Respiratory Toxicity Research Articles

A comparison study of test organism species and methodologies for combined toxicity assay of copper ions and zinc ions.

The general toxicity assays for evaluating the risk of aquatic environment were commonly based on single-species test organism models. Thus, the lack and conflict of the different responses among species had hindered researchers to assess the real toxicity of a target toxicant. Therefore, the difference between the test species and their corresponding methodologies was investigated in this work and three species, Escherichia coli, Saccharomyces cerevisiae and Misgurnus anguillicaudatus (a fish), were chosen as the test organism for typical prokaryotes, eukaryotes, and vertebrates, respectively. More specifically, we investigated (i) the individual and combined toxicity of Cu2+ and Zn2+ by the three test organisms; (ii) the different evaluation manners for the test organisms, including IC50 and toxic unit (TU) model for microorganisms by respiratory toxicity assay and enzyme-substrate assay, while survival time for fish; and (iii) the states of test organism, including suspended and immobilized states for microorganisms. The combined effects, includingsynergistic (Vt < Vp), antagonistic (Vt > Vp) and additive effects for the three species, were complex as that they were usually dose-dependent and could be changed by the different evaluation manners. The present work was useful for enriching of the associated theory and the insights from this work could open the way for further practical risk assessments.

Mucin corona delays intracellular trafficking and alleviates cytotoxicity of nanoplastic-benzopyrene combined contaminant

Nanoplastics have recently become a worldwide concern as newly emerging airborne pollutants, which can associate with polycyclic aromatic hydrocarbons (PAHs) and form combined contaminant nanoparticles (CCNPs). After being inhaled in the respiratory system, the CCNPs would first encounter the mucous gel layer being rich in mucin. Herein, polystyrene-benzopyrene (PS@Bap) NPs were prepared as CCNPs model and their interaction with mucin and the resultant biological responses were studied. It was observed that mucin corona stably attached to the CCNPs surface, which significantly altered the fate of the CCNPs in lung epithelial cells (A 549 cell line). The mucin corona would 1) stably adsorbed on PS@Bap at the early stages of endocytosis until degraded during the lysosomal transport and maturation process, 2) delay intracellular trafficking of PS@Bap and the progress of Bap detached from PS, 3) enhance uptake of PS@Bap but reduce the cytotoxicity elicited by PS@Bap, as indicated by cell viability, generation of reactive oxygen species, impairment on mitochondrial function, and further cell apoptosis. In addition, in vivo study also verified the enhanced effect of PS on the development of an acute lung inflammatory response induced by Bap. This study highlights the significance of incorporating the effects of mucin for precisely assessing the respiratory system toxicity of nanoplastics based CCNPs in atmospheric environments.

RIFM fragrance ingredient safety assessment, 2-benzyl-2-methylbut-3-enenitrile, CAS Registry Number 97384-48-0

The existing information supports the use of this material as described in this safety assessment.2-Benzyl-2-methylbut-3-enenitrile was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-benzyl-2-methylbut-3-enenitrile is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to 2-benzyl-2-methylbut-3-enenitrile is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). Data show that there are no safety concerns for 2-benzyl-2-methylbut-3-enenitrile for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-benzyl-2-methylbut-3-enenitrile is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2-benzyl-2-methylbut-3-enenitrile was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Toxicities of PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Immunotherapy, especially immune-checkpoint inhibitors (PD-1 and PD-L1 inhibitors), is now one of the mainstays of cancer treatment. Several studies have analyzed treatment-related toxicities of immunotherapy. However, small sample size, rough and unspecific stratification, and lack of comparison (pure sing-arm studies) are common limitations. Detailed organ- and system-specific toxicities remain not clear enough. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science and others (CNKI), from database inception to Mar 31, 2020, for randomized controlled trials (RCTs) related to PD-1/PD-L1 inhibitors that had available toxicity data. We excluded non-randomized trials. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. We calculated the pooled relative risks (RRs) and corresponding 95% confidence intervals (95% CIs) using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on toxicity grade (severity), system and organ, treatment regimens in the intervention arm and control arm, PD-1/PD-L1 inhibitor drug type, and cancer histotype. We applied the five-point Jadad ranking system to evaluate the quality of the selected studies. We performed multivariate meta-regression analyses to explore the proportion of between-study variance. Findings: A total of 29 eligible RCTs including 8067 patients were selected for the meta-analysis based on specified inclusion and exclusion criteria. Patients treated with PD-1/PD-L1 inhibitors were at lower risks of overall toxicities (all grades: RR 0.91, 95% CI 0.89-0.92; grade 3~4: RR 0.76, 95% CI 0.74-0.78), including gastrointestinal toxicity (all grades: RR 0.68, 95% CI 0.60-0.77; grade 3~4: RR 0.71, 95% CI 0.43-1.20), hematologic toxicity (all grades: RR 0.66, 95% CI 0.51-0.85; grade 3~4: RR 0.55, 95% CI 0.37-0.83), and treatment event leading to discontinuation (all grades: RR 0.78, 95% CI 0.72-0.84; grade 3~4: RR 0.58, 95% CI 0.49-0.67); but were at higher risks for respiratory toxicity (all grades: RR 1.74, 95% CI 1.33-2.28; grade 3~4: RR 1.92, 95% CI 1.45-2.55) and endocrine toxicity (all grades: RR 1.70, 95% CI 0.62-4.69; grade 3~4: RR 1.29, 95% CI 0.45-3.69). The subgroup analyses indicated that when compared with the control, toxicity comparison tendency for PD-1/PD-L1 inhibitors varied with the toxicity grade, affected system and organ, treatment regimens in the intervention arm and control arm, drug type, and cancer histotype. The male-female ratio was a statistically significant variable in the Meta-Regression analysis (I2=89.1, τ2=0.01, and P=0.001). Interpretation: For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and CTLA-4 inhibitors. However, for some specific toxicities including respiratory, cutaneous, and endocrine toxicities, the case was the opposite. The toxicity grade, system and organ, treatment regimens, drug type, and cancer histotype were all influencing factors. To our knowledge, this was by far the most comprehensive meta-analysis of RCTs on toxicities of immune-checkpoint inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations. Funding Statement: This work was supported by the Beijing Municipal Natural Science Foundation (No. 7204293 and No. 19G10077), the Special Research Fund for Central Universities, Peking Union Medical College (No. 3332019053), the Beijing Hope Run Special Fund of Cancer Foundation of China (No. LC2019B03 and No. LC2019L07), the Natural Science Foundation of China (No. 81872160), and National Key R&D Program of China (No. 2018YFC1315000 and No. 2018YFC1315003). The funders have no conflicts of interests. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The analysis followed the Strengthening the Reporting of observational Studies in Epidemiology (STROBE) guidelines. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College institutional review board approved this study as exempt.

RIFM fragrance ingredient safety assessment, propyl propionate, CAS Registry Number 106-36-5

Summary: The existing information supports the use of this material as described in this safety assessment. Propyl propionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that propyl propionate is not genotoxic. Data on propyl propionate provide a calculated margin of exposure (MOE) >100 for the repeated dose toxicity, reproductive toxicity, and local respiratory toxicity endpoints. Data from read-across analog pentyl propionate (CAS # 624-54-4) show that there are no safety concerns for propyl propionate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; propyl propionate is not expected to be phototoxic/photoallergenic. For the hazard assessment based on the screening data, propyl propionate is not persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, propyl propionate was not able to be risk screened as there were no reported volumes of use for either North America or Europe in the 2015 IFRA Survey.

RIFM fragrance ingredient safety assessment, dodecane, CAS Registry Number 112-40-3

Dodecane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog nonane (CAS # 111-84-2) show that dodecane is not expected to be genotoxic. Data on read-across analog undecane (CAS # 1120-21-4) provide a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet/visible (UV/vis) spectra; dodecane is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to dodecane is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; dodecane was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene, CAS Registry Number 125352-06-9

Summary: The existing information supports the use of this material as described in this safety assessment. Pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene is not genotoxic. Data on pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene provide a calculated MOE >100 for the repeated dose toxicity endpoint. Data on read-across analog 4-(3-phenylpropyl)pyridine (CAS # 2057-49-0) provide a calculated MOE >100 for the reproductive toxicity endpoint. The skin sensitization endpoint was completed using the DST for reactive materials (64 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class III material, and the exposure is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; pyridine, 4-ethenyl-, reaction products with 3a,4,7,7a-tetrahydrodimethyl-4,7-methano-1H-indene was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are

Effect of DPYD, MTHFR, ABCB1, XRCC1, ERCC1 and GSTP1 on chemotherapy related toxicity in colorectal carcinoma

ABCB1, DPYD, MHTFR, XRCC1, ERCC1, GSTP1 and UGT1A1 genetic variants affect proteins related to CRC chemotherapy toxicity.A retrospective cohort study was conducted in 194 CRC patients.In first line treatment, DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 4.85; p = 0.03); GSTP1 G-allele (OR = 3.01; p = 0.005) and MTHFR rs1801133 T allele (OR = 2.51; p = 0.03) with respiratory toxicity; GSTP1 G-allele with cardiovascular toxicity (OR = 4.05; p = 0.01); ERCC1 rs11615 GG genotype with neurological toxicity (OR = 3.98; p = 0.01) and with asthenia (OR = 2.91; p = 0.08); XRCC1 rs1799782 T allele (OR = 0.31; p = 0.03) and GSTP1 G-allele (OR = 1.81; p = 0.01) with cutaneous toxicity. In second line treatment, XRCC1 rs1799782 T-allele was associated with asthenia (OR = 0.17; p = 0.03) and XRCC1 rs25487 T-allele with gastrointestinal toxicity (OR = 3.03; p = 0.005). After stratifying by treatment, in the 5-Fluorouracil group, the DPYD rs17376848 AG genotype was associated with hematological toxicity (OR = 2.76; p = 0.003), ABCB1 rs1045642 T-allele with the need of treatment adjustment due to toxicity (OR = 3.06; p = 0.01), and rs1045642 CC genotype with gastrointestinal toxicity (OR = 5.80; p = 0.03). In the capecitabine group, the MTHFR rs1801131 CC genotype was associated with asthenia (OR = 3.48; p = 0.009). In the oxaliplatin group, rs1045642 TT genotype was associated with the need to adjust treatment (OR = 0.32; p = 0.02), ERCC1 rs11615 GG genotype with asthenia (OR = 3.01; p = 0.01) and rs1615 GSTP1 GG genotype with respiratory toxicity (OR = 5.07; p = 0.009).ABCB1 rs1045642 T-allele reduces the need for treatment modification with both 5FU and oxaliplatin. Although several biomarkers predicted different toxic effects, they cannot be considered as risk factors for severe toxicity.

RIFM fragrance ingredient safety assessment, 2-methyl-4-(camphenyl-8)-cyclohexanone, CAS Registry Number 68901-22-4

2-Methyl-4-(camphenyl-8)-cyclohexanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-methyl-4-(camphenyl-8)-cyclohexanone is not genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class III material, and the exposure to 2-methyl-4-(camphenyl-8)-cyclohexanone is below the TTC (0.0015 mg/kg/day, 0.0015 mg/kg/day, and 0.47 mg/day, respectively). The skin sensitization endpoint was completed using the Dermal Sensitization Threshold (DST) for reactive materials (64 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-methyl-4-(camphenyl-8)-cyclohexanone is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2-methyl-4-(camphenyl-8)-cyclohexanone was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, undecane, CAS Registry Number 1120-21-4

The existing information supports the use of this material as described in this safety assessment. Undecane was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog nonane (CAS # 111-84-2) show that undecane is not expected to be genotoxic. Data on undecane provide a calculated Margin of Exposure (MOE) >100 for the repeated dose and reproductive toxicity endpoints. Based on existing data and the application of the Dermal Sensitization Threshold (DST), undecane does not present a safety concern for skin sensitization under the current, declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; undecane is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to undecane is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; undecane was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC [Predicted Environmental Concentration/Predicted No Effect Concentration]), are <1.

RIFM fragrance ingredient safety assessment, 2-decanone, CAS Registry Number 693-54-9

The existing information supports the use of this material as described in this safety assessment.2-Decanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 2-heptanone (CAS # 110-43-0) show that 2-decanone is not expected to be genotoxic. Data on read-across analog 2-heptanone (CAS # 110-43-0) provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-decanone is not expected to be phototoxic/photoallergenic. For the local respiratory endpoint, a calculated MOE >100 was provided by the read-across analog 4-methyl-2-pentanone (CAS # 108-10-1). The environmental endpoints were evaluated; for the hazard assessment based on the screening data, 2-decanone is not persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, 2-decanone was not able to be risk screened as there were no reported volumes of use for either North America or Europe in the 2015 IFRA Survey.

RIFM fragrance ingredient safety assessment, ethyl lactate, CAS registry number 97-64-3

The existing information supports the use of this material as described in this safety assessment. Ethyl lactate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data on ethyl lactate show that ethyl lactate is not genotoxic and provided a calculated Margin of Exposure (MOE) > 100 for the repeated dose toxicity, reproductive toxicity, and local respiratory endpoints. Data from ethyl lactate and additional material ethyl (L)-lactate (CAS # 687-47-8) show that there are no safety concerns for ethyl lactate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; ethyl lactate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; ethyl lactate was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 2-propanol, 1,1′,1′,1'-(1,2-ethanediyldinitrilo)tetrakis-, CAS Registry Number 102-60-3

Summary: The existing information supports the use of this material as described in this safety assessment.2-Propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from the target material and read-across analog 1,1',1''-nitrilotripropan-2-ol (CAS # 122-20-3) show that 2-propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- is not expected to be genotoxic. Data on 2-propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- provide a calculated margin of exposure (MOE) >100 for the repeated dose toxicity and reproductive toxicity endpoints and show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class III material, and the exposure to 2-propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; 2-propanol, 1,1',1',1'-(1,2-ethanediyldinitrilo)tetrakis- was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Oxido-inflammatory responses and histological alterations in rat lungs exposed to petroleum product fumes.

Petroleum products-petrol, kerosene, and diesel-composed of volatile organic constituents contribute to air pollution. Exposure of gas station attendants (GSAs) to petroleum products fumes (PPFs) may account for occupation-related predisposition to respiratory toxicity and disease pathogenesis. We simulated GSA exposure to PPF inhalation and examined their effect on oxido-inflammatory responses, toxicity, and histopathological alterations in rat lungs, following 8-hours daily exposure for 60 and 90 days. Reactive oxygen and nitrogen species (RONS), oxidative stress and inflammatory biomarkers, namely: superoxide dismutase (SOD), reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione-S-transferase (GST), TNF-α, IL-1β, xanthine oxidase (XO), nitric oxide (NO) activity were evaluated. Besides, histopathological examination of the lungs and trachea of exposed rats, PPF exposure resulted in significant (P < .05) increases in RONS, biomarkers of oxidative stress, pro-inflammation cytokines, and reduced (P < .05) GSH levels in rats, secondary to histopathological alteration in lungs and trachea cytoarchitecture examined in an exposure-duration-dependent manner. We conclude, therefore, that the observed biochemical and histological changes create a microenvironment that is permissive to diseases pathogenesis of the respiratory system via oxido-inflammatory mechanistic pathways.

RIFM fragrance ingredient safety assessment, 2-methylpropyl pentanoate, CAS Registry Number 10588-10-0

The existing information supports the use of this material as described in this safety assessment.2-Methylpropyl pentanoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl 2-methylbutyrate (CAS # 7452-79-1) show that 2-methylpropyl pentanoate is not expected to be genotoxic and provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across analog isoamyl acetate (CAS # 123-92-2) show that there are no safety concerns for 2-methylpropyl pentanoate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-methylpropyl pentanoate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 2-methylpropyl pentanoate was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Biomarkers of Exposure among USA Adult Hookah Users: Results from Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2014).

Hookah smoking has become common in the USA, especially among young adults. This study measured biomarkers of exposure to known tobacco product toxicants in a population-based sample of exclusive, established hookah users. Urinary biomarker data from 1753 adults in Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study were used to compare geometric mean concentrations of biomarkers of exposure in exclusive, established past 30-day hookah users to never users of tobacco. Geometric mean ratios were calculated comparing hookah user groups with never users adjusting for age, sex, race/ethnicity, education, past 30-day marijuana use, secondhand smoke exposure and creatinine. Past 30-day hookah users (n = 98) had 10.6 times the urinary cotinine level of never tobacco users. Compared to never tobacco users, past 30-day hookah users had 2.3 times the level of the carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), a metabolite of the tobacco-specific nitrosamine (TSNA) 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 1.3 times higher polycyclic aromatic hydrocarbons (PAHs) 3-hydroxyfluorene and 1-hydroxypyrene, 1.8 times higher levels of acrylonitrile, 1.3 times higher levels of acrylamide, and 1.2 times higher levels of acrolein exposure. These data indicate that hookah use is a significant source of exposure to nicotine, carcinogens, and respiratory toxicants.

Hazardous air pollutant exposure as a contributing factor to COVID-19 mortality in the United States

To date, COVID-19 has claimed more than 100 000 American lives. Early inquiry suggests preexisting conditions are key risk factors contributing to COVID-19 mortality and air pollution exposure could exacerbate this relationship. Building on prior research linking deaths from respiratory viruses to air pollution exposures, we investigate how 2014 National Air Toxics Assessment hazardous air pollutants (HAPs) respiratory hazard quotient and respiratory hazard index are related to COVID-19 mortality. Our focus on HAPs builds upon the knowledge base linking poor air quality to COVID-19 mortality, since most (if not all) earlier studies only include criteria pollutants. Herein, we examine the relationship between HAP exposure and US-based COVID-19 mortality, while controlling for socioeconomic status, population health indicators, and exposure to PM2.5 and ozone. We fit county-level negative binomial mixed models, predicting COVID-19 mortality as a function of HAP respiratory toxicity levels and relevant covariates. We include models for combined exposure to HAPs, as well as for specific pollutants. We find that an increase in the respiratory hazard index is associated with a 9% increase in COVID-19 mortality. Although differing in magnitude, this association holds for individual HAPs acetaldehyde, and diesel PM. These findings help us to understand variation in US-based COVID-19 mortality rates, reinforce existing research linking air pollution to mortality, and emphasize the importance of regulatory efforts to limit air pollution exposure risk.

RIFM fragrance ingredient safety assessment, 4-ethylbenzaldehyde, CAS Registry Number 4748-78-1

The existing informationsupportsthe use of this material as described in this safety assessment. 4-ethylbenzaldehyde was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization, and environmental safety. Data on the read-across analog benzaldehyde (CAS # 100-52-7) show that 4-ethylbenzaldehyde is not expected to be genotoxic and provide a calculated margin of exposure (MOE) >100 for the repeated dose toxicity endpoint. Data on read-across analog 3,4-dimethylbenzaldehyde (CAS # 5973-71-7) provide a calculated MOE >100 for the developmental and reproductive toxicity endpoints. Data on read-across analog cuminaldehyde (CAS # 122-03-2) provided 4-ethylbenzaldehyde a No Expected Sensitization Induction Level (NESIL) of 1100 μg/cm². The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). The phototoxicity/photoallergenicity endpoints were evaluated based on data; 4-ethylbenzaldehyde is not phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-ethylbenzaldehyde was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 2-phenylpropionaldehyde, CAS Registry Number 93-53-8

Summary: The existing information supports the use of this material as described in this safety assessment.2-Phenylpropionaldehyde was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data on read-across analogs 3-phenylbutanal (CAS # 16251-77-7) and isopropylphenylbutanal (CAS # 125109-85-5) show that this material is not expected to be genotoxic. Data from the target material provide a calculated margin of exposure (MOE) >100 for the repeated dose toxicity endpoint and a No Expected Sensitization Induction Level (NESIL) of 380 μg/cm2 for the skin sensitization endpoint. The developmental and reproductive toxicity and the local respiratory toxicity endpoints were completed using the threshold of toxicological concern (TTC) for a Cramer Class I material (0.03 mg/kg/day and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 2-phenylpropionaldehyde is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2-phenylpropionaldehyde was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 3,7-dimethyl-3,6-octadienal, CAS registry number 55722-59-3

Summary: The existing information supports the use of this material as described in this safety assessment.3,7-Dimethyl-3,6-octadienal was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog citral (CAS # 5392-40-5) show that 3,7-dimethyl-3,6-octadienal is not expected to be genotoxic and provided a calculated margin of exposure (MOE) >100 for the repeated dose toxicity and developmental and reproductive endpoints. Data from the read-across analog citronellal (CAS # 106-23-0) provided 3,7-dimethyl-3,6-octadienal a No Expected Sensitization Induction Level (NESIL) of 7000 μg/cm2 for the skin sensitization endpoint. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3,7-dimethyl-3,6-octadienal is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to 3,7-dimethyl-3,6-octadienal is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 3,7-dimethyl-3,6-octadienal was found not to be persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.