scholarly journals Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis

2016 ◽  
Vol 35 (5) ◽  
pp. 543-557
Author(s):  
Vic Ciaravino ◽  
Dina Coronado ◽  
Cheryl Lanphear ◽  
Alan Hoberman ◽  
Sanjay Chanda
Keyword(s):  
Reproductive Performance ◽  
Dose Group ◽  
Female Rats ◽  
Oral Gavage ◽  
Pharmaceutical Agent ◽  
The Us ◽  
Adverse Effect Level ◽  
Effect Level ◽  
F2 Generation ◽  
F1 Generation

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/d from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/d dose group. Excess salivation was observed in the 60 and 100 mg/kg/d dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/d, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was ≥100 mg/kg/d, based on the lack of test article-related changes.

Maternal food restriction in rats of the F0 generation increases retroperitoneal fat, the number and size of adipocytes and induces periventricular astrogliosis in female F1 and male F2 generations

2017 ◽  
Vol 29 (7) ◽  
pp. 1340 ◽  
Author(s):  
A. O. Joaquim ◽  
C. P. Coelho ◽  
P. Dias Motta ◽  
L. F. Felício ◽  
E. F. Bondan ◽  
...  
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Food Restriction ◽  
Bodyweight Gain ◽  
Male Offspring ◽  
Acidic Protein ◽  
Female Rats ◽  
Juvenile Period ◽  
Gfap Expression ◽  
F2 Generation ◽  
F1 Generation

The present study investigated whether male offspring (F2 generation) from female rats (F1 generation) whose mothers (F0 generation) were food restricted during gestation inherit a phenotypic transgenerational tendency towards being overweight and obese in the juvenile period, in the absence of food restriction in the F1/F2 generations. Dams of the F0 generation were 40% food restricted during pregnancy. Bodyweight, the number and size of larger and small hypodermal adipocytes (HAs), total retroperitoneal fat (RPF) weight and the expression of glial fibrillary acidic protein (GFAP) in periventricular hypothalamic astrocytes (PHAs), as determined by immunohistochemistry, were evaluated in both generations. In the female F1 generation, there was low bodyweight gain only during the juvenile period (30–65 days of age), a decrease in the size of small adipocytes, an increase in the number of small adipocytes, an increase in RPF weight and an increase in GFAP expression in PHAs at 90–95 days of age. In males of the F2 generation at 50 days of age, there was increased bodyweight and RPF weight, and a small number of adipocytes and GFAP expression in PHAs. These data indicate that the phenotypic transgenerational tendency towards being overweight and obese was observed in females (F1) from mothers (F0) that were prenatally food restricted was transmitted to their male offspring.

Toxicity Assessment of 4-Amino-2-Nitrotoluene

2013 ◽  
Vol 32 (2) ◽  
pp. 113-122 ◽  
Author(s):  
John T. Houpt ◽  
Glenn J. Leach ◽  
Larry R. Williams ◽  
Mark S. Johnson ◽  
Gunda Reddy
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Weight Gain ◽  
Body Weight Gain ◽  
Toxicity Study ◽  
Female Rats ◽  
Male Rats ◽  
Toxicity Data ◽  
Adverse Effect Level ◽  
Effect Level

4-Amino-2-nitrotoluene (4A2NT; CAS 119-32-4) is a degradation product of 2,4-dinitrotoluene. The toxicity data on 4A2NT are limited. Therefore, we collected toxicity data from rats to assess environmental and human health effects from exposures. The approximate lethal dose for both sexes was 5000 mg/kg. A 14-day toxicity study in rats was conducted with 4A2NT in the feed at concentrations of 0, 125, 250, 500, 1000, and 2000 ppm. Based on a 14-day oral dose range toxicity study with 4A2NT in the feed, 2000 ppm was selected as highest concentration for a subsequent 90-day study. An oral 90-day subchronic toxicity study in rats was conducted with concentrations of 0, 500, 1000, or 2000 ppm of 4A2NT in the feed. The calculated consumed doses of 4A2NT in the feed were 0, 27, 52, or 115 mg/kg/d for males and 0, 32, 65, or 138 mg/kg/d for females. A no-observed adverse effect level could not be determined. The lowest observed adverse effect level was 27 mg/kg/d for males and 32 mg/kg/d for female rats based upon decreased body weight gain. The decreased body weight gain in male rats was the most sensitive adverse event observed in this study and was used to derive a benchmark dose (BMD). A BMD of 23.1 mg/kg/d and BMD with 10% effect level of 15.5 mg/kg/d were calculated for male rats, which were used to derive an oral reference dose (RfD). The human RfD of 1.26 μg/kg/d was derived using current United States Environmental Protection Agency guidelines.

Lack of Trigeminal Nerve Toxicity in Rats Exposed to Trichloroethylene Vapor for 13 Weeks

2006 ◽  
Vol 25 (6) ◽  
pp. 531-540 ◽  
Author(s):  
Ralph R. Albee ◽  
Pamela J. Spencer ◽  
Keith A. Johnson ◽  
Greg J. Bradley ◽  
Brian R. Marable ◽  
...  
Keyword(s):  
Trigeminal Nerve ◽  
Auditory Brainstem ◽  
Female Rats ◽  
Male Rats ◽  
Fischer 344 ◽  
Clinical Observations ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Brainstem Response ◽  
Effect Level

Male and female Fischer-344 rats were exposed to 1,1,2-trichloroethylene (TCE) at 250, 800, or 2500 ppm for 6 h/day, 5 days/week, for 13 weeks. Weekly body weights and daily clinical observations were recorded and a functional observational battery (FOB) was performed monthly. Postexposure neurotoxicological evaluations included an electrodiagnostic evaluation of auditory function, the trigeminal nerve, and a comprehensive neuropathological examination. After 8 weeks of exposure, female, but not male, rats exposed to 2500 ppm were slightly more reactive to handling than the controls but not after 13 weeks of exposure. After 13 weeks, female rats exposed to 2500 ppm TCE were slightly more active during the 1-min observation period than the controls. There were no treatment-related differences in grip performance, landing foot splay, or on the trigeminal nerve–evoked potential at any dose. At 2500 ppm TCE, mild frequency-specific hearing deficits were observed, including elevated tone-pip auditory brainstem response thresholds. Focal loss of hair cells in the upper basal turn of the cochlea was observed in 2500 ppm–exposed rats. Except for the cochleas of 2500 ppm–exposed rats, no treatment-related lesions were noted during the neuro-histopathologic examination. The no-observable-adverse-effect level for this study was 800 ppm based on ototoxicity at 2500 ppm.

scholarly journals A 90-day toxicity and genotoxicity study with high-purity phenylcapsaicin

2018 ◽  
Vol 2 ◽  
pp. 239784731877306 ◽  
Author(s):  
Torbjørn Rage Paulsen ◽  
Sebastian Stiller ◽  
Klaus Weber ◽  
Claudia Donath ◽  
Gudrun Schreiband ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Clinical Chemistry ◽  
Human Lymphocytes ◽  
Recovery Period ◽  
Clinical Signs ◽  
Gene Mutations ◽  
Oral Gavage ◽  
Adverse Effect Level ◽  
Dose Oral ◽  
Effect Level

To evaluate the safety of the synthetic capsaicin analogue phenylcapsaicin (PheCap; 7-phenylhept-6-yne-acid-hydroxy-3-mathoxylbenzylamide, CAS no 848127-67-3), a 90-day repeated dose oral gavage of 0, 30, 100 or 250 mg/kg body weight (bw)/day toxicity study with a 28-day recovery period was conducted using Wistar rats. Examinations of clinical signs, body and organ weight, haematology, urinalysis, clinical chemistry, food consumption and macroscopic, as well as histopathological tissue examinations were carried out for signs of toxicity. Degenerative, but reversible changes in the liver at 250 mg/kg bw/day, and local irritating effects in the stomach at 100 and 250 mg/kg bw/day were found. These findings were associated with test item-related clinical symptoms, that is, diarrhoea, salivation and moving of bedding material. PheCap did neither cause gene mutations by base pair changes or frame shifts in the genome of the tester stains Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537 or TA 102 nor induce structural and/or numerical chromosomal damage in human lymphocytes. Therefore, it can be concluded that PheCap is not genotoxic. The No Observed Adverse Effect Level (NOAEL) of PheCap for systemic toxicity is considered to be at 100 mg/kg bw/day which is based on degenerative changes in the liver. Due to irritating effects in the stomach, the NOAEL for local effects was established at 30 mg/kg bw/day.

Juvenile Toxicity Rodent Model to Study Toxicological Effects of Bisphenol A (BPA) at Dose Levels Derived From Italian Children Biomonitoring Study

2019 ◽  
Vol 173 (2) ◽  
pp. 387-401 ◽  
Author(s):  
Roberta Tassinari ◽  
Laura Narciso ◽  
Sabrina Tait ◽  
Luca Busani ◽  
Andrea Martinelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adverse Effect ◽  
Bisphenol A ◽  
Female Rats ◽  
Toxicological Effects ◽  
General Toxicity ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Italian Children ◽  
Dose Levels

Abstract Bisphenol A (BPA) is a plasticizer with endocrine disrupting properties particularly relevant for children health. Recently BPA has been associated with metabolic dysfunctions but no data are yet available in specific, long-term studies. This study aimed to evaluate BPA modes of action and hazards during animal juvenile life-stage, corresponding to childhood. Immature Sprague-Dawley rats of both sexes were orally treated with 0 (vehicle only—olive oil), 2, 6, and 18 mg/kg bw per day of BPA for 28 days, from weaning to sexual maturity. Dose levels were obtained from the PERSUADED biomonitoring study in Italian children. Both no-observed-adverse-effect-level (NOAEL)/low-observed-adverse-effect-level (LOAEL) and estimated benchmark dose (BMD) approaches were applied. General toxicity, parameters of sexual development, endocrine/reproductive/functional liver and kidney biomarkers, histopathology of target tissues, and gene expression in hypothalamic-pituitary area and liver were studied. No mortality or general toxicity occurred. Sex-specific alterations were observed in liver, thyroid, spleen, leptin/adiponectin serum levels, and hypothalamic-pituitary gene expression. Thyroid homeostasis and liver were the most sensitive targets of BPA exposure in the peripubertal phase. The proposed LOAEL was 2 mg/kg bw, considering as critical effect the liver endpoints, kidney weight in male and adrenal histomorphometrical alterations and osteopontin upregulation in female rats. The BMD lower bounds were 0.05 and 1.33 mg/kg bw in males and females, considering liver and thyroid biomarkers, respectively. Overall, BPA evaluation at dose levels derived from children biomonitoring study allowed to identify sex-specific, targeted toxicological effects that may have significant impact on risk assessment for children.

Evaluation of genotoxicity and subchronic toxicity of standardized rose hip extract

2017 ◽  
Vol 37 (7) ◽  
pp. 725-741 ◽  
Author(s):  
A Nagatomo ◽  
M Oguri ◽  
N Nishida ◽  
M Ogawa ◽  
A Ichikawa ◽  
...  
Keyword(s):  
Oral Dose ◽  
Chinese Hamster ◽  
Gene Mutations ◽  
Ethanol Extract ◽  
Female Rats ◽  
Toxicity Studies ◽  
Male And Female Rats ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Rose Hip

Rose hip is the fruit of the rose plant, which is widely used in food, cosmetics and as a traditional medicine. Therefore, rose hip is considered safe and has a sufficient history of consumption as food. However, few studies have reported on the safety of rose hip extracts in toxicological analyses. Thus, to evaluate the safety of rosehip polyphenol MJ (RHPMJ), an aqueous ethanol extract standardized with the trans-tiliroside content, we performed genotoxicity and 90-day repeated oral dose toxicity studies in compliance with the Organisation for Economic Co-operation and Development-Good Laboratory Practice. RHPMJ did not induce gene mutations in reverse mutation tests of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA strains and did not induce chromosomal aberrations in cultured Chinese hamster lung (CHL/IU) cells. Moreover, micronucleus tests using rat bone marrow showed RHPMJ had no micronucleus-inducing potential. Finally, 90-day repeated oral dose toxicity studies (100–1000 mg/kg) in male and female rats showed no treatment-related toxicity in rats. These data indicate that the RHPMJ had no genotoxicity and a no-observed-adverse-effect level greater than 1000 mg/kg in rats.

Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

2020 ◽  
Vol 39 (5) ◽  
pp. 365-378 ◽  
Author(s):  
Paul Baldrick ◽  
Mary Ellen Cosenza ◽  
Tessie Alapatt ◽  
Brad Bolon ◽  
Melissa Rhodes ◽  
...  
Keyword(s):  
Weight Of Evidence ◽  
Drug Marketing ◽  
Toxicity Studies ◽  
Final Study ◽  
The Us ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Animal Toxicity ◽  
The Many ◽  
Threshold Setting

A challenge for all toxicologists is defining what study findings are actually adverse versus non-adverse in animal toxicity studies, and which ones are relevant for generating a no observed adverse effect level (NOAEL) to assess human risk. This article presents views on this challenge presented by toxicologists, toxicologic pathologists, and regulatory reviewers at the 2019 annual meeting of the American College of Toxicology during a workshop entitled “Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings.” The speakers noted that setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals, and that a “weight of evidence” approach often is more useful than a rigid threshold-setting algorithm. Regulators from the US Food and Drug Administration and European Union told how assessment of adverse nonclinical findings is undertaken to allow clinical studies to commence and drug marketing approvals to succeed, along with the process that allows successful dialogs with regulators. Nonclinical case studies of findings judged to be adverse versus non-adverse were presented in relation to the many factors that might halt or delay clinical development. The process of defining adverse findings and the NOAEL in final study reports was discussed, as well as who should be involved in the process.

A Preliminary 13-Week Oral Toxicity Study of Ginger Oil in Male and Female Wistar Rats

2011 ◽  
Vol 30 (6) ◽  
pp. 662-670 ◽  
Author(s):  
Kottarapat Jeena ◽  
Vijayastelter B. Liju ◽  
Ramadasan Kuttan
Keyword(s):  
Wistar Rats ◽  
Hematological Parameters ◽  
Zingiber Officinale ◽  
Female Rats ◽  
Oral Toxicity ◽  
Male And Female ◽  
Male And Female Rats ◽  
Adverse Effect Level ◽  
Female Wistar Rats ◽  
Effect Level

Zingiber officinale Roscoe, ginger, is a major spice extensively used in traditional medicine. The toxicity profile of ginger oil was studied by subchronic oral administration for 13 weeks at doses of 100, 250, and 500 mg/kg per day to 6 groups of Wistar rats (5/sex per dose). Separate groups of rats (5/sex per group) received either paraffin oil (vehicle) or were untreated and served as comparative control groups. There was no mortality and no decrease in body weight or food consumption as well as selective organ weights during the study period. Administration of ginger oil to rats did not produce any treatment-related changes in hematological parameters, hepatic, renal functions, serum electrolytes, or in histopathology of selected organs. The major component of ginger oil was found to be zingiberene (31.08%), and initial studies indicated the presence of zingiberene in the serum after oral dosing. These results confirmed that ginger oil is not toxic to male and female rats following subchronic oral administrations of up to 500 mg/kg per day (no observed adverse effect level [NOAEL]).

Toxicologic Characterization of a Novel Explosive, Guanidinium 3,4-Dinitropyrazolate (GDNP), in Female Rats and Ames Mutagenicity Assay

2012 ◽  
Vol 31 (5) ◽  
pp. 441-453 ◽  
Author(s):  
Larry R. Williams ◽  
Valerie H. Adams ◽  
Shannon M. Wallace ◽  
Mark S. Johnson
Keyword(s):  
Adverse Effect ◽  
Tap Water ◽  
Water Solution ◽  
Military Training ◽  
Lethal Dose ◽  
Female Rats ◽  
Oral Exposure ◽  
Bacterial Strains ◽  
Adverse Effect Level ◽  
Effect Level

Sustainable use of military training ranges requires the development of compounds that have a minimal impact to the environment when used in a weapon system. Guanidinium 3,4-dinitropyrazolate (GDNP) is a novel explosive compound of interest for application in some weapon systems. Little is known of its toxicologic properties. To ensure the health of potentially exposed personnel and the environment, initial toxicity investigations were conducted and the results were compared with another widely used energetic (hexahydro-1,3,5-trinitro-1,3,5-triazine [RDX]). In a microplate Ames assay, GDNP was not cytotoxic to bacterial tester strains at concentrations less than 100 μg/mL. However, GDNP was mutagenic to 4 of 5 bacterial strains with and without S9 metabolic incubation at concentrations as low as 0.7 μg/mL. Unlike RDX, GDNP did not have an affinity for the γ-aminobutyric acid(A) receptor convulsant site and was predicted to not induce seizure. After acute oral dosing in female rats, the median lethal dose in female rats of GDNP in tap water solution was determined to be 720 mg/kg. Daily oral exposure to 500 mg/kg per d of GDNP for 14 days caused weight loss, increased liver and spleen weights, and adverse histopathologic events in kidney and spleen. These adverse events were not observed in animals receiving lower doses of GDNP. In this study, the lowest-observed-adverse-effect-level from oral exposure to GDNP for 14 days was 500 mg/kg per d and the no-observable-adverse-effect-level was 152 mg/kg per d.

Developmental Toxicity of Thiodiglycol in Sprague-Dawley Rats

2007 ◽  
Vol 26 (4) ◽  
pp. 365-371 ◽  
Author(s):  
John T. Houpt ◽  
Lee C. B. Crouse ◽  
Richard A. Angerhofer ◽  
Glenn J. Leach ◽  
Gunda Reddy
Keyword(s):  
Adverse Effect ◽  
Developmental Toxicity ◽  
Female Rats ◽  
Main Study ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Body Weights ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Dose Levels

Thiodiglycol (TG), a hydrolysis product of sulfur mustard (HD), is a potential contaminant of soil and water at certain military sites. To establish developmental toxicity criteria for TG, an oral developmental toxicity study was conducted in Sprague-Dawley rats. Neat thiodiglycol (99.9 %) was administered orally to mated female rats from gestation days (GDs) 5 through 19. The day of positive mating was considered day 0. A pilot study was conducted with TG at dose levels 250, 500, 1000, 2000, or 5000 mg/kg to select suitable doses for the main study. In the main study, three groups of rats (25/group) received TG by gavage at dose levels of 430, 1290, or 3870 mg/kg/day. A fourth group served as a sham control. On day 20 of gestation, all females were euthanized and a cesarean section performed. Litters were examined for soft tissue and skeletal alterations. Maternal toxicity was limited to dams receiving TG at 3870 mg/kg/day. At this dose, body weights and food consumption were reduced during certain periods of gestation. Fetuses derived from those dams exhibited a nonstatistically significant increased incidence of variations when compared to controls. Fetal body weights in the 3870 mg/kg/day group were significantly lower than controls. There was no increased incidence of anomalies when thiodiglycol-treated fetuses were compared to controls. It was concluded that TG did not produce terata. Developmental toxicity (decreased fetal weights and associated delays in development) occurred only at the maternally toxic dose of 3870 mg/kg. It appears that 1290 mg/kg/day could be considered no observed adverse effect level (NOAEL) for oral developmental toxicity. The lowest observed adverse effect level (LOAEL) was 3870 mg/kg for maternal toxicity.

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