United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/002F
Final
11-06-2012
Provisional Peer-Reviewed Toxicity Values for
Boron Trichloride
(CASRN 10294-34-5)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Alan J. Weinrich, CIH, CAE
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ambuja Bale, PhD, DABT
National Center for Environmental Assessment, Washington, DC
Geniece M. Lehmann, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
li
Boron Trichloride
-------
TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 18
Oral Exposure 18
Inhalation Exposure 20
ANIMAL STUDIES 24
Oral Exposure 24
Inhalation Exposure 33
OTHER DATA 35
Acute Lethality Studies 35
Short-Term Exposure 36
Toxicokinetics 37
Genotoxicity 39
Nutrition Studies 40
Other Toxicity Data Related to pH of Hydrogen Chloride 41
DERIVATION 01 PROVISIONAL VALUES 44
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfDs FOR BORON
TRICHLORIDE 45
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfCs FOR BORON
TRICHLORIDE 46
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR BORON TRICHLORIDE 48
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR (WOE) 48
PROVISIONAL ORAL SLOPE FACTOR (p-OSF) DERIVATION 49
PROVISIONAL INHALATION UNIT RISK (p-IUR) DERIVATION 49
APPENDIX A. PROVISIONAL SCREENING VALUES 50
APPENDIX B. RELEVANT DATA TABLES 51
APPENDIX C. BMD OUTPUTS 61
APPENDIX C. BMD OUTPUTS 61
APPENDIX D. REFERENCES 62
in
Boron Trichloride
-------
COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
iv
Boron Trichloride
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
BORON TRICHLORIDE (CASRN 10294-34-5)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
1
Boron Trichloride
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11-6-2012
INTRODUCTION
Boron trichloride gases have been used as soldering fluxes for alloys of aluminum, iron,
zinc, tungsten, and Monel®; in the plasma etching of aluminum alloys, tungsten, and tungsten
silicide; to remove nitrides, carbides, and oxides in the refining of aluminum, magnesium, zinc,
and copper alloys; to treat the melt in the casting of aluminum; as a source of boron in high
energy fuels and rocket propellants; to douse fires in heat treating ovens that contain magnesium
products; as reagents in the synthesis of drug candidates for a range of diseases; and in the fiber
industry as raw materials needed to produce pyrolytic boron nitride and boron fiber, components
of high-tech composite structures (ATSDR, 2007). Figure 1 shows the chemical structure of
boron trichloride. Table 1 presents the physicochemical properties of boron trichloride.
Figure 1. Chemical Structure of Boron Trichloride
Table 1. Physicochemical Properties of Boron Trichloride
Property (unit)
Value
Reference
CASRN
10294-34-5
HSDB (2011a)
Molecular formula
BC13
Molecular weight
117.17 g/mol
Physical state/Appearance
Colorless fuming liquid at low temperatures
Odor
Pungent, suffocating odor
Boiling Point (°C)
12.5
Melting point (°C)
-107
Vapor density (g/cm3)v
4.03 (Air = 1)
Vapor pressure (kPa at 27°C)
166
Water solubility
Hydrolyzes upon contact with water into H3B 03 and HC1
Other solubilities
Decomposes in alcohol to H3B 03 and HC1
ATSDR (2007)
Flash point
No data
Flammability in air
Nonflammable
Dissociation constant pKa
No data
Density (g/cm3)
1.3728 at 0°C
Partition coefficient (Log Kow)
No data
Synonyms
Trichloroborane, trichloroboron
2
Boron Trichloride
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11-6-2012
No RfD, RfC, or cancer assessment for boron trichloride is included in the IRIS database
(U.S. EPA, 2011). However, there is an IRIS Toxicological Review document for boron and
compounds (CASRN 7440-42-8; U.S. EPA, 2004) that derives a RfD of 0.2 mg/kg-day, based on
dietary gestational exposure to boric acid (Price et al., 1996a; Heindel et al., 1992). IRIS
determined that the data were inadequate to support derivation of a RfC or a cancer assessment
for boron and compounds. IRIS also reports a RfC of 0.02 mg/m3 for inhalation exposure to
hydrogen chloride, a hydrolysis product of boron trichloride. Boron trichloride is not on the
Drinking Water Standards and Health Advisories List, but there is a lifetime Health Advisory
(HA) for boron (U.S. EPA, 2009) that is based upon the IRIS assessment.
No RfDs or RfCs for boron trichloride are reported in the Health Effects Assessment
Summary Tables (HEAST), but there are subchronic and chronic RfCs for elemental boron,
based on respiratory tract irritation in humans (U.S. EPA, 1997). The HEAST also list a
subchronic RfC and a chronic RfC for boron trifluoride (U.S. EPA, 1997). The Chemical
Assessments and Related Activities (CARA) list (U.S. EPA, 1994) does not contain any
documents for boron trichloride but lists a Health Effects Assessment (U.S. EPA, 1987) and a
Health and Environmental Effects Document (U.S. EPA, 1991) for boron and compounds.
The toxicity of boron trichloride has not been reviewed by the ATSDR (2011). However,
ATSDR has reviewed the toxicity of boron in its Toxicological Profile for Boron (ATSDR,
"3
2007), which derives an inhalation acute minimal risk level (MRL) of 0.01 mg/m for boron and
an oral MRL of 0.2 mg/kg-day for both acute and intermediate duration exposures to boron. The
World Health Organization (WHO, 2011) has not set guidelines for boron trichloride exposure.
However, it set a provisional guideline of 0.5 mg/L for boron in drinking water, based on a
tolerable daily intake (TDI) of 0.16 mg/kg-day (WHO, 2003). CalEPA (2008) has not derived
toxicity values for boron trichloride or boron.
No occupational exposure limits for boron trichloride have been derived by the American
Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute for
Occupational Safety and Health (NIOSH, 2005), or the Occupational Safety and Health
Administration (OSHA, 2011). However, NIOSH (2005) and OSHA (2011) have set
occupational recommended and permissible exposure limits, respectively, for boron trifluoride,
boron tribromide, and boron oxide. ACGIH (2001a,b,c, 2005, 2011) also derived threshold limit
"3
values (TLV) for occupational exposures to boron trifluoride (TLV-Ceiling = 2.8 mg/m ), boron
tribromide (TLV-Ceiling =10 mg/m3), boron oxide (TLV-TWA =10 mg/m3), and inorganic
"3
borates (TLV-TWA = 2 mg/m as inhalable particulate).
The International Agency for Research on Cancer (IARC, 2011) has not reviewed the
carcinogenic potential of boron trichloride, and the compound is not included in the 12th Report
on Carcinogens (NTP, 2011). CalEPA (2008) has not derived a quantitative estimate of the
carcinogenic potential of boron trichloride.
The only toxicity values proposed were draft acute exposure guideline levels (AEGLs)
for inhaled boron trichloride (U.S. EPA, 2000), including the following for 8-hour exposures,
with key studies listed parenthetically:
"3
• AEGL-1 (nondisabling): 0.6 ppm (2.9 mg/m ) based on the no-effect-level of hydrogen
chloride (HC1) in exercising human asthmatics (Stevens et al., 1992);
3
Boron Trichloride
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FINAL
11-6-2012
"3
• AEGL-2 (disabling): 0.9 ppm (4.3 mg/m ) based on studies in mice and rats with HC1
(Barrow et al., 1977; Stavert et al., 1991);
"3
• AEGL-3 (lethal) for an 8-hour exposure of 3.5 ppm (17 mg/m ) based on a 1-hour LC50
for boron trichloride in male rats (Vernot et al., 1977).
HC1 was used as the basis for the proposed AEGL-1 and AEGL-2 because boron
trichloride undergoes rapid hydrolysis to form hydrochloric acid, boric acid and heat in moist air
(U.S. EPA, 2000; AT SDR, 2007).
Boron trichloride acute inhalation toxicity is most likely from the irritant effects of its
hydrolysis product, hydrochloric acid (U.S. EPA, 2000). Inhalation of boron trichloride results
in edema and irritation of the upper respiratory tract (Braker and Mossman, 1980). Boron
trichloride has not been found to occur in water because it hydrolyzes to boric acid and HC1 in
aqueous media (ATSDR, 2007). Boric acid acts as an electron acceptor, accepting a hydroxide
ion from water to form boron hydroxide (ATSDR, 2007).
Literature searches were conducted on sources published from 1900 through April 4,
2011 for studies relevant to derivation of provisional toxicity values for boron trichloride,
CASRN 10294-34-5. Searches were conducted using EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy
Information Administration, Information Bridge, and Energy Citations Database; EBSCO:
Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); WHO; and Worldwide Science.
The following sources outside of HERO were searched for health-related values: ACGIH,
ATSDR, CalEPA, EPA IRIS, HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2,
NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Boron is a nonmetal element that always is found in nature covalently bonded to oxygen
as some form of borate, such as boric acid or tetraborate (ATSDR, 2007; U.S. EPA, 2004); it
never is found as the free element (HSDB, 201 lb). The boron-oxygen bonds are very strong and
will not be broken except under extreme laboratory conditions. Inorganic borate compounds in
the body are present as boric acid. Boric acid is the only boron compound identified in urine
following boron ingestion and has repeatedly been found to account for >90% of the ingested
boron dose (WHO, 1998).
4
Boron Trichloride
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11-6-2012
Boron trichloride hydrolyzes easily in water, moist air, or ethanol to boric acid and HC1
(ATSDR, 2007) (see Table 1), as represented by the following equation:1
BC13 + 3 H20 -»• H3BO3 + 3 HC1
With the exception of acute inhalation lethality studies, there are no toxicological data on
boron trichloride. Therefore, available literature is reviewed for boron, predominantly as boric
acid, and for HC1, to determine which component might drive the oral or inhalation toxicity of
BCI3. Available data on hydrolysis, reactivity, and toxicokinetics support this approach
(U.S. EPA, 2000; ATSDR, 2007).
Tables 2 and 3 present potentially relevant toxicological data available for the hydrolysis
products of boron trichloride: boric acid and hydrogen chloride, respectively. Doses of boric
acid have been provided in mg-B/kg-day for all studies reported in Table 2.
Assuming that hydrolysis is complete or near complete.
5
Boron Trichloride
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11-6-2012
Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
Human
1. Oral (mg/kg-d)a
Acute
2 infants (gender not
reported), case report,
duration not reported
30.4-94.7
Diarrhea, erythema, vomiting,
face and skin rash
None
Not run
30.4
Baker et al. (1986)
(Boron as boric
acid)
7 infants (gender not
reported), case report,
duration not reported
Not reported
Seizures
None
Not run
None
O'Sullivan and
Taylor (1983)
(Honey-borax)
Number and gender
not reported, case
report, 15 d
2.5-24.8
Indigestion, dermatitis,
alopecia, anorexia
2.5
Not run
3.68
Culver and Hubbard
(1996)
(Boron as boron
compounds,
unspecified)
Subchronic
Number and gender
not reported, case
report, duration not
reported
25-35
Nausea, vomiting, skin flush
2.5b
Not run
25
Culver and Hubbard
(1996) (Boron as
boron compounds,
unspecified)
Chronic
"Nearly 1000" male
workers;
epidemiology
0.02, 0.06
(control
groups), 0.45,
1.8
Reduced sperm Y:X ratio
None
Not run
0.45
Scialli etal. (2010)
Developmental
None
Reproductive
None
Carcinogenic
None
6
Boron Trichloride
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
2. Inhalation (mg/m3)a
Subchronic
None
Chronic
Number and gender
not reported,
occupational, duration
not reported
Not reported
Dermatitis, nasal irritation,
nose bleeds, cough, shortness
of breath
None
Not run
None
Birmingham and
Key (1963) (Boron
as boron
compounds,
unspecified)
Concomitant
exposure to other
compounds
82, male,
occupational, at least 1
yr
Not reported
Respiratory symptoms
(focused expiratory volume)
None
Not run
None
Ury (1966)
(Sodium borate
dust)
629, 96% males,
occupational, >5 yr
1.1-14.6
Symptoms of respiratory
irritation
None
Not run
1.1
Garabrant et al.
(1984, 1985)
(Boric acid or boron
oxide)
113, 96% males,
occupational, >5 yr
4.1 (Range
1.2-8.5)
Eye irritation, dryness of
mouth, nose, or throat, sore
throat, cough during work
shift
None
Not run
4.1
Garabrant et al.
(1984)
(Boric acid or boron
oxide)
336, gender not
reported, occupational,
>5 yr
1.1-14.6
No exposure-related change in
pulmonary function. Nasal,
eye and throat irritation;
cough and breathlessness.
None
Not run
~5
Wegman et al.
(1994)
(Boric acid or boron
oxide)
7
Boron Trichloride
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
Developmental
None
Reproductive
28, male,
occupational, >10 yr
(Range
22-80)
Low sperm count, reduced
sperm motility, elevated
fructose content of seminal
fluid, decreased sexual
function
None
Not run
22
Tarasenko et al.
(1972) (Boron as
boric acid)
Concomitant
exposure to other
compounds, study
limited by poor
reporting
542, male,
occupational, average
= 15.8 yr
<0.82 mg/m3
to 5.05
Standardized birth ratios
None
Not run
5.05
Whorton et al.
(1992, 1994a,b)
(Boron as sodium
borates)
68, female,
occupational, not
reported
Not reported
No change in fertility or
offspring gender ratio
None
Not run
None
Whorton et al
(1992) (Sodium
borates)
904, female,
occupational, not
reported
Not reported
No association with
spontaneous abortions
None
Not run
None
Swanetal. (1995)
(Boron compounds
unspecified)
Concomitant
exposures to other
compounds.
Carcinogenic
None
8
Boron Trichloride
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
Animal
1. Oral (mg/kg-d)a
Subchronic
10 male/10
female/group,
Sprague-Dawley rat,
dietary, 90 d
0,2.6, 8.8,
26.3, 87.5,
262.5
Mortality at 262.5 mg/kg-d;
clinical toxicity; decreased
body weight at 87.5 mg/kg-d,
and testicular atrophy in one
rat at 26.3 mg/kg-d.
8.8
Not run
26.3
Weir and Fisher
(1972) (Boron as
boric acid)
10 male/10
female/group, B6C3F,
mouse, dietary, 13 wk
M: 0, 34, 70,
141,281,563
F: 0, 47, 97,
194, 388, 776
>60% mortality and clinical
signs at highest dose; body
weight decreased in both
sexes; blood effects in both
sexes and testicular
atrophy/degeneration in males
at three highest doses
M: 70
F: 97
Not run
M: 141
F: 194
NTP (1987), Dieter
(1994)
(Boron as boric
acid)
5 male/5
female/group, beagle
dog, dietary,
90 d
M: 0,0.33,
3.9, 30.4;
F: 0, 0.24,
2.5,21.8
Testes primary target organ
only in high-dose group.
Testicular atrophy, tubular
degeneration. No effects at
lower doses. Some high-dose
blood effects in both sexes
M: 3.9
F: 2.5
Not run
M: 30.4
F: 21.8
Weir and Fisher
(1972) (Boron as
boric acid).
Chronic
35 male/35
female/group,
Sprague-Dawley rat,
dietary, 104 wk
0,5.9, 17.5,
58.5
Effects restricted to highest
dose. Clinical signs,
decreased body weight,
testicular atrophy
17.5
Not run
58.5 (FEL)
Weir and Fisher
(1972)
(Boron as boric
acid)
9
Boron Trichloride
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
50 male/50
female/group, B6C3F,
mouse, dietary,
103 wk
0, 48, 96
Increased mortality in
low-dose males. Testicular
atrophy, interstitial
hyperplasia, increase in
splenic lymphoid depletion
only at highest dose
None
Not run
48 (FEL)
NTP (1987), Dieter
(1994)
(Boron as boric
acid)
4 male/4
female/group, beagle
dog, dietary,
104 wk
Interim sacrifice at
52 wk
0, 1.4,2.9, 8.8
No effects observed at 52 or
104 wk
8.8
Not run
None
Weir and Fisher
(1972) (Boron as
boric acid).
Highest dose tested
is a NOAEL
4 male/4
female/group, beagle
dog, dietary, 38 wk
Interim sacrifice at
26 wk
25-d postdosing
recovery.
0, 29.2
Some testicular atrophy and
spermatogenic arrest observed
at both sacrifice periods.
Recovery during 25-d
postdosing period
None
Not run
29.2
Weir and Fisher
(1972) (Boron as
boric acid). Only
one dose tested
Developmental
29 time-mated
females/group
Sprague-Dawley rat,
dietary, GDs 0-20 or
dietary GDs 6-15
0,13.6, 28.5,
57.7
(GDs 0-20)
0,942
(GDs 6-15)
Maternal toxicity in mid-
and high-dose group.
Prenatal mortality increased at
high-dose. Decreased fetal
weight at all doses. Skeletal
and other malformations or
variations at mid- and
high-dose
Maternal: 13.6
Developmental:
None
Not run
Developmental:
10.3C
Maternal: 28.5
Developmental:
13.6
Heindel et al.
(1992,1994) NTP
(1990a) (Boron as
boric acid).
PSd
10
Boron Trichloride
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
60 time-mated
females/group CD
rat, dietary,
GDs 0-20 (Phase I)
0,3.3, 6.3,
9.6,13.3,25
No maternal toxicity. Fetal
body weights decreased in
two highest-dose groups.
Increased skeletal, but not
external or visceral,
malformations in two
highest-dose groups
Maternal: 25
Developmental:
9.6
Not run
Developmental:
10.3C
Maternal: ND
Developmental:
13.3
NTP (1994),
Price et al. (1996a)
(Boron as boric
acid)
PSd
60 female/group CD
rat, dietary,
GD 0-PND 21
(Phase II)
0,3.2, 6.5, 9.7
12.9,25.3
Increased mortality in
high-dose pups during
PNDs 0-4 was within
historical control range. No
differences in pup weights
from PNDs 0-21. Only
skeletal malformation
postnatal period time was
short rib XIII
Maternal: 25.3
Developmental:
12.9
Not run
Maternal: ND
Developmental:
25.3
NTP (1994),
Price et al. (1996a)
(Boron as boric
acid)
PS
28-29 time-mated
females/group CD-I
mouse, dietary,
GDs 0-17
0, 43.4, 79.0,
175.3
Kidney and liver maternal
effects at mid- and high-dose.
Fetal body weights decreased
at mid- and high-dose. Some
increases in resorption rates
and fetal skeletal
malformations at high-dose
Maternal: 43.4
Developmental:
43.4
Not run
Maternal: 79.0
Developmental:
79.0
Heindel et al. (1992,
1994), NTP (1989)
(Boron as boric
acid)
11
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
30 artificially
inseminated
females/group New
Zealand White rabbit,
gavage, GDs 6-19
0, 10.9,21.9,
43.7
No mortality. At high-dose,
vaginal bleeding, reduced
live litters, reduced litter size,
reduced fetal body weights,
and increased visceral
malformations in live
fetuses/litter. No effects at
other doses
Maternal: 21.9
Developmental:
21.9
Not run
Maternal: 43.7
Developmental:
43.7
Heindel et al. (1994)
(Boron as boric
acid)
Reproductive
10 male/group
Sprague-Dawley rat,
drinking water, 30, 60,
90 d
0,0.042,0.14,
0.84
No effects on male fertility in
breeding studies. No effects
on body weight, weights of
testis, prostate, seminal
vesicles, plasma FSH, plasma
LH
0.84
Not run
None
Dixon etal. (1976)
(Boron as borax)
18 male/group
Sprague-Dawley rat,
drinking water, 30,
60 d.
0, 25, 50, 100
At mid- and high-dose,
decrease in liver, testis,
epididymis weights.
Dose-related tubular germinal
aplasia, reduced fertility at
mid- and high-dose
25
Not run
50
Lee etal. (1978);
Dixon etal. (1979)
(Boron as borax)
6 male/group
Sprague-Dawley rat,
single-dose gavage,
evaluation at 2, 14, 28,
or 57 d postdosing
0,350
Increase in abnormal caput
and cauda epididymal sperm
morphology, decrease in
percentage of motile cauda
spermatozoa on Day 28.
Return to control levels of all
sperm parameters in all
treated animals by Day 57
None
Not run
None
Linder et al. (1990)
(Boron as boric
acid.)
Time-response
study
12
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
8 male/group
Sprague-Dawley rat,
single-dose gavage,
evaluation at 14 d
postdosing
0, 44, 87, 175,
350
Effects on spermiation,
epididymal sperm
morphology, and caput sperm
reserves at two highest doses
87
Not run
175
Linder et al. (1990)
(Boron as boric
acid)
8 male/group/16
female/group,
Sprague-Dawley rat,
dietary, through F3
generation
0,5.9, 17.5,
58.5
At high-dose, no litters
produced, no spermatozoa in
atrophied testes in males,
decrease in ovulation in
females. No progeny when
females mated to control
males. No effects on
reproduction or pathology in
low- and mid-dose groups
17.5
Not run
58.5 (FEL)
Weir and Fisher
(1972) (Boron as
boric acid)
Continuous breeding
protocol: I
Cohabitation and
fertility
20 pairs/group
(dosed),
40 pairs/group
(control), CD-I
mouse, dietary, paired
for 14 wk of breeding
(F0)
M: 0, 26.6
111,220
F: 0, 31.8
152, 257
At high-dose, no progeny
produced (FEL). At
mid-dose, progressive fertility
and reproductive indices
decreased with subsequent
matings. At low-dose, no
treatment-related effects
26.6
Not run
111
NTP (1990b);
Fail et al. (1991)
(Boron as boric
acid)
Males more
sensitive species
13
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry3
Critical Effects
NOAEL'
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notes
Continuous breeding
protocol: II
Multigeneration
reproductive toxicity
(Fl)
20 male/20
female/group (dosed),
40 male/40 female
(control), CD-I
mouse, dietary, up to
27 wk
M: 0, 26.6
111,220
F: 0, 31.8,
152, 257
At low-dose, increased
weights of uterus, kidney and
adrenal glands, shortened
estrus cycle inFl females.
No fertility effects. Decrease
in mean F2 pup weights, Only
low-dose tested; insufficient
or no Fl mice from mid- and
high-dose groups, respectively
None
Not run
26.6
NTP (1990b);
Fail et al. (1991)
(Boron as boric
acid)
LOAEL is lowest
dose tested. Males
more sensitive
species
Carcinogenic
None
2. Inhalation (mg/m3)a
Acute
Rats, mice guinea pigs
(sex and species not
reported;
10-15/group).
Exposure duration
either 7 hr for 1 d or
7 hr daily for 2 d;
cages used either
continuously for 7 hr
or substituted (with
clean cages) every
2 hr due to formation
of irritant and
corrosive oily
decomposition
products depositing on
cage surfaces.
BC13 air
nominal
concentrations
of 20, 50, and
85 or 100 ppm
(4.2, 10, 18
and
20 mg/m3).
100% (10/10) mortality at 20
and 50 ppm in rats and mice,
30% (3/10) mortality in rats
and 100% (10/10) mortality in
mice at 85 ppm, all guinea
pigs (10/10) survived at all
doses, following 7-hr
continuous exposure. At
100 ppm, 14/15 mice and
10/10 guinea pigs died.
Pathology showed chemical
irritation to lungs and skin
surfaces (paws, mouth)
directly exposed to cage
surfaces. No mortality at any
dose in rats whose cages were
cleaned every 2 hr
Not determined
Not run
4.2 (FEL)
Stokinger and
Spiegl (1953)e
Most mortality
attributed to contact
with deposited
decomposition
products. BC13 used
as chemical
intermediate in
"special processes"
in the production of
uranium
14
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Table 2. Potentially Relevant Data for Boric Acid and Boron Compounds
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL
LOAEL3
Reference
(Comments)
Notes
Subchronic
4-70 albino male and
female rats for
10-24 wk
0, 24, 54, 146
No effects on a variety of
endpoints, at 24 mg/m3,
increase in urinary creatinine
None
Not run
24
Wilding et al.
(1959)
(Boron as boron
oxide aerosols)
3 dogs (sex and
species not reported),
23 wk
0, 18
No effects
18
Not run
None
Wilding et al.(1959)
(Boron as boron
oxide aerosols)
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous
(weekly) exposure. Values from animal developmental studies are not adjusted to a continuous exposure. FEL = frank effect level.
bNOAEL estimated by study authors.
°U.S. EPA (2004) used BMDL05 calculated by Allen et al. (1996) from the combined data of Price et al. (1996a) and Heindel et al. (1992) to derive the RfD for IRIS.
dU.S. EPA (2004) IRIS used to derive the RfD; PS = Principal studies.
eNot discussed in the IRIS Toxicological Profile (U.S. EPA, 2004).
15
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Table 3. Potentially Relevant Data for Hydrogen Chloride
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAELab
Reference
(Comments)
Notes
Human
1. Oral (mg/kg-d)a
None
2. Inhalation (mg/m3)a
Acute
Number, gender, and
duration not reported
7-150
7 mg/m3 = no irritation,
15 mg/m3 = irritation of
mucous membrane,
75-150 mg/m3 =
intolerable irritation
7 mg/m3
Not run
15
Stahl (1969)
5 male/5 female,
controlled human
exposure, 45 min
1.2 or 2.7
No effects on pulmonary
function
2.7 mg/m3
Not run
None
Stevens et al.
(1992)
Animal
1. Oral3
Subchronic
Wistarrats. Number
and sexes varied by
experiment. 7, 9, and
12 wk dietary exposure
Dietary pH 1.8-5.9
pH 2.8 = decreased
plasma pH
pH 2.54 = 3/8 rats died
pH = 3.09
Not run
pH = 2.8
Upton &
L'Estrange (1977)
2. Inhalation (mg/m3)a
Subchronic
31 male/31
female/group
Sprague-Dawley and
Fischer 344 rat, 6 hr/d,
5 d/wk, 90 d
HEC = 0,6.1, 12.3,
30.5
Minimum to mild
rhinitis, lesions in nasal
cavity
None
Not run
HEC = 6.1
Toxigenics (1984)
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Table 3. Potentially Relevant Data for Hydrogen Chloride
Category
Number of
Male/Female Species,
Study Type, and
Duration
Dosimetry"
Critical Effects
NOAEL'
BMDL/
BMCLa
LOAELab
Reference
(Comments)
Notes
31 male/31
female/group B6C3F,
mouse, 6 hrs/d, 5 d/wk,
90 d
HEC = 0,6.1, 12.3,
30.5
Eosinophilic globules in
epithelial lining of nasal
tissue
None
Not run
HEC = 6.1
Toxigenics (1984)
Chronic
100 male/100
female/group
Sprague-Dawley rat,
6 hrs/d, 5 d/wk,
lifetime
HEC = 0, 6.1
Epithelial or squamous
hyperplasia in nasal
mucosa
None
Not run
HEC = 6.1
Albert et al.
(1982);
Sellakumar et al.
(1985). Only one
dose tested. Used
to derive
U.S. EPA (1995)
RfC
PSC
Developmental
8-15 rat (strain and sex
not reported), F0: 1 hr
(before mating), Fl: age
of 2-3 mo.
450 (F0)
52 (Fl)
F0: Mortality, severe
dyspnea, cyanosis; Fl:
Abnormalities in organs
None
Not run
None
Pavlova (1976)
Data poorly
reported; no
control group
Number not identified,
Female rat (strain and
number not identified),
1 hr (before mating)
450
Mortality in 20-30% of
rats, decrease in blood
oxygen saturation,
kidney, liver, spleen
damage
None
Not run
None
Pavlova (1976)
Data poorly
reported; no
control group
""Dosimetry, NOAELs, BMDL/BMCLs, and LOAELs are converted to human equivalent dose (HED in mg/kg-day) or human equivalent concentration (HEC in mg/m3)
units. HECs are noted for inhalation studies. Oral animal studies used feed or daily gavage as the route of administration; therefore, the HEDs are equivalent to the
animal daily doses for noncancer effects.
bNot reported by the study author but determined from data. FEL = frank effect level.
°U.S. EPA (2004) IRIS used to derive the RfD; PS = Principal study.
17
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HUMAN STUDIES
Oral Exposure
Boron Trichloride
No oral studies of boron trichloride in humans were identified. However, accidental or
other exposures are discussed below.
Boric Acid and Boron Compounds
The subchronic and chronic p-RfDs for boron trichloride are based on the IRIS RfD
for boron and compounds. The IRIS toxicological review (U.S. EPA, 2004) has discussed and
evaluated the oral toxicity data for boron and compounds, deriving a RfD of 0.2 mg/kg-day
based on decreased fetal weights in rats following maternal dietary gestational exposure to boric
acid (Price et al., 1996a; Heindel et al., 1992). Tables B1-B5, in conjunction with the study
descriptions in this report, present the relevant data from these developmental toxicity studies
(see U.S. EPA, 2004 for a more comprehensive review of supporting and other studies). These
and other data are discussed below and summarized in Table 2.
WHO (1998) and U.S. EPA (2004) summarized information concerning ingestion of
boric acid and other boron compounds through accidental poisonings and other occurrences.
Symptoms of boron poisoning include vomiting, abdominal pain, diarrhea, lethargy, headache,
lightheadedness, and rash. The minimum lethal dose of boric acid by oral exposure was
approximately 15-20 g in adults, 5-6 g in children, and 2-3 g in infants.
Baker et al. (1986) reported symptoms of boron toxicity in two infant siblings (gender not
reported) who ingested formulas accidentally prepared from a boric acid eyewash solution.
Ingested doses were estimated at 30.4-94.7 mg-Boron/kg-day (mg-B/kg-day). The infant whose
ingestion was estimated at 30.4 mg-B/kg-day had serum concentrations of 9.79 mg-B/mL and an
initial face and skin rash but later became asymptomatic. The other infant who ingested about
94.7 mg-B/kg-day had a serum boron concentration of 25.7 mg-B/mL, with symptoms of
diarrhea, erythema of the diaper area, and vomiting.
O'Sullivan and Taylor (1983) reported seizures and other effects in seven infants (gender
not reported) who ingested boron in a honey-borax mixture that had been applied to their
pacifiers. Borax is hydrated sodium borate (Na2B4O7-10H2O). However, the medical records of
five of the infants suggested that they may have had familial reduced convulsive thresholds.
When the honey-borax treatment ended, the seizures stopped as well. The collected data on
presumptive boron ingestion and measured serum boron concentrations (details of analytic
methods not provided) were not internally consistent and did not conform to what was known
about boron toxicokinetics and blood concentrations.
Boron compounds have been used for a variety of medical and nonmedical purposes over
the years. Culver and Hubbard (1996) reported daily doses in the range of 25-35 mg-B/kg
administered to patients (number and gender not reported) undergoing boron neutron capture
therapy for brain tumors (duration of exposure not reported). Nausea and vomiting occurred at
25 mg-B/kg, and additional symptoms, noted at 35 mg-B/kg, included skin flush. One patient
exhibited severe dermal and gastrointestinal (GI) symptoms after subcutaneous infusion of a
boric acid solution (70 mg-B/kg). After hydration and diuresis, the patient recovered.
18
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In the 19th Century, boron was used to treat epilepsy, malaria, urinary tract infections, and
exudative pleuritis. It was administered to treat epilepsy at daily doses ranging from
2.5-24.8 mg-B/kg-day (Culver and Hubbard, 1996). Clinical signs and symptoms of toxicity in
patients (number and gender not reported) given >5 mg-B/kg-day included indigestion,
dermatitis, alopecia, and anorexia. One 19* Century adult male epilepsy patient, for whom data
were reported, developed indigestion, dermatitis, and anorexia when treated at a daily dose of
5.0 mg-B/kg-day for 15 days (Desage, 1923). When this dose was reduced to 2.5 mg-B/kg-day,
the symptoms disappeared. In other cases, no symptoms were reported in subjects ingesting less
than 3.68 mg-B/kg-day. Based on the human data summarized, Culver and Hubbard (1996)
concluded the NOAEL for human exposure to boron compounds was about 2.5 mg/kg-day.
Scialli et al (2010) published an extensive review of the human data from a series of
17 peer-reviewed papers presenting an evaluation of data from Chinese boron workers with
biological boron measurements higher than had been reported previously in humans. Though
this evaluation included mixed inhalation and oral exposures, the data are more relevant to a RfD
because the predominant route was via oral exposure. These papers, which were published
subsequent to the IRIS review (U.S. EPA, 2004), were the first to include analyses of semen
characteristics and, thus, provided more sensitive metrics for identifying male reproductive
effects. Among the nearly 1000 male workers studied, a subset of 16 was identified as having
unusually high boron exposures in drinking water, along with their occupational exposures,
resulting in total mean daily exposures of 125-mg boron (1.8 mg/kg-day). The only change
noted among exposed workers (75) with mean daily exposures of 31.3-mg boron
(0.45 mg/kg-day) was a small but statistically significant reduction in sperm Y:X ratio, when
compared to people in the two control groups with total mean daily boron exposures of 4.25 mg
and 1.40 mg (0.06 and 0.02 mg-B/kg-day). However, there appeared to be no relationship
between sperm Y:X ratio and biological concentrations of boron within the exposure groups,
suggesting that Y:X ratio was more related to group membership than to boron exposure. In
addition, the exposed workers exhibited none of the reproductive effects consistently reported
among experimental mice, rats, and dogs, and none of these experimental animals exhibited
dose-related changes in fetal gender ratios, or any other effect suggestive of a reduced sperm
Y:X ratio. Although 0.45 mg/kg-day is identified as a LOAEL for reduced sperm Y:X ratio,
Scialli et al. (2010) stated that "Y:X ratio is not known to be associated with impaired semen
quality, reproductive success, or offspring health" and concluded that "there is no clear evidence
of male reproductive effects attributable to boron in this study of highly exposed workers."
Thus, these findings are consistent with those of earlier human studies, summarized above and
used in the IRIS assessment, which used much less defined human metrics of reproductive
effects among workers with smaller occupational exposures to boron compounds.
Hydrogen Chloride
In both humans and animals, the toxicity of HC1 following ingestion has been due to local
effects on the mucous membranes at the site of absorption (HSDB, 201 lc). In case reports of
patients who have swallowed HC1—either accidentally or intentionally—the primary
characteristics have been massive necrosis in the esophagus, stomach, duodenum, and pancreas;
in approximately half of these cases the patient died (HSDB, 201 lc). WHO (1982) noted that
the concentration of the HC1 solution following ingestion was more important than the volume
with regard to both the severity of symptoms and the outcome. Potential oral toxicity of HC1
based on its pH is discussed in a subsequent section of this review.
19
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Inhalation Exposure
Boron Trichloride
No inhalation studies of boron trichloride in humans were located in the literature.
Winker et al. (2008) reported on potentially genotoxic effects among semiconductor workers,
who were exposed to boron trichloride and boron trifluoride in complex mixtures of chemical
waste. Frequency of micronuclei was significantly higher among exposed workers than among
controls, and this frequency was reduced to control levels 12 years after exposure control
measures were instituted. However, air monitoring both before and after institution of the
exposure controls showed that worker exposures to boron trichloride and boron trifluoride were
consistently below detection limits, providing no quantitative data that might be useful for
deriving toxicity values.
Boric Acid and Boron Compounds
The IRIS toxicological review (U.S. EPA, 2004) has discussed human inhalation toxicity
data for boron and compounds. Overall, well-conducted occupational epidemiology studies
showed few chronic effects following inhalation exposure to boric acid and other boron
compounds in work environments. Some studies found acute irritation of mucous membranes of
the eyes and upper respiratory tract during workplace exposure. However, the studies were
conducted in mining and manufacturing facilities with concomitant exposures to other chemical
compounds, which might have confounded the association between health outcomes and
exposure to boron compounds.
Birmingham and Key (1963) investigated the respiratory and irritant effects of
occupational exposure to boron compounds in a borax mining and production facility. While
specific quantitative data were not provided, worker complaints of dermatitis, nasal irritation,
nose bleeds, cough, and shortness of breath were associated with boron dust concentrations (not
measured) that were sufficiently elevated to interfere with normal visibility.
Ury (1966) used a cross-sectional study design with 629 workers to assess respiratory
effects using data collected from questionnaires, spirometry, and roentgenography. The study
was inconclusive, but Ury (1966) did report finding suggestive evidence for an association
between respiratory effects and inhalation exposure to dehydrated sodium borate dust. Ury's
analysis was based on focused expiratory volume (FEV) measures and questionnaire data on
respiratory symptoms in a subgroup of 82 men working for at least 1 year in jobs with elevated
boron exposure (calcining and fusing processes) as compared with 547 men in other employment
categories.
Garabrant et al. (1984, 1985) studied a group of 629 workers (93% of those eligible)
employed for a minimum of 5 years at the plant, who worked at jobs with borax exposures.
Approximately 92% of study participants were white males, 4% were nonwhite males, and 4%
were women, with a mean age of 40.2 years. Workers were assigned to one of four borax
exposure categories (mean concentrations in ascending order of 1.1-, 4.0-, 8.4-, or 14.6-mg/m3
borax, respectively) and assessed for frequency of reported acute and chronic respiratory
symptoms, using questionnaire response data. Statistically significant, positive dose-related
trends were reported for the following (in order of decreasing frequency): dryness of mouth,
nose, or throat; eye irritation; dry cough; nose bleeds; sore throat; productive cough; shortness of
breath; and chest tightness. There was a wide range of variability in the frequency of symptoms
within exposure groups; in the highest exposure group, symptoms frequency ranged from 5% to
20
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33%. Pulmonary function was unaffected by borax exposure, and no differences in the results of
chest X-rays were noted between groups. The study authors concluded that exposure to borax at
the concentrations reported in this study may cause respiratory irritation, which could lead to
chronic bronchitis without impairment of pulmonary function.
In a subanalysis, Garabrant et al. (1984) reported that 113 workers (91% white males,
5 nonwhite males, 4% women) in job categories with boric acid or boron oxide exposures had
statistically significantly higher rates of eye irritation; dryness of mouth, nose, or throat; sore
throat; and productive cough, as compared with 214 workers who had not been occupationally
exposed to either boric acid or boron oxide but had held at least one job that involved low
exposure to borax. Mean combined exposure to boron oxide and boric acid was 4.1 mg/m3
"3
(range = 1.2 to 8.5 mg/m ). Garabrant et al. (1984) concluded that the inhalation of boron oxide
and boric acid produced upper respiratory and eye irritation at airborne concentrations less than
10 mg/m3.
Wegman et al. (1994) conducted pulmonary function retesting of 336 participants in the
Garabrant et al. (1985) study, 7 years following the original study. Of these, 306 had
"acceptable" pulmonary function test results in both studies. No information on the genders or
ethnicities of the subjects was given. Mean age was 44 years. The rates of decline in FEVi
(forced expiratory volume in 1 second) and FVC (forced vital capacity) were very similar to
those expected because of aging, based on national population data. Thus, Wegman et al (1994)
concluded that cumulative chronic borate exposure over the years 1981-1988 was not related to
the change in pulmonary function. Wegman et al. (1994) further examined the association
between the occurrence of episodes of acute respiratory symptoms, exposure concentrations, and
the approximate time between symptoms onset and the beginning of exposure during the work
shift in a subgroup of 106 subjects. Exposure was assessed by personal aerosol monitors.
Incident rate for each symptom was expressed as the ratio of the number of symptomatic
episodes to the number of person-hours for which the individual was exposed. Risk ratios—
defined as the ratio of the probability of symptoms in the exposed to the probability in the
comparison group—were estimated for each symptom. Categories of increasing exposure
concentrations then were defined, and the incidence was estimated within each category. To
adjust for confounding due to smoking, age, and recent colds, the associations then were
estimated in a series of logistic regression models. A separate model was fitted to the data for
each of the five most common symptom outcomes. Symptoms rate ratios were then compared
between exposed and comparison populations, and a one-tailed binomial distribution test for
significance was performed. Statistically significant (p < 0.001) exposure-related increases in
eye, nasal, and throat irritation; cough; and breathlessness were associated with elevated borate
exposure, assessed using either a 6-hour or 15-minute time-weighted average. Nasal irritation
appeared to increase most rapidly with increasing exposure, with notable increases starting at
about 5 mg/m3 for either exposure duration. The follow-up findings were consistent with those
from the earlier study showing irritation and upper respiratory tract symptoms in the absence of
exposure-related decreases in pulmonary function, suggesting that the symptoms resulted from
acute exposures and resolved when exposures were terminated.
Tarasenko et al. (1972) reported low sperm count, reduced sperm motility, and elevated
fructose content of seminal fluid in semen analysis of 6 workers who were part of a group of
28 male Russian workers exposed for 10 or more years to high levels of vapors and aerosols of
"3
boron salts (22-80 mg/m ) during the production of boric acid. The results indicated that the
21
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exposed workers had decreased sexual function compared with 10 workers who had no contact
with boric acid. However, Tarasenko et al. (1972) reported no differences in data from wives of
the men in the exposed and control groups. The precise nature of the data for wives is not
known. This study was published in the Russian literature, and cited by Whorton et al. (1992,
1994a,b). This study was judged to be of limited value for toxicity determinations due to the
small sample size; sparse details on subjects regarding smoking habits, diet, other chemical
exposures; and lack of methodology information on semen analysis (U.S. EPA, 2004). However,
the results suggested that airborne occupational exposure to boron salts in the range
"3
22-80 mg/m might cause decreased sexual function in male workers.
In response to the Tarasenko et al. (1972) report and the reports of reproductive effects in
animal studies, Whorton et al. (1992, 1994a,b) initiated a controlled epidemiology study of
reproductive effects in U.S. workers exposed to sodium borates. The site of the study was a
borax mining and production facility in the United States with 542 men participating (72% of the
753 eligible male employees) by answering a questionnaire Whorton et al. (1994a,b). The
"3
median exposure of the men in the study was approximately 2.23 mg/m sodium borate (roughly
0.31 mg-B/m3), with an average length of employment of 15.8 years. Reproductive function was
assessed by (1) comparing the number of live births by workers' wives during the workers'
employment period (+9 months following commencement of work through +9 months following
termination of work) to standardized birth ratios (SBRs) in national fertility tables for
U.S. women, matched on maternal age, race, parity, and calendar year; and (2) comparing the
gender ratio in the workers' offspring with national gender ratios compiled for the United States.
Overall, the study participants were more fertile than the national sample, with
529 observed births vs. 466.6 expected births, SBR = 113,p< 0.01 (Whorton et al., 1994a,b).
An excess of births in the study population occurred even though study males had a 5-fold higher
rate of vasectomies (36% vs. 7% national average). No exposure-response relationship in SBR
was noted when mean exposure concentrations were divided into five equal-size categories
3 3
ranging from <0.82 mg/m to 5.05 mg/m . The SBR was statistically significantly elevated for
both the low- and high-dose groups and was close to expected for the three mid-dose groups. An
examination of SBR for all participants by 5-year increments from 1950 to 1990 showed no
statistically significant trend in either direction over time. Although there was an increase in
percent female offspring in the worker cohort (52.7% vs. 48.8% in controls), this finding was not
statistically significant and appeared to be unrelated to paternal airborne exposure to sodium
borate. Interpretation of study results is made difficult by the lack of a local or matched control
group and the use of an insensitive measure of sexual function.
In another study, Whorton et al. (1992) assessed 68 female workers for reproductive
function. Although the SBR for live births was <100, the reduction in birth rate was not
statistically significant. No statistically significant differences in birth rates or offspring gender
ratios were observed between exposed and control groups when the results were analyzed by
exposure categories. Whorton et al. (1992) concluded that exposure to inorganic borates did not
appear to adversely affect fertility in the population studied. However, the small sample size of
exposed women limited the sensitivity of the study.
Swan et al. (1995) investigated the relationship between exposure to chemical and
physical agents used in the semiconductor manufacturing industry and incidence of spontaneous
abortion in female employees at 14 industry plants between 1986 and 1989. The study
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population consisted of 904 current and former female employees who became pregnant while
working at one of these facilities. Exposure classifications were based on jobs held at conception
and exposures to specific agents during the first trimester. No statistically significant association
was found between exposure to boron and spontaneous abortion risk (p > 0.05). This study was
limited by a number of factors—including co-occurring exposures to numerous chemicals and
lack of dose-response information.
Hydrogen Chloride
IRIS (U.S. EPA, 1995) has evaluated the inhalation toxicity data for HC1, deriving a RfC
"3
of 0.02 mg/m , based on hyperplasia of the nasal mucosa, larynx and trachea in rats
(Sellakumar et al., 1985;2 Albert et al., 1982). Relevant data are summarized below.
HC1 is intensely irritating to the mucous membranes of the eyes, nose, throat, and
respiratory tract (HSDB, 201 lc). Brief exposure to 35 ppm (52 mg/m3) caused throat irritation
as well as sneezing, laryngitis, chest pain, hoarseness, and a feeling of suffocation (WHO, 1982).
The greatest impact was on the upper respiratory tract; exposure to high concentrations have led
to rapid swelling and spasm of the throat, and suffocation. Symptoms of high-exposure
concentrations include immediate onset of rapid breathing, blue coloring of the skin, and
narrowing of the bronchioles. In both humans and animals, the toxicity of HC1 after inhalation is
due to the local effect on the mucous membranes at the site of absorption.
Epidemiologic studies examining the relationship between HC1 vapor exposure among
workers and risk of lung or brain cancer showed no association, using a variety of exposure
metrics (IARC, 1992).
According to Stahl (1969), there were no known systemic effects of HC1 inhalation in
humans (number, gender, and duration not reported), and only local effects on membranes of the
eyes and upper respiratory tract have been observed. Irritation was not reported at airborne
3 3
concentrations of approximately 7 mg/m (4.7 ppm). An airborne concentration of 15 mg/m
(10 ppm) caused irritation of the mucous membranes following initial exposure; however,
tolerance or acclimation occurred with increasing exposure duration. At exposure concentrations
ranging from 75-150 mg/m3 (50.3-100.5 ppm), irritation was reported as "intolerable," and no
"3
adaptation occurred. These data suggest a short-term LOAEL of 15 mg/m for transient irritation
of the mucous membranes of the eyes and upper respiratory tract among humans, with a NOAEL
"3
of 7 mg/m .
In a controlled human exposure study, Stevens et al. (1992) exposed five asthmatic
3 3
volunteers per gender to 0.8- (1.2 mg/m ) or 1.8-ppm (2.7 mg/m ) HC1 for 45 minutes.
Pulmonary function tests were performed immediately after exposure, and results were compared
to baseline levels. No exposure-related effects were reported in pulmonary function tests or in
symptoms, including forced expiratory volume in 1 second, forced vital capacity, maximal flow
at 50 and 75% of vital capacity, respiratory resistance, and peak flow. These data suggest a
45-minute NOAEL of 2.7 mg/m3 among asthmatic humans, with no LOAEL.
2U.S. EPA (1995) Summary text for HC1 on IRIS incorrectly cites this as Sellakumar et al., 1994.
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ANIMAL STUDIES
Oral Exposure
Boron Trichloride
No studies were identified.
Boric Acid and Boron Compounds
The IRIS toxicological review (U.S. EPA, 2004) has discussed and evaluated oral
toxicity data for boron and compounds, deriving a RfD of 0.2 mg/kg-day based on
decreased fetal weights in rats following maternal dietary gestational exposure to boric acid
(Price et al., 1996a; Heindel et al., 1992). Appendix B presents the relevant data from these
developmental toxicity studies (see Tables B.1-B.5). These data provide the basis for the
p-RfDs for boron trichloride. Other data are described below.
Weir and Fisher (1972) conducted subchronic and chronic duration studies with
Sprague-Dawley rats and dogs, as well as a follow-up subchronic study in dogs. In the
subchronic rat study, Weir and Fisher (1972) administered boric acid (purity not reported) in the
diet to 10 rats/sex/group for 90 days at concentrations of 0-, 52.5-, 175-, 525-, 1750-, or 5250-
ppm boron. These dietary concentrations are approximately equivalent to 0, 2.6, 8.8, 26.3, 87.5,
and 262.5 mg-B/kg-day, respectively, estimated using an EPA (1988) standard adjustment factor
of 0.35 kg for body weight and 0.05 for the food factors. At the highest dose tested, mortality
was observed in all rats of both sexes, and complete testicular atrophy was observed in all males
at the second highest dose. Other signs of toxicity in the two highest-dose groups included rapid
respiration, eye inflammation, swelling of the paws, and desquamation of the skin on paws and
tails.
Weir and Fisher (1972) evaluated statistical significance for body- and organ-weight
changes using conventional statistical tests comparing treated and control rats and usingp < 0.05
as the level of significance. No further description of statistics was reported. At the second
highest dose of boric acid (87.5 mg/kg-day), body weights were statistically significantly
reduced (44% decrease in males and 13% decrease in females as compared with respective
controls). In this dose group, the following significant organ-weight changes relative to controls
were also observed: (1) decreased absolute kidney, spleen, liver, adrenal, and testis weights in
males; (2) decreased absolute spleen, liver, and ovary weights in females; (3) decreased relative
liver and testis weights in males and decreased relative liver weights in females; (4) increased
relative brain and thyroid weights in males and females and increased adrenal weight in males.
At lower doses, no consistent treatment-related organ-weight effects were observed.
Microscopic examination showed complete testicular atrophy at 87.5 mg-B/kg-day in all males
and partial testicular atrophy at 26.3 mg-B/kg-day in one male. No treatment-related effects
were observed at the lowest dose tested. Weir and Fisher (1972) did not identify a LOAEL or a
NOAEL. However, a 90-day LOAEL and NOAEL of 26.3 and 8.8 mg-B/kg-day, respectively,
are considered for testicular atrophy in male rats.
In the subchronic dog study, Weir and Fisher (1972) fed groups of beagles (5/sex/group)
boric acid (purity not reported) for 90 days at dietary concentrations, of 0-, 17.5-, 175-, or
1750-ppm boron. These dietary concentrations are equivalent to 0, 0.33, 3.9, and
30.4 mg-B/kg-day in male beagles, and 0, 0.24, 2.5, and 21.8 mg-B/kg-day in females, based on
measured body weight and food consumption. With the exception of one high-dose male who
died during the study, no mortality or clinical signs of toxicity were observed. As in rats (i.e.,
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Weir and Fisher, 1972) and mice (i.e., NTP, 1987; Dieter, 1994), the testes were the primary
target of boron toxicity. Decreases in both absolute and relative testes weights were observed in
the high-dose group. Microscopic pathology revealed severe testicular atrophy in all high-dose
male dogs, with complete degeneration of the spermatogenic epithelium in four dogs. No
testicular lesions were found in the lower-dose groups. Accumulation of hemosiderin pigment in
the liver, spleen, and kidney—indicating breakdown of red blood cells—was observed in
high-dose male and female beagles treated with boric acid. Relative thyroid weights in males
were decreased, and liver weights in females were increased at the high dose. Some pathology in
the thyroid and adrenal glands of high-dose females also was observed. Weir and Fisher (1972)
did not identify a NOAEL. However, based on testicular effects, breakdown of red blood cells,
and thyroid and adrenal gland pathology, 90-day LOAELs of 30.4 and 21.8 mg-B/kg-day and
NOAELs of 3.9 and 2.5 mg-B/kg-day in male and female beagles, respectively, are considered
for this study.
In a 13-week study, NTP (1987; Dieter, 1994) fed groups of 10 male and 10 female
B6C3Fi mice diets containing 0-, 1200-, 2500-, 5000-, 10,000-, or 20,000-ppm boric acid
(>99.7% purity), calculated by the study authors to correspond to 0, 34, 70, 141, 281, and
563 mg-B/kg-day for males and 0, 47, 97, 194, 388, and 776 mg-B/kg-day for females,
respectively. At the highest doses, greater than 60% mortality was observed, and clinical signs
of toxicity included hyperkeratosis and acanthosis of the stomach. At dietary concentrations
5000 ppm and greater, degeneration or atrophy of the seminiferous tubules was observed in
males, and weight gain was decreased in animals of both sexes. NTP (1987; Dieter, 1994) did
not identify a NOAEL or LOAEL. Based on histopathology in the seminiferous tubules, the
13-week NOAEL and LOAEL are 70 and 141 mg-B/kg-day, respectively, in male mice.
NTP (1987; Dieter, 1994) also fed male and female B6C3Fi mice (50/sex/group) a diet
containing 0-, 2500-, or 5000-ppm boric acid (>99.7% purity) for 103 weeks. These
concentrations were equivalent to boric acid doses of approximately 0, 275, and 550 mg/kg-day
(0, 48, and 96 mg-B/kg-day), respectively, calculated based on food consumption values
obtained during Week 4. These doses for the chronic bioassay were selected from the
subchronic study. Tests of significance included the product-limit procedure by Kaplan and
Meier for probability of survival, Cox's test for equality, and Tarone's life-table test for possible
dose-related trends in survival. For other adverse effects, Fisher's Exact test for pair-wise
comparisons, Cochran-Armitage test for dose-related trends, life-table analysis adjusting for
intercurrent mortality, and incidental tumor analysis were conducted. Level of significance was
p < 0.05.
Survival of the treated male mice was statistically significantly lower than that of controls
after Week 63 in the low-dose group and after Week 84 in the high-dose group, but female
mortality was unaffected by treatment (NTP, 1987; Dieter, 1994). The sensitivity of the
carcinogenicity evaluation in males may have been compromised by the high mortality rates in
all groups including controls. Mean body weights of high-dose mice were 10-17%) lower than
those of controls. Pathological findings were limited to testicular atrophy and interstitial cell
hyperplasia in high-dose males and a dose-related increase in the incidences of splenic lymphoid
depletion, also in males. No other treatment-related, nonneoplastic lesions were observed. The
study authors did not identify a NOAEL. However, based on increased mortality in male mice,
48 mg-B/kg-day is identified as a FEL, with no associated NOAEL.
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An increased incidence in hepatocellular carcinoma was noted in low-dose males relative
to controls (5/50, 12/50, 8/49 for control, low-, and high-dose groups, respectively) as was the
combined incidence of adenoma or carcinoma (14/50, 19/50, 15/49 for control, low-, and
high-dose groups, respectively). The increases were statistically significant by life-table tests but
not by incidental tumor tests. NTP (1987) considered the incidental tumor test to be more
suitable for statistical analysis because liver tumors were not associated with mortality and their
incidences were lower than, or within the range of, historical control tumor rates for male mice in
the laboratory. Other tumors were not considered to be test compound related. No tumors were
observed in female mice. NTP (1987) concluded that boric acid was not carcinogenic in mice
under the conditions of the study.
In a chronic rat study, Weir and Fisher (1972) fed Sprague-Dawley rats (35/sex/group
and 70/sex/control group) a diet containing 0-, 117-, 350-, or 1170-ppm boron as boric acid
(purity not reported) for 104 weeks. These dietary concentrations correspond approximately to
0, 5.9, 17.5, and 58.5 mg-B/kg-day, estimated by using an EPA (1988) standard adjustment
factor of 0.35 kg for body weight and 0.05 for the food factors. In the 58.5-mg/kg-day group,
signs of clinical toxicity were observed, and decreased body-weight gain was accompanied by
reduced food consumption. Testicular atrophy was observed in all high-dose (58.5-mg/kg-day)
males at 6, 12, and 24 months. The seminiferous epithelium was atrophied, and the tubular size
in the testes was decreased. Absolute and relative testes weights were reduced, and relative brain
and thyroid weights were increased in this dose group. Weir and Fisher (1972) reported that no
other effects were observed in the highest-dose groups, and no adverse findings of any sort were
observed at the two lowest doses. Weir and Fisher (1972) identified a chronic NOAEL of
17.5 mg-B/kg-day for testicular effects, decreased body-weight gain, and signs of clinical
toxicity. A LOAEL of 58.5 mg/kg-day is identified for this study, based on the same adverse
effects. The lack of carcinogenic findings in this study led NTP (1987) to conclude that there
were no carcinogenic effects of boric acid in rats.
In the chronic dog study, Weir and Fisher (1972) administered boric acid (purity not
reported) by dietary admix to groups of beagles (4/sex/group) at concentrations of 0-, 58-, 117-,
or 350-ppm boron (0, 1.4, 2.9, and 8.8 mg-B/kg-day, respectively) for 2 years (Weir and Fisher,
1972). Interim sacrifice was at 52 weeks. Following 104 weeks of exposure, a subgroup of
beagles was given a 13-week "recovery" period prior to terminal sacrifice. Sperm samples used
for counts and motility testing were taken only from the control and high-dose male dogs
immediately prior to the 2-year sacrifice. Statistical tests were not conducted. Mortality over the
course of the study did not appear to be treatment related. Weir and Fisher (1972) considered
neither semen characteristics nor histopathology of any target organ, including tumors, to be
associated with boric acid administration. The study authors identified a 2-year NOAEL of
8.8 mg/kg-day, the highest dose tested, based on no "apparent" effects on body weight, organ
weights, and necropsy findings as compared with controls in male or female beagles. A LOAEL
is not identified in this study.
In a follow-up dog study, Weir and Fisher (1972) administered boric acid (purity not
reported) in the diet to groups of 4 beagles (4/sex/group) at concentrations of 0- and 1170-ppm
boron (29.2 mg-B/kg-day) for up to 38 weeks. Interim sacrifice for two beagles in each group
was at 26 weeks; terminal sacrifice was at 38 weeks. One of the two beagles in each 38-week
subgroup was sacrificed after a 25-day "recovery" period. In controls, one of the two males
sacrificed at 26 weeks had decreased spermatogenesis, and no effects were reported in the other
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male. One control male sacrificed at 38 weeks had decreased spermatogenesis, and the other had
testicular atrophy. In the treated beagles, both males sacrificed at 26 weeks showed evidence of
severe testicular atrophy and spermatogenic arrest. The male sacrificed at 38 weeks showed
similar testicular effects. Absolute and relative testes weights also were decreased in these
beagles. Following the "recovery" period, absolute and relative testes weights were similar
between control and treated dogs, and microscopic examination revealed the presence of
moderately active spermatogenic epithelium in the single treated dog sacrificed at this time. The
study authors suggested that boron-induced testicular degeneration in dogs may be reversible
upon cessation of exposure, although this statement was based on findings in only one beagle. It
is difficult to interpret the findings of this follow-up study due to the small number of animals
examined and the relatively short time duration of exposure as compared to the 2-year study.
Statistical tests were not conducted because of the low number of animals. Nonetheless, based
on testicular effects, the study authors identified a 26-week and 38-week LOAEL of
29.2 mg-B/kg-day for beagle dogs.
Numerous studies have been conducted investigating the developmental and reproductive
toxicity of oral boric acid and other boron compounds. Heindel et al. (1992, 1994) and NTP
(1990a) administered boric acid (98-99% purity) in the diets to timed-mated female
Sprague-Dawley rats (29/group) at concentrations of 0, 0.1, 0.2, or 0.4% from Gestation Days
(GDs) 0-20 (see Tables B. 1 and B.2). Based on measured food consumption, the diet provided
about 0-, 78-, 163-, or 330 mg-Boric acid/kg-day (equivalent to 0, 13.6, 28.5, and
57.7 mg-B/kg-day). Additional groups of 14 female rats each received boric acid at 0 or 0.8% in
the diet (0 or 94.2 mg-B/kg-day) only on GDs 6-15. Food and water intake and body weights—
as well as clinical signs of toxicity—were monitored throughout pregnancy. On GD 20, the rats
were sacrificed; the livers, kidneys, and intact uteri were weighed; corpora lutea were counted;
and maternal kidneys were assessed histopathologically. Live fetuses were removed, weighed,
and subsequently examined for external, visceral, and skeletal malformations. The study
followed GLP standards.
Bartlett's test was used to examine homogeneity of variance, and General Linear Models
(GLM) test for linear trend was used to determine the significance of dose-response relationships
(Heindel et al., 1992, 1994). The significance of dose effects, replicate effects, and
(dose x replicate) interactions was determined by analysis of variance (ANOVA). When
ANOVA revealed a statistically significant (p < 0.05) dose-response effect, Williams or
Dunnett's multiple comparison tests were used to compare each exposed group to the concurrent
control group. One-tailed tests were used for all pair-wise comparisons except maternal body
and organ weights, water and feed consumption, and fetal body weight.
Heindel et al. (1992, 1994) and NTP (1990a) reported that no maternal mortality was
observed, and neither maternal food nor water intake differed statistically significantly (p < 0.05)
from controls—except in the 0.8% (94.2 mg-B/kg-day) group, where both intakes decreased on
GDs 6-9 and increased on GDs 15-18. Statistically significant maternal effects attributed to
treatment in rats were (1) a decrease in body-weight gain during treatment at feed concentrations
of 0.4% (57.7 mg-B/kg-day) and greater; (2) an increase in relative liver and kidney weights at
0.2%) (28.5 mg-B/kg-day) and greater boric acid in feed; and (3) an increase in absolute kidney
weight at 0.8% (94.2 mg-B/kg-day). Minimal nephropathy was observed in maternal kidneys,
but the incidence and severity were not dose related. Pregnancy rates ranged between 90 and
100%) for all groups. At the 0.8%> (94.2 mg-B/kg-day) dose, prenatal mortality was increased, as
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evidenced by increased fetal resorptions, increased late fetal deaths, and decreased number of
live fetuses per litter. Mean fetal body weight per litter was statistically significantly reduced
(p < 0.05) in a dose-dependent manner in all treated groups relative to controls: 94, 87, 63, and
46% of the corresponding control body-weight means for the 13.6, 28.5, and 57.7 mg-B/kg-day
groups, respectively.
At dietary concentrations of 0.2% (28.5 mg-B/kg-day) and greater, Heindel et al. (1992,
1994) and NTP (1990a) reported the following statistically significant (p < 0.05) effects: (1) an
increase in the percentage of litters with malformed fetuses; (2) an increase in the percentage of
litters with at least one malformed fetus; and (3) an increase in the incidence of litters with one or
more fetuses with a skeletal malformation. At 0.2% in diet (28.5 mg-B/kg-day), malformations
consisted primarily of the axial skeleton and anomalies of the eyes, the central nervous system
(CNS), and the cardiovascular system. At both 0.4% (57.7 mg-B/kg-day) and 0.8%
(94.2 mg-B/kg-day) dietary concentrations, the incidences of litters with one or more pups with
visceral and gross malformations were statistically significantly increased (p < 0.05), with the
most commonly-occurring malformations being enlarged lateral ventricles of the brain and
agenesis or shortening of rib XIII. Based on the changes in organ weights, the study authors
identified a 21-day maternal LOAEL of 28.5 mg-B/kg-day and a maternal NOAEL of
13.6 mg-B/kg-day in rats. Based on the decrease in fetal body weight on a per-litter basis in rats,
the study authors identified a developmental LOAEL of 13.6 mg-B/kg-day, the lowest dose
tested; a developmental NOAEL could not be determined.
In a follow-up two-phase study, NTP (1994) and Price et al. (1996a) dosed timed-mated
female CD rats (60/group) from either GDs 0-20 (Phase I) or Postnatal Days (PND) 0-21
(Phase II) with dietary boric acid (99% purity) at feed concentrations of 0, 0.025, 0.05, 0.075,
0.1, or 0.2%) (see Tables B.3-B.5). Equivalent daily doses were 0, 3.3, 6.3, 9.3, 13.3, and
25.0 mg-B/kg-day for dams dosed from GDs 0-20 (Phase I) and 0, 3.2, 6.5, 9.7, 12.9, and
25.3 mg-B/kg-day for dams dosed from GD 0-PND 21 (Phase II). The study was
GLP-compliant. Throughout gestation, rats were monitored for body weight, clinical condition,
and food and water intake. In Phase I, reproductive and teratology evaluations were conducted.
In Phase II, pups were evaluated for mortality, body weight, and morphology (external, visceral,
and skeletal).
In Phase I, neither maternal mortality nor clinical signs of maternal preimplantation loss
were affected by treatment (NTP, 1994; Price et al., 1996a). Fetal body weights were
statistically significantly decreased in the two highest-dose groups on GD 20. The incidence of
external or visceral malformations and variations did not differ, either on a per-litter or per-fetus
basis, between treated and control rats. However, a statistically significant increase in the
incidence of fetuses with skeletal malformations or variations on a per-litter basis was observed
in the two highest-dose groups. The study authors considered the increased incidence in short
rib XIII to be a skeletal malformation, although they noted that others consider it a skeletal
variation (Price et al., 1996a). The study authors considered a statistically significant increase in
the incident of wavy ribs to be a skeletal variation. The number of rudimentary extra ribs on
lumbar I decreased with increasing dose, both in terms of number of litters in which it was
observed and of number of offspring per litter. These findings were not statistically significant,
although there was a statistically significant trend. The biological significance of this result is
not clear. Based on decreased fetal body weights, NTP (1994) and Price et al. (1996a) identified
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a developmental LOAEL of 13.3 mg-B/kg-day and NOAEL of 9.6 mg-B/kg-day in rats for
Phase I of this study.
In the Phase II study, neither maternal mortality nor clinical signs of maternal
preimplantation loss were affected by treatment (NTP, 1994; Price et al., 1996a). In the pups, a
trend test (Cochrane-Armitage) suggested a dose-related statistically significant increase in
postnatal mortality during PNDs 0-4 and PNDs 0-21 but not between PNDs 4-21 (NTP, 1994;
Price et al., 1996a, see Table B.4). However, the observed mortality rate in the high-dose group
was within the range of historical controls for this species and strain (Charles River, 1993).
According to Price et al. (1996a): "During lactation, the number and percentage of pup
deaths/litter exhibited increasing trends, but the number of implantation sites/litter, cumulative
offspring mortality (i.e., percentage of implantation sites) and number of live pups/litter did not
differ among groups. Thus, there was no definitive evidence for an adverse effect on offspring
viability from conception through weaning" (p. 181).
Pup body weights did not differ among groups during PNDs 0-21, demonstrating that the
decrease in fetal body weights observed in Phase I on GD 20 did not persist during the postnatal
period. The incidence of external or visceral malformations and variations did not differ, either
on a per-litter or per-fetus basis, between treated and control rats. However, the percentage of
pups per litter with short rib XIII (a skeletal malformation) was still elevated on PND 21 in the
high-dose group. The incidence of wavy rib (a skeletal variant), observed to be statistically
significantly increased in the two highest-dose groups on GD 20, did not differ from controls by
the end of the lactation period. The statistically significant trend in decreased incidences of
rudimentary extra rib on Lumbar I, observed on GD 20, did not occur on PND 21. Based on
skeletal malformations (short rib XIII), NTP (1994; Price et al., 1996a) identified the
developmental NOAEL and LOAEL for the postgestational phase (II) of this study as 12.9 and
25.3 mg-B/kg-day, respectively.
Heindel (1992, 1994) and NTP (1989) studied the developmental effects of boric acid in
mice and rabbits. Groups of 28-29 CD-I mice were exposed to boric acid (98-99% purity) in
the diet on GDs 0-17 using the same experimental design as in the first Price et al. (1996a) rat
study. The feed concentrations of boric acid were 0, 0.1, 0.2, or 0.4% (approximately equivalent
to 0, 43.4, 79.0, or 175.3 mg-B/kg-day). Studies were GLP compliant. Tables B.6 and B.7
summarize these findings. Survival rates, pregnancy rates, and maternal weight gains corrected
for gravid uterine weight were not affected by treatment. However, maternal body weights at
GD 17 were statistically significantly reduced (10—15% relative to concurrent controls) in the
high-dose group. The following effects were also observed in the dams: (1) statistically
significant increases in relative kidney and absolute liver weights at the high-dose relative to
controls; and (2) a dose-related increase in maternal renal tubular dilation and/or regeneration (0,
2, 8, and 10 animals in the 0-, 43.4-, 79.0-, and 175.3-mg-B/kg-day dose groups, respectively).
The only developmental effects were statistically significant increases in the percentage of litters
with one or more resorptions and in the percentage of resorptions per litter at
175.3 mg-B/kg-day. Mean fetal body weights were statistically significantly decreased in the
two highest-dose groups on GD 17 relative to concurrent controls. The percentage of malformed
fetuses per litter increased statistically significantly in the high-dose group, and the most frequent
malformation was short rib XIII. Based on kidney effects in the dam, the study authors
identified the maternal mouse 18-day NOAEL and LOAEL as 0.1% (43.4 mg-B/kg-day) and
0.2% (79.0 mg-B/kg-day), respectively. Based on a decrease in mean fetal body weights at
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maternally toxic doses, the study authors identified the developmental NOAEL and LOAEL as
also 43.4 mg-B/kg-day and 79.0 mg/kg-day, respectively, in mice.
Price et al. (1996b) and Heindel et al. (1994) gavaged artificially inseminated New
Zealand White rabbits (30/group) with boric acid (99% purity) in an aqueous vehicle at doses of
0, 62.5, 125, or 250 mg/kg/day (0, 10.9, 21.9, and 43.7 mg-B/kg-day) on GDs 6-19 and
sacrificed them on GD 30. The study followed GLP standards. Treatment-related mortality was
not observed. The only clinical sign of toxicity was vaginal bleeding, noted in 2 to 11 rabbits per
day in the high-dose group during the postexposure (GDs 19-30) interval. None of these rabbits
carried live fetuses when sacrificed on GD 30. Decreased food intake was observed in the
high-dose group on GDs 6-15, followed by a rebound in food intake in mid- and high-dose
females on GDs 25-30, which was after treatment termination. Body weight on GDs 9-30 and
the number of corpora lutea per dam were decreased in the high-dose group. Relative kidney
weights increased in high-dose dams, but there was no change in either absolute kidney weights
or in absolute and relative liver weights. At the high-dose, the following frank effects were
observed: (1) a 90% resorption rate per litter compared to 6% in concurrent controls; (2) a
statistically significant increase in the percentage of pregnant females with no live fetuses
(73%) compared with 0%> in controls); and (3) a statistically significant decrease in the number of
live fetuses per litter on GD 30 (2.3 fetuses/litter compared with 8.8 fetuses/litter in controls).
Fetal body weights per litter at the high-dose were depressed relative to control, but, due to the
small number of live fetuses in the high-dose group, this finding was not statistically significant.
The incidence of malformations in live fetuses per litter was statistically significantly elevated at
the high dose, primarily associated with cardiovascular defects that were predominantly located
in the interventricular septum. In contrast, the incidence of skeletal malformations was
comparable among groups. No reproductive or developmental effects were found in the low-
and mid-dose groups. Based on clinical signs and reproductive effects in the dams and visceral
malformations in the fetus, the study authors identified 14-day maternal and developmental
LOAEL and NOAEL of 250 mg-Boric acid/kg-day (43.7 mg-B/kg-day) and 125 mg-Boric
acid/kg-day (21.9 mg-B/kg-day), respectively, in rabbits.
In a subchronic reproductive toxicity study, Dixon et al. (1976) gave male
Sprague-Dawley rats (10/group) 0, 0.3, 1.0, or 6.0 mg-B/L, as borax (11%> boron, purity not
given) in drinking water for 30, 60, and 90 days. Equivalent daily doses were 0, 0.042, 0.14, and
0.84 mg-B/kg-day, respectively. No changes in male fertility were observed, as assessed by
breeding studies. Similarly, no effects of treatment were noted for body weight; testis, prostate,
and seminal-vesicle weights; serum chemistry parameters; plasma concentrations of follicle
stimulating hormone (FSH) and luteinizing hormone (LH); and fructose, zinc, and acid
phosphatase concentrations in the prostate. The study did not report whether GLP standards
were followed. The majority of data was presented in graphical form, and statistical tests used
for analysis were not given. The study authors did not identify a NOAEL. As no
treatment-related effects were reported, the 30-90-day male rat NOAEL is identified as
0.84 mg-B/kg-day, the highest dose tested in this study.
In a follow-up dietary study at much higher doses, Lee et al. (1978) and Dixon et al.
(1979) administered diets containing 0-, 500-, 1000-, or 2000-ppm boron (as borax; purity not
reported), approximately equivalent to 0, 25, 50, and 100 mg-B/kg-day, respectively, to male
Sprague-Dawley rats (18/group) for 30 or 60 days. Statistical differences between control and
experimental groups were calculated using the Student's Mest. Level of significance was
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p < 0.05. Although the study appears to have been well conducted, it did not report whether
GLP standards were followed. In the two highest-dose groups, liver, testis, and epididymis
weights were statistically significantly decreased. Although seminiferous tubule diameters
showed a statistically significant dose-dependent decrease in all treatment groups, this decrease
was associated only with a statistically significant loss of germinal cell elements at the two
highest doses. Other effects included complete seminiferous tubule aplasia at the highest dose
and statistically significant dose- and duration-dependent elevation of plasma FSH—but not of
plasma LH or testosterone. Serial mating studies, analyzed using the Fisher nonparametric test
withp < 0.05 as the level of significance, showed that fertility was reduced at the two highest
doses without any concomitant changes in copulatory behavior. The study authors did not
identify a NOAEL. Based on findings of tubular germinal aplasia, a NOAEL and LOAEL of 25
and 50 mg-B/kg-day, respectively, are identified for this study.
Linder et al. (1990) evaluated the time response and dose response of male rat
reproductive end points after single- and repeated-dosing (14 days) via gavage administration of
boric acid. Although the study did not report whether GLP standards had been followed, the
experiments were conducted in EPA laboratories. In the time-response experiment,
Sprague-Dawley rats (6/group) were given single doses of 0- or 2000 mg-Boric acid/kg (0 or
350 mg-B/kg, respectively) by gavage and were sacrificed at 2, 14, 28, and 57 days after dosing.
In the dose-response experiment, groups of eight male rats were administered single doses of 0-,
250-, 500-, 1000-, or 2000-mg-Boric acid/kg (0, 44, 87, 175, or 350 mg-B/kg) by gavage and
were sacrificed 14 days later. In both the time-response and the dose-response studies, the above
doses were the total of two doses administered at 9:00 a.m. and 4:00 p.m. on the same day. The
following statistical tests were performed: (1) ANOVA and Duncan's multiple range test for
sperm counts; and (2) Wilcoxon scores and the Kurskal-Wallis tests for evaluation of sperm
motility and morphology. The level of statistical significance was set at/? < 0.05. No
statistically significant clinical signs of toxicity were observed during the study. In the
time-response study, statistically significant effects on Day 28 included an increase in abnormal
caput and cauda epididymal sperm morphology, and a decreased percentage of motile cauda
spermatozoa with reduced straight-line swimming velocities. The sperm parameters in all
animals had returned to control values by Day 57 postdosing. In the dose-response study,
adverse effects on spermiation (discharge of spermatozoa from the testis), epididymal sperm
morphology, and caput sperm reserves appeared in the two highest-dose groups (175 and
350 mg-B/kg). The study authors identified a 14-day NOAEL of 87 mg/kg in male rats. Based
on spermatogenic effects, a 14-day LOAEL of 175 mg/kg is identified for this study.
In a reproductive toxicity study, Weir and Fisher (1972) gave male and female
Sprague-Dawley rats (8 males/group and 16 females/group) dietary boric acid (purity not given)
at feed concentrations approximately equivalent to 0, 5.9, 17.5, or 58.5 mg-B/kg-day for three
generations. Weir and Fisher (1972) reported no adverse effects on reproduction or gross
pathology in rats in the low- and mid-dose groups. In the high-dose group, no progeny were
produced, no spermatozoa were found in the atrophied testes, and females showed statistically
significantly decreased ovulation. Mating high-dose females with control males resulted in no
litters. Based on frank effects on fertility and accompanying changes in germinal tissues,
58.5 mg-B/kg-day is identified as a three-generation frank effect level (FEL) in rats. A
three-generation NOAEL of 17.5 mg-B/kg-day is identified in rats for this study. No LOAEL is
determined because frank effects were observed at the next highest dose (58.5 mg-B/kg-day).
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In a continuous breeding protocol, NTP (1990b) and Fail et al. (1991) studied the
reproductive toxicity of boric acid in Swiss CD-I mice in three phases. In the cohabitation phase
of this protocol, 11-week-old male and female F0 mice (40 pairs/control group and 20 pairs/dose
group) were fed a diet containing 0-, 1000-, 4500-, or 9000-ppm boric acid (99% purity) for up
to 27 weeks. Equivalent daily dietary doses were estimated to be 0, 26.6, 111, and
220 mg-B/kg-day for males and 0, 31.8, 152, and 257 mg-B/kg-day for females. GLP standards
were followed. Following 1 week of treatment, the F0 mice were caged as breeding pairs and
dosed in feed for 14 weeks. The following statistical analyses were used: (1) fertility parameters
were tested using the nonparametric multiple comparison procedures of Dunn or Shirley, as
modified by Williams; (2) data expressed as a proportion, such as number fertile per number
cohabited, were evaluated using the Cochran-Armitage test for a dose-related trend; and (3) the
Kruskal-Wallis test was used for crossover mating trials to assess equality of response among
dose groups, while multiple comparison tests used the method of Dunn. The level of
significance wasp < 0.05.
In the high-dose group, impaired fertility was complete, and none of the mated pairs
produced litters. The initial fertility index (percentage of cohabited pairs in at least one litter)
was not statistically significantly altered in the mid-dose group, but the progressive fertility index
(percentage of fertile pairs that produced four litters) was decreased relative to controls; the trend
toward a lower fertility index in this group started with the first mating and progressed in
severity with subsequent matings. The number of litters per pair, the number and proportion of
live pups per litter, live pup body weight, and adjusted (for litter size) pup body weight also were
statistically significantly lower. No effects on fertility were observed in the low-dose group
relative to controls. Males were considered to be the more sensitive species. Based on fertility
indices and reproductive toxicity effects, NTP (1990b; Fail et al., 1991) identified a "probable"
study NOAEL for the F0 generation (cohabitation) male mice of 26 mg-B/kg-day. Based on
fertility indices and reproductive toxicity effects, a reproductive LOAEL of 111 mg-B/kg-day in
mice is identified for this phase of the study.
The second phase of the continuous breeding protocol involved crossover studies
between control and treated mice (NTP, 1990b). These crossover studies demonstrated a
reduction in fertility in mid-dose males mated to control females but not in mid-dose females
mated to control males (NTP, 1990b; Fail et al., 1991). However, mid-dose females in the latter
group had a longer gestational period and delivered pups with lower body weights (adjusted for
litter size) than control females. Measurement of semen parameters and examination of
testicular histopathology showed the following: (1) high- and mid-dose males had statistically
significantly reduced testis and epididymis weights and a dose-related atrophy of seminiferous
tubules; (2) mid-dose males had decreased sperm concentration, increased percentages of
abnormal sperm, and other abnormalities in spermatogenic and testicular morphology; and
(3) low- and mid-dose males showed statistically significant reductions in sperm motility. Due
to either the absence of sperm in 12 of 15 observed males and the severe reduction in sperm
counts in the other 3 males, NTP (1990b) and Fail et al. (1991) could not fully evaluate sperm
motility and morphology in the high-dose group. No morphological or histopathological
changes in the reproductive tract were noted in either low-dose F0 males or in treated F0 females
at all doses. These data suggest a reproductive LOAEL of 26.6 mg/kg-day with no NOAEL for
reduced sperm motility among male mice, and a developmental NOAEL of 31.8 mg/kg-day and
LOAEL of 152 mg/kg-day among female mice for longer gestational periods and pups with
lower body weights.
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In the third phase of the study, NTP (1990b; Fail et al., 1991) treated F1 mice with the
same doses as their parents and bred to produce the F2 generation. The high-dose F0 group did
not produce any litters, and there were too few animals in the mid-dose F1 group to test the
effects of treatment on F1 fertility. Therefore, only the low-dose F1 group and a group of
concurrent controls were bred. In low-dose F1 animals, effects on fertility were observed
relative to controls. However, increased weights of the uterus, kidney, and adrenal glands, and
shortened estrus cycle lengths were observed in adult F1 females from this group. The mean
F2 pup weight in the low-dose group, adjusted for litter size, was statistically significantly lower
than that in the control group. Based on F1 maternal toxicity and a decrease in mean F2 pup
weight, the reproductive and developmental LOAEL for this phase of the study are identified as
the lowest doses tested, 26.6 and 31.8 mg-B/kg-day for males and females, respectively, with no
NOAEL.
Hydrogen Chloride
No studies were identified.
Inhalation Exposure
Boron Trichloride
Stokinger and Spiegl (1953) exposed rats, mice, and guinea pigs (sex, strain, and species
not specified; purity not specified; 10-15 animals/species/group) to 20-, 50-, or 85-ppm BCI3
"3
(4.2, 10, and 18 mg/m ), 7 hours/day, for 1 or 2 days. Due to the hygroscopic and hydrolytic
nature of this compound, the vapor decomposed into hydrolysis products immediately upon
contact with air (nature of hydrolysis products not specified but presumed to include HC1) and
settled as an oily liquid onto cage surfaces. Mortality was 100% at 20 and 50 ppm and 30% at
85 ppm in rats and 0% in all groups of guinea pigs. In mice, mortality was 100% in all dose
groups. The study authors attributed the observed high mortality to settling of the oily
decomposition products onto all cage surfaces. In a subsequent experiment, rats, mice, and
guinea pigs were exposed to 20, 50, or 100 ppm for the same time period, but their cages were
exchanged for clean ones every 1 to 2 hours. Mortality was significantly reduced. In rats, no
mortality occurred in any dose group. In mice and guinea pigs, mortality was limited to only the
high-dose group (14/15 mice and 10/10 guinea pigs). Pathological findings indicated that BCI3
was a severe skin and respiratory irritant. Irritation occurred on those skin areas that came into
direct contact with the cage surfaces, particularly the paws and mouth. The study authors
concluded that BCI3 and its hydrolysis products were highly lethal to rats and mice—but not to
"3
guinea pigs—at nominal vapor concentrations of 20 ppm (4.2 mg/m ) or greater. However,
cleaning the cages every 1 to 2 hours resulted in no mortality occurring in rats at nominal vapor
"3
concentrations of up to 100 ppm (20 mg/m ) and in mice and guinea pigs at nominal vapor
concentrations of up to 50 ppm (10 mg/m3). This study was conducted to determine the type of
personal protection respirators needed for workers involved in the production of large quantities
of uranium by "special processes," of which BCI3 and other boron halides were chemical
intermediates. Exposure concentrations were considered approximate, and no measurement or
characterization of the hydrolysis products was conducted. Thus, for this review, no acute
quantitative values are reported.
Boric Acid and Boron Compounds
Inhalation toxicity of boron and compounds has been discussed in the IRIS toxicological
review (U.S. EPA, 2004) and is summarized below.
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Only one boron-oxide inhalation exposure study, which reports on exposures in rats and
dogs, was available in the literature. Wilding et al. (1959) exposed a group of 70 albino rats,
"3
including both males and females, to an average concentration of 0 or 77 mg/m of boron oxide
aerosols (0 or 24 mg-B/m3) 6 hours/day, 5 days/week, for 24 weeks. An additional group of four
3 3
rats was exposed to 175 mg/m (54 mg-B/m ) for 12 weeks, and 10 rats were exposed to
470 mg/m3 (146 mg-B/m3) for 10 weeks using the same exposure regime. Three dogs (sex and
3 3
breed not reported) were exposed to 57 mg/m (18 mg-B/m ) for 23 weeks. At a concentration
of 470 mg/m3, the aerosol was reported to form a dense cloud of fine particles, and the rats were
covered with dust. The only clinical sign of toxicity was a slight reddish exudate from the nose
of rats exposed to this concentration, which was attributed to local irritation. Body-weight gain
"3
was reduced by about 9% in the 470-mg/m exposed rats, but this difference is not considered to
be toxicologically significant, because body-weight decreases of less than or equal to 10% are
not considered by EPA to be sufficiently large as to constitute an adverse effect (U.S. EPA,
2002). No organ effects were reported in rats exposed to 77 mg/m3 of boron oxide aerosols
"3
(24 mg-B/m ) for 24 weeks, although it should be noted that only limited histopathology was
conducted on the testes. There was a statistically significant drop in urine pH and an increase in
3 3
urine volume in rats exposed to 77 mg/m (24 mg-B/m ). Wilding et al. (1959) hypothesized that
this was due to the formation of boric acid from boron oxide by hydration in the body and the
"3
diuretic properties of boron oxide. At 77 mg/m , a statistically significant increase in urinary
creatinine also was noted. No effect on serum chemistry, hematology, organ weights,
histopathology, bone strength, or liver function was reported in either rats or dogs, although not
all end points were studied in all exposure groups. It is not known if this study followed GLP
standards; however, it has numerous limitations in study design and reporting.
Hydrogen Chloride
IRIS (U.S. EPA, 1995) has evaluated the inhalation toxicity data for HC1, deriving a RfC
of 0.02 mg/m3 based on hyperplasia of the nasal mucosa larynx and trachea in rats
(Sellakumar et al., 1985; Albert et al., 1982). The inhalation data for HC1 are discussed below
and summarized in Table 3.
In a 90-day inhalation study, Toxigenics (1984) exposed 31/sex/strain/species
Sprague-Dawley and Fisher 344 rats and B6C3Fi mice to HC1 vapors of 0, 10, 20, or 50 ppm (0,
"3
15, 30, or 75 mg/m , respectively) for 6 hours/day, 5 days/week, for 90 days. Mortality in rats or
mice during the study was not exposure related. The only effects reported as adverse were in
nasal tissues: histopathologic examination showed minimum-to-mild rhinitis and concentration-
and time-dependent lesions in the anterior portion of the nasal cavity in both strains of rats in all
"3
exposed groups. In mice exposed to 50 ppm (75 mg/m ), cheilitis and accumulation of
macrophages in the peripheral tissues were observed at study termination. Eosinophilic globules
in the epithelial lining of the nasal tissues were observed in mice in all exposure groups.
Toxigenics (1984) did not identify a NOAEL or LOAEL for this study. However, a 6 hours/day,
3 3
5 days/week, 90-day LOAEL is identified as 15 mg/m (LOAELhec = 6.1 mg/m ) for both rats
and mice, based on effects in the nasal tissues.
The chronic study by Albert et al. (1982) and Sellakumar et al. (1985) is chosen as
the principal study for the derivation of the subchronic and chronic p-RfDs for boron
trichloride. The study authors exposed Sprague-Dawley rats (100/sex/exposure group) to 0- (air
only) and 10-ppm (15 mg/m3) HC1 vapor for 6 hours/day, 5 days/week, for a lifetime (i.e., until
natural death; data were reported for up to 128 weeks). Although the study was well conducted,
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compliance with GLP standards was not reported. All rats were observed daily, weighed
monthly, and sacrificed at the end of the study. All rats were necropsied, with histologic sections
prepared from the nasal cavities, lungs, trachea, larynx, liver, kidneys, testes, and other organs.
No differences in body weights or survival were observed in rats exposed to HC1, when
compared with controls. An increase in the incidence of epithelial or squamous hyperplasia in
the nasal mucosa among exposed rats, compared with controls, was reported (62% in treated vs.
51% in controls; n = 99/group). Squamous metaplasia of the nasal mucosa was reported in 9%
of exposed and 5% of control rats. Table B.8 presents these data. A higher rate of occurrence of
hyperplasia was also reported in the laryngeal-tracheal segment of the respiratory tract (24% in
exposed versus 6% in control rats (U.S. EPA, 1995). However, numerical data for this end point
could not be determined because individual animal data were not available and incidence data
did not distinguish between animals who had hyperplasia in both the larynx and the trachea and
those with hyperplasia in either the larynx or the trachea. No squamous metaplasia in the
laryngeal-tracheal segment was noted in any animals in either group. The severity of observed
effects was not reported. The study authors did not identify a LOAEL or a NOAEL. However,
based on the observed effects, the single dose tested, 10 ppm (15 mg/m3; LOAELhec =
"3
6.1 mg/m ), is identified as a chronic LOAEL.
Reproductive and developmental studies following inhalation of HC1 are limited to two
studies, presented in one paper by Pavlova (1976). In the first study, two groups of 8 to
15 female rats (strain and sex not reported) were exposed to 302-ppm (450 mg/m3) HC1 for
1 hour. One group was exposed 12 days prior to mating and the other group on GD 9. In both
groups, signs of severe dyspnea and cyanosis were noted, and mortality occurred in one-third of
the adult rats. Fetal mortality was reported to be statistically significantly higher in pregnant rats
exposed during pregnancy, likely due to maternal toxicity occurring at this exposure
concentration. When the progeny were subjected to an additional exposure of 35 ppm
(52 mg/m3) at the age of 2-3 months, "functional abnormalities" in the organs of the progeny
were similar to those found in the mothers. In the second study in the same paper, Pavlova
(1976) exposed female rats (number and strain not reported) to 302-ppm (450 mg/m3) HC1 for
1 hour prior to mating. Exposure killed 20-30% of the rats. In rats surviving 6 days after
exposure, a decrease in blood oxygen saturation was noted, and kidney, liver, and spleen damage
also was reported. In addition, there were unspecified changes to the rats' estrus cycles.
Appropriate controls were not utilized in these studies, and the findings were not well
characterized in the publication. Therefore, neither a LOAEL nor a NOAEL for these studies is
identified.
OTHER DATA
Acute Lethality Studies
Boron Trichloride
Inhalation of boron trichloride results in edema and irritation of the upper respiratory
tract in humans (HSDB, 201 la). The only available data on acute inhalation of boron trichloride
are lethality tests in which the LC50 (1-hour) for male rats was 2541 ppm (12,140 mg/m3)
(Vernot et al., 1977), and the LC50 (1-hour) for female rats was 21,100 mg/m3 (HSDB, 201 la).
Boric Acid and Boron Compounds
In general, ingested boron appears to be more lethal in rats than in dogs or mice.
Single-dose oral LD50 values for boric acid were
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• 898 mg/kg (157 mg-B-kg) in an unspecified rat strain (Smyth et al., 1969)
• 600 mg/kg (105 mg-B/kg) in Sprague-Dawley rats (Weir and Fisher, 1972)
• 550 mg/kg (96 mg-B/kg) in Long-Evans rats (Weir and Fisher, 1972).
No deaths were reported in dogs exposed to a single dose of 3977 mg-Boric acid/kg
(696 mg-B/kg) (Weir and Fisher, 1972). No single-dose LD50 studies in mice were available;
however, NTP (1987) reported mortality rates of 20 and 60% in males given 14 daily doses of
12,900- or 21,000 mg-Boric acid/kg-day (2251- and 3671 mg-B/kg-day) in the diet, respectively;
no mortality was observed in mice given 5300 mg/boric acid/kg-day (926 mg-B/kg-day).
Treated mice were lethargic; they also exhibited discolored spleens, livers, and renal medullae,
and hyperplasia and dysplasia of the forestomach (NTP, 1987).
"3
The 4-hour LC50 for boric acid and other borates was greater than 2 mg-B/m in rats
(Hubbard, 1998). No fatalities were observed in rats exposed for 6 hours/day, 5 days/week,
to 470 mg-Boron oxide/m3 (73 mg-B/m3) for 10 weeks, 175 mg-Boron oxide/m3 (27 mg-B/m3)
3 3
for 12 weeks, or 77 mg-Boron oxide/m (12 mg-B/m ) for 24 weeks, or dogs exposed to
57 mg-Boron oxide/m (9 mg-B/m3) for 23 weeks (Wilding et al., 1959).
Hydrogen Chloride
Reported 30-minute LC50 values for HC1 in rats and mice were 4701 and 2644 ppm,
respectively; the LC50 values for 5-minute exposures were 40,989 and 13,750 ppm for rats and
mice, respectively (Darmer et al., 1974). Thus, it appears that airborne HC1 exposure is more
lethal to mice than rats. No immediate deaths occurred among rabbits or guinea pigs exposed for
5 minutes to a concentration of 5500 mg/m3 (3685 ppm), but 100% mortality was noted in both
"3
these animal species exposed to 1000 mg/m (670 ppm) for 6 hours/day, for 5 days (WHO,
1982).
In other acute toxicity studies, delayed mortality in mice was reported to be associated
with short-term exposures that did not lead to immediate death but resulted in animals dying
days to several weeks following acute exposure (WHO, 1982). This mortality was attributed to
the occurrence of nasal and pulmonary infections due to the disruption of normal epithelial
mechanisms, which function to prevent bacterial infection and invasion in the intact animal. In
support of this interpretation, focal superficial ulceration of the respiratory epithelium, at its
junction with the squamous epithelium of the external nares, was reported in mice 24 hours after
a single 10-minute exposure to 17 ppm (25-30 mg/m3) (WHO, 1982).
Short-Term Exposure
Boron Trichloride
No short-term exposure studies of boron trichloride were located in the literature.
Boric Acid and Boron Compounds
Cherrington and Chernoff (2002) conducted a series of short-term mouse studies to assess
the relationship between developmental toxicity and the timing of boric acid dosing during
organogenesis. The findings showed that
• at oral doses of 500 and 750 mg/kg-day, the nature and extent of skeletal malformations
were dose dependent;
• the most frequent malformations were of the ribs; and
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• the effects of boric acid on fetal body weight and rib malformation were independent of
each other and appeared to be related to the timing of the dose during the period of
organogenesis (GDs 6-10).
Cherrington and Chernoff (2002) concluded that the accumulation of the adverse effect,
rather than the accumulation of boric acid, was associated with the timing of the high-dose
chemical insult and suggested that boric acid interfered with gastrulation and presomitic
mesoderm formation under the conditions of these studies.
Hydrogen Chloride
The histopathological effects in the upper respiratory tracts of mice were studied 24 hours
"3
after a single 10-minute exposure to HC1 (HSDB, 201 lc). Exposure to 25 mg/m (17 ppm)
caused superficial ulcerations in the respiratory epithelium. Increasing the exposure to
"3
195-417 mg/m (131-280 ppm) resulted in mucosal ulceration in the adjacent respiratory
epithelium and at a higher dose of 738 mg/m3 (493 ppm); effects also were noted on the
"3
squamous epithelium of the external nares. At concentrations of 2940 mg/m (1973 ppm) or
more, effects were noted on parts of the squamous, respiratory, and olfactory epithelium of the
upper respiratory tract. Mucosal damage also was observed.
Kaplan et al. (1988) exposed male baboons (3/group) to 0-, 500-, 5000-, or 10,000-ppm
"3
(745, 7450, and 14,900 mg/m , respectively) HC1 for 15 minutes and observed them for
3 months. A dose-related increase in respiratory rate and minute volume immediately following
exposure was observed. Decreased arterial oxygen (PO2) was noted at the higher concentrations,
but measurements at 3 days and 3 months following exposure did not show any abnormalities.
Burleigh-Flayer et al. (1985) exposed male guinea pigs via inhalation to 0-, 320-, 680-,
1040-, and 1380-ppm HC1 for 1-6 minutes and measured respiratory rate and induction of
"3
sensory or pulmonary irritation. This study indicated sensory irritation at 320 ppm (477 mg/m )
with an exposure of 6 minutes, while less severe irritation was noted at concentrations of
"3
680 ppm (1013 mg/m ) or higher during a 1-minute exposure. The concentration of HC1
exposure was inversely related to the time of onset interval of pulmonary irritation.
Toxicokinetics
Boron Trichloride
Boron trichloride decomposes rapidly in the presence of moisture to boric acid and
hydrochloric acid (U.S. EPA, 2004). Thus, oral, inhalation, or dermal exposure will result in
production of these decomposition products. Toxicokinetic studies of boron trichloride have not
been reported in either humans or animals. Discussion of the toxicokinetics of boron trichloride
is based on its two hydrolysis products, boric acid and HC1, as follows:
BCI3 + 3 H20 -> H3BO3 + 3 HC1
Boric Acid and Boron Compounds
The IRIS Toxicological Profile (U.S. EPA, 2004) has discussed the toxicokinetic data for
boron compounds, which are summarized below.
Boron is found in nature covalently bound to oxygen as some form of borate, such as
boric acid or tetraborate. Inorganic borate compounds in the body are present as boric acid
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(WHO, 1998). The boron-oxygen bonds are very strong and will not be broken except under
extreme laboratory conditions. Therefore, the results of studies on the toxicity of boron and
compounds generally are applicable to boric acid.
Orally ingested elemental boron also hydrolyzes into boric acid. Boric acid has been the
only boron compound identified in urine following boron ingestion and has repeatedly been
found to account for greater than 90% of the ingested boron dose (WHO, 1998). Studies with
boron demonstrate that boric acid is well absorbed from the GI tract. In single- and repeated oral
dosing studies in human volunteers, Schou et al. (1984) and Job (1973) have shown that more
than 90% of boron in water was excreted in the urine over 4 days after treatment. Ingestion of
boron as boric acid in food or in dietary supplements resulted in 84-90%) recovery in the urine
(Kent and McCance, 1941; Naghii and Samman, 1997), demonstrating that at least this
percentage of the test compound was absorbed. These studies demonstrated that a high
percentage of administered oral dose is absorbed in humans. In animal studies, absorption is
similarly rapid and extensive, with more than 90%> of orally administered boron being recovered
in the urine within 1-3 days postdosing (U.S. EPA, 2004).
Boron also is well absorbed during inhalation exposure, although available data do not
permit a quantitative analysis of the extent of inhalation absorption. Culver et al. (1994) showed
that workers in mid- and high-exposure categories at a borax production facility had statistically
significantly increased blood concentrations of boron following a work day. Due to the large
size of borate dust particles in the workplace, it was unclear how much of the inhaled boron was
actually absorbed through the respiratory tract. Culver et al. (1994) suggested that much of the
systemic boron might have been due to absorption through the mucous membranes in the upper
respiratory tract or via clearance by mucociliary activity and subsequent ingestion. Urinary
boron concentrations also have been reported to be higher in rats exposed to airborne boron
aerosols as compared with control rats (Wilding et al., 1959).
Boric acid has not been readily absorbed through intact skin following topical application
to adult humans and newborn infants (Draize and Kelley, 1959; Friis-Hansen et al., 1982).
However, Stuttgen et al. (1982) reported that boron as boric acid in an aqueous jelly vehicle has
been readily absorbed through damaged skin (such as that resulting from eczema, psoriasis, and
urticaria) following topical application, as evidenced by increased blood and urinary boron
concentrations in these subjects. In contrast, skin-damaged individuals treated topically with
boric acid in an emulsifying ointment showed no increase in urinary boron concentrations,
indicating that the form of the vehicle plays a key role in the extent of dermal absorption
(U.S. EPA, 2004). Nielson (1970) reported similar findings in laboratory rats.
Following absorption by either the oral or inhalation route, boric acid and other borate
compounds primarily have been present in the body as undissociated boric acid. Based on data
from studies in rats, boric acid uniformly distributes in soft tissues (such as liver, kidney, and
muscle) outside the blood compartment, with lower concentrations found in adipose tissue and
appreciably higher concentrations (i.e., close to 50%>) accumulating in bone. No appreciable
accumulation has been shown to occur in the testis or the epididymis of rats (U.S. EPA, 2004).
The primary route of elimination in human and rodents has been via the urine. Excretion
studies have shown that greater than 90%> of an orally administered dose of boric acid is rapidly
excreted unchanged in the urine following treatment (Jansen et al., 1984, Schou et al., 1984).
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Minor elimination pathways include feces, saliva, and sweat (Jansen et al., 1984). Studies of
renal clearance (U.S. Borax, 2000; Pahl et al., 2001; Vaziri et al., 2001) showed that clearance
rates of boric acid are greater in female rats than female humans and that both pregnant rats and
pregnant women cleared boron somewhat more efficiently than nonpregnant rats and women.
The relative rat:human clearance values were approximately 3.6:1 and 4.9:1 for pregnant and
nonpregnant females, respectively, and were in close agreement with differences in kinetic
parameters of approximately 4:1 predicted by allometric scaling (U.S. EPA, 2004). The variance
of boron clearance in humans was slightly greater than in rats (0.35%), and the coefficient of
variation (CV) was 4-fold higher in humans than in rats. However, EPA (2004) concluded,
"Overall, the available pharmacokinetic data support a high degree of qualitative similarity (lack
of metabolism, highly cleared through renal filtration mechanisms, and apparently consistent
extravascular distribution characteristics) between the relevant experimental species and
humans" (p. 29).
Hydrogen Chloride
Toxicokinetic studies have not been conducted with HC1. HC1 is corrosive at high
concentrations. However, at low concentrations, chloride ions are essential to normal body
functions, and protons (hydrogen ions) and chloride ions are normal constituents of body fluids.
Localized irritant and corrosive effects are thought to result from pH change (local deposition of
H+) rather than effects of HC1, because dissociation into hydrogen and chloride ions is very rapid
(HSDB, 201 lc). It is generally believed that exposure to hydrogen chloride does not result in
effects on organs some distance from the portal of entry (WHO, 1982).
Genotoxicity
Boron Trichloride
No studies were identified.
Boric Acid and Boron Compounds
The IRIS Toxicological Profile (U.S. EPA, 2004) discussed the genotoxicity data for
boron compounds, which are summarized below.
Bacterial and mammalian cell assays have not shown evidence of boric acid
mutagenicity. In Salmonella typhimurium strains TA 1535, TA 1537, TA 1538, TA 98, and
TA 100, boric acid was not mutagenic with or without S9 metabolic activation (Benson et al.,
1984; Haworth et al., 1983; NTP, 1987; Stewart, 1991). Boric acid was either not mutagenic
(Iyer and Szybalski, 1958; Szybalski, 1958) or produced equivocal results (Demerec et al., 1951)
in the streptomycin-dependent Escherichia coli Sd-4 assay. Results in mammalian mutagenicity
test systems all were negative. Boric acid did not induce unscheduled DNA synthesis in primary
cultures of male F344 rat hepatocytes (Bakke, 1991), forward mutations in L5178Y mouse
lymphoma cells with or without S-9 activation (NTP, 1987), mutations at the thymidine kinase
locus in the L5178Y mouse lymphoma cells with or without microsomal activation, or
chromosome aberrations or sister chromatid exchanges in Chinese hamster ovary cells with or
without S-9 metabolic activation (NTP, 1987). In a standard mouse micronucleus assay, boric
acid did not induce either chromosomal or mitotic spindle abnormalities in bone marrow
erythrocytes (O'Loughlin, 1991).
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Hydrogen Chloride
Genotoxicity and mutagenicity test findings for HC1 have been generally negative except
for one study in which positive results were attributed to the contamination of the culture
medium. Negative results were reported in the Ames mutagenicity test with Salmonella
typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538, with and without
metabolic activation; in a mitotic recombination assay with Saccharomyces cerevisiae D4, with
and without metabolic activation; and in a reverse mutation test with Escherichia coli (HSDB,
201 lc). In mammalian cell assays, HC1 did not cause mutations at the thymidine kinase locus in
L5178Y mouse lymphoma cells, with or without metabolic activation. HC1 was positive for
chromosomal aberrations in Chinese hamster ovary cells without metabolic activation (HSDB,
2011c).
Nutrition Studies
Boron and Boron Compounds
Boron has been known, since the 1920s, to be an essential micronutrient in plants. Boron
is a trace element, which is suspected to be essential in mammals, but the data are inadequate to
verify this (Nielsen et al., 1987; Nielsen, 1991, 1992, 1994, 1996; Mertz, 1993; Hunt, 1994). A
number of animal and human clinical studies have yielded findings supporting the nutritional
essentiality of boron. Nielsen (1994) has shown that boron is needed for macromineral and
cellular metabolism at the membrane level. Experimental boron nutrition research demonstrates
that boron affects the metabolism or utilization of essential minerals (including calcium,
magnesium, and copper), carbohydrates and fats (such as glucose and triglyceride), nitrogen,
estrogen, and reactive oxygen species in a range of body tissues including blood, brain, and
skeleton (Nelson, 1996). Physiological concentrations of supplemental dietary boron inhibit
several enzymes involved in propagating an inflammatory response, and, thus, boron may play a
role in the reduction of inflammatory disease (Hunt, 1994). Boron appears to be crucial to the
utilization of calcium by bone, and supplementation with boron may arrest or reduce osteopenia
and osteoporosis; Hunt (1994) has shown that boron also modulates release of insulin and
metabolism of vitamin D. In human clinical studies, daily supplementation with 0.25 mg-B/day
was associated with a reduction in nutritional and metabolic stress. Based on these clinical
studies, Nielsen (1991) concluded that the basal requirement for boron is likely to be greater than
0.25 mg/day (0.0036 mg/kg-day).
Limited survey data indicate that the average dietary intake of boron in the United States
is 0.5-3.1 mg/day (Nielsen, 1991), approximately equivalent to 0.007-0.04 mg/kg-day. Dietary
boron can be obtained from consumption of fruits, vegetables, nuts, legumes, and wine. Dietary
boron consumption in Europe may be higher than that in North America because of higher rates
of wine consumption (ECETOC, 1995). The Institute of Medicine (IOM, 2002) has established
tolerable upper intake levels (UL), but not a Recommended Dietary Intake (RDI), for boron. A
UL for infants was not set. For children and adolescents aged 1-3, 4-8, 9-13 years, the ULs for
boron are 3, 6, and 11 mg/day, respectively. For young adults of both genders, including
pregnant and lactating females aged 14-18 years, the UL for boron is 17 mg/day. For older
adults, including pregnant and lactating females aged 19-50 years, the UL for boron is
20 mg/day (IOM, 2002).
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Other Toxicity Data Related to pH of Hydrogen Chloride
Chemistry Related to Hydrolysis of Boron Trichloride
Boron trichloride hydrolyzes easily in water, moist air, or ethanol to boric acid and HC1
(ATSDR, 2007), as represented by the following equation.
BC13 + 3 H20 -> H3BO3 + 3 HC1
Because boron trichloride rapidly and completely decomposes in water, the pH of a
saturated solution is equivalent to that of concentrated hydrochloric acid. A concentrated
solution of hydrochloric acid has a HC1 concentration of 12.338 mol/L (Lide, 2002). This
"3
corresponds to a pH of-1.1. This would require a mass of 481 g of boron trichloride to be
decomposed into HC1 and dissolved into water for every liter of solution.4
However, if boron trichloride reacts with water in an environment that is open to the
atmosphere, the HC1 gas produced from decomposition will not fully dissolve into solution. The
amount of a gas that dissolves into a liquid solvent is directly proportional to its partial pressure
above the liquid. This is demonstrated by Henry's Law given below (Zumdahl and Zumdahl,
2010):
P = kC
Where
P = Partial pressure of the gas above the solution5
k = Henry's law constant for the given solute/solvent combination
C = Concentration of the gas dissolved
Following entry into the upper GI tract, boron trichloride would be largely hydrolyzed.
Oral Toxicity Related to pH
The pH of the upper GI tract is about 6 and would provide considerable buffering of an
ingested HC1 solution. Animal studies have shown that an ingested pH in the range of
approximately 2.8 to 3.5 is not likely to induce adverse effects (Clausing and Gottshalk, 1989;
Upton and L'Estrange, 1977). Humans routinely and without incident consume a variety of
carbonated soft drinks, energy drinks, and juices, which are acidic, with pHs as low as 2.5.
Approximate beverage pHs for sample beverages include the following (Ehlen et al., 2008):
• Orange juice = 3.5
• Coca Cola® = 2.7
• Diet Coke® = 2.9
• Gatorade® = 2.8
• Red Bull® = 2.8
3pH = -log[H+], Hydrogen chloride is a strong acid and fully dissociates in water, therefore, H+= [HC1].
pH = -log(12.338) = —1.1.
4Molar ratio given by reaction equation 3:1, HC1:BC13.
12.338 molHCl x 1 mol BCW3 mol HC1 x 117.17 gBCl3 = 481gBCl3.
5The partial pressure of a gas is defined as the pressure the gas would exert if it were alone in a container (Zumdahl
and Zumdahl, 2010).
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Most wines have a pH between 2.9 and 3.9 (Petersen, 2010).
Additional Oral Toxicity Data for Hydrogen Chloride
Oral Exposure in Humans
In patients who survived following ingestion of highly concentrated solutions of HC1
(exact concentration generally unknown), delayed gastric scarring and gastric outlet obstruction
or stricture have been common. Surgical intervention and resection usually were necessary;
Tucker and Gerrish (1960) reported that the major target organ of orally-ingested strong acids
was the stomach, although up to 20% of cases also included the esophagus. When acids come
into contact with the columnar epithelium cells of the stomach, active muscular spasms are
initiated, and the acid is retained there long enough to cause burns, scarring, and other severe
corrosive damage. Accidental HC1 ingestion by two children produced marked strictures of the
stomach, which became worse over time and necessitated surgical removal and resection
(Tucker and Gerrish, 1960).
Oral Exposure in Animals
Few repeat-dose oral studies on HC1 are available. The majority of these studies were
conducted during and prior to the 1970s and did not conform to GLP or other national or
international standards. Most reports lacked basic information such as number or strain of
animals, treatment protocol and other study details, and statistical analyses, and were further
limited by incomplete reporting of results, particularly pathology and histopathology. Many of
the data summaries were found only in secondary documents, and original papers or reports were
either unavailable or published in foreign language journals, with or without English abstracts.
Upton and L'Estrange (1977) examined the effects of dietary supplementation with
hydrochloric acid on food intake and metabolism of the rat. Three experiments were conducted
to observe the relationship between amount of acid added to the diet and dietary pH on a variety
of blood and bone parameters in young and adult Wistar rats. When compared on the basis of
amount of acid added to the diet and dietary pH, Upton and L'Estrange (1977) reported tolerance
of the young and adult rats for the dietary HC1 to be similar. They further concluded that the
observed toxicity was due not to the strength of the acid but to the total amount added per
kilogram of diet. These studies were performed to examine the physiological effects of mineral
acid loading and are of interest because they address the buffering capacity of the diet relative to
the acid load. For this review, the estimated daily dietary equivalents for all experiments were
calculated using appropriate standard factors for body weight and food intake (U.S. EPA, 1988).
Upton and L'Estrange (1977) did not conduct pathology or histopathology of the GI tract
in any of the experiments. However, these data demonstrated that dietary pHs of 3.09 to 3.5 in
weanling rats and of 2.8 in adult rats had no effects on measured parameters, other than reduced
plasma CO2 or pH. Corresponding daily doses were 3.08 to 3.3 mg/kg-day for weanlings and
2.1 mg/kg-day for adults.
Clausing and Gottschalk (1989) conducted a 21-week experiment with male Wistar rats
to examine a number of variables, including the effects of acidification of drinking water by
hydrochloric acid. Effects of untreated tap water were compared with water acidified to either
pH 3 or pH 2. Study design and the range of measured endpoints were not summarized in the
abstract, and it does not appear that pathology or histopathology of the GI tract was assessed.
The authors reported that acidification resulted in statistically significantly reduced proteinuria
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and decreased urine volume after ingesting water with a pH of 2 and concluded that acidification
of drinking water with hydrochloric acid in rodent studies should not be lower than pH 3. It is
not known from the abstract whether the study followed GLP guidelines or if other effects were
reported.
Acute Oral Toxicity
OECD (2002) reported acute oral LD50 values for HC1 among female rats of
238-277 mg/kg from one 1966 German study by Hoechst (1966); however, neither clinical nor
pathological observations were reported. An unpublished acute oral rat study by Monsanto
(1976) gave only qualitative descriptions of GI effects without reporting the HC1 concentration
solutions that produced these outcomes. Effects included ulceration of stomach, acute
inflammation of intestine, discoloration of the liver, and hyperemia of the lung (Monsanto,
1976). An LD50 for rabbits of 900 mg/kg was reported for HC1 in a 1923 Monsanto study, which
did not report experimental details and, thus, was given a low reliability rating by OECD (2002).
The utility of this information for hazard characterization is not clear.
Peptic ulcers and esophagitis have been observed in experimental animals following
acute oral treatment. Esophagitis was also observed in cats treated with hydrochloric acid
(pH 1-1.3) for 1 hour (HSDB, 2011c).
Short-Term Oral Exposures
Matzner and Windwer (1937; as cited in JECFA, 1967) fed groups of 10-60 rats (strain
not specified) basal diets and drinking water containing either 0.3% (3000 mg/L) hydrochloric
acid; 0.3% (3000 mg/L) acid plus 20% (200,000 mg/L) pepsin; or 20% (200,000 mg/L)
inactivated pepsin plus 0.1% (1000 mg/L) acid for 16 days. For this review, the estimated daily
intakes of hydrochloric acid, using standard factors for body weight and food intake for adult rats
of unknown strain (U.S. EPA, 1988) are calculated as 435 mg/kg-day for the 0.3% group and
145 mg/kg-day for the 0.1% group. One set of rats in each dose group was fasted for 48 hours
before and allowed access to food and fluid on the third day, and this cycle was repeated five
times. All groups receiving hydrochloric acid in their drinking water developed peptic ulcer-like
lesions if subjected to fasting, but no lesions were seen in any of the nonfasting groups.
Histologically, Matzner and Windwer (1937; as cited in JECFA, 1967) reported focal gastric
submucosal edema with extension to the epithelium and muscle layer with inflammatory cellular
infiltration and ulceration. This study report was not located in the open literature and, because
of its age, is unlikely to have followed GLP standards. However, the gastric pathology and
histology described in affected rats are similar to those described in human case reports in which
concentrated solutions of hydrogen chloride are ingested either accidentally or intentionally (e.g.,
Tucker and Garrish, 1960; OECD, 2002).
In case reports, the pH and concentration are not generally reported. In Tucker and
Garrish (1960), hydrogen chloride is described as a strong acid. Two case reports of children
consuming what appears to be commercial-grade hydrogen chloride preparations are described;
one child is reported as having consumed 2 ounces, whereas the quantity ingested by the other
child is not given (Tucker and Garrish, 1960).
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DERIVATION OF PROVISIONAL VALUES
Table 4 A presents a summary of the reference values, while Table 4B shows that no
cancer values are derived in this assessment for boron trichloride. The subchronic and chronic
p-RfDs for boron trichloride are based on the IRIS RfD for boron and compounds
(U.S. EPA, 2004), and the subchronic and chronic p-RfCs for boron trichloride are based
on the IRIS RfC for hydrogen chloride (U.S. EPA, 1995).
Table 4A. Summary of Noncancer Reference Values for
Boron Trichloride and Related IRIS Values
Toxicity
Type
(units)
Species/
Sex
Critical Effect3
p-Reference
Value
POD
Method3
POD3
UFC3
Principal Studies3
bcl3
Subchronic
p-RfD
(mg/kg-d)
Rat/M,F
Decreased fetal
body weights
2
BMDLo5
10.3 Boron
66
Price et al., 1996a;
Heindel et al., 1992
bcl3
Chronic
p-RfD
(mg/kg-d)
Rat/M,F
Decreased fetal
body weights
2
BMDLo5
10.3 Boron
66
Price et al., 1996a;
Heindel et al., 1992
IRIS Boron
RfD
(mg/kg-d)
Rat/M,F
Decreased fetal
body weights
2 x 10"1
bmdl05
10.3 Boron
66
Price et al., 1996a;
Heindel et al., 1992
bcl3
Subchronic
p-RfC
(mg/m3)
Rat/M,F
Hyperplasia of
nasal mucosa,
trachea, and
larynx
2 x 10"2
LO A EI—¦ 111 / ¦
6.1 HC1,
chronic
300
Albert etal., 1982;
Sellakumaretal., 1994
bcl3
Chronic
p-RfC
(mg/m3)
Rat/M,F
Hyperplasia of
nasal mucosa,
trachea, and
larynx
2 x 10"2
LO A EI—¦ 111 / ¦
6.1 HC1,
chronic
300
Albert etal., 1982;
Sellakumaretal., 1994
IRIS HCL
RfC (mg/m3)
Rat/M,F
Hyperplasia of
nasal mucosa,
trachea, and
larynx
2 x 10"2
LOAELhec
6.1 HC1,
chronic
300
Albert etal., 1982;
Sellakumaretal., 1994
aCrtical effects, POD Methods, PODs, UFcs, and Principal Studies are those used by IRIS to derive the RfD for
Boron and Compounds (U.S. EPA, 2004) or RfC for HC1 (U.S. EPA, 1995).
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Table 4B. Summary of Cancer Values for Boron Trichloride
Toxicity Value
Reference Value
Tumor Type or
Precursor Effect
Species/Sex
Principal Study
p-OSF
N/A
p-IUR
N/A
N/A = not available
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfDs FOR BORON
TRICHLORIDE
The subchronic and chronic p-RfDs for boron trichloride are based on the IRIS RfD
for boron and compounds, with stoichiometric conversions that account for the chlorine in
the BCI3 molecule. No human or animal oral toxicity studies for oral exposure to boron
trichloride are available. Table 2 summarizes potentially relevant data for boron and other boron
compounds. The IRIS toxicological review (U.S. EPA, 2004) has derived a RfD of
0.2 mg/kg-day for boron and compounds, based on decreased fetal weights in rats following
maternal dietary gestational exposure to boric acid (Price et al., 1996a; Heindel et al., 1992,
1994). (See Tables B. 1-B.5). The data from these studies were combined for benchmark dose
modeling by EPA (2004).
The RfD (U.S. EPA, 2004) for boron and compounds is based on a BMDL05 of
59 mg-Boric acid/kg-day (10.3 mg-B/kg-day) calculated by Allen et al. (1996) from the
combined data of Price et al. (1996a) and Heindel et al. (1992, 1994) for decreased fetal body
weights in rats, and a composite uncertainty factor of 66. Because this POD has been used in
IRIS and because available data indicate that the boric acid hydrolysis product is the likely
source for potential toxicity from oral exposure to BCI3, the IRIS RfD for boron and compounds
is used in this document to derive the chronic and subchronic p-RfDs for boron trichloride.
To account for molecular weight, the RfD of 0.2 mg/kg-day for boron is adjusted using
the boron trichloride-to-boron molecular weight ratio of 117.17 g BCVmol/lO.Sl g-B/mol =
10.84. Therefore, a chronic p-RfD for boron trichloride, based on the RfD for boron and
compounds is derived as follows:
Chronic p-RfDBoron Trichloride — IRIS RfDboron x (MWboron trichloride ~ MWboron) ~ UFd
= 0.2 mg-B/kg-day x (117.17 g BC^/mol ^
10.81 g-B/mol)
= 0.2 mg-B/kg-day x 10.84
= 2 mg/kg-day
In the absence of subchronic data, the IRIS RfD for boron, is also adopted as the
subchronic p-RfD for boron trichloride after stoichiometric conversion.
As the p-RfDs for boron trichloride are derived explicitly from the IRIS RfD for boron,
the uncertainties associated with the point of departure (POD) for boron, as well as confidence in
the principal study and database for boron, all contribute to uncertainty for boron trichloride.
Confidence in the boron study, database, and RfD are all high. According to EPA (2004):
45 Boron Trichloride
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Confidence in the principal developmental studies is high; they are well-designed
studies that examined relevant developmental endpoints using a large number of
animals. Similar developmental effects were noted in rats, mice, and rabbits.
Confidence in the data base is high due to the existence of several subchronic and
chronic studies, as well as adequate reproductive and developmental toxicology
data. High confidence in the RfD follows.
For boron trichloride, there is additional potential uncertainty due to the contribution to
oral toxicity from the second hydrolysis breakdown product, HC1. However, what is known
about the toxicokinetics and potential for systemic oral toxicity of HC1 does not suggest that HC1
is likely to have an additive or synergistic effect on developmental toxicity, the critical end point
for derivation of the boron RfD. In addition, point-of-entry effects are unlikely from contact
with the HC1 hydrolyzed from a 2-liter solution of the adult daily dose of boron trichloride at the
p-RfD. Therefore, the overall confidence in the chronic and subchronic p-RfDs for boron
trichloride, based on the boron RfD, is high (see Table 5).
Table 5. Confidence Descriptor for Subchronic and Chronic p-RfDs for Boron Trichloride
Confidence Categories
Designation"
Discussion
Confidence in Study
H
Confidence in the principal developmental studies for boron is high:
they are well-designed studies that examined developmental end
points of boron using a large number of animals. Similar
developmental effects were noted in rats, mice, and rabbits.
Confidence in Database
H
Confidence in the database for boron is high due to the existence of
several subchronic and chronic studies, as well as adequate
reproductive and developmental toxicology data for boron. It is
unlikely that hydrogen chloride hydrolyzed from boron trichloride
has an additive or synergistic effect on developmental toxicity.
Confidence in Chronic
p-RfDb
H
The overall confidence in the p-RfD is high.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfCs FOR BORON
TRICHLORIDE
The subchronic and chronic p-RfCs for boron trichloride are based on the IRIS RfC
for hydrogen chloride (U.S. EPA, 1995). With the exception of the acute animal studies by
Stokinger and Spiegl (1953) and Vernot (1977), no human or animal inhalation toxicity studies
of boron trichloride are available.
Table 2 summarizes potentially relevant inhalation data for boron compounds.
Epidemiologic studies in the workplace have reported respiratory and nasal tract irritation from
inhalation exposure to high concentrations of boron compounds. Epidemiologic studies do not
provide evidence for boron-induced human reproductive toxicity. The only available repeated
exposure inhalation toxicity animal study for boron compounds is Wilding et al. (1959), in which
albino rats and dogs were exposed to boron oxide aerosols at various concentrations for various
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"3
exposure durations. Minimal eye irritant effects at the highest concentration tested, 470 mg/m ,
were attributed to direct ocular contact with billowing dust particles. No histopathology was
observed in the testes, although only limited microscopic examinations were conducted.
Table 3 summarizes potentially relevant inhalation data for hydrogen chloride, the other
hydrolysis product of boron trichloride. It is well established that boron trichloride immediately
hydrolyzes to boric acid and HC1 when exposed to water or water vapor (U.S. EPA, 2000;
ATSDR, 2007). Human and animal data have shown that the adverse effects of inhalation
exposure to HC1 occur primarily in the upper respiratory tract, and to a lesser extent, further
along the portal of entry for inhalation (WHO, 1982). Localized irritant and corrosive effects are
thought to result from pH change (local deposition of H+) rather than hydrogen chloride, per se,
because dissociation into hydrogen and chloride ions is very rapid (HSDB, 201 lc).
IRIS (U.S. EPA, 1995) derived a chronic RfC of 0.02 mg/m3 for HC1, based on a chronic
"3
rat LOAEL of 15 mg/m (Albert et al., 1982; Sellakumar et al., 1985) for hyperplasia of the nasal
mucosa, trachea, and larynx. IRIS (U.S. EPA, 1995) calculated a LOAELadj of 2.5 mg/m3, and
a LOAELnEcfora gas:respiratory effect in the extrathoracic and tracheobronchial regions of
6.1 mg/m3, and applied a composite uncertainty factor of 300.
"3
To account for molecular weight, the HC1 RfC of 0.02 mg/m is adjusted using the boron
trichloride-to-HCl molecular weight ratio of [117.17 g BCl3/mol]/[36.46 g HCl/mol] and the
3:1 molecular hydrolysis ratio. Because each molecule of boron trichloride hydrolyzes to three
molecules of hydrogen chloride, the chronic p-RfC for boron trichloride is calculated from the
IRIS RfC for HC1, as follows:
Chronic p-RfC = IRIS RfCHci x (MWboron trichloride - [3 x MWrci])
= 0.02 mgHCl/m3 x (117.17 g-BCl3/mol -
[3 x 36.46 g HCl/mol])
= 0.02 mg HCl/m3 x 1.07 BC13/HC1
_2 3
= 2 x 10 mg/m boron trichloride
In the absence of data for effects of sub chronic-duration inhalation exposure to HC1, the
subchronic p-RfC for boron trichloride also is derived from the chronic data and is the same as
the chronic p-RfC of 2 x 10~2 mg/m3.
The uncertainties associated with the POD for HC1, as well as confidence in the principal
study, database, and RfC for HC1 all contribute to the uncertainty for boron trichloride.
According to EPA (1995):
The chronic study used only one dose and limited toxicological measurements.
The supporting data consist of two subchronic bioassays; the database does not
provide any additional chronic or reproductive studies. Therefore, low
confidence was recommendedfor the study, database, and the RfC.
Therefore, the overall confidence in the chronic p-RfC for boron trichloride is based on
the HC1 database confidence of low. For boron trichloride, there is additional uncertainty due to
the potential contribution to inhalation toxicity from the other hydrolysis breakdown product,
boric acid. What is known about the toxicokinetics and the potential for portal-of-entry
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inhalation toxicity of boron suggests that boron may also contribute in an additive or synergistic
way to the irritant and corrosive mucosal effects induced by HC1. However, the contributions of
the boric acid hydrolysis product to the portal-of-entry inhalation effects of HC1 are likely to be
small. See Table 6 for the confidence descriptors for the chronic p-RfC for boron trichloride.
Table 6. Confidence Descriptor for Chronic p-RfC for Boron Trichloride
Confidence Categories
Designation"
Discussion
Confidence in Study
L
Confidence in the principal study for HC1 is low because it used only
one dose and had limited toxicological measurements.
Confidence in Database
L
Confidence in the database is low due to only two subchronic studies
on HC1. Reproductive and developmental studies following
inhalation of HC1 are limited to two poorly reported animal studies.
Contributions of boric acid to the portal-of-entry inhalation effects of
HC1 are likely to be small.
Confidence in Chronic
p-RfCb
L
The overall confidence in the p-RfC is low.
aL = low, M = medium, H = high.
bThe overall confidence cannot be greater than lowest entry in table.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR BORON TRICHLORIDE
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR (WOE)
No human or animal data are available to inform a carcinogenicity assessment of boron
trichloride. The database for boron trichloride does not include human epidemiologic studies or
subchronic or chronic animal bioassays. However, boron trichloride is rapidly hydrolyzed to
boric acid and HC1; the carcinogenic potential of boron trichloride is likely to be similar to that
of either of these two substances. IRIS (U.S. EPA, 2004) has described the carcinogenicity data
of boron and boron compounds as being "Inadequate for an Assessment of the Human
Carcinogenic Potential," using guidelines equivalent to those in EPA's Guidelines for
Carcinogen Risk Assessment (U.S. EPA, 2005), and no newer carcinogenicity data are available.
No human or animal data are available on the carcinogenicity of HC1. The EPA has not
classified HC1 for carcinogenicity. IARC has classified HC1 in Group 3, Inadequate Evidence
for Carcinogenicity in Humans and in Experimental Animals (IARC, 1992). Thus, the
provisional carcinogenicity descriptor for exposure to boron trichloride is "Inadequate
Information to Assess Carcinogenic Potential" (see Table 7).
48
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11-6-2012
Table 7. Cancer WOE Descriptor for Boron Trichloride
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to Humans "
N/A
N/A
No human cancer studies are available
for boron trichloride or for its
hydrolysis products, boric acid and
hydrogen chloride.
"Likely to Be Carcinogenic
to Humans "
N/A
N/A
No strong animal cancer data are
available, and no weaker human and
animal data are available for boron
trichloride or for its hydrolysis
products, boric acid and hydrogen
chloride.
"Suggestive Evidence of
Carcinogenic Potential"
N/A
N/A
No carcinogenicity data are available
for boron trichloride or its hydrolysis
products.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
U.S. EPA (2004) has used this WOE
descriptor for the carcinogenicity
data on boron and boron
compounds; IARC (1992) used a
similar WOE descriptor for the
carcinogenic potential of hydrogen
chloride.
"Not Likely to Be
Carcinogenic to Humans "
N/A
N/A
No data are available that suggest
boron trichloride or its hydrolysis
products do not have carcinogenic
potential.
PROVISIONAL ORAL SLOPE FACTOR (p-OSF) DERIVATION
No p-OSF can be derived due to a lack of carcinogenicity data.
PROVISIONAL INHALATION UNIT RISK (p-IUR) DERIVATION
No p-IUR can be derived due to a lack of carcinogenicity data.
49
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11-6-2012
APPENDIX A. PROVISIONAL SCREENING VALUES
Appendix A is not applicable.
50
Boron Trichloride
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11-6-2012
APPENDIX B. RELEVANT DATA TABLES
Table B.l. Maternal Toxicity in CD-I Rats Exposed to
Dietary Boric Acid on GDs 6-15 and GDs 0-20a
Doses
Boric Acid as mg-B/kg-day,
GDs 0-20
Boric Acid as mg-B/kg-day,
GDs 6-15
0
13.6
28.5
57.7
0
94.2
No. dams treated
(pregnant at
sacrifice)
29 (28)
29 (28)
29 (26)
29 (26)
14(14)
14(14)
Maternal weight gain (g)b
Gestation
(GDs 0-20)
160.6 ±0.8**
157.5 ±3.0
156.6 ±3.6
143.6 ±3.9*
157.8 ±6.1
102.5 ±5.3*
Treatment
(GDs 6-15)
54.0 ±2.9
22.9 ±3.1*
Corrected
weight gain0
71.2 ±2.9**
72.1 ±2.1
74.6 ±3.1
81.4 ±2.5*
66.6 ±4.8
66.2 ±6.2
Gravid uterine
weight
88.4 ±2.6**
85.3 ±2.1
82.0 ±2.0
62.1 ±3.1*
88.9 ±3.6
36.2 ±4.4*
Maternal body
weight (g)b on
GD 20
409 ±5
405 ±4
404 ±4
393 ±5
417 ±6
364 ±5*
Maternal liver weightb
Absolute (g)
17.15 ±0.25
17.59 ±0.27
17.86 ±0.30
17.54 ±0.35
17.27 ±0.40
17.12 ±0.59
Relative (%
body weight)
4.20 ±0.05**
4.35 ±0.06
4.42 ±0.07*
4.46 ±0.07*
4.15 ±0.07
4.70 ±0.13*
Maternal right kidney weightb
Absolute (g)b
1.23 ±0.02**
1.25 ±0.02
1.35 ±0.06
1.32 ±0.03
1.21 ±0.03
1.37 ±0.04*
Relative (%
body weight)
0.302 ±0.006**
0.309 ±0.006
0.335 ±0.016*
0.338 ±0.007*
0.289 ±0.009
0.376 ±0.009*
aNTP (1990a); Heindel (1992).
includes all dams pregnant at sacrifice; mean ± standard error of the mean (SEM).
Gestational weight gain minus gravid uterine weight.
p < 0.05 by pair-wise comparison to the control group.
p < 0.05, test for linear trend.
51
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11-6-2012
Table B.2. Developmental Toxicity in CD Rats following Maternal Exposure to
Dietary Boric Acid on GDs 0-20 or 6-15a
Doses
Boric Acid as mg-B/kg-day, GDs 0-20
Boric Acid as mg-B/kg-day,
GDs 6-15
0
13.6
28.5
57.7
0
94.2
All pregnant damsb
28
28
26
26
14
14
Number of implantation
sites/litter0
15.9 ±0.3
16.4 ±0.4
16.2 ±0.3
16.1 ±0.4
16.0 ±0.5
15.8 ±0.5
Resorptions/litter0
3.5 ± 1.0
5.9 ± 1.2
3.4 ±0.8
8.6 ±3.9
4.4 ± 1.9
36.2 ±8.7*
% Litters with one or more
resorptions
39
61
46
46
36
100
% Late fetal deaths/litter°'d
0.0 ±0.0
0.3 ±0.3
0.0 ±0.0
0.0 ±0.0
0.0 ±0.0
2.4 ± 1.6*
% Litters with one or more late
fetal deaths
0
4
0
0
0
21
% Adversely affected
implants/litter°'d
5.46 ±
1.35**
8.66 ± 1.90
11.17 ± 2.16*
53.58 ±5.63*
7.06 ±2.41
77.71 ±6.77*
% Litters with one or more
adversely affected implants'1
50**
75*
85*
100*
50
100*
Dams with live litters6
28
28
26
25
14
14
Number of live fetuses/litter0
15.4 ±0.4
15.4 ±0.5
15.7 ±0.4
15.4 ±0.5
15.4 ±0.7
9.7 ± 1.6*
Average fetal body weight (g)/litter°
Male fetuses
3.779 ±
0.061**
3.554 ±
0.051*
3.280 ±0.053*
2.405 ±
0.059*
3.820 ±0.068
1.778 ±
0.153*
Female fetuses
3.609 ±
0.059**
3.364 ±
0.046*
3.130 ±0.050*
2.266 ±
0.046*
3.646 ±0.064
1.814 ±
0.060*
% Malformed fetuses/litter0'f
2.1 ±0.8**
2.6 ± 1.4
7.8 ±2.4*
50.2 ±5.4*
2.8 ± 1.4
72.6 ±8.1*
% Litters with one or more malformed fetuses
All malformations
21**
21
50*
100*
29
100*
Gross malformations
4
0
4
4
7
71*
Visceral malformations
7
4
0
36*
14
86*
Skeletal malformations
14**
18
46*
100*
14
100*
% Fetuses/litter with variations0^
21.2 ±3.2
7.7 ± 1.4*
8.8 ± 1.9*
27.2 ±4.4
24.2 ±4.9
59.5 ±6.8*
% Litters with variations
96
71*
58*
92
93
100
aNTP (1990a); Heindel (1992).
includes all dams pregnant at sacrifice; litter size = number of implantation sites per dam.
°Reported as mean ± standard error of the mean (SEM).
dAdversely affected implants = nonlive implants plus malformed fetuses.
"Includes only dams with live fetuses; litter size = number of live fetuses per dam.
fOnly live fetuses were examined for malformations and variations.
p < 0.05 by pair-wise comparison to the control group.
"p < 0.05, test for linear trend or test for linear trend on proportions.
52
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Table B.3. Maternal Toxicity in CD Rats Exposed to Dietary Boric Acid on GDs 0-20 in Phase I
(Teratology) Study and on PNDs 0-20 in Phase II (Postnatal) Studies"
Dosesb
Boric Acid as mg-B/kg-day
Phase I
0
3.3
6.3
9.3
13.3
25.0
Phase II
0
3.2
6.5
9.7
12.9
25.3
Dams treated (per study phase)
28-34
28-34
28-34
28-34
28-34
29-34
Dams removed (Total)0
1
0
0
0
1
1
Dams pregnant (%)
Phase I (Teratology)
27 (96)
29 (91)
27 (96)
29 (100)
30 (97)
27 (90)
Phase II (Postnatal)
29 (94)
29 (96)
28 (88)
27 (94)
25 (89)
28 (97)
Selected Maternal Weight Changes (g)d e
Phase I (Gestation; GDs 0-20)f
150 ±5
157 ±4
153 ±4
146 ±5
150 ±4
140 ±5
Phase I (Gravid uterine weight)
88 ±4
90±3§
91 ± 3
85 ± 4
86 ±4
79 ±3
Selected Maternal Organ Weights4
e
Relative right kidney weight (g) (% body weight)8
Phase I (GD 20)
0.29 ±0.01
0.31±0.01§
0.29 ±0.01
0.30 ±0.01
0.30 ±0.01
0.32 ±0.01*
Phase II (PND 21)
0.46 ±0.01
0.46 ±0.01
0.47 ±0.01
0.49 ±0.02
0.45 ±0.01
0.48 ±0.01
aNTP, (1994); Price et al., (1996a).
''Phase I, teratologic evaluation; Phase II, postnatal evaluation.
°Each dam was removed for one of the following reasons: PND 0 not determined (Phase II), early delivery of a litter (Phase I),
or sipper tube malfunction (Phase I). No dam was euthanized or sacrificed in extremis prior to study termination.
dMean ± standard error of the mean (SEM).
eOnly maternal body and organ (absolute and relative liver and kidney) weight changes that were statistically significant by
pair-wise comparison to concurrent vehicle control (p < 0.05) or those which showed a statistically significant linear trend
(p < 0.05) are reported in this table. No maternal effects were observed for any parameters during Phase II at any dose.
fWeight gain during gestation minus gravid uterine weight.
8Kidney weight ^ body weight
'p < 0.05; test for linear trend.
"p < 0.05; Dunnett's test or Williams' test; pair-wise comparison to the concurrent vehicle control group.
53
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11-6-2012
Table B.4. Selected Developmental Toxicity Parameters in CD Rats following
Maternal Exposure to Boric Acid in Feed on GDs 0-20 for Phase I (Teratology Study)
and on PNDs 0-21 for Phase II (Postnatal Study)"
Dosesb
Boric Acid as mg-B/kg-day
Phase I
0
3.3
6.3
9.3
13.3
25.0
Phase II
0
3.2
6.5
9.7
12.9
25.3
Dams (%) delivering litters°'d
GD < 22
26(90)
22 (81)§
22(79)
25(86)
16(64)
19(68)
GD 23
3(10)
5(10)
6(21)
4(14)
9(36)
9(32)
Resorptions/litter on GD 20e
9.5 ±3.6
3.3 ± 10
2.6 ±0.8
3.9 ±0.8
6.7 ±3.4
4.8 ±1.1
% Litters with one or more
resorptions on GD 20
70
34*
53
32*
37*
48
Postnatal mortality/litter6
PNDs 0-4§
0.55 ±0.31
1.17±0.49§
1.80 ± 1.02
1.35 ±0.51
1.83 ±0.71
2.80 ±0.76
PNDs 4-21
0.76 ±0.45
1.14 ±0.47
0.84 ±0.49
0.38 ±0.27
1.00 ±0.48
0.45 ±0.31
PNDs 0-20§
0.93 ±0.39
2.28±0.74§
2.64 ± 1.08
2.08 ± 0.72
2.83 ± 0.77
3.25 ±0.76
Live litters
GD 20
26
29
27
29
29
27
PND21
29
27
27
29
25
27
Average fetal or pup weights in grams per-litter°
Male fetuses or pups
GD 20
3.71 ±0.05
3.64±0.05§
3.62 ±0.05
3.60 ±0.07
3.48 ±0.05*
3.23 ±0.06*
PND0
6.61 ±0.10
6.79 ±0.13
6.68 ±0.13
6.53 ± 0.11
6.49 ±0.13
6.59 ± 0.11
PND21
43.25 ± 1.71
47.82 ± 1.91
44.29 ± 1.70
41.99±1.39
43.76 ± 1.16
42.56 ± 1.19
Female fetuses or pupse
GD 20
3.52 ±0.05
3.47±0.04§
3.45 ±0.06
3.38 ±0.06
3.27 ±0.05*
3.04 ±0.05*
PND0
6.21 ± 0.11
6.34 ±0.09
6.26 ±0.15
6.18 ± 0.10
6.29 ±0.16
6.20 ±0.10
PND21
41.22 ± 1.61
44.88 ± 1.57
42.20 ± 1.77
40.27 ± 1.21
43.94 ± 1.84
40.45 ± 1.09
Offspring with skeletal malformations and variations
% Offspring/litter with skeletal malformations6
GD20§
2.0 ±0.7
0.9±0.6§
1.6 ±0.6
2.5 ±0.7
3.5 ± 1.2
4.3 ± 1.5
PND21§
0.0 ±0.0
2.0±0.8*§
0.6 ±0.6
0.2 ±0.2
1.3 ±0.8
3.9 ± 1.8*
% Litters with skeletal malformationsf
GD 20
27
10
22
34
31
30
PND21
0
22*
4
3
12
22*
% Offspring/litter with skeletal variations'^
GD 20
10.0 ±2.0
3.4 ± 1.0
6.5 ± 1.8
5.3 ± 1.4
7.4 ±2.1
12.1 ±3.0
PND21
6.8 ± 1.9
9.6 ±2.4
4.9 ± 1.3
4.9 ± 1.5
4.4 ± 1.6
4.8 ± 1.9
54
Boron Trichloride
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11-6-2012
Table B.4. Selected Developmental Toxicity Parameters in CD Rats following
Maternal Exposure to Boric Acid in Feed on GDs 0-20 for Phase I (Teratology Study)
and on PNDs 0-21 for Phase II (Postnatal Study)"
Dosesb
Boric Acid as mg-B/kg-day
Phase I
0
3.3
6.3
9.3
13.3
25.0
Phase II
0
3.2
6.5
9.7
12.9
25.3
% Litters with skeletal variationsf
GD 20
60
34
52
41
55
63
PND21
41
52
44
34
36
33
% Offspring/litter with short rib XIIIef
GD 20
0.0 ±0.0
0.0±0.0§
0.2 ±0.2
0.6 ±0.5
1.4 ±0.7*
3.2 ± 1.2*
PND21
0.0 ±0.0
1.5±0.6§
0.6 ±0.6
0.2 ±0.2
0.6 ±0.5
3.9 ± 1.8*
% Litters with short rib XIIIf
GD 20
0
0
4
7
14
22*
PND21
0
19
4
3
8
22*
% Offspring/litter with wavy ribe'f
GD 20
0.0 ±0.0
0.3 ±0.3§
0.0 ±0.0
0.8 ±0.7
2.1 ±0.9*
9.9 ±3.0*
PND21
0.0 ±0.0
0.0 ±0.0
0.3 ±0.3
0.2 ±0.2
0.0 ±0.0
0.0 ±0.0
% Litters with wavy ribf
GD 20
0
3§
0
7
21*
48*
PND21
0
0
4
3
0
0
aNTP (1994); Price et al. (1996a).
bPhase I, teratologic evaluation; Phase II, postnatal evaluation,
includes all dams in Phase II that delivered a litter.
dThe overall test for differences among groups for GDs 21, 22, and 23 was not statistically significant (p = 0.315). When the
proportions were expressed as
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FINAL
11-6-2012
Table B.5. Selected Developmental Toxicity Parameters in CD Rats following Maternal
Exposure to Boric Acid in Feed on GDs 0 to 20 for Phase I (Teratology Study) and on PNDs 0-21
for Phase II (Postnatal Study)"
Dosesb
Boric Acid as mg-B/kg-day
Phase I
0
3.3
6.3
9.3
13.3
25
Phase II
0
3.2
6.5
9.7
12.9
25.3
Dams (%) delivering litters°'d
GD < 22
26(90)
22 (81)§
22(79)
25(86)
16(64)
19(68)
GD 23
3(10)
5(10)
6(21)
4(14)
9(36)
9(32)
Resorptions/litter on GD 20e
9.5 ±3.6
3.3 ± 10
2.6 ±0.8
3.9 ±0.8
6.7 ±3.4
4.8 ± 1.1
% Litters with one or more
70
34*
53
32*
37*
48
resorptions on GD 20
Postnatal mortality/litter6
PNDs 0-4
0.55 ±0.31
1.17±0.49§
1.80 ± 1.02
1.35 ±0.51
1.83 ±0.71
2.80 ±0.76
PNDs 4-21
0.76 ±0.45
1.14 ±0.47
0.84 ±0.49
0.38 ±0.27
1.00 ±0.48
0.45 ±0.31
PNDs 0-21
0.93 ±0.39
2.28±0.74§
2.64 ± 1.08
2.08 ±0.72
2.83 ± 0.77
3.25 ±0.76
Live litters
GD 20
26
29
27
29
29
27
PND21
29
27
27
29
25
27
Average fetal or pup weight (g) on a per-litter°
Male fetuses or pupse
GD 20
3.71 ±0.05
3.64±0.05§
3.62 ±0.05
3.60 ±0.07
3.48 ±0.05*
3.23 ±0.06*
PND0
6.61 ±0.10
6.79 ±0.13
6.68 ±0.13
6.53 ± 0.11
6.49 ±0.13
6.59 ± 0.11
PND21
43.25 ± 1.71
47.82 ± 1.91
44.29 ± 1.70
41.99 ± 1.39
43.76 ± 1.16
42.56 ± 1.19
Female fetuses or pupse
GD 20
3.52 ±0.05
3.47±0.04§
3.45 ±0.06
3.38 ±0.06
3.27 ±0.05*
3.04 ±0.05*
PND0
6.21 ± 0.11
6.34 ±0.09
6.26 ±0.15
6.18 ± 0.10
6.29 ±0.16
6.20 ±0.10
PND21
41.22 ± 1.61
44.88 ± 1.57
42.20 ± 1.77
40.27 ± 1.21
43.94 ± 1.84
40.45 ± 1.09
Summary of offspring/litter with skeletal malformations and variations
% Offspring/litter with skeletal malformations6
GD 20
2.0 ±0.7
0.9±0.6§
1.6 ±0.6
2.5 ±0.7
3.5 ± 1.2
4.3 ± 1.5
PND21
0.0 ±0.0
2.0±0.8*§
0.6 ±0.6
0.2 ±0.2
1.3 ±0.8
3.9 ± 1.8*
% Litters with skeletal malformations
GD 20
27
10
22
34
31
30
PND21
0
22*
4
3
12
22*
% Offspring/litter with short rib XIIe'f
56
Boron Trichloride
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FINAL
11-6-2012
Table B.5. Selected Developmental Toxicity Parameters in CD Rats following Maternal
Exposure to Boric Acid in Feed on GDs 0 to 20 for Phase I (Teratology Study) and on PNDs 0-21
for Phase II (Postnatal Study)"
Dosesb
Boric Acid as mg-B/kg-day
Phase I
0
3.3
6.3
9.3
13.3
25
Phase II
0
3.2
6.5
9.7
12.9
25.3
GD 20
0.0 ±0.0
0.0±0.0§
0.2 ±0.2
0.6 ±0.5
1.4 ±0.7*
3.2 ± 1.2*
PND21
0.0 ±0.0
1.5±0.6§
0.6 ±0.6
0.2 ±0.2
0.6 ±0.5
3.9 ± 1.8*
% Litters with short rib XIIIf
GD 20
0
0§
4
7
14
22*
PND21
0
19
4
3
8
22*
% Litters with skeletal variations
GD 20
60
34
52
41
55
63
PND21
41
52
44
34
36
33
% Offspring/litter with skeletal variations'^
GD 20
10.0 ±2.0
3.4 ± 1.0
6.5 ± 1.8
5.3 ± 1.4
7.4 ±2.1
12.1 ±3.0
PND21
6.8 ± 1.9
9.6 ±2.4
4.9 ± 1.3
4.9 ± 1.5
4.4 ± 1.6
4.8 ± 1.9
% Litters with wavy ribf
GD 20
0
3§
0
7
21*
48*
PND21
0
0
4
3
0
0
% Offspring/litter with wavy ribe f
GD 20
0.0 ±0.0
0.3 ±0.3§
0.0 ±0.0
0.8 ±0.7
2.1 ±0.9*
9.9 ±3.0*
PND21
0.0 ±0.0
0.0 ±0.0
0.3 ±0.3
0.2 ±0.2
0.0 ±0.0
0.0 ±0.0
aNTP (1994); Price et al. (1996a).
''Phase I, teratologic evaluation; Phase II, postnatal evaluation.
Includes all dams in Phase II that delivered a litter.
'The overall X2 test for differences among groups for GDs 21, 22, and 23 was not statistically significant (p = 0.315).
When the proportions were expressed as
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FINAL
11-6-2012
Table B.6. Selected Maternal Toxicity Parameters Following Exposure
of CD-I Mice to Boric Acid in Feed on GDs 0-17a
Boric Acid as mg-B/kg-day
Doses
0
43.4
79.0
175.3
No. dams treated (pregnant at sacrifice)
29 (27)
28 (27)
29 (27)
28 (26)
Maternal weight gain (g)b
Gestation/treatment period
21.4±0.8§
21.7 ± 0.5
21.1 ±0.7
16.0 ±1.1*
Corrected weight gainc
4.5 ±0.3
5.6 ±0.3
4.9 ±0.4
4.7 ±0.5
Gravid uterine weight (g)
16.9 ± 0.7§
16.1 ±0.5
16.1 ±0.6
12.1 ±0.6*
Maternal body weight (g) on GD 17
49.3 ± 1.1§
48.3 ±0.8
49.0 ± 1.0
43.1 ± 1.1*
Maternal liver weightb
Absolute (g)
2.36 ± 0.04§
2.36 ±0.04
2.38 ±0.05
2.15 ±0.06*
Relative (% body weight)
4.95 ±0.08
5.02 ±0.07
5.00 ±0.09
5.13 ±0.07
Maternal right kidney weightb
Absolute (g)
0.20 ± 0.01§
0.19 ± 0.01
0.21 ±0.01
0.22 ±0.01
Relative (% body weight)
0.41 ± 0.02§
0.41 ±0.02
0.45 ±0.02
0.54 ±0.04*
Renal histopathology
Renal tubular dilation and/or regenerationd
0/10
2/10
8/10
10/10
aNTP (1990a); Heindel et al. (1992).
bIncludes all dams pregnant at sacrifice, mean ± standard error of the mean (SEM).
Gestational weight gain minus gravid uterine weight.
dNumber affected/number examined.
*p < 0.05 by pairwise comparison to the control group.
'p < 0.05, test for linear trend.
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Table B.7. Selected Developmental Toxicity Parameters following Maternal Exposure
of CD-I Mice to Boric Acid in Feed on GDs 0-17a
Doses
Boric Acid as mg-B/kg-day
0
43.4
79.0
175.3
All littersb
27
27
27
26
Number of implantation sites/litter0
12.4 ±0.6
12.0 ±0.4
12.1 ±0.4
12.1 ±0.5
% Resorptions/litterc
6.1 ± 1.6§
6.2 ± 1.3
4.8 ± 1.4
19.3 ±4.5*
% Litters with one or more resorptions0
44
56
37
73*
% Late fetal deaths/litterc
0.9 ±0.6
2.0 ±0.9
0.6 ±0.4
1.6 ±0.8
% Litters with one or more late fetal deaths
7
19
7
15
% Adversely affected implants/litterc
9.5 ± 1.8§
12.4 ±2.3
6.9 ± 1.5
27.4 ±4.9*
Live littersd
Number of live fetuses/litterc
11.5 ±0.6
10.9 ±0.3
11.4 ±0.4
10.0 ±0.7
Average fetal body weight (g)/litterc
Male fetuses0
1.08 ± 0.02§
1.03 ±0.03
0.96 ±0.02*
0.71 ±0.02*
Female fetuses
1.04 ± 0.02§
0.99 ±0.02
0.92 ±0.02*
0.69 ±0.01*
% Malformed fetuses/litterc
2.7 ± 1.2§
4.5 ± 1.9
1.6 ±0.7
9.1 ±2.4*
% Litters with one or more malformed fetuses
All malformations
22
22
19
44
Gross malformations
7
4
4
16
Visceral malformations
4
7
6
4
Skeletal malformations
11
15
15
28
% Litters with variations
96
66*
70*
80
% Fetuses with variations/litterc
29.1 ±3.5
18.8 ± 4.1*
11.9 ± 2.4*
26.3 ±5.9
aNTP (1990a); Heindel et al. (1992).
bIncludes all dams pregnant at sacrifice; litter size = number of implantation sites per dam.
°Mean ± standard error of the mean (SEM).
includes only dams with live fetuses; litter size = number of live fetuses per dam.
*p < 0.05, group comparisons versus controls
'p < 0.05, test for linear trend.
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Table B.8. Histopathology in the Nasal Mucosa of Rats Exposed to HC1 via Inhalation,
6 Hours/Day, 5 Days/Week, Until Natural Death—Up to 128 Weeksa'b
Hydrogen Chloride
10 ppm (15 mg/m3)c
Controls (Air Only)
Nasal mucosa
No. animals examined
99
99
Epithelial or squamous
hyperplasia
62
51
Squamous metaplasia
9
5
"Sellakumar et al. (1985); U.S. EPA (1995).
incidence of hyperplasia in the laryngeal-tracheal segment was increased to 24% in exposed animals vs. 6% in
controls; however, individual animal data were not available, and incidence data did not distinguish between
animals who had hyperplasia in both the larynx and the trachea and those with hyperplasia in either the larynx or
the trachea (i.e., some animals were double-counted).
Statistical significance not reported for any nonneoplastic effects in this study.
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APPENDIX C. BMD OUTPUTS
Please see Appendix B of the IRIS Toxicological Profile for Boron and Compounds
(U.S. EPA, 2004, pp. 125-130) for details of the BMD analysis.
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