The Developmental Toxicity of Boric Acid in
`Mice, Rats, and Rabbits
`Jerrold J. Heindel 1, Catherine J. Price2, and Bernard A. Schwetz13
`'Developmental and Reproductive Toxicology Group, National Toxicology Program, National Institute of
`Environmental Health Sciences, Research Triangle Park, North Carolina; 2Chemistry and Life Sciences, Center
`for Life Sciences and Toxicology, Research Triangle Institute, Research Triangle Park, North Carolina
`Boric acid (BA) is a naturally occurring agent used in manufacturing processes and numerous consumer products. Because of the potential for both
`industrial and consumer exposure to boron-containing compounds, and the lack of developmental toxicity data, the National Toxicology Program
`evaluated the potential for boric acid to cause developmental toxicity in pregnant Swiss (CD-1) mice, Sprague-Dawley rats (n = 26-28/group), and
`New Zealand rabbits (n = 1 8-23/group). BA was provided in the feed to mice and rats at 0, 0.1, 0.2, or 0.4% throughout gestation to attain steady-
`state exposure as early as possible during development. Average doses (mg/kg/day) were 248, 452, or 1003 for mice, and 78, 163, or 330 in rats.
`A separate group of rats received 0.8% BA in the feed, or 539 mg/kg/day only on gestation days (gd) 6 to 15. Rabbits were given BA (0, 62.5, 125,
`or 250 mg/kg) by gavage administration on gd 6 to 19. Maternal body weight, food and/or water consumption and signs of toxicity were monitored
`at regular intervals. At termination, gd 17 (mice), 20 (rats), or 30 (rabbits), the uterus was examined to determine the number of resorptions, dead, or
`live fetuses. Fetuses were weighed and live fetuses were examined for external, visceral, and skeletal defects. Mouse dams exhibited mild renal
`lesions (.248 mg/kg/day BA), increased water intake and relative kidney weight (1003 mg/kg/day BA), and decreased weight gain during treat-
`ment. Maternal rats exhibited increased liver and kidney weights at 2163 mg/kg/day BA, altered water and/or food intake at >163 mg/kg/day BA,
`and decreased weight gain at >330 mg/kg/day BA. In rabbits, signs of toxicity included decreased food consumption during treatment, and vaginal
`bleeding associated with pregnancy loss at 250 mg/kg/day. Maternal body weight (gd 9 to 30), weight gain during treatment, and gravid uterine
`weight decreased at 250 mg/kg/day. Relative maternal kidney weight (but not absolute weight) was increased at 250 mg/kg/day, but microscopic
`evaluation did not indicate any renal pathology associated with BA exposure. BA is a developmental toxicant in all three species. The lowest-
`observed-adverse-effect level (LOAEL) for developmental toxicity was 78 mg/kg/day for rats (fetal weight reduction), 250 mg/kg/day for rabbits
`(prenatal mortality and malformations), and 452 mg/kg/day for mice (fetal weight reduction). The no-observed-adverse-effect levels (NOAELs) for
`developmental toxicity in these species were <78 mg/kg/day (rats), 125 mg/kg/day (rabbits), and 248 mg/kg/day (mice). With regard to maternal
`toxicity, the rat was the most sensitive (163 mg/kg/day), while both the mouse and rabbit showed maternal toxicity at 250 mg/kg/day. Thus,
`developmental toxicity occurred below maternally toxic levels in the rat, and only in the presence of maternal toxicity in mice or rabbits. - Environ
`Health Perspect 102(Suppl 7):107-112 (1994)
`Key words: boric acid, developmental toxicity, malformations, maternal toxicity, NOAEL
`
`Introduction
`Boric acid is a naturally occurring agent
`used in manufacturing processes and
`numerous consumer products (1-3). At
`high concentrations, boric acid is a repro-
`ductive toxicant in mice (4) and rats (5-7).
`While males appear to be the predominandy
`affected sex (4), other investigators have
`shown that pregnancy in mice can also be
`disrupted by boric acid exposure. A single
`dose of boric acid (500-3000 mg/kg) to
`mice on the first day of pregnancy disrupted
`pregnancy because of failure of blastulation
`in mice (2). There is also evidence that
`
`This paper was presented at the International
`Symposium on Health Effects of Boron and Its
`Compounds held 16-17 September 1992 at the
`University of California, Irvine, California.
`Address correspondence to Dr. J. J. Heindel,
`National Toxicology Program/National Institute of
`Environmental Health Sciences, P.O. Box 12233
`(MD#3-03), Research Triangle Park, NC 27709.
`Telephone (919) 541-0781. Fax (919) 541-4704 E-mail
`Heindel J@NIEHS.NIH.Gov
`3Current address: National Center for Toxicological
`Research, 3900 NCTR Rd., Jefferson AL 72079
`
`boric acid decreased ovulation in rats (3).
`Teratogenic effects such as rumplessness
`and microphthalmia have been reported in
`chick embryos treated with boric acid
`(8,9). There has been a report of increased
`malformations (especially congenital
`cataracts) among children of pregnant
`women who used boric acid as a topical
`antimicrobial agent (10).
`Because of the high industrial produc-
`tion of boric acid, the potential for human
`exposure to products containing boric acid,
`and data indicating the reproductive toxici-
`ty and possible developmental toxicity of
`boric acid, the National Toxicology
`Program (NTP) designed studies to define
`the potential for boric acid to cause devel-
`opmental toxicity in mice, rats, and rabbits.
`This was accomplished in studies in which
`the females were dosed orally with boric
`acid shortly after mating and continued
`until the day prior to natural parturition,
`or during any specific periods within this
`time frame. Both maternal and develop-
`mental toxicity end points were evaluated.
`
`Detailed reports of these studies are avail-
`able (11-13) and the studies in mice and
`rats have been published (14). A summary
`of the results of these three studies is pre-
`sented here.
`Materials and Methods
`Chemical Boric acid (CAS no. 10043-35-
`3) was determined to be 99% pure by
`infrared spectroscopy.
`Animals and Husbandry. Adult
`Caesarean-originated, barrier-sustained
`Crl:CD-1 (ICR) VAF / Plus outbred Swiss
`albino (CD-1) mice (Charles River
`Laboratories, Portage, MI); Crl:CD BR
`VAF/Plus outbred Sprague-Dawley (CD)
`rats (Charles River Laboratories, Raleigh,
`NC); and New Zealand rabbits (Hazelton
`Research Products, Denver, PA) were used
`for these studies (Table 1).
`Treatment. Time-mated rats or mice
`were given boric acid in the feed continu-
`ously from the morning of gestation day
`(gd) 0 to the morning of gd 20 (rats) or gd
`17 (mice) at doses of 0, 0.1, 0.2, or 0.4%,
`
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`
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`HEINDEL ETAL.
`
`Table 1. Specific protocol.
`Species
`No. dams/group
`Mode of exposure
`Dosing interval
`Concentration in feed
`Dose/ unit body weight
`Termination
`
`Sprague-Dawley rat
`26-28
`Feed
`gd 0-20 (gd 6-15)
`0, 0.1, 0.2, 0.4, (0.8%)
`0, 78, 163, 330, 538 mg / kg / day
`gd 20
`
`Swiss CD 1 mice
`
`26-28
`Feed
`gd 0-17
`0, 0.1, 0.2, 0.4%
`0, 248, 452, 1003 mg / kg / day
`gd 17
`
`New Zealand rabbit
`18-23
`Gavage
`gd 6-19
`
`0, 62.5, 125, 250 mg / kg / day
`gd 30
`
`Embryonal/Fetal Effects. Prenatal mor-
`tality was significantly increased in the
`0.8% dose group (36% resorptions per lit-
`ter) relative to the control group (4%
`resorptions per litter) that resulted in a
`decrease in live litter size. Significant
`increases in both the percentage of
`embryonic loss (resorptions) and late fetal
`deaths per litter contributed to the
`observed increase in prenatal mortality
`after exposure on gd 6 to 15. Average
`fetal body weight per litter was also
`reduced in all boric acid-treated groups,
`ranging from a 6 to 7% decrease at the
`lowest dose level to about a 50% decrease
`at the highest dose level. The percentage
`
`of malformed fetuses per litter and the
`percentage of litters containing at least
`one malformed fetus were increased at all
`doses studied. The incidence of litters
`with one or more fetuses with a skeletal
`malformation increased at 0.2 to 0.8%
`boric acid doses; the incidence of litters
`with one or more pups with a visceral or
`external malformation was increased at
`dosages of 0.4 and 0.8%, respectively. A
`variety of malformations was noted,
`including anomalies of the eyes, the cen-
`tral nervous system, the cardiovascular
`system, and the axial skeleton. The most
`commonly observed malformations in the
`0.4 and 0.8% dosage groups were
`
`Table 2. Summary of maternal and embryonal/fetal responses of Sprague-Dawley rats to boric acid administered
`on gestational days 0 to 20 or 6 to 15.
`
`Boric acid, mg / kg / day (% in feed)
`0-20
`163
`(0.2%)
`
`330
`(0.4%)
`
`78
`(0.1 %)
`
`6-15
`539
`(0.8%)
`
`Trend
`
`or from gd 6 through 15 (0.8% dose, rats
`only). Rabbits were artificially inseminated
`(15,16) and given boric acid by gavage
`(62.5, 125, or 250 mg/kg/day in distilled
`water) on gd 6 through 19 (Table 1).
`Administration of boric acid by gavage was
`chosen for the rabbit study because rabbits
`are erratic eaters.
`Evaluations. End points used to define
`maternal toxicity during boric acid treat-
`ment included food and water consump-
`tion, body weight, signs of toxicity, liver
`and kidney weights, kidney histology, and
`uterine weight. Animals were killed on gd
`17 (mice), gd 20 (rats), or gd 30 (rabbits).
`End Points. End points used to define
`developmental toxicity were embryonal / fetal
`weight and structural malformations and
`variations observed during examinations.
`Live fetuses were weighed and examined
`for malformations and variations by stan-
`dard techniques (17-20).
`Statistics. Statistical analysis of the data
`was made as described previously, using the
`litter as the statistical unit (11-14).
`Results
`Rau
`Maternal Effects. Summarizing across all
`exposure groups, maternal effects included
`increased relative liver and kidney weights
`at .0.2%, and decreased weight gain dur-
`ing treatment and gestation at .0.4%.
`Corrected body weight gain (i.e., gesta-
`tional weight gain minus the gravid uter-
`ine weight) was not affected, except for a
`significant increase when compared to the
`control group at 0.4% boric acid (Table
`1). Microscopic evaluation of maternal
`showed
`minimal
`kidney
`sections
`nephropathy in a few rats, but neither the
`incidence nor the severity of the changes
`was dose related. Exposure to boric acid
`from gd 0 to 20 resulted in increased food
`intake with no significant dose-related
`effect on water intake. Exposure to 0.8%
`boric acid resulted in decreased water and
`food intake early during the treatment
`period with a rebound increase in food
`intake on gd 15 to 18 and an apparent,
`but not significant, increase in water
`intake over this same period.
`
`Maternal
`Total treated
`Number removed
`Deaths
`Pregnancy rates, %
`Body weight before treatment
`Body weight change during treatment
`Body weight change, corrected
`Relative food consumption
`Clinical signs of toxicity
`Number corpora lutea /dam
`Gravid uterine weight
`Relative liver weight
`Relative kidney weight
`Renal pathology
`Embryonal /fetal
`% resorptions or fetal deaths /litter
`-
`-
`% litters with resorptions or deaths
`% litters with 100% prenatal mortality
`-
`Number live fetuses/ litter
`-
`4.
`Average female body weight/litter
`4.
`Average male body weight/ litter
`T
`% malformed fetuses/litter
`% litters with malformations
`TI
`T
`T
`All
`t
`-
`-
`-
`External
`T
`I
`-
`-
`Visceral
`1t
`1
`1
`T
`Skeletal
`T
`4
`4
`-
`% fetuses with variations /litter
`-
`4.
`4
`-
`-
`-
`% litters with variations
`a Arrows indicate direction of the trend or significant change from the control group (p<0.05). b Dashes indicate
`no significant change from control.
`
`4. a
`1'
`-
`
`-
`Jl
`1
`I
`
`29
`0
`0
`90
`-
`
`-
`1
`
`-
`-
`
`-
`-
`-
`-
`4.
`4.
`II
`
`29
`0
`0
`97
`
`-
`-
`
`-
`-
`
`-
`
`-
`-
`-
`-
`4
`4
`-
`
`-
`-
`-
`
`I -
`
`29
`0
`0
`90
`-
`,j,,
`T
`
`-
`4.
`
`-
`-
`-
`-
`4
`4
`
`14
`0
`0
`100
`-
`
`4.
`
`J1
`4
`
`1
`1
`T
`4
`4.
`4.
`1
`
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`Environmental Health Perspectives
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`
`DEVELOPMENTAL TOXICITY OF BORIC ACID
`
`Table 3. Summary of maternal and embryonal /fetal responses of CD-1 mice to boric acid administered on gesta-
`tional days 0 to 17.
`
`Boric acid, mg/ kg/ day (% in feed)
`452
`248
`(0.1 %)
`(0.2%)
`
`1003
`(0.4%)
`
`Trend
`
`28
`0
`0
`96
`
`_
`
`-
`
`-
`-
`-
`1T
`
`-
`
`-
`-
`-
`
`4-a
`
`-
`
`'1
`4,
`1
`I
`
`1
`-
`
`4-
`4-
`I
`
`Maternal
`Total treated
`Number removed
`Deaths
`Pregnancy rates, %
`Body weight before treatment
`Body weight change during treatment (gd 0-17)
`Body weight change (corrected)
`Relative food consumption )gd 0-17)
`Clinical signs of toxicity
`Number corpora lutea / dam
`Gravid uterine weight
`Relative liver weight
`Relative kidney weight
`Renal pathology
`Embryonal /fetal
`% resorptions or fetal deaths/litter
`% litters with resorptions or deaths
`% litters with 100% prenatal mortality
`Number live fetuses/litter
`Average female body weight/ litter
`Average male body weight/ litter
`% malformed fetuses / litter
`% litters with malformations
`All
`External
`Visceral
`Skeletal
`% fetuses with variations/litter
`4-
`4-
`-
`% litters with variations
`4-
`4,
`-
`a Arrow indicate direction of the trend or significant change from the control group )p<0.05). b Dashes indicate no
`significant change from control.
`
`29
`0
`0
`93
`
`-
`
`-
`
`-
`-
`-
`
`-
`
`,l,
`1-
`-
`
`28
`0
`0
`93
`
`4
`
`4-
`4-
`1
`
`I
`
`enlarged lateral ventricles of the brain (0
`and 0.5% of the fetuses, respectively),
`and agenesis or shortening of the thir-
`teenth rib (6 and 45% of the fetuses,
`respectively) (Table 2).
`Mice
`Maternal Effects. Maternal toxicity associat-
`ed with boric acid treatment induded effects
`on body weight gain and organ weights.
`Maternal body weight was reduced below
`control values by 10 to 15% during late
`treatment in the high-dose group.
`Treatment with 0.4% boric acid also caused
`reductions in maternal weight gain during
`treatment, but weight gain corrected for
`uterine weight was not affected. Food and
`water intake were not affected. Gravid uter-
`ine weight was decreased at the high-dose
`level. At necropsy, pale kidneys were noted
`in several boric acid-treated dams, particu-
`larly in the high-dose group, and one dam
`treated with 0.4% boric acid had fluid accu-
`mulation in the kidney. Relative kidney
`weight was increased in the 0.4% group and
`microscopic examination of maternal kid-
`neys revealed a dose-related increase in the
`incidence of renal tubular dilatation (with or
`without regeneration), 0/ 10, 2/ 10, 8 /10
`and 10/10; control to high-dose group,
`respectively.
`Embryonal/Fetal Effects. boric acid
`treatment (0.1-0.4%) during gestation was
`not associated with preimplantation loss, the
`number of implantation sites per litter being
`comparable among treatment groups (Table
`3). However, boric acid treatment was asso-
`ciated with significant adverse postimplanta-
`tion effects, particularly in the high-dose
`group. The percentage of resorptions per lit-
`ter increased from 6% in the control group
`to 19% by exposure to 0.4% boric acid, and
`fetal body weight was reduced by 33% com-
`pared to controls. Treatment with 0.2%
`boric acid was also associated with a signifi-
`cant, but less severe, fetal body weight
`reduction of 11%.
`Boric acid also had effects on fetal mor-
`phologic development. The most frequent-
`ly observed malformations in the 0.4%
`boric acid-treated litters were skeletal
`defects, particularly short rib XIII (in the
`4% dosage-treated fetuses). In contrast, the
`occurrences of fetuses per litter with mal-
`formations were fewer in the low- and mid-
`dose group than in the control group. In
`particular, the incidence of full or rudi-
`mentary lumbar I rib(s) was observed less
`frequently in fetuses of boric acid-treated
`mice. The presence of a rib at lumbar I
`(classified as an anatomic variation in this
`species and strain) was decreased in a dose-
`
`related manner as follows: the incidence of
`a full rib(s) at lumbar I was 12, 8, 1, and
`1%, respectively, and the incidence of rudi-
`mentary lumbar I rib(s) was 16, 7, 3, and
`3%, respectively.
`Rabbits
`Maternal Effects. At 250 mg / kg / day,
`maternal food consumption was decreased
`during the first 10 days of treatment (gd
`6-15), was comparable among groups
`during the final days of treatment (gd
`15-19), and was increased during the peri-
`od immediately following treatment (gd
`19-25). It was also increased in both the
`125 and 250 mg/kg/day groups relative
`to controls during the final days of gesta-
`tion (gd 25-30). Maternal body weight
`(gd 9-30), weight during treatment, and
`gravid uterine weight were each decreased
`at 250 mg/kg/day. Corrected maternal
`weight change was increased at both 125
`and 250 mg/kg/day. Maternal relative
`liver weight was comparable among
`groups, while relative kidney weight was
`increased at 250 mg/kg/day. However,
`
`there was no histopathologic evidence for
`any boric acid-induced renal toxicity.
`Embryonal/Fetal Effects. No definitive
`evidence of developmental toxicity was
`observed following exposure of pregnant
`does to either 62.5 or 125 mg/kg/day
`boric acid during the period of major
`organogenesis (gd 6-19). At 250
`mg/kg/day, developmental toxicity
`included a high average-rate-of-resorption
`(90% of implants per litter vs 6% for con-
`trols), as well as a high percentage of does
`with complete prenatal loss (73% of litters
`vs 0% for controls) (Table 4). In contrast,
`the incidence of late fetal deaths was low in
`all groups (<2.8% per litter) and showed
`no systematic relationship to boric acid
`exposure. Average fetal body weight per lit-
`ter was 92% that of controls at the high
`dose, but this difference did not reach sta-
`tistical significance. In part, the absence of
`a significant fetal weight effect reflects the
`small sample size for this parameter (only
`six litters in the high-dose group survived
`to gd 30, as compared to 18 to 23 litters in
`the other study groups).
`
`Volume 102, Supplement 7, November 1994
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`
`HEINDEL ETAL.
`
`Table 4. Summary of maternal and embryonal /fetal responses of New Zealand rabbits to boric acid administered
`on gestational days 6 to 19.
`
`Boric acid, mg / kg /day per os)
`62.5
`125
`
`Trend
`
`250
`
`Maternal
`Total treated
`Number removed
`Deaths
`Pregnancy rates, %
`Body weight before treatment (gd 0 or 6)
`Body weight change before treatment (gd 0-6)
`Body weight change during treatment
`(gd 6-9)
`(gd 9-19)
`Body weight change after treatment (gd 19-30)
`Body weight change (corrected)
`Relative food consumption
`(gd 0 to 6)
`(gd 6 to 19)
`(gd 19 to30)30
`Clinical signs of toxicity
`Number corpora lutea /dam
`Gravid uterine weight
`Relative liver weight
`Relative kidney weight
`Renal pathology
`Embryonal / fetal
`% resorptions or fetal deaths/ litter
`% litters with resorptions or deaths
`% litters with 100% prenatal mortality
`Number live fetuses/litter
`Average female body weight/ litter
`Average male body weight/ litter
`% malformed fetuses/litter
`% litters with malformations
`All
`External
`Visceral
`Skeletal
`Skeletal (cardiovascular)
`% fetuses with variations/litter
`% litters with variations
`aDashes indicate no significant change from control. bArrows indicate direction of the trend or significant change
`from the control group (p<0.05).
`
`23
`0
`0
`85
`_
`
`_
`-
`-
`
`-
`
`-
`
`-
`
`-
`-
`-
`-
`
`-
`
`-
`
`-a
`
`b
`1
`4-
`
`4-
`
`4-
`
`-
`
`I
`-
`-
`4-
`
`1
`
`I
`
`20
`0
`0
`85
`_
`
`_
`-
`4-
`
`-
`
`4
`
`-
`
`-
`-
`-
`-
`
`-
`
`-
`
`22
`0
`0
`96
`_
`
`4
`4-
`4-
`
`1
`
`1
`
`1
`I
`1
`4-
`
`I
`
`I
`
`enlarged aorta in 0% (0/159), and 36%
`(5/14) of fetuses examined in control and
`high-dose groups, respectively.
`The percentage of fetuses with anatomi-
`cal variations was not significantly elevated
`above that of controls in any of the boric
`acid-exposed groups.
`Discussion
`Three mammalian species have been evalu-
`ated during gestation for developmental
`toxicity of boric acid at exposure levels
`which did not cause maternal mortality
`(Table 5). In all three species, boric acid
`was developmentally toxic to the develop-
`ing embryo /fetus. In two of the species,
`mice and rabbits, the developmental toxici-
`ty occurred at doses which were high
`enough to cause some maternal toxicity. In
`rats, minimal developmental toxicity (a 6%
`decrease in fetal weight) was measured at a
`dosage of 78 mg/kg/day in the absence of
`detectable maternal toxicity. In comparing
`the results of these three studies, it is
`important to note that the rat and mouse
`studies were feed studies, while the rabbit
`study was a gavage study. Extrapolating
`from the data of Treinen and Chapin (7),
`it is probable that the rodents reached
`steady-state blood and tissue levels of boric
`acid by the fourth day of exposure. While
`kinetic data following once-a-day gavage
`studies are not available, one would expect
`the profile of blood levels to be substantial-
`ly different from those of a feed study.
`Thus, while some of the dose levels
`(mg/kg/day) overlap, one cannot assume
`comparable exposures at critical target sites.
`Nonetheless, a comparison in Table 5
`shows that the lowest-observed-adverse-
`effect levels (LOAELs) for developmental
`toxicity were 78 mg/kg/day for rats (fetal
`weight reduction), 250 mg/kg/day for
`rabbits (prenatal mortality and malforma-
`tions) and 452 mg/kg/day for mice (fetal
`weight reduction). The no-observed-
`adverse-effect level (NOAELs) for develop-
`mental toxicity were <78 mg/kg/day
`(rats), 125 mg/kg/day (rabbits), and 248
`mg/kg/day (mice). Rabbits were the
`species most sensitive to boric acid-induced
`prenatal mortality and malformations,
`while mice were the most resistant, based
`on the doses and routes of administration
`employed in these studies.
`Boric acid treatment of rats and mice
`resulted in increased resorptions in the
`presence of normal numbers of implanta-
`tion sites, decreased fetal weights, and
`increased numbers of malformations. The
`predominant malformation in both species
`was agenesis, or shortening of the 13th rib,
`
`The overall incidence of malformed
`fetuses per litter was increased at 250
`mg/kg/day boric acid (81% per litter vs
`26% for controls), but not at 62.5 or 125
`mg/kg/day (26 and 30% per litter, respec-
`tively). When general classes of malforma-
`tions were analyzed, the percentage of
`fetuses per litter with either external or vis-
`ceral malformations was increased at the
`high dose, but the incidence of skeletal
`malformations was comparable among
`groups.
`External malformations were observed
`with the following incidence among indi-
`vidual fetuses in the control through high-
`dose groups, respectively: 0.6% (1/159),
`1.1% (2/175). 0.7% (1/153), and 14.3%
`(2/14). Although the overall incidence of
`external malformations was increased at the
`high dose of boric acid, distinctive
`
`dose-response patterns for individual mal-
`formations were not observed.
`The incidence of fetuses with visceral mal-
`formations was 8.2% (13/159), 6.3%
`(11/175), 7.8% (12/153), and 7.9%
`(11 /14) in the control through high-dose
`groups, respectively (Table 4). Malforma-
`tions of the cardiovascular (CV) system
`(great vessels and heart) were the most fre-
`quently observed abnormality. A post hoc
`analysis of CV malformations revealed a
`significant increase in the incidence of
`fetuses per litter with major CV defects at
`the high dose (72 vs 3% for controls). CV
`malformations whose incidence appeared
`to be elevated by boric acid exposure (espe-
`cially at the high dose) included interven-
`tricular septal defects in 0.6% of the con-
`trol-group fetuses examined (1 / 159), and
`57% (8 / 14) of the high-dose fetuses; an
`
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`Table 5. Comparison of results for boric acid exposure in pregnant rats, mice, and rabbits.
`Dose, mg /kg/daya
`Maternal effects
`Rat, feed
`78
`163
`
`NOAEL
`t food intake
`T liver and kidney weights
`1 food and water intake
`T liver and kidney weights
`I gestational weight gain
`T corrected weight gain
`1 food and water intake
`T liver and kidney weights
`4-treatment weight gain
`4- gestational weight gain
`
`1 renal lesions
`T renal lesions
`T renal lesions
`4 gestational weight gain
`T kidney weight
`I food and water intake
`
`330
`
`539
`
`Mice, feed
`248
`452
`1003
`
`Rabbits, gavage
`62.5
`125
`
`250
`
`NOAEL
`T weight gain (gd 0-30)
`T corrected weight gain
`T food intake (gd 25-30)
`4 weight gain (gd 6-19)
`T corrected weight gain
`T relative kidney weight
`T vaginal bleeding
`I food intake (gd 6-15)
`T food intake (gd 25-30)
`a The following routes and periods of exposure were used: rats (0.1, 0.2, 0.4% in feed on gd 0-20; 0.8% in feed on
`gd 6-15); mice (0.1, 0.2, 0.4% in feed on gd 0-17); rabbits by gavage 5 ml/kg on gd 6-19.
`
`Embryonal /fetal effects
`
`4-fetal weight
`4-fetal weight
`T fetuses malformed
`4 gravid uterine weight
`4-fetal weight
`T fetuses malformed
`
`4- gravid uterine weight
`4-fetal weight
`T prenatal mortality
`I fetuses malformed
`
`NOAEL
`4-fetal weight
`4 gravid uterine weight
`4-fetal weight
`T prenatal mortality
`T fetuses malformed
`
`NOAEL
`
`4- gravid uterine weight
`T totally resorbed litters
`1 prenatal mortality
`1 fetuses malformed
`
`DEVELOPMENTAL TOXICITY OF BORIC ACID
`
`36 or 76% resorptions, respectively, at
`539 mg/kg/day (gd 6-15) (14), or at
`617 mg/kg/day (gd 0-20) (NTP pilot
`study). In contrast, mice were relatively
`resistant to such effects, and showed only
`20% resorptions/litter after exposure to
`1003 mg/kg/day throughout gestation
`(gd 0-17) (15).
`With regard to maternal toxicity, the
`rat was the most sensitive
`(163
`mg/kg/day), while both the mouse and
`rabbit showed maternal toxicity at 250
`mg/kg/day. Kidney weight was increased
`in all three species, but histologic kidney
`lesions were detected only in the mouse
`study. Indeed, on the basis of kidney his-
`tology the maternal NOAEL was less than
`248 mg/kg/day.
`Conclusion
`In summary, boric acid caused develop-
`mental toxicity in three species: rat,
`mouse, and rabbit. Developmental toxici-
`ty occurs with doses of boric acid in the
`range of 80 to 400 mg/kg/day, given
`either throughout gestation or only dur-
`ing major organogenesis. Developmental
`toxicity manifests as decreased fetal body
`weight and increased malformations; pre-
`natal death, depending on the dose and
`species, usually occurs in the presence of
`maternal toxicity. These data must be
`interpreted with respect to the level of
`human exposure and sensitivity in order
`assess potential risk to human health. In
`this regard, recent studies have shown that
`the highest exposures to boron achieved as
`a result of dietary intake plus worker
`exposure were 0.38 mg boron/kg/day or
`approximately 1.9 mg/kg/day of boric
`acid (22).
`
`1.
`
`2.
`
`3.
`
`4.
`
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`
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`depended upon both the daily dose and
`the period of administration. Rats showed
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`Volume 102, Supplement 7, November 1994
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`ANACOR EX. 2010 - 5/6
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