NTP technical report on the toxicity studies of Cresols (CAS Nos. 95-48-7, 108-39-4, 106-44-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Abstract

Cresols are monomethyl derivatives of phenol, and are found as constituents of coal tar, in various industrial solvents and resins, and in some essential oils. In 28-day toxicity studies, F344/N rats and B6C3F1 mice of both sexes were given o-cresol, m-cresol, p-cresol, or m/p-cresol (60:40) at concentrations from 300 ppm to 30,000 ppm in the diet. In 90-day studies, o-cresol or m/p-cresol (60:40) were added to the diet in concentrations as high as 30,000 ppm to F344/N rats and 20,000 ppm (o-cresol) or 10,000 ppm (m/p-cresol) to B6C3F1 mice. In the 28-day studies, all rats survived (5 per sex per dose), but some mice given o-cresol at 30,000 ppm, or m-cresol or p-cresol at 10,000 ppm or 30,000 ppm died before the end of the studies. Feed consumption was depressed during the first study week in all high- dose groups of animals and weight gains were generally less than controls in groups given 10,000 or 30,000 ppm in the four 28-day studies. Increased relative liver weights and kidney weights were noted in both rats and mice given concentrations of cresols as low as 3,000 ppm. However, there were no consistent microscopic changes associated with these weight increases. Bone marrow hypoplasia and uterus, ovary and occasional mammary gland atrophy were seen primarily at the highest dietary concentration, but also at 10,000 ppm with certain cresols. An effect specific to the p- cresol and m/p-cresol studies was atrophy and regenerative changes in the nasal epithelia and forestomach, presumably a direct result of the irritant effects of the chemical or its vapors. Results of reproductive tissue evaluations and estrus cycle characterizations with o-cresol and m/p-cresol gave no indication of adverse effects to the male reproductive system, but the estrus cycle was lengthened in rats and mice receiving the higher concentrations of o-cresol and rats receiving m/p-cresol. In the 90-day studies, no deaths of rats (20 per sex per dose) or mice (10 per sex and dose) could clearly be related to administration of either o-cresol or m/p-cresol. Hematology, clinical chemistry, and urinalysis results were generally unremarkable in all studies, although an accumulation of bile acids in high-dose rats was considered evidence of a deficit in hepatocellular function resulting from ingestion of the chemical. Results of microscopic analyses were consistent with findings in the 28-day studies, and revealed evidence of mild bone marrow hypocellularity in rats and forestomach hyperplasia in mice given diets containing the higher concentrations of o-cresol. Evidence of nasal irritation was present in rats and mice receiving feed containing m/p-cresol. Additional lesions in rats receiving m/p-cresol included bone marrow hypocellularity and uterine atrophy. The cresol isomers exhibited a generally similar pattern of toxicities in rats and mice. Dietary concentrations of 3,000 ppm appeared to be minimal effect levels for increases in liver and kidney weights and deficits in liver function. Histopathologic changes, including bone marrow hypocellularity, irritation to the gastrointestinal tract and nasal epithelia, and atrophy of female reproductive organs, occasionally occurred at 10,000 ppm, but were more common at the high-dose of 30,000 ppm. Synonyms: phenol, 2-methyl-(9CI); 2-cresol; o-cresylic acid; 1-hydroxy-2-methylbenzene; 2-hydroxytoluene; o-hydroxytoluene; 2-methylphenol; o-methylphenol; o-methylphenylol; o-oxytoluene; RCRA Waste Number U052; o-toluol; UN 2076; phenol, 3-methyl-(9CI); 3-cresol; m-cresole; m-cresylic acid; 1-hydroxy-3-methylbenzene; 3-hydroxytoluene; m-hydroxytoluene; m-kresol; 3-methylphenol; m-methylphenol; m-oxytoluene; RCRA Waste Number U052; m-toluol; UN 2076; phenol, 4-methyl- (9CI); 4-cresol; p-cresylic acid; 1-hydroxy-4-methylbenzene; 4-hydroxytoluene; p-hydroxytoluene; p-kresol; 1-methyl-4-hydroxybenzene; p-methylhydroxy- benzene; 4-methylphenol; p-methylphenol; p-oxytoluene; RCRA Waste Number U052; p-toluol; p-tolyl alcohol; UN 2076. (NOTE: These studies were supported in part by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund (Superfund) by an interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service.)