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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 1 of 22
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`
`BIOLOGICAL TRACE ELEMENT RESEARCHi--
`
`Published under the auspices of the International Association of Bioinorganic Scientists
`Official Journal of the World Biomedical Selenium Society
`Gerhard N. Schrauzer • Editor-in-Chief
`Biological Trace Element Research Institute • San Diego, CA
`Manuel F. Flores-Arce• Managing Editor
`Laboratory of Trace Elements and Environmental Toxicology, Instituto Tecnologico de Tijuana, Mexico
`Charles H. Hill• Editor• College of Agriculture and Life Sciences• North Carolina State University •
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`
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`·
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`
`Editorial Board
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`R. Osterberg, Swedish University of Agricultural
`Sciences, Uppsala, Sweden
`W. Pories, East Carolina School of Medicine,
`Greenville, NC
`P. D. Saltman, University of California, La Jolla, CA
`H. H. Sandstead, University of Texas, Galveston, TX
`B. Sarkar, Hospital for Sick Children, Toronto, Canada
`J.E. Spallholz, Texas Tech University, Lubbock, TX
`F. W. Sunderman, Jr., University of Connecticut
`Medical School, Farmington, CT
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`Xi'an Shaanxi, PROC
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`
`Volume 66, Numbers 1-3, Winter 1998
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`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 2 of 22
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`

`
`Biological Trace Element Research
`
`Vol. 66, Nos. 1-3, Winter 1998
`
`Proceedings of the Second International Symposium
`
`on the Health Effects of
`
`Boron
`and Its Compounds
`
`October 22-24, 1997
`
`GUEST EDITORS
`
`B. DWIGHT CULVER
`FRANK M. SULLIVAN
`
`F. JAY MURRAY
`}AMES R. COUGHLIN
`PHILIP L. STRONG
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 3 of 22
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`

`
`Biological Trace Element Research
`
`Vol. 66, Nos. 1-3, Winter 1998
`
`CONTENTS
`
`Second International Symposium on the Health Effects of Boron and Its Compounds:
`Introduction
`B. Dwight Culver ...................................................................................................................... 1
`
`Considerations in the Determination of Boron at Low Concentrations
`R. Gregory Downing,* Philip L. Strong, B. Michael Hovanec, and
`Jack Northington ................................................................................................................ 3
`
`A Round-Robin Determination of Boron in Botanical and Biological Samples
`R. Gregory Downing* and Philip L. Strong ...................................................................... 23
`
`Isotope Ratio Determination in Boron Analysis
`Ram N. Sah* and Patrick H. Brown ................................................................................... 39
`
`Measurement of Borate in Occupational Environments
`Robert A. Smith* and Frederick M. Ascher[ ...................................................................... 55
`
`A Comparison of Worker Exposure to Inhalable and Total Dust, Inorganic Arsenic,
`and Borates Using Tw:i Types of Particulate Sampling Assemblies in a Borate
`Mining and Processing Facility
`M.A. Katchen, * V. A. Puhalovich, R. Swaroop, and B. D. Culver .............................. 59
`
`Dietary Boron Intakes of Selected Populations in the United States
`Susan L. Meacham* and Curtiss D. Hunt .......................................................................... 65
`
`Multicountry Estimation of Dietary Boron Intake
`Charlene Rainey* and Leslie Nyquist ................................................................................ 79
`. Sources of Human Exposure: Overview of Water Supplies as Sources of Boron
`fames R. Coughlin ................................................................................................................... 87
`
`In Vivo Percutaneous Absorbtion of Boron as Boric Acid, Borax, and Disodiurn
`Octaborate Tetrahydrate in Humans: A Summary
`Ronald C. Wester,* Xiaoying Hui, Howard I. Maibach, Kathleen Bell,
`Michael J. Schell, D. Jack Northington, Philip L. Strong,
`and B. Dwight Culver ..................................................................................................... 101
`
`In Vitro Percutaneous Absorbtion of Boron as Boric Acid, Borax, and Disodiurn
`Octaborate Tetrahydrate in Human Skin: A Summary
`Ronald C. Wester,* Tracy Hartway, Howard I. Maibach, Michael/. Schell,
`D. f ack Northington, B. Dwight Culver, and Philip L. Strong ............................. 111
`
`Boron Exposure from Consumer Products
`Margaret Richold .................................................................................................................. 121
`
`Distribution of Boron in the Environment
`Peter Argust ........................................................................................................................... 131
`
`The Isotopic Composition of Anthropogenic Boron and Its Potential Impact
`on the Environment
`Avner Vengosh ....................................................................................................................... 145
`
`A Review of Boron Effects in the Environment
`Paul D. Howe ......................................................................................................................... 153
`
`*For papers with multiple authorship,the asterisk identifies the author to \-\horn correspondence
`and reprint requests should be addressed.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 4 of 22
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`

`
`Biological Trace Element Research
`
`Vol. 66, Nos. 1-3, Winter 1998
`
`CONTENTS
`
`Relationships Betw=en Boron Concentrations and Trout in the Firehole River,
`Wyoming: Historical Information and Preliminary Results of a Field Study
`foseph S. Meyer,* Ann M. Boelter, Daniel F. Woodward, f ack N. Goldstein,
`Ai"da M. Farag, and Wayne A. Hubert···························································~············· 167
`
`Review of the Scientific Basis for Establishing the Essentiality of Trace Elements
`Walter Mertz .......................................................................................................................... 185
`
`Determining Human Dietary Requirements for Boron
`Barbara Sutherland,* Phil Strong, and fanet C. King .................................................. 193
`Regulation of Enzymatic Activity: One Possible Role of Dietary Boron in Higher
`Animals and Humans
`Curtiss D. Hunt ..................................................................................................................... 205
`
`The Nutritional and Metabolic Effects of Boron in Humans and Animals
`S. Samman, * M. R. Naghii, P. M. Lyons Wall, and A. P. Verus ................................. 227
`
`Adverse Reproductive and Developmental Effects in Xenopus from
`Insufficient Boron
`Douglas f. Fort,* Timothy L. Propst, Enos L. Stover, Philip L. Strong,
`and F. fay Murray ............................................................................................................ 237
`
`The Response of Trout and Zebrafish Embryos to Low and High Boron
`Concentrations Is U-Shaped
`Ruby l. Rowe, Collen Bouzan, Sam Nabili, and Curtis D. Eckhert* ......................... 261
`
`Assessing the Effects of Low Boron Diets on Embryonic and Fetal Development
`in Rodents Using In Vitro_an4 In Viv:o Model Systems
`Louise Lanoue, Marie W. Taubeneck; fesus Muniz, Lynn A. Hanna,
`Philip L. Strong, F. fay Murray, Forrest H. Nielsen, Curtiss D. Hunt,
`and Carl L. Keen* ............................................................................................................. 271
`
`The Importance of Boron Nutrition for Brain and Psychological Function
`fa mes G. Penland .................................................................................................................. 299
`
`The Justification for Providing Dietary Guidance for the Nutritional Intake of Boron
`Forrest H. Nielsen ................................................................................................................. 319
`
`A Comparative Review of the Pharmacokinetics of Boric Acid in Rodents
`and Humans
`F. Jay Murray ......................................................................................................................... 331
`
`Comparative Toxicology of Borates
`Susan A. Hubbard ................................................................................................................. 343
`
`Developmental Effects of Boric Acid in Rats Related to Maternal Blood Boron
`Concentrations
`Catherine f. Price,* Philip L. Strong,
`F. fay Murray, and Margaret M: Goldberg ................................................................ 359
`
`*For papers with multiple authorship,the asterisk identifies the author to -whom correspondence
`and reprint requests should be addressed.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 5 of 22
`
`

`
`Biological Trace Element Research
`
`Vol. 66, Nos. 1-3, Winter 1998
`
`CONTENTS
`
`Effects of Boric Acid on Axial Skeletal Development in Rats
`Michael G. Narotsky, * fudith E. Schmid, fames E. Andrews,
`and Robert J. Kavlock .................................................................................................... 373
`
`The Effects of Dietary Boric Acid on Bone Strength in Rats
`Robert E. Chapin,* Warren W. Ku, Mary Alice Kenney, and Harriet McCoy ......... 395
`
`Comparison of Infertility Rates in Communities from Boron-Rich and
`Boron-Poor Territories
`E. Tiiccar, A.H. Elhan, * Y. Yavuz, and B. S. Sayli ....................................................... 401
`
`An Assessment of Fertility in Boron-Exposed Turkish Subpopulations:
`2. Evidence That Boron Has No Effect on Human Reproduction
`Bekir Sitki Sayli .................................................................................................................... 409
`
`The Effect of Essentiality on Risk Assessment
`George C. Becking ................................................................................................................. 423
`
`International Programme on Chemical Safety (IPCS) Environmental Health Criteria
`on Boron Human Health Risk Assessment
`George C. Becking* and Bing-Heng Chen ........................................................................ 439
`
`Boron Tolerable Intake: Re-evaluation of Toxicokinetics for Data-Derived
`Uncertainty Factors
`Michael Dourson, *Andrew Maier, Bette Meek, Andrew Renwick,
`Edward Ohanian, and Kenneth Poirier ...................................................................... 453
`
`Summary of Research Needs
`Frank M. Su.l!ivan_ a1J,d B. Dwight Culver* ................ .-............. :·~·······················--············· 4~5
`
`Author Index ....................................................................................................................... 469
`
`Subject Index ...................................................................................................................... .471
`
`"For papers with multiple authorship, the asterisk identifies the author to whom correspondence
`and reprint requests should be addressed.
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 6 of 22
`
`

`
`©Copyright 1998 by Humana Press Inc.
`All rights of any nature, whatsoever, reserved.
`0163-4984/98/6601-3--0001 $08.25
`
`Second International Symposium
`on the Health Effects of Boron
`and Its Compounds
`Introduction
`
`The Second International Symposium on the Health Effects of Boron
`and Its Compounds, October 22-24, 1997, brought together investigators
`interested in the effects of boron in biological and environmental systems
`at toxicological, pharmacological, and nutritional levels. A majority of
`the principal investigators working in these areas reported the results
`of the studies they have conducted over the past five years. Important
`contributions were made also by participants interested in the research
`methods required to measure these effects, especially at low-exposure
`levels where the complex chemistry of boron must be taken into account.
`Studies pointing to the nutritional importance of boron have been
`-conducted-over the past 20 years, and at the 1992 symposium, a number
`of studies investigating the nutritional role of boron were presented.
`However, it was not until this present symposium that the essentiality of
`boron for some vertebrate species was demonstrated.
`As was the case with the First International Symposium held in
`1992, it was hoped that this symposium would, by presenting as com(cid:173)
`pletely as possible the current state of knowledge about boron and its
`compounds, stimulate research into issues identified by the participants.
`The concluding article in this volume is an effort to underline future
`research needs.
`
`Biological Trace Element Research
`
`1
`
`Vol. 66, 1998
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1054 - Page 7 of 22
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`

`
`©Copyright 1998 by Humana Press Inc.
`All rights of any nature, whatsoever, reserved.
`0163-4984/98/6601-3-0343 $11.75
`
`Comparative Toxicology of Borates
`SUSAN A. HUBBARD
`Borax Europe Limited, Guildford, GU2 5RQ, UK
`
`ABSTRACT
`
`Inorganic borates, including boric acid, Na, ammonium, K,
`and Zn borates generally display low acute toxicity orally, der(cid:173)
`mally, and by inhalation. They are either not irritant or mild skin
`and eye irritants. Exceptions owing to physiochemical properties
`do occur.
`Longer-term toxicological studies have been reported mainly on
`boric acid or borax where the properties are generally similar on an
`equivalent boron (B) basis. The critical effects in several species ·are
`male reproductive toxicity and developmental toxicity. The doses that
`cause these effects are far higher than any levels to which the human
`population could be exposed. Humans would need to consume daily
`some 3.3 g of boric acid (or 5.0 g borax)-to ingest the same dose level
`as the lowest animal NOAEL. No effects on fertility were seen in a
`population of workers exposed to borates or to a population exposed
`to high environmental borate levels.
`There is remarkable similarity in the toxicological effects of
`boric acid and borax across different species. Other inorganic borates
`that simply dissociate to boric acid are expected to display similar
`toxicity, whereas those that do not dissociate simply to boric acid
`may display a different toxicological profile.
`Index Entries: Borates; boric acid; borax; reproductive toxicity;
`developmental toxicity.
`
`INTRODUCTION
`
`A number of detailed reviews of the toxicology of borates have been
`published (1-5). The majority of toxicological studies of borates have
`involved either boric acid (H3B03) or disodium tetraborate decahydrate,
`known as borax (Na2B407'10H20). Studies of other inorganic borates,
`including Na tetraborates, octaborate, perborates, metaborates, and
`ammonium, K, and Zn borates have largely been confined to acute toxi(cid:173)
`cological studies. The inorganic borates that have been tested for acute
`
`Biological Trace Element Research
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`343
`
`Vol 66, 1998
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`

`
`344
`
`l
`
`I
`
`Hubbard
`
`Table 1
`Major Inorganic B Compounds and Their Oral LD50 Values
`LD50 mg/kg
`Reference
`rat
`
`Boric acid
`Boric oxide (anhydrous boric acid)
`
`Disodium tetraborate decahydrate (Borax)
`Disodium tctraborate pentahydrate
`Anhydrous disodium lelraborale
`
`Na2B.07 • 10Hp
`Na2B.O, •5H20
`Na2B40 7
`
`Disodium octaborate letrahydrate
`
`Sodium metaborale dihydrale
`Sodium metaborate tetrahydrate
`
`Disodium pcrborale tetrahydrate
`Disodium perborale monohydrate
`
`NaB02• 2H20
`NaB02• 4H20
`
`NaB0 3 •4H20
`NaB03. • H20
`
`2660- 4100
`> 2000
`
`4500- 6000
`3200- 3400
`> 2000
`
`2550
`
`> 2000
`2300
`
`21, 22
`24
`
`21
`23
`25
`
`30
`
`26
`27
`
`2100, 2243
`l 120- 2100
`
`32 reviewed
`in 2
`
`Diammonium tctraborale tetrahydrate
`Ammonium pentaborale tetrahydrale
`
`(Nl-l.JiB.O, • 4H20
`NH4B50 8 • 4H 20
`
`>4200 (mice)
`> 4200 (mice)
`
`Potassium tctraborale tclrahydrate
`
`K2B40 7 • 4H20
`
`3700
`
`Zinc borate 2.3.3.5
`Zinc borate 4.1.1
`
`2Zn0 • 3 8 20.i • 3.5 H20
`4Zn0 • 8 20 3 • H20
`
`> 10000
`>5000
`
`28
`28
`
`29
`
`31
`32
`
`toxicity are listed in Table 1. Only boric acid and borax fl.ave been evalu(cid:173)
`ated in longer-term studies.
`Most of these simple inorganic borates exist predominantly as undis(cid:173)
`sociated boric acid in dilute aqueous solution at physiological pH, lead(cid:173)
`ing to the conclusion that the main species in the plasma of mammals is
`likely to be undissociated boric acid. Differences in physiochemical prop(cid:173)
`erties may lead to other species existing in water, such as:
`1. The formation of hydrogen peroxide with Na perborate.
`2. The formation of strongly alkaline solutions with Na
`meta.borate.
`3. Strongly acid solutions with the boron (B) halides.
`
`These physiochemical properties may lead to differences in toxico(cid:173)
`logical response.
`For comparative purposes, dose levels of borates have been expressed
`in terms of B equivalents based on the fraction of B on a mol-wt basis. To
`obtain the equivalent dose of B, a dose of boric acid is multiplied by 0.175,
`whereas a dose of borax is multiplied by 0.113. These conversion factors
`are important, since some studies express dose in terms of B, whereas
`other studies express the dose in units of boric acid or borax. The B
`equivalents used are a generic designation rather than a designation of
`the element B.
`
`Biological Trace Element Research
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`Vol. 66, 1998
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`

`
`Hubbard
`
`Comparative Toxicology of Borates
`
`345
`
`)so Values
`Reference
`
`21, 22
`24
`
`21
`23
`25
`
`30
`
`26
`27
`
`32 reviewed
`in 2
`
`28
`28
`
`29
`
`31
`32
`
`have been evalu-
`
`unantly as undis-
`1logical pH, lead(cid:173)
`ta of mammals is
`;iochemical prop(cid:173)
`as:
`1erborate.
`lS with Na
`
`!es.
`
`rences in toxico-
`
`e been expressed
`mol-wt basis. To
`tltiplied by 0.175,
`inversion factors
`lS of B, whereas
`:>r borax. The B
`a designation of
`
`TOXICOKINETICS
`
`Toxicokinetics has been reviewed elsewhere (6). Studies have gener(cid:173)
`ally been carried out on boric acid as a representative inorganic borate.
`The toxicokinetics of boric acid and other hydrated forms of Na borates
`are very similar in animals and humans. Borates are readily absorbed
`orally in humans and animals (7-11); are not metabolized in either ani(cid:173)
`mals or humans; are excreted via the urine with a reported half-life <12 h
`in rats (12) and an estimated mean plasma half-life of 13.4 h in humans,
`with >94% of B excreted in the urine over a 96-h period (13,14). Borates
`are poorly absorbed through intact skin in both humans (15-17) and
`animals (7,18), and although they can be absorbed through damaged
`skin, absorption is dependent on the carrier (19,20).
`
`ACUTE TOXICITY
`
`The borates are in general of low acute oral toxicity in mammals,
`including rats and mice. An accidental poisoning case in cows and a
`further study in goats do not suggest that these species are more sen(cid:173)
`sitive to the effects of borates with respect to acute toxicity (34,35). The
`LDsos of those borates tested are shown in Table 1. For most borates,
`LDsos range from 2000 to 5000 mg /kg. The study design, in particular
`fixed-dose studies (dose fixed at 2000 mg/kg), does not allow a closer
`definition of the actual LDso (21-23). The LD5o for Zn borate 2.3.3.5 and
`Zn borate 4.1.1 is 10,000 mg/kg and >5000 mg/kg, respectively (31,32).
`The lower LD50 for Na perborate monohydrate ( <2000 mg/kg) may
`reflect gastrointestinal irritancy and generation of H20 2 (33). No signifi(cid:173)
`cant differences in acute oral toxicity were seen in mice and dogs in the
`limited studies available, although dogs exhibit an emetic effect in
`response to high doses of borates. The main symptoms of toxicity seen
`in all species tested were central nervous system (CNS) depression,
`ataxia, and convulsions.
`Humans do not seem to be any more sensitive than other mammals
`with respect to acute toxicity, although it is difficult to make a good
`quantitative judgment (36). Lethal dose figures of 15-20 g of boric acid
`have generally been cited in the literature, but there are very few actual
`acute cases reported and the basis for these figures is unclear. In contrast,
`of 784 more recent reports of accidental ingestions, none were reported
`as fatal and 88.3% were asymptomatic. The estimated dose range was
`10 mg to 88.8 g (14). However, a single intake of 30 g of boric acid was fatal
`in one case (37). Symptoms of acute effects may include nausea, vomit(cid:173)
`ing, gastric discomfort, skin flushing, excitation, convulsions, depression,
`and vascular collapse. Other data come from multiple exposures. In two
`infants, symptoms of irritability, vomiting, diarrhea, and erythema were
`observed, with no lasting effects (38).
`
`Vol. 66, 1998
`
`Biological Trace Element Research
`
`Vol. 66, 1998
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`

`
`346
`
`Hubbard
`
`Low acute inhalation toxicity was observed in those borates tested.
`The 4-h LC50 is >2 mg/m3 for boric acid, borax, disodium tetraborate
`pentahydrate, and disodium octaborate tetrahydrate and >4.95 mg/m3
`for Zn borate 4.1.1 (39-43). By contrast, B halides have high acute
`inhalation toxicity owing to the formation of hydrochloric or hydroflu(cid:173)
`oric acid in aqueous medium (44,45). As would be expected owing to
`the low skin absorption, the acute dermal toxicity was low for those
`borates tested (LD50 > 10 g/kg for Zn borate 2.3.3.5; >2 g/kg for Zn
`borate 4.1.1, boric acid, boric oxide, disodium octaborate, Na tetrabo(cid:173)
`rate anhydrous, and pentaborate, and >1 g/kg for Na tetraborate deca(cid:173)
`hydrate) (45-50).
`Boric acid and borax are used at concentrations of 5% in cosmetics
`in the US and in talc in Europe, up to 3% in other cosmetics in Europe,
`and up to 0.5% in oral hygiene products in Europe and elsewhere (16,51).
`As expected, generally inorganic borates are not skin irritants or are very
`mild irritants (23,52-59). Although Na metaborates are very alkaline in
`solution (0.1 % is ~ pH 10.0), an irritancy study indicated that there was
`no skin irritancy associated with Na metaborate tetrahydrate (57). This
`may be owing to its low alkaline reserve, which would prevent the pro(cid:173)
`duction of a high pH in contact with the skin.
`Evidence for eye irritation is less clear and probably reflects differ(cid:173)
`ences in physiochemical properties. Boric acid is not an eye irritant in
`rabbits, nor are disodium octaborate tetrahydrate and Zn borates
`(16,60-64). Severe eye irritation was observed in rabbit studies with
`borax and disodium tetrabornte pentahydrate, whereas moderate irrita(cid:173)
`tion was seen with Na perborate monohydrate and tetrahydrate
`(33,65-67). Boric oxide is also a mild eye irritant. The Na metaborates
`are likely to be eye irritants owing to their alkalinity, but the low alka(cid:173)
`line reserve is likely to reduce the severity of this effect. However, in
`50 years of occupational exposure to Na tetraborates, no significant
`adverse effects on the human eye have been observed. Rabbit eye stud(cid:173)
`ies are known to overestimate human eye hazard. Boric acid and borax
`are used at up to 5% in eye washes in the US, a concentration approach(cid:173)
`ing a saturated solution (16).
`No borate tested has displayed skin sensitization (2,68-73). No evi(cid:173)
`dence of skin sensitization has been seen in humans exposed occupa(cid:173)
`tionally to Na borates or in a human patch test with a 3% aqueous boric
`acid solution (73,74).
`A study of workers exposed occupationally to Na borates up to lev(cid:173)
`els of 14 mg Na borates/m3 (the nuisance dust level is 10 mg/m3) indi(cid:173)
`cated no significant respiratory effects (i.e., nose, eye, and throat
`irritation). No significant difference in response was found between
`workers exposed to different types of Na borate dusts. No effect on pul(cid:173)
`monary function or other health effects were observed in workers
`exposed chronically to borates (75).
`
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`Hubbard
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`Comparative Toxicology of Borates
`
`347
`
`10se borates tested.
`sodium tetraborate
`·and >4.95 mg/m3
`:; have high acute
`hloric or hydroflu(cid:173)
`expected owing to
`was low for those
`5; >2 g/kg for Zn
`1orate, Na tetrabo(cid:173)
`:i tetraborate deca-
`
`Jf 5% in cosmetics
`smetics in Europe,
`. elsewhere (16,51).
`:ritants or are very
`·e very alkaline in
`ted that there was
`hydrate (57). This
`:l prevent the pro-
`
`bly reflects differ(cid:173)
`an eye irritant in
`and Zn borates
`Jbit studies with
`s moderate irrita(cid:173)
`md tetrahydrate
`! Na metaborates
`but the low alka(cid:173)
`:ect. However, in
`·s, no significant
`Rabbit eye stud(cid:173)
`c acid and borax
`ration approach-
`
`2,68-73). No evi(cid:173)
`exposed occupa(cid:173)
`% aqueous boric
`
`orates up to lev-
`10 mg/m3) indi(cid:173)
`~ye, and throat
`found between
`Jo effect on pul(cid:173)
`red in workers
`
`MOTAGENICITY AND CARCINOGENICITY
`
`A number of in vitro mutagenicity studies, including bacterial muta(cid:173)
`tion assays in Salmonella typhimurium and Escherichia coli, gene mutation
`in mammalian cells (L5178Y mouse lymphoma, V79 Chinese hamster
`cells, C3H/10Tl/2 cells), bacterial DNA-damage assay, unscheduled
`DNA synthesis (hepatocytes), chromosomal aberration, and sister chro(cid:173)
`matid exchange in mammalian cell (Chinese hamster ovary, CHO cells),
`have been carried out on boric acid, borax, or disodium octaborate
`tetrahydrate. No evidence of mutagenic activity was observed (76-80). In
`addition, no mutagenic activity was seen in vivo in a mouse bone mar(cid:173)
`row micronucleus study on boric acid (81). For Na perborate tetra(cid:173)
`hydrate, a weakly positive response in S. typhimurium in the absence of
`a metabolizing system was most likely owing to the production of H20:u
`a well-known phenomenon. This effect disappeared in the presence of a
`metabolizing system (82,83). Zn borates were negative in S. typhimurium
`(84,85), but Zn borate 4.1.1 was weakly mutagenic in a chromosome aber(cid:173)
`ration study in Chinese hamster lung (CHL) cells consistent with there
`being a high bioavailable Zn dose in the in vitro system (86). The weight
`of evidence supports a conclusion that Zn is not genotoxic in vivo, but
`the nature of some salts leads to greater bioavailability in in vitro systems
`allowing Zn to exert an effect on the genetic material on the cell (87). Inor(cid:173)
`ganic borates are not mutagenic in vitro with the exception of Zn borate
`4.1.1 and Na perborates, but all inorga~ic borates tested are not muta(cid:173)
`genic in vivo.
`
`SOBCHRONIC AND CHRONIC TOXICITY
`STUDIES
`
`A number of studies in which rats were fed boric acid or borax in
`their diet or drinking water for periods of 70-90 d indicated that the main
`target organ for toxicity was the testis. In addition to testicular atrophy,
`animals receiving doses of 88 mg B /kg body wt/ d for 90 d in their diet
`exhibited weight loss and, at higher doses, rapid respiration, inflamed
`eyes, swollen paws, and desquamation of the skin on the paws (21,76).
`In long-term feeding studies on boric acid and borax in both rats and
`dogs, no carcinogenic effects were observed (21). Also in a US National
`Toxicology Program (NIP) bioassay in mice, no carcinogenic effects were
`observed at doses of boric acid of 75 mg B/kg body wt/d and 200 mg
`B/kg body wt/d (76).
`.
`.
`In these studies, testicular effects were noted that are discussed m
`more detail below. In humans, multiple exposure results in various
`symptoms that may appear singly or together, and include dermatitis,
`alopecia, loss of appetite, nausea, vomiting, diarrhea, and focal or gener-
`
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`
`Biological Trace Element Research
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`348
`
`Hubbard
`
`alized CNS irritation or convulsions. Much data come from the mid-
`1800s to around 1940, when boric acid and borax were used systemati(cid:173)
`cally for a variety of medical conditions, including amenorrhea, malaria,
`epilepsy, urinary tract infection, and exudative pleuritis (88). In infants,
`similar symptoms were observed in babies given a honey-borax mixture
`on pacifiers (89, 90). Daily oral doses in adults ranged from 1 to 14 g/ d.
`Repeated doses in the 6-10 g/ d range were given for as long as several
`weeks. Reduction of dose to 1 g/ d in one case resulted in the symptoms
`disappearing. In all cases, withdrawal of treatment resulted in recovery
`from effects with no sequelae observed. Very few deaths were recorded by
`Kliegel, and those that occurred may have been owing to the underlying
`medical problem or to the combination of