Toxicity anilines

Some of these differences can be attributed to variations in detoxication mechanisms. For example, the loss of consciousness induced in several species of laboratory animals by hexobarbital (a barbiturate derivative that depresses the central nervous system (CNS)) shows marked differences these are attributable to the activity of the detoxication enzyme that inactivates this chemical. In the mouse, the activity of the detoxifying enzyme is 16-fold greater than that in the dog, which is reflected by 12 min of hexobarbital-induced sleep in the mouse versus 315 min of sleep in the dog. There are other examples of species-related differences in the ability to detoxify chemicals that consequently result in differences in toxicity. Other examples include the industrial chemicals, ethylene glycol and aniline. Ethylene glycol is metabolized to oxalic acid, which is responsible for its toxicity, or to carbon dioxide. The rank order of ethylene glycol toxicity in animals is as follows cat rat rabbit this is the same for the extent of oxalic acid production. Aniline is metabolized in the cat and dog mainly to o-aminophenol, and these species are more prone to toxicity however, in the rat and hamster aniline is metabolized mainly to I-aminophenol and thus these species are less susceptible to aniline toxicity. 

Other Reactants. Other reactants are used in smaller amounts to provide phenoHc resins that have specific properties, especially coatings appHcations. Aniline had been incorporated into both resoles and novolaks but this practice has been generally discontinued because of the toxicity of aromatic amines. Other materials include rosin (abietic acid), dicyclopentadiene, unsaturated oils such as tung oil and linseed oil, and polyvalent cations for cross-linking. 

Based on tests with laboratory animals, aniline may cause cancer. The National Cancer Institute (NCI) and the Chemical Industry Institute of Toxicology (CUT) conducted lifetime rodent feeding studies, and both studies found tumors of the spleen at high dosage (100 —300 mg/kg pet day of aniline chloride). CUT found no tumors at the 10—30 mg/kg per day feeding rates. The latter value is equivalent to a human 8-h inhalation level of 17—50 ppm aniline vapor. In a short term (10-d) inhalation toxicity test by Du Pont, a no-effect level of 17 ppm aniline vapor was found for rats. At high levels (47—87 ppm), there were blood-related effects which were largely reversible within a 13-d recovery period (70). 

Vulcanization was first reported in 1839 with the discovery that heating natural mbber with sulfur and basic lead carbonate produced an improvement in physical properties (2). In 1906, aniline was the first organic compound found to have the abiUty to accelerate the reaction of sulfur with natural mbber (3). Various derivatives of aniline were soon developed which were less toxic and possessed increased acceleration activity. 

Non-basic materials, including nitro compounds were removed from aniline in 40% H2SO4 by passing steam through the soln for Ih. Pellets of KOH were added to liberate the aniline which was steam distd, dried with KOH, distd twice from zinc dust at 20mm, dried with freshly prepared BaO, and finally distd from BaO in an allglass apparatus [Few and Smith J Chem Soc 753 7949]. Aniline is absorbed by skin and is TOXIC... 

Propidium iodide (3,8-diamino-5-(3-diethylaminopropyl)-6-phenylphenantridinium iodide methiodide) [25535-16-4] M 668.4, m 210-230 (dec), pKeskd 4 (aniline NH2), pKesi(2) (EtN2). Recrystd as red crystals from H2O containing a little KI. It fluoresces strongly with nucleic acids. [Eatkins J Chem Soc 3059 7952.] TOXIC. 

NOTE - Petrochemical plants also generate significant amounts of solid wastes and sludges, some of which may be considered hazardous because of the presence of toxic organics and heavy metals. Spent caustic and other hazardous wastes may be generated in significant quantities examples are distillation residues associated with units handling acetaldehyde, acetonitrile, benzyl chloride, carbon tetrachloride, cumene, phthallic anhydride, nitrobenzene, methyl ethyl pyridine, toluene diisocyanate, trichloroethane, trichloroethylene, perchloro-ethylene, aniline, chlorobenzenes, dimethyl hydrazine, ethylene dibromide, toluenediamine, epichlorohydrin, ethyl chloride, ethylene dichloride, and vinyl chloride. 

Cerniglia CE, IP Ereeman, C van Baalen (1981) Biotransformation and toxicity of aniline and aniline derivatives in cyanobacteria. Arch Microbiol 130 272-275. 

N-Hydroxylation of aniline and 4-chloroaniline by rainbow trout to hydroxylamines that could plausibly account for the subchronic toxicity of the original compounds (Dadyetal. 1991). 

Tabuenca JM (1981) Toxic-allergic syndrome caused by ingestion of rapseed oil denatured with aniline. Lancet 318(8246) 567-568... 

The disulphonated DAST derivative 11.25 containing four anilino groups per molecule is effective in liquid detergent formulations and much cheaper to manufacture than the monosulphonated DAST brightener 11.67, which was withdrawn from the market in the late 1980s. It has been necessary to purify compound 11.25 specially for use in detergents, in order to eliminate traces of residual unreacted aniline as far as possible, owing to the toxic properties of this impurity. 

Aniline, which is used not only to synthesise drugs, pesticides and explosives but also as a building block for materials such as polyurethane foams, rubber, azo dyes, photographic chemicals and varnishes, is manufactured at a quantity of approximately three million tons each year [61]. The toxic effects of aniline include increased nitration of proteins in the spleen [62]. 

The presence of chemically reactive structural features in potential drug candidates, especially when caused by metabolism, has been linked to idiosyncratic toxicity [56,57] although in most cases this is hard to prove unambiguously, and there is no evidence that idiosyncratic toxicity is correlated with specific physical properties per se. The best strategy for the medicinal chemist is avoidance of the liabilities associated with inherently chemically reactive or metabolically activated functional groups [58]. For reactive metabolites, protein covalent-binding screens [59] and genetic toxicity tests (Ames) of putative metabolites, for example, embedded anilines, can be employed in risky chemical series. 

Several studies with rats support the AEGL-3 values. A 10-min exposure to aniline at 15,302 ppm resulted in no toxic effects, and a 4-h exposure at 359 ppm resulted in severe toxic effects but no deaths. Dividing these values by a total uncertainty factor of 100 and scaling across time using C%t=k results in values similar to those derived from the Kim and Carlson (1986) study. Studies with repeated exposures of rats resulted in additional effects on the blood and spleen, but concentrations up to 87 ppm, 6 h/d, 5 d/w for 2 w were not disabling or life-threatening. 

The derived AEGLs are listed in Table 1-1. Because aniline is absorbed through the skin in quantities sufficient to induce systemic toxicity, a skin notation was added to the summary table. The reported odor threshold for aniline ranges from 0.012 to 10 ppm. Therefore, the odor of aniline will be noticeable by most individuals at the AEGL-1 concentrations. The odor is somewhat pungent but not necessarily unpleasant. 

Aniline may be absorbed following inhalation, ingestion, and dermal exposures. The inhalation toxicity of aniline was studied in several animal species, but only one study that utilized multiple exposure concentrations for sublethal effects was located. Data from human studies lack specific details or exposures... 

No developmental and reproductive toxicity data on humans concerning aniline were identified in the available literature. 

Human toxicity data are limited to secondary citations. Because these citations provided no experimental details, they cannot be considered reliable. Deaths have occurred from aniline ingestion and skin absorption, but doses were unknown. Reviews of the older literature indicate that a concentration of 5 ppm was considered safe for daily exposures, concentrations of 7 to 53 ppm produced slight symptoms after several hours, a concentration of 40 to 53 ppm was tolerated for 6 h without distinct symptoms, a concentration of 130 ppm may be tolerated for 0.5 to 1 h without immediate or late sequalae, and 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemoglobin levels of up to 72% were measured. Recoveries occurred with a minimum of medical intervention following cessation of exposure. 

Oberst et al. (1956) exposed nine male Wistar rats to aniline at 5 ppm for 6 h/d, 5 d/ w for up to 26 w. Exposed rats developed a mild hemoglobinemia (0.6%) with some blueness of the skin during w 23 of exposure. Based on the slight increase of methemoglobin content and the absence of spleen toxicity, U.S. EPA (1994) considered this concentration a free-standing no-observed-adverse-effect level (NOAEL). 

No studies addressing developmental or reproductive effects following acute inhalation exposure to aniline were located. However, because effects on development and reproduction arise after systemic uptake, oral administration of aniline can be considered for evaluating potential developmental and reproductive toxicity. Aniline (administered as aniline hydrochloride) readily crosses the placental barrier in rodents (Price et al. 1985). 

---