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EC number: 701-337-2 | CAS number: -
The purpose of this study was to assess the systemic toxic potential, including assessment of plasma, erythrocyte and brain cholinesterase activity, of Fyrolflex RDP when administered to CD rats by oral gavage over a 13-week period.
Four groups (Groups 3, 4, 5 and 6), each comprising ten male and ten female Sprague-Dawley rats, received Fyrolflex RDP at doses of 30, 100, 300 or 1000 mg/kg/day. A similarly constituted control group received the vehicle, corn oil, at the same volume dose as treated groups. A further ten male and ten female satellite animals were allocated to Group 1, a control group and Groups 3, 4 and 6. A further five male and five female satellite animals were allocated to Group 5. An additional ten male and ten female Sprague-Dawley rats were assigned to Group 2 as satellite animals as an additional control group. They were used for blood cholinesterase (plasma and erythrocyte) and brain cholinesterase evaluations.
During the study, clinical observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, visual water consumption, ophthalmoscopy, hematology (peripheral blood), blood chemistry, blood and brain cholinesterase activity, organ weight,
macropathology and histopathology investigations were undertaken.
The homogeneity and stability was confirmed for Fyrolflex RDP in corn oil formulations at nominal concentrations of 1 mg/mL and 200 mg/mL during distribution between the bottles, during magnetic stirring for 2 hours, ambient temperature storage for up to 1 day and refrigerated storage for up to 15 days. The mean concentrations of Fyrolflex RDP in test formulations analyzed for the study were within +10/-15% of nominal concentrations, confirming accurate formulation with the exception of Week 1 Group 4 that was -20.0%.
There were no deaths and no treatment related clinical signs were observed following dose administration. Dosing signs were limited to salivation at 100, 300 and 1000 mg/kg/day and chin rubbing in all treated groups, considered to be associated with palatability of the
formulated test material. There was no effect of treatment on sensory reactivity, grip strength, motor activity or
ophthalmic examination. The haematological examination of peripheral blood performed after 13 weeks of treatment revealed statistically significant low mean cell haemoglobin at 300 and 1000 mg/kg/day in males and at 100, 300 and 1000 mg/kg/day in females (males: 94.3% (p<0.01), 93.8%
(p<0.01); females: 97.0% (p<0.05), 95.4% (p<0.01) and 92.9% (p<0.01)), respectively, when compared with Control and mean cell hemoglobin concentration at 300 and 1000 mg/kg/day in males and at 30, 100, 300 and 1000 mg/kg/day in females (males: 95.1% (p<0.01), 95.1%
(p<0.01); females: 98.6% (p<0.05), 98.3% (p<0.05), 97.2% (p<0.01) and 96.0% (p<0.01), respectively, when compared with Control.
Report Envigo Study Number: RD67DH Page 9.
The biochemical examination of the blood plasma performed during Week 13 of treatment for males and females revealed low or statistically significantly low alkaline phosphatase concentrations at 30, 100, 300 and 1000 mg/kg/day (males: 87.3%, 73.5% (p<0.05), 88.2% (p<0.05), 71.6% (p<0.01); females: 51.3% (p<0.01), 46.3% (p<0.01), 38.8% (p<0.01) and 40.0% (p<0.01)), respectively, when compared with Control. Total protein values were statistically significantly increased in males and females at 30, 100, 300 and 1000 mg/kg/day
(males: 104.6% (p<0.05), 104.6% (p<0.05), 104.6% (p<0.05), 106.2 (p<0.01); females: 101.4%, 107.0% (p<0.05), 108.5% (p<0.01) and 114.1% (p<0.01)), respectively when compared with Control.
Statistically significant, dosage-related differences in mean plasma cholinesterase was evident in males and females at 30, 100, 300 and 1000 mg/kg/day when compared to both Control Groups. Mean erythrocyte cholinesterase was statistically significantly inhibited in
females at 1000 mg/kg/day when compared to Control Group 1 and 2 (71.8% p<0.05 and 65.1% p<0.01, respectively). At 1000 mg/kg/day, mean erythrocyte cholinesterase in males was also low when compared to Control Groups 1 and 2, however this was not statistically significant (79.8%
and 81.5%, respectively). Mean brain cholinesterase in males at 1000 mg/kg/day was statistically significantly low when compared to Control Group 2 (95.2% p<0.05), however there value was comparable to the Control Group 1 mean and no similar finding was evident in
Mean adjusted liver weights showed a statistically significant dose-dependent increase in males and females at 30, 100, 300 and 1000 mg/kg/day (Males: 109.4% (p<0.05), 112.3% (p<0.01), 118.3% (p<0.01) and 130.0% (p<0.01); Females: 114.6% (p<0.01), 130.4%
(p<0.01), 155.6% (p<0.01) and 155.6% (p<0.01)), respectively when compared with Control.
The mean adjusted adrenal weights showed a dose-dependent increase in females at 30, 100, 300 and 1000 mg/kg/day (103.5%, 115.8% (p<0.05), 117.5% (p<0.05) and 119.3% (p<0.05)), respectively when compared with Control, although no similar finding was evident in males.
Abnormally dark livers were seen in two females receiving 300 mg/kg/day and seven females receiving 1000 mg/kg/day. Minimal or slight hypertrophy of the hepatocytes was seen in males and females dosed at 100, 300 or 1000 mg/kg/day and minimal or slight hypertrophy of the follicular cells was seen in males and females dosed at 100, 300 or 1000 mg/kg/day.
Based on these results it was concluded that the no adverse effect level (NOAEL) for systemic toxicity was 1000 mg/kg/day. There was no adverse effect of treatment at any dose level, the detailed behavioral assessments were unaffected and there were no adverse histopathological findings.
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