The threshold of toxicological concern for prenatal developmental toxicity in rabbits and a comparison to TTC values in rats

The Threshold of Toxicological Concern for prenatal developmental toxicity in rats and rabbits

“…The earlier evaluation of our database for prenatal developmental toxicity studies in rabbits following oral exposure (OECD guideline 414) demonstrated a NOAEL for maternal and developmental toxicity in 48 cases (van Ravenzwaay et al, 2012). The 5th percentile for the NOAEL value for maternal effects as well as for developmental effects was 5 mg/kg bw/d.…”

“…We assumed that not all the observed developmental toxicity was related to maternal toxicity, and that consequently a good number of potential modes of action for developmental toxicity were covered. As the reference values used to calculated TTCs in our previous publications (van Ravenzwaay et al, 2011, 2012) were rather similar, but obtained from pesticides, which includes at least some classes of chemistry (e.g. triazoles) with modes of action known to cause selective developmental toxicity, it would seem that at least for pesticides and industrial chemicals there is sufficient data to validate the correctness of the presented values, without a particular risk that certain modes of action with a very high potency would not be covered.…”

Rethinking developmental toxicity testing: Evolution or revolution?

“…The need for additional testing to characterize endpoint specific hazards also can be assessed based on estimated human exposures being below a threshold of toxicological concern (TTC; van Ravenzwaay, ; Kroes et al, ). The TTC method empirically derived a distribution of effect levels for maternal and developmental toxicity for a large number of tested chemicals.…”

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

“…Moving away from the cancer bioassays, analyzing a reference database of more than 600 substances tested in more than 2,900 sub-chronic and chronic toxicity studies, Munro et al (1990Munro et al ( , 1996Munro et al ( , 1999 Cheeseman et al, 1999;Felter et al, 2009;Müller et al, 2006 General toxicity 0.025 -1 (depending on Cramer classes) Munro et al, 1996Munro et al, , 1999 Munro et al, 1996Munro et al, , 1999Escher et al, 2010;Bernauer et al, 2008Genotoxicity 0.025 -2 Rulis 1986, 1989Kroes et al, 2005;Müller et al, 2006 Carcinogenicity (genotoxic) 0.0025 Kroes et al, 2005;Cheeseman et al, 1999 Carcinogenicity (non-genotoxic) 0.025 -0.75 Kroes et al, 2005; (depending on Ames test and acute toxicity) Cheeseman et al, 1999 Acute toxicity (inhalation) 4 -1,000 μg/m 3 Grant et al, 2007;Escher et al, 2010 Neurotoxicity 0.3 Munro andKroes, 1998;Kroes et al, 2000 Developmental toxicity 1 a -8 -131 Munro and Kroes, 1998; (depending on Cramer class) Bernauer et al, 2008;0.5 -1 μg/m 3 (inhalation) van Ravenzwaay et al, 2011;Laufersweiler et al 2012 Reproductive toxicity 1 -100 Bernauer et al, 2008;van Ravenzwaay et al, 2011van Ravenzwaay et al, , 2012van Ravenzwaay et al, , 2017 Estrogenic endocrine disruption 0.025 Kroes et al, 2000 Immunotoxicity 0.15 -1,000 Kroes et al, 2000;Hartung and Corsini, 2013 Skin sensitization (dermal) 0.91 -900 μg/cm 2 Sa...…”

“…Furthermore, using either maternal toxicity data of the same substances or expanding to include the Kroes et al (2005) data, a TTC of 8 μg/kg/day was obtained. The same group (van Ravenzwaay et al, 2012) identified 104 rabbit studies with values for maternal and developmental toxicity (48 from BASF, 56 from literature) using the 5 th percentile for developmental toxicity of these mostly active ingredients, a TTC value of 4 μg/ kg bw/d was calculated using a safety factor of 500 to account for the relatively small database. Laufersweiler et al (2012) expanded this approach to 300 chemicals with reproductive and developmental data, deducing a TTC of 6 μg/kg bw/day.…”