Lls (Pfuhler et al. 2020). For chemical substances which might be mainly linked with dermal exposure, the use of reconstructed human skin models has been explored and protocols happen to be created to get a reconstructed skin micronucleus test (RSMN) (Curren et al. 2006; Mun et al. 2009) and also a RS Comet assay (i.e., 3D Skin Comet) (Reisinger et al. 2018) based on the finest suited skin tissues (Curren et al. 2006; Pfuhler et al. 2011; Reisinger et al. 2018). The improvement of OECD test guidelines based on these tests is at the moment ongoing.Acute systemic toxicityIn the Regulation (EC) No 1272/2008 (CLP) (2020f), acute toxicity hazard categories and acute toxicity CYP26 Species estimates defining the respective categories are primarily based on animal information, although categories for particular target organ toxicity following single exposure are based on evidence from humans and/or from experimental animals. Animal studies to assess adverse effects and LD50 or LC50 value of tested compounds (which could outcome from a single exposure, generally carried out with high doses in the test substance), are thought to permit determination or estimation of a range of serious acute toxic effects including mortality. Substances is often allocated to among four toxicity categories based on acute toxicity by the oral, dermal or inhalation route in accordance with the numeric criteria. Below Reach (2020g), and as described within the ECHA Guidance (2017b), the assessment of acute systemic toxicity is amongst the regular details requirements for substances manufactured or imported into the EU in quantities of 1 tonne or far more per year (tpy), and typical information specifications are specified in Annexes VII and VIII. Acute toxicity testing will not be necessary if the substance is corrosive towards the skin. In distinct, as indicated below Annex VII ( 1 tpy), acute toxicity study(ies) by way of the oral route of exposure is(are) needed, and waiving is permitted if a study on acute toxicity by the inhalation route is offered. ForArchives of Toxicology (2021) 95:1867substances manufactured or imported in to the EU in quantities of ten tpy (beneath Annex VIII), also to acute toxicity study(ies) by means of the oral route of exposure, information on at the very least 1 other route of exposure is requested, based around the nature of the substance as well as the likely route of human exposure. As described in Column two of section 8.five.three of Annex VIII, waiving of acute dermal toxicity testing is further allowed if: (i) the substance does not meet the criteria for classification for acute toxicity or STOT-SE (distinct target organ toxicity-single exposure) by the oral route, and (ii) no systemic effects happen to be observed in in vivo research with dermal exposure (e.g., skin irritation, skin sensitisation) or, within the absence of an in vivo study by the oral route, no systemic effects immediately after dermal exposure are predicted on the basis of IRAK1 Accession non-testing approaches [e.g., read across, (Q) SAR studies]. In line with this, WoE-based adaptation towards the typical details requirement might be adopted for acute oral toxicity research, especially for substances to become registered at Annex VIII tonnage level and above (i.e., registrations at 10 tpy), for which an oral sub-acute toxicity study (OECD TG 407) (OECD 2008a) or the combined repeated dose toxicity study together with the reproduction/developmental toxicity screening test (OECD TG 422) (OECD 2016f) is necessary. This WoE adaptation proposed by ECHA (ECHA 2017b) applies to low toxicity substances (i.e., those that happen to be to not be c.