TECHNICAL REPORT DATA
ffttar retd Iniouetiom OH tht merer btfort completing]
NO.
£PA/600/8-88/021
2.
3. RECIPIENT'S ACCESSION NO.
PB88-178710/AS
4. TITLE ANO SUBTITLE
Health Effects Assessment for boron and Compounds
B. REPORT DATE
B. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME ANO AOORESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
13. TYPE OF REPORT ANO PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and -carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical (s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS c. COS ATI Field/Group
. DISTRIBUTION STATEMENT
Public
It. SECURITY CLASS (This Rtport)
Unclassified
:;1. NO. OF PAGES
20. SECURITY CLASS (Thtip*t*>
Unclassified
:«. PRiCE
CPA P«n» 2220.1 (*•». 4-77) PNCVIOWS KOITION is OMOLCTC
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EPA/600/8-88/021
May, 1987
HEALTH EFFECTS ASSESSMENT
FOR BORON AND COMPOUNDS
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U.S. Environmental Protection Agency
B.vion 5, LiM-ary (5PL-i~!
2JO S. Dear-born Street, Room 1670
Chicago, IL 60604
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DISCLAIMER
This, document has been reviewed In accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with boron and
compounds. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE .and the CHEMFATE/OATALOG data bases. The basic
literature searched supporting this document 1s current up to May, 1986.
Secondary sources of Information have also been relied upon 1n the prepara-
tion of this report and represent large-scale health assessment efforts that
entail extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980. Guidelines and Methodology Used In the Prepara-
tion of Health Effect Assessment Chapters of the Consent Decree
Water Criteria Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quan-
tity Determinations Based on Chronic Tox1c1ty Data. Prepared by
the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste and Emergency Response, Washington, DC.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose. Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfD$o)
exposures.
111
-------
The RfO (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfOg) or Inhalation (RfOj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1983).
For compounds for which there Is sufficient evidence of cardnogenlcHy
RfOg and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
-------
ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Boron Is an element normally consumed by humans at quantities ranging
from'1.3 to 9-20 mg/day, depending on the diet (Snyder et al., 1975).
Despite the high estimates of human boron Intake, animal studies Indicate
that the slope of the dose-response curve 1s steep, with testlcular atrophy
occurring at doses relatively near the NOELs. To protect against these
effects an RfOgg and RfDg of 6.2 mg/day for a 70 kg human 1s recom-
mended. This value 1s derived from a NOEL of 350 ppm boron (8.8 mg/kg/day)
In a 2-year dietary study with rats (Heir and Fisher, 1972). Overt signs of
tox1c1ty and severe testlcular degeneration were observed 1n this study at
1170 ppm, the only higher dose tested. No data concerning the toxic effects
of boron following Inhalation exposure were located 1n the available litera-
ture; therefore, Inhalation risk assessment values cannot be calculated. A
CS of 21.6 was based on testlcular atrophy and spermatogenlc arrest In dogs
fed a diet containing 1170 ppm boron for 26 weeks (Weir and Fisher, 1972).
-------
ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE. .
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcT)
Pane
. . . 1
. . . 3
. . . 3
. . . 4
. . . 5
. . . 5
. . . 5
. . . 9
. . . 9
. . . 9
. . . 11
11
. . . 11
. . . 15
. . . 15
17
. . . 17
17
. . . 17
17
. . . 17
. , 17
. . . 19
. . . 20
. , . 20
. . . 20
. . . 20
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfD) 20
6.2.1. Oral (Rf00) 20
6.2.2. Inhalation (RfDi) [ 22
6.3. CARCINOGENIC POTENCY (q^) 22
6.3.1. Oral 22
6.3.2. Inhalation ', ' ' * 24
7. REFERENCES 25
APPENDIX: Summary Table for Boron 29
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LIST OF ABBREVIATIONS
BCF Bloconcentratlon factor
CS Composite score
DNA Deoxyr1bonucle1c acid
FEV Forced expiratory volume
FSH Follicle stimulating hormone
LH Lutelnlzlng hormone
MED Minimum effective dose
MTD Maximum tolerated dose
NOEL No-observed-effect level
PEL Permissible exposure level
ppm Parts per million
RBC Red blood cell
RfD Reference dose
Inhalation reference dose
Oral reference dose
RfD§i Subchronlc Inhalation reference dose
RfD$0 Subchronlc oral reference dose
RVd Dose-rating value
RVe Effect-rating value
TLV Threshold limit value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Boron 1s a nonmetalllc element, which belongs to Group III A of the
periodic table, and has an oxidation state of *3 (Hawley, 1981). Although
boron 1s widespread 1n nature, H has been estimated to constitute only
0.001% of the earth's crust, usually occurring as alkali or alkaline earth
borates, or as boric add (Bower, 1978). Physical properties of boron and
some of Us compounds are listed 1n Table 1-1.
Boron In the form of boron oxide, boric acid and sodium or other metal
borates will probably be emitted to the atmosphere from anthropogenic
sources as partlculate matter or aerosol. Boron should be removed from the
atmosphere by wet and dry deposition. The dry deposition half-life for air-
borne partlculates 1s usually on the order of days, depending upon particle
size and characteristics (Nrlagu, 1979). The fate of boron 1n water and
soil could not be located In the available literature. Measured BCFs range
from 52-198 1n various fish. Tsui and McCart (1981) suggest that boron will
not bloaccumulate significantly In aquatic organisms. The relatively high
water solubility of boric add and sodium borate suggests that this compound
will not accumulate 1n sediments. Since these compounds of boron are stable
In aqueous solution, and there are no known processes, of their removal from
aquatic media, boron may persist In aquatic media.
Olllh -1- 02/11/87
-------
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-------
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Two studies Indicate that boron Is readily absorbed 1n humans by the
gastrointestinal tract. In the study by Kent and McCane (1941), two women
Ingested a total of 352 mg boron over a 3-day period. During the first week
following boron Intake, 93-94% of the boron consumed was recovered In the
urine. Aas Jansen et al. (1984), after determining basal levels of boron
excreted In the urine, administered 750 mg boric add (131 mg boron) 1n 100
mi water to three men. Three other male volunteers consumed as much as
possible of a water-emulsifying ointment containing 2.97% boric add on
biscuits. The amount of ointment swallowed varied from 24.9-49.6 g
(129.5-257.8 mg boron). Urine was collected and analyzed for boron for 96
hours following boron consumption. The experiment was repeated 2 weeks
later and the Individuals who drank boron 1n water now consumed ointment and
those that ate ointment now drank boron 1n water. Results showed that at 96
hours following boron Intake, 93.9% of the boron consumed In water was
excreted 1n the urine, while 92.4% of the boron from the ointment was
excreted 1n the urine. Boron was still being excreted during the last
12-hour period, so that continuation of the study may have resulted In more
complete recovery of Ingested boron.
Magour et al. (1982) provided 3-week-old Ulstar rats with 100 ppm boron
In their drinking water for 21 days and monitored blood and tissue boron
concentrations. Blood concentrations continued to rise throughout the
treatment period while boron In the liver and brain approached control
levels. The Investigators stated that the decreasing levels of boron 1n the
liver and brain suggest the development of a homeostatlc mechanism that
eliminates boron from the liver and brain against a concentration gradient.
Oil In -3- 10/28/86
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2.2. INHALATION
Pertinent data regarding the absorption of boron following Inhalation
exposure could not be located In the available literature.
Oil In -4- 10/28/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. In a study by Weir and Fisher (1972), groups of 10 young
male and 10 young female Sprague-Oawley rats were fed diets containing borax
or boric add at 0, 52.5, 175, 525, 1750 or 5250 ppm as boron equivalents
for 90 days. Body weights and food consumption were measured weekly. At
necropsy, organ weights were recorded and organs were preserved for hlsto-
pathologlcal examination.
All rats fed 5250 ppm boron died within 3-6 weeks. Rats fed 1750 ppm
did not die, but showed signs similar to rats fed 5250 ppm, Including rapid
respiration, Inflamed eyes, swollen paws and desquamated skin on the paws
and tails. When handled, the rats appeared excited. Males fed 1750 ppm
boron had shrunken scrotums during the last weeks of the study. At 1750 ppm
boron, boric add reduced growth and food consumption 1n males and females,
while borax reduced growth and food utilization efficiency only 1n males.
A number of organ weights were significantly different from controls.
Males fed boron compounds at 1750 ppm boron had significant decreases 1n
weights of liver, spleen, kidneys and testes; borax at 1750 ppm boron also
resulted In a reduction In brain weight, while boric add lowered adrenal
weights. In female rats fed 1750 ppm boron (both compounds), weights of
liver, spleen and ovaries were reduced, and boric acid reduced adrenal
weights, A number of other organ weight changes were noted, but did not
seem to be dose-related and varied with the sex of the rat and form of boron
Ingested.
Necropsies on the rats that died (all at 5250 ppm and one each from 52.5
and 1750 ppm boron levels from borax) showed congestion of liver and kidneys
and bright red lungs; In several rats the brain appeared swollen, gonads
Olllh -5- 10/28/86
-------
were small and the pancreas was thickened. H1stopatho1og1cal examination of
the tissues showed complete atrophy of the testes In all males fed 1750 ppm,
partial atrophy 1n four males at 525 ppm from borax and 1n one male at 525
ppm from boric add. One male at 525 ppm from borax was found to have
spermatogenlc arrest. At 1750 ppm boron from borax, the adrenals of most
males and several females showed a slight to moderate Increase 1n I1p1d
content and In the size of the cells In the zona retlcularls. The adrenals
of four male rats fed boric add at 1750 ppm boron showed similar changes to
a lesser degree.
Ue1r and Fisher (1972) also fed groups of five young male and five young
female beagle dogs borax or boric add 1n the diet at boron equivalents of
0, 17.5, 175 or 1750 ppm for 90 days. In addition to the parameters
examined In the rats, hematological and biochemical parameters were also
examined 1n the dogs.
One male dog at 1750 ppm boron as borax died of diarrhea on day 68 and
showed congested kidneys and severe congestion of mucosa of the small and
large Intestines. Other dogs at all dosing concentrations were essentially
normal 1n appearance, behavior, elimination, body weights and food consump-
tion. Two male and three female dogs fed borax at 1750 ppm boron had
decreased packed cell volume and hemoglobin values. Other hematologlcal and
biochemical values were within normal limits.
Borax and boric add at 1750 ppm boron caused significant decreases In
th/ro1d- and testes-to-body weight ratios 1n male dogs. At 1750 ppm boron,
only boric add resulted In a decrease In testes-to-body weight ratios. At
1750 ppm boron as borax, Increases In brain-to-body weight ratios occurred,
and boric add at the same level of boron resulted 1n Increases of I1ver-to-
body weight ratios In both male and female dogs.
Olllh -6- 02/11/87
-------
Borax and boric acid at 1750 ppm resulted In severe testlcular atrophy
In all male dogs. RBC destruction, Indicated by the presence of hemoslderln
In the retlcular cells of the liver and spleen and the proximal tubules of
the kidney, was somewhat greater In dogs fed borax than those fed boric
add. In borax-treated dogs and In boric acid-treated female dogs, the
adrenal zona retlcularls was consistently Increased In width. Boric add at
1750 ppm boron also Increased the width of the zona glumerulosa 1n the
adrenals of female dogs. The zona fasclculata was somewhat decreased In
width. No hlstologlcal changes were observed In dogs fed <175 ppm of boron
1n boric add.
Weir and Fisher (1972) also fed beagle dogs boron 1n the diet for up to
2 years. Groups of four male and four female dogs were fed borax or boric
add at 0, 58, 117 or 350 ppm as boron. An additional test group of dogs
was fed borax or boric acid at 1170 ppm boron In the diet for 38 weeks. One
female and one male dog from each of the groups fed for up to 2 years were
sacrificed at 1 year. The parameters examined were similar to those
described for the rat study.
No effects on appearance, behavior, body weights or food consumption
were noted In dogs fed at 58, 117 and 350 ppm boron for 2 years. In
addition, organ weights, organ-to-body ratios, histopathologlcal findings
and hematologlcal and biochemical values were within normal limits. In dogs
fed at 1170 ppm boron, the only effects observed were testlcular changes.
Severe testlcular atrophy and spermatogenlc arrest were observed In two dogs
sacrificed at 26 weeks. At 38 weeks, two dogs were placed on control food
for 25 days. When these dogs were sacrificed, there was some evidence of
recovery of spermatogenesls 1n one dog.
Olllh -7- 02/11/87
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In a study by Seal and Weeth (1980), groups of 15 male weanling
Long-Evans hooded rats were provided with water containing 0, 150 or 300 mg
boron/I (ppm) as Na.B^O.j.lOH-0 (borax) for 70 days. The rats
were fed diets containing ~54 ppm boron. At necropsy, organ and body
weights were recorded. Blood was collected to determine packed cell volume
and plasma biochemical parameters. The right femur was weighed and frozen
for further analytical determinations, and the testes and epldldymldes were
examined for the presence of sperm.
Rats that drank water containing boron at 150 and 300 mg/i had body
weights 7.8 and 19.8% less than control rats, respectively. The rats that
drank water with boron at 300 mg/l were overtly smaller In body size with
long toenalls, atrophlc scrota! sacs and coarse halrcoats. Weights of the
testes, seminal vesicles, spleen and right femurs were significantly less 1n
both treated groups of rats.
At 300 mg/l boron 1n the drinking- water, only 3/15 rats had sperma-
tozoa present which the Investigators noted was significantly lower than the
numbers of control and 150 mg/i rats without spermatozoa. Actual numbers
of rats without spermatozoa at 0 and 150 mg/l were not reported. Seminal
vesicles of boron-treated rats at both concentrations were atrophlc.
Plasma trlglycerlde concentrations were 14.0 and 31.2% lower than
controls 1n rats consuming 150 and 300 mg boron/i, respectively. Total
protein content of plasma was 10.7% lower In rats drinking water at 300 mg
boron/I. The hematocrlt of the high-dose rats was 6.8% lower than con-
trols. Seal and Weeth (1980) suggested that the changes 1n protein levels
might Indicate an Interference with Intestinal absorption. Another possible
Indication of malabsorptlon was that percent fat was 53% lower In bones of
Olllh -8- 02/11/87
-------
'rats at both boron concentration levels. According to Latner (1975),
Intestinal malabsorptlon results primarily 1n decreased llpld absorption.
Calcium content of the femur was also reduced at 300 mg/i.
3.1.2. Inhalation. The only subchronlc Inhalation study located was a
study by Rusch et al. (1986) that examined the effects of boron trlflourlde
dlhydrate exposure 1n rats. In this study, groups of 20 male and 20 female
Fischer 344 rats were exposed to liquid aerosols of boron trlfluorlde
dlhydrate at 0, 2.0, 6.0 or 17 mg/m3, 6 hours/day, 5 days/week for 13
weeks. Mean body weights and hematologlcal parameters of exposed rats were
comparable with controls. An exposure-related depression of serum protein
concentrations (up to 16%) was observed. Flourlde concentrations 1n serum
and bone were Increased 1n a dose-related manner. During hlstologlcal
examination, necrosis of the renal tubular epithelium was observed 1n two
rats exposed to 17 mg/m3.
The authors compared total urinary fluorine to urinary fluoride and
estimated that <50% of the total boron trlfluorlde dlhydrate dissociated to
free fluoride. Toxic effects may have been a result of fluorine exposure as
well as boron exposure, compromising the usefulness of this study In risk
assessment.
3.2. CHRONIC
3.2.1. Oral. Schroeder and Kitchener (1975) administered sodium meta-
borate In drinking water at 5 ppm boron to 54 Swiss mice of both sexes
throughout their Hfespan. The mice were fed a diet low 1n all trace
elements. A group of 54 male and 54 female mice provided with water without
boron served as controls. Body weights were recorded at Intervals through-
out the study. Mice were allowed to die naturally, at wh'.ch time they were
dissected and examined for tumors.
Olllh -9- 02/11/E7
-------
No consistent differences In body weights compared with controls were
noted 1n the boron-treated mice. Boron at 5 ppm 1n the drinking water did
not significantly affect the longevity of mice as compared with controls.
Boron was also not found to be tumorlgenlc.
Weir and Fisher (1972) fed groups of 35 male and 35 female Sprague-
Dawley rats diets containing borax or boric add at 117, 350 or 1170 ppm as
boron equivalent for up to 2 years. A group of 70 male and 70 female rats
fed the basal diet served as controls. Body weight, food consumption and
toxic signs were recorded regularly. Hematologlcal studies and urlnalysls
of representative rats from each group were completed at Intervals through-
out the study. Five rats of both sexes from each dosing group were sacri-
ficed at 6 and 12 months. The surviving rats were sacrificed at 2 years.
Organ weights were recorded and organs were examined for hlstopathologlcal
alterations.
Signs that were observed beginning at the second month 1n rats fed diets
at 1170 ppm boron Included coarse halrcoats, scaly tails, a hunched
position, swelling and desquamatlon of the pads of the paws, abnormally long
toenalls, shrunken scrotum, Inflamed eyelids and bloody discharge of the
eyes. These effects became more frequent and pronounced by the end of the
first year, but stayed relatively the same during the second year. Boron at
1170 ppm also lowered food consumption during the first 13 weeks and
suppressed growth throughout the study.
Packed cell volume and hemoglobin values were low at many Intervals
during the study. Levels were significantly decreased 1n male and female
rats fed borax and female rats fed boric add at 1170 ppm boron. Biochemi-
cal analyses and urlnalysls values were within the normal range 1n all
treated rats.
Olllh -10- 02/11/87
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Testes weights and testes-to-body weight ratios were significantly
decreased 1n rats fed 1170 ppm boron. At the high-dose level, brain and
thyroid-to-body weight ratios were significantly higher than controls.
Testes were atrophlc In all male rats fed at 1170 ppm at 6, 12 and 24
months. Microscopic examination showed atrophied seminiferous epithelium
and decreased tubular size 1n the testes. No hlstologlcal alterations were
observed 1n rats fed 350 or 117 ppm boron.
3.2.2. Inhalation. ACGIH (1986) reported a cross-sectional study by
Hogan (1965) and Dry (1966) of workers exposed to dehydrated sodium borate
dust at a milling facility In California. Analysis of FEV data and the
Incidence of respiratory Illness among 82 men who had worked In a high
exposure area for at least 1 year compared with 547 workers who had never
worked there showed that poor respiratory health might be associated with
Inhalation exposure to dehydrated sodium borate dust. Exposure concentra-
tions of dust were not reported but at .times were said to be high enough to
Interfere with visibility. Longitudinal studies were recommended (Dry,
1966), but have not been conducted.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. In the Soviet Union (Krasovskll et il., 1976), men using
drinking water from sources with varying boron content were given question-
naires concerning sexual function. Analysis of the Information collected
suggested a tendency towards reduction of function 1r, men using water with
high boron content. The concentration of boron In the water where effects
were noted provided a dose on the level of 0.3 mg/kg as determined by the
Investigators. Details of this study, Including the parameters examined and
Information about confounding factors, were not provided.
Olllh -11- 02/11/87
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Krasovsk11 et al. (1976) also described a reproductive study using rats.
White male rats were supplied with drinking water containing boric add that
provided boron at levels of 0, 0.015, 0.05 or 0.3 mg/kg/day for 6 months.
Control rats received tap water.
At 0.3 mg/kg/day, blood aldolase activity was significantly Increased
(p<0.01). This Increase was noticeable during the second month of treat-
ment. The weight factors of the gonads and the mobility time of spermato-
zolds from the 0.3 mg/kg/day treated rats were decreased. At this level,
boron also caused a reduction In sperm number and acid and osmotic resis-
tance, and a decrease In the DNA content of raw gonad tissue. At 0.05
mg/kg/day, a reduction of spermatozold mobility and count was noted. The
results of this study led the Investigators to state that the 0.015 mg/kg
should be considered Inactive.
In a study by Olxon et al. (1976), male Sprague-Oawley rats were provid-
ed with dMnklrvg water containing borax'at boron concentrations of 0.3, 1.0
or 6.0 mg/i for 90 days. The authors stated that assuming rats drink an
average of 35 mi water/day the maximum boron dose can be estimated at 0.84
mg/kg/day. No effects on male reproduction were noted In this study. Boron
did not affect FSH or LH In the plasma. No changes were noted In clinical
serum chemistry or weights of the body, testls, prostate or seminal vesicle.
Fructose, zinc and add phosphatase levels 1n the prostate were not changed.
Serial breeding studies of treated rats showed no effects on male fertility.
In a study by Lee et al. (1978), groups of 18 male Sprague-Oawley rats
were provided with diets containing borax at boron concentrations of 0, 500,
1000 or 2000 ppm for 30 or 60 days. Fool consumption was measured weekly
and the rats Ingested 12.5, 25 or 50 mg boron/day. Body weights were
measured weekly. Other parameters examined after 30 and 60 days of boron
Olllh -12- 02/11/87
-------
exposure were testlcular and epldldymal histology, activities of selected
testlcular and prostatlc enzymes, boron concentrations In plasma and testes,
plasma FSH, LH and testosterone concentrations; a 12-week serial breeding
study was also conducted.
None of the treated rats showed any signs of systemic toxlclty or
significant decreases 1n body weights or food consumption when compared with
controls. Testes of rats treated at 500 ppm boron showed no morphological
changes at 30 or 60 days. At 30 days, testes from rats treated at 1000 ppm
boron showed marked reduction of spermatocytes, spermatlds and mature
spermatozoa. By 60 days, most germinal elements were absent. Testes from
rats treated at 2000 ppm showed a loss of germinal elements, Including
premelotlc cells at 30 days; complete germinal aplasla was observed at 60
days.
Activities of testlcular and prostatlc enzymes associated with post-
melotlc spermatogenlc cells were significantly decreased (p<0.05) In rats
fed at 1000 and 2000 ppm boron at 30 and 60 days.
In all treated rats, mean plasma FSH concentration was Increased
(p<0.05). This Increase was dose-related and was greater at 60 days. LH
plasma concentrations were within normal limits at all dose levels at 30
days. At 60 days, LH concentrations were highly variable, with concentra-
tions Increased In half of the treated rats. These Increases did not cause
the mean concentration at each treatment to be statistically significant.
Testosterone plasma concentrations were within the normal range.
Boron concentrations In the plasma and testes of control rats varied
from 0.1-0.3 ppm. In rats fed 500 ppm boron, plasma and testes boron con-
centrations were 0.9 ppm at 30 days, Increasing to 2.6 ppm 1n the plasma and
2.1 ppm In the testes at 60 days. Results In the 1000 and 2000 ppm treated
Olllh -13- 02/11/87
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.rats gave some Indication of boron accumulation In the testes. At 30 days,
plasma concentrations were 3.8 and 5.5 ppm In rats fed 1000 and 2000 ppm,
respectively (concentrations of boron In the testes were not measured at 30
days). At 60 days, plasma concentrations had risen to 4.3 and 6.8 ppm and
testes concentrations were 6.1 and 8.5 ppm for the rats fed at 1000 and 2000
ppm, respectively.
Serial matlngs were performed by placing a virgin female rat with a male
rat for 1 week to test reproductive functions. The matlngs were begun at
the end of the 30- and 60-day exposure periods and continued for 12 weeks.
The results of the serial mating studies Indicated that, at 500 ppm boron,
pregnancy rate, litter size and appearance of litters were normal. These
results were found 1n rats treated for 30 and 60 days. At 1000 ppm boron,
the pregnancy rate was reduced during the first 3 weeks after 30 days of the
boron diet and for 4 weeks following 60 days of treatment. At 2000 ppm.
pregnancy rates were significantly reduced for 8 weeks with only a partial
recovery observed at week 9-10, following 30 days of boron treatment. After
60 days of boron treatment at 2000 ppm, no pregnancies were observed during
the 12-week mating period. These rats were mated for an additional 20 weeks
with no pregnancies occurring. Litters that resulted from matlngs of rats
treated at lower boron levels were normal 1n size, Indicating that boron-
Induced Infertility 1s a result of germ cell depletion rather than dominant
lethal effects.
A multlgeneratlon study uas conducted by Weir and Fisher (1972), 1n
which groups of 8 male and 16 female Sprague-Dawley rats were fed diets
containing borax or boric ac'd at 117, 350 or 1170 ppm boron. The rats were
fed the boron-enriched diet* for 14 weeks before mating and maintained on
the diets throughout the study. After the 14-week feeding period, one male
Olllh -14- 02/11/87
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•and two females were placed 1n breeding cages. The first generation (F, )
was culled to eight pups/Utter and raised through weaning when they were
discarded. The parents were rebred to produce their second Utter (F,b),
which was reduced to eight pups/Utter. At weaning, 16 females and 8 males
each from the control and test groups were picked at random for the second
parental (P?) generation. The P_ generation was bred to produce F_
and F_. Utters. The F_. Utter was the P_ generation, which was bred
2b 2b 3
to produce the F and F Utters.
No adverse effects on reproduction were observed 1n rats fed diets con-
taining 117 or 350 ppm as boron equivalent. At 1170 ppm boron, no Utters
were produced. Matlngs of females fed at 1170 ppm to control males also
were unsuccessful. Microscopic examination of the testes showed lack of
viable sperm In all males at 1170 ppm boron. In females fed 1170 ppm boron,
decreased ovulatlon was apparent In the majority of ovaries examined.
3.3.2. Inhalation. Pertinent data regarding teratogenlc and other repro-
ductive effects following Inhalation exposure to boron could not be located
In the available literature.
3.4. TOXICANT INTERACTIONS
Magour et al. (1982) studied the effect of boron on ethanol and hexo-
barbltal sleeping time 1n female Wlstar rats. For the hexobarbltal study,
groups of ten 4-week-old rats were provided with drinking water containing
100 mg/i boron for 8 days or were Injected once Intraperltoneally with 42
mg/kg boron. On day 8 or 45 minutes after boron Injection, all rats were
Injected Intraperltoneally with 100 mg/kg sodium hexobarbltal. For the
ethanol study, twenty 3-month-old rats were Injected Intraperltoneally with
42 mg boron/kg 45 minutes before they were Injected with ethanol at 3 g/kg.
Olllh -15- 02/11/87
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In rats provided with boron In the drinking water at TOO ppm for 8 days,
hexobarbltal sleeping time was significantly Increased by 21%. Boron con-
centrations In the brains of these rats were 2.5 vg/g, which were 5 times
higher than boron concentrations 1n the brains of control rats. Hexobarbl-
tal sleeping time determined 45 minutes after a boron Injection was signifi-
cantly Increased by 17% above controls, with boron concentrations In the
brain at 10 yg/g. Ethanol sleeping time was significantly Increased by
32% when ethanol Injection was followed an Injection of boron. Boron
concentrations 1n the brains of these rats were 16 ng/g.
HexabarbHal and ethanol sleeping times can be prolonged 1f the metabo-
lism of these compounds are Inhibited. The authors state that there 1s no
evidence Indicating that boron affects drug metabolizing enzymes; therefore,
they believe that "central rather than peripheral mechanisms may be respon-
sible for the observed effect of boron on sleeping times."
Elsalr et al. (1980) gave rabbits drinking water that provided a fluo-
ride dose of 40 mg/kg. or water that provided fluoride (40 mg/kg) and boron
at 15.4 mg boron/kg. The simultaneous administration of boron with fluoride
was found to reduce the adverse effects of fluoride on calcium phosphorus
metabolism. The effects on fluoride-Induced depression of food Intake and
body weights and radlographlc evidence of skeletal changes were lessened by
the addition of boron.
Olllh -16- 02/11/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carcinogenic potential of boron 1n humans
following oral or Inhalation exposure could not be located In the available
literature.
4.2. BIOASSAYS
4.2.1. Oral. Schroeder and Kitchener (1975) saw no Increase In tumor
Incidence 1n mice provided with water containing boron at 5 ppm throughout
their llfespan. Two-year studies using rats and dogs (Heir and Fisher,
1972) also revealed no Increase In tumor Incidences (see Section 3.2.1.).
4.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of boron 1n laboratory animals following Inhalation exposure could not be
located In the available literature.
4.3. OTHER RELEVANT DATA
In reproductive studies (Lee et aK, 1978; Weir and Fisher, 1972), no
Indication of dominant lethal effects were noted (see Section 3.3.1.).
Pertinent data regarding other qualitative Indicators of carcinogenic
potency of boron could not be located 1n the available literature.
4.4. HEIGHT OF EVIDENCE
Chronic oral studies using mice (Schroeder and Mltchener, 1975) and rats
and dogs (Weir and Fisher, 1972) provide no evidence that boron Is carcino-
genic. Boron has not been tested for mutagenlcHy. The weight of evidence
1n animals Is judged to be Inadequate because, although It appears that the
study using rats (Heir and Fisher, 1972) was performed at the NTD, the study
using mice (Schroeder and Kitchener, 1975) probably was not. Also data to
evaluate the effects by Inhalation 1s lacking as well as mutagenldty data.
Oil In -17- 04/30/87
-------
this lack of evidence for carclnogenlcHy Indicates that boron can be placed
In IARC.Group 3, Insufficient evidence of carclnogenldty. According to the
U.S. EPA classification scheme (U.S. EPA, 1986), boron Is a Group D
chemical, not classifiable, due to Inadequacy of available evidence.
Olllh -18- 04/30/87
-------
5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1986) and OSHA (1985) 11st standards for various boron compounds.
The ACGIH (1986) celling limit and the OSHA (1985) PEL for boron trlfluorlde
are both 1 ppm or 3 mg/m3. For boron oxide, the ACGIH (1986) TLV Is 10
mg/m3 while the OSHA (1985) PEL Is 15 mg/m3. Only ACGIH (1986) lists
standards for borates; a TLV of 1 mg/m3 for anhydrous and pentahydrate and
5 mg/m3 for decahydrate (borax). ACGIH (1986) also lists 1 ppm (10
mg/m3) as the celling limit for boron trlbomlde, but states that reference
should be made to hydrogen bromide for Its toxlclty.
U.S. EPA (1971) has promulgated tolerances for total boron of 30 ppm 1n
or on cotton seed and 8 ppm 1n or on citrus fruits. These levels Include
boron compounds that have been applied as well as naturally occurring boron.
Olllh -19- 02/11/B7
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOc)
O
6.1.1. Oral (RfDSQ). An RfO$0 can be calculated from the NOEL of 350
ppm found 1n a 2-year dietary study using dogs (Weir and Fisher, 1972). In
this study, boron 1n the form of boric add or borax was added to the diets
of dogs at 0, 58, 117 or 350 ppm for 2 years or 1170 ppm for 38 weeks.
Information about the level of boron 1n the basal diet was not provided so
that the total boron consumed by the dogs may have been higher. Using the
NOEL of 350 ppm or 8.75 mg/kg/day, assuming a food factor for dogs of 0.025
(U.S. EPA, 1985) and an uncertainty factor of 100 (10 for 1nterspec1es
extrapolation and 10 to protect sensitive Individuals), an RfD§Q of 0.088
mg/kg/day or 6.2 mg/day for a 70 kg human Is derived.
6.1.2. Inhalation (RfOg,). The only Inhalation study of a boron
compound examines the subchronlc tox1c1ty of boron tMfluoMde dlhydrate 1n
rats (Rusch et al., 1986). Because the.toxic effects observed 1n this study
may have been a result of fluoride as well as boron, an RfD-j for boron
will not be derived from this study.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfOQ). An RfOQ of 0.175 mg/kg/day or 12.3 mg/day for a
70 kg human can be calculated by applying an uncertainty factor of 100 to
the rat NOEL of 350 ppm (17.5 mg/kg/day assuming a food factor for rats of
0.05) found In the 2-year oral study by Weir and Fisher (1972). In this
study, rats were fed diets containing 0, 117, 350 or 1170 ppm added aoron.
Boron levels In the basal diet were not provided so that actual boron Intake
levels may have been higher. This less conservative RfOQ 1s not recom-
mended because 1t seems to be near the effect level 1n rats. In the study
by Seal and Ueeth (1980), a total boron Intake of 23.7 mg/kg/day (added
Olllh -20- 05/07/87
-------
.boron in drinking water at 150 mg boron/l and 54 ppm boron In the basal
diet, assuming rats weigh 0.35 kg and drink 0.049 I water/day and assuming
a food factor of 0.05) resulted 1n decreased body weights and atroplc
seminal vesicles 1n rats In a 70-day study. An Intake of 47.4 mg/kg/day
estimated from a drinking water concentration of 300 mg boron/l 1n the
same study resulted In Interference 1n spermatogenesls, Indicating a
relatively steep dose-response curve. The reproductive rat study by Weir
and Fisher (1972) also provides evidence that the dose-response curve 1s
steep. In this study, male and female rats fed a diet containing added
boron at 1170 ppm (58.5 mg/kg/day) were sterile 1n 14 weeks.
The Weir and Fisher (1972) 2-year study using dogs provides additional
evidence Indicating that the slope of the boron dose-response curve 1s
steep. In dogs fed diets containing 1170 ppm added boron (29.25 mg/kg/day),
severe testlcular atrophy and spermatogenlc arrest was observed after 26
weeks of treatment. These changes were not observed at 350 ppm (8.8
mg/kg/day).
More support for a more conservative RfDQ value Is provided 1n the
study by Lee et al. (1978). In this study, boron levels 1n the plasma and
testes of rats fed boron 1n the diet were determined at 30 and 60 days of
boron treatment. At all dose levels (500, 1000 and 2000 ppm 1n diet, Inves-
tigators estimated Intakes of 12.5, 25 and 50 mg/kg/day) higher plasma boron
concentrations were found at 60 days than at 30 days. At the low dose,
levels of boron 1n the testes were Increased at 60 days. In the two higher
dose groups, testes boron concentrations at 60 days were higher than plasma
boron concentrations. These results Indicate that excretion of boron may be
limited so that at relatively high boron Intake, boron concentrations 1n the
plasma and testes Increase over time. Because the factors limiting boron
Olllh -21- 05/07/87
-------
excretion are not known, keeping boron Intake levels low may reduce boron
accumulation, which may prevent the toxic effects that can result from boron
exposure.
The animal data Indicate that a more conservative RfDn for human boron
Intake 1s appropriate; therefore, the RfO_0 value of 6.2 mg/day 1s recom-
mended for an RfDQ. An additional 10 for use of a subchronlc NOEL 1s not
deemed necessary. This Intake level for humans should be safe since boron
consumption levels have been estimated to be as high as 9-20 mg/day or as
low as 1.3 mg/day, depending on the diet (Synder et al., 1975). Boron
Intake will be high 1n Individuals consuming large quantities of fruits and
vegetables; fruits and vegetables contain more boron than grains (Kent and
McCane, 1941). When more Information concerning the factors that limit the
excretion of boron 1n humans and animals becomes available, 1t may be
possible to revise the RfD_ value to a higher level.
The derived CS values and calculation method are presented 1n Table 6-1.
The subchronlc and chronic studies were chosen for derivation of CSs because
the effects associated with boron treatment were observed at lower doses.
The highest CS, 21.6, was calculated from the dietary dog study by Weir and
Fisher (1972). In this study, beagle dogs fed diets containing 1170 ppm
added boron had spermatogenlc arrest and severe testlcular atrophy.
6.2.2. Inhalation (RfD.). Pertinent data regarding the toxic effects
of boron following chronic Inhalation exposure In rats rould not be located
1n the available literature; therefore, an RfD, cannot be derived.
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Chronic oral studies of boron (Schro?der and Kitchener,
1975; Weir and Fisher, 1972) are not adequate for an evaluation of cardno-
genlclty; therefore, an oral q * cannot be calculated.
Olllh -22- 05/07/87
-------
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6.3.2. Inhalation. Pertinent data regarding the carcinogenic potential
of boron following Inhalation exposure could not be located In the available
literature; therefore, an Inhalation q * cannot be calculated.
Olllh -24- 02/11/87
-------
7. REFERENCES
Aas Jansen, J., J.S. Schou and B. Aggerbeck. 1984. Gastrointestinal
absorption and j_n vitro release of boric add from water-emulsifying oint-
ments. Food Chem. Toxlcol. 22(1): 49-53.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of Threshold Limit Values and Biological Exposure Indices, 5th
ed. Cincinnati, OH. p. 60, 61, 63.
Bower, J.G. 1978. Boron, elemental. In.: K1rk-0thmer Encyclopedia of
Chemical Technology, Vol. 4, 3rd ed., M. Grayson and 0. Eckroth, Ed. John
Wiley and Sons, Inc., New York. p. 62.
D1xon, R.L., I.P. Lee and R.J. Sherlns.- 1976. Methods to assess reproduc-
tive effects of environmental chemicals: Studies of cadmium and boron admin-
istered orally. Environ. Health Perspect. 13: 59-67.
Elsalr, J.R.M, R. Oenlne, M. Reggabl, et al. 1980. Boron as a preventive
antidote In acute and subacute fluoride Intoxication 1n rabbits: Its action
on fluoride and calcium-phosphorus metabolism. Fluoride. 13(3): 129-138.
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 144.
Hogan. W.D. 1965. Boron Study Preliminary Report. Bureau Occup. Health,
California State Dept. Public Health. (CHed In ACGIH. 1986)
Olllh -25- 02/11/87
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Kent, N.L. and R.A. McCane. 1941. The absorption and excretion of minor
elements. Blochem. J. 35: 837-844.
Krasovskll, G.N., S.P. Varshavskaya and A.I. BoMsov. 1976. Toxic and
gonadotroplc effects of cadmium and boron relative to standards for these
substances In drinking water. Environ. Health Perspect. 13: 69-75.
Latner, A.L. 1975. Clinical Biochemistry, 7th ed. W.B. Saunders Co.,
Philadelphia, PA. (Cited In Seal and Weeth, 1980)
Lee, I.P., R.J. Sherlns and R.I. D1xon. 1978. Evidence for Induction of
germinal aplasla In male rats by environmental exposure to boron. Toxlcol.
Appl. Pharmacol. 45(2): 577-590.
Magour, S., P. Schramel, J. Ovcar and H: Maser. 1982. Uptake and distribu-
tion of boron In rats: Interaction with ethanol and hexobarbltal In the
brain. Arch. Environ. Contam. Toxlcol. 11(5): 521-525.
Nrlagu, J.O. 19*9. Copper In the atmosphere and precipitation. jji: Copper
Environment, J.O. Nrlagu, Ed. John Wiley and Sons, New York. p. 43-75.
OSHA (Occupational Safety and Health Administration). 1985. Safety and
Health Standards. Code of Federal Regulations. 29 CFR 1910.1000.
Rusch, G.M., G.fl. Hoffman, R.F. McConnell and W.E. Rlnehart. 1986. Inhala-
tion toxldty studies with boron trlfluoMde. Toxlcol. Appl. Pharmacol.
83(1): 69-78.
Olllh -26- 02/11/87
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Schroeder, H.A. and M. MHchener. 1975. Life-term effects of mercury,
methyl mercury and nine other trace metals on mice. J. Nutr. 105(4):
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Olllh -28- 02/11/87
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