Chlorosilane Acute Inhalation Toxicity and Development of an LC50 Prediction Model

The acute inhalation toxicity of 10 chlorosilanes was investigated in Fischer 344 rats using a 1-h whole-body vapor inhalation exposure and a 14-day recovery period. The median lethal concentration (LC50₁) for each material was calculated from the nominal exposure concentrations and mortality. Experimentally derived LC50₁ values for monochlorosilanes (4257–4478 ppm) were greater than those for dichlorosilanes (1785–2092 ppm), which were greater than those for trichlorosilanes (1257–1611 ppm). Apparent was a strong structure-activity relationship (r² = .97) between chlorine content and LC50₁ value. Estimated LC50₁ values for mono-, di-, and trichlorosilanes were determined to be 3262, 1639, and 1066 ppm, respectively, utilizing this relationship and the lower limit of the 95% prediction interval. The LC50₁ values determined in this series of studies were greater than that reported for hydrogen chloride (3124 ppm), when expressed on a chlorine equivalence basis (3570–5248 ppm), demonstrating that the acute toxicity of these chlorosilanes is similar to or less than that for hydrogen chloride. The good correlation between chlorine content and LC50₁ provides a sound basis for estimation of LC50₁ for chlorosilanes not already evaluated. The use of structure–activity relationships is consistent with the chemical industry and federal agency initiatives to reduce, refine, and/or replace the use of animals in testing without compromising the quality of health and safety assessments.     

Alternative acute inhalation toxicity testing by determination of the concentration-time-mortality relationship: experimental comparison with standard LC50 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 LC50 (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, LT50 (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 LC50 procedure according to the OECD guideline 403. However, the new method has several additional advantages such as: (A) LC50 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. (B) The obtained relationship contains considerably more valuable information for risk assessment than the LC50 value.(ABSTRACT TRUNCATED AT 250 WORDS)     

LD50 versus acute toxicity

Conclusions Based on today's extensive experience on acute toxicity testing of chemical substances, and on the outcome of specific studies (Schütz and Fuchs 1982; Müller and Kley 1982; Lorke in preparation; Günzel et al. in preparation), it is now possible to conduct acute toxicity studies with the sacrifice of fewer animals and even to increase at the same time, the quality of the data obtained. Whereas for drugs, data on acute toxicity usually represents only part of the information available, for other chemical substances, acute toxicity may be the only data available, thus asking for more extensive examination of the animals used 'for this kind of study.     

Mosquito coil smoke inhalation toxicity. Part I: validation of test approach and acute inhalation toxicity

Burning mosquito coils indoors to repel mosquitoes is a common practice in many households in tropical countries. The evaluation and assessment of the inhalation toxicity of smoke emitted from mosquito coils appear to be particularly challenging due to the complex nature of this type of exposure atmosphere. The potential health implications of the gases, volatile agents and particulate matter emitted from burning coils or incense have frequently been addressed; however, state-of-the-art inhalation toxicity studies are scarce. The focus of this paper was comparatively to evaluate and assess the appropriateness and practical constraints of the whole-body versus the nose-only mode of exposure for inhalation toxicity studies with burning mosquito coils. With regard to the controlled exposure of laboratory animals to complex smoke atmospheres the nose-only mode of exposure had distinct advantages over the whole-body exposure, which included a rapid attainment of the inhalation chamber steady state, minimization of particle coagulation and uncontrolled adsorption of condensate onto the chamber surfaces. While in whole-body chambers a different kinetic behaviour of volatile and particulate constituents was found which caused inhomogeneous, i.e. artificially enriched atmospheres with volatile components at the expense of aerosols, the nose-only mode of exposure provided maximum exposure intensities without losses of the particulate phase of the exposure atmosphere. Collectively, the results obtained support the conclusion that the dynamic nose-only mode of exposure is experimentally superior to the quasistatic whole-body exposure mode which provides the least control over exposure atmospheres and the outcome highly contingent on selected experimental factors. Acute inhalation toxicity studies in rats suggest that the most critical metrics of exposure are apparently related to (semi)volatile upper respiratory tract sensory irritants, whilst the asphyxic component, carbon monoxide, plays a role only at overtly irritant exposure levels. However, this study was conducted at exposure concentrations much higher than encountered by people in residential settings and the effects observed under these conditions may not be relevant to hazards from exposures at common use levels. Neither an acute 8 h exposure of rats nor the 1 h sensory irritation study in mice and rats provided experimental evidence that irritant particle-related effects had occurred in the lower respiratory tract. In summary, the protocols devised evaluate and assess the acute inhalation toxicity of mosquito coil smoke demonstrating that the nose-only mode of exposure of rats to the smoke of mosquito coils is suitable to assess the toxic potency of different coils. The nose-only mode has clear advantages over the whole-body exposure mode. The inhalation studies conducted show unequivocally that acute toxic effects are difficult to produce with this type of product even under rigorous testing conditions.     

Evaluation of acute inhalation toxicity for chemicals with limited toxicity information

A large reference database consisting of acute inhalation no-observed-adverse-effect levels (NOAELs) and acute lethality data for 97 chemicals was compiled to investigate two methods to derive health-protective concentrations for chemicals with limited toxicity data for the evaluation of one-hour intermittent inhalation exposure. One method is to determine threshold of concern (TOC) concentrations for acute toxicity potency categories and the other is to determine NOAEL-to-LC(50) ratios. In the TOC approach, 97 chemicals were classified based on the Globally Harmonized System of Classification and Labeling of Chemicals proposed by the United Nations into different acute toxicity categories (from most toxic to least toxic): Category 1, Category 2, Category 3, Category 4, and Category 5. The tenth percentile of the cumulative percentage distribution of NOAELs in each category was determined and divided by an uncertainty factor of 100 to derive the following health-protective TOC concentrations: 4microg/m(3) for chemicals classified in Category 1; 20microg/m(3) for Category 2; 125microg/m(3) for both Categories 3 and 4; and 1000microg/m(3) for Category 5. For the NOAEL-to-LC(50) ratio approach, 55 chemicals with NOAEL exposure durations < or = 24 hour were used to calculate NOAEL-to-LC(50) ratios. The tenth percentile of the cumulative percentage distribution of the ratios was calculated and divided by an uncertainty factor of 100 to produce a composite factor equal to 8.3x10(-5). For a chemical with limited toxicity information, this composite factor is multiplied by a 4-hour LC(50) value or other appropriate acute lethality data. Both approaches can be used to produce an estimate of a conservative threshold air concentration below which no appreciable risk to the general population would be expected to occur after a one-hour intermittent exposure.     

Mechanism of acute inhalation toxicity of alkanes and aliphatic alcohols

This study investigated the mechanism of non-specific toxicity of non-reactive volatile organic compounds by using data reported in the literature. Inhalation toxicity data, in terms of LC(50) for alcohols and alkanes in rodents, were examined in relation to their partitioning behaviour in the biological system. Regression analysis of the data showed that, after the elimination of the kinetic influence in the absorption process, lethal toxicity increases linearly with the octanol-air partition coefficient in a homologous series. Comparing this relationship with that for anaesthesia, it could be concluded that lethal toxicity of the test chemical series probably acts on the lipid bilayer plasma membrane through a non-specific biophysical mechanism similar to anaesthesia. The critical concentration hypothesis appears to be valid for lethal toxicity of the test series. It was also shown that toxicity data for the test series by other routes, namely oral, intraperitoneal and intravenous, give a similar toxicity-partition relationship to that by inhalation.     

Species comparison of acute inhalation toxicity of ozone and phosgene

A comparison of the concentration-response effects of inhaled ozone (O3) and phosgene (COCl2) in different species of laboratory animals was made in order to better understand the influence of the choice of species in inhalation toxicity studies. The effect of 4-h exposures to ozone at concentrations of 0.2, 0.5, 1.0, and 2.0 ppm, and to COCl2 and 0.1, 0.2, 0.5, and 1.0 ppm was determined in rabbits, guinea pigs, rats, hamsters, and mice. Lavage fluid protein (LFP) accumulation 18-20 h after exposure was used as the indicator of O3- and COCl2-induced pulmonary edema. All species had similar basal levels of LFP (250-350 mg/ml) when a volume of saline that approximated the total lung capacity was used to lavage the collapsed lungs. Ozone effects were most marked in guinea pigs, which showed significant effects at 0.2 ppm and above. Mice, hamsters, and rats showed effects at 1.0 ppm O3 and above, while rabbits responded only at 2.0 ppm O3. Phosgene similarly affected mice, hamsters, and rats at 0.2 ppm and above, while guinea pigs and rabbits were affected at 0.5 ppm and above. Percent recovery of lavage fluid varied significantly between species, guinea pigs having lower recovery than other species with both gases. Lavage fluid recovery was lower following exposure to higher levels of O3 but not COCl2. Results of this study indicate that significant species differences are seen in the response to low levels of O3 and COCl2. These differences do not appear to be related in a simple manner to body weight.     

A proposal for the reduction of animal numbers required for the acute toxicity to fish test (LC50 determination)

Juvenile rainbow trout (Salmo gairdneri) were exposed to 10 common industrial and agricultural chemicals in a series of acute toxicity tests to provide data for the evaluation of the test design currently employed in hazard assessment for novel chemicals in the aquatic environment. Analysis of these data revealed that the widely employed design of 10 fish at each of 5 concentrations covering one order of magnitude could be modified to one of 7 fish at each of 4 concentrations with minimal reduction in the precision of the result (i.e., the LC₅₀ value). The adoption of this modification to test design, however, would result in a reduction of approximately 40% of the number of experimental animals used in bioassay programmes.     

A comparative assessment of the acute inhalation toxicity of vanadium compounds

Vanadium compounds have become important in industrial processes, resulting in workplace exposure potential and are present in ambient air as a result of fossil fuel combustion. A series of acute nose-only inhalation toxicity studies was conducted in both rats and mice in order to obtain comparative data on the acute toxicity potential of compounds used commercially. V₂O₃, V₂O₄, and V₂O₅, which have different oxidation states (+3,?+4,?+5, respectively), were delivered as micronized powders; the highly water-soluble and hygroscopic VOSO₄ (+4) could not be micronized and was instead delivered as a liquid aerosol from an aqueous solution. V₂O₅ was the most acutely toxic micronized powder in both species. Despite its lower overall percentage vanadium content, a liquid aerosol of VOSO₄ was more toxic than the V₂O₅ particles in mice, but not in rats. These data suggest that an interaction of characteristics, i.e., bioavailability, solubility and oxidation state, as well as species sensitivity, likely affect the toxicity potential of vanadium compounds. Based on clinical observations and gross necropsy findings, the lung appeared to be the target organ for all compounds. The level of hazard posed will depend on the specific chemical form of the vanadium. Future work to define the inhalation toxicity potential of vanadium compounds of various oxidation states after repeated exposures will be important in understanding how the physico-chemical and biological characteristics of specific vanadium compounds interact to affect toxicity potential and the potential risks posed to human health.     

Assessments of lung toxicity to Acrawax C following acute inhalation exposure

Acrawax is a trademark for a series of synthetic waxes which are used as flatteners in paint, and lubricants in plastics, and these materials have been routinely regarded as nuisance dusts. Due to a paucity of information regarding the pulmonary toxicity of this material, we investigated the effects of acute inhalation of Acrawax C in rats. CD rats were exposed to aerosols of Acrawax C for 6 hours at 112 mg/m3. Fluids and cells from sham and exposed animals were recovered by bronchoalveolar lavage (BAL) and measured for cellular and biochemical parameters at 0, 24, 48, 172 hrs (8 days), and 1 month postexposure. Pulmonary macrophages (PM) were cultured and studied for in vitro and in vivo phagocytosis, as well as surface morphology. The lungs of additional animals exposed to Acrawax were fixed for assessment by histopathology, and transmission electron microscopy. Our results showed that Acrawax C exposure produced a mild inflammatory response at 24 hours postexposure, but cell differentials were not significantly different from controls at 48 hrs after exposure. BAL levels of lactate dehydrogenase, alkaline phosphatase and protein were slightly different from controls only at 8 days postexposure, and had returned to control values by 1 month of recovery. Acrawax exposure had no adverse effects on either morphology or the phagocytic capacity of pulmonary macrophages recovered from exposed animals. Histopathologic analysis of lung tissue from Acrawax C-exposed rats revealed normal lung architecture. Based on acute studies, our results suggest that the response to inhaled Acrawax C is not substantially different from the response to other nuisance dusts such as carbonyl iron and titanium dioxide.     

The development of an automated ward independent delirium risk prediction model

International Journal of Clinical Pharmacy - Background A delirium is common in hospital settings resulting in increased mortality and costs. Prevention of a delirium is clearly preferred over...     

两种LC乙醇提取物急性毒性试验毒性比较

目的通过两种LC乙醇提取物的急性毒性试验,比较二者的毒性。方法24h内小鼠单次灌胃给予两种LC乙醇提取物,观察毒性反应及死亡情况,测定最大耐受量、最小致死量。结果LC乙醇提取物Ⅰ的最大耐受量为5．243g／kg．bw,最小致死量为6．554g／kg．bw;LC乙醇提取物Ⅱ的最大耐受量为5．760g／kg．bw,最小致死量为7．200g／kg．bw。结论LC乙醇提取物Ⅰ的毒性略比LC乙醇提取物Ⅱ大。     

Statistical evaluation of the fixed concentration procedure for acute inhalation toxicity assessment

The conventional method for the assessment of acute inhalation toxicity (OECD Test Guideline 403, 1981) uses death of animals as an endpoint to identify the median lethal concentration (LC50). A new OECD Testing Guideline called the Fixed Concentration Procedure (FCP) is being prepared to provide an alternative to Test Guideline 403. Unlike Test Guideline 403, the FCP does not provide a point estimate of the LC50 but aims to identify an airborne exposure level that causes clear signs of nonlethal toxicity. This is then used to assign classification according to the new Globally Harmonized System of Classification and Labelling scheme (GHS). The FCP has been validated using statistical simulation rather than by in vivo testing. The statistical simulation approach predicts the GHS classification outcome and the numbers of deaths and animals used in the test for imaginary substances with a range of LC50 values and dose-response curve slopes. This paper describes the FCP and reports the results from the statistical simulation study assessing its properties. It is shown that the procedure will be completed with considerably less death and suffering than Test Guideline 403, and will classify substances either in the same or a more stringent GHS class than that assigned on the basis of the LC50 value.     

药物重要脏器毒性及其早期预测方法的探讨

毒性是导致药物研发失败的主要原因之一。为了避免在药物开发晚期发现毒性导致的昂贵代价,尽早确定药物潜在的毒性问题非常重要。通过对药物产生的肝脏、心脏和肾脏毒性的机制进行分析,并对现有的毒性预测方法进行综述,提出可以从代谢产物反应活性、离子转运体、离子通道等3方面综合分析药物产生毒性的可能性,从而提高重要脏器严重毒性预测的准确性。     

Shortcomings of LD50-values and acute toxicity testing in animals.

Abstract The author argues that the standard practice of determining an LD₅₀ with 95% confidence limits is a waste of animals since the extra statistical precision is undermined by numerous other factors. For example, the LD₅₀ of a given chemical often varies by at least 10-fold between different animal species and strains. Also, environmental factors can result in substantial differences in the LD₅₀ of a given chemical in a given animal strain. Therefore, the use of this measure as a general index of toxicity, as a guide to further pharmacological or toxicological studies, or as a guide to human toxicity involves unnecessary and needless taking of animal life. These points will be amplified and substantiated by actual examples. Finally, the author will make some suggestions as to what could constitute a satisfactory acute animal test given current scientific and regulatory needs.     

Acute inhalation toxicity of diiodotetrafluoroethane

Acute inhalation toxicity studies with diiodotetrafluoroethane in rats following an exposure of 4 h to concentrations of 6—197.5 ppm show that 16.5 ppm to 197.5 ppm impaired dose-related the animals' attitude and posture, motoricity, autonomie reactions and respiratory function. At concentrations of more than about 90 ppm death occurred as a result of cardiac and circulatory failure.On the basis of these results it could be demonstrated that the no-effect level is 6 ppm and the approximate mean lethal concentration (LC₅₀) would be 75 ppm.     

Subchronic inhalation toxicity of methanol

The subchronic inhalation toxicity of methanol was evaluated in rats and monkeys. Animals were exposed to 0, 500, 2000, and 5000 ppm methanol vapor for 6 h/d, 5 d/w, for 4 wk. The only treatment-and dose-related effect noted was that of mucoid nasal discharge in rats, which was considered reflective of upper respiratory tract irritation. No consistent treatment-related effects were found for organ or body weights or for histopathologic or ophthalmoscopic examinations. Overall, these findings support the use of the present American Council of Governmental Industrial Hygienists threshold limit value (TLV) of 200 ppm and short-term exposure limit (STEL) of 250 ppm for exposure to methanol vapor.     

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.     

The acute inhalation toxicity in rats from the pyrolysis products of four fluoropolymers

Male Sprague-Dawley rats (225–250 g) were exposed to the thermal degradation products from four fluoropolymers. The three polymers containing vinylidene fluoride and hexafluoropropene (VF₂/HFP) were pyrolyzed at 550° and 800°C, whereas polytetrafluoroethylene (PTFE) was pyrolyzed at 625 and 800°C. At the lower temperatures, the pyrolysate from the copolymer of vinylidene fluoride and hexafluoropropene (VF₂/HFP) was less toxic than the pyrolysates from either the terpolymer of vinyidene fluoride, hexafluoropropene, and tetrafluoroethylene (VF₂/HFP/TFE) or the copolymer of vinylidene fluoride and hexafluoropropene with “additives” (VF₂/HFP-A). However, the pyrolysates from the VF₂/HFP-containing materials produced less toxic products than the pyrolysate from PTFE at 625°C. When the pyrolysis temperature was increased to 800°C, very little difference was noted between the pyrolysis toxicity for any of the VF₂/HFP-containing polymers with the most toxic pyrolysate again produced by PTFE. Carbon monoxide levels were all sublethal. No correlation could be established between hydrolyzable fluoride levels and the lethality of the pyrolysates. Death following exposure occurred within 48 hr due to acute pulmonary edema and hemorrhage. Survival of this acute phase was followed by alveolar lymphocytic infiltration and peribronchial tissue proliferation.     

Acute inhalation toxicity studies in several animal species of an ethylene oxide/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.