Nitrous oxide (N2O) is classified as a reproductive toxicant (Repr. 1B, H360D) under the EU CLP Regulation based on developmental toxicity findings in non-guideline rat studies conducted in the 1970s and 1980s. Those studies reported malformations and embryolethality after continuous 24-h exposures to high and anesthetic concentrations of N2O, but provided limited data on maternal toxicity and may have been confounded by hypoxia. A new prenatal developmental toxicity study was conducted in Wistar rats according to OECD Test Guideline 414 and following Good Laboratory Practice (GLP). Mated females (21–24 per group) were exposed nose-only to target concentrations of 0 (air control), 150,000; 380,000; or 750,000 ppm N2O for 6 h/day from gestation day (GD) 6 to GD 19. All test atmospheres contained ≥ 25

Ensuring the safety of fragrances is a priority for both consumers and industry. The Research Institute for Fragrance Materials (RIFM) conducts risk assessments using a transparent framework. In the past, evaluating systemic toxicity relied on animal studies mandated by regulatory requirements; however, RIFM has not conducted new animal toxicity studies for over a decade. Of note, the doses used in these studies far exceed everyday exposure to fragrance ingredients. While toxicologists recognize the gap between test doses and real exposure, it may not be obvious to an average fragrance user. To illustrate this, the No-Observed-Adverse-Effect Levels (NOAEL) and Human Equivalent Doses (HED) of benzaldehyde and p-cymene were determined. As benzaldehyde and p-cymene occur in fragrances and foods, we used intake in food and fragrance use as a comparator. For fragrance exposure, the Creme RIFM Aggregate Exposure model was utilized. Results showed that adverse effect levels require ingesting about 166,000 almonds (for benzaldehyde) or 307,407 raspberries (for p-cymene) daily, or applying 276,660 sprays of benzaldehyde and 37,220 sprays of p-cymene daily. The selected exposure scenarios emphasize that data from animal studies must be viewed in the context of human exposure, highlighting advances in exposure science for realistic risk assessment.

The decision by the co-Editor-in-Chief of Regulatory Toxicology and Pharmacology, Prof. Martin van den Berg, to retract the 2000 review article by Williams, Kroes, and Munro has elicited widespread criticism within the scientific community. Issued in late 2025, the retraction decision cites procedural concerns including potential ghostwriting, undisclosed conflicts of interest, and omission of certain unpublished studies, invoking Committee on Publication Ethics guidelines despite lacking evidence of fraud or scientific flaws. This editorial argues that the retraction decision involves editorial overreach and misapplication of the guidelines. The alleged omissions stemmed from proprietary data access limitations that were disclosed in the original paper. Subsequent reviews by several independent expert panels and regulatory authorities with access to all glyphosate data, including the studies cited by the retracting editor, reached similar conclusions. Claims of ghostwriting were previously investigated and found lacking, including a declaration by EFSA as to the clarity of the conflict disclosures. The retraction's timing, reliance on litigation documents, and apparent biases that were not disclosed in the retraction notice raise questions of ideological interference. Absent substantive rebuttals based on scientific merit rather than speculative claims of inappropriate authorship and data access, this retraction decision sets a dangerous precedent for retroactive censorship, potentially chilling beneficial industry-academic collaborations and eroding trust in the integrity of scientific publishing. With the strongest conviction, we assert that retracting a paper without scientific flaws isn't protection-it is censorship. We therefore call for the immediate reversal of this flawed and unjustified retraction to preserve trust in peer-reviewed literature.

Many government agencies and expert groups have estimated a safe dose (aka a “reference dose,” [RfD]) for perfluorooctane sulfonate (PFOS). Notably, these agencies have derived safe doses that vary over at least 600-fold range. The range is larger still if one includes the U.S. Environmental Protection Agency (USEPA) current science-policy position under the Safe Drinking Water Act, which is that the only safe dose of PFOS is zero. This wide range in safe dose-estimates is surprising, since PFOS is a relatively well-studied, and ubiquitous, chemical. The Steering Committee of the Alliance for Risk Assessment (ARA) called for health-scientists interested in attempting to understand and, if possible, narrow this range of estimates. An advisory committee of eight scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three teams comprised of 24 scientists from nine countries. Each team independently reviewed toxicologic and epidemiologic data, and developed PFOS safe dose-estimates. All three teams concluded that currently available epidemiologic data could not form a reliable basis for PFOS safe dose-assessments. In contrast, results of bioassays of PFOS in laboratory monkeys and rats did provide usable bases from which serum-concentration-based “points of departure” were derived. After applying several, necessarily imprecise, uncertainty factors, the three groups derived PFOS safe dose-estimates that ranged, narrowly, from 20 to 100 nanograms (ng) of PFOS/kg body weight/day. In contrast, USEPA’s current (United States Environmental Protection Agency (USEPA) (2024) Human health toxicity assessment for perfluorooctane sulfonic acid (PFOS) and Related Salts. EPA Document No. 815R24007.) estimate of the safe dose is 0.1 ng of PFOS/kg-day.

Read-across (RAx) and grouping of chemicals into categories are well-known concepts in toxicology. Recently, ECHA proposed a grouping approach for branched-chain carboxylic acids (BCAs) including more than 60 branched-chain saturated carboxylic acids for hazard identification. Grouping was based only on structural considerations. Due to developmental effects of two members, ECHA postulated that "all short carbon chain acids ... are likely reproductive and developmental toxicants". This work analyzes available data for BCAs. The number of compounds in the group can be significantly reduced by eliminating metal and organic salts of BCAs, compounds of unknown or variable composition, and complex reaction products or biological materials (UVCB compounds). For the resulting reduced number of compounds, grouping is supported by similar physicochemical data and expected similar biotransformation. However, analysis of adverse effects for compounds in the group and mechanistic information show that BCAs, as a class, do not cause developmental effects in rats. Rather, developmental toxicity is limited to selected BCAs with specific structures that share a common mode of action (histone deacetylase inhibition). Thus, the proposed grouping is unreasonably wide and the more detailed analyses show that structural similarity alone is not sufficient for grouping branched-chain carboxylic acids for developmental toxicity.

Abstract Background Exposure to poly- and perfluoroalkyl substances (PFAS) may affect infant and childhood health through immunosuppression. However, the findings of epidemiological literature examining relationships between prenatal/childhood PFAS exposure and vaccine response and infection in humans are still inconclusive. The aim of this review was to examine the effects of PFAS exposure on vaccine antibody response and infection in humans. Methods The MEDLINE/Pubmed database was searched for publications until 1 February 2023 to identify human studies on PFAS exposure and human health. Eligible for inclusion studies had to have an epidemiological study design and must have performed logistic regression analyses of gestational or childhood exposure to PFAS against either antibody levels for pediatric vaccines or the occurrence of children’s infectious diseases. Information on baseline exposure to PFAS (in ng/mL), the age of PFAS exposure (gestational or in years), and the outcome was measured, potentially leading to multiple exposure-outcome comparisons within each study was collected. Percentage change and standard errors of antibody titers and occurrence of infectious diseases per doubling of PFAS exposure were calculated, and a quality assessment of each study was performed. Results Seventeen articles were identified matching the inclusion criteria and were included in the meta-analysis. In general, a small decrease in antibody response and some associations between PFAS exposure and childhood infections were observed. Conclusions This meta-analysis summarizes the findings of PFAS effects on infant and childhood immune health. The immunosuppression findings for infections yielded suggestive evidence related to PFAS exposure, particularly PFOS, PFOA, PFHxS, and PFNA but moderate to no evidence regarding antibody titer reduction. Systematic review registration The research protocol of this systematic review is registered and accessible at the Open Science Framework (https://doi.org/10.17605/OSF.IO/5M2VU).

Although inflammation is a normal and beneficial response, it is also a key event in the pathology of many chronic diseases, including pulmonary and systemic particle-induced disease. In addition, inflammation is now considered as the key response in standard settings for inhaled particles and a critical endpoint in OECD-based sub-acute/ chronic animal inhalation testing protocols. In this paper, we discuss that whilst the role of inflammation in lung disease is undeniable, it is when inflammation deviates from normal parameters that adversity occurs. We introduce the importance of the time course and in particular, the reversibility of inflammation in the progression towards tissue remodelling and neoplastic changes as commonly seen in rat inhalation studies. For this purpose, we used sub-chronic/ chronic studies studies with synthetic amorphous silicas (SAS) and reactive crystalline silica (RCS) as a source of data to describe the time-course of inflammation towards and beyond adversity. Whilst amorphous silicas induce an acute but reversible inflammatory response, only RCS induces a persistent, progressive response after cessation of exposure, resulting in fibrosis and carcinogenicity in rodents and humans. This suggests that the use of inflammation as a fixed endpoint at the cessation of exposure may not be a reliable predictor of particle-induced lung pathology. We therefore suggest extending the current OECD testing guidelines with a recovery period, that allows inflammation to resolve or progress into altered structure and function, such as fibrosis.

Polyolefin pipes used in drinking water distribution systems require a number of functional additives to ensure stability and durability. Some of these additives and/or their degradation products may migrate from the pipes into the drinking water. Previously, a number of branched chain alkylphenol degradants have been identified in drinking water; these were termed "Arvin substances" and numbered Arvin 1-10. As potential genotoxicity is a human health safety concern, the genotoxicity of Arvin substances is reviewed based on comprehensive in vitro and in vivo data available. Results obtained from genotoxicity studies addressing mutagenicity and clastogenicity are available for nine of the ten Arvin substances. These nine Arvin substances were consistently negative in bacterial mutagenicity studies. Divergent results were obtained in clastogenicity assays with some positive responses induced by the branched chain alkylphenols Arvin 1, 2, and 4, often accompanied by significant cytotoxicity. However, Arvin 1, 2, and 4 did not induce micronuclei or genotoxicity in vivo during follow-up testing. The other Arvin compounds did not show genotoxic activity in vitro. In conclusion, regarding human health risk characterization, the Arvin compounds are not considered genotoxic agents based on the available data.

The respiratory health effects of Synthetic Amorphous Silica (SAS) have been studied in human epidemiological research. This article presents a historical overview and review of nine occupational worker studies that have been conducted so far on this topic. The combined study population of all of these studies included 1172 employees, and exposure concentrations ranged from < 1 mg/m(3) to 100 mg/m(3). In two studies with a total of 293 workers, the incidence of silicosis was investigated after long-term exposure to precipitated SAS, and no cases of silicosis were found (Plunkett and Dewitt, 1962; Volk, 1960). In another study, the spirometry results of 40 workers were normal (Vitums et al., 1977). In a study of 28 workers, 4 cases of silicosis were identified, but it is possible that contamination with cristobalite occurred and detailed information about the amorphous silica origin was not provided (Mohrmann and Kahn, 1985). Ferch et al. (1987) found that lung impairment was associated with confounding factors (smoking) but not with exposure to precipitated SAS in a study of 143 workers. Choudat et al. (1990) reported a reduction in forced expiratory flow in a group exposed to precipitated SAS compared to a control group. Still, they found no correlation between the extent of exposure and pulmonary function was found in a study of 131 workers. Wilson et al. (1979) also failed to show a significant association between the degree of exposure to precipitated SAS and annual changes in lung function in a study of 165 workers. In the most recent and most extensive study (Taeger et al., 2016; Yong et al., 2022) in Germany, involving 462 factory workers, no association between inhalable or respirable SAS dust exposure and respiratory health was reported. Based on the available data, there is no evidence-base to support a relationship between SAS and respiratory health in humans.

1,1,2-Trifluoroethene (HFO-1123) is anticipated for use as a refrigerant with low global warming potential. Inhalation studies on HFO-1123 in rats indicated a low potential for toxicity (NOAELs ≥ 20,000 ppm). In contrast, single inhalation exposure of Goettingen ® minipigs (≥ 500 ppm) and New Zealand white rabbits (≥ 1250 ppm) resulted in severe toxicity. It has been suggested that these pronounced species-differences in toxicity may be attributable to species-differences in biotransformation of HFO-1123 via the mercapturic acid pathway. Therefore, the overall objective of this study was to evaluate species-differences in glutathione (GSH) dependent in vitro metabolism of HFO-1123 in susceptible versus less susceptible species and humans as a basis for human risk assessment. Biotransformation of HFO-1123 to S -(1,1,2-trifluoroethyl)- L -glutathione (1123-GSH) and subsequent cysteine S-conjugate β-lyase-mediated cleavage of the corresponding cysteine conjugate (1123-CYS) was monitored in hepatic and renal subcellular fractions of mice, rats, minipigs, rabbits, and humans. While 1123-GSH formation occurred at higher rates in rat and rabbit liver S9 compared to minipig and human S9, increased β-lyase cleavage of 1123-CYS was observed in minipig kidney cytosol as compared to cytosolic fractions of other species. Increased β-lyase activity in minipig cytosol was accompanied by time-dependent formation of monofluoroacetic acid (MFA), a highly toxic compound that interferes with cellular energy production via inhibition of aconitase. Consistent with the significantly lower β-lyase activity in human cytosols, the intensity of the MFA signal in human cytosols was only a fraction of the signal obtained in minipig subcellular fractions. Even though the inconsistencies between GSH and β-lyase-dependent metabolism do not allow to draw a firm conclusion on the overall contribution of the mercapturic acid pathway to HFO-1123 biotransformation and toxicity in vivo, the β-lyase data suggest that humans may be less susceptible to HFO-1123 toxicity compared to minipigs.

• Ethyl 3-phenylpropionate; a safety assessment based on RIFM's criteria. • A safety assessment based on 7 human health endpoints plus environmental. • All endpoints were cleared using target data, read-across, and/or TTC.

Hazardous properties of a large number of esters of 4-hydroxybenzoic acid (parabens) have been proposed by ECHA to be assessed as a group. We recommend to restrict the grouping approach to short chain esters, i.e. methyl, ethyl, propyl and butyl paraben which are very similar in chemical structures, physicochemical properties, toxicokinetics, and hazardous properties. While these parabens show a weak estrogenicity in some in vitro or in vivo screening assays, they do not induce estrogen-receptor-mediated adverse effects in intact animals. Therefore, there is no support regarding classification and labeling of endocrine disruption or reproductive toxicity of these parabens.

Inhalation toxicity testing of particulate materials is mandated for classification. According to CLP, particulate materials should be tested as marketed and many particulate materials are marketed as non-respirable particles. However, OECD TG 413 requires exposure to particle sizes that are respirable and reach the alveoli. The requirement for exposure of rats to respirable particles is thus in contrast to CLP and requires the application of high shear forces. The exposure to artificially small particles causes a number of issues that hamper the interpretation of the results of the testing. These issues are aerosol altering in the exposure system, assessment of the adversity of the inflammatory lung responses, inclusion of recovery groups, and extrapolation of the results to humans exposed under occupational condition. In addition, effects of many particulate materials after testing according to OECD 413 are not intrinsic properties, but a general reaction of the lung to the deposited material, show very similar NOAECs for chemical diverse materials, and often are completely reversible.

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health.

While trifluoroacetic acid has limited technical uses, the highly water-soluble trifluoroacetate (TFA) is reported to be present in water bodies at low concentrations. Most of the TFA in the environment is discussed to arise from natural processes, but also with the contribution from decomposition of environmental chemicals. The presence of TFA may result in human exposures. For hazard and risk assessment, the mammalian toxicity of TFA and human exposures are reviewed to assess the margin of exposures (MoE). The potential of TFA to induce acute toxicity is very low and oral repeated dose studies in rats have identified the liver as the target organ with mild liver hypertrophy as the lead effect. Biomarker analyses indicate that TFA is a weak peroxisome proliferator in rats. TFA administered to rats did not induce adverse effects in an extended one-generation study and in a developmental toxicity study or induce genotoxic responses. Based on recent levels of TFA in water and diet, MoEs for human exposures to TFA are well above 100 and do not indicate health risks.

Mintlactone (chemical name 3,6-dimethyl-5,6,7,7a-tetrahydro-1-benzofuran-2(4H)-one, CAS Number 13341-72-5) is a fragrance and flavor ingredient with reported uses in many different cosmetics, personal care, and household products. In order to evaluate the genotoxic potential of mintlactone, in vitro and in vivo genotoxicity tests were conducted. Results from bacterial mutagenicity tests varied across different batches of differing purity with positive results observed in TA98 only. An in vivo comet assay was also considered to be positive in livers of female mice but negative in male mice. In contrast, in vitro and in vivo micronucleus tests, as well as 3D skin comet/micronucleus tests, were negative, indicating no chromosomal or DNA damage. The underlying causes for these contradictory results are not clear. It appears that the purity and/or stability of the test material may be an issue. In the absence of dependable scientific information on the purity and/or storage stability of mintlactone, its safety for use as a fragrance ingredient cannot be substantiated.