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46205301.DER.pdf
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46205301
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Trichlorfon
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52-68-6
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057901
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Sheets, L.; Hastings, T. (2003) A Developmental Neurotoxicity Screening Study with Technical Grade Trichlorfon (Dylox) in Wistar Rats. Project Number: 01/D72/CT. Unpublished study prepared by Bayer Corp. 1150 p.
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2003.0
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In a developmental neurotoxicity study (MRID 46205301) Dylox® Technical (Trichlorphon; 100.0-100.4% a.i.; Batch #: 103-0228) was administered in the diet to pregnant Crl:WI (Glx/BRL/Han) IGS BR rats (30/dose) at doses of 0, 150, 500 or 1750 ppm (equivalent to 0, 13.4, 49.0, and 145.6 mg/kg/day during gestation and 0, 33.1, 103.4, and 264.6 mg/kg/day during lactation) from gestation day (GD) 0 through lactation day (LD) 21. Dams were allowed to deliver naturally. All surviving dams were sacrificed on LD 21 (weaning). The P females that did not deliver a litter were sacrificed on GD 24. Brain and blood cholinesterase activity were determined in the dams (6-9/dose) on LD 21, in the pups culled on post-natal day (PND) 4 (representing as many litters as possible), and in the Subset D pups (5-10 pups/sex/dose, representing 15-20 litters) on PND 21. The remaining pups and dams not selected for further evaluations were sacrificed and discarded without further examination. On PND 4, 15-23 litters/dose were standardized (6-8 pups/litter with approximately equal numbers of males and females) to reduce variation. Subsequently, 1-2 pups/litter/dose were allocated to Subsets A-D for examinations of detailed clinical signs and functional observational battery, motor activity, auditory startle habituation, passive avoidance and water maze learning and memory tests, brain weight and measurements, ophthalmology, neuropathology, and/or brain and blood cholinesterase determinations. Select offspring were sacrificed at PND 21 for brain weights and measurements and neuropathology, and the remaining offspring were sacrificed at PND 75 (±5 days). Satisfactory positive control data were provided, but the lab proficiency was not demonstrated for the various behavioral tests.
Maternal Toxicity
There were no clinical signs of toxicity in any treated female. Two females in the 1750 ppm dose were found dead one each on Lactation Day (LD) 10 and 20 and another was sacrificed at LD 20 after the last of her pups was found dead, without clinical signs of toxicity or injury. There were no treatment-related FOB findings recorded during gestation or lactation. The fertility index was decreased (not statistically significant) at 500 (decr. 7%) and 1750 (decr. 10%) ppm. These values were within the range of controls in other studies. The mating index was 100% for all dose groups.
Compound related effects in the parental females were death at the high dose and reduction in cholinesterase activity (p<=0.05) in a dose-related manner as follows: (i) in plasma by 43-55% at >= 500 ppm; (ii) in erythrocytes by 26-71% in all treated groups; and (iii) in brain by 16-72% in all treated groups. Other treatment related effects were decreased body weight (decr. 7%; p<=0.05) and body weight gain (decr. 53% ) in the 1750 ppm females during lactation.
The LOAEL for maternal systemic toxicity is 150 ppm (13.4 mg/kg/day; LDT) based on the inhibition of red blood cell cholinesterase activity. A NOAEL for maternal systemic toxicity is not established.
Offspring
Litter data were not summarized adequately in the study report and no conclusions can be made regarding the pup mortality and survival. No treatment-related clinical signs were reported at any dose.
Body weight and weight gain of pups were significantly decreased at the mid (8%) and high dose (37%) by PND 21, but not at the low dose. Cumulative body weight gains (PNDs 0-4 and 4-21) were decreased (p<=0.01) by 31-43% in the 1750 ppm group. Cumulative body weight gains (PNDs 4-21) were decreased (p<=0.05) by 8-9% in the 500 ppm group. Gradual recovery of body weights occurred during the post weaning period.
Sexual maturation (prepuptial separation and vaginal patency) was delayed by 4-6% (p<=0.05) in the 1750 ppm group, but this effect may have been related to decreased growth. Body weight was decreased (p<=0.01) by 9-10% at sexual maturation in these animals. Pupil constriction was evident in all control and treated pups at PND 21. Ophthalmology examination revealed no treatment-related effects.
No treatment-related effects were observed during the functional observational battery. Increased motor and locomotor activity was seen in the high dose group offspring males and females on PND 17. Habituation was unaffected by treatment. Decreased (p<=0.05) maximum amplitude of the auditory startle reflex was observed in all blocks at PND 22 in the 1750 ppm group (decr. 50-63%). Decreased (p<=0.05) amplitude was also observed in 1 or 2 blocks in the 150 and 500 ppm groups (decr. 27-34%) at PND 22. Total amplitude at PND 22 decreased dose-dependently in both sexes (decr. 19-61%). Incidental decreases (p<=0.05) were observed in all treated females in 1 or 2 blocks at PND 38, and these effects were unrelated to dose. Habituation was demonstrated and was unaffected by treatment. In the passive avoidance test, a statistically significant decrease (decr. 17%; p<=0.05) in the latency period of Trial 1 in the Retention session was observed in males at the highest dose on PND 29. In the water maze test, there was a minor increase in errors in the 1750 ppm females at PNDs 58-62 during trial 2 of the learning phase (0.9 treated vs 0.2 controls).
Terminal body weights were decreased (p<=0.05) in the 1750 ppm males and females (decr. 29-42%) and in the 500 ppm females (decr. 13%, perfused only) at PND 21, and in the 1750 ppm males (decr. 9-11%) on PND 75. Absolute brain weights (perfused or non-perfused) were 7-18% significantly (p<0.05) less than in the controls in the 1750 ppm male and female pups sacrificed on PND 21. Absolute brain weight of the other groups were unaffected. At study termination, the absolute non-perfused brain and cerebullum [cerebellum] weights were decreased (p<0.05) by 18% and 13% respectively in the 1750 ppm group male pups and cerebellum length was decreased 7% in the 1750 ppm males at study termination.
Macroscopic neuropathological examination revealed no treatment-related gross pathological findings in any treated group at either PND 21 or 75 (±5 days). Microscopic neuropathological examination revealed no treatment-related effects on histopathology findings or linear brain measurements in any treated group at either PND 21 or 75. Various lesions were observed, but the incidence was minor, such as (n=10) minimal perivascular cuffing in the lumbar spinal cord in one 1750 ppm perfused female at ~PND 70 (vs 0 controls), hydrocephalus and brain atrophy in one 150 ppm female at ~PND 70 (vs 0 controls).
At 1750 ppm, plasma and erythrocyte cholinesterase levels were decreased (p<=0.05) by 25% and 28%, respectively, in the pooled male and female samples at PND 4. On PND 21, plasma and brain cholinesterase levels were decreased (p<=0.05) in both sexes by 29-39% and 16-23%, respectively. Additionally on PND 21, decreases (p<=0.05) were also observed in brain cholinesterase levels in the 500 ppm males (decr. 7%) and the 150 and 500 ppm females (decr. 7-11%). However the decrease in the brain ChE activity level in the 150 ppm female pups was attributed to the unusually high control levels and thus not considered to be treatment related.
The LOAEL for the offspring toxicity is 150 ppm (13.4 mg/kg/day) based on decreased startle amplitude in males and females on PND 22. An offspring NOAEL is not established.
This study is classified Acceptable/Non Guideline and may be used for regulatory purposes, however it does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426 (draft) at this time pending a comprehensive review of all available positive control data.
[Note - This classification scheme is applicable only to Developmental Neurotoxicity (DNT) studies. The DNT Work Group determined that this study can be classified as Acceptable. This study does not satisfy the guideline requirements for a developmental neurotoxicity study and is classified as NonGuideline pending review of all available positive control data. Jess Rowland, 07/26/2005]
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; GD 0 to LD 21
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52426.0
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2005-07-26
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2005-08-16
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Added by
Madison Feshuk
on Apr 25, 2022
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