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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 (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSHER). 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 from 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 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous 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, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have 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 RfOs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. A
carcinogenic potency factor, or q-j* (U.S. EPA, 1980), Is provided Instead.
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 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required 1n the event of a release
as specified under the CERCLA. These two RQs (chronic toxldty and cardno-
genldty) represent two of six scores developed (the remaining four reflect
1gn1tab1lHy, 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 1n U.S.
EPA. 1983 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Furfural 1s a colorless, oily liquid with an aromatic odor, which 1s
similar to that of benzaldehyde or almonds (Hlndholz, 1983; McK1ll1p and
Sherman, 1980). It 1s mlsdble with most common organic solvents and 1s
slightly soluble In water (McK1ll1p and Sherman, 1980). In 1977, five U.S.
manufacturers of furfural (at nine production sites) had a combined produc-
tion range of 41 to >210 million pounds (U.S. EPA, 1977). Currently, two
manufacturers at three production sites produce an unknown volume of this
chemical (SRI, 1986). Furfural 1s commercially manufactured from agricul-
tural feedstocks such as oat hulls, rice hulls, cereal grasses, corncobs and
sugarcane by-products (McK1ll1p and Sherman, 1980). The use pattern for
furfural Is as follows (Lawler, 1977): furfural alcohol (33X), solvents
(16X), tetrahydrofuran (9%), miscellaneous (3%), and exports (39X).
The dominant environmental fate process for furfural 1n the atmosphere
is expected to be vapor phase oxidation by hydroxyl radicals and ozone. In
a normal ambient atmosphere, the furfural oxidation half-life was estimated
to be 20.4 minutes (U.S. EPA, 1987a). In water, mlcroblal degradation 1s
likely to be the dominant fate process. Tests using four natural river
waters have shown that microorganisms can reduce an Initial furfural concen-
tration of 1.0 to 0 ppm 1n <3 days (Ettlnger et al., 1954). Hydrolysis,
adsorption to sediment and bloconcentratlon are not expected to be Important.
Based on the significant blodegradatlon 1n natural water, 1t 1s predicted
that this process will be the dominant degradation process 1n soil.
Estimated K values (9-40) Indicate a very high degree of soil mobility
for furfural. In the absence of degradation processes, furfural may leach
through soil to groundwaters; however, mlcroblal attack of furfural may be
rapid enough to significantly diminish the Importance of leaching.
1v
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Furfural 1s a naturally occurring compound. It Is present In various
essential oils (Wlndholz, 1983) and In a variety of fruits, such as pine-
apples, apples, limes, peaches, strawberries, raspberries and mandarin
oranges (NRC, 1982; Nicholas, 1973). It was detected In drinking water
(Lucas, 1984; Shackelford and Keith, 1976; Kool et al., 1982), 1n Lake
Michigan water (Konasewlch et al., 1978), 1n wastewater effluents from
chemical, paper and synthetic rubber manufacturing facilities (Shackelford
and Keith, 1976; Keith, 1974), In ambient air of the Southern Black Forest
(Juttner, 1986) and In tobacco smoke (Schmeltz et al., 1977; Johnstone and
Pllmmer, 1959). Furfural can be emitted to the ambient atmosphere 1n dlesel
exhaust (Graedel, 1978; Hampton et al., 1982), 1n emissions from forest
fires (Graedel, 1978), In emissions from wood burning fireplaces (LIpaM et
al., 1984; K1e1nd1enst et al., 1986) and 1n volatile plant emissions
(Graedel, 1978).
There was relatively Uttle Information available concerning toxldty of
furfural to aquatic biota. LC.Q values for fish ranged from 16 mg/i for
bluegllls, Lepomls macrochlrus (Turnbull et al., 1954) to 29 mg/i for the
golden orfe, Leudscus 1dus (Juhnke and Ludemann, 1978). LC5Q values for
Daphnla magna ranged from 13-36 mg/i (BMngmann and Kuehn, 1977; Hessov,
1975). The lowest reported toxic concentration was 0.6 mg/l, the
threshold for Inhibition of cell multiplication 1n the flagellate protozoan,
Entoslphon sulcaturo (Brlngmann and Kuehn, 1980). Data concerning marine
species could not be located 1n the available literature as cited 1n
Appendix A. The lowest concentration reported to be toxic to aquatic plant
species was 2.7 mg/i, the toxldty threshold for Inhibition of cell
multiplication 1n the blue-green alga, H1crocyst1s aeruqlnosa (Brlngmann and
Kuehn, 1978).
-------
Furfural appears to be readily absorbed after oral, Inhalation or
cutaneous exposure (Jodyn1s-L1ebert and Laboda, 1982; Flek and Sedlvec,
1978). Metabolism appears to be rapid, with furoylglydne the major metabo-
lite 1n orally exposed animals (Jodynls-Llebert and Laboda, 1982} and In
humans exposed by Inhalation (Flek and Sedlvec, 1978). 2-FuranacryluMc
add 1s a secondary metabolite 1n humans and furolc acid Is a metabolite of
animals, but not of humans. The major route of excretion after either oral
or inhalation exposure appears to be the urine (Jodynls-Llebert and Laboda,
1982; Flek and Sedlvlc, 1978). Unchanged furfural was not Identified 1n the
urine of humans or animals.
Furfural was not carcinogenic 1n an 81-week Inhalation study where
hamsters were exposed to 293 ppm (1151 mg/ma), 7 hours/day, 5 days/week
for 52 weeks (Feron and Kruysse, 1978). The NTP (1987) has sponsored a
gavage study using rats and mice, but hlstopathology 1s In progress, and
results are not available. Sh1m1zu (1986) reported that livers of rats made
clrrhotlc by dietary pretreatment with furfural were more sensitive to the
carcinogenic effects of FAA, as evidenced by the occurrence of preneoplastlc
hyperplastlc nodules In 16/16 rats compared with 2/16 rats treated with FAA
without pretreatment with furfural. In an experiment In which furfural was
coadmlnlstered with BAP Intratracheally to hamsters, furfural was associated
with a reduced period of latency but not with an Increased Incidence In
respiratory tumors (Feron, 1972). Furfural, however, did appear to Increase
the Incidence of BAP-lnduced perHracheal tumors In this study. In a
subsequent experiment, Inhalation exposure of hamsters to furfural had no
effect on the Incidence of tumors Induced by Intratracheal administration of
BAP or subcutaneous administration of d1ethyln1trosam1ne (Feron and Kruysse,
1978).
v1
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Furfural was negative (Sasaki and Endo, 1978; Soska et al., 1981;
Harriett et al., 1985), equivocal (Mortelmans et al., 1986) or only weakly
positive (Zdzlenkka et al., 1978; Loquet et al., 1981) 1n mutation tests In
microorganisms. Positive results 1n a sex-linked recessive lethal test and
negative results In a reciprocal translocatlon test were reported In 0.
melanoqaster (Woodruff et al., 1985). Positive results were also reported
In CHO cells (Stlch et al., 1981) and In human lymphocytes (Gomez-Arroyo and
Souza, 1985). Data were not located regarding the developmental or
reproductive toxldty of furfural.
The olfactory epithelium appears to be the target organ 1n hamsters
exposed to furfural by Inhalation. Feron et al. (1979) observed disruption
and atrophy In the olfactory epithelium of hamsters exposed to 115 ppm (448
mg/ma) but not to 20 ppm (77 mg/m3), 6 hours/day, 5 days/week for 13
weeks. Similar lesions were observed In hamsters exposed to a TWA concen-
tration of 293 ppm (1151 mg/m3), 7 hours/day, 5 days/week for 52 weeks
(Feron and Kruysse, 1978). In dogs, fatty liver degeneration was reported
at 130 ppm (511 mg/m3), 6 hours/day, 5 days/week for 4 weeks (AIHA, 1965).
No adverse effects were reported at 63 ppm (248 mg/m3). In humans exposed
occupaUonally, 1.9-14 ppm (7-53 mg/m*) has been associated with headache
and Irritation (Korenman and Resnlk, 1930) and 30-130 mg/m3 has been
associated with hepatitis and disorders of the nervous system.
Data Indicate that the liver 1s the target organ of furfural In rats and
mice exposed orally to the compound. In rats treated by gavage with 11, 22,
45, 90 or 180 mg/kg 5 days/week for 13 weeks, mortality was associated with
>90 mg/kg and hepatocytlc cytoplasmlc vacuollzatlon was seen In all treated
groups (SRI, 1981a). Mice appear to be more resistant than rats when
administered furfural orally. In mice treated by the same schedule as
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rats with doses of 75, 150, 300, 600 or 1200 mg/kg, high mortality occurred
at >600 mg/kg (SRI, 1981b). Degenerative, necrotlc and Inflammatory liver
lesions were noted at >150 mg/kg but not at 75 mg/kg.
The available data do not suggest a carcinogenic role for furfural.
Therefore, according to the U.S. EPA (1986b) guidelines for carcinogenic
risk assessment, furfural should be assigned to EPA Group 0, not
classifiable as to cardnogenldty 1n humans. RfOs for Inhalation exposure
to furfural were based on the NOAEL of 20 ppm (77 mg/m3), 6 hours/day, 5
days/week 1n the 13-week hamster study by Feron et al. (1979). The
subchronlc Inhalation RfO was 0.1 mg/kg/day or 9 mg/day for a 70 kg human
and the chronic Inhalation RfO was 0.01 mg/kg/day or 0.9 mg/day for a 70 kg
human. RfDs for oral exposure of hamsters to furfural were based on the
LOAEL of 11 mg/kg, 5 days/week (7.9 mg/kg/day) In the 13-week gavage study
by SRI (1981a). The subchronlc oral RfD was 0.008 mg/kg/day or 0.6 mg/day
for a 70 kg human. The chronic oral RfO was 0.8 yg/kg/day. Or 0.06 mg/day
for a 70 kg human. An RQ of 100 was based on the hepatocellular cytoplasmlc
vacuollzatlon observed In rats at 7.9 mg/kg/day (SRI, 1981a).
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TABLE OF CONTENTS
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 4
1.5. SUMMARY. 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Chemical Degradation Processes 5
2.1.2. Physical Removal Processes. 5
2.2. WATER . 5
2.2.1. Hydrolysis 5
2.2.2. Photolys1s/Photoox1dat1on 5
2.3.3. M1crob1al Degradation 6
2.2.4. Volatilization. 7
2.2.5. Adsorption 7
2.2.6. B1oconcentrat1on 7
2.3. SOIL 8
2.3.1. M1crob1al Degradation 8
2.3.2. Chemical Degradation. .... 8
2.3.3. Adsoprtlon 8
2.3.4. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. HATER 10
3.2. FOOD 10
3.3. INHALATION 11
3.4. DERMAL 11
3.5. SUMMARY 11
4. AQUATIC TOXICITY 13
4.1. ACUTE TOXICITY 13
4.2. CHRONIC EFFECTS 13
4.3. PLANT EFFECTS 13
4.4. SUMMARY 13
1x
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TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETCS 16
5.1. ABSORPTION 16
5.2. DISTRIBUTION 16
5.3. METABOLISM 16
5.4. EXCRETION 17
5.5. SUMMARY 17
6. EFFECTS 19
6.1. SYSTEMIC TOXICITY 19
6.1.1. Inhalation Exposures 19
6.1.2. Oral Exposures 22
6.1.3. Other Relevant Information 24
6.2. CARCINOGENICITY 25
6.2.1. Inhalation 25
6.2.2. Oral 25
6.2.3. Other Relevant Information 25
6.3. MUTAGENICITY .27
6.4. TERATOGENICITY 30
6.5. OTHER REPRODUCTIVE EFFECTS 30
6.6: SUMMARY 30
7. EXISTING GUIDELINES AND STANDARDS .... 33
7.1. HUMAN 33
7.2. AQUATIC 33
8. RISK ASSESSMENT 34
8.1. CARCINOGENICITY 34
8.1..1. Inhalation 34
8.1.2. Oral 34
8.1.3. Other Routes 34
8.1.4. Weight of Evidence . . . 34
8.1.5. Quantitative Risk Estimates 35
8.2. SYSTEMIC TOXICITY 35
8.2.1. Inhalation Exposure 35
8.2.2. Oral Exposure . . 37
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TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 39
9.1. BASED ON SYSTEMIC TOXICITY 39
9.2. BASED ON CARCINOGENICITY 43
10. REFERENCES 44
APPENDIX A: LITERATURE SEARCHED 58
APPENDIX B: SUMMARY TABLE FOR FURFURAL 61
x1
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LIST OF TABLES
No. Title Page
1-1 1977 U.S. Production Data for Furfural 3
4-1 Acute Toxldty of Furfural to Freshwater Organisms 14
6-1 Genotoxldty Testing of Furfural 28
9-1 Toxldty Summary for Furfural 40
9-2 Composite Scores for Furfural 41
9-3 Furfural: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 42
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LIST OF ABBREVIATIONS
BAP Benzo(a)pyrene
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CS Composite score
DEN D1ethyln1trosam1ne
DNA DeoxyMbonuclelc add
FAA N-2-fluorenylacetamlde
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LCso Concentration lethal to SOX of recipients
1050 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppb . Parts per billion
ppm Parts per million
RQ Reportable quantity
RV,j Dose-rating value
RVe Effect-rating value
S6PT Serum glutamlc pyruvlc transamlnase
STEL Short-term eposure level
TLV Threshold limit value
TWA Time-weighted average
UV Ultraviolet
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Furfural 1s the common chemical name, but this compound Is also known as
fural, furfurole. 2-furaldehyde, 2-furancarbonal, fur furaldehyde, 2-furan-
carboxaldehyde, pyromudc aldehyde and artificial oil of ants (Ulndholz,
1983; SRI, 1986). The structure, Molecular weight, empirical formula and
CAS Registry number for furfural are as follows:
Molecular weight: 96.08
Empirical formula: CjH.O.
CAS Registry number: 98-01-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Furfural Is a colorless, oily liquid with an aromatic odor, which Is
similar to that of benzaldehyde or almonds (Hlndholz. 1983; McKlllIp and
Sherman. 1980). It 1s mlsclble with most common organic solvents, but It Is
only slightly mlsclble with saturated aliphatic hydrocarbons (McKlllIp and
Sherman, 1980). Selected physical properties are listed below:
Melting point: -36.5'C
Boiling point: 161.7*C
Specific gravity:
(20/4°C) 1.1598
Mater solubility (ppm)
at 20°C: 83,000
at 25'C: 77,800
Vapor pressure (mm Hg)
at 18.5°C: 1.0
at 20.0'C: 1.5
at 42.6*C: 5.0
McKlllIp and Sherman, 1980
McK1111p and Sherman, 1980
McKlllIp and Sherman. 1980
McKlllIp and Sherman, 1980
Tewarl et al.. 1982
Perry and Green, 1984
Weber et al.. 1981
Perry and Green. 1984
0069d
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01/06/88
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Log Kou: 0.41 Hansch and Leo, 1981
Flash point:
(open cup) 68°C Wlndholz, 1983
A1r conversion 1 mg/m3 = 0.251 ppm Verschueren, 1983
factors at 20°C: 1 ppm » 3.991 mg/m3
A1r odor threshold: 0.006-5 ppm Ruth, 1986
0.078 ppm (v/v) Amoore and Hautala, 1983
Water odor threshold: 3.5 ppm Amoore and Hautala, 1983
Furfural Initially turns yellow to brown and then polymerizes on
exposure to air and light (Wlndholz, 1983). The polymerization 1s greatly
accelerated In the presence of heat, adds or alkali (Wlndholz, 1983;
R1dd1ck et at., 1986; McKlllIp and Sherman, 1980). The chemical properties
of furfural are similar to aromatic aldehydes, with some differences that
are attributable to the furan ring (McK1l11p and Sherman, 1980).
1.3. PRODUCTION DATA
Production data are presented In Table 1-1. In 1977, five U.S. manufac-
turers of furfural at nine production sites had a combined production range
of 41 to >212 million pounds. Seven companies Imported a minimum of 1-10
million pounds of this chemical In the United States In 1977. SRI (1986)
reported that Pentech Corporation (Belle Glade, FL and Omaha, NE) and the
Quaker Oats Co. (Cedar Rapids, IA) currently manufacture furfural;
Information on the current U.S. production volume of this chemical was not
located.
Furfural 1s produced commercially from agricultural source feedstocks.
These feedstocks Include cereal grasses, rice hulls, cottonseed hulls, oat
hulls, corncobs, by-products of sugarcane harvesting, and wood and wood
products. The major precursors of furfural contained 1n these plant
materials are the pentosan polysacchaMdes. Commercial dlgestors are used
0069d -2- 01/06/88
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TABLE 1-1
1977 U.S. Production Data for Furfural*
Producer/Location
Manufacturer/Importer
Production Range
(pounds)
Quaker Oats
Pasadena, TX
Belle Glade, FL
Cedar Rapids, IA
Memphis, TN
Omaha, NE
Chicago, IL
Flambeau Paper Co.
Park Falls, HI
Delaware City Plant
Delaware City, DE
Lemoyne Plant
Axis, AL
Polak's Frutal Works
Mlddletown, NY
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Importer
manufacturer
manufacturer
manufacturer
manufacturer
and Importer
1-10 million
10-50 million
10-50 million
10-50 million
10-50 million
1-10 million
10-100 thousand
0.1-1.0 million
0.1-1.0 million
confidential
EM Laboratories
Elmsford, NY
Hercules, Inc.
Wilmington, DE
ICC Industries
New York, NY
Fallek Chem.
New York, NY
Stebblns Eng. & Mfg.
Water town. NY
Importer
Importer
Importer
Importer
Importer
confidential
confidential
confidential
none
none
*Source: U.S. EPA, 1977
0069d
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06/25/87
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to hydrolyze the pentosans to pentoses, which are subsequently cyclodehydro-
genated to furfural (McKllllp and Sherman, 1980).
1.4. USE DATA
The use pattern for furfural 1s as follows (Lawler, 1977): furfural
alcohol (33%), solvents (16X), tetrahydrofuran (9X), miscellaneous (3%), and
exports (39X). As a solvent, furfural has applications 1n extraction
(petroleum and lube oil refining, butadiene separation) and 1n resin formu-
lations (McKllllp and Sherman, 1980). The miscellaneous uses Include
chemical Intermediate use In the synthesis of resins and other chemicals
(McKllllp and Sherman, 1980).
1.5. SUMMARY
Furfural 1s a colorless, oily liquid with an aromatic odor, which 1s
similar to that of benzaldehyde or almonds (Wlndholz, 1983; McKllllp and
Sherman, 1980). It Is mlsdble with most common organic solvents and 1s
slightly soluble 1n water (McKllllp and Sherman, 1980). In 1977, five U.S.
manufacturers of furfural (at nine production sites) had a combined produc-
tion range of 41 to >210 million pounds (U.S. EPA, 1977). Currently, two
manufacturers at three production sites produce an unknown volume of this
chemical (SRI, 1986). Furfural 1s commercially manufactured from agricul-
tural feedstocks such as oat hulls, rice hulls, cereal grasses, corncobs and
sugarcane by-products (McKllllp and Sherman, 1980). The use pattern for
furfural 1s as follows (Lawler, 1977): furfural alcohol (33X), solvents
(16X). tetrahydrofuran (9X), miscellaneous (3X), and exports (39X).
0069d -4- 01/06/88
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on Us relatively high vapor pressures (see Section 1.2.),
furfural Is expected to exist almost entirely 1n the vapor phase In the
atmosphere.
2.1.1. Chemical Degradation Processes. The dominant removal mechanism
for furfural 1n the atmosphere Is expected to be vapor phase oxidation by
photochemically-produced hydroxyl radicals and ozone. The rate constants
for the reaction with hydroxyl radicals and with ozone are estimated to be
2.296X10"11 and 7.0x10"" cm3/molecule-sec, respectively, at 25°C
(U.S. EPA, 1987a). Given typical atmospheric concentrations of 8xl09 for
hydroxyl radicals/cm3 and 6x10" ozone molecules/cm3, an atmospheric
furfural half-life of 20.4 minutes 1s estimated (U.S. EPA, 1987a).
2.1.2. Physical Removal Processes. The relatively high water solubility
of furfural (83,000 ppm at 20°C) suggests that atmospheric wash-out 1s
possible; however, the rapid rate at which furfural reacts chemically In the
atmosphere should preclude physical removal.
2.2. WATER
2.2.1. Hydrolysis. Pertinent data regarding the environmental hydrolysis
of furfural could not be located 1n the available literature as cited 1n
Appendix A. Aldehydes, however, are generally not susceptible to hydrolysis
under environmental conditions (Lyman et al., 1982; McK1l11p and Sherman,
1980).
2.2.2. Photolys1s/Photoox1dat1on. Since furfural absorbs UV light of
wavelengths >300 nm (Hlraoka and SHnlvasan, 1968), direct photolysis 1s
possible; however, photolysis rate data were not available to estimate the
relative significance, 1f any, of direct photolysis 1n water.
0069d -5- 01/06/88
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M111 and Mabey (1985) estimated the half-life for the reaction of alde-
hydes (as a general chemical class) with hydroxyl radicals In sunlit natural
water to be between 10 and 11 days. The reaction of aldehydes with peroxy
radicals 1n natural water, however, Is not significant (Mill and Mabey,
1985). This suggests that furfural oxidation by photochemically-produced
hydroxyl radicals 1n natural water may be Important 1n Us removal from
water.
2.2.3. M1crob1al Degradation. Available data Indicate that microblal
degradation will be an Important and possibly dominant fate process for
furfural In natural water.
Ettlnger et al. (1954) examined the blodegradatlon and persistence of
furfural 1n four natural river waters: the B1g Miami River, the Little
Miami River and two Ohio River waters. The die-away tests Initially
Involved treating each water with 1.0 ppm furfural and measuring, the
disappearance rate. In all four waters, the furfural concentration dropped
to 0 1n <3 days. Subsequent tests measured the disappearance rate upon
redoslng the waters with 10 or 25 ppm furfural. A maximum of 12 days was
required to reduce the furfural concentration to zero. Control tests were
conducted to determine the stability of furfural 1n water 1n the absence of
seeding organisms. A reduction of furfural concentration from 1.5 to 0.1
ppm took >30 days under this condition. Based on their test results, the
authors concluded that most surface waters contain organisms that are
capable of degrading furfural and that acclimated organisms can readily
destroy elevated levels of the compound.
Results of the Japanese MITI blodegradatlon test (which utilizes an
activated sludge Inoculum) show that furfural Is readily biodegradable
(Sasaki, 1978; Kawasaki, 1980). PUter (1976) used a batch system and an
0069d -6- 01/06/88
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activated sludge Inoculum to test the blodegradabHUy of a number of
organic compounds; the test results Indicated that furfural Is readily
biodegradable. Furfural was found to be at least partially degradable by
anaerobic bacteria 1n both the presence and absence of other carbon sources
In batch bloassay tests (Benjamin et al., 1984).
2.2.4. Volatilization. Based on a vapor pressure of 1.5 mm Hg and a
water solubility of 83,000 ppm (see Section 1.2.), the Henry's Law constant
for furfural at 20°C was estimated to be 2.3xlO~6 atm-mVmol. This
value of Henry's Law constant Indicates that volatilization from water Is
likely to be slow, although some significant volatilization may occur from
shallow rivers. Using the method outlined 1n Lyman et al. (1982), the
volatilization half-life of furfural from a river 1 m deep flowing 1 m/sec
with a wind velocity of 3 m/sec was estimated to be 15.5 days. The volatil-
ization rate from deeper bodies of water or less rapidly moving bodies of
water will be slower. Therefore, with the exception of shallow, rapidly
moving bodies of water, volatilization Is not likely to be competitive with
blodegradatlon In the removal of furfural from the aquatic environment.
2.2.5. Adsorption. Given Us high water solubility (83,000 ppm) and low
log KQW (0.41), significant partitioning of furfural from the water column
to suspended partlculate matter or to sediment 1s not likely to occur.
2.2.6. Bloconcentratlon. The BCF of an organic chemical can be estimated
from the following regression equations (Lyman et al., 1982):
. log BCF * 0.76 log KQw - 0.23 (2-1)
log BCF = 2.791 - 0.564 log US (1n ppm) (2-2)
For furfural, BCF values calculated from Equations 2-1 and 2-2 are both -1
using a log K of 0.41 and a water solubility of 83,000 ppm. These BCF
values Indicate that furfural Is not expected to bloconcentrate In aquatic
organisms.
0069d -7- 06/25/87
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2.3. SOIL
2.3.1. M1crob1al Degradation. Pertinent data regarding the m1crob1a!
degradation of furfural In soil could not be located 1n the available
literature as dted In Appendix A. As discussed In Section 2.2.3.,
degrading furfural rapidly; most surface waters contain mlcroblal organisms
that are capable of this suggests that blodegradatlon Is also likely to be
rapid 1n most types of soil.
2.3.2. Chemical Degradation. Pertinent data regarding the chemical
degradation of furfural In soil could not be located 1n the available
literature as dted In Appendix A. Hydrolysis 1s not likely to occur based
on the chemical structure of furfural. Given Us aldehyde structure,
furfural may be susceptible to free radical oxidation 1n soil; however, no
data are available to support this possibility.
2.3.3. Adsorption. The K of an organic chemical can be esUndated
from the following regression equations (Lyman et al., 1982):
log KQC = 3.64 - 0.55 log US (In ppm) (2-3)
log KQC =0.544 log KQW * 1.377 (2-4)
For furfural, the respective K values calculated from Equations 2-3 and
2-4 are 9 and 40 based on a water solubility of 83,000 ppm and a log K
of 0.41. These K values Indicate a very high degree of soil mobility
(Swann et al., 1983); therefore, furfural Is susceptible to significant
leaching 1n soil. In the absence of degradation processes, furfural may
leach through soil to groundwaters; however, mlcroblal attack of furfural
may be sufficiently rapid to significantly diminish the Importance of
leaching.
2.3.4. Volatilization. Given the vapor pressure of furfural (1.5 mm Hg
at 20°C), significant evaporation from dry surfaces Is expected to occur.
0069d -8- 01/06/88
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Sufficient data are not available to predict the Importance of evaporation
from moist soils, but data regarding evaporation from water (see Section
2.2.4.) Indicate that volatilization from moist soil may not be significant.
2.4. SUMMARY
The dominant environmental fate process for furfural In the atmosphere
Is expected to be vapor phase oxidation by hydroxyl radicals and ozone. In
a normal ambient atmosphere, the furfural oxidation half-life was estimated
to be 20.4 minutes (U.S. EPA, 1987a). In water, mlcroblal degradation 1s
likely to be the dominant fate process. Tests using four natural river
waters have shown that microorganisms can reduce an Initial furfural concen-
tration of 1.0 to 0 ppm In <3 days (Ettlnger et al., 1954). Hydrolysis,
adsorption to sediment and bloconcentratlon are not expected to be
Important. Based on the significant blodegradatlon 1n natural water, H 1s
predicted that this process will be the dominant degradation process In
soil. Estimated K values (9-40) Indicate a very high degree of soil
mobility for furfural. In the absence of degradation processes, furfural
may leach through soil to groundwaters; however, mlcroblal attack of
furfural may be rapid enough to significantly diminish the Importance of
leaching.
0069d -9- 01/06/88
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3. EXPOSURE
Furfural 1s a naturally occurring compound. It 1s present In various
essential oils (Wlndholz, 1983) and In a variety of fruits, such as pine-
apples, apples, limes, peaches, strawberries, raspberries and mandarin
oranges (NRC, 1982; Nicholas, 1973).
A National Occupational Hazard Survey conducted between 1972 and 1974
estimated that -15,400 U.S. workers may be occupationally exposed to
furfural annually (NIOSH, 1984).
3.1. HATER
Lucas (1984) detected furfural 1n Ottumwa, IA drinking water collected
In September 1976. Shackelford and Keith (1976) and Kool et al. (1982)
qualitatively detected furfural 1n finished drinking water, but did not
specify the locations.
Konasewlch et al. (1978) detected furfural at a concentration of 2 ppb
In Lake Michigan water collected near the Chicago Central Water Works.
Furfural was Identified 1n effluent wastewaters generated at unspecified
chemical and paper plants (Shackelford and Keith, 1976). A furfural concen-
tration of 1.7 ppb was detected 1n a wastewater effluent from a synthetic
rubber manufacturing facility (Keith, 1974). U.S. EPA (1987b) dted only
one reporting station for furfural, where a concentration of 2 ppb was
reported.
3.2. FOOD
As noted above, furfural occurs naturally In a variety of fruits. It
has also been Identified as a volatile component of baked potatoes (Coleman
et al., 1981), fried bacon and pork (Ho et al., 1983), and roasted filbert
0069d -10- 06/25/87
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nuts (Klnlln et al., 1972). Furfural was detected In processed cassava
products (Dougan et al., 1983); cassava, a root vegetable, 1s a major food
staple of the tropics.
Furfural was detected 1n 2/12 samples of human breast milk (samples were
collected from volunteers In Bayonne, NJ, Jersey City, NJ, Brldgevllle. PA
and Baton Rouge, LA (Pelllzzarl et al., 1982).
3.3. INHALATION
Furfural can be emitted to the ambient atmosphere 1n dlesel exhaust
(Graedel, 1978; Hampton et al., 1982), 1n emissions from forest fires
(Graedel, 1978), In emissions from wood burning fireplaces (LIpaM et al.,
1984; Klelndlenst et al., 1986), and 1n volatile plant emissions (Graedel,
1978). Using pine, cedar, oak and ash wood, LIpaM et al. (1984) measured
the furfural emission rate to range from 0.030-0.225 g/kg of burned wood.
Furfural was Identified as a component of tobacco smoke (Schmeltz et
al., 1977; Johnstone and Pllmmer, 1959) and tobacco (Johnstone and Pllmmer,
1959).
Juttner (1986) qualitatively detected furfural In the ambient forest air
of the Southern Black Forest In Germany. Other ambient atmospheric moni-
toring data could not be located In the available literature as cited 1n
Appendix A.
3.4. DERMAL
Pertinent dermal monitoring data could not be located In the available
literature as dted 1n Appendix A.
3.5. SUMMARY
Furfural 1s a naturally occurring compound. It Is present In various
essential oils (Ulndholz, 1983) and 1n a variety of fruits, such as pine-
apples, apples, limes, peaches, strawberries, raspberries and mandarin
0069d -11- 06/25/87
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oranges (NRC, 1982; Nicholas, 1973). Approximately 15,400 workers may be
occupatlonally exposed to furfural annually (NIOSH, 1984). It was detected
In drinking water (Lucas, 1984; Shackelford and Keith, 1976; Kool et al.,
1982), In Lake Michigan water (Konasewlch et al., 1978), In wastewater
effluents from chemical, paper and synthetic rubber manufacturing facilities
(Shackelford and Keith, 1976; Keith, 1974), 1n ambient air of the Southern
Black Forest (Juttner, 1986) and 1n tobacco smoke (Schmeltz et al., 1977;
Johnstone and Pllmmer, 1959). Furfural can be emitted to the ambient atmo-
sphere 1n dlesel exhaust (Graedel, 1978; Hampton et al., 1982), In emissions
from forest fires (Graedel, 1978), In emissions from wood burning fireplaces
(LIpaM et al., 1984; Klelndlenst et al., 1986) and In volatile plant
emissions (Graedel, 1978).
0069d -12- 06/25/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The available data concerning toxldty of furfural to freshwater fish
and Invertebrates are presented In Table 4-1. LC5Q values for fish ranged
from 16 mg/l for bluegllls, Lepomls macrochlrus (Turnbull et al., 1954) to
29 mg/l for the golden orfe, Leudscus Idus (Juhnke and Ludemann, 1978).
LC50 values for Daphnla magna ranged from 13-36 mg/l (Brlngmann and
Kuehn, 1977; Hessov, 1975). The lowest reported toxic concentration was 0.6
mg/l, the threshold for Inhibition of cell multiplication In the flagel-
late protozoan, Entoslphon sulcatum (Brlngmann and Kuehn, 1980). No data
concerning marine species were found In the available literature.
4.2. CHRONIC EFFECTS
Pertinent data regarding chronic toxldty of furfural to aquatic organ-
Isms could not be located In the available literature as dted 1n Appendix A.
4.3. PLANT EFFECTS
Brlngmann and Kuehn (1978) reported 8-day toxldty thresholds of 2.7 and
31 mg/l for Inhibition of cell multiplication In the blue-green alga,
H1crocyst1s aeruqlnosa. and the green alga, Scenedesmus quadrkauda. Brlng-
mann and Kuehn (1980) reported a 16-hour toxldty threshold of 16 mg/l for
Inhibition of cell multiplication 1n the bacteria, Pseudomonas putlda.
4.4. SUMMARY
There was relatively little Information available concerning toxldty of
furfural to aquatic biota. LC5Q values for fish ranged from 16 mg/l for
bluegllls, Lepomls macrochlrus (Turnbull et al., 1954) to 29 mg/l for the
golden orfe, Leudscus 1dus (Juhnke and Ludemann, 1978). LC5Q values for
Daphnla magna ranged from 13-36 mg/l (Brlngmann and Kuehn, 1977; Hessov,
1975). The lowest reported toxic concentration was 0.6 mg/l, the
0069d -13- 06/25/87
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TABLE 4-1
Acute Toxlclty of Furfural to Freshwater Organisms*
Species
Concentration
(mg/i)
Effect
Reference
FISH
Blueglll
Lepomls macrochlrus
Mosqultoflsh
Gambusla afflnls
Golden orfe
Leuclscus Idus
Harlequin fish
Rasbora heteromorpha
16
1.2
24
29
12
23
10
48-hour LC5Q
calculated safe
concentration
96-hour LCso.
turbid water
48-hour LC5Q
48-hour LC0.
48-hour LCso
estimated thresh-
Turnbull
et al., 1954
Wallen et al.,
1957
Juhnke and
Luedemann, 1978
Alabaster, 1969
old concentration
INVERTEBRATES
Flagellate protozoan
Entoslphon sulcatum
Euqlena qracllls
Chllomonas paramedum
0.6 72-hour toxlclty
threshold, In-
hibition of cell
multiplication
>512 killing or
bleaching concen-
tration, 1 week
3.9 toxlclty threshold
Inhibition of cell
multiplication
Brlngmann and
Kuehn, 1980
HcCalla, 1965
Brlngmann
et al., 1980
Water flea
Daphnla roagna
29
13
36
25
13
24-hour ECsQ,
Immobilization
24-hour EC0.
Immobilization
24-hour LCso
24-hour LCQ
72-hour LCso
Brlngmann and
Kuehnn, 1982
Brlngmann and
Keuhn, 1977
Hessov, 1975
*A11 results were determined In static exposures.
0069d
-14-
06/25/87
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threshold for Inhibition of cell multiplication In the flagellate protozoan,
Entoslphon sulcatum (BMngmann and Kuehn, 1980). No data concerning marine
species were found In the available literature. The lowest concentration
reported to be toxic to aquatic plant species, was 2.7 mg/i, the toxldty
threshold for Inhibition of cell multiplication In the blue-green alga,
HHcrocystls aeruglnosa (BMngmann and Kuehn, 1978).
0069d -15- 06/25/87
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5. PHARHACOKINETICS
5.1. ABSORPTION
Jodynls-Llebert and Laboda (1982) administered an unspecified oral dose
of furfural to rats and recovered the equivalent of 60X of the dose from the
urine as Us metabolite, furoylglydne. Although the rate of gastrointes-
tinal absorption cannot be determined from these data, these data suggest
that at least 60X of an oral dose 1s absorbed from the gastrointestinal
tract of rats. Furfural appears to be absorbed readily from the respiratory
tract. Flek and Sedlvec (1978) measured the concentration of furfural In
Inspired and expired air of volunteers over an 8-hour period. Pulmonary
retention, estimated at 77.9X, did not appear to be affected by either the
concentration or duration of exposure.
Percutaneous absorption of furfural occurs In humans exposed to a
contaminated atmosphere. Flek and Sedlvec (1978) stated that the amount
absorbed by the skin corresponds to -20-30X of the amount retained by the
respiratory tract. Increasing the ambient temperature or the relative
humidity Increases percutaneous uptake. Immersion of the hand In liquid
furfural to the level of the wrist for 15 minutes resulted In percutaneous
absorption of an amount equivalent to that which would be retained by the
respiratory tract during Inhalation of air containing 10 mg/m3 for 8 hours
or 20 mg/m3 for 4 hours. No other details were provided.
5.2. DISTRIBUTION
Pertinent data regarding the tissue distribution of furfural could not
be located In the available literature as cited In Appendix A.
5.3. METABOLISM
Furoylglydne appears to be the principal metabolite of furfural after
oral administration to rats (Jodyn1s-L1ebert and Laboda, 1982); -60X of an
unspecified dose of furfural was recovered as furoylglydne In the urine.
0069d -16- 06/25/87
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Metabolites excreted by other routes were not reported. Furoylglydne
appears to be the predominant metabolite 1n humans exposed by Inhalation
(Flek and Sedlvek, 1978). The aldehyde group Is probably first oxidized to
an acid group, which 1s then conjugated with glydne (Brabec, 1981). A
metabolite of secondary Importance 1n humans Is 2-furanacrylur1c add. Both
metabolites apparently were Identified 1n the urine. Dogs and rabbits also
excrete furolc add. The metabolism of furfural appears to be rapid as
Indicated by a half-life of 2-2.5 hours In humans exposed by Inhalation
(Flek and Sedlvlc, 1978).
5.4. EXCRETION
The major excretory route for orally administered furfural appears to be
the urine. About 60X of an unspecified oral dose given to rats was
recovered as furoylglydne 1n the urine (Jodynls-llebert and Laboda, 1982).
Unchanged furfural was not Identified 1n the urine.
The urine also appears to be the major excretory route In humans exposed
by Inhalation (Flek and Sedlvec, 1978). Metabolites, but not unchanged
compound, were reported 1n the urine. In humans exposed by Inhalation. <1X
of the retained dose was exhaled as unchanged compound. Excretion by other
routes has not been reported.
5.5. SUMMARY
Furfural appears to be readily absorbed after oral, Inhalation or cuta-
neous exposure (Jodynls-llebert and Laboda, 1982; Flek and Sedlvec, 1978).
Metabolism appears to be rapid, furoylglydne being the major metabolite in
orally exposed animals (Jodynls-Uebert and Laboda, 1982) and 1n humans
exposed by Inhalation (Flek and Sedlvec, 1978). 2-Furanacrylur1c add Is a
secondary metabolite In humans and furolc acid 1s a metabolite of animals,
0069d -17- 01/06/88
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but not of humans. The major route of excretion after either oral or
Inhalation exposure appears to be the urine (Jodynls-Uebert and Laboda,
1982; Flek and Sedlvlc, 1978). Unchanged furfural was not Identified In the
urine of humans or animals.
0069d -18- 06/25/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Feron et al. (1979) exposed groups of 10 male
and 10 female 5-week-old Syrian golden hamsters to atmospheres containing 0,
20, 115 or 552 ppm (0, 77, 448 or 2165 mg/m3), 6 hours/day, 5 days/week
for 13 weeks. Parameters of toxldty evaluated Included general condition,
body weight, hematology, urlnalysls, serum chemistry, Indicators of liver
damage (I.e., serum alkaline phosphatase), gross necropsy examination,
relative weights of major organs and hlstopathologlc appearance of major
organs and tissues. All hamsters were sacrificed on the day after the last
exposure. At 552 ppm, hamsters showed signs of Irritation throughout the
experimental period. Transient restlessness for the first 2 weeks was
observed In the 115 ppm group. A slight reduction In growth, which was.more
apparent In the males, was observed In hamsters at 552 ppm (p<0.05). There
were no effects on hematology or urlnalysls. SGPT appeared to be elevated
In males at 552 ppm (p<0.05). Although several relative organ weights
differed significantly from controls, these occurrences appeared to be
random, with the exception of elevated relative liver weights In males at
552 ppm, which was possibly attributed to treatment with furfural. Hlsto-
pathologlc lesions were limited to the nasal cavity and consisted of disrup-
tions and atrophy of the olfactory epithelium In the absence of rhinitis or
signs of Irritation of the respiratory epithelium. This lesion was noted at
115 and 552 ppm, with both the Incidence and Intensity of the lesion
occurring In a concentration-related manner. Thus, exposure to 20 ppm
appears to represent a NOAEL for this study.
0069d -19- 06/25/87
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AIHA (1965) reported the results of an unpublished study In dogs. No
effects were reported In dogs exposed to 63 ppm (248 mg/m3), 6 hours/day,
5 days/week for 4 weeks; however, fatty degeneration of the liver was
reported at 130 ppm (511 mg/m3). In another study, rats exposed to 200
mg/m3, 5 hours/day, 6 days/week for 12 weeks had disruption of the
hypothalamlc-hypophyseal-adrenal system resulting 1n altered neurochemlcal
parameters (Brzezlnskl et al., 1978). Altered alkaline phosphatase activity
and disturbed calcium and phosphorus metabolism were also reported 1n rats
exposed 5 hours/day, 6 days/week for 3 months (Oledzka and S1korsk1, 1981);
abstracts of this study reported different concentrations 1n air, 10 and 20
mg/m3. Pecora et al. (1961) reported that exposure to 60 ppm (236
mg/m3), 4 hours/day for 80 days caused no toxic effects 1n rabbits.
Concentrations of 140-160 ppm (550-630 mg/m3) were associated with Irrita-
tion of the eyes and respiratory tract and death In 16-20 days. Concentra-
tions of 240-280 ppm (943-1100 mg/m3) resulted 1n death 1n 8-10 days.
6.1.1.2. CHRONIC — Conflicting reports exist regarding the toxldty
of occupational exposure to furfural. Bugyl and Lepold (1949) reported
numbness of the tongue and oral mucosa, loss of the sense of taste and
breathing difficulty In workers at a furfural plant, which lacked adequate
ventilation. Korenman and Resnlk (1930) associated headache, Itching of the
throat and eye Irritation with concentrations of 1.9-14 ppm (7-53 mg/m9).
Usmanov and Akhmedkhodzhaeva (1961) diagnosed hepatitis and functional
disorders of the nervous system In workers exposed to 0.03-0.13 mg/i
(30-130 mg/m>). Pawlowlcz et al. (1984) studied the effects of furfural
exposure on the respiratory tract of exposed workers 1n a butadiene plant.
Furfural concentration did not exceed 7.3 mg/m3. Results of a question-
naire Indicated that 12/51 (23%) of those exposed had chronic bronchitis.
0069d -20- 01/06/88
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SplrometMc testing, however, did not confirm the presence of bronchitis.
In a more recent review, Dunlop and Peters (1953) stated that an occasional
skin allergy 1s the only adverse reaction to long-term exposure to furfural
when ventilation Is adequate.
One chronic animal Inhalation experiment with furfural was located.
Feron and Kruysse (1978) exposed groups of 18 male and 18 female 6-week-old
Syrian golden hamsters to furfural vapor 7 hours/day, 5 days/week for 52
weeks followed by a 29-week observation period. A similar group of air.
exposed controls was maintained. Exposure was to 400 ppm (1550 mg/m3) for
9 weeks, 330 ppm (1280 mg/m3) during weeks 10-20 and 250 ppm (970 mg/ma)
during weeks 21-52, resulting In a TUA concentration of 293 ppm (1151
mg/m3). Concentrations were reduced during the exposure period because of
marked reduction of growth and to avoid early mortality. At the end of the
exposure period, three males and three females from each group were sacri-
ficed for hematology, limited clinical chemistry, gross necropsy examina-
tion, organ weight determinations and hlstopathology. Survivors were
sacrificed at 81 weeks and examined similarly.
Exposed hamsters showed signs of Irritation and developed a yellowish
brown discoloration of the hair coat. Exposed hamsters of both sexes had
significantly reduced body weights during the exposure period, but there was
a tendency to regain weight similar to controls after the exposure period.
Exposure to furfural had no effects on clinical chemistry, hematology or
relative organ weights. Pathologic lesions, restricted to the nasal epithe-
lium, consisted of degeneration and atrophy of the olfactory epithelium and
disruption of the Bowman's glands. A comparison of the nasal lesions at the
end of the 29-week recovery period with those observed Immediately at termi-
nation of exposure gave no Indication that the lesions had either regressed
or progressed during the recovery period.
0069d -21- 06/25/87
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6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — SRI (1981a) treated groups of 10 male and 10
female 46-day-old Flscher-344 rats by gavage with furfural In corn oil at 0
(vehicle control), 11, 22, 45, 90 or 180 mg/kg, 5 days/week for 13 weeks.
Terminal sacrifice was begun the day after the last treatment. Parameters
of toxldty evaluated Included clinical observation, body weights, gross
necropsy examination of all rats, relative organ weights of several major
organs of all groups and complete hlstopathology of controls, 90 and 180
mg/kg rats. In addition, lungs and livers from all 11, 22 and 45 mg/kg rats
were examined histopathologlcally. All the females and nine males at 180
mg/kg and one male and four females at 90 mg/kg died. All but one of the
deaths at 90 mg/kg were attributed to gavage error. The most significant
treatment-related clinical sign was red fluid from the nose and mouth, which
occurred In males at >90 mg/kg and 1n females at 180 mg/kg. At necropsy,
gross alterations attributed to treatment were restricted to enlarged livers
1n four males at 180 mg/kg. A slightly Increased relative liver weight 1n
male rats at 90 mg/kg may also have been associated with treatment. Liver
weights were not elevated In a dose-related manner and statistical analysis
was not performed. Biologically significant hlstopathologlc lesions were
restricted to the lungs and liver. Perlvascular and perlbronchlolar edema
was seen 1n an apparently randomly distributed number of control and treated
rats of both sexes and was attributed to the lung perfuslon technique used
1n tissue preparation 1n this study. Liver lesions, restricted to male
rats, consisted of minimal to moderate cytoplasmlc vacuollzatlon confined
largely to the centrllobular regions. This lesion was observed 1n controls
and In all treated groups. The Incidence was clearly not dose-related,
0069d -22- 01/06/88
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but was present In only three controls and 1n at least seven males 1n each
of the treated groups, except In males at 180 mg/kg that probably died
before the lesion had time to develop.
SRI (1981b) also treated groups of 10 male and 10 female 53- to 57-day-
old B6C3F1 mice with furfural In corn oil by gavage at 0 (vehicle controls),
75, 150, 300, 600 or 1200 mg/kg, 5 days/week for 13 weeks. Parameters of
toxldty evaluated were as described for the 13-week SRI (1981a) rat study
described above except that comprehensive hlstopathologlc examination was
performed on all Interim death mice, controls, and those 1n the 300, 600 and
1200 mg/kg groups. In addition, lungs and livers from all 75 and 150 mg/kg
mice were examined h1stopatho1og1cally. All mice 1n the 1200 mg/kg group
and nine males and nine females In the 600 mg/kg group died; the deaths were
attributed to treatment. Deaths of one female at 150 mg/kg and one female
In the control group were attributed to gavage error. Clinical signs
associated with furfural toxldty were confined to mice at >600 mg/kg and
Included Inactivity, ruffled fur, labored breathing, recumbency and opacity
of the eyes In both sexes and posterior paralysis In females. Body weight
gain was depressed In males -53% and In females -13% at 600 mg/kg. No
adverse effects on body weight were noted at <300 mg/kg. The only toxlco-
loglcally significant gross necropsy lesion was "prominent lobular liver
architecture" In 1200 and 600 mg/kg males and 600 mg/kg females. Relative
liver weights were elevated -16X In males and ~27% 1n females at 300 mg/kg,
-•7% 1n females at 150 mg/kg and ~12% In females at 75 mg/kg. The toxlco-
loglc significance of the elevated relative liver weight 1n 75 mg/kg females
1s not clear. Biologically significant hlstopathologlc lesions were
restricted to the liver. Liver lesions, which consisted of various stages
of degeneration, coagulatlve necrosis and subchronlc Inflammation, appeared
0069d v -23- 01/06/88
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to be more severe In males, and occurred In both sexes In a dose-related
manner at >150 mg/kg. Lesions at 150 mg/kg were described as minimal to
moderate. Lesions 1n the lungs, which consisted of peMvascular and peM-
bronchlolar edema occurred 1n control and treated mice and were attributed
to the lung perfuslon technique used 1n tissue preparation.
6.1.2.2. CHRONIC — Pertinent data regarding the toxldty of chronic
oral exposure to furfural could not be located 1n the available literature
as dted 1n Appendix A.
6.1.3. Other Relevant Information. Oral LD5Q values for furfural
Include 50-100 mg/kg (Brabec, 1981), 65 mg/kg (NIOSH, 1987), 127 mg/kg (Sax,
1984) and 135 mg/kg (AIHA, 1965) for rats, 400 mg/kg for mice {NIOSH, 1987;
Sax, 1984), 541 mg/kg for guinea pigs, and 2300 mg/kg for dogs (Sax, 1984).
Single large oral doses are associated primarily with CNS effects (Brabec,
1981; AIHA, 1965).
Furfural vapors are Irritating to skin, eyes and mucous membranes and
the liquid Is dangerous to the eyes (Sax. 1984; AIHA, 1965; Wlndholz, 1983).
Thresholds for odor detection of the vapor have been reported as 0.024-20.0
mg/m3 (0.006-5 ppm) (Ruth, 1986) and 0.078 ppm (Amoore and Hautala,
1983). The odor 1s reported to be similar to almonds. The threshold for
Irritation Is listed as 48 mg/ma. Furfural 1s also said to be a
photosensltlzer (Hamilton and Hardy, 1974).
Nakahara and Mori (1942) described a series of experiments In which rats
were fed diets containing furfural to produce liver cirrhosis. Diets con-
sisted of polished or unpolished rice with or without fish meal and carrot
supplement. The period of feeding ranged from 38-548 days. The Investi-
gators noted that furfural volatility precluded accurate estimation of
animal dosages. Nominal dietary concentrations ranged from 1-5% furfural.
Mortality was generally high. Liver cirrhosis was consistently produced.
0069d -24- 01/06/88
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These data confirm the liver as the target organ of furfural toxldty 1n the
rat, but are not useful for quantitative risk assessment.
6.2. CARCINOGENICITY
6.2.1. Inhalation. The only data regarding the cardnogenldty of
furfural by Inhalation exposure are from the 81-week study 1n hamsters by
Feron and Kruysse (1978) described 1n detail In Section 6.1.1.2. In this
study, groups of 18 males and 18 females were exposed to a TWA concentration
of 0 or 293 ppm (1151 mg/m3), 7 hours/day, 5 days/week for 52 weeks
followed by an observation period of 29 weeks for all but three males and
three females from each group, which were sacrificed at the end of the
exposure period. There was no Indication of a carcinogenic effect of
furfural 1n this study.
6.2.2. Oral. Pertinent data regarding the cardnogenldty of furfural
associated with oral exposure could not be located 1n the available litera-
ture as cited 1n Appendix A. The NTP (1987) sponsored a gavage study using
rats and mice, but hlstopathology 1s currently In progress and the results
are not yet available.
6.2.3. Other Relevant Information. Sh1m1zu (1986) Investigated the
ability of furfural-Induced hepatic cirrhosis to potentiate the carcinogenic
effects of orally administered FAA 1n rats. Groups of 16 male Wlstar rats
treated with furfural In the diet for 120 days to produce liver cirrhosis
were then treated with 0 or 0.03X FAA 1n the diet for 3 weeks followed by
control diet for 1 week. Another group was treated with FAA without the
furfural pretreatment. Hyperplastlc nodules of the liver, considered to be
preneoplastlc changes, did not occur In rats treated with furfural alone,
occurred 1n 2/16 rats treated with FAA alone and occurred 1n 16/16 rats
treated with furfural followed by FAA. The Investigators concluded that
liver cirrhosis enhances the carcinogenic effect of FAA.
0069d -25- 01/06/88
-------
Feron (1972) Investigated the effect of coadmlnlstratlon of furfural on
the Incidence of BAP-lnduced respiratory tract tumors In Syrian golden
hamsters. Groups of 35 males and 35 females were given Intratrachael
Instillations of 0.2 ma of 1.5X furfural, 0.2 ml of 0.5X BAP or 0.2 ml
of the combination In 0.9% saline once weekly for 36 weeks. A group of 35
males treated similarly with 0.9X saline for 36 weeks served as the control
group. Three males and three females from each treated group and three
control males were sacrificed at 30 weeks for Interim necropsy Information;
the survivors were sacrificed at 78 weeks. Treatment with saline (control)
or furfural alone Induced no respiratory tract tumors. BAP alone Induced
respiratory tract tumors 1n 19 male and 22 female hamsters and BAP and
furfural Induced respiratory tract tumors In 15 males and 15 females.
Although the Incidence of respiratory tract tumors In BAP and furfural
treated hamsters was no higher than 1n the BAP-treated group, H appeared
that furfural may have reduced the latency period of BAP-lnduced respiratory
tract tumors. The Investigator also noted the development of perltracheal
tumors 1n 2 females 1n the BAP alone group and In 9 males and 11 females In
the BAP and -furfural group. Feron (1972) concluded that furfural had no
carcinogenic activity of Us own, but was cocardnogenlc with BAP.
In a subsequent experiment, Feron and Kruysse (1978) exposed groups of
18 male and 18 female Syrian golden hamsters to a TWA concentration of 293
ppm (1151 mg/m3) furfural 7 hours/day, 5 days/week for 52 weeks followed
by a 29-week observation period (see Section 6.1.1.2.). Similar groups of
hamsters were exposed to a TWA concentration of 293 ppm furfural 7 hours/
day, 5 days/week and simultaneously given 52 weekly Intratracheal Instilla-
tions of 0.2 ml of saline or saline containing BAP at 0.175 or 0.35X, or
52 weekly subcutaneous Injections of 0.2 ml of saline or saline containing
DEN at 0.0625X, to evaluate the cocarclnogenlcUy of furfural with these
0069d -26- 01/06/88
-------
known respiratory tract carcinogens. The Incidence of respiratory tract
tumors was not greater In furfural/BAP- or furfural/DEN- treated hamsters
than 1n those treated with BAP or DEN alone. The Investigators concluded
that Inhalation exposure to furfural had no cocardnogenlc activity with BAP
or OEN.
6.3. MUTAGENICITY
The genotoxldty of furfural has been tested 1n several systems as
summarized In Table 6-1. Results 1n reverse mutation tests with Salmonella
typhlmuMum were generally negative (Sasaki and Endo, 1978; Soska et al.,
1981; Marnett et al., 1985) or equivocal (Mortelmans et al., 1986).
Positive results were reported only In strain TA100 and were generally weak,
the number of reverted colonies on treated plates exceeded control plates by
a factor of ~2 (Zdzlenlcka et al., 1978; Loquet et al., 1981). Furfural was
negative 1n the DNA repair test 1n Escher1ch1a coll. the prophage Induction
test 1n lysogenlc E.. coll and the chloroplast bleaching test 1n Euglena
graclHs (Soska et al., 1981). Woodruff et al. (1985) reported positive
results 1n the sex-linked recessive lethal test 1n DrosophUa melanogaster
1n an adult Injection but not 1n an adult feeding protocol; negative results
were reported 1n the reciprocal translocatlon test 1n 0. melanoqaster.
Few data were located regarding the mutagenldty of furfural In
mammalian test systems. Positive results were reported for the chromosomal
aberration test In CHO cells In culture (Stlch et al., 1981). A relatively
high proportion of chromatld breaks and exchanges were observed 1n the
absence of metabolic activation. Adding Swiss rat S-9 appeared to strongly
Increase the magnitude of the response. A concentration-dependent Increase
1n the Incidence of sister chromatld exchanges was observed In cell cultures
of exposed lymphocytes from healthy human subjects (Gomez-Arroyo and Souza,
0069d -27- 01/06/88
-------
TABLE 6-1
Genotoxlclty Testing of Furfural
§
a.
i
to
CD
t
o
9>
rj
Assay
Reverse
Mutation
Reverse
Mutation
Reverse
Mutation
Reverse
•utatlon
Reverse
Mutation
Reverse
Mutation
DMA repair
test
Prophage
Inductest
Chloroplast
bleaching test
Sex-linked
recessive
lethal
Reciprocal
translocatlon
test
Indicator
Organ ls«
S. tvphlMuMuM
TA98. TA100
S. typhlMurluM
TA98. TA100.
TA1535
S. typhlMurluM
TA98. TA100
S. typhlMurluM
TA100. TA98.
TA1535. TA1537
S. typhlMurluM
TA100
S. typhlwrtuM
TA104
i- coM.
several strains
E. coll. lysogens
GV5027R. 4015
£. qracllls
strain Z
0. Melanogaster
P.. Melanoqaster
Purity
purified
NR
NR
97. ex
purity
checked
highest
purity
available
purity
checked
purity
checked
purity
checked
97. ex
97. ex
Application
plate
Incorporation
plate
Incorporation
plate
Incorporation
plate
Incorporation
plate
Incorporation
plate
Incorporation
spot test
spot test
NR
adult feeding or
adult Injection
adult Injection
Concentration
or Dose
0-15 nt/plate
0.05-60 M«ole/
plate
NR
0-6666 tig/plate
NR
<1 t*o1/p1ate
10 ng/dlsk
several concen-
trations NR
<300 tig/Mt
(toxic)
25.000 or 25.500
PPM. respectively
25.500 PDM
Activating
SysteM
»S-9
±S-9
»S-9
»S-9
none
none
none
none
none
NA
NA
Response Coonent
» Positive only In TA100;
» toxic at >7 pi/plate
Weakly positive In TA100
* only
Prelncubated 15 Minutes
before plate Incorporation
Prelncubated 20 Minutes;
results from 2nd of two
testing laboratories
equivocal
Tested at lower than cell-
kllllng concentrations
TA104 More sensitive to
carbonyl conpound-lnduced
•utagenlclty than TA100
NC
NC
NC
» Positive response In
Injection experiment
NC
Reference
Zdztenlcka
et al.. 1978
Loquet
et al.. 1981
Sasaki and
Endo. 1978
NorteUuns
et al.. 1986
Soska
et al.. 1981
Narnett
et al.. 1985
Soska
et al.. 1981
Soska
et al.. 1981
Soska
et al.. 1981
Woodruff
et al.. 1985
Woodruff
et al.. 1985
-------
TABLE 6-1 (cont.)
Assay
Chroaosoaal
aberration
test
Sister
chroaattd
exchange
Indicator
Organ Isa
CHO cells
hunan
lymphocytes
Purity Application Concentration
or Dose
MR cell culture 0-40 aN
NR cell culture 0.035. 0.07 or
0.14 aN
Activating Response
Systea
»S-9 »
»
none *
Coatent
More strongly » with S-9
Concentration -dependent
response at two higher
concentrations
Reference
Stlch
et al.. 1981
Goaex -Arroyo
and Souza.
1985
NR « Not reported; NC - no coawnt; NA - not applicable
CO
CO
-------
1985). Metabolic activation was not used 1n this system. An Increased
Incidence of sister chromatld exchanges was not observed In lymphocytes from
occupationally exposed workers compared with unexposed workers.
6.4. TERATOGENICITY
Pertinent data regarding the developmental toxldty of furfural could
not be located In the available literature as cited In Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of furfural could
not be located 1n the available literature as cited In Appendix A.
6.6. SUMMARY
Furfural was not carcinogenic 1n an 81-week Inhalation study where
hamsters were exposed to 293 ppm (1151 mg/m3), 7 hours/day, 5 days/week
for 52 weeks (Feron and Kruysse, 1978). The NTP (1987) has sponsored a
gavage study using rats and mice, but hlstopathology Is In progress and
results are not yet available. Shlmlzu (1986) reported that livers of rats
made drrhotlc by dietary pretreatment with furfural were more sensitive to
the carcinogenic effects of FAA, as evidenced by the occurrence of
preneoplastlc hyperplastlc nodules In 16/16 rats compared with 2/16 rats
treated with FAA without pretreatment with furfural. In an experiment In
which furfural was coadmlnlstered with BAP Intratracheally to hamsters,
furfural was associated with a reduced period of latency but not with an
Increased Incidence 1n respiratory tract tumors (Feron, 1972). Furfural.
however, did appear to Increase the Incidence of BAP Induced peMtracheal
tumors In this study. In a subsequent experiment, Inhalation exposure of
hamsters to furfural had no effect on the Incidence of tumors Induced by
Intratracheal administration of BAP or subcutaneous administration of
diethylnltrosamlne (Feron and Kruysse, 1978).
0069d -30- 01/06/88
-------
Furfural was negative (Sasaki and Endo, 1978; Soska et al., 1981;
Harriett et al., 1985), equivocal (Mortelmans et al., 1986) or only weakly
positive (Zdz1en1cka et al., 1978; Loquet et al., 1981) In mutation tests 1n
microorganisms. Positive results In a sex-linked recessive lethal test and
negative results In a reciprocal translocatlon test were reported 1n D.
melanoqaster (Woodruff et al., 1985). Positive results were also reported
1n CHO cells (Stlch et al., 1981) and In human lymphocytes (Gomez-Arroyo and
Souza, 1985). Data were not located regarding the developmental or
reproductive toxldty of furfural.
The olfactory epithelium appears to be the target organ 1n hamsters
exposed to furfural by Inhalation. Feron et al. (1979) observed disruption
and atrophy In the olfactory epithelium of hamsters exposed to 115 ppm (448
mg/m3) but not to 20 ppm (77 mg/m3), 6 hours/day, 5 days/week for 13
weeks. Similar lesions were observed 1n hamsters exposed to a TWA concen-
tration of 293 ppm (1151 mg/m3), 7 hours/day, 5 days/week for 52 weeks
(Feron and Kruysse, 1978). In dogs, fatty liver degeneration was reported
at 130 ppm (511 mg/m3), 6 hours/day, 5 days/week for 4 weeks (AIHA, 1965).
No adverse effects were reported at 63 ppm (248 mg/m3). In humans exposed
occupationally, 1.9-14 ppm (7-53 mg/m3) has been associated with headache
90 mg/kg and hepatocytlc cytoplasmlc vacuollzatlon was seen 1n all treated
groups (SRI, 1981a). Mice appear to be more resistant than rats to the
effects of orally administered furfural. In mice treated by the same
0069d -31- 01/06/88
-------
schedule as rats with doses of 75, ISO, 300, 600 or 1200 rug/kg, high
mortality occurred at >600 mg/kg (SRI, 1981b). Degenerative, necrotlc and
Inflammatory liver lesions were noted at >150 mg/kg but not at 75 mg/kg.
0069d -32- 06/25/87
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The recommended ACGIH (1986a) TLV-THA for furfural Is 2 ppm (-8 mg/m3)
based primarily on Irritation In humans exposed occupatlonally to 5-16 ppm
(-20-63 mg/m3) (ACGIH, 1986b). The TLV corresponds to the maximum allow-
able concentration permitted 1n East Germany and the Soviet Union (ACGIH,
1986b; Sedlvec and Flek, 1978). ACGIH (1986a) currently recommends a STEL
for furfural of 10 ppm (-40 mg/m3). The OSHA (1985) standard for furfural
1s currently 5 ppm (-20 mg/m3). Both the TLV-TWA and the OSHA standard
have a "skin" notation because furfural 1s readily absorbed dermally.
U.S. EPA-NIH (1987) lists a recommended drinking water limit of 98 ppm,
but the basis for this recommendation Is unclear.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms. from
the effects of furfural could not be located In the available literature as
cited In Appendix A.
Q069d -33- 06/25/87
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Data were not located regarding the carclnogenlclty
1n humans of Inhalation exposure to furfural. In the only animal study
available, no carcinogenic effects were observed In hamsters exposed to a
TWA concentration of 293 ppm (1151 mg/m3} furfural, 7 hours/day, 5
days/week for 52 weeks, followed by a 29-week observation period {Feron and
Kruysse, 1978).
8.1.2. Oral. The NTP (1987) has sponsored a gavage study using rats and
mice, but hlstopathology 1s In progress and the results are not yet
available.
8.1.3. Other Routes. Sh1m1zu (1986) noted a marked Increase In the Inci-
dence of FAA-lnduced hyperplastlc nodules In rats previously treated with
furfural to Induce hepatic cirrhosis. Feron (1972) observed an Increased
Incidence of perUracheal tumors In hamsters treated by Intratracheal Infu-
sion with furfural In combination with BAP compared with those treated with
BAP alone. The Investigator concluded that furfural had cocarclnogenlc
activity with BAP. In a later experiment, feron and Kruysse (1978) observed
no evidence In hamsters for cocardnogen1c1ty of Inhaled furfural and Intra-
tracheal Instillation of BAP or subcutaneous Injection of DEN.
8.1.4. Height of Evidence. Data were not located regarding the carclno-
genlclty of furfural In humans and the data regarding the evidence for
carclnogenlclty of furfural to animals are Inadequate. Therefore, according
to the U.S. EPA (1986b) guidelines for carcinogenic risk assessment,
furfural should be assigned to EPA Group 0, not classifiable as to
carclnogenlclty In humans.
0069d -34- 01/06/88
-------
8.1.5. Quantitative Risk Estimates. Data were Inadequate for estimating
the carcinogenic potency of furfural to humans for oral or Inhalation
exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES ~ A NOAEL and LOAEL for
subchronlc Inhalation exposure were defined In a 13-week hamster study
(Feron et al., 1979). In this experiment, groups of 10 male and 10 female
hamsters were exposed to 0, 20, 115 or 552 ppm (0, 77, 448 or 2165 mg/m3),
6 hours/day, 5 days/week for 13 weeks. The critical effect appeared to be
disruption and atrophy of the olfactory epithelium, which occurred In a
concentration related manner with respect to Incidence and Intensity at >115
ppm. No adverse effects were reported at 20 ppm. In an unpublished study
In dogs reported by AIHA (1965), no effects were noted at 63 ppm. (248
mg/m3), 6 hours/day, 5 days/week for 4 weeks, but fatty liver degeneration
was noted at 130 ppm (511 mg/m3). Abstracts of a 3-month rats study by
Oledzka and S1korsk1 (1981) reported altered alkaline phosphatase activity
and disturbed calcium and phosphorus metabolism associated with Inhalation
exposure to furfural. One abstract reported the concentration as 10 mg/m3
and the other as 20 mg/m3, 5 hours/day, 6 days/week. Because data were
not available for evaluation of this study and because Feron et al. (1979)
did not report altered serum alkaline phosphatase 1n hamsters exposed to a
much higher concentration, 2165 mg/m3, the Oledzka and S1korsk1 (1981)
data are not considered In quantitative risk assessment. The NOAEL of 20
ppm (77 mg/m3) 1s the most appropriate basis for an RfD for subchronlc
Inhalation exposure to furfural. Expanded to continuous exposure, the
concentration of 77 mg/m3 corresponds to 13.8 mg/m3. From body weight
0069d -35- 01/06/88
-------
data provided by the Investigators an average body weight of 0.105 kg can be
estimated. From a formula provided by U.S. EPA (1985) an Inhalation rate of
0.099 mVday 1s calculated and an equivalent dosage of 13.0 mg/kg/day Is
estimated. Applying an uncertainty factor of 100, 10 for Interspedes
extrapolation and 10 for Intraspedes variability, results In an RfO for
subchronlc Inhalation exposure to furfural of 0.1 mg/kg/day, or 9 mg/day for
a 70 kg human. Confidence 1n this RfD 1s low as explained 1n Section
8.2.1.2.
8.2.1.2. CHRONIC EXPOSURES — Occupational studies report Irritation
at exposures as low as 1.9 ppm (7 mg/m3) (Korenman and Resnlk, 1930) and
hepatitis and CNS effects at 30 mg/m3 (Usmanov and Akhmedkhodzhaeva,
1961). Adequate data from these studies were not available for evaluation.
Dunlop and Peters (1953) stated that an occasional skin allergy Is the only
adverse reaction to long-term exposure to furfural when ventilation 1s
adequate. ACGIH (1986a) recommended a TUA-TLV of 2 ppm (-8 mg/m3) to
protect against Irritation 1n the workplace. In the only chronic animal
study, Feron and Kruysse (1978) exposed hamsters to furfural at a TWA con-
centration of 293 ppm (1151 mg/m3), 7 hours/day, 5 days/week for 52 weeks
followed by a 29-week observation period. Degradation and atrophy of the
olfactory epithelium occurred and this study failed to define a NOAEL for
chronic Inhalation exposure.
An RfD of 6 mg/day for chronic Inhalation exposure to furfural could be
derived by expanding the TUA-TLV of 2 ppm (8 mg/m3) to continuous exposure
and by applying an uncertainty factor of 10 to unusually sensitive Individ-
uals. Since the TUA-TLV Is Intended to protect against Irritation but not
necessarily against toxldty, the TUA-TLV 1s rejected as a basis for the
RfD. A more sound approach 1s to apply an additional uncertainty factor of
10 to the subchronlc NOAEL to expand from subchronlc to chronic exposure.
0069d -36- 01/06/88
-------
Application of an additional factor of 10 to the NOAEL of 13.0 mg/kg/day In
the subchronlc study by Feron et al. (1979) results In an RfD for chronic
Inhalation exposure to furfural of 0.01 mg/kg/day or 0.9 mg/day for a 70 kg
human. Because the cardnogenlclty, chronic toxldty, developmental and
reproductive toxldty of furfural have not been Investigated adequately,
only low confidence can be placed 1n this value.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Oral exposure
studies are restricted to 13-week gavage experiments, which Indicated that
the liver Is the target organ of furfural 1n rats and mice. In groups of 10
male and 10 female rats treated with 11, 22, 45, 90 or 180 mg/kg, 5
days/week, mortality was associated with >90 mg/kg and hepatocytlc
cytoplasmlc vacuollzatlon was seen In all treated groups (SRI, 1981a). The
lesions were described as mild to moderate, and the low dose level of 11
mg/kg may be considered a LOAEL 1n rats. Mice appear to be more resistant
than rats to the effects of orally administered furfural. In mice treated
by the same schedule as rats but with doses of 75, 150, 300, 600 or 1200
mg/kg, high mortality occurred at >600 mg/kg (SRI, 1981b). Degenerative,
necrotlc and Inflammatory liver lesions were noted at >150 mg/kg but not at
75 mg/kg. Lacking a suitable NOAEL, the LOAEL of 11 mg/kg, 5 days/week In
rats may serve as the basis for an RfO for subchronlc oral exposure to
furfural (SRI, 1981a). Multiplication by 5 days/7 days results In an
expanded dosage of 7.9 mg/kg/day. Application of an uncertainty factor of
1000, 10 to estimate a NOAEL from a LOAEL, 10 to extrapolate from rats to
humans, and 10 to protect unusually sensitive Individuals results In an RfD
for subchronlc exposure to furfural of 0.008 mg/kg/day, or 0.6 mg/day for a
70 kg human. Confidence 1n this RfD 1s low because the key study, the
0069d -37- 01/06/88
-------
13-week gavage study (SRI, 1981a) did not Identify a NOAEL for liver effects
In rats, the more sensitive of the species tested, and because the
carclnogenldty, developmental and reproductive toxldty of furfural have
not been Investigated adequately.
8.2.2.2. CHRONIC EXPOSURES — Data were not located regarding chronic
oral exposure to furfural. In the absence of suitable chronic data, an RfD
for chronic oral exposure to furfural may be estimated from the subchronlc
oral RfD by application of an additional uncertainty factor of 10 to the
LOAEL of 7.9 mg/kg/day. An RfO of 0.8 pg/kg/day or 0.06 mg/day for
chronic oral exposure to furfural Is calculated. Confidence 1n this RfD Is
low as explained 1n Section 8.2.2.1. and because chronic oral exposure data
are lacking.
0069d -38- 01/06/88
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Information regarding the systemic toxlclty of furfural was reviewed 1n
Chapter 6. Data potentially useful for deriving CSs based on systemic
toxldty are available from subchronlc Inhalation, occupational and oral
studies and are summarized In Table 9-1. Effects associated with Inhalation
exposure to furfural Include nonreverslble disruption of the olfactory
epithelium In hamsters (Feron et al., 1979; Feron and Kruysse, 1978), and
headache and Irritation of the eyes and throat In occupatlonally exposed
humans (Korenman and Resnlk, 1930). Oral exposure to furfural Is associated
with mortality and liver lesions In rats and mice (SRI, 1981a,b).
CSs for these effects are calculated and presented In Table 9-2. A CS
for lesions of the olfactory epithelium 1s calculated only from the sub-
chronic data of Feron et al. (1979) because the effect was observed Iri the
subchronlc study at a level lower than that of the chronic study. Although
the occupational study by Korenman and Resnlk (1930) 1s not adequately
reported to be considered In quantitative risk assessment, a CS 1s calcu-
lated from these data for comparison. CSs for mortality and liver effects
were calculated only from the rat data (SRI, 1981a) because rats were more
sensitive than mice to these effects.
CSs range from 6.0 for headache and Irritation 1n humans to 27 for
mortality In rats. The CSs Indicate that orally exposed rats are more
sensitive than occupatlonally exposed humans or hamsters exposed by Inhala-
tion. Although human data are available, the CS of 27 associated with an RQ
of 100 1s chosen to represent the systemic toxldty of furfural (Table 9-3).
0069d -39- 06/25/87
-------
TABLE 9-1
Toxtclty Summary for Furfural
o.
1
o
1
Q
0»
IS)
Route
Inhalation
Inhalation
Inhalation
Oral
Oral
Oral
Oral
'Calculated
weight of
"Calculated
'Calculated
^Reference
•Reference
Species/
Strain
hamster/
Syr Ian
golden
hamster/
Syr Ian
golden
human/
NA
rat/F344
rat/F344
mouse/
B6C3F1
mouse/
B6C3F1
Sex/
Number
N/10.
F/10
N/18,
F/18
NR/NR
N/10.
F/10
N/10.
F/10
N/10.
F/10
N/10,
F/10
by mutlttplylng the
70 kg.
Average
Body
Height
0.105°
0.099°
70<
0.350*
0.350*
0.03f
0.03f
animal dose
as the mean body weight for males
Purity/
Vehicle
purity
checked
purity
checked
MR
99.6V
corn oil
99.6V
corn oil
99.6V
corn oil
99.6V
corn oil
expressed as
and females
Exposure
115 ppm (448 mg/m»)
6 hours/day, 5 days/
week or 13 weeks
TUA concentration of
293 ppm (1151 mg/m»)
7 hours/day, 5 days/
week or 52 weeks
1.9-14 ppm (7-53
mg/m*) occupational
90 mg/kg. 5 days/week
for 13 weeks
11 mg/kg. 5 days/week
for 13 weeks
600 mg/kg, 5 days/
week for 13 weeks
150 mg/kg. 5 days/
week for 13 weeks
Transformed
Animal Dose
(mg/kg/day)
75. Oc
226. 3C
NA
64.3
7.9
429
107
Equivalent
Human Dosea
(mg/kg/day)
8.59
25.4
0.11 at
1.9 ppm
11.0
1.4
32.3
8.07
mg/kg/day by the cube root of the ratio of the animal
from data provided by the
by expanding to continuous exposure and applying the formula 0.7488xbw°-
human body weight (U.S
rat body weight
(U.S.
. EPA. 1980)
EPA. 1980)
Investigators.
* (U.S. EPA. 1985)
Response Reference
Mild disruption and Feron et al..
atrophy of olfactory 1979
epithelium
Decreased body Feron and
weight, destruction Kruysse. 1978
of olfactory epi-
thelium
Headache. Irritation Korenman and
of eyes and throat Resnlk. 1930
Mortality SRI. 1981a
Minimum to moderate SRI. 1981a
hepatocellular cyto-
plasmlc vacuollzatton
In males
Mortality SRI. 19815
Degeneration, focal SRI. 19815
necrosis and Inflam-
mation of the liver
body weight to the reference human body
to estimate Inhalation rate.
'Reference mouse body weight (U.S. EPA. 1980)
NR = Not reported; NA = not applicable
-------
o
o»
tO
TABLE 9-2
Co*posHe Scores for Furfural
Route
Inhalation
Inhalation
Oral
Oral
Spec les
hamster
human
rat
rat
Animal Dose
(mg/kg/day)
75.0
NA
64.3
7.9
Chronic
Human NED9
(•g/day)
60.1«>
50
77»
9.8»»
RVd
2.8
3.0
2.7
4.0
Effect RVe
Disruption and atrophy 6
of olfactory epithelium
Headache and Irritation 2
of eyes and throat
Mortality 10
Moderate hepatocellular 5
vacuollzatlon
CS
16.8
6.0
27
20
RQ
1000
1000
100
1000
Reference
Feron et al..
1979
Korenman and
Resnlk. 1930
SRI. 1981 a
SRI. 1981a
'Calculated by Multiplying the equivalent hiwan dose expressed In term of mg/kg/day by 70 kg to express the Chronic Human NED In terms of
•g/day for a 70 kg human.
DAn uncertainty factor of 10 was applied to expand from subchrontc to chronic exposure.
en
oo
-------
TABLE 9-3
FURFURAL
Minimum Effective Dose (MEO) and Reportable Quantity (RQ)
Route: oral
Dose*: 77 mg/day
Effect: mortality
Reference: SRI, 1981a
RVd: 2.7
RVe 10
Composite Score: 27
RQ: 100
*Equ1valent human dose
0069d -42- 01/06/88
-------
Selection of the CS based on the oral rat data represents the more conserva-
tive approach and gives preference to data from a study In which dosage was
carefully controlled. Furthermore, data regarding the toxldty of oral
exposure of humans to furfural are limited, and occupational exposures are
difficult to quantify.
9.2. BASED ON CARCINOGENICITY
The only data regarding the cardnogenldty of furfural by Inhalation
exposure are from an 81-week hamster study by Feron and Kruysse (1978)
described In detail In Section 6.1.1.2. In this study, groups of 18 males
and 18 females were exposed to a TWA concentration of 0 or 293 ppm (0 or
1151 mg/m3), 7 hours/day, 5 days/week for 52 weeks, followed by a 29-week
observation period for all but three males and three females from each
group, which were sacrificed at the end of the exposure period. There was
no Indication of a carcinogenic effect of furfural 1n this study.
Pertinent data regarding the cardnogenlclty of furfural after oral
exposure could not be located In the available literature as cited In
Appendix A. The NTP (1987) has sponsored a gavage study using rats and
mice, but hlstopathology 1s 1n progress and the results are not yet
available.
Data were not located regarding the cardnogenldty of human exposure to
furfural and the chemical was assigned to EPA Group D. Data were not suffi-
cient for estimation of a potency factor for furfural and hazard ranking
based on cardnogenldty Is not possible.
0069d -43- 01/06/88
-------
10. REFERENCES
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»
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Zdzlenlcka, H., B. Tudek, M. Zlelenska and T. Szymczyk. 1978. Mutagenlc
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0069d
~57- 06/25/87
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In February, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be 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).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.O. 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. 28. John Wiley and
Sons. NY. p. 2879-3816.
Clayton, G.D. 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.
0069d -58- 06/25/87
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer 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. WHO, IARC, 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.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. 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). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, 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.
0069d -59- 06/25/87
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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 ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish 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.
0069d -60- 06/25/87
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APPENDIX B
Summary Table for Furfural
Species
Inhalation Exposure
Subchronlc haaster
Chrontc haaster
Carctnogenlclty ID
Oral Exposure
Subchronlc rat
Chronic rat
Carclnogenlclty 10
IMPORTABLE QUANTITIES
Based on Chrontc Toxlclty:
Based on Carclnogenlclty:
Exposure Effect
•'&•*•;.
>-|; '
20 ppa (7? ag/a*). 6 olfactory degeneratloh
hours/day. 5 days/week at higher levels. .- .;
for 13 weeks . ;„ .' C
20 ppa (77 ag/a*). 6 olfactory degeneration
hours/day. 5 days/week at higher levels * "•
for 13 weeks
ID ID /
11 ag/kg, 5 days/week. alld hepatocellular
13 weeks (7.9 ag/kg/day) vacuollzatlon
11 ag/kg. S days/week. «11d hepatocellular
13 weeks (7.9 ag/kg/day) vacuollzatlon
ID ID
100
10
RfD Reference
0.1 ag/kg/day or Feron
9 ag/day for a et al.. 1979
70 kg human
0.01 ag/kg/day or Feron
0.9 ag/day for a et al.. 1979
70 kg human
ID 10
0.008 ag/kg/day SRI. 1981a
or 0.6 ag/day
0.8 vg/kg/day or SRI. 1981 a
0.06 ag/day
10 10
SRI. 1981a
10
10 - Insufficient data
in
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oo
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