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The majority of repeated dose toxicity studies are available for the oral route. For risk assessment, however, data are needed from the relevant exposure route, i.e. inhalation or dermal. Instead of conducting additional animal studies, route-to-route (R2R) extrapolation may be performed. To explore uncertainties associated with this approach, we derived extrapolation factors (EF) based on no/lowest effect levels (NOELs/LOELs) in the Fraunhofer RepDose ® database. For R2R extrapolation oral-to-inhalation 246 study pairs on 110 chemicals were analyzed. Systemic effects triggered the LOELs in the underlying inhalation studies in 49.2%, local effects in 21.9% and both local and systemic effects in 30.9% of the data pairs. For systemic effects in inhalation studies an EF of 2.2 (95% confidence interval: 1.2-3.1) was derived, for local effects, the EF was 4.4 (95% confidence interval: 2.0-8.6), and the EF without distinguishing local or systemic effects (any EF) was 3.2 (95%, confidence interval: 1.7-5.0). Calculation with LOELs instead of NOELs, exposure duration and intrinsic properties of the chemical (toxicity or physicochemical properties) did not influence the EF significantly. For R2R extrapolation oral-to-dermal 46 study pairs on 28 chemicals were analyzed. An overall EF of 0.4 (95%, confidence interval: 0.2-0.9) was obtained. Here, we found a significant difference of EFs for low and high toxic chemicals. Overall, we conclude that reliable systemic NOELs/LOELs can be obtained for inhalation studies via R2R extrapolation from oral studies. Based on the data for any EF we propose to use an EF of 3, which covers also the uncertainty that unexpected local effects may occur in an inhalation study. For the dermal route, our dataset was too small to allow general conclusions, but the results so far do suggest that the current ECHA guidance is conservative when assuming that dermal absorption is as high as oral absorption., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The European chemicals' legislation REACH aims to protect man and the environment from substances of very high concern (SVHC). Chemicals like endocrine disruptors (EDs) may be subject to authorization. Identification of (potential) EDs with regard to the environment is limited because specific experimental assessments are not standard requirements under REACH. Evidence is based on a combination of in vitro and in vivo experiments (if available), expert judgement, and structural analogy with known EDs., Objectives: The objectives of this study are to review and refine structural alerts for the indication of potential estrogenic and androgenic endocrine activities based on in vitro studies; to analyze in vivo mammalian long-term reproduction studies with regard to estrogen- and androgen-sensitive endpoints in order to identify potential indicators for endocrine activity with regard to the environment; to assess the consistency of potential estrogenic and androgenic endocrine activities based on in vitro assays and in vivo mammalian long-term reproduction studies and fish life-cycle tests; and to evaluate structural alerts, in vitro assays, and in vivo mammalian long-term reproduction studies for the indication of potential estrogenic and androgenic endocrine disruptors in fish., Results: Screening for potential endocrine activities in fish via estrogenic and androgenic modes of action based on structural alerts provides similar information as in vitro receptor-mediated assays. Additional evidence can be obtained from in vivo mammalian long-term reproduction studies. Conclusive confirmation is possible with fish life-cycle tests. Application of structural alerts to the more than 33,000 discrete organic compounds of the EINECS inventory indicated 3585 chemicals (approx. 11%) as potential candidates for estrogenic and androgenic effects that should be further investigated. Endocrine activities of the remaining substances cannot be excluded; however, because the structural alerts perform much better for substances with (very) high estrogenic and androgenic activities, there is reasonable probability that the most hazardous candidates have been identified., Conclusions: The combination of structural alerts, in vitro receptor-based assays, and in vivo mammalian studies may support the priority setting for further assessments of chemicals with potential environmental hazards due to estrogenic and androgenic activities.

Studies on reproductive toxicity need high numbers of test animals. Therefore, we investigated whether chemical structural features (SF) in combination with in vitro data on specific adverse outcome pathways (AOPs) may be used for predicting reproductive toxicity of untested chemicals. Using the OECD Toolbox and expert judgment, we identified 89 structure groups for 275 chemicals for which the results of prenatal developmental toxicity or multigeneration studies were present in the Fraunhofer database on Fertility and Developmental Toxicity in experimental animals (FeDTex) database. Likewise, we evaluated 220 chemicals which had been tested in reporter gene assays on endocrine ((anti)estrogenic and (anti)androgenic) properties in the CALUX(®) test battery. There was a large spread of effect levels for substances within the chemical structure groups for both, in vivo and in vitro results. The groups of highest concern (diphenyl derivatives, planar conjugated systems with fused rings, phenols and organophosphates) correlated quite well, however, between the in vivo and in vitro data on estrogenic activity. For the 56 chemicals represented in both databases, lowest effect doses in vivo correlated well with the estrogenic activity in vitro. These results suggest that a panel of assays covering relevant AOPs and data on metabolism and toxicokinetics may allow prediction of relative reproductive or development toxicity potency within the identified chemical structure groups., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Numerous studies on reproductive toxicity are expected to be necessary under the EU program on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Therefore, it is important to analyse existing testing strategies including also the recently implemented extended one-generation reproduction toxicity study (EOGRTS, OECD guideline 443). For this purpose the responsiveness of the different generations and developmental stages in studies on reproductive toxicity is analysed and critical targets of reproductive toxicity are identified by using the Fraunhofer FeDTex database. The F1 generation is identified as most responsive generation in more than 50% of one-generation and multi-generation reproduction studies. Within the F1 generation the adult stage is mostly affected compared to the prenatal or postnatal stage. The target analysis in F1 has revealed alterations in body weight as highly sensitive for all developmental stages. Other important targets are the liver, kidney, testes, prostate, sperm parameters as well as developmental landmarks. The findings in the F2 generation have shown a higher responsiveness than F1 only in 3% of the studies. Although in 29 studies new effects are observed in F2 offspring compared to F1 irrespective of dose levels, overall no severe new effects have emerged that would change classification and labelling and justify an F1 mating. The presented data support the importance of F1 for risk assessment and demonstrate that the study design of the EOGRTS is a suitable alternative to two-generation studies. However, compared to a conventional one-generation study the EOGRTS may identify additional effects but will change risk assessment with respect to NOELs only in rare cases., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A database for repeated dose toxicity data has been developed. Studies were selected by data quality. Review documents or risk assessments were used to get a pre-screened selection of available valid data. The structure of the chemicals should be rather simple for well defined chemical categories. The database consists of three core data sets for each chemical: (1) structural features and physico-chemical data, (2) data on study design, (3) study results. To allow consistent queries, a high degree of standardization categories and glossaries were developed for relevant parameters. At present, the database consists of 364 chemicals investigated in 1018 studies which resulted in a total of 6002 specific effects. Standard queries have been developed, which allow analyzing the influence of structural features or PC data on LOELs, target organs and effects. Furthermore, it can be used as an expert system. First queries have shown that the database is a very valuable tool.