The threshold of toxicological concern for prenatal developmental toxicity in rabbits and a comparison to TTC values in rats.
The Threshold Toxicological Concern (TTC) is based on the concept that reasonable assurance of safety can be given if exposure is sufficiently low. We report on the evaluation of BASF's data for oral developmental toxicity studies in rabbits with 48 NOAEL values for maternal and developmental toxicity. The 5th percentile of the NOAEL distributions was calculated to be 5mg/kgbw/d for both maternal and developmental toxicity. From literature 56 compounds tested in rabbits were taken and combined with values from BASF's studies. The 5th percentile value for developmental toxicity of these 104 studies (mostly active ingredients) was 2mg/kgbw/d. Thus, a TTC value of 4μg/kgbw/d was calculated using a safety factor of 500 to account for relatively small database. This value is in the same range as the TTC value for developmental toxicity in rats of 8μg/kgbw/d. The lower value may serve as guidance to determine whether further evaluation is needed or whether to rely on a TTC value for industrial chemicals or low concentration (environmental) contaminants if exposure is sufficiently low. A comparison of 30 compounds tested at BASF in both species, suggests that rabbits are not more sensitive than rats. We encourage others to publish data on rabbit developmental toxicity.
BASF SE, Experimental Toxicology and Ecology, Z 470, D-67056 Ludwigshafen, Germany. bennard.ravenzwaay@basf.com
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van Ravenzwaay
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Dammann
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Buesen
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Flick
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Schneider
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D047109:Fetal Development / Q000187:drug effects*; D018811:Maternal Exposure / Q000009:adverse effects*; D019055:No-Observed-Adverse-Effect Level; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D013723:Teratogens / Q000145:classification / Q000633:toxicity*; D018675:Toxicity Tests; D015262:Xenobiotics / Q000145:classification / Q000633:toxicity*
D013723:Teratogens; D015262:Xenobiotics