title: Internal threshold of toxicological concern values: enabling route-to-route extrapolation.
abstract: The TTC concept uses toxicological data from animal testing to derive generic human exposure threshold values (TTC values), below which the risk of adverse effects on human health is considered to be low. It uses distributions of no-observed-adverse-effect levels (NOAELs) for substances. The 5th percentile value is divided by an uncertainty factor (100) to give a TTC value. As the toxicological data underpinning the TTC concept are from tests with oral exposure, the exposure is to be understood as an external oral exposure. For risk assessment of substances with a low absorption (by the oral route, or through skin), the internal exposure is more relevant than the external exposure. European legislation allows that tests might not be necessary for substances with negligible absorption with low internal exposure. The aim of this work is to derive internal TTC values to allow the TTC concept to be applied to situations of low internal exposure. The external NOAEL of each chemical of three databases (Munro, ELINCS, Food Contact Materials) was multiplied by the bioavailability of the individual chemical. Oral bioavailability was predicted using an in silico prediction tool (ACD Percepta). After applying a reduced uncertainty factor of 25, we derived internal TTC values. For Cramer class I, the internal TTC values are 6.9 μg/kg bw/d (90 % confidence interval: 3.8-11.5 mg/kg bw/d); for Cramer class II/III 0.1 μg/kg bw/d (90 % confidence interval: 0.08-0.14 μg/kg bw/d).
authors.affiliation: Institute for Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin, Berlin, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Partosch
authors.forename: Hans
authors.initials: H
authors.lastname: Mielke
authors.forename: Ralf
authors.initials: R
authors.lastname: Stahlmann
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.forename: Susan
authors.initials: S
authors.lastname: Barlow
authors.forename: Ursula
authors.initials: U
authors.lastname: Gundert-Remy
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D016208:Databases, Factual; D005060:Europe; D033161:Government Regulation; D019055:No-Observed-Adverse-Effect Level; D012016:Reference Values; D018570:Risk Assessment; D020711:Threshold Limit Values; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards; D015262:Xenobiotics / Q000145:classification / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D015262:Xenobiotics