Developmental neurotoxicity (DNT) studies are designed to investigate whether pre- or post-natal exposure to a toxicant affects neural development. Imidacloprid was administered in the diet to mated Sprague Dawley rats. The females were treated from gestation day 0 to 20 and then continued through the lactation day 21 at doses of 0, 100, 250 and 750 ppm, corresponding to an average daily intake of 0, 8, 19 and 54.7 mg/kg/day during gestation. The pups were indirectly exposed to imidacloprid for a total of 41 days (20 days in utero and 21 days via lactation). After weaning on postnatal day 21 pups were given untreated feed.
Brain tissue from 10 pups/sex/group were analyzed on postnatal days 11 and 75. On post-natal day 11, female pups from the 750 ppm group had a decreased caudate putamen width and a substantial reduction in the thickness of the corpus callosum. Morphometric brain measurements were not performed in the intermediate and low dose groups.
The No-Observed-Effect-Level (NOEL) was estimated to be 5.5 mg/kg/day by applying a default factor of 10 to the observed effect level of 54.7 mg/kg/day. Because decreases in brain structures could theoretically result from a single exposure in utero, the estimated NOEL of 5.5 mg/kg/day could be used to estimate the risk of acute exposure to imidacloprid in women of childbearing age.
The US reviewers determined that "Developmental toxicity No-Observed-Effect-Level (NOEL) cannot be determined because intermediate groups were not evaluated in the presence of a conspicuous change in 750 ppm in morphometric measurements" and that "Study is not acceptable and appears not be upgradeable. The apparent corpus callosum change in 750 ppm females at postnatal day 11 indicates a need to analyze intermediate groups".
The Chief of the California Office of Environmental Health Hazard Assessment (OEHHA) reviewing this risk assessment stated (memorandum dated September 30, 2005): "If an acute regulatory value of 5.5 mg/kg were adopted, margins of exposure (MOEs) ... for acute dietary exposures (99th percentile point estimates, tier 2) would range from 71 for children 1-2 years of age to 239 for females 13-39 years of age. The MOE for children would, therefore, reflect an exposure level of concern for this population subgroup".
MOE is a quotient of the NOEL and the exposure level. A MOE of 100 was generally considered prudent for protection of humans against imidacloprid toxicity.
In a memorandum dated February 9, 2006, the Chief of the California Department of Pesticide Regulation, replied " the estimated NOEL was used to estimate only the acute MOEs for women of childbearing age. These MOEs were 366 and 239 at the 95th and 99th percentiles, respectively; and thus exceeded the general health protective benchmark MOE of 100".
Source: California Environmental Protection Agency - Imidacloprid Risk Characterization Document, February 9, 2006 (attached)
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