Acute Inhalation Toxicity Research Articles

Comparative Acute Inhalation Toxicity of a Saline Suspension and an Ethanol Solution of T-2 Mycotoxin in Mice

AbstractWe compared retention, distribution, toxicity, and histopathological change in mice after exposure to aerosols of T-2 suspended in saline or dissolved in ethanol. We found that the LC50 for mice exposed for 10 min to an aerosol of a saline suspension of T-2 was 0.035 ± 0.02 mg T-2 per liter air, which was lower than the LC50 (0.380 ± 0.08 mg T-2 per liter air) for an aerosol of T-2 dissolved in ethanol. However, within about 15 min postexposure, most of the T-2 deposited in the respiratory tract was translocated from the respiratory tract regardless of whether the T-2 aerosol was from a saline suspension or ethanol solution. Also, although T-2 is an inflammatory agent to dermis and gastrointestinal epithelium, T-2 from either aerosol did not produce any histological evidence of inflammation in the respiratory tract.

Acute inhalation toxicity of high concentrations of silane in male ICR mice.

In order to examine the toxicity of silane, male ICR mice were exposed to silane for 30 min (n = 8), 1 or 4 h (n = 12) at concentrations of 2500, 5000, 7500 (30-min experiment only) or 10,000 ppm. In the 1- and 4-h experiments, 12 mice were divided into two sub-groups: four for 2-day observation and eight for 2-week observation. The mortality was six deaths out of eight mice exposed to 10,000 ppm for 4 h. No deaths occurred in any of the other experiments. In the mice sacrificed 2 days after the exposure, acute renal tubular necrosis was observed at 10,000 ppm (1-h exposure) or at 2500 ppm or more (4-h exposure). Reduction in body weight, increase in relative kidney weight and blood urea nitrogen (BUN) level, and splenic atrophy and inflammatory changes of the nasal mucosa were also seen in the 10,000 ppm-4 h exposure group. In the mice sacrificed 2 weeks after the exposure, tubulo-interstitial nephritis (TIN) developed at 7500 ppm or more (30-min exposure) or at 5000 ppm or more (1- and 4-h exposure). BUN increased in a dose-dependent manner, and BUN in TIN positive mice was significantly higher than that in TIN negative mice (1- and 4-h exposure). No histopathological changes were observed in the glomeruli. These results indicate that the LC50 of silane in mice is between 5000 and 10,000 ppm for 4-h exposure and is greater than 10,000 ppm for 1-h or 30-min exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and subacute inhalation toxicity of silane 1000 ppm in mice.

Male ICR mice were exposed to silane 1000 ppm, a concentration 200 or 2000 times higher than the recommended occupational exposure limits by many countries and academic associations, for 1, 2, 4, and 8 h (phase I study) and for 6 h/day, 5 days/week, over 2 and 4 weeks (phase II study). Hematological and biochemical studies were performed, and the animals were examined for histopathological lesions of the cornea, nasal cavity, respiratory tract, lung, liver, kidney, spleen, pancreas, thymus, thyroid, bone marrow, salivary glands, esophagus, and testis. All mice in both studies survived until they were sacrificed. In the phase I study, no exposure-related changes were found as a result of the hematological, biochemical, or histopathological examinations. In the phase II study, hematological and biochemical examinations failed to reveal any exposure-related changes, but mild irritation, manifested in the form of a small amount of exudate (eight out of ten animals), and inflammatory cells and/or necrotic cells on the nasal mucosa (six out of ten animals) was observed in the mice exposed to silane for 4 weeks. These findings suggest that silane toxicity and irritation are not severe.

Inhalation toxicity of chromium from Whetlerite dust in rats

The acute inhalation toxicity and metabolic fate of chromium and copper from Whetlerite dust in rats were investigated. Groups of male and female, Sprague-Dawley rats were exposed to Whetlerite dust and base carbon dust as outlined in the OECD Limit Test guidelines. At 14, 28 and 180 days post-exposure, rats were evaluated for gross pathological changes and tissues were collected for chromium and copper determination. Four deaths occurred during or post-exposure, but did not appear to be compound related. No gross pathological changes were observed at necropsy in either group. Organ chromium concentrations were below detection limits of 0.5 μg Cr/g dry tissue in both exposure groups. According to OECD guidelines, neither Whetlerite dust nor base carbon dust demonstrated an acute inhalation toxicity.

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: Experimental comparison with standard LC 50 testing

A new design for acute inhalation toxicity testing was evaluated and compared with results obtained according to OECD guideline 403. The new design consists of a range-finding test, which is compatible with a conventional limit test, and can be followed by determination of a concentration-time-mortality relationship, enabling calculation of LC 50 (50% mortality exposure concentration) values. By exposing pairs of rats for different periods of time to about four different test concentrations in a nose-only exposure unit, LT 50 (50% mortality exposure time) values were obtained for five pairs of animals per concentration. The mortality data of the approximate 20 time-concentration combinations were used to calculate the probit relationship. Estimated mortality responses from these probit relations were compared with mortality figures obtained by exposing groups of five male rats and five female rats whole-body according to conventional toxicity testing. In general, there was good correspondence between the estimated and the observed mortality response. In our hands, the determination of the concentration-time-mortality relationship takes about the same number of animals (40–50) as the conventional LC 50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: 1. (A) LC 50 values are obtained over a 10-fold range in time, with the potential of decreasing the number of animals used when regulations require acute toxicity data for different periods of exposure. 2. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC 50 value. 3. (C) The method is less sensitive to small fluctuations in test substance concentrations which is important especially for substances with steep concentration-response curves. The results of this investigation indicate the need for reconsideration and adaptation of the OECD guideline 403 on acute inhalation toxicity testing.

The Development of a Standard Reference Material for Calibration of the University of Pittsburgh Smoke Toxicity Method for Assessing the Acute Inhalation Toxicity of Combustion Products.

A standard reference material (SRM 1049) has been developed for the University of Pittsburgh smoke toxicity method. SRM 1049 is a nylon 6/6 and has the molecular structure of [–NH(CH2)6NHCO(CH2)4CO–]n. This SRM is for calibrating the apparatus and providing confidence that the method is being conducted in a correct manner and that the equipment is functioning properly. The certified figure of merit is a LC50 value plus its 95% prediction interval which were calculated and found to be 4.4 + 3.4 g. The 95% prediction interval indicates the range in which the next determined LC50 value would be expected to fall. Thus, if an investigator were to test this SRM under their laboratory conditions according to the specifications of the University of Pittsburgh test procedure and found the LC50 value fell within the certified 95% prediction interval, the probability is good that the test is being conducted correctly.

Acute Inhalation Toxicity of Decalin in Rodents

Acute Inhalation Toxicity of Decalin in Rodents

Mammalian toxicity of empenthrin (Vaporthrin, S-2852F)

1. Acute toxicity: Empenthrin ((RS)-(EZ)-1-ethynyl-2-methyl-2-pentenyl (1R)-cis/trans-chrysanthemate) caused some toxic signs such as muscular fibrillation, tremor, hypersensitivity, decrease of spontaneous activity, ataxic gait, lymb paralysis, irregular respiration, excretion of oily substance, loose stool and urinary incontinence in oral acute toxicity studies at 1000 mg/kg and above in rats, and at 2000 mg/kg and above in mice. The oral LD50 value was estimated greater than 5000 mg/kg (male) and greater than 3500 mg/kg (female) in rats and greater than 3500 mg/kg (both sexes) in mice. In both rats and mice, the toxic signs were not found at 2000 mg/kg by dermal administration. The dermal LD50 value was estimated greater than 2000 mg/kg (both sexes) in both rats and mice. The LC50 value in rats for the acute inhalation toxicity of empenthrin was estimated to be greater than 4610 mg/m3 for both sexes. The LC50 value in mice was determined to be 2700 mg/m3 for male and 2300 mg/m3 for female. Mice showed higher sensitivity to empenthrin than rats. 2. Reproductive and developmental toxicity: Empenthrin was orally administered to fetal organogenesis periods of rats at the dose levels of 50, 150 and 500 mg/kg, and of rabbits at 100, 300 and 1000mg/kg. Maternal toxicity was found at 500 mg/kg in rats and at 300 mg/kg or more in rabbits. There were no teratogenicity, no embryotoxicity and no fetal retardation in rats or rabbits. In addition, there were no adverse effects on F1 pups growth, development or reproductive performance. 3. Subchronic toxicity: Empenthrin was orally administered to male and female SD rats at dose levels of 0 (corn oil), 10, 100 and 300 mg/kg for 26 weeks. Clinical signs, body weight, food and water consumption were monitered, and hematological, blood biochemical, ophthalmological and histopathological examination were carried out. As a result, changes related to administration of empenthrin were observed mainly in the liver and kidneys in rats receiving 100 mg/kg or more. Therefore, the no-effect-level of empenthrin is determined to be 10 mg/kg in both sexes of rats in this study.

Inhalation Exposure Technology, Dosimetry, and Regulatory Issues

Inhalation toxicology technology has provided the scientific community with important advances in studies of inhaled toxicants. These advances include new and more efficient exposure systems (e.g., flow-past nose-only exposure systems), and improved approaches to inhalation chamber environmental control (e.g., temperature, humidity, air quality). Practical problems and approaches to testing and operating inhalation exposure systems and the advantages and disadvantages of the major inhalation exposure types (e.g., whole-body, nose-only) are discussed. Important aspects of study design, such as high level particulate exposures resulting in large lung burdens (e.g., greater than or equal to 2 mg/g of lung), slowed pulmonary clearance rates, and nonspecific toxicity are considered, along with practical issues of comparative dosimetry. Regulatory guidelines have continued to present challenges in designing and conducting acute, subchronic, and chronic inhalation studies. The important regulatory issue of performing acute inhalation toxicity studies at high aerosol concentrations and "respirable" particle size distribution is discussed.

A Standard Reference Material for Calibration of the Cup Furnace Smoke Toxicity Method for Assessing the Acute Inhalation Toxicity of Combustion Products.

A standard reference material (SRM 1048) has been developed for use with the cup furnace smoke toxicity method. This SRM is to be used to calibrate the apparatus and to enable the user to have confidence that the method is being conducted in a correct manner and that the equipment is functioning properly. The toxicological results from this SRM should not be used to compare with those of other materials (i.e., to determine if the combustion products of a test material are more or less toxic than those from this SRM). SRM 1048 is an acrylonitrile-butadiene-styrene (ABS) and is the same as SRM 1007B which is used for calibrating the flaming mode of the Smoke Density Chamber test method (ASTM E-662 and NFPA 258). For the purposes of calibrating the cup furnace smoke toxicity method, LC50 and N-Gas values plus their respective 95% confidence limits have been determined and certified for two combustion modes (flaming and nonflaming) and two observation periods (for the 30 min exposure only and for the 30 min exposure plus a 14 d post-exposure period). The certified LC50 values plus 95% confidence intervals (in g/m3) are 27 ± 3 (30 min, flaming); 25 ± 3 (30 min+ 14 d, flaming); 58 ± 15 (30 min, nonflaming); and 53 + 12 (30 min+ 14 d, nonflaming). The certified N-Gas values plus 95% confidence intervals are 1.4 ± 0.2 (30 min, flaming); 1.5 ± 0.2 (30 min+ 14 d, flaming); 1.2 ± 0.2 (30 min, nonflaming); and 1.4 ± 0.2 (30 min+ 14 d, nonflaming). It is recommended that this SRM be used with the N-Gas approach to calibrate the cup furnace smoke toxicity method rather than to determine the complete LC50 values. The N-Gas approach has the advantage of providing information on the gases responsible for the lethalities as well as the toxic potency of the smoke. In addition, the N-Gas approach reduces the number of experimental animals, the time necessary to complete the calibration, and the expense.

Acute toxicity in the rat following either oral or inhalation exposure

A survey of 108 chemicals was conducted to determine the relationship between acute oral and acute inhalation toxicity data in the rat. LD 50 or LC 50 values were compared after classification of each chemical in terms of relative toxicity. A positive correlation (0.53, P < 0.001) between the classification of toxicity for the oral and inhalation routes was determined. However, the magnitude of this correlation was such that the predictive value of one for the other was limited. For a complete acute toxicity profile, it does not appear as if the determination of acute toxicity by one of those routes would yield a reliable estimate of toxicity by the other route.

Acute and subacute inhalation toxicity studies of a new broad spectrum insect repellent, N, N-diethylphenylacetamide

N, N-Diethylphenylacetamide (DEPA) is an inexpensive, long-acting and broad spectrum insect repellent. The acute LC 50 for a 4-h exposure of DEPA aerosol was found to be 1.451 mg l −1 (1.290–1.633) in male and 1.375 mg l −1 (1.307–1.447) in female rats. DEPA did not cause delayed deaths. Acute exposure to 0.9 LC 50 revealed that liver might be a target organ for DEPA toxicity. On subacute exposures to 0.2, 0.6 and 0.8 LC 50 for 6 h per day, 5 days a week for 2 weeks, there was no significant change in the 0.2 LC 50 group, as evaluated by the body weight gain and organ body weight ratio. The minimal changes observed in the 0.6 LC 50 group were of reversible type as the animals recovered on cessation of exposure. A massive concentration of 0.8 LC 50 produced lethal effects. The study shows that DEPA has a low mammalian toxicity by inhalation as was found earlier with cutaneous application of the insect repellent.

Effects of Mode of Exposure on Acute Inhalation Toxicity of Chloropicrin Vapor in Rats

全身, 鼻部, 皮膚の三つの暴露様式で8週齢のフィッシャー系雄性ラットにクロルピクリン (CP) 蒸気を4時間暴露し, その急性毒性を決定した. 全身暴露の半数致死濃度 (LC50) は14.4ppm, 鼻部暴露のLC50は6.6ppmであった. 25.0ppmのCP蒸気を皮膚暴露された動物では, 死亡は認められなかった. 全身暴露実験では, 毒性効果の発現パターンは2相性であり, 第1相は暴露終了後から3日間であり, 第2相は暴露後6～14日目の間であった. 両時期には主として呼吸器に対する刺激症状および傷害が認められた. 死亡の大部分が暴露後24時間以内に認められ, 残りは暴露後8～9日目に高濃度暴露群において認められた. 鼻部暴露実験では, 毒性効果は第1相においてのみ発現し, 全身暴露実験において認められたものに類似していた. 死亡のすべてが, 暴露後24時間以内に認められた. 皮膚暴露実験では, 毒性効果はまったく認められなかった. これらの結果から, CP蒸気の全身暴露による急性経皮毒性はその急性吸入毒性に比べて非常に弱く, 無視できる程度であるが, 鼻部暴露中の拘束はその急性吸入毒性を増強させることが判明した.

Inhalation Toxicology of 1,4-Butanediol

Abstract1,4-Butanediol is a clear, slightly viscous liquid with a low vapor pressure used in manufacturing polyester glycols and polyurethanes. The material has a low order of acute inhalation toxicity with a 4-h ALC of 15 mg/l in male rats. In the repeated dose study, groups of 10 male Crl:CD rats were exposed nose-only, 6 h/day, 5 days/wk for 2 wk to aerosol concentrations of either 0, 0.20, 1.7, or 5.2 mg/l. Rats were given pathological, urinalysis, and clinical chemical examinations after the last (tenth) exposure and after a 2-wk recovery period. No adverse effects were observed in rats exposed to either 0.20 or 1.1 mg/l. Rats exposed to 5.2 mg/l had depressed body weight evident after the third exposure. After 10 exposures, these rats had increased erythrocyte count and hematocrits and decreased serum cholesterol concentrations. Pathological examination showed slight atrophy of lymphoid cells in the thymus and depressed mean heart weights in these rats. No adverse effects were observed after 2 wk of...

Acute inhalation toxicity of cetylpyridinium chloride

Cetylpyridinium chloride (CPC) is a quaternary ammonium salt and cationic surfactant. It has been used as a biocide in personal hygiene products and a charge control additive in some reprographic toners. CPC is orally toxic to rats, mice and rabbits and can cause severe eye irritation. Acute inhalation toxicity studies of CPC and other quaternary ammonium salts have not, however, been reported. Groups of five rats per sex were exposed to aerosols containing 0 (control), 0.05, 0.07, 0.13 and 0.29 mg CPC/litre for 4 hr and observed for toxicity and ocular effects for 14 days thereafter. All animals were subjected to autopsy and the eyes were examined microscopically. The LC 50 (sexes combined) of CPC was 0.09 mg/litre with upper and lower 95% confidence limits of 0.13 and 0.07 mg/litre, respectively. Clinical signs of toxicity included weight loss, nasal discharge, chromodacryorrhoea, respiratory difficulty and eye irritation, and all these non-lethal effects were reversible. Acute inflammation of the cornea, iris and/or aqueous humour were found in one, seven and four of 10 rats exposed to 0.07, 0.13 and 0.29 mg CPC/litre, respectively. Corneal epithelial hyalinization, without evidence of ongoing inflammation, was found in three additional rats among the 10 exposed to 0.29 mg CPC/litre.

Acute Inhalation Toxicity Studies in Several Animal Species of An Ethylene ox Ide/Propylene Oxide Copolymer (Ucon 50-Hb-5100)

An acute inhalation toxicity study in several species of animals with an ethylene oxide/propylene oxide copolymer (EO/PO) having a molecular weight of 4000 [UCON-50-HB-5100, CAS #9038-95-3] was designed to determine if any species variation could be shown. Species tested included: rats, mice, hamsters, guinea pigs, and dogs. The test material was administered as a respirable liquid aerosol for 4 hours at target concentrations of 50, 100, 200, and 500 mg/m3. A vehicle control group was exposed to a distilled water aerosol. The 4 hours LC50's were calculated to be 147 mg/m3 [rats], 174 mg/m3 [mice], 293 mg/m3 [guinea pigs] and 511 mg/m [hamsters]. The dog LC50 was determined to be greater than 500 mg/m3 since all the test animals survived exposure to this concentration. These values show that rats and mice were the most sensitive species with a declining response in guinea pigs, hamsters and dogs. Lung weights were increased at all exposure concentrations in rats, mice and hamsters. Lung weights were increased in guinea pigs at exposure concentrations of 100 mg/m3 and above. Lung weights in dogs were increased only at the 500 mg/m3 exposure concentration. Significant pathological changes were limited to the lungs and were more common in animals which died prior to scheduled sacrifice. Grossly, these lung changes consisted of red discoloration, edema, emphysema, and surface irregularities. Microscopic findings in the lungs included acute congestion and hemorrhage and, less commonly, acute interstitial inflammation.

Acute inhalation toxicity of soman and sarin in baboons

Adult baboons ( Papio sp.; 8–12 kg) were anesthetized with sodium pentobarbital (20 mg/kg iv). The animals were instrumented for measurement of mean blood pressure (MBP), pulmonary artery pressure (PAP), ECG, arterial and mixed venous blood gases, lung volumes, lung pressures, and efferent phrenic nerve activity. Bronchoalveolar lavage (BAL) was performed. Studies were done prior to exposure, at intervals during the first 4 hr postexposure, and at 4 and 28 days after exposure. Control animals received a sham exposure to 2-propanol ( N = 5). Soman (pinacolyl methylphosphonofluoridate) at 13.14 μg/kg (2 × LD50) was vaporized into the upper airway in a second group of animals ( N = 5), and sarin (isopropyl methylphosphonofluoride) 30 μg/kg (2 × LD50) was vaporized into a third group of animals ( N = 4). Controls showed no change in any parameter either immediately after diluent exposure or during the monitoring period. Soman and sarin produced a decline in MBP and bradyarrhythmias that were reversed with atropine. Apnea occurred in all soman- and sarin-exposed animals within 5 min postexposure, and was associated with absence of phrenic nerve signal. Ventilation was mechanically supported until the animal could maintain normal arterial blood gases during spontaneous breathing. BAL studies revealed an increase in total white cell population and neutrophils at 4 hr in all three groups. There were signs of impaired hemodynamics and persistent lung injury for 4 days that resolved by 28 days after exposure. In conclusion, inhalation of soman and sarin in the baboon is associated with cardiac arrhythmias, development of apnea, and a significant decrease in MBP. Inhalation exposure also resulted in a persistent influx of neutrophils and hypoxemia.

Acute and sub-acute inhalation toxicity of germanium metal powder in rats

An acute (4-hr) and a sub-acute (4-wk) inhalation toxicity study of germanium metal powder (purity 99.8%, mean particle size 2.0–2.4 μm) were carried out in young adult Wistar rats. Exposure of five male and five female rats to 3.86 or 5.34 g/m 3 for 4 hr resulted in the death of one rat at each exposure level. Four groups of five male and five female rats were exposed to 0, 9.9, 65.1 or 251.4 mg/m 3 for 6 hr/day, 5 days/wk for 30 days. Two additional (recovery) groups of five male and five female rats exposed to 0 or 251.4 mg/m 3 were kept untreated for 31 days after exposure. At the end of the treatment period, fasting blood glucose was decreased in males exposed to the high concentration. In females of this group, blood creatinine and urea levels, and urine volumes were increased, but urine density was decreased. Increased blood creatinine levels and urine volume and decreased urine density were also observed in females exposed to 65.1 mg/m 3. The absolute and relative lung weights were increased in rats in the mid- and high-concentration groups. Histopathological examination revealed: accumulation of particulate material in the lungs of all treated groups, accumulation of alveolar macrophages in the mid- and high-concentration groups, and alveolitis mainly in the high-concentration group. After the 4-wk recovery period, urine volume was increased in males that had been exposed to germanium. In exposed rats of both sexes, lung weights were still increased and histopathological changes were present, but to a lesser extent than at the end of the exposure period. It was concluded that the 4-hr LC 50 value of germanium metal powder in rats is > 5.34 g/m 3. The no-adverse-effect level in the 4-wk study was 9.9 mg/m 3 air.

Acute inhalation toxicity of microcystin-LR with mice: D. A. Creasia (U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701-5011, U.S.A.)

Acute inhalation toxicity of microcystin-LR with mice: D. A. Creasia (U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701-5011, U.S.A.)

Acute inhalation toxicity of T-2 mycotoxin in the rat and guinea pig

In this study, concentration-response parameters were determined for rats and guinea pigs systematically exposed to an aerosol of T-2 toxin. The LC50 for a 10-min exposure to T-2 toxin aerosol was 0.02 mg T-2/liter air for rats and 0.21 mg T-2/liter air for guinea pigs. Data from total T-2 deposition in rats and guinea pigs exposed to their respective LC50 aerosol concentration gave an LD50 of 0.05 mg T-2/kg body weight for the rat and 0.4 mg T-2/kg body weight for the guinea pig. These data show that inhaled T-2 toxin is approximately 20 times more toxic to the rat (0.05 mg T-2/kg body wt inhaled vs 1.0 mg T-2/kg body wt ip) and at least twice as toxic to the guinea pig (0.4 mg T-2/kg body wt inhaled vs 1–2 mg T-2/kg body wt ip) than ip administered T-2 toxin. Histopathologic examination of major organs in both the rat and guinea pig after respiratory exposure to T-2 toxin indicated that lesions were similar to those described after systemic administration of the toxin. Gross and microscopic alterations of respiratory tract tissue after T-2 aerosol exposure were minimal and could not account for the increase in toxicity.