Acute Mammalian Toxicity

There is a substantial body of government literature for CK. Toxicity studies have been driven by its potential as a war gas. While these data are no longer classified, they are not generally available. Accordingly, those studies are summarized below and relevant data are presented for the general audience. 

For this chapter, a total of 89 individual median lethal IH dosages (LCtso) and 16 PSs were found and/or calculated (see Section 9.6). Every attempt was made to identify and remove duplicate data points. Data from anesthetized animals were not used (when known). The following is a breakdown of this database, collected or calculated from 16 studies/sources dating back to WWI  

In addition to the UK and US research, toxicity data were also reported by Flury and Zernick (1931). However, their data were not used in the present 

S This was particularly a problem for studies where there were numerous progress reports before the publication of the final report. 

Species Method PS PS SE Groups Total Time tVf min m ) m- ) LD50 (mg) Weight 

---

Substances with very high acute mammalian toxicity Substances with very high acute or chronic aquatic toxicity Neurotoxins... 

BallantyneB, Swanston DW The comparative acute mammalian toxicity of 1-chloroace-tophenone (CN) and 2-chlorobenzylidene malononitrile (CS). Arch Toxicol 40 75-95, 1978... 

Among the different classes of organic insecticides in use today, the methylcarbamate esters rank at or near the top in acute mammalian toxicity and in many cases the methylcarbamates are as toxic to mammals as they are to insects O). For... 

Another example of this conversion of P=S found in pesticides to P = 0 is the oxidation of malathion in the atmosphere. Malathion itself is not a HAP and has relatively low acute mammalian toxicity because it is degraded by mammalian carboxylesterases. It is effective as a pesticide because in insects, it is activated to malaoxon, an acetylcholinesterase inhibitor. However, malathion itself typically contains impurities such as isomalathion whose mammalian toxicities are greater... 

Cholinesterase inhibitor. High acute mammalian toxicity. LD50 (oral, rats) 300-850 mg/kg. LC50 (rainbow trout, 96 hours) 380 ppb.3 Toxic to bees, fish and other animals. If taken internally will cause headaches, giddiness, blurred vision, nervousness, weakness, nausea, cramps, diarrhea, discomfort in the chest, sweating, pinpoint pupils, tearing, salivation, and vomiting.2 TLV-TWA 0.1 mg/m3.4... 

LD50 (oral mice) 3500 mg/kg.2 LD50 (oral rat) 4000 mg/kg.2 LC50 (rainbow trout, 96 hours) 6.7 mg/L.3 Very low, acute mammalian toxicity. Avoid inhaling mist. A mild eye irritant.1... 

Cronin, M.T.D. and Dearden, J.C. (1995b). QSAR in Toxicology. 2. Prediction of Acute Mammalian Toxicity and Interspecies Correlations. Quant.Struct.-Act.Relat., 14,117-120. 

Eldred, D.V. and Jurs, P.C (1999a). Prediction of Acute Mammalian Toxicity of Organophos-phorus Pesticide Compounds from Molecular Structure. Chem.Res.ToxicoL, 10,75-99. 

Cronin MTD. Dearden JC. QSAR in toxicology 2. Prediction of acute mammalian toxicity and interspecies correlations. Quant Struct-Act Rel 1995 14(2) 117-20. 

Eldred DV, Jurs PC. Prediction of acute mammalian toxicity of organophosphorus pesticide compounds from molecular structure. SAR QSAR Environ Res 1999 10 75-99. 

Pyrethroid insecticides (deltamethrin, NRDC 157, cismethrin), DDT analogs ( p,j> -DDT, (>,j> -DDT, methoxychlor, EDO), and a DDT-pyrethroid hybrid compound (GH401) enhanced veratridine-dependent sodium uptake by mouse brain synaptosomes The effectiveness of these compounds in the sodium uptake assay was in good agreement with their acute mammalian toxicities. , -DDT also enhanced veratridine-dependent sodium uptake by fish brain synaptosomes These findings demonstrate the utility of ion flux assays to study interactions of insecticides with sodium channels in the central nervous system and to explore species differences in insecticide target site sensitivity ... 

Dilley JV, Tyson CA, and Newell GW, Mammalian Toxicological Evaluation of TNT Waste Waters. Volume 11 Acute and Sub Acute Mammalian Toxicity of TNT and the LAP Mixture, SRI International Menlo Park, CA, Contract No. DAMD17-76-C-6050, Report No. ADA 080957, U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, MD, 1978. 

Pretilachlor has a low level of acute mammalian toxicity. Acute oral ld jg for rats is 6099 mg/kg. 

DPX-T 6376 has a low order of acute mammalian toxicity. The acute oral to... 

Ballantyne, B. and Swanston, D.W., The comparative acute mammalian toxicity of... 

Bruce DW, Hiltbrink BE and DeBois KP (1963) The acute mammalian toxicity of rare earth nitrates and oxides. Toxicol Appl Pharmacol 5 750—759. 

In the Green Screen the hazards of a chemical are defined by its potential to cause acute or chronic adverse effects in humans or wildlife, its fate in the environment, and certain physi-cal/chemical properties of concern to human health. Acute mammalian toxicity (lethality) and irritation of the skin or eye are examples of acute adverse effects that can result from inhalation, ingestion, or dermal contact with a chemical. Chronic effects occur after repeated exposures and include cancer and adverse effects to the reproductive, neurological, endocrine, or immune systems. 

In the patent literature, many claims and some data can be found about insecticidal and acaricidal activities of strobilurins. Attempts to optimize insecticidal performance did not lead to a commercial product. It seems that, with strobilurins, sufficient insecticidal activity can only be obtained if the compound has very high lipophilicity and very high metabolic stability. This combination of properties gave numerous compounds with excellent insecticidal activity but also with unacceptably high acute mammalian toxicity, so that candidates were abandoned rather early in the research phase. It seems impossible to separate the tight connection between insecticidal and mammalian toxicity in this particular case. Similar problems have been reported for respiration inhibitors of Complex I [82a]. 

Mammalian Toxicology (Table 29.2.3.9) Thiamethoxam (13) is rapidly and completely absorbed and readily eliminated predominantly as parent through the urine. It has low acute mammalian toxicity when applied to rats either orally (LDso = 1563 mg kg ), dermally (LD50 > 2000 mg kg ) or by inhalation [LC50 (4 h) = >3720 mg m j, putting it into WHO hazard class III. Thiamethoxam (13) was found non-irritant to skin and eyes and devoid of a skin sensitizing potential [13, 36, 37]. 

Table 30.1.5 shows the safety profile of pymetrozine (1) it has a low acute mammalian toxicity and an excellent safety profile for most non-target arthropods, birds, and fish. Pymetrozine (1) is of low risk to beneficial insects in the field and is therefore very well suited for use in IPM programs [1-4, 27, 35]. 

The main problem with applying QSAR techniques to data on acute mammalian toxicity is the generally composite nature of the observed effects of the contaminants the chemicals may affect various sites in different ways and be influenced by metabolic activation and deactivation. These concurrent processes may differ, even among series of apparently homologous compounds, not only in their relative contributions to the overall effect, but also in their qualitative nature. When this complex situation is rated by a single parameter, such as an LD50, this measure will not represent a single well-defined interaction or endpoint as is a prerequisite for sound QSARs. 

In the rat, the observed effects of oral LD50 reflect both the intrinsic toxicity at the ultimate biophase site of action and the factors influencing distribution, membrane transport, protein binding, metabolism and excretion. The manifestation of acute mammalian toxicity is hence a much more complex response than can be described with the use of log alone, although individual processes such as bioavailability and adsorption depend on lipophilic-ity. The fit to a common QSAR model requires that each of these processes has similar structural dependences, qualitatively and quantitatively, within a given class of compounds. If a different process becomes predominant (i.e. rate limiting), the structure-toxicity relationship must alter thus the compound will be an outlier even when the principal mechanism of intrinsic toxicity remains the same. 

Table 5.13 Examples of QSAR models for estimating acute mammalian toxicity after oral administration of toxicants log LD5Q correlations with various parameters... 

Synthesised commercially from glucose. Used in amine resolution and as a precursor in vitamin C synth. Inexpensive starting material for chiral syntheses. Antilipidaemic, low acute mammalian toxicity. Monohydrate. Mp 103° dec. Mg -21.6 (c, 2.28 in MeOH). Log P 0.34 (calc). 

Table 1. Acute Mammalian Toxicities for Encapsulated and EC Formulations of Methyl Parathion and Diazinon ...

In the second half of the past centnry, synthetic insecticides became much more important mainly due to reduced acute mammalian toxicity. Nevertheless nicotine formnlations are still nowadays nsed widely throughout the world as relatively cheap insecticides (Domino 1999). Recently, dispersions of nicotine oleate (oil phase-integrated) stabilized by sodinm caseinate (aqueous solution) and similar emulsions of different nicotine salts with Tween 80 as an emulsifier have been proposed as formulations for botanical insecticides with reduced mammalian toxicity (Casanova et al. 2005 and references therein)... 

Johnson, S. R. and Jurs, P. C. (1997) Prediction of acute mammalian toxicity from molecular structure for a diverse set of substituted anilines using regression analysis and computational neural networks. Comput. Assist. Lead Find. Optim., [Eur. Symp. Quant. Structure-Activity Relationships QSAR and Molecular Modeling], 11th, pp. 31 8, Lausanne, Switzerland. 

---