A 28-Day Repeated Oral Administration Study of Mechanically Fibrillated Cellulose Nanofibers According to OECD TG407.

The impact of oral administration of mechanically fibrillated cellulose nanofibers (fib-CNF), a commonly used nanofiber, on toxicity and health remains unclear, despite reports of the safety and beneficial effects of chitin-based nanofibers. Thus, evaluating the oral toxicity of fib-CNF in accordance with OECD Test Guideline 407 (TG407) is essential. This study aimed to assess the safety of orally administered fib-CNF through an acute toxicity study in rats, following the OECD TG407 guidelines for 4 weeks. CNF "BiNFi-s" FMa-10005, derived from mechanically fibrillated pulp cellulose, was administered via gavage to male and female Crl:CD(SD) rats at doses of 50, 150, 500, and 1000 mg/kg/day for 28 days, with a control group receiving water for injection. The study evaluated the toxic effects of repeated administration, and the rats were monitored for an additional 14 days post-administration to assess recovery from any toxic effects. The results showed no mortality in either sex during the administration period, and no toxicological effects related to the test substance were observed in various assessments, including general condition and behavioral function observations, urinalysis, hematological examination, blood biochemical examination, necropsy findings, organ weights, and histopathological examination. Notably, only female rats treated with 1000 mg/kg/day of CNF exhibited a consistent reduction in body weight during the 14-day recovery period after the end of treatment. They also showed a slight decrease in pituitary and liver weights. However, hematological and blood biochemical tests did not reveal significant differences, suggesting a potential weight-suppressive effect of CNF ingestion.

Evaluating the conduct and reporting of the T-cell dependent antibody response in the Extended One-Generation Reproductive Toxicity study provided under the EU REACH regulation.

The European Union (EU) Chemicals Strategy for Sustainability regards chemicals that affect the immune system among the most harmful ones. The Extended One-Generation Reproductive Toxicity study (EOGRTS; Organisation for Economic Co-Operation and Development (OECD) Test Guideline (TG) 443), addresses, among others, potential effects of chemicals on development. In specific cases, the EOGRTS is performed with addition of a so-called cohort 3, that addresses potential effects on the developing immune system, by means of a central assay measuring the T-cell dependent antibody response (TDAR). This assay is based on an interplay of antigen presentation, T-cell help and antibody production by B-cells, and together comprises a functional immune response. In the context of the EOGRTS review project of the European Chemicals Agency (ECHA), we evaluated 15 available TDARs for compliance with conduct and reporting requirements. Collectively, the majority of the TDAR studies were considered to be adequately conducted. We however observed: (i) the protocols differed by the antigen used (sheep red blood cells (SRBC) or KLH), the route of administration (intravenous, intraperitoneal, or subcutaneous), prime or prime/boost immunizations, and whether IgG was measured. (ii) There was major variation in the effects of the positive control for immunosuppression, cyclophosphamide. (iii) Proficiency was not always shown. (iv) Statistical analysis was not always done or reported. (v) Results of effects on lymphocyte populations or other immunotoxicity observations obtained in cohort 1 (or 2) of the EOGRTS were not always discussed together with results of the TDAR. Taken together, next to an improved quality of reporting, this may suggest a need to better define the conduct of the TDAR in OECD TG 443 and OECD Guidance Document (GD) 151, at least for certain aspects.

Predicting the binding affinity of chemicals to estrogen receptor using Hansen solubility parameters.

Receptor-binding tests for the receptors of various substances are widely employed to identify drug candidates and predict the biological effects of chemical substances. Here, the results of chemicals binding to estrogen receptor (ER) reported in a validation study of the Organization for Economic Cooperation and Development TG 455 and the Hansen solubility parameter (HSP) values of the test substances were compared and examined using the Hansen sphere method, thus predicting potential HSPs that correspond to the ER-binding domain of agonists. Based on the results of the validation study and the HSP values of the test chemicals, a Hansen solubility sphere was created, and the ER potential parameter corresponding to the ER was obtained. The binding potential of the test substances to ER was predicted by comparing this potential parameter with the HSP of each test substance. These results indicate that ER binding properties can be predicted with high accuracy using the concept of HSP.

Methodology for developing data-rich Key Event Relationships for Adverse Outcome Pathways exemplified by linking decreased androgen receptor activity with decreased anogenital distance.

The Adverse Outcome Pathway (AOP) framework has gained widespread acceptance in toxicological disciplines as a tool for aiding chemical hazard assessment. Despite increased activity in AOP development, progress towards a high volume of fully endorsed AOPs has been slow, partly due to the challenging task of constructing complete AOPs according to the AOP Developer's Handbook. To facilitate greater uptake of new knowledge units onto the open-source AOP-wiki platform, a pragmatic approach was recently proposed. This approach involves considering Key Event Relationships (KERs) for individual development through systematic approaches, as they represent essential units of knowledge from which causality can be inferred; from low complexity test data to adverse outcomes in intact organisms. However, more broadly adopted harmonized methodologies for KER development would be desirable. Using the AOP Developer's Handbook as a guide, a KER linking 'decreased androgen receptor (AR) activity' with 'reduced anogenital distance (AGD)' was developed to demonstrate a methodology applicable for future developments of KERs requiring systematic literature retrieval approaches.

A 90-day preclinical toxicological evaluation in rats of a highly purified and concentrated mulberry leaf extract.

Mulberry (genus Morus) leaves have long been used as a human food, especially in Asia, and animal feed. More recently, mulberry leaf extracts have been introduced as a convenient way to consume mulberry for non-nutritional functional effects. Reducose® 5% is an Morus alba leaf extract that has been highly purified and standardized to a content of 5 ± 0.5% 1-deoxynojirimycin, a naturally present polyhydroxylated piperidine alkaloid analog of D-glucose. This extract has previously been evaluated in acute and subacute (28-day) oral toxicity studies in which no adverse effects of the test item were observed in mice or rats, respectively. Due to continued and growing interest in the extract in multinational markets, we have now further investigated potential toxic effects in subchronic (90-day) oral toxicity study in male and female Han:WIST rats. The test item was administered at doses of 850, 1700, and 2550 mg/kg bw/day, and did not cause adverse effects in clinical signs, body weight development, clinical pathology, gross pathology, or histopathology in comparison to the vehicle-control group. The no-observed-adverse-effect-level was determined to be 2550 mg/kg bw/day. These results add to the existing body of both preclinical and clinical work relevant to the safety of the extract and of interest to regulators in various global markets.

Comparison of two biological systems used for phototoxicity testing: Cellular and tissue.

The OECD has approved two similar methods for testing the phototoxic potency of chemicals. The first method, OECD 432, is based on the cytotoxicity properties of materials to the mouse 3T3 (clone A31) cell line (fibroblasts) after exposure to light. The second method, OECD 498, is based on the same properties but using reconstructed human epidermis - EpiDerm (stratified keratinocytes). The aim of this study was to compare these two methods using statistical tests (specificity, sensitivity, negative predictive value, positive predictive value and accuracy) and non-statistical characteristics (e.g. price and experimental duration, amount of material, level of complications, cell type, irradiation dose). Both tests were performed according to the relevant guidelines using the same 11 control substances. Higher performance values were observed for OECD 432 in both phototoxic and non-phototoxic classifications. The accuracy of OECD 432 was 90.9%, while that of OECD 498 was 72.7%. OECD 432 was also shorter and less expensive. On the other hand, OECD 498 was less complicated, and used human cells with stratum corneum, which better reflects real skin. This method can also be used with oily substances that are poorly soluble in water. However, both methods are important for testing the phototoxic properties of materials, and can be used alone or in a tiered strategy.

Metabolism of alcohol ethoxylates (AEs) in rat, hamster, and human hepatocytes and liver S9: a pilot study for metabolic stability, metabolic pathway, and metabolites identification in vitro and in silico.

Alcohol ethoxylates (AEs) are a well-known class of non-ionic surfactants widely used by the personal care market. The aim of this study was to evaluate and characterize the in vitro metabolism of AEs and identify metabolites. Five selected individual homologue AEs (C8EO4, C10EO5, C12EO4, C16EO8, and C18EO3) were incubated using human, rat, and hamster liver S9 fraction and cryopreserved hepatocytes. LC-MS was used to identify metabolites following the incubation of AEs by liver S9 and hepatocytes of all three species. All AEs were metabolized in these systems with a half-life ranging from 2 to 139 min. In general, incubation of AE with human liver S9 showed a shorter half-life compared to rat liver S9. While rat hepatocytes metabolized AEs faster than human hepatocytes. Both hydrophobic alkyl chain and hydrophilic EO head group groups of AEs were found to be target sites of metabolism. Metabolites were identified that show primary hydroxylation and dehydrogenation, followed by O-dealkylation (shortening of EO head groups) and glucuronidation. Additionally, the detection of whole EO groups indicates the cleavage of the ether bond between the alkyl chain and the EO groups as a minor metabolic pathway in the current testing system. Furthermore, no difference in metabolic patterns of each individual homologue AE investigated was observed, regardless of alkyl chain length or the number of EO groups. Moreover, there is an excellent agreement between the in vitro experimental data and the metabolite profile simulations using in silico approaches (OECD QSAR Toolbox). Altogether, these data indicate fast metabolism of all AEs with a qualitatively similar metabolic pathway with some quantitative differences observed in the metabolite profiles. These metabolic studies using different species can provide important reference values for further safety evaluation.

The role of green growth and institutional quality on environmental sustainability: A comparison of CO2 emissions, ecological footprint and inverted load capacity factor for OECD countries.

Green growth is of great importance in terms of solving environmental problems and achieving sustainable development goals. However, the existing literature has not investigated how green growth affects environmental degradation and environmental sustainability variables. In light of this gap, this study aims to analyse the impact of green growth and institutional quality on CO2 emissions, ecological footprint and inverse load capacity factor in OECD countries by constructing three different models. The results of the analysis indicate that (i) green growth exerts a significant mitigating and differentiating effect on CO2, ecological footprint and inverted load capacity factor in the long run. This is evidenced by a 1% increase in green growth reducing CO2, ecological footprint and inverted load capacity factor by 0.563%, 0.373% and 0.198%, respectively. (i) The impact of green growth on CO2 and inverted load capacity factor in the long run is negative and statistically significant; (ii) the impact of green growth on CO2 and inverted load capacity factor in the short run is negative and statistically significant; (iii) the impact of institutional quality on deterioration is positive and significant in the long run; (iv) the impact of population on deterioration and sustainability is significant and mixed. The findings indicate that decision-makers in OECD countries should review green energy policies when setting the sustainable development goals, as environmental sustainability is more challenging than reducing pollution.

Assessment of oral toxicity and safety profile of cyanidin: acute and subacute studies on anthocyanin.

Aim: Purified anthocyanins lack a detailed safety profile, prompting the need for comprehensive oral toxicity research. Materials & methods: Sprague-Dawley rats aged 8 weeks received 300 mg/kg cyanidin orally for 14 days in acute toxicity (OECD 423). In the subacute study (OECD 407), adult SD rats were administered 7.5, 15 and 30 mg/kg/day cyanidin orally for 28 days. Results: Acute toxicity indicated an LD50 exceeding 300 mg/kg/day without adverse effects. Subacute toxicity at 7.5-30 mg/kg/day showed well-tolerated responses in both genders. No significant alterations in organ weights, hematological parameters, liver/kidney functions or adverse histopathological findings were observed. Conclusion: Oral cyanidin administration demonstrated high safety and tolerance in rats, establishing a NOAEL at 30 mg/kg/day, affirming cyanidin's safety for oral use.

Anthocyanins, natural pigments found in fruits and vegetables, lack a detailed safety profile. This study investigated the oral toxicity of cyanidin, a common anthocyanin. Acute toxicity testing in rats showed no adverse effects at doses up to 300 mg/kg. In the subacute study, doses of 7.5­30 mg/kg/day over 28 days were well tolerated, with no significant negative effects on organ function or histopathology. The findings suggest that cyanidin is safe for oral use in rats, with a No Observed Adverse Effect Level (NOAEL) established at 30 mg/kg/day.

Rat studies reveal cyanidin, a common anthocyanin, shows high oral safety at doses up to 300 mg/kg/day, paving the way for safer dietary supplement use. #Toxicology #SafetyResearch.

Analyzing the impact of fiscal conditions on private health expenditures in OECD countries: a quantile ARDL investigation.

Organization for Economic Co-operation and Development (OECD) countries have embraced the aim of universal health coverage, as established in Sustainable Development Goal (SDG) 3.8. This goal guarantees access to quality healthcare services without financial hardship or poverty. Additionally, it requires correct and adequate financing sources. A country with weak protection for its population tends to spend less on healthcare and experiences a high share of out-of-pocket payments (OOPs), increasing the likelihood of people falling into poverty. This study aims to understand the relationship and causal effects between macroeconomic and public fiscal conditions and private health expenditure in OECD countries between 1995 and 2019. We retrieved OECD data for 26 OECD countries for the period 1995-2019. Panel AutoRegressive Distributed Lag (PARDL) and panel quantile AutoRegressive Distributed Lag (PQARDL) models were estimated to examine the relationship between private health expenditures and macroeconomic and public fiscal variables. Our results reveal a positive influence of government debt and economic freedom on private health expenditures. They also show a negative influence of the government budget balance, government health expenditures, and economic growth on private health expenditures. These results collectively suggest that public fiscal conditions will likely impact private health expenditures. The findings of this study raise concerns about the equity and financial protection objectives of universal health coverage in OECD countries.

Reference chemical database for the development and validation of in vitro alternatives to skin irritation and comparison of the performance of RhE models.

After EU ban on animal testing for cosmetics in 2013, there has been an increasing global interest in alternatives test methods. To development for alternatives test method, we need to get the toxic data about in vitro and in vivo of chemicals. However, database sometimes provide limited in vivo and in vitro data on chemicals. Further, the data generated using the OECD TG439 (in vitro skin irritation) are scattered in difference databases, and it is not easy to navigate through them. Therefore, we complied 'Reference Chemical Database System for Skin Irritation Alternative Test (RCDS-Skin Irritation)' to allow easy, one-stop access to test chemical information. We established the systematic RCDS-Skin Irritation by collecting physiochemical properties, CAS number, human data, and in vivo (OECD TG404) data from overseas chemicals database including European Chemicals Agency (ECHA) etc., and in vitro data using Reconstructed human Epidermis (RhE) (OECD TG439). As a result, we developed the RCDS-Skin Irritation that contains information on 149 chemicals including the data we generated by performing tests using EpiDerm™ SIT, SkinEthic™ RHE and KeraSkin™ SIT. Therefore, the RCDS-Skin Irritation established based on our study will provide insight for safety assessment of chemicals and for development of alternative test methods.

Quantitative read-across structure-activity relationship (q-RASAR): A novel approach to estimate the subchronic oral safety (NOAEL) of diverse organic chemicals in rats.

We have developed a quantitative safety prediction model for subchronic repeated doses of diverse organic chemicals on rats using the novel quantitative read-across structure-activity relationship (q-RASAR) approach, which uses similarity-based descriptors for predictive model generation. The experimental -Log (NOAEL) values have been used here as a potential indicator of oral subchronic safety on rats as it determines the maximum dose level for which no observed adverse effects of chemicals are found. A total of 186 data points of diverse organic chemicals have been used for the model generation using structural and physicochemical (0D-2D) descriptors. The read-across-derived similarity, error, and concordance measures (RASAR descriptors) have been extracted from the preliminary 0D-2D descriptors. Then, the combined pool of RASAR and the identified 0D-2D descriptors of the training set were employed to develop the final models by using the partial least squares (PLS) algorithm. The developed PLS model was rigorously validated by various internal and external validation metrics as suggested by the Organization for Economic Co-operation and Development (OECD). The final q-RASAR model is proven to be statistically sound, robust and externally predictive (R2 = 0.85, Q2LOO = 0.82 and Q2F1 = 0.94), superseding the internal as well as external predictivity of the corresponding quantitative structure-activity relationship (QSAR) model as well as previously reported subchronic repeated dose toxicity model found in the literature. In a nutshell, the q-RASAR is an effective approach that has the potential to be used as a good alternative way to improve external predictivity, interpretability, and transferability for subchronic oral safety prediction as well as ecotoxicity risk identification.

Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-3. Aquatic exposure and hazard of aliphatic diisocyanate-based prepolymers.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Building species trait-specific nano-QSARs: Model stacking, navigating model uncertainties and limitations, and the effect of dataset size.

A strong need exists for broadly applicable nano-QSARs, capable of predicting toxicological outcomes towards untested species and nanomaterials, under different environmental conditions. Existing nano-QSARs are generally limited to only a few species but the inclusion of species characteristics into models can aid in making them applicable to multiple species, even when toxicity data is not available for biological species. Species traits were used to create classification- and regression machine learning models to predict acute toxicity towards aquatic species for metallic nanomaterials. Afterwards, the individual classification- and regression models were stacked into a meta-model to improve performance. Additionally, the uncertainty and limitations of the models were assessed in detail (beyond the OECD principles) and it was investigated whether models would benefit from the addition of more data. Results showed a significant improvement in model performance following model stacking. Investigation of model uncertainties and limitations highlighted the discrepancy between the applicability domain and accuracy of predictions. Data points outside of the assessed chemical space did not have higher likelihoods of generating inadequate predictions or vice versa. It is therefore concluded that the applicability domain does not give complete insight into the uncertainty of predictions and instead the generation of prediction intervals can help in this regard. Furthermore, results indicated that an increase of the dataset size did not improve model performance. This implies that larger dataset sizes may not necessarily improve model performance while in turn also meaning that large datasets are not necessarily required for prediction of acute toxicity with nano-QSARs.

Development of a defined approach for eye hazard identification of solid chemicals according to the three UN GHS categories.

Currently there are two OECD-adopted defined approaches (DA) for eye hazard identification of non-surfactant liquids (OECD TG 467). The current study aimed to develop a DA for eye hazard identification of solid chemicals according to the three UN GHS categories (Cat.1, Cat. 2, No Cat.): the DAS. The DAS combines two test methods described in OECD TG 437 and TG 492. The DAS was developed based on in-depth statistical analysis of a database on solids containing in vitro and historically curated in vivo Draize eye test data. The performance of the DAS was assessed by comparing the predictions with the classification based on in vivo Draize eye test data, on the one hand, and with the performance criteria established by the OECD expert group, on the other hand. In a first tier of the DAS, the SkinEthic™ HCE EIT method (TG 492) is used to distinguish No Cat. from classified substances. For classified substances, the BCOP LLBO method (TG 437) is used to identify Cat. 1, and the remaining solids are predicted Cat. 2. In summary, 77.4% Cat. 1 (N=31), 52.3% Cat. 2 (N=18), and 70.0% of No Cat. (N=60) solids were correctly identified compared to the classification based on the Draize eye test. The percentage of correct predictions met the minimum OECD performance values of 75% Cat. 1, 50% Cat. 2, and 70% No Cat., and the percentage of mispredictions was below the established maximum values. Therefore, inclusion of the DAS in OECD TG 467 has been achieved.

Defined approaches combine information from different non-animal testing methods in a specific way and interpret the results according to a fixed procedure. Such defined approaches are already available as full replacements of animal testing to assess the eye hazard of liquid chemicals (OECD Test Guideline 467). This study used two OECD-adopted in vitro methods, based on human cells and corneas from cattle, to create a defined approach that can be used for solid chemicals. The performance of the procedure was assessed against data from previous animal tests for 109 solid chemicals. The results have already led to this defined approach being adopted by the OECD TGs programme for inclusion in TG 467. With the adoption of the new defined approach, non-animal human relevant strategies are now available for eye hazard assessment of liquids and solids, reducing the need for animal testing.

Academic Productivity in Ophthalmology and Its Correlation to National Economic Indicators Among the OECD Countries: A Bibliometric Analysis.

PURPOSE: Prompted by the clinical concern that limited healthcare resources allocation affects physicians' research productivity, this study examines the association between bibliometric indices of ophthalmologic research and national economic indicators in Organisation for Economic Co-operation and Development (OECD) countries. METHODS: The Scimago Journal and Country rank source was searched for research productivity data in ophthalmology among OECD countries between 1996 and 2019. Bibliometric indices included: documents number, number and percent of citable documents, citations number, citations per document, and H-index. The updated economic indicators of each country (gross domestic product [GDP] per capita, health spending as percent of GDP (health expenditure), gross domestic expenditure on research, and development as percent of GDP [GERD]) were collected from the World Bank and the OECD websites. Correlation between economic and bibliometric metrics and multivariate linear regression analyses were performed. RESULTS: Among 267,444 documents analyzed, correlation analysis found a strong correlation between health expenditure and H index (r = 0.711, p < 0.001); a moderate correlation between health expenditure and documents number (r = 0.589, p < 0.001), number of citable document (r = 0.593, p < 0.001) and citations number (r = 0.673, p < 0.001); and a moderate correlation between GERD and H index (r = 0.564, p < 0.001). Multivariate regression analysis controlling for economic factors, population and language showed the independent association of these parameters with bibliometric indices. CONCLUSIONS: This study demonstrates a positive correlation between bibliometric indicators of ophthalmology research and economic factors, particularly health expenditure, among the OECD countries. Our results suggest an advantage of domestic investment in health to expand academic productivity in the field of ophthalmology.

Biodegradation of flavonoids - Influences of structural features.

Flavonoids, a class of natural products with a variety of applications in nutrition, pharmacy and as biopesticides, could substitute more harmful synthetic chemicals that persist in the environment. To gain a better understanding of the biodegradability of flavonoids and the influence of structural features, firstly, the ultimate biodegradation of 19 flavonoids was investigated with the Closed Bottle Test according to the OECD guideline 301 D. Secondly, regarding the fast abiotic degradation reported for several flavonoids with severe concentration decrease within hours and its possible impacts on the processes behind the ultimate biodegradation, primary degradation of 4 selected flavonoids was compared at conditions representing biodegradation, abiotic degradation, and mixed substrates by monitoring the flavonoids' concentrations with HPLC-UV/vis. Our results showed that 17 out of the 19 tested flavonoids were readily biodegradable. Structural features like a hydroxy group at C3, the C2-C3 bond order, a methoxy group in the B ring, and the position of the B ring in regard to the chromene core did not affect biodegradation of the tested flavonoids. Only flavone without any hydroxy groups and morin with an uncommon 2',4' pattern of hydroxy groups were non-readily biodegradable. Monitoring the concentration of 4 selected flavonoids by HPLC-UV/vis revealed that biodegradation occurred faster than abiotic degradation at CBT conditions with no other carbon sources present. The presence of an alternative carbon source tends to increase lag phases and decrease biodegradation rates. At this condition, abiotic degradation contributed to the degradation of unstable flavonoids. Overall, as a first tier to assess the environmental fate, our results indicate low risks for persistence of most flavonoids. Thus, flavonoids could represent benign substitutes for persistent synthetic chemicals.

Evaluation of the Genotoxicity of Almond Hull: Implications for Its Use as a Novel Food Ingredient.

Almond hull, a substantial byproduct comprising more than half of almond fresh weight, has recently gained attention due to its functionality and sustainability benefits. Despite heightened interest, information regarding its toxicity remains limited. In order to assess its genotoxic potential, we conducted Good Laboratory Practice-compliant in vitro and in vivo studies following Organization for Economic Co-operation and Development (OECD) guidelines. No evidence of toxicity or mutagenicity was observed in a bacterial reverse mutation assay using five tester strains, evaluating almond hull at concentrations up to 5 mg/plate, with or without metabolic activation. Almond hull did not induce chromosome structural damage in a chromosome aberration assay using Chinese hamster ovary cells, nor did it cause any spermatogonial chromosomal aberration in tested male BALB/c mice. To evaluate its ability to induce DNA damage in rodents, a combined micronucleus assay was conducted in KM mice of both sexes. Almond hull was administered at doses of 1250, 2500, and 5000 mg/kg/day via gavage once daily for 2 days. No adverse effects of almond hull were observed in the micronucleus assay. Our results indicate no evidence of the genotoxic potential of almond hull administered up to the maximum concentrations of 5 g/kg, as recommended by OECD guidelines.

Avoiding a reproducibility crisis in regulatory toxicology-on the fundamental role of ring trials.

The ongoing transition from chemical hazard and risk assessment based on animal studies to assessment relying mostly on non-animal data, requires a multitude of novel experimental methods, and this means that guidance on the validation and standardisation of test methods intended for international applicability and acceptance, needs to be updated. These so-called new approach methodologies (NAMs) must be applicable to the chemical regulatory domain and provide reliable data which are relevant to hazard and risk assessment. Confidence in and use of NAMs will depend on their reliability and relevance, and both are thoroughly assessed by validation. Validation is, however, a time- and resource-demanding process. As updates on validation guidance are conducted, the valuable components must be kept: Reliable data are and will remain fundamental. In 2016, the scientific community was made aware of the general crisis in scientific reproducibility-validated methods must not fall into this. In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs.

Influence of environmental technologies and income on the environment in OECD member countries transitioning to low carbon societies.

This paper focuses on examining the effects of per capita environmental technology development on the load capacity factor (LCF) within the context of OECD member countries during the period spanning 1990 to 2021. To investigate these relationships, we employ the AMG estimator and FM-LS estimator. Additionally, we explore the validity of the load capacity curve for these countries and estimate the inflection points in the income per capita-environmental sustainability relationship. Our findings lead us to the conclusion that there is no significant impact of environmental technologies on environmental sustainability. Furthermore, we observe a negative influence on the development of environmental technologies, which can be attributed to the negative externalities associated with their implementation and the lack of societal adoption. Moreover, our estimations reveal an inflection point at $45,251.90 in terms of GDP per capita, beyond which the sustainability condition of the studied countries improves.