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43829601.DER.pdf
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43829601
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Aldicarb
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116-06-3
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098301
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Weiler, M. (1995) Developmental Neurotoxicity Study with Aldicarb in Rats: Final Report: Lab Project Number: HWI 6224-213. Unpublished study prepared by Hazleton Wisconsin, Inc. 891 p.
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1995.0
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Aldicarb: In a developmental neurotoxicity study [MRID 43829601] groups of 30 presumed pregnant Sprague-Dawley (Crl: CD® BR VAF/Plus®) rats were administered Aldicarb [98.9%] by gavage at doses of 0, 0.05, 0.10, or 0.30 mg/kg/day on gestation day (GD) 6 through lactation day 10. The offspring were not administered the test material. Clinical observations, a functional observational battery (FOB), body weights, and reproductive data were recorded for the dams (F0). Pups (F1) were weighed, monitored for emergence of vaginal perforation or balanopreputial separation, observed until approximately postnatal day 65, and given neurobehavioral evaluations (FOB, motor activity, learning and memory test, auditory startle response). Plasma, red blood cell, and brain cholinesterase (ChE) activities were measured in both dams and pups. Neuropathological assessment of high dose and control pups were made on day 11 and day 65.
On treatment days, tremors were observed in as many as 11 and as few as 1 F0 dams given 0.3 mg/kg. Clinical signs seen in the FOB on gestation day 6 (GD6) in 0.3 mg/kg/day dams, were tremor (10/10), lacrimation (7/10), salivation (6/10), stained fur (7/10), hunched posture (4/10), ataxia (9/10), lip smacking (4/10), decreased body temperature and miosis (10/10). The mean number of rears was also reduced (p ¿ 0.05) in high dose dams (0.6) as compared to controls (7.9). During lactation, tremors or a few other signs were observed on days 0-2 in a few 0.3 mg/kg dams only. Clinical signs or changes in the FOB were not observed in any other dose group or the controls.
Mean maternal body weights of the 0.3 mg/kg/day group were significantly less (6%) than the controls beginning on GD 9 and continuing until GD20. Overall body weight gain during gestation was also significantly less in the 0.30 mg/kg/day dams (17%) in comparison to controls. During lactation, body weights of these dams were significantly (p ¿ 0.05) less than controls only on day 4. Recovery was evident in high-dose dams after cessation of treatment with day 21 body weights 100% of the control value. No differences were seen between body weights or in body weight gains of the 0.05 or 0.10 mg/kg/day groups during gestation or lactation.
Mean maternal plasma ChE (ca 80%) and red blood cell ChE (27%) activities were significantly reduced in 0.3 mg/kg dams on GD 7 and lactation day 7 as compared to controls. On GD 7, plasma ChE inhibition in 0.1 mg/kg dams was 40%, (not statistically significant), but much less later. No inhibition of ChE was seen in the brains of dams tested on lactation day 11 or in the plasma, red blood cell, or brain activity of the F1 males or females tested on lactation days 4, 10, or 11. In many cases, less than 5 rats were used, limiting the power or sensitivity of these measures.
No statistically significant effects were observed on duration of gestation, total number of pups delivered, pup survival indices, or per cent male pups. There were no differences between treated and control groups in the emergence of balanopreputial separation or vaginal perforation.
A few treatment related effects on FOB measures and motor activity changes were observed in the 0.1 or 0.3 mg/kg pups during lactation and post-weaning. Motor activity was significantly decreased, about 30%, in both 0.1 and 0.3 mg/kg males on day 17. A 29% decrease was also seen in the 0.05 mg/kg group, but it did not reach statistical significance. No differences in motor activity were seen on days 13 and 21. There is normally, and, here in control animals, an increase in motor activity on day 17 in relation to either day 13 or day 21. Dosed males showed reduced or absent increases on day 17 in relation to days 13 or 21. At day 60, motor activity was significantly increased in the 0.1 mg/kg males for the whole session (20%) and 30% for the 10-20 minute interval. For the 0.3mg/kg males overall activity was not significantly different (14% increase) but for the 10-20 min interval a significant 34% increase was seen.
FOB observations were made on F1 animals on postnatal days 14, 21, 35 and 63. On days 35 and 63 high-dose F1 males made significantly fewer rears (and fecal boli) in the open field. Number of rears were also reduced in high-dose females at day 35. Decreased hindlimb grip strength (20%) and splay (15%) were also found in mid and high dose females on Day 35.
On day 63, high dose males had increased latency to first step (12/20 waiting 9 seconds vs 3/20 controls); significantly reduced forelimb grip strength (20%); and an increased latency on the first trial (15 vs 10 secs), but not the second trial or average latency, to a heat stimulus. No consistent effects attributable to treatment were seen on startle reflexes and no differences found on speed or errors in the learning and memory test. In summary, while many of these measures are isolated, there do appear to be a number of significant differences noted in high dose males at all time points.
Pup body weights adjusted for litter size from high-dose dams were significantly lower than controls on lactation days 0 (8%), 4 (11-13%), and 7 (males and females), lactation day 11 (males), and lactation day 17 (females). Male and female pups from 0.1 mg/kg/day dams also had significantly lower body weights than controls on lactation days 7 and 17, 8% and 6%, respectively. Adjusted body weights from the mid- and high-dose dams were not significantly different by lactation day 21, where adjusted pup body weights were 95 and 93%, respectively, for males and 95 and 94%, respectively, for females of the corresponding control value. However, unadjusted mean body weights of these F1 male and female rats earlier given 0.1 and 0.3 mg/kg/day were still depressed consistently throughout the post-weaning period. Significant differences occurred at weeks 0, 2, and 4 for the mid- and high-dose males (6-8%; 10-15%) and high-dose females (13-7%), and at week 2 for the mid-dose females (4%). Body weight gain for 4 weeks after weaning was significantly less than controls for the mid- and high-dose males (ca 8%) but no differences in weight gains were seen in females.
Gross necropsies, brain weights and histological evaluations of the nervous system did not reveal aldicarb related effects. No significant treatment related changes in brain morphometric measurements on day 60 were noted.
Maternal toxicity at 0.30 mg/kg/day included clinical signs of toxicity such as tremor, salivation, and lacrimation, blood ChE inhibition, and 17% reduced body weight gain during gestation.
The maternal LOAEL is 0.10 mg/kg/day based on plasma ChEI of 40% on GD 7.
The maternal NOAEL is 0.05 mg/kg/day.
The offspring LOAEL is 0.10 mg/kg/day based on reduced body weights from birth through postweaning, and on decreased motor activity on day 17 in male pups.
The offspring NOAEL is 0.05 mg/kg/day.
While additional data on positive controls and morphometric data should be provided, this developmental neurotoxicity study in the rat is currently acceptable/nonguideline and satisfies the guideline requirement for a developmental neurotoxicity study (83-6; OPPTS 870.6300) in rats.
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Developmental-Neurotoxicity
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NA [83-6, Developmental Neurotoxicity]
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Oral
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No Duration Period; GD 6 to LD 10
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14218.0
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2007-10-16
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2021-02-17
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Added by
Madison Feshuk
on Apr 25, 2022
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