Challenges and opportunities for overcoming dog use in agrochemical evaluation and registration.

Progress in developing new tools, assays, and approaches to assess human hazard and health risk provides an opportunity to re-evaluate the necessity of dog studies for the safety evaluation of agrochemicals. A workshop was held where partic­ipants discussed the strengths and limitations of past use of dogs for pesticide evaluations and registrations. Opportunities were identified to support alternative approaches to answer human safety questions without performing the required 90-day dog study.

A new conceptional model for deriving average dermal absorption estimates from studies with multiple tested concentrations for non-dietary risk assessment of pesticides.

Dermal absorption values are used to translate external dermal exposure into potential systemic exposure for non-dietary risk assessment of pesticides. While the Environmental Protection Agency of the United States of America (US EPA) derives a common dermal absorption factor for active substances covering all related products, the European Food Safety Authority (EFSA) requests specific product-based estimates for individual concentrations covering the intended use rates. The latter poses challenges, because it disconnects exposure dose from applied dose in absorption studies, which may not be suitable in scenarios where concentration is not relevant.

An OECD TG 428 study ring trial with C-Caffeine demonstrating repeatability and robustness of the dermal absorption in vitro method.

The dermal absorption potential of C-Caffeine applied as a 4 mg/mL concentration (10 μL/cm finite dose) was investigated in six laboratories under Good Laboratory Practice conditions using an OECD TG 428-compliant in vitro assay with flow-through cells and split-thickness human skin. Potential sources of variation were reduced by a standardized protocol, test item and skin source. Particularly, skin samples from same donors were distributed over two repeats and between labs in a non-random, stratified design.

Recommendations on dose level selection for repeat dose toxicity studies.

Prior to registering and marketing any new pharmaceutical, (agro)chemical or food ingredient product manufacturers must, by law, generate data to ensure human safety. Safety testing requirements vary depending on sector, but generally repeat-dose testing in animals form the basis for human health risk assessments. Dose level selection is an important consideration when designing such studies, to ensure that exposure levels that lead to relevant hazards are identified.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process.

PBPK model reporting template for chemical risk assessment applications.

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals.

Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.

The European Food Safety Authority (EFSA) guidance (EFSA, 2017) for dermal absorption (DA) studies recommends stringent mass balance (MB) limits of 95-105%. EFSA suggested that test material can be lost after penetration and requires that for chemicals with <5% absorption the non-recovered material must be added to the absorbed dose if MB is <95%. This has huge consequences for low absorption pesticides.

Metabolism and disposition of [C]-methylcyclosiloxanes in rats.

Octamethylcyclotetrasiloxane (D) and decamethylcyclopentasiloxane (D) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D as a direct ingredient in personal care products has declined significantly over the past 20 years, although it may be present as a residual impurity in a variety of consumer products. D is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning.

Metabolism of C-octamethylcyclotetrasiloxane ([C]D) or C-decamethylcyclopentasiloxane ([C]D) orally gavaged in rainbow trout (Oncorhynchus mykiss).

Critical factors (uptake, distribution, metabolism and elimination) for understanding the bioaccumulation/biomagnification potential of Octamethylcyclotetrasiloxane (D) and Decamethylcyclopentasiloxane (D) siloxanes in fish were investigated to address whether these chemicals meet the "B" criteria of the Persistent, Bioaccumulative, and Toxic (PBT) classification. A metabolism study was conducted in rainbow trout whereby a 15mg [C]D/kg bw or [C]D/kg bw as a single bolus oral dose was administered via gavage. Of the administered dose, 79% (D) and 78% (D) was recovered by the end of the study (96-h).

Assessment of metabolic stability using the rainbow trout (Oncorhynchus mykiss) liver S9 fraction.

Standard protocols are given for assessing metabolic stability in rainbow trout using the liver S9 fraction. These protocols describe the isolation of S9 fractions from trout livers, evaluation of metabolic stability using a substrate depletion approach, and expression of the result as in vivo intrinsic clearance. Additional guidance is provided on the care and handling of test animals, design and interpretation of preliminary studies, and development of analytical methods.

In vitro study to determine decontamination of 3,5-dichloro-2,4,6-trifluoropyridine (DCTFP) from human skin.

This in vitro study determined the decontamination potential of soap and water, D-TAM skin cleanser, corn oil and the O'Dell reactive skin decontamination system to remove 3,5-dichloro-2,4,6-trifluoropyridine (DCTFP) from human skin after short exposure periods (10 and 30 min). The main result turned out to be the rapid volatility of DCTFP where half of the dose evaporated within 10 min and most of the dose was evaporated after 30 min. This rapid volatility was confirmed in an additional study where DCTFP rapidly evaporated from inert plastic disks (70% loss in 10 min).

Inhalation dosimetry modeling with decamethylcyclopentasiloxane in rats and humans.

Decamethylcyclopentasiloxane (D(5)), a volatile cyclic methyl siloxane (VCMS), is used in industrial and consumer products. Inhalation pharmacokinetics of another VCMS, octamethylcyclotetrasiloxane (D(4)), have been extensively investigated and successfully modeled with a multispecies physiologically based pharmacokinetic (PBPK) model. Here, we develop an inhalation PBPK description for D(5), using the D(4) model structure as a starting point, with the objective of understanding factors that regulate free blood and tissue concentrations of this highly lipophilic vapor after inhalation in rats and humans.

The effect of route, vehicle, and divided doses on the pharmacokinetics of chlorpyrifos and its metabolite trichloropyridinol in neonatal Sprague-Dawley rats.

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single versus divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol, were measured at multiple times through 24 h.