SEPA
United States
Environmental Protection
Agency
E PA/690/R-20/003F j August 2020 | FINAL
Provisional Peer-Reviewed Toxicity Values for
Glycidaldehyde
(CASRN 765-34-4)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United Statts
^•&r"nU Environmental Protection
X#L-I FTk Agency
EPA/690/R-20/003F
August 2020
https://www.epa.gov pprtv
Provisional Peer-Reviewed Toxicity Values for
Glycidaldehyde
(CASRN 765-34-4)
Center for Public Health and 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
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Daniel D. Petersen, MS, PhD, DABT, ATS
Center for Public Health and Environmental Assessment, Cincinnati, OH
John Stanek, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's Center for Public Health and Environmental Assessment.
in
Glycidaldehyde
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 2
INTRODUCTION 3
METHODS 7
Literature Search 7
Screening Process 7
LITERATURE SEARCH AND SCREENING RESULTS 8
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 10
HUMAN STUDIES 13
Oral Exposures 13
Inhalation Exposures 13
ANIMAL STUDIES 13
Oral Exposures 13
Inhalation Exposures 13
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 15
Genotoxicity 15
Supporting Animal Studies 16
Metabolism/Toxicokinetic Studies 17
Mode-of-Action/Mechanistic Studies 17
DERIVATION 01 PROVISIONAL VALUES 29
DERIVATION 01 ORAL REFERENCE DOSES 29
Derivation of Subchronic Provisional Reference Dose 29
Derivation of Chronic Provisional Reference Dose 29
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 29
Derivation of Subchronic Provisional Reference Concentration 29
PROVISIONAL CARCINOGENICITY ASSESSMENT 30
APPENDIX A. LITERATURE SEARCH STRATEGY 31
APPENDIX B. DETAILED PECO CRITERIA 33
APPENDIX C. SCREENING PROVISIONAL VALUES 34
APPENDIX D. DATA TABLES 37
APPENDIX E. REFERENCES 38
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
LD50
median lethal dose
ACGIH
American Conference of Governmental
LOAEL
lowest-observed-adverse-effect level
Industrial Hygienists
MN
micronuclei
AIC
Akaike's information criterion
MNPCE
micronucleated polychromatic
ALD
approximate lethal dosage
erythrocyte
ALT
alanine aminotransferase
MOA
mode of action
AR
androgen receptor
MTD
maximum tolerated dose
AST
aspartate aminotransferase
NAG
7V-acetyl-P-D-glucosaminidase
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level
Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity
number
relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPHEA
Center for Public Health and
RGDR
regional gas dose ratio
Environmental Assessment
RNA
ribonucleic acid
CPN
chronic progressive nephropathy
SAR
structure activity relationship
CYP450
cytochrome P450
SCE
sister chromatid exchange
DAF
dosimetric adjustment factor
SD
standard deviation
DEN
diethylnitrosamine
SDH
sorbitol dehydrogenase
DMSO
dimethylsulfoxide
SE
standard error
DNA
deoxyribonucleic acid
SGOT
serum glutamic oxaloacetic
EPA
Environmental Protection Agency
transaminase, also known as AST
ER
estrogen receptor
SGPT
serum glutamic pyruvic transaminase,
FDA
Food and Drug Administration
also known as ALT
FEVi
forced expiratory volume of 1 second
SSD
systemic scleroderma
GD
gestation day
TCA
trichloroacetic acid
GDH
glutamate dehydrogenase
TCE
trichloroethylene
GGT
y-glutamyl transferase
TWA
time-weighted average
GSH
glutathione
UF
uncertainty factor
GST
glutathione-S-transferase
UFa
interspecies uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFC
composite uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFd
database uncertainty factor
HEC
human equivalent concentration
UFh
intraspecies uncertainty factor
HED
human equivalent dose
UFl
LOAEL-to-NOAEL uncertainty factor
i.p.
intraperitoneal
UFS
subchronic-to-chronic uncertainty factor
IRIS
Integrated Risk Information System
U.S.
United States of America
IVF
in vitro fertilization
WBC
white blood cell
LC50
median lethal concentration
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
GLYCIDALDEHYDE (CASRN 765-34-4)
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 at least two Center for Public
Health and Environmental Assessment (CPHEA) scientists and an independent external peer
review by at least 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.
Currently available PPRTV assessments can be accessed on the U.S. Environmental
Protection Agency's (EPA's) PPRTV website at https://www.epa.gov/pprtv. PPRTV
assessments are eligible to be updated on a 5-year cycle to incorporate new data or
methodologies that might impact the toxicity values or characterization of potential for adverse
human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. EPA Superfund and Technology Liaison
(https://www.epa.gov/research/fact-sheets-regional-science).
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.
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This work was conducted
under the CPHEA Program Quality Assurance Project Plan (PQAPP) and the QAPP titled
Preparation of Provisional Toxicity Value (PTV) Documents (L-CPAD-0032718-QP). As part of
the QA system, a quality product review is done prior to management clearance. A Technical
Systems Audit may be performed at the discretion of QA staff.
All PPRTV assessments receive internal peer review by a panel of CPHEA scientists and
an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
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purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
Other U.S. 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 content of this PPRTV assessment should be directed to the
U.S. EPA Office of Research and Development (ORD) CPHEA website at
https://www.epa.gov/pprtv/forms/contact-us-about-pprtvs.
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INTRODUCTION
Glycidaldehyde (CASRN 765-34-4) is an epoxy aldehyde compound. It is registered
with Europe's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
program (HCHA. 2018) but is not listed on the U.S. EPA's Toxic Substances Control Act
(TSCA) public inventory (U.S. HP A. 2018c).
Glycidaldehyde is used as a research chemical and as medication for animals. Former
uses of glycidaldehyde were as a cross-linking agent for textile treatment (i.e., finishing of wool),
leather tanning, and fat liquoring (Nl.M, 2017). It is synthesized by hydrogen peroxide
epoxidation of acrolein (Nl.M, 2017).
The empirical formula for glycidaldehyde is C3H4O2 (see Figure 1). A list of
physicochemical properties for glycidaldehyde is provided in Table 1. Glycidaldehyde is a
reactive, colorless liquid with high water solubility. In the air, glycidaldehyde will exist in the
vapor phase, based on its estimated vapor pressure of 32.7 mm Hg. It will be degraded in the
atmosphere by reacting with photochemically produced hydroxyl radicals and have a half-life of
22.8 hours (0.95 days), calculated from an estimated reaction rate constant of
1.69 x I0~n cm7molecule-second at 25°C (Nl.M, 2017). Based on its vapor pressure,
glycidaldehyde is expected to volatilize from dry soil surfaces. Low volatilization, however, is
expected from water or moist soil surfaces based on the compound's estimated Henry's law
constant of 4.34 x 10 7 atm-m3/mole. The estimated Koc for glycidaldehyde indicates potential
for mobility in soil but negligible potential to adsorb to suspended solids and sediment in aquatic
environments; although glycidaldehyde may react with organic matter if it is released to the
environment (Nl.M, 2017). There are no experimental hydrolysis data available for
glycidaldehyde, but the chemical is expected to undergo hydrolysis based on analogy with the
structurally similar compound glycidol (CASRN 556-52-5), which has a reported hydrolysis
half-life at pH 7 of 12 hours to 4 days.
Figure 1. Glycidaldehyde (CASRN 765-34-4) Structure
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Table 1. Physicochemical Properties of Glycidaldehyde (CASRN 765-34-4)
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
112.5a
Melting point (°C)
-62a
Density (g/cm3 at 20 °C)
1.140b
Vapor pressure (mm Hg)
32.7 (predicted average)0
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mol/L)
9.28 (predicted average)0
Octanol-water partition constant (log Kow)
-0.664 (predicted average)0
Henry's law constant (atm-m3/mol)
4.34 x 10 (predicted average)0
Soil adsorption coefficient log Koc (L/kg)
6.32 (predicted average)0
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
1.69 x 10-Ila
Atmospheric half-life (d)
0.95a
Relative vapor density (air = 1)
2.58a
Molecular weight (g/mol)
72.06a
Flash point (open cup in °C)
31a
aNLM (2017).
bPatnaik (2007).
Data were extracted from the U.S. EPA CompTox Chemicals Dashboard (glycidaldehyde, CASRN 765-34-4.
DTXSID 9020665; https://comptox.epa.gov/dashboard/DTXSID9020665. Accessed May 2, 2019).
NA = not applicable.
A summary of available toxicity values for glycidaldehyde 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 Glycidaldehyde (CASRN 765-34-4)
Source
(parameter)3'b
Value (applicability)
Notes
Reference0
Noncancer
IRIS (RfD)
4 x 10 4 mg/kg-d
Based on weight gain retardation, enlarged
adrenals, hydropic renal pelvis, and
hematopoietic effects in a subchronic
inhalation study in rats using a
route-to-route extrapolation.
U.S. EPA (2005)
HEAST (sRfD)
4/10 3 mg/kg-d
Based on decreased weight gain and kidney
effects using route-to-route extrapolation
and absorption factor of 0.5 from a
subchronic inhalation study in rats.
U.S. EPA (2018b)
HEAST (RfC)
1 x 10 3 mg/m3
Based on decreased weight gain and kidney
effects in a subchronic inhalation study in
rats.
U.S. EPA (2018b)
HEAST (sRfC)
1 x 10 2 mg/m3
Based on decreased weight gain and kidney
effects in a subchronic inhalation study in
rats.
U.S. EPA (2018b)
DWSHA
NV
NA
U.S. EPA (2018a)
ATSDR
NV
NA
ATSDR (2019)
IPCS
NV
NA
IPCS (2018)
CalEPA
NV
NA
CalEPA (2011);
CalEPA (2011);
CalEPA (2017)
OSHA
NV
NA
OSHA (2017b):
OSHA (2017a)
NIOSH
NV
NA
NIOSH (2016)
ACGIH
NV
NA
ACGIH (2018)
DOE (PAC)
PAC-1: 0.39 ppm
PAC-2: 4.3 ppm
PAC-3: 26 ppm
Based on TEELs.
DOE (2016)
USAPHC
(air-MEG)
1-hr critical: 75 mg/m3
1-hr marginal: 1.5 mg/m3
1-hr negligible: 0.2 mg/m3
1-yr negligible: 0.0068 mg/m3
1-hr values based on TEELs; 1-yr value
based on HEAST subchronic value.
U.S. APHC (2013)
Cancer
IRIS (WOE)
Classification B2: probable
human carcinogen
Based on an increased incidence of
malignant tumors in rats and mice following
subcutaneous injection of glycidaldehyde
and of skin carcinomas following dermal
application to mice. Supported by
mechanistic data (mutagenicity, reactivity of
epoxide and aldehyde groups) and
carcinogenicity of structurally related
epoxide compounds. No human data
available.
U.S. EPA (2005)
HEAST
NV
NA
U.S. EPA (2018a)
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Table 2. Summary of Available Toxicity Values for Glycidaldehyde (CASRN 765-34-4)
Source
(parameter)3'b
Value (applicability)
Notes
Reference0
DWSHA
NV
NA
U.S. EPA (2018a)
NTP
NV
NA
NTP (2016)
IARC (WOE)
Group 2B: possibly
carcinogenic to humans
Based on sufficient evidence in
experimental animals.
IARC (1999);
IARC (2018)
CalEPA (WOE)
Listed as causing cancer under
Proposition 65
NA
CalEPA (2018a):
CalEPA (2018b)
ACGIH
NV
NA
ACGIH (2018)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DOE = U.S. Department
of Energy; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment
Summary Tables; IARC = International Agency for Research on Cancer; IPCS = International Programme on
Chemical Safety; IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety
and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration;
USAPHC = U.S. Army Public Health Command.
Parameters: MEG = military exposure guideline; PAC = protective action criteria; RfC = reference concentration;
RfD = reference dose; sRfC = subchronic reference concentration; sRfD = subchronic reference dose;
TEEL = temporary emergency exposure limit; WOE = weight of evidence.
°Reference date for the HEAST data is the date the online source was accessed. All other reference dates are the
publication date for the databases.
NA = not applicable; NV = not available.
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METHODS
Literature Search
Four online scientific databases (PubMed, Web of Science [WOS], TOXLINE, and Toxic
Substances Control Act Test Submissions [TSCATS] via TOXLINE) were searched by
U.S. EPA's Health and Environmental Research Online (HERO) staff and stored in the HERO
database.1 The literature search focused on chemical name and synonyms (identified as
"valid/validated" or "good" via the CompTox Chemicals Dashboard2 and ChemSpider3) with no
limitations on publication type, evidence stream (i.e., human, animal, in vitro, in silico), or health
outcomes. Full details of the search strategy for each database are presented in Appendix A.
The initial database searches were conducted in February 2018 and updated in May 2019 and
March 2020.
Screening Process
Two screeners independently conducted a title and abstract screen of the search results
using DistillerSR4 to identify study records that met the Population, Exposure, Comparator,
Outcome (PECO) eligibility criteria (see Appendix B for a more detailed summary):
• Population: Humans, laboratory mammals, and other animal models of established
relevance to human health (e.g., Xenopus embryos); mammalian organs, tissues, and
cell lines; and bacterial and eukaryote models of genetic toxicity.
• Exposure: In vivo (all routes), ex vivo, and in vitro exposure to the chemical of
interest, including mixtures to which the chemical of interest may contribute
significantly to exposure or observed effects.
• Comparator: Any comparison (across dose, duration, or route) or no comparison
(e.g., case reports without controls).
• Outcome: Any endpoint suggestive of a toxic effect on any bodily system or
mechanistic change associated with such effects. Any endpoint relating to disposition
of the chemical within the body.
Records that were not excluded based on title and abstract screening advanced to full-text
review using the same PECO eligibility criteria. Studies that have not undergone peer review
were included if the information could be made public and sufficient details of study methods
and findings were included in the report. Full-text copies of potentially relevant records
identified from title and abstract screening were retrieved, stored in the HERO database, and
independently assessed by two screeners using DistillerSR to confirm eligibility. At both
title/abstract and full-text review levels, screening conflicts were resolved by discussion between
the primary screeners with consultation by a third reviewer to resolve any remaining
disagreements. Studies that were unclear at the title/abstract level advanced to full-text review.
During title/abstract or full-text level screening, studies that were not directly relevant to the
PECO, but could provide supplemental information, were categorized (or "tagged") relative to
1 U.S. EPA's HERO database provides access to the scientific literature behind U.S. EPA science assessments. The
database includes more than 2,500,000 scientific references and data from the peer-reviewed literature used by
U.S. EPA to develop its regulations.
2CompTox Chemicals Dashboard: https://comptox.epa.gov/dashboard/DTXSID9020665.
'ChemSpider: http://www.chemspider.com/Chemical-Structure. 12461 .html?rid=565c63c9-aa2f-44cb-b979-
9cc783134953.
4DistillerSR is a web-based systematic review software used to screen studies available at
https://www.evidencepartners.com/products/distillersr-svstematic-review-software.
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the type of supplemental information they provided (e.g., review, commentary, or letter with no
original data; conference abstract; toxicokinetics; mechanistic information aside from in vitro
genotoxicity studies, studies on routes of exposure other than oral and inhalation; studies of acute
exposure only, etc.). Conflict resolution was not required during the screening process to
identify supplemental information (i.e., tagging by a single screener was sufficient to identify the
study as potential supplemental information).
LITERATURE SEARCH AND SCREENING RESULTS
The database searches yielded 177 unique records. Of the 177 studies identified, 40 were
excluded during title and abstract screening, 137 were reviewed at the full-text level, and
75 were considered relevant to the PECO eligibility criteria (see Figure 2). This included
1 in vivo animal study and 74 in vitro genotoxicity studies. The detailed search approach,
including the query strings and PECO criteria, are provided in Appendix A and Appendix B,
respectively.
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Literature Searches (through 2018)
PubMed
(i) = 41)
wos
(n = 33)
TOXLINE
(n = 120)
TSCATS
(n = 100)
Other Sources
(n= 162)
I
TITLE AND ABSTRACT SCREENING
Title and Abstract Screening
(177 records after duplicate removal)
FULL-TEXT SCREENING
Excluded (n= 40)
Not relevant to PECO (n = 40)
Full-Text Screening
(n = 137)
J
Studies Considered Further (n - 77)
Human health effect studies (n = 0)
Animal health effect studies (n = 3)
Genotoxicity studies (n = 74)
Excluded (n = 29)
Not relevant to PECO (n = 29)
Tagged as Supplemental/Other (n - 31)
Other routes of exposure besides oral and
inhalation {n = 5), acute toxicity studies
(n = 0), mechanistic studies {in vitro or in
vivo} (/? = 0), ADME/PBPK studies (n = 5), and
review articles (n = 17)
Figure 2. Literature Search and Screening Flow Diagram for
Glycidaldehyde (CASRN 765-34-4)
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer evidence
bases, respectively, for glycidaldehyde and include all potentially relevant acute, repeated
short-term, subchronic, and chronic studies, as well as reproductive and developmental toxicity
studies identified from the literature screening results. Principal studies are identified in bold.
The phrase "statistical significance" and the term "significant," used throughout the document,
indicates ap-walue of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Glycidaldehyde (CASRN 765-34-4)
Category3
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
No adequate studies identified.
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
Subchronic
10 M, Long-Evans rat; 4 hr/d,
5 d/wk, 12 wk
Reported nominal concentrations:
0,10,20, 40,80 ppm
0,3.5,7.0,14,
28
Hematological changes in the
bone marrow
3.5
7.0
Hineetal. (l%n
PS,
PR,
IRIS
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated
exposure for >30 days <10% lifespan for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% lifespan for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 20021.
bDosimetry: Doses are presented as ADDs (mg/kg-day) for oral noncancer effects and as HECs (mg/m3) for inhalation noncancer effects. The HEC from animal studies
was calculated using the equation for ER effects from a Category 3 gas (U.S. EPA. 19941: HECer = (ppm x molecular weight ^ 24.45) x (hours per day
exposed 24) x (days per week exposed 7) x ratio of animal:human blood-gas partition coefficients (default of 1 applied).
°Notes: IRIS = study used for Integrated Risk Information System RID value U.S. EPA (2005): PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; ER = extrarespiratory; HEC = human equivalent concentration; IRIS = Integrated Risk Information System;
LOAEL = lowest-observed-adverse-effect level; M = male(s); ND = no data; NOAEL = no-observed-adverse-effect level.
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Table 3B. Summary of Potentially Relevant Cancer Data for Glycidaldehyde (CASRN 765-34-4)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetry
Critical Effects
Reference
(comments)
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
No adequate studies identified.
2. Inhalation (mg/m3)
ND
ND = no data.
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HUMAN STUDIES
Oral Exposures
No oral studies in humans have been identified.
Inhalation Exposures
Him et ill. (1961)
In a sensory threshold study, student and staff member volunteers (8-12/group) were
exposed to glycidaldehyde vapor at nominal concentrations of 1, 2.5, 5, 10, or 20 ppm (2.9, 7.4,
15, 29, or 59 mg/m3)5 for 5 minutes in a whole-body chamber designed for human exposures.
Subjects scored clinical signs of irritation on a scale of 0-4 every minute during exposure,
including olfactory cognition, eye irritation, nose irritation, pulmonary discomfort, and central
nervous system (CNS) effects.
Glycidaldehyde was irritating to the eyes and mucous membranes in exposed subjects.
Olfactory cognition was reported in all subjects except one volunteer exposed to 29 mg/m3.
Nose irritation was reported in all subjects at >7.4 mg/m3 and 7/9 subjects at 2.9 mg/m3. Eye
irritation was reported in 3/9, 4/11, 7/8, 10/10, and 11/12 subjects at 2.9, 7.4, 15, 29, and
59 mg/m3, respectively. Average eye irritation score increased with increasing concentration,
and profuse tearing was observed in 7/12 subjects at 59 mg/m3. Similarly, pulmonary discomfort
scores increased with increasing concentration, with discomfort reported in 2/9, 3/11, 2/8, 7/10,
and 9/12 subjects at 2.9, 7.4, 15, 29, and 59 mg/m3, respectively. Seven subjects complained of a
sore throat at the highest concentration. CNS effects were infrequent and limited to mild to
moderate headache in one or two subjects at 2.9, 29, and 59 mg/m3.
Sensory irritation was evident in subjects at all concentrations tested; however, because
all reported data are subjective, this study is not considered adequate to identify a no-observed
adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) value in
humans. Furthermore, the volunteers were only exposed for 5 minutes, thus using these data to
derive provisional reference concentrations (p-RfCs) would require extrapolation from a
5-minute exposure to subchronic and/or chronic exposure. Therefore, this study is not included
in Table 3A.
ANIMAL STUDIES
Oral Exposures
No adequate repeated-dose oral studies have been identified.
Inhalation Exposures
Subchronic Studies
Hine et al. (1961)
Male Long-Evans rats (10/group) were exposed to glycidaldehyde vapor (purity not
reported) at nominal concentrations of 0, 10, 20, 40, or 80 ppm (0, 29, 59, 120, or 240 mg/m3)5
for 4 hours/day, 5 days/week, for 12 weeks (whole-body exposure is assumed). Analytical
concentrations were not reported. The animals were observed for mortality and their weights
were monitored; however, the frequency of observations and body-weight measurements were
not reported. Blood samples for hematology (total leukocytes, percent polymorphonuclear
leukocytes [% PMNs], total erythrocytes, and hemoglobin) were collected before exposure, after
Concentration in mg/m3 = concentration in ppm x molecular weight (72.06 g/mol) 24.45.
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17 exposures (3.5 weeks), and at study termination. At necropsy, the animals were examined for
gross abnormalities, and the following organs were collected and weighed: thymus, spleen, testis,
liver, kidney, and lung. Bone marrow was extracted from each femur (one sample was used for
nucleated cell count and the other was used to determine the M:E ratio [undefined by study
authors but presumed to be the myeloid-to-erythroid (M:E) ratio]). Histopathology was
performed on the spleen, liver, kidney, and lung. Statistical analysis of body weight, relative
organ weight, and hematological data was performed, but the statistical test used was not
specified.
The incidence of mortality was 1/10, 0/10, 1/10, 2/10, and 8/10 in the 0-, 29-, 59-, 120-,
and 240-mg/m3 groups, respectively. Pneumonia was described as the cause of death for rats in
the 0-, 59-, and 120-mg/m3 groups. At 240 mg/m3, 8/10 rats died after only four exposures and
the remaining 2 animals were euthanized after the fifth exposure. Body-weight gain over the
course of the study was significantly decreased by 27 and 23% at 59 and 120 mg/m3,
respectively, compared with controls (see Table D-l). No exposure-related changes in
hematological endpoints were observed in the surviving animals at 3.5 or 12 weeks. The two
surviving rats exposed to 240 mg/m3 for 5 days, however, showed low leukocyte counts and a
significant increase in % PMNs, although the study authors did not specify which control data
were used for comparison. Nucleated bone marrow cells were significantly decreased by
44-48% at exposure concentrations >59 mg/m3 (see Table D-l). The M:E ratio was variable
across groups, and no significant treatment-related changes were noted (see Table D-l).
Statistically significant changes observed in relative organ weights at 12 weeks were
increased relative testes weight and decreased relative thymus and spleen weights
(see Table D-l). Absolute organ-weight data were not reported. The significant increases in
relative testes weight at 59 and 120 mg/m3 (and the statistically nonsignificant 15% increase in
relative liver weight at 59 mg/m3) may reflect reduced body weight in these exposure groups.
Therefore, the biological relevance of increased relative testes and liver weights is unclear. The
significant decreases in relative spleen and thymus weight at 120 mg/m3, however, indicate that
those organs lost weight (relative to controls) to a larger degree than the body overall. These
changes likely reflect a target organ effect of glycidaldehyde, although the study authors noted a
potential for large experimental error due to the small size of the thymus which can make it
difficult to get precise weight measurements.
Gross necropsy findings were a "striking reduction in body fat" in animals that died or
were sacrificed by Day 5 at 240 mg/m3, reduced body fat and small spleens at 120 mg/m3, and
single rats with enlarged adrenals or hydropic renal pelvis at 59 mg/m3. No histopathological
lesions were observed in the spleen, liver, kidney, or lungs of rats exposed to <120 mg/m3.
Splenic abscess, focal hepatic necrosis, and tubular degeneration of kidneys were "usually"
observed in rats that died or were sacrificed following exposure to 240 mg/m3 for up to 5 days
(incidence data not reported).
A NOAEL of 29 mg/m3 and a LOAEL of 59 mg/m3 are identified for this study based on
hematological changes in the bone marrow. Decreased body-weight gain at 59 mg/m3 was not
used as the basis for the LOAEL because the response at which this effect is considered to be
biologically relevant is unknown. Decreased thymus weight at 29 mg/m3 was not used as the
basis for the LOAEL due to the lack of supporting dose-response (small, statistically
nonsignificant decrease at 59 mg/m3), lack of reported variance data, lack of absolute
14
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organ-weight data, and the considerable potential for experimental error acknowledged by the
study authors. The high concentration of 240 mg/m3 is a frank effect level (FEL) based on rapid
mortality of exposed rats. The nominal concentrations of 0, 29, 59, 120, and 240 mg/m3
correspond to human equivalent concentration (HEC) values of 0, 3.5, 7.0, 14, and 28 mg/m3 for
extrarespiratory (ER) effects.6
Chronic/Carcinogenicity Studies
No adequate studies have been identified.
Reproductive/Developmental Studies
No studies have been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Table 4A provides an overview of genotoxicity studies of glycidaldehyde and Table 4B
provides an overview of other supporting animal studies on glycidaldehyde.
Genotoxicity
The genotoxicity of glycidaldehyde has been studied in a variety of assays both in vitro
and in vivo. The available studies are summarized below (see Table 4A for more details). Data
indicate that glycidaldehyde is mutagenic and directly interacts with deoxyribonucleic acid
(DNA), forming DNA adducts and causing DNA damage. There is also some evidence that
glycidaldehyde is clastogenic and induces cell transformation.
Glycidaldehyde is mutagenic in Salmonella typhimurium both in the presence and
absence of metabolic activation (Dunkel et al.. 1984; Bartsch et al.. 1983; Bartsch et at., 1980;
Rosenkranz et at.. 1980; Shell Oil. 1980; Dunkel. 1979; Rosenkranz and Poirier. 1979; Simmon.
1979b; Wade et al.. 1979). In all studies that specified results by tester strain, mutagenicity was
observed in S. typhimurium strains evaluating base-pair mutations (TA100, TA1530, TA1535),
but not strains evaluating frame-shift mutations (TA98, TA1536, TA1537, TA1538, TA1531,
TA1532, TA1533) (Dunkel et al.. 1984; Bartsch et al.. 1983; Bartsch et al.. 1980; Rosenkranz et
al.. 1980; Shell Oil, 1980; Rosenkranz and Poirier, 1979; Simmon, 1979b; Wade et al.. 1979).
Similarly, in the intraperitoneal (i.p.) host-mediated assay, mutations were induced in
S. typhimurium strain TA 1530, but not TA 1538 (Simmon et al.. 1979). Glycidaldehyde was also
mutagenic in Escherichia coli WP-2 strain (Dunkel et al.. 1984). bacteriophage T4-infected
E. coli (Corbett et al.. 1970). and Klebsiella pneumoniae (Knaap et al.. 1982; Voogd et al..
1981). Mutations were not induced in Saccharomyces cerevisiae in vitro or in the host-mediated
assay [Izard (1983) as cited in IARC (1999); Simmon et al. (1979)1.
Glycidaldehyde is mutagenic in the mouse lymphoma thymidine kinase assay
(TK+/- —~ TK-/-) (Amacher and Turner, 1982) but did not induce forward mutations in the
mouse lymphoma hypoxanthine-guanine phosphoribosyltransferase (HGPRT) mutation assay
(Knaap et al.. 1982). Dominant lethal mutations were not induced in mice exposed via i.p.
injection (Shell Oil. 1980).
' HEC calculated by treating glycidaldehyde as a Category 3 gas and using the following equation from U.S. EPA
(1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animal:human), using a default coefficient of 1 because
blood-gas partition coefficients for glycidaldehyde were not located for rats or humans.
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Glycidaldehyde induced sex-linked recessive lethals and chromosome loss in Drosophila
melanogaster following exposure via injection (Vogel et al.. 1993; Vogel. 1989; Vogel et al..
1986; Knaap et al.. 1982). Vogel etal. (1993; 1990) led to a prediction that glycidaldehyde is a
DNA cross-linking agent based on ratio >2 for chromosomal loss:sex-linked recessive lethals in
I), melanogaster. When I), melanogaster mutants with deficiencies in DNA repair (unscheduled
DNA synthesis) were used, the number of sex-linked recessive lethals increased 9-12-fold.
Glycidaldehyde also caused increased cytotoxicity in the repair-deficient PolA- E. coli strain
with and without metabolic activation (Rosenkranz and Poiricr. 1979; Fluck et al.. 1976).
Evidence of DNA repair was also observed in human lung fibroblast cells exposed to
glycidaldehyde in vitro (Mitchell. 1976).
Glycidaldehyde is a reactive DNA alkylating agent that readily forms DNA adducts.
Stable cyclic deoxyadenosine DNA adduct formation has been observed in skin DNA of mice
following dermal exposure to glycidaldehyde (Steiner et al.. 1992a). The major adduct was
identified as 3-P-D-deoxyribofuranosyl-7(hydroxymethyl)-3//-imidazo[2,1 -/]purine-3'-
monophosphate. In isolated calf thymus DNA, the same major DNA adduct was identified when
DNA was incubated at a pH of 7.0. However, when the pH was increased to 10.0, the major
DNA adduct was 5,9-dihydro-7-(hydroxymethyl)-9-oxo-3-P-D-deoxyribofuranosyl-3//-
imidazo[l,2-a]purine-3'-monophosphate (Steiner et al.. 1992a). In other studies with isolated
DNA, deoxyadenosine, deoxycytosine, and deoxyguanosine adducts were identified at varying
levels depending on the pH of the test system (Kohwi. 1989; Van Duuren and Loewengart.
1977). Adduct formation and structures have been extensively characterized in isolated
nucleotides and nucleosides. These studies, along with those summarized in Table 4A, indicate
that glycidaldehyde forms exocyclic etheno ring adducts, with guanine adducts formed
preferentially at basic pH levels and adenine and cytosine adducts formed preferentially at acidic
pH levels (Hang et al.. 2002; Chenna et al.. 2000; Golding et al.. 1996; Steiner et al.. 1992b;
Golding et al.. 1990; Golding et al.. 1986a. b; Nair and Turner. 1984; Goldschmidt et al.. 1968).
A single study in Syrian hamster embryo (SHE) cells showed increased micronuclei
(MN) following in vitro exposure to glycidaldehyde (Fritzenschaf et al.. 1993). Glycidaldehyde
also induced cell transformation in SHE cells and mouse Balb/3T3 cells (Dunkel et al.. 1981;
Pienta. 1980a. b). Mitotic recombination was induced in S. cerevisiae D3 cells exposed to
glycidaldehyde with or without metabolic activation (Simmon. 1979a).
Supporting Animal Studies
Supporting animal studies include acute lethality studies, an oral carcinogenicity study
that is considered inadequate based on inadequate frequency of exposure (1 day per week during
course of study) and small size of animal groups (five per group), and dermal and subcutaneous
(s.c.) injection carcinogenicity studies. These studies are summarized below (see Table 4B for
additional details).
Acute Lethality Studies
Acute lethality studies reported oral median lethal dose (LDso) values of 232 and
200 mg/kg in rats and mice, respectively, an inhalation median lethal concentration (LCso) value
of 252 ppm in rats, and a dermal LDso value of 249 mg/kg in rabbits (Simmon et al.. 1979; Hine
et al .. 1961). Glycidaldehyde was reported to be moderately irritating to the skin of rabbits (Hine
etal.. 1961).
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Supporting Studies for Carcinogenic Effects in Animals
An oral carcinogenicity study by Van Duuren et al. (1966) found no gastric or other
tumors in five mice treated with 33 mg/animal glycidaldehyde via gavage in tricaprylin once
weekly. However, the study design is considered inadequate for tumor assessment because of
inadequate exposure regimen and the small number of animals tested per group.
The incidences of skin papillomas and malignant skin tumors were increased in mice
derm ally exposed to - 100 mg glycidaldehyde in acetone or benzene 3 times/week for life (Van
Duuren et al.. 1967a; Van Duuren et al.. 1965). Based on statistics conducted by the U.S. EPA
for the purposes of this PPRTV assessment, the incidences of both tumor types were
significantly increased in both studies, compared with respective controls. Glycidaldehyde was a
weak skin tumor initiator relative to 7,12-dimethylbenz[a]anthracene (DMBA) in mice in studies
conducted using croton resin/oil as a promotor (Shamberger et al.. 1974; Van Duuren et al..
1965).
In injection assays, weekly lifetime s.c. injections of glycidaldehyde produced
statistically significant increases in malignant injection-site tumors in rats and mice (Van Duuren
et al.. 1967b; Van Duuren et al.. 1966). Based on statistics conducted by the U.S. EPA for the
purposes of this PPRTV assessment, the incidence of malignant tumors at the injection site was
significantly increased in mice exposed to 3.3 mg/animal-week and rats exposed to
33 mg/animal-week, compared with respective controls. No statistically significant increases
were seen in mice at 0.1 mg/animal-week or rats at 1 mg/animal-week. However, injection
assays like dermal studies cannot be used for quantitative tumor assessment given the route of
exposure.
Metabolism/Toxicokinetic Studies
No studies were found regarding absorption, distribution, or excretion of glycidaldehyde.
Based on toxicity and mortality following oral, inhalation, and dermal exposure in animals (Hine
et al .. 1961). absorption of glycidaldehyde can occur through all three routes.
Metabolism data for glycidaldehyde are limited to in vitro data. Glycidaldehyde is
converted into glyceraldehyde by epoxide hydrase in rat liver and lung preparations (Patel et al..
1980). Glycidaldehyde is also a substrate for rat lung and liver cytosol ic glutathione
^'-transferases (GST), with the rate of glutathione conjugation observed in liver cytosol twice the
rate observed in lung cytosol (Patel et al.. 1980). Fiellstedt et al. (1973) also reported that
glycidaldehyde is a substrate for purified rat liver glutathione epoxide transferase. Based on the
reactivity of glycidaldehyde (due to one epoxide and one aldehyde group). Van Duuren et al.
(1966) predicted rapid hydrolysis in the acidic pH of the stomach.
Mode-of-Action/Mechanistic Studies
As discussed in the "Genotoxicity" section and Table 4A, glycidaldehyde is a
DNA-alkylating agent that shows mutagenic activity in many assay systems. Because a cancer
assessment is not provided in this document, a detailed discussion of the carcinogenic mode of
action (MOA) for glycidaldehyde was not conducted.
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
(reverse)
Salmonella typhimurium
TA1535, TA100
0-0.6 |iIVI/platc
+
NDr
Plate incorporation assay. Dose-related increase in
revertants/plate. The concentration needed to
produce 500 revertants/plate was reported as 19 and
15 |iIVI for TA1535 and TA100, respectively.
Bartsch et al.
(1983): Bartsch
etal. (1980)
Mutation
(reverse)
S. typhimurium
TA1535, TA100
0,0.24,0.3,
0.61, 1.22 mM
+
NDr
Liquid incubation assay. The number of
mutants/mM-min incubation was reported as 2.56
and 4.15 for TA1535 and TA100, respectively.
Bartsch et al.
(1983)
Mutation
(reverse)
S. typhimurium
TA1535, TA1537, TA1538,
TA98, TA100
0.3, 1.0, 3.3, 10,
33.3, 100,
333.3 ng/plate
+
(TA1535,
TA100)
±
(TA1537,
TA98)
(TA1538)
NDr
Plate incorporation and/or preincubation assays
performed in 4 different laboratories.
Glycidaldehyde induced mutations in TA100 and
TA1535 without metabolic activation. Findings
were mixed or equivocal for TA1537 and TA98, and
negative for TA1538.
Dunkel et al.
(1984)
Mutation
(reverse)
S. typhimurium
TA1535, TA1537, TA1538,
TA98, TA100
0.3, 1.0, 3.3, 10,
33.3, 100,
333.3 ng/plate
+
(strains NS)
+
(strains NS)
Plate incorporation assay. Glycidaldehyde induced
mutations with and without metabolic activation
with liver S9 from uninduced and
Aroclor 1254-induced rat, mouse, and hamster in
three separate laboratories. Magnitude of induction
and strain-specific results were not reported.
Dunkel (1979)
Mutation
(reverse)
S. typhimurium
TA1535
0,0.5, 1, 5, 10,
50, 100 ng/plate
+
NDr
Preincubation assay. Dose-related increase in
revertants/plate in 4 separate experiments from a
single laboratory.
Rosenkranz et
al. (1980)
Mutation
(reverse)
S. typhimurium
TA1535, TA1538
0,0.01,
0.1 |iL/platc
+
(TA1535)
(TA1538)
+
(TA1535)
(TA1538)
Plate incorporation assay. Revertants increased
>3 5-200-fold without metabolic activation and
7-100-fold with metabolic activation in TA1535
(base-substitution mutant). Negative in TA1538
(frame-shift mutant).
Rosenkranz and
Poirier (1979)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Mutation
(reverse)
S. typhimurium
TA1530, TA1531, TA1532,
TA1533
NS
+
(TA1530)
(TA1531,
TA1532,
TA1533)
NDr
Plate incorporation assay. Revertants increased
16-fold in TA1530 (base-substitution mutant); no
increased observed in other mutants (frame-shift
mutants).
Shell Oil (1980)
Mutation
(reverse)
S. typhimurium
TA100, TA98
0, 50,
1,000 ng/plate
+
(TA100)
(TA98)
+
(TA100)
(TA98)
Plate incorporation assay. Revertants increased
>13-fold in TA100 (base-substitution mutant) with
or without metabolic activation; no increase
observed in TA98 (frame-shift mutant). Cytotoxic
without metabolic activation at 1,000 |ig/plate in
both strains.
Shell Oil (1980)
Mutation
(reverse)
S. typhimurium
TA100, TA98
0,0.5, 1,2, 5,
10, 20 ng/plate
+
(TA100)
(TA98)
+
(TA100)
(TA98)
Plate incorporation assay. Revertants increased in a
dose-related manner in TA100 (base-substitution
mutant) with or without metabolic activation
(>twofold increase at all tested concentrations); no
increase observed in TA98 (frame-shift mutant).
Shell Oil (1980)
Mutation
(reverse)
S. typhimurium
TA1535, TA1536, TA1537,
TA1538, TA98, TA100
10 ng/plate
+
(TA1535,
TA100)
(TA1536,
TA1537,
TA1538, TA98)
NDr
Plate incorporation assay. The number of
revertants/place increased >30-fold and >20-fold in
TA1535 and TA100, respectively, with exposure.
Simmon
(1979b)
Mutation
(reverse)
S. typhimurium TA100 and
TA98
0.01,0.05,0.20,
10 mg/plate
+
(TA100)
(TA98)
+
(TA100)
(TA98)
Plate incorporation assay. Revertants increased in
dose-related manner in TA100 (base-substitution
mutant) with or without metabolic activation
(>twofold increase at all tested concentrations); no
increase observed in TA98 (frame-shift mutant).
Cytotoxic at 10 mg/plate in both strains.
Wade et al.
(1979)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Mutation
(reverse)
Escherichia coli WP-2 uvrA
0.3, 1.0, 3.3, 10,
33.3, 100,
333.3 ng/plate
+
NDr
Repeated twice in each of 4 labs. Glycidaldehyde
consistently induced mutations without metabolic
activation.
Dunkel et al.
(1984)
Mutation
(forward)
Bacteriophage T4-infected
E. coli
NS
+
NDr
Glycidaldehyde induced A/T- and G/C-based pair
transitions and phase shift mutations. No
cytotoxicity observed.
Corbett et al.
(1970) labstractl
Mutation
(forward)
Klebsiella pneumoniae
0,0.01,0.02,
0.1,0.2, ImM
+
NDr
Fluctuation test. Dose-related increase in mutations
at all concentrations tested. Mutation frequency
increased 2-64-fold. No cytotoxicity observed.
Knaap et al.
(1982)
Mutation
(forward)
K. pneumoniae
0,0.005,0.01,
0.02,0.1,0.2,
1 mM/L
+
NDr
Fluctuation test. Dose-related increase in mutations
at all concentrations tested (1.7- to 69-fold).
Voogd et al.
(1981)
DNA repair
E. coli PolA+ and PolA-
(DNA polymerase-deficient)
5, 10,
25 |iL/\yc11
+
+
Disc diffusion assay. Preferential inhibition of
DNA-repair deficient PolA- strain at 5 and
25 |iL/\yc11. Metabolic activation did not increase
inhibition.
Fluck et al.
(1976)
DNA repair
E. coli PolA+ and PolA-
(DNA polymerase-deficient)
1 nL
+
NDr
Disc diffusion assay. Preferential inhibition of
DNA-repair deficient PolA- strain.
Rosenknmz and
Poirier (1979)
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
(reverse)
Saccharomyces cerevisiae
S211, S138
Up to
11,000 |ig/mL
NDr
Glycidaldehyde did not induce revertants.
Izard (1973) as
cited in I ARC
(1999)
Mitotic
recombination
S. cerevisiae D3
0.05%
(weight/vol or
vol/vol)
+
+
Mitotic recombination induced with or without
metabolic activation. Induction greater with
metabolic activation.
Simmon
(1979a)
Genotoxicity studies in mammalian cells—in vitro
Mutation
(TK+/- ->
TK-/-)
Mouse lymphoma L51788Y
cells
0,8.9, 11.9,
15.8,21.1,28.2,
37.6,
50.1 ng/mL
NDr
+
TK mutation assay. Mutations increased >twofold
at all tested concentrations. Cell survival was <60%
of control at >21.1 |ig/mL.
Amacher and
Turner (1982)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Mutation
(forward)
Mouse lymphoma L51788Y
cells
0,0.01,0.03,
0.1 mM
-
NDr
HGPRT mutation assay. Cell survival was
decreased >25% at >0.03 mM.
Knaao et al.
(1982)
MN
SHE cells
NS
+
NDr
Assay run in triplicate. Reproducible,
dose-dependent, and statistically significant increase
in MN observed with exposure.
Fritzenschaf et
al. (1993)
UDS
Diploid human lung
fibroblasts
(WI38 cells)
0-102 M
+
NDr
Increased UDS (>twofold) detected at 10 3 M.
Mitchell (1976)
Cell
transformation
Mouse Balb/3T3 cells
0, 0.008, 0.04,
0.2, 1.0 ng/mL
+
NDr
Each concentration tested in 15-20 plates. A
>twofold increase in the mean number of
transformed foci/plate was observed at 1.0 |ig/mL.
No cytotoxicity reported.
Dunkel et al.
(1981)
Cell
transformation
SHE cells
0,0.1, 1.0, 10,
100 iig/mL
+
NDr
Each concentration tested in 6-12 plates. The
number of transformed colonies was increased at
1.0 |ig/mL. Cytotoxic at >10 |ig/mL.
Dunkel et al.
(1981)
Cell
transformation
SHE cells
0.1-100 ng/mL
+
NDr
Cell transformation was observed at 0.1 and
1 ng/mL.
Pienta (1980a):
Pienta (1980b)
Genotoxicity studies—in vivo
Dominant
lethal
Male mice (5/group) were
exposed once to
glycidaldehyde in corn oil
via i.p. injection. Males
were mated to unexposed
females 2 and 3 wk
postexposure. Females
sacrificed 15 d after first day
of mating.
0, 1.0 mM/kg
NA
No increases in frequency of dominant lethal
mutations.
Shell Oil (1980)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Mutation
(host-mediated
assay)
Mice were exposed once to
glycidaldehyde via i.m.
injection. S. typhimurium
TA1530 orTA1538 was
injected i.p. into mouse, and
animals were sacrificed 4 hr
later. S. typhimurium were
removed, cultured, and
evaluated for mutants after
2d.
456 mg/kg
+
(TA1530)
(TA1538)
NA
Mutation frequency was significantly increased
2.5-fold in exposed group with TA1530. No change
in mutation frequency was observed in TA1538.
Simmon et al.
(1979)
Mutation
(host-mediated
assay)
Mice were exposed once to
glycidaldehyde via gavage.
S. cerevisiae was injected
i.p. into mouse, and animals
were sacrificed 4 hr later.
S. cerevisiae were removed,
cultured, and evaluated for
mutants after 2-3 d.
200 mg/kg
NA
Mutation frequency was increased 0.7-fold in
exposed group.
Simmon et al.
(1979)
DNA adduct
CH3 mice were dermally
exposed to glycidaldehyde in
acetone for 24 hr. Exposed
skin was evaluated for DNA
adducts.
0, 2,
10 mg/animal
+
NA
Stable cyclic dA adducts formed in a dose-related
manner in skin DNA of treated animals. Adducts
were identified as 3-p-D-deoxyribofuranosyl-
7-(hydro.\vmcth\i)-3//-imidazo [2,1 -/']purine-3 '-
monophosphate. No dG adducts were detected in
epidermal DNA.
Steiner et al.
(1992a)
Genotoxicity studies in invertebrates in vivo
SLRL
Drosophila melanogaster
males were exposed via
injection and mated to five
consecutive batches of
unexposed females. Flies
were evaluated for SLRL.
0, 1, 10, 25, 42,
50 mM
+
NA
% SLRL was increased at >25 mM. Survival was
not affected.
Knaap et al.
(1982)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
SLRL
Excision repair-proficient
D. melanogaster males were
exposed via injection and
mated to unexposed excision
repair-deficient {Base)
females for 2-3 d/brood.
Flies were evaluated for
SLRL.
10 mM
+
NA
% SLRL was significantly increased in treated flies;
% SLRL was 0.87-0.96%, after correction for
0.10% spontaneous SLRLs.
Voeel et al.
(1993)
SLRL
Excision repair-deficient
D. melanogaster {Base)
males were exposed via
injection and mated with
untreated excision
repair-proficient (exr ) or
excision repair-deficient
(iiiei-'"'1) females 24 hr after
injection. Flies were
evaluated for SLRL.
10 mM
+
NA
The number of SLRLs was increased 12-fold in
mei-9L1 females, compared with exr . 20 mM was
noted as a lethal dose for mei-9LI females.
Voeel (1989)
SLRL
Excision repair-proficient
D. melanogaster {exr+)
males were exposed (method
NS) and mated with
untreated excision
repair-proficient (exr ) or
excision repair deficient
(meifemales.
NS
+
NA
The number of SLRLs was increased 9.7-fold in
mei-9L1 females, compared with exr+.
Voeel et al.
(1986)
Chromosome
loss
D. melanogaster males
(Rl[2]yB; Bs Yy+) were
exposed via injection and
mated to unexposed females
(y w spl sn3) to produce
2 broods. Flies were
evaluated for ring-X loss.
0, 10 mM
+
NA
Significant induction of chromosome loss in treated
flies (-2-3% induction compared with controls).
Voeel et al.
(1993)
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Table 4A. Summary of Glycidaldehyde (CASRN 765-34-4) Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in subcellular systems
DNA adduct
Calf thymus DNA, tested at
pH 7 or 10
9.5 nM
+
NDr
At pH 7: stable cyclic dA adducts were formed.
Major adduct identified as
3-(}-D-dco\y ribofuranosy l-7-(hydro\y methyl )-3//-
imidazo [2,1 -/]purine-3 '-monophosphate.
At pH 10: stable cyclic dA adducts were formed.
Major adduct identified as
5,9-dihydro-7-(hydroxymethyl)-9-oxo-3-p-D-
dco \y ri b o 111 ra no sy 1 -3 / /- i m i da zo [ 1,2-a]purine-3
monophosphate. Small amounts of the major adduct
formed at pH 7.0 were also observed.
Steiner et al.
(1992a)
DNA adduct
Calf thymus DNA, tested at
pH 10
1.25 mM
+
NDr
dG adducts detected.
Van Duuren and
Loeweneart
(1977)
DNA adduct
Linear or supercoiled
plasmid DNA, tested at
pH 4-8
0,0.1,0.5, 1,
2 nL
+
NDr
Linear: dG adducts detected at pH 5-8; dA adducts
detected at pH 4.
Supercoiled: dA and dC adducts detected at pH 5-8;
dA and dG detected at pH 4.
Kohwi (1989)
a+ = positive; ± = equivocal; - = negative.
dA = deoxyadenosine; dC = deoxycytosine; dG = deoxyguanosine; DNA = deoxyribonucleic acid; HGPRT = hypoxanthine-guanine phosphoribosyltransferase;
i.m. = intramuscular; i.p. = intraperitoneal; MN = micronuclei; NA = not applicable; NDr = not determined; NS = not specified; SHE = Syrian hamster embryo;
SLRL = sex-linked recessive lethal; TK = thymidine kinase; UDS = unscheduled DNA synthesis.
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Table 4B. Other Glycidaldehyde (CASRN 765-34-4) Studies
Test3
Materials and Methods
Results
Conclusions
References
Supporting evidence—noncancer effects in animals following exposure via any route
Acute (oral)
Rats (6/group; sex and strain NS) were
exposed to glycidaldehyde once via
gavage at 1, 50, 500, 5,000, or
15,000 mg/kg.
Mortality incidence was 0/6, 0/6, 5/6, 6/6,
and 6/6 at 1, 50, 500, 5,000, and
15,000 mg/kg, respectively. Death
occurred within 10-15 min at
15,000 mg/kg, 45 min-6 hr at
5,000 mg/kg, and 6 hr-4 d at 500 mg/kg.
Rat oral LD50 (95% CI) =
232 (108-500) mg/kg.
Mine et al. (1961)
Acute (oral)
The oral LD5o was determined in adult
male Swiss-Webster mice using a
24-hr observation period. Additional
study details were not provided.
Mouse oral LD5o = 200 mg/kg.
Mouse oral LD5o = 200 mg/kg.
Simmon et al. (1979)
Acute (inhalation)
Rats (6/group; sex and strain NS) were
acutely exposed to glycidaldehyde via
inhalation at 127, 174, 275, or
430 ppm. An additional group was
exposed to saturated air. Duration of
exposure was not reported.
Mortality incidence was 0/6, 0/6, 5/6, and
5/6 at 127, 174, 275, and 430 ppm,
respectively, and 6/6 at saturated air
concentrations. Death occurred within
65-85 min at saturation and between 7 and
48 hr at 275-430 ppm.
Rat inhalation LC50 (95% CI) =
252 (200-316) ppm.
Hine et al. (196D
Acute (dermal)
Rabbits (3/group; sex and strain NS)
were acutely exposed to
glycidaldehyde via dermal exposure at
44, 350, or 2,820 mg/kg. Duration of
exposure was not reported.
Incidence of mortality was 0/3, 2/3, and
3/3 for 44, 350, and 2,820 mg/kg,
respectively. Time of death was 10-24 hr
for 350 mg/kg and 2-4 hr for 2,820 mg/kg.
Moderate skin irritation was reported.
Rabbit dermal LD50 =
249 (195-318) mg/kg.
Glycidaldehyde is a moderate skin
irritant.
Hine et al. (196D
Supporting evidence—cancer effects in animals following exposure via any route
Cancer assay (oral)
S-D rats (5 F/group) were administered
0 or 33 mg/animal glycidaldehyde in
0.5 mL tricaprylin via gavage 1 d/wk
for life. Animals were examined for
palpable tumors during exposure and
underwent gross necropsy at death.
Median survival was 329 d in treated rats
and 525 d in vehicle controls. No tumors
were observed in control or exposed rats in
the gastric tract nor distant sites.
Glycidaldehyde was not
carcinogenic under the conditions
of this assay. However, the study
design is considered inadequate for
tumor assessment due to inadequate
animal numbers (5/group).
Van Duuren et al.
(1966)
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Table 4B. Other Glycidaldehyde (CASRN 765-34-4) Studies
Test3
Materials and Methods
Results
Conclusions
References
Cancer assay (dermal)
ICR/Ha Swiss mice (41 F) were
administered -100 mg glycidaldehyde
(10% solution in acetone) to clipped
dorsal skin 3 d/wk for life. Additional
groups (100 F/group) served as
untreated and acetone controls.
Endpoints evaluated included survival,
skin condition, and tumor incidence.
Median survival was 419 to >526 d in
untreated and acetone control mice and
445 d in treated mice. Mild skin irritation
(slight hair loss and crusting) was reported
in glycidaldehyde treated mice. Skin
papillomas were observed in 6/41 treated
rats; no papillomas were observed in the
control groups. Observed papillomas
progressed into malignant skin tumors in
3/6 mice with papillomas.
Glycidaldehyde was carcinogenic
under the conditions of this assay.
Based on statistics conducted for
this review, both the incidences of
skin papillomas and malignant skin
tumors were significantly increased
in treated mice, compared with
vehicle and untreated controls.
Van Duuren et al.
f 1967a)
Cancer assay (dermal)
Swiss mice (30 F) were administered
-100 mg glycidaldehyde (3% solution
in benzene) to clipped dorsal skin
3 d/wk for life. Additional groups
(60 F/group) served as untreated and
benzene controls. Endpoints evaluated
included survival, skin condition, and
skin tumor incidence.
Median survival was 441 d in untreated
controls, 498 d in benzene controls, and
496 d in treated mice. Moderate skin
irritation (persistent hair loss and crusting)
was reported in glycidaldehyde-treated
mice. Skin papillomas were observed in
8/30 treated mice. Skin carcinomas were
also observed in 8/30 treated mice. No
papillomas or carcinomas were observed in
the control groups.
Glycidaldehyde was carcinogenic
under the conditions of this assay.
Based on statistics conducted for
this review, both the incidences of
skin papillomas and carcinomas
were significantly increased in
treated mice, compared with
vehicle and untreated controls.
Van Duuren et al.
(1965)
Initiation-promotion
assay (dermal)
5 groups of Swiss mice (30 F/group)
were used in this assay. Group 1
(G + C) was dermally exposed once to
2.5 mg glycidaldehyde in 0.25 mL
acetone, unexposed for 3 wk, then
dermally exposed to 0.1% croton oil
5 d/wk for 27 wk. Group 2 (C only)
was dermally exposed to 0.1% croton
oil 5 d/wk for 27 wk only. Groups 3
and 4 were acetone and unexposed
controls, respectively. Group 5
(DMBA + C) was a DMBA-positive
initiation control. Endpoints evaluated
included skin tumor incidence.
Skin tumor (keratoacanthoma) incidence
was 40% at Wk 30 in the G + C group
(first tumor at 16 wk) and 95% in the
DMBA + C group (first tumor at 5 wk).
Tumor incidences in C-only and acetone
and untreated control groups were not
reported.
Glycidaldehyde was a weak tumor
initiator compared with DMBA
under the conditions of this assay.
Shamfoerger et al.
(1974)
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Table 4B. Other Glycidaldehyde (CASRN 765-34-4) Studies
Test3
Materials and Methods
Results
Conclusions
References
Initiation-promotion
assay (dermal)
4 groups of Swiss mice (20 F/group)
were used in this assay. Group 1
(G + C) was dermally exposed once to
1 mg glycidaldehyde, unexposed for
2 wk, then dermally exposed to 1 mg
croton resin 3 d/wk for life. Group 2
(G only) was exposed once to 1 mg
glycidaldehyde and observed for life.
Group 3 (C only) was dermally
exposed to 1 mg croton resin 3 d/wk
for life. Group 4 (DMBA + C) was a
DMBA-positive initiation control.
Endpoints evaluated included survival
and skin tumor incidence.
Median survival was 348 d in the G-only
group, 439 d in the C-only group, 386 d in
the G + C group, and 276 d in the
DMBA + C group. Skin papilloma
incidence was 0/20, 1/20, and 2/20 in the
G-only, C-only, and G + C groups,
respectively. The days to first tumor were
426 d in the C-only group and 264 d in the
G + C group. No skin carcinomas were
observed in any of these groups.
In the DMBA + C group, 9/20 mice had
skin papillomas and 8/20 mice had skin
carcinomas. Time to first papilloma and
carcinoma was 51 and 110 d, respectively.
Glycidaldehyde was a weak tumor
initiator compared with DMBA
under the conditions of this assay.
Van Duuren et al.
(1965)
Cancer assay (s.c.)
S-D rats (20 F/group) were
administered 0 (2 groups) or
33 mg/animal glycidaldehyde via s.c.
injection in 0.1 mL tricaprylin 1 d/wk
for life. Injections were given in the
left axillary area. An untreated control
group of 30 F rats was included as
well. Endpoints evaluated included
survival and tumor incidence.
Median survival time was 483-537 d in
control rats and 425 d in treated rats.
Subcutaneous sarcomas were observed at
the injection site in 5 (25%) treated rats.
No tumors were observed at the injection
site in any of the control groups.
Glycidaldehyde was carcinogenic
under the conditions of this assay.
Based on statistics conducted for
this review, the incidence of s.c.
sarcomas at the injection site was
significantly increased in treated
rats, compared with vehicle and
untreated controls.
Van Duuren et al.
(1967b)
Cancer assay (s.c.)
S-D rats (50 F/group) were
administered 0 or 1 mg/animal
glycidaldehyde via s.c. injection in
0.1 mL tricaprylin 1 d/wk for life.
Injections were given in the left
axillary area. An untreated control
group of 50 F rats was included as
well. Endpoints evaluated included
survival and tumor incidence.
Median survival was 554 d in untreated
controls, >565 d in vehicle controls, and
545 d in treated rats. A malignant
fibrosarcoma was observed at the injection
site in one treated rat and benign injection
site fibroadenomas were observed in three
additional treated rats. An injection-site
adenocarcinoma was recorded in one
vehicle control animal.
Glycidaldehyde was not
carcinogenic under the conditions
of this assay.
Van Duuren et al.
(1966)
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Table 4B. Other Glycidaldehyde (CASRN 765-34-4) Studies
Test3
Materials and Methods
Results
Conclusions
References
Cancer assay (s.c.)
ICR/Ha Swiss mice (30-50 F/group)
were administered 0, 0.1, or
3.3 mg/animal glycidaldehyde via s.c.
injection in 0.05 mL tricaprylin 1 d/wk
for life. Injections were given in the
left axillary area. Each exposure group
had concurrent vehicle and untreated
control groups (30-50 F/group).
Endpoints evaluated included survival
and tumor incidence.
Median survival was 415-431 d in
untreated controls, 368-535 d in vehicle
controls, 593 d at 0.1 mg/animal, and
472 d at 3.3 mg/animal. Malignant tumors
(fibrosarcoma, squamous cell carcinomas,
adenocarcinomas) were observed at the
injection site in 6 and 23% of mice at
0.1 and 3.3 mg/animal, respectively. One
animal with benign papillary tumor was
also observed at 3.3 mg. No malignant
tumors were observed at the injection site
in any of the vehicle or untreated control
groups.
Glycidaldehyde was carcinogenic
under the conditions of this assay.
Based on statistics conducted for
this review, the incidence of
malignant tumors at the injection
site was significantly increased at
3.3 mg/animal, compared with
vehicle and untreated controls.
Van Duuren et al.
(1966)
"Acute = exposure for <24 hours (U.S. EPA. 2002).
CI = confidence interval; DMBA = 7,12-dimethylbenz(a)anthracene; F = female(s); LC5o = median lethal concentration; LD50 = median lethal dose; NS = not specified;
s.c. = subcutaneous; S-D = Sprague-Dawley.
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DERIVATION OF PROVISIONAL VALUES
DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic Provisional Reference Dose
The database for oral toxicity of glycidaldehyde is limited to acute lethality studies
(Simmon et al.. 1979; Hine et al.. 1961) and an inadequate cancer study (Van Duuren et al..
1966). precluding derivation of a subchronic provisional reference dose (p-RfD).
Derivation of Chronic Provisional Reference Dose
A chronic p-RfD value was not derived because an oral RfD is available on U.S. EPA's
Integrated Risk Information System (IRIS) database (U.S. HP A. 2005). The IRIS oral RfD is
based on the subchronic inhalation study by Hine et al. (1961) via route-to-route extrapolation.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic Provisional Reference Concentration
The database of potentially relevant studies for deriving a subchronic p-RfC for
glycidaldehyde is limited to a single 12-week inhalation study in male rats (Hine et al.. 1961).
The study examined a variety of endpoints in rats after 12 weeks of exposure and included a
control plus four concentration groups. However, study limitations included lack of analytical
concentrations, use of one sex (male), histopathology on a limited set of organs, inadequate data
reporting for several endpoints (lack of variance data, lack of absolute organ weights, lack of
incidence data), and lack of study design and methods description (e.g., exposure chamber
conditions, generation of atmospheres). Based on these limitations, the study was not considered
appropriate to use as the basis of a provisional toxicity value. However, this study was used for
the derivation of "screening-level" values for subchronic and chronic inhalation exposure to
glycidaldehyde (see Appendix C).
A summary of noncancer provisional reference values for glycidaldehyde is shown in
Table 5.
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Table 5. Summary of Noncancer Reference Values for Glycidaldehyde (CASRN 765-34-4)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
(HED/HEC)
UFc
Principal
Study
Subchronic
p-RfD (mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
Oral RfD value of 4 x 10 4 me/ke-d is available on IRIS (U.S. EPA. 2005).
Screening
subchronic p-RfC
(mg/m3)
Rat/M
Hematological changes
in bone marrow
1 X 10-2
NOAEL
3.5
300
Mine et al.
(1961)
Screening
chronic p-RfC
(mg/m3)
Rat/M
Hematological changes
in bone marrow
1 x 10-3
NOAEL
3.5
3,000
Hine et al.
(1961)
HEC = human equivalent concentration; HED = human equivalent dose; IRIS = Integrated Risk Information
System; M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfD = reference dose
UFC = composite uncertainty factor.
PROVISIONAL CARCINOGENICITY ASSESSMENT
A provisional cancer assessment was not prepared for glycidaldehyde because IRIS (U.S.
EPA. 2005) includes a cancer assessment for this compound. Based on the weight of evidence
(WOE), IRIS classified glycidaldehyde as a B2 probable human carcinogen, although data were
not adequate for deriving quantitative estimates of carcinogenic risk by oral or inhalation
exposure (see Table 6).
Table 6. Summary of Cancer Risk Estimates for Glycidaldehyde (CASRN 765-34-4)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Risk Estimate
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)-1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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APPENDIX A. LITERATURE SEARCH STRATEGY
Non-date-limited literature searches were conducted in February 2018 and updated in
May 2019 for studies relevant to the derivation of provisional toxicity values for glycidaldehyde
(CASRN 765-34-4). Synonyms included in the search were oxirane-2-carbaldehyde,
2-oxiranecarboxaldehyde, oxirane-carboxaldehyde, 2,3-epoxypropionaldehyde,
2,3-epoxy-l-propanal, 2,3-epoxypropanal, and epoxypropanal. Searches were conducted using
U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature.
HERO searches the following databases: PubMed, TOXLINE (including the Toxic Substances
Control Act Test Submissions [TSCATS] database), and Web of Science (WOS). In addition,
the following databases were searched outside of HERO: U.S. EPA Chemical Data Access Tool
(CDAT), U.S. EPA ChemView, Defense Technical Information Center (DTIC), European
Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), European Chemicals
Agency (ECHA), U.S. EPA Health Effects Assessment Summary Tables (HEAST), International
Programme on Chemical Safety (IPCS) INCHEM, U.S. EPA Integrated Risk Information
System (IRIS), Japan Existing Chemical Data Base (JECDB), National Toxicology Program
(NTP), and Organisation for Economic Co-operation and Development (OECD), including
eChemPortal. The following additional sources were checked for regulatory values: American
Conference of Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and
Disease Registry (ATSDR), California Environmental Protection Agency (CalEPA), U.S. EPA
Office of Water (OW), International Agency for Research on Cancer (IARC), Occupational
Safety and Health Administration (OSHA), and World Health Organization (WHO).
LITERATURE SEARCH STRINGS
PubMed
"Glycidaldehyde" OR "2-Oxiranecarboxaldehyde" OR "2, 3-Epoxypropionaldehyde" OR
"2,3-Epoxy-l-propanal" OR "2,3-Epoxypropanal" OR "2,3-Epoxypropionaldehyde" OR
"Epoxypropanal" OR "Oxirane-carboxaldehyde"
WOS
TS=("Glycidaldehyde" OR "2-Oxiranecarboxaldehyde" OR "2, 3-Epoxypropionaldehyde" OR
"2,3-Epoxy-l-propanal" OR "2,3-Epoxypropanal" OR "2,3-Epoxypropionaldehyde" OR
"Epoxypropanal" OR "Oxirane-carboxaldehyde" OR "765-34-4") AND ((WC=("Toxicology"
OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR
"Reproductive Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR
"Allergy" OR "Public, Environmental & Occupational Health") OR SU=("Anatomy &
Morphology" OR "Cardiovascular System & Cardiology" OR "Developmental Biology" OR
"Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR "Hematology" OR
"Immunology" OR "Neurosciences & Neurology" OR "Obstetrics & Gynecology" OR
"Oncology" OR "Ophthalmology" OR "Pathology" OR "Pediatrics" OR "Pharmacology &
Pharmacy" OR "Physiology" OR "Public, Environmental & Occupational Health" OR
"Respiratory System" OR "Toxicology" OR "Urology & Nephrology" OR "Reproductive
Biology" OR "Dermatology" OR "Allergy")) OR (TS="rat" OR TS="rats" OR TS="mouse" OR
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TS="murine" OR TS="mice" OR TS="guinea" OR TS="muridae" OR TS=rabbit* OR
TS=lagomorph* OR TS=hamster* OR TS=ferret* OR TS=gerbil* OR TS=rodent* OR
TS="dog" OR TS="dogs" ORTS=beagle* OR TS="canine" ORTS="cats" OR TS="feline" OR
TS="pig" OR TS="pigs" ORTS="swine" OR TS="porcine" OR TS=monkey* OR
TS=macaque* OR TS=baboon* OR TS=marmoset* OR TS="child" OR TS="children" OR
TS=adolescen* OR TS=infant* OR TS="WORKER" OR TS="WORKERS" OR TS="HUMAN"
OR TS=patient* OR TS=mother OR TS=fetal OR TS=fetus OR TS=citizens OR TS=milk OR
TS=formula OR TS=epidemio* OR TS=population* OR TS=exposure* OR TS=questionnaire
OR SO=epidemio*) OR TI=toxic*)A. 1.3 TOXLINE
TOXLINE
@AND+@OR+(Glycidaldehyde+"2-Oxiranecarboxaldehyde"+"2,
3-Epoxypropionaldehyde"+"2,3-Epoxy-l-propanal"+"2,3-Epoxypropanal"+"2,3-Epoxypropional
dehyde"+Epoxypropanal+"Oxirane-carboxaldehyde"+@TERM+@rn+765-34-4)+@org+(ANEU
PL+BIOSIS+CIS+DART+EMIC+EPIDEM+HEEP+HMTC+IPA+RISKLINE+MTGABS+NIO
SH+NTIS+PESTAB+PPBrB)+@AND+not+@org+p(ubmed+pubdart)
TSCATS
@TERM+@rn+"765-34-4"+@org+TSCATS
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APPENDIX B. DETAILED PECO CRITERIA
Table B-l. Population, Exposure, Comparator, and Outcome (PECO) Criteria
PECO Element
Evidence
Population
Humans, laboratory mammals, and other animal models of established relevance to human
health (e.g.. Xenopus embryos); mammalian organs, tissues, and cell lines; and bacterial and
eukaryote models of genetic toxicity.
Exposure
In vivo (all routes), ex vivo, and in vitro exposure to the chemical of interest, including
mixtures to which the chemical of interest may contribute significantly to exposure or
observed effects.
Comparator
Any comparison (across dose, duration, or route) or no comparison (e.g., case reports without
controls).
Outcome
Any endpoint suggestive of a toxic effect on any bodily system, or mechanistic change
associated with such effects. Any endpoint relating to disposition of the chemical within the
body.
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APPENDIX C. SCREENING PROVISIONAL VALUES
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional toxicity values for glycidaldehyde. However,
information is available for this chemical, which although insufficient to support deriving a
provisional toxicity value under current guidelines, may be of use to risk assessors. In such
cases, the Center for Public Health and Environmental Assessment (CPHEA) summarizes
available information in an appendix and develops a "screening value." Appendices receive the
same level of internal and external scientific peer review as the provisional reference values to
ensure their appropriateness within the limitations detailed in the document. Users of screening
toxicity values in an appendix to a PPRTV assessment should understand that there could be
more uncertainty associated with the derivation of an appendix screening toxicity value than for
a value presented in the body of the assessment.
Derivation of a Screening Subchronic Provisional Reference Concentration
The database of potentially relevant studies for deriving a subchronic p-RfC for
glycidaldehyde is limited to a single 12-week inhalation study in male rats (Hinc et al.. 1961).
The critical effect identified in this study was decreased hematological changes in the bone
marrow at >59 mg/m3 (human equivalent concentration [HEC] = 7.0 mg/m3). Hematological
changes (e.g., changes in leukocytes) were also observed in rabbits that were exposed to
glycidaldehyde via the intravenous (i.v.) route (Hinc et al.. 1961); these data support the
selection of hematological changes in the bone marrow of rats as the critical effect for deriving
the subchronic p-RfC. No effects were observed at 29 mg/m3 (HEC = 3.5 mg/m3).
The no-observed-adverse-effect level (NOAEL) (HEC) of 3.5 mg/m3 for male rats was
calculated by using U.S. EPA (1994) methodology for an extrarespiratory effect as follows:
Exposure concentration adjustment for continuous exposure:
NOAELadj = NOAEL (ppm) x (MW ^ 24.45) x (hours per day
exposed ^ 24 hours) x (days per week exposed ^ 7 days)
= 10 ppm x (72.06 g/mol 24.45) x (4 hours 24 hours) x
(5 days ^ 7 days)
= 29 mg/m3 x (4 hours ^ 24 hours) x (5 days ^ 7 days)
= 3.5 mg/m3
HEC conversion for extrarespiratory effects:
NOAEL (HEC) = NOAELadj x Hb/g-A - Hb/g-H
= 3.5 mg/m3 x 1
= 3.5 mg/m3
where
Hb/g-A Hb/g-H = the ratio of the blood-gas (air) partition coefficient of the
chemical for the laboratory animal species to the human value.
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In the absence of data for glycidaldehyde for male rats, the default value of 1 was used,
as specified in U.S. EPA (1994) guidance.
Data reporting for the Hine et al. (1961) study is inadequate for benchmark dose (BMD)
modeling because variance data were not reported for the critical endpoint. Therefore, the
NOAEL (HEC) of 3.5 mg/m3 is selected as the point of departure (POD) for deriving the
screening subchronic p-RfC.
The screening subchronic p-RfC of 1 x 10 2 mg/m3 is derived by applying a composite
uncertainty factor (UFc) of 300 (reflecting an interspecies uncertainty factor [UFa] of 3, an
intraspecies uncertainty factor [UFh] of 10, and a database uncertainty factor [UFd] of 10) to the
selected POD of 3.5 mg/m3, as follows:
Screening Subchronic p-RfC = POD (HEC) ^ UFc
= 3.5 mg/m3 ^ 300
= 1 x 10 2 mg/m3
Table C-l summarizes the uncertainty factors for the screening subchronic p-RfC for
glycidaldehyde.
Table C-l. Uncertainty Factors for the Screening Subchronic p-RfC for
Glycidaldehyde (CASRN 765-34-4)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans using toxicokinetic cross-species dosimetric adjustment for systemic effects from a
Cateeorv 3 sas. as specified in U.S. EPA (1994) guidelines for deriving RfCs.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The inhalation
database for glycidaldehyde is limited to an acute lethality study and a subchronic inhalation study in
rats. There are no reproductive or developmental toxicity studies available by inhalation or oral
exposure. Furthermore, the principal study did not examine nasal effects, which could be a target
organ for glycidaldehyde-induced toxicity given that it is a water-soluble reactive aldehyde;
compounds of this nature (e.g., acrolein) have been shown to cause nasal effects in toxicity studies.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of information
to assess toxicokinetic and toxicodynamic variability of glycidaldehyde in humans.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the subchronic POD was derived from subchronic data.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; RfC = reference concentration; UF = uncertainty factor(s);
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
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Derivation of a Screening Chronic Provisional Reference Concentration
No chronic inhalation studies were identified for glycidaldehyde. Therefore, the 12-week
inhalation study in male rats (Hine et al.. 1961) used as the basis for the screening subchronic
p-RfC is selected as the basis for the screening chronic p-RfC. As discussed above, the POD
from this study is a NOAEL (HEC) of 3.5 mg/m3 for hematological changes in the bone marrow.
The screening chronic p-RfC of 1 x 10~3 mg/m3 is derived by applying a UFc of 3,000
(reflecting a UFa of 3, a UFh of 10, a UFd of 10, and a subchronic-to-chronic uncertainty factor
[UFs] of 10) to the selected POD of 3.5 mg/m3.
Screening Chronic p-RfC = POD (HEC) UFc
= 3.5 mg/m3 ^ 3,000
= 1 x 10 3 mg/m3
Table C-2 summarizes the uncertainty factors for the screening chronic p-RfC for
glycidaldehyde.
Table C-2. Uncertainty Factors for the Screening Chronic p-RfC for
Glycidaldehyde (CASRN 765-34-4)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans using toxicokinetic cross-species dosimetric adjustment for systemic effects from a
Cateeorv 3 sas. as specified in U.S. EPA (1994) guidelines for deriving RfCs.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The inhalation
database for glycidaldehyde is limited to an acute lethality study and a subchronic inhalation study in
rats. There are no chronic inhalation studies. There are no reproductive or developmental toxicity
studies available by inhalation or oral exposure. Furthermore, the principal study did not examine
nasal effects, which could be a target organ for glycidaldehyde-induced toxicity given that it is a
water-soluble reactive aldehyde; compounds of this nature (e.g., acrolein) have been shown to cause
nasal effects in toxicity studies.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of glycidaldehyde in humans.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
10
A UFS of 10 is applied because the chronic POD was derived from subchronic data.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; RfC = reference concentration; UF = uncertainty factor(s);
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
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APPENDIX D. DATA TABLES
Table D-l. Selected Data for Male Long-Evans Rats Exposed to Glycidaldehyde
(CASRN 765-34-4) via Inhalation for 12 Weeks (4 Hours/Days, 5 DaysAVeek)3
Nominal Concentration in mg/m3 (HECer)
Endpoint
0
29 (3.5)
59 (7.0)
120 (14)
240 (28)
Survival13
9/10 (90%)
10/10 (100%)
9/10 (90%)
8/10 (80%)
0/10° (0%)
Body-weight gain4 e (%)
109
107 (-2%)
80* (-27%)
84* (-23%)
NA
Relative organ weights4 e
Thymus (%)
0.0587
0.0364* (-38%)
0.0501 (-15%)
0.0415* (-29%)
NA
Spleen (%)
0.335
0.338 (+0.9%)
0.364 (+9%)
0.217* (-35%)
NA
Testes (%)
0.904
0.991 (+10%)
1.088* (+20%)
1.001* (+11%)
NA
Liver (%)
3.34
3.25 (-3%)
3.85 (+15%)
3.45 (+3%)
NA
Kidney (%)
0.665
0.654 (-2%)
0.684 (+3%)
0.700 (+5%)
NA
Lung(%)
0.405
0.494 (+22%)
0.487 (+20%)
0.434 (+7%)
NA
Bone marrow6'f
Nucleated cells (x 108)
2.27
1.86 (-18%)
1.19* (-48%)
1.24* (-45%)
0.62f (-44%)
M:E ratio
2.7
3.6 (+33%)
5.1 (+89%)
4.3 (+59%)
2.4 (-11%)
Total Leukocytes
0 Exposures
14,000
13,000
13,000
12,400
9,900
17 Exposures
15,600
13,600
15,200
12,000
7,300 (5 exposures)
60 Exposures
15,000
13,700
15,800
12,000
Leukocytes
(% Polymorphonuclear)
0 Exposures
13
25
22
17
10
17 Exposures
21
20
18
11
54* (5 exposures)
60 Exposures
27
29
19
23
Erythrocytes (x 106)
0 Exposures
7.1
7.4
7.5
7.4
6.9
17 Exposures
7.2
8.7
9.5
8.5
8.7 (5 exposures)
60 Exposures
8.7
8.9
9.2
9.8
Hemoglobin (%)
0 Exposures
16.3
16.0
16.3
16.0
16.0
17 Exposures
17.0
17.2
18.4
16.9
17.3 (5 exposures)
60 Exposures
19.8
19.8
19.4
20.1
aHine et al. (196D.
bValues denote number of animals showing changes + total number of animals examined (% incidence).
°8/10 animals died after 4 exposures; the 2 surviving animals were sacrificed after the fifth exposure.
dData are means (no variance data reported); n = 8-10/group (see "survival" row).
"Value in parentheses is % change relative to control = ([treatment mean - control mean] + control mean) x 100.
fData are means (no variance data were reported); n = 8-10/group at 12 weeks for groups exposed to <120 mg/m3;
n = 2 surviving rats at 5 days for the 240-mg/m3 group.
* Significantly different from control (p < 0.05), as reported by the study authors.
f Significantly different from reference value of 1.10 x 108 for a 100-g rat, as reported by the study authors (the
average body weight of these two rats was 122 g).
ER = extrarespiratory; HEC = human equivalent concentration: M:E = myeloid to erythroid; NA = not applicable.
37
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