Acute lethal

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The propensity of nitriles to release cyanide subsequent to metaboHsm is the basis of their acute toxicity. Nitriles that form tertiary radicals at their alpha carbon atoms (eg, isobutyronitrile, 2-methylbutyronitrile) are substantially more acutely lethal than nitriles that form secondary radicals at their alpha carbons (eg, butyronitrile, propionitnle). Cyanohydrins are acutely toxic because they are unstable and release cyanide quickly. Alpha-aminonitriles are also acutely toxic, presumably by analogy with cyanohydrins. 

Table 8. Acute Lethal Doses of Lanthanide Chlorides for Mice...

Considerable caution is necessary in making quantitative comparisons between different materials, even when considering the same toxic end point. This can be conveniendy illustrated using, as an example, death in response to a single exposure, ie, acute lethal toxicity. Studies to determine acute lethal toxicity by a particular route are usually conducted as described below. 

Although acute lethal toxicity has been used as an example, the principles discussed apply ia general to other forms of toxicity capable of being quantitated ia terms of dose—response relationships. 

Table 5. Acute Lethal Doses of Soluble Barium Compounds ...

An acute lethal dose (LC q) for vapor exposure to 1,1,2-trichloroethane in the rat is 2000 ppm for a 4-h exposure. The same lethal effect occurs at 18,000 ppm vapor during 3 h exposure to 1,1,1-trichloroethane. The oral LD q for 1,1,2-trichloroethane in rats is 0.1—0.2 g/kg, classifying it as moderately toxic (109). Liver and kidney damage occurs at even lower dosages. Skin adsorption is a possible route of overexposure. 

Renal Effects. Acute nephrosis has been reported in humans after acute, lethal intoxication (Fazekas 1971) by methyl parathion (Wofatox). This may be a secondary effect of hypoxia related to the neurologic effects of methyl parathion on vascular smooth muscle and on the electrical conduction system of the heart. It could also be related to therapeutic efforts. 

Terziev G, Dimitrova N, Rusev E. 1974. Eorensic medical and forensic chemical study of acute lethal poisinnins with Thiodan. Eolia Med 16 325-329. 

Acute Lethality. Samples of 2,7-dichlorodibenzo-p-dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin, hexachlorodibenzo-p-dioxin, and octachloro-dibenzo-p-dioxin were evaluated for acute oral lethality in the following animals. 

Parenteral lethality was determined by injecting rabbits of mixed sexes intraperitoneally with 31.6, 63, 126, 252, and 500 /xg/kg of 2,3,7,8-TCDD as a 0.01% corn oil suspension control rabbits were injected with corn oil. The rabbits were housed in individual holding cages and were observed for signs of toxicity for four weeks. The LDso s were calculated by the Weil modification of the Thompson method 14, 15) or by the Litchfield and Wilcoxon method (9). The acute lethality studies were terminated when it was evident that the survivors were not showing signs of toxicity. 

Death following treatment with a lethal dose of 2,3,7,8-TCDD is often delayed for several weeks. Among the animals which died following treatment, approximately half the deaths occurred between 13 and 18 days after treatment, with one animal dying as late as 43 days after a single oral dose. In mice and rabbits, there is a marked individual difference in susceptibility to this compound which makes it difficult to conduct acute lethality studies. 

In addition to acute lethal poisonings, episodes of dermatitis and/or irritation... 

In attempting to quickly elucidate the possible mechanisms of action of a toxin, there are a number of obvious routes to take. In the case of a toxin which has a rapid and acute lethal action, the route is especially obvious, but with toxins having effects on growth and differentiation, the best approach is more obscure. 

Marine toxins are not always acutely toxic. This may be particularly so for toxins which are used to deter competing occupants for living space since they often have comparatively slow actions on growth. With such toxins, the procedures for the evaluation of acutely lethal toxins cannot apply. However, interesting discoveries may be made by using the simplest of screen of alcoholic extracts for cytolytic actions as exemplified in Table I of Shier 109),... 

Hackett, R.B. Obrosky, K.W. Borne, R.F. and Water, I.W. Acute phencyclidine poisoning in the unanesthetized dog Pathophysio-ionic profile of acute lethality. Toxi rnloav 19 11-20, 1981. 

Fate. Preliminary investigations directed at adapting the method of Averell and Norris (2) to the analysis of animal tissues indicated that if precautions were taken to avoid emulsions the method could be used satisfactorily. Tissue samples of about 5 grams were most convenient, and the usual reagent and tissue blanks were run simultaneously. Following the administration of an acutely lethal intravenous dose to a dog it was found that parathion could be recovered from the urine, liver, bile, kidney, spleen, and lung. 

Following oral administration of a lethal dose to a dog (25 mg. per kg. wettable powder) tissues taken immediately after death analyzed as follows no parathion recovered from bladder bile, liver, kidney, abdominal fat, saliva, or intestine small quantities (2 to 7 p.p.m.) of parathion recovered from oxalated blood, spleen, lung, brain, and spinal cord. The urinary bladder was strongly contracted and no urine could be collected. The results of these two experiments indicate a universal distribution of parathion following acutely lethal doses. 

Parathion is uniformly distributed throughout the body following acutely lethal doses, but there is no evidence of storage in any of the tissues studied even after long terms of feeding. 

In a series of acute lethality studies, lethargy and inactivity were noted in rats exposed for 4 hours to lethal concentrations of DTNSRDC N501 (6,430 mg/m3) (MacEwen and Vemot 1983). Kyphosis was observed in rats exposed to 880-5,030 mg/m3 of a polyalphaolefin hydraulic fluid designated as B85-174 (Kinkead et al. 1987b). Because of the uncertainty of whether the kyphosis is a neurological or muscular effect, this effect is discussed in both the Musculoskeletal Effects and Neurological Effects sections. No other information was located on neurological effects in animals after inhalation exposure to polyalphaolefin hydraulic fluids. 

In a series of acute lethality studies on U.S. military fluids, single gavage doses (4,250 or 5,000 mg/kg) of one of several polyalphaolefin hydraulic fluids did not produce signs of neurological toxicity in rats within... 

Available data are restricted to acute lethality studies in rats exposed to four water-in-oil emulsion hydraulic fluids or a mineral oil hydraulic fluid for 4—6 hours. No deaths or body weight alterations occurred at exposure concentrations ranging from 180 to 210 mg/m3 for the water-in-oil fluids and 1,130 mg/m3 for the mineral oil fluid. The data are inadequate for acute inhalation MRL derivation. No data regarding intermediate or chronic inhalation exposure to mineral oil hydraulic fluids were located. 

The available data did not adequately identify target organs or effects. In acute lethality studies in rats gavaged with 5,000 mg/kg doses of the water-in-oil emulsion hydraulic fluids or mineral oil hydraulic fluids, no deaths or body weight changes occurred. One of these fluids was tested for neurotoxicity in chickens without effects. 

No data were located regarding toxic effects in humans following oral exposure to polyalphaolefin hydraulic fluids. No deaths or body weight changes occurred in rats in a series of acute lethality studies with nine polyalphaolefin hydraulic fluids at doses ranging from 4,250 to 5,000 mg/kg. One of these fluids was also tested for neurotoxicity in chickens, and did not produce effects at 4,250 mg/kg. The available data have not identified a target organ or effect for these fluids. The data are inadequate for MRL derivation. No intermediate or chronic oral MRLs for polyalphaolefin hydraulic fluids were derived due to the lack of data. 

Acute lethality studies in animals exposed by inhalation, ingestion, or dermal contact to several mineral oil hydraulic fluids indicate that mineral oil fluids are not potent toxicants. Mineral oil hydraulic fluids produced no deaths in rats after 4-hour exposures to aerosol concentrations of 110-210 mg/m3 or gavage administration of single doses <5,000 mg/kg (Kinkead et al. 1987a, 1988). Rabbits, likewise, did not die after single 24-hour exposures to occluded dermal doses of several mineral oil hydraulic fluids <2,000 mg/kg (Kinkead et al. 1985, 1987a, 1988). 

Polyalphaolefin Hydraulic Fluids. Aside from the acute lethality of inhalation exposure to certain polyalphaolefin hydraulic fluids, little is known regarding the toxic effects produced by these materials. Additional animal studies to identify the possible toxic effects of exposure to these materials may provide information relevant to the investigation of methods for reducing the toxic effects. 

Acute lethal concentrations (LC50s) for hydrogen sulfide in rats have been reported to range from 335 to 587 ppm (Prior et al. 1988 Tansy et al. 1981). There are no reports of fatalities in humans or animals exposed solely by the oral route or dermal routes. 

Mefenamic is a nonsteroidal anti-inflammatory drug used to treat pain, including menstrual pain. Hata et al. [11] treated that drug with P. sordida, and obtained a 90% reduction in mefenamic acid concentration (initial concentration 24 mg L ) after 6 days. The system produced four metabolites, identified as 3 -hydroxymethyl-mefenamic acid, 3 -hydroxymethyl-5-hydroxymefenamic acid, 3 -hydroxmethyl-6 -hydroxymefenamic acid, and 3 -carboxymefenamic acid. Moreover, the authors confirmed that the fungus almost completely removed the acute lethal toxicity of mefenamic towards the freshwater crustacean Thamnocephalus platyurus after 6 days of treatment, suggesting that the metabolites are less toxic than the parental compound. 

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