Toxicology and Carcinogenesis Studies of Cresols (CAS No. 1319-77-3) in Male F344/N Rats and Female B6C3F1 Mice (Feed Studies)
Chemical Formula: C7H8O - Molecular Weight: 108.14
Cresols are high volume production chemicals with a variety of industrial uses. Cresols are used in cleaners, disinfectants, solvents, degreasing compounds, paintbrush cleaners, fumigants, photographic developers, ore flotation processes, explosives, and synthetic food flavors. Cresols are also used as a motor oil additive, textile scouring agent, and surfactant. The chemical acts as an intermediate in the production of phenolic resins and phosphate esters (tricresyl phosphate and cresyl diphenyl phosphate); an intermediate in the manufacture of chemicals, dyes, plastics, and antioxidants; and an organic intermediate in the manufacture of herbicides. Cresols were nominated for study by the National Institute of Environmental Health Sciences because of the potential for occupational and consumer exposure and the lack of chronic toxicity data. Male F344/N rats and female B6C3F1 mice were exposed to a 60:40 mixture of m- and p-cresol (m-/p-cresol) (greater than 99.5% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes.
2-YEAR STUDY IN RATS
Groups of 50 male rats were fed diets containing 0, 1,500, 5,000 or 15,000 ppm m-/p-cresol (equivalent to average daily doses of approximately 70, 230, or 720 mg cresols/kg body weight) for 105 weeks. Survival of all exposed groups was similar to that of the control group. Mean body weights of the 15,000 ppm group were less than those of the control group throughout the study. Due to lack of palatability, feed consumption by the 15,000 ppm group was less than that by the control group during the first week of the study but increased to control levels by the second week of the study.
Renal tubule adenomas occurred in three rats in the 15,000 ppm group, and the incidence exceeded the historical control range. One additional renal tubule adenoma was found in a 15,000 ppm rat in an extended examination of kidney step sections. The incidence of hyperplasia of the transitional epithelium of the renal pelvis was significantly increased in the 15,000 ppm group. The severity of nephropathy was slightly increased in the 15,000 ppm group.
Exposure to cresols resulted in significantly increased incidences of hyperplasia of the goblet cells and respiratory epithelium of the nose in all exposed groups of rats. The incidences of squamous metaplasia of the respiratory epithelium were significantly increased in the 5,000 and 15,000 ppm groups, and the incidence of inflammation was significantly increased in the 15,000 ppm group. The incidence of eosinophilic focus of the liver was significantly increased in the 15,000 ppm group.
2-YEAR STUDY IN MICE
Groups of 50 female mice were fed diets containing 0, 1,000, 3,000, or 10,000 ppm m-/p-cresol (equivalent to average daily doses of approximately 100, 300, or 1,040 mg cresols/kg body weight) for 104 to 105 weeks. Survival of all exposed groups was similar to that of the control group. Mean body weights of the 3,000 and 10,000 ppm groups were less than those of the control group after weeks 12 and 9, respectively. Feed consumption by the 10,000 ppm group was decreased compared to that by the control group.
The incidence of squamous cell papilloma of the forestomach was significantly greater in the 10,000 ppm group than in the control group.
Exposure to cresols resulted in significantly increased incidences of bronchiolar hyperplasia of the lung in all exposed groups of mice. The incidences of respiratory epithelial hyperplasia of the nose were significantly increased in the 3,000 and 10,000 ppm groups. The incidences of thyroid gland follicular degeneration were significantly increased in all exposed groups of mice, and the incidence of eosinophilic focus of the liver was significantly increased in the 10,000 ppm group.
Cresols did not exhibit mutagenicity in tests conducted by the NTP. Each of the individual cresol isomers (m-, o-, and p-) and m-/p-cresol was tested for mutagenicity in several strains of S. typhimurium and in E. coli strain WP2, with and without exogenous metabolic activation; results with all individual compounds and the mixture were negative. o-Cresol and m-/p-cresol were evaluated for induction of micronuclei (biomarkers of chromosomal damage) in peripheral blood erythrocytes of male and female mice following 13 weeks of exposure in the diet (NTP, 1992); no increases in the frequencies of micronucleated erythrocytes were seen in male or female mice in either study.
Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenetic activity of 60:40 m-/p-cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma. There was some evidence of carcinogenic activity of 60:40 m-/p-cresol in female B6C3F1 mice based on the increased incidence of forestomach squamous cell papilloma.
Exposure to 60:40 m-/p-cresol resulted in increased incidences of nonneoplastic lesions in the kidney (hyperplasia), nose (inflammation, hyperplasia, and metaplasia), and liver (eosinophilic focus) of rats. Increased incidences of nonneoplastic lesions were observed in the respiratory tract (hyperplasia in the nose and lung), thyroid gland (follicular degeneration), and liver (eosinophilic focus) of mice exposed to m-/p-cresol.
Synonyms for mixture: Cresol; dicresol; m-/p-cresol; m,p-cresol; methylphenol, mixed; mixed cresols; phenol, methyl-, mixed
Synonyms for m-cresol (60%): 3-Cresol; 1-hydroxy-3-methylbenzene; 3-hydroxytoluene; 1-methyl-3-hydroxybenzene; 3-methylphenol; m-cresol; m-cresylic acid; m-hydroxytoluene; m-methylphenol; m-methylphenylol; m-oxytoluene; m-toluol; phenol, 3-methyl-
Synonyms for p-cresol (40%): 4-Cresol; 1-hydroxy-4-methylbenzene; 4-hydroxytoluene; 1-methyl-4-hydroxybenzene; 4-methylphenol; p-cresol; p-cresylic acid; p-hydroxytoluene; p-methylphenol; p-methylphenylol; p-oxytoluene; p-toluol; paramethyl phenol; phenol, 4-methyl
|0, 1,500, 10,000 or 15,000 ppm||0, 1,000, 3,000 or 10,000 ppm|
|Body weights||15,000 ppm group less than the control group||3,000 and 10,000 ppm groups less than the control group|
|Survival rates||33/50, 34/50, 33/50, 31/50||41/50, 43/50, 44/49, 42/50|
Kidney: pelvis, transitional epithelium, hyperplasia (0/50, 0/50, 2/50, 8/50); severity of nephropathy (1.4, 1.4, 1.7, 2.1)
Lung: bronchiole, hyperplasia (0/50, 42/50, 44/49, 47/50)
Nose: respiratory epithelium, hyperplasia (0/50, 0/50, 28/49, 45/49)
Thyroid gland: follicular degeneration (7/48, 24/48, 24/49, 21/50)
Liver: eosinophilic focus (1/50, 0/50, 2/49, 12/50)
Forestomach: squamous cell papilloma (0/50, 1/50, 1/49, 10/50)
|Equivocal findings||Kidney: renal tubule adenoma (standard evaluation - 0/50, 0/50, 0/50, 3/50; standard and extended evaluations combined - 0/50, 0/50, 0/50, 4/50)||None|
|Level of evidence of carcinogenic activity||Equivocal evidence||Some evidence|
|Bacterial Mutagenicity||Salmonella typhimurium gene mutations (m-, o-, and p-cresol and m-/p-cresol mixture):||
Negative in strains TA97, TA98, TA100, TA1535, and TA1537 and in Escherichia coli
WP2 uvrA pKM101 with and without S9
Mouse peripheral blood in vivo
(o-cresol and m-/p-cresol mixture):
Report Date: July 2008