FINAL DRAM
ECAO-CIN- United States ECAO-CIN-G056
GQ56 Environmental Protection September, 1989
EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CROTONALDEHYDE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati OH 45268 U.S. Environmental Protection Agency
' . P'-;iori 5, I -i>iy:.ry (.M'L-1S)
Z:>i. o. DjjrDoi.i £t-oet, I
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months prior to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented, provided sufficient data
are available. For systemic toxicants, these Include reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the llfespan. This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980), 1s provided.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genldty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxldty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
IgnltabllHy, reactivity, aquatic toxldty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer based RQs are defined in U.S.
EPA, 1984 and 1986a, respectively.
111
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER ..... 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.2. WATER 5
2.3. SOIL 6
2.4. SUMMARY 6
3. EXPOSURE 8
3.1. AIR, WATER AND OTHER MEDIA 8
3.2. SUMMARY 8
4. ENVIRONMENTAL TOXICOLOGY 10
4.1. AQUATIC TOXICOLOGY 10
4.1.1. Acute Effects on Fauna 10
4.1.2. Chronic Effects on Fauna 10
4.1.3. Effects on Flora 11
4.1.4. Effects on Bacteria 11
4.2. TERRESTRIAL TOXICOLOGY 11
4.2.1. Effects on Fauna. . 11
4.2.2. Effects on Flora . 11
4.3. FIELD STUDIES 11
4.4. AQUATIC RISK ASSESSMENT 11
4.5. SUMMARY 13
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 15
5.3. METABOLISM 15
5.4. EXCRETION 16
5.5. SUMMARY 16
1v
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TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 17
6.1. SYSTEMIC TOXICITY 17
6.1.1. Inhalation Exposure 17
6.1.2. Oral Exposure 17
6.1.3. Other Relevant Information 19
6.2. CARCINOGENICITY 22
6.2.1. Inhalation 22
6.2.2. Oral 22
6.2.3. Other Relevant Information 24
6.3. MUTAGENICITY 24
6.4. TERATOGENICITY 24
6.5. OTHER REPRODUCTIVE EFFECTS 27
6.6. SUMMARY 27
7. EXISTING GUIDELINES AND STANDARDS 29
7.1. HUMAN 29
7.2. AQUATIC 29
8. RISK ASSESSMENT 30
8.1. CARCINOGENICITY 30
8.1.1. Inhalation 30
8.1.2. Oral 30
8.1.3. Other Routes 30
8.1.4. Weight of Evidence 30
8.1.5. Quantitative Risk Estimates 31
8.2. SYSTEMIC TOXICITY 33
8.2.1. Inhalation Exposure 33
8.2.2. Oral Exposure 33
9. REPORTABLE QUANTITIES 36
9.1. BASED ON SYSTEMIC TOXICITY 36
9.2. BASED ON CARCINOGENICITY 39
10. REFERENCES 41
APPENDIX A: LITERATURE SEARCHED 54
APPENDIX B: CANCER DATA SHEET FOR DERIVATION OF q-|* FOR
ORAL EXPOSURE 57
APPENDIX C: SUMMARY TABLE FOR CROTONALDEHYDE 58
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LIST OF TABLES
No. Title Page
6-1 Incidence of Neoplastlc Nodules and Hepatocellular
Carcinomas 1n Male F344 Rats Treated with Crotonaldehyde
(>99% pure) In the Drinking Water . . 23
6-2 Mutagenldty Data for Crotonaldehyde . 25
9-1 Effects of Oral Exposure to Crotonaldehyde Considered
for Derivation of Candidate Composite Scores 37
9-2 Crotonaldehyde: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 38
9-3 Derivation of Potency Factor (F) for Crotonaldehyde 40
v1
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
BOOT Biological oxygen demand, theoretical
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyr1bonucle1c add
GMAV Genus mean acute value
GMCV Genus mean chronic value
LCso Concentration lethal to 50% of recipients
(and all other subscripted levels)
LDH Lactate dehydrogenase
MED Minimum effective dose
MLE Maximum likelihood estimate
MTD Maximum tolerated dose
NAOPH N1cot1nam1de adenlne dlnucleotlde phosphate
(reduced form)
NOEL No-observed-effect level
ppm Parts per million
RD50 Median effective dose for respiratory depression
RfD Reference dose
RQ Reportable quantity
RV. Dose-rating value
RVg Effect-rating value
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
UV Ultraviolet
v/v Volume per volume
w/v Weight per volume
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The chemical commonly known as crotonaldehyde Is called 2-butenal by the
9th Chemical Index of the American Chemical Society. It Is also known as
crotonal, crotonlc aldehyde, propylene aldehyde and beta-methyl acroleln
(U.S. EPA, 1988a). The empirical formula, molecular formula, molecular
weight and CAS Registry number of crotonaldehyde are as follows:
CH3-CH=CHCHO
Molecular formula: C,H,0
4 o
Molecular weight: 70.09
CAS Registry number: 4170-30-3
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Crotonaldehyde Is a colorless to straw-colored liquid at ambient
temperatures with a pungent, suffocating odor (HSOB, 1988; Hawley, 1981).
It occurs In two Isomerlc forms, c1s and trans. The c1s- form 1s also known
as the syn- or Z- form. Similarly, the trans- form 1s also called the antl-
or E- form. Although the CAS Registry number for the mixture Is 4170-30-3,
the Registry number for the els- form 1s 15798-64-8 and for the trans- form,
123-73-9. Commercial crotonaldehyde Is primarily the trans- Isomer. It Is
very soluble 1n water and mlsdble 1n all proportions with many common
organic solvents Including ethanol, ethyl ether and benzene (Hawley, 1981).
A few relevant physical properties of this compound are given below:
Melting point: -75°C Verschueren, 1983
Boiling point: 104.1°C Rlddlck et al., 1986
Density: 0.8516 g/cm3 at 20°C Rlddlck et al., 1986
Water solubility: 156,000 mg/i at 20°C Rlddlck et al., 1986
Vapor pressure: 38 mm Hg at 25°C Rlddlck et al., 1986
0138d -1- 07/19/89
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Henry's Law constant: 0.02x10 3 atm-mVmol Gaffney et al.. 1987
Flash point: 12.7°C Hawley, 1981
A1r odor threshold: 0.12 ppm (v/v) Amoore and Hautala,
1983
Water odor threshold: 0.42 ppm (w/v) Amoore and Hautala,
1983
A1r conversion factor: 1 ppm (v/v)= 2.87
mg/m3 at 25°C
Chemically, crotonaldehyde can be reduced to alcohol by a variety of
reducing reagents. It can be oxidized to crotonlc acid by mild oxidizing
agents and to acetic add by strong oxidizing agents (Gutsche and Pasto,
1975). When pure, crotonaldehyde polymerizes readily to Us dlmer and
trimer. Because such res1n1f1cat1on and oxidation occur 1n air (products
varying from yellow to brown) this compound Is difficult to store (Baxter,
1979).
1.3. PRODUCTION DATA
Crotonaldehyde Is manufactured by condensation of acetaldehyde to aldol
1n the presence of caustic soda, followed by dehydration with acetic add
and purification by distillation (HSOB, 1988). As of 1987, only one
company, Eastman Kodak Co., Klngsport, TN, manufactures this chemical 1n an
Industrial quantity 1n the United States (SRI, 1987; USITC, 1987). The
current production volume Is not available, but It has been reported
(Baxter, 1979) that -1.1 million pounds was sold In the United States In
1977.
1.4. USE DATA
Crotonaldehyde Is used 1n the manfacture of n-butanol, sorblc add and
crotonlc acid. Smaller amounts of crotonaldehyde are used In the prepara-
tion of rubber accelerators, flavoring agents, surface active agents,
0138d -2- 07/19/89
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Insecticides and fertilizers. It 1s also used as tear gas, as a fuel
warning agent, 1n other organic synthesis, In leather tanning and as an
alcohol denaturant (Hawley, 1981; Baxter, 1979).
1.5. SUMMARY
Crotonaldehyde Is a colorless to straw-yellow liquid with a pungent,
suffocating odor. It occurs In two Isomerlc forms, c1s and trans. Commer-
cial crotonaldehyde 1s composed primarily of the trans- Isomer. It 1s very
soluble In water and mlsdble 1n all proportions with ethanol, ethyl ether
and benzene (HSDB, 1988; Hawley, 1981). Crotonaldehyde 1s usually produced
by aldol condensation of acetaldehyde, followed by acidification of the
product (HSDB, 1988). As of 1987, only Eastman Kodak Co., Klngsport, TN,
manufactures this chemical In the United States (SRI, 1987; USITC, 1987).
The current U.S. production volume of crotonaldehyde 1s not available. It
1s used 1n the manufacture of n-butanol, sorblc acid and crotonlc add.
Smaller amounts of this chemical are used as a fuel warning agent, as tear
gas, 1n organic synthesis operations, In the tanning Industry, and as an
alcohol denaturant, as well as 1n the preparation of rubber accelerators,
flavoring agents, surface active agents, Insecticides and fertilizers
(Hawley, 1981; Baxter, 1979).
0138d -3- 09/19/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
There Is a paucity of data on the fate of crotonaldehyde In the atmo-
sphere. The first absorption band of crotonaldehyde 1s at 260-385 nm, with
an absorption maximum at 328 nm (Calvert and Pitts, 1966). Therefore, this
compound 1s expected to absorb sunlight from the troposphere (wavelength
>290 nm} and may undergo photochemical reactions. As a result of absorption
of UV light of longer wavelength (such as sunlight), however, crotonaldehyde
undergoes excitation to a higher energy state, followed by the subsequent
deactlvatlon of the excited molecules. Only a small amount of polymeriza-
tion and CO formation may occur with sunlight. For example, the quantum
yields of polymer and CO formation are only 0.02 and near 0, respectively,
at 360 nm, although these yields Increased with the decrease of wavelengths
(Calvert and Pitts, 1966). The oxidation of crotonldehyde by H0» 1n the
atmosphere Is probably the most Important mechanism. The rate constant for
this reaction 1s S.S-S^xlO'11 cm3/molecule-sec (Atkinson, 1985; Gusten
et al., 1984). Assuming a diurnal mean H0» concentration of 5xl05
radicals/cm3 (Gusten et al., 1984) and assuming that the reaction proceeds
with a pseudo first-order mechanism, the half-life of this reaction Is -11
hours.
The vapor pressure of crotonaldehyde (38 mm Hg at 25°C) Is such that It
would exist almost entirely In the vapor phase In the atmosphere (Elsenrelch
et al., 1981). Because of Its high water solubility, the removal of vapor-
phase crotonaldehyde by wet deposition seems likely. Because of the lack of
experimental data, It 1s difficult to predict the overall significance of
the process 1n the removal of crotonaldehyde from the atmosphere.
0138d -4- 07/19/89
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2.2. WATER
Adequate published data are not available that will allow the assessment
of the fate of crotonaldehyde In aquatic media. The fate of the chemical
based on abiotic processes, such as photolysis, hydrolysis and chemical
reactions with oxldants and reductants that may be present 1n natural
waters, has not been reported. Based on Us photolytlc behavior In air (see
Section 2.1.). photolysis of crotonaldehyde 1n water may not be significant.
The compound does not contain any functional group that 1s amenable to
hydrolysis. The oxidation of crotonaldehyde by HOp* present 1n natural
water may be a significant process, but no kinetic data are available In the
literature to assess the significance of the process.
The blodegradatlon of crotonaldehyde by both pure cultures and mixed
microorganisms has been reported. The bacterial culture £_._ fluerescens
Isolated from bacterial suspensions from sewage treatment plants oxldatlvely
blodegraded this compound (Klrchner et a!., 1983). A 10-day Incubation of
crotonaldehyde by the standard dilution method using sewage as seed
resulted In 57% blodegradatlon of the compound with respect to Us BOOT
(Heukeleklan and Rand, 1955). With a laboratory seed culture developed from
domestic sewage as the source of unaccllmated microorganisms, blodegradatlon
equivalent to 60% of theoretical oxygen demand was observed 1n 10 days.
With acclimated microorganisms, the blodegradatlon was faster, accounting
for ~70% of theoretical oxygen demand In 10 days. It was also determined
that this compound may be toxic to microorganisms, with toxic thresholds for
unaccllmated and acclimated microorganisms of 14 and 36 ppm, respectively
(Stack, 1957). The anaerobic blotranformatlon of crotonaldehyde to methane
by acclimatized anaerobic microorganisms developed on upflow filters from
mixed reactors was reported by Chou et al. (1979). At an Initial concentra-
tion of 100 ppm, 95% of the compound was converted Into methane 1n 110 days.
0138d -5- 07/19/89
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Therefore, H can be concluded that blodegradatlon of crotonaldehyde may be
a significant process under both aerobic and anaerobic conditions.
Because of Us high water solubility, significant removal of croton-
aldehyde by sorptlon to suspended solids and sediment In water 1s not
likely. From Us Henry's Law constant (H) of 2xlO~5 atm-mVmol and the
volatility characteristics associated with various ranges of H (Lyman et
a!., 1982), It 1s expected that significant volatilization of this compound
from water will occur.
2.3. SOIL
No data regarding the fate of crotonaldehyde In soil were available In
the literature cited In Appendix A. However, based upon the physical
properties of the compound and Us fate In air and water, the following can
be concluded about Us fate In soils. Neither photolysis nor hydrolysis Is
expected to be significant 1n the loss of the compound. Oxldatlve loss of
the compound In the aerobic part of the soil 1s a possibility, but has not
been documented. Loss of the compound through blodegradatlon/blotransforma-
tlon and volatilization from soil surfaces, however, may be significant
processes. Because of Us high water solubility, sorptlon of the compound
to soil particles may not be strong; and In sandy soil containing low
organic carbon, some leaching of the compound from soil to groundwater may
occur.
2.4. SUMMARY
There 1s a paucity of data on the fate of crotonaldehyde In all environ-
mental media. The oxidation of crotonaldehyde by H0« 1n the atmosphere Is
probably the most Important process. Based on the rate constant of this
process (Gusten et al.f 1984; Atkinson, 1985), the estimated half-life of
the compound 1s -11 hours In the air. Because of Us high water solubility,
0138d -6- 09/19/89
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the removal of vapor-phase crotonaldehyde by wet deposition may be a
significant removal process, but no experimental data are available to
verify this. Photolysis In the air may not be a significant removal process
(Calvert and Pitts, 1966). Both blodegradatlon (Heukeleklan and Rand, 1955;
Stack, 1957) and volatilization are expected to be Important 1n water.
Neither photolysis nor hydrolysis may be a significant process 1n water. No
data are available In the literature that permit estimation of Us residence
time 1n water. In soil, both blodegradatlon and volatilization from soil
surfaces may be Important. Because of Us expected poor sorptlon capacity
1n soil, crotonaldehyde may leach Into groundwater, particularly from sandy
soil.
0138d -7- 07/19/89
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3. EXPOSURE
3.1. AIR. WATER AND OTHER MEDIA
Crotonaldehyde has been detected 1n the exhaust of both gasoline- and
dlesel-powered vehicles (Hampton et al., 1982). The levels of crotonalde-
hyde 1n the exhaust gases of four different automobiles under different
engine operating conditions ranged from 0.07-1.35 ppm (Nlshlkawa et al.,
1987). Crotonaldehyde emission at rates varying from none to 0.116 g/kg
have been detected from wood-burning fireplaces. Split logs were found to
emit less Crotonaldehyde than the corresponding quartered logs, presumably
because of the higher burn rate and combustion efficiency of the split logs
(Llparl et al., 1984). Despite the known sources of emission of this
compound In the atmosphere, no ambient air monitoring data are available.
The STORET data base of the U.S. EPA (1988b)t which contains data on the
levels of pollutants 1n ambient water, effluents, sediments and biota,
contains no data on Crotonaldehyde. This compound has been detected quali-
tatively 1n the wastewater from a photographic Industry. However, no
Crotonaldehyde was detected 1n wastewaters from 33 other Industries and
Publicly Owned Treatment plants (Bursey and PelUzzarl, 1982). The compound
has been detected qualitatively In mother's milk In 1 of 12 women residing
In four urban areas (Br1dgev1lle, PA; Bayonne, NJ; Jersey City, NJ; Baton
Rouge, LA) In the United States (Pell1zzar1 et al., 1982). In a National
Occupational Exposure Survey conducted by NIOSH as of May, 1988, 1t 1s
reported that -100 people In the United States are occupationally exposed to
this compound (NIOSH, 1988).
3.2. SUMMARY
Although Crotonaldehyde has been detected In exhaust gases from
gasoline- and dlesel-powered vehicles (Nlshlkawa et al., 1987; Hampton et
0138d -8- 07/19/89
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al., 1982) and 1n emissions from wood-burning fireplaces (L1par1 et a!.,
1984), Its levels In ambient air remain unknown. This compound was detected
qualitatively 1n the wastewater from a photographic Industry, but not 1n the
wastewater of Publicly Owned Treatment plants and over 30 other Industries
(Bursey and PelllzzaM, 1982). Crotonaldehyde was detected In the milk of 1
of 12 women residing 1n urban areas of the United States, although the
source(s) of the compound were not Identified (PelllzzaM et al., 1982).
According to NIOSH (1988), ~100 workers 1n the United States are occupation-
ally exposed to this compound.
0138d -9- 07/19/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Effects on Fauna. Union Carbide Corporation (1974) reported
that the 24-, 48- and 96-hour IC values for crotonaldehyde for fathead
minnows, Plmephales promelas. under static exposure conditions were all
2.8 mg/l.
Dawson et al. (1977) assessed the acute toxlclty of crotonaldehyde to
the freshwater blueglll sunflsh, Lepomls macrochlrus. and the saltwater
tidewater sllverslde, Menldla berylUna. 1n static assays. Potable well
water was used as the holding and dilution water 1n studies with bluegllls,
and the same potable water was used as a base to prepare a synthetic sea-
water for holding and dilution water In studies with sllversldes. Bluegllls
were maintained 1n aquaria In a temperature-controlled room held at 23°C.
SHversldes were maintained In aquaria In a temperature-controlled room held
at 20PC. Test solutions were aerated as needed during the freshwater
assays, but not during the first 24 hours. Test solutions with sllversldes,
however, were aerated constantly during the 96-hour assay. Dawson et al.
(1977) reported 96-hour LC5Qs of 3.5 and 1.3 mg/l for blueglll and
sllversldes, respectively.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY Pertinent data regarding the toxic effects of
chronic exposure of aquatic fauna to crotonaldehyde were not located In the
available literature cited 1n Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION -- No measured steady-state
BCF value for crotonaldehyde was found In the literature. Based on the
regression equation, log BCF = 2.791 - 0.564 log S (Lyman et al., 1982) and
a water solubility of 156,000 mg/l (see Section 1.2.), a BCF value of 0.73
0138d -10- 07/19/89
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Is estimated for this compound. This value suggests that crotonaldehyde
should not bloaccumulate significantly In aquatic organisms.
4.1.3. Effects on Flora. Pertinent data regarding the effects of expo-
sure of aquatic flora to crotonaldehyde were not located 1n the available
literature cited In Appendix A.
4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to crotonaldehyde were not located In the
available literature cited In Appendix A; however, 1t 1s suggested In
Section 2.2. of this document that crotonaldehyde may be toxic to micro-
organisms.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Pertinent data regarding the effects of
exposure of terrestrial fauna to crotonaldehyde were not located 1n the
available literature cited In Appendix A.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to crotonaldehyde were not located 1n the
available literature dted 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of crotonaldehyde on flora and
fauna 1n the field were not located 1n the available literature cited 1n
Appendix A.
4.4. AQUATIC RISK ASSESSMENT
Insufficient data regarding the effects of exposure of aquatic fauna and
flora to crotonaldehyde preclude the development of a freshwater criterion
(Figure 4-1). Development of a criterion for crotonaldehyde 1n freshwater
will require acute assays with a salmonld, benthlc and planktonlc crusta-
ceans, an Insect, a representative from a non-chordate/arthropod phylum and
0138d -11- 07/19/89
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I
i
i F arn i i y
*i
I'd or date (S&lriionid-f ish)
#£
Cnordate iwarrnwater fish)
#j
L-;ortiate (fish or amphibian)
#A
Crustacean tplanktonic)
*tt-
Crustacean (benthic)
*fk
Insect an
*tv
non-Hr thro pod /-Chord ate
fcfi
New Insect an or phylum
represent at : ve
*y
aigae
#10
Vascular plant
I'Eii'i TYPL-" j
Acute*
NO
£. 8"
3. 5e
NH
Nft
Nfi
Nft
NH
N«
Nft
Chronic"
Nf^l
Nft
Nft
NH
NH
N^i
Nfi
Nf-!
Nft
NH
BCi-
NH
Nf-i
NH
NH
NH
NH
NH
NH
NH
NH
Nrt=Not ftvailable »96-hour LC«« in mg/L for fathead minnows Pirneohale;
promelas «9fc-hour LC«« in mg/L for bluegill sunfish Leporn is macro-
ch irus
FIGURE 4-1
Organization chart for listing GHAVs, GHCVs and BCFs required to derive
numerical water quality criteria by the method of U.S. EPA/OWRS (1985) for
the protection of freshwater aquatic life from exposure to crotonaldehyde
0138d
-12-
07/19/89
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an Insectan family or phylum not represented previously. Development of a
criterion will also require at least two chronic assays with fauna, one
assay with an alga or vascular plant, and at least one bloconcentratlon
study.
Insufficient data regarding the effects of exposure of aquatic fauna and
flora to crotonaldehyde also preclude the development of a saltwater
criterion (Figure 4-2). Development of a criterion for crotonaldehyde 1n
saltwater will require acute assays with a member of the chordate family and
a non-arthropod/chordate family, a crustacean, representatives from three
non-chordate families not represented previously and a species from a family
not represented previously. Development of a criterion will also require at
least two chronic assays with fauna, one assay with an alga or vascular
plant and at least one bloconcentratlon study.
4.5. SUMMARY
Values for 96-hour LC5_s of 2.8 (Union Carbide Corporation, 1974), 3.5
and 1.3 mg/i (Dawson et al., 1977), respectively, were reported for
exposure of fathead minnows, blueglll sunflsh and tidewater sllversldes to
crotonaldehyde. A BCF value of 0.73 1s estimated for crotonaldehyde. It Is
not likely that this compound will bloaccumulate significantly In aquatic
organisms.
0138d -13- 09/19/89
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tyj Tvi-1
! F a."-, i i y
*n.
Chordate
s
Lhordat e
*ri
non ftrt nropod / -Lhordat e
*'i
Lr ust acE'ctn i Myi i a / l-'snae. i a ;
4tb
non Choroate
*tL
nori-Lnor-date
#V
non-Chord ate
*B
other-
«'=>
algae
ttiO
Vascular plant
i
ficute*
1.3»
N<-t
Nft
Nn
NO
Nft
N^
NPl
NH
NP
Cnror. ic"
Nf-i
NM
N(-!
Nl'l
NM
NM
NM
NM
NM
NH
ECF-
NM
NM
Nf-i
NM
I
NM
NM
NM
NM
Nft
NM
Nft=Not ftvailable 96-hour LC9o in mg/L for tidewater silversides
Menid la beryl 1ina
FIGURE 4-2
Organization chart for listing GMAVs, GMCVs and BCFs required to derive
numerical water quality criteria by the method of U.S. EPA/OWRS (1985) for
the protection of saltwater aquatic life from the exposure to crotonaldehyde.
0138d
-14-
07/19/89
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5. PHARMACOKINETICS
5.1. ABSORPTION
Pertinent data regarding the absorption of crotonaldehyde were not
located 1n the available literature dted In Appendix A.
5.2. DISTRIBUTION
Crotonaldehyde was detected In the milk of 1/12 of lactatlng women who
had been exposed to pollutants In an urban environment for at least 1 year
(Pell1zzar1 et al., 1982). This may Indicate that crotonaldehyde 1s
fat-soluble and distributed to areas high In fat content. Data correlating
specific exposure to crotonaldehyde with Us appearance In mother's milk
were not available.
5.3. METABOLISM
Minimal data concerning the metabolism of crotonaldehyde were found.
Gray and Barnsley (1971) Injected young adult male albino and black hooded
rats subcutaneously with crotonaldehyde In olive oil at 0.75 mmol/kg bw (53
mg/kg) and Identified metabolites In urine collected over 24 hours. A
metabolite Identified as 3-hydroxy-l-methylpropyl mercapturlc acid repre-
sented amounts varying from 6-15% of the administered dose. In. vitro
reaction of crotonaldehyde with glutathlone In buffer (nonenzymlc reaction)
resulted In rapid sulfhydryl depletion from the system, which the Investi-
gators suggested Involved addition of the thlol group of glutathlone to the
double bond of crotonaldehyde. The Investigators postulated that In the
rat, crotonaldehyde Is converted to 3-hydroxy-l-methylpropyl mercapturlc
acid following conjugation with glutathlone. Crotonaldehyde 1s a poor sub-
strate for rat mltochondrlal aldehyde dehydrogenase (Cederbaum and Dicker,
1982), and Is poorly oxidized by rat liver mltochondrlal fractions (Dicker
0138d -15- 07/19/89
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and Cederbaum, 1984), suggesting that oxidation 1s not as Important a
pathway for the metabolism of crotonaldehyde as It 1s for other aldehydes
such as acetaldehyde.
5.4. EXCRETION
The monitoring study by PelUzzarl et al. (1982) discussed above
suggests that crotonaldehyde may be excreted In the milk of lactatlng women.
Gray and Barnsley (1971) recovered from the urine metabolites equivalent to
6-15% of a 53 mg/kg dose administered subcutaneously to rats. The collec-
tion period was 24 hours.
5.5. SUMMARY
Little data are available regarding the pharmacoklnetlcs of crotonalde-
hyde. Information regarding Us absorption and distribution 1s not known,
except that It may be fat soluble (PelUzzaM et al., 1982). It has been
suggested that crotonaldehyde 1s metabolized In rats through conjugation
with glutathlone followed by hydrolysis to a mercapturlc add derivative
(Gray and Barnsley, 1971), which Is excreted In the urine. Crotonaldehyde
may also be excreted during lactation (PelUzzarl et al., 1982).
0138d , -16- 07/19/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure. Pertinent data regarding the effects of
Inhaled crotonaldehyde were not located In the available literature cited In
Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC -- TRL (1986) administered crotonaldehyde (purity
not reported) In water by gavage to groups of 30 male and 30 female Sprague-
Dawley rats dally for 91-93 days. Dosage levels were 0, 5, 15 or 45 mg/kg/
day. Parameters evaluated Included clinical signs and behavior, food con-
sumption, body weight and ophthalmoscopy at pretreatment and at 13 weeks.
An Interim sacrifice was performed on 10 rats/sex/group after 6 weeks of
exposure. Comprehensive hematology, serum chemistry and urlnalysls tests
were performed at pretreatment, at the Interim sacrifice and at termination.
Comprehensive hlstopathologlc examination was performed at termination on
control and high-dose rats. In addition, selected organs and all gross
lesions were examined hlstopathologlcally from low- and middle-dose rats.
Clinical signs, Including hypoactlvlty, salivation and labored breath-
Ing, were restricted to the high-dose group and occurred for <1 hour after
dosing. Food consumption and body weights of high-dose males were reduced
significantly during part of the experiment, but there were no significant
differences 1n body weights at termination. Treatment-related hlstopatho-
loglc lesions were restricted to hyperkeratosls (and one rat/sex with
patakeratosls) of the forestomach 1n all high-dose rats, with the exception
of one rat that died early of unrelated causes. There were no chemical-
related effects on ophthalmoscoplc appearance of the eyes, on cllnlcopatho-
loglc variables or on organ weights.
0138d -17- 07/19/89
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More recently, Wolfe et al. (1987) administered crotonaldehyde (purity
not reported) 1n corn on by gavage to groups of 10 male and 10 female F344
rats and equal numbers of B6C3F1 mice for 13 weeks at dosages of 0, 2.5, 5,
10, 20 or 40 mg/kg/day. Mortality attributed to treatment was observed In
rats of both sexes at >5 mg/kg/day, 1n addition to hyperplasla of the
epithelium of the forestomach In both sexes at >10 mg/kg/day, and hyper-
keratosls, ulceratlon, moderate necrosis, and acute Inflammation of the
forestomach at 40 mg/kg/day. Acute Inflammatory lesions of the nose were
observed In male rats at >20 mg/kg/day and In female rats at >5 mg/kg/day.
Mean body weights were significantly decreased 1n high-dose male rats at
termination. No statistical analysis or Incidence data were provided In
this abstract. All the mice survived treatment. Inflammatory stomach
lesions similar to those seen In rats were also seen In mice, but only at 40
mg/kg/day.
Moutschen-Dahmen et al. (1976) reported damage to sperm following
subchronlc oral exposure of mice to crotonaldehyde (Section 6.5.).
6.1.2.2. CHRONIC -- Male F344 rats (23-27/group) received crotonalde-
hyde (>99tt pure) at 0, 0.6 or 6.0 mM (0, 42 or 421 mg/l) 1n their drinking
water for 113 weeks starting at 6 weeks of age (Chung et al., 1986). Param-
eters of toxlclty evaluated were drinking water consumption, body weight,
survival, and hlstopathologlcal examination of major organs and gross
lesions. Water consumption was estimated at 20 ml/rat/day at 0.6 mM and
15 ml/rat/day at 6.0 mM. Survival rates of treated animals did not differ
significantly from controls, but the rats receiving the high dosage of
crotonaldehyde consistently had -10% lower body weights than control animals
starting at about the eighth week of exposure (statistical significance not
reported). Moderate to severe liver damage, Including fatty metamorphosis,
0138d -18- 07/19/89
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focal liver necrosis, flbrosls, cholestasls and roononuclear Infiltration,
was found In 10/23 rats that received the high dose. There was no other
mention of nonneoplastlc lesions. At the low dose, there was a signifi-
cantly (p<0.001) Increased Incidence of heptocellular carcinomas, combined
with neoplastlc nodules (Section 6.2.2.).
6.1.3. Other Relevant Information. In acute studies, respiratory Irrita-
tion occurs In humans exposed to crotonaldehyde for 10-15 minutes at ~4 ppm
(11 mg/m3) (S1m and Rattle, 1957; U.S. EPA, 1986a). The smoke from
burning syringes, which contains crotonaldehyde, Irritates people's eyes; no
quantitative data were available (Mehta and Llverlght, 1986)
Animal studies Indicate that crotonaldehyde Inhalation results In
respiratory functional changes, weight loss and, at high concentrations,
death. Male B6C3F1 mice and male Swiss-Webster mice (20-32 g) were exposed
for 10 minutes to crotonaldehyde (purity 85-99%) at concentrations of 0.8-8
ppm, estimated from graphic data provided by the Investigators (Stelnhagen
and Barrow, 1984). Respiratory rates determined by a body plethysmographlc
method were recorded during preexposure, exposure and recovery periods. The
average maximum decrease 1n respiratory rate for each group of 3-4 animals
was computed and plotted against the exposure concentration. The RD was
4.88 ppm (14.0 mg/m3) for B6C3F1 mice and 3.53 ppm (10.1 mg/m3) for
Swiss-Webster mice. Babluk et al. (1985) stated that the RD for male
F344 rats was 23.2 ppm (66.5 mg/m3). Ikeda et al. (1980), however, found
that 1n rabbits, Inhalation of crotonaldehyde at 10 ppm (28.7 mg/m3) for
10 minutes Increased respiration and heartbeat. Rats (male, Wlstar,
12/group) exposed to crotonaldehyde vapors at 100-3200 ppm (287-9173
mg/m3) for 5 minutes to 4 hours also showed respiratory distress and
weight loss (dose response data not provided) (Rlnehart, 1967). The LC5Q
0138d -19- 07/19/89
-------
for rats for a 30-nrinute exposure was reported to be 600 ppm (1720 mg/m3)
by Rlnehart (1967), 1400 ppm (4013 mg/ma) by the U.S. EPA (1986a) and 1500
ppm (4300 mg/m3) by Skog (1950).
The acute oral LD5Q for rats has been reported to be 175 mg/kg
(BorMston Labs, 1980a), 200 mg/kg (Mellon Institute, 1948) and 160-300
mg/kg (Kodak Labs, 1986). An 1ntraper1tonal LD5Q 1n mice was estimated at
52.5 mg/kg (Moutschen-Dahmen et al., 1976). BorMston Labs (1980b) reported
a dietary study 1n which groups of five male and five female Sprague-Dawley
rats were fed diets containing crotonaldehyde at equivalent dosages of 0,
22, 44, 88 or 175 mg/kg/day for 14 days. Parameters of toxlclty evaluated
Included general appearance and behavior, food consumption and feed effi-
ciency, body weight, gross appearance at necropsy and absolute and relative
liver and kidney weights. No compound-related effects were observed.
Crotonaldehyde Injected Intravenously Into cats and rabbits (15-20
mg/kg) usually decreased blood pressure and altered respiration (Skog,
1952). Crotonaldehyde Injected Intraperltoneally Into NMRI mice (average
weight, 25 g; 60-70 mg/kg/day for 5 days) resulted In thymlc necrosis,
splenic atrophy, decreased body weight, Increased plasma cortlcosterone
levels, depletion of the perlarteMolar lymphatic sheaths In thymus-
dependent areas and Increased plasma LDH (Warholm et al., 1984). The 2-fold
maximum Increase In LDH activity occurred 10 hours postlnjectlon. The
authors reported that similar results were seen with weekly Injections,
although specific data were not reported. Pretreatment with crotonaldehyde
reduced the rise In LDH In response to a second dose, Indicating that
tolerance developed (Warholm et al., 1984). In a study of ant Humor drugs.
Cox and Abel (1979) found that 6-methylcyclophospham1de metabolized to
crotonaldehyde when Injected Intraperltoneally Into rats. Crotonaldehyde
0138d -20- 09/19/89
-------
then caused a slight degree of cystitis In the urinary tract, although much
less than that seen with acroleln, which Is a common metabolite of other
antltumor drugs.
Crotonaldehyde applied dentally undiluted at 0.01 ml caused reddened
skin on five volunteers (Mellon Institute, 1941). Repeated application led
to the development of confluent vesicles, probably the result of sensHlza-
tlori from the earlier treatments. In another study, the threshold skin
Irritating concentration was found to be 0.12% 1n plant oil (Balnova and
Madzhunov, 1984). When applied to the skin for 48 hours, crotonaldehyde
(0.75%) Increased water vapor loss (van der Valk et al., 1985). Because of
the results of a 4-hour patch test on New Zealand rabbits, crotonaldehyde
(0.5 mil liquid, concentration unknown) was classified as a corrosive
substance (Industrial Labs, 1972).
In. vitro tests show that crotonaldehyde decreased cytochrome P450 In
hepatic mlcrosomes, decreased NADPH-cytochrome c reductase activity (Cooper
et al., 1987a), and Inhibited mitochondria! oxidation of acetaldehyde and
formaldehyde (Dicker and Cederbaum, 1984). Crotonaldehyde Inhibited leudne
Incorporation, and thus protein synthesis, 1n rat liver slices without
altering oxygen consumption (Perln et al., 1972). In addition, crotonalde-
hyde Inhibited surface sulfhydryls, and therefore the production of super-
oxide anlon radical OZ, In human polymorphonuclear leukocytes and rat
pulmonary macrophages (W1tz et al., 1987). It also Inhibited prostaglandln
E synthesis and phagocytosis 1n zymosan-stlmulated resting pulmonary macro-
phages (Grundfest et al., 1982), as well as alpha-naphthyl acetate esterase
activity In rat liver slices (Kurz and Goslar, 1974).
Crotonaldehyde Inhibited chemotaxls of polymorphonuclear leukocytes
(Bridges et al., 1977), and had cytotoxlc effects on ascltes tumor cells 1n
0138d -21- 07/19/89
-------
mice (Holmberg and "Malmfors, 1974). It also caused dllostasls In embryonic
chick tracheal cells In culture (Pettersson et a!., 1982; Dalhamn and
Rosengren, 1971), which may be significant In understanding Its respiratory
Irritant effects.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled crotonaldehyde were not located 1n the available literature cited In
Appendix A.
6.2.2. Oral. Crotonaldehyde (>99% pure, 1n 85% aqueous solution) was
given to male F344 rats (23-27/group) In the drinking water at concentra-
tions of 0, 0.6 or 6.0 mM (0, 42 or 421 mg/8.) for 113 weeks starting at 6
weeks of age (Chung et al., 1986) (Table 6-1). Survival rates did not differ
significantly from controls, but rats at 6.0 mM crotonaldehyde showed -10%
decrease In body weight starting about the eighth week of treatment (statis-
tical significance not provided). The control rats showed no liver tumors
or neoplastlc nodules. Rats that received 0.6 mM crotonaldehyde had a 33%
(9/27) Incidence of hepatocellular neoplasms (Including neoplastlc nodules
and heptocellular carcinomas) and an 85% (23/27) Incidence of altered liver
foci, which are considered precursors of neoplasms (see Table 6-1). At the
higher dose, the Incidence of liver tumors was 4% (1/23) and the Incidence
of altered liver foci was 57% (13/23). Altered liver foci were observed In
1/23 control rats. The decreased Incidence of neoplastlc and preneoplastlc
lesions at the higher dose was not explained. Bladder tumors, an unusual
finding, were noted In 2/27 animals given 0.6 mM crotonaldehyde, but not In
controls or high-dose rats. There were tumors 1n other organs, but the
Incidence did not differ from controls.
0138d -22- 07/19/89
-------
TABLE 6-1
Incidence of Neoplastlc Nodules and Hepatocellular Carcinomas
1n Hale F344 Rats Treated with Crotonaldehyde
(>99% pure) 1n the Drinking Water*
Concentration
(nM)
0 (0 mg/l)
0.6 (42 mg/l)
6.0 (420 mg/l)
Duration of
Treatment
(weeks)
113
113
113
Tumor Incidence
(p value)
0/23
9/23 (p<0.001)
1/23 (NS)
Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Quality of Evidence
Compound was administered by a relevant route of
exposure at two doses; the MTD appeared to be
obtained; adequate numbers of animals per group
survived to be at risk for late developing tumors;
adequate duration of exposure
Only one strain, species and sex was used; the high
dose group showed an unexplained low Incidence of
tumors
Adequate
*Source: Chung et al., 1986
NS = Not statistically significant
0138d
-23-
07/19/89
-------
6.2.3. Other Relevant Information. Other relevant Information regarding
the cardnogenldty of crotonaldehyde was not located In the available
literature cited 1n Appendix A.
6.3. MUTAGENICITY
Results of the Ames test were mixed, possibly because different methods
were used (Table 6-2). The liquid suspension method Indicated that croton-
aldehyde Is mutagenlc (Neudecker et a!., 1981; Lutz et al., 1982; Ru1z-Rub1o
et al., 1984; Ujlnsky and Andrews, 1980), while studies using the plate
method showed negative results (Simmon et al., 1977; Florin et al., 1980;
Cooper et al., 1987b). False positives might also have resulted from
mistaking pinpoint colonies for revertants (Cooper et al., 1987b, 1988).
Crotonaldehyde was negative for mltotlc recombination In Saccharomyces
cerevlslae strain 03 (Simmon et al., 1977).
Crotonaldehyde was administered In the food (0 or 4000 ppm) or by Injec-
tion (0 or 3500 ppm) to adult male Drosophlla melanoqaster (Woodruff et al.,
1985). The Injected animals showed a significant Increase over controls In
the percent lethals (0.36% vs. 0.05%). There was no difference 1n the
sex-linked lethal mutations In the animals that received the substance In
their food. The Injected animals also showed a significant Increase In
reciprocal translocatlons.
Crotonaldehyde was shown to be positive for both Induction of chromosome
aberrations and sister chromatld exchanges In Chinese hamster ovary cells
(Galloway et al., 1987). In another 1n vitro experiment, crotonaldehyde was
shown to react without metabolic activation with DNA to form cyclic adducts
(Chung et al., 1984).
6.4. TERATOGENICITY
Pertinent data regarding the teratogenlclty of crotonaldehyde were not
located In the available literature cited In Appendix A.
0138d -24- 07/19/89
-------
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6.5. OTHER REPRODUCTIVE EFFECTS
Strain Q mice were given crotonaldehyde (2 g/l) In their drinking
water for 50 days. The authors calculated that the animals drank 5 ml/day
of liquid and Ingested -300 mg/kg/day of crotonaldehyde. Abnormalities In
spermatogenesls were found, Including polyploldy 1n all stages, abnormal
pairing at metaphase I, and Increased numbers of spermatozoa without
acrosomes. The occurrence of these abnormalities ranged from 1-16%. More
pronounced effects were seen when crotonaldehyde was given as a single
IntrapeMtoneal dose (30 mg/kg). Data for control groups were not given,
but the effects of crotonaldehyde were compared with those of butylaldehyde,
which was shown to be more-toxic (Moutschen-Dahmen et a!., 1976).
6.6. SUMMARY
Thirty-minute LC5Qs for rats range from 600-1500 ppm (Rlnehart, 1967;
Skog, 1950). No Information regarding subchronlc or chronic Inhalation
exposure to crotonaldehyde was located; however, both humans and animals
experience acute respiratory distress upon exposure to crotonaldehyde vapors
(Sim and Rattle, 1957; Stelnhagen and Barrow, 1984; Ikeda et al., 1980;
Rlnehart, 1967). The substance Is also Irritating to the skin (Mellon
Institute, 1941; van der Valk et al., 1985; Balnova and Madzhunov, 1984).
Oral LD5Q values In rats range from 160-300 mg/kg (U.S. EPA, 1986a;
BorMston Labs., 1980a; Mellon Institute, 1948). An Intraperltonal LD5Q
1n mice was estimated at 52.5 mg/kg (Moutschen-Dahman et al., 1976).
Information regarding subchronlc consumption of crotonaldehyde by mice In
their drinking water Indicates that long-term exposure can cause damage to
sperm (Moutschen-Dahmen et al., 1976). Long-term exposure of rats to
crotonaldehyde 1n their drinking water Induced a moderate to severe degree
of liver damage (Including tumors) and weight loss (Chung et al., 1986).
0138d -27- 07/19/89
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There Is also evidence that crotonaldehyde 1s a carcinogen In animals.
A chronic study In rats showed that crotonaldehyde given In the drinking
water Increased the Incidence of liver tumors (Chung et al., 1986). The
results of this study are somewhat confounded In that the higher dose
produced tumors 1n only 1/23 rats, while the lower dose produced tumors In
9/23 animals; however, the Incidence of altered liver foci (considered to be
precursors of neoplasms) was 13/23 In the high-treatment group. Mutagen-
1c1ty studies 1n Salmonella showed negative results when the plate method
was used (Simmon et al., 1977; Florin et al., 1980), but positive results
when the liquid suspension method was used (Neudecker et al., 1981; Ujlnsky
and Andrews, 1980). Crotonaldehyde was negative for mltotlc recombination
1n S. cerevlslae (Simmon et al., 1977). Positive results were found In
tests of sex-linked lethal mutations (by Injection only) and reciprocal
translocatlons 1n DrosophUa (Woodruff et al., 1985) and chromosome
aberrations and sister chromatld exchanges 1n Chinese hamster ovary cells
(Galloway et al., 1987).
0138d -28- 07/19/89
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The OSHA standard Is 2 ppm, or ~6 mg/m3 (OSHA, 1985). The ACGIH
(1986) TLV-TWA Is also 2 ppm, or ~6 mg/m3, and Is Intended to protect
against eye and respiratory Irritation. The TLV 1s based on the determina-
tion by ACGIH (1986) that crotonaldehyde 1s -5-20 times less Irritating than
acroleln, a structurally similar aldehyde. A previous STEL has been
eliminated.
U.S. EPA (1986a) reports a final RQ for crotonaldehyde of 100.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to crotonaldehyde were not located In the available literature
cited In Appendix A.
0138d -29- 07/19/89
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. There are no data regarding the cardnogenlcHy of
Inhaled crotonaldehyde.
8.1.2. Oral. Crotonaldehyde (99% pure, In 85% aqueous solution) was
given 1n the drinking water [0, 0.6 or 6.0 mM (0, 42 or 421 mg/ml)] to
male F344 rats (23-27/group) for 113 weeks starting at 6 weeks of age (Chung
et al., 1986). Survival rates did not differ significantly from controls,
but rats receiving 6.0 mM crotonaldehyde showed a decrease In body weight of
-10% (statistical significance not given). Control rats had no Hver tumors
or neoplastlc nodules. Rats receiving 0.6 mM crotonaldehyde had a 33%
(9/27) Incidence of heptocellular neoplasms and an 85% (23/27) Incidence of
altered liver fod, which are considered to be precursors of neoplasms.
With the higher dose, the Incidence of liver tumors was 4% (1/23) and the
Incidence of altered liver foci was 57% (13/23). The decreased Incidence of
neoplastlc and preneoplastlc lesions at the higher dose was unexplained.
Bladder tumors, an unusual finding, were noted 1n 2/27 animals given 0.6 mM
crotonaldehyde, but not In controls or In the high-dose group. There were
tumors 1n other organs, but the Incidence did not differ from controls.
8.1.3. Other Routes. There Is no evidence to Indicate that croton-
aldehyde Is carcinogenic by other routes.
8.1.4. Weight of Evidence. There are no data regarding the cardnogen-
lcHy of crotonaldehyde to humans, and evidence that crotonaldehyde 1s
carcinogenic 1n animals 1s limited. A chronic study 1n rats showed that
crotonaldehyde given 1n the drinking water Increased the Incidence (p<0.001)
of liver tumors 1n male rats (Chung et al., 1986). This study Is somewhat
limited, however, In that the higher dose produced fewer tumors than the
lower dose, and only one sex of one species was tested.
0138d -30- 07/19/89
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Mutagenldty studies Indicate that crotonaldehyde Is a weak mutagen.
Studies In Salmonella show negative results when the plate method 1s used,
but positive results when the liquid suspension method 1s used (see Table
6-2). Mutations are also found 1n tests of sex-linked lethal mutations and
reciprocal translocatlons In Drosophlla (Woodruff et al., 1985) and In tests
of chromosome aberrations and sister chromatld exchanges In Chinese hamster
ovary cells (Galloway et al., 1987).
Crotonaldehyde has accordingly been assigned to EPA Group C, possible
human carcinogen (U.S. EPA, 1986a).
8.1.5. Quantitative.
8.1.5.1. INHALATION Inhalation carclnogenlcHy data were Insuffi-
cient to estimate carcinogenic potency. The positive drinking water study
by Chung et al. (1986) may, however, be considered for estimation of cancer
potency by Inhalation exposure. In this study, an Increased Incidence of
liver neoplasms was observed 1n male rats exposed to 0.6 Mm crotonaldehyde
1n drinking water for 113 weeks. In addition, a low Incidence of bladder
tumors (2/27), an unusual occurrence 1n rats, was observed at this dosage.
Both tumor types occurred at a site distant from the portal of entry,
suggesting that crotonaldehyde may be carcinogenic once absorbed following
any route of exposure. The mutagenlclty data Indicate that crotonaldehyde
Is a direct-acting mutagen, that 1s, 1t need not be metabolized to an active
Intermediate to exert genotoxlc effects. This observation suggests that
crotonaldehyde may be a direct-acting carcinogen as well. It seems appro-
priate, therefore, to consider crotonaldehyde an equally potent carcinogen
by either oral or Inhalation exposure, when potency estimation 1s based on
absorbed dosage.
0138d -31- 07/19/89
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The pharmacoklnetlc data are Insufficient to permit estimation of
Internal dosage following either oral or Inhalation exposure. It seems
reasonable to assume, however, that gastrointestinal absorption may approach
100% and that Inhalation absorption may be near 50%. The q * of 1.9
(mg/kg/day)"1 for oral exposure calculated 1n Section 8.1.5.2. may be con-
sidered a potency estimate for Internal dose of crotonaldehyde, regardless
of the route of exposure. The potency factor of 1.9x10 {mg/kg/day)"1 Is
therefore multiplied by 0.5 to reflect 50% Inhalation absorption 1n the
calculation of risk-specific concentrations In ambient air. Assuming a
reference human body weight of 70 kg and a respiratory rate of 20 mVday,
ambient air concentrations of 3.7xlO"5, 3.7xlO~* and 3.7xlO~7 mg/m3
are associated with Increased cancer risks of lx!0~5, IxlO"6 and
IxlO"7, respectively.
8.1.5.2. ORAL The only study that examined the carclnogenlclty of
crotonaldehyde by the oral route showed Increased heptocellular neoplasms
from drinking water exposure In rats (Chung et al.,1986); therefore, these
data were used to calculate the q *. Benign and malignant tumors were
pooled. Drinking water concentrations of 0, 0.6 (42 mg/l) and 6.0 mM (421
mg/l) were used. The Investigators estimated water consumption at 20
mi/rat/day at 0.6 mM and 15 ml/rat day at 6.0 mM, and estimated total
dosages of crotonaldehyde at 9.5 and 70.0 mmol 1n the two exposed groups.
From the body weight curves provided by the Investigators, average body
weights of 0.425 kg were estimated for rats at 0 and 0.6 mM, and 0.375 kg
for rats at 6.0 mM. Based on an exposure period of 113 weeks (791 days),
the total dosages estimated by the Investigators and the body weights
estimated from the graphs, transformed animal dosages of 0, 2.0 and 17
mg/kg/day are estimated for 0, 0.6 and 6.0 mM, respectively. To transform
0138d -32- 09/19/89
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these animal dosages to equivalent human dosages, the following equation was
1/3
used: equivalent human dose = (body weight of rat/body weight of human)
x animal dose. The equivalent human doses were therefore 0, 0.36 and 3.0
mg/kg/day. The duration of the exposure period and study was 113 weeks,
which 1s longer than the average lifetime for rats; therefore, no correction
factor for length of exposure was used. The Incidences of liver tumors for
the three groups were 0/23, 9/27 and 1/23, respectively. The low Incidence
of tumors at the high dose 1s difficult to explain, since survival was good
In all groups. Data from the highest dose group were excluded because they
did not fit the model when the Ch1-square goodness of fit statistic was
evaluated. Using the multistage model of Howe and Crump (1982), the 95%
lower limit on dose at a confidence limit for a risk of lx!0~5 Is
5.35x10"*. The human q * = 1.9 (mg/kg/day)'1.
The concentration of the chemical In the drinking water associated with
a risk level of 10~5 was calculated by dividing the risk level of 10~5
by the q,*, and then multiplying by 70 kg and dividing by 2 l to give a
concentration of 1.8x10"* mg/l. Concentrations associated with risk
levels of 10~6 and 10"7 are 1.8xlO~s and 1.8x10"* mg/l, respectively.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. No data are available regarding the toxldty
of crotonaldehyde produced by subchronlc or chronic Inhalation, and Inhala-
tion RfDs are not derived.
8.2.2. Oral Exposure.
8.2.2.1. SUBCHRONIC Subchronlc toxldty data suggest that rats are
more sensitive than mice to the effects of crotonaldehyde. Wolfe et al.
(1987) exposed rats and mice of both sexes by gavage to crotonaldehyde In
corn oil at doses of 0, 2.5, 5, 10, 20 or 40 mg/kg/day for 13 weeks.
0138d -33- 09/19/89
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Mortality attributed to treatment was observed at >5 mg/kg/day, forestomach
lesions occurred at >10 mg/kg/day, and female rats exhibited Inflammatory
nasal lesions at >5 mg/kg/day. All mice survived treatment at <40
mg/kg/day; however, forestomach lesions were observed at that dosage.
Crotonaldehyde appears to be more toxic to rats 1n gavage studies when
given 1n corn oil than when given In water. In contrast to the study by
Wolfe et al. (1987), 1n which mortality was observed at >5 mg/kg/day for
crotonaldehyde In corn oil, TRL (1986) reported no mortality 1n rats at 45
mg/kg/day when the test chemical was given 1n water. Effects reported In
this study at 45 mg/kg/day Included transient clinical signs and hyper-
keratotlc lesions of the forestomach. There were no effects at 5 or 15
mg/kg/day. Chung et al. (1986) similarly reported no effect on mortality In
a 2-year drinking water study using rats exposed to 6 mM (17 mg/kg/day).
No RfO can be derived from any of the chronic or subchronlc studies
available. In the Wolfe et al. (1987) study, both treatment-related
mortality and acute nasal Inflammation were seen at the lowest dose tested
(2.5 mg/kg/day). Effects were reported only at 45 mg/kg/day (highest dose
tested) In the TRL (1986) study, but the 2.5 mg/kg/day LOAEL from Wolfe et
al. (1987) Is below the lowest dose tested (5 mg/kg/day) In the TRL study.
The chronic study (Chung et al., 1986) reported hepatocellular carcinomas
and other neoplastlc growths at the lowest dose tested (0.6 mM, equivalent
to 2 mg/kg/day), and no NOAEL was established. Further, no reproductive or
teratogenlclty studies could be located, while a recent review (U.S. EPA,
1985) revealed that the structurally similar aldehyde acroleln Is terato-
genlc. In consideration of the effect (mortality) observed at the lowest
dose tested 1n any study (Wolfe et al., 1987), and confounded by the
weakness of the health effects data base, no subchronlc oral RfD can be
derived for crotonaldehyde.
0138d -34- 07/19/89
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8.2.2.2. CHRONIC The only available chronic oral toxlclty study of
crotonaldehyde (Chung et al., 1986) shows that F344 rats that received 6 mM
In their drinking water for 113 weeks had lower body weights than controls
or rats receiving 0.6 mM. Other nonneoplastlc effects observed at 6.0 mM
were moderate to severe liver lesions. Nonneoplastlc lesions, other than an
85% (23/27) Incidence of altered liver fod, were not mentioned at 0.6 mM,
but 1t 1s not clear how completely such lesions may have been reported
because the focus of the experiment was on carclnogenlcHy rather than on
the systemic toxlclty of crotonaldehyde.
The significance of the weight loss at 6.0 mM 1s unclear; rats In this
group consumed drinking water at 15 ml/day compared with 20 ml/day at
0.6 mM. These values are substantially below the 49 ml/day reference
values for rats adopted by U.S. EPA (1986b), and may well be attributed to
the adverse organoleptlc properties of crotonaldehyde. It Is possible that
decreased water consumption may have Influenced reduced food consumption,
resulting 1n decreased body weights.
Nonetheless, regardless of the reason for decreased water Intake at the
higher concentration, the 0.6 mM level (2.0 mg/kg/day based upon data
provided by the Investigators) represents the NOAEL for the decreased body
weight effect. Further, since this effect was observed only In the high-
dose group and no significant Increase In tumor Incidence was found 1n that
group, the body weight decrement cannot be definitively associated with
carclnogenlcHy. However, since a statistically significant Incidence of
Hver tumors (p<0.001) was reported at the next lowest dosage 1n this study,
and In consideration of the absence of reproductive and teratogenldty data
and the paucity of supporting subchronlc and/or chronic studies, It would be
Imprudent to derive an oral RfD based upon the decreased body weight effect.
Therefore, no chronic oral RfD Is established for crotonaldehyde.
0138d -35- 09/19/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
There were no relevant Inhalation studies; effects were observed In oral
studies that are relevant for derivation of CSs (Table 9-1). In the only
chronic study available, Chung et al. (1986) reported reduced body weights
and liver damage (fatty metamorphosis, focal necrosis, flbrosls, cholestasls
and mononuclear Infiltration) at 6 mM (17 mg/kg/day}. A significant
Increase In hepatocellular tumors was observed at 0.6 mM (2 mg/kg/day),
however, rendering the use of the high-dose data Inappropriate for RQ
derivation.
In subchronlc studies, Wolfe et al. (1987) reported mortality In rats
treated at >5 mg/kg/day. Acute Inflammatory lesions of the nose were also
observed In female rats at the same dosage, but were not seen In males until
20 mg/kg/day. Hyperplasla, hyperkeratosls and/or ulceratlon of the epithe-
lium of the forestomach were reported at dosages >10 mg/kg/day. Forestomach
lesions similar to those seen 1n rats were also observed 1n mice at 40
mg/kg/day. The lesions and clinical signs reported by TRL (1986) at 45
mg/kg/day are not considered because Wolfe et al. (1987) reported mortality
at a substantially lower dosage.
A CS was calculated only for mortality In rats reported by Wolfe et al.
(1987). The MED was thus calculated to be 6.0 mg/day, equivalent to an
RVd of 4.33. Mortality Is assigned an RVg of 10. The CS 1s therefore
43.3, equivalent to an RQ of 10. CSs were not calculated for reduced body
weight and liver damage 1n rats (Chung et al., 1986) or Inflammatory lesions
of the forestomach 1n mice (Wolfe et al., 1987) because the equivalent human
dose for these effects was greater than that for mortality 1n rats. The CS
of 43.3, equivalent to an RQ of 10, Is selected for the chronic toxlclty of
crotonaldehyde (Table 9-2).
0138d -36- 09/19/89
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TABLE 9-1
Effects of Oral Exposure to Crotonaldehyde Considered for Derivation
of Candidate Composite Scoresa»b
Species/
Strain
Average
Body
Weight
(kg)
Transformed
Exposure Animal Dose
(mg/kg/day)
Equivalent
Human Dosec
(mg/kg/day)
Effect
Rat/F344 0.35d
5 mg/kg/day
by gavage
for 13 weeks
0.086 Mortality (both
sexes), nasal
lesions 1n
females
Mouse/
B6C3F1
0.03e
40 mg/kg/day
by gavage
for 13 weeks
40
3.0 Inflammatory
lesions of
forestomach
aSource: Wolfe et al., 1987
bThere were 20 animals of each sex at the start of the experiment. The
vehicle was corn oil and the purity of the compound was not reported.
transformed animal dose multiplied by the cube root of the ratio of
animal to reference human (70 kg) body weight
Reference rat body weight (U.S. EPA, 1986b)
Reference mouse body weight (U.S. EPA, 1986b)
0138d
-37-
09/19/89
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TABLE 9-2
Crotonaldehyde
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral (gavage)
Dose*: 6.0 mg/day
Effect: mortality
RVd: 4.33
RVe: 10
Composite Score: 43.34
RQ: 10
Reference: Wolfe et al.t 1987
*Equ1valent human dose
0138d -38- 09/19/89
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9.2. BASED ON CARCINOGENICITY
The animal evidence for carclnogenlclty Is limited, and 1n the absence
of human data, assignment to EPA Group C was Indicated. As discussed 1n
Chapter 8, a q,* was calculated for crotonaldehyde based on data for
hepatocellular neoplasms 1n rats (see Table 6-1} (Chung et al., 1986). The
same data can be used to calculate the F factor (Table 9-3). The trans-
formed doses were calculated as described In Chapter 8. The 1/ED,_ was
calculated using the multistage model without the data from the high-dose
group because the data did not fU the model when this group was Included.
The absence of tumors 1n the high-dose group cannot be attributed to reduced
survival because survival rates were very good 1n all groups. The MLE of
dose at the confidence limit for a risk of 0.1000 Is 0.935464X10'1. The F
factor, 1/ED,Q, Is 11. Because the F factor 1s between 1 and 100, croton-
aldehyde Is ranked In Potency Group 2. Chemicals 1n EPA Group C and Potency
Group 2 are given a LOW hazard ranking under CERCLA. The assigned RQ Is 100.
0138d -39- 09/19/89
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TABLE 9-3
Derivation of Potency Factor (F) for Crotonaldehyde
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle:
Body Weight:
Duration of treatment:
Duration of Study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental dose:
Transformed dose:
Human equivalent dose:
Tumor Incidence:
Human 1/ED-|Q (F factor):
Chung et al., 1986
drinking water
rat
F344
male
water
low dose, 0.425 kg; high dose, 0.375 kga
113 weeks
113 weeks
113 weeks
liver
hepatocellular carcinomas, neoplastlc nodules
0, 0.6, 6 mH
0, 2.0, 17.0 mg/kg/day
0, 0.36, 3.0 mg/kg/day
0/23, 9/27, 1/23°
11
Estimated from graph
&Data for the high-dose group were excluded from the F factor derivation.
0138d
-40-
09/19/89
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National Occupational Exposure Survey (NOES). On-line: Nay 10, 1988.
NIOSH, Department of Health and Human Services, Cincinnati, Ohio. p. 79.
Nlshlkawa, H., T. Hayakawa and T. Sakal. 1987. Determination of acroleln
and Crotonaldehyde 1n automobile exhaust gas by gas chromatography with
electron-capture detection. Analyst. 112: 859-862.
OSHA (Occupation Safety and Health Administration). 1985. Occupational
Standards Permissible Exposure Limits. 29 CFR 1910.1000. p. 655.
PelUzzarl, E.D., T.D. Hartwell, B.S.H. Harris, R.D. Waddell, D.A. WhUaker
and M.D. Erlckson. 1982. Purgeable organic compunds In mother's milk.
Bull. Environ. Contam, Toxlcol. 28: 322-328.
Perln, A., A. Sessa, G. Scalabrlno, A. Arnaboldl and E. Claranfl. 1972.
Anti-tumor activity of aliphatic aldehydes. V. Preferential Inhibition of
protein synthesis In normal or neoplastlc tissues In relation to molecular
structure. Eur. J. Cancer. 8(1): 111-119.
0138d -48- 09/19/89
-------
Pettersson, B., M. Curvall and C.R. Enzell. 1982,, Effects of tobacco smoke
compounds on the ciliary activity of the embryo chicken trachea jji vitro.
Toxicology. 23(1): 41-55.
Rlddlck, J.A., W.B. Bunger and T.K. Sakano, Ed. 1986. Techniques of Chem-
istry. Vol. II. Organic Solvents Physical Properties and Methods of Purifi-
cation, 4th ed. John Wiley and Sons, Inc., New York. p. 335.
Rlnehart, W. 1967. The effect on rats of single exposures to crotonalde-
hyde vapor. Am. Hyg. Assoc. J. 28: 561-566.
Ru1z-Rub1o, M., C. Hera and C. Pueyo. 1984. Comparison of a forward and a
reverse mutation assay In Salmonella typhlmurlum measuring L-arab1nose
resistance and hlstldlne prototrophy. Embo. J. 3(6): 1435-1440.
Sim, V.M. and R.E. Pattle. 1957. Effect of possible smog Irritants on
human subjects. J. Am. Ned. Assoc. 165: 1908-1913.
Simmon, V.F., K. Kauhanen and R.G. Tardlff. 1977. Mutagenlc activity of
chemicals Identified In drinking water. In: Progress In Genetic Toxicology.
D. Scott, B.A. Bridges and F.H. Sobels, Ed. Elsevler/North-Holland.
Amsterdam, p. 249-258.
Skog, E. 1950. A toxlcologlcal Investigation of lower aliphatic aldehydes.
I. Toxlclty of formaldehyde, propnaldehyde and butylaldehyde; as well as
acroleln and crotonaldehyde. Acta. Pharmacol. 6: 299-318.
0138d -49- 09/19/89
-------
Skog, E. 1952. Anaesthetic and haemolytlc action of lower aliphatic alde-
hydes and their effect on respiration and blood pressure. Acta. Pharmacol.
Toxlcol. 8: 275-289.
SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical
Producers, United States of America. SRI International, Menlo Park, CA.
p. 551.
Stack, V.T. 1957. Toxlclty of alpha, beta-unsaturated carbonyl compound to
microorganisms. Ind. Eng. Chem. 49: 913-917.
Stelnhagen, U.K. and C.S. Barrow. 1984. Sensory Irritation structure-
activity study of Inhaled aldehydes In B6C3F1 and Swiss-Webster mice.
Toxlcol. Appl. Pharmacol. 72(3): 495-503.
TRL (Toxldty Research Laboratories). 1986. Rat Oral Subchronlc Toxlclty
Study. Compound: Crotonaldehyde. Conducted for Research Triangle Insti-
tute, Research Triangle Park, NC.
Union Carbide Corporation. 1974. Environmental Impact Product Analysis:
Acute Aquatic Toxlclty Testing with cover letter dated 5/2/86. EPA/OTS
878216446.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
0138d -50- 09/19/89
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U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Toxlclty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for Acroleln.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC. EPA/600/X-85/369. NTIS PB88-171269.
U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1987. Reportable Quantity Document for Crotonaldehyde. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC.
U.S. EPA. 1988a. SANSS (Structure and Nomenclature Search System) Data
Base. On-Hne.
U.S. EPA. 1988b. STORE! Data Base. On-line: May 10, 1988.
0138d -51- 09/26/89
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U.S. EPA/OURS (Office of Mater Regulations and Standards). 1985. Guide-
lines for Deriving Numerical National Water Quality Criteria for the Protec-
tion of Aquatic Organisms and Their Uses. U.S. EPA, Washington, DC.
p. 22-58, 98. PB85-227049/XAB.
USITC (U.S. International Trade Commission). 1987. Synthetic Organic
Chemicals United States Production and Sales, 1986. USITC Publ. 2009,
Washington, DC. p. 226, 238.
van der Valk, P.G., J.P. Nater and E. Bleumlnk. 1985. The Influence of low
concentrations of Irritants on skin barrier function as determined by water
vapor loss. Derm. Beruf. Umwelt. 33(3): 89-91. (Taken from TOXBIB 85:
284515)
Vershueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Relnhold Co., New York. p. 410-411.
Warholm, M., B. Holmburg, J. Hogberg, T. Kronevl and A. Gotharson. 1984.
The acute effects of single and repeated Injections of acroleln and other
aldehydes. Int. J. Tissue React. 6(1): 61-70.
Wltz, G., N.J. Lawrle, M.A. Amoruso and B.D. Goldstein. 1987. Inhibition
by reactive aldehydes of superoxlde anlon radical production from stimulated
polymorphonuclear leukocytes and pulmonary alveolar macrophages: Effects of
cellular sulfhydryl groups and NADPH oxldase activity. Blochem. Pharmacol.
36(5): 721-726.
0138d -52- 09/19/89
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Wolfe, 6.W., M. Rodwln, J.E. French and G,A, Parker. 1987. Thirteen-week
subchronlc toxlclty study of crotonaldehyde (CA) 1n F344 rats and B6C3F1
mice. lexicologist. 7(1): 209. (Abstract)
Woodruff, R.C., J.M. Mason, R. Valencia and S. Z1mmer1ng. 1985. Chemical
mutagenesls testing 1n DrosophHa. V. Results of 53 coded compounds test
for the National Toxicology Program. Environ. Mutagen. 7(5): 677-681,
688-689, 696-702.
0138d -53- 09/19/89
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research 1n Progress
These searches were conducted In May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0138d -54- 09/19/89
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Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0138d -55- 09/19/89
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In addition, approximately 30 compendia of aquatic toxlclty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0138d -56- 09/19/89
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APPENDIX B
Cancer Data Sheet for Derivation of q-j* for Oral Exposure
Compound: crotonaldehyde
^Tr..1 : jr
Reference: Chung et al., 1986
Spec1es/strain/sex: rat/F344/male
Length of exposure (le) = 113 weeks
Length of experiment (Le) = 113 weeks
Llfespan of animal (L) = 113 weeks
Tumor site and type: liver neoplastlc nodules and hepatocellular carcinomas
Route/vehicle: drinking water
Experimental
Doses or
Exposures
0
0.6 mM
(42 mg/l)
6.0 mM
(421 mg/l)
Transformed
Animal Dose
(mg/kg/day)
0
2.0
17
Average Animal
Body Weight
(kg)
0
0.425
0.375
Equivalent
Human Dose
(mg/kg/day)
0
0.36
3.0
Incidence
No. Responding/
No. Tested
0/23
9/27
l/23t
tData for the high-dose group were excluded from q-|* derivation
because their Inclusion led to a poor fit.
Human q-|* = 1.9 (mg/kg/day}~a
T< S. L];nv;nru.i^ital Prni,action Ag&n>;y
,j_- : :,:... ...Vrfet, T-'ri.>3 1670
,t-^v.5i'->, lL 60604
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