#1., United States
kS^laMJIjk Environmental Protection
^^iniiil mmAgency
EPA/690/R-15/001F
Final
11-12-2015
Provisional Peer-Reviewed Toxicity Values for
Benzaldehyde
(CASRN 100-52-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Dan Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
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
Benzaldehyde
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 5
HUMAN STUDIES 10
Oral Exposures 10
Inhalation Exposures 10
ANIMAL STUDIES 10
Oral Exposures 10
Inhalation Exposures 16
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 18
Genotoxicity Studies 18
Supporting Human Studies 25
Supporting Animal Toxicity Studies 25
Metabolism/Toxicokinetic Studies 26
Mode-of-Action/Mechanistic Studies/Therapeutic action 26
DERIVATION OI PROVISIONAL VALUES 31
DERIVATION OF ORAL REFERENCE DOSES 32
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 32
Derivation of Chronic Provisional RfD (Chronic p-RfD) 35
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 35
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 35
MODE-OF-ACTION (MOA) DISCI SSION 36
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 37
Derivation of Provisional Oral Slope Factor (p-OSF) 37
Derivation of Provisional Inhalation Unit Risk (p-IUR) 38
APPENDIX A. SCREENING PROVISIONAL VALUES 39
APPENDIX B. DATA TABLES 40
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 48
APPENDIX D. REFERENCES 52
in
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere
Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD
Number
QSAR
quantitative structure-activity
CBI
covalent binding index
relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day
known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
y-glutamyl transferase
known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
BENZALDEHYDE (CASRN 100-52-7)
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.eov/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.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
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).
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INTRODUCTION
Benzaldehyde, CASRN 100-52-7, occurs naturally in many plants, including cherry, fig,
and peach fruit and carnation flowers (Ulker et al.. 2013). In some mushrooms, benzaldehyde
serves as a natural antibacterial compound (Anderson, 2006). Of 300 different foods evaluated
for the presence of benzaldehyde, 150 have been found to contain the compound naturally (Feron
et al.. 1991). Levels up to 8.9 ppm are found in some fruits. Cinnamon can contain up to
3,000 ppm. Benzaldehyde is a member of the family of "essential oils" in plants, (vanillin, for
example, is 4-hydroxy-3-methoxy benzaldehyde), which have antimicrobial and antifeedant
properties to discourage parasitism and herbivory. Benzaldehyde is produced by some insects
and acts as a chemical defense mechanism or pheromone (Anderson, 2006).
Benzaldehyde is used as a preservative in food, cosmetics, and personal care products
(Ulker et al, 2013) and as an intermediate in the manufacture of odorants and flavoring
chemicals such as aromatic alcohols (HSDB. 2014). Benzaldehyde is considered to be
"generally recognized as safe" (GRAS) for its intended use as a flavor ingredient (Adams et al..
2005). and the Cosmetic Ingredient Review (C1R) Expert Panel concluded that benzaldehyde is
safe for use in cosmetic products (Anderson. 2006). Benzaldehyde is also a starting material for
various pharmaceuticals, such as ampicillin, and for pesticides, such as dibenzoquat, and is used
as a solvent for resins, oils, cellulose acetates, nitrites, and ethers. Benzoic acid and some
photographic chemicals are produced using benzaldehyde (HSDB. 2014). Benzaldehyde has
been used as a pesticide and bee repellant, but is no longer listed as an active ingredient in any
registered pesticide products (HSDB. 2014).
Benzaldehyde is an oily liquid with a high vapor pressure and a moderate measured
Henry's law constant. These properties indicate that some volatilization from both dry and moist
surfaces is expected to occur (HSDB. 2014). Benzaldehyde is susceptible to degradation by
direct photolysis both as a liquid and as a vapor. In addition, benzaldehyde in the atmosphere
will react with photochemically generated hydroxyl radicals and has an estimated atmospheric
half-life of 30 hours (HSDB. 2014). Benzaldehyde"s high water solubility and relatively low
estimated soil adsorption coefficient indicate that the chemical, if released into the environment,
is likely to leach to groundwater or undergo runoff after a rain event. Thus, removal from soil by
leaching with water is expected to compete with volatilization, depending on the local conditions
(wet, dry, etc.). The molecular formula for benzaldehyde is C7H6O (see Figure 1).
Physicochemical properties for benzaldehyde are provided in Table 1.
°%^H
Figure 1. Benzaldehyde Structure
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Table 1. Physicochemical Properties for Benzaldehyde (CASRN 100-52-7)3
Property (unit)
Value
Physical state
Liquid (almond-scented oil)
Boiling point (°C)
179
Melting point (°C)
-26
Density (g/cm3 at 15°C)
1.050
Vapor pressure (mm Hg at 25 °C)
1.27
pH (unitless)
ND
pKa (unitless)
14.9
Solubility in water (mg/L at 25 °C)
6,950
Octanol-water partition constant (log Kow)
1.48
Henry's law constant (atm-m3/mol at 20°C)
2.6 x 10-5
Soil adsorption coefficient Koc (mL/g)
11.lb
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
1.29 x 10-11
Atmospheric half-life (hr)
30
Relative vapor density (air =1)
3.66
Molecular weight (g/mol)
106.13
•'HSDB (2014).
bU.S. EPA (2012c).
ND = no data.
Literature searches were conducted on sources published from 1900 through September
2015 for studies relevant to the derivation of provisional toxicity values for benzaldehyde
(CASRN 100-52-7). Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. The following databases were
searched: PubMed, ToxLine (including TSCATS1), and Web of Science. The following
databases were searched outside of HERO for health-related values: ACGIH, ATSDR, Cal/EPA,
U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA OW, U.S. EPA TSCATS2/TSCATS8e, NIOSH,
NTP, OSHA, and RTECS.
A summary of available toxicity values for benzaldehyde from U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for
Benzaldehyde (CASRN 100-52-7)
Sou rce/Parameterab
Value (applicability)
Notes
Reference
Noncancer
IRIS (RfD)
1 x 10 1 mg/kg-d
Based on forestomach lesions and kidney toxicity
in an oral rat subchronic-duration study
U.S. EPA f 1988a)
HEAST
(subchronic RfD)
1 mg/kg-d
Based on kidney effects and forestomach lesions
in an oral rat study
U.S. EPA (201 la)
HEEP (ADI)
0.214 mg/kg-d
Based on forestomach lesions in an oral rat study
U.S. EPA (1985)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2015)
WHO (ADI)
0-5 mg/kg BW as
benzoic acid equivalents
No safety concern at current levels of intake when
used as a flavoring agent
WHO (1967):
WHO (2002):
JECFA (2003)
Cal/EPA
NV
NA
Cal/EPA (2015a):
Cal/EPA (2015b):
Cal/EPA (2014)
OSHA
NV
NA
OSHA (2011):
OSHA (2006)
NIOSH
NV
NA
NIOSH (2015)
ACGIH
NV
NA
ACGIH (2015)
AIHA (WEEL)
2 ppm (8.7 mg/m3)
8-hr TWA; established to prevent respiratory and
eye irritation from chronic exposure
AIHA (2011):
AIHA (1998)
AIHA (WEEL)
4 ppm (17.4 mg/m3)
STEL, 15 min; established to prevent respiratory
and eye irritation from short-term exposure
AIHA (2011):
AIHA (1998)
Cancer
IRIS
NV
NA
U.S. EPA (2015)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2015)
Cal/EPA
NV
NA
Cal/EPA (2011):
Cal/EPA (2015a):
Cal/EPA (2015b)
ACGIH
NV
NA
ACGIH (2015)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; AIHA = American Industrial
Hygiene Association; ATSDR = Agency for Toxic Substances and Disease Registry; Cal/EPA = California
Environmental Protection Agency; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health
Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profile; IARC = International
Agency for Research on Cancer; IRIS = Integrated Risk Information System; NIOSH = National Institute for
Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health
Administration; WHO = World Health Organization.
Parameters: ADI = acceptable daily intake; RfD = reference dose for chronic oral exposure; STEL = short-term
exposure level; TWA = time-weighted average; WEEL = workplace environmental exposure level.
NA = not applicable; NV = not available; BW = body weight.
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3 A and 3B provide an overview of the relevant database for benzaldehyde and
include all potentially relevant and repeated short-term-, subchronic-, and chronic-duration
studies. Principal studies are identified. The phrase "statistical significance," used throughout
the document, indicates ap-value of < 0.05 unless otherwise noted.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Benzaldehyde (CASRN 100-52-7)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
Short-term0
5 M/5 F, F344 rat,
gavage in corn oil,
5 d/wk, 16 d
0, 100, 200, 400, 800,
1,600
ADD: 0,71.4, 143,
286, 571, 1,143
Mortality, reduced body weight in
survivors
286
DU
571 (FEL)
NTP (1990):
Kluwe et al. (1983)
PR
Short-term0
5 M/5 F, B6C3Fi
mouse, gavage in corn
oil, 5 d/wk, 16 d
0, 200, 400, 800,
1,600, 3,200
ADD: 0, 143, 286,
571, 1,143,2,286
Mortality
286
DU
1,143
(FEL)
NTP (1990);
Kluwe etal. (1983)
PR
Subchronicd
10 M/10 F, F344 rat,
gavage in corn oil,
5 d/wk, 13 wk
0, 50,100, 200, 400,
800
ADD: 0,36,71.4,
143, 286,571
M: Mortality; reduced body
weight (in survivors);
necrotic/degenerative lesions of
the brain, liver, and kidney;
hyperplasia and hyperkeratosis
of the forestomach
F: Necrotic/degenerative lesions
of the brain, liver, and kidney;
hyperplasia and hyperkeratosis
of the forestomach
286
DU
571 (FEL)
NTP (1990);
PS,
PR,
IRIS
Kluwe et al. (1983)
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Table 3A. Summary of Potentially Relevant Noncancer Data for Benzaldehyde (CASRN 100-52-7)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAELa
BMDL/
BMCLa
LOAELa
Reference
(comments)
Notesb
Subchronicd
10 M/10 F, B6C3Fi
mouse, gavage in corn
oil, 5 d/wk, 13 wk
0, 75, 150, 300, 600,
1,200
ADD: 0, 54, 107, 214,
429, 857
M: Mortality, renal tube
degeneration of the kidney
F: No adverse effects
M: 429
F: 857
DU
M: 857
(PEL)
F: ND
NIP (1990);
Kluwe et al. (1983)
PR
Subchronicd
5-10 M/5-10 F,
Osborne-Mendel rat,
diet, 16 wk
0, 10,000
ADD: M: 0, 870
ADD: F: 0, 950
No adverse effects
M: 870
F: 950
DU
NDr
Hasan etal. (1967)
PR
(Confidence in
NOAEL is low because
data reporting is
inadequate for
independent review)
Chronic6
50 M/50 F, F344 rat,
gavage in corn oil,
5 d/wk, 103 wk
0, 200, 400
ADD: 0, 143,286
M: Mortality; hyperplasia of the
pancreas in males
F: No adverse effects
M: 143
F: 286
DU
M: 286
(PEL)
F: ND
NIP (1990)
PR
Chronic6
50 M/50 F, B6C3Fi
mouse, gavage in corn
oil, 5 d/wk, M: 104 wk,
F: 103 wk
M: 0, 200, 400
F: 0, 300, 600
ADD: M: 0, 143, 286
ADD: F: 0, 214, 429
Hyperplasia of the forestomach
M: 143
F: NDr
NDr
M: 286
F: 214
NIP (1990)
PR
Chronic6
5-10 M/5-10 F,
Osborne-Mendel rat,
diet, 27-28 wk
M: 0, 1,000
F: 0, 1,000
ADD: M: 0, 70
ADD: F: 0, 77
No adverse effects
M: 70
F: 77
DU
NDr
Hasan etal. (1967)
(Confidence in
NOAEL is low because
data reporting is
inadequate for
independent review.)
PR
Reproductive/
Developmental
ND
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Table 3A. Summary of Potentially Relevant Noncancer Data for Benzaldehyde (CASRN 100-52-7)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL3
LOAEL3
Reference
(comments)
Notesb
2. Inhalation (mg/m3)a
Short-term0
14 M/14 F, S-D rat,
whole-body inhalation,
6 hr/d, 14 d
0, 500, 750,
1,000 ppm
0, 2,170, 3,260,
4,341 mg/m3
HECet: 0, 87.0, 128,
170f
HECer: 543, 815, and
1,085
Histopathological changes in nasal
epithelium, including goblet cell
metaplasia in males and mild
morphological changes in females
NDr
DU
87
Lahametal. (1991)
PR
Subchronicd
ND
Chronic6
ND
Reproductive/
Developmental
ND
aDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-day) for oral noncancer effects and a human equivalent
concentration (HEC in mg/m3) for inhalation noncancer effects.
bNotes: IRIS = utilized by IRIS; PS = principal study; PR = peer reviewed; NPR = not peer reviewed.
cShort-term = repeated exposure for 24 hour to <30 days (U.S. EPA. 20021.
dSubchronic = repeated exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species).
'Chronic = repeated exposure for >10% lifespan for humans (more than approximately 90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021.
fHECET = (ppm x molecular weight ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x RGDRet (animal:human).
ADD = adjusted daily dose; DU = data unsuitable to BMD modeling; F = female(s); FEL = frank effect level; M = male(s); NA = not applicable; ND = no data;
NDr = not determined; S-D = Sprague-Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for Benzaldehyde (CASRN 100-52-7)
Number of Male/Female,
Strain, Species, Study Type,
BMDL/
Reference
Category
Study Duration
Dosimetry3
Critical Effects
BMCLa
(comments)
Notesb
Human
1. Oral (mg/kg-d)a
ND
2. Inhalation (mg/m3)a
ND
Animal
1. Oral (mg/kg-d)a
Carcinogenicity
50 M/50 F, F344 rat, gavage
0, 200, 400
No evidence of carcinogenicity
NA
NTP (1990)
PR
in corn oil, 5 d/wk, 103 wk
HED: 0, 34.3, 68.6
Carcinogenicity
50 M/50 F, B6C3Fi mouse,
M: 0,200,400
"Some" evidence of carcinogenicity in both sexes
M: NDr
N I P (1990)
PS, PR
gavage in corn oil, 5 d/wk,
F: 0,300,600
based on significant increases in forestomach
F: 25.7
103-104 wk
papillomas in females, a "near-significant" trend
HED: M: 0,20.0,40.0
for increased forestomach papillomas in males,
HED: F: 0,30.0,60.0
and statistically significant increases in
preneoplastic forestomach lesions (hyperplasia) in
both sexes
2. Inhalation (mg/m3)a
ND
aDosimetry: The units for oral exposures are expressed as HEDs (mg/kg-day). HEDs = dose x (days per week 7) x species-specific DAFs (based on the animal:human
BW1/4 ratio recommended by U.S. EPA (2011b). mouse:human ratio = 0.14; rat:human ratio = 0.24)
bNotes: PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; HED = human equivalent dose; F = female; M = male; NA = not applicable; ND = no data; NDr = not determined.
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HUMAN STUDIES
Oral Exposures
Although no epidemiology studies have examined the effects of benzaldehyde following
oral exposure, benzaldehyde is considered a GRAS chemical for use as a food additive for
flavoring at levels currently used (IPCS, 2001). There is a single reported case of a person dying
after consuming 2 ounces of benzaldehyde (HSDB, 2010).
Inhalation Exposures
The effects of inhalation exposure to benzaldehyde have not been evaluated in humans.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure in animals to benzaldehyde have been evaluated in rats and
mice in two short-term-duration (N I P. 19901 three subchronic-duration (N I P. 1990). and three
chronic-duration studies (NIP. 1990; Hagan et al.. 1967). two of which assessed carcinogenicity
(NIP. 1990). Klu we et al. (1983) provided a preliminary publication of the NTP (1990)
short-term- and sub chron i c-durati on data. The NTP (1990) report provides more comprehensive
information on study details and results. Some inconsistencies exist between the two
publications, which are noted in the study summaries below. For the purposes of this
assessment, only data from the NTP (1990) publication are considered.
Short-Term-Duration Studies
NTP (1990); Kluwe et al. (1983) (Rat study)
Groups of F344/N rats (5/sex/group) were administered benzaldehyde (99.5% pure) at
doses of 0, 100, 200, 400, 800, or 1,600 mg/kg-day in corn oil via gavage, 5 days/week for a total
of 12 doses over a 16-day period. The corresponding adjusted daily doses (ADDs) are 71.4, 143,
286, 571, and 1,143 mg/kg-day, respectively. Animals were examined twice per day for clinical
signs of toxicity and weighed on Days 1 and 8, and at study termination. No hematology,
clinical chemistry, or urinalysis evaluations were performed. Animals were sacrificed and
necropsied at study termination. Microscopic examination of tissues was not performed. The
study authors did not conduct statistical analyses of data. However, statistical analyses have
been conducted for this review for mortality and body weight data (Fisher's exact test and
student's Mest; 2-tailed).
All rats administered 1,600 mg/kg-day died on Day 2. In the 800-mg/kg-day group,
2/5 rats of each sex died prior to study termination. No other mortalities were observed
(see Table B-l). No clinical signs of toxicity were observed in the surviving rats, according to
NTP (1990); however, Kluwe et al. (1983) noted that hyperexcitability, tremors, or inactivity
were seen throughout the study in animals of both sexes at 800 and 1,600 mg/kg-day. Mean
final body weights in surviving animals in the 800-mg/kg-day group were statistically
significantly decreased by 14% in males and 11% in females, compared with controls; body
weights in other exposure groups were within 10% of control values (see Table B-l). No gross
lesions attributable to benzaldehyde exposure were observed.
A no-observed-adverse-effect level (NOAEL) of 400 mg/kg-day (ADD 286 mg/kg-day)
and a lowest-observed-adverse-effect level (LOAEL) (frank effect level [FEL]) of
800 mg/kg-day (ADD 571 mg/kg-day) are identified for increased mortality. Significant
decreases in body weight (>10%) were also observed in rats at the FEL.
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NTP (1990); Kluwe etal. (1983) (Mouse study)
Groups of B6C3Fi mice (5/sex/group) were administered benzaldehyde (99.5% pure) at
doses of 0, 200, 400, 800, 1,600, or 3,200 mg/kg-day in corn oil via gavage, 5 days/week for a
total of 12 doses over a 16-day period. The corresponding ADDs are 0, 143, 286, 571, 1,143,
and 2,286 mg/kg-day, respectively. Animals were examined twice per day for clinical signs of
toxicity and were weighed on Days 1 and 8, and at study termination. No hematology, clinical
chemistry, or urinalysis evaluations were performed. Animals were sacrificed and necropsied at
study termination. Microscopic examination of tissues was not performed. The study authors
did not conduct statistical analyses of data.
All mice administered 1,600 or 3,200 mg/kg-day died by Day 3. In the 800-mg/kg-day
group, 1/5 males died on Day 10. No other mortalities were observed. No clinical signs of
toxicity were observed during the study. Mean final body weights of the surviving mice were
comparable between the exposed and control groups. No gross lesions attributable to
benzaldehyde exposure were observed.
A LOAEL (FEL) of 1,600 mg/kg-day (ADD 1,143 mg/kg-day) is identified for increased
mortality. The single male death at the next lowest dose, 800 mg/kg-day, may have been
chemical related, but due to the low incidence, there is considerable uncertainty, which precludes
identifying this dose as either a LOAEL (FEL) or a NOAEL. The next lower dose,
400 mg/kg-day (ADD 286 mg/kg-day), was a clear NOAEL for lack of adverse effects following
exposure to benzaldehyde.
Subchronic-Duration Studies
NTP (1990); Kluwe etal. (1983) (Rat study)
In the subchronic study ultimately chosen as the principal study, groups of F344 rats
(10/sex/group) were administered benzaldehyde (99.5% pure) at doses of 0, 50, 100, 200, 400, or
800 mg/kg-day in corn oil via gavage, 5 days/week for 13 weeks. The corresponding ADDs are
0, 36, 71.4, 143, 286, and 571 mg/kg-day, respectively. Analytical measurement indicated that
dosing formulations were within ±10% of nominal concentrations. Animals were examined
twice per day for clinical signs of toxicity. All animals were weighed at study initiation, weekly
thereafter, and again at study termination. No hematology, clinical chemistry, or urinalysis
evaluations were performed. All animals that died or were sacrificed at study termination were
subject to gross necropsy, except for those that were autolyzed or cannibalized. Complete
histopathological examinations were conducted on all control animals and animals in the
400- and 800-mg/kg-day groups. Although Kluwe et al. (1983) reported that some organs
(i.e., liver, right kidney, thymus, heart, lungs, right testis, and brain) were weighed, the NTP
(1990) report does not mention this. Appropriate statistical tests were conducted for lesion
incidence data. Statistical analyses have been conducted for this review for mortality and body
weight data (Fisher's exact test and student's Mest; 2-tailed).
Mortalities observed prior to study termination included 6/10 males and 3/10 females in
the 800-mg/kg-day group, 1/10 females in the 400-mg/kg-day group, and 1/10 females in the
control group (see Table B-2). The mean final body weight of the four surviving male rats in the
800-mg/kg-day group was significantly decreased by 26% compared with controls; body weights
in other exposure groups were within 10% of control values (see Table B-2). No clinical signs of
toxicity were reported by NTP (1990); however, Kluwe et al. (1983) reported hyperactivity,
trembling, and periodic inactivity in 800-mg/kg-day males and females throughout the study.
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Organ weights were not reported by NTP (1990); however, Kluwe et al. (1983) reported marked
reductions in absolute and relative-to-brain weights of the thymus and testis in surviving
800-mg/kg-day males, and slight increases in liver, kidney, thymus, and heart weights in
surviving 800-mg/kg-day females (quantitative data not provided). Statistically significant
increases in the incidences of histopathological lesions were observed in the brain, liver, kidneys,
and forestomach of males and females at 800 mg/kg-day compared with controls
(see Table B-3). Observed lesions in these rats included minimal to marked brain lesions in all
highest-dose rats (degeneration and necrosis of the cerebellum, mineralization of the cerebellum,
and/or necrosis of hippocampal neurons), liver and kidney lesions in 30-40% of highest-dose
rats (liver and kidney tubule degeneration and/or necrosis), and mild to moderate hyperplasia
and/or hyperkeratosis of the forestomach in 50-80% of highest-dose rats. These lesions were
not observed in rats administered 400 mg/kg-day (histopathology was not performed at lower
doses) according to NTP (1990); however, Kluwe et al. (1983) reported that 2/10 males
administered 400 mg/kg-day had forestomach hyperplasia and hyperkeratosis. Kluwe et al.
(1983) noted that the significance of the forestomach lesions in animals administered
benzaldehyde was unclear, but the presence of these lesions may indicate a mildly irritating
effect on the gastric mucosa.
A NOAEL of 400 mg/kg-day (ADD 286 mg/kg-day) and a LOAEL (FEL) of
800 mg/kg-day (ADD 571 mg/kg-day) are identified for increased mortality in males,
significantly reduced body weight (>10%) in male survivors, and significant increases in
degenerative and necrotic lesions of the brain, liver, and kidney, and hyperplasia and
hyperkeratosis of the forestomach in males and females.
NTP (1990); Kluwe et al. (1983) (Mouse study)
Groups of B6C3Fi mice (10/sex/treatment group) were administered benzaldehyde
(99.5% pure) at doses of 0, 75, 150, 300, 600, or 1,200 mg/kg-day in corn oil via gavage,
5 days/week for 13 weeks. Analytical measurement indicated that dosing formulations were
within ±10%) of nominal concentrations. The corresponding ADDs are 0, 54, 107, 214, 429, or
857 mg/kg-day, respectively. Animals were examined twice per day for clinical signs of
toxicity. Animals were weighed at study initiation, weekly thereafter, and again at study
termination. No hematology, clinical chemistry, or urinalysis evaluations were performed. All
animals that died or were sacrificed at study termination were subject to gross necropsy, except
for those that were autolyzed or cannibalized. Although Kluwe et al. (1983) reported that some
organs (i.e., same organs as those weighed in the 13-week study in rats) were weighed, the NTP
(1990) report does not mention this. Organ weights were not reported by NTP (1990); however,
Kluwe et al. (1983) indicated that no organ weight changes attributable to exposure were
observed. Complete histopathological examinations were conducted on all control and
1,200-mg/kg-day males and females, and on all 600-mg/kg-day males. The kidneys and liver of
all 300-mg/kg-day males, and the spleen, stomach, and kidneys of all 600-mg/kg-day females,
were also examined. Statistical analyses were reportedly conducted by the study authors, but
results were not provided.
Nine of 10 males and 1/10 females administered 1,200 mg/kg-day died during the first
week of dosing. The surviving male at 1,200 mg/kg-day died during Week 4. No other
mortalities were observed. Terminal body weights of surviving mice were within 10% of control
values. No clinical signs of toxicity were observed. The only histopathological lesion attributed
to exposure was mild to moderate renal tubule degeneration observed in 1/10 males (but not
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statistically significant) in the 600-mg/kg-day group and all (10/10) males in the
1,200-mg/kg-day group.
A NOAEL of 600 mg/kg-day (ADD 428 mg/kg-day) and a LOAEL (FEL) of
1,200 mg/kg-day (ADD 857 mg/kg-day) are identified for increased mortality. Increased
incidence of renal tubule degeneration was also observed in males at the FEL.
Hasan etal. (1967)
In a study screening various food flavoring chemicals for adverse effects, groups of
Osborne-Mendel rats were administered benzaldehyde (purity not reported) in diet at
concentrations of 0 or 10,000 ppm for 16 weeks. Groups exposed to benzaldehyde contained
five rats/sex. The control groups contained 10 rats/sex. Using reference values for body weight
and food consumption for Osborn-Mendel rats for a subchronic-duration study (U.S. EPA.
1988b). the estimated daily intakes are 870 mg/kg-day in males and 950 mg/kg-day in females.
While the study report indicates that diets containing some of the flavorings tested were analyzed
to determine the loss of the compound from the diet over a 7-day period, there is no indication
that the benzaldehyde diets were tested for benzaldehyde concentration, homogeneity, or
stability. Animal body weight, food consumption, and general condition were evaluated weekly.
Hematology parameters, including white blood cell (WBC) counts, red blood cell (RBC) counts,
hematocrit, and hemoglobin, were measured at study termination. Clinical chemistry and
urinalysis evaluations were not performed. At study termination, animals were sacrificed and
examined macroscopically. Viscera were removed and the following organs were weighed:
liver, kidneys, spleen, heart, and testes. These same organs, as well as the remaining abdominal
and thoracic viscera and one hind leg (to provide bone, bone marrow, and muscle), were
preserved for histopathological examination from three to four rats/sex in the control and treated
groups. The organs examined for histopathological changes were not specified in the study
report.
The study authors indicated that no adverse effects attributable to benzaldehyde exposure
were observed. No further details were provided. The administered dose of 870 mg/kg-day in
males and 950 mg/kg-day in females is an apparent free-standing NOAEL based on a lack of
adverse effects. However, confidence in this NOAEL is low because reporting is inadequate for
independent review of the findings.
Chronic-Duration/Carcinogenicity Studies
NTP (1990) (Rat study)
Groups of F344 rats (50/sex/treatment group) were administered benzaldehyde
(97.8-99.5% pure, with 0.38% benzoic acid and 0.21-0.24%) water) at doses of 0, 200, or
400 mg/kg-day in corn oil via gavage, 5 days/week for 103 weeks. Analytical measurements
indicated that dosing formulations were within ±10% of target concentrations. The
corresponding ADDs are 0, 143, and 286 mg/kg-day, respectively. Animals were examined
twice per day for clinical signs of toxicity. Animals were weighed at study initiation, once per
week for 13 weeks and then once per month thereafter, and at study termination. No
hematology, clinical chemistry, or urinalysis evaluations were performed. At study termination,
all animals were sacrificed and subjected to gross necropsy. Complete histopathological
examinations were conducted on the controls, low-dose males, high-dose males and females, and
all animals that died before study termination. Complete histopathological examinations were
conducted on low-dose males because mortality in high-dose males exceeded the control group
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by 15%. In low-dose females, only potential target organs were examined microscopically,
including adrenal glands, bone, brain, clitoral gland, eyes, gross lesions, heart, kidneys, liver,
lungs, pituitary gland, spinal cord, spleen, and stomach.
A significant, dose-related trend was observed for decreased survival in male rats. Using
pairwise comparison, survival was significantly decreased in high-dose males (42%) compared
to control males (74%) (see Table B-4). Survival in exposed females was comparable to control
females. No clinical signs of toxicity were reported, and body weights were similar between
exposed and control rats. The only nonneoplastic (preneoplastic) lesion attributed to
benzaldehyde exposure was a significant increase in the incidence of pancreatic hyperplasia
(nodular masses <3 mm in diameter) in high-dose males, compared with controls
(see Table B-4). A slight, yet statistically significant, increase in the incidence of adenomas
(nodular masses >3 mm in diameter) in the pancreas was also observed in high-dose males;
however, the incidence of adenomas was within the historical control incidence range of
pancreatic acinar cell neoplasms at the study laboratory, and only slightly above the mean
historical control incidence (see Table B-4). Therefore, these tumors were not considered to be
treatment-related by the study authors.
There was a statistically significant increase in the incidence of mononuclear cell
leukemia (largely due to an increase in Stage 1 leukemia) in the male rats of both treatment
groups that showed a statistically significant, dose-related trend (see Table B-4). While the
incidence of mononuclear cell leukemia was statistically significantly increased in high-dose
males when either the life table test or logistic regression test was used for analysis, the
incidence was only statistically significantly increased in the low-dose group when the life table
test was used and not when the logistic regression test was used. The study authors considered
the logistic regression test to be more appropriate for this analysis due to the relatively large
proportion of Stage 1 leukemia. When the incidence of Stages 2 or 3 (combined) leukemia was
examined, there was no statistically significant treatment-related increase. Therefore, the study
authors did not consider the slight increase in the incidence of leukemia in males to be
treatment-related. A statistically significant increase in the incidence of malignant
mesotheliomas was noted in low-dose males (see Table B-4); however, this finding was
considered to be unrelated to treatment due to the lack of a significant response at the high dose.
There were no histopathological lesions in exposed females that were significantly increased
relative to controls. The study authors concluded that there was no evidence of carcinogenicity
in male or female rats under the conditions of this study.
A NOAEL of 200 mg/kg-day (ADD 143 mg/kg-day) and a LOAEL (FEL) of
400 mg/kg-day (ADD 286 mg/kg-day) are identified in male rats based on decreased survival
and increased hyperplasia of the pancreas. A free-standing NOAEL of 400 mg/kg-day is
identified for female rats, based on a lack of adverse effects attributable to exposure. There was
no clear evidence of carcinogenicity in male or female rats.
NTP (1990) (Mouse study)
Groups of B6C3Fi mice (50/sex/group) were administered benzaldehyde (97.8-99.5%)
pure, with 0.38% benzoic acid and 0.21-0.24%) water) at doses of 0, 200, or 400 mg/kg-day
(males) or 0, 300, or 600 mg/kg-day (females) in corn oil via gavage, 5 days/week for
103 (females) or 104 (males) weeks. Analytical measurements indicated that dosing
formulations were within ±10% of target concentrations. The corresponding ADDs are 0, 143,
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and 286 mg/kg-day for males and 0, 214, and 429 mg/kg-day for females, respectively. Initially,
a large number of gavage-associated deaths occurred in the females; therefore, the study with the
female mice was restarted. Animals were examined twice per day for clinical signs of toxicity.
Animals were weighed at study initiation, once per week for 13 weeks, and then once per month
thereafter, and at study termination. No hematology, clinical chemistry, or urinalysis evaluations
were performed. All animals were sacrificed and subject to gross necropsy at study termination.
Complete histopathological examinations were conducted on the controls, high-dose males and
females, and all animals that died before study termination. Histopathological examination of
the stomach was also conducted in the low-dose group.
Survival, clinical signs, and body weights were comparable between exposed and control
groups. There was a statistically significant increase in the incidence of focal hyperplasia of the
forestomach in males in the high-dose group and in females in both treatment groups
(see Table B-5). Female mice had a statistically significant increase in the incidence of
squamous cell papillomas of the forestomach at both doses with a statistically significant,
dose-dependent trend. There was also a slight, but not statistically significant, increase in the
incidence of squamous cell papillomas of the forestomach in male mice of the high-dose group
that was above the historical control incidence (see Table B-5). The study authors concluded
that there was some evidence of carcinogenic activity of benzaldehyde in male and female mice,
based on the increased incidences of neoplastic and preneoplastic lesions of the forestomach.
In males, a NOAEL of 200 mg/kg-day (ADD 143 mg/kg-day) and a LOAEL of
400 mg/kg-day (ADD 286 mg/kg-day) are identified for increased incidence of forestomach
hyperplasia. In females, a LOAEL of 300 mg/kg-day (ADD 214 mg/kg-day), with no NOAEL,
was identified for increased incidence of forestomach hyperplasia. There was some evidence of
carcinogenicity under the conditions of this study based on an increase in the incidence
squamous cell papilloma and hyperplasia of the forestomach.
Jla&in etal (1967)
In a study screening various food flavoring chemicals for adverse effects, groups of
Osborne-Mendel rats were administered dietary benzaldehyde (purity not reported) at
concentrations of 0 or 1,000 ppm for 27-28 weeks. Groups exposed to benzaldehyde contained
five rats/sex. The control groups contained 10 rats/sex. Using reference values for body weight
and food consumption for Osborn-Mendel rats in a chronic-duration study (U.S. LP A. 1988b).
the estimated daily intakes are 70 mg/kg-day in males and 77 mg/kg-day in females. Study
design and endpoints evaluated are identical to those described above for the 16-week study by
the same authors.
The study authors indicated that no adverse effects attributable to benzaldehyde exposure
were observed. No further details were provided. The administered dose of 70 mg/kg-day
(ADD 70 mg/kg-day) in males and 77 mg/kg-day (ADD 77 mg/kg-day) in females is an apparent
free-standing NOAEL based on a lack of adverse effects. However, confidence in this NOAEL
is low because reporting is inadequate for independent review of the findings.
Reproductive/Developmental Studies
No studies have been identified.
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Inhalation Exposures
The effects of inhalation exposure in animals to benzaldehyde have been evaluated in one
short-term-duration study (I.aham et al.. 1991).
Laham etal. (1991)
Groups of Sprague-Dawley (S-D) rats (14/sex/group) were exposed to benzaldehyde
(>98% pure) at concentrations of 0, 500, 750, or 1,000 ppm via whole-body inhalation for
6 hours/day for 14 consecutive days. These concentrations are equivalent to 0, 2,170, 3,260, and
4,341 mg/m3, respectively. Control groups were exposed to filtered air, and kept in a separate
room to avoid contamination from animals in the benzaldehyde-treatment groups. The exposure
concentrations were selected based on a range-finding test that indicated zero mortality in the
same rat strain after one 6-hour exposure at concentrations up to 1,000 ppm (4,341 mg/m3).
During the 14-day study, chamber concentrations were determined every 6 minutes in each
chamber; however, analytically determined concentrations were not provided in the study report.
Animals were examined daily for clinical signs of toxicity. Animals were weighed after 2, 8,
and 14 exposures. Rectal temperatures were obtained within 30 minutes after 2, 7, and
14 exposures, and 20 hours after the last exposure. Blood was collected at necropsy from
4-6 rats/group for hematology (hematocrit [Hct], hemoglobin [Hb], erythrocyte count [RBC],
mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular
hemoglobin concentration [MCHC], total leucocyte count [WBC], and acetylcholinesterase
[AChE] in RBCs) and clinical chemistry (blood urea nitrogen [BUN], total protein, albumin,
alanine aminotransferase [ALT], aspartate aminotransferase [AST], y-glutamyl transferase
[GGT], alkaline phosphatase [ALP], lactate dehydrogenase, creatine phosphokinase,
alpha-hydroxybutyrate dehydrogenase, cholinesterase, bilirubin, cholesterol, glucose, inorganic
phosphorus, triglycerides, calcium, chloride, magnesium, potassium, sodium, and amylase).
Urinalysis evaluations were not performed.
As available in surviving animals, seven rats/sex/group were sacrificed and necropsied
72 hours after the last exposure. The remaining animals were whole-body perfused and prepared
for future examination with an electron microscope. The brain, heart, kidneys, liver, lungs, and
spleen were collected and weighed at terminal sacrifice prior to fixation for histology
examination. Other tissues that were histologically examined included the adrenal glands, small
and large intestines, larynx, rhinopharynx, stomach, trachea, testes or ovaries, thyroid, and
urinary bladder. The nasal tissues from rats in the control, low-dose, and high-dose groups were
decalcified and processed for histology, with special attention paid to the respiratory, olfactory,
and stratified squamous epithelia. Animals that were found moribund were immediately
necropsied and tissues were examined microscopically. The study authors performed
appropriate statistical tests.
Mortalities during the first week of exposure included 10/14 females and 1/14 males
exposed to 4,341 mg/m3 and 1/14 females exposed to 3,260 mg/m3. During the second week,
two additional females exposed to 3,260 mg/m3 were found dead or were sacrificed due to
morbidity. Rats exposed to 4,341 mg/m3 showed several clinical signs of toxicity following
exposure, including aggression and tremors when handled, extreme sensitivity to noise, abnormal
gait, frequent seizures, positive Straub sign, piloerection, diuresis, and reduced breathing rate.
There were signs of nasal and ocular irritation that appeared to be concentration related, but the
specifics were not reported. Formation of excessive amounts of porphyrin pigments was noted
around eyes and nares, primarily in animals exposed to 4,341 mg/m3. All benzaldehyde-treated
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groups showed a slight (<6%), but statistically significant, decrease in mean body temperature
after 2, 7, and 14 exposures; body temperatures returned to normal within 20 hours after the
cessation of exposure. A statistically significant decrease in terminal body weight was reported
in all male groups; however, mean body weights were within 10% of the control mean for all
groups (see Table B-6). Mean body weights of females were unaffected by exposure.
Several changes in hematology and clinical chemistry parameters were noted in exposed
rats, relative to controls (see Tables B-7 and B-8). Statistically significant changes in RBC
parameters were minimal (<13% different from control), including decreased hemoglobin and
hematocrit in males and females at 4,341 mg/m3, decreased RBCs in females at 4,341 mg/m3,
and decreased MCH and MCHC in males at >3,260 mg/m3. Significant changes in WBCs
included a significant 7-10-fold increase in monocytes at >2,170 mg/m3 in females and a 35%
increase in WBC count at 4,341 mg/m3 in males. For clinical chemistry, significant increases in
serum AST levels (31—152%) were observed in males and females from all exposure groups.
Other significant clinical chemistry changes were observed in females from all exposure groups,
compared to controls, including an 8-11% decrease in serum albumin, a 5—7% decrease in serum
total protein, and a 26—3 5% decrease in serum cholinesterase levels. Serum ALT was
significantly elevated by 34% at 3,260 mg/m3 in females, but not at 4,341 mg/m3. Both absolute
and relative liver weights were significantly elevated in all exposed female groups; however, the
increase was greatest at 2,170 mg/m3 (30—31%) and lowest at 4,341 mg/m3 (15%)
(see Table B-6). In males, a significant 18% increase in relative liver weight was reported at
2,170 mg/mg3. No other organ weight changes were reported in exposed animals compared with
controls (data not provided).
Serum chemistry findings and liver weight changes were not accompanied by
histopathological changes. The only specific histopathological change attributed to
benzaldehyde exposure was goblet cell metaplasia, mainly in the respiratory epithelium lining of
the nasal septum. This finding was noted in 4/7 males at both 2,170 and 4,341 mg/m3 (the
3,260-mg/m3 group was not examined) with no differences in severity between the groups. In
females, 1/7 control animals had slight goblet cell metaplasia, while 3/7 in the 2,170-mg/m3
group and 1/7 in the 4,341-mg/m3 group (the 3,260-mg/m3 group was not examined) had "mild
morphological changes" in the nasal tissues. However, due to the large number of female deaths
at 4,340 mg/m3 during the first week of exposure (10/14), only four females in this group (4/14)
were exposed to benzaldehyde for 14 days. The study authors indicated no other signs of
inflammation or alterations in the nasal tissues.
A LOAEL of 2,170 mg/m3 (HECet 87.0 mg/m3) is identified in exposed rats based on
histopathological changes in the nasal tissue (extrathoracic region), including goblet cell
metaplasia in males and mild morphological changes in females. Evidence for liver effects in
females was also observed at the LOAEL, including increased liver weight accompanied by
clinical chemistry changes in females; however, no morphological changes were observed in the
liver. No NOAEL is identified. For effects in the extrathoracic (ET) region of rat respiratory
tract, nominal inhalation concentrations of 500, 750, and 1,000 ppm (2,170, 3,260, and
4,341 mg/m3) have been converted to human equivalent concentrations (HECets) of 87.0, 128,
and 170 mg/m3, respectively, by treating benzaldehyde as a Category 1 gas and using the
following equation (U.S. LP A. 1994):
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HECet = (ppm x MW -h 24.45)
x (hours/day exposed ^ 24)
x (days/week exposed ^ 7) x RGDRet
where:
MW = molecular weight
RGDRet = extrathoracic regional gas dose ratio
= RGDrat/RGDh uman
Extrathoracic regional gas doses (RGD) have been calculated as follows:
RGD = VE - SAet
where:
Ve = minute volume
= 171 mL/minute in rats and 13,800 mL/minute in humans
SAet = surface area of the extrathoracic region
= 15 cm2 in rats and 200 cm2 in humans
As inhaled benzaldehyde was also associated with extrarespiratory (ER) effects in the
liver, nominal concentrations of 500, 750, and 1,000 ppm (2,170, 3,260, and 4,341 mg/m3) were
converted to HECers of 543, 815, and 1,085 mg/m3, respectively, by treating benzaldehyde as a
Category 3 gas and using the following equation (U.S. EPA, 1994):
HECer = (ppm x MW -h 24.45)
x (hours/day exposed ^ 24)
x (days/week exposed ^ 7)
x ratio of blood:gas partition coefficient (animal:human)
where:
MW = molecular weight
The value for the rat blood:air partition coefficient for benzaldehyde is greater than the
human blood:air partition coefficient, so the default ratio of 1 was applied.
Subchronic-Duration Studies
No studies have been identified.
Chronic-Duration/Carcinogenicity Studies
No studies have been identified.
Reproductive/Developmental Studies
No studies have been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Genotoxicity Studies
The potential genotoxicity of benzaldehyde has been evaluated in numerous in vitro
studies; no in vivo mammalian studies have been located. Available studies are summarized
below (see Table 4A for more details). In general, available data indicate that benzaldehyde is
not mutagenic, but evidence indicates that benzaldehyde may cause deoxyribonucleic acid
(DNA) damage and clastogenic effects.
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The vast majority of mutagenicity studies indicate that benzaldehyde is not mutagenic in
vitro. All available studies using traditional Salmonella typhimurium tester strains indicate that
benzaldehyde is not mutagenic with or without metabolic activation (Dillon et aL 1998; Gee et
al.. 1998; Tennant and Ashbv. 1991; N I P. 1990; Vamvakas et aL 1989; Nohmi et aL 1985;
Haworth et aL 1983; Kasamaki et aL 1982; Florin et al. 1980; Ranson et al. 1980; Rockwell
and Raw, 1979; Sasaki andEndo, 1978). Using base-specific tester strains TA7001, TA7002,
TA7003, TA7004, TA7005, and TA7006 both with and without metabolic activation. Gee et al.
(1998) reported mutagenicity only in TA7005 with metabolic activation (TA7005 specifically
detects G:C —~ A:T mutations). In L5178Y TK ± mouse lymphoma cells, one study reported
mutations at near-cytotoxic concentrations (Mcgregor et al. 1991; NTP. 1990). while another did
not observe mutagenicity at similar doses (Microbiological Associates. 1991). Benzaldehyde did
not cause sex-linked recessive lethal mutations in Drosophila melanogaster (NTP. 1990;
Woodruff et al. 1985).
A limited number of studies indicate that benzaldehyde is clastogenic in vitro.
Benzaldehyde induced chromosomal aberrations (CAs) in Chinese hamster lung cells without
metabolic activation (but not with metabolic activation) and in Chinese hamster B241 cells
(metabolic conditions unknown) (Sofuni et al.. 1985; Kasamaki et al.. 1982); however, CAs were
not induced in Chinese hamster ovary (CHO) cells with or without activation (NTP. 1990;
Galloway et al.. 1987). Sister chromatid exchanges (SCEs) were observed in CHO cells and
human lymphocytes exposed to benzaldehyde without metabolic activation; induction was
equivocal in CHO cells with metabolic activation (NTP. 1990; Jansson et al.. 1988; Galloway et
al.. 1987).
The evidence indicates that benzaldehyde may cause DNA damage, but is not conclusive.
In the Bacillus subtilis rec assay, benzaldehyde showed equivocal evidence of DNA damage in
one study (Matsui et al.. 1989) and no evidence of DNA damage in a second study [Oda et al.
(1978) as cited in Adams et al. (2005)1. Using the comet assay, dose-dependent DNA damage
was observed in J). melanogaster larvae exposed to benzaldehyde (Demir and Kava. 2013). In
human cells exposed to benzaldehyde in vitro, DNA damage was significantly increased in
human lymphocytes (Demir et al.. 2010) and DNA protein cross-links were formed in human
Burkitt lymphoma cells (Kuykendall et al.. 2007). However, DNA cleavage was not observed in
extracellular purified supercoiled DNA (PM2 bacteriophage) exposed to benzaldehyde (Becker
et al.. 1996).
19
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Table 4A. Summary of Benzaldehyde Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results3
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Mutation
S. typhimurium TA98, TA1537
(traditional tester strains)
S. typhimurium TA7001, TA7002,
TA7003, TA7004, TA7005, TA7006
(base-specific tester strains);
individually and as a mix
50-1,000 ng/mL
+
TA7005
TA98,
TA1537,
TA7001,
TA7002,
TA7003,
TA7004,
TA7006,
and mixture
The liquid fluctuation test method
was used. The concentration at
which the number of revertants
was increased in TA7005 with
metabolic activation was not
reported. TA7005 detects
G:C —> A:T mutations.
Geeetal. (1998)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537
0, 10, 33, 100,
333,
1,000 jig/plate
Cytotoxicity was observed at
1,000 (ig/plate.
Tetmant and
Ashbv (1991):
NTP (1990);
Haworth et al.
(1983)
Mutation
S. typhimurium TA100, TA102,
TA104
0, 33, 100, 333,
1,000,
3,333 (ig/plate
Cytotoxicity was observed at
3,333 (ig/plate.
Dillon et al.
(1998);
Tetmant and
Ashbv (1991);
NTP (1990)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537
3 nmol
—
—
Florin etal. (1980)
Mutation
S. typhimurium TA98, TA100,
TA2637
0, 50, 100, 200,
500, 1,000,
2,000 ng/plate
Article was published in a
Japanese language journal, but the
abstract and tables are in English.
Nohmi et al.
(1985)
Mutation
S. typhimurium TA98, TA100
0.05-500 ng/plate
—
—
Kasamaki et al.
(1982)
Mutation
S. typhimurium TA98, TA100
0.05-100 |iL/platc
ND
—
Rockwell and Raw
(1979)
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Table 4A. Summary of Benzaldehyde Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results3
Comments
References
Without
Activation
With
Activation
Mutation
S. typhimurium TA98, TA100
50-300 |iL/platc
ND
Plates were treated with 24-hr
urine from benzaldehyde-treated
rats in the presence of S9; amount
administered to rats was not
reported.
Rockwell and Raw
(1979)
Mutation
S. typhimurium TA98, TA100
NR
Sasaki and Endo
(1978)
[abstract only]
Mutation
S. typhimurium TA100
0.1, 1, 10, 100,
1,000 ng/plate
—
ND
Raoson et al.
(1980)
Mutation
S. typhimurium TA100
0.1-2,000
nmol/plate
—
—
Vamvakas et al.
(1989)
DNA damage (rec-assay)
B. subtilis strains H17 (recE+) and
M45 (rccE )
2,000 mg/L
±
Based on S-probit analysis,
benzaldehyde had DNA-damaging
potential. However, repaired
survival analyses did not indicate
DNA damage; 2,000 mg/L was the
highest concentration of
benzaldehyde giving 50% survival
turbidity of the recE± strains (the
other concentrations of
benzaldehyde tested not reported).
Matsui et al.
(1989)
DNA damage (rec-assay)
B. subtilis strains H17 (recE+) and
M45 (recE-)
21 ng/plate
ND
Japanese article with English
summary.
Oda et al. (1978)
as cited in Adams
et al. (2005)
Genotoxicity studies in nonmammalian eukaryotic organisms
Sex-linked recessive
lethal mutation
Canton-S wild-type D. melanogaster
(adult males); feeding or injection
exposure
Feeding: 0,
1,150 ppm
Injection 0,
2,500 ppm
NA
No induction of sex-linked
recessive lethal mutations was
observed via either route.
NTP (1990);
Woodruff et al.
(1985)
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Table 4A. Summary of Benzaldehyde Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results3
Comments
References
Without
Activation
With
Activation
DNA damage
(comet assay)
Hemocytes from D. melanogaster,
72-hr-old larvae (third instar); feeding
exposure
0, 5, 10, 25,
50 mM
+
NA
Dose-dependent increases in DNA
damage were observed at
concentrations >10 mM, based on
statistically significant (p < 0.05)
increases in % DNA tail
(>10 mM), tail moment
(>10 mM), and tail length
(>25 mM) assay parameters.
Demir and Kava
(2013)
Genotoxicity studies in mammalian cells—in vitro
Mutation
L5178Y TK ± mouse lymphoma cells
0, 100, 200, 300,
400, 450, 475,
500, 525, 550,
575, 600, 625,
650 (ig/mL
ND
Mutagenesis was not observed at
doses that did not cause
cytotoxicity; concentrations
>625 (ig/mL caused cytotoxicity.
Microbiological
Associates (1991)
Mutation
L5178Y TK ± mouse lymphoma cells
0, 50, 100, 200,
400, 800 (ig/mL
(Trial 1)
0, 80, 160, 320,
480, 640 (ig/mL
(Trial 2)
+
ND
Concentrations >640 ng/mL were
cytotoxic; mutations were induced
at concentrations of 400 ng/mL
(Trial 1) and 480 ng/mL (Trial 2).
Mcereeor et al.
(1991);
NTP (1990)
Chromosomal aberrations
(CAs)
Chinese hamster ovary (CHO) cells
0, 50, 160,
500 |ig/mL
without activation
0, 160, 500,
1,600 iig/mL with
activation
NTP (1990);
Gallowav et al.
(1987)
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Table 4A. Summary of Benzaldehyde Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results3
Comments
References
Without
Activation
With
Activation
CAs
Chinese hamster lung cells
0, 0.8, 1.0 mg/mL
without activation
0,0.8, 1.0,
1.2 mg/mL with
activation
+
Article was published in a
Japanese language journal, but the
abstract and tables are in English.
Induction of CAs was observed at
1.0 mg/mL without S9.
Sofuni et al.
(1985)
CAs
Chinese hamster B241 cell line
50 nM
+
The maximal frequency of
aberration was observed at 50 nM
without visible cytotoxicity; other
test concentrations were not
reported. It is unclear whether
positive results were observed
with or without metabolic
activation (both conditions were
evaluated).
Sofuni et al.
(1985);
Kasamaki et al.
(1982)
Sister chromatid
exchange (SCE)
CHO cells
0, 5, 16, 50,
160 |ig/mL
without activation
0, 160, 500,
1,600 |ig/mL with
activation
+
±
Induction of SCEs was observed at
concentrations >50 ng/mL without
S9 and >1,600 ng/mL with S9.
The study authors considered
benzaldehyde to be positive for the
induction of SCEs in the absence
of S9 and weakly positive in the
presence of S9.
NTP (1990);
Gallowav et al.
(1987)
SCE
Human lymphocytes
0-2.0 mM
+
ND
Benzaldehyde was observed to
induce SCE in a dose-related
manner.
Jansson et al.
(1988)
DNA damage
(comet assay)
Human lymphocytes
0, 1, 5, 10, 25,
50 mM
+
ND
Benzaldehyde increased DNA tail
moment at 10 and 25 mM, and
percent tail DNA increased at
exposures >10 mM.
Demir et al. (2010)
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Table 4A. Summary of Benzaldehyde Genotoxicity
Endpoint
Test System
Dose/
Concentration
Results3
Comments
References
Without
Activation
With
Activation
DNA protein cross-link
(DPX)
Burkitt lymphoma cells (BLC);
preparation of samples for DPX
analysis was performed at both 4 and
65°C
0,0.01,0.1, 1,5,
10, 25 mM
+
ND
Benzaldehyde caused significantly
increased DPXs at concentrations
>5 mM with 4°C washing and at
25 mM with 65°C washing.
Cytotoxicity (<60% cell viability)
was noted at >10 mM.
Kuvkendall et al.
(2007)
Genotoxicity studies with extracellular purified DNA
DNA cleavage
PM2 bacteriophage (supercoiled DNA)
Up to 15 mM
ND
Benzaldehyde did not induce
DNA cleavage; however,
benzaldehyde with CuCb (up to
2 mM) caused a dose-dependent
increase in DNA cleavage.
Becker et al.
(1996)
a+ = positive, ± = equivocal or weakly positive, - = negative, NA = not applicable, ND = no data, NR = not reported.
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Supporting Human Studies
Human health effects data are extremely limited. No adverse side effects were observed in a
preliminary clinical trial that administered benzaldehyde in the form of P-cyclodextrin
benzaldehyde (CBDA) orally or rectally at a dose of 2.5 mg CBDA/kg, 4 times/day for 2 weeks to
2 years (10 mg CBDA/kg-day) to terminal cancer patients (Kochi et al.. 1980). CBDA is 8.3%
benzaldehyde, so the approximate daily intake of benzaldehyde was 0.83 mg/kg-day; however, this
study is difficult to interpret because no controls were used. No association between exposure to
flavoring agents (including benzaldehyde) and impaired pulmonary function was observed in a
cross-sectional study of flavoring manufacturing company workers; no exposure information was
provided (Ronk et al.. 2013). A case study reported the death of a young woman who drank 60 mL
(approximately 900 mg/kg) of benzaldehyde, (based on a density of 1.050 g/mL and reference body
weight of 70 kg); the time between consumption and death was not provided [Dadlez (1928) as
cited in Anderson (2006)1. Findings at autopsy included a yellowish-white pulp in the stomach, a
whitish, dry, and flushed mucous membrane, hyperemia in the small intestine, and ecchymotic spots
on the pleura and pericardium.
Benzaldehyde may cause allergic skin reactions in certain individuals. In a case-report, a
pastry chef with chronic urticaria tested positive to benzaldehyde in a patch test (Seite-Belle/./.a et
al.. 1994). Allergic contact dermatitis to benzaldehyde has also been reported in workers at a
perfume factory (Schubert. 2006). Another study reported that only 1/50 patients with sensitivity to
a fragrance mix containing benzaldehyde tested positive to benzaldehyde in a patch test [Becker et
al. (1994) as cited in Anderson (2006)1.
Supporting Animal Toxicity Studies
A number of supporting animal toxicity studies were identified (see Table 4B for additional
details), including:
• An oral reproductive study in rats available only as summary in a secondary source that
reported no significant effects following exposure to 5 mg/kg-day via gavage every other
day for 32 weeks prior to mating, although it was noted that pregnancy rate was
decreased in exposed dams [Sporn et al. (1967) as cited in Adams et al. (2005)1.
• A teratogenicity screen in chick embryos that reported a low teratogenic potential for
benzaldehyde ( Abramovici and Rachmuth-Roi/.man. 1983).
• A sub chronic-duration intraperitoneal (i.p.) study in rats that reported nasal and
bronchial lesions after injection with 1 mg/day for 12 weeks (Schweinsberg et ai. 1986).
• Acute oral lethality studies that reported median lethal dose (LD50) values of
800-2,850 mg/kg in rats, 800-1,600 mg/kg in mice, and 1,000 mg/kg in guinea pigs
[Jenner et al. (1964) and Sporn et al. (1967) as cited in Adams et al. (2005); Taylor et al.,
(1964) as cited in Anderson (2006); Schafer and Bowles (1985) as cited in IPCS (2001);
Eastman Kodak (1991)1.
• An acute inhalation study that reported reduced motor activity in mice following a
1 -hour exposure to undiluted benzaldehyde vapors (Buchbauer et al. 1993).
• Two acute inhalation studies that reported RC50 (concentration that causes 50%
response) values for reduced respiratory rate (indicating sensory irritation) of
>6,177 mg/m3 in rats and 1,450—1,710 mg/m3 in mice (Babiuk et al.. 1985; Steinhagen
and Barrow. 1984).
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• An acute inhalation lethality study that reported an LC50 value >5,504 mg/m3 in rats
(Eastman Kodak. 1991).
• Two acute skin irritation studies in guinea pigs; one reported no irritation (I)uPont.
2000) and one reported moderate skin irritation (Eastman Kodak, 1991).
• Five skin sensitization studies in guinea pigs; four reported no sensitization (DuPont
2000; Confidential. 1992. 1991b; Eastman Kodak. 1991) and one reported mild
sensitization (Confidential. 1991a).
• An acute dermal lethality study that reported an LD50 value >20 mL/kg (Eastman Kodak.
1991).
• One ocular study that reported eye irritation with transient corneal damage (Eastman
Kodak. 1991).
Metabolism/Toxicokinetic Studies
The absorption, distribution, metabolism, and elimination of benzaldehyde are well
characterized and summarized below based on reviews by Adams et al. (2005), Anderson (2006),
and IPCS (2006).
Benzaldehyde is rapidly absorbed following oral or inhalation exposure. Based on in vitro
testing of human cadaver skin, dermal absorption occurs at a rate of 1,970 ± 720 |ig/cm2-hour in
pure liquid form and 450 ± 70 |ig/cm2-hour in the saturated aqueous form. Following absorption,
peak concentrations are reached in well-perfused tissues by 1.5 minutes and poorly perfused tissues
by 12 minutes; after peak concentrations are achieved, benzaldehyde is rapidly cleared from tissues
(half-life of -10 minutes) in a linear fashion.
The principal metabolic path for benzaldehyde is rapid oxidization to benzoic acid via
first-order kinetics; benzoic acid is then conjugated with glycine to form hippuric acid. A minor
metabolic path is reduction into benzyl alcohol, which can react with glutathione as the sulfate
conjugate to form benzylmercapturic acid. After biotransformation, benzaldehyde is almost
exclusively eliminated via excretion in the urine in the form of hippuric acid (-70% of administered
dose); other urinary metabolites include benzoyl glucuronic acid, benzyl glucuronide, free benzoic
acid, and small amounts of benzylmercapturic acid. Urinary clearance is rapid, with metabolites
detectable as early as 1.5 minutes following inhalation exposure.
Mode-of-Action/Mechanistic Studies/Therapeutic action
Mode-of-Action/Mechanistic Studies
Mechanistic studies regarding toxic effects of benzaldehyde exposure are limited [reviewed
by Anderson (2006)1. Benzaldehyde has been shown to inhibit liver and lung metabolic enzymes,
including CYP2B, CYP1 Al, alcohol dehydrogenase, aryl hydrocarbon hydroxylase, and glutathione
peroxidase. Benzaldehyde has also been shown to induce lipid peroxidation and generation of
reactive oxygen species. Observed weight loss in rats following short-term and subchronic
administration of high oral doses of benzaldehyde reported by NTP (1990) may be due to induction
of li poly sis and glucose metabolism [reviewed by Anderson (2006)1.
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Table 4B. Other Supporting Studies
Test
Materials and Methods
Results
Conclusions
References
Reproductive (oral)
10 breeding age rats of an unspecified strain
were administered approximately 0 or 5 mg/kg-d
benzaldehyde via gavage every other day in oil
(unspecified) for 32 wk. It is unclear if both
males and females were exposed or just females.
Rats were mated at D 75 and 180 and the
following parameters were examined for each
mating: number of pregnant females, number of
offspring, pup body weights, and pup vitality.
No statistically significant differences were
reported between the treatment and control
groups. However, it was noted that fewer
females in the benzaldehyde-treated group
became pregnant compared with the
control group (no data were provided).
Available data are
inadequate to make a
NOAEL/LOAEL
determination.
Sporn et al., (1967) as
cited in Adams et al.
(2005)
Developmental
(injection)
168 chicken embryos (white Leghorn x Rhode
Island red strain) were injected
suprablastodermically withO, 0.025, 0.125, 0.25,
0.5, 1.25,2.5, 3.75, 5.00, 12.5, or
25.00 |iIVI/embryo benzaldehyde in olive oil on
the third d of development. The numbers of
dead embryos and embryos with malformations
were determined daily until D 12 of
development. Various other flavoring additives
were evaluated in this study.
The optimal teratogenic dose (OTD),
defined as "the concentration inducing a
maximum teratogenic effect beyond the
limits of the embryonic LD5o," was
25.00 |iIVI/cmbryo. At the OTD, the
percentage of abnormal embryos was
36.6% (compared with 7.9% in controls)
and the percent mortality was 48.3%
(compared with 17.8% in controls). The
OTD for benzaldehyde was higher than the
OTD for the majority of other flavoring
additives.
The teratogenic potential
of benzaldehyde is low
compared with other
flavoring agents.
Abramovici and
Rachmuth-Roizman
(1983)
Subchronic (i.p.)
Female SIV-50 rat (20/group) were administered
1 mg/d benzaldehyde via intraperitoneal (i.p.)
injection for up to 12 wk; histopathological
examination with a focus on the respiratory tract
organs.
After 12 wk of benzaldehyde treatment,
rats exhibited goblet cell hyperplasia,
hyperplasia of the peribronchial lymphatic
system, mucous epithelial atrophy, and
accompanying perivasculitis.
Perivasculitis may have
resulted from damage to
the vessel walls or an
allergic reaction.
Schweiushers et al. (1986)
Acute lethality
(oral)
Rats (10/group; unspecified strain and sex) were
exposed once to benzaldehyde at doses of
200-3,200 mg/kg. Animals were observed for
mortality and clinical signs of toxicity for 2 wk.
Body weights were recorded prior to exposure
and at the end of the 2-wk observation period.
All rats exposed to >1,600 mg/kg died;
none of the rats exposed to <1,600 mg/kg
died. Observed deaths occurred 1.5-4.5 hr
after dosing. Clinical signs of toxicity
included weakness, rough coat, diarrhea,
and bloody urine.
Oral LD5o in
rats = 800-1,600 mg/kg
Eastman Kodak (1991)
Acute lethality
(oral)
White rats were exposed once to benzaldehyde at
various (unspecified) doses. No further details
were available.
No details were provided.
Oral LD5o in
rats = 2,850 mg/kg
Sporn et al., (1967) as
cited in Anderson (2006)
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Table 4B. Other Supporting Studies
Test
Materials and Methods
Results
Conclusions
References
Acute lethality
(oral)
Rats (10/sex/group) were exposed once to
benzaldehyde via gavage at various (unspecified)
doses. No further details were available.
All observed deaths occurred within 18 hr.
Prior to death, rats showed depression or
coma.
Oral LD50 (95% CI) in
rats = 1,300 mg/kg
(1,110-1,540 mg/kg)
Jenner et al., (1964) as
cited in Anderson (2006)
Acute lethality
(oral)
Osborne-Mendal and Sherman rats were exposed
once to benzaldehyde at various (unspecified)
doses. No further details were available.
All observed deaths occurred within 18 hr.
Prior to death, rats showed depression or
coma.
Oral LD50 in
rats = 1,300 mg/kg
Taylor et al., (1964) as
cited in Anderson (2006)
Acute lethality
(oral)
Mice (10/group; unspecified strain) were
exposed once to undiluted benzaldehyde at doses
of 200-3,200 mg/kg. Animals were observed
for mortality and clinical signs of toxicity for
2 wk. Body weights were recorded prior to
exposure and at the end of the 2-wk observation
period.
All mice exposed to >1,600 mg/kg died;
none of the mice exposed to <1,600 mg/kg
died. Observed deaths occurred 4-48 hr
after dosing. Clinical signs of toxicity
included weakness, ataxia, prostration,
rough coat, sides "caved in".
Oral LD50 in
mice = 800-1,600 mg/kg
Eastman Kodak (1991)
Acute lethality
(oral)
Mice were exposed once to benzaldehyde at
various (unspecified) doses via the diet. No
further details were available.
No details were provided.
Oral LD50 in
mice = 1,200 mg/kg
Schafer and Bowles
(1985) as cited in IPCS
(2001)
Acute lethality
(oral)
Guinea pigs (number and strain unspecified)
were exposed once to benzaldehyde via gavage
at various (unspecified) doses. No further details
were available.
All observed deaths occurred between 1 hr
and 4 d after exposure. Prior to death,
guinea pigs showed diuresis, tremors,
intestinal irritation, and hemorrhage.
Oral LD50 (95% CI) in
guinea
pigs = 1,000 mg/kg
(800-1,250 mg/kg)
Jenner et al., (1964) as
cited in Anderson (2006)
Acute (inhalation)
Swiss outbred mice (sex and number
unspecified) were exposed to undiluted
benzaldehyde vapors for 1 hr. Motor activity
was compared to unexposed controls.
Motor activity was decreased by 43.69% in
benzaldehyde-exposed mice, compared
with controls.
Benzaldehyde vapors
have a mild sedative
effect.
Buchbauer et al. (1993)
Acute (inhalation)
Male F344 rats (4/group) were exposed
whole-body to increasing benzaldehyde
concentrations in 10-min intervals (separated by
5-min recovery period) with or without a 9-d
preexposure to 15 ppm formaldehyde (6 hr/d).
The sensory irritation response was determined
by measuring respiratory rate depression. The
concentration needed to cause a 50% decrease in
respiratory rate (RC50) was calculated.
The RC50 was not identified; the RC30 was
determined to be 1,423 ppm without
formaldehyde preexposure. Preexposure to
formaldehyde did not significantly alter the
sensory irritation response.
Inhalation RC50 in rats
>1,423 ppm
(6,177 mg/m3)
Babiuk et al. (1985)
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Table 4B. Other Supporting Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (inhalation)
Male B6C3Fi and Swiss-Webster mice
(3/strain/group) were exposed head-only to
increasing benzaldehyde concentrations in
10-min intervals (separated by 5-min recovery
period). The sensory irritation response was
determined by measuring respiratory rate
depression. The concentration to cause a 50%
decrease in respiratory rate (RD50) was
calculated.
RC50 value (95% CI) in ppm:
B6C3Fi mice: 394 (312-522)
Swiss-Webster mice: 333 (244-506)
Inhalation RC50 in
mice = 333-394 ppm
(1,450-1,710 mg/m3)
Steinfaaeen and Barrow
(1984)
Acute lethality
(inhalation)
3 rats (unspecified strain) were exposed to
1,268 ppm for 6 hr. Animals were observed for
mortality and clinical signs of toxicity for 2 wk.
Body weights were recorded prior to exposure
and at the end of the 2-wk observation period.
No mortalities were observed. Transient
clinical signs included eye blinking,
nose-rubbing, accelerated respiration, and
vasodilation.
Inhalation LC50
>1,268 ppm
(5,504 mg/m3)
Eastman Kodak (1991)
Acute (dermal)
Benzaldehyde was tested for skin irritation and
sensitization in 10 guinea pigs; it is unclear what
concentration was used.
Benzaldehyde was nonirritating and
nonsensitizing.
Benzaldehyde is not a
skin irritant.
Benzaldehyde is not a
skin sensitizer.
[>11 Pont (2000)
Acute (dermal)
Benzaldehyde was evaluated for skin
sensitization in guinea pigs (10/group). Guinea
pigs were given an initial intradermal injection of
0.1 mL of 3.0% benzaldehyde in paraffin oil
followed by a challenge of topically applied
7-15% benzaldehyde in petrolatum (occluded
for 24 hr). Skin was evaluated at 24 and 48 hr.
No positive reactions were observed.
Benzaldehyde is not a
skin sensitizer.
Confidential (1992)
Acute (dermal)
Benzaldehyde was evaluated for skin
sensitization in guinea pigs (10/group). Guinea
pigs were given an initial intradermal injection of
0.1 mL of 2.7% benzaldehyde in paraffin oil
followed by 3 challenges of topically applied
0.24-2.4% benzaldehyde in petrolatum
(occluded for 24 hr). Skin was evaluated at 24
and 48 hr.
No positive reactions were observed.
Benzaldehyde is not a
skin sensitizer.
Confidential (1991b)
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Table 4B. Other Supporting Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (dermal)
Benzaldehyde was evaluated for skin
sensitization in guinea pigs (10/group). Guinea
pigs were given an initial intradermal injection of
0.1 mL of 2.7% benzaldehyde in paraffin oil
followed by 2 challenges of topically applied
2.1% benzaldehyde in petrolatum, and a third
challenge of 0.64% benzaldehyde in petrolatum
(occluded for 24 hr). Skin was evaluated at 24
and 48 hr.
In Challenge 1 and 2, 2/10 animals had a
positive response. In Challenge 3,
0/10 animals had a positive response.
Based on response rate
of 20%, benzaldehyde is
classified as a weak
sensitizer.
Confidential (1991a)
Acute (dermal)
Gauze pads soaked in 5-20 mL/kg undiluted
benzaldehyde were applied to depilated skin of
guinea pigs (3/group) for 24 hr. Guinea pigs
were observed for mortality, skin changes, and
clinical signs of toxicity for 2 wk. Body weights
were recorded prior to exposure and at the end of
the 2-wk observation period.
Benzaldehyde was a moderate skin irritant.
The study authors noted that animals
receiving the highest dose gained less
weight than animals receiving the lowest
dose (data not provided). No mortalities
were observed.
Benzaldehyde is a
moderate skin irritant.
Dermal LD50 >20 mL/kg
Eastman Kodak (1991)
Acute (dermal)
Benzaldehyde was evaluated for skin
sensitization in guinea pigs (5/group). Skin was
evaluated for 48 hr. No further information was
reported.
Benzaldehyde was nonsensitizing.
Benzaldehyde is not a
skin sensitizer.
Eastman Kodak (1991)
Acute (ocular)
1 drop of undiluted benzaldehyde was dropped in
the eye of a rabbit. The eye was monitored for
48 hr.
Immediate irritant effects were noted, with
corneal damage within 24 hr. Only
erythema persisted at 48 hr.
Benzaldehyde is an eye
irritant, causing transient
corneal damage.
Eastman Kodak (1991)
CI = confidence interval.
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Therapeutic Action
Benzaldehyde has been proposed as an antitumor/carcinostatic agent. An early clinical
trial suggested that oral or rectal administration of benzaldehyde in the form of CBDA may halt
or reverse tumor progression (Kochi et al.. 1980) (see experimental details above in "Supporting
Human Studies"). However, results are difficult to interpret due to inconsistent treatment
durations, various tumor types, and lack of control subjects. No additional antitumor studies in
humans have been identified. In animal models, benzaldehyde has led to the reduction of tumor
weights in mice implanted with adenocarcinomas; however, it was either ineffective or only
marginally effective against the advancement of terminal solid tumors in dogs and cats [reviewed
by Anderson (2006)1. Numerous in vitro studies indicate that benzaldehyde is cytotoxic,
antiproliferative, and/or induces apoptosis in primary or transformed mammalian cell lines
[reviewed by Anderson (2006)1.
Benzaldehyde has also been proposed as an antiallergy agent. Oral benzaldehyde
treatment reduced allergic responses in murine models of allergic asthma and rhinitis; the
proposed mechanism was via inhibition of hypoxia-inducible factor 1 (HIF-la) and vascular
endothelial growth factor (VEGF) (Jang et al.. 2014). Additionally, oral benzaldehyde treatment
reduced ovalbumin (OA)-induced bronchoconstriction, decreased eosinophils, neutrophils, and
bronchoconstrictor mediators, LTC4/D4/E4, in bronchoalveolar lavage fluid, and increased
bronchodilator mediator, prostaglandin E2 (PGE2), in bronchoalveolar lavage fluid in
OA-sensitized guinea pigs (I.acroix et al.. 2002).
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
Table 5. Summary of Noncancer Reference Values for Benzaldehyde (CASRN 100-52-7)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Subchronic p-RfD
(mg/kg-d)
Rat/male
and female
Mortality and reduced body
weight in males;
necrotic/degenerative
lesions of the brain, liver,
and kidney, and hyperplasia
and hyperkeratosis of the
forestomach in both sexes
2 x KT1
NOAELhed
68.6
300
NTP
(1990)
Chronic p-RfD
Oral RfD value is available on IRIS.
Subchronic p-RfC
NDr
Chronic p-RfC
NDr
NDr = not determined.
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Table 6. Summary of Cancer Reference Values for Benzaldehyde (CASRN 100-52-7)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
Provisional oral slope factor (p-OSF) (mg/kg-d) 1
Mouse/female
Forestomach
squamous cell
papilloma
4 x 1(T3
NTP (1990)
Provisional inhalation unit risk (p-IUR) (lng/in3) 1
NDr
NDr = not determined.
DERIVATION OF ORAL REFERENCE DOSES
The database of potentially relevant studies for derivation of oral reference values for
benzaldehyde includes 16-day, 13-week, and 2-year studies in rats and mice sponsored by the
NTP (N I P. 1990; Kluwe et ai, 1983) and 16- and 28-week studies in rats (Hagan et aL 1967).
A subchronic provisional oral reference dose (p-RfD) is derived based on the available studies.
A chronic p-RfD is not derived because there is an oral RfD value on EPA's IRIS database.
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
The NTP (1990) subchronic-duration study in rats was selected as the principal study for
derivation of the subchronic p-RfD. Critical effects from this study were mortality in males;
reduced body weight in surviving males; necrotic and degenerative lesions of the brain, liver, and
kidney in males and females; and proliferative lesions in the forestomach in males and females.
Justification of the Principal Study
A comparison of the results from the 13-week gavage studies in rats and mice (NTP.
1990) indicated that the rat was more sensitive than the mouse. In the rat, mortality of males
occurred at a lower dose than in mice, lesions were found in the brain, liver, and forestomach, in
addition to the kidney (in mice, only kidney lesions were observed), and lesions were found in
both sexes (no effects were seen in female mice). Therefore, the subchroni c-durati on NTP
(1990) rat study was selected as the principal study for derivation of the subchronic p-RfD. This
study is a peer-reviewed published study with an adequate number of dose groups and dose
spacing, sufficient group sizes, and quantitation of results to describe dose-response relationships
for the critical effects in rats associated with subchronic oral exposure to benzaldehyde.
Short-term-duration gavage studies in rats and mice were not selected as principal studies
because of the brief exposure duration (NTP. 1990). Chronic-duration studies in rats and mice
(NTP. 1990) demonstrated effects at lower doses than the subchroni c-durati on studies, but were
not selected as principal studies for the subchronic p-RfD derivation due to the near-lifetime
exposure duration.
Justification of the Critical Effect
Mortality was increased at the lowest doses causing adverse effects across short-term,
subchronic, and chronic exposure durations, although limited to males of both species in the
subchronic-duration studies and male rats in the chronic-duration studies (see Table 3 A).
Mortality was the most sensitive effect identified in the short-term-duration NTP (1990) studies
in both rats and mice. Reduced body weight was also seen in survivors among the rats.
Mortality was also among the most sensitive effects found in the subchroni c-durati on NTP
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(1990) rat and mouse studies, although in these studies, it occurred only in males, and organ
effects were observed as well (necrotic/degenerative lesions of the brain, liver, and kidney, and
hyperplasia and hyperkeratosis of the forestomach in male and female rats; degenerative kidney
lesions in male mice). In the chronic-duration studies (N I P. 1990) mortality was again among
the critical effects in male rats; in this case, hyperplasia of the pancreas was seen in surviving
animals. Proliferative lesions in the forestomach were the most sensitive findings in chronically
exposed mice, at the same dose that caused mortality in male rats. Mortality, reduced body
weight, and lesions occurring at the same dose were selected as cocritical effects for derivation
of the sub chronic p-RfD.
Approach for Deriving the Subchronic p-RfD
The NOAELadd of 286 mg/kg-day is the selected point of departure (POD) for derivation
of the subchronic p-RfD. Data for all cocritical endpoints were not amenable to benchmark dose
(BMD) modeling because all effects were seen only in the high-dose group.
In Recommended Use of Body Weight4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA. 2011b). the Agency endorses a hierarchy of approaches to derive
human equivalent oral exposures from data from laboratory animal species, with the preferred
approach being physiologically based toxicokinetic modeling. Other approaches may include
using some chemical-specific information, without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses body-weight scaling to the 3/4 power
(i.e., BW3/4) as a default to extrapolate toxicologically equivalent doses of orally administered
agents from all laboratory animals to humans for the purpose of deriving an RfD under certain
exposure conditions. More specifically, the use of BW3/4 scaling for deriving an RfD is
recommended when the observed effects are associated with the parent compound or a stable
metabolite but not for portal-of-entry effects.
A validated human physiologically based pharmacokinetic (PBPK) model for
benzaldehyde is not available for use in extrapolating doses from animals to humans. In
addition, the selected POD of 286 mg/kg-day is based on systemic effects, which are not
portal-of-entry effects. Therefore, scaling by BW3/4 is relevant for deriving human equivalent
doses (HEDs) for this effect.
Following U.S. EPA (2011b) guidance, the POD for the subchronic study in rats (NTP,
1990) is converted to a HED through the application of a DAF derived as follows:
DAF = (BWa1/4 - BWh1/4)
where:
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a reference BW„ of 0.25 kg for rats and a reference BWh of 70 kg for humans (U.S.
EPA. 1988b). the resulting DAF is 0.24. Applying this DAF to the NOAELadd of
286 mg/kg-day yields a NOAELhed of 70 mg/kg-day, as follows:
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NOAELhed = NOAELadd (mg/kg-day) x DAF
= 286 mg/kg-day x 0.24
= 70 mg/kg-day
The subchronic p-RfD for benzaldehyde, based on a NOAELhed of 70 mg/kg-day for
mortality, decreased body weight, and degenerative tissue lesions, is derived as follows:
Subchronic p-RfD = NOAELhed ^ UFc
= 70 mg/kg-day -^300
= 2 x 10"1 mg/kg-day
Table 7 summarizes the UFs for the subchronic p-RfD for benzaldehyde.
Table 7. Uncertainty Factors for Subchronic p-RfD for Benzaldehyde
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for residual uncertainty associated with
extrapolating from animals to humans when cross-species dosimetric adjustment (HED
calculation) is performed.
UFh
10
A UFh of 10 is applied to account for human-to-human variability in susceptibility in the
absence of quantitative information to assess the toxicokinetics and toxicodynamics of
benzaldehyde in humans.
UFd
10
A UFd of 10 has been applied because there are no acceptable two-generation
reproductive or developmental toxicity studies for benzaldehyde via the oral route.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the critical study has a subchronic duration.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
The confidence in the subchronic p-RfD for benzaldehyde is medium as explained in
Table 8 below.
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Table 8. Confidence Descriptors for the Subchronic p-RfD for Benzaldehyde
Confidence Categories
Designation3
Discussion
Confidence in principal study
M
The confidence in the principal study is medium. The study
was of appropriate duration and included histopathology, but
organ weight, hematology, and clinical chemistry analyses were
not conducted. The study identified a NOAEL, but frank
effects were seen at the lowest effect level (LOAEL).
Confidence in database
M
The confidence in the database is medium. The database
includes NTP-sponsored short-term-, subchronic-, and
chronic-duration studies in male and female rats and mice.
However, clinical chemistry and hematology were not
performed in these studies. Hematology was assessed in the
16-wk studv bv Hasan et al. (1967); however, data reoortine in
this study are inadequate for independent review. Additionally,
no two-generation reproduction studies or developmental
studies are available. A single-generation reproduction study
indicated possible effects on reproduction, even though no
statistically significant changes were found; however, this
report was only available as a summary in a secondary source,
and numerical data were not available for independent review
|Sporn et al. (1967) as cited in Adams et al. (2005)1.
Confidence in subchronic p-RfD
M
The overall confidence in the subchronic p-RfD is medium.
aM = medium.
Derivation of Chronic Provisional RfD (Chronic p-RfD)
A chronic p-RfD value is not derived because an oral RfD value is available on EPA's
IRIS database.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Human and animal data are inadequate to derive subchronic or chronic provisional
inhalation reference concentrations (p-RfCs) for benzaldehyde. There is a single
short-term-duration inhalation study available for benzaldehyde inhalation in rats (l.aham et al„
1991). This study is of insufficient duration to serve as basis for an inhalation reference value.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
The cancer weight of evidence (WOE) for oral exposure to benzaldehyde is "Suggestive
Evidence of Carcinogenic Potential;" the cancer WOE for inhalation exposure to benzaldehyde
is "Inadequate Information to Assess Carcinogenic Potential" (see the details below and in
Table 9).
Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, the database for
oral exposure to benzaldehyde provides suggestive evidence of carcinogenic potential. This
descriptor is based on a significant increase in forestomach papilloma in female mice, a
near-significant trend for increased forestomach papilloma in male mice, and significant
increases in preneoplastic forestomach lesions (hyperplasia) in male and female mice exposed to
benzaldehyde via gavage for 104 weeks, which NTP (1990) considered to provide "some
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evidence of carcinogenicity." There was no evidence of carcinogenicity in rats in a companion
2-year bioassay (N I P. 1990). and no other relevant human or animal data were located.
Following U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, the database for
inhalation exposure to benzaldehyde provides inadequate information to assess carcinogenic
potential. No human or chronic-duration animal inhalation studies have been identified.
Table 9. Cancer Weight-of-Evidence Descriptor for Benzaldehyde
Possible WOE
Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to
Humans "
NS
NA
There are no human data to support this.
"Likely to Be
Carcinogenic to
Humans "
NS
NA
Results from available animal studies are not
sufficient to support this, and no human data are
available.
"Suggestive Evidence of
Carcinogenic Potential"
Selected
Oral
NTP (1990) conducted carcinogenicity studies
in rats and mice. In mice, NTP concluded there
was "some evidence of carcinogenicity" based
on significant increases in forestomach
papilloma in females, a "near-significant" trend
for increased forestomach papilloma in males,
and significant increases in preneoplastic
forestomach lesions (hyperplasia) in both sexes.
In rats, there was no evidence of
carcinogenicity.
"Inadequate
Information to Assess
Carcinogenic Potential"
Selected
Inhalation
There are no human or animal inhalation
carcinogenicity studies available.
"Not Likely to Be
Carcinogenic to
Humans "
NS
NA
The available data do not support this.
NA = not applicable, NS = not selected.
MODE-OF-ACTION (MOA) DISCUSSION
The Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 2005) define MOA ".. .as a
sequence of key events and processes, starting with interaction of an agent with a cell,
proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action for any given chemical include
"mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression" (pp. 1-10).
A carcinogenic MOA of benzaldehyde is not known. The available evidence suggests
that benzaldehyde is equivocally mutagenic, but may cause DNA damage and clastogenic effects
(see "Genotoxicity Studies" section for more details). Forestomach tumors in female mice
following chronic oral exposure to benzaldehyde (N I P. 1990) might be hypothesized to result
from cytotoxicity followed by sustained regenerative cell proliferation. In support, forestomach
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hyperplasia was increased in a dose-related manner in both male and female mice following
chronic exposure to benzaldehyde (N I P. 1990). and the cytotoxicity of benzaldehyde has been
demonstrated in numerous in vitro studies [reviewed by Anderson (2006)1. However,
benzaldehyde has also been shown to have antiproliferative and apoptotic effects on transformed
cell lines, and is a proposed anticancer agent [reviewed by Anderson (2006)1. No firm
conclusion regarding possible MO As for benzaldehyde carcinogenicity can be made, and a
mutagenic mode of action cannot be ruled out. Thus, a linear approach is applied as
recommended by U.S. EPA (2005).
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
An NTP 2-year bioassay in rats and mice was available for the development of a
provisional oral slope factor (p-OSF) (NTP. 1990). This study was conducted in accordance
with good laboratory practice (GLP) principles, was peer reviewed, and meets the standards of
study design and performance with respect to the number of animals used, the examination of
potential toxicity endpoints, and the presentation of information.
No clear evidence of carcinogenicity was observed in the rat study. However, in the
mouse study, NTP (1990) concluded that there was "some evidence of carcinogenicity" in male
and female mice based on increases in the incidences of squamous cell papilloma and
hyperplasia of the forestomach. The increased incidence of squamous cell papilloma was only
statistically significant in female mice, but "near significant (p = 0.057)" in males. Forestomach
tumor incidence in female mice was selected for BMD modeling. Prior to modeling, all doses
were converted to HEDs using BW3/4 scaling, as recommended by the U.S. EPA (2011b); see the
Derivation of a Sub chronic p-RfD section for more details. Following U.S. EPA (2011b)
guidance, the administered doses for the chronic-duration study in mice are converted to HED
doses through the application of a DAF derived as follows:
DAF = (BWa1/4 - BWh1/4)
where:
DAF = dosimetric adjustment factor
BWa = animal body weight
BWh = human body weight
Using a reference BWa of 0.025 kg for mice and a reference BWh of 70 kg for humans
(U.S. EPA, 1988b), the resulting DAF is 0.14. HED doses of 30.0 or 60.1 mg/kg-day in females
were calculated as follows:
Low-doseHED
High-doseHED
= low-dose (mg/kg-day) x (days per week/7) x DAF
= 214 mg/kg-day x (5/7) x 0.14
= 30.0 mg/kg-day
= high-dose (mg/kg-day) x (days per week/7) x DAF
= 429 mg/kg-day x (5/7) x 0.14
= 60.1 mg/kg-day
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Based on BMD modeling, a 10% benchmark dose lower confidence limit human
equivalent dose (BMDLiohed) of 25.7 mg/kg-day was calculated (see Table 10; additional BMD
details in Appendix C). The BMDLiohed of 25.7 mg/kg-day was used as the POD for derivation
of the p-OSF.
Table 10. BMD Model Results for Derivation of the p-OSFa
Reference
Tumor
Endpoint
Model Type
Goodness-of-Fit
/7-Value
AIC
BMDiohed
(mg/kg-d)
BMDLiohed
(mg/kg-d)
p-OSF
(mg/kg-d)1
NTP
(1990)
Forestomach
squamous cell
papilloma in
female mice
Multistage-cancer-
1st order
0.7076
71.86
40.6
25.7
4 x 10-3
"All modeling was conducted using U.S. EPA BMDS (Version 2.5). BMD analysis details are available in
Appendix C.
The p-OSF is derived as follows:
p-OSF = Benchmark response (BMR) ^ BMDLiohed
= 0.10 ^ 25.7 mg/kg-day
= 4.0 x 10"3 (mg/kg-day)-1
Derivation of Provisional Inhalation Unit Risk (p-IUR)
The lack of data on the carcinogenicity of benzaldehyde following inhalation exposure
precludes the derivation of a quantitative estimate (p-IUR) for inhalation exposure.
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APPENDIX A. SCREENING PROVISIONAL VALUES
No provisional screening values are derived.
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APPENDIX B. DATA TABLES
Table B-l. Survival and Terminal Body Weights of Male and Female F334/N Rats
Administered Benzaldehyde via Gavage 5 Days/Week for 16 Days"
Parameter
Dose Group, mg/kg-d (ADD, mg/kg-d)b
0(0)
100 (71.4)
200 (143)
400 (286)
800 (571)
1,600 (1,143)
Males
Survival
5/5
(100%)
5/5
(100%)
5/5
(100%)
5/5
(100%)
3/5
(60%)
0/5°
(0%)
Terminal body weight (g)d
238 ±6
228 ±6
(-4%)
229 ±4
(-4%)
240 ±4
(+1%)
204 ± 8°
(-14%)
NAe
Females
Survival
5/5
(100%)
5/5
(100%)
5/5
(100%)
5/5
(100%)
3/5
(60%)
0/5°
(0%)
Terminal body weight (g)d
151 ± 2
140 ± 2°
(-7%)
145 ±3
(-4%)
154 ±4
(+2%)
135 ±2C
("11%)
NAe
•'N I P ( 1990).
bADD (adjusted daily dose) = dose x (5 days/7 days).
Statistically significantly different from controls atp< 0.05, as calculated for this review (Fisher's exact test,
student's t-test; 2-tailed).
dValues are expressed as mean ± standard error of the mean (SEM) (percent change compared with control) for rats
surviving to 16 days; % change control = [(treatment mean - control mean)/control mean] x 100
eNA = not applicable; no body weight data were presented by the study authors due to 100% mortality in the
highest dose animals.
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Table B-2. Survival and Terminal Body Weights of Male and Female F334/N Rats
Administered Benzaldehyde via Gavage 5 Days/Week for 13 Weeks3
Parameter
Dose Group, mg/kg-d (ADD, mg/kg-d)b
0(0)
50 (36)
100 (71.4)
200 (143)
400 (286)
800 (571)
Males
Survival
10/10
(100%)
10/10
(100%)
10/10
(100%)
10/10
(100%)
10/10
(100%)
4/10°
(40%)
Terminal body weight (g)d
340 ±5
338 ±6
(-1%)
346 ±6
(+2%)
349 ±6
(+3%)
329 ±8
(-3%)
252 ± 5°
(-26%)
Females
Survival
9/10
(90%)
10/10
(100%)
10/10
(100%)
10/10
(100%)
9/10
(90%)
7/10
(70%)
Terminal body weight (g)d
203 ±3
196 ±4
(-3%)
203 ±3
(+0%)
200 ±4
(-1%)
203 ±3
(+0%)
213 ±4
(+5%)
•'N1TP ( 1990).
bADD (adjusted daily dose) = dose x (5 days/7 days).
Statistically significantly different from controls atp< 0.05, as calculated for this review (Fisher's exact test,
student's t-test; 2-tailed).
dValues are expressed as mean ± SEM (percent change compared with control) for rats surviving to 16 days;
% change control = [(treatment mean - control mean)/control mean] x 100.
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Table B-3. Histopathological Findings in Male and Female F344 Rats Administered
Benzaldehyde via Gavage 5 Days/Week for 13 Weeks"
Parameter13
Dose Group, mg/kg (ADD, mg/kg-d)c
0
400 (286)
800 (571)
Males
Brain
Cerebellum degeneration
0/10 (0%)
0/10 (0%)
9/10** (90%)
Cerebellum necrosis
0/10 (0%)
0/10 (0%)
10/10** (100%)
Cerebellum mineralization
0/10 (0%)
0/10 (0%)
7/10** (70%)
Hippocampus necrosis
0/10 (0%)
0/10 (0%)
6/6** (100%)
Forestomachd
Hyperplasia
0/10 (0%)
0/10 (0%)
6/10** (60%)
Hyperkeratosis
0/10 (0%)
0/10 (0%)
5/10* (50%)
Liver
Degeneration
0/10 (0%)
0/10 (0%)
4/10* (40%)
Necrosis
0/10 (0%)
0/10 (0%)
3/10 (30%)
Kidney
Tubule degeneration
0/10 (0%)
0/10 (0%)
4/10* (40%)
Tubule necrosis
0/10 (0%)
0/10 (0%)
3/10 (30%)
Females
Brain
Cerebellum degeneration
0/9 (0%)
0/10 (0%)
10/10** (100%)
Cerebellum necrosis
0/9 (0%)
0/10 (0%)
10/10** (100%)
Cerebellum mineralization
0/9 (0%)
0/10 (0%)
0/10 (0%)
Hippocampus necrosis
0/9 (0%)
0/10 (0%)
10/10** (100%)
Forestomachd
Hyperplasia
0/9 (0%)
0/10 (0%)
8/10** (80%)
Hyperkeratosis
0/9 (0%)
0/10 (0%)
6/10** (60%)
Liver
Degeneration
0/9 (0%)
0/10 (0%)
4/10* (40%)
Necrosis
0/9 (0%)
0/10 (0%)
0/10 (0%)
Kidney
Tubule degeneration
0/9 (0%)
0/10 (0%)
4/10* (40%)
Tubule necrosis
0/9 (0%)
0/10 (0%)
3/10 (30%)
aNTP (1990). Note: not all dose groups were examined histologically.
bResults are expressed as the number of animals with lesions/number of animals examined (%).
°ADD (adjusted daily dose) = dose x (5 days/7 days).
'Kinwe et al. (1983) reported that 2/10 males had forestomach hyperplasia and hyperkeratosis at 400 mg/kg-day;
this finding was used to identify a NOEL and LOAEL of 200 and 400 mg/kg-day for the 1988 IRIS assessment
(U.S. EPA. 2003).
* Statistically significantly different from control (p < 0.05); as determined by the study authors.
**Statistically significantly different from control (p < 0.01); as determined by the study authors.
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Table B-4. Survival and Select Neoplastic and Preneoplastic Lesions in Male F344 Rats
Administered Benzaldehyde via Gavage 5 Days/Week for 103 Weeks3
Parameterb
Dose Group, mg/kg (ADD, mg/kg-d)c
0
200 (143)
400 (286)
Survival
37/50f (74%)
29/50 (58%)
21/50* (42%)
Pancreas
Hyperplasia
Adenomad
6/49 (12%)
3/49 (6%)
6/49 (12%)
2/49 (4%)
12/48f * (25%)
7/48f * (15%)
Mesothelium
Mesothelioma"
0/50 (0%)
5/50* (10%)
2/50 (4%)
Hematopoeitic system
Mononuclear cell leukemia
All stagesf
Stage 1
Stage 2 and 3 (combined)
10/50f (20%)
4/50 (8%)
6/50 (12%)
17/50* (34%)
10/50 (20%)
7/50 (14%)
16/50* (32%)
7/50 (14%)
9/50 (18%)
aNTP (1990).
bResults expressed as the number of animals observed with lesion/number of animals examined for that lesion (%
incidence). Statistical results in the control column represent the trend test, while the statistical results in the
dosed columns represent pairwise comparisons with the vehicle control.
°ADD (adjusted daily dose) = dose x (5 days/7 days).
dThe historical control incidence range of pancreatic acinar cell neoplasms (adenomas or carcinomas combined) at
the study laboratory is 0/49-11/50 (0-22%). The mean historical control incidence at the study laboratory
(mean ± SD) is 36/397 (9 ± 9%). The mean historical control incidence in NTP studies (mean ± SD) is 107/2,011
(5 ± 7%).
eThe mean historical control incidence for mesotheliomas at the study laboratory (mean ± SD) is 15/450 (3 ± 3%).
The mean historical control incidence in NTP studies (mean ± SD) is 78/2,099 (4 ± 3%).
fThe mean historical control incidence of leukemia at the study laboratory (mean ± SD) is 45/450 (10 ± 8%). The
mean historical control incidence in NTP studies (mean ± SD) is 361/2,099 (17 ± 9%).
* Statistically significantly different from controls at p< 0.05, as reported by the study authors.
f Statistically significant dose-related trend (p < 0.05), as reported by the study authors.
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Table B-5. Survival and Neoplastic and Preneoplastic Forestomach Lesions in
Male and Female B6C3Fi Mice Exposed to Benzaldehyde via Gavage
5 Days/Week for 103-104 Weeks"
Parameterb
Exposure Group mg/kg-d (ADD, mg/kg-d)c
Males
0
200 (143)
400 (286)
Survival
32/50 (64%)
33/50 (66%)
31/50 (62%)
Focal hyperplasia
7/50 (14%)
8/50 (16%)
16/50** (32%)
Squamous cell papillomad
1/50 (2%)
2/50 (4%)
5/50N S (10%)
Females
0
300 (214)
600 (429)
Survival
30/50 (60%)
27/50 (54%)
35/50 (70%)
Focal hyperplasia
12/50 (24%)
23/50* (46%)
39/50** (78%)
Squamous cell papillomad
0/50f (0%)
5/50* (10%)
6/50* (12%)
•'N I P ( 1990).
bResults expressed as the number of animals observed with lesion/number of animals examined for that lesion
(% incidence). Statistical results in the control column represent the trend test, while the statistical results in the
dosed columns represent pairwise comparisons with the vehicle control.
°ADD (adjusted daily dose) = dose x (5 days/7 days).
dThe mean historical control incidence of squamous cell papillomas and/or carcinomas (combined) of the
forestomach at the study laboratory (mean ± SD) is 8/445 (2 ± 4%) for males and 8/446 (2 ± 3%) for females. The
mean historical control incidence reported in NTP studies (mean ± SD) is 39/2,033 (2 ± 3%) for males and
33/2,047 (2 ± 3%) for females.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
f Statistically significant dose-related trend (p < 0.05), as reported by the study authors.
N s "Near-significant" dose-related trend (p = 0.057), as reported by the study authors.
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Table B-6. Survival and Terminal Body and Liver Weights of Male and Female
Sprague-Dawley Rats Exposed to Benzaldehyde via Inhalation 6 Hours/Day for 14 Days"
Parameter
Exposure, mg/m3 (HECi:R)b
0
2,170 (543)
3,260 (815)
4,341 (1,085)
Male
Survival
14/14 (100%)
14/14 (100%)
14/14 (100%)
13/14 (93%)
Terminal body weight0 (g)
348 ±5
327 ± 4** (-6%)
322 ± 4*** (-7%)
322 ± 6** (-7%)
Liver
Relative0 (g)
Liver-to-body weight ratio
NRd
2.50 ±0.08
NR
2.96 ± 0.02* (+18%)
NR
NR
NR
NR
Female
Survival
14/14 (100%)
14/14 (100%)
11/14 (79%)
4/14 (29%)
Terminal body weight0 (g)
224 ±2
227 ± 2 (+1%)
222 ± 1 (-1%)
221 ± 5 (-1%)
Liver
Absolute0 (g)
Liver-to-body weight ratio
6.10 ±0.08
2.70 ±0.10
8.00 ±0.02* (+31%)
3.52 ±0.06 (+30%)*
7.60 ± 0.02* (+25%)
3.40 ± 0.02* (+26%)
7.00 ± 0.02* (+15%)
3.10 ±0.20* (+15%)
aLahametal. (1991).
bHECER = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week exposed + 7) x ratio of blood:gas
partition coefficient (animal:human) [default value of 1].
°Weights expressed as mean± SEM (percent change compared with control) for rats surviving until sacrifice on
Day 14; % change control = [(treatment mean - control mean)/control mean] x 100.
dNR = values were not reported by the study authors, however, the authors stated there were no significant
increases in these treated group.
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
***Statistically significantly different from control (p < 0.001), as reported by the study authors.
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Table B-7. Selected Hematology Parameters of Male and Female Sprague-Dawley Rats
Exposed to Benzaldehyde via Inhalation 6 Hours/Day for 14 Days3
Parameterb
Exposure, mg/m3 (HECer)c
0
2,170 (543)
3,260 (815)
4341 (1,085)
Male
RBCs (x 1012/L)
6.3 ±0.1
6.3 ±0.1 (+0%)
7.1 ±0.2* (+13%)
6.2 ± 0.05 (-2%)
Hematocrit (L/L)
0.37 ±0.004
0.37 ± 0.009 (+0%)
0.41 ±0.007* (+11%)
0.35 ± 0.004* (-5%)
Hemoglobin (g/L)
140.0 ±2.0
137.0 ±3.0 (-2%)
144.0 ± 2.0 (+3%)
125.0 ±2.0* (-11%)
MCH (pg)
22.2 ±0.3
21.7 ±0.2 (-2%)
20.3 ± 0.2* (-9%)
20.2 ±0.3* (-9%)
MCHC (g/L)
378.4 ±2.0
370.3 ± 2.0 (-2%)
351.2 ± 1.0* (-7%)
357.0 ±3.0* (-6%)
WBCs (x 109/L)
9.4 ±0.5
11.5 ± 1.2 (+22%)
11.0 ± 1.0 (+17%)
12.7 ± 0.2* (+35%)
Monocytes (x 109/L)
0.12 ±0.06
0.20 ± 0.1 (+67%)
0.31 ±0.08 (+158%)
0.06 ± 0.03 (-50%)
Female
RBCs (x 1012/L)
6.3 ±0.1
6.4 ±0.1 (+2%)
6.4 ±0.1 (+2%)
5.8 ±0.1* (-8%)
Hematocrit (L/L)
0.34 ±0.004
0.35 ± 0.006 (+3%)
0.36 ± 0.005 (+6%)
0.33 ±0.003* (-3%)
Hemoglobin (g/L)
133.0 ±2.0
133.0 ± 1.0 (+0%)
133.0 ±2.0 (+0%)
125.0 ± 2.0* (-6%)
MCH (pg)
21.1 ± 0.3
20.8 ± 0.4 (-1%)
20.8 ± 0.2 (-1%)
21.6 ±0.5 (+2%)
MCHC (g/L)
391.2 ±5.0
380.0 ± 6.0 (-3%)
369.4 ±3.0* (-6%)
378.8 ± 6.0 (-3%)
WBCs (x 109/L)
7.5 ±0.8
9.7 ± 0.7 (+29%)
9.0 ± 1.7 (+20%)
8.2 ± 1.0 (-6%)
Monocytes (x 109/L)
0.02 ±0.008
0.19 ±0.05* (+850%)
0.21 ±0.03* (+950%)
0.15 ±0.02* (+650)
aLaham et al. (1991).
bResults expressed as mean ± SEM (percent change compared with control) for 4-6 rats/group; % change
control = [(treatment mean - control mean)/control mean] x 100.
°HECer = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week exposed + 7) x ratio of blood-gas
partition coefficient (animal:human) [default value of 1].
* Statistically significantly different from control (p < 0.05); as reported by the study authors.
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Table B-8. Selected Clinical Chemistry Parameters of Male and Female Sprague-Dawley
Rats Exposed to Benzaldehyde via Inhalation 6 Hours/Day for 14 Days"
Parameterb
Exposure, mg/m3 (HECer)c
0
2,170 (543)
3,260 (815)
4,341 (1,085)
Male
Albumin (g/L)
32.0 ±0.2
32.0 ± 0.5 (0%)
33.0 ±0.4** (+3%)
35.0 ± 4.0 (+9%)
Total protein (g/L)
55.0 ±0.8
54.0 ± 1.0 (-2%)
56.0 ± 0.8 (+2%)
55.0 ± 1.0 (+0%)
Cholinesterase (U/L)
648.7 ±21.2
643.2 ± 15.4 (-1%)
639.0 ± 11.8 (+1%)
735.0 ±33.0 (+13%)
AST (U/L)
88.5 ±5.7
123.0 ±6.5 ** (+39%)
139.6 ± 8.5*** (+58%)
116.2 ±5.7 **
(+31%)
ALT (U/L)
39.3 ±6.0
48.3 ± 1.4 (+23%)
53.6 ±2.9 (+36%)
44.3 ± 1.9 (+13%)
Female
Albumin (g/L)
36.0 ±0.5
33.0 ±0.4** (-8%)
32.0 ±0.5*** (-11%)
32.0 ±0.2***
(-11%)
Total protein (g/L)
61.0 ± 1.0
58.0 ± 0.8* (-5%)
56.0 ± 0.7** (-8%)
58.0 ± 0.2* (-5%)
Cholinesterase (U/L)
1,348.8 ±41.1
870.0 ± 32.7*** (-35%)
900.9 ± 46.9*** (-33%)
993.8 ±87.2*
(-26%)
AST (U/L)
73.0 ±4.6
108.7 ± 2.6*** (+49%)
184.1 ± 30.3** (+152%)
115.3 ±8.6**
(+58%)
ALT (U/L)
35.0 ± 1.5
44.3 ± 5.0 (+27%)
46.8 ± 4.4* (+34%)
39.0 ±2.9 (+11%)
aLaham et al. (1991).
bResults expressed as mean ± SEM (percent change compared with control) for 4-6 rats/ group; % change
control = [(treatment mean - control mean)/control mean] x 100.
°HECer = (ppm x MW + 24.45) x (hours/day exposed + 24) x (days/week exposed + 7) x ratio of blood:gas
partition coefficient (animal:human) [default value of 1].
* Statistically significantly different from control (p < 0.05), as reported by the study authors.
**Statistically significantly different from control (p < 0.01), as reported by the study authors.
***Statistically significantly different from control (p < 0.001), as reported by the study authors.
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODEL-FITTING PROCEDURE FOR CANCER INCIDENCE DATA
The model-fitting procedure for dichotomous cancer incidence is as follows. The
Multistage-Cancer Model in the EPA's benchmark dose software (BMDS) (Version 2.6) is fit to
the incidence data using the extra risk option. The multistage-cancer model is run for all
polynomial degrees up to n~ 1 (where n is the number of dose groups including control). An
adequate model fit is judged by three criteria: (1) goodness-of-fit p-value (p < 0.1), (2) visual
inspection of the dose-response curve, and (3) scaled residual at the data point (except the
control) closest to the predefined benchmark response (BMR). Among all of the models
providing adequate fit to the data, the benchmark dose lower confidence limit (BMDL) for the
best fitting multistage-cancer model as judged by the goodness-of-fitp-walue and Akaike's
information criterion (AIC) is selected as the point of departure (POD). In accordance with U.S.
EPA (2012b) guidance, benchmark dose (BMD) and BMDL values associated with an extra risk
of 10% are calculated.
BMD MODELING TO IDENTIFY POTENTIAL PODs FOR p-OSF DERIVATION
The following data set was selected for BMD modeling:
• Incidence data for forestomach squamous cell papilloma in female B6C3Fi mice
administered benzaldehyde via gavage 5 days/week for 104 weeks (N I P. 1990).
Increased Incidence of Forestomach Squamous Cell Papilloma in Female Mice Exposed to
Benzaldehyde for 104 Weeks
The procedure outlined above was applied to the data for forestomach squamous cell
papilloma in female B6C3Fi mice administered benzaldehyde via gavage 5 days/week for
104 weeks (N I P. 1990) (see Table C-l). Table C-2 summarizes the BMD modeling results.
Both multistage cancer models provided adequate fit to the incidence data, with the 2-degree
multistage cancer model converging upon the 1-degree. Thus, the BMDLiohed of
25.7 mg/kg-day from the 1-degree model is selected for this end point (see Figure C-l and the
BMD text output for details).
Table C-l. Combined Incidence of Forestomach Squamous Cell Papilloma in Female
B6C3Fi Mice Administered Benzaldehyde via Gavage 5 Days/Week for 104 Weeks"
HED (mg/kg-d)b
0
30.0
60.1
Sample size
50
50
50
Incidence
0
5
6
•'N' T'P (1990).
bGavage doses were converted to ADDs by multiplying the administered gavage dose by (5/7) days/week and
converted into HEDs using BW3'4 scaling.
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Table C-2. BMD Modeling Results for Incidence of Forestomach Squamous Cell
Papilloma in Female B6C3Fi Mice Administered Benzaldehyde via Gavage
5 Days/Week for 104 Weeks
X2 Goodness-of-Fit
BMDio
BMDLio
Model
/j-value"
Scaled Residualsb
AIC
(mg/kg-d, HED)
(mg/kg-d, HED)
Multistage-cancer (l-degree)cd
0.7076
0.675
71.8645
40.61
25.67
Multistage-cancer (2-degree)0
0.7076
0.675
71.8645
40.61
25.67
aValues <0.1 fail to meet conventional goodness-of-fit criteria.
bScaled residuals for dose group close to the BMD.
Tower restricted to >1.
dSelected model.
BMD = maximum likelihood estimate of the dose associated with the selected BMR; BMDL = 95% lower
confidence limit on the BMD (subscripts denote BMR: i.e., io = dose associated with 10% extra risk); DF = degrees
of freedom
Multistage Cancer Model, with BMR of 10% Extra Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
Multistage Cancer
Linear extrapolation
0.25
0.2
0.15
o
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Text Output for Multistage (1-degree) Model for Incidence of Forestomach Squamous Cell
Papilloma in Female B6C3Fi Mice Administered Benzaldehyde via Gavage 5 Days/Week
for 104 Weeks OTP. 1990)
Multistage Model. (Version: 3.4; Date: 05/02/2014)
Input Data File: E:/PPRTV/clearance review/Benzaldehyde/Dan
BMD/msc_Benzaldehyde Cancer_Mscl-BMR10.(d)
Gnuplot Plotting File: E:/PPRTV/clearance review/Benzaldehyde/Dan
BMD/msc_Benzaldehyde Cancer_Mscl-BMR10.pit
Mon Sep 21 17:15:47 2015
BMDS Model Run
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl) ]
The parameter betas are restricted to be positive
Dependent variable = Effect
Independent variable = Dose
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 2
Total number of specified parameters = 0
Degree of polynomial = 1
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
Background = 0.0137196
Beta(1) = 0.00213056
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
Beta(1)
Beta (1) 1
Parameter Estimates
95.0% Wald Confidence
Interval
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Variable
Limit
Background
Beta(1)
0.00412911
Estimate
0
0.00259473
Std. Err.
NA
0.000782862
Lower Conf. Limit Upper Conf.
0. 00106035
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-34.6004
-34.9323
-39.3266
# Param's Deviance Test d.f. P-value
3
1 0.663714 2 0.7176
1 9.45234 2 0.00886
AIC:
71.8645
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
30.0000
60.0000
0.0000
0. 0749
0.1442
0.000
3.744
7.209
0.000
5.000
6.000
50.000
50.000
50.000
0. 000
0. 675
-0.487
Chi^2 =0.69
d.f. = 2
P-value = 0.7076
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 40.6055
BMDL = 25.6719
BMDU = 74.7426
Taken together, (25.6719, 74.7426) is a 90 % two-sided confidence
interval for the BMD
Cancer Slope Factor = 0.00389531
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