o>
en
""^States
Environmental Protection
Agency AUQUSt, 1989
aEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 6LYCIDALDEHYDE
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
DRAFT: DO NOT CITE OR QUOTE
to NOTICE
^ This document 1s a preliminary draft. It has not been formally released
"By the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It 1s being circulated for comments
on Us technical accuracy and policy Implications.
-------
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
-------
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 1n "Appendix: Literature Searched."
Literature search material Is 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 Is 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 I.e., for an Interval 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 RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
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-
genlclty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, 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
-------
EXECUTIVE SUMMARY
Glyddaldehyde (CAS number 765-34-4} 1s currently referred to as
oxlranecarboxaldehyde by CAS (SANSS, 1988). At room temperature, this
compound Is a colorless liquid with a pungent, aldehyde-Uke odor (Nine et
al., 1981). It 1s mlsclble 1n water and most common organic solvents. It
appears that glycldaldehyde has never been commercially produced or used In
the United States (IARC, 1976).
If released to the atmosphere, glycldaldehyde Is expected to exist
primarily 1n the vapor phase. The dominant removal mechanism appears to be
reaction with photochemically generated hydroxyl radicals (estimated
half-life of 18 hours). Glycldaldehyde may also be removed from the
atmosphere by wet deposition. If released to water, glycldaldehyde would be
susceptible to chemical hydrolysis. Its hydrolytlc half-life In water at
neutral pH and 25°C Is predicted to be <28 days. Reaction with singlet
oxygen or alkyl peroxy radicals, adsorption to suspended solids and
sediments, and volatilization are not expected to be significant fate
processes 1n natural water. If released to moist soil, glycldaldehyde would
be susceptible to chemical hydrolysis. In the absence of fairly rapid
degradatlve processes, glycldaldehyde has the potential to be quite mobile
and may leach Into groundwater. Volatilization from moist soil surfaces Is
not expected to be an Important fate process. If released to dry soil,
glycldaldehyde 1s expected to volatilize fairly rapidly from the soil
surface.
Pertinent data regarding levels of glycldaldehyde In ambient air, water
or food were not located 1n the available literature cited 1n Appendix A.
1v
-------
Similarly, data pertinent to dermal exposure are not available. Glycldalde-
hyde occurs 1n sunflower oil, and Us concentration Increases with that of
peroxide during storage, causing a deterioration of flavor (IARC, 1976).
Glycldaldehyde has been detected 1n randd samples of commercial lard (IARC,
1976).
A calculated BCF value of 0.16 for glycldaldehyde suggests that glydd-
aldehyde will not bloaccumulate significantly In aquatic organisms.
Studies concerning the pharmacoklnetlcs of glycldaldehyde were not
located In the literature; however, some of Us biological properties can be
Inferred from Us chemical structure. As a member of the epoxlde class,
glycldaldehyde 1s considered to be an alkylatlng agent with added reactivity
because they are In the carbonyl group (Ehrenberg and Hussaln, 1981). In
low pH solutions (such as 1n the stomach), glycldaldehyde presumably
undergoes a rapid acid-catalyzed hydrolysis, which could explain the lack of
carcinogenic effect when given orally to rats (Van Duuren et al., 1966)
(Section 6.2.).
Data regarding the systemic toxldty of glycldaldehyde are limited to
the subchronlc Inhalation study (rats) and several parenteral administra-
tion studies (rabbits and dogs), all reported by Hlne et al. (1961). In the
Inhalation study, rabbits were exposed to vapors of glycldaldehyde 4
hours/day, 5 days/week for 12 weeks. The concentrations used were 0, 10,
20, 40 and 80 ppm of glycldaldehyde. A dose-related decrease In body weight
was observed at >20 ppm. Autopsies revealed no gross abnormalHes other
than a dose-related depletion of body fat. A treatment-related decrease In
marrow cells was also noticed at 80 ppm. Changes In some hematologlcal
parameters are difficult to assess because of Incomplete reporting of the
data. There were no adverse compound-related effects at 10 ppm.
-------
Single Intravenous Injections of glycldaldehyde In rabbits at >25 mg/kg
produced general signs of parasympathetlc stimulation. No significant
hematologlcal effects were seen (H1ne et al., 1961). Repeated Intravenous
Injections of glycldaldehyde at 25 mg/kg led to a decrease 1n the leukocyte
count In rabbits, but not In dogs (Hlne et al., 1961).
A dose-related Irritation of the respiratory tract was observed In human
volunteers exposed for 5 minutes to vapors of glycldaldehyde at >1 ppm (Nine
et al., 1961). Effects on the central nervous system were limited to mild
to moderate headaches.
Data regarding the carclnogenlclty of Inhaled glycldaldehyde are not
available. Glycldaldehyde was not carcinogenic when administered by gavage
to rats In single weekly doses of 33 mg for 70 weeks (Van Duuren et al.,
1966). Skin painting of a solution of 3% glycldaldehyde 1n benzene, 3 times
weekly for life, resulted 1n an Incidence of 27% local tumors In mice (Van
Duuren et al., 1965). When the same protocol was used but glycldaldehyde
was applied as a 10% solution In acetone, the Incidence of local tumors was
only 7% (Van Duuren et al., 1967a). In both cases, the solvents alone did
not Induce tumors. Moreover, positive controls receiving d1benz[a,h]anthra-
cene In either benzene or acetone had approximately the same Incidence of
tumors (77% In benzene, 80% 1n acetone), Indicating the significance of the
solvent In the dermal carcinogenic properties of glycldaldehyde.
Subcutaneous Injections of 0.1 or 3.3 mg of glycldaldehyde 1n trycap-
rlUn once weekly 1n mice Induced a 6 and 23% Incidence, respectively, of
malignant tumors at the site of Injection (Van Duuren et al., 1966). In
rats, subcutaneous Injections of 1 or 33 mg of glycldaldehyde 1n trycaprllln
produced Incidences of 2 and 25% of local malignancies, respectively (Van
Duuren et al., 1966, 1967b).
v1
-------
The overall evidence Indicates that glycldaldehyde has genotoxlc
properties. Studies on reverse mutation In Salmonella typhlmuMum (McCann
et al., 1975; Rosencranz and Lelfer, 1980; Simmon, 1979a; Simmon et al.,
1979; Hade et al., 1979) and Klebslella pneumonlae (Voogd et al., 1981) gave
positive results. The DNA repair assay was positive In EscheMchla coll
(Fluck et al., 1976; Rosencranz and Lelfer, 1980) and Saccharomyces
cerevlslae (Simmon, 1979b). Glycldaldehyde was mutagenlc In mammalian cell
systems such as Syrian hamster embryo cells and the mouse lymphoma cell
preparation (Amacher and Turner, 1982; Dunkel et al., 1981; Plenta, 1980),
as well as In Drosophlla melanogaster (Knaap et al., 1982).
No reports are available regarding the teratogenlc or other reproductive
effects of glycldaldehyde.
Although there were no human data, animal data were sufficient to
suspect that glycldaldehyde may be a human carcinogen, and the compound was
assigned to EPA Group B2. Data were Insufficient, however, for quantitative
estimation of cancer potency for either oral or Inhalation exposure. An RfD
of 0.01 mg/m3 was derived for subchronlc Inhalation exposure to glycld-
aldehyde from the NOAEL of 10 ppm (29 mg/m3) 1n the 12-week Intermittent
exposure study by H1ne et al. (1961). An RfD of 0.001 mg/m3 was derived
for chronic Inhalation exposure by application of an uncertainty factor of
10 to the subchronlc Inhalation RfD of 0.01 mg/m3.
An equivalent Ingested dose of 1.1 mg/kg/day was estimated from the
NOAEL of 29 mg/m3 1n the subchronlc Inhalation study using rats by Mine et
al. (1961). Application of an uncertainty factor of 300 yielded an RfD of
4.0xlO~3 mg/kg/day for subchronlc oral exposure to glycldaldehyde.
Application of an additional uncertainty factor of 10 yielded an RfD of
4.0xlO~4 mg/kg/day for chronic oral exposure.
-------
An RQ of 100 pounds was derived for the chronic toxldty of glyddalde-
hyde based on Increased mortality 1n the subchronlc Inhalation study by H1ne
et al. (1961). Data were Insufficient for derivation of a cancer-based RQ.
-------
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 2
2. ENVIRONMENTAL FATE AND TRANSPORT 3
2.1. AIR 3
2.1.1. Reaction with Hydroxyl Radicals 3
2.1.2. Physical Removal Processes . . . 3
2.2. WATER 3
2.2.1. Hydrolysis 3
2.2.2. Oxidation 4
2.2.3. Photolysis 4
2.2.4. M1crob1al Degradation 4
2.2.5. Volatilization 4
2.2.6. Adsorption 4
2.3. SOIL 4
2.3.1. Degradation 4
2.3.2. Adsorption 5
2.3.3. Volatilization 5
2.4. SUMMARY 5
3. EXPOSURE 7
4. ENVIRONMENTAL TOXICOLOGY. . . 8
4.1. AQUATIC TOXICOLOGY 8
4.1.1. Acute Toxic Effects on Fauna 8
4.1.2. Chronic Effects on Fauna 8
4.1.3. Effects on Flora 8
4.1.4. Effects on Bacteria 8
4.2. TERRESTRIAL TOXICOLOGY 9
4.2.1. Effects on Fauna 9
4.2.2. Effects on Flora 9
4.3. FIELD STUDIES 9
4.4. AQUATIC RISK ASSESSMENT 9
4.5. SUMMARY 9
1x
-------
TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETCS 10
5.1. ABSORPTION 10
5.2. DISTRIBUTION 10
5.3. METABOLISM 10
5.4. EXCRETION 11
5.5. SUMMARY 11
6. EFFECTS 12
6.1. SYSTEMIC TOXICITY 12
6.1.1. Inhalation Exposure 12
6.1.2. Oral Exposure 13
6.1.3. Other Relevant Information 13
6.2. CARCINOGENICITY 17
6.2.1. Inhalation 17
6.2.2. Oral 17
6.2.3. Other Relevant Information 17
6.3. MUTAGENICITY 21
6.4. TERATOGENICITY 24
6.5. OTHER REPRODUCTIVE EFFECTS 24
6.6. SUMMARY 24
7. EXISTING GUIDELINES AND STANDARDS -. 27
7.1. HUMAN 27
7.2. AQUATIC 27
8. RISK ASSESSMENT 28
8.1. CARCINOGENICITY 28
8.1.1. Inhalation 28
8.1.2. Oral 28
8.1.3. Other Routes 28
8.1.4. Weight of Evidence 29
8.1.5. Quantitative Risk Estimates 29
8.2. SYSTEMIC TOXICITY 30
8.2.1. Inhalation Exposure 30
8.2.2. Oral Exposure 31
-------
TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 33
9.1. BASED ON SYSTEMIC TOXICITY 33
9.2. BASED ON CARCINOGENICITY 35
10. REFERENCES 39
APPENDIX A: LITERATURE SEARCHED 48
APPENDIX B: SUMMARY TABLE FOR GLYCIDALDEHYDE 51
APPENDIX C: DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
FOR EXPOSURE TO GLYCIDALDEHYDE 52
x1
-------
LIST OF TABLES
No. Title Page
6-1 Range-Finding Toxldty Data on Glycldaldehyde 14
6-2 Incidence of Benign and Malignant Tumors 1n Animals
Exposed to Glycldaldehyde 20
6-3 Mutagenlclty Testing of Glycldaldehyde 22
9-1 Inhalation Toxldty for Glycldaldehyde Using 10 Hale
Long-Evans Rats 34
9-2 Inhalation Composite Scores for Glycldaldehyde
Using the Rat 36
9-3 Glycldaldehyde: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 37
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AEL Adverse effect level
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
CS Composite score
DNA Deoxyrlbonuclelc add
PEL Frank effect level
HEC Human equivalent concentration
Koc Soil sorptlon coefficient
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% 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
.PMN Polymorphonuclear cells
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
v/v Volume per volume
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Glycldaldehyde 1s currently referred to as oxlranecarboxaldehyde by CAS.
Other synonyms for this compound are eplhydrlnaldehyde, glycldal, glyddyl-
aldehyde and 2,3-epOxypropanal (SANSS, 1988). The structure, CAS Registry
number, empirical formula and molecular weight are as follows:
0 H
/ \ /
CH2-CH-C=0
Molecular weight: 72.1
Empirical formula: C3H4°2
CAS Registry number: 765-34-4
1.2. PHYSICAL AND CHEMICAL PROPERTIES
At room temperature, glycldaldehyde 1s a colorless liquid with a
pungent, aldehyde-like odor (H1ne et al., 1981). It Is completely soluble
1n most common solvents and 1s Insoluble 1n petroleum ether (H1ne et al.,
1981). Both the aldehyde and epoxlde group of glycldaldehyde are reactive
(IARC, 1976). Selected physical and chemical properties are as follows:
Melting point: -62°C Dean, 1985
Boiling point: 112-3°C at 760 mm Dean, 1985
Vapor pressure at 25°C: 27 mm Hg (estimated) U.S. EPA, 1987a
Water solubility at 25°C: mlsdble IARC, 1976
Log Kow: -0.73 (estimated) U.S. EPA, 1987b
Specific gravity, 20/4°C: 1.1403 IARC, 1976
Flashpoint, Tag open cup: 88°F H1ne et al., 1981
Air conversion factors 1 ppm = 2.94 mg/m3 H1ne et al., 1981
at 25°C: 1 mg/m3 = 0.339 ppm H1ne et al., 1981
0137d -1- 04/13/89
-------
1.3. PRODUCTION DATA
According to IARC (1976), glyddaldehyde can be prepared by the reaction
of acroleln with hydrogen peroxide or sodium hypochlorHe; however, It has
never been commercially produced or used 1n the United States.
1.4. USE DATA
This compound may be used as a chemical Intermediate 1n the manufacture
of glycerine, as a cross-Unking agent for textile treatment, leather
tanning and protein 1nsolub1l1zat1on, as an antiviral agent In Immune serums
for foot-and-mouth virus, and as a vapor phase disinfectant (IARC, 1976;
H1ne et al., 1981).
1.5. SUMMARY
Glyddaldehyde (CAS number 765-34-4) Is currently referred to as
oxlranecarboxaldehyde by CAS (SANSS, 1988). At room temperature, this
compound Is a colorless liquid with a pungent, aldehyde-like odor (Mine et
al., 1981). It Is mlsclble 1n water and most common organic solvents. It
appears that glyddaldehyde has never been commercially produced or used In
the United States. (IARC, 1976).
0137d -2- 04/13/89
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data regarding the environmental fate and transport of glydd-
aldehyde were located 1n the available literature. When possible, predic-
tions regarding environmental fate and transport were derived from physical
properties or molecular structure.
2.1. AIR
Based on an estimated vapor pressure of 27 mm Hg at 25°C (U.S. EPA,
1987a), glycldaldehyde Is expected to exist almost entirely In the vapor
phase 1n the atmosphere (E1senre1ch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson
(1987), the rate constant for the reaction of glycldaldehyde vapor with
photochemically generated hydroxyl radicals 1n the atmosphere has been
estimated to be 21.3xlO~12 cm3/molecule-sec at 25°C. Assuming an
average ambient hydroxyl radical concentration of 5xl03 molecules/cm3
(Atkinson, 1985), the hydroxyl reaction half-life has been estimated to be
18 hours.
2.1.2. Physical Removal Processes. Based on the water solubility of
glycldaldehyde, 1t appears that this compound would be highly susceptible to
removal from the atmosphere by wet deposition.
2.2. MATER
2.2.1. Hydrolysis. Based on Us molecular structure, glycldaldehyde
would probably be susceptible to chemical hydrolysis under environmental
conditions (Harris, 1982). It 1s speculated that 1t would hydrolyze at a
slightly faster rate than glyddol, a structurally slmlHar compound. The
hydrolytlc half-life for glyddol 1n water at neutral pH and at 25°C Is -28
days (Mabey and Mill, 1978). Hydrolysis Is expected to proceed faster under
addle conditions.
0137d -3- 04/13/89
-------
2.2.2. Oxidation. Glycldaldehyde 1s not expected to undergo significant
chemical oxidation with free radicals present 1n most natural waters (Jaber
et al., 1984).
2.2.3. Photolysis. Data regarding photolysis of glyddaldehyde 1n water
were not located 1n the available literature cited 1n Appendix A.
2.2.4. M1crob1al Degradation. Data regarding blodegradatlon of glydd-
aldehyde In water were not located In the available literature cited In
Appendix A.
2.2.5. Volatilization. Using the H1ne and Mookerjee (1975) method of
bond contributions to Intrinsic hydrophlllc character, the Henry's Law
constant for glyddaldehyde has been estimated to be S.llxlO"7
atm-mVmol at 25°C. Based on this value of Henry's Law constant and
following the method of Thomas (1982), the volatilization half-life from a
river 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec has been
estimated to be 61 days. This value suggests that volatilization from
surface water would be a relatively minor loss mechanism.
2.2.6. Adsorption. Experimental data regarding adsorption of glydd-
aldehyde to suspended solids and sediments 1n water were not located 1n the
available literature cited In Appendix A; however, the low log KQW value
and the complete water solubility of this compound suggest that adsorption
to sediments and suspended solids 1n water would not be a significant fate
process.
2.3. SOIL
2.3.1. Degradation. The molecular structure of glyddaldehyde suggests
that H would be susceptible to chemical hydrolysis 1n moist soil (Harris,
1982). Since the estimated hydrolytlc half-life of this compound In water
at pH 7 Is <28 days (see Section 2.2.1.), 1t 1s expected that H would have
0137d -4- 03/21/89
-------
a similar half-life 1n neutral soils. Data regarding other degradation
processes 1n soil were not located 1n the available literature cited In
Appendix A.
2.3.2. Adsorption. A K of 10 was estimated for glycldaldehyde using
a log K of -0.73 and the following recommended linear regression equa-
tion (U.S. EPA, 1987b; Lyman, 1982): log KQC = 0.544 log KQW + 1.377.
This K value, as well as the complete water solubility of glycldaldehyde
(IARC, 1976), suggests that this compound would be very mobile In moist soil
and may percolate Into groundwater In the absence of fairly rapid degrada-
tlve processes In soil (Swann et al., 1983). In view of the polarity of
this compound, apparently there Is a possibility that glycldaldehyde may
adsorb to partlculate matter carrying an electrostatic charge; however,
there 1s no evidence to support this supposition.
2.3.3. Volatilization. An estimated vapor pressure of 27 mm Hg at 25°C
(U.S. EPA, 1987a) suggests that glycldaldehyde would volatilize fairly
rapidly from dry soil surfaces. Rapid Infiltration of glycldaldehyde Into
soil and a relatively low value for Henry's Law constant suggests that
volatilization from moist soil surfaces would be an Insignificant fate
process.
2.4. SUMMARY
If released to the atmosphere, glycldaldehyde 1s expected to exist
primarily In the vapor phase. The dominant removal mechanism appears to be
reaction with photochemically generated hydroxyl radicals (estimated half-
life of 18 hours). Glycldaldehyde may also be removed from the atmosphere
by wet deposition. If released to water, glycldaldehyde would be suscept-
ible to chemical hydrolysis. Its hydrolytlc half-life In water at neutral
pH and 25°C 1s predicted to be <28 days. Reaction with singlet oxygen or
0137d -5- 04/13/89
-------
alky! peroxy radicals, adsorption to suspended solids and sediments, and
volatilization are not expected to be significant fate processes 1n natural
water. If released to moist soil, glyddaldehyde would be susceptible to
chemical hydrolysis. In the absence of fairly rapid degradatlve processes,
glyddaldehyde has the potential to be quite mobile and may leach Into
groundwater. Volatilization from moist soil surfaces Is not expected to be
an Important fate process. If released to dry soil, glyddaldehyde Is
expected to volatilize fairly rapidly from the soil surface.
0137d -6- 03/21/89
-------
3. EXPOSURE
Pertinent data regarding levels of glyddaldehyde In ambient air, water
or food were not located In the available literature dted 1n Appendix A.
Similarly, data pertinent to dermal exposure are not available. Glydd-
aldehyde occurs In sunflower oil, and Us concentration Increases with that
of peroxides during storage, causing a deterioration of flavor (IARC,
1976). Glyddaldehyde has been detected In randd samples of commercial
lard (IARC, 1976).
0137d -7- 04/13/89
-------
4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Pertinent data regarding the
effects of acute exposure of aquatic fauna to glyddaldehyde were not
located In the available literature dted 1n Appendix A.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY — Pertinent data regarding the effects of chronic
exposure of aquatic fauna to glyddaldehyde were not located In the
available literature dted In Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — No measured steady-state
BCF value for glyddaldehyde was found In the literature. Based on the
regression equation, log BCF = 0.76 log K - 0.23 (Lyman et al., 1982)
and a log K value of -0.73 (see Section 1.2.), a BCF value of 0.16 1s
estimated for this compound. This value suggests that glyddaldehyde should
not bloaccumulate significantly 1n aquatic organisms.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY — Pertinent data regarding the toxic effects of
exposure of aquatic flora to glyddaldehyde were not located In the
available literature cited In Appendix A.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloconcen-
tratlon potential of glyddaldehyde In aquatic flora were not located 1n the
available literature dted In Appendix A.
4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to glyddaldehyde were not located 1n the
available literature cited 1n Appendix A.
0137d -8- 03/21/89
-------
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Pertinent data regarding the effects of
exposure of terrestrial fauna to glyddaldehyde were not located 1n the
available literature dted 1n Appendix A.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to glycldaldehyde were not located In the
available literature cited 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of glycldaldehyde on flora and
fauna 1n the field were not located In the available literature dted In
Appendix A.
4.4. AQUATIC RISK ASSESSMENT
No data were available regarding the effects of exposure of aquatic
fauna and flora to glycldaldehyde, preventing the development of freshwater
and saltwater criteria by the method of U.S. EPA/OURS (1986).
4.5. SUMMARY
A calculated BCF value of 0.16 for glycldaldehyde suggests that
glycldaldehyde will not bloaccumulate significantly In aquatic organisms.
0137d -9- 04/13/89
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
LUtle Information 1s available concerning the absorption of glydd-
aldehyde. LD5Q or LC,Q values, however, have been determined In rats
and rabbits after administration of glyddaldehyde orally, by Inhalation,
and by topical application to the skin, which Indicates that absorption can
occur by these three routes (Hlne et al., 1961).
5.2. DISTRIBUTION
In a study by Nine et al. (1961), rats exposed repeatedly to vapors of
glyddaldehyde showed adverse effects 1n the spleen, liver, kidney, adrenals
and bone marrow, Indicating possible distribution of the chemical (or Us
metabolites) Into those organs and tissues.
5.3. METABOLISM
Pertinent data regarding the metabolism of glyddaldehyde were not
located In the available literature cited 1n Appendix A. Glyddaldehyde Is,
however, expected to be a highly reactive compound because of Us blfunc-
tlonalUy (I.e., the presence of epoxlde and carbonyl groups) (Van Duuren et
al., 1963). When Ingested, glyddaldehyde Is "likely to be hydrolyzed
rapidly 1n the low pH gastric environment (Van Duuren et al., 1966);
however, quantitative data were not located. li± vivo, epoxldes can be
metabolized to dlhydrodlols by epoxlde hydratases or transformed Into more
excretable products by conjugation via glutath1one-S-transferase (Manson,
1980). Manson (1980), however, reported that small, highly reactive
molecules such as glyddaldehyde are most likely disposed nonenzymatlcally,
since they are not good substrates for epoxy hydratase. Glyddaldehyde has
been shown to react with guanoslne, one of the purlne bases present 1n DNA,
to form adducts that may alter the genetic Integrity of the DNA molecule
0137d -10- 03/21/89
-------
(Goldschmldt et al., 1968; Van Duuren and Loewengart, 1977; Na1r and Turner,
1984; Goldlng et al., 1986; Bleasdale et al., 1986).
5.4. EXCRETION
Data regarding the excretion of glycldaldehyde were not located 1n the
available literature cited 1n Appendix A.
5.5. SUMMARY
Studies concerning the pharmacoklnetlcs of glycldaldehyde were not
located 1n the literature; however, some of Us biological properties can be
Inferred from Us chemical structure. As a member of the epoxlde class,
glycldaldehyde Is considered to be an alkylatlng agent with added reactivity
because they are 1n the carbonyl group (Ehrenberg and Hussaln, 1981). In
low pH solutions (such as In the stomach), glycldaldehyde presumably
undergoes a rapid acid-catalyzed hydrolysis, which could explain the lack of
carcinogenic effect when given orally to rats (Van Duuren et al., 1966)
(Section 6.2.).
0137d -11- 04/13/89
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC — The only subchronlc Inhalation study Identi-
fied from the literature Is that of H1ne et al. (1961), In which adult male
Long-Evans rats (156-200 g) were exposed (method not described) to vapors of
glyddaldehyde 4 hours/day, 5 days/week for 12 weeks. The concentrations
used were 10, 20, 40 and 80 ppm of glyddaldehyde. Each group was composed
of 10 rats. A control group was exposed to uncontamlnated air. Observation
and gross and microscopic examination of tissues and organs of rats exposed
to 10 ppm of glyddaldehyde revealed no abnormalities. In the group exposed
to 20 ppm of glyddaldehyde, there was one death after 34 exposures; this
death was attributed to pneumonia. Rats 1n this group showed a significant
(p<0.05) reduction 1n the rate of weight gain. Also, one case of enlarged
adrenals and another case of hydropic renal pelvis were reported In the 20
ppm group. Two deaths were reported at the 40 ppm level after 25 and 26
exposures. H1stolog1cal examination of these two animals revealed pneumonia
and depletion of body fat. The survivors In the 40 ppm group showed a
significant (p<0.05) retardation In the rate of weight gain, but no gross
morphological changes other than a significant reduction 1n spleen weight.
In the group exposed to 80 ppm glyddaldehyde, 80% mortality occurred after
4 days of exposure. Rats In this group had no gross abnormalities other
than severe depletion of body fat. H1stolog1cal examination of the tissues
showed abscesses In the spleen, focal necrosis of the liver and focal
degeneration of the proximal and distal tubules of the kidney. The two
survivors sacrificed on the fifth day showed low leukocyte counts. A
0137d -12- 04/13/89
-------
significant (p<0.05) Increase In the testes/body weight ratio was observed
1n the 20 and 40 ppm groups, but this could have been due to the retardation
1n the rate of body weight gain (H1ne et al., 1961). Rats exposed to 10 and
40 ppm of glyddaldehyde had a significant (p<0.05) Increase 1n the
thymus/body weight ratio. The significance of the latter 1s unclear, since
rats 1n the 20 ppm group did not show this effect. Hematologlcal profiles
among the survivors In all groups showed that glyddaldehyde had no effect
on the number, distribution or morphology of the leukocytes, on the
erythocyte count, or on hemoglobin concentration. Rats In the 20 and 40 ppm
groups had a significant (p<0.001) decrease In the number of nucleated cells
of the bone marrow.
6.1.1.2. CHRONIC — Pertinent data regarding the systemic toxldty of
chronic Inhalation exposure to glyddaldehyde were not located 1n the
available literature cited In Appendix A.*
6.1.2. Oral Exposure. Pertinent data regarding the systemic toxldty of
subchronlc or chronic oral exposure to glyddaldehyde were not located In
the available literature cited 1n Appendix A.
6.1.3. Other Relevant Information. H1ne et al. (1961) presented acute
oral, dermal and Inhalation toxldty for glyddaldehyde obtained as
unpublished data from Shell Development Co. These data are summarized In
Table 6-1. The oral LD5Q In rats and the dermal LD5_ In rabbits were
similar, at 232 and 249 mg/kg, respectively.
H1ne et al. (1961) studied the effect of single Intravenous Injections
of glyddaldehyde (probably In saline) on the hematopoletlc system of
rabbits. Groups of three male New Zealand rabbits (2.9-3.4 kg) were used.
A positive control group was Injected with mechlorethamlne hydrochlorlde to
Induce effects on the hematopoletlc system. No untreated control group was
0137d -13- 04/13/89
-------
o
CO
-o
Q.
TABLE 6-1
Range-Finding Toxlclty Data on Glycldaldehyde*
Route Species
Intragastrlc rat
Percutaneous rabbit
Respiratory rat
Dose
(my /kg or ppm)
1
50
500
5.000
15.000
44
350
2.820
127
174
275
430
saturated
Mortality Ratio
0/6
0/6
5/6
6/6
6/6
0/3
2/3
3/3
0/6
0/6
5/6
5/6
6/6
Time of Death
6 hours - 4 days
45 minutes - 6 hours
10-15 minutes
10-24 hours
2-4 hours
9-32 hours
j
7-48 hours
65-85 minutes
LD5Q or LC50
(my/kg or ppm)
232
(108-500)
249
(195-318)
252
(200-316)
'Source: Hlne et al.. 1961
o
co
CO
to
-------
used, but blood was drawn before treatment to establish pretreatment
hematologlc values. The first administration of 100 mg/kg of glycldaldehyde
caused an Immediate lethal seizure In a rabbit; consequently, this dose was
not repeated. Rabbits that were pretreated with pentobarbltal to prevent
convulsions and received a dose of 50 mg/kg of glycldaldehyde showed signs
of parasympathetlc stimulation lasting ~3 hours. The only effect seen with
a dose of 25 mg/kg was lacrlmatlon In 1/3 rabbits. Several hematologlcal
parameters were determined at 0, 3, 7, 10 and 21 days after treatment In the
groups given doses of 25 and 50 mg/kg glycldaldehyde. No significant
changes were seen regarding leukocyte and erythrocyte counts, concentration
of hemoglobin or percentage of PMN. The report of the hematologlcal
parameters 1s of questionable significance, since the normal range values
for rabbits were not given. Positive control rabbits showed less pronounced
parasympathetlc effects, but showed marked effects on the hematologlcal
system.
The effects of repeated Intravenous Injections of glycldaldehyde In male
New Zealand rabbits was also studied by H1ne et al. (1961). Glycldaldehyde
was administered 1n four weekly Injections of 25 mg/kg (vehicle not stated)
to three male New Zealand rabbits (3-3.4 kg), which were held for 3 addi-
tional weeks before killing. Although not stated specifically by the
authors, . 1t appears that the rabbits may have been treated with sodium
pentobarbltal prior to glycldaldehyde administration to suppress
convulsions. There 1s no mention of any control barbltuate group being
used. Glycldaldehyde did not produce signs of chronic Intoxication. One
animal died of barbltuate overdose after the sixth Injection and displayed
on examination tubular necrosis of the testes, and one of the two killed
after 6 weeks had focal chronic cholangltls. No other gross or microscopic
0137d -15- 04/13/89
-------
abnormalities were found 1n the viscera. After 3 weeks of treatment, a
decrease 1n the leukocyte count was observed, which the authors attributed
to glyddaldehyde; the erythrocyte count and hemoglobin concentration
remained unchanged. The significance of these results 1s questionable,
however, since there 1s no report of normal control values, and the
dispersion of the experimental values obtained after treatment 1s not given.
H1ne et al. (1961) administered four weekly Intravenous Injections of 25
mg/kg glyddaldehyde (25% 1n propylene glycol) to two mongrel dogs (sex not
specified), and observed them for 7 weeks. No gross morphological altera-
tions were seen upon necropsy In either dog; however, one exhibited pyelo-
nephritis with acute and chronic changes. No significant hematologlcal
effects were observed.
H1ne et al. (1961) also conducted a sensory threshold study on volun-
teers exposed 1n an Inhalation chamber to glyddaldehyde vapors. Each group
(8-12 Individuals) was exposed to 1, 2.5, 5, 10 or 20 ppm glyddaldehyde 1n
the air for 5 minutes. Responses were recorded at Intervals of 1 minute.
All subjects could recognize the odor of glyddaldehyde even at the lowest
concentration used. The degree of eye and nose Irritation Increased as the
concentration of glyddaldehyde Increased, becoming severe at 20 ppm.
Sneezing and soreness of the throat and nasopharynx were reported at 5 ppm.
Severe pulmonary discomfort became evident at the 10 ppm level. Little
effect on the central nervous system (mild to moderate headache) was seen
even at the highest concentration (20 ppm).
H1ne et al. (1981) also reported that exposure to humans resulted 1n
marked skin Irritation with retarded healing and bronzing of the skin.
Sensltlzatlon was also reported 1n several cases.
Glyddaldehyde was found to Inactivate spores of Bacillus globlgll
completely In <4 hours when the spores were exposed to a concentration of
0137d -16- 04/13/89
-------
4-5 mg of glyddaldehyde/a of air at 28°C and relative humidities of
83-86% (Dawson, 1962). In addition, Dawson (1962) demonstrated that there
was a 99.99% reduction 1n the Initial population of Staphylococcus aureus In
2.5 minutes after exposure to 3-4 mg of glyddaldehyde/8. of air at 28°C
and a relative humidity of 75%.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled glyddaldehyde were not located In the available literature cited In
Appendix A.
6.2.2. Oral. Van Duuren et al. (1966) provide the only Investigation of
orally administered glycldaldehydes carcinogenic effects. Five female
Sprague-Dawley rats, age 51-57 days and weighing 120-125 g, were given 33 mg
glyddaldehyde (purity not reported) 1n 0.5 ml of trlcaprylln by gastric
Intubation once weekly for 70 -weeks. The rats were examined for palpable
tumors on a regular basis and a complete autopsy was performed after
sacrifice or natural death. Concurrent controls receiving trlcaprylln only
were used. Glyddaldehyde did. not Induce gastric tumors or tumors at other
sites. In a group of six female rats that received a single IntragastMc
treatment of 50 mg of 7,l2-d1methylbenz[a]anthracene as a positive control,
two f Ibroadenomas, two mammary adenocardnomas and one lymphoma were
observed. No tumors were seen 1n rats receiving trlcaprylln alone.
6.2.3. Other Relevant Information. Van Duuren et al. (1965) tested the
carcinogenic properties of glyddaldehyde by skin application to thirty,
8-week-old female Swiss mice. The backs of the mice were clipped free of
hair and ~100 mg of a solution of 3% glyddaldehyde (purity not reported) 1n
benzene was applied with a brush 3 times weekly, for life. A positive
0137d -17- 04/13/89
-------
control group of 30 female mice received an application of a 0.2% solution
of d1benz[a,h]anthracene In benzene. Benzene alone, or no solution at all
was applied to the skin of two negative control groups of 60 female mice.
Individual body weights were monitored regularly. Paplllomas that persisted
>4 weeks and then regressed were Included 1n the cumulative number of
tumors. All tumors were examined microscopically after the mice died. The
median survival time was 496 days 1n the glyddaldehyde group, 498 days In
the benzene group, 441 days 1n the untreated group and 313 days In the
positive control group. The Incidence of skin carcinomas was 27% In the
glyddaldehyde group and 77% 1n the positive control group. No carcinomas
were observed In the negative control groups. Other sites of tumor
Induction were not monitored. Glyddaldehyde Induced hair loss and crusting
persisting for >3 months, recurring two or more times during the experiment.
Using the same protocol described above. Van Duuren et al. (1967a)
applied glyddaldehyde (purity not reported) as a 10% solution 1n acetone
thrice weekly at the rate of -100 mg/appHcatlon to the skin of 41 female
Swiss mice. Paplllomas developed In 6/41 mice and malignant skin tumors
developed 1n 3/6 mice with paplllomas, whereas the Incidence of malignant
tumors 1n positive controls using acetone as solvent was 80%. Data were not
presented for the Incidence of tumors In negative controls. In addition,
glyddaldehyde dissolved 1n acetone was less Irritating to the skin than
glyddaldehyde dissolved 1n benzene.
The carcinogenic effects of subcutaneous Injections of glyddaldehyde 1n
mice and rats were also studied by Van Duuren et al. (1966). Eight-week-old
female ICR/Ha Swiss mice and 6-week-old female Eastern Sprague-Dawley rats
were used. Subcutaneous Injections were given once weekly for life 1n the
left axillary area. Two groups of mice (50/group) received 0.1 or 3.3 mg of
0137d -18- 04/13/89
-------
glycldaldehyde In 0.05 mil of tricaprylln. Two additional groups
(50/group) received the solvent alone or no treatment at all. Groups of 50
rats received either 1 mg of glycldaldehyde In 0.1 ml of tricaprylln, the
solvent alone, or no treatment at all. Positive controls were maintained 1n
both rats and mice by Injection of 7,l2-d1methylbenz[a]anthracene. The
condition of the animals was monitored regularly throughout the experiment.
A complete autopsy was performed at the time of death. A 6% Incidence of
malignant tumors developed at the Injection site In mice receiving the
lowest dose of glycldaldehyde. In those given the highest dose, the
Incidence was 23%. No tumors were seen at the site of Injection In control
animals. Glycldaldehyde produced only one malignant tumor at the Injection
site In rats. The Incidence of tumors at distant sites In both rats and
mice was not significantly different than the Incidence seen In
solvent-treated or untreated animals. In a follow-up study, Van Duuren et
al. (1967b) reported that subcutaneous Injection of 33 mg of glycldaldehyde
1n rats Induced a 25% Incidence of local sarcomas. The protocol used was
the same as that of Van Duuren et al. (1966), except for the dosage used.
Shamberger et al. (1974) reported that glycldaldehyde had Initiator
properties 1n female Swiss mice. The authors applied 2.5 mg of glycld-
aldehyde In 0.25 mi of acetone once to the shaved backs of groups of
thirty 55-week-old mice. Three weeks after Initiation, 0.1% croton oil In
acetone was applied as a promoter for 5 days/week for 27 weeks. By week 30,
glycldaldehyde-treated mice had an Incidence of 42% of skin tumors; however,
the tumor Incidences for acetone treated and untreated animals were not
provided (Table 6-2).
0137d -19- 08/07/89
-------
o
CJ
-J
o.
TABLE 6-2
Incidence of Benign and Malignant Tumors In Animals Exposed to Glyddaldehyde
o
o
GO
-X
O
CO
10
Species/Strain
Rats/Sprague-
Dawley
Mice/Swiss
H1ce/ICR/Ha
aTumor Incidence
bTumor(s) assumed
cThree of the six
Exposure
33 mg 1n 0.5 ml
of trlcaprylln
1 mg 1n 0.1 ml
of trlcaprylln
33 mg 1n 0.1 ml
of trlcaprylln
-100 mg of 3%
glyddaldehyde
-100 mg as a 10X
solution 1n acetone
0.1 mg 1n 0.05 ml
of trlcaprylln
3.3 mg 1n 0.05 ml
of trlcaprylln
Route
gavage
subcutaneous
Injection
subcutaneous
Injection
topical
application
topical
application
subcutaneous
Injection
subcutaneous
Injection
= number of animals with tumors/number
to occur on skin or
Observed
Tumor Type
none
benign
malignant
benign
malignant
benign
malignant
benign
malignant
benign
malignant
benign
malignant
of animals
Organ
NA
NA h
sk1nb
NA
sk1nb
skin
skin
sk1nb
skin
NA
skin
sk1nb
sk1nb
tested
Tumor
Incidence3
0/5
0/50
1/50
0/20
5/20
8/30
8/30
6/41
3/41
0/50
3/50
1/30
7/30
(OX)
(OX)
(2X)
(OX)
(25X)
(27X)
(27X)
(15X)
(7X)C
(OX)
(6X)
(3X)
(23X)
Reference
Van Duuren
et al., 1966
Van Duuren
et al.. 1966
Van Duuren
et al., 1967b
Van Duuren
et al., 1965
Van Duuren
et al., 1967a
Van Duuren
et al., 1966
Van Duuren
et al., 1966
within subcutaneous tissue
mice with benign tumors (paplllomas)
developed malignant
tumors.
NA = Not applicable
-------
6.3. MUTAGENICITY
Data regarding the mutagenlclty testing of glyddaldehyde are presented
1n Table 6-3. Studies of reverse mutation with glyddaldehyde In Salmonella
typhlmurlum In the presence or absence of activating systems gave positive
results 1n strains TA1535 and TA100 (HcCann et al., 1975; Rosencranz and
Lelfer, 1980; Simmon, 1979a; Simmon et al., 1979; Wade et al., 1979), which
are sensitive to base-pair substitutions (Glatz, 1979). Simmons (1979a)
noted that base-pair substitutions are commonly Induced by DNA-alkylat1ng
agents. Glyddaldehyde has been shown to be a DNA-alkylatlng agent, forming
adducts by reacting with guanoslne, a purlne base (see Section 5.3.).
Positive mutagenldty was reported 1n Klebslella pneumonlae (Knaap et al.,
1982; Voogd et al., 1981) using the reverse mutation test. Simmon (1979b)
found glyddaldehyde to be mutagenlc 1n Saccharomyces cerevlslae In the
mltotlc recombination assay and the plate Incorporation technique; however,
the same assay was negative when the 1ntraper1toneal host assay method was
used (Simmon et al., 1979). Glyddaldehyde was mutagenlc In Escherlchla
go 11 as judged by the DNA repair assay (Fluck et al., 1976; Rosencranz and
Lelfer, 1980). Glyddaldehyde was not mutagenlc In mouse lymphoma cells
when tested with the HGPRT-defldent phenotype test (Knaap et al., 1982),
but positive mutagenldty was found In the same Indicator when the forward
mutation assay was used (Amacher and Turner, 1982). Glyddaldehyde was
mutagenlc 1n Syrian hamster embryo cell systems In cell transformation
assays (Dunkel et al., 1981; Plenta, 1980). In addition, glyddaldehyde was
found to be mutagenlc 1n Drosophlla melanogaster as shown by the recessive
lethal test (Knaap et al., 1982).
0137d -21- 08/07/89
-------
TABLE 6-3
Mutagenlclty Testing of Glycldaldehyde
o
co
Q.
1
ro
rvj
i
o
CD
O
-J
V.
CO
Assay
Reverse mutation
Reverse mutation
Reverse mutation
Reverse mutation
Reverse mutation.
host-mediated
Reverse mutation,
host-mediated
Reverse mutation
Fluctuation test,
reverse mutation
ONA repair
DNA repair
Nutations
Indicator/
Organism
Salmonella
typhlmurlum
TA9B
TA100
S. typhlmurlum
TA100, TA1535
S. typhlmurlum
S. typhlmurlum
TA1535
TA1536
TA1537
TA153B
TA98
TA100
S. typhlmurlum
TA1530
TA153B
S. typhlmurlum
TA1535
K. pneumonlae
K. pneumonlae
E. coll
P3478
E. coll
polymerase-
deMdent
Bacterlophage
T4
Compound
and/or
Purity
NR
NR
NR
NR
NR
NR
NR
NR
99X
NR
NR
Application
plate
Incorporation
plate
Incorporation
plate
Incorporation
plate
Incorporation
Intraperltoneal
host assay
Intraperltoneal
host assay
plate
Incorporation
plate
Incorporation
plate .
Incorporation
plate
Incorporation
liquid
Incubation
Concentration Activating
or Dose System
10-200 tig/Plate + (S-9)
20 jig/plate none
1 yl none
10 jig/plate none
456 mg/kg NA
Intramuscular
200 mg/kg single NA
oral dose
0.005-1 mN none
0.01-1 mM none
5-25 pi/plate rat liver
extract
1 nl/plate none
NR none
Response Comment
+ Dose-related response
* In TA100
1
+ NC
* Strains not reported
Dose-related Increase In
* mutagenlcHy with TA1535
| 1n doses 0-20 vg/plate
+ Adult male Swiss-Webster
mice used as hosts
* Adult male Swiss-Webster
mice used as hosts
* Dose-related effect
+ NC
* 1 Response was not dose-
related
* NC
+ Base pair and frame-
shift mutation
Reference
Wade et al..
1979
HcCann et al.,
1975
Rosencranz and
LeUer. 1980
Simmon, 1979a
Simmon et al.,
1979
Simmon et al.,
1979
Voogd et al.,
1981
Knaap et al..
1982
Fluck et al..
1976
Rosenkranz and
Heifer, 1980
Corbett
et al.. 1970
-------
TABLE 6-3 (cont.)
o
to
a.
i
CO
0
CD
^^
^^
O
-J
\
CD
Assay
Nilotic
recombination
Nilotic recombi-
nation, host-
mediated
HGPRT-defldent
phenotype test
Forward mutation
Unscheduled DNA
synthesis
Cell
transformation
Neoplastlc
transformation
Neoplastlc
transformation
Recessive lethal
tesl
NA = Not applicable;
Indicator/
Organism
S. cerevlslae
S. cerevlslae
D3
L5178y mouse
lymphoma cells
mouse lymphoma
L5178/TK
human flbrob-
blasts
Syrian hamster
embryo cell
syslem
Balb/3T3 cells
Syrian hamster
embryo cells
Drosophlla
roelanogester
NC » no comment;
Compound
and/or Application Concentration Activating
Purity or Dose System
NR plate 0.05X v/v S-9
Incorporation none
NR Intraperltoneal 200 mg/kg NA
host assay single oral
dose
NR plate 0.01-0.1 mN none
Incorporation
NR plate 0-50 jig/mi S-9
Incorporation
NR cell culture NR none
NR liquid medium 0.1-100 jig/ml none
NR plate 0.008-1.0 pg/ml none
Incorporation
NR plate 0.1-100 pg/ml none
Incorporation
NR NA 1-50 mN NA
NR = not reported
Response Comment
+ Less recomblnogenlc
+ activity In presence
of S-9
Adult male Swiss-Webster
mice used as hosts
Highly cytotoxU at the
concentration used
* NC
+ Taken from secondary
source
+ NC
+ No clear dose-related
responses
+ No clear dose-related
responses
+ Positive response at
1 >25 mN; glyclaldehyde
was dissolved 1n 0.7%
saline and Injected 1n
the abdomen of male flies
Reference
Simmon, 1979b
Simmon et al.,
1979
Knaap et al..
1982
Amacher and
Turner. 1982
Mitchell.
1976
Plenta. 1980
Dunkel et al..
1981
Dunkel et al.,
1981
Knaap et al..
1982
-------
6.4. TERATOGENICITY
Pertinent data regarding the teratogenldty of glyddaldehyde were not
located 1n the available literature cited 1n Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of glyddaldehyde
were not located 1n the available literature dted 1n Appendix A.
6.6. SUMMARY
Data regarding the systemic toxldty of glyddaldehyde are limited to
the subchronlc Inhalation study using rats and several parenteral
administration studies using rabbits and dogs, all reported by Hlne et al.
(1961). In the Inhalation study, rabbits were exposed to vapors of
glyddaldehyde 4 hours/day, 5 days/week for 12 weeks. The concentrations
used were 0, 10, 20, 40 and 80 ppm of glyddaldehyde. A dose-related
decrease In body weight was observed at >20 ppm. Autopsies revealed no
gross abnormalHes other than a dose-related depletion of body fat. A
treatment-related decrease In marrow cells was also noticed at 80 ppm.
Changes 1n some hematologlcal parameters are difficult to assess because of
Incomplete reporting of the data. There were no adverse compound-related
effects at 10 ppm.
Single Intravenous Injections of glyddaldehyde In rabbits at >25 mg/kg
produced general signs of parasympathetlc stimulation. No significant
hematologlcal effects were seen (H1ne et al., 1961). Repeated Intravenous
Injections of glyddaldehyde at 25 mg/kg led to a decrease In the leukocyte
count In rabbits, but not In dogs (H1ne et al., 1961).
A dose-related Irritation of the respiratory tract was observed In human
volunteers exposed for 5 minutes to vapors of glyddaldehyde at >1 ppm (Nine
et al., 1961). Effects on the central nervous system were limited to mild
to moderate headaches.
0137d -24- 08/07/89
-------
Data regarding the carclnogenlclty of Inhaled glyddaldehyde are not
available. Glyddaldehyde was not carcinogenic when administered by gavage
to rats In single weekly doses of 33 mg for 70 weeks (Van Duuren et al.,
1966). Skin painting of a solution of 3% glyddaldehyde 1n benzene, 3 times
weekly for life, resulted 1n an Incidence of 27% local tumors 1n mice (Van
Duuren et al., 1965). When the same protocol was used but glyddaldehyde
was applied as a 10% solution In acetone, the Incidence of local tumors was
only 7% (Van Duuren et al., 1967a). In both cases, the solvents alone did
not Induce tumors. Moreover, positive controls receiving d1benz[a,h]anthra-
cene 1n either benzene or acetone had approximately the same Incidence of
tumors (77% 1n benzene, 80% In acetone), Indicating the significance of the
solvent 1n the dermal carcinogenic properties of glyddaldehyde.
Subcutaneous Injections of 0.1 or 3.3 mg of glyddaldehyde In trycap-
rlUn once weekly In mice Induced a 6 and 23% Incidence, respectively, of
malignant tumors at the site of Injection (Van Duuren et al., 1966). In
rats, subcutaneous Injections of 1 or 33 mg of glyddaldehyde In trycapMHn
produced Incidences of 2 and 25% of local malignancies, respectively (Van
Duuren et al., 1966, 1967b).
The overall evidence Indicates that glyddaldehyde has genotoxlc prop-
erties. Studies on reverse mutation In Salmonella typh1mur1um (McCann et
al., 1975; Rosencranz and Lelfer, 1980; Simmon, 1979a; Simmon et al., 1979;
Wade et al., 1979) and Klebslella pneumonlae (Voogd et al., 1981) gave
positive results. The DNA repair assay was positive In EscheMchla coll
(Fluck et al., 1976; Rosencranz and Lelfer, 1980) and Saccharomyces
cerevlslae (Simmon, 1979b). Glyddaldehyde was mutagenlc In mammalian cell
systems such as Syrian hamster embryo cells and the mouse lymphoma cell
preparation (Amacher and Turner, 1982; Dunkel et al., 1981; Plenta, 1980),
as well as In Drosophlla melanogaster (Knaap et al., 1982).
0137d -25- 08/07/89
-------
No reports are available regarding the teratogenlc or other reproductive
effects of glyddaldehyde.
0137d -26- 08/07/89
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The U.S. EPA (1987c) has verified an oral RfD of 0.0004 mg/kg/day for
glycldaldehyde based on the rat subchronlc Inhalation study by H1ne et al.
(1961).
Other pertinent guidelines and standards, Including EPA ambient water
and air quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA
tolerances for raw agricultural commodities or foods, and ACGIH, NIOSH or
OSHA occupational exposure limits were not located In the available
literature cited 1n Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from expo-
sure to glycldaldehyde were not located 1n the available literature cited In
Appendix A.
0137d -27- 08/07/89
-------
8. RISK ASSESSMENT
Statements concerning available literature 1n this document refer to
published, quotable sources and are 1n no way meant to Imply that confiden-
tial business Information (CBI), which this document could not address, are
not 1n existence. From examination of the bibliographies of the CBI data,
however, H was determined that CBI data that would alter the approach to
risk assessment or the risk assessment values presented herein do not exist.
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenlcKy of
glycldaldehyde following Inhalation exposure were not located In the
available literature cited 1n Appendix A.
8.1.2. Oral. In a gavage study conducted by Van Duuren et al. (1966),
glycldaldehyde tested negative 1n female Sprague-Dawley rats. The Informa-
tion provided by this study 1s limited, however, since only one dose level
was used, rats were treated once weekly, there were only five rats/group and
only female rats were used.
8.1.3. Other Routes. Topical application of a solution of 3% glycld-
aldehyde In benzene to the skin of 8-week-old female mice for their lifetime
produced a 27% Incidence of skin carcinomas compared with no tumors In
control rats (Van Duuren et al., 1965). Glycldaldehyde applied as a 10%
solution 1n acetone to the skin of mice produced a 7% Incidence of local
tumors (Van Duuren et al. 1967a). In both dermal application studies there
were 8-10 rats per cage; therefore, the rats could have Hcked the solution
from each other's back, contributing to the uncertainty of the dose applied.
A weekly subcutaneous Injection for life of 0.1 or 3.3 mg glycldaldehyde
1n mice produced a dose-related Increase In the Incidence of malignant
0137d -28- 08/07/89
-------
tumors at the Injection site, 6% with the low dose and 23% with the high
dose (Van Duuren et al., 1966). Rats treated once a week with subcutaneous
Injections of 1 or 33 mg of glyddaldehyde for life had 2 and 20%
Incidences, respectively, of malignant tumors at the site of Injection (Van
Duuren et al., 1966, 1967b).
8.1.4. Weight of Evidence. No data were available regarding the cardno-
genlcHy of glyddaldehyde 1n humans. One oral study with rats Indicated no
evidence of a carcinogenic effect; however, only one dose level and only
five animals were tested. In two skin painting studies with either acetone
or benzene as a solvent and In subcutaneous Injection studies at low doses,
exposure to glyddaldehyde produced positive evidence for cardnogenldty In
mice. On the contrary, similar low doses of glyddaldehyde 1n subcutaneous
studies with rats did not show positive evidence of cardnogenldty, yet
higher doses of the compound 1n rats did result 1n a notable occurrence of
malignant tumors. Further suggesting cardnogenlclty, glyddaldehyde was
positive In most genotoxldty tests and predicted to form adducts based upon
structure. Due to positive results with skin painting In two studies with
mice, positive results for site of Injection tumors In mice and rats and
positive results 1n genotoxldty tests, the welght-of-evldence supports that
glyddaldehyde be placed according to the EPA classification scheme In Group
B2: chemicals for which there are no human data, but sufficient animal data
to establish evidence of possible cardnogenldty to humans.
8.1.5. Quantitative Risk Estimates. The lack of suitable Inhalation and
oral cardnogenlclty data precludes the derivation of carcinogenic potency
factors for glyddaldehyde.
0137d -29- 08/07/89
-------
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — The only
subchronlc Inhalation study available from the literature 1s that of H1ne et
al. (1961). In this study, male rats of the Long-Evans strain (10/group)
were exposed to vapors of glycldaldehyde 4 hours/ day, 5 days/week for 12
weeks at concentrations of 0, 10, 20, 40 and 80 ppm. As Indicated In
Section 6.1.1.1., rats exposed to 10 ppm glycldaldehyde (NOAEL) had no gross
or microscopic alterations of tissues and organs. Exposure to >20 ppm
glycldaldehyde Induced a dose-related decrease In body weight gain and a
decrease 1n the number of nucleated bone marrow cells. One case of enlarged
adrenals and another of hydropic renal pelvis were noted 1n the 20 ppm
(LOAEL) group. Two deaths occurred 1n the 40 ppm group, whereas eight rats
died 1n the 80 ppm group after only 4 days of exposure. No significant
treatment-related effects were noticed regarding red cell counts, leukocyte
counts or hemoglobin concentration.
Confidence 1n the key study 1s low because the exposure protocol was
Inadequately reported and because experimental group sizes were small.
Confidence In the data base 1s low because there are no data that support
the NOAEL 1n the H1ne et al. (1961) study.
8.2.1.2. CHRONIC EXPOSURE — In the absence of chronic Inhalation
studies, a provisional chronic Inhalation RfD can be calculated by applying
an additional uncertainty factor of 10 to the derivation of the subchronlc
RfD, thus obtaining a value of 0.001 mg/m3. The level of confidence In
the chronic Inhalation RfD 1s low for the same reasons stated In Section
8.2.1.1.
0137d -30- 08/07/89
-------
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Because of the
lack of oral data, a subchronlc oral RfD can be calculated using the
subchronlc Inhalation data from the Mine et al. (1961) study. The exposure
concentration of 10 ppm (29 mg/m3) expanded to continuous exposure,
multiplied by the reference breathing rate for rats of 0.223 mVday and
divided by the reference body weight for rats of 0.35 kg (U.S. EPA, 1986b),
1s equivalent to an Inhaled dosage of 2.20 mg/kg/day. In the absence of
pharmacoklnetlc data, It 1s appropriate to assume 50% absorption from the
respiratory tract and 100% absorption from the gastrointestinal tract. The
Inhaled dosage of 2.20 mg/kg/day multiplied by the ratio of the respiratory:
gastrointestinal absorption factors yields an equivalent oral dosage of 1.10
mg/kg/day. Application of an uncertainty factor of 300 [10 to extrapolate
from rats to humans, 10 to protect unusually sensitive Individuals and 3 to
reflect deficiencies In the data base (see Section 8.2.1.1.}] results In an
RfD for subchronlc oral exposure of 3.7x10~3 mg/kg/day, which Is rounded
to 4x10~3 mg/kg/day.
Confidence In the key study, data base and RfD are low for the reasons
discussed 1n Section 8.2.1.1. In addition, confidence In the RfD Is low
because of the uncertainties associated with route-to-route extrapolation.
It 1s likely that this RfD 1s unnecessarily protective, because of the
expectation that glyddaldehyde would be hydrolyzed rapidly 1n the add pH
of the stomach (Van Duuren et al., 1966), and an Ingested dose would be
largely unavailable for absorption and distribution. Therefore, the
appropriateness of route-to-route extrapolation In deriving an RfD for
glyddaldehyde should be reconsidered.
0137d -31- 08/07/89
-------
8.2.2.2. CHRONIC EXPOSURE -- The verified oral RfD (U.S. EPA, 1987c)
1s based on the subchronlc oral Inhalation study In rats conducted by H1ne
et al. (1961). This study was described 1n detail In Section 6.1.1.1. and
briefly In Section 8.2.1.1. The NOAEL of 10 ppm (29 mg/m3) from the Hlne
et al. (1961) study was converted to an equivalent dose of 1.1 mg/kg/day
using the following conversion factors: 4/24 hours/day, 5/7 days/week, rat
breathing rate of 0.223 mVday, rat body weight of 0.350 kg and 50%
respiratory absorption factor. Applying an uncertainty factor of 3000 (10
for Interspedes variability, 10 for sensitive human subpopulatlons, 10 for
extrapolation to chronic exposure and 3 for lack of supporting data), a
chronic oral RfD rounded to 4xlO~4 mg/kg/day (0.026 mg/day for a 70 kg
person) 1s derived. Confidence In this RfD 1s low as explained 1n Section
8.2.2.1.
As discussed In Section 8.2.2.1., the advisability of route-to-route
extrapolation for estimating equivalent oral doses from Inhalation exposure
1s questionable because glycldaldehyde Is probably hydrolyzed rapidly 1n the
add environment of the stomach and 1s relatively unavailable for absorption
and distribution to the tissues. This phenomenon may be reflected In the
30-fold difference 1n human equivalent dose between the oral LDrQ (the PEL
at 3000 mg/kg/day) and the equivalent oral dosage associated with death
after 4 days of exposure (the PEL at 100 mg/kg/day). The limited nature of
the data base Is reflected In the lack of a region of contradiction and also
In a large region of ambiguity. The verified oral chronic RfD of 4xlO~4
mg/kg/day, or 3x10~3 mg/day for a 70 kg human, 1s well below the boundary
for adverse effects.
0137d -32- 08/07/89
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty of glycldaldehyde was discussed In Chapter 6 and
dose-response data are summarized 1n Table 9-1. The only data available for
deriving CSs are those from the subchronlc Inhalation study conducted by
H1ne et al. (1961). In this study, male Long-Evans rats were exposed to
vapors of glycldaldehyde at dosages of 0, 10, 20, 40 and 80 ppm 4 hours/
day, 5 days/week for 12 weeks. As Indicated In Section 6.1.1.1., treatment-
related effects Included hlstologlcal changes at >20 ppm and mortality (from
pneumonia) at 40 ppm. High mortality occurred In the group exposed to 80
ppm after only 4 days of exposure; therefore, this effect 1s considered
acute, and Inappropriate for calculating a CS. In the group exposed to 20
ppm of glycldaldehyde, one death occurred after 34 exposures; however, the
rat was not In a condition suitable for necropsy when found, leaving the
cause of death uncertain. An enlarged adrenal and hydropic change 1n the
kidney were noticed 1n two animals of the the 20 ppm dosage group;
therefore, an RV of 5 may be appropriate. In the group exposed to 40 ppm
glycldaldehyde, two deaths occurred after 25 and 26 exposures. Hlstologlcal
examination Indicated that the rats died of pneumonia. Analysis of these
Incidence data with the Fischer exact test Indicates that the two deaths at
40 ppm are not statistically significant when compared with the control
group or the group exposed to 10 ppm. Nevertheless, the death of 8/10 rats
exposed to 80 ppm for 4 days strongly suggests that the deaths observed at
40 ppm were compound-related, and the mortality effect Is considered for
generation of a candidate CS.
Multiplying the 20 and 40 ppm (59 and 118 mg/m3, respectively) by 4
hours/24 hours, 5 days/7 days, 0.223 mVday (rat breathing rate), and
0137d -33- 08/07/89
-------
TABLE 9-1
Inhalation Toxldty for Glyddaldehyde Using 10 Male Long-Evans Ratsa»b
Exposure0
Transformed
Animal Dose0*
(mg/kg/day)
Equivalent
Human Dose6
(mg/kg/day)
Response
10 ppm
(29 mg/m3)
20 ppm
(59 mg/m3)
40 ppm
(118 mg/m3)
80 ppm
(236 mg/m3)
2.3
4.5
8.95
18.2
0.39
0.77
1.53
3.11
No gross or microscopic abnormal-
ities; no hematologlcal abnormal-
ities (NOAEL)
One death from pneumonia after
34 exposures; decrease 1n body
weight again; enlarged adrenals,
hldroplc renal pelvis; signifi-
cant decrease In nucleated marrow
cells; Increase 1n testes-to-body
weight ratio; no other hlsto-
loglcal or gross abnormalities
Two deaths from pneumonia at 25
and 26 exposures; depletion of
body fat; significant decrease
In body weight gain; significant
decrease In spleen weight; sig-
nificant decrease 1n nucleated
marrow cells; no other hlsto-
loglcal or gross abnormalities
Eight deaths at day 4; severe
depletion of body fat; abscesses
1n spleen, liver necrosis, kidney
degeneration; low leukocyte
count; significant decrease 1n
nucleated marrow cells
aSource: H1ne et al., 1961
bThe reference rat body weight was 0.350 kg (U.S. EPA, 1986b). The vehicle/
physical state was air and the purity of the compound was not reported.
cppm x molecular weight/24.45 = mg/m3 (U.S. EPA, 1988)
^Calculated by multiplying the concentration In mg/m3 by the number of
hours/day, number of exposures/duration of study by the rat Inhalation rate
[0.223 m3/day (U.S. EPA, 1986b) and dividing by the reference rat body
weight (0.35 kg)].
Calculated by multiplying the animal transformed dose by the cube root of
the ratio of the animal body weight to the human body weight (70 kg).
0137d
-34-
08/07/89
-------
dividing by 0.35 kg (rat body weight) results In transformed Inhaled animal
doses of 4.6 and 9.1 mg/kg/day, respectively. Multiplying the transformed
animal doses by the cube root of the ratio of rat body weight to human
reference body weight (70 kg) gives human equivalent doses of 0.79 and 1.56
mg/kg/day. These doses are then multiplied by 70 kg and divided by 10 (to
extrapolate from subchronlc to chronic exposure), giving human MEDs of 5.36
mg/day for hydropic renal pelvis and 10.71 mg/day for death (Table 9-2).
The CSs for hydropic renal pelvis and death are then 22.0 and 39.6, respec-
tively, both of which correspond to RQs of 100. The higher CS of 39, which
corresponds to an RQ of 100, 1s chosen as representative of the hazard
associated with chronic exposure to glyddaldehyde (Table 9-3). An earlier
evaluation (U.S. EPA, 1987d) declined to derive an RQ for glycldaldehyde,
presumably because the H1ne et al. (1961) study had not been located.
9.2. BASED ON CARCINOGENICITY
Studies regarding the carclnogenldty of glyddaldehyde were reviewed 1n
Section 6.2. The only oral study available 1s that of Van Duuren et al.
(1966), 1n which glycldaldehyde was not carcinogenic to rats when adminis-
tered as a single weekly dose of 33 mg by gavage for 70 weeks.
Glyddaldehyde Induced local malignant tumors 1n mice when applied
dermally 3 times/week for life, either as a 3% solution 1n benzene or as a
10% solution 1n acetone (Van Duuren et al., 1965, 1967a). Subcutaneous
Injections 1n mice of 0.1 or 3.3 mg glyddaldehyde, once a week for life,
Induced a dose-related Increase In the Incidence of tumors at the site of
Injection (Van Duuren et al., 1966). In rats, subcutaneous Injections of 1
or 33 mg glyddaldehyde once weekly for life produced a significant dose-
related Increase In the Incidence of local tumors (Van Duuren et al., 1966,
1967b).
0137d -35- 08/07/89
-------
TABLE 9-2
Inhalation Composite Scores for Glyddaldehyde Using the Rata
Animal Dose
(mg/kg/day)
Chronic
Human MEDb
(mg/day)
RVd Effect
RVe CS RQ
4.48
8.95
5.36
10.71
4.41 Enlarged adrenals,
hydropic renal
pelvis, body weight
changes, hemato-
poletlc effects
3.96 Increased mortality
10
22.0 100
39.6 100
aSource: Nines et al., 1961
bThe human equivalent dose was divided by an uncertainty factor of 10 to
approximate chronic exposure and multiplied by 70 kg to express the human
MED In terms of mg/day for a 70 kg human.
0137d
-36-
08/07/89
-------
TABLE 9-3
Glycldaldehyde
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: Inhalation
Spedes/sex: rat/m
MED*: 107.1 mg/day
Duration: 12 weeks
Effect: Increased mortality
RVd: 3.9
RVe: 10
Composite Score: 39
RQ: 100
Reference: H1ne et al., 1961
*Equ1valent human dose
0137d -37- 08/07/89
-------
Pertinent data regarding the cardnogenlclty of glyddaldehyde after
Inhalation exposure were not located 1n the available literature cited 1n
Appendix A. Based on the available animal data, glyddaldehyde was assigned
to EPA Group B2. The lack of an adequate quantitative data base precludes
derivation of a carc1nogen1dty-based RQ for glyddaldehyde.
0137d -38- 08/07/89
-------
10. REFERENCES
Amacher, D.E. and G.N. Turner. 1982. Mutagenlc evaluation of carcinogens
and non-carcinogens In the L5178Y/TK assay utilizing postmltochondrlal
fractions (S9) from normal rat liver. Mutat. Res. 97: 49-65.
Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reactions of
hydroxyl radical with organic compounds under atmospheric conditions. Chem.
Rev. 85: 69-201.
Atkinson, R. 1987. A structure-activity relationship for the estimation of
rate constants for the gas-phase reactions of OH radicals with organic
compounds. Intern. J. Chem. Kinetics. 19: 799-828.
Bleasdale, C., B.T. Go!ding, P.K. Slalch and W.P. Watson. 1986. Cyclic
nuclelc-add adducts from chloroacetaldehyde and glyddaldehyde. Human
Toxlcol. 5(2): 138.
Corbett, T.H., C. Heldelberger and W.F. Dove. 1970. Determination of the
mutagenlc activity to bacterlophage T4 of carcinogenic and noncarclnogenlc
compounds. Hoi. Pharmacol. 6(6): 667-679.
Crockett, P.W., B. KlUan, K.S. Crump and R.B. Howe. 1985. Descriptive
Methods for Using Data from Dissimilar Experiments to Locate a No-Adverse-
Toxic-Effects Region 1n the Dose-Duration Plane. Prepared under Contract
No. 68-01-6807 for Environmental Criteria Assessment Office, U.S. EPA,
Cincinnati, OH.
0137d -39- 08/07/89
-------
Dawson, F.W. 1962. Glycldaldehyde vapor as disinfectant. Am. 3. Hyg. 76:
209-215.
Dean, J.A., Ed. 1985. Lange's Handbook of Chemistry, 13th ed. McGraw-Hill
Book Co., New York. p. 7-425.
Dunkel, V.C., R.J. Plenta, A. S1vak and K.A. Traul. 1981. Comparative
neoplastlc transformation responses of BALB3T3 cells, Syrian hamster embryo
cells, and Rauscher murlne leukemia virus-Infected Fischer 344 rat embryo
cells to chemical carcinogens. J. Natl. Cancer Inst. 67: 1303-1315.
Durkln, P. and W. Meylan. 1988. User's Guide for D2PLOT: A Program for
Dose/Duration Graphs. Prepared under Contract No. 68-C8-0004 for Environ-
mental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH.
Ehrenberg, L. and S. Hussaln. 1981. Genetic toxldty of some Important
epoxldes. Mutat. Res. 86: 1-113.
Elsenrelch, S.J., B.B. Looney and 3.D. Thornton. 1981. Airborne organic
contaminants of the Great Lakes ecosystem. Environ. Scl. Technol. 15(1):
30-38.
Pluck, E.R., L.A. Polrler and H.W. Rue"Mus. 1976. Evaluation of a DNA
polymerase-deflclent mutant of E_. coll for the rapid detection of carcino-
gens. Chem. B1ol. Interact. 15: 219-231.
0137d -40- 08/07/89
-------
Glatz, 6.A. 1979. Short-term bloassays for environmental mutagens and
carcinogens. 3. Am. Hater Works Assoc. 3: 396-402.
Goldlng, B.T., P.K. Slalch and W.P. Watson. 1986. The structures of
adducts from the reaction between guanoslne and glyddaldehyde (oxlrane-
carbaldehyde). J. Chem. Soc.-Chem. Commun. N7 p. 515-517.
Goldschmldt, B.M., T.P. Blazej and B.L. Van Duuren. 1968. Reaction of
guanoslne and deoxyguanoslne with glyddaldehyde. Tetra. Lett. 13:
1583-1586.
Harris, J.C. 1982. Rate of hydrolysis. In: Handbook of Chemical Property
Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed. McGraw
H111 Book Co., New York. p. 7-1 to 7-48.
Hlne, J. and P.K. Mookerjee. 1975. The Intrinsic hydrophlUc character of
organic compounds. Correlations 1n terms of structural contributions. J.
Org. Chem. 40(3): 292-298.
Hlne, C.H., R.J. Guzman, H.K. Dunlap, R. Lima and G.S. Loquvam. 1961.
Studies on the toxldty of glyddaldehyde. Arch. Environ. Health. 2: 23-30.
H1ne, C., V.R. Rowe, E.R. White, K.I. Darmer and G.T. Youngblood. 1981.
Epoxy Compounds. In_: Patty's Industrial Hygiene and Toxicology, 3rd ed.,
G.D. Clayton and F.E. Clayton, Ed. John Wiley and Sons, New York.
p. 2249-2257.
0137d -41- 08/07/89
-------
IARC (International Agency for Research on Cancer). 1976. IARC monographs
on the evaluation of carcinogenic risk of chemicals to humans. Vol. II,
WHO, Lyons, France, p. 175-181.
Jaber, H.M., W.R. Mabey, A.T. Liu, T.W. Chou and H.L. Johnson. 1984. Data
aqulsltlon for environmental transport and fate screening for compounds of
Interest to the Office of Emergency and Remedial Response. EPA-600/6-84-
011. SRI International, Menlo Park, CA. NTIS PB84-245281. p. 93.
Knaap, A.G., C.E. Voogd and P.G. Kramers. 1982. Comparison of the
mutagenlc potency of 2-chloroethanol, 2-bromoethanol, 1,2-epoxybutane,
eplchlorohyde 1n an glyddaldehyde 1n Klebslella pneumonlae. Drosophlla
melanogaster and L5178Y mouse lymphoma cells. Mutat. Res. 101(3): 199-208.
Lyman, U.3. 1982. Adsorption coefficient for soils and sediments. Iji:
Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and
D.H. Rosenblatt, Ed. McGraw H111 Book Co., New York. p. 4-1 to 4-33.
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handook of Chemical
Property Estimation Methods. Environmental Behavior of Compounds.
McGraw-Hill Book Co., New York. p. 5-4 to 5-5.
Mabey, W. and T. Mill. 1978. Critical review of hydrolysis of organic
compounds 1n water under environmental conditions. J. Phys. Chem. Ref.
Data. 7: 383-415.
0137d -42- 08/07/89
-------
Manson, M.M. 1980. Epoxldes: Is there a human health problem. Br. J. Ind.
Med. 37(4): 317-336.
McCann, J., E. Choi, E. Yamasakl and B.N. Ames. 1975. Detection of
carcinogens as mutagens In the Salmonella mlcrosome test: Assay of 300
chemicals. Proc. Natl. Acad. Sc1. USA. 72: 5135-5139.
Mitchell, A.D. 1976. Potential prescreens for chemical carcinogens:
Unscheduled DNA synthesis. SRI Report, 70 p. (Cited In Mitchell et al.,
1983)
Mitchell, A.D., D.A. Casdano, M.L. Meltz, et al. 1983. Unscheduled DNA
synthesis tests: A report of the U.S. Environmental Protection Agency
Gene-Tox Program. Mutat. Res. 123(3): 363-410.
Nalr, V. and G.A. Turner. 1984. Determination of the structure of the
adduct from guanoslne and glyddaldehyde. Tetra. Lett. 25(3): 247-250.
Plenta, R.J. 1980. Evaluation and relevance of the Syrian hamster embryo
cell system. Appl. Methods Oncol. 3: 149-169.
Rosenkranz, H.S. and Z. Lelfer. 1980. Determining the DNA-mod1fy1ng
activity of chemicals using DNA polymerase-defldent Escher1ch1a coll.
Chem. Mutagens. 6: 109-147.
SANSS (Structure and Nomenclature Search System). 1988. Chemical Informa-
tion System (CIS) computer data base. On-Hne May 13, 1988.
0137d -43- 08/07/89
-------
Shamberger, R.J., T.L. Andreone and C.E. Willis. 1974. Ant1ox1dants and
cancer. IV. Initiating activity of malonaldehyde as a carcinogen. J. Natl.
Cancer Inst. 53(6): 1771-1773.
Simmon, V.F. 1979a. In. vitro mutagenldty assays of chemical carcinogens
and related compounds with Salmonella typhlmurlum. J. Natl. Cancer Inst.
62: 893-899.
Simmon, V.F. 19795. in vitro assays for recomblnogenlc activity of chemi-
cal carcinogens and related compounds with Saccharomyces cerevlslae D3. J.
Natl. Cancer Inst. 62: 901-909.
Simmon, V.F., M.S. Rosenkranz, E. Zelger and L.A. Po1r1er. 1979. Mutagenlc
activity of chemical and related compounds 1n the Intraperltoneal host-
mediated assay. 0. Natl. Cancer Inst. 62: 911-918.
Swann, R.L., D.A. Laskowskl, P.J. HcCall, K. VanderKuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
Thomas, R.6.. 1982. Volatilization from water. In: Handbook of Chemical
Property Estimation Methods, H.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed.
McGraw Hill Book Co., New York. p. 15-1 to 15-34.
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.
0137d -44- 08/07/89
-------
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. 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. 1987a. Graphical Exposure Modeling System (GEMS). Personal
Computer Version. PCCHEM April 1987. U.S. EPA, Research Triangle Park.
U.S. EPA. 1987b. Graphical Exposure Modeling System (GEMS). CLOGP
computer program. Office of Toxic Substances. U.S. EPA, Washington, DC.
U.S. EPA. 1987c. Integrated Risk Information System (IRIS). Reference
dose (RfD) for oral exposure for glyddaldehyde. Online. (Verification
date 12/15/87.) Office of Health and Environmental Assessment, Environ-
mental Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1987d. Reportable Quantity Document for Glycldaldehyde.
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.
0137d -45- 08/07/89
-------
U.S. EPA/OURS (Office of Water Regulations and Standards). 1986. Guide-
lines for Deriving Numerical Water Quality Criteria for the Protection of
Aquatic Organisms and their Uses. U.S. EPA, Washington, DC. p. 22-58, 98.
Van Duuren, B.L. and G. Loewengart. 1977. Reaction of DNA with glyddalde-
hyde. Isolation and Identification of a deoxyguanoslne reaction product.
J. B1ol. Chem. 252(15): 5370-5371.
Van Duuren, B.L., N. Nelson, L. Orris, E.D. Palmes and F.L. Schmltt. 1963.
Cardnogenlclty of epoxldes, lactone and peroxy compounds. J. Natl. Cancer
Inst. 31: 41-55.
v
Van Duuren, B.L., L. Orris and N. Nelson. 1965. CardnogenlcHy of
epoxldes, lactones and peroxy compounds. J. Natl. Cancer Inst. 35(4):
707-717.
Van Duuren, B.L., L. Lengseth, L. Orris, G. Teebor, N. Nelson and M.
Kuschner. 1966. CardnogenlcHy of epoxldes, lactones and peroxy com-
pounds. IV. Tumor response In epithelial and connective tissue 1n mice and
rats. J. Natl. Cancer Inst. 37(6): 825-838.
Van Duuren, B.L., L. Langseth, B.M. Goldschmldt and L. Orris. 1967a.
CardnogenlcHy of epoxldes, lactones and peroxy compounds. VI. Structure
and carcinogenic activity. J. Natl. Cancer Inst. 39(6): 1217-1228.
0137d -46- 08/07/89
-------
Van Duuren, B.L., L. Langseth, L. Orris, M. Baden and M. Kuschner. 1967b.
Cardnogenldty of epoxldes, lactones and peroxy compounds. V. Subcutaneous
Injection 1n rats. J. Natl. Cancer Inst. 39: 1213-1216.
Voogd, C.E., J.J. Van Deer Stel and J.J. Jacobs. 1981. Hutagenlc action of
aliphatic epoxldes. Hutat. Res. 89: 269-282.
Hade, M.J., J.W. Moyer and C.H. Nine. 1979. Mutagenlc action of a series
of epoxldes. Mutat. Res. 66: 367-371.
0137d -47- 08/07/89
-------
APPENDIX A
LITERATURE SEARCHED
This HEED Is 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 1n May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
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 1n 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.
0137d -48- 08/07/89
-------
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.
Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey 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. Lieu, 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 1n
Programs. Registration Standards and the Data Call 1n 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.
0137d -49- 08/07/89
-------
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 F1sh 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.
0137d -50- 08/07/89
-------
APPENDIX B
Sunraary Table for Glycldaldehyde
Species
Inhalation Exposure
Subchronlc rat
Chronic rat
Carclnogentctty ID
VI Oral Exposure
i
Subchronlc rat
Chronic rat
Carclnogenlclty ID
RE PORTABLE QUANTITIES
Based on chronic toxtclty:
Based on carctnogenlctty:
Exposure
10 ppn (29 ng/fl*). 4 hours/
day, 5 days/week for 12 weeks
(NEC. 3.5 ng/n»)
10 ppra (29 ng/n*). 4 hours/
day. 5 days/week for 12 weeks
(NEC. 3.5 mg/m>)
ID
1.1 ng/kg/day '
1.1 ng/kg/day
ID
100
ID
Effect RfD or q]*
Decreased body weight 0.01 ng/m»
gain and kidney effects
at higher levels
Decreased body weight 0.001 mg/ra"
gain and kidney effects
at higher levels
ID ID
Decreased body weight 4.0xlO"« ng/kg/day
gain and kidney effects
at higher levels
Decreased body weight 4.0x10"* ng/kg/day
gain and kidney effects
at higher levels
ID ID
Reference
Hlne et al., 1961
Nine et al.. 1961
ID
Nine et al.. 1961
Nine et al.. 1961
ID
Nine et al., 1961
ID
CD
ID = Insufficient data
CO
-------
APPENDIX C
DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO GLYCIDALDEHYDE
C.I. DISCUSSION
Dose/duration-response graphs for Inhalation exposure to glycldaldehyde
generated by the method of Crockett et a "I. (1985) using the computer
software by Durkln and Meylan (1988) are presented 1n Figures C-l and C-2.
Data used to generate these graphs are presented In Section C.2. In the
generation of these figures, all responses are classified as adverse (PEL,
AEL or LOAEL) or nonadverse (NOEL or NOAEL) for plotting. Figure C-l
presents the experimental Intermittent exposures expanded to reflect
continuous exposure. Figure C-2 presents the expanded concentrations scaled
to equivalent human concentrations by applying a body weight ratio adjust-
ment factor.
A dose/duration-response graph for oral exposure to glycldaldehyde
generated by the method of Crockett et al. (1985) using the computer program
designed by Durkln and Meylan (1988) 1s presented 1n Figure C-3 and the data
used 1n the generation of this graph are presented 1n Section C.2. The
available data points represent an oral LD5Q In rats and equivalent oral
dosages estimated by route-to-route extrapolation from the 12-week rat
Inhalation study by H1ne et al. (1961).
The boundary for adverse effects (solid line) 1s drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure. From this point, an Infinite line 1s extended upward, parallel to
the dose axis. The starting point Is then connected to the lowest adverse
effect dose or concentration at the next longer duration of exposure. This
process 1s continued to the lowest adverse effect dose or concentration at
0137d -52- 08/07/89
-------
A
n
81
8
A
lea
18--
0.901
-------
1688
I I i I 1
I III
I I 1
I
ft
188 -
A
H
18
I I i t l_
0.001
-------
leeec
91
v
Id
i
z
a
z
19C -
e.eei
(Oral Exposure)
|
e.ei 8.1
HUNAN EQUIV DURATION (fraction lifcspan)
Key:
F - FEL
L - LOAEL
N - NOAEL
FIGURE C-3
Dose/Duration - Response Graph for Oral Exposure to Glyddaldehyde:
Envelope Method
0137d
-55-
08/07/89
-------
the longest duration of exposure. From this point, a line Is extended to
the right, parallel to the duration axis. The region of adverse effects
lies above the adverse effects boundary.
The boundary for no-adverse-effects (dotted line) Is similarly drawn by
Identifying the highest no-adverse-effects dose or concentration at the
shortest duration of exposure. From this point, a line parallel to the
duration axis 1s extended to the dose or concentration axis. This point Is
then connected to the next lower no-adverse-effect dose or concentration at
a longer duration of exposure. When this process can no longer be
continued, a line Is dropped parallel to the dose or concentration axis to
the duration axis. The region of no-adverse effects lies below the no-
adverse effects boundary. At both ends of the graph between the adverse
effects and no-adverse effects boundaries are regions of ambiguity. The
area (1f any) resulting from Intersection of the adverse effects and no-
adverse effects boundaries Is defined as the region of contradiction. The
only significant feature of these graphs 1s the large region of ambiguity,
which reflects the paucity of the data base.
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Chemical Name: Glycldaldehyde
CAS Number: 765-34-4
Document Title: Health and Environmental Effects Document on Glycldaldehyde
Document .Number: Pending
Document Date: Pending
Document Type: HEED
0137d -56- 08/07/89
-------
RECORD #1
Species:
Sex:
Effect:
Route:
Rats
NS
PEL
Gavage
Dose: 232.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 9
Comment:
Citation:
Oral 1050
Mine et al., 1961
RECORD #2:
Species:
Sex:
Effect:
Route:
Rats
Male
NOAEL
Oral (NOS)
Dose:
Duration
Duration
Exposure:
Observation:
1.110
12.0 weeks
12.0 weeks
Number Exposed: 10 10 10
Number Responses: 0 NR NR
Type of Effect: WGTNS HYPRT HISTO
Site of Effect: BODY ADRNL KIDNY
Severity Effect: 334
Comment: Extrapolated from Inhalation exposure to 10 ppm (29 mg/m3)
4 hours/day, 5 days/week for 12 weeks, assumed Inhalation
factor of 0.5
Citation: H1ne et al., 1961
0137d
-57-
08/07/89
-------
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Dose:
Duration Exposure:
Duration Observation:
10
NR
HYPRT
ADRNL
3
10
NR
HISTO
KIDNY
4
10
NR
WGTDC
OTHER
4
2.240
12.0 weeks
12.0 weeks
Comment: See comments previous record; exposure concentration was 20
ppm. Body weight gain was significantly reduced.
Citation: Mine et al., 1961
RECORD #4:
Species:
Sex:
Effect:
Route:
Rats
Hale
PEL
Oral (NOS)
Dose:
Duration
Duration
Exposure:
Observation:
4.480
5.0 weeks
5.0 weeks
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
10
2
DEATH
BODY
9
10
NR
WGTDC
BODY
4
10
NR
WGTDC
SPLEN
4
Comment: See comments previous record; exposure concentration = 40
ppm. Deaths occurred after 25 and 26 exposures and were
attributed to pneumonia.
Citation: Hlne et al., 1961
0137d
-58-
08/07/89
-------
RECORD #5:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 8.950
Duration Exposure: 4.0 days
Duration Observation: 4.0 days
10
8
DEATH
BODY
9
10
2
NECRO
LIVER
5
10
2
DEGEN
KIDNY
5
Comment: See comments previous record; exposure concentration = 80
ppm. Eight deaths occurred at day 4. Leukocyte count was
significantly low.
Citation: H1ne et al., 1961
RECORD #6:
Species: Rats
Sex: Hale
Effect: NOAEL
Dose:
Duration Exposure:
Duration Observation:
3.510
12.0 weeks
12.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
NR
WGTDC
BODY
3
10 10 10
0 0 NR
HYPRT DEGEN DEATH
ADRNL KIDNY BODY
369
Comment:
Citation:
RECORD #7:
10 ppm (29.5 mg/m3)
H1ne et al., 1961
4 hours/day, 5 days/week.
Species: Rats
Sex: Male
Effect: LOAEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
NR
WGTDC
BODY
3
Dose:
Duration Exposure:
Duration Observation:
10 10 10
0 0 NR
HYPRT DEGEN DEATH
ADRNL KIDNY BODY
369
7.020
12.0 weeks
12.0 weeks
Comment: 20 ppm (59.0 mg/m3)
weight gain reduced.
Citation: H1ne et al., 1961
see previous record; 1 death, body
0137d
-59-
08/07/89
-------
RECORD #8:
Species:
Sex:
Effect:
Route:
Rats
Hale
PEL
Inhalation
Number Exposed: 10
Number Responses: NR
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 3
Dose: 14.050
Duration Exposure: 5.0 weeks
Duration Observation: 5,0 weeks
10
0
HYPRT
ADRNL
3
10
0
DEGEN
KIDNY
6
10
NR
DEATH
BODY
9
Comment: 40 ppm (119 mg/m3), see previous records;
weeks, reduced rate of body weight gain.
Citation: Hlne et al., 1961
2 deaths within 5
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Inhalation
Dose:
Duration
Duration
Exposure:
Observation:
28.100
4.0 days
4.0 days
Number Exposed: 10
Number Responses: NR
Type of Effect: WGTDC
SHe of Effect: BODY
Severity Effect: 3
10
0
HYPRT
ADRNL
3
10
0
DEGEN
KIDNY
6
10
NR
DEATH
BODY
9
Comment: 80 ppm (236 mg/m3); see previous records; 80% death In 4
days.
Citation: H1ne et al., 1961
NR = Not reported
0137d
-60-
08/07/89
------- |