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Nomination Summary for Boron (N21802)

Nominated Substances: Boron

Nomination Date: 12/08/2017

Nominator: Minnesota Department of Health

Rationale: The Minnesota Department of Health, Risk Assessment Unit, recently finished conducting a chemical review of boron to determine the level of boron in drinking water that is safe to ingest. While conducting the review and determining the water guidance, a critical data gap became apparent. There is a lack of information on the exposure and sensitivity to boron, during the neonatal period. Developmental studies involving in utero exposure-only resulted in body weight reduction in fetal rats (Heindel 1992, Price 1996a). At a similar level of boron exposure, fetal skeletal malformations also occurred (Heindel 1992, Price 1996a). These fetal effects are observed in multiple species: rats, mice (Heindel 1992), and rabbits (Price 1996b). However, after birth, there are no reports that adequately survey neonate toxicity. Boron is known to affect bone health and aid in the effectiveness of calcium, vitamin D, and magnesium (Pizzorno 2015). The neonatal period is a time of active bone growth and may represent a period sensitive to boron levels in the body. Young infants are among the most heavily exposed life stages. Based on the dietary boron ingestion values from Rainey 2002 and body weight data from US EPA 2011, the estimated mean and 95th percentile dietary intake in infants age 0 – 6 months of age are 0.116 and 0.457 mg/kg-d, respectively. The US EPA Health Advisory for children is 3 mg/L. Using mean and 95th percentile water intake rates (US EPA 2011) and the US EPA Health Advisory of 3 mg/L, results in mean and 95th percentile intakes of 0.31 and 0.66 mg/kg-d, respectively, for infants in this age group from water alone. This is significant since these intake rates exceed the current US EPA IRIS (2004) reference dose (RfD) of 0.2 mg/kg-d and the World Health Organization’s (2011) tolerable daily dose (TDI) of 0.17 mg/kg-d. Although sparse, human data is beginning to emerge on the correlation between fetal effects and maternal boron exposure (Igra 2016, Harari 2012). Newborns in Argentina were weighed and their heights and head circumferences were recorded and compared to their mothers’ boron serum blood levels (Igra 2016). (The mothers’ drinking water had boron concentrations between 0.3 and 10.8 mg/L. Boron dietary levels were not determined). Serum boron concentrations above 80 µg/L were inversely associated with newborn birth length. An increase of 10 µg/L in the third trimester corresponded with shorter (0.9 cm) and lighter (120 g) newborns. It is interesting that human boron exposures are beginning to parallel the reduced fetal weights observed in animal studies. In a study that consisted of mothers and their newborns from Argentina and Chile (Harari 2012), boron concentrations were measured in newborns’ first urine release, and then at 2-4 weeks, 2-4 months, and 4-6 months after. Urine boron levels were highest in the first newborn urine release (highest boron urine concentration was 14 mg/L). Urine boron levels then immediately decreased. However, exclusively breast-fed infants had lower concentrations of boron in their urine than those infants that were not exclusively breast-fed; and remained lower throughout the study. It is becoming important to have toxicological information on the non-breast-fed infant. In addition to the in utero exposure only studies mentioned above, the current database also contains one multigenerational study performed in rats (Weir and Fisher, 1972), and one continuous breeding study utilizing CD-1 mice (Fail 1991). Each of these studies have multiple limitations. Direct dosing to the neonates was not conducted and it is unclear what level of exposure to the neonates occurred. In addition, Fail used mice that were continuously bred to produce five litters, and due to sterility at the mid and high dose, were unable to provide a dose response for the F1 and F2 generations. Due to the high potential for exposure to newborns and the lack of existing toxicological data on early life sensitivity to boron, we are requesting that NTP perform a direct dosing neonatal toxicity study to determine potential adverse effects. Information from this study will fill in a large and important data gap in the toxicity profile for boron. References Fail, P. A., George, J. D., Seely, J. C., Grizzle, T. B., & Heindel, J. J. (1991). Reproductive toxicity of boric acid in Swiss (CD-1) mice: assessment using the continuous breeding protocol. Fundam Appl Toxicol, 17(2), 225-239. Harari, F., Ronco, A. M., Concha, G., Llanos, M., Grander, M., Castro, F., . . . Vahter, M. (2012). Early-life exposure to lithium and boron from drinking water. Reprod Toxicol, 34(4), 552-560. Heindel, J. J., Price, C. J., Field, E. A., Marr, M. C., Myers, C. B., Morrissey, R. E., & Schwetz, B. A. (1992). Developmental toxicity of boric acid in mice and rats. Fundam Appl Toxicol, 18(2), 266-277. Igra, A. M., Harari, F., Lu, Y., Casimiro, E., & Vahter, M. (2016). Boron exposure through drinking water during pregnancy and birth size. Environ Int, 95, 54-60. Pizzorno, L. (2015). Nothing Boring About Boron. Integrative Medicine, 14(4), 35-48. Price, C. J., Strong, P. L., Marr, M. C., Myers, C. B., & Murray, F. J. (1996). Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation. Fundam Appl Toxicol, 32(2), 179-193. Price, C. J., Marr, M. C., Myers, C. B., Seely, J. C., Heindel, J. J., & Schwetz, B. A. (1996b). The developmental toxicity of boric acid in rabbits. Fundam Appl Toxicol, 34(2), 176-187. Rainey, C. J., Nyquist, L. A., Coughlin, J. R., & Downing, R. G. (2002). Dietary Boron Intake in the United States: CSFII 1994-1996. Journal of Food Composition and Analysis, 15, 237-250. U.S. Environmental Protection Agency (EPA) - IRIS. (2004). Boron and Compounds - Chemical Assessment Summary. Washington, D.C. Retrieved from https://cfpub.epa.gov/ncea/iris/iris_documents/documents/subst/0410_summary.pdf U.S. Environmental Protection Agency (EPA) - Office of Research and Development. (2011). Exposure Factors Handbook: 2011 Edition. Retrieved from https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=236252 Weir, R. J., Jr., & Fisher, R. S. (1972). Toxicologic studies on borax and boric acid. Toxicol Appl Pharmacol, 23(3), 351-364. World Health Organization. (2011). Guidelines for Drinking-water Quality - Fourth Edition. Retrieved from http://apps.who.int/iris/bitstream/10665/44584/1/9789241548151_eng.pdf

NTP Principles: not specified

Status: In Review


Agents and Status

The following information relates to the specific agent and may include history from earlier or later nominations for this same agent.


CASRN: 10043-35-3

Agent Name: Boric acid