Citrinin and endosulfan induced maternal toxicity in pregnant Wistar rats: pathomorphological study

Dietary exposures to environmental food pollutants such as mycotoxin(s) or pesticide(s) have gained immense significance due to their adverse effects on production and reproduction in animal and human populations. The present investigation was conducted to evaluate the maternal toxicity of citrinin (CIT) and endosulfan administered per os either alone or in combination in pregnant rats during gestational days 6-20. CIT (group I, 10 mg kg(-1) feed, through diet) and endosulfan (group II, 1 mg kg(-1) body weight, by oral intubation) when administered either alone or in combination (group III) in Wistar rats caused clinical signs of toxicity and pathomorphological changes in all the toxin treated groups, the severity being more pronounced in the combination treatment compared with that observed in the control (group IV). The rate of fetal resorptions was highest (22.22%) in the combination treatment followed by endosulfan (16.48%) and CIT (12.50%) treatment groups compared with the control group (3.86%). The histopathological changes such as engorged vasculature, vacuolar degeneration and karyomegaly in liver; congestion, tubular degeneration and cast formation in kidneys; vascular changes and hemosiderosis in uterus and lymphocytic depletion and apoptosis in the lymphoid organs were recorded in the animals of the toxin treated groups. The lesions were consistent and more severe in the combination treatment group compared with the individual treatment groups, suggesting an additive interaction of CIT and endosulfan in inducing maternal toxicity in Wistar rats.     

Developmental toxicity of benzyl benzoate in rats after maternal exposure throughout pregnancy

The maternal and fetal toxicity of benzyl benzoate, commonly used as antiparasitic insecticide, was evaluated in pregnant rats after a daily oral dose of 25 and 100 mg/kg. Biochemical, histopathological, and morphological examinations were performed. Dams were observed for maternal body weights and food and water consumption and subjected to caesarean section on (GD) 20. Maternal and fetal liver, kidney, heart, brain, and placenta were examined histopathologically under light microscope. Maternal and fetal liver and placenta were stained immunohistochemically for vascular endothelial growth factor (VEGF). Morphometric analysis of fetal body lengths, placental measurements, and fetal skeletal stainings was performed. Statistically significant alterations in biochemical parameters and placental and skeletal measurements were determined in treatment groups. In addition to histopathological changes, considerable differences were observed in the immunolocalization of VEGF in treatment groups. These results demonstrated that benzyl benzoate and its metabolites can transport to the placenta and eventually enter the fetuses. © 2011 Wiley Periodicals, Inc. Environ Toxicol 29: 40–53, 2014.     

Comparative subcutaneous repeated toxicity study of enoxaparin products in rats

Enoxaparin is a low-molecular-weight heparin widely used for the prevention and treatment of thromboembolism. With the development of several enoxaparin biosimilars, real medical concerns about their safety and efficacy have been raised. This repeated dose toxicity study consists of preclinical toxicological evaluation of a biosimilar biological version of enoxaparin, the drug product “Enoxa”, compared to the enoxaparin reference drug product, “Lovenox”. Eighty white Wistar rats were treated with “Enoxa” versus the reference product, using subcutaneous therapeutic and toxic doses, varying from 3.5 to 100 mg/kg/day. Dose levels were adjusted and ultimately fixed at 3.5 and 20 mg/kg/day as therapeutic and toxic doses, respectively. A sodium chloride solution (0.9%) was used as the control, and the comparative study was conducted over periods of 14 and 28 days. Comparable effects were observed with few adverse effects at the administration dose of 20 mg/kg/day, for both enoxaparin biosimilar and reference products. Interestingly, mortality started only at high doses of 40 mg/kg/day and reached 25% at 100 mg/kg/day for both products. These results, as part of the recommended biosimilarity monitoring, demonstrated comparable toxicity profiles of “Enoxa” and “Lovenox” products in rats. Continuing investigation of biosimilarity on humans to confirm safety and efficacy is suggested.     

Developmental toxicity of hexachloronaphthalene in Wistar rats. A role of CYP1A1 expression

Hexachloronaphthalene (HxCN) is one of the most toxic congeners of polychlorinated naphthalenes (PCNs). This study assesses the prenatal toxicity of HxCN after daily administration at doses of 0.1–1.0 mg/kg b.w. to pregnant Wistar rats during organogenesis. We evaluated also the expression of CYP1A1 mRNA and protein in the livers of dams and fetuses, as well as the placenta. The results indicate that 0.3 mg/kg b.w. was the lowest HxCN toxic dose for dams (LOAEL) while a dose of 0.1 mg/kg b.w. was sufficient to impair the intrauterine development of embryos/fetuses without maternal toxicity. Regardless of the applied dose, HxCN generated embryotoxic effects. Dose-dependent fetotoxic effects were associated with HxCN exposure. HxCN was found to be a strong inducer of maternal and fetal CYP1A1. Expression of CYP1A1 mRNA in the placenta appears to be the most sensitive marker of HxCN exposure.     

Acute and subacute oral toxicity of copper oxide nanoparticles in female albino Wistar rats

The extensive use of copper oxide nanoparticles (CuO‐NPs) in various industries and their wide range of applications have led to their accumulation in different ecological niches of the environment. This excess exposure raises the concern about its potential toxic effects on various organisms including humans. However, the hazardous potential of CuO‐NPs in the literature is elusive, and it is essential to study its toxicity in different biological models. Hence, we have conducted single acute dose (2000 mg/kg) and multiple dose subacute (30, 300 and 1000 mg/kg daily for 28 days) oral toxicity studies of CuO‐NPs in female albino Wistar rats following OECD guidelines 420 and 407 respectively. Blood analysis, tissue aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and acetylcholinesterase, superoxide dismutase, catalase, lipid malondialdehyde and reduced glutathione assays, and histopathology of the tissues were carried out. The higher dose treatments of the acute and subacute study caused significant alterations in biochemical and antioxidant parameters of the liver, kidney and brain tissues of the rat. In addition, histopathological evaluation of these three organs of treated rats showed significantly high abnormalities in their histoarchitecture when compared to control rats. We infer from the results that the toxicity observed in the liver, kidney and brain of treated rats could be due to the increased generation of reactive oxygen species by CuO‐NPs.     

Protective effect of the ethanolic and methanolic leaf extracts of Madhuca longifolia against diclofenac-induced toxicity in female Wistar albino rats

BackgroundDiclofenac is commonly prescribed Non-Steroidal Anti-Inflammatory Drug (NSAIDs) as it has anti-inflammatory, analgesic and anti-pyretic properties. Long term usage and over-dosage of diclofenac is associated with adverse effects like drug-induced liver injury, gastrointestinal and renal toxicity. The therapeutic uses of medicinal plants have gained a prominent role in recent years. Madhuca longifolia is a tree found throughout India, which is known to have several pharmacological activities. The aim of our study is to investigate the potential effect of the ethanolic and methanolic leaf extracts of M. longifolia against diclofenac-induced toxicity.MethodsThe rats used for the experiment were divided into seven groups. Group-1 was the normal control. Group-2 was administered with diclofenac (50 mg/kg b.w./day/ip) on the 4^th and the 5^th day. Group-3 was treated with diclofenac and ELEML (500 mg/kg b.w./day/po) on all 5 days. Group-4 was treated with diclofenac and MLEML (500 mg/kg b.w./day/po) on all 5 days. Standard drug silymarin (25 mg/kg b.w./day/po) was given to the rats of group-5 along with diclofenac. Group-6 and group–7 were treated with ethanolic leaf extract and methanolic leaf extract of M. longifolia respectively. After the study period, the rats were evaluated for parameters like liver and renal markers, antioxidants and histopathological changes.ResultsThis study has proved the beneficial effect of ethanolic and methanolic leaf extract of M. longifolia against diclofenac-induced toxicity wherein ethanolic leaf extract showed a better result than methanolic leaf extract.ConclusionOur study has concluded the beneficial effect of ethanolic and methonolic leaf extract of Madhuca longifolia against DFC-induced toxicity. This study proves that it has potential effect on hepato, renal and gastro toxicity in female Wistar albino rats. It can further be studied to understand its mechanism in treating toxicity.     

Acute oral toxicity study of magnesium oxide nanoparticles and microparticles in female albino Wistar rats

Advancements in nanotechnology have led to the development of the nanomedicine, which involves nanodevices for diagnostic and therapeutic purposes. A key requirement for the successful use of the nanoparticles (NPs) in biomedical applications is their good dispensability, colloidal stability in biological media, internalization efficiency, and low toxicity. Therefore, toxicological profiling is necessary to understand the mechanism of NPs and microparticles (MPs). MgO NPs have attracted wide scientific interest due to ease of synthesis, chemical stability and unique properties. However, their toxic effects on humans should also be of concern with the increased applications of nano MgO. The present study was aimed to assess the toxicological potential of MgO NPs in comparison to their micron counterparts in female Wistar rats. Toxicity was evaluated using genotoxicity, histological, biochemical, antioxidant and biodistribution parameters post administration of MgO particles to rats through oral route. The results obtained from the investigation revealed that the acute exposure to the high doses of MgO NPs produced significant (p < 0.01) DNA damage and biochemical alterations. Antioxidant assays revealed prominent oxidative stress at the high dose level for both the particles. Toxicokinetic analysis showed significant levels of Mg accumulation in the liver and kidney tissues apart from urine and feces. Further, mechanistic investigational reports are warranted to document safe exposure levels and health implications post exposure to high levels of NPs.     

The role of oxidative stress in diazinon-induced tissues toxicity in Wistar and Norway rats

Diazinon (DZN) is an organophosphate pesticide widely used in agricultural to control insects and in veterinary medicine to control ectoparasites. This study investigated the induction of oxidative stress in the brain, heart, and spleen of Wistar and Norway rats treated with acute doses of DZN. Female Wistar and Norway rats were treated with 25, 50, 100, and 200?mg/kg of DZN by intraperitoneal injection. The animals were sacrificed 24?h after treatment, and tissues were isolated and analyzed. The result of this study shows that DZN at higher doses increased the level of malondialdehyde, superoxide dismutase and glutathione S-transferase activities and decreased glutathione (GSH) level, lactate dehydrogenase, and cholinesterase activities in the brain, heart, and spleen of both rat strains. At these concentrations, DZN toxicity also lead to a significant decrease in catalase (CAT) activity in all tissues of Wistar rat and brain of Norway rat, while it increased heart CAT activity in Norway rat. However, the alteration of these parameters was observed at lower doses of DZN in Wistar rat. These results suggest that DZN at higher doses induces the production of free radicals and oxidative stress in rat tissues and strains by alteration of antioxidant enzyme activity, depletion of GSH, and increasing lipid peroxidation. Induction of oxidative stress in DZN-treated rats is in the order of brain > heart > spleen. Wistar rats appear to be more sensitive to the effects of DZN on oxidative stress induction compared to Norway rat.     

Developmental toxicity of auranofin in zebrafish embryos

Auranofin (AF) is used in clinic for the treatment of rheumatoid arthritis, repurposing of AF as an anticancer drug has just finished a phase I/II clinical trial, but the developmental toxicity of AF remains obscure. This study focused on its developmental toxicity by using zebrafish embryos. Zebrafish embryos were exposed to different concentrations (1, 2.5, 5, 10 μm ) of AF from 2 h post‐fertilization (hpf) to 72 hpf. At 72 hpf, two major developmental defects caused by AF were found, namely severe pericardial edema and hypopigmentation, when embryos were exposed to concentrations higher than 2.5 μm . Biochemical detection of oxidative stress enzyme combined with expressions of a series of genes related to oxidative stress, cardiac, metal stress and pigment formation were subsequently tested. The superoxide dismutase activity was decreased while malondialdehyde content was accumulated by AF treatment. The expression of oxidative stress‐related genes (sod1 , gpx1a , gst ), pigment‐related genes (mitfb , trp‐1a ) and one metal stress‐related gene ctr1 were all decreased by AF exposure. The expressions of cardiac‐related genes (amhc , vmhc ) and one metal‐related gene hsp70 were found to be significantly upregulated by AF exposure. These findings indicated the potential developmental toxicity of AF on zebrafish early development. Copyright © 2016 John Wiley & Sons, Ltd.     

Developmental toxicity of orally administered pineapple leaf extract in rats

The extract of pineapple leaves (EPL) has anti-diabetic and anti-dyslipidemic effects and can be developed into a promising natural medicine. This study was conducted to evaluate EPL’s effects on developmental parameters in order to provide evidence of its safety before potential medical use. Five groups were included: a negative control that was given distilled water daily, a positive control that was dosed 7 mg/kg cyclophosphamide (CP) every two days, and three groups that were respectively dosed 2.0, 1.0, and 0.5 g/kg EPL daily. Female rats were dosed during the organogenesis period of gestation days (GD) 7-17 and terminated on GD 20. A series of parameters were examined. Data revealed that CP significantly reduced maternal body weight gains, caused maternal organ weight alterations, reduced female fertility, disturbed fetal growth and development, and caused marked teratogenic effects on fetal appearances, skeleton and internal organs. Distilled water and the three high doses of EPL did not cause any of the aforementioned effects. This study concluded that orally administered EPL is safe to rats during embryonic development.     

Embryo-fetal development toxicity of prenatal exposure to penequine hydrochloride intramuscularly in rats.

The potential for penequine hydrochloride to induce maternal and embryo-fetal developmental toxicity was evaluated in Wistar rats. The drug was administered intramuscularly (i.m.) at dose levels of 0, 10, 30 or 50mg/kg/day to groups of pregnant rats from day 6 to 15 of gestation. All dams were observed for maternal body weights, food consumption and any abnormal change, and subjected to caesarean-section on gestation day (GD) 20; all fetuses obtained from caesarean-section were assessed by external inspection, visceral and skeletal examinations. In the 50mg/kg/day group, maternal toxicity included an increase in the incidence of abnormal clinical signs, and decrease in the body weight and body weight gain. Developmental toxicity included an increase in the postimplantation loss, a decrease in the litter size, and a reduction in the gravid uterus weight. In addition, a statistically non-significant increase in the incidence of fetal external, visceral, and skeletal alterations including malformations and variations were seen in high-dose group. There were no treatment-related findings in maternal clinical and intrauterine observations, and fetal morphological examinations in mid-, low-dose and control groups. Thus, under the conditions of this study, the no-observed-adverse-effect-level (NOAEL) and lowest-observed-adverse-effect-level (LOAEL) of penequine hydrochloride for both maternal and embryo-fetal toxicity in the Wistar rats were considered to be 30mg/kg/day and 50mg/kg/day, which are approximately 900 and 1500 above the therapeutic dosage, respectively.     

Toxicological evaluation of Yulangsan polysaccharide in Wistar rats: A 26-week oral gavage study

Although numerous studies have proven the medicinal values of Yulangsan polysaccharide (YLSP), the toxicity of this active ingredient is unknown. In the acute toxicity study, a single oral administration of 24 g/kg YLSP caused neither toxicological symptoms nor mortality, and the LD₅₀ was estimated >24 g/kg. In the chronic toxicity study, we administered doses of 0, 0.6, 1.2 and 2.4 g/kg YLSP in rats by oral gavage for 26 weeks followed by a 3-week recovery period. There was no mortality or remarkable clinical signs observed during this 26-week study. Additionally, there were no toxic differences in the following parameters: body weight, food consumption, hematology, clinical biochemistry, organ weight, and macroscopic findings. There were no adverse effects on histopathology observed in males or female rats treated with YLSP. Based on the results, the no-observed-adverse-effect-level of YLSP in rats is greater than 2.4 g/kg when administered orally for 26 consecutive weeks.     

Developmental toxicity evaluation of gallium nitrate in mice

Gallium nitrate, a drug with antitumor activity, is presently undergoing clinical trials as a chemotherapeutic agent for the treatment of certain malignancies. Since there are very limited published animal toxicity data available, this study was conducted to investigate the potential adverse developmental effects of this drug. Pregnant Swiss mice were administered intraperitoneally gallium nitrate at 12.5, 25, 50, and 100 mg/kg/day on days 6, 8, 10, 12, and 14 of gestation. Monitors for maternal toxicity were body weight, food consumption and clinical signs. At sacrifice (day 18) maternal weight, liver and kidney weights, and gravid uterine weights were measured. Gestational parameters monitored were numbers of total implants, resorptions, postimplantation losses, and dead fetuses. Live fetuses were sexed, weighed, and examined for external, internal and skeletal malformations and variations. Maternal toxicity was noted in all the gallium nitrate-treated groups. Embryo/fetal toxicity was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations (12.5, 25, 50 and 100 mg/kg). No significant increase in the incidence of malformations was observed at 12.5, 25, or 50 mg/kg. The no-observable-adverse-effect level (NOAEL) for both maternal and developmental toxicity of gallium nitrate was <12.5 mg/kg.     

Anticardiolipin antibodies in spontaneously hypertensive rats (SHR), stroke-prone SHR and normal Wistar rats

1. Anticardiolipin antibodies (ACA) can be detected in the serum of patients with autoimmune disturbances, ischaemic heart disease, myocardial infarction, neurological disorders and other medical conditions. Elevated values of these autoantibodies can be associated with recurrent fetal loss, arterial and venous thrombosis and thrombocytopenia. 2. In the present study, we investigated the presence of ACA in three rat strains, namely normal Wistar rats (WR), spontaneously hypertensive rats Okamoto-Aoki (SHR) and stroke-prone SHR (SHRSP). All animals were examined at four ages: 1, 4, 10 and 12 months of age. Anticardiolipin antibodies were determined by ELISA. 3. Anticardiolipin antibody levels in normal WR, which were used as controls, were lowest at 1 month and increased significantly from the 4th month on. At the prehypertensive age (1 month), ACA levels in SHR and SHRSP were significantly higher compared with control WR, decreased with age and were significantly lower at 4, 10 and 12 months compared with age-matched WR. 4. These differences may be a result of immunological disorders in SHR.     

Pre- and postnatal toxicity of the commercial glyphosate formulation in Wistar rats

Glyphosate is the active ingredient and polyoxyethyleneamine is the surfactant present in the herbicide Roundup formulation commercialized in Brazil. The aim of this study was to assess the reproductive effects of glyphosate-Roundup on male and female offspring of Wistar rats exposed during pregnancy and lactation. Dams were treated orally with water or 50, 150 or 450 mg/kg glyphosate during pregnancy (21-23 days) and lactation (21 days). These doses do not correspond to human exposure levels. The results showed that glyphosate-Roundup did not induce maternal toxicity but induced adverse reproductive effects on male offspring rats: a decrease in sperm number per epididymis tail and in daily sperm production during adulthood, an increase in the percentage of abnormal sperms and a dose-related decrease in the serum testosterone level at puberty, and signs of individual spermatid degeneration during both periods. There was only a vaginal canal-opening delay in the exposed female offspring. These findings suggest that in utero and lactational exposure to glyphosate-Roundup may induce significant adverse effects on the reproductive system of male Wistar rats at puberty and during adulthood.     

人脐带间质干细胞对大鼠的免疫毒性研究

目的:研究人脐带间质干细胞(UCMSC)对Wistar大鼠的免疫毒性作用。方法:SPF级Wistar大鼠112只分为4组:溶媒组(给予溶媒5 ml/kg)、低剂量组(给予人UCMSC 1×107个/kg)、高剂量组(给予人UCMSC 5×107个/kg)和对照组(给予大鼠UCMSC 1×107个/kg)。每组28只大鼠,雌雄各14只。大鼠尾静脉注射给药,2周1次,共注射4次。给UCMSC后每周进行受体鼠临床移植物抗宿主病(GVHD)评分,末次注射UCMSC后1、13周检测血IgG、IgM含量,CD3+、CD4+、CD8+T细胞数量,并对大鼠淋巴结、胸腺、脾脏进行脏器系数计算和组织病理学检查。结果:给予UCMSC后,各组大鼠的GVHD评分值均为0。末次给予UCMSC后1周,低、高剂量组雌性大鼠IgG[(0.65±0.12)、(0.63±0.14)g/L]和IgM含量[(0.06±0.01)、(0.06±0.01)g/L]明显高于溶媒组雄性大鼠[(0.41±0.17)g/L、(0.04±0.01)g/L,P<0.01或P<0.05];高剂量组雄性大鼠IgM含量[(0.05±0.01)g/L]明显高于溶媒组雄性大鼠[(0.03±0.01)g/L,P<0.01];对照组雌性、雄性大鼠IgM[(0.06±0.02)、(0.05±0.02)g/L]也明显高于溶媒组(P<0.01或P<0.05)。末次给予UCMSC后13周,各剂量组雌、雄性大鼠IgG、IgM与溶媒组相比差异均无统计学意义(均P>0.05)。末次给予UCMSC后1周,低、高剂量组雌性大鼠的脾脏系数[分别为(0.274±0.016)%、(0.294±0.019)%]明显高于溶媒组[(0.232±0.012)%,P<0.01];高剂量组雄性大鼠的脾脏系数[(0.242±0.027)%]明显高于溶媒组[(0.202±0.012)%,P<0.01];对照组雌、雄性大鼠脾脏系数[分别为(0.261±0.019)%、(0.236±0.014)%]也明显高于溶媒组(P<0.05或P<0.01)。末次给予UCMSC后13周各组大鼠的脾脏和胸腺系数差异均无统计学意义(均P>0.05)。各组大鼠CD3+、CD4+、CD8+T细胞百分比及CD4+/CD8+比值均在正常范围内。各组大鼠胸腺、脾脏和肠系膜淋巴结组织病理学检查均未见明显异常。结论:人脐带间质干细胞可引起正常Wistar大鼠免疫球蛋白含量和脾脏系数的升高,该作用具有一过性和可逆性。     

Developmental toxicity of homobrassinolide in Wistar rats

Brassinosteroids (BRs) are close analogues of animal cholesterol. Brassinosteroids have shown their great value as yield promoters of a variety of plants. In view of its steroidal moiety and recent use in agriculture in many countries, the teratogenic potential of homobrassinolide (HBR) was evaluated in Wistar rats. Homobrassinolide was administered by oral gavage at doses 0, 100, and 1000 mg/kg body weight in water during gestation days (GD) 6 to 15 in groups of 20 mated females. Maternal and embryo-fetal toxicity was analyzed by studying the effects such as clinical signs, mortality/morbidity, abortions, body weight, feed consumption, and pregnancy data, gravid uterine weights, implantation losses, litter size, external, visceral, and skeletal malformations. No treatment-related effect was observed on any of the maternal/fetal end points in any dose group. From the results, it can be concluded that HBR is nonteratogenic at doses as high as up to 1000 mg/kg body weight in Wistar rats.     

南五味子软胶囊对大鼠长期毒性的实验研究

目的观察南五味子软胶囊连续灌胃给药13周对大鼠产生的毒性反应。方法南五味子软胶囊分别以1.2、0.438、0.16g.kg-1.d-1灌胃给药,每周给药6 d,试验周期为13周,各试验组剩余的1/2动物观察4周恢复期变化。按中药新药长期毒性试验要求观察动物的一般状况、体重变化、血液细胞学及生化学指征、解剖及组织病理学检查。结果各剂量药组与对照组大鼠比较,白天自发活动减少,高剂量组减少最为明显,但夜间活动无明显差异。血液及生化指标与对照组相比无明显差异,脏器未出现给药相关的病变。结论南五味子软胶囊长期灌胃服用未见毒性反应,长期服用安全。     

Developmental and reproductive toxicity evaluation of toluene vapor in the rat II. Developmental toxicity

The developmental toxicity of toluene was evaluated via whole body inhalation exposure, in pregnant Sprague Dawley rats exposed to toluene (99.9% pure) from gestation day (GD) 6–15 inclusive, 6 h/day, at concentrations of 0, 250, 750, 1500 and 3000 ppm (0, 938, 2812, 5625 and 11250 mg/m³). Doses were selected from a preliminary study performed over a range of concentrations from 0 to 5000 ppm, in which maternal and fetal toxicity were observed at 2000 ppm and above. This study has been cited in various regulatory documents and is presented here to allow greater accessibility to results and conclusions.

Toluene induced clinical signs in pregnant dams (ataxia, hyper-responsivity, increased water intake, decreased food consumption) at 3000 ppm, ataxia and hyper-responsivity at 1500 ppm, and reduced maternal body weight gain at 1500 during the exposure period only and at 3000 ppm from initiation of exposure to GD20. At Caesarean section on GD20, no adverse effects on implantation, number and viability of fetuses, or fetal sex distribution were observed. Litter weight and mean fetal weight was reduced at 3000 ppm and mean fetal weight was reduced at 1500 ppm. Instances of reduced or unossified skeletal elements occurred at the same dose levels. Mean fetal weight was also reduced at 250 ppm but not at 750 ppm. Extensive statistical analysis of fetal body weight data support the conclusion that there is no toxicologically significant dose-related effect on fetal body weight at or below 750 ppm. Low incidences (≤2.5%) of various malformations occurred in the 250, 1500, and 3000 ppm groups; there was no increase in the incidence of specific or total malformations with increased exposure and thus these were not attributed to toluene.

In this Toluene study, the maternal toxicity NOAEL was 750 ppm with a defined maternal and developmental toxicity LOAEL of 1500 ppm.     

Toxicity of artemisinin [Artemisia annua L.] in two different periods of pregnancy in Wistar rats

Artemisinin compounds are important for treating multidrug-resistant malaria; however, the possible resorption and abnormalities observed in animal reproduction studies may contraindicate artemisinin use during the first trimester. To evaluate whether artemisinin interferes with developmental outcomes at different periods of pregnancy, Wistar rats were treated by gavage with increasing doses of 7, 35 and 70 mg/kg/day from gestational day [GD] 7 to 13 or 14 to 20. Viable embryos and post-implantation losses, and progestagens and testosterone levels, were monitored in the former treatment group and pregnancy and outcomes data, post-implantation losses and male and female developmental endpoints of the offspring were evaluated in the latter treatment group. Results indicate toxicity for both periods of treatment, with lower sensitivity at later stages of pregnancy. The results showed that dosing with 35 or 75 mg/kg of artemisinin caused high percentages of post-implantation losses that correlated with a trend to lower maternal progestagens and a significant maternal testosterone decrease. These findings demonstrate that oral administration of artemisinin can adversely effect post-implantation development and pregnancy in the rat.