectively. A fourth group of 14 dams, which had free access to standard lab chow throughout gestation, served as a control group for the 0% EDC group. Another group of 73 pregnant dams, used as surrogate dams for offspring of the alcohol-treated and LC (laboratory chow) groups, received free access to standard lab chow. Litters were culled to 10 pups each, five of each sex when possible; the timing of the culling was not provided. Pups were evaluated for learning on postnatal day (PND) 20 using a water-filled T-maze. Each rat was required to reach a criterion of five consecutive errorless trials with a maximum of 20 trials per session. Data were analyzed as the number of trials required to satisfy a learning criterion of 5, 4, 3, 2, or 1 errorless trials. The latency for each trial (time in seconds to swim from the starting position to the correct goal) and the number of errors (incorrect turns in the maze) were also analyzed. All maternal animals survived the study. No treatment-related effects on maternal clinical signs, body weight or reproductive performance were observed. Pup survival was not affected by treatment. A dose-dependent decrease in average pup weight was observed for PNDs 7, 14 and 20. No significant differences due to alcohol, gender or interaction of these factors were apparent between the liquid diet groups for a learning criterion of either four or five consecutive errorless trials. A high error rate was apparent for all groups, including the control group indicating that the criteria were too difficult. The alcohol-exposed offspring needed a significantly greater number of trials to meet the learning criterion of three consecutive errorless trials. A significant linear trend indicated that the number of trials required to meet the criterion was directly related to the level of in utero alcohol exposure. No significant differences due to alcohol, gender or the interaction of these factors were apparent between the liquid diet groups for a criterion of one or two errorless trials. A low error rate was evident for all groups, indicating the criterion was too lenient. This study is classified Unacceptable/Nonguideline. Argus Research Laboratories, Inc., has not demonstrated proficiency in this study for detecting neurobehavioural changes (learning) in preweaning pups (20 PND) using a water-filled T-maze (lack of confirmatory numerical summary and individual animal data) due to treatment of the Crl:COBS®CD®(SD)BR dams with ethanol. The in life time period was not provided. However it was sometime prior to 1993. This positive control study does not satisfy any guideline requirement. ******************** MRID 46179301h: In a validation study (MRID 46179301h), the brains of 10 and 12 day-old Crl:CD®BR VAF/Plus® rats (5/sex/age group) were processed and evaluated for nine gross and microscopic morphometric measurements. The sex of the pups was inadvertently not recorded at the time the brains were taken; therefore, the data for the two sexes were combined. The mean values of all measurements were higher for the 12 day-old pups than for the 10 day-old pups but the mean value increase was rather minimal for some areas, such as the corpus callosum and the external germinal layer of the cerebellum. Brain weight was significantly greater in the 12 day-old pups compared to the 10 day-old pups. For all nine morphometric areas, there was an overlap between the day 10 and day 12 pup data. The hippocampal gyrus thickness was the most variable measurement, with variation seen between the two sides of the same brain. Statistically significantly greater values in 12 day-old pups included the following: anterior-posterior length of the cerebrum, thickness of the frontal cortex, width of the caudate-putamen and height of the cerebellar cortex. This study is classified Acceptable/Nonguideline. Argus Research Laboratories, Inc., has demonstrated proficiency in this study for performing brain morphometric measurements in untreated preweaning (PND 10-12) Crl:CD®BR VAF/Plus® rats. The in life time period was not provided. However it was sometime prior to 1998. This method validation study does not satisfy any guideline requirement.
• STUDY_TYPE: Developmental-Neurotoxicity
• GUIDELINE_COMMENT: NA [870.6300, Developmental neurotoxicity study]
• ADMIN_ROUTE: Oral
• DOSE_PERIOD: No Duration Period; MRID 46179301 contains eight different DNT positive control studies.
• txr: 54819.0
• memoDate: 2012-03-28
• UpdateDate: 2017-07-21
• Comments:

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