This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

Introduction

1.               The UK Health Security Agency (UKHSA) advises the Drinking Water Inspectorate (DWI) on potential health risks from chemicals in drinking water. Following EU exit, the DWI is reviewing the regulatory standards for some chemicals in drinking water, including boron. UKHSA is seeking advice from the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) with respect to an appropriate health-based guidance value (HBGV) for Boron.

2.               This discussion paper examines the toxicity studies on boron which underpin the evaluations by different authoritative bodies.

3.               The COT is asked to consider these studies, the interpretations by the various authoritative bodies and determine an appropriate Tolerable Daily Intake (TDI) to support an update to the boron drinking water standard in the UK.

Background

4.               COT has previously reviewed the available toxicity data on boron and boric acid in 1994 and 1995. It determined a No Observed Adverse Effect Level (NOAEL) of 9.6 milligrams per kilogram body weight per day (mg/kg bw/day) (rounded up to 10 mg/kg bw/day) for critical adverse effects in developmental studies in rats (reduced fetal weight and skeletal effects). Applying a default safety factor of 100, the Tolerable Daily Intake (TDI) was calculated as 0.1 mg/kg bw/day (COT,1995).

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

5.               Boron (CAS No. 7440-42-8) is a naturally occurring element in the earth’s crust. Common borate compounds include boric acid, salts of boric acid (e.g., sodium tetraborates, which are also referred to as borax), and boron oxide.

6.               Boron originates from both natural and anthropogenic sources. Natural sources include the weathering of boron-containing rocks and soils, seawater spray, volcanic activity, and geothermal emissions (Coughlin, 1996). Anthropogenic sources include industrial manufacturing, fossil fuel combustion, pesticide application, and agricultural irrigation.  In drinking water, most boron comes from detergents, fertilizers, and wastewater. Natural processes like weathering contribute more significantly to environmental boron levels compared to anthropogenic activities (US EPA, 2008). Human exposure to boron through drinking water occurs primarily in areas with boron-rich aquifers or where borates are released from industrial or agricultural sources (WHO, 2009).

7.               Boron has a molecular weight of 10.81 g/mol and does not exist in its elemental form in nature. In both water and soil, its fate is largely governed by pH, which determines whether boron exists primarily as undissociated boric acid (dominant at acidic pH) or as borate ions (dominant at alkaline pH above the pKa of 9.2). Both species are highly soluble and remain in solution, not readily removed by natural processes. Adsorption to soil or sediment, which is maximized around pH 7.5 to 9.0, decreases at higher pH, reducing boron’s capacity to bind to soil surfaces. In calcium-rich waters, borate ions can form complexes with calcium, altering boron speciation and its behaviour in aquatic environments (WHO, 2009; Health Canada, 2023).

8.               Boric acid (commonly denoted H3BO3 or H3BO4), exhibits high solubility (49 g/L), and has a low octanol–water partition coefficient (logKow = 0.175). Other borate compounds, such as sodium tetraborate and boron oxide, are also highly soluble and stable, with their distribution influenced by pH, local geology, and water composition. The chemical and toxicological properties of boric acid and other borates are considered similar on a molar boron equivalent basis when dissolved in water or biological fluids (WHO, 2009).

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

Toxicokinetics

9.               Inorganic borates readily hydrolyze to boric acid in the gut and uptake is almost exclusively (> 98%) as undissociated boric acid, which is likely absorbed by passive, non-mediated diffusion (Pahl et al., 2001). Once absorbed, it distributes evenly across body fluids and soft tissues in both humans and experimental animals, with a higher accumulation in bones (2-3 times higher than in soft tissues) (Forbes et al. 1954; Chapin et al. 1998). Boron crosses the placenta in humans and has been detected in placental and umbilical cord blood. Boron is not metabolized in the body. It is excreted largely unchanged in the urine, with renal clearance governing the excretion process (Murray, 1998).

Toxicity

10.               The toxicity of boron has been reviewed by WHO (2009), ATSDR (2010), and Health Canada (2023). Boron toxicity primarily affects the reproductive and developmental systems, as demonstrated in both human and animal studies. In humans, lethal cases of boron ingestion have shown effects on the liver, kidneys, central nervous system, gastrointestinal system, and skin, with death primarily attributed to respiratory failure (ATSDR, 2010; Health Canada, 2023). The minimal lethal dose of ingested boron (as boric acid) was reported to be 2–3 g in infants, 5–6 g in children, and 15–20 g in adults (WHO, 2009).

11.               Oral exposure animal studies have demonstrated that the reproductive system and the developing fetus are the most sensitive targets of boron toxicity. Adverse developmental effects have been identified for both acute and intermediate-duration exposures. Developmental toxicity observed in animal models, including decreased fetal weight, skeletal abnormalities (e.g., rib malformations), and visceral anomalies. High doses of boron caused significant reproductive effects in animals. Male rats showed histological alterations in the testes, sperm effects, disturbed spermatogenesis, and complete loss of viable sperm with prolonged exposure. Female rats experienced impaired ovulation and were unable to conceive when exposed to boron over 14 weeks (ATSDR, 2010; Health Canada, 2023). Further detail on the critical studies in animals is provided below.

12.               Prolonged exposure has been linked to gastrointestinal and renal injury, while acute high intake (≥184 mg boron/kg/day) often leads to nausea and vomiting in humans. Although boron is not considered an essential nutrient for humans, low levels may confer some benefits to bone health and cognitive function (ATSDR, 2010; Health Canada 2023).

13.               This discussion paper examines the toxicity studies on boron by Heindel et al. (1992), Price et al. (1996) and Weir and Fisher (1972) which are used by authoritative bodies as the critical studies for their health-based guidance values. In addition, other toxicity studies showing effects at similar dose levels are summarised. The table presented in Annex A, summarises the findings of these different studies. 

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

14.               While the Heindel et al. (1992) paper states only conduct under contract to the National Toxicology Program and the National Institute of Environmental Health Sciences (NTP/NIEHS), the follow up paper (Price et al. 1996) reports funding under the sponsorship of U.S. Borax Inc.

15.               Heindel et al. (1992) conducted studies involving timed-mated Sprague-Dawley rats (29 per group) fed diets containing 0, 0.1, 0.2, or 0.4% boric acid from gestation day (GD) 0 to 20. The estimated boric acid doses were 0, 78, 163, and 330 mg/kg bw/day (0, 13.6, 28.5, and 57.7 mg B/kg bw/day). Additional groups of 14 rats received 0 or 0.8% boric acid (539 mg/kg bw/day or 94.2 mg B/kg bw/day) from GD 6 to 15 to minimize preimplantation loss and early embryo lethality identified in preliminary studies. Monitoring included food and water intake, body weights, and clinical toxicity signs throughout pregnancy. On GD 20, the animals were sacrificed, and organ weights, uterine contents, and maternal kidney histology (10 randomly selected dams/group) were evaluated. Fetal examination included assessment of weight, external and visceral malformations, and skeletal anomalies, with significance set at p < 0.05.

16.               Maternal Findings: There was no maternal mortality observed. On GD 12-20, food intake increased by 5-7% at 0.2% and 0.4% boric acid, whereas water consumption remained unaffected. Food and water intake decreased at 0.8% on GD 6–9 and increased on GD 15–18. Treatment had no effect on the pregnancy rates (90–100%). Increased relative liver and kidney weights (0.2% and higher), increased absolute kidney weight (0.8%), and reduced body weight gain (0.4% and higher) were among the dose-related maternal effects. Corrected body weight gain was unaffected except for an increase at 0.4%. Maternal kidneys showed minimal nephropathy, but it was not dose dependent.

17.               Fetal Findings: Prenatal mortality increased at 0.8% boric acid, with more resorptions and late fetal deaths per litter, and fewer live fetuses per litter. Fetal body weight decreased in a dose-dependent manner, with weights at 94%, 87%, 63%, and 46% of controls for 0.1%, 0.2%, 0.4%, and 0.8%, respectively. Malformations were significantly increased at 0.2% and higher, primarily affecting the eyes, CNS, cardiovascular system, and axial skeleton. Common malformations included brain ventricle enlargement and rib XIII agenesis/shortening. Skeletal variations such as wavy ribs were observed, especially at 0.8%.

18.               The authors concluded a maternal LOAEL of 0.2% boric acid (28.5 mg B/kg bw/day), with a maternal NOAEL of 0.1% (13.6 mg B/kg bw/day) and a fetal LOAEL of 0.1% boric acid (13.6 mg B/kg bw/day), with no NOAEL identified.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

19.               The Price et al. (1996) study was conducted as a follow-up to the Heindel et al. (1992) study, addressing its limitation of not identifying a fetal NOAEL. The Price et al (1996) paper states “This laboratory investigation was conducted at Research Triangle Institute under the sponsorship of U.S. Borax Inc”.

20.               Price et al. investigated the effects of dietary boric acid (0, 0.025, 0.05, 0.075, 0.1, and 0.2%) on timed-mated CD rats (60 per group) during GD 0-20. The calculated boric acid doses were 19, 36, 55, 76, and 143 mg/kg/day (3.3, 6.3, 9.6, 13.3, and 25 mg B/kg bw/day). The study comprised two phases with 14-17 rats per group per phase per replicate for Phase I. The study does not clearly state the number of rats assessed in Phase II.

21.               Phase I Teratology Evaluation: Phase I of this experiment was considered the teratology assessment and was terminated on GD 20, when uterine contents were evaluated. No maternal deaths or clinical symptoms were observed across any dose groups during this phase. Maternal body weights were comparable among groups throughout most of gestation, but trend analysis showed statistically significant decreases in maternal body weight (on GD 19 and GD 20) and weight gain (for GD 15-18 and GD 0-20) associated with higher doses. In the high-dose group, gravid uterine weight was reduced by 10% compared to controls, which was statistically significant (p<0.05). The authors attributed this trend of reduced body weight and weight gain during late gestation to diminished gravid uterine weight. Corrected maternal weight gain (gestational weight gain minus gravid uterine weight) remained unaffected. Minimal decreases in maternal food intake were noted only in the high dose group and only during the first three days of dosing. Water intake increased in exposed groups after GD 15. Additionally, the number of ovarian corpora lutea, uterine implantation sites, and the percentage of preimplantation loss were unaffected by boric acid exposure.

22.               Phase 1 - Offspring Findings: Offspring body weights on GD 20 were significantly reduced in the 13.3 and 25 mg B/kg bw/day groups, with weights in the dose groups being 99%, 98%, 97%, 94%, and 88% of control values for the low to high doses, respectively. No treatment-related increases in external or visceral malformations or variations were noted when evaluated either collectively or individually. However, skeletal malformations and variations assessed collectively showed a significant increase in the percentage of affected fetuses per litter. Dose-dependent increases were specifically observed for short rib XIII, classified as a malformation, and for wavy rib or wavy rib cartilage, categorized as variations. Statistical analysis confirmed significant increases in short rib XIII and wavy rib incidence in the 13.3 and 25 mg B/kg bw/day groups compared to controls. Additionally, a statistically significant trend (p<0.05) was identified for reductions in rudimentary extra ribs on lumbar I, a variation, although only the high-dose group showed a biologically relevant but not statistically significant decrease in this feature.

23.               For Phase I, the lowest observed adverse effect level (LOAEL) was determined to be 0.1% boric acid (13.3 mg B/kg bw/day) based on decreased fetal body weight. The NOAEL was established at 0.075% boric acid (9.6 mg B/kg bw/day).

24.               Phase II Postnatal Evaluation: In Phase II, dams were allowed to deliver and rear their litters until postnatal day (PND) 21. The calculated average boric acid doses for these dams were 19, 37, 56, 74, and 145 mg/kg bw/day (3.2, 6.5, 9.7, 12.9, and 25.3 mg B/kg bw/day). This phase was designed to evaluate whether skeletal defects observed in control and exposed pups in Phase I persisted or changed during the first 21 days postnatally. Among live-born pups, a significant trend test revealed an increased number and percentage of dead pups between PND 0 and 4, particularly in the high-dose group. However, this increase in early postnatal mortality was not significantly different from controls and fell within the range of control values recorded in other studies from the same laboratory. Between PND 4 and 21, no further increases in mortality were observed.

25.               On PND 0, the initiation of Phase II, boric acid exposure did not significantly affect the body weight of offspring across dose groups, with weights at 102%, 101%, 99%, 101%, and 100% of control values for the low- to high-dose groups, respectively. Body weights remained unaffected through to termination of Phase II on PND 21, indicating that fetal body weight deficits observed during gestation did not persist into the postnatal period.

26.               The percentage of pups per litter exhibiting short rib XIII remained elevated on PND 21 in the highest dose group (0.2% boric acid, 25.3 mg B/kg bw/day). However, no instances of wavy ribs were observed on PND 21, and neither treated nor control pups exhibited an extra rib on lumbar I.

27.               Based on the findings, the authors reported the NOAEL for Phase II to be 12.9 mg B/kg bw/day, while the lowest observed adverse effect level (LOAEL) was 25.3 mg B/kg bw/day.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

28.               The sub chronic and chronic toxicity of borax and boric acid has been studied in rats and dogs administered these compounds in the diet (Weir and Fisher, 1972). While no funding is reported, references are made to work by the U.S. Borax Research Corp.

29.               Sub-chronic Oral Toxicity in SD Rats: Weir and Fisher (1972) investigated boron toxicity in Sprague-Dawley rats. Groups of 10 rats per sex per dose were fed diets containing borax or boric acid for 90 days at concentrations of 0, 52.5, 175, 525, 1750, and 5250 ppm boron (equivalent to approximately 0, 2.6, 8.8, 26.3, 87.5, and 262.5 mg B/kg bw/day, based on a food intake factor of 0.05 (IPCS, 2009)). Both borax and boric acid produced 100% mortality at the highest dose and complete atrophy of the testes in all males fed diets containing 87.5 mg B/kg bw/day. Toxic effects at the two highest doses (87.5 mg B/kg bw/day and 262.5 mg B/kg bw/day) included rapid breathing, eye inflammation, paw swelling, and skin desquamation on paws and tails.

30.                At 2.6 mg B/kg bw/day, increased weights of the brain, spleen, kidneys, and ovaries were noted in females fed borax, while females fed boric acid showed increased liver weight; no changes were observed in males. At 8.8 mg B/kg bw/day, only increased kidney weights were reported in males fed borax. However, these changes were absent at 26.3 mg B/kg bw/day for both compounds. At 87.5 mg B/kg bw/day, significant (p<0.05) reductions in body weight and the weights of the liver, kidneys, spleen, and testes were observed. Lower doses showed inconsistent organ weight changes.

31.               Microscopic analysis revealed complete testicular atrophy at 87.5 mg B/kg bw/day for all males and partial atrophy at 26.3 mg B/kg bw/day in four males fed borax and one fed boric acid. The organ weight changes observed at 2.6 mg B/kg bw/day were not dose-dependent and were not corroborated in subsequent chronic studies by the same researchers.

32.               The authors identified a NOAEL of 8.8 mg B/kg bw/day based on testicular atrophy and a LOAEL of 26.3 mg B/kg bw/day for systemic toxicity in rats after sub chronic dietary exposure study.

33.               Sub-chronic Oral Toxicity in Beagle Dogs: 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 bw/day; female: 0.24, 2.5 and 21.8 mg B/kg bw/day) and compared with an untreated control group of 5 dogs/sex (Weir and Fisher, 1972; U.S. Borax Research Corp., 1963). On day 68 of the study, a high-dose male dog died as a result of complications of diarrhoea 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.

34.               At the high dose, mean testes weight was decreased 44% (9.6 g) in males fed borax and 39% (10.5 g) in males fed boric acid 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 (175 ppm) boric acid group.

35.               Microscopic pathology revealed severe testicular atrophy in all high-dose male dogs, with complete degeneration of the spermatogenic epithelium in 4/5 cases. No testicular lesions were found in the lower-dose groups.

36.               Haematological effects were also observed in high-dose dogs. Decreases were found for both haematocrit (15 and 6% for males and females, respectively) and haemoglobin (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; increased brain:body weight ratio (borax) and liver:body weight ratio (boric acid) in females; 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; increased width of the zona reticularis (borax males and females, boric acid females); and zona glomerulosa (boric acid females) in the adrenal gland.

37.           This study identified a LOAEL of 1750 ppm boron (male: 30.4 mg B/kg bw/day; female: 21.8 mg B/kg bw/day) and a NOAEL of 175 ppm boron (male: 3.9 mg B/kg bw/day; female: 2.5 mg B/kg bw/day) based on testicular atrophy and haemoglobin destruction in dogs following sub chronic exposure.

38.           Chronic Oral Toxicity in SD Rats: In the chronic study, Weir and Fisher (1972) fed Sprague-Dawley rats a diet containing 0, 117, 350, or 1170 ppm boron as borax or boric acid for 2 years (approximately 0, 5.9, 17.5, or 58.5 mg B/kg bw/day). The study was designed to assess systemic toxicity; only tissues from the brain, pituitary, thyroid, lung, heart, liver, spleen, kidney, adrenal, pancreas, small and large intestine, urinary bladder, testes, ovary, bone, and bone marrow were examined histopathologically. Tumours were not mentioned in the report. There were 70 rats/sex in the control groups and 35/sex in the groups fed boron compounds. At high dose, rats receiving both boron compounds had decreased food consumption during the first 13 weeks of study and suppressed growth throughout the study. Signs of toxicity at this exposure level included swelling and desquamation of the paws, scaly tails, inflammation of the eyelids, and bloody discharge from the eyes. Testicular atrophy was observed in all high-dose males at 6, 12, and 24 months. The seminiferous epithelium was atrophied, and the tubular size in the testes was decreased. Testes weights and testes:body weight ratios were significantly (p<0.05) decreased.

39.           Brain and thyroid:body weight ratios were significantly (p<0.05) increased at 1170 ppm. No treatment-related effects were observed in rats receiving 350 or 117 ppm boron as borax or boric acid.

40.           This study identified a LOAEL of 1170 ppm (58.5 mg B/kg bw/day) and a NOAEL of 350 ppm (17.5 mg B/kg bw/day) for testicular effects. Based on effects observed in the high-dose group, it appears that a maximum tolerated dose (MTD) was achieved in this study.

41.           Chronic Oral Toxicity in Beagle Dogs: In the chronic toxicity study, groups of beagle dogs (4/sex/dose/compound) were administered borax or boric acid in the diet at concentrations of 0, 58, 117, and 350 ppm boron (0, 1.4, 2.9, and 8.8 mg B/kg bw/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. Four 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. Sperm samples used for counts and motility testing were taken only on the control and high-dose male dogs prior to the 2-year sacrifice.

42.           At a dose level of 8.8 mg B/kg bw/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 bw/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 to be "not compound-induced." Tumours were not reported.

43.           In a follow-up to this study, groups of beagle dogs (4/sex/dose/compound) were given borax or boric acid in the diet at concentrations of 0 and 1170 ppm boron (0 and 29.2 mg B/kg bw/day) for up to 38 weeks (Weir and Fisher, 1972; U.S. Borax Research Corp., 1967). New control dogs (4 males) were used for this follow up study. Two were sacrificed at 26 weeks and two at 38 weeks. At the 26-week sacrifice, one of two had spermatogenesis and (5%) atrophy. One was reported as normal. At 38 weeks, one had decreased spermatogenesis, and the other had testicular atrophy. The test animals had about an 11% decrease in the rate of weight gain when compared with control animals, throughout the study. Interim sacrifice of two animals from each group at 26 weeks revealed severe testicular atrophy and spermatogenic arrest in male dogs treated with either boron compound. Testes weight, testes:body weight ratio, and testes:brain weight ratios were all decreased. Effects on other organs were not observed. Exposure was stopped at 38 weeks; at this time, one animal from each group was sacrificed and the remaining animal from each group was placed on the control diet for a 25-day recovery period prior to sacrifice.

44.           After the 25-day recovery period, testes weight and testes weight:body weight ratio were similar to controls in both boron-treated males, and microscopic examination revealed the presence of moderately active spermatogenic epithelium in one of the dogs. The researchers suggested that this finding, although based on a single animal, indicates that boron-induced testicular degeneration in dogs may be reversible upon cessation of exposure. When the 2-year and 38-week dog studies are considered together, an overall NOAEL and LOAEL for systemic toxicity can be established at 8.8 and 29.2 mg B/kg bw/day, respectively, based on testicular atrophy and spermatogenic arrest.

45.           Multigenerational study in SD rats: In a multigenerational study, Weir and Fisher (1972) administered 0, 117, 350, or 1170 ppm boron (approximately 0, 5.9, 17.5, or 58.5 mg B/kg bw/day) as borax or boric acid in the diet to groups of 8 male and 16 female Sprague-Dawley rats. No adverse effects on reproduction or gross pathology were observed in the rats dosed with 5.9 or 17.5 mg B/kg bw/day that were examined to the F3 generation. Litter size, weights of progeny, and appearance were normal when compared with controls. The test groups receiving 58.5 mg B/kg bw/day boron from either compound were found to be sterile. In these groups, males showed lack of spermatozoa in atrophied testes, and females showed decreased ovulation in the majority of the ovaries examined. An attempt to obtain litters by mating the treated females with the males fed only the control diet was not successful. A LOAEL of 58.5 mg B/kg bw/day and a NOAEL of 17.5 mg B/kg bw/day based on sterility and testicular atrophy were identified from this study.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

46.               This section summarises several other studies that have contributed to the understanding of the toxic effects of boron across species and exposure durations, which show effects at similar dose levels to the Heindel et al (1992), Price et al. (1996) and Weir and Fisher (1972) studies, and drawn from the ATSDR (2010) review.

47.               Dixon et al. (1976) studied the effects of sodium tetraborate on reproduction in male rats following acute and subchronic exposure. In the acute study, adult male Sprague–Dawley rats (10 animals per group) were given single oral doses of sodium tetraborate at 0, 45, 150 or 450 mg boron/kg bw. Fertility was assessed by serial mating trials in which each male was mated with a series of untreated virgin females in sequential 7 day periods (for up to 70 days). The females were sacrificed 9 days after the end of their breeding periods (when they could be 9–16 days pregnant), and uteri and fetuses were examined, though no evaluation is reported. Male rats were sacrificed on days 1 and 7, and at subsequent 7-day intervals, for histopathological examination of the testes. No effect on male fertility was found at any dose in this study. Testicular lesions were not reported. For this study, a US EPA evaluation of boron reported a NOAEL of 450 mg boron/kg bw for reproductive effects in male rats following single-dose oral exposure. In the sub-chronic study, rats were exposed to drinking water boron concentrations of 0.3, 1.0 and 6.0 (maximum dose equivalent to 0.84 mg B/kg bw/day). Groups were selected randomly at 30, 60 and 90 days and noted for body weight and weight of the testis, prostate, and seminal vesicles as well as changes in serum chemistry (sodium, potassium, chloride, carbon dioxide, total proteins, albumin, calcium, alkaline phosphatase, total bilirubin, blood urea nitrogen (BUN), glucose and serum glutamic-oxalic transaminase (SGOT), serum glutamic pyruvate transaminase, fructose, zinc and phosphate). Boron treatment did not affect LH and FSH in plasma. The sub-chronic tests failed to indicate any reproductive effects, changes in serum chemistry and body weight and weight of the testis, prostate, and seminal vesicles.

48.               A study by Lee et al. (1978) investigated the effects of dietary boron exposure on male Sprague-Dawley rats by administering 0, 500, 1000, and 2000 ppm of boron (as borax) in food for 30 to 60 days (equivalent to 0, 2.8, 5.7, and 11.3 mg B/kg bw/day). Eighteen male rats per group were examined for changes in fertility, testicular and epididymal histology, enzyme activities, hormone levels, and boron accumulation. Rats receiving 500 ppm (2.8 mg B/kg bw/day) showed no significant adverse effects. However, exposure to 1000 and 2000 ppm resulted in testicular atrophy, germ cell depletion, reduced seminiferous tubular diameter, and increased testicular boron levels. These morphological changes were linked to decreased activities of post-meiotic germ cell markers, while other enzyme activities increased, likely due to the relative enrichment of Sertoli cells and spermatogonia. Hormonal analysis revealed elevated plasma FSH, variable LH changes, and normal testosterone levels. Serial mating studies demonstrated dose-dependent reductions in fertility, with prolonged infertility at the highest dose. Rats exposed to 2000 ppm (11.3 mg B/kg bw/day) exhibited persistent germinal aplasia and infertility, lasting at least 8 months post-exposure. The NOAEL was determined to be 2.8 mg B/kg bw/day, based on testicular atrophy. These findings suggest that boron accumulation in the testes leads to progressive germ cell depletion and long-term reproductive dysfunction.

49.               Dixon et al. (1979) investigated the effects of dietary boron exposure to boron on male Sprague-Dawley rats by administering 0, 500, 1000, and 2000 ppm of boron (as borax) in food for 30 to 60 days (equivalent to 0, 25, 50, and 100 mg B/kg bw/day). Eighteen male rats per group were examined for correlations between enzyme activity (hyaluronidase (H), lactate dehydrogenase isoenzyme-X (LDH-X), dehydrogenases of sorbitol (SDH), a-glycerophosphate (GPDH), glucose--phosphate (G6PDH), malate (MDH), glyceraldehyde-3-phosphate (G3PDH), and isocitrate (ICDH)) and testicular histology and androgen activities of the male accessory organs. There was a significant decrease in tubular diameter across all the doses in the 60-day treatment groups. Male fertility was unaffected at 500 ppm. There was significant loss of germinal elements, testicular atrophy, reduced spermatocytes and spermatogenic cells at 1000 ppm. At 2000 ppm, several germinal aplasia, testicular atrophy, infertility and irreversible damage was noted in some cases. There was no dose-related decrease in litter size or fetal death in utero. Plasma FSH levels were elevated at higher doses, however, LH and testosterone remained unchanged. No dominant lethal effects were observed, and a testicular boron concentration of 6-8 ppm was associated with infertility. Overall, the authors established a NOAEL of 25 mg B/kg bw/day based on dose-related tubular germinal aplasia, which was noted to be reversible at low doses.

50.               Seal and Weeth (1980) conducted a 70-day study on Long-Evans hooded rats to further evaluate boron toxicity in drinking water and investigate its physiological effects at high concentrations. Male rats (15 per group) were given 0, 150, or 300 mg B/L, corresponding to recalculated doses of 0, 23.7, and 44.7 mg B/kg bw/day. Rats exposed to 150 mg B/L showed a 7.8% reduction in body weight, while those at 300 mg B/L had a 19.8% decrease. High-dose rats exhibited atrophic scrotal sacs, coarse fur, and elongated toenails. Testes and seminal vesicle weights significantly reduced, and spermatogenesis was severely impaired at 300 mg B/L, with only 3 out of 15 rats producing spermatozoa. Plasma protein and triglycerides were reduced at high doses, and bone calcium levels decreased at 300 mg B/L, indicating possible bone metabolism disruption. The study identified 23.7 mg/kg bw/day as the lowest observed adverse effect level (LOAEL) based on impaired spermatogenesis.

51.               Settimi et al. (1982) studied the effects of sodium tetraborate exposure in 2 month old Wistar rats. Male rats (20 per dose group) received either 0 or 3 g/L sodium tetraborate (0 – 20.8 mg B/kg bw/day as reported by ATSDR, 2010) in drinking water for 3 to 14 weeks. The study found increased cerebral succinate dehydrogenase activity after 10 and 14 weeks, along with elevated RNA concentration and acid proteinase activity in the brain at 14 weeks. In the liver, NADPH-cytochrome c reductase activity and cytochrome b5 content in the microsomal fraction decreased after 10 and 14 weeks, while cytochrome P-450 concentration was reduced at 14 weeks. There were no significant effects on body weight or liver, kidney, and testis weights compared to controls. The results support the hypothesis that the borate anion exerts its toxic effects by interfering with flavin metabolism in flavoprotein-dependent pathways.

52.               Fail et al. (1991) evaluated the potential reproductive toxicity of boric acid in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding protocol. Male and female mice were exposed to boric acid through feed at concentrations of 0, 1000, 4500, or 9000 ppm (0, 27, 111 and 220 B/kg bw/day) for 27 weeks.  Fertility effects were observed during a 14-week cohabitation period, where 4500 ppm partially reduced fertility, and 9000 ppm resulted in complete infertility, with no litters, dead or alive, produced at the highest dose. Among litters born at 4500 ppm, live litter size and body weight were significantly reduced. A crossover mating trial confirmed that males were the most affected, as 4500 ppm-exposed males mated with control females had significantly lower fertility rates and mating indices. Necropsy findings after 27 weeks of exposure showed dose-related reductions in male reproductive organ weights, increased abnormal sperm morphology, decreased sperm concentration and motility, and seminiferous tubule degeneration. In females, 4500 ppm exposure led to significantly reduced kidney/adrenal and liver weights, while kidney/adrenal weight reductions were also seen in males. Further assessment of the F1 generation, where the last litters of control and 1000 ppm females were reared to 74 days and mated within their treatment groups, showed normal fertility but decreased adjusted mean body weight in F2 pups. Overall, males were identified as the most sensitive sex for boron toxicity.

53.               Harris et al. (1992) conducted a study on Swiss CD-1 mice to assess reproductive and developmental toxicity of boric acid. Male and female mice were orally exposed via gavage, with the female group receiving daily doses for 19 days and co-habited with treated male mice after 7 days to evaluate reproductive toxicity, and a second group exposed during gestation (GD 8-14) and allowed to litter for observations through to postnatal day 4 (PND 4) to assess developmental toxicity. Dose levels used were 0, 120, 400 and 1200 mg/kg/day boric acid (0, 29.8, 69.92 and 209.76 B/kg bw/day). Significant testicular toxicity, including germ cell loss and reduced testis weight, was observed at the highest dose (1200 mg/kg/day). No effects were seen on epididymal weight or sperm density. Pregnant females at high doses exhibited increased post-implantation loss, and there was a reduction in live births at the highest dose, though no neonatal mortality occurred between postnatal days 1 and 4.

54.               In a study conducted by Ku et al. (1993), the reversibility of testicular lesions was evaluated in F344 rats administered boric acid in feed at concentrations of 0, 3,000, 4,500, 6,000, or 9,000 mg/kg (0, 26, 38, 52 or 68 mg B/kg bw/day) for 9 weeks. Recovery was assessed for up to 32 weeks post-treatment. Mild spermiation inhibition was observed at 3000 ppm from week 5, while 4500 ppm caused severe spermiation inhibition by week 2, leading to a 72–97% reduction in epididymal sperm count. Higher doses (6000 and 9000 ppm) resulted in progressive testicular atrophy, appearing by week 9 at 6000 ppm and as early as week 6 at 9000 ppm. Even after 32 weeks post-treatment, no recovery from testicular atrophy was observed in higher dose groups. No boron accumulation in the testes beyond levels found in blood was detected during the 9-week exposure period. Following treatment, serum and testis boron levels in all dose groups declined to background levels. Increased serum FSH and LH levels indicated a gonadotropin response to testicular damage.

55.           Chapin et al. (1997) investigated whether elevated dietary boric acid levels affected bone-related parameters, including serum electrolytes, bone structure, and strength. In the first study, male rats consumed diets containing 3000, 4500, 6000, or 9000 ppm boric acid (52.5, 78.8, 105 or 157.5 mg B/kg bw/day) for nine weeks, with serum calcium, phosphorous, potassium, chloride, and boron levels monitored during and after exposure. The second study included both male and female rats consuming diets with 200, 1000, 3000, or 9000 ppm boric acid (3.5, 17.5, 52.5 or 157.5 mg B/kg bw/day) for 12 weeks, assessing serum calcium, phosphorous, and magnesium levels, bone boron concentration, and bone structure and strength. The control diet contained 20–40 ppm boric acid. The authors have not provided a reason for this. Serum and bone boron concentrations were measured at weekly intervals and at 8, 16, 24, and 32 weeks post-exposure. Boron concentrations in bone were elevated in all treated groups, reaching up to four times the levels found in serum. Following cessation of exposure, serum and urinary boron levels returned to control values, while boron levels in bone remained three times higher than control levels up to 32 weeks post-exposure.

56.           Yoshizaki et al. (1999) conducted a three-week study on Wistar rats to evaluate the effects of boric acid on male reproductive parameters. Male rats (20 per group) received oral doses of 50, 150, and 500 mg/kg/day of boric acid (8.8, 26, 88 mg B/kg bw/day) via drinking water. Results showed that all parameters of epididymal sperm analysis were affected at the highest dose (500 mg/kg/day), with sperm number, motility, velocity, and amplitude of lateral head displacement also impacted at 150 mg/kg/day. Morphological examinations revealed seminiferous tubule atrophy and multinucleated giant cells in the testes at 500 mg/kg/day. The NOAEL in this study was 50 mg boric acid/kg bw/day (equivalent to 8.8 mg boron/kg bw/day).

57.           Sabuncuoglu et al. (2006) exposed male albino Sprague–Dawley rats (24 per group) to boric acid at doses of 0, 100, 275, or 400 mg/kg bw/day (0, 17.5, 48.1 and 70 mg B/kg bw/day). Kidneys were collected on days 10, 30, and 45 following sacrifice, and kidney weights, boron concentrations, and histopathological changes were assessed. Significant boron accumulation was observed in kidney tissue across all experimental groups, with a marked decrease in boron concentration on day 45 compared to day 30. Histopathological degenerative changes, particularly in proximal tubular cells, were dose- and time-dependent. The study concluded that subacute boric acid exposure led to dose-dependent kidney tissue damage in all exposed groups.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

58.               Following publication of a new WHO drinking water guideline value in 1993, which was lower than the UK regulatory limit for drinking water at the time, the COT was asked to consider the toxicity data. In 1994, the COT provisionally agreed with the WHO (1993) NOAEL of 8.8 mg/kg bw/day for boron and acknowledged that the testis was a target organ for boron toxicity. However, the COT requested further information before finalising its conclusions. This included considering a review of borates by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and a US National Toxicology Program (NTP) developmental toxicity study in rats (that would later be published by Price et al., 1996a) that was a follow up to an earlier Heindel et al., 1992 developmental toxicity study in rats. 

59.               In 1995, the COT considered this additional information. The COT noted reported reduction in relative testis weight (without histological changes) following a dose of 4.4 mg/kg bw/day of boron in a 90-day oral study of boric acid in dogs (Weir and fisher 1972). However, this was not seen in a 2-year study in dogs at higher doses where no convincing evidence of testicular toxicity was observed at boron doses of 8 to 9 mg/kg bw/day (Weir and Fisher 1972). The COT considered that the dog studies reported by Weir and Fisher 1972 were unreliable due to small animal numbers in the experimental groups and inadequacies in the histopathological descriptions. The COT agreed that the follow up developmental study in rats was of good quality and demonstrated a NOAEL of 9.6 mg born/kg bw/day for adverse effects of boron. Overall, the COT concluded that a NOAEL of around 10 mg/kg bw/day could be set based on the rat developmental studies.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

60.               The evaluations conducted by various authoritative bodies are summarised below in order of publication.

World Health Organisation (WHO, 1993)

61.               In 1993, WHO derived a tolerable daily intake for boron of 0.088 mg/kg bw/day.

62.                For this evaluation, the WHO considered the critical effect of boron to be testicular atrophy in a 2 year dog study (assumed to be Weir and Fisher 1972), with a NOAEL of 8.8 mg B/kg bw/day. A total uncertainty factor of 100 for interspecies and intraspecies variability was applied (WHO, 1993).

European Centre for Ecotoxicology and Toxicology of Chemical (ECETOC, 1995)

63.               ECETOC considered that acute and long-term exposure studies of boron indicated that testis was a target organ. Borates were not considered to be genotoxic or carcinogenic. A risk assessment was carried out based on reproductive and developmental effects as this was considered the most sensitive endpoint.

64.                The NOAEL was based on boron intake from the diet noted in the Weir and Fisher 1972, Lee et al., 1978 and Ku et al., 1993a studies in rats and the Fail et al., 1971 study in mice. The 2-year study in dogs by Weir and Fisher in 1972 was not considered for this due to several inadequacies. Based on these studies, the LOAEL for reproductive toxicity was determined to be 17.5 mg B/kg bw. The NOAEL and LOAEL for testicular changes in rodents was noted to be 17 mg B/kg bw and 26 mg B/kg bw, respectively. Developmental toxicity studies in rats (Heindel et al., 1992; Price et al.,1994), mice (Heindel et al.,1992) and rabbits (NTP, 1991) noted that rats were the most sensitive species with a NOAEL of 9.6 mg B/kg bw. Different NOAELs were determined for 3 different endpoints. Considering interspecies and intraspecies differences, the possible TDIs were calculated to be 35 mg B/day (0.583 mg/kg bw/day) for fertility, 34 mg B/day (0.567 mg/kg bw/day) for testicular effects and 19.2 mg B/day (0.32 mg/kg bw/day) for developmental effects. The TDI of 19.2 mg B/day (0.32 mg/kg bw/day) was agreed and considered adequate to protect human health.

Expert Group on Vitamins and Minerals (EVM, 2003)

65.                The NOAEL of 9.6 mg/kg bw/day from the Price et al., 1996 study was used to establish a Safe Upper Level (SUL). Reproductive toxicity was identified as the most sensitive endpoint and an uncertainty factor of 10 for inter-species variation and 6 for intra-species variation (based on a factor of 1.8 to account for variation in glomerular filtration in women and a factor of 3.2 to account for variability in toxicodynamics) as proposed by Dourson et al (1998) was used to derive a Safe Upper Level (SUL) of 0.16 mg boron/kg bw/day.

World Health Organization (WHO, 2009)

66.               In 2009, WHO derived a further tolerable daily intake (TDI) for boron of 0.2 mg/kg bw/day (WHO, 2009).

67.               The WHO considered the critical effect of boron to be decreased fetal body weight in rats, for which the NOAEL was 9.6 mg B/kg bw/day (Price et al., 1996). Multiple developmental end point data from the Heindel et al. (1992) and Price et al. (1996) studies were pooled and subjected to multiple benchmark dose analyses (Allen et al. 1996). The 95% lower confidence limit on the benchmark dose associated with a 5% reduction in mean fetal body weight (BMDL05) was calculated to be 10.3 mg B/kg bw/day. This BMDL05 is close to the Price et al. (1996) NOAEL of 9.6 mg B/kg bw/day.  A total uncertainty factor of 60 was applied to the BMDL − 10 for interspecies variation and 6 for intraspecies variation based on a factor of 1.8 to account for variation in glomerular filtration in women and a factor of 3.2 to account for variability in toxicodynamics, as proposed by Dourson et al (1998). This was used to establish a TDI of 0.17 mg/kg bw/day, rounded to 0.2 mg/kg bw/day.

Agency for Toxic Substances and Disease Registry (ATSDR, 2010)

68.               The ATSDR has derived an intermediate-duration oral Minimal Risk Level (MRL) for boron of 0.2 mg/kg bw/day. An MRL is an estimate of the daily human exposure to a substance that is likely to be without appreciable risk of adverse non-cancer health effects over a specified duration of exposure; the intermediate duration used in this instance covers exposures between 15 and 365 days.

69.               ATSDR noted that the available intermediate-duration oral database clearly identifies the developing fetus as the most sensitive target of toxicity. Two studies in rats (Heindel et al. 1992; Price et al. 1996) identified LOAELs of 13–13.6 mg B/kg bw/day for decreases in fetal body weight and skeletal malformations (only identified in the Price et al. 1996 study). These LOAELs are lower than the NOAEL of 30 mg B/kg bw/day identified for reproductive toxicity in a 3-generation study (Weir and Fisher 1972) and NOAELs of 35 or 45 mg B/kg bw/day for haematological and dermal effects (Weir and Fisher 1972) (ATSDR, 2010).

70.           The BMDL05 of 10.3 mg boron/kg/day based on decreased fetal body weight in rats derived by Allen et al. 1996 (described above) was divided by a chemical-specific uncertainty factor of 66 (3.3 for toxicokinetic extrapolation from animals to humans, 3.16 for toxicodynamic extrapolation from animals to humans, 2.0 for variability in human toxicokinetics, and 3.16 for variability in human toxicodynamics) resulting in an intermediate-duration oral MRL of 0.2 mg B/kg bw/day (rounded value).

European Food Safety Authority (EFSA, 2013)

71.           In 2013, the EFSA also considered that the male reproductive system in animals is a target for boron toxicity. From a developmental study in rats (Price et al., 1996a), a NOAEL of 9.6 mg B/kg bw/day for developmental toxicity (decreased fetal weight) was identified. Application of a total uncertainty factor of 60 (6 for intraspecies variation based on a factor of 1.8 to account for variation in glomerular filtration in women and a factor of 3.2 to account for variability in toxicodynamics and 10 for interspecies variation) produced a TDI of 0.16 mg/kg bw/day (EFSA 2013).

Health Canada

72.           A BMDL05 of 2.90 mg/kg bw/day (using the US EPA BMD Software (v2.7)) was estimated for the testicular effects (decreased testicular weight) in dogs in the study by Weir and Fisher 1972. A total uncertainty factor of 300 (10 for interspecies variability, 10 for intraspecies variability and 3 for database uncertainties, including that histological changes may occur at lower doses than those associated with testicular weight) was applied which produced a TDI of 0.01 mg/kg bw/day (Health Canada, 2023).

73.           Health Canada noted that if an alternative NOAEL were used from the study in rats by Price et al., 1996, then an alternative TDI of 0.18 mg/kg bw/day could be estimated. By using the data from Price et al., (1996) study based on decreased fetal body weight, Health Canada derived a BMDL05 of 10.6 mg B/kg bw/day using the US EPA BMD Software (v2.7). It was acknowledged that this value was consistent with the BMDL05 established by Allen et al. (1996) using the same dataset. A total uncertainty factor of 60 (6 for intraspecies variability, 10 for interspecies variability) was applied to this BMDL05, which produced a TDI of 0.18 mg/kg bw/day (Health Canada, 2023).

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

74.               Boron is readily absorbed in the gastrointestinal tract, primarily as boric acid. Once absorbed, it distributes evenly across body fluids and soft tissues with a higher accumulation in bones (2–3 times higher than in soft tissues). Boron crosses the placenta in humans and has been detected in placental and umbilical cord blood. Boron is not metabolized in the body, instead it is excreted largely unchanged in the urine.

75.               Boron toxicity primarily affects the reproductive and developmental systems, as demonstrated in both human and animal studies. Although boron is not considered an essential nutrient for humans, low levels may confer some benefits to bone health and cognitive function. Oral exposure animal studies have demonstrated that the reproductive system and the developing foetus are the most sensitive targets of boron toxicity. Adverse developmental effects have been identified for both acute and intermediate-duration exposures.

76.               A number of studies on boron are available, with a wide range of NOAEL/BMDL values reported. The toxicity of boron has been reviewed by a range of authoritative bodies. The differences in the HBGVs derived by these bodies is due to differences in interpretation of the critical studies, NOAEL/BMDL values selected, and uncertainty factors applied. Table 1 below summarises these values and the uncertainty factors used.

Table 1: Comparison of NOAEL/BMDLs, uncertainty factors and HBGV values from different authoritative bodies.

77.               Members are invited to consider the following questions:

i)             From the studies presented, is the Committee able to identify a Point of Departure on which the assessment of boron should be based?

ii)           Is the Committee able to derive a health-based guidance value for boron and if so, what uncertainty factors does the Committee propose to use with the Point of Departure?

iii)          Are there any other uncertainties or considerations the Committee would like to highlight in evaluating boron?

iv)         Does the Committee have any other comments?

Secretariat

August 2025

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

This is a paper for discussion. This does not represent the views of the Committee and should not be cited.

Agency for Toxic Substances and Disease Registry (ATSDR) (2010) Toxicological profile for Boron. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. ATSDR Boron Tox Profile

Allen, B.C., Strong, P.L., Price, C.J., Hubbard, S.A. and Daston, G.P., 1996. Benchmark dose analysis of developmental toxicity in rats exposed to boric acid. Fundamental and Applied Toxicology, 32(2), pp.194-204.

Chapin, R. E., Ku, W. W., Kenney, M. A., McCoy, H., Gladen, B., Wine, R. N., Wilson, R. and Elwell, M. R., 1997. The effects of dietary boron on bone strength in rats. Fundamental and Applied Toxicology, 35, pp.205–215.

Chapin, R.E., Ku, W.W., Kenney, M.A. and McCoy, H., 1998. The effects of dietary boric acid on bone strength in rats. Biological Trace Element Research, 66, pp.395-399.

COT (Committee on Toxicity) (1995) Annual report: Boron in drinking water and food. p. 6. cotannualreport1995.pdf

Coughlin, J.R., 1996. Inorganic borates: Chemistry, human exposure, and health and regulatory guidelines. The Journal of Trace Elements in Experimental Medicine: The Official Publication of the International Society for Trace Element Research in Humans, 9(4), pp.137-151.

Dixon R.L., Lee I.P. and Sherins R.J., 1976. Methods to assess reproductive effects of environmental chemicals: studies of cadmium and boron administered orally. Environmental Health Perspectives, 13, pp.59-67.

Dixon R.L., Sherins R.J. and Lee I.P., 1979. Assessment of environmental factors affecting male fertility. Environmental Health Perspectives, 30, pp.53-68.

Dourson, M., Maier, A., Meek, B., Renwick, A., Ohanian, E., Poirier, K. (1998) Re-evaluation of toxicokinetics for data-derived uncertainty factors. Biological Trace Element Research 66, 453-463.

ECETOC, 1995. Reproductive and general toxicology of some inorganic borates and risk assessment for human beings (Technical Report No. 63). 

EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS), 2013. Scientific Opinion on the re‐evaluation of boric acid (E 284) and sodium tetraborate (borax) (E 285) as food additives. EFSA Journal, 11(10), p.3407. Re-evaluation of boric acid (E 284) and sodium tetraborate (E 285) as food additives | EFSA

EVM, 2003. Boron – in Safe Upper Levels for Vitamins and Minerals pages 164-171. vitmin2003.pdf

Fail, P. A., George, J. D., Seely, J. C., Grizzle, T. B. and Heindel, J. J., 1991. Reproductive toxicity of boric acid in Swiss (CD-1) mice: Assessment using the continuous breeding protocol. Fundamental and Applied Toxicology, 17, pp.225–239.

Forbes, R.M., Cooper, A.R. and Mitchell, H.H., 1954. On the occurrence of beryllium, boron, cobalt, and mercury in human tissues.

Harris, M. W., Chapin, R. E., Lockhart, A. C. and Jokinen, M. P., 1992. Assessment of a short-term reproductive and developmental toxicity screen. Fundamental and Applied Toxicology, 19, pp.186–196.

Health Canada (2023) Boron: Guidelines for drinking water quality. Health Canada, Ottawa. Guidelines for Canadian drinking water quality boron: Overview - Canada.ca

Heindel, J.J., Price, C.J., Field, E.A., Marr, M.C., Myers, C.B., Morrissey, R.E. and Schwetz, B.A., 1992. Developmental toxicity of boric acid in mice and rats. Fundamental and applied toxicology, 18(2), pp.266-277. Developmental toxicity of boric acid in mice and rats - ScienceDirect

IPCS, 2009. Principles and methods for the risk assessment of chemicals in food. Environmental Health Criteria 240, Principles and methods for the risk assessment of chemicals in food (EHC 240, 2009)

Ku, W. W., Chapin, R. E., Wine, R. N. and Gladen, B. C., 1993. Testicular toxicity of boric acid (BA): Relationship of dose to lesion development and recovery in the F344 rat. Reproductive Toxicology, 7, pp.305–319.

Lee, I. P., Sherins, R. J. and Dixon, R. L., 1978. Evidence for induction of germinal aplasia in male rats by environmental exposure to boron. Toxicology and Applied Pharmacology, 45, pp.577–590.

Murray, F.J., 1998. A comparative review of the pharmacokinetics of boric acid in rodents and humans. Biological trace element research, 66, pp.331-341.

Pahl, M.V., Culver, B.D., Strong, P.L., Murray, F.J. and Vaziri, N.D., 2001. The effect of pregnancy on renal clearance of boron in humans: a study based on normal dietary intake of boron. Toxicological Sciences, 60(2), pp.252-256.

Price, C. J., M. C. Marr, and C. B. Myers. "Determination of the No-Observable-Adverse-Effect Level (NOAEL) for Developmental Toxicity in Sprague-Dawley (CD) Rats Exposed to Boric Acid in Feed on Gestational Days 0 to 20, and Evaluation of Postnatal Recovery through Postnatal Day 21." Research Triangle Park (NC): Research Triangle Institute (RTI Identification No. 65C-5657-20O) (1994).

Price, C.J., Strong, P.L., Marr, M.C., Myers, C.B. and Murray, F.J., 1996. Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation. Fundamental and applied toxicology, 32(2), pp.179-193. Developmental Toxicity NOAEL and Postnatal Recovery in Rats Fed Boric Acid during Gestation - ScienceDirect

Sabuncuoglu, B. T., Kocaturk, P. A., Yaman, O., Kavas, G. O., and Tekelioglu, M., 2006. Effects of subacute boric acid administration on rat kidney tissue. Clinical Toxicology, 44(3), pp.249–253.

Seal, B. S. and Weeth, H. J., 1980. Effect of boron in drinking water on the male laboratory rat. Bulletin of Environmental Contamination and Toxicology, 25, pp.782–789.

Settimi, L., Elovaara, E. and Savolainen, H., 1982. Effects of extended peroral borate ingestion on rat liver and brain. Toxicology Letters, 10, pp.219–223.

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Weir Jr, R.J. and Fisher, R.S., 1972. Toxicologic studies on borax and boric acid. Toxicology and applied pharmacology, 23(3), pp.351-364. Toxicologic studies on borax and boric acid - ScienceDirect

WHO, 1993. Boron – in Guidelines for drinking-water quality, 2nd edition: Volume 1 – Recommendations page 43-44. Guidelines for drinking-water quality, 2nd edition: Volume 1 - Recommendations

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Yoshizaki, H., Izumi, Y., Hirayama, C., Fujimoto, A., Kandori, H., Sugitani, T., and Ooshima, Y., 1999. Availability of sperm examination for male reproductive toxicities in rats treated with boric acid. The Journal of Toxicological Sciences, 24(3), pp.199–208.