Cresol toxicity

The National Toxicology Program (NTP) is performing subchronic tests of cresol toxicity in which either o-cresol or mixed cresol isomers are given to rats and mice in the feed. In addition, studies of the effects of cresols on reproduction and fertility in mice are being performed by the NTP. The results of these studies are not yet available. 

Cresol (toxic and volatile Handle it, and all solutions containing it, in a fume hood). 11 Sephadex G-15 (Pharmacia, Uppsala, Sweden)... 

Triaryl phosphates are produced from the corresponding phenols (usually mixtures) by reaction with phosphoms oxychloride, usually in the presence of a catalyst (94—96). They are subsequently distilled and usually washed with aqueous bases to the desired level of purity. Tricresyl phosphate was originally made from petroleum-derived or coal-tar-derived cresyflc acids, ie, cresols, variously admixed with phenol and xylenols. Discovery of the toxicity of the ortho-cresyl isomers led manufacturers to select cresols having very Httle ortho-isomer. 

A particular mode of neurotoxicity was discovered for tricresyl phosphate that correlated with the presence of the o-cresyl isomer (or certain other specific aLkylphenyl isomers) in the triaryl phosphates. Many details of the chemistry and biochemistry of the toxic process have been elucidated (139,140,143—146). The use of low ortho-content cresols has become the accepted practice in industrial production of tricresyl phosphate. Standard in vivo tests, usually conducted with chickens sensitive to this mode of toxicity, have been developed for premarket testing of new or modified triaryl phosphates. As of 1992, the EPA called for extensive new toxicity and environmental data on this group of products (147). The Vederal e ster AoQ xm. ci. calling for this... 

Triaryl phosphates are produced by reaction of phosphoms oxychloride with phenoHc compounds at 100—200°C with magnesium or aluminum chloride catalyst. Past use of cresols and xylenols from coal tar or petroleum is replaced for lower toxicity and cost by synthetic phenoHcs, primarily isopropyl phenol, /-butyl phenol, and phenol itself A range of viscosities is achieved by selection and proportioning of the phenols and their isomers used for the starting material. 

Phenol. Phenol monomer is highly toxic and absorption by the skin can cause severe blistering. Large quantities can cause paralysis of the central nervous system and death. Ingestion of minor amounts may damage kidneys, Hver, and pancreas. Inhalation can cause headaches, dizziness, vomiting, and heart failure. The threshold limit value (TLV) for phenol is 5 ppm. The health and environmental risks of phenol and alkylated phenols, such as cresols and butylphenols, have been reviewed (66). 

Solubility and Solvent Resistance. The majority of polycarbonates are prepared in methylene chloride solution. Chloroform, i7j -l,2-dichloroethylene, yy -tetrachloroethane, and methylene chloride are the preferred solvents for polycarbonates. The polymer is soluble in chlorobenzene or o-dichlorobenzene when warm, but crystallization may occur at lower temperatures. Methylene chloride is most commonly used because of the high solubiUty of the polymer (350 g/L at 25°C), and because this solvent has low flammabiUty and toxicity. Nonhalogenated solvents include tetrahydrofuran, dioxane, pyridine, and cresols. Hydrocarbons (qv) and aUphatic alcohols, esters (see Esters, organic), or ketones (qv) do not dissolve polycarbonates. Acetone (qv) promotes rapid crystallization of the normally amorphous polymer, and causes catastrophic failure of stressed polycarbonate parts. 

Fire Hazards - Flash Point (deg. F) 175 - 185 OC 178 CC Flammable Umits in Air (%) LEL 1.4 (ortho) 1.1 (meta or para) Fire Extinguishing Agents Water, dry chemical, carbon dioxide, and foam Fire Extinguishing Agents Not To Be Used Not pertinent Special Hazards of Combustion Products Flammable toxic vapors given off in a fire Behavior in Fire Sealed closed containers can build up pressure if exposed to heat (fire) Ignition Temperature (deg. f) 1110 (o-cresol) 1038 (m-or p-cresol) Electrical Hazard Data not available Burning Rate Data not available,... 

Cresol is a toxic chemical that can be absorbed via the skin and may cause damage to the kidney, the liver, and nervous system. The objective of this problem is to reduce cresol concentration in any discharged wastewater stream to 5 ppraw or less. 

When some values seem questionable a question mark in brackets is added next to these values. If two very different values are given for one substance the doubtful data source is noted. For instance, for o-cresol, two LD50 values for the rat orally are mentioned as follows LD50 o-r 121 1350 (Merck). This means that the 1350 value that seems high and that applies to a phenol that is particularly corrosive and toxic (see Code du travail (ie Labour Code)) was suggested by the Merck Index. 

In view of the greater toxicity often observed with derivatives of o-cresol compared with derivatives of phenol itself, it seemed worth while to prepare di-(o-methylcycZohexyl) phosphoro-fluoridate. At a concentration of 0-65 mg./l. only three out of a batch of twenty-three animals (rabbits, guinea-pigs, rats and mice) were killed. The animals which died (the rabbits) exhibited muscular twitchings, but myosis was not very marked. 

In Australian tenebrionid beetles, defensive compounds and their patterns seem to be of only low chemotaxonomic value. However, the aforementioned aromatic compounds are restricted to the genus Tribolium. Abdominal defensive compounds were used as chemosystematic characters in order to construct a phylogenetic tree for the genus Tribolium [330]. The defensive secretion of adults of Tenebrio molitor was shown to contain toluquinone 7 and m-cresol 89 [333]. The quantification of benzoquinones in single individuals of Tribolium castaneum at different days after adult eclosion indicates that the amount of toxic quinone only shows a maximum subsequent to cuticle sclerotization. Obviously, there is a need for an adequate cuticular barrier for self-protection from these defensive compounds [334]. 

The phenolic functional group consists of a hydroxyl attached directly to a carbon atom of an aromatic ring. The OH group can also be the consequence of further oxidation or combination with other pollutants such as pesticides, aldehydes, and alcohols (i. e., 2,4-D, cyclic alcohols, cresols, naphthols, quinones, nitrophenols, and pentachlorophenol compounds) forming new more toxic compounds [17,42,160]. 

Deichmann WB, Witherup S. 1944. Phenol studies. VI The acute and comparative toxicity of phenol and o-, m-, and/ -cresols for experimental animals. J Pharmacol Exp Ther 80 233-240. 

Hattula. M.L., Reunanen, H., and Arstila. A.U. Toxicity of 4-chloro-o-cresol to rat light microscopy and chemical observations. Bull. Environ. Contam. Toxicol, 21(4/5) 492-497,1979. 

Several cases of ingestion have shown cresol to be corrosive to body tissues and to cause toxic effects on the vascular system, liver, kidneys, and pancreas. ... 

In rat liver tissue, p-cresol was 5- to 10-fold more toxic than the o- or -isomers as determined by the degree of cell killing. Furthermore, the toxicity ofp-cresol was dependent on the formation of a reactive intermediate, and it was suggested that the mechanism of toxicity for p-cresol may differ from that of the o- and 7 -isomers. 

Agency or Toxic Substances and Disease Registry (AFSDR) Toxicological Profile for Cresols o-Cresol, p-Cresol, m-Cresol. US Department of Flealth and Fluman Services, Public Flealth Service, TP-91/11, 148pp, 1992... 

Thompson DC, Perera K, Fisher R, et al Cresol isomers comparison of toxic potency in rat liver slices. Toxicol Appl Pharmacol 125 51-58, 1994... 

Toxicology. 2,6-Di-tert-butyl-p-cresol or BHT is of relatively low acute toxicity in animals, and there is no evidence of either acute or chronic effects among exposed workers. 

Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for Dinitro-cresols, 175pp. Atlanta, GA, US Dept of Health and Human Services, Public Health Service, 1995... 

Toxieology. 4,4 -Thiobis(6-rrrr-butyl-w-cresol) (TBBC) is of low systemic toxicity in animals allergic contact dermatitis has been reported in humans. 

There are three isomers of cresol o-cresol, p-cresol, and m-cresol. These are described in detail in Chapter 3. In the following discussion, the effects of o-cresol and p-cresol, which have similar toxicities, are generally described prior to those of m-cresol, which is somewhat less toxic. Occasionally, data were available regarding the effects of cresol mixtures (containing the three isomers in varying proportions) and cresylic acids (technical mixtures containing other substances in addition to the three cresol isomers). These are generally discussed after the individual isomers. 

Studies of the inhalation toxicity of cresols have not been adequately detailed. The exposures involved mixtures of vapors and aerosols that were not characterized sufficiently to estimate exposure levels reliably. Furthermore, methods for evaluating the toxicological end points were not adequately described. Therefore, no LSE table or figure containing levels of significant exposure was constructed for this route. Nevertheless, certain general conclusions can be drawn from the reports regarding the toxic potential of inhaled cresols. These are discussed below. 

In rabbits, dermal LD50 values for cresols were 890, 300, 2,830, and 2,000 mg/kg for o-, p-, m-, and mixed cresols, respectively (Vernot et al. 1977). These values are recorded in Table 2-2. Based on these LD50 values, p-cresol appears to be more toxic dermally than o-cresol, with m-cresol being the least toxic of the three isomers. 

Intermediate oral MRLs for all three cresol isomers could have been calculated based on NOAEL values of 30 mg/kg/day for neurological effects in two-generation reproductive studies in rats (BRRC 1989a, 1989b, 1989c). However, these intermediate oral MRLs were not derived because they would have been less protective than the acute MRLs. This apparent anomaly reflects the fact that lower doses were employed in the developmental toxicity study used as the basis for the acute MRLs than in longer term studies. Dermal MRLs were not derived for cresols due to the lack of an appropriate methodology. 

Studies in animals have shown that cresols can be lethal when exposure is through the inhalation, oral, or dermal routes. The lethal exposure levels varied from 1,350 to 2,020 mg/kg in orally exposed rats and 300 to 2,830 mg/kg in dermally exposed rabbits, depending on the isomer tested. By either route, m-cresol was the least toxic isomer. Lethal levels were not determined in inhalation studies, but one study (Campbell 1941) reported that brief repeated inhalation exposures produced lethality at concentrations that were not lethal when a single, longer exposure period was used. The estimated lethal dose in humans (2,000 mg/kg) is within the range of values reported in other species. Other observations regarding the lethality of cresols to animals might also apply to acutely-exposed humans. 

---