Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-1336mzz-E) (2018)

2019 ◽  
Vol 35 (3) ◽  
pp. 204-210

Trans-1,1,1,4,4,4-hexafluoro-2-butene (HFO-133mzz-E) is an odorless gas that finds uses as a foam transfer agent, heat transfer fluid, and specialty gas. The acute 4-h LC50 (in rats) for HFO-133mzz-E is > 17,000 ppm; it was not an eye or dermal irritant in 3- and 13-week repeated-dose inhalation studies in rats at concentrations up to 1.5% (15,000 ppm). HFO-133mzz-E was not a cardiac sensitizer at 70,000 ppm in a standard epinephrine challenge study in Beagle dogs. In a 3-week, repeated-dose (non-GLP) inhalation range-finding study in male and female rats, HFO-133mzz-E concentrations of 7500 and 15,000 ppm were determined to be well-tolerated. In the follow-up, GLP-compliant, 28-day repeated-dose inhalation study (as per OECD 412), male and female rats were exposed to 0, 1000, 10,000, or 15,000/20,000 ppm (20,000 ppm concentration was decreased to 15,000 ppm after week 1 because of deaths and body weight loss). The study no-observed-adverse-effect level (NOAEL) was established at 10,000 ppm based on reduced body weight gain and mortality observed at 15,000 ppm. In a 90-day GLP-compliant repeated-dose study (as per OECD 413), male and female rats were exposed to 0, 1000, 5000, 7500, or 15,000 ppm HFO-133mzz-E. Three male rats exposed to 15,000 ppm HFO-133mzz-E died during exposure; clinical signs such as restlessness, blepharospasm, and myoclonic jerks were also observed, during the first month of the study, at 15,000 ppm. There were no significant gross or histopathological organ/tissue lesions attributable to HFO-133mzz-E exposure. The study NOAEL was established at 7500 ppm. In a GLP prenatal developmental study (OECD 414), groups of time-mated nulliparous female rats were exposed via inhalation to 0, 1000, 5000, 7500, or 15,000 ppm HFO-1336mzz-E beginning on gestation day (GD) 6 up to and including GD 19. Under the conditions of this study, the NOAEL for maternal and fetal effects was established at 7500 ppm. HFO-1336mzz-E was not genotoxic in either in vitro or in vivo assays. Based on the results of the 90-day inhalation study, 7500 ppm was determined to be the NOAEL and was selected as the point of departure for the derivation of the 8-h time-weighted average (TWA), health-based workplace environmental exposure level (WEEL) value. This subchronic inhalation NOAEL was adjusted to account for duration of exposure, interindividual variability, and intraindividual variability. The resulting 8-h TWA WEEL value of 400 ppm is fully expected to provide a significant margin of safety against the production of any potential adverse health effects in workers following long-term inhalation exposure to HFO-1336mzz-E.

2005 ◽  
Vol 24 (4_suppl) ◽  
pp. 25-39 ◽  
Author(s):  
Yasunori Nakamura ◽  
Izuki Bando ◽  
John H. Mennear ◽  
Bruce K. Bernard

The objective of these repeated-dose, 8-week studies was to assess the toxicological potential of a synthetic tripeptide, L-valyl-L-prolyl-L-proline (VPP), when administered to Charles River rats and Beagle dogs. Groups of 20 male and 20 female rats were fed powdered diets containing sufficient VPP to afford daily doses of 0, 2, 8, or 16 mg/kg body weight (BW)/day. Groups of five male and five female dogs were administered 0, 2, 8, or 16 mg/kg BW/day in hard gelatin capsules. Antemortem evaluative parameters for both species included grossly observable clinical signs, body weight and food consumption, clinical pathology (hematology, clinical chemistry, urinalysis), and ophthalmological examinations. Dogs also received electrocardiographic examinations. Postmortem evaluations in both species included complete necropsy, determination of major organ weights, and histopathological examination of specimens from approximately 50 organs and tissues. All rats and dogs survived to the scheduled termination of the studies and neither species exhibited evidence of VPP effects on appetite or body weight gain/maintenance. Ophthalmic examinations revealed occasional lens clouding in rats, but this occurred in all groups and was not attributable to VPP. Some clinical pathology parameters in both species were occasionally altered, but there was no evidence that this was dose-related. Electrocardiographic examinations in dogs revealed no VPP-associated changes. Mid- and high-dose male rats (but not females) had slightly reduced mean pituitary and kidney weight parameters, whereas mid- and high-dose females had slightly increased mean uterus:body weight ratios. There were no microscopic correlates for these minor changes. Ten percent to 20 % of all female rats (but not males) exhibited corticomedullary mineralization of the kidney and gliosis of the optic nerve, and 10% to 20% of males (but not females) had thymic hemorrhage. Postmortem evaluations of dogs revealed no VPP-related effects on organ weights or either macro- or microscopic appearances of organs. The results of these studies provided no evidence of either local or systemic toxicity. Similarly, there was no evidence of neurotoxicity that might have been detected by the appearance of physical or behavioral changes during gross observations of animals. Although these results do not identify target organs for VPP toxicity, the no-observable-effect level and maximally tolerated dose are both greater than 16 mg/kg/day when administered to male and female rats and dogs for 8 consecutive weeks. Based upon food enhancement levels of VPP currently being evaluated, the resultant margin of safety (160) is substantial.


2008 ◽  
Vol 100 (6) ◽  
pp. 1192-1199 ◽  
Author(s):  
Pascale Rozan ◽  
Amine Nejdi ◽  
Sophie Hidalgo ◽  
Jean-François Bisson ◽  
Didier Desor ◽  
...  

Ageing is associated with changes in physiology and morphology; nutritional strategies to decrease morbidity and to prolong life are of high interest. The aim of the study was to investigate the effects of lifelong supplementation with an oligofructose-enriched inulin on morphological and biological markers and lifespan in male and female rats. Male and female rats, age 3 months, were randomised into two groups to receive either a diet with 10 % of an oligofructose-enriched inulin (Synergy1) or a standard diet (control) for 27 months. The rats were weighed every 2 weeks and their food intake was evaluated on four successive days every 4–6 weeks. Samples were taken at 12, 18 and 24 months of age. During the whole intervention period, male rats receiving Synergy1 (SYN1-M) displayed lower body weight, cholesterol and plasma triacylglycerolaemia compared with the controls (Cont-M). The survival rate at 24 months of age of SYN1-M rats was 35·3 % greater than that of Cont-M rats. In female rats, the Synergy1 supplementation (SYN1-F) group also reduced body weight, cholesterol and triacylglycerolaemia levels, but results were less consistent over the experiment. The survival rate at 24 months of age in SYN1-F rats was 33·3 % greater compared with that of the control (Cont-F) group. To conclude, lifelong intervention with Synergy1 improved biological markers during ageing and survival rate (lifespan) of rats.


2000 ◽  
Vol 19 (3) ◽  
pp. 185-192 ◽  
Author(s):  
B I Ghanayem ◽  
S M Ward ◽  
B Chanas ◽  
A Nyska

Administration of 2-butoxyethanol (BE) to rodents causes acute hemolytic anemia, and metabolic activation of BE to butoxyacetic acid (BAA) is required for the development of this effect. Recent studies have shown that female rats treated with BE exhibit a variety of histopathologic lesions that are absent in males and many of these lesions are attributed to the hemolytic effects of BE. Current studies were designed to compare the acute hematotoxicity of BE in male and female F344 rats. Rats were treated with 250 mg BE/kg body weight or water (control; 5 ml/kg) by gavage. At 4, 8, or 24 h after dosing, rats were anesthetized, blood was collected by cardiac puncture, and various blood parameters were measured. BE resulted in a time-dependent swelling of erythrocytes as evidenced by an early increase in hematocrit (Hct) and mean cell volume (MCV) in male rats. In contrast, increased Hct in female rats did not accompany an increase in MCV. It is likely that hemolysis was so severe at 4 h that Hct exhibited a decline in female rats at that time point. Subsequently, red blood cell (RBCs), hemoglobin concentration (Hgb), and Hct declined as hemolysis progressed. However, the onset of BE-induced hemolysis was faster in female compared to male rats. These effects were also associated with a significant increase in the spleen weight to body weight ratio. Blood smears were also prepared and morphological changes evaluated by light microscopy included stomatocytosis, spherocytosis, and schistocytosis. Furthermore, aggregation of RBCs in female rats as evidenced by increased formation of rouleaux was observed at 24 h after BE administration. These effects were observed earlier and more frequently in female rats. No differences in the sensitivity of RBCs obtained from male and female rats and exposed to butoxyacetic acid (BAA) in vitro was observed as determined by measuring the packed cell volume. In conclusion, these data suggest that female rats are more sensitive to hemolysis and morphological alterations of erythrocytes induced by BE during the first 24 h after exposure compared to males. It is likely that the greater sensitivity of female rats to BE effects on RBCs may account for the reported development of thrombosis and tissue infarction in female rats.


1989 ◽  
Vol 257 (6) ◽  
pp. R1417-R1422 ◽  
Author(s):  
S. Rivest ◽  
Y. Deshaies ◽  
D. Richard

The purpose of this study was to investigate the effects of a chronic intracerebroventricular administration of corticotropin-releasing factor (CRF) on energy balance of male and female rats. One week after their delivery to the laboratory, both male and female rats were divided into two groups. One group in each sex was treated with human/rat CRF, while another group was infused with the vehicle. Chronic administration of CRF was accomplished by means of miniosmotic pumps connected to a cannula that was stereotaxically directed into the third ventricle. Food intake and body weight were measured each day during the study. After 14 days of treatment, the rats were killed by decapitation. Energy, fat, and protein contents of the carcasses were quantified. Serum testosterone and estradiol were assayed in males and females, respectively. Administration of CRF significantly reduced body weight gain and food intake in male rats. No significant difference in those variables was observed between female rats treated with CRF and their controls infused with saline. Similarly, metabolizable energy intake and body energy gain were reduced in male rats infused with CRF, whereas no difference was observed between female animals treated with CRF and those infused with saline. In male rats, body fat and body protein contents were lower in CRF-treated than in saline-infused rats. In female rats, CRF did not affect body composition. Serum testosterone in male rats and serum estradiol in female animals were reduced after chronic infusion of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)


2016 ◽  
Vol 35 (6) ◽  
pp. 683-691 ◽  
Author(s):  
Tennille K. Marx ◽  
Róbert Glávits ◽  
John R. Endres ◽  
Philip A. Palmer ◽  
Amy E. Clewell ◽  
...  

Morus alba L. (white mulberry) leaves are one of the oldest recognized traditional Chinese medicines. More recently, M alba leaves and their constituents, particularly iminosugars (or azasugars), have garnered attention for their ability to maintain normal blood glucose concentrations, an effect identified in both animal studies and human clinical trials. Reducose (Phynova Group Limited) is a commercial water-soluble extract of M alba leaves standardized to 5% 1-deoxynojirimycin (DNJ), an iminosugar with α-glucosidase inhibition properties. Although there is an extensive history of consumption of M alba leaves by humans and animals worldwide, suggesting that the leaves and their extracts have a relatively good safety profile, we are unaware of safety assessments on an extract containing a higher amount of DNJ than that occurs naturally. The current 28-day repeated dose oral toxicity study in rats, conducted according to Organisation for Economic Co-operation and Development guidelines, was carried out to assess the safety of Reducose. Male and female Hsd.Han Wistar rats (4 groups of 10 animals/sex) were administered Reducose via gavage at doses of 0, 1,000, 2,000 and 4,000 mg/kg body weight (bw)/d. No treatment-related mortality or adverse effects (per clinical observations, body weight/weight gain, food consumption, ophthalmoscopy, clinical pathology, gross pathology, organ weights, or histopathology) were observed, and no target organs were identified. The no observed adverse effect level was determined to be 4,000 mg/kg bw/d for both male and female rats, the highest dose tested.


1995 ◽  
Vol 11 (2) ◽  
pp. 151-165 ◽  
Author(s):  
Joseph D. Cirvello ◽  
Ann Radovsky ◽  
James E. Heath ◽  
Daniel R. Farnell ◽  
Charles Lindamood

t-Butyl alcohol (TBA) was administered in drinking water to F344/N rats and B6C3F1 mice for two years using 60 animals/dose/sex/species. Male rats received doses of 0, 1.25, 2.5, or 5 mg/ml and females received 0, 2.5, 5, or 10 mg/ml, resulting in average daily doses of approximately 85, 195, or 420 mg TBA/kg body weight for males and 175, 330, or 650 mg/kg for females. Ten rats per group were evaluated after 15 months. Male and female mice received doses of 0, 5, 10, or 20 mg/ml, resulting in average daily doses of approximately 535, 1,035, or 2,065 mg TBA/kg body weight for males and 510, 1,015, or 2,105 mg/kg for females. Survival was significantly reduced in male rats receiving 5 mg/ml, female rats receiving 10 mg/ml, and male mice receiving 20 mg/ml. Long-term exposure to TBA produced increased incidences of renal tubule adenoma and carcinoma in male rats; transitional epithelial hyperplasia of the kidney in male and female rats; follicular cell adenoma of the thyroid in female mice; and follicular cell hyperplasia of the thyroid and inflammation and hyperplasia of the urinary bladder in male and female mice. In addition, a slight increase in follicular cell adenoma or carcinoma of the thyroid (combined) in male mice may have been related to the administration of TBA.


2020 ◽  
Author(s):  
Ming Song ◽  
Fang Yuan ◽  
Xiaohong Li ◽  
Xipeng Ma ◽  
Xinmin Yin ◽  
...  

Abstract Background: Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the US. Diet copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner, and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods: Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6mg/kg and 1.5mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma ALT, AST and liver histology were evaluated. Fecal microbial contents were analyzed by 16S rRNA sequencing. Fecal and cecal short chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS).Results: Male and female rats exhibit similar trends of changes in the body weight, body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions: Our data demonstrated sex differences in the alterations of gut microbial activities and hepatic steatosis in response to dietary copper-fructose interaction in rats. Tissue-specific responses to dietary copper and fructose likely contribute to the sex differences in gut microbial activity and metabolic phenotype.


2015 ◽  
Vol 34 (6) ◽  
pp. 491-499 ◽  
Author(s):  
Ilseob Shim ◽  
Hyun-mi Kim ◽  
Sangyoung Yang ◽  
Min Choi ◽  
Gyun-baek Seo ◽  
...  

Talc is a mineral that is widely used in cosmetic products, antiseptics, paints, and rubber manufacturing. Although the toxicological effects of talc have been studied extensively, until now no detailed inhalation study of talc focusing on oxidative stress has been done. This repeated 4 weeks whole-body inhalation toxicity study of talc involved Sprague-Dawley rats. Male and female groups of rats were exposed to inhaled talc at 0, 5, 50, and 100 mg/m3 for 6 hours daily, 5 days/week for 4 weeks. The objective was to identify the 4-week inhalation toxicity of talc and investigate antioxidant activity after exposure to talc. There were no treatment-related symptoms or mortality in rats treated with talc. Glucose (GLU) was decreased significantly in male rats exposed to 50 and 100 mg/m3 of talc. Histopathological examination revealed infiltration of macrophages on the alveolar walls and spaces near the terminal and respiratory bronchioles. In male and female rats exposed to 100 mg/m3 talc, expression of superoxide dismutase 2, a typical biological indicator of oxidative damage, was significantly increased. Thus, inhalation of talc induces macrophage aggregations and oxidative damage in the lung.


1983 ◽  
Vol 2 (6) ◽  
pp. 371-378 ◽  
Author(s):  
Peter J. Becci ◽  
Kenneth A. Voss ◽  
William D. Johnson ◽  
Michael A. Gallo ◽  
John G. Babish

Wistar rats (25/ sex • group) and CD-1 mice (30/sex • group) were fed either a control diet or diet supplemented with N,N-dimethylformamide at the levels of 215, 750, and 2500 ppm for rats and 160,540, and 1850 ppm for mice. The duration of feeding was 104 days for rats and 119 days for mice. Body weight gain, food consumption, hematological and clinical chemical data, ophthalmic, gross, and microscopic examinations were used to study possible toxic or pathologic effects. A significant reduction in body weight gain was noted for male and female rats at the high dosage level. Food consumption in male rats at the high-dosage level and female rats at both the middle- and high-dosage levels was decreased. A significant dose-related increase in relative liver weights was noted in male and female rats. Absolute liver weights of male rats were comparable among groups, however, a dose-related increase was noted in female rats. No significant differences among groups were noted in body weight and food consumption data for mice. A significant dose-related increase in relative and absolute liver weights was noted in male and female mice. Histopathological evaluation revealed no evidence of a toxic effect related to feeding of N.N-dimethylformamide to Wistar rats and CD-1 mice. The increase in liver weight is considered to be a normal phenomenon (physiological adaptation) required for the biotransformation of N,N-dimethylformamide. The lack of hepatotoxicity in the present study may be the result of feeding N,N-dimethylf ormamide over waking hours versus bolus dosing (in other studies) in which hepatotoxicity was noted.


1973 ◽  
Vol 74 (1) ◽  
pp. 88-104 ◽  
Author(s):  
T. Jolín ◽  
M. J. Tarin ◽  
M. D. Garcia

ABSTRACT Male and female rats of varying ages were placad on a low iodine diet (LID) plus KClO4 or 6-propyl-2-thiouracil (PTU) or on the same diet supplemented with I (control rats). Goitrogenesis was also induced with LID plus PTU in gonadectomized animals of both sexes. The weight of the control and goitrogen treated animals, and the weight and iodine content of their thyroids were determined, as well as the plasma PBI, TSH, insulin and glucose levels. The pituitary GH-like protein content was assessed by disc electrophoresis on polyacrylamide gels. If goitrogenesis was induced in young rats of both sexes starting with rats of the same age, body weight (B.W.) and pituitary growth hormone (GH) content, it was found that both the males and females developed goitres of the same size. On the contrary, when goitrogenesis was induced in adult animals, it was found that male rats, that had larger B.W. and pituitary GH content than age-paired females, developed larger goitres. However, both male and female rats were in a hypothyroid condition of comparable degree as judged by the thyroidal iodine content and the plasma PBI and TSH levels. When all the data on the PTU or KClO4-treated male and female rats of varying age and B.W. were considered together, it was observed that the weights of the thyroids increased proportionally to B.W. However, a difference in the slope of the regression of the thyroid weight over B.W. was found between male and female rats, due to the fact that adult male rats develop larger goitres than female animals. In addition, in the male rats treated with PTU, gonadectomy decreased the B.W., pituitary content of GH-like protein and, concomitantly, the size of the goitre decreased; an opposite effect was induced by ovariectomy on the female animals. However, when goitrogenesis was induced in weight-paired adult rats of both sexes, the male animals still developed larger goitres than the females. Among all the parameters studied here, the only ones which appeared to bear a consistent relationship with the size of the goitres in rats of different sexes, treated with a given goitrogen, were the rate of body growth and the amount of a pituitary GH-like protein found before the onset of the goitrogen treatment. Moreover, though the pituitary content of the GH-like protein decreased as a consequence of goitrogen treatment, it was still somewhat higher in male that in female animals. The present results suggest that GH may somehow be involved in the mechanism by which male and female rats on goitrogens develop goitres of different sizes, despite equally high plasma TSH levels.


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