The threshold of toxicological concern for prenatal developmental toxicity.
The Threshold Toxicological Concern (TTC) is based on the concept that reasonable assurance of safety can be given if exposure is sufficiently low. Originally based on the evaluation of carcinogenicity studies more recently TTC evaluations for other toxicological end points have been published. Here we report on the evaluation of our data base for oral developmental toxicity studies (OECD 414) in rats with 92 and 93 NOAEL values for maternal and developmental toxicity, respectively. The 5th percentile of the NOAEL distributions were calculated to be 4 mg/kg bw/d for maternal and 5mg/kg bw/d for developmental toxicity. Adding the data for developmental toxicity provided by Kroes et al. (2004), a joint evaluation of 111 individual NOAEL values resulted in a 5th percentile value of 4 mg/kg bw/d. Using a safety factor of 500 (to account for a possible underrepresentation of chemical classes) on the 5th percentile a TTC value for developmental toxicity of 8 μg/kg bw/d based on the combined data and for maternal toxicity of 8 μg/kg bw/d based on our data base was calculated. Within the REACH context this value may serve as guidance whether to perform an animal experiment or to rely on a TTC value if estimated exposure is sufficiently low.
van Ravenzwaay
B
B
BASF SE, Experimental Toxicology and Ecology, Z 470, D-67056 Ludwigshafen, Germany. bennard.ravenzwaay@basf.com
Dammann
M
M
Buesen
R
R
Schneider
S
S
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000284:Administration, Oral; D000818:Animals; D003663:Decision Trees; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D047109:Fetal Development / Q000187:drug effects*; D005865:Gestational Age; D018811:Maternal Exposure; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D018570:Risk Assessment; D013329:Structure-Activity Relationship; D018675:Toxicity Tests