The changing outlook of psychedelic drugs: The importance of risk assessment and occupational exposure limits.

Serotonergic psychedelics, such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine (DMT), and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), are currently being investigated for the treatment of psychiatric disorders such as depression and anxiety. Clinical trials with psilocybin and LSD have shown improvement in emotional and psychological scores. Although these drugs are reported to be safe in a controlled environment (such as clinical trials), exposure to low doses of these drugs can result in psychedelic effects, and therefore, occupational safety is an important consideration to prevent adverse effects in the workplace from low daily exposure. This article will discuss the factors involved in the derivation of occupational exposure limits (OELs) and risk assessment of these psychedelic drugs. To support the OEL derivations of psychedelic drugs, information regarding their mechanism of action, adverse effect profiles, pharmacokinetics, clinical effects, and nonclinical toxicity were considered. Additionally, psilocybin and LSD, which are the most extensively researched psychedelic substances, are employed as illustrative examples in case studies. The OELs derived for psilocybin and for LSD are 0.05 and 0.002 µg/m3 , respectively, which indicates that these are highly hazardous compounds, and it is important to take into account suitable safety measures and risk-management strategies in order to minimize workplace exposure.

Core temperature and heart rate at the upper limit of the prescriptive zone.

The expressed goal of limiting workplace heat stress exposures to a core temperature (Tc ) of 38°C traces back to a 1969 World Health Organization Technical Report (WHO Series 412). The actual goal was to limit exposures to the upper limit of the prescriptive zone (ULPZ). To explore the physiological strain at the ULPZ, progressive heat stress protocol data from Penn State University (PSU) and University of South Florida (USF) below and at the ULPZ were used to articulate the relation of Tc and heart rate (HR) to metabolic rate (MR) with consideration of acclimatization state, clothing, exposure condition (PreULPZ vs. ULPZ), and sex. Regression models demonstrated the association of MR and sex with Tc and HR. At the ULPZ, women had systematically higher values of Tc and HR than men at the same MR likely due to higher relative demands. There was no effect for acclimatization state and clothing. As expected for individuals, Tc was practically constant below the ULPZ and HR exhibited increasing values approaching the ULPZ. At 490 W, the high MR cited in the WHO document, the mean Tc for men was near the 38°C limit with systematically lower Tc at lower MRs.

Use of the benchmark-dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N-nitrosamines.

N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry. The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 µg/m3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 µg/m3 ), followed by nitrosopyrrolidine (NPYR) (0.4 µg/m3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 µg/m3 ), nitrosomorpholine (NMOR) (OEL = 1 µg/m3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5 µg/m3 ). Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

[Butane-2-one oxime as a potential carcinogen for humans - evidence and effects on businesses resulting from reclassification]. / Oksym butan-2-onu jako potencjalny czynnik rakotwórczy dla ludzi ­ dowody i skutki dla przedsiebiorstw wynikajace ze zmiany klasyfikacji.

Evidence of a change in the carcinogenicity category of butan-2-one oxime (MEKO) and the results of this change for manufacturing and using companies was presented and assessed. The online databases of scientific journals were reviewed, taking into account the reports on the harmonization of MEKO classification and labeling at EU level available on the ECHA website. Commission Regulation (EU) 2020/1182 introduced harmonized classification and labeling of MEKO for carcinogenicity to category 1B. The induction of tumors, the nature and importance of tumors for humans, and the sensitivity of the 2 species tested, both sexes - all of these factors support the classification of MEKO into the carcinogenicity category 1B. On the other hand, MEKO is negative in genotoxicity studies, including in mammalian cells and in vivo in animals. This is the argument that the classification of MEKO as carcinogen category 2 remains appropriate. The change in the MEKO carcinogenicity category results in legal consequences for companies, such as compliance with the conditions of REACH restriction, which includes restrictions on placing MEKO on the market for sale to the general public, keeping a register of works that require contact with MEKO or its mixtures containing MEKO in a concentration ≥0.1%. According to the opinion of MEKO suppliers, there is currently no practical MEKO substitute that has been so well researched, despite attempts to find it in recent years. The risk of additional liver cancer in the case of 40-year occupational exposure to MEKO is 4:100 000 at a concentration of approx. 0.7 mg/m3, and it is an acceptable risk in accordance with the arrangements adopted in Poland. Compliance with the permissible concentrations of MEKO in the air of the working environment at this level should protect employees against the carcinogenic effect of MEKO. Med Pr. 2022;73(6):457-70.

Occupational exposure to BTEX and styrene in West Asian countries: a brief review of current state and limits.

The aim of introducing occupational exposure limits (OELs) is to use them as a risk management tool in order to protect workers' health and well-being against harmful agents at the workplace. In this review we identify OELs for benzene, toluene, ethylbenzene, xylene (BTEX), and styrene concentrations in air and assess occupational exposure to these compounds through a systematic literature search of publications published in West Asian countries from 1980 to 2021. OELs for BTEX and styrene have been set in Iran and Turkey to levels similar to those in European countries and the US. The search yielded 49 full-text articles that cover studies of exposure assessment in six countries, but most (n=40) regard Iran. Average occupational exposure to benzene of workers in oil-related industries is higher than recommended OEL, while average occupational exposure to other compounds is lower than local OELs (where they exist). Currently, information about levels of occupational exposure to BTEX and styrene is insufficient in West Asian countries, which should be remedied through OEL regulation and application. Furthermore, coherent research is also needed to determine actual levels of occupational exposure, dose-responses, and the economic and technical capacity of local industries to address current issues.

Exposure Assessment of Silver and Gold Nanoparticles Generated During the Synthesis Process in a South African Research Laboratory.

During the synthesis of engineered nanomaterials (ENMs), various occupational exposures occur, leading to health consequences. To date, there is paucity of studies focused on modeling the deposition of nanoparticles emitted from ENMs synthesis processes. This study aimed to characterise and assess exposure to gold (AuNPs) and silver nanoparticles (AgNPs) during a synthesis process in a research laboratory in South Africa. AuNPs and AgNPs synthesis processes were monitored for an hour in a laboratory using a Scanning Mobility Particle Sizer. The monitoring was conducted at a height of 1.2-1.5 m (m) and 1.5 m away from the hood, assuming a 30 cm (cm) breathing circumference zone. Each synthesis process was monitored thrice to generate reliable point estimates, which were used to assess exposure over 8 hours. A time-weighted average concentration was calculated and compared to the derived 8-h occupational exposure limit (OEL) for AgNPs (0.19 µg/m3) and the proposed provisional nano reference value for AuNPs (20,000 particles/cm3). The Multiple-Path Particle Dosimetry model was used to calculate the deposition and retention of both AuNPs and AgNPs. NPs emitted during the synthesis process were dominant in the nuclei (79% for AuNPs and 54% for AgNPs), followed by the Aitken (12% for AuNPs and 29% for AgNPs), with fewer particles in the accumulation mode (9.2% for AuNPs and 17% for AgNPs). AuNPs and AgNPs generated during the synthesis process were determined at 1617.3 ± 102 cm3 (0.046 µg/m3) and 2,687 cm3 ± 620 (0.077 µg/m3), respectively. For the three exposure scenarios, none exceeded the occupational exposure limit for both AuNPs (provisional) and AgNPs (OEL). Workers in the synthesis laboratory are exposed to a concentration below the recommended occupational exposure limit for silver and the proposed provisional nano reference value for gold. Although, the concentrations to which laboratory workers are exposed to are below safe levels, the assessment of the lung deposition patterns indicate a high particle lung retention which raise concerns about long term safety of workers.

Identifying nonhazardous substances in pharmaceutical manufacturing and setting default health-based exposure limits (HBELs).

Contract Development and Manufacturing Organizations (CDMOs) that manufacture large, diverse portfolio of chemical and pharmaceutical substances require pragmatic risk-based decisions with respect to the safe carry-over between different chemical entities, as well as for worker protection. Additionally, CDMOs may not have access to primary study data, or data are generally lacking for a specific substance. While pharmaceuticals require the establishment of health-based exposure limits (HBELs) (e.g., occupational exposure limits [OELs] and permitted daily exposure [PDE] limits), the limits for nonhazardous substances could be set in a protective and pragmatic way by using default values, when internally required. Because there is no aligned definition provided by authorities, nor agreed default values for nonhazardous substances, we provide a decision tree in order to help qualified experts (such as qualified toxicologists) to identify the group of nonhazardous substances and to assign default HBEL values for specific routes of exposure. The nonhazardous substances discussed within this publication are part of the following subgroups: (I) inactive pharmaceutical ingredients, (II) pharmaceutical excipients or cosmetic ingredients, (III) substances Generally Recognized as Safe (GRAS), and (IV) food ingredients, additives, and contact materials. The proposed default limit values are 1 mg/m3 for the OEL and 50 mg/day for the PDE oral and intravenous (IV) route.

[Health hazards resulting from occupational exposure to enfluran - overview of tests and analysis of admissible concentration values]. / Zagrozenia zdrowotne wynikajace z narazenia zawodowego na enfluran ­ przeglad badan i próba analizy wartosci dopuszczalnych stezen.

The aim of this work is to analyze the health hazards of enflurane exposure and to analyze the occupational exposure limits (OEL). The method of obtaining evidence based on a review of online databases of scientific journals was used. Enflurane is an inhalation anesthetic. Malignant hyperthermia, seizures, arrhythmias, respiratory depression and hypotension have been observed in patients. Occupational exposure to enflurane may occur in healthcare professionals. The target organ for enflurane is the central nervous system with a critical consequence of deterioration in psychomotor performance. In studies on volunteers recruited from the medical staff of operating rooms exposed to enflurane, a significant deterioration in the results of the Simple Reaction Time Test was shown. World experts' groups assume that the LOAEC (lowest observed adverse effect concentration) value for the deterioration of psychomotor test results is 5-10% of the MAC value (minimal anesthetic concentration), i.e., 6342-12 684 mg/m3. Assessment of the nephrotoxic potential of enflurane has shown that it is unlikely to occur because biotransformation of enflurane in humans results in a low peak serum fluoride concentration of 15 µmol/l. Early reports about liver damage in patients were not be supported. Occupational exposure epidemiological studies have raised concerns about the effects of anesthetic gas mixtures on the abortion rate or on fetal development and birth defects in children, but none of these studies specifically determined the type and concentration of anesthetic gases used. The carcinogenicity and mutagenicity studies were negative. Occupational exposure to enflurane is not monitored in Poland, as no standard value has been established for it in the air of the working environment. It is necessary to quickly introduce this anesthetic along with the applicable limit value to the OEL list. Med Pr. 2022;73(1):51-69.

Approaches for setting occupational exposure limits in the pharmaceutical industry.

The use of pharmaceutical drugs has provided a cure for many diseases. However, unintended exposure to drugs in the manufacturing workplace can cause significant health hazards to workers. It is important to protect the workforce from these deleterious effects by limiting exposure to an acceptable level, the occupational exposure limit (OEL). OEL is defined as airborne concentrations (expressed as a time-weighted average for a conventional 8-h workday and a 40-h work week) of a substance to which nearly all workers may be repeatedly exposed (for a working lifetime) without adverse effects. Determination of OELs has become very challenging over time, requiring an overall assessment of the preclinical and clinical data of the drug being manufactured. Previously, to derive OEL values, toxicologists used animal no-observed-adverse-effect level (NOAEL) data, which have been replaced with the overall assessment of animal and human data, placing a higher emphasis on human health-based data. A major advantage of working with human pharmaceuticals is that sufficient clinical data are available for them in most cases. The present manuscript reviews the latest knowledge regarding the derivation of occupational exposure limits as health-based exposure limits (HBELs) for pharmaceuticals. We have provided examples of OEL calculations for various drugs including levofloxacin (CAS No. 100986-85-4), dienogest (CAS no. 65928-58-7), and acetylsalicylic acid (ASA, CAS no. 50-78-2) using human data. This report will benefit professionals in the OEL domain in understanding this highly important, growing, and challenging field.

Altered toxicological endpoints in humans from common quaternary ammonium compound disinfectant exposure.

Humans are frequently exposed to Quaternary Ammonium Compounds (QACs). QACs are ubiquitously used in medical settings, restaurants, and homes as cleaners and disinfectants. Despite their prevalence, nothing is known about the health effects associated with chronic low-level exposure. Chronic QAC toxicity, only recently identified in mice, resulted in developmental, reproductive, and immune dysfunction. Cell based studies indicate increased inflammation, decreased mitochondrial function, and disruption of cholesterol synthesis. If these findings translate to human toxicity, multiple physiological processes could be affected. This study tested whether QAC concentrations could be detected in the blood of 43 human volunteers, and whether QAC concentrations influenced markers of inflammation, mitochondrial function, and cholesterol synthesis. QAC concentrations were detected in 80 % of study participants. Blood QACs were associated with increase in inflammatory cytokines, decreased mitochondrial function, and disruption of cholesterol homeostasis in a dose dependent manner. This is the first study to measure QACs in human blood, and also the first to demonstrate statistically significant relationships between blood QAC and meaningful health related biomarkers. Additionally, the results are timely in light of the increased QAC disinfectant exposure occurring due to the SARS-CoV-2 pandemic. MAIN FINDINGS: This study found that 80 % of study participants contained QACs in their blood; and that markers of inflammation, mitochondrial function, and sterol homeostasis varied with blood QAC concentration.

Trifluoroiodomethane (CF3I) (2019).

Trifluoroiodomethane (CF3I) is a colorless and odorless gas used primarily as a fire suppressant. CF3I has low acute inhalation toxicity. The no-observed adverse effect level (NOAEL) of CF3I for cardiac sensitization in dogs was 2000 ppm. The potential effects of 4-week inhalation exposure in both rats and mice have been examined. In rats, the NOAEL was 10,000 ppm, and in mice, the NOAEL was 10,000 ppm. In a subchronic inhalation study in rats, the lowest observed adverse effect level (LOAEL) was 20,000 ppm for thyroid-related effects; the study NOAEL (for non-thyroid-related effects) was 20,000 ppm. In a reproductive/developmental inhalation toxicity study in rats, 20,000 ppm CF3I produced minimal general toxicity and no indication of reproductive or developmental toxicity. The LOAEL for parental toxicity (based on thyroid hormone effects) was 2000 ppm; excluding thyroid effects, the parental NOAEL was 7000 ppm CF3I. The observed effects on the thyroid in rats were considered of less relevance to human risk assessment than the other observed systemic effects because of known species-specific differences in sensitivity to thyroid hormone perturbations. There are no chronic toxicity or carcinogenicity studies available. CF3I had mixed results in various in vitro and in vivo genotoxicity assays. The NOAEL of 7000 ppm from the reproductive/developmental inhalation study was used as the point of departure (POD) for workplace environmental exposure level (WEEL) value development. This POD was adjusted to account for interindividual variability, duration of exposure, and database limitations. The resulting 8-h time-weighted average WEEL value of 500 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to CF3I. A 15-min short-term exposure limit of 1500 ppm was also established to protect workers from potential cardiac effects produced by acute, high-dose inhalation of CF3I.

Establishing a health-based recommended occupational exposure limit for nitrous oxide using experimental animal data - A systematic review protocol.

Nitrous oxide (N 2 O) is widely used as inhalation analgesic and anaesthetic in medical, paramedical, and veterinary practice. Previous evaluations resulted in classification of N 2 O as a possible risk factor for adverse reproductive health outcomes based on evidence from animal data. Available human data were considered inadequate, partly due to the possibility that other risk factors, such as co-exposures to other inhalation anaesthetics may have contributed to the adverse outcomes. As no substantial new human evidence has emerged since previous evaluations, this protocol describes a planned systematic review of the evidence obtained from animal studies. The aim is to assess the available evidence on the effects of N 2 O on reproductive and developmental outcomes in animals to inform a health-based recommended occupational exposure limit (OEL) for N 2 O. Comprehensive search strategies were designed to retrieve animal studies addressing N 2 O exposure from PubMed, EMBASE, and Web of Science. Screening of the studies retrieved will be performed by at least two independent reviewers, while discrepancies will be resolved by reaching consensus through repeated review and discussions. Articles will be included according to criteria specified in this protocol. Outcome data relevant for reproduction and development will be extracted and risk of bias will be assessed by two independent reviewers using the SYRCLE's risk of bias tool. Primary reproductive and developmental outcomes of interest will be the number of resorptions, malformations, and birth weight. We will focus on dose-response studies that allow to derive an OEL with the benchmark dose (BMD) approach. Adverse outcomes occurring at doses that are equivalent to the exposures occurring in human occupational settings will be particularly relevant for dose-response modelling. The proposed review has not been performed before. We will follow the procedures specified in this protocol. We will adhere to guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), adapted for animal studies. Ethical approval will not be required, as the review will use existing data available in the public domain.

A risk assessment framework for self-management of poorly soluble low toxic nanomaterials.

The safety of nanomaterials is still being debated and the risk should be assessed using the latest available information. As for poorly soluble low toxic (PSLT) nanomaterials, the US National Institute for Occupational Safety and Health estimated the occupational exposure limit (OEL) for titanium dioxide (TiO2) based on a particle surface area (SA) metric. The Organisation for Economic Co-operation and Development (OECD) suggested a tiered exposure assessment approach. This article proposes a risk assessment framework for self-management of PSLT particles. Lung burden (described in SA units), which had positive correlation with low observed adverse effect levels for PSLT particles, is chosen as the dose metric. In-house OEL is determined for individual workplaces. For materials with limited data, we suggest evaluating in-house OEL by utilizing the no observed adverse effect level (NOAEL) for TiO2, as a representative PSLT nanomaterial. As for the exposure assessment, workplace concentration is first measured with simple equipment (ex. optical particle counter, OPC), and respirator performance is taken into account if it is unavoidable as a last resort. This framework enables efficient risk assessment for PSLT particles by assuming worst cases for each step, and considering the particle characteristics and operational conditions in each workplace.

An occupational exposure limit (OEL) approach to protect home healthcare workers exposed to common nebulized drugs.

Home healthcare is a growing area of employment. Assessment of occupational health risks to home health care workers (HHCWs) is important because in many cases the unique characteristics of the home environment do not facilitate the level of exposure control afforded to caregivers in hospitals and other fixed patient care sites. This assessment is focused on health risks to HHCWs from exposure to pharmaceutical drugs used to treat asthma and other respiratory diseases, which are commonly administered to patients in aerosolized form via nebulizers. We developed risk-based exposure limits for workers in the form of occupational exposure limits (OEL) values for exposure to nebulized forms of the three most common drugs administered by this method: albuterol, ipratropium, and budesonide. The derived OEL for albuterol was 2 µg/day, for ipratropium was 30 µg/day, and for budesonide was 11 µg/day. These OELs were derived based on human effect data and adjusted for pharmacokinetic variability and areas of uncertainty relevant to the underlying data (human and non-human) available for each drug. The resulting OEL values provide an input to the occupational risk assessment process to allow for comparisons to HHCW exposure that will guide risk management and exposure control decisions.

1,1,2,2-Tetrafluoroethane (HFC-134) (2018).

1,1,2,2-Tetrafluoroethane (HFC-134) is a colorless gas used as a foam expansion agent and heat transfer fluid. HFC-134 has a low acute inhalation toxicity with an LC50 of >244,000 ppm. The no-observed adverse effect level (NOAEL) and lowest-observed adverse effect level for cardiac sensitization (in epinephrine-challenged beagle dogs) were 75,000 and 100,000 ppm, respectively. A subacute 4-week GLP inhalation toxicity study exposed male and female Crl: CD®BR rats (10/sex) to 0, 2000, 10,000, or 50,000 ppm via whole-body inhalation. Transient and non-dose-response-related body weight changes were observed throughout the exposure period, but no statistically significant, test substance-related adverse effects were observed in any clinical observations, chemistry, hematology, or pathology. This study identified a NOAEL for HFC-134 of 50,000 ppm, the highest exposure level tested. HFC-134 is not genotoxic in in vitro studies; however, no in vivo studies are available. No developmental or maternal toxicity was found in female rats exposed to HFC-134 up to 50,000 ppm via whole-body inhalation in two different studies. Based on data for a similar material (HFC-134a), HFC-134 is not expected to be extensively metabolized or to cause genetic toxicity or carcinogenicity. The HFC-134 workplace environmental exposure level (WEEL) is based primarily on the subacute 4-week inhalation toxicity study in rats with the NOAEL of 50,000 ppm selected as the point of departure for the derivation of the 8-h TWA, health-based WEEL value. The developmental toxicity study also had a NOAEL of 50,000 ppm and was the highest exposure level tested. The subacute inhalation NOAEL was adjusted to account for interindividual variability, subacute to chronic duration, animal to human extrapolation, daily duration of exposure, and residual uncertainty. In addition, the lack of adverse effects noted in the toxicology studies for HFC-134a was considered. The resulting 8-h TWA WEEL value of 1000 ppm is expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFC-134.

Cytostatics as hazardous chemicals in healthcare workers' environment.

Cytostatics not only induce significant side-effects in patients treated oncologically but also pose a threat to the health of occupationally exposed healthcare workers: pharmacists, physicians, nurses and other personnel. Since the 1970s numerous reports from various countries have documented the contamination of working areas with cytostatics and the presence of drugs/metabolites in the urine or blood of healthcare employees, which directly indicates the occurrence of occupational exposure to these drugs. In Poland the significant scale of occupational exposure to cytostatics is also confirmed by the data collected in the central register of occupational carcinogens/mutagens kept by the Nofer Institute of Occupational Medicine. The assessment of occupational exposure to cytostatics and health risks constitutes employers' obligation. Unfortunately, the assessment of occupational risk resulting from exposure to cytostatics raises a number of concerns. Provisions governing the problem of workers' health protection are not unequivocal because they derive from a variety of law areas, especially in a matter of hazard classification and safety data sheets for cytostatics. Moreover, no legally binding occupational exposure limits have been set for cytostatics or their active compounds, and analytical methods for these substances airborne and biological concentrations are lacking. Consequently, the correct assessment of occupational exposure to cytostatics, the evaluation of health hazards and the development of the proper preventive strategy appear difficult. The authors of this article described and discussed the amendments to the European provisions concerning chemicals in the light of employers' obligations in the field of employees' heath protection against the consequences of exposure to cytostatics. Some modifications aimed at a more effective health protection of workers occupationally exposed to cytostatics were also proposed. Int J Occup Med Environ Health. 2019;32(2):141-59.

1,1,1,3,3,3-Hexamethyldisilazane (2018).

1,1,1,3,3,3-Hexamethyldisilazane (HMDZ) is used industrially to treat the surface of silica, as an intermediate adhesion promoter or silylating agent in the semiconductor industry, as a chemical modifier of inorganic fillers, and as a water scavenger silicone sealant. In animal studies, HMDZ is considered to be slightly to at most moderately toxic following acute administration via oral, dermal, and inhalation routes of exposure. HMDZ is neither an eye irritant nor was it dermally irritating under semiocclusive conditions; however, it caused dermal necrosis in two studies under occlusive conditions. HDMZ is not genotoxic or mutagenic in in vitro assays and was not reproductively or developmentally toxic in an inhalation screening study in rats. Short-term and subacute, high-dose inhalation exposure to HMDZ produced respiratory tract irritation, reduced feed consumption, changes in clinical chemistry parameters, and reversible central nervous system depression in rats. In a 90-day inhalation exposure study in rats, HMDZ exposure-related effects were observed in the kidneys of male rats but were determined to be alpha-2µ-nephropathy, thus, not relevant to humans. Based on the results of the 90-day (subchronic) inhalation study, 75 ppm was determined to be the no-observed adverse effect level (NOAEL) and was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, interindividual variability, and intraindividual variability. The resulting 8-h TWA WEEL value of 10 ppm is fully expected to provide a significant margin of safety against any potential adverse health effects in workers following long-term inhalation exposure to HMDZ vapor. A 15-min short-term exposure limit of 50 ppm was also established to protect workers from reversible effects produced by acute, high-dose inhalation of HMDZ vapor. A skin notation (Skin) is warranted because of the potential for the dermal route to significantly contribute to the overall exposure to HMDZ.

Cis-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-Z) (2018).

Cis-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-Z) is a clear, colorless liquid that finds uses as a foam-blowing agent, refrigerant, fire extinguishing agent, and solvent. HFO-1336mzz-Z is not an acute dermal or eye irritant and has very low acute toxicity via inhalation exposure (4-h lethal concentration (LC50) > 102,000 ppm). The no-observed adverse effect level (NOAEL) and lowest-observed adverse effect level (LOAEL) for cardiac sensitization (in epinephrine-challenged dogs) were 12,500 ppm and 25,000 ppm, respectively. In a GLP, subacute (4-week) repeat-dose inhalation study in Crl: CD(SD) male and female rats at exposure concentrations of 0, 2500, 5000, or 10,000 ppm, the only significant observations attributed to exposure were reduced body weight, reduced body weight gain, and reduced food consumption. The study NOAEL was determined to be 2500 ppm. Two separate GLP, 13-week repeat-dose inhalation studies (Organisation for Economic Cooperation and Development (OECD) 413) have been conducted on HFO-1336mzz-Z using male and female Crl: CD (SD) rats. In the first study, exposure concentrations were 0, 500, 1500, or 10,000 ppm, and in the second study, 0, 3000, 4000, 5000, or 7500 ppm. The only significant exposure-related observations in the first study were reductions in body weights, food consumption, and food efficiency in males and females at 10,000 ppm (study NOAEL = 1500 ppm). In the second study, done in part to better define the NOAEL, reductions in body weight and food consumption were observed in males at 7500 ppm; there were no exposure-related observations on these end points in females. Therefore, the study NOAEL was established at 5000 ppm for males and 7500 ppm for females. HFO-1336mzz-Z has also been examined for its potential to produce developmental toxicity in both Crl: CD(SD) rats (0, 500, 1500, or 10,000 ppm) and New Zealand White rabbits (0, 2500, 5000, 7500, or 15,000 ppm) according to GLP and OECD 414. The NOAEL for both maternal and fetal effects in rats was 1500 ppm and the NOAELs for maternal effects and fetal effects in rabbits were 5000 ppm and 7500 ppm, respectively. A non-GLP, two-generation reproductive pilot study, for a planned multigenerational study noted reduced body weight and body weight gain in males at 1500 ppm and above; the NOAEL for this pilot study was set at 500 ppm. There are no chronic toxicity/carcinogenicity studies available, and HFO-1336mzz-Z was not genotoxic/mutagenic in in vitro and in vivo studies. The NOAEL for male rats of 5000 ppm (based on reductions in body weight and food consumption) from the 13-week inhalation study was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, inter-individual variability, and intra-individual variability. The resulting 8-h TWA WEEL value of 500 ppm is fully expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFO-1336mzz-Z vapor.

Derivation of an occupational exposure limit for diacetyl using dose-response data from a chronic animal inhalation exposure study.

Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8 hour time-weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2 year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50 ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC10 ) and the associated 95% lower confidence bound (BMCL10 ), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics-physiologically based pharmacokinetic (CFD-PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8 hour TWA OEL values with a range of 0.16-0.70 ppm. The recommended 8 hour TWA OEL for diacetyl vapor of 0.2 ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health-protective.