Respiratory Toxicity Research Articles

RIFM fragrance ingredient safety assessment, 3,7-dimethyl-1,3,6-octatriene, CAS registry number 13877-91-3

The existing information supports the use of this material as described in this safety assessment. 3,7-Dimethyl-1,3,6-octatriene was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from 3,7-dimethyl-1,3,6-octatriene and read-across analog myrcene (β-myrcene; CAS # 123-35-3) show that 3,7-dimethyl-1,3,6-octatriene is not expected to be genotoxic and provide a calculated margin of exposure (MOE) >100 for the repeated dose toxicity and developmental and reproductive toxicity endpoints. The skin sensitization endpoint was completed using the dermal sensitization threshold (DST) for non-reactive materials (900 μg/cm 2 ); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3,7-dimethyl-1,3,6- octatriene 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-1,3,6-octatriene is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 3,7-dimethyl-1,3,6- octatriene 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 oncentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, glyceryl monooleate, CAS Registry Number 111-03-5

The existing information supports the use of this material as described in this safety assessment.Glyceryl monooleate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that glyceryl monooleate is not genotoxic. Data on glyceryl monooleate 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 reactive materials (64 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; glyceryl monooleate 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 glyceryl monooleate is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; glyceryl monooleate 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 (VoU) in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

RIFM fragrance ingredient safety assessment, 2-mercaptopropionic acid, CAS Registry Number 79-42-5

The existing information supports the use of this material as described in this safety assessment. 2-Mercaptopropionic acid was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-mercaptopropionic acid 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 I material, and the exposure to 2-mercaptopropionic acid is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 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-mercaptopropionic acid is not expected to be phototoxic/photoallergenic. For the hazard assessment based on the screening data, 2-mercaptopropionic acid is not persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, 2-mercaptopropionic acid 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, p-tolualdehyde, CAS Registry Number 104-87-0

The existing information supports the use of this material as described in this safety assessment.p-Tolualdehyde was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, and environmental safety. Data from read-across analog benzaldehyde (CAS # 100-52-7) show that p-tolualdehyde is not expected to be genotoxic. Data from read-across analog cuminaldehyde (CAS # 122-03-2) provided p-tolualdehyde a No Expected Sensitization Induction Level (NESIL) of 1100 μg/cm2 for the skin sensitization endpoint. The repeated dose toxicity, developmental and reproductive toxicity, and local respiratory toxicity endpoints were completed using the threshold of toxicological concern (TTC) for a Cramer Class I material, and the exposure to p-tolualdehyde is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on data from read-across analog 4-ethylbenzaldehyde (CAS # 4748-78-1); p-tolualdehyde is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; p-tolualdehyde 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.

Respiratory and Systemic Toxicity of Inhaled Artificial Asian Sand Dust in Pigs.

Air pollution, particularly caused by Asian sand dust (ASD) and particulate matter (PM), has become one of the leading threats to public health. However, the majority of studies have primarily focused on epidemiological assessment, and in vivo toxicities of certain air pollutants have been poorly elucidated in medium/large-size laboratory animals. To investigate the impact of ASD in domestic animals, 16 Landrace pigs were exposed to an artificial ASD sandstorm for 6 h. All animals were divided in four cages, and a commercial yellow soil was used for generating artificial mineralogical particles. Blood samples were collected, and necropsies were performed before exposure and 6, 12, 24, and 72 h after exposure. Complete blood cell count and the levels of serum biochemical enzymes, blood gas, electrolytes, and a variety of inflammatory cytokines were evaluated. In addition, histopathological examination was conducted. Various test results proved acute lower airway disorders with systemic inflammation in pigs. To our knowledge, this study is the first to describe experimental research in domestic animals concerning the damage caused by artificial ASD exposure. The results of this study suggest that ASD has importance in terms of not only public health but also of ultimate economic losses in the pork industry.

Spirometric Measurement among Polyurethane Foam Mattress-making Workers of India.

Background:The polyurethane foam (PUF) mattress-making workers are exposed to isocyanates which are known respiratory toxicants and cause effect on pulmonary volumes and flows. Thus, the study was with a rationale to measure the changes in pulmonary flow and volumes due to isocyanates among PUF mattress-making workers.Materials and Methods:The study included 183 male workers from seven PUF making units of western and northern India. Using the interview technique as a tool for data collection, demographic and occupational details of the subjects were recorded on the predesigned and pretested pro forma. The mean of spirometric parameters was compared using one-way ANOVA and t-test. The relation between spirometric parameters and anthropometric parameters was analyzed using the correlation coefficient.Results:The spirometry showed that out of 183 participants, 165 (90.2%) subjects had normal spirometry, 13 (7.1%) had restrictive impairment, and 4 (2.2%) had obstructive impairment. All the mean spirometric values showed a declining trend with increasing age, while only forced expiratory volume in first second and forced vital capacity25%–75% showed a declining trend with increasing duration of employment. The spirometric measurements had a negative correlation with age and positive correlation with height.Conclusion:The spirometric values representing the airway flow were affected. The associated factors include age and duration of exposure.

A novel imine-linked covalent organic framework for rapid detection of methyl paraoxon.

Methyl paraoxon (MP) has attracted more and more attention in recent years because of its severe neurotoxicity and respiratory toxicity. Therefore, it is very urgent to develop new and sensitive MP detection methods for health protection and public safety. Covalent organic frameworks (COFs) are widely used in fluorescence detection because they can effectively transmit and amplify probe signals with multiple identical binding sites within an extended framework. Here, COFML-DHTA nanosheet material was synthesized by the solvothermal reaction of melem (ML) and 2,5-dihydroxyterephthalaldehyde (DHTA). The resulting COFML-DHTA exhibits remarkable luminescence quenching toward MP due to the relationship of competitive absorption and Förster resonance energy transfer between MP and COFML-DHTA. COFML-DHTA can be used for sensitive and selective detection of MP in a wide concentration range of 0.57 ng mL-1 to 30 μg mL-1 with a detection limit of 0.19 ng mL-1. The material has good chemical stability, excellent selectivity, good reusability and hydrophilicity, which provide more possibilities for COFs in the detection of pesticides.

A 7-month inhalation toxicology study in C57BL/6 mice demonstrates reduced pulmonary inflammation and emphysematous changes following smoking cessation or switching to e-vapor products

Cigarette smoking causes serious diseases, including lung cancer, atherosclerotic coronary artery disease, peripheral vascular disease, chronic bronchitis, and emphysema. While cessation remains the most effective approach to minimize smoking-related disease, alternative non-combustible tobacco-derived nicotine-containing products may reduce disease risks among those unable or unwilling to quit. E-vapor aerosols typically contain significantly lower levels of smoke-related harmful and potentially harmful constituents; however, health risks of long-term inhalation exposures are unknown. We designed a 7-month inhalation study in C57BL/6 mice to evaluate long-term respiratory toxicity of e-vapor aerosols compared to cigarette smoke and to assess the impact of smoking cessation (Cessation group) or switching to an e-vapor product (Switching group) after 3 months of exposure to 3R4F cigarette smoke (CS). There were no significant changes in in-life observations (body weights, clinical signs) in e-vapor groups compared to the Sham Control. The 3R4F CS group showed reduced respiratory function during exposure and had lower body weight and showed transient signs of distress post-exposure. Following 7 months of exposure, e-vapor aerosols resulted in no or minimal increase in pulmonary inflammation, while exposure to 3R4F CS led to impairment of lung function and caused marked lung inflammation and emphysematous changes. Biological changes observed in the Switching group were similar to the Cessation group. 3R4F CS exposure dysregulated the lung and nasal tissue transcriptome, while these molecular effects were substantially lower in the e-vapor group. Results from this study demonstrate that in comparison with 3R4F CS, e-vapor aerosols induce substantially lower biological responses including pulmonary inflammation and emphysematous changes, and that complete switching from CS to e-vapor products significantly reduces biological changes associated with CS in C57BL/6 mice.

In vitro prediction of clinical signs of respiratory toxicity in rats following inhalation exposure

To date there are no OECD validated alternative approaches to study toxicity following inhalation exposure to airborne chemicals. The available OECD test guidelines for acute inhalation toxicity aim to estimate a value of the lethal air concentration of the test chemical leading to the death of 50% of the exposed animals (LC50), to satisfy hazard classification and labelling requirements. This paper explores the view that alternative approaches must compare to outcomes of existing guideline methods to become accepted and implemented in a regulatory context. This case study describes the initiatives taken to validate the lung surfactant bioassay, an in vitro cell-free method, and discusses the challenges faced. While the lung surfactant bioassay could not predict the GHS classification for acute inhalation toxicity of 26 chemicals, the assay successfully predicted the clinical signs of respiratory toxicity observed during or shortly after exposure in vivo as reported in registration dossiers. The lung surfactant bioassay is a promising alternative approach to assess the potential of chemicals to cause changes to respiration remaining after exposure (indicating decreased lung function), and can be combined with other test methods in an integrated approach to testing and assessment of inhaled substances.

An adverse outcome pathway for lung surfactant function inhibition leading to decreased lung function

Inhaled substances, such as consumer products, chemicals at the workplace, and nanoparticles, can affect the lung function in several ways. In this paper, we explore the adverse outcome pathway (AOP) that starts when inhaled substances that reach the alveoli inhibit the function of the lung surfactant, and leads to decreased lung function. Lung surfactant covers the inner surface of the alveoli, and regulates the surface tension at the air–liquid interface during breathing. The inhibition of the lung surfactant function leads to alveolar collapse because of the resulting high surface tension at the end of expiration. The collapsed alveoli can be re-opened by inspiration, but this re-opening causes shear stress on cells covering the alveoli. This can damage the alveolar-capillary membrane integrity, allowing blood components to enter the alveolar airspace. Blood components, such as albumin, can interact with the lung surfactant and further inhibit its function. The collapse of the alveoli is responsible for a decrease in the surface area available for blood oxygenation, and it reduces the volume of air that can be inhaled and exhaled. These different key events lead to decreased lung function, characterized by clinical signs of respiratory toxicity and reduced blood oxygenation. Here we present the weight of evidence that supports the AOP, and we give an overview of the methods available in vitro and in vivo to measure each key event of the pathway, and how this AOP can potentially be used in screening for inhalation toxicity.

The oxidative capacity of indoor source combustion derived particulate matter and resulting respiratory toxicity

Indoor air pollution sources with emissions of fine particles (PM2.5), including environmental tobacco smoke (ETS) and incense smoke (IS) deteriorate indoor air quality and may cause respiratory diseases in humans. This study characterized the emission factors (EFs) of five types of tobacco and incense in Hong Kong using an environmental chamber. Human alveolar epithelial cells (A549) were exposed to PM2.5 collected from different indoor sources to determine their cytotoxicity. The PM2.5 EF of ETS (109.7±36.5 mg/g) was higher than IS (97.1±87.3 mg/g). The EFs of total polycyclic aromatic hydrocarbons (PAHs) and carbonyls for IS were higher than ETS, and these two combustion sources showed similar distributions of individual PAHs and carbonyls. Oxidative damage and inflammatory responses (i.e. DNA damage, 8-hydroxy-desoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6)) of A549 cells was triggered by exposure to PM2.5 generated from ETS and IS. Different indoor sources showed different responses to oxidative stress and inflammations due to the accumulation effects of mixed organic compounds. High molecular weight PAHs from incense combustion showed higher correlations with DNA damage markers, and most of the PAHs from indoor sources demonstrated significant correlations with inflammation. Exposure to anthropogenic produced combustion emissions such as ETS and IS results in significant risks (e.g. lung cancer) to the alveolar epithelium within the distal human respiratory tract, of which incense emissions posed a higher cytotoxicity.

MBCL-33. RARE PULMONARY TOXICITY IN THREE MEDULLOBLASTOMA PATIENTS UNDERGOING ANTIANGIOGENIC METRONOMIC COMBINATION THERAPY

BACKGROUNDMetronomic and targeted anti-angiogenesis therapy (MEMMAT) has emerged as a promising treatment for recurrent/progressive medulloblastoma. This treatment includes bevacizumab, oral agents (thalidomide, celecoxib, fenofibrate, etoposide & cyclophosphamide) and intrathecal chemotherapy (etoposide & cytarabine). Common toxicities include myelosuppression, nausea, and infection. Mild respiratory toxicities can occur. We report three cases with significant respiratory toxicity.METHODSAn IRB approved chart review was performed of three children with recurrent medulloblastoma on MEMMAT treatment and meaningful pulmonary toxicity. Literature review found no reports of similar findings.RESULTSPatient ages ranged from 3 to 11 years old. Patients completed a mean of 6.33 months on treatment. There was no history of chronic respiratory disease prior to starting MEMMAT. Patient #1 developed chronic cough requiring multiple respiratory and anti-infective treatments; CT scan demonstrated airspace opacities concerning for chronic inflammatory change. Each new viral infection led to significant respiratory distress. He eventually died from respiratory failure with large cystic lesions noted on CT. Patient #2 developed a chronic cough not responsive to antibiotics or respiratory treatments. Images reported airspace disease, bronchiectasis, and chronic inflammatory state. Patient #3 developed chronic cough without improvement despite antibiotics and inhaled respiratory treatments; images were suggestive of small airway disease. All three patients required numerous hospitalizations and additional treatment.CONCLUSIONWith MEMMAT, many side effects are expected though respiratory symptoms have rarely been reported. Our cases highlight the possible important correlation of pulmonary toxicity while being treated on MEMMAT, and its impact on patients’ overall health and quality of life.

RIFM fragrance ingredient safety assessment, methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate, CAS Registry Number 81752-87-6

The existing information supports the use of this material as described in this safety assessment. Methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate is not genotoxic. Data on methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate provide a calculated Margin of Exposure (MOE) >100 for the repeated dose toxicity endpoint. The reproductive and local respiratory toxicity endpoints were evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material, and the exposure to methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data show that there are no safety concerns for methyl-2,2-dimethyl-6-methylene-1-yclohexanecarboxylate for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl-2,2-dimethyl-6-methylene-1-cyclohexanecarboxylate 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, 3,4,4a,5,8,8a(Or 3,4,4a,7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran, CAS Registry Number 72429-08-4

The existing information supports the use of this material as described in this safety assessment. 3,4,4a,5,8,8a (Or 3,4,4a,7,8,8a)-Hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran 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 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran 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 non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3,4,4a, 5,8,8a (Or 3,4,4a,7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 3,4,4a, 5,8,8a (Or 3,4,4a, 7,8,8a)-hexahydro-3,3,6,7-tetramethyl-1H-2-benzopyran 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.

Long-term Testis Cancer Survivors in Canada—Mortality Risks in a Large Population-based Cohort

BackgroundTestis cancer (TC) patients are young with excellent cancer prognosis. Hence, the risk of late-onset treatment-related morbidity and mortality is of concern due to longer survival after treatment. ObjectiveWe set to characterize long-term survival of TC patients through a Canadian population dataset. Design, setting, and participantsWe used a population-based dataset, the Canadian Census Health and Environment Cohort (CanCHEC), to identify individuals diagnosed with TC between 1991 and 2010. We compared them with all other male individuals without TC. Outcome measurements and statistical analysisThe primary outcome was mortality due to cardiovascular disease (CVD) or nontesticular malignancy. Mann-Whitney or chi-square test was used where applicable. Data were analyzed using a Cox proportional hazard model with and without matching. Results and limitationsWe identified 1950 individuals with TC. We compared them with 1 300 295 men with no TC. There were 335 deaths in the study group during the study period (17.2%) with a mean follow-up of 19.6 yr. TC patients were at increased risk of death from secondary malignancies (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.39–1.91; p < 0.0001) with specific risks for hematologic neoplasms (HR 3.86, 95% CI 2.78–5.37; p < 0.001) and other malignancies (HR 2.41, 95% CI 1.76–3.29; p < 0.001). Gastrointestinal, hematologic, and respiratory toxicities were the most common secondary malignancies leading to death. When stratified according to histology, nonseminoma (NS) patients were at significantly increased risk of death from CVD (HR 2.03, 95% CI 1.27–3.25; p = 0.0032). Individuals with seminoma were at increased risk of death from other nontestis neoplasms (HR 1.46, 95% CI 1.17–1.82; p = 0.0007), specifically hematologic neoplasms (HR 2.09, 95% CI 1.18–3.72; p = 0.0118). ConclusionsNS patients are at increased risk of CVD-related death, whereas seminoma patients are at increased risk of death from non–testis-related malignancies. Patient summaryWe report long-term mortality following diagnosis of testis cancer. Nonseminoma patients have an increased risk of death from cardiovascular disease, while seminoma patients have an increased risk of death from secondary malignancies.

RIFM fragrance ingredient safety assessment, 2-cyclohexylcyclohexanone, CAS Registry Number 90-42-6

Summary: The existing information supports the use of this material as described in this safety assessment.2-Cyclohexylcyclohexanone was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data and read-across to 2-tert-butylcyclohexanone (CAS # 1728-46-7) show that 2-cyclohexylcyclohexanone is not expected to be genotoxic. Data on read-across material 2-sec-butylcyclohexanone (CAS # 14765-30-1) 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 UV spectra; 2-cyclohexylcyclohexanone 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 II material, and the exposure to 2-cyclohexylcyclohexanone is below the TTC (0.47 mg/day). The environmental endpoints were evaluated; 2-cyclohexylcyclohexanone 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-octanol, CAS Registry Number 589-98-0

Summary: The existing information supports the use of this material as described in this safety assessment.3-Octanol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 3-hexanol (CAS # 623-37-0) show that 3-octanol is not expected to be genotoxic. Data on 3-octanol provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity endpoint. Data on read-across analog 2-octanol (CAS # 123-96-6) provide a calculated MOE >100 for the reproductive toxicity endpoint 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; 3-octanol 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; 3-octanol 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-thiophenecarboxylic acid, ethyl ester, CAS Registry Number 2810-04-0

The existing information supports the use of this material as described in this safety assessment. 2-Thiophenecarboxylic acid, ethyl ester was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 2-thiophenecarboxylic acid, ethyl ester 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-thiophenecarboxylic acid, ethyl ester 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 non-reactive materials (900 μg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 2-thiophenecarboxylic acid, ethyl ester is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 2-thiophenecarboxylic acid, ethyl ester 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 <1.

RIFM fragrance ingredient safety assessment, hexyl 2-hydroxypropionate, CAS Registry Number 20279-51-0

Summary The existing information supports the use of this material as described in this safety assessment. Hexyl 2-hydroxypropionate 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 lactate (CAS # 97-64-3) show that hexyl 2-hydroxypropionate is not expected to be genotoxic, 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; hexyl 2-hydroxypropionate 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; the exposure is below the TTC (1.4 mg/day). The environmental endpoints were evaluated. For the hazard assessment based on the screening data, hexyl 2-hydroxypropionate is not persistent, bioaccumulative, and toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards. For the risk assessment, hexyl 2-hydroxypropionate 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.

Invited review: human air-liquid-interface organotypic airway tissue models derived from primary tracheobronchial epithelial cells-overview and perspectives.

The lung is an organ that is directly exposed to the external environment. Given the large surface area and extensive ventilation of the lung, it is prone to exposure to airborne substances, such as pathogens, allergens, chemicals, and particulate matter. Highly elaborate and effective mechanisms have evolved to protect and maintain homeostasis in the lung. Despite these sophisticated defense mechanisms, the respiratory system remains highly susceptible to environmental challenges. Because of the impact of respiratory exposure on human health and disease, there has been considerable interest in developing reliable and predictive in vitro model systems for respiratory toxicology and basic research. Human air-liquid-interface (ALI) organotypic airway tissue models derived from primary tracheobronchial epithelial cells have in vivo–like structure and functions when they are fully differentiated. The presence of the air-facing surface allows conducting in vitro exposures that mimic human respiratory exposures. Exposures can be conducted using particulates, aerosols, gases, vapors generated from volatile and semi-volatile substances, and respiratory pathogens. Toxicity data have been generated using nanomaterials, cigarette smoke, e-cigarette vapors, environmental airborne chemicals, drugs given by inhalation, and respiratory viruses and bacteria. Although toxicity evaluations using human airway ALI models require further standardization and validation, this approach shows promise in supplementing or replacing in vivo animal models for conducting research on respiratory toxicants and pathogens.