Background
Teratogenicity as well as toxicity to the reproduction success of organisms are summarized under reproductive toxicity. At present, alternative methods are not yet available to fully replace vivo studies for the assessment of these endpoints. Relevant in vivo studies comprise developmental and reproductive toxicity studies (DART studies) which are used to identify potential adverse effects and to derive thresholds below which DART effects can be excluded.
Alternative in silico methods like the recently published DART predictor (Gao, Huang et al. 2025), the OECD QSAR toolbox or DART decision tree by Wu et al. ({Wu, 2013 #19}) identify chemicals of potential concern but do not provide hazard identification or a potency estimate. These in silico predictions are therefore not able to replace DART studies but can be used in a weight of evidence approach to prioritize compounds for additional in vivo testing or assessment factors.
Read-across is being used to replace de novo testing but is limited to analogs with relevant and high quality DART studies. A recent study developed a hybrid approach combining chemical similarity features with predictions from QSAR methods ({Pandey,2024#18}). Repeat dose toxicity (RDT) data are more frequently available than developmental and/or reproductive toxicity (DART) studies, and it is observed that often, NOAELs from RDT studies do correlate with NOAELs from DART studies. On average, for several reasons not to be expanded on here, RTD NOAELs are more sensitive (Blackburn, K., et al. (2015); Bernauer et al. 2008; van Ravenzwaay et al. 2011, 2012 and 2017; Laufersweiler et al. 2012). However, some cases exist where RTD NOAELs would not be protective of DART effects, so that an additional safety factor would be warranted in risk assessment. Based on this hypothesis the World Health Organization (WHO) and Health Canada have e.g. recommended a default factor of up to 10 for assessments based on incomplete datasets, including missing DART studies (Mitchell et al. 2004). Already in 2015, Blackburn et al. ({Blackburn, 2015 #6} evaluated the applicability of uncertainty factors, by comparing NOAEL RDT/DART ratios for about 180 compounds from rat studies. Since this time many more studies have been published, which can be used to mature the assessment framework proposed by Blackburn et al. by providing a larger (data)base for UF derivation and assessing how new or updated in silico tools can serve to identify structures for which application of the UF is appropriate. It might also be possible, within an assessment framework, to apply specific UF to different substance classes based on structural properties and/or degree of knowledge about the structure. The approach should also be applicable to UVCBs.
Objectives
The objectives of the project are to:
- Broaden the dataset collected by Backburn et al. collect relevant datasets for substances with data on repeated dose toxicity studies and in addition at least one study on developmental and/or reproductive toxicity from different reliable sources/databases.
- Develop data inclusion / exclusion criteria. Assess the quality of the studies, assign for each compound NOAEL and LOAEL values per study and endpoints.
- Analyze N(L)OAEL ratios of RDT/Developmental and Reproductive Toxicity studies for individual compounds and compound classes.
- Provide all data and decisions in a publicly available database, led by FAIR principles
- Identify outliers and search for data on their mode of action and target organ
- Where justified by the data available, derive data-driven, evidence-based uncertainty factors to account for missing or incomplete DART studies in risk assessment, either for only reproductive and/or developmental toxicity or both, including their applicability domains and how they could be applied in a decision framework, including UVCBs.
Scope
By developing evidence-based uncertainty factors for extrapolation of N(L)OAELs derived from RDT to DART endpoints, this project aims to reduce uncertainty in risk assessment when DART studies are not required by regulations, e.g. for low to mid-volume chemicals. It will also assess the applicability domain of the proposed approach, explore the need for group-specific or endpoint-specific (i.e. developmental versus reproductive toxicity) uncertainty factors, and remaining uncertainties that can serve as input to inform a broader framework and be addressed in future work.
Out of scope
In vitro models and testing strategies for DART are out of scope for this project, as well as identification of developmental or reproductive toxicants.
Deliverables
- Database on relevant toxicity studies and information and decisions applied for derivation of uncertainty factors for individual compounds/compound classes, including UVCBs
- Report on the derivation of uncertainty factors by defining a clear approach and their application in a knowledge-based decision framework, highlighting the remaining uncertainties
- Guidance for future work to implement RDT-derived DART POD in a broader framework
Partnering / Co-funding
Applicants should provide an indication of additional partners and funding opportunities that can be appropriately leveraged as part of their proposal. Partners can include, but are not limited to industry, government/regulatory organizations, research institutes, etc. Statements from potential partners should be included in the proposal package.
Fit with LRI objectives / Possible regulatory and policy impact involvements / Dissemination
Applicants should provide information on the fit of their proposal with LRI objectives and an indication on how and where they could play a role in the regulatory and policy areas. Dissemination plans should also be laid down. For LRI objectives visit the website page: About Cefic-LRI – Cefic-Lri
DEADLINE FOR SUBMISSIONS: January 17, 2027 at 11:59 PM CET.
Please see www.cefic-lri.org/funding-opportunities/apply-for-a-grant/ for general LRI objectives information, project proposal form and further guidance for grant applications. Please note that if awarded the project, the institute must be able to accept Belgian Law (or an equivalent European legal framework) in the contract. If there are questions, please email lri@cefic.be.
Related links
References
Gao, Y., Y. Huang, X. Chen, S. Cui, Y. Jiang, X. Chen, Y. Zhao, W. Liu and S. Zhuang (2025). "DART Predictor: A Multi-Label Attention Model for High-Throughput Screening of Chemicals with Developmental and Reproductive Toxicity (DART)." Environmental Science \& Technology 59(46): 24853-24862.
Mitchell, E. et al., 2004. Evaluating chemical and other agent exposures for reproductive and developmental toxicity. J. Toxicol. Environ. Health Part A 67, 1159–1314.
Blackburn, K., et al. (2015). "A strategy for safety assessment of chemicals with data gaps for developmental and/or reproductive toxicity." Regulatory Toxicology and Pharmacology 72(2): 202-215.
Pandey, S. K. and K. Roy (2024). "Development of hybrid models by the integration of the read-across hypothesis with the QSAR framework for the assessment of developmental and reproductive toxicity (DART) tested according to OECD TG 414." Toxicol Rep 13: 101822.
Wu, S., et al. (2013). "Framework for identifying chemicals with structural features associated with the potential to act as developmental or reproductive toxicants." Chem Res Toxicol 26(12): 1840-1861
Bernauer et al. (2008) “Exposure-triggered reproductive toxicity testing under the REACH legislation: A proposal to define significant/relevant exposure.” Toxicology Letters 176(1): 68-76
Van Ravenzwaay et al. (2011) “The threshold of toxicological concern for prenatal developmental toxicity.” Regulatory Toxicology Pharmacology 59(1):81-90
Van Ravenzwaay et al. (2012) “The threshold of toxicological concern for prenatal developmental toxicity in rabbits and a comparison to TTC values in rats.” Regulatory Toxicology Pharmacology 64(1):1-8.
Van Ravenzwaay et al. (2017) “The Threshold of Toxicological Concern for prenatal developmental toxicity in rats and rabbits.” Regulatory Toxicology Pharmacology 88:157-172.
Laufersweiler et al. (2012) “Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern.” Regulatory Toxicology Pharmacology 62(1):160-82.
