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45457501g.der.pdf
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45457501g
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D-amphetamine and chlorpromazine
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51-63-8, 69-09-0
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600091, 600006
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Pitt, J. (2001) Positive and Historical Control Data for Neurotoxicity Studies: Lab Project Number: WIL-2001-1: WIL-99140: WIL-99144. Unpublished study prepared by WIL Research Laboratories, Inc. 128 p.
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2001.0
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The following DNT positive control data have been evaluated resulting in the following classifications:
MRID 45457501a: In a motor activity positive control study (MRID 45457501a), a group of 24 six-week-old untreated Sprague-Dawley Crl:CD®(SD)IGS BR rats (12/sex) were monitored in an SDI Photobeam Activity System. The study objective was to determine the optimum duration of the test session and the test interval that would result in normal activity levels by the last 20% of the session following placement in a novel environment (habituation). The monitoring period was 120 minutes; counts were tallied in one- and five-minute intervals or subsessions. No other neurobehavioral procedures were performed.
Individual animal data were not presented and male and female data were combined. Using the one-minute subsessions, habituation was evident after 36 minutes. Based on five-minute subsessions, habituation was evident by 45 minutes. Therefore, a 60-minute motor activity test with five-minute subsessions is adequate for determining habituation in young untreated rats.
This method validation study is classified Acceptable/Nonguideline. It does not however, constitute an adequate positive control study for motor activity. WIL Research Laboratory has optimized conditions for motor activity tests in postweaning (6 wk) Sprague-Dawley Crl:CD®(SD)IGS BR rats using SDI Photobeam Activity System for the time period around 1999 (in life period of study). This study satisfies the purpose for which it was intended. It does not however, constitute an adequate positive control study for motor activity. This method validation study does not satisfy any guideline requirement.
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MRID 45457501b: In a positive control startle response study (MRID 45457501b), groups of 4-5 week old Sprague-Dawley rats (8/sex/dose) were given an intraperitoneal injection of Iminodipropionitrile (IDPN, lot# 90906AT) for three consecutive days at doses of 0 (physiological saline), 200, or 400 mg/kg bw. Habituation of the acoustic startle response was tested in all animals 4 and 11 days after the last treatment, and pre-pulse inhibition of the acoustic startle response was tested in all animals 12 days after treatment. Startle response measurements were made using the SR-Lab Startle Response System. Testing was done in a sound-attenuated room equipped with a white-noise generator set to operate at approximately 70 db. No other observations or neurobehavioral tests were performed.
Data were presented graphically, separately for males and females. Habituation of the startle response was demonstrated for both sexes in the control and 200 mg/kg/day groups and at both 4 and 11 days post-treatment. Startle response (Vmax and Vavg) was greatly reduced in males in the 400 mg/kg/day group on both testing days. Latency to the Vmax (Tmax) was increased on both testing days for males in the 400 mg/kg/day group. Females in the 400 mg/kg/day group also had decreased amplitude and increased latency on both days compared with the controls, but the magnitude of effect was not as great as that of the males, and some recovery to control levels was noted by day 11.
At 12 days after treatment, both sexes in the control and 200 mg/kg/day groups showed habituation with increasing intensity of the pre-pulse. Males in the 400 mg/kg/day group had a drastically reduced Vmax and Vavg and greatly increased Tmax with no change in the magnitude of effect with increasing pre-pulse intensity. Females in the 400 mg/kg/day group also had decreased amplitude and increased latency compared with controls with effects seen mainly for trials without a pre-pulse and at 70 db.
This study is classified Unacceptable/Nonguideline. WIL Research Laboratory has not demonstrated (due to reporting deficiencies) proficiency in this study for detecting startle response with habituation due to IDPN treatment in postweaning (4-7 wk) pups (in life time period unspecified). Although the WIL study report presented graphical data indicating ability to detect changes the study report does not meet present OPPTS 870.6300 guidelines. The: 1) in life dates of the study were absent. 2) There was no numerical data (individual animal and mean (SD) data) presented to support the graphical representation of the data. 3) Animal body weights were only summarized as means, range or individual animal weights
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MRID 45457501c: In a motor activity positive control study (MRID 45457501c), five groups of 6 week old Sprague-Dawley Crl:CD®(SD)IGS BR rats (12/sex/group) were administered 0, 2 or 4 mg/kg of d-Amphetamine sulfate (ip injection) or 5 or 10 mg/kg of Chlorpromazine HCl (ip) then tested in a SDI Photobeam Activity System.
d-Amphetamine sulfate-treated male and female rats demonstrated a dose-dependent increase in total motor activity counts compared to controls. No interval data were provided. Chlorpromazine HCl caused a dose-dependent decrease in total activity counts in both males and females that was statistically significant at both dose levels (p<0.01). No interval data were provided.
This study is classified Unacceptable/Nonguideline. WIL Research Laboratory has not demonstrated proficiency in this study for detecting changes in Motor Activity tests in postweaning (6 wk) Sprague-Dawley Crl:CD®(SD)IGS BR rats due to d-Amphetamine sulfate or Chlorpromazine HCl treatment for the time period around 1999 (in life period of study). Although the WIL study report presented data indicating ability to detect changes, the study report does not meet present OPPTS 870.6200 or 870.6300 guidelines due to reporting deficiencies. 1) There was no individual animal data. 2) Interval data for the motor activity sessions (subsessions) need to be provided to demonstrate habituation. This positive control study does not satisfy any guideline requirement.
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MRID 45457501d: Studies were conducted on untreated Sprague Dawley Crl:CD®(SD)IGS BR rats to provide historical control data for auditory startle habituation and brain morphometry (MRID 45457501d). Habituation of the acoustic startle response was tested in rats on PND 20 (two rats/sex/litter from five litters). Startle response measurements were made using the SR-Lab Startle Response System in a sound-attenuated room. Data were presented graphically, separately for males and females. Habituation of the startle response and pre-pulse inhibition of the startle response were demonstrated in both sexes.
Brain morphometry measurements were obtained but not presented on one pup/sex from six litters (PND 11) for eleven defined brain regions. The data from the study will provide historical control data for Sprague-Dawley rats at the Laboratory.
This method validation study is classified Acceptable/Nonguideline. It does not however, constitute an adequate positive control study for motor activity. WIL Research Laboratory has demonstrated proficiency in testing acoustic startle response tests showing habituation and pre-pulse inhibition in preweaning (PND 20) Sprague Dawley Crl:CD®(SD)IGS BR rats using the SR-Lab Startle Response System for the time period around 1999 (in life period of study). This study does not constitute acceptable positive control data. This method validation study does not satisfy any guideline requirement. The data from the morphometry study will provide historical control data for Sprague-Dawley rats (PND 11) at the Laboratory.
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MRID 45457501e: In a positive control neurotoxicity study (MRID 45457501e), 5 rats/sex/group were administered a single dose of IDPN (90% a.i., Batch# not given) by gavage at doses of 0 or 2000 mg/kg. Deionized water was used as the negative control; the test article was dosed neat. A functional observational battery (FOB) was conducted by eight trained technicians following the onset of clinical signs. No details of the FOB methods or age and strain of rat used were given.
No data were included with the report. In a short results section it was stated that findings for all endpoints of the FOB were consistent between technicians for both treated and control animals.
Based on insufficient data, it is not possible to determine whether the testing facility demonstrated proficiency in conducting the FOB or in inter-observer reliability.
This study is classified Unacceptable/Nonguideline. WIL Research Laboratory has not demonstrated (due to reporting deficiencies) inter-observer reliability or proficiency in this study for detecting FOB changes due to IDPN treatment in rats (strain and age unspecified). The: 1) in life dates of the study were absent, 2) protocol details very limited, and 3) raw data were limited (sometimes only presented graphically). These reporting deficiencies limit the usefulness of the study to validate DNT studies. Presentation of the study dates, additional protocol detail (for example, details of the methods and scoring criteria for the FOB) and raw data for this study are necessary in order to confirm that the laboratory has proficiency for detecting the changes. A complete review of the data was not conducted. This positive control study does not satisfy any guideline requirement.
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MRID 45457501f: In a positive control study (MRID 45457501f): 1) four groups of 24 rats (12/sex/group) were administered 0, 5, 10 or 20 mg/kg/day of acrylamide (99%) 5 days/wk for 4 weeks (route not specified). Functional Observational Battery (FOB) testing was performed 1 hr to 28 days after the first dosing. Motor activity testing was conducted at the end of the treatment period (methods not described). A histological examination for peripheral and central nervous system pathology was conducted on 6 rats/sex/group from the control and high dose groups.
2) one group of 10 rats (5/sex) were administered (7.5 mg/kg) a single intraperitoneal injection of trimethyltin chloride. Fifteen days after dosing the animals were euthanized and histopathology examined as for acrylamide above.
Acrylamide: The FOB results were presented in tabular form as dose group affected, but without incidence data. Acrylamide-treated male and female rats from the 10 and 20 mg/kg/day treatment groups demonstrated differences relative to controls during the 14, 21, and 28 day evaluations, which became more apparent with each successive time point. Biologically significant lesions indicative of neurotoxicity were observed in the acrylamide-treated rats (20 mg/kg). Differences as compared to controls were described in the report, but the data were not provided to evaluate.
Trimethyltin chloride: The report stated that there was neuronal loss in the dentate gyrus and one of the male rats exhibited chromatolysis in the gasserian ganglion neurons.
Insufficient data are presented in the study report to assess proficiency in conducting tests on neurotoxicants like acrylamide and observing changes in the FOB and nervous system histology.
This study is classified Unacceptable/Nonguideline. WIL Research Laboratory has not demonstrated (due to reporting deficiencies) proficiency in this study for detecting Motor Activity, FOB and neuropathology changes due to acrylamide treatment and neuropathology changes due to trimethyltin chloride (age of rats not specified) for the time period around 1991 (in life date). Although the WIL study report presented some tabular data indicating ability to detect FOB changes, the study report does not meet present requirements for positive control data needed for a developmental neurotoxicity study. 1) There were no details on the animals used in the study. 2) There were no numerical data (individual animal and mean (SD) data) presented to support the conclusions of the investigator for Motor activity, FOB or Neuropathology. 3) There were no details on the statistical methods used. This positive control study does not satisfy any guideline requirement.
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MRID 45457501g: In a motor activity positive control study (MRID 45457501g), four groups of 24 rats (12/sex/group) were administered single doses of 0, 0.5, 1.0 or 2.0 mg/kg d-amphetamine sulfate (ip injection) then tested 20 minutes and 24 hours post-treatment in a Digiscan Micro Animal Motor Activity System. Functional Observational Battery (FOB) testing was also performed 1, 6 and 24 hours after dosing. After a rest period of one day, the same rats were injected (ip) with single doses of 0, 2.5, 5.0, or 10 mg/kg chlorpromazine HCl and the affect on motor activity and FOB endpoints tested. Motor activity profiles for untreated male and female rats (16/sex) were measured during an entire 24 hr light-dark cycle.
d-Amphetamine sulfate-treated males and female rats demonstrated a dose-dependent increase in total and ambulatory motor activity counts as compared to controls at 20 minutes post-treatment, but not at 24 hrs. All increases were statistically significant for all three dose levels (p<0.05). d-Amphetamine sulfate treatment increased the number of rearing episodes in high dose males and altered posture in the mid-dose females during the 1-hour post-treatment evaluation.
Chlorpromazine HCl caused dose-dependent decreases in total and ambulatory activity counts in both males and females at 20 minutes post-treatment, but not at 24 hrs. Decreases were observed at all dose levels in male rats, but statistically significant (p<0.05) only at the mid-dose level. In females, the differences observed in total count were statistically significant for all three dose levels, but only at the mid- and high dose levels for the ambulatory counts. The FOB results were presented in tabular form as dose group affected, but without incidence data. Chlorpromazine HCl-treatment caused alterations in palpebral closure, respiratory rate, mobility, gait, gait score, and body temperature at 1 hr post-treatment.
Motor activity profiles: The results were similar to those reported in the published literature. Reliability studies on the motor activity testing system were conducted on 48 rats/sex/group across four consecutive days using two separate devices. The devices appeared to give similar results as the standard deviations for each pairing overlapped substantially.
This study is classified Unacceptable/Non-guideline. WIL Research Laboratory has not demonstrated (due to reporting deficiencies) proficiency in this study for detecting changes in FOB and Motor Activity tests in rats (age, strain and source are unspecified) due to d-Amphetamine sulfate or Chlorpromazine HCl treatment for the time period around 1990 (in life period of study). Although the WIL study report presented some numerical and graphical data indicating ability to detect changes, the results could not be confirmed due to the limited data presented (see deficiency section for details). This positive control study does not satisfy any guideline requirement.
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Other
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NA [81-9, Developmental neurotoxicity (use 870.3650 or 870.6300 instead of this)]
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Intraperitoneal
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No Duration Period; Positive Control Studies; Other studies were by the oral route
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54597.0
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2012-03-20
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2016-08-31
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Added by
Madison Feshuk
on Apr 25, 2022
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