Epoxides, toxic

RambeckB, Salke-Treumann A, May T, BoenigkHE. Valproicacid-inducedcarbamazepine-10,11-epoxide toxicity in children and adolescents. Eur Neurol (1990) 30, 79-83. 

Pyrethroids from Chiysanthemic Acid. The unsaturated side chains of the aHethrolone alcohol moieties of the natural pyrethrins are readily epoxidized by microsomal oxidases and converted to diols, thus detoxifying the insecticides. Esterification of chrysanthemic acid (9), R = CH3, with substituted ben2yl alcohols produces usehil insecticides barthrin [70-43-9J, 2-chloro-3,4-methylenedioxyben2yl (+)-i7j ,/n7 j -chrysanthemate, and dimethrin [70-38-2] 2,4-dimethylben2yl (+)-i7j ,/n7 j -chrysanthemate. These have alimited spectmm of insecticidal activity but are of very low mammalian toxicity, ie, rat oralLD s >20,000 mg/kg. 

Endrin [72-20-8] is l,2,3,4,10,10-hexachloro-l,4,4t ,5,8,8t -hexahydro-6,7-epoxy-l,4- <7o, <7o-5,8-dimethanonaphthalene (35) (mp 245 dec, vp 0.022 mPa at 25°C) and is soluble in water to 23 / g/L. It is produced by a Diels-Alder reaction of hexachloronorbomadiene with cyclopentadiene, followed by epoxidation. This reaction produces the endo,endo isomer of dieldrin, which is less stable and more toxic with rat LD q values of 17.8 and 7.5 (oral) and 15 (dermal) mg/kg. It is used as a cotton insecticide but because of its high toxicity to fish it has been restricted. 

Arsenic Peroxides. Arsenic peroxides have not been isolated however, elemental arsenic, and a great variety of arsenic compounds, have been found to be effective catalysts ia the epoxidation of olefins by aqueous hydrogen peroxide. Transient peroxoarsenic compounds are beheved to be iavolved ia these systems. Compounds that act as effective epoxidation catalysts iaclude arsenic trioxide, arsenic pentoxide, arsenious acid, arsenic acid, arsenic trichloride, arsenic oxychloride, triphenyl arsiae, phenylarsonic acid, and the arsenates of sodium, ammonium, and bismuth (56). To avoid having to dispose of the toxic residues of these reactions, the arsenic can be immobi1i2ed on a polystyrene resia (57). 

Dmg metaboHsm may also produce toxic materials. Thus, the aromatic hydroxylation of hydrocarbons such as ben2pyrene produces the highly reactive and carcinogenic 1,2-epoxides. 

The majority of 2-methylphenol is used in the production of novolak phenoHc resins. High purity novolaks based on 2-methylphenol are used in photoresist appHcations (37). Novolaks based on 2-methylphenol are also epoxidized with epichlorohydrin, yielding epoxy resins after dehydrohalogenation, which are used as encapsulating resins in the electronics industry. Other uses of 2-methylphenol include its conversion to a dinitro compound, 4,6-dinitro-2-methylphenol [534-52-1] (DNOC), which is used as a herbicide (38). DNOC is also used to a limited extent as a polymerization inhibitor in the production of styrene, but this use is expected to decline because of concerns about the toxicity of the dinitro derivative. 

Molybdenum hexacarbonyl [Mo(CO)6] has been vised in combination with TBHP for the epoxidation of terminal olefins [44]. Good yields and selectivity for the epoxide products were obtained when reactions were performed under anhydrous conditions in hydrocarbon solvents such as benzene. The inexpensive and considerably less toxic Mo02(acac)2 is a robust alternative to Mo(CO)6 [2]. A number of different substrates ranging from simple ot-olefms to more complex terpenes have been oxidized with very low catalytic loadings of this particular molybdenum complex (Scheme 6.2). The epoxidations were carried out with use of dry TBHP (-70%) in toluene. 

Toxicity. The peroxy acid is highly toxic and may cause death or permanent injury after very short exposure to small quants (Ref 12) Uses. Peroxyacetic acid is the most important epoxidation reagent used today because of its economical availability and ease of use with a wide variety of reactants (Ref 10). It also finds wide usage as an organic oxidizing agent (Ref 11) Refs 1) Beil 2, 169, (78), [174] [379 ... 

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Thus, as with studies on the double-crested cormorant in the Great Lakes (see Chapter 16 in Walker et al. 2006), there is evidence of a continuing (although reduced) effect of p,p -DDE on reproductive success even after environmental levels had fallen and eggshell thinning was much less. This raises the possibility that p,p -DDE may have had toxic effects other than eggshell thinning on these species (Nisbet 1989). There is the further complication that other OCs such as PCBs, dieldrin, and hep-tachlor epoxide were present in the same samples and may have had toxic effects. 

As mentioned earlier (Figure 5.5), aldrin and heptachlor are rapidly metabolized to their respective epoxides (i.e., dieldrin and heptachlor epoxide) by most vertebrate species. These two stable toxic compounds are the most important residues of the three insecticides found in terrestrial or aquatic food chains. In soils and sediments, aldrin and heptachlor are epoxidized relatively slowly and, in contrast to the situation in biota, may reach significant levels (note, however, the difference between aldrin and dieldrin half-lives in soil shown in Table 5.8). The important point is that, after entering the food chain, they are quickly converted to their epoxides, which become the dominant residues. 

Luo W, Fan W, Xie H, ling L, Ricicki E, Vouros P, et al. Phenotypic anchoring of global gene expression profiles induced by A -hydroxy-4-acetylaminobiphenyl and benzo[a]pyrene diol epoxide reveals correlations between expression profiles and mechanism of toxicity. Chem Res Toxicol 2005 18 619-29. 

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