High Production Volume Chemicals Research Articles

Urinary bisphenol A concentrations in girls from rural and urban Egypt: a pilot study

BackgroundExposure to endocrine active compounds, including bisphenol A (BPA), remains poorly characterized in developing countries despite the fact that behavioral practices related to westernization have the potential to influence exposure. BPA is a high production volume chemical that has been associated with metabolic dysfunction as well as behavioral and developmental effects in people, including children. In this pilot study, we evaluate BPA exposure and assess likely pathways of exposure among girls from urban and rural Egypt.MethodsWe measured urinary concentrations of total (free plus conjugated) species of BPA in spot samples in urban (N = 30) and rural (N = 30) Egyptian girls, and compared these concentrations to preexisting data from age-matched American girls (N = 47) from the U.S. National Health and Nutrition Examination Survey (NHANES). We also collected anthropometric and questionnaire data regarding food storage behaviors to assess potential routes of exposure.ResultsUrban and rural Egyptian girls exhibited similar concentrations of urinary total BPA, with median unadjusted values of 1.00 and 0.60 ng/mL, respectively. Concentrations of urinary BPA in this group of Egyptian girls (median unadjusted: 0.70 ng/mL) were significantly lower compared to age-matched American girls (median unadjusted: 2.60 ng/mL) according to NHANES 2009-2010 data. Reported storage of food in plastic containers was a significant predictor of increasing concentrations of urinary BPA.ConclusionsDespite the relatively low urinary BPA concentrations within this Egyptian cohort, the significant association between food storage behaviors and increasing urinary BPA concentration highlights the need to understand food and consumer product patterns that may be closing the gap between urban and rural lifestyles.

Isolation of a phenol-utilizing marine bacterium from Durban Harbour (South Africa) and its preliminary characterization as Marinobacter sp. KM2

Many aromatic hydrocarbons assigned to the so-called high production volume chemicals (HPVCs) are frequently encountered constituents of wastewaters that end up in the sea. Although the pollutant-degrading capabilities of freshwater bacteria are well known, the catabolism of pollutants by marine bacteria has received limited attention. A marine bacterium with the ability to aerobically utilize phenol - an HPVC and common aromatic pollutant - as its sole source of carbon and energy, was isolated from water samples from Durban Harbour, South Africa. The isolate, designated strain KM2, was assigned to the genus Marinobacter based on a variety of phenotypic properties and by analysis of the 16S rRNA gene sequence. The isolate displays an absolute growth requirement for NaCl which cannot be offset by replacement of NaCl with other salts. In addition to 4-methylphenol and 3,4-dimethylphenol, it utilizes a range of aliphatic hydrocarbons such as butan-1-ol and hexadecane under aerobic conditions. The transient formation of an intermediate exhibiting the UV-Vis spectral characteristics for 2-hydroxymuconic semialdehyde in cultures growing on phenol suggests that the isolate catabolizes this compound via the meta cleavage pathway. These results indicate that members of the genus Marinobacter might participate in the elimination of aromatic pollutants in South African marine environments.

Dietary Bioaccumulation of Perfluorophosphonates and Perfluorophosphinates in Juvenile Rainbow Trout: Evidence of Metabolism of Perfluorophosphinates

The perfluorophosphonates (PFPAs) and perfluorophosphinates (PFPiAs) are high production volume chemicals that have been observed in Canadian surface waters and wastewater environments. To examine whether their occurrence would result in contamination of organisms in aquatic ecosystems, juvenile rainbow trout (Oncorhynchus mykiss) were separately exposed to a mixture of C6, C8, and C10 monoalkylated PFPAs and a mixture of C6/C6, C6/C8, and C8/C8 dialkylated PFPiAs in the diet for 31 days, followed by 32 days of depuration. Tissue distribution indicated preferential partitioning to blood and liver. Depuration half-lives ranged from 3 to 43 days and increased with the number of perfluorinated carbons present in the chemical. The assimilation efficiencies (α, 7-34%) and biomagnification factors (BMFs, 0.007-0.189) calculated here for PFPAs and PFPiAs were lower than those previously observed for the perfluorocarboxylates (PFCAs) and perfluorosulfonates (PFSAs) in the same test organism. Bioaccumulation was observed to decreased in the order of PFSAs > PFCAs > PFPAs of equal perfluorocarbon chain length and was dependent on the charge of the polar headgroup. Bioaccumulation of the PFPiAs was observed to be low due to their rapid elimination via metabolism to the corresponding PFPAs. Here, we report the first observation of an in vivo cleavage of the carbon-phosphorus bond in fish, as well as, the first in vivo biotransformation of a perfluoroalkyl acid (PFAA). As was previously observed for PFCAs and PFSAs, none of the BMFs determined here for the PFPAs and PFPiAs were greater than one, which suggests PFAAs do not biomagnify from dietary exposure in juvenile rainbow trout.

Determination of benzothiazoles and benzotriazoles by using ionic liquid stationary phases in gas chromatography mass spectrometry. Application to their characterization in wastewaters

Benzothiazoles (BTHs) and benzotriazoles (BTRs) belong to a high production volume chemicals widely used in both industrial and household applications. Since they are recalcitrant to biodegradation, they are widespread in the environment. However, the BTHs and BTRs determination in environmental matrices is hindered by the coelution with coextracted organic matter and the poor selectivity in mass spectrometry due to the low mass of their diagnostic ions. Accordingly, this study examines the selectivity and suitability of new commercially available ionic liquid (IL) stationary phases for GC–MS and their application to the determination of BTHs and BTRs in wastewater samples. Five different IL columns were tested and the best results in terms of resolution, peak symmetry and analysis time were obtained with the SLB-IL59.

First evidences of the occurrence of polycyclic synthetic musk fragrances in surface water systems in Italy: Spatial and temporal trends in the Molgora River (Lombardia Region, Northern Italy)

The polycyclic synthetic musks (PCMs) such as galaxolide (HHCB), tonalide (AHTN) and celestolide (ABDI) are important ingredients in fragrances for consumer products because of their typical musky scent. In EU, PCMs are classified as HPVC (High Production Volume Chemicals). Furthermore, it has been recognized that these substances are only partially degraded in domestic sewers. For both reasons these chemicals are considered ubiquitous contaminants of aquatic systems. Monitoring data are available for the Northern region of the EU, but it is not known whether they are also representative for the Southern EU countries. The lack of data upon the environmental exposure in Southern EU can be significant, since use patterns and volumes differ from country to country. This is particularly true for Italy that has the largest detergent consumption per capita in EU. Due to this, the objective of the present study was to investigate the occurrence of selected PCMs in the Molgora River (Lombardia region, Italy). To our knowledge it represents the first overview of PCM occurrence in the Italian water bodies. Water samples were collected seasonally in seven sampling stations located before and after the 3 sewage treatment plants present along the river, which serve about 300,000 inhabitants. The spatial and temporal profiles of contamination are described. A comparison of the results with existing monitoring data of other European regions indicated a significant higher level of PCM pollution of the Molgora River and the need to extend the monitoring campaigns to other Italian water bodies, in order to achieve a better knowledge of the levels of PCM contamination in this country.

Immunotoxicant Screening and Prioritization in the Twenty-first Century

Current immunotoxicity testing guidance for drugs, high production-volume chemicals, and pesticides specifies the use of animal models to assess potential biomarkers of immune system effects (e.g., lymphoid organ and bone marrow indices, histopathology) or actual measures of immune function (e.g., responses to challenge with antigens or pathogens). These assays are resource intensive and often require special training or experience to ensure reliable results. Alternative in vitro assays to detect immunosuppression and allergic hypersensitivity have the potential to reduce animal use and testing costs and increase immunotoxicity screening and prioritization efforts. Alternative models to detect immunosuppression tend to address broad modes of action because suppression may be caused by a wide variety of events; current in vitro models access the supply of innate and adaptive immune system cells as well as cellular markers associated with function, including gene expression, protein synthesis, and proliferation. Events leading to the induction of allergic hypersensitivity, particularly contact hypersensitivity, are more restricted, and alternative methods currently exploit chemical properties and activation of defined cell populations to detect and estimate the potency of skin sensitizers.

A Critical Evaluation of the 2011 ECHA Reports on Compliance with the REACH and CLP Regulations and on the Use of Alternatives to Testing on Animals for Compliance with the REACH Regulation

On 30 June 2011, the European Chemicals Agency published two reports, one on the functioning of the REACH system, the other on the use of alternatives to animal testing in compliance with that system. The data presented are based on information gained during the first registration period under the REACH system, which included high production volume chemicals and substances of very high concern, which have the most extensive information requirements. A total of 25,460 registration dossiers were received, covering 3,400 existing, so-called 'phase-in', substances, and 900 new, so-called 'non-phase-in', substances. Data sharing and the joint submission of data are reported to have worked successfully. In the registration dossiers for these substances, results from new animal tests were included for less than 1% of all the endpoints; testing proposals (required for 'higher-tier' information requirements) were submitted for 711 in vivo tests involving vertebrate animals. The registrants mainly used old, existing experimental data, or options for the adaptation (waiving) of information requirements, before collecting new information. For predicting substance toxicity, 'read-across' was the second most-used approach, followed by 'weight-of-evidence'. In vitro toxicity tests played a minor role, and were only used when the respective test methods had gained the status of regulatory acceptance. All in all, a successful start to the REACH programme was reported, particularly since, in contrast to most predictions, it did not contribute to a significant increase in toxicity testing in animals.

Occurrence, distribution and fluxes of benzotriazoles along the German large river basins into the North Sea

Benzotriazole (BT) and tolyltriazole (TT) are high production volume chemicals which are used in various industrial and household applications. In this study, the distribution of benzotriazoles in the estuaries of different rivers of central Europe and in the North Sea was analyzed by solid-phase extraction (SPE) and liquid chromatography-mass spectrometry (HPLC-MS/MS). BT as well as TT was detected in all water samples. The concentrations for total benzotriazoles (BTs) ranged from 1.7 to 40 ng/L in the North Sea in costal areas. Concentrations in rivers are from 200 to 1250 ng/L, respectively. The mass flux of total benzotriazoles from the major rivers of central Europe into the North Sea was calculated to 78 t/a, dominated by the Rhine with an individual flux of 57 t/a of BTs. The analysis of the distribution profile in the North Sea showed that the decrease of the concentration was mostly caused by dilution and that the benzotriazoles are poorly degradable in the North Sea. This paper presents the first report of benzotriazoles in the marine environment.

The radiosensitizing potential of glutaraldehyde on MCF7 breast cancer cells as quantified by means of the G2-chromosomal radiosensitivity assay

Glutaraldehyde (GA) is a high production volume chemical that is very reactive with a wide spectrum of medical, scientific and industrial applications. Concerning the genotoxic and carcinogenic effect of GA, controversial results have been reported, while in humans no studies with positive carcinogenic results for GA have been published. However, our previous study concerning the combined effects of exposure to both GA and ionising radiation (IR) in peripheral blood lymphocytes of healthy donors has shown that non-genotoxic doses of the chemical induces a statistically significant increase in chromosomal radiosensitivity. The lack of information concerning the radiosensitizing potential of GA on cancerous cells triggered us to test the radiosensitizing effect of GA on breast cancer cells (MCF7). For this purpose the G2-chromosomal radiosensitivity assay (G2-assay) was used. The assay involves G2-phase irradiation and quantitation of the chromosomal fragility in the subsequent metaphase. The experimental data show that 48h exposure to GA, at doses that are not clastogenic to MCF7 breast cancer cells enhances G2-chromosomal radiosensitivity of this cell line. In an effort to evaluate whether the observed increase in GAs-induced G2-chromosomal radiosensitization is linked to GA-induced alterations in the cell cycle and feedback control mechanism, Mitotic Index analysis was performed. The results have shown that such a mechanism cannot be directly related to the observed GA-induced increase in G2-chromosomal radiosensitivity. Since increased G2-chromosomal radiosensitivity has been linked with cancer proneness, the radiosensitizing effect of GA at non-clastogenic doses highlights its potential carcinogenic profile.

Global Distribution of Linear and Cyclic Volatile Methyl Siloxanes in Air

The global distribution of linear and cyclic volatile methyl silxoanes (VMS) was investigated at 20 sites worldwide, including 5 locations in the Arctic, using sorbent-impregnated polyurethane foam (SIP) disk passive air samplers. Cyclic VMS are currently being considered for regulation because they are high production volume chemicals that are potentially persistent, bioaccumulative, and toxic. Linear and cyclic VMS (including L3, L4, L5, D3, D4, D5, and D6) were analyzed for in air at all urban, background, and Arctic sites. Concentrations of D3 and D4 are significantly correlated, as are D5 and D6, which suggests different sources for these two pairs of compounds. Elevated concentrations of D3 and D4 on the West coast of North America and at high elevation sites suggest these sites are influenced by trans-Pacific transport, while D5 and D6 have elevated concentrations in urban areas, which is most likely due to personal care product use. Measured concentrations of D5 were compared to modeled concentrations generated using both the Danish Eulerian Hemispheric Model (DEHM) and the Berkeley-Trent Global Contaminant Fate Model (BETR Global). The correlation coefficients (r) between the measured and modeled results were 0.73 and 0.58 for the DEHM and BETR models, respectively. Agreement between measurements and models indicate that the sources, transport pathways, and sinks of D5 in the global atmosphere are fairly well understood.

Kinetics modeling and reaction mechanism of ferrate(VI) oxidation of benzotriazoles

Benzotriazoles (BTs) are high production volume chemicals with broad application in various industrial processes and in households, and have been found to be omnipresent in aquatic environments. We investigated oxidation of five benzotriazoles (BT: 1H-benzotriazole; 5MBT: 5-methyl-1H-benzotriazole; DMBT: 5,6-dimethyl-1H-benzotriazole hydrate; 5CBT: 5-chloro-1H-benzotriazole; HBT: 1-hydroxybenzotriazole) by aqueous ferrate (Fe(VI)) to determine reaction kinetics as a function of pH (6.0-10.0), and interpreted the reaction mechanism of Fe(VI) with BTs by using a linear free-energy relationship. The pK(a) values of BT and DMBT were also determined using UV-Visible spectroscopic method in order to calculate the species-specific rate constants, and they were 8.37 ± 0.0 and 8.98 ± 0.08 respectively. Each of BTs reacted moderately with Fe(VI) with the k(app) ranged from 7.2 to 103.8 M(-1)s(-1) at pH 7.0 and 24 ± 1 °C. When the molar ratio of Fe(VI) and BTs increased up to 30:1, the removal rate of BTs reached about >95% in buffered milli-Q water or secondary wastewater effluent. The electrophilic oxidation mechanism of the above reaction was illustrated by using a linear free-energy relationship between pH-dependence of species-specific rate constants and substituent effects (σ(p)). Fe(VI) reacts initially with BTs by electrophilic attack at the 1,2,3-triazole moiety of BT, 5MBT, DMBT and 5CBT, and at the N-OH bond of HBT. Moreover, for BT, 5MBT, DMBT and 5CBT, the reactions with the species HFeO(4)(-) predominantly controled the reaction rates. For HBT, the species H(2)FeO(4) with dissociated HBT played a major role in the reaction. The results showed that Fe(VI) has the ability to degrade benzotriazoles in water.

Toxicogenomics Applied to In Vitro Carcinogenicity Testing with Balb/c 3T3 Cells Revealed a Gene Signature Predictive of Chemical Carcinogens

Information on the carcinogenic potential of chemicals is primarily available for High Production Volume (HPV) products. Because of the limited knowledge gain from routine cancer bioassays and the fact that HPV chemicals are tested only, there is the need for more cost-effective and informative testing strategies. Here we report the application of advanced genomics to a cellular transformation assay to identify toxicity pathways and gene signatures predictive for carcinogenicity. Specifically, genome-wide gene expression analysis and quantitative real time polymerase chain reaction (qRT-PCR) were applied to untransformed and transformed mouse fibroblast Balb/c 3T3 cells that were exposed to either 2, 4-diaminotoluene, benzo(a)pyrene, 2-acetylaminoflourene, or 3-methycholanthrene at IC20 conditions for 24 and 120 h, respectively. Then, bioinformatics was applied to define toxicity pathways and a gene signature predictive of the carcinogenic risk of these chemicals. Although bioinformatics revealed distinct differences for individual chemicals at the gene-level pathway, analysis identified common perturbation that resulted in an identification of 14 genes whose regulation in cancer tissue had already been established. Strikingly, this gene signature was identified in short-term (24 and 120 h) untransformed and transformed cells (3 weeks), therefore demonstrating robustness for its predictive power. The developed testing strategy thus identified commonly regulated carcinogenic pathways and a gene signature that predicted the risk for carcinogenicity for three well-known carcinogens. Overall, the testing strategy warrants in-depth validation for the prediction of carcinogenic risk of industrial chemicals in in vitro carcinogenicity assay.

Semivolatile Endocrine-Disrupting Compounds in Paired Indoor and Outdoor Air in Two Northern California Communities

Interest in the health effects of potential endocrine-disrupting compounds (EDCs) that are high production volume chemicals used in consumer products has made exposure assessment and source identification a priority. We collected paired indoor and outdoor air samples in 40 nonsmoking homes in urban, industrial Richmond, CA, and 10 in rural Bolinas, CA. Samples were analyzed by GC-MS for 104 analytes, including phthalates (11), alkylphenols (3), parabens (3), polybrominated diphenyl ether (PBDE) flame retardants (3), polychlorinated biphenyls (PCBs) (3), polycyclic aromatic hydrocarbons (PAHs) (24), pesticides (38), and phenolic compounds (19). We detected 39 analytes in outdoor air and 63 in indoor air. For many of the phenolic compounds, alkylphenols, phthalates, and PBDEs, these represent some of the first outdoor measures and the first analysis of the relative importance of indoor and outdoor sources in paired samples. Data demonstrate higher indoor concentrations for 32 analytes, suggesting primarily indoor sources, as compared with only 2 that were higher outdoors. Outdoor air concentrations were higher in Richmond than Bolinas for 3 phthalates, 10 PAHs, and o-phenylphenol, while indoor air levels were more similar between communities, except that differences observed outdoors were also seen indoors. Indoor concentrations of the most ubiquitous chemicals were generally correlated with each other (4-t-butylphenol, o-phenylphenol, nonylphenol, several phthalates, and methyl phenanthrenes; Kendall correlation coefficients 0.2−0.6, p < 0.05), indicating possible shared sources and highlighting the importance of considering mixtures in health studies.

Using multiple regression in estimating (semi) VOC emissions and concentrations at the European scale

This paper proposes a simple method for estimating emissions and predicted environmental concentrations (PECs) in water and air for organic chemicals that are used in household products and industrial processes. The method has been tested on existing data for 63 organic high–production volume chemicals available in the European Chemicals Bureau risk assessment reports (RARs). The method suggests a simple linear relationship between Henry’s Law constant, octanol–water coefficient, use and production volumes, and emissions and PECs on a regional scale in the European Union. Emissions and PECs are a result of a complex interaction between chemical properties, production and use patterns and geographical characteristics. A linear relationship cannot capture these complexities; however, it may be applied at a cost–efficient screening level for suggesting critical chemicals that are candidates for an in–depth risk assessment. Uncertainty measures are not available for the RAR data; however, uncertainties for the applied regression models are given in the paper. Evaluation of the methods reveals that between 79% and 93% of all emission and PEC estimates are within one order of magnitude of the reported RAR values. Bearing in mind that the domain of the method comprises organic industrial high–production volume chemicals, four chemicals, prioritized in the Water Framework Directive and the Stockholm Convention on Persistent Organic Pollutants, were used to test the method for estimated emissions and PECs, with corresponding uncertainty intervals, in air and water at regional EU level.

Re-evaluating the list of high-production chemicals predicted to become Arctic contaminants

The large number of historical and current organic chemicals in commerce, and the ability of these compounds to make their way from industrial to remote regions, has resulted in concerted efforts to predict which chemicals have the capacity to migrate from where they are used/disposed to areas such as the Arctic. A suite of 120 high production volume chemicals has been recently screened from an initial dataset of >100,000 compounds and listed as potential Arctic contaminants. In the current work, we critically assess members of this proposed list for their possible rapid reactivity in environmental systems that would prevent substantial accumulation or transport in the environment and accumulation in vivo, as well as whether the investigated physicochemical properties are adequate for the intended environmental screening purposes.

Re-evaluating the list of high-production chemicals predicted to become Arctic contaminants

AbstractThe large number of historical and current organic chemicals in commerce, and the ability of these compounds to make their way from industrial to remote regions, has resulted in concerted efforts to predict which chemicals have the capacity to migrate from where they are used/disposed to areas such as the Arctic. A suite of 120 high production volume chemicals has been recently screened from an initial dataset of &gt;100,000 compounds and listed as potential Arctic contaminants. In the current work, we critically assess members of this proposed list for their possible rapid reactivity in environmental systems that would prevent substantial accumulation or transport in the environment and accumulation in vivo, as well as whether the investigated physicochemical properties are adequate for the intended environmental screening purposes.

Emergency planning and preparedness for the deliberate release of toxic industrial chemicals

Introduction. Society in developed and developing countries is hugely dependent upon chemicals for health, wealth, and economic prosperity, with the chemical industry contributing significantly to the global economy. Toxic industrial chemicals. Many chemicals are synthesized, stored, and transported in vast quantities and classified as high production volume chemicals; some are recognized as being toxic industrial chemicals (TICs). Chemical accidents involving chemical installations and transportation are well recognized. Such chemical accidents occur with relative frequency and may result in large numbers of casualties with acute and chronic health effects as well as fatalities. Deliberate release. The large-scale production of TICs, the potential for widespread exposure and significant public health impact, together with their relative ease of acquisition, makes deliberate release an area of potential concern. Risk prioritization. The large numbers of chemicals, together with the large number of potential release scenarios means that the number of possible forms of chemical incident are almost infinite. Therefore, prior to undertaking emergency planning and preparedness, it is necessary to prioritize risk and subsequently mitigate. Risk mitigation. This is a multi-faceted process, including implementation of industrial protection layers, substitution of hazardous chemicals, and relocation away from communities. Residual risk provides the basis for subsequent planning. Emergency planning and preparedness. Risk-prioritized emergency planning is a tool for identifying gaps, enhancing communication and collaboration, and for policy development. It also serves to enhance preparedness, a necessary prelude to preventing or mitigating the public health risk to deliberate release. Planning is an iterative and on-going process that requires multi-disciplinary agency input, culminating in the formation of a chemical incident plan complimentary to major incident planning. Preparedness is closely related and reflects a state of readiness. It is comprised of several components, including training and exercising. Toxicologists have a role to play in developing syndromic surveillance, recognizing clinical presentation of chemical incidents, developing toxicological datasheets, and the requisition and stockpiling of medical countermeasures. Conclusions. The chemical industry is global and many chemicals are synthesized and transported in vast quantities. Many of these chemicals are toxic and readily available, necessitating the need for identifying and assessing hazard and risks and subsequently planning and preparing for the deliberate release of TICs.

In silico screening for unmonitored, potentially problematic high production volume (HPV) chemicals prone to sequestration in biosolids

Thousands of high production volume (HPV) chemicals are used in the US at rates exceeding 450,000 kg (1 million pounds) per year, yet little is known about their fates during wastewater treatment and upon release into the environment. We utilized a recently introduced empirical model to predict the fraction of the mass loading (in raw sewage) that is expected to persist in digested sludge following conventional municipal treatment of chemical-laden sewage. The model requires only two readily available input parameters, a compound's log K(OW) value and a dimensionless curve fitting parameter (p(fit)). Following refinement of the fitting parameter and cross-validation of the model using the Jackknife method, we predicted the mass fractions of 207 hydrophobic HPV chemicals (log K(OW) of ≥ 4.0) that are expected to accumulate in digested municipal sludge during conventional wastewater treatment. Using this screening approach in conjunction with information from toxicity databases, we identified 11 HPV chemicals that are of potential concern due to (i) their propensity to accumulate and persist in sludge (>50% of mass loading), (ii) unfavorable ecotoxicity threshold values, and (iii) structural characteristics suggestive of environmental persistence following release of these HPV chemicals on land during biosolids recycling. The in silico screening approach taken in this study highlights existing environmental monitoring needs and may guide risk management strategies for biosolids disposal.

Ecotoxicity Prediction Using 3D Descriptors

A vast quantity of chemicals are present in our environment and are considered indispensable to our high technological society. However, there are some chemicals that are hazardous and that can extensively impact both human health and the global environment. In Japan, ecotoxicity tests of chemical substances have been conducted with the goal of contributing to the Organization for Economic Cooperation and Development (OECD) evaluation program for harmful high-production volume (HPV) chemicals since 1995. To date, only about 500 compounds have been tested. There is a possibility that quantitative structure-activity relationships (QSARs) may enable us to predict environmental toxicities and fates as well as the physical and chemical properties of compounds; therefore, the toxicity prediction by QSARs is a possible alternative to the measurements of their ecotoxicities. In this study, we generated QSAR models from toxicity tests of Daphnids using only 3D descriptors to examine the availability of particular 3D descriptors for predicting of the ecotoxicity of compounds with various structures. Predicton accuracy of the model generated in this study was adequate and improved compared to that of the model using only the n-octanol/water partition coefficient, logP(o/w).

Toxicity assessment strategies, data requirements, and risk assessment approaches to derive health based guidance values for non-relevant metabolites of plant protection products

In Europe, limits for tolerable concentrations of “non-relevant metabolites” for active ingredients (AI) of plant protection products in drinking water between 0.1 and 10 μg/L are discussed depending on the toxicological information available. “Non-relevant metabolites” are degradation products of AIs, which do not or only partially retain the targeted toxicities of AIs. For “non-relevant metabolites” without genotoxicity (to be confirmed by testing in vitro), the application of the concept of “thresholds of toxicological concern” results in a health-based drinking water limit of 4.5 μg/L even for Cramer class III compounds, using the TTC threshold of 90 μg/person/day (divided by 10 and 2). Taking into account the thresholds derived from two reproduction toxicity data bases a drinking water limit of 3.0 μg/L is proposed. Therefore, for “non-relevant metabolites” whose drinking water concentration is below 3.0 μg/L, no toxicity testing is necessary. This work develops a toxicity assessment strategy as a basis to delineate health-based limits for “non-relevant metabolites” in ground and drinking water. Toxicological testing is recommended to investigate, whether the metabolites are relevant or not, based on the hazard properties of the parent AIs, as outlined in the SANCO Guidance document. Also, genotoxicity testing of the water metabolites is clearly recommended. In this publication, tiered testing strategies are proposed for non-relevant metabolites, when drinking water concentrations >3.0 μg/L will occur. Conclusions based on structure–activity relationships and the detailed toxicity database on the parent AI should be included. When testing in animals is required for risk assessment, key aspects are studies along OECD-testing guidelines with “enhanced” study designs addressing additional endpoints such as reproductive toxicity and a developmental screening test to derive health-based tolerable drinking water limits with a limited number of animals. The testing strategies are similar to those used in the initial hazard assessment of high production volume (HPV) chemicals. For “non-relevant metabolites” which are also formed as products of the biotransformation of the parent AI in mammals, the proposed toxicity testing strategies uses the repeat-dose oral toxicity study combined with a reproductive/developmental screening as outlined in OECD test guidelines 407 and 422 with integration of determination of hormonal activities. For “non-relevant metabolites” not formed during biotransformation of the AI in mammals, the strategy relies on an “enhanced” 90-day oral study covering additional endpoints regarding hormonal effects and male and female fertility in combination with a prenatal developmental toxicity study (OECD test guideline 414). The integration of the results of these studies into the risk assessment process applies large minimal margins of exposure (MOEs) to compensate for the shorter duration of the studies. The results of the targeted toxicity testing will provide a science basis for setting tolerable drinking water limits for “non-relevant metabolites” based on their toxicology. Based on the recommendations given in the SANCO guidance document and the work described in this and the accompanying paper, a concise re-evaluation of the Guidance document is proposed.