Developmental Toxicity of 1,2-Dichloropropane (PDC) in Rats and Rabbits Following Oral Gavage

1,2-Dichloropropane (PDC) was evaluated for its potential causeembryonal/fetal toxicity and teratogenicity in pregnant ratsand rabbits. PDC was administered via oral gavage at dose levelsof 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation(rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through19 (rabbits). Fetuses were examined on Gestation Day 20 (rats)or Day 28 (rabbits). Maternal toxicity was observed in bothrats and rabbits at the high dose levels. Rats given 125 mg/kg/dayof PDC showed clinical signs of toxicity and decreased bodyweight and body weight gain. Rabbits given 150 mg/kg/day PDCshowed changes in hematologic parameters and decreased bodyweight gain. Although maternal toxicity was apparent, no indicationteratogenicity was observed in rat or rabbit fetuses at anydose level. Significant increases in the incidence of delayedossification of skull bones, considered secondary to decreasedmaternal body weight gain, were observed in rats given 125 mg/kg/dayand rabbits given 150 mg/kg/day. No maternal or developmentaleffects were observed in rats given 10 or 30 mg/kg/day or inrabbits given 15 or 50 mg/kg/day of PDC. Based on the resultsof these studies the maternal and developmental NOELs in ratsand rabbits were 30 and 50 mg/kg/day, respectively.     

Developmental toxicity of diethanolamine applied cutaneously to CD rats and New Zealand White rabbits

Diethanolamine (DEA) was administered cutaneously to pregnant CD rats and New Zealand White rabbits during the periods of major organogenesis, Gestation Days 6-15 for rats and 6-18 for rabbits. Doses employed were 0, 150, 500, and 1500 mg/kg/day for rats and 0, 35, 100, and 350 mg/kg/day for rabbits. Rat dams exhibited reduced body weight at 1500 mg/kg/day, skin irritation and increased kidney weights at 500 and 1500 mg/kg/day, and a slight microcytic anemia with abnormal red blood cell morphology at all dose levels. Rat fetuses had increased incidences of six skeletal variations at 1500 mg/kg/day. Lower doses were without effect on the fetuses. Rabbit dams administered 350 mg/kg/day exhibited various skin lesions, reduced food consumption, and color changes in the kidneys but no hematological changes. Body weight gain was reduced at >/=100 mg/kg/day. There was no evidence of maternal toxicity at 35 mg/kg/day and no evidence of developmental toxicity in rabbits at any dose level. Developmental toxicity was observed only in the rat and only at doses causing significant maternal toxicity, including hematological effects. Due to a dose discrepancy, the no observable effect level (NOEL) for DEA developmental toxicity in rats was adjusted to 380 mg/kg/day. In rabbits, the embryonal/fetal NOEL was 350 mg/kg/day.     

Pharmacokinetic interaction of Diabecon (D-400) with rifampicin and nifedipine.

In the present study, Diabecon (D-400), a herbomineral anti-diabetic preparation, was studied for its pharmacokinetic interaction with the commonly used drugs rifampicin and nifedipine. Interaction of Diabecon with rifampicin: The pharmacokinetic interaction of rifampicin and Diabecon (D-400) was studied in animal models as well as in healthy human volunteers. Twelve rabbits were divided into two groups of six each. Animals in group I were treated with rifampicin (100 mg/kg body weight, p.o.) and group II with rifampicin (100 mg/kg body weight, p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for a period of 8 days. Rifampicin levels in plasma were estimated on day 1 and day 8 at 2, 4, 6 and 8 h after drug administration. On the basis of these findings, a clinical study in 9 healthy human volunteers aged 25-35 years and weighing 50-75 kg was initiated. They were given 450 mg of rifampicin once only on day 1 and from the second day onwards were given 2 tablets of Diabecon (D-400) twice daily for 7 days. On day 9, another dose of rifampicin (450 mg) was given along with 2 tablets of Diabecon (D-400). Blood samples were collected at 2, 4, 6 and 8 h after drug administration on day 1 and day 9 to estimate the rifampicin levels in plasma. Interaction of Diabecon with nifedipine: In another study, 12 rabbits were divided into two groups of 6 each. Group I animals were treated with nifedipine (2.5 mg/kg body weight, p.o.) and Group II animals were treated with nifedipine (2.5 mg/kg body weight, p.o.) and Diabecon (D-400) (1 g/kg body weight, p.o.) for a period of 8 days. On day 1 and day 8, blood samples were collected at 1, 2, 4 and 6 h after drug administration and plasma nifedipine levels were estimated. The results of these three studies revealed that Diabecon (D-400) did not alter the pharmacokinetic profiles of rifampicin and nifedipine.     

Developmental toxicity of Spinosad administered by gavage to CD® rats and New Zealand White rabbits

The insecticide Spinosad was administered by gavage to pregnant CD® rats at 0, 10, 50 or 200 mg/kg/day on gestation days (gd) 6–15 and to New Zealand White rabbits at 0, 2.5, 10 or 50 mg/kg/day on gd-7–19. Rats and rabbits were monitored for clinical signs of toxicity and body weight gains. At gd-21 (rats) or gd-28 (rabbits), maternal organ weights, reproductive parameters, fetal body weights, and fetal external, visceral and skeletal structures were evaluated. Rats given 200 mg/kg/day exhibited a 4% lower body weight on gd-12 and decreased body weight gains on gd-6–16 relative to controls. There was no maternal toxicity at 10 or 50 mg/kg/day, and no developmental toxicity in rats at any dose level. Rabbits given 50 mg/kg/day exhibited decreased feed consumption, reduced fecal output, body weight loss during the initial dosing period (gd-7–10) and a non-statistically significant decrease (31%) in body weight gain during the dosing period (gd-7–20). Two litters aborted due to maternal inanition. There were no maternal effects at lower doses, and no signs of developmental toxicity at any dose. Thus, the maternal no-observed-effect levels (NOEL) were 50 and 10 mg/kg/day in rats and rabbits, respectively, and the embryonal/fetal NOELs were 200 mg/kg/day in rats and 50 mg/kg/day in rabbits.     

Developmental (embryo-fetal toxicity/teratogenicity) toxicity studies of synthetic crystalline lycopene in rats and rabbits.

Synthetic crystalline lycopene is a nutritional supplement to increase dietary intake of lycopene, an antioxidant carotenoid. Its potential oral developmental toxicity was studied in rats and rabbits. Each study included 3 control groups (water and matrix for Lycopene 10 CWD or LycoVit 10%), 3 Lycopene 10 CWD groups [500, 1500 and 3000 (rats)/2000 (rabbits) mg/kg/day] and 1 LycoVit 10% group [3000 mg/kg/day (rats)/2000 (rabbits)]. The high dosages were at maximum achievable concentrations and dosage volumes (15 and 10 ml/kg for rats and rabbits, respectively) of the highly viscous test material suspensions. Dosages were administered on gestation days (GDs) 6 through 19 (rats) or GDs 6 through 28 (rabbits). Endpoints evaluated included viability, body weight, feed consumption, necropsy observations [GD 20 (rats)/GD 29 (rabbits)], uterine contents and fetal viability, gender, body weight and morphology (skeletons double-stained). Feed consumption and weight gain were essentially unaffected in rats and rabbits, despite intubation problems in both species and reduced gastrointestinal motility and mortality in rabbits attributable to the physical properties of the gels. Neither Lycopene 10 CWD nor LycoVit 10% caused direct maternal or developmental toxicity in rats or rabbits at dosages as high as 3000 or 2000 mg/kg/day, respectively.     

Developmental toxicity studies of 2-(difluoromethyl)-dl-ornithine (DFMO) in rats and rabbits.

DFMO, an irreversible inhibitor of ornithine decarboxylase (ODC), is under development as a chemopreventive drug against cancers with pronounced proliferative phases. In support of human clinical trials, preclinical developmental toxicity studies were conducted in pregnant rats and rabbits. Rats were treated during GD 6-17, and fetuses were obtained by C-section on GD 20. Rabbits were treated during GD 7-20, and fetuses were obtained by C-section on GD 29. The dose range-finding study in rats (5/group at 0, 50, 125, 300, 800, or 1000 mg/kg/day) revealed maternal toxicity at doses > or = 800 mg/kg/day (decreased body weights and food consumption) and developmental toxicity at doses > or = 300 mg/kg/day (increased early resorptions and reduced fetal body weights). In the main study, rats (25/group) received 0, 30, 80, or 200 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 200 mg/kg/day as significantly decreased fetal weights and increased incidence of litters with skeletal variations of 14th rudimentary rib, 14th full rib, and/or 27th presacral vertebrae. There were no treatment-related fetal skeletal malformations or external or visceral anomalies at any dose level. The dose range-finding study in rabbits (5/group at 0, 30, 60, 120, 240, or 500 mg/kg/day) revealed developmental toxicity at doses > or = 60 mg/kg/day (increased resorptions and reduced fetal body weights) in the absence of maternal toxicity. In the main study, rabbits (20/group) received 0, 15, 45, or 135 mg/kg/day. Developmental toxicity in the absence of maternal toxicity was observed at 135 mg/kg/day as nonsignificantly increased early resorptions, decreased implantation sites, decreased viable fetuses, and reduced fetal weights. There were no external, visceral, or skeletal anomalies at any dose level. Thus, in the main developmental toxicity studies, DFMO produced developmental but not maternal toxicity at 200 and 135 mg/kg/day in rats and rabbits, respectively. Accordingly, in rats, the maternal no-observable-effect level (NOEL) was 200 mg/kg/day and the fetal NOEL was 80 mg/kg/day; while in rabbits the maternal NOEL was 135 mg/kg/day and the fetal NOEL was 45 mg/kg/day. These fetal NOELs are several-fold higher than the dose level currently used in Phase II and III clinical trials (approximately 13 mg/kg).     

Developmental toxicity studies in rats and rabbits with 3,5,6-trichloro-2-pyridinol, the major metabolite of chlorpyrifos.

3,5,6-Trichloro-2-pyridinol (TCP), the primary metabolite of chlorpyrifos and chlorpyrifos-methyl, was evaluated for potential developmental toxicity. Groups of 32-34 bred female Fischer 344 rats were given 0, 50, 100, or 150 mg TCP/kg/day by gavage on gestation days 6-15; the fetuses were evaluated on gestation day 21. Similarly, groups of 16 inseminated female New Zealand White rabbits were given 0, 25, 100, or 250 mg TCP/kg/day by gavage on gestation days 7-19, and fetuses were evaluated on gestation day 28. No clinical signs of toxicity attributed to TCP were noted in either species. In rats, at 150 mg/kg/day, maternal effects included slight decreases in feed consumption, significantly depressed body weight gain (25% relative to controls) resulting in significantly lower maternal terminal body weights, and increased relative liver weight. At 100 mg/kg/day, maternal body weight gain in rats was depressed approximately 22%. Among rabbits, maternal effects were limited to the group given 250 mg/kg/day, which lost an average of approximately 70 g during the treatment period (vs. 140 g in the controls). There were no effects on fetal weight or viability, nor were there significant increases in any fetal alteration in either species. A slightly higher (not statistically significant) than usual incidence of central nervous system anomalies occurred in rabbits, but these anomalies were found in both treated and control groups in this study as well as contemporaneous studies of unrelated compounds. This, and the fact that these anomalies were not seen with the parent compound, chlorpyrifos, suggest that their origin was spontaneous. Thus, TCP was not considered fetotoxic or teratogenic in either rats or rabbits, even at dose levels that produced maternal toxicity.     

Hepatotoxicity induced by the herbicide atrazine in the rat

The hepatotoxicity of atrazine was investigated by studying clinical parameters related to hepatic function and by electron microscopy. Three groups to male albino rats (Wistar strain) received 100, 200 and 400 mg of atrazine/per kg of body weight/per day, for 14 days. One group received 600 mg atrazine/per kg of body weight/per day, for 7 days. At termination of dosing, the animals were sacrificed and blood was drawn for the determination of serum total lipids, glucose, alanine aminotransferase (ALT) and alkaline phosphatase (SAP). A dose dependent decrease in serum glucose concentration was observed in all the groups. In contrast, a dose relate increase in total serum lipids, was apparent at all dose levels studied. Activity of serum ALT and SAP increased approximately 60% and 200% respectively in rats given 600 mg atrazine/kg bw for 7 days. The liver was examined grossly and microscopically. Electron microscopy disclosed no changes in the hepatocytes of rats treated with the low dose (100 mg/kg bw). At high doses, electron microscopy revealed hepatocytic proliferation and degeneration of smooth endoplasmic reticulum, lipid accumulation and alteration of bile canaliculi proportional to dose and duration of treatment.     

A teratology study on vomitoxin (4-deoxynivalenol) in rabbits

Diets containing 4-deoxynivalenol (vomitoxin) of greater than 98% purity were fed to rabbits on days 0-30 of gestation. The dietary concentrations of 4-deoxynivalenol were 0, 0.00075, 0.0015, 0.003, 0.006, 0.012 and 0.024% and the daily intakes of deoxynivalenol were 0, 0.3, 0.6, 1.0, 1.6, 2.0 and 1.8 mg/kg body weight/day, respectively. A pair-fed group was given a feed intake equivalent to that in the 1.6-mg/kg group. The only significant effects that were observed in foetuses examined at day 30 of gestation occurred only at doses that caused reductions in both the body weight and feed intake of does. The foetal effects consisted of a 100% incidence of resorption in the 1.8- and 2.0-mg/kg groups and decreased mean foetal weight in the 1.0- and 1.6-mg/kg and pair-fed groups. The doses that did not appear to be maternotoxic (0.6 and 0.3 mg/kg) did not show any adverse effects in foetuses at term. Vomitoxin given in the diet during pregnancy failed to show any evidence of teratogenic potential in rabbits.     

Oral (drinking water) developmental toxicity studies of bromodichloromethane (BDCM) in rats and rabbits

Crl:CD(SD)IGS BR VAF/Plus (Crl SD) rats and Hra(NZW) SPF rabbits were tested for potential developmental toxicity from bromodichloromethane (BDCM) provided continuously in the drinking water during gestation (gestation days [GDs] 6 to 21 in rats and GDs 6 to 29 in rabbits). Concentrations of 0, 50, 150, 450, or 900 ppm of BDCM were used for rats; 0, 15, 150, 450, or 900 ppm were used for rabbits (in dose range-finding studies, 1350 ppm was excessively maternotoxic to both species). Investigated maternal parameters included viability, clinical signs, water and feed consumption, and body weights. Maternal gross lesions, gravid uterine weights, abnormal placentas, and numbers of corpora lutea, implantation sites, live and dead fetuses, and early and late resorptions were observed at time of Caesarean sectioning (GD 21 in rats; GD 29 in rabbits). Body weights, sex ratios, and morphological abnormalities (external, soft tissue, and skeletal) were noted in the fetuses. Mean consumed doses of BDCM were calculated to be 0, 2.2, 18.4, 45.0, or 82.0 mg/kg/day for the rats, and 0, 1.4, 13.4, 35.6, or 55.3 mg/kg/day for the rabbits (approximate human intake is 0.8 microg/kg/day [0.0008 mg/kg/day] in adults). In pregnant rats, toxicologically important, statistically significant effects included reduced absolute (g/day) and relative (g/kg/day) water consumption values at > or =50 ppm (2.2 mg/kg/day) and reduced body weight gains (also when corrected for gravid uterine weight) and absolute (g/day) and relative (g/kg/day) feed consumption values at >450 ppm (45.0 mg/kg/day). These parameters were also significantly reduced at > or =450 ppm (35.6 mg/kg/day) in pregnant rabbits (significant weight loss occurred in the rabbits at 900 ppm, i.e., 55.3 mg/kg/day). Thus, the maternal no-observable-adverse-effect level (NOAEL) for BDCM was 150 ppm, i.e., 18.4 and 13.4 mg/kg/day in rats and rabbits, respectively. No adverse effects on embryofetal viability, growth, sex ratio, gross external, soft tissue, or skeletal morphology occurred at 900 ppm in rats or rabbits. Minimal delays in the ossification of forepaw phalanges and hindpaw metatarsals and phalanges occurred in rat fetuses at 900 ppm; delays were considered marginal, reversible, and associated with severely reduced maternal weight gain. Therefore, the developmental NOAEL for rats was 450 ppm (45.0 mg/kg/day), whereas in rabbits it was 900 ppm (55.3 mg/kg/day). These NOAELs are 56,250 and 69,120 times the human adult exposure level of 0.0008 mg/kg/day, respectively. Based on the results of these studies, BDCM should not be identified as a risk to development of human conceptuses.     

4-硝基二苯胺-4'-硫代氨基甲酸(O)苯酯的抗血吸虫作用及毒性

本文证明硝硫氰胺(C 9333-(Go/CGP 4540)类的衍生物4-硝基二苯胺-4′-硫代氨基甲酸(O)苯酯(代号7720)有与硝硫氰胺同等强度的抗血吸虫作用。用粗粉混悬液灌胃治疗小白鼠实验性血吸虫病,7720和硝硫氰胺的CD₅₀分别为79.0μmol/kg/d(即28.8mg/kg/d)×5日和83.4μmol/kg/d(即22.6mg/kg/d)×5日。7720 16或32 mg/kg/d×5d已可使所试全部病免达寄生虫学治愈。未能测出小白鼠灌胃急性LD₅₀。通过对幼年大白鼠体重增长影响的观察,家犬亚急性毒性试验及内脏组织病理学检查等提示本药经口给药无严重毒性反应。本文还证明4-硝基-4′-异硫氰基二苯醚对家兔实验性血吸虫病亦有较佳疗效。     

Teratogenic Evaluation of Diglycidyl Ether of Bisphenol A (DGEBPA) in New Zealand White Rabbits following Dermal Exposure

Teratogenic Evaluation of Diglycidyl Ether of Bisphenol A (DGEBPA)in New Zealand White Rabbits Following Dermal Exposure. BRESLIN,W. J., KIRK, H. D., AND JOHNSON, K. A. (1988). Fundam. ApplToxicol 10, 736–743. Diglycidyl ether of bisphenol A (DGEBPA)was tested for its potential to cause embryo/fetal toxicityand teratogenicity in pregnant rabbits. DGEBPA was applied dailyto the clipped skin of New Zealand White rabbits for approximately6 hr/day at dose levels of 0 (polyethylene glycol 400, vehiclecontrol), 30, 100, or 300 mg/kg body weight/ day on Days 6 through18 of gestation. Fetuses were examined for external, visceral,and skeletal alterations on Day 28 of gestation. Maternal toxicitywas observed among pregnant rabbits in the 300 mg/kg/day dosegroup as evidenced by moderate to severe erythema, fissures,hemorrhage, and slight edema at the exposure site. Similar,but less severe skin lesions were observed in pregnant rabbitsin the 100 mg/kg/day exposure group. A slight erythema at thesite of application was observed in dams in the 30 mg/kg/daydose group. The erythema in rabbits from the low dose groupwas indistinguishable from the erythema caused by the occlusivebandages/ jackets used to hold the test material in place and,thus, was not considered toxicologically significant. No evidenceof embryo/fetal toxicity or teratogenicity was observed at anydose level. Thus, the embryo/fetal no-observed-effect levelfor dermally applied DGEBPA was 300 mg/kg body weight/day, themaximum tolerated dose.     

昆明山海棠提取物对新西兰兔的胚胎-胎仔发育毒性研究

目的:研究昆明山海棠提取物对妊娠动物、胚胎及胎仔发育的影响。方法:取交配成功的新西兰雌兔,按体质量随机区组法分为溶剂对照组、阳性对照组(环磷酰胺,20 mg/kg)和昆明山海棠提取物高、中、低剂量组(15.0、7.50、3.75 g/kg,以生药量计),每组均至少18只。溶剂对照组和昆明山海棠提取物各剂量组雌兔在妊娠第6～18天灌胃水或相应昆明山海棠提取物药液,5mL/kg,每天1次;阳性对照组雌兔在妊娠第10～13天于颈部皮下注射环磷酰胺,1 mL/kg,每天1次。依据《药物生殖毒性研究技术指导原则》相关要求,在实验期间观察并记录雌兔的一般情况、体质量和摄食量,并于妊娠第28天时对其实施安乐死,解剖后观察并记录其主要脏器、带胎子宫、胎盘子宫、胎盘、卵巢以及着床腺、吸收胎、死胎、活胎、黄体等相关指标,并对胎仔进行体质量、外观形态、内脏和骨骼发育等相关指标的检查。结果:与溶剂对照组比较,昆明山海棠提取物各剂量组孕兔的体质量、体质量增长、摄食量、主要脏器,孕兔妊娠、生殖功能以及胚胎形成和胎仔的生长发育、外观形态、内脏和骨骼发育等相关指标均未见明显异常改变(P>0.05);阳性对照组上...     

Subchronic toxicologic studies using cyclamate-Na in dogs

2 male and 2 female beagle dogs were fed cyclamate-Na in daily doses of 0 (control), 150, 500, 1500 mg/kg of body weight with the diet. Liquid feces occurred only after feeding 1500 mg/kg/day during the first few days of the experiment. Haematological, clotting and clinical chemistry parameters were unchanged in the groups up to the level of 1500 mg/kg/day. No effects were noted in carbohydrate and fat metabolism, nor in ECG or blood pressure. Gross pathology and histopathology did not reveal any change in any dose group. Daily fed doses of cyclamate-Na up to 1500 mg/kg body weight were well tolerated for three month in the dog.     

Impaired behaviour, learning and memory, in adult mice neonatally exposed to hexabromocyclododecane (HBCDD)

Brominated flame-retardants (BFRs) are a diverse group of global environmental pollutants. In the present study, we show that neonatal exposure to hexabromocyclododecane (HBCDD) can cause developmental behavioural defects that are similar to those recently reported for PBDEs and certain PCBs. Furthermore, HBCDD appears to be as potent as PBDEs in inducing developmental neurotoxic effects in mice.

In this study, neonatal NMRI mouse pups were given either a single oral dose of 0.9 mg HBCDD/kg body weight, 13.5 mg HBCDD/kg body weight, or a 20% fat emulsion vehicle on postnatal day 10. At the age of 3 months, the mice were observed regarding spontaneous behaviour and concerning learning and memory capability. Mice exposed to 0.9 mg HBCDD or to 13.5 mg HBCDD/kg body weight showed a significantly altered spontaneous behaviour, manifested as a hyperactive condition and reduced habituation. Learning and memory, as observed in a Morris water maze, was also significantly affected in mice given the higher dose of HBCDD.     

Teratogenic potential of carbaryl given to rabbits and mice by gavage or by dietary inclusion.

The teratogenic potential of the insecticide carbaryl (1-naphthyl methylcarbamate) was evaluated in New Zealand rabbits and CF-1 mice. Rabbits were given 150 or 200 mg carbaryl/kg/day by gavage from Days 6 through 18 of gestation. Mice were given 100 or 150 mg carbaryl/kg/day by gavage or were given a diet containing 5660 ppm of carbaryl (1166 mg carbaryl/kg body wt/day) from Days 6 through 15 of gestation. An increased incidence of omphalocele was observed among the offspring of rabbits given 200 mg carbaryl/kg/day, which was a maternally toxic dose, and another case was observed among the offspring of rabbits given 150 mg/kg/day, a dosage which produced mild maternal toxicity. In comparison, carbaryl was not teratogenic in mice given maternally toxic doses of the compound either by gavage or by dietary inclusion.     

Effects of administering caffeine to pregnant rats either as a single daily dose or as divided doses four times a day

From day 6 to day 20 of pregnancy, rats were treated with caffeine in a total daily dose of 10 or 100 mg/kg by gavage, either as a single bolus dose or as four divided doses given at 3-hr intervals throughout the day. Controls were given distilled water at the same times. Maternal body weight and food and water consumption were reduced in the two groups receiving a total of 100 mg caffeine/kg/day and in the group given 2.5 mg/kg four times daily. Dose-related decreases in foetal weight, placental weight and crown-rump length and dose-related retardation of skeletal ossification were observed. Major foetal abnormalities, mainly ectrodactyly, were seen only in the group given 100 mg caffeine/kg in a single daily dose.     

Embryonic susceptibility of Microtus ochrogaster (common prairie vole) to phenyl mercuric acetate

Pregnant M. ochrogaster received single intraperitoneal (i.p.) doses of 0.06, 0.125, 0.25, 1.2, or 5 mg phenyl mercuric acetate (PMA)/kg of body weight on day 8, 9, or 10 of gestation or 0.5 mg PMA/kg on day 7, 8, 9, 10, 11, or 12 of gestation. No toxicity was exhibited, and no abnormal fetuses were observed in any group. An embryocidal effect that dependend on dose and stage of development was determined by increased numbers of resorption sites; resorption sites were dose-dependent, and the embryocidal effect decreased as the embryo matured. A dose of 0.06 mg PMA/kg of body weight produced no resorptions when given on day 8 or day 10 of gestation; 0.125 mg/kg or 0.25 mg/kg produced no resorptions if given on day 10; 0.5 mg/kg resulted in live fetuses and resorptions in the same uterus when given on days 7 through 11; the same dose on day 12 produced all live fetuses; and 1, 2, or 5 mg PMA/kg given on day 8, 9, or 10 of gestation caused total embryo resorption. The i.p. LD₅₀ of PMA in Microtus ochrogaster adult females was 10 mg/kg of body weight.     

Toxicity of coenzyme Q(10): a report of 90-day repeated dose toxicity study in rats

Potential toxicity of CoQ(10) was studied in rats by oral gavage for 90 days at 500, 1500, and 3000 mg/kg.day. A 15-day recovery period after the administration period was investigated. Body weight and food consumption were measured throughout the study. Meanwhile, clinical observations were recorded. Hematological and blood chemistry parameters were evaluated at both the end of the dosing period and the end of the recovery period. Gross-pathologic and histopathologic examination was performed on select tissues from all animals. No adverse changes in mortality and clinical signs occurred. The body weights of males in the 1500 mg/kg dosage group were slightly reducted; likewise, the food consumption in 3000 mg/kg female rats decreased, but this is not a dose-dependent behavior. Significant change of liver function (TRIGL) and CHOL did not show a dose-dependent effect. Weight of ovary and ovary-to-body weight ratio decreased in the 1500 mg/kg dosage groups. Meanwhile, the uterus -to-body weight ratio increased the in 3000 mg/kg dosage groups. However, there were no significant histopathological changes observed in ovary and uterus: so they were not considered to be adverse. It suggested that CoQ(10) is relatively safe on the test dosage administration. Nevertheless, appetite the body weight, blood lipid and liver function should be observed during long-term clinical administration of this drug with high dosage. Overall, CoQ(10) was well tolerated by male and female rats at dose levels up to 3000 mg/kg.day.     

Evaluation of the teratogenic potential of cocoa powder and theobromine in New Zealand White rabbits

Studies were conducted to determine the teratogenic potential of theobromine (TBR) and cocoa powder (CP) in rabbits. TBR was given either by gavage at dose levels of 0, 25, 75, 125 or 200 mg/kg body weight/day or administered in the diet at 0, 0.0625, 0.125 or 0.1875% (approximately 0, 21, 41 or 63 mg/kg/day, respectively). CP was given at 2.5, 5.0 or 7.5% of the diet (approximately 25, 50 or 75 mg methylxanthines/kg body weight/day). The duration of exposure was from days 6 to 29 of gestation. Significant maternal mortality (40%) and reduced food consumption were observed at 200 mg TBR/kg/day. Mean foetal weights were similar to those of the control group at 25 or 75 mg TBR/kg/day, but decreases in foetal body weight and increases in various malformations and developmental variations were observed in groups given 125 or 200 mg/kg/day. Insufficient litters were available for examination in the 200-mg/kg/day dose group because of maternal toxicity/lethality (repetitive exposure by gavage to 200 mg TBR/kg approached the maternal LD50). In the dietary CP studies, three does died and three aborted, but these deaths and abortions were not treatment related. No maternal deaths occurred during dietary TBR exposure. Maternal weight gain and food consumption, and the mean number of corpora lutea were unaffected by either dietary CP or TBR. Neither foetotoxicity nor teratogenicity was associated with dietary ingestion of CP or TBR. The foetuses exposed to 0.125% or 0.1875% TBR had a significantly higher incidence of incompletely ossified or absent sternebrae, whereas exposure to 0.1875% or 7.5% CP resulted in corresponding effects on metacarpal bones, indicating a delay in osteogenesis. The predominant compound found in serum after TBR ingestion was unchanged TBR, and there was no evidence of bioaccumulation of TBR in serum during gestation. The highest levels of CP or TBR used in these studies was 38 times greater than the maximum consumption level reported for humans in marketing surveys, and corresponds to a consumption of greater than 7.5 lb milk chocolate/day.