Data derived extrapolation factors (DDEFs) for rat to human interspecies extrapolation for the HPPD inhibitor mesotrione.

In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a "data-derived" adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of ∼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.

Pantolactams as androgen receptor antagonists for the topical suppression of sebum production.

A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.

Enantiopure 2-substituted glyceraldehyde derivatives by aza-Claisen rearrangement or C-alkylation of enamines.

2-Alkyl derivatives of butane-2,3-diacetal (BDA) protected glyceraldehyde were stereoselectively prepared by aza-Claisen rearrangement of N-allyl-enammonium ions or C-alkylation of enamines. This allows rapid and convenient access to densely functionalized chiral building blocks.

Magnesium nitride as a convenient source of ammonia: preparation of primary amides.

The use of magnesium nitride (Mg 3N 2) as a convenient source of ammonia has been explored for the direct transformation of esters to primary amides. Methyl, ethyl, isopropyl, and tert-butyl esters are converted to the corresponding carboxamides in good yields (75-99%).

Magnesium nitride as a convenient source of ammonia: preparation of dihydropyridines.

Magnesium nitride (Mg 3N 2) has been investigated for the preparation of dihydropyridines. This is a commercially available, bench-stable solid that generates ammonia upon treatment with protic solvents. The main features of the process are the facile reaction setup and good yields obtained in the majority of cases.