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Comprehensive assessment of reproductive toxicity of dimoxystrobin: No classification warranted
S308
Abstracts / Toxicology Letters 258S (2016) S62–S324
cancer classifications of chemicals previously reviewed by the U.S. EPA. In vivo data from guideline studies were extracted from the U.S. EPA Toxicity Reference Database. Of the 147 compounds with rat subchronic and mouse/rat carcinogenicity study outcomes, 54% had a tumor outcome in at least one species. The presence of subchronic histopathologic or hormonal risk markers yielded a sensitivity (Sn) of 65%, a specificity (Sp) of 54%, and a negative predictive value (NPV) of 57% for any tumor outcome. When tested against cancer classifications requiring quantitative risk assessment (qRA), subchronic effects provided 73% Sn, 38% Sp, and 75% NPV. In comparison, bioactivity in a battery of 42 in vitro cytotoxicity assays from the U.S. EPA ToxCast library provided 57% Sn and Sp and 49% NPV for any tumor outcome and 67% Sn, 56% Sp, and 80% NPV for cancer classifications not requiring qRA. These findings indicate that short-term effects may inform prioritization of chemicals for potential cancer risk, but that integration of additional data streams are needed to improve model performance. This abstract does not necessarily represent the views or policies of the U.S. EPA. http://dx.doi.org/10.1016/j.toxlet.2016.06.2051 P22-008 Neuroprotective role of melatonin in kainic acid induced neurotoxicity: A role of neurotransmitter system and calcium V.K. Mehta ∗ , M. Bhatnagar, R. Chittora
P22-009 Comprehensive assessment of reproductive toxicity of dimoxystrobin: No classification warranted S. Melching Kollmuss, C. Werner, I. Fegert ∗ Basf Se, Ludwigshafen, Germany Dimoxystrobin is a European-registered pesticidal active ingredient. Toxicologically it interferes with the iron transport in rodents, which leads to lower serum iron levels and anemia in rats. Dimoxystrobin is classified with Repr. 2, H361d (suspected of damaging the unborn child). The classification decision for R63 – taken at ECB – was based on impaired offspring body weight development, an assumed higher sensitivity of offspring vs. adult animals and heart effects seen in the 2-generation toxicity study. In a thorough re-evaluation of the data it could be shown that the impaired offspring body weight effects at the high dose of the 2-generation toxicity study only developed postnatally, when the pups are directly exposed to dimoxystrobin-treated diet. Further the cardiomegalies – seen in some 21-day old pups of the high dose – are known to be a secondary effect to anemia and were proven to be reversible. No developmental effects were seen in the rat and rabbit prenatal developmental toxicity study. In two new studies, clear NOAELs were determined in offspring and young rats, which were not lower than the adult NOAELs. Thus it was confirmed, that
ML Sukhadia University, Udaipur, India Nitric oxide (NO) plays a role in the pathophysiology of excitotoxicity. It is also possible that increase in Ca2+ overload and NO-mediated events are involved in neuronal loss during status epilepticus (SE). We investigated the effects of melatonin on NADPH-d positive hippocampal neurons after kainic acid (KA) induced SE in rats. Cytosolic Ca2+ and acetylcholine esterase (AChE) activity in all respective groups was studied. KA was administered, with a single dose of 10 mg/kg/bw. KA treated rats were given melatonin at a dose of 20 mg/kg/bw (for 21 days). On the last day of treatment, animals were transcardially perfused with 4% paraformaldehyde under deep thiopental anesthesia. Cryostat sections (20 m) were cut and stained for NADPH-d and AChE positive neurons. KA exposed animals showed significantly increased number of NO positive neurons in the dorsal and ventral blade of the dentate gyrus (DG), hilus, CA1 and CA3 area of hippocampus, with a parallel increase in intracellular free Ca2+ ion concentration. AChE activity in KA treated animals showed a significant decline in the hippocampal regions. KA +melatonin treated animal groups showed reduced number of NADPH-d positive neurons in DG, hilus, CA1, CA3 areas and a decline in cytosolic Ca2+ concentration and AChE expression, as compared to KA treated group. Our study suggests that the enhanced levels of Ca2+ and nitric oxide play an important role in kainate induced excitotoxicity. Inhibition of NO production may be another means whereby melatonin can reduce oxidative damage and seems to play important role in neuroprotection. http://dx.doi.org/10.1016/j.toxlet.2016.06.2052
- Pups and young rats were not more sensitive than adult animals - Effects on offspring body weight development occurred only after direct dimoxystrobin exposure - Reversible heart effects in offspring are not a developmental effect. Based on a comprehensive re-evaluation of existing and new data of dimoxystrobin it can be concluded that a classification for reproduction toxicity is scientifically not justified and should be reconsidered. http://dx.doi.org/10.1016/j.toxlet.2016.06.2053 P22-010 15-Day intact adult male rat assay with alpha-cypermethrin M. Kemény 1 , H.A. Marxfeld 1 , R. Buesen 1 , A. Chukwudebe 2 , B. Van Ravenzwaay 1 , I. Fegert 1,∗ 1 2
BASF SE, Ludwigshafen, Germany BASF Corporation, Research Triangle Park, USA
Objective: Cypermethrin (8 isomers) and the related betacypermethrin (4 isomers of Cypermethrin) are reported to adversely affect testes and spermatogenesis in the 15-day intact male adult rat assay via a mechanism involving reduced androgen receptor (AR) expression (Hu et al., 2011; Li et al., 2013; Liu et al., 2010). This study investigated the effects of alphacypermethrin (a-cyp; consists of 2 common cypermethrin/betacypermethrin isomers) in a comparable 15-day intact male adult rat assay. Methods: Based on results of a range-finder study and published literature, doses of 0, 2.0, 3.5, and 6.6 mg/kg bw/day a-cyp in corn oil (1 ml/kg bw) were gavaged daily to male Wistar rats (N = 15) for 15 days. Signs of toxicity were monitored daily during treatment. After cessation, sperm parameters, body
Abstracts / Toxicology Letters 258S (2016) S62–S324
cancer classifications of chemicals previously reviewed by the U.S. EPA. In vivo data from guideline studies were extracted from the U.S. EPA Toxicity Reference Database. Of the 147 compounds with rat subchronic and mouse/rat carcinogenicity study outcomes, 54% had a tumor outcome in at least one species. The presence of subchronic histopathologic or hormonal risk markers yielded a sensitivity (Sn) of 65%, a specificity (Sp) of 54%, and a negative predictive value (NPV) of 57% for any tumor outcome. When tested against cancer classifications requiring quantitative risk assessment (qRA), subchronic effects provided 73% Sn, 38% Sp, and 75% NPV. In comparison, bioactivity in a battery of 42 in vitro cytotoxicity assays from the U.S. EPA ToxCast library provided 57% Sn and Sp and 49% NPV for any tumor outcome and 67% Sn, 56% Sp, and 80% NPV for cancer classifications not requiring qRA. These findings indicate that short-term effects may inform prioritization of chemicals for potential cancer risk, but that integration of additional data streams are needed to improve model performance. This abstract does not necessarily represent the views or policies of the U.S. EPA. http://dx.doi.org/10.1016/j.toxlet.2016.06.2051 P22-008 Neuroprotective role of melatonin in kainic acid induced neurotoxicity: A role of neurotransmitter system and calcium V.K. Mehta ∗ , M. Bhatnagar, R. Chittora
P22-009 Comprehensive assessment of reproductive toxicity of dimoxystrobin: No classification warranted S. Melching Kollmuss, C. Werner, I. Fegert ∗ Basf Se, Ludwigshafen, Germany Dimoxystrobin is a European-registered pesticidal active ingredient. Toxicologically it interferes with the iron transport in rodents, which leads to lower serum iron levels and anemia in rats. Dimoxystrobin is classified with Repr. 2, H361d (suspected of damaging the unborn child). The classification decision for R63 – taken at ECB – was based on impaired offspring body weight development, an assumed higher sensitivity of offspring vs. adult animals and heart effects seen in the 2-generation toxicity study. In a thorough re-evaluation of the data it could be shown that the impaired offspring body weight effects at the high dose of the 2-generation toxicity study only developed postnatally, when the pups are directly exposed to dimoxystrobin-treated diet. Further the cardiomegalies – seen in some 21-day old pups of the high dose – are known to be a secondary effect to anemia and were proven to be reversible. No developmental effects were seen in the rat and rabbit prenatal developmental toxicity study. In two new studies, clear NOAELs were determined in offspring and young rats, which were not lower than the adult NOAELs. Thus it was confirmed, that
ML Sukhadia University, Udaipur, India Nitric oxide (NO) plays a role in the pathophysiology of excitotoxicity. It is also possible that increase in Ca2+ overload and NO-mediated events are involved in neuronal loss during status epilepticus (SE). We investigated the effects of melatonin on NADPH-d positive hippocampal neurons after kainic acid (KA) induced SE in rats. Cytosolic Ca2+ and acetylcholine esterase (AChE) activity in all respective groups was studied. KA was administered, with a single dose of 10 mg/kg/bw. KA treated rats were given melatonin at a dose of 20 mg/kg/bw (for 21 days). On the last day of treatment, animals were transcardially perfused with 4% paraformaldehyde under deep thiopental anesthesia. Cryostat sections (20 m) were cut and stained for NADPH-d and AChE positive neurons. KA exposed animals showed significantly increased number of NO positive neurons in the dorsal and ventral blade of the dentate gyrus (DG), hilus, CA1 and CA3 area of hippocampus, with a parallel increase in intracellular free Ca2+ ion concentration. AChE activity in KA treated animals showed a significant decline in the hippocampal regions. KA +melatonin treated animal groups showed reduced number of NADPH-d positive neurons in DG, hilus, CA1, CA3 areas and a decline in cytosolic Ca2+ concentration and AChE expression, as compared to KA treated group. Our study suggests that the enhanced levels of Ca2+ and nitric oxide play an important role in kainate induced excitotoxicity. Inhibition of NO production may be another means whereby melatonin can reduce oxidative damage and seems to play important role in neuroprotection. http://dx.doi.org/10.1016/j.toxlet.2016.06.2052
- Pups and young rats were not more sensitive than adult animals - Effects on offspring body weight development occurred only after direct dimoxystrobin exposure - Reversible heart effects in offspring are not a developmental effect. Based on a comprehensive re-evaluation of existing and new data of dimoxystrobin it can be concluded that a classification for reproduction toxicity is scientifically not justified and should be reconsidered. http://dx.doi.org/10.1016/j.toxlet.2016.06.2053 P22-010 15-Day intact adult male rat assay with alpha-cypermethrin M. Kemény 1 , H.A. Marxfeld 1 , R. Buesen 1 , A. Chukwudebe 2 , B. Van Ravenzwaay 1 , I. Fegert 1,∗ 1 2
BASF SE, Ludwigshafen, Germany BASF Corporation, Research Triangle Park, USA
Objective: Cypermethrin (8 isomers) and the related betacypermethrin (4 isomers of Cypermethrin) are reported to adversely affect testes and spermatogenesis in the 15-day intact male adult rat assay via a mechanism involving reduced androgen receptor (AR) expression (Hu et al., 2011; Li et al., 2013; Liu et al., 2010). This study investigated the effects of alphacypermethrin (a-cyp; consists of 2 common cypermethrin/betacypermethrin isomers) in a comparable 15-day intact male adult rat assay. Methods: Based on results of a range-finder study and published literature, doses of 0, 2.0, 3.5, and 6.6 mg/kg bw/day a-cyp in corn oil (1 ml/kg bw) were gavaged daily to male Wistar rats (N = 15) for 15 days. Signs of toxicity were monitored daily during treatment. After cessation, sperm parameters, body