Is there any added value of the second generation in the Extended One-Generation Reproductive Toxicity Study (EOGRTS)? A retrospective analysis of 24 EOGRTS.

The Extended One-Generation Reproductive Toxicity Study (EOGRTS) is a standard information requirement under Registration, Evaluation, Authorization and restriction of Chemicals (REACH) in Europe. Inclusion of an F2 generation is considered useful if this impacts hazard identification or when it provides additional information altering the reproductive or developmental No Observed Adverse Effect Level (NOAEL) and subsequent risk assessment. In this retrospective analysis the added value of the F2 generation in 24 EOGRTS was evaluated.

Review of dose setting for the extended one-generation reproductive toxicity studies (OECD TG 443): Considerations on ECHA's dose level selection recommendations.

During 2020, The European Chemicals Agency (ECHA) began evaluating the OECD Test Guideline 443: Extended One Generation Reproductive Toxicity Study (EOGRTS) to analyze specific aspects related to study design, conduct and toxicological findings. A significant outcome of this ECHA evaluation focused on adequate dose level selection. Subsequently, ECHA published recommendations for DART studies, however, these recommendations seemingly do not align with the principles of the 3Rs, animal welfare or human safety goals, specifically, regarding three aspects.

Lack of direct bone effect of tofacitinib, a JAK inhibitor, in juvenile rats and evaluation of the association between offspring growth and femur length.

Bone has recently emerged as a target organ for some Janus kinase (JAK) inhibitors in adult and/or juvenile animal toxicity studies. Oral administration of tofacitinib, a JAK inhibitor, was not associated with clinical or macroscopic effects on bone growth and development in a rat juvenile animal study (JAS) with tofacitinib dosing starting on postnatal day (PND) 21. However, given that previous JAS did not include a targeted evaluation of bone, inclusive of microscopic examination, an additional rat JAS was conducted to further assess this risk.

Extended One-Generation Reproductive Toxicity (EOGRT) study of benzoic acid in Sprague Dawley rats.

Benzoic acid (BA) was administered in the diet to male and female Sprague Dawley Crl:CD(SD) rats in an OECD Test Guideline 443 Extended One-Generation Reproductive Toxicity (EOGRT) study to test for effects that may occur as a result of pre- and postnatal exposure. The study included cohorts of F offspring to evaluate potential effects of benzoic acid on reproduction, the developing immune system, and the developing neurological system with the inclusion of learning and memory assessments. Benzoic acid was incorporated in the diet at concentrations of 0, 7,500, 11,500, and 15,000 mg/kg diet (ppm).

Trichloroethylene in drinking water throughout gestation did not produce congenital heart defects in Sprague Dawley rats.

Background: Trichloroethylene (TCE) was negative for developmental toxicity after inhalation and oral gavage exposure of pregnant rats but fetal cardiac defects were reported following drinking water exposure throughout gestation. Because of the deficiencies in this latter study, we performed another drinking water study to evaluate whether TCE causes heart defects.

Methods: Groups of 25 mated Sprague Dawley rats consumed water containing 0, 0.

Practical considerations for developmental thyroid toxicity assessments: What's working, what's not, and how can we do better?

Thyroid hormones (THs; T3 and T4) play a role in development of cardiovascular, reproductive, immune and nervous systems. Thus, interpretation of TH changes from rodent studies (during pregnancy, in fetuses, neonates, and adults) is critical in hazard characterization and risk assessment. A roundtable session at the 2017 Society of Toxicology (SOT) meeting brought together academic, industry and government scientists to share knowledge and different perspectives on technical and data interpretation issues.

Report from the BfR expert hearing on practicability of hormonal measurements: recommendations for experimental design of toxicological studies with integrated hormonal end points.

This publication summarizes discussions that were held during an international expert hearing organized by the German Federal Institute for Risk Assessment (BfR) in Berlin, Germany, in October 2017. The expert hearing was dedicated to providing practical guidance for the measurement of circulating hormones in regulatory toxicology studies. Adequate measurements of circulating hormones have become more important given the regulatory requirement to assess the potential for endocrine disrupting properties for all substances covered by the plant protection products and biocidal products regulations in the European Union (EU).

Reproductive and developmental toxicity of potassium perfluorohexanesulfonate in CD-1 mice.

Potassium perfluorohexanesulfonate (KPFHxS) was evaluated for reproductive/developmental toxicity in CD-1 mice. Up to 3 mg/kg-d KPFHxS was administered (n = 30/sex/group) before mating, for at least 42 days in F males, and for F females, through gestation and lactation. F pups were directly dosed with KPFHxS for 14 days after weaning.

Rethinking developmental toxicity testing: Evolution or revolution?

Background: Current developmental toxicity testing adheres largely to protocols suggested in 1966 involving the administration of test compound to pregnant laboratory animals. After more than 50 years of embryo-fetal development testing, are we ready to consider a different approach to human developmental toxicity testing?

Methods: A workshop was held under the auspices of the Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute to consider how we might design developmental toxicity testing if we started over with 21st century knowledge and techniques (revolution). We first consider what changes to the current protocols might be recommended to make them more predictive for human risk (evolution).

Lack of immunotoxic effects of repeated exposure to atrazine associated with the adaptation of adrenal gland activation.

T cell-dependent IgM antibody production and natural killer cell (NKC) activity were assessed in SD rats orally administered atrazine for 28 days to males (0, 6.5, 25, or 100 mg/kg/day) or females (0, 3, 6, or 50 mg/kg/day), or 30 or 500 ppm in diet (3 or 51 mg/kg/day). Anti-asialo GM1 antibodies (NKC) and cyclophosphamide (antibody-forming cell assay [AFC]) served as positive controls.

Subchronic, reproductive, and maternal toxicity studies with tertiary butyl acetate (TBAC).

Tertiary-butyl acetate (TBAC) was tested for subchronic toxicity in rats and mice and reproductive toxicity in rats at inhalation concentrations of 0, 100, 400 or 1600ppm. An oral maternal toxicity study was conducted in rats at dose levels of 0, 400, 800, 1000 and 1600mgkg(-1)d(-1). In the inhalation studies, hematology, clinical chemistry, urinalysis, gross pathology and the majority of body weight and feed consumption values were unaffected.

Placental transfer of (125)Iodinated humanized immunoglobulin G2Δa in the Sprague Dawley rat.

Antibody-like biopharmaceuticals cross the placenta by utilizing transport pathways available for transfer of maternal antibodies to the conceptus. To characterize the timing and magnitude of this transfer in the rat, embryo/fetal biodistribution of maternally administered radiolabeled humanized IgG2 was quantified over the course of gestation using gamma counting and whole body autoradiography. The result was humanized IgG2 found in rat embryo/fetal tissues as early as gestation day 11 with a >1000-fold increase in the amount of total IgG2 by day 21.

Identification and sequencing of a novel rodent gammaherpesvirus that establishes acute and latent infection in laboratory mice.

Gammaherpesviruses encode numerous immunomodulatory molecules that contribute to their ability to evade the host immune response and establish persistent, lifelong infections. As the human gammaherpesviruses are strictly species specific, small animal models of gammaherpesvirus infection, such as murine gammaherpesvirus 68 (γHV68) infection, are important for studying the roles of gammaherpesvirus immune evasion genes in in vivo infection and pathogenesis. We report here the genome sequence and characterization of a novel rodent gammaherpesvirus, designated rodent herpesvirus Peru (RHVP), that shares conserved genes and genome organization with γHV68 and the primate gammaherpesviruses but is phylogenetically distinct from γHV68.

Quantitative assessment of mammary gland development in female Long Evans rats following in utero exposure to atrazine.

In this study, we quantified the effects of in utero exposure to the herbicide atrazine on subsequent mammary gland development. Atrazine was administered to pregnant female Long Evans rats from gestation days 13-19 at doses of 0, 6.5, 50, or 100 mg/kg/day.