Derived No-effect Levels Research Articles

Toxicity reference values for force health protection: Provisional occupational exposure guidelines

Force Health Protection programs in the U.S. Air Force endeavor to sustain the operational readiness of the warfighters. We have previously identified hundreds of chemical substances of interest and toxicity reference value (TRV) knowledge gaps that constrain risk based-decision-making for potential exposures. Multiple approaches to occupational TRV estimation were used to generate possible guideline values for 84 compounds (18% of the substances of interest). These candidate TRVs included values from international databases, chemical similarity (nearest neighbor) approaches, empirical adjustments to account for duration differences, quantitative activity relationships, and thresholds of toxicological concern. This present work describes derivation of provisional TRVs from these candidate values. Rodent bioassay-derived long-term worker Derived No-Effect Levels (DNELs) were deemed presumptively the most reliable, but only 19 such DNELs were available for the 84 substances with TRV gaps. In the absence of DNELs, the quality of the approaches and consistency among candidate values were key elements of the weight of evidence used to select the most suitable guideline values. The use of novel nearest-neighbor approaches, empirical adjustment of short term TRVs, and occupational exposure bands were found to be options that would allow occupational TRV estimation with reasonable confidence for nearly all substances evaluated.

Toxicity reference values (TRVs) for force health protection: Gap identification and TRV prediction

The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.

Assessment of the suitability of selected non-measuring models for dermal exposure estimation for the purposes of assessing compliance of working conditions with restrictions 71 and 76 in Annex XVII of the REACH regulation

Occupational exposure to chemicals occurs mainly through inhalation and the skin. The inhalation exposure assessment is regulated by law, while in Poland the method of conducting measurements for dermal exposure has not been indicated in the law. However, due to the restrictions 71 and 76 from Annex XVII of REACH for 1-methyl-2-pyrrolidone (NMP) and N,N-dimethylformamide (DMF), exposure assessment by the dermal route is necessary. These restrictions require to ensure that exposure of workers is below the derived no-effect levels (DNELs) for dermal exposure. The aim of the work was assessment of suitability of selected non-measurement forecasting models for the estimation of dermal occupational exposure to chemicals for the purposes of assessing compliance of working conditions with the restrictions 71 and 76 of the REACH regulation. Three tools estimating dermal exposure, recommended by European Chemical Agency (ECHA), were selected: ECETOC TRA, RISKOFDERM and IH SkinPerm, which were used to estimate 2 exemplary workplaces. Results of the estimations of dermal exposure showed that non-measuring models are useful for fulfilling the obligations under restrictions 71 and 76 of Annex XVII of REACH. The type of exposure scenario and amount of data available for the workplace are crucial for the selection of the model. The ECETOC TRA was considered the best model for this type of analysis, whose main advantages are direct comparison of the output data in mg/kg/day with the DNEL value and use of standardized descriptors system. Exposure modeling is a good and cheap way to determine the dermal exposure magnitude at workplaces, also to comply with the requirements of restrictions 71 and 76 of Annex XVII of REACH. The application of modeling in the case of occupational exposure by the dermal route is one of the solutions when it is necessary to comply with the DNEL for dermal exposure. Med Pr Work Health Saf. 2023;74(6):487-500.

Increasing exposure to the UV filters octocrylene and 2-ethylhexyl salicylate in Germany from 1996 to 2020: Human biomonitoring in 24-h urine samples of the German Environmental Specimen Bank (ESB)

The UV filters octocrylene (OC) and 2-ethylhexyl salicylate (EHS) are commonly used in sunscreens and frequently detected in environmental media. However, knowledge on human exposures is scarce.In this human biomonitoring (HBM) study, we analyzed concentrations of exposure biomarkers specific to OC (CPAA, DOCCA, 5OH-OC) and EHS (5OH-EHS, 5oxo-EHS, 5cx-EPS) in 24-h urine samples (n = 420) from the German Environmental Specimen Bank (ESB). These samples were collected from German students (20–29 years; 30 males/30 females per year) between 1996 and 2020 (4-year intervals; collection in winter).We found continuously increasing OC and EHS exposures (Jonckheere-Terpstra; p < 0.001) documented by very few to no samples with concentrations of the most sensitive biomarkers CPAA and 5cx-EPS above the limit of quantification (LOQ) in 1996 (5 % and 0 %, respectively) and reaching 100 % and 93 % above the LOQ in 2016, with median concentrations of 4.79 and 0.071 µg/L, respectively. In 2020, biomarker concentrations slightly decreased to 3.12 µg/L CPAA (97 %>LOQ) and 0.060 µg/L 5cx-EPS (88 %>LOQ). This general trend was confirmed by the other biomarkers, however at lower detection rates. Based on metabolite excretion in the 24-h urine samples and human toxicokinetic data, we calculated maximum daily intakes (DI) of 17 µg/(kg bw * d) OC and 59 µg/(kg bw * d) EHS. Based on a derived no-effect level (DNEL) of 0.8 mg/(kg bw * d), the OC exposures of individuals in our study did not indicate any health risk. Similarly, for EHS all biomarker concentrations were well below the HBM-I values of 12 µg/L 5OH-EHS and 11 µg/L 5cx-EPS.Our data proves the general applicability of specific OC and EHS metabolites for HBM in the general population and shows clearly increasing exposures. Higher (co-)exposures must be expected in populations with increased sunscreen use such as (summer) vacationers, children and outdoor workers.

Risk assessment of the asthma-induction potential of substances in spray products for car cabin detailing – based on EU’s Chemical Agents Directive, using harmonised classifications and quantitative structure-activity relationship (QSAR)

Exposure to spray-formulated products for car cabin detailing is a potential risk for asthma induction. With a focus on the asthma-related endpoints sensitisation and irritation of the lungs, we performed an occupational risk assessment based on requirements in the EU Chemical Agents Directive. We identified 71 such spray products available in Denmark. We identified ingredient substances in safety data sheets and screened for harmonised classifications of respiratory sensitisation and airway irritation. For respiratory sensitisation, we also applied quantitative structure-activity relationship (QSAR). We modelled the exposure during 15 min of work inside a car cabin, and determined the risk ratio of the products by further applying occupational exposure limits – mainly derived no-effect levels (DNELs) from the European Chemicals Agency (ECHA) set on respiratory irritation. Four substances had a harmonised classification for respiratory irritation (bronopol, 2-phenoxyethanol, 2-methoxypropanol, and butan-1-ol). Seven substances were positive in the QSAR model for respiratory sensitisation (monoethanolamine, bronopol, glycerol, methyl salicylate, benzoic acid, ammonium benzoate, and sodium benzoate). Two vinyl treatment products had a risk ratio > 1 based on the level of sodium benzoate and its DNEL set on respiratory irritation. Two products had risk ratios of 0.69 and 0.73, respectively, based on 2-methyl-2 H-isothiazol-3-one and its acute DNEL set on respiratory irritation. In conclusion, 10 substances that may pose a risk for asthma induction were identified in the products. Two of the 71 products had a risk ratio > 1, meaning they may pose an asthma-induction risk in the modelled exposure scenario and using respiratory irritation DNELs from ECHA.

Monitoring the exposure to ethoxyquin between 2000 and 2021 in urine samples from the German Environmental Specimen Bank

Human Biomonitoring (HBM) of emerging chemicals gained increasing attention within the EU in recent years. After evaluating the metabolism, we established a new HBM method for ethoxyquin (EQ), a feed additive, which was banned in 2017 due to concerns regarding the possible exposure of the general population to it and its highly toxic precursor p-phenetidine. The method was applied to 250 urine samples from the Environmental Specimen Bank collected between 2000 and 2021. The major metabolite EQI was quantified in the majority of the study samples illustrating the ubiquitous exposure of the non-occupationally exposed population. A rather constant exposure was observed until 2016 with a significant decline from 2016 to 2021. This drop falls within the EU wide ban of the chemical as a feed additive from June 2017 which led to a gradual removal until its complete suspension in June 2020. The daily intake (DI) was evaluated with respect to the reported derived no-effect level (DNEL) to estimate the potential health risks from EQ exposure. The median DI of 0.0181 µg/kg bw/d corresponds to only 0.01 % of the DNEL. Even the observed maxima up to 13.1 µg/kg bw/d only accounted for 10 % of the DNEL. Nevertheless, the values suggest a general exposure with the risk of higher burden in a low fraction of the population. In regard to the EQ associated intake of the carcinogen and suspected mutagen p-phenetidine, this level of exposure cannot be evaluated as safe. The recent decrease and the broad exposure substantiate the need for future HBM campaigns in population representative studies to further investigate the observed reductions, potentially find highly exposed subgroups and clarify the impact of the ban as feed additive on EQ exposure.

3. 1-Metylo-2-pirolidon. Dokumentacja proponowanych dopuszczalnych wielkości narażenia zawodowego

1-Methyl-2-pyrrolidone (NMP) exists as a hygroscopic liquid. This substance is produced and / or imported to the European Economic Area in large quantities (10.000–100.000 t/year). According to the information on the ECHA website, the substance has been registered under the REACH regulation, inter alia, by two registrants from Poland. NMP is mainly used as an industrial solvent in the production of chemicals and in the industrial production. In April 2018, the European Commission limited the use of NMP due to its properties which are posing a risk to human health. Restriction 71 of Annex XVII to REACH applies to manufacturing, placing on the market and using NMP. The derived no effect level (DNEL) values for worker exposure have been determined to be 14.4 mg/m3 for inhalation exposure and 4.8 mg/kg/day for dermal exposure. The NMP documentation with the proposed NDS value was revised due to the non-compliance of the NDS value applicable in Poland (NDS 40 mg/m3) with the DNEL value recommended by the Risk Assessment Committee: DNELinh.14.4 mg/m3. Introducing a standard at the level of the DNEL value would allow the use of NMP also in a concentration equal to or greater than 0.3%. For NMP, the critical effect is respiratory irritation, chemosensory effects and reproductive toxicity. It was proposed to keep the NDS NMP value applicable in Poland, i.e. 40 mg/m3. The basis for this value was respiratory irritation and chemosensory effects. Due to the irritating effect of the compound, the TLV value was left equal to 80 mg/m3. The proposed values are consistent with the values adopted in the European Union, contained in Directive 2009/161/EU. The DSB value was established at 20 mg 2-HMSI/g creatinine. The substance was labeled with the notation „skin”, „I” and with the notation „Ft”. This article discusses the problems of occupational safety and health, which are covered by health sciences and environmengig.

Occupational risk of nano-biomaterials: Assessment of nano-enabled magnetite contrast agent using the BIORIMA Decision Support System

The assessment of the safety of nano-biomedical products for patients is an essential prerequisite for their market authorization. However, it is also required to ensure the safety of the workers who may be unintentionally exposed to the nano-biomaterials (NBMs) in these medical applications during their synthesis, formulation into products and end-of-life processing and also of the medical professionals (e.g., nurses, doctors, dentists) using the products for treating patients. There is only a handful of workplace risk assessments focussing on NBMs used in medical applications. Our goal is to contribute to increasing the knowledge in this area by assessing the occupational risks of magnetite (Fe3O4) nanoparticles coated with PLGA-b-PEG-COOH used as contrast agent in magnetic resonance imaging (MRI) by applying the software-based Decision Support System (DSS) which was developed in the EU H2020 project BIORIMA.The occupational risk assessment was performed according to regulatory requirements and using state-of-the-art models for hazard and exposure assessment, which are part of the DSS. Exposure scenarios for each life cycle stage were developed using data from literature, inputs from partnering industries and results of a questionnaire distributed to healthcare professionals, i.e., physicians, nurses, technicians working with contrast agents for MRI. Exposure concentrations were obtained either from predictive exposure models or monitoring campaigns designed specifically for this study. Derived No-Effect Levels (DNELs) were calculated by means of the APROBA tool starting from in vivo hazard data from literature. The exposure estimates/measurements and the DNELs were used to perform probabilistic risk characterisation for the formulated exposure scenarios, including uncertainty analysis. The obtained results revealed negligible risks for workers along the life cycle of magnetite NBMs used as contrast agent for the diagnosis of tumour cells in all exposure scenarios except in one when risk is considered acceptable after the adoption of specific risk management measures. The study also demonstrated the added value of using the BIORIMA DSS for quantification and communication of occupational risks of nano-biomedical applications and the associated uncertainties.

Exposure Assessment of Toxicologically Relevant Volatile Organic Compounds Emitted from Polymer-Based Costume Masks.

Plastic costume masks regularly exhibit unpleasant odors that may be associated with the emissions of volatile organic compounds (VOCs). Upon inhalation, VOCs might adversely affect the wearer's health if the exposure exceeds regulatory threshold values. The VOCs emitted from a selection of costume masks (n = 12) were characterized semiquantitatively with a screening method based on GC/MS measurements in dynamic headspace sampling mode. Furthermore, odors associated with the masks were evaluated by a sensory panel. Two masks emitted particularly high concentrations of ethylbenzene, xylenes, and cyclohexanone and exhibited the most intense and unpleasant odors, which were described as rubber-like, pungent, and leather-like. To simulate and assess the inhalation exposures for wearers of these masks, an innovative experimental setup based on a doll's head was developed, with sampling of emitted volatiles on adsorption material and subsequent analysis by thermal desorption-GC/MS. The measured inhalable concentrations of cyclohexanone exceeded the derived no-effect level (DNEL) for systemic effects on the general population over several hours of wearing, and also after repeated use. Importantly, the cyclohexanone DNEL was reevaluated in relation to a recent study on inhalation toxicity in rodents and was found to be significantly lower (1.4 mg·m-3) compared to the industry-derived values (10-20 mg·m-3), thus aggravating the health risks associated with inhalation exposure from some of the costume masks tested. Finally, a comparison of the inhalable concentrations derived from the simulated exposure assessments with those derived from measurements in miniaturized emission test chambers indicate that microchambers represent a useful tool for high-throughput analysis. The influences of temperature and inhalation/exhalation flow rates on VOC exposures were also studied.

The REACH registration process: A case study of metallic aluminium, aluminium oxide and aluminium hydroxide

The European Union’s REACH Regulation requires determination of potential health and environmental effects of chemicals in commerce. The present case study examines the application of REACH guidance for health hazard assessments of three high production volume (HPV) aluminium (Al) substances: metallic aluminium, aluminium oxide, and aluminium hydroxide. Among the potential adverse health consequences of aluminium exposure, neurotoxicity is one of the most sensitive targets of Al toxicity and the most critical endpoint. This case study illustrates integration of data from multiple lines of evidence into REACH weight of evidence evaluations. This case study then explains how those results support regulatory decisions on classification and labelling. Challenges in the REACH appraisal of Al compounds include speciation, solubility and bioavailability, application of assessment factors, read-across rationale and differences with existing regulatory standards. Lessons learned from the present case study relate to identification and evaluation of toxicologic and epidemiologic data; assessing data relevance and reliability; development of derived no-effect levels (DNELs); addressing data gaps and preparation of chemical safety reports.

Human biomonitoring in urine samples from the Environmental Specimen Bank reveals a decreasing trend over time in the exposure to the fragrance chemical lysmeral from 2000 to 2018

2-(4-tert-butylbenzyl)propionaldehyde (trade names, e.g. lysmeral or lilial) is a fragrance chemical frequently used in cosmetic products where it is labelled as Butylphenyl methylpropional. A recently developed LC-MS/MS method for the analysis of four lysmeral metabolites (tert-butylbenzoic acid (TBBA), lysmerol, lysmerylic acid, and hydroxy-lysmerylic acid) was applied to 329 urine samples from the Environmental Specimen Bank collected between 2000 and 2018. The two major metabolites TBBA and lysmerol were found in quantifiable concentrations in almost all samples in this study and correlated significantly. Hence, both analytes proved to be specific biomarkers indicating the broad exposure to lysmeral. A significant decline was found for TBBA and lysmerol for the monitored years with the most pronounced decrease from 2012 to 2015. The daily intake (DI) was used to evaluate potential health risks with respect to the derived no-effect level (DNEL) as a threshold for exposure of the general population. The median DI (1.63 μg/kg bw/d) and the 95th percentile (4.69 μg/kg bw/d) corresponded to 2.6% and 7.5% of the lowest DNEL (62.5 μg/kg bw/d for oral administration), respectively. Even though a decreasing trend in exposure was observed the data still calls for efforts to reduce the exposure towards lysmeral since metabolites of lysmeral were detected in nearly all samples and adverse effects cannot be excluded. Clearly, these results need to be substantiated by HBM campaigns in population representative samples like the German Environmental Survey in adults (GerES VI) to provide more robust data for the adult population.

A scoping survey of attitudes towards occupational exposure limits and REACH derived no effect levels for workers among chemical risk managers at Swedish workplaces.

Setting and implementing occupational exposure limits (OELs) is one of the measures taken to protect workers from adverse effects of hazardous chemicals. The EU Regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) introduced an additional kind of exposure guidance values for workers; namely, the derived no effect level (DNEL) for workers' inhalation exposure (worker DNEL). About 500 substances have a Swedish OEL, while roughly 5000 substances have a worker DNEL derived by REACH registrants. This work aims to investigate how the Swedish OELs and worker DNELs are perceived at Swedish workplaces, and whether worker DNELs are considered a possible alternative to OELs when the latter are lacking. An online questionnaire was designed and sent to Swedish companies identified through the European Chemicals Agency's database of registered substances (N = 126) and the Swedish Chemicals Agency's registry of companies that import or manufacture notifiable chemical products (N = 227). The response rates were 52% and 38%, respectively. The respondents stated that they were using the Swedish OELs and most of them considered these to be a suitable risk management tool. As about one-third of the respondents expressed that they had some experience in using substances without the Swedish OELs, there are certain data gaps that worker DNELs may fill. One-third of the respondents familiar with worker DNELs stated that they would consider using worker DNELs for substances without the Swedish OELs. However, nearly half of the respondents reported to be unfamiliar with worker DNELs. Poor familiarity with DNELs may pose an obstacle to properly recognizing DNELs' potential as well as the possible limitations of individual DNELs. There is a need for education about DNELs, as well as for tools facilitating the evaluation of DNELs and OELs from other sources in cases where the applicable Swedish OEL is lacking. Int J Occup Med Environ Health. 2020;33(5):611-20.

Non-occupational exposure to phthalates in Finland

The aim of this study was to assess phthalate exposure of non-occupationally exposed working aged population in Finland. Studied phthalates included diethyl phthalate (DEP), di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), benzyl butyl phthalate (BzBP), dicyclohexyl phthalate (DCHP), di(2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-propylheptyl) phthalate (DPHP), and di-n-octyl phthalate (DnOP). Sample collection campaign took place in 2015.Metabolites of DEP, DnBP and DiBP were detected in all the first morning void urine samples of the non-occupationally exposed volunteers (n = 60; 42 women and 18 men; aged 25–63). Metabolite of BBP and secondary metabolites of DEHP and DiNP were detected in >90% of the samples. MCHP (1.7%), MEHP (18.3%), cx-MiNP (8.3%) and MnOP (1.7%) were less frequently detected. MiNP and OH-MPHP were not detected in any of the urine samples.The observed levels were mostly comparable to the levels published in the adult population in Europe and the US. One notable difference was the observed higher exposure of the Finnish study population to DnBP in comparison to the German, Austrian, Norwegian and US populations. The levels of individual phthalates did not often correlate very well with each other. In most cases, higher exposure to phthalates was seen in females in comparison to males, which is in accordance with other studies.The urinary levels were compared to the biomonitoring equivalents (BEs), which were calculated on the basis of published DNELs (derived no-effect levels). The P95 levels of individual phthalates remained below the respective BEs, the highest risk characterization ratio (RCR) being 0.88 for DnBP and the second highest 0.34 for DiBP. For other phthalates, the RCRs were below 0.2. Using the P95 levels, combined exposure to DnBP, DiBP, DEHP and BBP resulted in risk characterization ratio exceeding 1. This suggests a need to limit the exposure to these phthalates.

Comparison between Communicated and Calculated Exposure Estimates Obtained through Three Modeling Tools.

This study aims to evaluate the risk assessment approach of the REACH legislation in industrial chemical departments with a focus on the use of three models to calculate exposures, and discuss those factors that can determine a bias between the estimated exposure (and therefore the expected risk) in the extended safety data sheets (e-SDS) and the expected exposure for the actual scenario. To purse this goal, the exposure estimates and risk characterization ratios (RCRs) of registered exposure scenarios (ES; “communicated exposure” and “communicated RCR”) were compared with the exposure estimates and the corresponding RCRs calculated for the actual, observed ES, using recommended tools for the evaluation of exposure assessment and in particular the following tools: (i) the European Centre for Ecotoxicology and Toxicology of Chemicals Targeted Risk Assessment v.3.1 (ECETOC TRA), (ii) STOFFENMANAGER® v.8.0 and (iii) the Advanced REACH Tool (ART). We evaluated 49 scenarios in three companies handling chemicals. Risk characterization ratios (RCRs) were calculated by dividing estimated exposures by derived no-effect levels (DNELs). Although the calculated exposure and RCRs generally were lower than communicated, the correlation between communicated and calculated exposures and RCRs was generally poor, indicating that the generic registered scenarios do not reflect actual working, exposure and risk conditions. Further, some observed scenarios resulted in calculated exposure values and RCR higher than those communicated through chemicals’ e-SDSs; thus ‘false safe’ scenarios (calculated RCRs > 1) were also observed. Overall, the obtained evidences contribute to doubt about whether the risk assessment should be performed using generic (communicated by suppliers) ES with insufficient detail of the specific scenario at all companies. Contrariwise, evidences suggested that it would be safer for downstream users to perform scenario-specific evaluations, by means of proper scaling approach, to achieve more representative estimates of chemical risk.

Biomonitoring data on young adults from the Environmental Specimen Bank suggest a decrease in the exposure to the fragrance chemical 7-hydroxycitronellal in Germany from 2000 to 2018.

7-Hydroxy-3,7-dimethyl-1-octanal, also known as 7-hydroxycitronellal (7-HC, CAS No. 107-75-5) is a synthetic fragrance widely used in cosmetic and hygiene products. Because of its wide spread use and its known sensitizing properties, 7-HC was selected as one of 50 chemicals within the frame of the cooperation project between the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) and the German Chemical Industry Association (VCI) to develop a suitable human biomonitoring (HBM) method in order to assess the exposure of the general population in Germany. Within this scope, the recently published analytical method for urinary 7-hydroxycitronellylic acid (7-HCA), the major metabolite of 7-HC, was applied to 329 24h-urine samples of young adults (20 to 29 years) collected between 2000 and 2018 and stored in the Environmental Specimen Bank (ESB). The widespread exposure to 7-HC as already observed in a pilot study with 40 volunteers could be confirmed with quantifiable concentrations of 7-HCA in all 329 study samples (mean: 14.9ng/mL; median: 8.1ng/mL). A significant, chronological decrease in 7-HCA levels was found for the monitored years (2000, 2004, 2008, 2012, 2015, 2018). The most pronounced decline occurred between 2000 and 2004 (means: 34.37 versus 23.31, medians: 20.97 versus 12.49 μg/24h; p<0.01). On average, females exhibited higher levels of urinary 7-HCA compared to males (29.34 versus 17.21 μg/24h, p<0.05). Based on the urinary 7-HCA excretion, the daily intake (DI) of 7-HC normalized for body weight (bw) was estimated. Over all sampling years, average DI in females was significantly higher compared to males (0.99 versus 0.46μg/kgbw/d). Assuming dermal exposure as the main route of 7-HC intake, the mean DIs correspond to <0.1% of the derived no effect level (DNEL) of 1,100μg/kgbw/d defined by the European Chemical Agency (ECHA). The presented results for the exposure to the widely used fragrance 7-HC in Germany can be substantiated by applying the described methodology to the representative cohort of the launched German Environmental Survey in adults (GerES VI).

Industry Derived Occupational Exposure Limits: A Survey of Professionals on the Dutch System of Exposure Guidelines.

The Netherlands’ system for occupational exposure limits (OELs) encompasses two kinds of OELs: public and private. Public OELs are set by the government. Private OELs are derived by industry and cover all substances without a public OEL. In parallel, the regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) has introduced an exposure guidance value similar to the OEL, namely the Derived No-Effect Level (DNEL) for workers’ inhalation exposure. This study aimed to investigate issues encountered by occupational health professionals regarding private OELs, and how they perceive the DNELs for workers in relation to private OELs. Towards this aim, we sent out a web-based questionnaire to the members of the Dutch professional organization for occupational hygienists (Nederlandse Vereniging voor Arbeidshygiëne [NVVA], n = 513) and to members of the Dutch professional organization for safety engineers (NVVK, n = 2916). Response rates were 27% (n = 139) and 7% (n = 198), respectively. More occupational hygienists (59%) than safety engineers (17%) reported to derive private OELs themselves. Our respondents reported several challenges with the derivation of private OELs. Fifty-one percent of the occupational hygienists and 20% of the safety engineers stated to see a role of REACH Registrants’ worker DNELs as private OELs. However, more than half of our respondents were undecided or unfamiliar with worker DNELs. In addition, stated opinions on where worker DNELs fit in the hierarchy of private OELs varied considerably. To conclude, both these professional groups derive private OELs and stated that they need more guidance for this. Furthermore, there is a lack of clarity whether worker DNELs may qualify as private OELs, and where they would fit in the hierarchy of private OELs.

Threshold of Toxicological Concern (TTC) for Botanical Extracts (Botanical-TTC) derived from a meta-analysis of repeated-dose toxicity studies

Threshold of Toxicological Concern (TTC) is a promising approach for evaluating the human health risk for systemic toxicity when there is a lack of toxicological information. The threshold for systemic toxicity is reportedly 1800, 540, and 90 μg/day for Cramer I–III chemical structures, according to Munro’s structural decision tree, and 0.15 μg/day for genotoxic compounds. However, the concept of TTC has been developed for single substances; therefore, the applicability of TTC for mixtures remains unclear. To expand application of probability approach for mixtures, a validation study using the point of departures (PoDs) derived from mixtures is required.In the present study, we investigated novel TTC of botanical extracts (Botanical-TTC) for cosmetics from a meta-analysis based on the PoDs derived from repeated dose toxicity testing in botanical extracts. Accordingly, 213 PoDs were determined by repeated-dose toxicity studies and divided using a default uncertainty factor of 100 combined with the extrapolation factor of study duration to calculate the derived-no-effect-level (DNEL) and derived-minimal-effect-level (DMEL). The minimum DNEL/DMEL was 1.6-fold higher than the Cramer III TTC. In addition, because human health risk below the 1 st percentile value (663 μg/day) was considered as extremely limited, the exposure level can be proposed as Botanical-TTC.

Vapor Compounds Released from Nicotine-Free Inhalators as a Smoking-Cessation Aid

The health risks of cigarette smoking have been reported to increase continuously, while it is estimated to be responsible for the death toll of more than seven million people globally each year. In an effort to reduce the risk involved in cigarette smoking, nicotine-free inhalators have been developed as smoking-cessation aids. To evaluate the feasibility of nicotine-free inhalators in such respect, we investigated the composition of volatile organic compounds (VOCs) released from the consumption of nicotine-free inhalators of which major components include natural essential oils and traditional Chinese medicinal herbs. Vapor samples from nicotine-free inhalators were generated and collected for analysis using an e-cigarette auto-sampler. The vapor samples were captured onto a multi-bed sorbent tube sampler and a 2,4-dinitrophenylhydrazine (DNPH) cartridge for the quantitative analysis with the aid of thermal desorption-gas chromatography/mass spectrometry and high-performance liquid chromatography, respectively. A total of 29 VOCs were determined in vapor samples at concentrations below 0.2 ppm. Concentrations of (+)-isomenthone and acrolein slightly exceeded the derived no-effect level (DNEL) or sensory irritation level. However, VOCs were below the concentration exposure limit, according to the Occupational Safety and Health Administration (OSHA). According to our study, most of the aroma compounds and VOCs released from nicotine-free inhalator were lower than the DNEL or sensory irritation level. Consequently, it is found that nicotine-free inhalators could be safe to use in reference to toxic guidelines for inhalation exposure. However, if the use of nicotine-free inhalators is over prolonged period, it can also increase the risk of exposure to potentially toxic compounds.

A quantitative risk assessment for skin sensitizing plant protection products: Linking derived No-Effect levels (DNELs) with agricultural exposure models

Chemical skin sensitizers produce allergic contact dermatitis, which is one of the most frequent occupational diseases associated with chemical exposures. Skin exposure is the major route of exposure when using plant protection products (PPPs). Therefore, skin sensitization is an important factor to be addressed during the regulatory risk assessment of PPPs. The main regulatory decision criterion considered when performing risk assessment for skin sensitizers is the dose applied. The equally important criteria “potency of the substance” is insufficiently considered by two potency categories as potency may vary up to five orders of magnitude. “Frequency of exposure” to the skin sensitizer is not considered at all. Consequently, an improved risk assessment methodology is essential to adequately assess health risks from skin sensitizers, especially for agricultural operators using PPPs. A quantitative risk assessment (QRA) approach for addressing PPPs sensitizing potential is proposed here. This QRA combines a methodology to derive a substance-specific threshold for skin sensitizers, a Derived No-Effect Level (DNEL), and an agricultural exposure model used for assessing chronic health risks of PPPs. The proposed QRA for skin sensitizing PPPs is a clear improvement over current risk assessment to ensure the safe use of skin sensitizers in an occupational context.

Evaluation of risk assessment approaches of occupational chemical exposures based on models in comparison with measurements

Risk assessments of chemicals in work places are needed to protect workers’ health and safety. Several different strategies can be used for conducting risk assessments. The aim of this study was to investigate approaches to risk assessment of chemicals based on exposure assessment models relative to occupational exposure limits values (OELs) and derived no-effect levels (DNELs) and in comparison with measurements relative to OELs. A second aim was to evaluate the modelled recommended outcome and compare it with measurements of exposure. In this study, 29 situations were assessed with ECETOC TRA, Stoffenmanager® 5.1 and ART. Personal exposure measurements were also performed. The percentage of measured exposure exceeding the recommended output was calculated to investigate the level of conservatism. All the modelled exposures were compared with OELs and DNELs where possible, and the GM of the measured exposure was compared with OELs (risk quotas). For ECETOC TRA, 31% of measured exposure exceeded modelled exposure. For Stoffenmanager® it was 17% and for ART and ART B it was 3% and 0% respectively. Hence, according to our data, ECETOC TRA is the least conservative. An investigation of the risk quotas showed that ECETOC TRA had 4 false safe situations, meaning the risk was low when the model was used but was high when measurements were used. This may lead to underestimating risks. All models had an elevated proportion, ECETOC TRA and ART the highest, of false unsafe situations meaning the risk was low when measurements were used but high when models were used.