2,4-Dichlorophenol is a chemical intermediate used principally in the manufacture of the herbicide 2,4-dichlorophenoxyacetic acid. Toxicology and carcinogenesis studies were conducted by feeding diets containing 2,4-dichlorophenol (greater than 99% pure) for 14 days, 13 weeks, or 2 years to groups of F344/N rats and B6C3F1 mice of each sex. Genetic toxicology tests were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells.
Fourteen-day and thirteen-week studies
In the 14-day studies, male and female rats and mice were given diets containing 2,4-dichlorophenol at concentrations up to 40,000 ppm. One high dose male mouse died before the end of the studies; no deaths occurred in any other group, and no compound-related lesions were seen at necropsy in rats or mice. In the 13-week studies, groups of 10 rats and 10 mice of each sex were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm 2,4-dichlorophenol. All rats lived to the end of the studies, whereas all mice that received 40,000 ppm died during the first 3 weeks of the studies. Final mean body weights of rats that received 20,000 or 40,000 ppm and of male mice that received 20,000 ppm were at least 10% lower than those of controls. Bone marrow atrophy in rats and necrosis and syncytial alteration (multinucleated hepatocytes) in the liver of male mice were compound-related effects. Two-year studies were conducted by feeding diets containing 0, 5,000, or 10,000 ppm 2,4-dichlorophenol to groups of 50 male rats and 50 male and 50 female mice for 103 weeks. Groups of 50 female rats received diets containing 0, 2,500, or 5,000 ppm.
Body weight and survival
Mean body weights of high dose male and female rats, high dose male mice, and both dosed groups of female mice were generally lower than those of controls. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: control, 33/50; low dose, 25/50; high dose, 32/50; female rats: 34/50; 43/50; 40/50; male mice: 33/50; 32/50; 31/50; female mice: 45/50; 40/50; 43/50). The average daily feed consumption by rats in the low dose and high dose groups was 94%-97% that by the controls. The estimated daily mean consumption of 2,4-dichlorophenol was 210 or 440 mg/kg for low dose or high dose male rats and 120 or 250 mg/kg for low dose or high dose female rats. The average daily feed consumption by mice in the low dose and high dose groups was 97% and 78% of that by the controls for males and 94% and 85% for females. The estimated daily mean consumption of 2,4-dichlorophenol was 800 or 1,300 mg/kg for low dose or high dose male mice and 430 or 820 mg/kg for low dose or high dose female mice.
Nonneoplastic and neoplastic effects
There were no compound-related increased incidences of neoplastic lesions in rats or mice. The incidence of mononuclear cell leukemia was decreased in dosed male rats relative to that in controls (control, 31/50; low dose, 17/50; high dose, 17/50); the incidence of malignant lymphomas was decreased in high dose female mice (4/50) relative to that in controls (12/50). Syncytial alteration of hepatocytes was observed at increased incidences in dosed male mice (11/50; 33/49; 42/48).
The mutagenic effect of 2,4-dichlorophenol in S. typhimurium strain TA1535 was considered to be equivocal only in the presence of hamster S9; 2,4-dichlorophenol produced no increases in revertant colonies in strains TA98, TA100, or TA1537 with or without exogenous metabolic activation. 2,4-Dichlorophenol increased trifluorothymidine (Tft) resistance in the mouse L5178Y assay without metabolic activation; it was not tested with activation. In cultured CHO cells, 2,4-dichlorophenol did not induce chromosomal aberrations but did significantly increase the frequency of sister chromatid exchanges (SCEs) both in the presence and absence of S9.
The data, documents, and pathology materials from the 2-year studies of 2,4-dichlorophenol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report.
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity for male F344/N rats fed diets containing 5,000 or 10,000 ppm 2,4-dichlorophenol or for female F344/N rats fed diets containing 2,500 or 5,000 ppm 2,4-dichlorophenol. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 5,000 or 10,000 ppm 2,4-dichlorophenol.