Boric acid is a component of cosmetics and pharmaceuticals and is also used in numerous industrial processes. Earlier long-term studies did not demonstrate a carcinogenic effect in Sprague-Dawley rats. Because of potential widespread human exposure, corroborative evidence was sought in a second species. Toxicology and carcinogenesis studies were conducted by feeding technical-grade boric acid (99.7% pure) to groups of male and female B6C3F1 mice for 14 days, 13 weeks, and 2 years.
In the 14-day studies (five mice per group), mortality occurred in mice fed 25,000 ppm, 50,000 ppm, or 100,000 ppm boric acid; hyperplasia and/or dysplasia of the forestomach was also seen in these dose groups. No compound-related gross pathologic or histopathologic effects were seen in male or female mice exposed at concentrations up to 12,500 ppm in feed. In the 13-week studies, groups of 10 male and 10 female mice were fed boric acid at concentrations up to 20,000 ppm; 8 male mice and 1 female mouse receiving 20,000 ppm and 1 male receiving 10,000 ppm boric acid died before the end of the studies. Male and female mice receiving 20,000 ppm boric acid weighed 23% and 18% less, respectively, than did the controls at the end of the studies. Testicular atrophy in 8/10 male mice, hyperkeratosis and acanthosis of the stomach in 8/10 male and female mice, and extramedullary hematopoiesis of the spleen in all male and female mice receiving 20,000 ppm boric acid indicated that the testis, stomach, and spleen were potential target organs in the 2-year studies. Based on these results, 2-year toxicology and carcinogenesis studies were conducted by feeding diets containing boric acid at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male and 50 female mice.
Survival of high dose male mice after week 63 and of low dose mice after week 84 was lower than that of the controls (final survival: control, 41; low dose, 30; high dose, 22), which may have reduced the sensitivity of the carcinogenicity study; the numbers of female mice (33; 33; 37) that survived to the end of the studies were considered adequate for toxicologic evaluation. Body weight gain was reduced in each sex after week 30; mean final body weights were 7% and 13% below control values for exposed male mice and 7% and 20% below those of controls for exposed female mice. No chemically related clinical signs were reported.
At the top dose, boric acid caused an increased incidence of testicular atrophy (control, 3/49; low dose, 6/50; high dose, 27/47) and interstitial cell hyperplasia (0/49; 0/50; 7/47) inmale mice. The testicular atrophy was characterized by variable loss of spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa from the seminiferous tubules. The seminiferous tubules contained primarily Sertoli cells and variable numbers of spermatogonia. In some mice, there were accumulations of interstitial cells, indicating hyperplasia.
In low dose male mice, there were increased incidences of hepatocellular carcinomas (5/50; 12/50; 8/49) and hepatocellular adenomas or carcinomas (combined) (14/50; 19/50; 15/49) and an increased incidence of subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) (2/50; 10/50; 2/50). No increased incidence of subcutaneous tissue neoplasms was seen in male mice receiving 5,000 ppm. Because the incidence of subcutaneous tissue tumors is variable in historical controls, because there was no corresponding increase in the high dose male mice, and because the incidence of hepatocellular tumors was not significant by the incidental tumor test and was within the historical control range, neither of these tumors was considered to be related to the administration of boric acid.
Boric acid was not mutagenic in the Salmonella/microsome assay with Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. Boric acid was negative in the mouse lymphoma L5178Y/TK+/- assay and did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. All assays were preformed with and without metabolic activation.
The data, documents, and pathology materials from the 2-year studies of boric acid were audited at the NTP Archives. 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 carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. Testicular atrophy and interstitial cell hyperplasia were observed in high dose male mice. The decrease in survival of dosed male mice may have reduced the sensitivity of this study.