_I.A.4. Additional Studies/Comments (Oral RfD)
The subchronic and chronic toxicity of borax and boric acid was studied in dogs administered these compounds in the diet (Weir and Fisher, 1972; U.S. Borax Research Corp., 1963, 1966, 1967). In the supporting subchronic study, groups of beagle dogs (5/sex/dose/compound) were administered borax (sodium tetraborate decahydrate) or boric acid for 90 days at dietary levels of 17.5, 175, and 1750 ppm boron (male: 0.33, 3.9, and 30.4 mg B/kg-day; female: 0.24, 2.5, and 21.8 mg B/kg-day) and compared with an untreated control group of 5 dogs/sex (Weir and Fisher, 1972; U.S. Borax Research Corp., 1963). A high-dose male dog died as a result of complications of diarrhea on day 68 of the study with severe congestion of the mucosa of the small and large intestines and congestion of the kidneys. No clinical signs of toxicity were evident in the other dogs. The testes were the primary target of boron toxicity. At the high dose, mean testes weight was decreased 44% in males fed borax (9.6g) and 39% in males fed boric acid (10.5 g) compared with controls (17.2 g). Also at this dose, mean testes:body weight ratio (control: 0.2%; borax: 0.1%; boric acid: 0.12%) and mean testes:brain weight ratio (control: 22%; borax: 12%) were significantly reduced. Decreased testes:body weight ratio was also observed in one dog from the mid-dose boric acid group. Microscopic pathology revealed severe testicular atrophy in all high-dose male dogs, with complete degeneration of the spermatogenic epithelium in most cases. No testicular lesions were found in the lower dose groups. Hematological effects were also observed in high-dose dogs. Decreases were found for both hematocrit (15 and 6% for males and females, respectively) and hemoglobin (11% for both males and females) at study termination in borax-treated dogs. Pathological examination revealed accumulation of hemosiderin pigment in the liver, spleen and kidney, indicating breakdown of red blood cells, in males and females treated with borax or boric acid. Other effects in high-dose dogs were decreased thyroid:body weight ratio (control: 0.009%; borax: 0.006%; boric acid: 0.006%) and thyroid:brain weight ratio (control: 0.95%; borax: 0.73%) in males; also at the high dose were increases in brain:body weight ratio (borax) and liver:body weight ratios (boric acid) in females and a somewhat increased proportion of solid epithelial nests and minute follicles in the thyroid gland of borax-treated males, lymphoid infiltration and atrophy of the thyroid in boric-acid treated females, and increased width of the zona reticularis (borax males and females, boric acid females) and zona glomerulosa (boric acid females) in the adrenal gland. This study identified a LOAEL for systemic toxicity in dogs of 1750 ppm boron (male: 30.4 mg B/kg-day; female: 21.8 mg B/kg-day) and a NOAEL of 175 ppm boron (male: 3.9 mg B/kg-day; female: 2.5 mg B/kg-day) following subchronic exposure.
In the chronic toxicity study, groups of beagle dogs (4/sex/dose/compound) were administered borax or boric acid by dietary admix at concentrations of 0, 58, 117, and 350 ppm boron (0, 1.4, 2.9, and 8.8 mg B/kg-day) for 104 weeks (Weir and Fisher, 1972; U.S. Borax Research Corp., 1966). There was a 52-week interim sacrifice and a 13-week "recovery" period after 104 weeks on test article for some dogs. Control animals (4 male dogs) served as controls for the borax and boric acid dosed animals. One male control dog was sacrificed after 52 weeks, two male control dogs were sacrificed after 104 weeks, and one was sacrificed after the 13-week recovery period with 104 weeks of treatment. The one male control dog sacrificed after the 13-week recovery period demonstrated testicular atrophy. (ONE IS TOO MANY IMO). Sperm samples used for counts and motility testing were taken only on the control and high dosed male dogs prior to the 2-year sacrifice. At a dose level of 8.8 mg B/kg-day in the form of boric acid, one dog sacrificed at 104 weeks had testicular atrophy. Two semen evaluations (taken after 24 months treatment) were performed on dogs treated at the highest dose (8.8 mg B/kg-day). Two of two borax-treated animals had samples that were azoospermic and had no motility while one of two boric acid treated animals had samples that were azoospermic. The authors reported that there did not appear to be any definitive test article effect on any parameter examined. The study pathologist considered the histopathological findings as being "not compound-induced." Tumors were not reported.