Toxicity, acute

Acute toxicity refers to those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours. 

1 Chemicals can be allocated to one of five toxicity categories based on acute toxicity by the 

Exposure route Category 1 Category 2 Category 3 Category 4 Category 5 

Gases (ppmV) see Note (a) Note (b) 100 500 2500 5000 See detailed criteria in Note (f) 

NOTE Gases concentration are expressed in parts per million per volume (ppmV). 

Acute toxicity refers to the adverse effects, which occur within a given, usually short time, following a single, usually high exposure to a substance. In older literature, acute toxicity is sometimes used synonymously with lethal effect or LD50, which was the only endpoint in older acute toxicity tests. Nowadays, acute toxicity studies are designed to reveal more subtle effects. 

A general definition of the term acute toxicity is The adverse effects occurring within a given time, following a single exposure to a substance. The term usually excludes local irritant or corrosive effects arising from a single application of a substance to the skin or eye (Section 4.5) (EC 2003). 

Toxicological Risk Assessments of Chemicals A Practical Guide 

Acute dermal toxicity is the adverse effects occurring within a short time of dermal application of a single dose of a test substance. The duration of exposure in the OECD TG 402 is 24 h, at the end of which residual test substance should be removed. 

The majority of acute intoxications by metals is usually the result of suicide attempts. Occasionally, errors - for example in the laboratory or clinic, contaminated food, and, in rare cases, medical treatment - can lead to intoxication. Homicide may also be the cause. 

The acute toxic effects of metals cannot be considered as isolated phenomena, but rather as a part of the complete spectmm of activity and/or dose-activity relationship of a metal in a biological system (Williams 1981b). 

Preview Types of acutely toxic chemicals that present immediate hazards in chemistry courses are explained and examples of each type are given. 

Salt is white and pure—there is something holy in salt. 

Five technicians working in a laboratory ate lunch in a small nearby storeroom. After drinking cups of tea, three of them felt ill with a fuzzy head and pounding heart. Another technician drank two cups and developed violent cramp-like pains in his chest, and he was taken to the hospital believing he was suffering from a heart condition. A fifth technician drank only half of a cup of tea, but also felt ill. Finally, one of the technicians remembered that she had filled the tea kettle with laboratory distilled water that had been treated with sodium azide to prevent growth of bacteria, a common practice in some laboratories. All technicians recovered. 

What lessons can be learned from this incident  

This section describes acutely toxic chemicals that produce immediate toxic effects. Because these immediate effects are easier to recognize and study, we know much more about the effects of acute toxicants than about chronic toxicity which inherently requires longer time periods and lower doses. Nevertheless, we may not know all of the toxic effects of chemicals. In Section 4.1.1 you learned that the effects that chemicals cause depend on many factors, including dose and time. Salt, that holy substance praised by Hawthorne, is toxic with a LD50 of 3000 mg/kg, and children have died of salt poisoning. But salt is required in small doses for our well-being and we often use it hberally in our foods. Caffeine is toxic and has an oral LD50 in rats of 192 mg/kg., but you would have to drink about 100 cups of coffee to receive a lethal dose in a few hours. As discussed in Section 4.1.1, the dose makes the poison . Some chemicals may have more than one toxic effect, and the mechanisms of these effects vary markedly. 

Acute barbiturate toxicity is characterized by automatism, or a state of drug-induced confusion, in which patients lose track of how much medication they have taken and take more. Death results from respiratory failure. The treatment of poisoning consists of supporting the respiration, preven- 

The abrupt withdrawal from barbiturates may cause tremors, restlessness, anxiety, weakness, nausea and vomiting, seizures, delirium, and cardiac arrest. 

Toxicology studies are concerned with a variety of aspects, primarily with (1) Acute toxicity, (2) Irritation of skin and eyes, (3) Toxicity after repeated application, (4) Sensitization, (5) Mutagenicity, and (6) Cancerogenicity. 

The first step to determine whether a dye is hazardous is the appropriate evaluation or testing of the acute toxicity of dyes, as defined by the EU Directive 67/ 548/EEC (with numerous amendments). A comprehensive review on such data including skin and eye irritation of numerous commercial dyes, derived from Safety Data Sheets, showed that the potential for these acute toxic effects ( harmful or toxic ) was very low. Although the review stems from an early date, it can be asumed that the results are still valid today [5], 

Reactive dyes that caused respiratory or skin sensitization in workers on occupational exposure were compiled by ETAD [13], In the EU these dyes, which are all listed in the European Inventory of Existing Chemical Substances (EINECS), should be labeled accordingly (Table 8.1). 

The German Federal Institute for Consumer Protection and Veterinary Medicine (BgVV) evaluated the available literature and came to the conclusion that above all the following disperse dyes represent a health risk to consumers and should therefore not be used anymore for clothes (Table 8.2). 

Up to now there is no legal prohibition in any country, but some organizations, e.g., the International Association for Research and Testing in the Field of Textile Ecology (Oko-Tex), which bestows eco-labels on environmentally and toxicologi-cally proven textiles, refuses eco-labels for some dyes [17], 

Testing on animals may provide initial information on the effect of a possible shortterm exposure on human health. Acute toxicity is defined as the toxic effect of a substance after a single oral, dermal, or inhalative application. For acute oral toxicity, for instance, LD50 is defined as the amount of substance expressed in mg per kg body weight which has a lethal effect on 50% of the test animals after a single oral application. Such tests are useful in that they assess the toxicity of a material relative to that of other known compounds. 

108 Organic pigments have been examined concerning their acute oral lethal dose in rats. None of the studied pigments shows an LD50 value of less than 5000 mg/kg body weight [20], 

Another publication summarizes the results of testing 194 organic pigments for toxicity. The most important chemical types were represented [21]. None of the 

Pigments are passed via the gastro-intestinal tract and not discharged via the urethra. According to the results of these studies, organic pigments show practically no acute toxicity. 

Humans exposed by inhalation for a short time to high concentrations of SM go on to develop a variety of long term respiratory effects. There is a clear relationship between exposure dose and the severity of subsequent effects of SM, but no evidence to suggest that the severity of the long term effects bears any relationship to the severity of the acute response. 

1 Oral Exposure. There are few reports on the oral toxicity of SM. In one study, the oral lethal dose, 50% (LD50) of SM [administered in polyethylene glycol (PEG) 300 or dimethyl sulfoxide (DMSO), respectively] in female mice (groups of four) was 37 and 38 mg kg after 7 days, and 8 and 10 mg kg  

Lethality. Dacre and Goldman reported the percutaneous LD50 of SM to be 9 mg kg in the rat, 92 mg kg in the mouse, 20 mg kg in the dog, -100 mg kg in the rabbit, 20 mg kg in the guinea pig and 50 mg kg in the goat, although they do not quote the source for these estimates or the time after exposure when the estimates were made, and no details of the cause of death are given Le. systemic toxicity or as a result of skin injury). 

Sublethal Pathology. Venkateswaran et al7 investigated the systemic effects of sublethal percutaneous doses of SM (3.88, 7.75 or 15.5 mg kg in olive oil applied over a 1 cm area of close clipped skin) in groups of at least six mice. The authors do not describe precautions to prevent ingestion or the housing conditions of the animals after dosing. Animals were observed 

The differences in the onset times of various pathologies in different animal studies are probably due to the differences in doses and susceptibility of different species. 

A Textbook of Modern Toxicology, Third Edition, edited by Ernest Hodgson ISBN 0-471-26508-X Copyright 2004 John Wiley Sons, Inc. 

An additional consideration is noteworthy when comparing acute and chronic toxicity. All chemicals elicit acute toxicity at a sufficiently high dose, whereas all chemicals do not elicit chronic toxicity. Paracelsus often cited phrase all things are poison. .. the dose determines. .. a poison is clearly in reference to acute toxicity. Even the most benign substances will elicit acute toxicity if administered at a sufficiently high dose. However, raising the dose of a chemical does not ensure that chronic toxicity will ultimately be attained. Since chronic toxicity typically occurs at dosages below those 

LD50 is the dose that is lethal to 50 percent of the test animals LC50 is the concentration that is lethal to 50 percent of the test animals.  

Sensitization and irritation observed during acute toxicity studies may also be reportable. 

The available LDso data do not indicate marked differences in susceptibility between species (Tables 1-3). 

Studies in rabbits show that the ASC germicidal gel product and/or sodium chlorite have the potential to cause skin and eye irritation (Abdel-Rahman et al., 1982b Seta et al., 1991). A sensitization test of the germicidal liquid and gel in guinea-pigs involved intradermal injection of an initial dose of 50 mg followed by nine injections of 100 mg of each test substance over a period of 3 weeks. No sensitization effects were seen. Necrosis was seen following injection of the 

Species Sex Route (forni) LDso (mg chlorite/kg bw) Reference 

Rat Male Oral (liquid gennicidal 292 Abdel-Rahman et al. 

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I6I C. Warfarin baits need contain only 0 025% active principle, and rats are killed after ingesting about 5 doses the bait can be left down and the risk of acute toxicity to man or domestic animals is not serious. In common with other coumarin derivatives, warfarin reduces the clotting power of blood and death is caused by haemorrhages initiated by any slight injury. Warfarin is a vitamin K antagonist, and large oral doses of the vitamin can be given as an antidote. 

Lanthanum and its compounds have a low to moderate acute toxicity rating therefore, care should be taken in handling them. 

Neodymium has a low-to-moderate acute toxic rating. As with other rare earths, neodymium should be handled with care. 

Pure holmium has a metallic to bright silver luster. It is relatively soft and malleable, and is stable in dry air at room temperature, but rapidly oxidizes in moist air and at elevated temperatures. The metal has unusual magnetic properties. Few uses have yet been found for the element. The element, as with other rare earths, seems to have a low acute toxic rating. 

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 5. Acute Toxicity of Acrylic Acid and Esters...

With respect to acute toxicity, based on lethaHty in rats or rabbits, acryhc monomers are slightly to moderately toxic. Mucous membranes of the eyes, nose, throat, and gastrointestinal tract are particularly sensitive to irritation. Acrylates can produce a range of eye and skin irritations from slight to corrosive depending on the monomer. 

The toxicides of acrylic monomers range from moderate to slight. In general, they can be handled safely and without difficulty by trained personnel following estabhshed safety practices. Table 5 summarizes investigations of the toxicity of the common acrylic monomers in animals under acute toxicity conditions (67). 

In general, the acute toxicity of halogenated flame retardants is quite low. Tables 11—14 contain acute toxicity information from various manufacturers material safety data sheets (MSDS) for some of the flame retardants and intermediates Hsted in the previous tables. The latest MSDS should always be requested from the suppHer in order to be assured of having up-to-date information about the toxicity of the products as well as recommendations regarding safe handling. 

Environmental Considerations. The phosphate flame retardants, plasticizers, and functional fluids have come under intense environmental scmtiny. Results pubUshed to date on acute toxicity to aquatic algae, invertebrates, and fish indicate substantial differences between the various aryl phosphates (159—162). The EPA has summarized this data as well as the apparent need for additional testing (147). 

Mycotoxias fiad thek way kito the human diet by way of mold-contaminated cereal and legume crops, meat, and milk products. Com and peanuts probably represent the most common sources of mycotoxias ki the human diet. Many mycotoxias are acutely toxic as well as being poteat carckiogeas (86). 

Cyasin, a component of the nut of the cycad tree, a native of tropical environs, produces an acute toxicity in addition to drastically increasing the incidence of Lou Gerhig s disease (amyotropic lateral sclerosis). Cyasin is carcinogenic (102). 

The acute toxicity of DMF is relatively low. The LD q by oral ingestion ia rats is 2800 mg/kg and the LC for mice is 9400 mg/(2 h). Skin absorption is also an important route by which DMF can be iatroduced iato the body, and an LD q of 4720 mg/kg has been observed ia rabbit-skia exposure studies. 

Toxicity. Acute toxicity data for neopentyl glycol (1) are reported in Table 2. 

Toxicity. Acute toxicity data are reported ia Table 2 (11). 

Eastman Chemical Co., BASF, Mitsubishi Gas, and Union Carbide are manufacturers of this glycol. The U.S. price in June 1993 was 2.97/kg. Toxicity. Acute toxicity data for (9) appear in Table 2. 

The mode of action has not yet been elucidated but the manufacturer states that it probably behaves like the herbicide triflurolin and its congeners. These materials inhibit cell division by binding to tubuHn thereby internipting micro-tubule development. This, in turn, stops spindle fiber formation essential to mitosis and cell division. Experiments with C-labeled Prime+ show that it is acutely toxic to fish with estimated LC q (96 h) of less than 100 ppb for rainbow trout and bluegiU. sunfish. However, channel catfish did not exhibit any toxic response at the maximum attainable water concentration (10). 

Dihydroxybenzenes (DHBs) are slightly more acutely toxic than phenol (Table 5). Contact with dihydroxybenzene through oral, dermal, or respiratory routes can induce significant systemic exposure. Skin or eye effects have been demonstrated during chronic or accidental professional exposure. No systemic effect has been described in such circumstances. 

Since diketene is a strong eye irritant even at low levels, it has a strong warning effect. Diketene becomes unbearable before acute toxic levels are reached. Due to the risk of delayed lung edema, a physician should be consulted and the patient monitored carefully after exposure. 

Health nd Safety Factors. Isophorone is considered moderately toxic by ingestion and skin contact. Some rat tumor formation evidence has been found (264), but no demonstration as a human carcinogen has been proven. Isophorone is considered an Environmental Protection Agency (EPA) priority pollutant, and has a permissible acute toxicity concentration of 117, 000 ///L to protect freshwater aquatic life, 12, 900 ///L to protect saltwater aquatic life, and 5, 200 ///L to protect human life (265). Isophorone is mildly toxic by inhalation, but because of its low volatiUty it is not a serious vapor hazard. 

Human and animal studies indicate that inorganic manganese compounds have a very low acute toxicity by any route of exposure. The toxicity values for a given Mn compound are shown in Table 20 to depend on the species of test animal as well as the route of exposure. Manganese concentrations as high as 2000 ppm were found to be tolerated by test animals over a six-month period without any ill effects (208). 

Table 8. Acute Toxicity of Methacrylate and Related Monomers...

Methanol is not classified as carcinogenic, but can be acutely toxic if ingested 100—250 mL may be fatal or result in blindness. The principal physiological effect is acidosis resulting from oxidation of methanol to formic acid. Methanol is a general irritant to the skin and mucous membranes. Prolonged skin contact with methanol vapor or Hquid can cause dermatitis. Methanol vapor can cause eye and respiratory tract irritation, nausea, headaches, and dizziness. 

Toxicity. Many /V-nitrosamines are toxic to animals and cells in culture (4,6—8,88). /V-Nitrosodimethy1amine [62-75-9] (NDMA) is known to be acutely toxic to the Hver in humans, and exposure can result in death (89). Liver damage, diffuse bleeding, edema, and inflammation are toxic effects observed in humans as a result of acute and subacute exposure to NDMA. These effects closely resemble those observed in animals dosed with NDMA (89,90). 

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