Changing the dose metric for inhalation toxicity studies: Short-term study in rats with engineered aerosolized amorphous silica nanoparticles

Inhalation toxicity and exposure assessment studies for nonfibrous particulates have traditionally been conducted using particle mass measurements as the preferred dose metric (i.e., mg or μg/m³). However, currently there is a debate regarding the appropriate dose metric for nanoparticle exposure assessment studies in the workplace. The objectives of this study were to characterize aerosol exposures and toxicity in rats of freshly generated amorphous silica (AS) nanoparticles using particle number dose metrics (3.7?×?10⁷ or 1.8?×?10⁸ particles/cm³) for 1- or 3-day exposures. In addition, the role of particle size (d₅₀?=?37 or 83?nm) on pulmonary toxicity and genotoxicity endpoints was assessed at several postexposure time points. A nanoparticle reactor capable of producing, de novo synthesized, aerosolized amorphous silica nanoparticles for inhalation toxicity studies was developed for this study. SiO₂ aerosol nanoparticle synthesis occurred via thermal decomposition of tetraethylorthosilicate (TEOS). The reactor was designed to produce aerosolized nanoparticles at two different particle size ranges, namely d₅₀?=?～30?nm and d₅₀?=?～80?nm; at particle concentrations ranging from 10⁷ to 10⁸ particles/cm³. AS particle aerosol concentrations were consistently generated by the reactor. One- or 3-day aerosol exposures produced no significant pulmonary inflammatory, genotoxic, or adverse lung histopathological effects in rats exposed to very high particle numbers corresponding to a range of mass concentrations (1.8 or 86?mg/m³). Although the present study was a short-term effort, the methodology described herein can be utilized for longer-term inhalation toxicity studies in rats such as 28-day or 90-day studies. The expansion of the concept to subchronic studies is practical, due, in part, to the consistency of the nanoparticle generation method.     

Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats

Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-LRI project, NM-200 was tested in a two-generation reproduction toxicity study according to OECD guideline 416. Male and female rats were treated by oral gavage with NM-200 at dose levels of 0, 100, 300 and 1000 mg/kg bw/day for two generations. Body weight and food consumption were measured throughout the study. Reproductive and developmental parameters were measured and at sacrifice (reproductive) organs and tissues were sampled for histopathological analysis. Oral administration of NM-200 up to 1000 mg/kg bw/day had no adverse effects on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations. The NOAEL was 1000 mg/kg body weight per day.     

Subacute oral toxicity investigation of selenium nanoparticles and selenite in rats

Selenium (Se) nanoparticles have been proposed as food supplements. However, the particle formulation may exert unexpected toxicity. The aim was therefore to compare toxicity of low doses of Se nanoparticles and the dissolved, ionized Se species selenite. Female rats were dosed orally for 28?d with either: 0.05, 0.5, or 4?mg Se/kg body weight (bw)/day as 20?nm Se nanoparticles or 0.05 or 0.5?mg Se/kg bw/day as sodium selenite. Male rats were dosed 4?mg Se/kg bw/day as Se nanoparticles. Body weight and clinical appearance were recorded throughout the experiment. At necropsy, blood samples were taken for hematological and clinical chemistry analyses; organ weights were recorded. At the high-dose of Se nanoparticles, overt toxicity occurred and the female animals had to be euthanized prematurely, whereas the male animals were reduced in dose. At all doses of Se nanoparticles and at 0.5?mg Se/kg bw/day as selenite, a lower body weight gain as compared to vehicle occurred. Relative liver weight was increased for both Se formulations at 0.5?mg Se/kg bw/day. Creatinine clearance and urinary pH were affected in some Se dosed groups. There were no effects among dosed groups on brain neurotransmitters or on hematological parameters compared with controls. There were no histological changes in the livers of animals exposed to Se nanoparticles or to selenite. Based on effects on body weight and liver weight, selenium nanoparticles and ionic Se exerted similar toxicity. This suggests that a nanoparticle-specific toxicity of Se did not occur.     

Prenatal toxicity of synthetic amorphous silica nanomaterial in rats

Synthetic amorphous silica is a nanostructured material, which is produced and used in a wide variety of technological applications and consumer products. No regulatory prenatal toxicity studies with this substance were reported yet. Therefore, synthetic amorphous silica was tested for prenatal toxicity, according to OECD guideline 414 in Wistar rats following oral (gavage) administration at the dose levels 0, 100, 300, or 1000 mg/kg bw/d from gestation day 6–19. At gestation day 20, all pregnant animals were examined by cesarean section. Numbers of corpora lutea, implantations, resorptions, live and dead fetuses were counted. Fetal and placental weights were determined. Fetuses were examined for external, visceral and skeletal abnormalities. No maternal toxicity was observed at any dose level. Likewise, administration of the test compound did not alter cesarean section parameters and did not influence fetal or placental weights. No compound-related increase in the incidence of malformations or variations was observed in the fetuses. The no observed adverse effect level (NOAEL) was 1000 mg/kg bw/d.     

Pulmonary toxicity and global gene expression changes in response to sub-chronic inhalation exposure to crystalline silica in rats

Exposure to crystalline silica results in serious adverse health effects, most notably, silicosis. An understanding of the mechanism(s) underlying silica-induced pulmonary toxicity is critical for the intervention and/or prevention of its adverse health effects. Rats were exposed by inhalation to crystalline silica at a concentration of 15 mg/m³, 6 hr/day, 5 days/week for 3, 6 or 12 weeks. Pulmonary toxicity and global gene expression profiles were determined in lungs at the end of each exposure period. Crystalline silica was visible in lungs of rats especially in the 12-week group. Pulmonary toxicity, as evidenced by an increase in lactate dehydrogenase (LDH) activity and albumin content and accumulation of macrophages and neutrophils in the bronchoalveolar lavage (BAL), was seen in animals depending upon silica exposure duration. The most severe histological changes, noted in the 12-week exposure group, consisted of chronic active inflammation, type II pneumocyte hyperplasia, and fibrosis. Microarray analysis of lung gene expression profiles detected significant differential expression of 38, 77, and 99 genes in rats exposed to silica for 3-, 6-, or 12-weeks, respectively, compared to time-matched controls. Among the significantly differentially expressed genes (SDEG), 32 genes were common in all exposure groups. Bioinformatics analysis of the SDEG identified enrichment of functions, networks and canonical pathways related to inflammation, cancer, oxidative stress, fibrosis, and tissue remodeling in response to silica exposure. Collectively, these results provided insights into the molecular mechanisms underlying pulmonary toxicity following sub-chronic inhalation exposure to crystalline silica in rats.     

Twenty-eight-day inhalation toxicity study of silver nanoparticles in Sprague-Dawley rats

The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. Thus, the exposed population continues to increase as the applications expand. Although previous studies on silver dust, fumes, and silver compounds have revealed some insights, little is yet known about the toxicity of nano-sized silver particles, where the size and surface area are recognized as important determinants for toxicity. Thus, the inhalation toxicity of silver nanoparticles is of particular concern to ensure the health of workers and consumers. However, the dispersion of inhalable ambient nano-sized particles has been an obstacle in evaluating the effect of the inhalation of nano-sized particles on the respiratory system. Accordingly, the present study used a device that generates silver nanoparticles by evaporation/condensation using a small ceramic heater. As such, the generator was able to distribute the desired concentrations of silver nanoparticles to chambers containing experimental animals. The concentrations and distribution of the nanoparticles with respect to size were also measured directly using a differential mobility analyzer and ultrafine condensation particle counter. Therefore, the inhalation toxicity of silver nanoparticles was tested over a period of 28 days. Eight-week-old rats, weighing about 283 g for the males and 192 g for the females, were divided into 4 groups (10 rats in each group): a fresh-air control, a low-dose group (1.73 x 10(4)/cm3), a middle-dose group (1.27 x 10(5)/cm3), and a high-dose group (1.32 x 10(6) particles/cm3, 61 microg/m3). The animals were exposed to the silver nanoparticles for 6 h/day, 5 days/wk, for a total of 4 wk. The male and female rats did not show any significant changes in body weight relative to the concentration of silver nanoparticles during the 28-day experiment. Plus, there were no significant changes in the hematology and blood biochemical values in either the male or female rats. Therefore, the initial results indicated that exposure to silver nanoparticles at a concentration near the current American Conference of Governmental Industrial Hygienists (ACGIH) silver dust limit (100 microg/m3) did not appear to have any significant health effects.     

Subchronic inhalation toxicity of azinphos-methyl in rats

Azinphos-methyl was evaluated for its subchronic inhalation toxicity. The exposure of rats to concentrations of 0.195, 1.24, and 4.72 mg/m³, respectively, for 12 weeks, 6 hrs daily, 5 times weekly, resulted in effects only in those animals which inhaled aerosols of the highest concentration. This group showed a significant depression of the cholinesterase activity in plasma and erythrocytes. The males of this group had a lower body weight gain. The results are in agreement with the established maximum allowable concentration of 0.2 mg/m³.     

Pulmonary chemokine and mutagenic responses in rats after subchronic inhalation of amorphous and crystalline silica.

Chronic inhalation of crystalline silica can produce lung tumors in rats whereas this has not been shown for amorphous silica. At present the mechanisms underlying this rat lung tumor response are unknown, although a significant role for chronic inflammation and cell proliferation has been postulated. To examine the processes that may contribute to the development of rat lung tumors after silica exposure, we characterized the effects of subchronic inhalation of amorphous and crystalline silica in rats. Rats were exposed for 6 h/day, on 5 days/week, for up to 13 weeks to 3 mg/m(3) crystalline or 50 mg/m(3) amorphous silica. The effects on the lung were characterized after 6.5 and 13 weeks of exposure as well as after 3 and 8 months of recovery. Exposure concentrations were selected to induce high pulmonary inflammatory-cell responses by both compounds. Endpoints characterized after silica exposure included mutation in the HPRT gene of isolated alveolar cells in an ex vivo assay, changes in bronchoalveolar lavage fluid markers of cellular and biochemical lung injury and inflammation, expression of mRNA for the chemokine MIP-2, and detection of oxidative DNA damage. Lung burdens of silica were also determined. After 13 weeks of exposure, lavage neutrophils were increased from 0.26% (controls) to 47 and 55% of total lavaged cells for crystalline and amorphous silica, with significantly greater lavage neutrophil numbers after amorphous silica (9.3 x 10(7) PMNs) compared to crystalline silica (6.5 x 10(7) PMNs). Lung burdens were 819 and 882 microg for crystalline and amorphous silica, respectively. BAL fluid levels of LDH as an indicator of cytotoxicity were twice as high for amorphous silica compared to those of crystalline silica, at the end of exposure. All parameters remained increased for crystalline silica and decreased rapidly for amorphous silica in the 8-month recovery period. Increased MIP-2 expression was observed at the end of the exposure period for both amorphous and crystalline silica. After 8 months of recovery, those markers remained elevated in crystalline silica-exposed rats, whereas amorphous silica-exposed rats were not significantly different from controls. A significant increase in HPRT mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to crystalline, but not to amorphous silica. A significant increase in TUNEL staining was detected in macrophages and terminal bronchiolar epithelial cells of amorphous silica-exposed rats at the end of the exposure period; however, crystalline silica produced far less staining. The observation that genotoxic effects in alveolar epithelial cells occurred only after crystalline but not amorphous silica exposure, despite a high degree of inflammatory-cell response after subchronic exposure to both types of silica, suggests that in addition to an inflammatory response, particle biopersistence, solubility, and direct or indirect epithelial cell cytotoxicity may be key factors for the induction of either mutagenic events or target cell death.     

Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats

Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m³. Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m³) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC_50(4 h) for HBCD was higher than 5312 ± 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 ± 8.8, 545.8 ± 35.3, and 2166.0 ± 235.9 mg/m³ for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m³.     

Evaluation of the inhalation toxicity of arecoline benzoate aerosol in rats

Arecoline is a pharmacologically active alkaloid isolated from Areca catechu. There are no published data available regarding the inhalation toxicity of arecoline in animals. This study aimed to evaluate the inhalation toxicity of arecoline in vitro and in vivo. For this purpose, arecoline benzoate (ABA) salt was prepared to stabilize arecoline in an aerosol. The MTT assay determined the half-maximal inhibitory concentration values of ABA and arecoline in A549 cell proliferation to be 832 and 412 μg/ml, respectively. The toxicity of acute and subacute inhalation in Sprague–Dawley rats was evaluated using the guidelines of the Organization for Economic Cooperation and Development. For acute inhalation, the median lethal concentration value of ABA solvent was >5175 mg/m³. After the exposure and during the recovery period, no treatment-related clinical signs were observed. In the 28-Day inhalation toxicity test, daily nose-only exposure to 2510 mg/m³ aerosol of the ABA solvent contained 75 mg/m³ ABA for male rats and 375 mg/m³ ABA for female rats, which caused no observed adverse effects, except for the decreased body weight gain in male rats exposed to 375 mg/m³ ABA. In this study, the no observed adverse effect level (NOAEL) for the 28-day repeated dose inhalation of ABA aerosol was calculated to be around 13 mg/kg/day for male rats and 68.8 mg/kg/day for female rats, respectively.     

Progression of lung inflammation and damage in rats after cessation of silica inhalation.

Human epidemiologic studies have found that silicosis may develop or progress even after occupational exposure has ended, suggesting that there is a threshold lung burden above which silica-induced pulmonary disease progresses without further exposure. We previously described the time course of rat pulmonary responses to silica inhalation as biphasic, the initial phase characterized by increased but controlled pulmonary inflammation and damage. However, after a threshold lung burden was exceeded, rapid progression of silica-induced pulmonary disease occurred. To test the hypothesis that there is a threshold lung burden above which silica-induced pulmonary disease progresses without further exposure we initiated a study to investigate the relationship between silica exposure, the initiation and progression of silica-induced pulmonary disease, and recovery. Rats were exposed to silica (15 mg/m(3), 6 h/day) for either 20, 40, or 60 days. A portion of the rats from each exposure were maintained without further exposure for 36 days to examine recovery. The major findings of this study are: (1) silica-exposed rats were not in pulmonary overload, and lung silica burden decreased with recovery; (2) pulmonary inflammation, damage and lipidosis increased with recovery for rats exposed to silica for 40 and 60 days, but not 20 days; (3) histopathology revealed changes in silica-induced alveolitis, epithelial hypertrophy and hyperplasia, and alveolar lipoproteinosis consistent with bronchoalveolar lavage (BAL) endpoints; and (4) pulmonary fibrosis developed even when exposure was stopped prior to its initial development.     

Thirteen-week study of toxicity of fiber-like multi-walled carbon nanotubes with whole-body inhalation exposure in rats

Abstract

Cancer development due to fiber-like straight type of multi-walled carbon nanotubes (MWCNTs) has raised concerns for human safety because of its shape similar to asbestos. To set concentrations of MWCNT for a rat carcinogenicity study, we conducted a 13-week whole body inhalation study. F344 male and female rats, 6-week-old at the commencement of the study, were exposed by whole-body inhalation to MWCNT at concentrations of 0, 0.2, 1 and 5?mg/m³ with a generation and exposure system utilizing the cyclone sieve method. Measured concentrations in the exposure chambers were 0.20?±?0.02, 1.01?±?0.11 and 5.02?±?0.25?mg/m³ for 13 weeks. The MMAD (GSD) of MWCNT were 1.4–1.6?μm (2.3–3.0), and mean width and length were 94.1–98.0?nm and 5.53–6.19?μm, respectively, for each target concentration. Lung weights were increased 1.2-fold with 1?mg/m³ and 1.3-fold with 5?mg/m³ in both sexes compared to the controls. In the bronchoalveolar lavage fluid (BALF) analyses, inflammatory parameters were increased concentration-dependently in both sexes from 0.2?mg/m³. Granulomatous changes in the lung were induced at 1 and 5?mg/m³ in females and even at 0.2?mg/m³ in males. Focal fibrosis of the alveolar wall was observed in both sexes at 1?mg/m³ or higher. Inflammatory infiltration in the visceral pleural and subpleural areas was induced only at 5?mg/m³. In conclusion, we determined 0.2?mg/m³ as the low-observed-adverse-effect level (LOAEL) for respiratory tract toxicity in the present inhalation exposure study of rats.     

Five-day inhalation toxicity study of three types of synthetic amorphous silicas in Wistar rats and post-exposure evaluations for up to 3 months.

Evidence suggests that short-term animal exposures to synthetic amorphous silicas (SAS) and crystalline silica can provide comparable prediction of toxicity to those of 90-day studies, therefore providing the opportunity to screen these types of substances using short-term rather than 90-day studies. To investigate this hypothesis, the inhalation toxicity of three SAS, precipitated silica Zeosil 45, silica gel Syloid 74, and pyrogenic silica Cab-O-Sil M5 was studied in Wistar rats. Rats were exposed nose-only to concentrations of 1, 5 or 25mg/m(3) of one of the SAS 6h a day for five consecutive days. Positive controls were exposed to 25mg/m(3) crystalline silica (quartz dust), negative controls to clean air. Animals were necropsied the day after the last exposure or 1 or 3 months later. All exposures were tolerated without serious clinical effects, changes in body weight or food intake. Differences in the effects associated with exposure to the three types of SAS were limited and almost exclusively confined to the 1-day post-exposure time point. Silicon levels in tracheobronchial lymph nodes were below the detection limit in all groups at all time points. Silicon was found in the lungs of all high concentration SAS groups 1-day post-exposure, and was cleared 3 months later. Exposure to all three SAS at 25mg/m(3) induced elevations in biomarkers of cytotoxicity in bronchoalveolar lavage fluid (BALf), increases in lung and tracheobronchial lymph node weight and histopathological lung changes 1-day post-exposure. Exposure to all three SAS at 5mg/m(3) induced histopathological changes and changes in BALf only. With all three SAS these effects were transient and, with the exception of slight histopathological lung changes at the higher exposure levels, were reversible during the 3-month recovery period. No adverse changes were observed in animals exposed to any of the SAS at 1mg/m(3). In contrast, with quartz-exposed animals the presence of silicon in the lungs was persistent and toxicological effects differed from those seen with SAS both with regard to the type and severity as well as in the time-response profile. In quartz-exposed animals silicon in the tracheobronchial lymph nodes was below the detection limit but silicon was found in the lungs at comparable levels 0-, 1- and 3-months post-exposure. One-day post-exposure to quartz, elevations in biomarkers of cytotoxicity in BALf, increases in lung and tracheobronchial lymph node weight and histopathological lung changes were minimal. These effects were present at 1-month post-exposure and progressively more severe at 3-months post-exposure. Overall, the results of the current study are similar to those of other published studies that had a 90-day exposure period and both types of studies indicate that the lack of lung clearance is a key factor in the development of silicosis.     

Mosquito coil smoke inhalation toxicity. Part II: subchronic nose-only inhalation study in rats

This paper addresses the results of a subchronic inhalation study in rats exposed to the smoke of burning mosquito coils manufactured in Indonesia. The objective of the study was a comparative assessment of different mosquito coils, including a blank coil, utilizing the OECD No. 413 testing paradigm, however, with the focus on hazard identification at a single maximum tolerated exposure concentration rather than concentration-response. Groups of rats were nose-only exposed 6 h a day, 5 days a week for 13 weeks to an average particulate concentration of 30 mg m(-3) from either blank coils or coils that contain the insecticidal ingredient transfluthrin. Nose-only air-exposed rats served as a control. A range of markers of exposure have been characterized to define the most critical exposure metrics with regard to total suspended particulate matter (TSP) and potentially noxious volatile products of combustion. During the course of the exposure period the smoke-exposed rats showed clinical signs suggestive of acute upper respiratory tract sensory irritation. Body weights were mildly affected in the male rats, but food and water consumption were indistinguishable amongst the groups. Carboxyhemoglobin concentrations were approximately 11% throughout the exposure period in smoke exposed rats. Hematology, clinical pathology and urinalysis as well as the analysis of organ weights and histopathology of extrapulmonary organs and the lung did not reveal any evidence of adverse systemic or local effects, whereas in the anterior region of the nasal passages, and to some extent also in the larynx, irritant-related changes typical for water-soluble upper respiratory irritants were found. Markers of pulmonary inflammation or increased phagocytosis and lysosomal activity in bronchoalveolar lavage were indistinguishable amongst the groups. gamma-Glutamyltranspeptidase was significantly increased in the smoke exposure groups, which is taken as indirect evidence of an adaptive upregulation of the pulmonary antioxidant glutathione. In rats exposed to mosquito coil smoke containing transfluthrin, a somewhat increased frequency of alveolar macrophages with foamy appearance was identified through cytodifferentiation but not histopathology compared with the blank coil. From the specific staining of intracellular phospholipids, the notion is supported that this equivocal finding is probably related to an increased uptake of modified pulmonary surfactant rather than increased engulfment of insoluble particulate matter since pigmentation or clustering or intra-alveolar cells did not occur. The results of this subchronic inhalation study support the conclusion that smoke from burning mosquito coils in concentrations high enough to elicit acute upper respiratory tract irritation due to the presence of common wood-combustion products (such as aliphatic aldehydes) did not cause any adverse effect in the lower respiratory tract or any other extrapulmonary organ. The most critical mode of action is related to acute and readily perceivable sensory irritation. The concentration tested was estimated to be well above that occurring under more realistic exposure conditions. Therefore, overnight exposure to the smoke from burning mosquito coils (manufactured in Indonesia) is unlikely to be associated with any unreasonable health risk.     

Subacute toxicity evaluation in rats exposed to concrete and hwangto building environments

This study examined the potential adverse effects of the subacute exposure of rats to concrete and hwangto building environments. Polycarbonate was used as a comparison. Groups of 10 male rats were exposed to polycarbonate, concrete, or hwangto cages for a 4-week period in summer or winter. During the study period, the clinical signs, mortality, skin temperature, body weight, food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights, and histopathology were examined. The concentration of total volatile organic compounds (VOCs), temperature, and relative humidity in the each cages were also measured. There were no exposure-related effects in any group of the study examined in the summer. The temperature, relative humidity, and the concentration of VOCs in the cages were similar in all groups. However, in the winter study, significant differences in several parameters were detected among the groups. In the concrete group, there was an increase in the clinical signs, a reduction in the body weight gain, food intake, and liver weight, an increase in the lung weight, and an increase in the histopathological alterations in the lung and thymus. Infrared thermal analysis showed that the skin temperature of the rats in the concrete group was lower than that in the polycarbonate group. However, in the hwangto group, there was a decrease in the clinical signs and an increase in the body weight, food intake, and the weights of the heart, lung, spleen, and epididymides. Overall, the 4-week exposure of the rats to the concrete building environment had adverse effects on the clinical signs, skin temperature, body weight, and some organs in the winter but not in the summer. On the other hand, the exposure of hwangto building environment did not have any exposure-related adverse effects on the general health parameters and skin temperature in rats.     

青蒿酯钠静脉注射对犬的亚急性毒性

给犬iv青蒿酯钠每天一次,连续14d,90mg/kg使全部动物中毒死亡,45mg/kg中毒表现明显,2/6犬死亡,22.5mg/kg出现轻度中毒,11.25mg/kg未见明显毒副作用,可视为基本安全剂量。毒性作用的主要症状表现为呕吐、摄食量减少,重者出现粘液血便等;心电图Q-T间期延长,Q-T比值增大;化验及病理检查显示骨髓造血抑制,首先是红系成熟障碍,胆汁淤滞,内脏淤血,45mg/kg以上剂量还出现粒系成熟障碍及心、肝、肾、胃肠道、视网膜等组织实质性损伤及相应的血液学和血液生化变化。血液网织红细胞减少或消失仍是最敏感的指标。停药后28d各种变化基本恢复正常。     

Subacute toxicity of chitosan oligosaccharide in Sprague-Dawley rats

A subacute oral toxicity study of chitosan oligosaccharide was performed in Sprague-Dawley rats of both sexes. Each 36 male and female rats were administered by gavage with 500, 1,000 and 2,000 mg/kg/day for 4 weeks (7 days/week), respectively. Examinations regarding clinical signs, body weights, hematological and biochemical parameters, and histopathological examinations were carried out. There were no significant differences in behavior or external appearance, body weight and food consumption between control and treated rats. In addition, no significant differences in urinalysis, hematology, blood biochemistry, relative organ weights and histopathological findings were found in both control and treated rats. In conclusion, it was suggested that subacute toxicity of chitosan oligosaccharide was low and the no-observed adverse effect level was considered to be over 2,000 mg/kg in rats.     

Developmental toxicity study with 3-(methylthio)propionaldehyde vapor by whole-body exposure of Sprague-Dawley rats

Time-mated Sprague-Dawley rats were exposed whole body to analytically measured 3-(methylthio) propionaldehyde (3-MTP) vapor concentrations of 0 (air controls), 9.87, 58.3 and 127.8 ppm over gestational days (gd) 6-15 for 6 h day(-1). There was an exposure concentration-related maternal toxicity (clinical signs, body weight change and food consumption) that was marginal at 9.87 ppm. No effects on gestational parameters, fetal numbers and sex ratio or fetal body weights were noted. There was no increase in the incidence of either malformations or variations (total, external, visceral or skeletal). Thus, the no-observed-adverse-effect level (NOAEL) for development toxicity for exposure to 3-MTP vapor was 127.8 ppm.     

Methodological aspects of the determination of the acute inhalation toxicity of spray-can ingredients

Spray-can ingredients, if liberated in confined spaces, are potential health hazards for man. Thus, appropriate inhalation toxicity studies have to be performed in accordance with internationally recognized guidelines, e.g. the US Environmental Protection Agency: Federal Insecticide, Fungicide and Rodenticide Act (FIFRA no. 81-3) or OECD no. 403. One of the essential requirements of such guidelines is that test animals (preferably rats) be exposed to a steady-state concentration in a dynamic inhalation chamber for at least 4 hours. This is not easy to achieve with vapours released from a pressurized spray-can. The method described here makes it possible to expose experimental animals in an inhalation chamber to a steady-state concentration of intermittently released spray jets of constant doses per jet. Animal experiments and theoretical considerations (computer simulations) have shown that the method presented allows an up-to-date determination of the acute inhalation toxicity of spray-can ingredients.