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NTP Toxicology and Carcinogenesis Studies of t-Butylhydroquinone (CAS No. 1948-33-0) in F344/N Rats and B6C3F(1) Mice (Feed Studies).

Abstract

t -Butylhydroquinone is used as an antioxidant in cosmetic products such as lipsticks, eye shadows, perfumes, blushers, and skin care preparations at concentrations ranging from 0.1% to 1.0%; the chemical is also used at concentrations up to 0.02% in oils, fats, and meat products to prevent rancidity, and as a polymerization inhibitor for various polyunsaturated polyesters (CIR, 1986). t-Butylhydroquinone was nominated for toxicity and carcinogenicity testing by the Food and Drug Administration. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F(1) mice. Mice were exposed to t-butyl hydroquinone (99% pure) in feed for 13 weeks or 2 years. For rats, exposure to t-butylhydroquinone began in utero and continued through lactation. After weaning, pups were fed diets containing the same levels of t-butylhydroquinone as those given to their respective dams for 13 weeks or for up to 30 months. The oral route of administration was selected for these studies because t-butylhydroquinone is used as a food additive and human exposure occurs predominantly through this route. In addition to the oral route of exposure, rats were exposed prenatally because perinatal exposure to butylated hydroxytoluene (a structurally related chemical) induced hepatocellular neoplasms in rats. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells in vitro and in mouse bone marrow cells in vivo. 13-WEEK STUDY IN RATS: In the perinatal exposure phase of the 13-week study, groups of 10 female rats (F(0)) were fed 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone from 2 weeks prior to cohabitation until the F(1) pups were weaned. F(0) females exposed to 20,000 or 40,000 ppm did not litter. The number of pup deaths in the 5,000 and 10,000 ppm groups was greater than that in the control group, and the average number of surviving pups per litter in the 10,000 ppm group was less than that in the control group. Mean body weights of pups exposed perinatally to 5,000 or 10,000 ppm were lower than that of the controls at the time of weaning. Groups of 10 male and 10 female F(1) rats continued to receive diets containing 0, 2,500, 5,000, or 10,000 ppm t-butylhydroquinone for 13 weeks fol lowing weaning. These dietary levels corresponded to approximately 200, 400, or 800 mg t-butylhydro quinone/kg body weight (males) or 200, 400, or 750 mg/kg (females) per day. All rats survived to the end of the study. The final mean body weights of males and females in the 5,000 and 10,000 ppm groups were significantly lower than those of the controls, as was the mean body weight gain of males exposed to 10,000 ppm. However, interpretation of these findings was complicated by the significantly lower initial mean body weights of the 10,000 ppm groups. Differences in initial body weights were due to in utero exposure to t-butylhydroquinone. Feed consumption by exposed groups of rats was lower than that by controls at week 2, and feed consumption by 5,000 and 10,000 ppm males and 10,000 ppm females was slightly lower than that by controls at the end of the study. Hair discoloration in all exposed groups of rats, except females exposed to 2,500 ppm, was the only clinical observation considered related to chemical exposure. The mean spermatid count, spermatid heads per testis, and spermatid heads per gram of testis were significantly decreased in males exposed to 5,000 ppm. The estrous cycles of females exposed to 2,500 or 5,000 ppm were significantly longer than that of the controls. There were no biologically significant changes in clinical pathology parameters or in organ weights. Increased incidences of hyperplasia of the nasal respiratory epithelium were observed in males exposed to 5,000 ppm and males and females exposed to 10,000 ppm, and an increased incidence of nasal exudate was observed in males in the 10,000 ppm group. Increased incidences of pigmentation were observed in the spleen of male and female rats exposed to 5,000 or 10,000 ppm. Based on lower final mean body weights wer final mean body weights and decreased feed consumption in males and females exposed to 10,000 ppm t-butylhydroquinone, exposure concentrations selected for the long-term rat study were 1,250, 2,500, and 5,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm t-butylhydroquinone for 13 weeks. These dietary levels corresponded to approximately 440, 880, 1,950, 4,000, and 8,400 mg t-butylhydro quinone/kg body weight (males) or 500, 1,100, 2,200, 4,600, and 9,000 mg/kg body weight (females) per day. There were no exposure-related deaths. Final mean body weights and body weight gains of males and females exposed to 10,000, 20,000, or 40,000 ppm were significantly less than those of the controls. Feed consumption by exposed mice appeared to be similar to that by controls, but there was excessive scatter of feed by mice exposed to 10,000, 20,000, or 40,000 ppm. Therefore, feed consumption by male and female mice in these groups was likely less than that by controls. Significant increases in segmented neutrophil counts occurred at week 3 and at the end of the study in females exposed to 10,000 ppm and males and females exposed to 20,000 or 40,000 ppm. Left caudal, left epididymis, and left testis weights of males exposed to 10,000 or 40,000 ppm were generally significantly lower than those of the controls. The estrous cycle of females exposed to 40,000 ppm was significantly longer than that of the control group. There were no biologically significant differences in organ weights. Increased incidences and severities of mucosal hyperplasia were observed in the forestomach of males exposed to 20,000 or 40,000 ppm and in females exposed to 10,000, 20,000, or 40,000 ppm, and increased incidences of inflammation were observed in the nose and skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Increased incidences of hyperplasia also occurred in the skin of males and females exposed to 10,000, 20,000, or 40,000 ppm. Based on lower final mean body weights, increased incidences of inflammation of the nose and skin, increased incidences of forestomach mucosal hyperplasia, and increased severity of nonneoplastic lesions observed in mice exposed to 10,000, 20,000, or 40,000 ppm, exposure concentrations selected for the 2-year study were 1,250, 2,500, and 5,000 ppm.

LONG-TERM STUDY IN RATS:

In the perinatal exposure phase of the long-term study, groups of 60 female F(0) rats were fed diets containing 0, 1,250, 2,500, or 5,000 ppm t-butyl hydroquinone, beginning 2 weeks prior to cohabitation and continuing until F(1) pups were weaned. Following weaning, groups of 70 male and 70 female F(1) rats continued to receive diets containing 0, 1,250, or 5,000 ppm, and groups of 68 male and 68 female rats continued to receive diets containing 2,500 ppm. The duration of dosing in feed was 123 weeks post-weaning for males and 129 weeks for females. These exposure concentrations resulted in daily doses of approximately 50, 100, and 200 mg t-butylhydro quinone/kg body weight (males) or 60, 120, and 240 mg/kg (females). Ten male and ten female F(1) rats from each exposure group were evaluated at 3 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of females exposed to 5,000 ppm was significantly greater than that of the control group. The mean body weights of males and females exposed to 5,000 ppm were generally less than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by controls. Clinical findings of hair discoloration in exposed groups of males and females were considered to be related to chemical exposure. Pathology Findings: No increased neoplasm incidences in male or female rats were attributed to t-butylhydroquinone exposure. The incidences of mammary gland fibroadenoma and fibroadenoma or adenoma (combined) were significantly decreased in males exposed to 1,250 ppm and in all exposed groups of females; and combined incidences of mammary gland fibroadenoma, adenoma, or carcinoma were significantly decreased in all groups of exposed females. The decreases occurred with significant negative trends. Incidences of renal cysts and inflammation were generally increased in exposed groups of male rats. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 1,250, 2,500, or 5,000 ppm t-butylhydroquinone in feed for 104 to 105 weeks. These exposure concentrations resulted in daily doses of approximately 150, 300, or 600 mg t-butylhydroquinone/kg body weight (males) or 150, 300, or 700 mg/kg (females). As many as 10 males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights and Feed Consumption: Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights of the 5,000 ppm groups were generally lower than those of the control groups from week 13 until the end of the study. Feed consumption by exposed groups of males and females was similar to that by the controls. There were no biologically significant differences in clinical pathology parameters between control and exposed groups of mice. Pathology Findings: No increased incidences of neoplasms or nonneoplastic lesions in male or female mice were considered to be related to t-butylhydroquinone exposure.

GENETIC TOXICOLOGY:

t-Butylhydroquinone was not mutagenic in any of four strains of Salmonella typhimurium, with or without liver S9 metabolic activation enzymes. It did, however, induce sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the presence, but not the absence, of S9. No increase in the frequency of micronucleated erythrocytes was observed in bone marrow of male mice treated with t-butylhydroquinone.

CONCLUSIONS:

Under the conditions of this long-term feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. Under the conditions of this 2-year feed study, there was no evidence of carcinogenic activity of t-butylhydroquinone in male or female B6C3F(1) mice exposed to 1,250, 2,500, or 5,000 ppm. Exposure of rats to t-butylhydroquinone in feed resulted in decreased incidences of mammary gland neoplasms in males and females. Synonyms: Tert-butyl-hydroquinone; 2-(1,1-dimethylethyl)-1,4-benzenediol; 2-tert-butylhydroquinone; mono-tert-butylhydroquinone; tert-butyl-1,4-benzenediol: mono-tertiarybutylhydroquinone; 2-tert-butyl-1,4-benzenediol; 2-(1,1-dimethyl)hydroquinone; 2-(tert-butyl)-p-hydroquinone; TBHQ; MTBHQ Trade Names: Sustane; Tenox TBHQ; Banox 20BA

PMID:
12587017
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