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43883914.DER.pdf
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43883914
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Neodecanamide, N-methyl-
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105726-67-8
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079052
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Hoberman, A. (1993) Developmental Toxicity (Embryo-Fetal Toxicity and Teratogenic Potential) Study Including a Developmental Neurotoxicity Evaluation of Sample No.38674 Administered Orally via Gavage to Crl:CD BR VAF/Plus Presumed Pregnant Rats: Final Report: Lab Project Number: 403-007: 91-03: 91-003. Unpublished study prepared by Argus Research Labs, Inc. 1110 p.
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1993.0
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In a combined developmental toxicity (embryofetal toxicity and teratogenic potential) and developmental neurotoxicity study (MRID 43883914), N-methylneodecanamide (lot number 21709-17, 95.9% a.i.) was administered via gavage to 50 female Crl:CD BR VAF/Plus (Sprague-Dawley®) rats/dose at levels of 0, 40, 125, or 400 mg/kg/day on days 6 through 15 of presumed gestation for developmental toxicity evaluations (25 rats/sex/dose) or on days 6 of presumed gestation through day 11 of lactation (postpartum) for developmental neurotoxicity evaluations (25 rats/sex/dose). As requested by OPPTS, this DER addresses both the developmental toxicity and developmental neurotoxicity components of this study (§83-3, §83-6).
Dams in the 400 mg/kg/day dose group exhibited treatment-related mortality, increases (p=<0.01) in the incidence of clinical signs of toxicity (excess salivation, rales, ataxia, urine stained fur and decreased motor activity), reductions in the mean body weights on gestation days 9-16 (3.1-5.0%, p=<0.01 or 0.05), a 20.9% decrease (p=<0.01) in body weight gain for gestational days 6-16 (body weight gain increased over days 0-22 of lactation), decreases in feed consumption during gestation days 6-20 (13.7%, p=<0.01) and 0-20 (8.2-8.8%, p=<0.05) and days 8-12 of lactation (8.2%, p=<0.01).
At the 125 mg/kg/day dose level, maternal toxicity was characterized by treatment-related clinical signs (excessive salivation and rales) and slight (1.3%), but statistically significant (p=<0.01) reductions in feed consumption during the common treatment interval (days 6-9 of gestation).
Developmental toxicity was noted by a 4.6% statistically significant reduction in mean body weights in caesarean-derived male fetuses from dams administered 400 mg/kg/day test article from days 6-15 of gestation, a 7.3-11.7% statistically significant reduction in mean body weights in the naturally delivered F1 generation pups on days 5-22 of lactation and a 13.2% increase in brain/body weights on day 12 postpartum from dams administered 400 mg/kg/day test article from day 6 of gestation through day 11 of lactation (postpartum). The reduced body weights were greater in males than females. Although the lactational body weights were combined, the post-weaning body weights were especially depressed in the high dose males. These pup body weight effects persisted long after the treatment was discontinued in the dams, although feed consumption in all dose groups was comparable to the controls during post-weaning.
Neurotoxicity was suggested by minimally, but statistically significant affected motor activity on day 18 postpartum in male pups from dams administered 400 mg/kg/day test article from day 6 of gestation through day 11 of lactation (3/18 blocks for number of and 2/18 blocks for time spent in movement). In addition at day 18 postpartum, in all 18 blocks for males and in 14 of 18 blocks for females, time and number of movements were increased in the high-dose as compared to the controls, although the differences were statistically significant only at the blocks noted above for males. On day 14, the time and number of movements were increased for females at all dose levels compared to the controls; the differences were not statistically significant. Motor activity measurements at days 22 and 61 were comparable to the controls at all dose levels. The increases in motor activity at days 14 and 18 are considered transient indications of neurotoxicity.
The maternal LOAEL is 125 mg/kg/day, based on clinical signs of toxicity (including salivation, rales, ataxia, urine stained fur and decreased motor activity) and reduced mean feed consumption values. The maternal NOAEL is 40 mg/kg/day.
The developmental LOAEL is 400 mg/kg/day, based on reduced c-section-derived male fetuses, reduced pup weights (both sexes) during days 5-22 postpartum and in males on days 1-22, post-weaning. The developmental NOAEL is 125 mg/kg/day.
The developmental neurotoxicity LOAEL is 400 mg/kg/day, based on increases in motor activity measurements, only in male pups (only on day 18). Effects were transient and did not persist after dosing ceased after day 22 postpartum. The neurotoxicity NOAEL is 125 mg/kg/day.
This developmental toxicity/neurotoxicity study in the rat is classified Acceptable (guideline) and does satisfy the guideline requirement for a developmental toxicity/neurotoxicity study (OPPTS 870.3800, §83-3 (a) and §83-6) in the rat. [Note: OPP §83-3; OPPTS 870.3700 and OPP § 83-6; OPPTS 870.6300] However the registrant should 1) explain the discrepancy between the purity listed in this MRID (95.9%) as compared to that listed for this study in MRID 44211902 (95.8%) and the reproduction study with the same lot (96.08%) and 2) provide acceptable analytical data to confirm the purity of the test material and the actual concentrations of the dosing formulations.
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Developmental
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NA [83-3, Teratogenicity -- 2 Species|83-4, 2-generation repro.-rat|83-6, Developmental Neurotoxicity]
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Oral
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Treatment Range: 6 to 15 Gestation Days; also groups treated GD6-LD11
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12987.0
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1998-11-24
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2021-04-21
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Added by
Madison Feshuk
on Apr 25, 2022
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