Development of REACH Generic Exposure Scenarios for Substances Used as Coformulants in Plant Protection Products.

This article reviews the interactions between the REACH (Registration, Evaluation, Authorization and restriction of Chemicals) regulation and the plant protection product regulation for substances used as coformulants in the European Union, and describes generic exposure scenarios developed for their exposure and risk assessment. The REACH exposure scenarios describe the operational conditions and risk management measures used in the risk assessment of a coformulant, and as such these translate as the boundaries of safe use. The generic exposure scenarios are designed to be simple, and closely integrate with REACH use descriptors and customized exposure models. Clustering of application methods and exposure determinants resulted in four generic exposure scenarios, each covering professional workers or consumers, and application of products in liquid, granular form, or applied on seeds. When used in conjunction with appropriate exposure models, the generic exposure scenarios support efficient first-tier risk assessment of coformulants by utilizing a higher level of abstraction and conservatism than typically used in plant protection product assessments.

The mycotoxin patulin reacts with DNA bases with and without previous conjugation to GSH: implication for related α,ß-unsaturated carbonyl compounds?

The α,ß-unsaturated carbonyl group is recognized as alert for mutagenicity, attributed to (1) its direct reaction with DNA, counteractable by glutathione (GSH), and (2) oxidative stress caused indirectly by GSH depletion. Accordingly, the α,ß,γ,δ-unsaturated lactone patulin (PAT), a mycotoxin detected in fruits and products derived thereof, is known to induce gene, chromosome, and genome mutations in vitro, its mutagenicity correlating inversely with intracellular GSH levels. Thus, the reactivity of PAT against DNA bases and nucleosides in the absence and presence of GSH and glutathione S-transferases (GSTs) was investigated under cell-free conditions using HPLC mass spectrometry techniques for identification of reaction products. Adduct formation with all four nucleobases as well as with purine base nucleosides occurred even in the presence of GSH, revealing several adducts of PAT, mono- and disubstituted with nucleobases/nucleosides as well as novel GSH-PAT adducts. In addition, novel mixed GSH-PAT-nucleobase adducts were observed. These adducts exhibited a ketohexanoic acid-type structure of the PAT molecule, C6 substituted with GSH and linking C1 of PAT with nitrogens of nucleobases/nucleosides via an amide bond. Formation of GSH-PAT-adenine adducts was not prevented by GSTs, and excess of GSH needed to reduce their formation was higher than for PAT-adenine adducts. The formation of mixed GSH-DNA base adducts has not been described for PAT or any other α,ß-unsaturated carbonyl before, although the reaction mechanism seems to be applicable to a variety of α,ß-unsaturated carbonyls occurring in food and in the environment.

Environmental exposure assessment of co-formulants in plant protection products under REACH.

It is a regulatory requirement to assess co-formulants in plant protection products (PPP) under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation. The standard environmental exposure assessment framework for chemicals under REACH is a multicompartmental mass-balanced model and, at the local scale, is designed for use with urban (wide dispersive) or industrial (point source) emissions. However, the environmental release of co-formulants used in PPP is to agricultural soil and indirectly to waterbodies adjacent to a field and, for sprayed products, to the air. The Local Environment Tool (LET) has been developed to assess these specific emission pathways for co-formulants in a local-scale REACH exposure assessment, based on standard approaches and models used for PPP. As such, it closes a gap between the standard REACH exposure model's scope and REACH requirements to assess co-formulants in PPP. When combined with the output of the standard REACH exposure model, the LET includes an estimate of the contribution from other nonagricultural background sources of the same substance. The LET is an improvement over the use of higher tier PPP models for screening purposes because it provides a simple standardized exposure scenario. A set of predefined and conservatively selected inputs allows a REACH registrant to conduct an assessment without requiring detailed knowledge of PPP risk assessment methods or typical conditions of use. The benefit to the co-formulant downstream user (formulators) is a standardized and consistent approach to co-formulant assessment, with meaningful and readily interpretable conditions of use. The LET can serve as an example to other sectors of how to address possible gaps in the environmental exposure assessment by combining a customized local-scale exposure model with the standard REACH models. A detailed conceptual explanation of the LET model is provided here together with a discussion on its use in a regulatory context. Integr Environ Assess Manag 2023;19:1544-1554. © 2023 BASF SE, Bayer AG et al. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

REACH Worker Exposure Model for Co-formulants Used in Plant Protection Products.

Background: Substances used as co-formulants in plant protection products (PPP) may require registration under Regulation (EC) No. 1907/2006 (REACH), and additionally where an exposure assessment is required, this must take into consideration the specifics of the PPP use. Objectives: This work reports a customized screening level model developed to support human health risk assessment of operators, workers, and bystanders (OWB) for co-formulants used in PPP. The OWB model was designed to closely integrate with REACH generic exposure scenarios (GES) for PPP developed by the European Crop Protection Association (ECPA). The use of these tools in combination is expected to lead to a more standardized and hence efficient risk assessment of co-formulants. This study describes the basis for OWB exposure predictions as well as benchmarking against relevant REACH exposure models for equivalent tasks. The benchmarking was carried out to gain some insight into the initial assumption that the most commonly used tier 1 REACH model would be more conservative than the specific PPP models used for regulatory risk assessments under PPP legislation. Method: Existing exposure models with regulatory acceptance for the most common types of PPP and their professional and consumer uses were selected. The German BBA model was used to assess spray applications. Granule and seed dispersal was assessed using the US Environmental Protection Agency (EPA) Pesticide Handlers Exposure Database (PHED). ECETOC TRA was employed to assess exposure during certain tasks performed in seed treatment, not covered by these PPP models. Where the underlying models featured multiple exposure determinants, the exposure was calculated for all permutations, and the worst-case exposure selected and reported for use in risk assessment. The PPP models are based on measured data collected during actual application of PPP; hence, the worst-case exposure predicted was expected to reflect a realistic worst case for these tasks. Results: OWB was implemented as an Excel spreadsheet. Exposure models, parameters, and exposure and risk estimates are reported in a REACH-compliant output format to facilitate the registration of co-formulant uses. As would be expected, benchmarking OWB against the PPP-specific exposure models demonstrated equivalence with the worst-case prediction from these underlying PPP models. For the scenarios modelled, the tier 1 ECETOC TRA gave more conservative predictions than OWB. The reduction in conservatism is attributed to the underlying PPP models being based on measured data collected specifically during the use of PPP, compared to the data underlying ECETOC TRA, based mainly on industrial workplace uses. Conclusions: OWB provides inhalation and dermal exposure estimates for co-formulants used in PPP which are equivalent to the worst-case estimates from existing specialized PPP exposure models based on measured data. OWB has simplified information requirements in comparison to higher-tier REACH or PPP models. Use of OWB in combination with the defined ECPA GES facilitates an efficient and standardized REACH risk assessment and registration of co-formulant uses in PPP. A defined assessment framework and default inputs potentially decreases the anticipated inter-user variability compared with the use of higher-tier PPP or REACH models in this screening level context.