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46214501.DER.pdf
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46214501
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Dimethoate
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60-51-5
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035001
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Myers, D. (2004) Dimethoate Cross Fostering Study in CD Rats. Project Number: CHV/089/033185. Unpublished study prepared by Huntingdon Life Sciences, Ltd. 451 p.
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2004.0
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In a non-guideline cross fostering study (MRID 46214501), Dimethoate (99.1% a.i., batch # 20522-00) was administered by gavage to mated female Crl:CD®BR rats from gestation day (GD) 6 to post-natal day (PND) 10 at doses of 0 (100 dams), 3 mg/kg/day (25 dams) or 6 mg/kg/day (50 dams). Maternal animals were evaluated for mortality, clinical signs, body weight and body weight gain and reproductive parameters. A neurobehavioral screening in the hand and in the arena was conducted on GDs 12 and 18 and on PNDs 4 and 10. The maternal animals rearing a litter were sacrificed on PND 11 and subjected to gross necropsy. On PND 1 (approximately 6 hours after completion of parturition), approximately 50% of the control group litters containing 12 or more pups were cross fostered with dams treated at 3 or 6 mg/kg/day dimethoate (groups 1A and 1B, respectively). Approximately 25% of the litters were reared by their own control group dams (group 1C); the remainder of the dams were sacrificed and discarded without examination. Pups were not directly treated with dimethoate. All litters containing 12 or more pups from dams treated at 3 mg/kg/day dimethoate were cross fostered with control dams (group 2). In the 6 mg/kg/day group, approximately 50% of the litters containing 12 or more pups were cross fostered with control dams (group 3A); the remainder of the litters remained with the treated dams (group 3B). The target group size for cross fostering of at least 20 was achieved. Pup body weight and clinical observation data were recorded. Neurobehavioral screening including surface righting reflex, activity count and maximum pivoting angle was conducted on one male and one female offspring per litter per group on PNDs 4 and 10. Hematology and clinical chemistry parameters were assessed for 10 pups/sex/group. Offspring were sacrificed and necropsied on PND 11.
One dam at 6 mg/kg/day died on GD 16. Maternal clinical observations revealed an increase in the number of dams at 6 mg/kg/day which had hair loss on one or both forelimbs. There were no treatment-related effects on body weight and body weight gain during gestation. During lactation, minimal (9-13%) decreases in body weight gain were observed in dams treated postpartum with 3 and 6 mg/kg/day, and were considered only marginally adverse. The only effect of dimethoate treatment on reproductive performance appeared to be a higher proportion of 3 and 6 mg/kg/day dams with restlessness and scattering of their litters. Neurobehavioral assessments of dams did not identify any treatment-related effects.
An observed treatment-related increase in the number of pups with no milk in the stomach was observed at 3 and 6 mg/kg/day. Pup mortality was significantly increased early after cross-fostering (day 1-4) in groups 1B and 3B. However, pup mortality increased again from post-natal days 4-11 in groups 1A, 2, 3A, and 3B, suggesting that pup mortality was increased regardless of pre- or post-natal exposure to 3 or 6 mg/kg/day dimethoate. The incidence of total pup death (pre- plus postnatal) increased with a positive correlation to dose level and to the duration of treatment to the dams. Postnatal deaths appeared to be correlated to some extent with the incidences of maternal restlessness and litter scattering for groups 2, 3A, and 3B; however, these maternal behaviors were not the sole cause of pup mortality. Rather, a combination of pre and postnatal toxicity to pups and/or dams appears to have contributed to observed pup mortality. This study was not designed to distinguish between the maternal and offspring components of postnatal toxicity and mortality.
PND 1-11 pup body weight and body weight gain were decreased for groups treated postnatally with 6 mg/kg/day. Offspring neurobehavioral testing identified a delay in the PND 10 surface righting reflex of pups treated postnatally with 6 mg/kg/day. Treatment-related alterations in hematology measures included increased mean hematocrit and MCV levels, decreased mean MCHC values, and increased mean neutrophil and monocyte counts at 6 mg/kg/day. Clinical chemistry findings included significant treatment-related increases in mean urea at 3 mg/kg/day(both sexes combined) and 6 mg/kg/day (males and females analyzed separately), and significant decreases in mean creatine phosphokinase levels (both sexes combined and females analyzed separately) for pups treated both pre- and post-natally with 6 mg/kg/day. Necropsy findings of pups that survived to termination on PND 11 were unremarkable and unrelated to treatment. At 3 and 6 mg/kg/day, there were an increased number of pups that died or were sacrificed for humane reasons prior to study termination and that were found to have no milk in the stomach.
The maternal toxicity LOAEL for dimethoate in rats is 3 mg/kg/day based on clinical observations of forelimb hairloss, marginal reductions in body weight gain, and increased incidences of restlessness and scattering of pups. The maternal toxicity NOAEL was not identified.
The offspring toxicity LOAEL for dimethoate in rats is 3 mg/kg/day based on reduced milk consumption, increased levels of urea in the blood, and increased mortality. The offspring NOAEL was not identified. While maternal toxicity appeared to be associated with the decreased postnatal survival in this study, direct pre- and postnatal toxicity of the offspring to dimethoate could not be disregarded as significant contributing factors to overall offspring mortality.
This study is classified Acceptable/Non-guideline; it was designed to assess the effect of maternal exposure to dimethoate during gestation and the post-natal period on offspring mortality.
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Other
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NA [870.6300, Developmental neurotoxicity study]
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Oral
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No Duration Period; From GD 6 to PND 10
Cross fostering study
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52452.0
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2004-07-08
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2004-09-14
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Added by
Madison Feshuk
on Apr 25, 2022
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