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Ntp Technical Report On The Multigenerational Reproductive Toxicology Study Of Genistein Cas No 446 72 0 In Sprague Dawley Rats
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Book Synopsis NTP Technical Report on the Multigenerational Reproductive Toxicology Study of Genistein (cas No. 446-72-0) in Sprague-Dawley Rats by : National Toxicology Program (U.S.)
Download or read book NTP Technical Report on the Multigenerational Reproductive Toxicology Study of Genistein (cas No. 446-72-0) in Sprague-Dawley Rats written by National Toxicology Program (U.S.) and published by . This book was released on 2006 with total page 266 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Technical Report on Multigenerational Reproductive Toxicology Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (Feed Study) by : D. A. Casciano
Download or read book Technical Report on Multigenerational Reproductive Toxicology Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (Feed Study) written by D. A. Casciano and published by . This book was released on 2008-10 with total page 265 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genistein (GS) is a naturally occurring isoflavone that interacts with estrogen receptors and other molecular targets. Human exposure to GS is through consumption of soy products, incl. soy-based infant formula and dietary supp. Consumption of soy and GS has been assoc. with a variety of beneficial effects in animals and humans, but concerns have also been raised concerning potential adverse effects of GS, particularly with regard to reproductive toxicity and the induction or potentiation of carcinogenesis, due primarily to its weak estrogenic activity. Because of these concerns, GS was selected as one of the compounds to be examined in a protocol utilizing Sprague-Dawley rats to evaluate the effects of multigenerational and long-term exposures to doses of estrogenic agents that produce subtle reproductive tract lesions in developmentally exposed Sprague-Dawley rat pups. Illus.
Book Synopsis NTP Technical Report on the Reproductive Dose Range-finding Toxicity Study of Genistein (CAS No. 446-72-0) Administered in Feed to Sprague-Dawley Rats by : K. Barry Delclos
Download or read book NTP Technical Report on the Reproductive Dose Range-finding Toxicity Study of Genistein (CAS No. 446-72-0) Administered in Feed to Sprague-Dawley Rats written by K. Barry Delclos and published by . This book was released on 2007 with total page 72 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Toxicity Report on Reproductive Dose Range-Finding Study of Genistein (CAS No. 446-72-0) Administered in Feed to Sprague-Dawley Rats by : K. Barry Delclos
Download or read book Toxicity Report on Reproductive Dose Range-Finding Study of Genistein (CAS No. 446-72-0) Administered in Feed to Sprague-Dawley Rats written by K. Barry Delclos and published by DIANE Publishing. This book was released on 2008-04 with total page 320 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genistein is a naturally occurring isoflavone that interacts with estrogen receptors & multiple other molecular targets. Human exposure to Genistein is through consumption of soy products, including soy-based infant formula & dietary supplements. A series of short-term studies with Genistein was conducted with two goals: to obtain data necessary to establish dose levels for subsequent multi-generation reproductive & chronic toxicity studies; & to evaluate the effects of Genistein on endpoints outside the reproductive tract. This report focuses on the reproductive & toxicology endpoints. Data obtained in separate evaluations of behavioral, neuroanatomical, neurochemical, & immunological endpoints are also discussed. Illustrations.
Book Synopsis NTP Technical Report on the Toxicology and Carcinogenesis Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (feed Study). by : National Toxicology Program (U.S.)
Download or read book NTP Technical Report on the Toxicology and Carcinogenesis Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (feed Study). written by National Toxicology Program (U.S.) and published by . This book was released on 2008 with total page 240 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Multigenerational Reproductive Toxicology Study of Ethinyl Estradiol (CAS No. 57636) in SpragueDawley Rats (Feed Studies) by :
Download or read book Multigenerational Reproductive Toxicology Study of Ethinyl Estradiol (CAS No. 57636) in SpragueDawley Rats (Feed Studies) written by and published by DIANE Publishing. This book was released on with total page 316 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Technical Report on the Toxicology and Carcinogenesis Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (Feed Study) by : D. A. Casciano
Download or read book Technical Report on the Toxicology and Carcinogenesis Study of Genistein (CAS No. 446-72-0) in Sprague-Dawley Rats (Feed Study) written by D. A. Casciano and published by DIANE Publishing. This book was released on 2008-10 with total page 242 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genistein is an isoflavone that occurs in soy products incl. soy-based infant formulas. It is known as ¿environmental estrogens¿ which can affect the hormone activities and possibly reproductive function of wildlife and humans through exposure. Studies were conducted on 3 such chemicals to see if exposure to such chemicals could have any effect on animals¿ reproductive systems or development of cancers. Rats were exposed to genistein for part or all of the study period and examined at the end of 2 years. Exposure to Genistein for 2 years caused tumors of the mammary gland and pituitary gland in female rats. Exposure to Genistein for shorter durations was also assoc. with increased rates of pituitary gland and mammary gland tumors. Ill.
Book Synopsis Studies in Natural Products Chemistry by : Atta-ur- Rahman
Download or read book Studies in Natural Products Chemistry written by Atta-ur- Rahman and published by Elsevier. This book was released on 2012-12-31 with total page 511 pages. Available in PDF, EPUB and Kindle. Book excerpt: Natural products present in the plant and animal kingdom offer a huge diversity of chemical structures which are the result of biosynthetic processes that have been modulated over the millennia through genetic effects. With the rapid developments in spectroscopic techniques and accompanying advances in high-throughput screening techniques, it has become possible to isolate, and then determine the structures and biological activity of natural products rapidly, thus opening up exciting new opportunities in the field of new drug development to the pharmaceutical industry. The series also covers the synthesis or testing and recording of the medicinal properties of natural products. - Describes the chemistry of bioactive natural products - Contains contributions by leading authorities in the field - A valuable resource for natural product and medicinal chemistry
Download or read book Technical Report Series written by and published by . This book was released on 2010 with total page 214 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Modified One-generation Study of 2-ethylhexyl P-methoxycinnamate Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley SD) Rats with Prenatal, Reproductive Performance, and Subchronic Assessments in F1 Offspring by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Modified One-generation Study of 2-ethylhexyl P-methoxycinnamate Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley SD) Rats with Prenatal, Reproductive Performance, and Subchronic Assessments in F1 Offspring written by and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis NTP Technical Report on the Toxicology and Carcinogenesis Study of Ethinyl Estradiol (CAS No. 57-63-6) in Sprague-Dawley Rats (feed Study) by : National Toxicology Program (U.S.)
Download or read book NTP Technical Report on the Toxicology and Carcinogenesis Study of Ethinyl Estradiol (CAS No. 57-63-6) in Sprague-Dawley Rats (feed Study) written by National Toxicology Program (U.S.) and published by . This book was released on 2010 with total page 210 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Vinpocetine (CASRN 42971-09-5) in Sprague Dawley (Hsd: Sprague Dawley SD) Rats and New Zealand White (Hra: Nzw Spf) Rabbits (Gavage Studies) by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Vinpocetine (CASRN 42971-09-5) in Sprague Dawley (Hsd: Sprague Dawley SD) Rats and New Zealand White (Hra: Nzw Spf) Rabbits (Gavage Studies) written by and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Dimethylaminoethanol Bitartrate (CASRN 5988-51-2) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats (Gavage Studies) by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Dimethylaminoethanol Bitartrate (CASRN 5988-51-2) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats (Gavage Studies) written by and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Dimethylaminoethanol is a close structural analog of choline, an essential nutrient. Dietary supplements containing dimethylaminoethanol bitartrate, a salt of dimethylaminoethanol, are marketed to improve memory and general cognitive function due to the ability of dimethylaminoethanol to increase levels of acetylcholine in the brain. Human exposure to dimethylaminoethanol may also occur through occupational and industrial routes (e.g., spray painting, beverage can lacquering). Dimethylaminoethanol was nominated by the National Institute of Environmental Health Sciences (NIEHS) for toxicological characterization due to concerns for widespread human exposure through its use in industrial and consumer products. Because of the limited literature indicating that dimethylaminoethanol could be a teratogen and reproductive toxicant and because of the possibility for widespread exposure to the salt form of dimethylaminoethanol (dimethylaminoethanol bitartrate) as a dietary supplement in women of childbearing age, the National Toxicology Program (NTP) conducted prenatal developmental toxicology studies in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats. In these studies, time-mated female rats received dimethylaminoethanol bitartrate in sterile water by gavage from implantation on gestation day (GD) 6 to the day before expected parturition (GD 20). To identify dose levels that would appropriately challenge the model system, dimethylaminoethanol bitartrate-related maternal and fetal toxicity were examined in the dose range-finding study followed by the prenatal developmental toxicity study.DOSE RANGE-FINDING PRENATAL DEVELOPMENTAL TOXICITY STUDY: Groups of 10 time-mated female rats were administered 0, 250, 500, or 1,000\smg dimethylaminoethanol bitartrate/kg body weight per day (mg/kg/day) in sterile water by gavage from GD 6 to GD 20. Vehicle control (0\smg/kg) animals received sterile water. There were no indications of maternal or fetal toxicity in the dose range-finding study. All animals survived to study termination. There were no dose-related effects on maternal body weights, body weight gains, body weights corrected for live litter size, or feed consumption. The number of pregnant females, mean number of corpora lutea, dead fetuses, early and late resorptions, and fetal sex ratio were similar across all treatment groups. There was a significant positive trend in the mean number of live female fetuses per litter relative to dose. There were no exposure-related fetal findings. PRENATAL DEVELOPMENTAL TOXICITY STUDY: As no maternal toxicity was observed in the dose range-finding study, groups of 25 time-mated female rats were administered 0, 250, 500, or 1,000\smg/kg/day in sterile water by gavage from GD 6 to GD 20. Vehicle control (0\smg/kg) animals received sterile water. In this study, dimethylaminoethanol bitartrate was well tolerated and there were no significant effects on mortality, maternal body weights, body weight gains, body weights corrected for litter size, or feed consumption during gestation. In the 1,000 mg/kg/day group, one dam was euthanized moribund (GD 21) and one was found dead (GD 10); however, those deaths were not considered dose-related. Clinical observations were limited to single or sporadic incidences with the exception of brown or red vaginal discharge, which was observed between GD 14 and GD 21 in 10/20, 3/20, 4/20, and 10/24\sdams in the 0, 250, 500, and 1,000\smg/kg/day groups, respectively. There were no notable placental or other maternal gross observations at necropsy except for a significant, but not biologically relevant, positive trend in mean absolute liver weight. The number of pregnant females, mean number of corpora lutea, implantations, litter size, live fetuses per litter, and fetal sex ratio were similar across all treatment groups. External and visceral malformations were limited to common background findings and singular or sporadic incidences. There were no observed incidences of fetal head, specifically brain, abnormalities. Skeletal malformations and variations occurred predominantly in the ribs. A significant increase in the incidence of absent innominate artery (a variation) and total, short thoracolumbar ribs (a variation) was observed in the 1,000\smg/kg group, along with a significant positive trend. Additionally, there was a significant increase in the number of supernumerary sites, or ossification sites, in the skull in 1,000\smg/kg fetuses as well as a significant positive trend across all exposed groups. These effects might be reversible (supernumerary ribs) or of uncertain biological significance (supernumerary sites in the skull); however, in the absence of maternal toxicity or effects on fetal body weight, the increased incidences of extra ossification sites in two separate locations, each occurring through two different skeletal developmental pathways, suggest that these effects could be related to dimethylaminoethanol bitartrate exposure. CONCLUSIONS: Under the conditions of the prenatal study, there was equivocal evidence† of developmental toxicity of dimethylaminoethanol bitartrate in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats attributable to increased incidences of absent innominate artery, short thoracolumbar ribs, and supernumerary sites in the skull in the absence of overt maternal toxicity. Synonyms: 2-Dimethylaminoethanol bitartrate; 2-dimethylaminoethanol tartrate; dimethylethanolamine bitartrate; N,N-dimethylethanolamine- tartaric acid salt; ethanol, 2-(dimethylamino)-, [R(R*,R*)]-2,3-dihydroxybutanedioate; ethanol, 2-(dimethylamino)-, tartrate †See Explanation of Levels of Evidence for Developmental Toxicity.
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Tris(chloropropyl) Phosphate (CASRN 13674-84-5) in Sprague Dawley (Hsd: Sprague Dawley SD) Rats (Gavage Studies) by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of Tris(chloropropyl) Phosphate (CASRN 13674-84-5) in Sprague Dawley (Hsd: Sprague Dawley SD) Rats (Gavage Studies) written by and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Tris(chloropropyl) phosphate (TCPP) is used as a flame retardant in textiles, furniture (flexible polyurethane foam), and other related products. In addition, it is manufactured for use in construction materials (rigid polyurethane foam), electronic products, paints, coatings, and adhesives. Several flame retardants have been removed from products in commerce because of toxicity concerns, and TCPP has been considered as a replacement flame retardant for use in these products. Because of concerns for increased use, and thus increased human exposure, the Consumer Product Safety Commission nominated TCPP for toxicological testing by the National Toxicology Program. Additional information on the evaluation of the potential toxicity of TCPP is available at the Program's website (https://ntp.niehs.nih.gov/testing/status/agents/ts-m20263.html). The purpose of this report is to summarize and discuss TCPP effects on prenatal development. In these studies, time-mated female Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats received TCPP (95.7-97% pure) in 0.5% methylcellulose by gavage from implantation on gestation day (GD) 6 to the day before expected parturition (GD 20). Evidence of TCPP-related maternal and fetal toxicity was examined in the dose range-finding study followed by the standard prenatal developmental toxicity study.DOSE RANGE-FINDING PRENATAL DEVELOPMENTAL TOXICITY STUDY: Groups of 11 time-mated female rats were administered 0, 300, 650, or 1,000\smg TCPP/kg body weight per day (mg/kg/day) in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0\smg/kg) animals received aqueous methylcellulose. Maternal toxicity was observed in the 1,000\smg/kg group as evidenced by 7\sof\s11\sdams being either found dead or euthanized moribund. Associated clinical observations in the 1,000\smg/kg group included convulsion, tremors, prone, gasping, hypoactivity, hunched posture, nasal discharge, stained fur, piloerection, salivation, and rooting (pre- and postdosing), which occurred throughout gestation. One female in the 650\smg/kg group was euthanized moribund on GD\s16 with associated clinical observations including cold to touch, hypoactivity, paleness, ataxia, and labored breathing, which may have been related to TCPP exposure. All vehicle control and 300\smg/kg animals survived to study termination. No TCPP-related effects were found on maternal body weights, body weight gain, or feed consumption from GD\s6 to GD\s20. Additionally, there were no significant exposure-related effects on postimplantation loss, fetal body weights, or fetal sex ratio, although limited litters were available for assessment in the 1,000\smg/kg TCPP group because of maternal toxicity. Finally, there were no significant exposure-related external fetal findings (including examination of the palate). PRENATAL DEVELOPMENTAL TOXICITY STUDY: Because of the maternal toxicity observed at 1,000\smg/kg in the dose ranging-finding study, groups of 25 time-mated female rats were administered 0 (n\s=\s50), 162.5, 325, or 650\smg TCPP/kg/ body weight per day in 0.5% aqueous methylcellulose by gavage from GD 6 to GD 20. Vehicle control (0\sm/kg) animals received aqueous methylcellulose. Animals were added to the vehicle control group to obtain historical control data for both maternal and fetal findings in this strain of rat. In this study, TCPP was well tolerated and no exposure-related effects occurred on mortality, maternal body weights, body weight gains, or feed consumption during gestation. Low incidences of clinical observations including nasal discharge, salivation, twitches, ataxia, piloerection, audible respiratory sounds, and hyperactivity were observed in the 650\smg/kg group. Adverse clinical observations were not observed in other groups exposed to TCPP. There were no notable placental or other maternal gross observations at necropsy except for dose-related increases in absolute (9%, 16%, and 26% at 162.5, 325, and 650\smg/kg, respectively) and relative liver weights. No significant effects of TCPP were observed on postimplantation loss, mean fetal body weights, or fetal sex ratio. Likewise, no biologically relevant exposure-related malformations were found in external, visceral, and skeletal fetal exams of groups exposed to TCPP. CONCLUSIONS: Under the conditions of the prenatal study, no evidence of developmental toxicity† of TCPP was found in Hsd:Sprague Dawley(r) SD(r) rats administered 162.5, 325, or 650\smg/kg in the absence of overt maternal toxicity. Trade names: Amgard TMCP, Antiblaze 80, Antiblaze TMCP, Fyrol PCF †See Explanation of Levels of Evidence for Developmental Toxicity.
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of 2-((1-(4-Phenoxyphenoxy)propan-2-yl)oxy)pyridine (CASRN 95737-68-1) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats and New Zealand White (Hra:NZW SPF) Rabbits by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of 2-((1-(4-Phenoxyphenoxy)propan-2-yl)oxy)pyridine (CASRN 95737-68-1) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats and New Zealand White (Hra:NZW SPF) Rabbits written by and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 2-((1-(4-Phenoxyphenoxy)propan-2-yl)oxy)pyridine (MPEP) is a juvenile hormone mimetic pesticide used to control a variety of insects, including tsetse flies, cockroaches, and whiteflies, and is added to potable water in Zika virus-endemic areas to control mosquitoes. It has been proposed that MPEP might contribute to the increased incidence of microcephaly in babies born to mothers who could be consuming MPEP in potable water. Because limited information is available about the potential hazard of MPEP to pregnant women, the National Toxicology Program (NTP) conducted prenatal developmental toxicity studies of MPEP to assess possible harm to the developing conceptus and pregnant animal. In these studies, time-mated Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats and New Zealand White (Hra:NZW SPF) rabbits were administered MPEP in corn oil by gavage once daily from implantation on gestation day (GD)\s6 (rats) or GD\s7 (rabbits) to the day before expected parturition (GD\s20 for rats; GD\s28 for rabbits). In the prenatal developmental toxicity study in rats, fetuses were examined for evidence of MPEP fetal toxicity. A dose range-finding study in rabbits was conducted, followed by a prenatal developmental toxicity study, to confirm the absence of a response in a second species. An assessment of maternal and fetal MPEP concentrations following exposure demonstrated maternal-fetal transfer of MPEP in both rats on GD 18 and rabbits on GD 28.PRENATAL DEVELOPMENTAL TOXICITY STUDY IN RATS: Dose selection was informed by summary data provided for marketing approval, and an additional dose level was added to aid in dose-response characterization. Groups of 25\stime-mated female rats were administered 0, 62.5, 125, 250, or 500\smg MPEP/kg body weight/day (mg/kg/day) in corn oil by gavage once daily from GD\s6 to GD\s20. After initiation of dosing (GD \s6-9), dams administered either 250\sor 500\smg/kg/day displayed similar significantly decreased (~25%) mean body weight gains relative to vehicle control animals. This finding occurred concomitantly with significantly decreased (~11%) feed consumption in the 500\smg/kg/day group, demonstrating limited maternal toxicity. Exposure to MPEP did not affect any pregnancy or litter parameters. Fetal weight in the 500\smg/kg/day group was slightly lower (
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Modified One-generation Study of 2-Ethylhexyl P-Methoxycinnamate (CASRN 5466-77-3) Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats with Prenatal, Reproductive Performance, and Subchronic Assessments in F1\sOffspring by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Modified One-generation Study of 2-Ethylhexyl P-Methoxycinnamate (CASRN 5466-77-3) Administered in Feed to Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats with Prenatal, Reproductive Performance, and Subchronic Assessments in F1\sOffspring written by and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: 2-Ethylhexyl p-methoxycinnamate (EHMC), also known as octinoxate and octyl methoxycinnamate, is a common component of sunscreens, cosmetics, and personal care products. Mechanistic screening studies have purported that EHMC, and its metabolites, are capable of activating the estrogen receptor to varying degrees. The objective of this study was to characterize the potential for EHMC to adversely affect any phase of rat development, maturation, and ability to reproduce. The potential for EHMC to induce subchronic toxicity in the F1\sgeneration, to adversely affect the ability of the F1\sgeneration to reproduce viable F2\soffspring, and to adversely affect the F2\sembryo-fetal development was assessed in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats administered EHMC in 5K96 feed, a diet low in phytoestrogens, using the National Toxicology Program modified one-generation (MOG) study design. The dietary route of administration was selected to approximate continual exposure in group-housed animals. EHMC exposure via the diet, rather than topical application, was selected for this study to sustain internal exposure; if applied topically, the internal dose would have been influenced by intra- and interanimal grooming behavior. Exposure concentration selection for the MOG study was based on a dose range-finding study in which time-mated rats were exposed to 0, 2,250, 5,000, 10,000, or 20,000\sppm EHMC in the diet from gestation day (GD)\s6 through lactation day (LD)\s28. Dams exposed to 20,000\sppm displayed significantly decreased mean body weights on GD\s21 and body weight gain from GD\s6 through GD\s21. Dams exposed to 20,000\sppm displayed lower live litter size, and pups in this group displayed significantly decreased PND\s1 weights and lower postnatal viability resulting in the group being removed from study on postnatal day (PND)\s14. Pup body weights of the 10,000\sppm group were also lower than those in the control group. Therefore, exposure concentrations of 0, 1,000, 3,000, and 6,000\sppm were selected for the subsequent MOG study. Test article consumption was exposure concentration-proportional. EHMC intake for F0\sfemales in the 2,250, 5,000, 10,000, and 20,000\sppm groups, based on feed consumption and dietary concentrations for GD\s6 through GD\s21, was approximately 161, 365, 714, and 1,841\smg EHMC/kg body weight/day (mg/kg/day), respectively; from LD\s1 through LD\s14, EHMC intake was approximately 410, 925, and 1,615\smg/kg/day for the 2,250, 5,000, and 10,000\sppm groups, respectively.MODIFIED ONE-GENERATION STUDY: F0\sexposure began on GD\s6 and was continual. At weaning on PND\s28, F1\soffspring were assigned to the reproductive performance (up to 2/sex/litter, when available), prenatal (1/sex/litter), or subchronic cohort (1/sex from 10 litters). Upon sexual maturity, F1\smating and pregnancy indices were evaluated. In the prenatal cohort, F2\sprenatal development (litter size, fetal weight, and morphology) was assessed on GD\s21. In the reproductive performance cohort, littering indices, F2\sviability, and growth were assessed until PND\s28. The likelihood of identifying potential EHMC-induced adverse effects (similarity and magnitude thereof) at any phase of growth or development was increased by examining related endpoints and multiple pups within a litter throughout life, across cohorts, and across generations. EHMC did not induce overt F0\sor F1\smaternal toxicity or affect mating or pregnancy indices. Dam feed consumption and body weights were slightly lower during lactation in the 6,000\sppm group. EHMC exposure at 6,000\sppm was associated with significantly decreased F1\sand F2\spreweaning mean body weights, with an onset at approximately PND\s13, consistent with the beginning of pup feed consumption. Significantly decreased F1\spreweaning mean body weights were observed in males and females exposed to 3,000 or 6,000\sppm, whereas only F2\smale and female preweaning mean body weights of the 6,000\sppm group were significantly decreased relative to their respective control groups. Although mean body weight gains of males (PND\s28-105) and females (PND\s28-\s91) in all EHMC-exposed groups were similar to those of the respective control groups, postweaning F1\smale and female mean body weights of the 6,000\sppm group were significantly decreased by 5%-14% relative to the respective control animals. Both male and female mean body weights of the 3,000\sppm groups were significantly decreased by approximately 5% on PND\s28, but by PND\s56, their mean body weights were comparable to those of the control groups. Lower F1\spostweaning body weights were not associated with concurrent lower feed consumption. EHMC intake by F0\sfemales in the 1,000, 3,000, and 6,000\sppm EHMC groups, based on feed consumption and dietary concentrations from GD\s6 through GD\s21, was approximately 70, 207, and 419\smg/kg/day, respectively; from LD\s1 through LD\s13, EHMC intake was approximately 161, 475, and 920\smg/kg/day, respectively. EHMC intake by the F1\sgeneration postweaning (PND\s28 through PND\s91) in the 1,000, 3,000, and 6,000\sppm groups was approximately 80, 242, and 491\smg/kg/day (males) and 87, 263, and 528\smg/kg/day (females), respectively. EHMC intake by the adult F1\sfemales in the 1,000, 3,000, and 6,000\sppm groups was approximately 73, 220, and 435\smg/kg/day (GD\s0 through GD\s21) and 139, 418, and 842\smg/kg/day (LD\s1 through LD\s13), respectively. EHMC exposure did not alter anogenital distance or areola/nipple retention. The timing of weaning weight-adjusted vaginal opening (VO) and balanopreputial separation (BPS) was significantly delayed by approximately 2.1\sdays and 2.2\sdays, respectively, in the 6,000\sppm group. F1\srats exposed to 6,000\sppm EHMC displayed slightly more time in estrus. Reproductive performance (fertility and fecundity) was not affected by EHMC exposure. The numbers of live fetuses and pups were not affected. EHMC exposure was not associated with any effects on fetal weight or the incidences of external, visceral, or skeletal malformations. The 6,000\sppm group did exhibit a higher combined fetal incidence of lumbar\s1 rudimentary rib variants (approximately 10% versus 4% in the control group). In the subchronic cohort, no gross findings, changes in organ weights, or histopathological findings were attributed to EHMC exposure. CONCLUSIONS: Under the conditions of this modified one-generation (MOG) study, there was no evidence of reproductive toxicity of 2-ethylhexyl p-methoxycinnamate (EHMC) in Hsd:Sprague Dawley(r) SD(r) rats at exposure concentrations of 1,000, 3,000, or 6,000\sppm. Mating and littering were not affected significantly by EHMC exposure. Under the conditions of this MOG study, there was equivocal evidence of developmental toxicity of EHMC in Hsd:Sprague Dawley(r) SD(r) rats based on the observed postnatal effects on body weight that showed some indication of recovery by study end, delays in postnatal day\s28-adjusted vaginal opening and balanopreputial separation, which could have been influenced by the apparent transient effects on body weight, and time in estrus was slightly longer in EHMC-exposed females relative to that of the control group. No other signals consistent with alterations in estrogenic, androgenic, or antiandrogenic action were observed. EHMC exposure did not induce any specific fetal malformations.SYNONYMS: octinoxate; ethylhexyl methoxycinnamate; octyl methoxycinnamate; 2-propenoic acid, 3-(4-methoxyphenyl)-, 2-ethylhexyl ester; 2-ethylhexyl 3-(4-methoxyphenyl)prop-2-enoate.
Book Synopsis NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of 4-Methylcyclohexanemethanol (CASRN 34885-03-5) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats (Gavage Studies) by :
Download or read book NTP Developmental and Reproductive Toxicity Technical Report on the Prenatal Development Studies of 4-Methylcyclohexanemethanol (CASRN 34885-03-5) in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) Rats (Gavage Studies) written by and published by . This book was released on 2020 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The organic compound 4-methylcyclohexanemethanol (MCHM) is sold as a mixture and is used to reduce impurities in mined coal. On January 9, 2014, an estimated 10,000 gallons of a mixture containing 75% MCHM leaked into the Elk River upstream of the intake for West Virginia American Water Company's Elk River plant. Upon review of the available toxicity literature for MCHM, the Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry set a drinking water advisory level of 1\sppm for MCHM and nominated MCHM and other chemicals present in the Elk River spill to the National Toxicology Program (NTP) for toxicity evaluation. Because of the potential for exposure of pregnant women to MCHM and the absence of adequate developmental toxicity data, NTP conducted studies to characterize the toxicity of MCHM in an accepted regulatory in vivo rat model system that assesses the potential harm to the developing conceptus and pregnant rat. Time-mated pregnant Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats received MCHM (99.8% pure) in corn oil via gavage from implantation on gestation day (GD) 6 to GD 20, the day before expected parturition. The potential for MCHM to induce overt maternal and fetal toxicity was examined in a dose range-finding study followed by a prenatal developmental toxicity study. The guideline prenatal developmental toxicity studies discussed in this report provide important animal data that can be used to address the adequacy of the 1\sppm advisory level in protecting sensitive human populations.DOSE RANGE-FINDING PRENATAL DEVELOPMENTAL TOXICITY STUDY: Time-mated female rats (n\s=\s10/dose level) were administered 0, 150, 300, 600, or 900\smg MCHM/kg body weight per day (mg/kg/day) in corn oil by gavage (2\smL/kg) from GD\s6 to GD\s20. Control females (0\smg/kg) received corn oil vehicle. All dams in the 900\smg/kg group were euthanized on GD 7 or 8 due to clinical observations indicating overt toxicity (ataxia, cold to touch, clear ocular discharge, excessive salivation, lethargy/hypoactivity, and/or piloerection); three dams from the 600\smg/kg group displayed similar clinical observations and were removed from study. Body weight gain from GD\s6 to 21 in the 600\smg/kg group was 44% lower than that of the vehicle control and was associated with a 13% reduction in feed consumption during the same interval. No signs of maternal toxicity were observed in the 150 or 300\smg/kg dose groups. Dams administered 600\smg/kg displayed higher postimplantation loss (53%) and lower gravid uterine weight. MCHM exposure did not affect the number of live fetuses per litter or fetal sex ratio; however, fetal weights were 12% and 39% lower in the 300 and 600\smg/kg exposure groups, respectively. No external malformations or variations were attributed to MCHM exposure. PRENATAL DEVELOPMENTAL TOXICITY STUDY: Due to the maternal toxicity observed at 600 and 900\smg/kg in the dose range-finding study, time-mated female rats (n\s=\s25/dose level) were administered 0, 50, 100, 200, or 400\smg/kg/day in corn oil (2\smL/kg) by gavage from GD 6 to GD 20. Vehicle control animals (0\smg/kg) received corn oil vehicle. No clinical observations of toxicity were observed in dams in any dose group. Dams administered 400\smg/kg had significantly lower (11%) mean body weight gains compared to vehicle control dams. Dams administered MCHM had slightly higher feed consumption. Alterations in dam clinical chemistry included reductions in total protein and globulin concentrations that occurred in a dose-related manner in dams administered\s≥100\smg/kg. Dams administered 400\smg/kg exhibited lower gravid uterine weight. No exposure-related effects were found on the number of live fetuses per litter or fetal sex ratio. Fetal body weight was lower (15%) in the 400\smg/kg group. Visceral and skeletal examination identified several anomalies that were attributed to MCHM exposure. Misshapen adrenal glands (malformation) and discolored adrenal glands and kidneys (variations) were observed in fetuses in the 400\smg/kg group. Malformations and variations of the ribs, sternebrae, and vertebrae were also present in the same exposure group. Findings of misaligned costal cartilage (variation); seventh, right costal cartilage not fused to the sternum (malformation); and an increase in short, cervical supernumerary ribs (SNRs) and full, thoracolumbar SNRs (malformations) were significantly higher in the 400\smg/kg group. Together, the total incidence of all malformations of the ribs, sternebrae, SNRs, and vertebrae were present in 1.0%, 1.1%, 2.2%, 2.8%, and 15.8% of fetuses from the 0, 50, 100, 200, and 400\smg/kg groups; these findings were present in 13%, 14%, 14%, 26%, and 57% of litters, respectively. The maternal no-observed-effect level (NOEL) was 50\smg/kg based on MCHM-related changes in clinical chemistry at doses ≥100\smg/kg, reduced maternal body weight gain at 400\smg/kg, and overt toxicity observed at doses ≥600\smg/kg in the dose range-finding study. The minimal MCHM-related changes in maternal clinical chemistry would not be expected to affect fetal development. MCHM-related effects (lower fetal weight and specific and total axial skeletal malformations) were observed in fetuses exposed to 400\smg/kg, indicating a fetal NOEL of 200\smg/kg. These findings suggest a significant margin of exposure (>1,000-fold) exists between both the maternal and fetal NOELs in the rat and the estimated exposure of 0.04\smg/kg/day in pregnant women at the 1\sppm MCHM advisory level. CONCLUSIONS: Under the conditions of the prenatal study, there was clear evidence† of developmental toxicity of MCHM in Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats based on reduced fetal weight, adrenal malformations, and increased malformations of the axial skeleton (short cervical SNR, full thoracolumbar SNR, and costal cartilage not fused to the sternum). These findings occurred in fetuses of dams administered 400\smg/kg and in the absence of overt maternal toxicity. Synonyms: Cyclohexanemethanol, 4-methyl-; MCHM †See Explanation of Levels of Evidence for Developmental Toxicity.
