European Union Registration Research Articles

International Consortium to Advance Cross-Species Extrapolation of the Effects of Chemicals in Regulatory Toxicology.

International Consortium to Advance Cross-Species Extrapolation of the Effects of Chemicals in Regulatory Toxicology.

Is assuming additivity of single-metal toxicity thresholds a conservative approach to assessing risk of ecotoxicity from elevated soil concentrations of cobalt, copper, and nickel at contaminated sites?

Multiple metal-impacted soils are often realistic scenarios for risk assessments, but tools to address these are currently lacking. The objective of this work was to evaluate whether assuming concentration addition (CA) of metal mixture effects was conservative for prospective risk assessment of soils that were elevated mainly in Ni and Cu and somewhat with Co, Pb, or As. Observed whole mixture toxicity for field soils with aged metal mixtures was compared to the expected whole mixture toxicity, assuming additivity of prospective single-metal thresholds ("toxic units") for the mixture components. Bioavailability-adjusted single-metal toxicity thresholds expected for those field soils were the median hazard concentration affecting 5% of species (HC5-50) from the predicted no-effect concentration (PNEC) calculator and calculated from the species-specific dose-response multiple linear relationships (MLRs), all from the European Union Registration, Evaluation, Authorisation and Restriction of Chemicals (EU REACH) dossiers for metals. Generic single-metal toxicity thresholds were based on Canadian Council of Ministers of the Environment soil quality guidelines (CCME SQGs) for agricultural soils. Observed toxicity thresholds were from the community-based risk assessments conducted for Port Colborne and Sudbury, Ontario, Canada. Mostly, prospective single-metal toxicity thresholds were protective relative to the observed toxicity, although that was species or ecological process dependent. The bioavailability-adjusted single-metal thresholds were less conservative than the CCME SQG method, even though the former is based on site-specific EC10 values, and the latter is based on generic EC25 values. When within-site variability in soil properties was used to calculate the 5th and 95th CI for the HC5 sum of toxic units (∑TUs), CA was conservative for far fewer endpoints. In addition, the prospective ∑TUs were more conservative predictions of the observed whole mixture toxicities for Port Colborne soils than for Sudbury soils. The most appropriate balance of accuracy and conservatism for identifying low-level risk of the whole mixtures in these soils appeared to be the bioavailability-adjusted HC5-50, which was applicable to many endpoints and 2 quite different exposure concentration ratios. Integr Environ Assess Manag 2021;17:753-766. © 2020 SETAC.

Comparing Options for Deriving Chemical Ecotoxicity Hazard Values for the European Union Environmental Footprint, Part II.

ABSTRACTUsing the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) ecotoxicity data, this paper compares 3 different approaches to calculate final substance toxicity hazard values using the USEtox approach (chronic EC50 + acute EC50/2), using only acute EC50 equivalent data (EC50eq), and using only chronic no observed effect concentration equivalent (NOECeq) data. About 4008, 4853, and 5560 substance hazard values could be calculated for the USEtox model, acute only, and chronic only approaches, respectively. The USEtox model provides hazard values similar to the ones based on acute EC50 data only. Although there is a large amount of variability in the ratios, the data support acute EC50eq to chronic NOECeq ratios (calculated as geometric mean) of 10.64, 10.90, and 4.21 for fish, crustaceans, and algae respectively. Comparison of the calculated hazard values with the criteria used by the EU chemical Classification, Labelling, and Packaging regulation (CLP) shows the USEtox model underestimates the number of compounds categorized as very toxic to aquatic life and/or having long‐lasting effects. In contrast, use of the chronic NOEC data shows a good agreement with CLP. It is therefore proposed that chronic NOECeq are used to derive substance hazard values to be used in the EU Environmental Footprint. Due to poor data availability for some chemicals, the uncertainty of the final hazard values is expected to be high. Integr Environ Assess Manag 2019;15:796–807. © 2019 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Effects of Silver Nitrate are a Conservative Estimate for the Effects of Silver Nanoparticles on Algae Growth and Daphnia magna Reproduction.

Silver (Ag) salts have been shown to be highly toxic to freshwater organisms. There is nevertheless still a high level of uncertainty as to the aquatic effects of Ag nanoparticles (AgNPs), and how these relate to the effects of soluble Ag salts. As part of the substance evaluation for Ag of the European Union Registration, Evaluation, Authorisation, and Restriction of Chemicals regulation, we have generated new data to justify read-across from soluble Ag salts to AgNPs. The aquatic toxicity to algae growth and Daphnia magna reproduction, fate, and behavior of AgNO3 versus AgNPs were tested and compared. Chloride salts in the test media were replaced with equimolar concentrations of nitrate salts. Total Ag, "conventionally" dissolved Ag (0.45 µm), and "truly" dissolved Ag (3 kDa) were determined. Algae were the most sensitive test species to AgNO3 (10% effect concentration [EC10] 0.10 µg Ag/L) when expressed as conventionally dissolved Ag. The corresponding value for AgNPs was 0.26 µg/L. For D. magna reproduction, the lowest EC10 values were 3.49 µg Ag/L for AgNO3 and 33.4 µg Ag/L for AgNPs. Using measured Ag concentrations, AgNO3 was experimentally shown to be more toxic than AgNPs for all Ag fractions. We explain these observations by a different dissolution behavior of AgNO3 versus AgNPs. The results provide experimental confirmation that AgNO3 can be used as a conservative estimate for the aquatic effects of AgNPs at comparable Ag concentrations. Environ Toxicol Chem 2019;38:1701-1713. © 2019 SETAC.

Toxicity studies used in registration, evaluation, authorisation and restriction of chemicals (REACH): How accurately are they reported?

Toxicity studies on chemicals registered under the European Union's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation are provided as summaries instead of as a full study report. Because the registration data are used by regulatory agencies to identify chemicals of concern, the study summaries must accurately reflect the information in studies. A "study summary" should include sufficient information on the objectives, methods, results, and conclusions in the full study report in order for the relevance of the study to be determined. Sometimes a "robust study summary" is required, which should contain more detailed information to enable an independent assessment of the study. The aim of the present investigation is to examine how well published toxicity papers were reflected in study summaries submitted by registrants under REACH. Summaries of 20 published studies (peer-reviewed studies, including 1 abstract) were examined and broad categories of various types of observed differences were derived. The extent to which information in the published studies was reported, as well as how accurately the information was reflected, varied. How accurately the information was reflected also varied. Differences between the published studies and the summaries included simple typing errors, unclear and incomplete reporting, as well as the omission of information on, for example, study design, results, or interpretation of the results, which in some cases could be considered relevant for the risk assessment. This raises concerns regarding the accuracy of study summaries and their use for decision making. Moreover, the possibility for third parties to independently assess and scrutinize the summaries is limited. Considering that we rely on REACH registration data for chemical safety, all data used for risk assessment should be accessible for thorough examination and fully independent assessment. Integr Environ Assess Manag 2019;00:000-000. © 2019 SETAC.

Concentration dependence of in vitro biotransformation rates of hydrophobic organic sunscreen agents in rainbow trout S9 fractions: Implications for bioaccumulation assessment.

In vitro biotransformation studies were performed to support the bioaccumulation assessment of 3 hydrophobic organic ultraviolet filters (UVFs), 4-methylbenzylidene camphor (4-MBC), 2-ethylhexyl-4-methoxycinnamate (EHMC), and octocrylene. In vitro depletion rate constants (kdep ) were determined for each UVF using rainbow trout liver S9 fractions. Incubations performed with and without added cofactors showed complete (4-MBC) or partial (EHMC and octocrylene) dependence of kdep on addition of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), suggesting that hydrolysis of EHMC and octocrylene by NADPH-independent enzymes (e.g., carboxylesterases) is an important metabolic route. The concentration dependence of kdep was then evaluated to estimate Michaelis-Menten parameters (KM and Vmax ) for each UVF. Measured kdep values were then extrapolated to apparent whole-body biotransformation rate constants using an in vitro-in vivo extrapolation (IVIVE) model. Bioconcentration factors (BCFs) calculated from kdep values measured at concentrations well below KM were closer to empirical BCFs than those calculated from kdep measured at higher test concentrations. Modeled BCFs were sensitive to in vitro binding assumptions employed in the IVIVE model, highlighting the need for further characterization of chemical binding effects on hepatic clearance. The results suggest that the tested UVFs are unlikely to accumulate to levels exceeding the European Union Registration, Evaluation, Authorisation, and Restriction regulation criterion for bioaccumulative substances (BCF > 2000 L kg-1 ). However, consideration of appropriate in vitro test concentrations and binding correction factors are important when IVIVE methods are used to refine modeled BCFs. Environ Toxicol Chem 2019;38:548-560. © 2018 SETAC.

Comparing the Advanced REACH Tool's (ART) Estimates With Switzerland's Occupational Exposure Data.

The Advanced REACH Tool (ART) is the most sophisticated tool used for evaluating exposure levels under the European Union's Registration, Evaluation, Authorisation and restriction of CHemicals (REACH) regulations. ART provides estimates at different percentiles of exposure and within different confidence intervals (CIs). However, its performance has only been tested on a limited number of exposure data. The present study compares ART's estimates with exposure measurements collected over many years in Switzerland. Measurements from 584 cases of exposure to vapours, mists, powders, and abrasive dusts (wood/stone and metal) were extracted from a Swiss database. The corresponding exposures at the 50th and 90th percentiles were calculated in ART. To characterize the model's performance, the 90% CI of the estimates was considered. ART's performance at the 50th percentile was only found to be insufficiently conservative with regard to exposure to wood/stone dusts, whereas the 90th percentile showed sufficient conservatism for all the types of exposure processed. However, a trend was observed with the residuals, where ART overestimated lower exposures and underestimated higher ones. The median was more precise, however, and the majority (≥60%) of real-world measurements were within a factor of 10 from ART's estimates. We provide recommendations based on the results and suggest further, more comprehensive, investigations.

An Assessment of the Robustness of the COSHH-Essentials (C-E) Target Airborne Concentration Ranges 15 Years on, and Their Usefulness for Determining Control Measures.

The Health and Safety Executive (HSE) in Great Britain (GB), in association with its stakeholders, developed the Control of Substances Hazardous to Health (COSHH)-Essentials (C-E) control banding tool in 1998. The objective was to provide a simple tool for employers, particularly small and medium-sized enterprises (SMEs), to help select and apply appropriate measures for the adequate control of exposure to hazardous substances. The tool used hazard classification information (R-phrases) to assign substances to one of five health hazard groups, each with its respective 'target airborne concentration range'. The validity of the allocation of substances to a target airborne concentration range was demonstrated at the time using 111 substances that had a current health-based Occupational Exposure Limit (OEL) in GB. The C-E control banding approach remains an important tool to complement exposure assessment/monitoring and the selection and use of suitable control measures for hazardous substances. These include engineering controls and personal protective equipment (PPE). The C-E based control banding approach has been adopted around the world. This paper extends the original validation exercise, using a greater number of chemical substances, to establish whether the target airborne concentration ranges remain appropriate. This is of particular interest in light of the introduction of the Globally Harmonized System (GHS) for classification, in which R-phrases have now been replaced by hazard-statements (H-statements). The validation exercise includes substances with OELs published by nine bodies internationally; and the Derived No-Effect Levels (DNELs) assigned by registrants under the European Union-Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulations. When compared against 8-hour TWA OELs for 850 substances drawn from nine bodies and a limited number of DNELS, the C-E target airborne concentration ranges remain valid. This comparative work also informs a wider consideration around the practicality and the applicability of the C-E generic approach to facilitate the implementation of good practice control for a wide range of substances (more than 95%) which do not have any recognized OEL.

REACH compliant epoxides used in the synthesis of Fe(III)-based aerogel monoliths for target fabrication

Aerogel materials manufactured from metal oxides have been used as components in numerous high-energy density physics targets. These aerogels have been identified to be used as a future target material in the AWE fielded campaigns at the US National Ignition Facility. A wide variety of metal oxide aerogels are required for future campaigns and therefore a versatile manufacturing route is sought; as such, an epoxide-assisted sol–gel route was investigated. Under the European Union Registration, Evaluation, Authorization and Restriction of Chemicals legislation, the most commonly used epoxide, propylene oxide, is recognized as a substance of very high concern (SVHC). This work sought to investigate suitable alternative epoxides for use in target manufacture. The outcome was the identification of synthesis routes for stable metal oxide aerogel monoliths using epoxides not subject to the above restrictions.

Safety Management with Chemical Mapping Techniques- A Study

In the U.S., only a small portion of the chemicals utilized as a part of buyer items have been tried for human wellbeing impacts. What's more, with the present atmosphere in Congress, it feels improbable that we'll see any genuine change of the country's horribly obsolete synthetic security rules at any point in the near future. Meanwhile, researcher Thomas Hartung might have made the following best thing. In the least difficult terms, Hartung and associates took what is the world's biggest and wealthiest database of substance danger examination — a database created as per the European Union's Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) regulations — and composed a PC program that uses that information to foresee the poisonous quality of chemicals for which there is practically no security information.

Development of a bioavailability-based risk assessment approach for nickel in freshwater sediments.

To assess nickel (Ni) toxicity and behavior in freshwater sediments, a large-scale laboratory and field sediment testing program was conducted. The program used an integrative testing strategy to generate scientifically based threshold values for Ni in sediments and to develop integrated equilibrium partitioning-based bioavailability models for assessing risks of Ni to benthic ecosystems. The sediment testing program was a multi-institutional collaboration that involved extensive laboratory testing, field validation of laboratory findings, characterization of Ni behavior in natural and laboratory conditions, and examination of solid phase Ni speciation in sediments. The laboratory testing initiative was conducted in 3 phases to satisfy the following objectives: 1) evaluate various methods for spiking sediments with Ni to optimize the relevance of sediment Ni exposures; 2) generate reliable ecotoxicity data by conducting standardized chronic ecotoxicity tests using 9 benthic species in sediments with low and high Ni binding capacity; and, 3) examine sediment bioavailability relationships by conducting chronic ecotoxicity testing in sediments that showed broad ranges of acid volatile sulfides, organic C, and Fe. A subset of 6 Ni-spiked sediments was deployed in the field to examine benthic colonization and community effects. The sediment testing program yielded a broad, high quality data set that was used to develop a Species Sensitivity Distribution for benthic organisms in various sediment types, a reasonable worst case predicted no-effect concentration for Ni in sediment (PNECsediment ), and predictive models for bioavailability and toxicity of Ni in freshwater sediments. A bioavailability-based approach was developed using the ecotoxicity data and bioavailability models generated through the research program. The tiered approach can be used to fulfill the outstanding obligations under the European Union (EU) Existing Substances Risk Assessment, EU Registration, Evaluation, Authorisation, and Regulation of Chemicals (REACH), and other global regulatory initiatives. Integr Environ Assess Manag 2016;12:735-746. © 2015 SETAC.

Existing test data for the Act on Registration & Evaluation, etc. of Chemical Substances.

ObjectivesIn this study, the possibility of using existing test data provided in Korea and elsewhere for the registration of chemical substances was examined. Data on 510 chemical substances that are among the first subject to registration under the “Act on the Registration and Evaluation, etc. of Chemical Substances (K-REACH)” were analyzed.MethodsThe possibility of using existing data from 16 reference databases was examined for 510 chemical substances notified in July 2015 as being subject to registration.ResultsTest data with the reliability required for the registration of chemical substances under the K-REACH constituted 48.4% of the required physicochemical characteristics, 6.5% of the required health hazards, and 9.4% of the required environmental hazards.ConclusionsSome existing test data were not within the scope of this research, including data used for registration in the European Union (EU). Thus, considering that 350 of these 510 species are registered in EU Registration, Evaluation, Authorisation & Restriction of Chemicals, more test data may exist that can be utilized in addition to the data identified in this study. Furthermore, the K-REACH states that non-testing data (test results predicted through Read Across, Quantitative Structure- Activity Relationships) and the weight of evidence (test results predicted based on test data with low reliability) can also be utilized for registration data. Therefore, if methods for using such data were actively reviewed, it would be possible to reduce the cost of securing test data required for the registration of chemical substances.

Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial.

Objective:To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE).Methods:In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving ≥50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored.Results:Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (−38.4% vs −76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%).Conclusions:Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE.Classification of evidence:This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.

From incremental to fundamental substitution in chemical alternatives assessment

Several chemicals in consumer products are subject to binding or voluntary phase-out agreements that are based on international treaties such as the Stockholm Convention on Persistent Organic Pollutants or on regulatory frameworks such as the European Union's Registration, Evaluation, Authorization and Restriction of Chemicals (REACH). To facilitate a phase-out process, alternatives assessment is commonly applied as an emerging approach to identifying chemicals (or materials, processes, and behavior changes) serving as substitutes. Polybrominated diphenyl ethers (PBDEs), long-chain poly- and perfluorinated alkyl substances (PFASs), and polychlorinated biphenyls (PCBs) are well-known cases of chemicals where substitution processes can be studied. Currently, there are various challenges in assessing, evaluating and effectively introducing chemical alternatives. These challenges are mainly related to similarity in chemical structures and, hence, similar hazard profiles between phase-out and substitute chemicals, leading to a rather incremental than fundamental substitution. A hampered phase-out process, the lack of implementing Green Chemistry principles in chemicals design, and lack of Sustainable Chemistry aspects in industrial processes design constitute additional challenges. We illustrate the various challenges in the process of phasing out and successfully substituting hazardous chemicals in consumer products and provide guiding principles for addressing these challenges. We propose an integrated approach of all stakeholders involved toward more fundamental and function-based substitution by greener and more sustainable alternatives. Our recommendations finally constitute a starting point for identifying further research needs and for improving current alternatives assessment practice.

Sex as a variable in medicines assessment reports for licensing in the European Union. Can gender bias be excluded?

To analyse publically available official reports on the evaluation of European Union (EU) registration of new medicines (aimed at diseases affecting both sexes) in order to address the possibility of gender bias. Descriptive study reviewing two types of assessment reports corresponding to different EU registration procedures: European Public Assessment Reports (EPARs) for the centralised procedures (399 reports considered from 2001 to 2002 and 2008 to 2009) and Mutual Recognition or Decentralised Public Assessment Reports (MPARs) for the mutual recognition and decentralised procedures (2,704 reports, totality until 2009-inclusive). Two hundred and twenty-four EPARs fulfilled the study criteria. It can be deduced from those EPARs that women participated in at least one clinical trial in 215 (78.5 %) of the reports. In 49(17.9 %) of the EPARs, the study population is explicitly evaluated according to sex, ten (3.6 %) presenting results disaggregated by sex. Most sex-related differences are in safety and pharmacokinetics; six of the 22 cases (72.7 %) of safety differences and nine of the 23 cases (60.9 %) of pharmacokinetic differences are not discussed. In relation to MPARs, only 2,704 out of 15,621 registries (17 %) were published, which casts doubts on the representativity of the available reports. Those published reflect less participation by women than in the EPARs. From the incomplete sex-related data made public, it is difficult to conclude on the existence of gender bias in the evidence used for the evaluation of new medicines. It certainly cannot be excluded. It is therefore recommended that compliance with existing guidance for publication of reports is increased, so as to transparently reassure on the issue.

Addressing the temporal fit of institutions: the regulation of endocrine-disrupting chemicals in Europe

Munck af Rosenschöld, J., N. Honkela, and J. I. Hukkinen. 2014. Addressing the temporal fit of institutions: the regulation of endocrine-disrupting chemicals in Europe. Ecology and Society 19(4): 30. https://doi.org/10.5751/ES-07033-190430

European solvent industry group generic exposure scenario risk and exposure tool

The European Solvents Industry Group (ESIG) Generic Exposure Scenario (GES) Risk and Exposure Tool (EGRET) was developed to facilitate the safety evaluation of consumer uses of solvents, as required by the European Union Registration, Evaluation and Authorization of Chemicals (REACH) Regulation. This exposure-based risk assessment tool provides estimates of both exposure and risk characterization ratios for consumer uses. It builds upon the consumer portion of the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) Targeted Risk Assessment (TRA) tool by implementing refinements described in ECETOC TR107. Technical enhancements included the use of additional data to refine scenario defaults and the ability to include additional parameters in exposure calculations. Scenarios were also added to cover all frequently encountered consumer uses of solvents. The TRA tool structure was modified to automatically determine conditions necessary for safe use. EGRET reports results using specific standard phrases in a format consistent with REACH exposure scenario guidance, in order that the outputs can be readily assimilated within safety data sheets and similar information technology systems. Evaluation of tool predictions for a range of commonly encountered consumer uses of solvents found it provides reasonable yet still conservative exposure estimates.

On the quantification of intertest variability in ecotoxicity data with application to species sensitivity distributions

Ecotoxicological hazard assessment relies on species effect data to estimate quantities such as the predicted no-effect concentration. While there is a concerted effort to quantify uncertainty in risk assessments, the uncertainty due to intertest variability in species effect measurements is an overlooked component. The European Union Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) guidance document suggests that multiple toxicity records for a given chemical-species combination should be aggregated by the geometric mean. Ignoring this issue or applying unjustified so-called harmonization methods weakens the defensibility of uncertainty quantification and interpretation about properties of ecological models, for example, the predicted no-effect concentration. In the present study, the authors propose a simple and broadly theoretically justifiable model to quantify intertest variability and analyze it using Bayesian methods. The value of data in ecotoxicity databases is maximized by using (interval-)censored data. An exploratory analysis is provided to support the model. The authors conclude, based on a large ecotoxicity database of acute effects to aquatic species, that the standard deviation of intertest variability is approximately a factor (or fold-difference) of 3. The consequences for decision makers of (not) adjusting for intertest variability are demonstrated.

Generic Exposure Scenarios: Their Development, Application, and Interpretation under REACH

The European Union Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) Regulation (EC 1907/2006) places significant new obligations on the manufacturers or importers (M/Is) of chemicals in Europe. It also places new responsibilities on downstream users (DUs) of these chemicals i.e. those that purchase and use chemical products. In particular, for registered classified substances, the M/I is expected to communicate how any substance can be safely used without risk to man or the environment. This communication is in the form of an exposure scenario (ES), which is included in an Annex to the REACH extended safety data sheet. DUs then have certain obligations relating to adopting the control conditions described in the ES. The REACH Technical Guidance Documents lay down the expectations for the process of risk assessment that M/Is should adopt when developing ESs. But with many thousands of chemicals in daily commerce, it is also necessary to ensure that what is communicated to DUs not only meets the requirements of REACH but is also understandable to these groups, as well as being consistent across different chemical suppliers and supply chains. In cooperation with relevant DU groups, the European solvents industry has developed generic approaches for describing how solvents are commonly used, in order that these can subsequently be used as the basis for REACH registrations and related safety data sheet communications on health risk control. The utility of these approaches (termed 'generic exposure scenarios') is acknowledged under REACH and they are now publicly available for use both by M/Is and DUs.

A modular one-generation reproduction study as a flexible testing system for regulatory safety assessment

The European Union's Registration, Evaluation and Authorisation of Chemicals (REACH) legislation mandates testing and evaluation of approximately 30,000 existing substances within a short period of time, beginning with the most widely used "high production volume" (HPV) chemicals. REACH testing requirements for the roughly 3000 HPV chemicals specify three separate tests for reproductive toxicity: two developmental toxicity studies on different animal species (OECD Test Guideline 414) and a two-generation reproduction toxicity study (OECD TG 416). These studies are highly costly in both economic and animal welfare terms. OECD TG 416 is a fertility study intended to evaluate reproductive performance of animals in the P and F1-generations following repeated exposure to a test substance. It can also be used to detect adverse effects on structural and functional development. Thus, it has conventionally been preferred to the one-generation study (OECD TG 415). Recently, the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) proposed that routine two-generation studies could in most cases be replaced with an "enhanced" one-generation study (Reuter et al. [1]). The flexible design proposed by HESI-ACSA allows for the addition of one or more specialised modules, if triggered (e.g. production of a second generation or the investigation of classical developmental toxicity or developmental neuro- or immunotoxicity). Significantly, however, the HESI-ACSA proposal was designed for use in the safety assessment of pesticidal, as opposed to industrial, chemicals. Thus for the purposes of REACH, a streamlined one-generation study that also examines structural development would be the most efficient means of addressing current information requirements for HPV chemicals. This study represents a flexible testing system that can be modified to meet regulatory needs in a variety of sectors.