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46665001.der.pdf
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46665001
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Methyl bromide
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74-83-9
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053201
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Beck, M. (2005) An Inhalation Developmental Neurotoxicity Study of Methyl Bromide in Rats: Final Report. Project Number: WIL/186039, WIL/186039M, WIL/186039F. Unpublished study prepared by WIL Research Laboratories, Inc. 2909 p.
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2005.0
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Methyl bromide: In a developmental neurotoxicity study (MRID 46665001), Methyl bromide (99.9% a.i., lot # 4010PI136V) was administered by whole-body inhalation daily (6hrs/day) to 24 mated female Crl:CD®(SD)IGS BR rats/group at nominal concentrations of 0, 5, 25, or 50 ppm from gestation day (GD) 6-20. Females and their pups were also exposed 6 hours/day on lactation days (LDs) 5-20 to the same concentrations of methyl bromide. A Functional Observational Battery (FOB) was conducted on 12 dams/group on GDs 6 and 13 and LDs 10 and 21. On postnatal day (PND) 4, litters were standardized to eight pups; sexes were represented as equally as possible. Pups were weaned from their dam on PND 21. Dams were sacrificed after weaning. Twenty pups/sex/group were selected for FOB, acoustic startle response, locomotor activity as well as learning and memory assessments (different animals used for each L&M testing on PND 26 and 62) while 15 pups/sex/group were assigned to neuropathological, morphometric, and brain weight evaluations on PND 21 and 72. Pup physical development was evaluated by body weight. The age of sexual maturation (vaginal opening in females and preputial separation in males) was assessed.
One control female was sacrificed on gestation day 23 because of dystocia. All remaining animals survived to scheduled sacrifice. No clinical signs of toxicity were observed during the daily examinations, midway through the exposure (i.e., 3 hours. of exposure) or 1-2 hours post-exposure. No treatment-related changes were noted during the FOB on any testing day. Maternal body weight and food consumption were not affected by treatment at any time during the study. No treatment-related effects were observed in reproductive parameters and gross necropsy was unremarkable.
No treatment-related effect on the mean number of pups born, mean live litter size, percentage of males per litter, or pup survival was observed. No treatment-related abnormalities were noted post-weaning during weekly physical examination.
Pup body weight was similar between the treated and control groups on PNDs 1-11. However, on PNDs 13-21 pup weight was significantly decreased in females (↓8-10%, p ≤ 0.05 or 0.01) and slightly (n.s.) or significantly decreased males (↓6-8%) at the 50 ppm concentration. Mean body weight gain was also significantly decreased at this concentration in females on PNDs 7-17 (↓11-18%, p ≤ 0.05 or 0.01) and PND 4-21 (↓9%) as well as males on PND 13-17 (↓17%, p ≤ 0.01). Reduced body weight gain (≈↓13%) was also noted in males and females at the 25 ppm exposure level group during the PND 13-17 interval only. Post-weaning, absolute body weight at 50 ppm was significantly decreased through PND 56 for males (↓5-8%, p ≤ 0.05 or 0.01) and PND 42 for females (↓5-9%). Thereafter until study termination on PND 72, body weight was comparable between the treated and control groups in both sexes. Weight gain by the high-concentration males and females was significantly (p ≤ 0.01) lower than controls during the PND 28-35 interval. Body weight gain was similar between the treated and control groups for all intervals after PND 35. At the highest concentration tested, preputial separation was significantly (p ≤ 0.05) delayed by 1.4 days while vaginal opening was delayed by 1.6 days (p ≤ 0.01). Body weight in the treated males and females was similar to that of the control group at the time of acquisition.
No treatment-related FOB changes were observed in males or females on any testing day. Auditory startle response and learning and memory were not affected by treatment. No statistically significant difference in total activity or ambulatory activity was found between the treated and control groups on any testing day. On PND21, however, total and ambulatory activity were decreased in males and females at concentrations ≥ 25 ppm exposure. In these treated groups, the level of activity was reduced throughout the testing interval although the pattern of habituation was not affected.
Effects occurring on PND21 only at the 50 ppm concentration included: (i) decreased brain width (↓3%, males only), (ii) decreased brain weights (↓4-5%, both genders), and (iii) decreased length of the ventral limb dentate hilus (↓8%, females only). On PND72, a statistically significant increase in the base of lobule 9 (↑8%, p<0.05) was noted in males only at 50 ppm.
The maternal LOAEL for methyl bromide in rats is not identified and the maternal NOAEL is ≥ 50 ppm.
The offspring LOAEL for methyl bromide in rats is 25 ppm based on decreased motor activity on PND21. The offspring NOAEL is 5 ppm.
This study is classified Acceptable/Non-Guideline and does not satisfy the guideline requirement for a developmental neurotoxicity study in rats (OPPTS 870.6300, §83-6); OECD 426. It is noted that adequate positive control studies have been submitted to demonstrate proficiency of the testing facility only for FOB, motor activity, and auditory startle tests in young adult rats. Adequate positive control data have not been submitted for learning and memory, neuropathology or morphometrics. Another deficiency is the lack of morphometric assessments of the base of lobule 9 and length of the ventral limb dentate gyrus given the statistically significant changes (~8%, p < 0.05) observed in these two brain regions at the low- and mid-dose.
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Developmental-Neurotoxicity
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NA [870.6300, Developmental neurotoxicity study]
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Inhalation
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Treatment Range: 6 (GD)-20 (GD) Days;Whole-body exposure; 6 hours/day
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54629.0
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2019-10-04
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2019-10-10
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Added by
Madison Feshuk
on Apr 25, 2022
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