The Threshold of Toxicological Concern (TTC) concept can be applied to organic compounds with the known chemical structure to derive a threshold for exposure, below which a toxic effect on human health by the compound is not expected. The TTC concept distinguishes between carcinogens that may act as genotoxic and non-genotoxic compounds. A positive prediction of a genotoxic mode of action, either by structural alerts or experimental data, leads to the application of the threshold value for genotoxic compounds. Non-genotoxic substances are assigned to the TTC value of their respective Cramer class, even though it is recognized that they could test positive in a rodent cancer bioassay. This study investigated the applicability of the Cramer classes specifically to provide adequate protection for non-genotoxic carcinogens. For this purpose, benchmark dose levels based on tumor incidence were compared with no observed effect levels (NOELs) derived from non-, pre- or neoplastic lesions. One key aspect was the categorization of compounds as non-genotoxic carcinogens. The recently finished CEFIC LRI project B18 classified the carcinogens of the Carcinogenicity Potency DataBase (CPDB) as either non-genotoxic or genotoxic compounds based on experimental or in silico data. A detailed consistency check resulted in a dataset of 137 non-genotoxic organic compounds. For these 137 compounds, NOEL values were derived from high quality animal studies with oral exposure and chronic duration using well-known repositories, such as RepDose, ToxRef, and COSMOS DB. Further, an effective tumor dose (ETD10) was calculated and compared with the lower confidence limit on benchmark dose levels (BMDL10) derived by model averaging. Comparative analysis of NOEL/EDT10/BMDL10 values showed that potentially bioaccumulative compounds in humans, as well as steroids, which both belong to the exclusion categories, occur predominantly in the region of the fifth percentiles of the distributions. Excluding these 25 compounds resulted in significantly higher but comparable fifth percentile chronic NOEL and BMDL10 values, while the fifth percentile EDT10 value was slightly higher but not statistically significant. The comparison of the obtained distributions of NOELs with the existing Cramer classes and their derived TTC values supports the application of Cramer class thresholds to all non-genotoxic compounds, such as non-genotoxic carcinogens.

Box tree moth (BTM) Cydalima perspectalis (Walker, 1859) is the most harmful pest of different boxwood species in Europe and Asia including Caspian boxwood Buxus hyrcana in the Hyrcanian forests of Iran. Accessible and effective eco-friendly insecticides are required for the pest control. Thus, susceptibility of 2^nd and 4^th instar larvae of BTM to commercial formulation of Bacillus thuringiensis (Bt), two plant extract formulations, Bio1^® and Matrine^®, and three insect growth regulator (IGR) insecticides, chlorfluazuron, chromafenozide and diflubenzuron were investigated in laboratory bioassay. Except for diflubenzuron, significant mortality of both instar larvae was observed. At the endpoint of the experiments (96 h), 75.2–90% of second and 80–85% of fourth instar larvae had already died, as a result of feeding on leaves treated with the highest concentration of the insecticides. Furthermore, based on Probit analysis, Matrine^® exhibited the highest efficiency (lethal concentration LC₅₀ = 2.87 μL·L^–1) on 2^nd instar larvae and followed by Bio1^® (8.07 μL·L^–1), chlorfluazuron (173.3 μL·L^–1) and Bt (326.3 mg·L^–1). The LC₅₀ of Matrine^® and Bt for 4^th instar larvae were 1.75 μL·L^–1 and 335.8 mg·L^–1, respectively. Our study revealed that Matrine^® and chromafenozide could be alternatively used against BTM in situations where there is a permission and need to use insecticides.