FINAL DRAFT
United States
Env,ronmenta, Protection 500ECAOCING01 7
>EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CYCLOHEXYLAMINE
Prepared for
OFFICE OF SOLID HASTE 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DRAFT: DO NOT CITE OR*Q081t v*
•*•"* **' ' *',,'' '»-»* .' '" -,*'. '*
NOTICE "
This document Is 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 Is being circulated for comments
on Its technical accuracy and policy Implications.
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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.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is 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 In 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, 1s 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 RfDs Is 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. A
carcinogenic potency factor, or q-j* (U.S. EPA, 1980), 1s 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 toxlclty 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 toxlclty and carclno-
genldty) represent two of six scores developed (the remaining four reflect
Ignltablllty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer-based RQs are defined 1n U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
Cyclohexylamlne Is a liquid with a strong, fishy, amlne odor (Wlndholz,
1983). It 1s mlsclble with water and most common organic solvents
(Wlndholz, 1983} and Is a strong base (IARC, 1980). U.S. production demand
for cyclohexylamlne was -8.5 million pounds In 1984 (CMR, 1984). Two U.S.
manufacturers operate three production facilities with a combined annual
capacity of at least 18 million pounds (SRI, 1986). Cyclohexylamlne has the
following reported use pattern (CMR, 1984; Wlndholz, 1983): boiler water
treatment (60%); rubber chemicals (25%); chain terminator (8%); miscella-
neous. Including intermediates with manufacture of Insecticides, plastl-
clzers and photographic chemicals; catalysts; and metal extraction (7%). A
major use In the 1960s was In the production of cyclamate sweeteners (IARC,
1980). The use of cyclamate sweeteners was banned In 1970 by the U.S. Food
and Drug Administration.
The dominant environmental fate process for cyclohexylamlne In the atmo-
sphere 1s expected to be the vapor-phase reaction with hydroxyl radicals;
this reaction has an estimated half-life of 1.82 days In a normal atmosphere
(U.S. EPA, 1987). Reaction with nitrate radicals may also be a significant
removal process for atmospheric cyclohexylamlne (Atkinson and Carter, 1984);
however, kinetic data for this reaction are not available. If released to
the aquatic environment, mlcroblal degradation and volatilization are
expected to be the Important fate processes. Available blodegradatlon data
Indicate cyclohexylamlne to be significantly biodegradable with eutrophlc
lake water, river mud, sewage and activated sludges (Calamarl et al, 1980;
Novlck and Alexander, 1985; Wotzka et al., 1985; Rothkopf and Bartha, 1984).
1v
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Volatilization, adsorption to sediment and bloconcentratlon are not expected
to be significant. If released to soil, mlcroblal degradation 1s likely to
be an Important process. This Is based on Us blodegradatlon potential 1n
aquatic media. The estimated K value of 154 Indicates that In the
absence of significant degradation processes, cyclohexylamlne may leach
significantly through soil Into groundwater. The relatively high vapor
pressure of cyclohexylamlne suggests that volatilization from dry soil
surfaces may be a significant removal process; however, cyclohexylamlne 1s
not expected to volatilize from moist soil surfaces.
Cyclohexylamlne has not been reported to occur naturally In the environ-
ment (IARC, 1980); therefore, Us presence 1n the environment Is due to
anthropogenic sources, such as releases from production and user facilities.
It has been detected 1n wastewater effluents from tire and latex manufactur-
ing plants (Jungclaus et al., 1976; Shackelford and Keith, 1976) and In
trench leachates from low-level radioactive waste disposal sites (Francis et
al., 1980). An NOHS conducted between 1972 and 1974 estimated that 9532
U.S. workers may be exposed to cyclohexylamlne (NIOSH, 1984).
Among the three freshwater species for which there were data, the lowest
reported toxic concentration was 44 mg/l, a 96-hour LC5Q for rainbow
trout, Sal mo qalrdneM In soft water (CalamaM et al., 1980). In this
study, cyclohexylamlne was about twice as toxic In soft water (20 mg/l as
CaC03) as In hard water (320 mg/l as CaCOg). The lowest reported
toxic concentration for Invertebrates was 0.7 mg/l, a threshold for
Inhibition of cell multiplication of the protozoan, Entoslphon sulcatum
(Brlngmann and Kuehn, 1980). Among aquatic plants and bacteria, the
blue-green alga, Hlcrocystls aeruqlnosa. was the most sensitive species
tested, with a toxlclty threshold of 0.02 mg/l for Inhibition of cell
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multiplication (BMngmann and Kuehn, 1978). This was the lowest toxic
concentration reported for any species. Data for marine species could not
be located 1n the available literature as dted 1n Appendix A.
Based on excretion animal studies (Elliott et al., 1968; Renwlck and
Williams, 1972; Roberts and Renwlck, 1985) and human studies (Elchelbaum et
al., 1974; Renwlck and Williams, 1972), cyclohexylamlne 1s absorbed rapidly
and nearly completely after oral Intake. Excretion Is primarily through the
urine, and 61.6-90.2X of the radioactivity from a dose of 14C-cyclohexyl-
am1ne«HCl 1s recovered within 24 hours. Rabbits appear to metabolize
cyclohexylamlne most completely; however, with mice and humans, >90% of
urinary radioactivity 1s recovered as unmetabollzed compound (Renwlck and
Williams, 1972; Roberts and Renwlck, 1985). Pathways of metabolism Include
hydroxylatlon with and without deamlnatlon and partial conjugation of the
hydroxylatlon products. Steady-state plasma clearance rates of 33 and 66
ml/mlnute/kg were estimated for rats and mice, respectively (Roberts and
Renwlck, 1986). PUkln et al. (1969) showed that cyclohexylamlne could
freely cross the monkey placenta! barrier after Intravenous Infusion 1n the
mother.
There are no pertinent data regarding the chronic or subchronlc Inhala-
tion toxlclty of cyclohexylamlne In experimental animals. Ep1dem1olog1cal
or occupational exposure data could not be located 1n the available litera-
ture as cited In Appendix A.
Results of subchronlc feeding studies (Gaunt et al., 1974; ColUngs and
Klrkby, 1974; Mason and Thompson, 1977; 3ames et al., 1981; Brune et al.,
1978) have suggested that testlcular damage Is the major treatment-related
effect of dietary cyclohexylamlne. Findings 1n rats after administration of
200 mg/kg/day Included tubular atrophy, reductions In sperm count, sperm
motllUy and numbers of early and late spermatlds, Impaired spermatogenesls,
v1
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and a decrease 1n testlcular weights. Reproductive performance was not
Impaired, however, by administration of a diet containing 6000 ppm cyclo-
hexylam1ne»HCl for 10 months (Gaunt et al., 1974). James et al. (1981)
found similar effects on the spermatozoa of dogs treated for 9 weeks at ~240
mg/kg/day. No clearly Identifiable toxic effects were found with adminis-
tration of <200 mg/kg/day (Colllngs and Klrkby, 1974; Mason and Thompson.
1977; Brune et al., 1978).
Besides testlcular effects, the only other major consistent finding In
these subchronlc studies Involved Inhibition of body weight gain, usually
accompanied by decreases In food Intake. In separate paired feeding
studies, Gaunt et al. (1974) demonstrated that weight gain Inhibition was
probably a result of Increased metabolic rate.
Lifetime administration of 600, 2000 and 6000 ppm cyc1ohexylam1ne*HCl
to male and female Wlstar rats resulted 1n concentration-related Inhibitions
of body weight gain, and food and water consumption was statistically
significant at >600 ppm (Gaunt et al., 1976). Longevity was Increased by
treatment. The concentration of 6000 ppm was associated with severe
testlcular atrophy and Increased calcium deposits In testlcular tubules. At
2000 ppm (82 mg/kg/day), males had slight testlcular effects consisting of
an Increase In the number of tubules with few or no spermatlds. Based on
cited literature. Gaunt et al. (1976) stated that the extent of tubular
damage observed at 6000 ppm could not have resulted from the decreased food
consumption. In addition to this effect, females treated with 6000 ppm had
transient reductions 1n hemoglobin and PCV; both sexes given 6000 ppm had
decreases In neutrophll counts, Increases In lymphocyte numbers and
Increases In foamy pulmonary macrophages, and females exposed to 2000 and
6000 ppm had Increased relative thyroid weights.
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Hardy et al. (1976) treated groups of 48-50 ASH-CS1 mice of both sexes
with 300, 1000 or 3000 ppm cyclohexylam1ne-HCl orally for 80 weeks. The
Investigators collected blood samples, measured body and organ weights and
food and water consumptions, and performed comprehensive hlstopathologles on
24 tissues. The only treatment-related effects were hepatic. Males exposed
to >1000 ppm had Increases In foamy hepatic macrophages, and high-dose
females had a significant Increase 1n cell vacuolatlon and nuclear poly-
ploldy.
Oser et al. (1976) conducted 24-month oral toxldty studies on groups of
30 FDRL rats administered cyclohexylam1ne-HCl In a diet that provided
dosages of 15, 50, 100 or 150 mg/kg/day cyclohexylamlne; the rats were also
bred for mult 1 generational studies. Starting at 50 (female) and 100 (male)
mg/kg/day, treated rats showed Inhibition of body weight gain. Further
analysis revealed that these effects were a result of decreased food
consumption. Incidences of testlcular atrophy and bladder hyperplasla were
significantly elevated In the groups exposed to 50 and 150 mg/kg/day,
although reproductive performance In affected males (fertility Index) was
not significantly affected. Oser et al. (1976) did not consider the results
as biologically significant. When data were analyzed across generations,
the number of live births/litter was reduced at 150 mg/kg/day, and the rate
of pup growth was decreased slightly at the highest two concentrations.
CovaMance analysis suggested that the offspring effects were secondary to
decrements 1n maternal weight gain (Bopp et al., 1986).
In another multlgenerational experiment, Kroes et al. (1977) studied the
long-term toxldty of 0.5X dietary cyclohexylamlne from cyclohexylamlne
sulfate In groups of 50 Swiss SPF mice of both sexes. Twenty-one-month
experiments were conducted In three generations of mice. The only reported
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effect was a decrement In body weight gain that was not accompanied by
decreases 1n food Intake. In reproductive (4-month and perinatal) studies,
Kroes et al. (1977) observed that treatment was associated with decreased
numbers of Hveborn fetuses, reduced survival rates and lower numbers of
Implantations.
Other lifetime bloassays (rats and dogs) have not found significant
nonneoplastlc toxic effects of oral cyclohexylamlne administration, other
than Inhibitions In weight gain (Price et al., 1970; Schmahl, 1973;
Industrial B1o-Test Laboratories, 1981). Although Kroes et al. (1977)
reported a tendency toward delayed ossification 1n mouse fetuses prenatally
exposed to cyclohexylamlne, they provided no supporting data. Other
researchers (Kennedy et al., 1969; Oser et al., 1976; Lorke and Machemer,
1983) found no evidence of teratogenldty In fetuses of orally exposed
animals.
After oral exposure the LD5Q values for rats range from 156-614 mg/kg
(NAS, 1968; Smyth et al., 1969; Tanaka et al., 1973), and 7 hours of
Inhalation exposure to 1200 ppm (486 mg/m3) was fatal to all tested rats
(Watrous and Schulz, 1950). Acute exposure of cyclohexylamlne to humans was
associated with nausea, drowsiness and skin Irritation (Mallette and von
Haam, 1952; Watrous and Schulz, 1950). Cyclohexylamlne was a weak
sympathom1met1c agent after acute exposure (Classen et al., 1968), but Us
pressor effects were not observed after repeated exposures (Rosenblum and
Rosenblum, 1968; Schmahl, 1973).
Only one animal bloassay (Price et al., 1970) found evidence of a
tumorlgenlc potential for cyclohexylamlne and this potential was observed In
only one male rat with a rare bladder tumor. These Investigators reported a
study with 0.15, 1.5 or 15 mg/kg/day cyclohexylamlne sulfate administered 1n
1x
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the diet to groups of 25 male and 25 female Sprague-Oawley rats for 2
years. Among eight high-dose males and nine high-dose females surviving to
the end of the study, one male had an Invasive bladder carcinoma, which Is
an unusual tumor 1n rats. In a subsequent study, administration of a 10:1
cyclamate/saccharln mixture 1n the diet at 2500 mg/kg/day, supplemented with
125 mg/kg/day cyclohexylam1ne*HCl, resulted 1n an Increased Incidence of
nonmetastatlc and nonlnvaslve bladder paplllomas. The results of the Price
et al. (1970) study are questionable because calcification found In the
kidneys of six rats may have contributed to the observed Incidence. Also,
several more recent bloassays that used larger numbers of animals failed to
note any treatment-related differences In the Incidence of any tumor type,
and did not find a single Incidence of bladder tumors (Schmahl, 1973; Gaunt
et al., 1976; Hardy et al., 1976; Oser et al., 1976; Kroes et al., 1977).
The animal cancer data can best be characterized as negative; single bladder
tumor being considered spurious.
Cyclohexylamlne was nonmutagenlc, or only weakly mutagenlc, In various
mutation assays with prokaryotlc organisms (HcCann, 1976; Herbold, 1981;
Hortelmans et al., 1986; Voogd et al., 1973; Legator et al., 1982). In both
somatic cell and germ cell chromosomal aberration assays, cyclohexylamlne
yielded mixed results (Green et al., 1970; Legator et al., 1969; Turner and
Hutchlnson, 1974; D1ck et al., 1974; Machemer and Lorke, 1976). Results do
not appear to depend on dosage. Most studies (Epstein et al., 1972; Lorke
and Machemer, 1974; Machemer and Lorke, 1975; Chauhan et al., 1975) reported
negative results In dominant-lethal assays. In two assays (Green et al.,
1972; Epstein et al., 1972) In which questionable or positive findings were
reported, either postlmplantatlon loss was not studied or experimental
design made Interpretation difficult.
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Cyclohexylamlne was assigned a welght-of-evidence for cardnogenldty
EPA Group E. A subchronlc oral RfD of 0.3 mg/kg/day or 21 mg/day for a 70
kg human was based on a NOAEL of 30 mg cyclohexylamlne/kg/day In a 90-day
dietary study with cyclohexylam1ne-HCl In rats (Gaunt et al., 1974). An
RfD for chronic oral exposure to cyclohexylamlne of 0.2 mg/kg/day or 13
mg/day for a 70 kg human was based on a NOAEL of 18 mg/kg/day
cyclohexylamlne In rats associated with slightly reduced body weights and
testlcular degenerations In a 2-year dietary study with
cyclohexylam1ne«HCl (Gaunt et al., 1976). An RQ of 1000 was based on
reduced numbers of live young/Utter and reduced rate of growth of the pups
of rats In a multlgeneratlonal reproduction study (Oser et al., 1976).
x1
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS REGISTRY NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 3
1.5. SUMMARY 3
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Reaction with Hydroxyl Radicals 4
2.1.2. Physical Removal Processes 4
2.2. WATER 4
2.2.1. Hydrolysis 4
2.2.2. Photolysls/Photooxidatlon 5
2.2.3. Mlcroblal Degradation 5
2.2.4. Volatilization 6
2.2.5. Adsorption 6
2.2.6. B1oconcentrat1on 6
2.3. SOIL 6
2.3.1. Mlcroblal Degradation 6
2.3.2. Chemical Degradation 6
2.3.3. Adsorption/Leaching 6
2.3.4. Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 9
3.1. WATER 9
3.2. FOOD 9
3.3. INHALATION 10
3.4. DERMAL 10
3.5. SUMMARY 10
4. AQUATIC TOXICITY 11
4.1. ACUTE TOXICITY 11
4.2. CHRONIC EFFECTS 11
4.3. PLANT EFFECTS 11
4.4. SUMMARY 14
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TABLE OF CONTENTS (cont.)
Page
5. PHARMACOKINETCS 15
5.1. ABSORPTION 15
5.2. DISTRIBUTION 15
5.3. METABOLISM 16
5.4. EXCRETION 19
5.5. SUMMARY 20
6. EFFECTS 21
6.1. SYSTEMIC TOXICITY 21
6.1.1. Inhalation Exposures 21
6.1.2. Oral Exposures 21
6.1.3. Other Relevant Information 29
6.2. CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. Oral 30
6.2.3. Other Relevant Information 33
6.3. MUTAGENICITY 33
6.4. TERATOGENICITY 37
6.5. OTHER REPRODUCTIVE EFFECTS 38
6.6. SUMMARY 41
7. EXISTING GUIDELINES AND STANDARDS 46
7.1. HUMAN 46
7.2. AQUATIC 46
8. RISK ASSESSMENT 47
8.1. CARCINOGENICITY 47
8.1.1. Inhalation 47
8.1.2. Oral 47
8.1.3. Other Routes 48
8.1.4. Weight of Evidence 48
8.1.5. Quantitative Risk Estimates 49
8.2. SYSTEMIC TOXICITY 49
8.2.1. Inhalation Exposure 49
8.2.2. Oral Exposure 49
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TABLE OF CONTENTS (cont.)
Page
9. REPORTABLE QUANTITIES 55
9.1. BASED ON SYSTEMIC TOXICITY 55
9.2. BASED ON CARCINOGENICITY 58
10. REFERENCES 60
APPENDIX A: LITERATURE SEARCHED 75
APPENDIX B: SUMMARY TABLE FOR CYCLOHEXYLAMINE 78
x1v
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LIST OF TABLES
No. Title Page
4-1 Acute Tox1c1ty of Cyclohexylamlne to Aquatic Organisms. ... 12
4-2 Effects of Cyclohexylamlne on Aquatic Plants and Bacteria . . 13
6-1 Mutagenlclty Testing of Cyclohexylamlne 34
9-1 Oral Toxlclty Summary for Cyclohexylamlne 56
9-2 Oral Composite Scores for Cyclohexylamlne 57
9-3 Cyclohexylamlne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 59
xv
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
BOD Biological oxygen demand
BOOT Biological oxygen demand, theoretical
bw Body weight
CS Composite score
ECso Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
GC/MS Gas chromatography/mass spectrometry
GLC Gas-liquid chromatography
HPLC High performance liquid chromatography
l.p. Intraperltoneal
Koc Soil sorptlon coefficient standardized with respect
to organic carbon
K Octanol/water partition coefficient
LCsg Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
LD5_ Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
NOES National Occupational Exposure Survey
NOHS National Occupational Health Survey
ppb Parts per billion
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RV. Dose-rating value
RV& Effect-rating value
TLC Thin layer chromatography
TLV Threshold limit value
TWA Time-weighted average
xvl
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1. INTRODUCTION
1.1. STRUCTURE AND CAS REGISTRY NUMBER
Cyclohexylamlne 1s also known by the synonyms amlnocyclohexane, cyclo-
hexanamlne, CHA, hexahydroanlUne and hexahydrobenzenamlne (SANSS, 1987).
The structure, molecular weight, empirical formula and CAS Registry number
for cyclohexylamlne are as follows:
NH,
C«a /CH
^H.
Molecular weight: 99.17
Empirical formula: C,H.«N
D IJ
CAS Registry number: 108-91-8
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Cyclohexylamlne 1s a liquid at room temperatures and has a strong,
flsfry, amlne odor (Wlndholz, 1983). It 1s completely mlsclble with water
and with common organic solvents, such as alcohols, ethers, ketones, esters,
aliphatic hydrocarbons, aromatic hydrocarbons and chlorinated hydrocarbons
(Wlndholz, 1983). Selected physical properties of cyclohexylamlne are
presented below:
Freezing point: -18°C Parrlsh, 1983
Boiling point: 135°C Parrlsh, 1983
Specific gravity: 0.8647 (25/25'C) Wlndholz, 1983
Water solubility: completely mlsclble Parrlsh, 1983
Vapor pressure:
at 25°C 9 mm Hg Parrlsh, 1983
at 30.5°C 15 mm Hg Wlndholz. 1983
0064d -1- 09/30/87
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Log Kow: 1.49 Hansch and Leo, 1981
Flash point: 32.2°C (open cup) Hawley, 1981
A1r conversion 1 mg/m3 = 0.247 ppm Verschueren, 1983
factors at 25°C: 1 ppm = 4.056 mg/m3
A1r odor threshold: 2.6 ppm Amoore and Hautala, 1983
Water odor threshold: 25 ppm Amoore and Hautala, 1983
pKa at 24°C: 10.66 Weast, 1985
Cyclohexylamlne Is a strong base that forms salts with acids (IARC,
1980). It reacts with organic compounds containing an active halogen atom,
with acid anhydrides, and with alkene oxides (IARC, 1980). It 1s flammable
and Is considered a moderate fire risk (Hawley, 1981).
1.3. PRODUCTION DATA
U.S. production demand for cyclohexylamlne was -8.5 million pounds In
1984 (CMR, 1984). Demand 1n 1988 1s expected to reach 9.9 million pounds
(CMR, 1984). Imports of cyclohexylamlne through principal U.S. customs
districts In 1983 were reported to be 3.3 million pounds (USITC, 1984).
Cyclohexylamlne Is manufactured 1n the United States by A1r Products and
Chemicals In Wichita, KS, and by Celanese Corporation (Virginia Chemicals,
subsidiary) In Bucks, AL, and Portsmouth, VA (SRI, 1986). The annual
capacity of Air Product's facility Is 10 million pounds, while the annual
capacity of Celanese's Portsmouth facility 1s 8 million pounds (SRI, 1986).
Cyclohexylamlne can be manufactured commercially by the catalytic
hydrogenatlon of aniline, by the ammonolysls of cyclohexanol and by the
reduction of nltrocyclohexane (SandMdge and Staley, 1978). Air Products
uses the aniline hydrogenatlon method, while Celanese uses a cyclohexanol
feedstock (SRI, 1986).
0064d -2- 06/12/87
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1.4. USE DATA
Cyclohexylamlne has the following reported use pattern (CMR, 1984;
Ulndholz, 1983): boiler water treatment (60%); rubber chemicals (25%); chain
terminator (8%); miscellaneous, Including Intermediates In the manufacture
of Insecticides, plastldzers and photographic chemicals; catalysts; and
metal extraction (7%). Boiler water treatment Involves the use of cyclo-
hexylamlne as a corrosion Inhibitor for binding of carbon dioxide In
petroleum boiler systems (IARC, 1980).
In 1968, a major use of cyclohexylamlne was the production of cyclamate
sweeteners for beverages and food products (IARC, 1980). The U.S. Food and
Drug Administration banned the use of cyclamate sweeteners In 1970, which
significantly reduced the market for cyclohexylamlne.
1.5. SUMMARY
Cyclohexylamlne Is a liquid with a strong, fishy, amlne odor (Wlndholz,
1983). It Is mlsdble with water and most common organic solvents
(Ulndholz, 1983) and Is a strong base (IARC, 1980). U.S. production demand
for cyclohexylamlne was -8.5 million pounds In 1984 (CMR, 1984). Two U.S.
manufacturers operate three production facilities with a combined annual
capacity of at least 18 million pounds (SRI, 1986). Cyclohexylamlne has the
following reported use pattern (CMR, 1984; Wlndholz, 1983): boiler water
treatment (60%); rubber chemicals (25%); chain terminator (8%); miscella-
neous, Including Intermediates In the manufacture of Insecticides, plastl-
dzers and photographic chemicals; catalysts; and metal extraction (7%). A
major use 1n the 1960s was In the production of cyclamate sweeteners (IARC,
1980). The use of cyclamate sweeteners was banned In 1970 by the U.S. Food
and Drug Administration.
0064d -3- 06/12/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on Us relatively high vapor pressure (9 mm Hg at 25°C), cyclo-
hexylamlne will exist almost entirely 1n the vapor phase In the atmosphere
(Elsenrelch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. The rate constant for vapor-
phase reaction of cyclohexylamlne with photochemlcally produced hydroxyl
radicals In the atmosphere has been estimated to be 5.51xlO~12 cm3/
molecule-sec at 25°C, which corresponds to a half-life of 1.82 days 1n a
typical atmosphere containing 8xl05 hydroxyl radicals/cm3 (U.S. EPA,
1987). This relatively rapid reaction rate suggests that reaction with
hydroxyl radicals will be the dominant atmospheric fate process. Based on
reaction of atmospheric ozone with other amines (Atkinson and Carter, 1984),
reaction of ozone with cyclohexylamlne 1s not likely to be significant;
however, reaction with atmospheric nitrate radicals may be an Important
process for the loss of cyclohexylamlne from the atmosphere (Atkinson and
Carter, 1984). The kinetic data for this reaction are not available.
2.1.2. Physical Removal Processes. Cyclohexylamlne Is completely
mlsdble In water (Wlndholz, 1983); therefore, dissolution Into clouds with
subsequent rainfall and direct atmospheric washout are possible. Physical
removal from the atmosphere may not be Important, however, 1n relation to
reaction with hydroxyl radicals, since the reaction with hydroxyl radicals
1s quite rapid.
2.2. WATER
2.2.1. Hydrolysis. Experimental data pertaining to the aqueous environ-
mental hydrolysis of cyclohexylamlne could not be located In the available
literature as cited In Appendix A.
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2.2.2. Photolysls/Photooxidatlon. Pertinent data regarding the photoly-
sis or photooxldatlon of cyclohexylamlne In water could not be located In
the available literature as cited 1n Appendix A.
2.2.3. M1crob1al Degradation. The available blodegradatlon data Indicate
that cyclohexylamlne Is significantly biodegradable at concentrations that
would normally be encountered In the environment.
CalamaM et al. (1980) used a resplrometer assay to study the blodegra-
datlon of cyclohexylamlne over a 14-day period with three different Inocula
(river mud, sewage sludge and adapted sewage sludge) at three concentrations
of the amlne (10, 50 and 100 ppm). At a concentration of 10 ppm, 62.0-92.0%
BOOT was measured with 100% disappearance of the amlne In all Inocula. At
50 ppm, similar results were observed for the sewage Inocula, but no degra-
dation occurred with river mud Inocula. Although the reported differences
between the measured percent BOOT and disappearance values were not
explained by the authors, 1t appears that volatilization of the chemical and
other experimental limitations were responsible.
Novlck and Alexander (1985) examined the b1om1nera!1zat1on of cyclo-
hexylamlne 1n serum bottles at an Initial concentration of 10 ppb with
either a eutrophlc lake water or a sewage effluent as Inoculum. After an
Incubation period of 1 week 1n the sewage Inoculum, 63% of the cyclohexyla-
mlne had mineralized. A 4-week Incubation period was required to mineralize
53% of the cyclohexylamlne 1n the eutrophlc water.
Thorn and Agg (1975) listed cyclohexylamlne as a synthetic organic chemi-
cal that should be degradable by biological sewage treatment provided suit-
able acclimation can be achieved. BOO studies have shown that cyclohexyl-
amlne 1s degradable In activated sludges (Wotzka et al., 1985; Rothkopf and
Bartha, 1984).
0064d -5- 09/30/87
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2i2,4. VelatlHiatlon. Because cyclohexylamlne Is present predominantly
1n the protonated form under most environmental conditions (pH 5-9),
volatilization from water surfaces Is not expected to be significant.
2.2.5. Adsorption. Cyclohexylamlne Is completely mlsdble In water
(Wlndholz, 1983). Therefore, significant partitioning from the water column
to suspended organic matter or to sediment Is not expected to occur. The
log K value of 1.49 (Hansch and Leo, 1981) also Indicates that aquatic
adsorption will not be significant.
2.2.6. B1oconcentrat1on. Estimation of the BCF of an organic chemical
can be made from the following regression equation (Lyman et al., 1982):
log BCF = 0.76 log K - 0.23 (2-1)
For cyclohexylamlne, the BCF value calculated from Equation 2-1 1s ~8 based
on a log K of 1.49. This BCF value Indicates that cyclohexylamlne Is
not expected to bloconcentrate significantly In aquatic organisms.
2.3. SOIL
2.3.1. Hlcroblal Degradation. Mlcroblal degradation data specific to
soil were not located for cyclohexylamlne. As discussed 1n Section 2.2.3.,
cyclohexylamlne has been shown to blodegrade with eutrophlc lake water,
river mud and activated sludge. This Indicates that mlcroblal degradation
1s likely to occur 1n soil.
2.3.2. Chemical Degradation. Data pertaining to the chemical (abiotic)
degradation of cyclohexylamlne 1n soil could not be located In the available
literature as cited 1n Appendix A.
2.3.3. Adsorption/Leaching. The K of an organic chemical can be
estimated from the following regression equation (Lyman et al., 1982):
log K = 0.544 log K f 1.377 (2-2)
0064d -6- 06/12/87
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For cyclohexylamlne, the KQC value calculated from Equation 2-2 Is 154,
based on a log K of 1.49. This K value Indicates medium soil mobll-
ow oc
1ty (Swann et al., 1983). Therefore, In the absence of significant degrada-
tion processes, cyclohexylamlne 1s susceptible to significant leaching
through soil Into groundwater.
2.3.4. Volatilization. The vapor pressure of cyclohexylamlne (9 mm Hg at
25°C) suggests that significant evaporation from dry surfaces 1s likely to
occur. Volatilization from moist soil surfaces 1s not expected to be
significant because more protons are added to cyclohexylamlne under
environmental conditions.
2.4. SUMMARY
The dominant environmental fate process for cyclohexylamlne In the atmo-
sphere Is expected to be the vapor-phase reaction with hydroxyl radicals;
this reaction has an estimated half-life of 1.82 days 1n a normal atmosphere
(U.S. EPA, 1987). Reaction with nitrate radicals may also be a significant
removal process for atmospheric cyclohexylamlne (Atkinson and Carter, 1984);
however, kinetic data for this reaction are not available. If released to
the aquatic environment, mlcroblal degradation and volatilization are
expected to be the Important fate processes. Available blodegradatlon data
Indicate cyclohexylamlne to be significantly biodegradable with eutrophlc
lake water, river mud, sewage and activated sludges (Calamarl et al., 1980;
Novlck and Alexander, 1985; Wotzka et al., 1985; Rothkopf and Bartha, 1984).
Volatilization, adsorption to sediment and bloconcentratlon are not expected
to be significant. If released to soil, mlcroblal degradation 1s likely to
be an Important process. This Is based on Its blodegradatlon potential In
aquatic media. The estimated KQC value of 154 Indicates that In the
absence of significant degradation processes, cyclohexylamlne may leach
0064d -7- 09/30/87
-------
significantly through son Into groundwater. The relatively high vapor
pressure of cyclohexylamlne suggests that volatilization from dry soils may
be a significant removal process; however, cyclohexylamlne 1s not expected
to volatilize from moist soil surfaces.
0064d -8- 09/30/87
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3. EXPOSURE
Cyclohexylamlne has not been reported to occur naturally 1n the environ-
ment (IARC, 1980); therefore, Its presence 1n the environment Is due to
anthropogenic sources, such as releases from production and user facilities.
An NOHS conducted between 1972 and 1974 estimated that 9532 U.S. workers
may be exposed to cyclohexylamlne (NIOSH, 1984). The preliminary results of
a more recent survey, the NOES, which has been conducted In the 1980s, has
estimated that 3103 workers may be exposed to cyclohexylamlne (NIOSH, 1985);
however, this survey does not Include exposures to cyclohexylamlne from
trade-name products.
3.1. WATER
Cyclohexylamlne has been detected 1n the wastewater effluent of a tire
manufacturing plant at a concentration of 0.01 ppm (Jungclaus et al., 1976).
It has also been detected In the wastewater effluent of a latex manufactur-
ing plant (Shackelford and Keith. 1976). Francis et al. (1980) qualita-
tively Identified cyclohexylamlne In trench leachates collected from commer-
cially operated low-level radioactive waste disposal sites at Maxey Flats,
KY, and West Valley, NY.
The gross analysis for cyclohexylamlne available from the U.S. EPA
STORET Data Base cited 107 reporting stations. The mean concentration of
cyclohexylamlne was reported to be 1 ppm.
3.2. FOOD
Pertinent data regarding the monitoring of cyclohexylamlne In food could
not be located 1n the available literature as cited In Appendix A.
0064d -9- 09/30/87
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3.3, INHALATION
Pertinent data regarding the monitoring of cyclohexylamlne In ambient
air could not be located 1n the available literature as cited In Appendix A.
3.4. DERMAL
Pertinent data regarding the dermal monitoring of cyclohexylamlne could
not be located In the available literature as cited In Appendix A.
3.5. SUMMARY
Cyclohexylamlne has not been reported to occur naturally In the environ-
ment (IARC, 1980); therefore, Its presence 1n the environment 1s due to
anthropogenic sources, such as releases from production and user facilities.
It has been detected In wastewater effluents from tire and latex manufactur-
ing plants (Jungclaus et al., 1976; Shackelford and Keith, 1976) and 1n
trench leachates from low-level radioactive waste disposal sites (Francis et
al., 1980). An NOHS conducted between 1972 and 1974 estimated that 9532
U.S. workers may be exposed to cyclohexylamlne (NIOSH, 1984).
0064d -10- 06/12/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
The available Information regarding the toxlclty of cyclohexylamlne to
fish and aquatic Invertebrates 1s presented In Table 4-1. Among the three
freshwater species for which there were data, the lowest reported toxic
concentration was 44 mg/l, a 96-hour LC5Q for rainbow trout, Sal mo
galrdnerl. 1n soft water (CalamaM et a!., 1980). In this study, cyclo-
hexylamlne was about twice as toxic In soft water (20 mg/l as CaCO.) as
1n hard water (320 mg/l as CaCO.,}. The lowest reported toxic concentra-
tion for Invertebrates was 0.7 mg/l, a threshold for Inhibition of cell
multiplication of the protozoan, Entoslphon sulcatum (Brlngmann and Kuehn,
1980).
Data regarding marine species could not be located In the available
literature as cited 1n Appendix A.
4.2. CHRONIC EFFECTS
Pertinent data regarding the chronic toxlclty of cyclohexylamlne to
aquatic organisms could not be located 1n the available literature as cited
1n Appendix A.
4.3. PLANT EFFECTS
Data regarding the effects .of cyclohexylamlne on aquatic plants and
bacteria are presented In Table 4-2. The blue-green alga, Hlcrocystls
aeruglnosa. was the most sensitive species tested, with a toxlclty threshold
of 0.20 mg/l for Inhibition of cell multiplication (Brlngmann and Kuehn,
1978). This was the lowest toxic concentration reported for any species.
0064d -11- 09/30/87
-------
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00644
-13-
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-------
4.4. SUMMARY
Among the three freshwater species for which there were data, the lowest
reported toxic concentration was 44 mg/l, a 96-hour LC5Q for rainbow
trout, Salmo qalrdnerl. 1n soft water (CalamaM et al., 1980). In this
study, cyclohexylamlne was about twice as toxic 1n soft water (20 mg/l as
CaCO.) as 1n hard water (320 mg/l as CaCOJ. The lowest reported
toxic concentration for Invertebrates was 0.7 mg/l, a threshold for
Inhibition of cell multiplication of the protozoan, Entoslphon sulcatum
(BMngmann and Kuehn, 1980). Among aquatic plants and bacteria, the blue-
green alga, H1crocyst1s aeruglnosa. was the most sensitive species tested,
with a toxldty threshold of 0.20 mg/l for Inhibition of cell multiplica-
tion (Brlngmann and Kuehn, 1978). This was the lowest toxic concentration
reported for any species. Data for marine species could not be located 1n
the available literature as cited In Appendix A.
0064d -14- 09/30/87
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5. PHARMACOKINETICS
5.1. ABSORPTION
Renwlck and Williams (1972) orally administered 98.9% pure
[l-l4C]cyclohexylam1ne«HCl In water to three human male subjects at 25
mg/man. Radioactivity 1n urine and feces was measured for <72 hours after
dosing. Recovery from the urine of 92.IX of the administered label after 24
hours and 94.8X after 72 hours Indicates that gastrointestinal absorption
was rapid and virtually complete. Completeness of absorption was further
Indicated by the recovery of <1X of the administered radioactivity In the
feces at 72 hours. Elchelbaum et al. (1974) reported similar results In
volunteers administered 2.5, 5 or 10 mg/kg oral cyclohexylamlne. Between 86
and 95X of the dose was excreted In the urine 48 hours after administration.
No further details were available.
Female Wlstar rats and albino guinea pigs given single oral doses of 50
mg/kg of [l4-C]cyclohexylam1ne excreted 86.4 and 89.8X of the radio-
activity 1n the urine within 24 hours (Renwlck and Williams, 1972). A total
of 68X of administered radioactivity was recovered within 60 hours 1n the
urine of a rabbit given an oral dose of 0.17 g/kg [l4C]cyclohexylam1ne
(Elliott et al., 1968). These data Indicate that gastrointestinal absorp-
tion 1s rapid and fairly extensive 1n laboratory animals.
There were no data 1n the available literature regarding the extent of
absorption of cyclohexylamlne after Inhalation exposure.
5.2. DISTRIBUTION
PHkln et al. (1969) Intravenously Infused 50 yC1 (10 mg) of
[14C]-cyclohexylam1ne«HCl Into each of two gravid rhesus monkeys over a
period of 180 minutes and took samples from the maternal vena cava, 1nter-
placental vein and amnlotlc sac. Samples were taken at 15- to 30-mlnute
0064d -15- 09/30/87
-------
Intervals during Infusion and, 1n one monkey, for 1 hour after termination
of Infusion. Maternal and fetal blood levels of radioactivity were
virtually Identical at all time points, which Indicated the free diffusion
of cyclohexylamlne across the placental barrier.
5.3. METABOLISM
Male volunteers, female Wlstar rats and female guinea pigs given oral
[l4-C]cyclohexylam1ne at 25 mg (humans) or 50 mg/kg (rats and guinea pigs)
excreted between 78.2 and 87.OX of the administered radioactivity 1n the
24-hour urine as unchanged parent compound (Renwlck and Williams, 1972).
Unchanged compound represented between 87.1 and 96.5% of the total radio-
activity recovered 1n the 24-hour urine. Renwlck and Williams (1972)
assayed 24-hour urine samples from humans and animals given larger doses of
cyclohexylamlne for metabolites. Five female Wlstar rats received 500 mg/kg
(2.3 yC1 of label) [l4C]cyclohexylam1ne orally, three New Zealand white
rabbits received 100 mg/kg (9.4 yd) each by Intraperltoneal Injection,
three guinea pigs received 450 mg/kg (3.9 yC1) by oral or Intraperlto-
neal Injection and three humans received 200 mg (6.2 yd) orally. For all
four species, the compound' found 1n greatest quantity (constituting
58.0-86.9% of radioactivity administered and 61-94% of total urinary excre-
tion) was the unchanged parent compound. Postulated pathways of metabolism,
which were species-specific, are Illustrated In Figure 5-1. Rats excreted
four amlnocyclohexanols (constituting 4.5% of the administered radio-
activity) and cyclohexanol Itself (0.05%). Guinea pigs excreted six ring
hydroxylated compounds, Including two that were deamlnated (3.0%) and four
that were not (1.8%). Both deamlnation and hydroxylatlon occurred In
rabbits, where 14.2% of the administered radioactivity appeared as deaml-
nated oxidation products (alcohols, ketones, and dlols), and 12.7% appeared
0064d -16- 09/30/87
-------
NHOH
f
eye loh«xy Ihydroxy 1
cis-3-»«inocyclohcxanol
inocyclohexanol
trans-4-aainocyclohcx*nol
eyeloh*x*none
fycloh*x«nol
trans-cyclohaxane-1,2-di ol
FIGURE 5-1
Probable Routes of Metabolism of Cyclohexylamlne
Source: Renwtck and Williams. 1972
0064d
-17-
06/12/87
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as cyclohexylhydroxylamlne and various configurations of 3- and 4-amlno-
cyclohexanol. Rabbits appeared to metabolize cyclohexylamlne more com-
pletely than the other species tested. Renwlck and Williams (1972) Identi-
fied only two urinary metabolites In man. These products were cyclohexanol
(0.2%) and trans-cyclohexane-1,2-d1ol (1.4%); however, the Investigators
noted that the observed differences between the human and animal subjects
may have been due to marked differences 1n the sizes of the doses admin-
istered.
Renwlck and Williams (1972) also used acid hydrolysis on the samples to
determine the extent of conjugation of the urinary metabolites. Hydrolysis
substantially Increased the amount of radioactivity measured for all rat and
rabbit metabolites, for trans-cyclohexano-l,2-d1ol 1n guinea pigs and
humans, and for cyclohexanol In humans, which Indicated extensive
conjugation of these products.
Roberts and Renwlck (1985) administered single doses of [14C]cyclo-
hexylam1ne»HCl 1n water that provided 35, 200 or 500 mg/kg cyclohexylamlne
to groups of three male and three female Wlstar rats, three male DA rats and
three male GDI mice by gavage, subcutaneous or 1ntraper1toneal administra-
tion. Urine samples were taken for three 24-hour periods, and metabolite
formation 1n the first 24-hour sample was assessed using both TLC and HPLC.
Urinary product formation appeared to be Independent of dose or route of
administration, but sex, strain and species differences occurred. From
61.6-90.2% of the administered radioactivity was recovered 1n the 24-hour
urine of all species. The percentage of the recovered radioactivity that
was unchanged parent compound and various hydroxylated metabolites varied
with sex, species, strain and method of analysis (I.e., TLC vs. HPLC).
0064d -18- 09/30/87
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Generally, male DA rats and female Wlstar rats metabolized cyclohexylamlne
similarly, with 87.6-96.1% of the radioactivity In the urine consisting of
unchanged parent compounds. Male Wlstar rats metabolized the material
somewhat more extensively, with 75.9-84.9% of the urinary radioactivity
recovered as parent compound. Mice metabolized cyclohexylamlne minimally,
with 94.6-98.4% of the recovered radioactivity as unchanged cyclohexylamlne.
5.4. EXCRETION
As discussed In Section 5.1., Renwlck and Williams (1972) found that
92.1% of the administered radioactivity after an oral 25 mg dose of
[l4C]-cyclohexylam1ne»HCl was excreted 1n the 24-hour urine of male
volunteers. Elchelbaum et al. (1974) recovered 86-95% of a single 2.5-10
mg/kg oral dose of cyclohexylamlne from the 48-hour urine of volunteers.
Female Wlstar rats and guinea pigs excreted 86.4 and 89.8% of the radio-
activity 1n the 24-hour urine after a single oral 50 mg/kg dose. Fecal
excretion accounted for <1% of the administered radioactivity 1n humans,
0.6% In rats and 4.0% 1n guinea pigs 1n the 72 hours following dosing.
[14Cp?] levels In the expired air of rats were negligible 24 hours after
dosing, but constituted 0.5% of the administered radioactivity 1n guinea
pigs. For all species, the amount of radioactivity recovered was between
92.6 and 98.4% of the administered dose.
In male and female Wlstar rats, male DA rats and male GDI mice treated
with doses of 35-500 mg/kg cyclohexylamlne from 14C-cyclohexylam1ne-HCl
by oral, subcutaneous or Intraperltoneal administration, excretion In the
urine within 24 hours accounted for 61.6-91.2% of the dose of radioactivity
(Roberts and Renwlck, 1985). In male Wlstar rats at the highest dosage,
urinary excretion during the second 24 hours accounted for 11.9% of the dose
of radioactivity, which suggested saturation of renal excretion mechanisms.
0064d -19- 09/30/87
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In a later study, Roberts and Renwlck (1986) studied the kinetics of
cyclohexylamlne elimination In rats and mice. Elimination half-time
Increased with dose In both species, with effect of dose more marked In
rats. Steady-state plasma clearance rate of 33 ml/mlnute/kg was estimated
for rats and 66 mi/minute/kg for mice.
In a rabbit fed 0.17 g/kg ["CKyclohexylamlne, 13% of the radio-
activity was recovered from the urine In 10 hours, 39% In the next 20 hours
and 16% 1n the last 30 hours (Elliott et al., 1968). Breath measurements
revealed that 0.3% was excreted as [14CO-] and 0.2% was excreted as
ethanol-soluble material.
5.5. SUMMARY
Based on animal excretion studies (Elliott et al., 1968; Renwlck and
Williams, 1972; Roberts and Renwlck, 1985) and human studies (Elchelbaum et
al., 1974; Renwlck and Williams, 1972), cyclohexylamlne 1s absorbed rapidly
and nearly completely after oral Intake. Excretion Is primarily through the
urine, with 61.6-90.2% of the radioactivity from a dose of 14C-cyclohexyl-
amlne-HCl recovered within 24 hours. Rabbits appear to metabolize cyclo-
hexylamlne most completely and mice and humans least, with >90% of urinary
radioactivity recovered as unmetabollzed compound (Renwlck and Williams,
1972, Roberts and Renwlck, 1985). Pathways of metabolism Include hydroxyl-
atlon with and without deamlnation and partial conjugation of the hydroxyl-
atlon products. Steady-state plasma clearance rates of 33 and 66 mi/
minute/kg were estimated for rats and mice, respectively (Roberts and
Renwlck, 1986). Pltkln et al. (1969) showed that cyclohexylamlne could
freely cross the monkey placental barrier after Intravenous Infusion In the
mother.
0064d -20- 09/30/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. Pertinent data regarding the chronic and
subchronlc toxlclty of cyclohexylamlne after Inhalation exposure could not
be located 1n the available literature as cited In Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — In a 90-day study, Gaunt et al. (1974) fed
diets containing 0, 600, 2000 or 6000 ppm cyclohexylam1ne«HCl to groups of
15 Wlstar rats/sex. The Investigators estimated compound Intake at 41, 143
and 468 mg/kg/day 1n the three treated groups, respectively. It appears
that these values refer to cyclohexylam1ne-HCl rather than to the free
base. The rats given the two higher concentrations had reduced rates of
body weight gain and reduced food Intake. Paired feeding studies on
separate groups of 10 male rats showed that the reduction In food consump-
tion alone could not account for the decreased body weight. Rather,
measurements of oxygen consumption suggested a treatment-related Increase In
the basal metabolic rate. There were no compound-related effects on hema-
tology, serum chemistry, relative organ weights or hlstopathology, with the
exception of the testls. Females given the highest dietary level had a
slight reduction In renal concentrating ability, and 2000 and 6000 ppm males
had reduced testlcular weight with hlstologlcal evidence of reduced sperma-
togenesls; both the Incidence and severity occurred 1n a dose-related
manner. Complete arrest of spermatogenesls and loss of germinal epithelium
were observed In eight males In the 6000 ppm group. A re-analysis of the
slides (discussed by Bopp et al., 1986) revealed that all testlcular hlsto-
pathologlcal effects were confined to the high concentration group; however,
0064d -21- 06/12/87
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there were no Indications of reproductive Impairments In a group of males
fed a diet containing 600 ppm for 10 months, as assessed by the number of
fertile males or Utter size and growth.
Colllngs and Klrkby (1974) treated groups of 15-16 male rats with 0.01,
0.05, 0.1, 0.2, 0.5 or l.OX dietary cyclohexylam1ne»HCl for 90 days. The
relative testlcular weight of the rats administered l.OX was decreased, com-
pared with controls, and 13/15 of these rats had degeneration of the tubular
epithelium. Other treated rats did not show major changes from controls In
testlcular hlstopathology. In another 90-day study, Hason and Thompson
(1977) fed groups of 25 male Wlstar and 25 male Sprague-Dawley rats diets
containing 0.06, 0.2 and 0.6X cyclohexylam1ne»HCl for 90 days. Only the
high concentration group had testlcular effects, Including reductions In
testlcular weights, sperm count and motllHy, and Impaired spermatogenesls.
Because pair-fed controls did not have similar testlcular changes, the
results were not attributed to Inanition. Exposure to 0.2% produced a
statistically significant Inhibition 1n weight gain. James et al. (1981)
administered 200 mg/kg/day cyclohexylamlne base, of unspecified purity, by
gavage to 15 male weanling SPF rats for 9 weeks. The Investigators sacri-
ficed five rats from each group after weeks 4 and 9, and the remaining five
rats from each group were maintained for 13 weeks (untreated) to assess
reversibility of effects. Treated rats had significant reductions In circu-
lating testosterone levels and the number of late spermatlds, and the group
given 13 weeks of withdrawal had reduced numbers of pachytene spermatocytes
and early spermatlds. There were no differences between treated and control
groups In hlstologlcal parameters or relative organ weights. Brune et al.
(1978) fed groups of 100 male Sprague-Dawley rats diets that provided 50,
100, 200 or 300 mg cyclohexylamlne base/kg/day for 90 days. Dietary concen-
trations were adjusted to account for differences In body weight with age.
0064d -22- 09/30/87
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Significant decreases In body weight were found 1n the 200 and 300 mg/kg/day
groups, and rats at the highest dietary concentration had lower testlcular
weights, relative to pair-fed controls. Testlcular tubular alterations were
observed 1n rats In the 200 and, especially, In the 300 mg/kg/day groups,
with degenerative changes 1n the tubules, giant cell formation and complete
testlcular atrophy. The changes occurred 1n just a few rats that were
severely affected; most rats showed no evidence of testlcular damage.
James et al. (1981) also treated four sexually mature male beagle dogs
with cyclohexylamlne 1n corn oil by gavage for 9 weeks. Because of gastric
Irritation, It was necessary to use an Incremental gavage regime during the
first 9 days of dosing. Although the TWA dose was -240 mg/kg/day, ernes 1s
occurred after 12-35% of the doses. Relative to predoslng baseline control
levels, cyclohexylamlne decreased pachytene spermatocyte and early and late
spermatld counts, and Increased the percentage of colled-tall spermatozoa In
ejaculates. Sperm counts and the number of abnormal spermatozoa were not
different from baseline levels 1n two dogs after a 12-week recovery period.
Although reduction 1n the testlcular area of treated dogs after 4 and 8
weeks of treatment were found, relative testes weights were not affected
adversely.
In a 3-month study, Colllngs and Klrkby (1974) found that 2.5% dietary
cyclohexylam1ne-HCl was fatal to all rats after 5 days of dosing. Necrop-
sled rats had Intestinal hemorrhage. Rats fed diets containing 0.01-1.0%
cyclohexylamlne for 90 days showed no changes 1n blood pressure or In the
pressor response to noreplnephrlne.
6.1.2.2. CHRONIC — Gaunt et al. (1976) conducted a long-term bio-
assay of dietary cyclohexylam1ne*HCl administration In Wlstar rats of both
sexes. Forty-eight rats/sex were administered either 600, 2000 or 6000 ppm
0064d -23- 09/30/87
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cyclohexylam1ne»HCl of unspecified purity for 104 weeks. According to the
authors, these levels corresponded to cyclohexylam1ne-HCl Intakes of 24
(male) and 35 (female) mg/kg/day, 82 (male) and 120 (female) mg/kg/day, and
300 (male) and 440 (female) mg/kg/day, respectively. A negative control
group receiving only the basal diet was Included. The Investigators
recorded body weights and food and water consumption of all surviving rats,
collected blood samples from 10 rats/sex 1n the 0, 2000 and 6000 ppm groups,
and took urine samples from 10 control rats/sex and 10 rats/sex of the 6000
ppm group at various Intervals throughout the study. When the urine samples
were collected, tests were conducted to assess specific gravity during
periods of water deprivation and after a 25 ml/kg water load. Postmortem
examinations were performed on all rats found dead during the study, and on
all sacrificed rats at the end of 104 weeks; the weights of 12 organs were
recorded. Gaunt et al. (1976) performed hlstopathologlcal examinations on
H&E stained sections of 27 tissues, Including the urinary bladder.
The results showed a concentration-related decrease 1n cumulative
mortality, accompanied by concentration-related decreases In body weight and
food and water consumption for both sexes. The Investigators cited prior
literature which Indicated that voluntary reduction of food Intake was
associated with Increased longevity. The decreases In body weights were
statistically significant In all treated groups at all time points except 1n
low dose males at >92 weeks. Terminal body weights In low-dose rats were
reduced ~7X In males and ~11X 1n females (p<0.01); food consumption In these
groups was reduced <2%. Additionally, a number of other aberrations,
Including reduced Incidence of glomerulonephrosls and smaller relative
kidney weights, differences In serum urea and albumin concentrations,
Increased relative brain, stomach, small Intestine, cecum and ovary weights,
0064d -24- 09/30/87
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decreased heart and spleen weights, and reduced Incidences of other hlsto-
pathologlcal lesions were found at the higher concentrations. Gaunt et al.
(1976) did not consider these effects to be directly treatment-related, but
rather a result of the reduced food and water Intake In the exposed rats.
Females treated with 6000 ppm had reductions In hemoglobin and packed
cell volume during the first year of the study, and both sexes administered
the high concentration had decreases 1n neutrophll counts and Increases In
lymphocyte numbers during the second year. The Investigators considered
Increased relative thyroid weights In females treated with 2000 and 6000
ppm to be possibly treatment-related, although males did not have the same
abnormality. Also considered treatment-related were an Increased Incidence
of alveoli with foamy macrophages and severe testlcular damage 1n rats given
6000 ppm. Testlcular damage consisted of bilateral atrophy and Increased
calcium deposits In tubules. At 2000 ppm, damage was limited to an Increase
1n the number of tubules with few or no spermatlds. Gaunt et al. (1976)
considered these testlcular effects to be treatment-related. Testlcular
effects were not observed at 600 ppm. These findings confirm previous
results (Gaunt et al., 1974) (see Section 6.1.2.1.), which Indicated
testlcular damage after repeated oral exposure to cyclohexylamlne.
Hardy et al. (1976) administered 0, 300, 1000 or 3000 ppm dietary
cyclohexylam1ne-HCl to groups of 48 male and 50 female ASH-CS1 mice for 80
weeks. Compound purity was not specified 1n this report. Hales were
Individually housed, whereas females were housed five to a cage. At regular
Intervals throughout the study, body weights and food and water consumption
were measured on selected mice. The Investigators collected blood samples
during weeks 13, 26, 52 and 80 from 10 mice/sex In the control, 1000 ppm and
0064d -25- 09/30/87
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3000 ppm groups for standard hematologlcal assays. An examination of red
cell morphology and differential white cell analysis was conducted on
control and high concentration samples. Postmortem study of mice sacrificed
after 80-84 weeks of exposure Included a macroscopic examination for
abnormalities, weighing of 7 tissues and microscopic hlstopathology of 24
tissues.
Treatment resulted In no adverse effects on mortality, body or organ
weight changes or measures of food and water consumption. Hematologlcal
changes were not consistent across treatment groups and did not suggest a
compound-related response. Hlstopathologlcal examination of the bladder
submucosa revealed Increased foci of lymphocytes In males exposed to 1000
ppm, but not In males exposed to 3000 ppm. Females given 300 ppm had an
Increased Incidence of glomerulonephrosls, which was not observed at higher
concentrations. Both of these observations were considered spurious. The
only other hlstologlcal changes of note Involved the liver. Males In the
1000 ppm group had a significant (p<0.05) Increase In "foamy" hepatic macro-
phages. The Incidence of this finding In 3000 ppm males and all groups of
treated females was elevated but not statistically different from controls.
Females given 3000 ppm had a significant (p<0.05) Increase of minor changes
In the hepatocyte, Including cell vacuolatlon and polyploldy. This effect
was not observed 1n any male treated group or 1n females receiving a lower
concentration. Neither sex had treatment-related evidence of hepatic
necrosis, hyperplasla or Infarction.
In a 6-generat1on dietary study with 99X pure cyclohexylam1ne«HCl,
Oser et al. (1976) fed diets that provided cyclohexylamlne at 0, 15, 50, 100
or 150 mg/kg bw/day to groups of 30 FDRL strain rats/sex 1n the parental
(FjJ generation. During the course of a 24-month chronic toxldty study,
all FQ rats were bred six times (Section 6.5.). Oser et al. (1976)
0064d -26- 06/12/87
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observed the rats dally for behavior, appearance and survival, recorded body
weights and food consumption values at regular Intervals, and performed
hematologlcal, blood chemistry and urlnalysls studies on five rats/sex at 3,
6, 12, 18 and 24 months. Starting at the 65th week, urine sediments were
collected from all rats for detection of the urinary bladder parasite,
Trlchosomoldes crasslcauda. under low power magnification. At the termina-
tion of the study, bladder sections were fixed, stained with H&E and
examined histopathologlcally. Hlstologlcal examination was performed on at
least 20 organs from 15-20 rats/sex 1n the control and high concentration
groups and on 8 organs from >10 rats/sex 1n all other groups; organ weights
were recorded In all groups of rats sacrificed after 2 years.
Although there were statistically significant decreases In rate of
weight gain In treated males (starting at 100 mg/kg/day) and females (start-
Ing at 50 mg/kg/day), these effects were attributed to reduced food Intake.
Results suggested no treatment-related abnormalities In hematologlcal, blood
biochemical or urlnalysls tests, no differences among groups 1n the Inci-
dence of Trlchomoldes crasslcauda and no significant differences In mean
relative organ weights. Hlstologlcal findings revealed no differences
between treatment groups In microscopic pathology, except for small In-
creases In the Incidences of bladder mucosal thickening {when data were
pooled across sexes) and testlcular atrophy 1n rats treated with 50 and 150
mg/kg/day. The bladder findings were not considered by the authors to be
biologically significant, because of the lack of a concentration-response
relationship and the absence of neoplasms In the bladders of rats fed 150
.mg/kg/day. The Incidence of testlcular atrophy was statistically signifi-
cant at both 50 (9/13; Fisher Exact p=0.020) and 150 (12/20; Fisher Exact
p=0.035) mg/kg/day; however, the Incidence of atrophy was not elevated at
0064d -27- 06/12/87
-------
100 mg/kg/day, relative to the control Incidence of 5/19. The Investigators
noted that reduced fertility occurred at 150 ppm after the fourth and fifth
ma tings.
Kroes et al. (1977) studied the chronic effects of cyclohexylamlne In
three generations of Swiss SPF mice as part of a more extensive multlgenera-
tlonal study. The parental generation consisted of 50 mice/sex. All 50
FQ females were mated with 25 males to produce two F, generations
(Section 6.5.). Subsequent matings were conducted to produce a total of six
filial generations. Twenty-one-month toxlclty studies were then conducted
on the FQ, F_. and F, generations. Experimental mice of each
generation were administered 0.5% dietary cyclohexylamlne from
cyclohexylamlne sulfate containing "several" Impurities for 21 months. The
nature of these Impurities was not specified further. One hematologlcal
examination was conducted on 10 of the F. mice at 14 months, and two
examinations (at 12 and 21 months) were conducted on 10 mice of each of the
other two generations. Moribund mice and 21-month survivors were sacrificed
and examined macroscoplcally and microscopically. Kroes et al. (1977)
performed hlstologlcal examinations on 13 tissues, Including the urinary
bladder, which was fixed before slicing and staining. Findings Indicated
that cyclohexylamlne decreased body weight gains, although treated mice
lived longer than controls. The extent of the weight gain decrement was not
discussed. Food Intake measured 1n the F, generation only was not
od
affected by treatment. The Investigators found no other treatment-related
effects In any of the three long-term studies.
Several other lifetime bloassays using oral cyclohexylamlne have been
conducted. Price et al. (1970) reported a 2-year feeding study In which 25
Charles River rats/sex were exposed to 0, 0.15, 1.5 or 15.0 mg/kg bw/day
cyclohexylamlne sulfate. The Investigators found no significant differences
0064d -28- 09/30/87
-------
between groups In food consumption, mortality, blood chemistry, hematology
or nonneoplastlc pathology. Hales administered the high concentration were
reported to have a slight depression In weight gain. Schmahl (1973) studied
the sympathomlmetlc effects of cyclohexylamlne on the cardiovascular system
In a 30-month feeding study 1n which 52 Sprague-Dawley rats/sex were given
either 0 or 0.4X dietary cyclohexylamlne. Both sexes had a depression In
body weight gain relative to controls, but there were no effects on
longevity or blood pressure and no aberrant hlstopathology In the heart or
cardiovascular system of the treated rats. Groups of six beagle dogs were
treated with cyclohexylamlne sulfate In dally oral doses of 0, 0.15, 1.5 or
15 mg/kg/day (Industrial Bio-Test Laboratories, 1981). Treatment resulted
In no effect on growth, behavior, hematology, blood chemistry, urlnalysls or
hepatic or renal function tests. H1stolog1cal examinations on one dog/sex
after 1 year of treatment revealed no abnormalities, and organ weights were
not affected by cyclohexylamlne. Industrial Bio-Test Laboratories (1981)
Increased the doses 1n the remaining dogs to 50, 100 and 150 mg/kg/day.
Although the dogs lost weight after the Increase, the losses were transient.
No histopathologlcal changes were found 1n dogs dying \n. extremis or sacri-
ficed after 9.5 years on the study.
6.1.3. Other Relevant Information. Oral LD5Q values for cyclohexyl-
amlne 1n rats range from 156-614 mg/kg (NAS, 1968; Smyth et al., 1969;
Tanaka et al., 1973). Watrous and Schulz (1950) reported that a 7-hour
exposure to 1200 ppm (4867 mg/m3) cyclohexylamlne was fatal to all
rabbits, rats and guinea pigs, but that most animals tolerated 70 hours of
exposure to 150 ppm (608 mg/m3). They also noted that accidental
Industrial exposure to cyclohexylamlne vapors resulted 1n drowsiness, appre-
hension and nausea. Human operators exposed to 4-10 ppm (16-41 mg/m3) had
0064d -29- 09/30/87
-------
no symptoms. Mallette and von Haam (1952) observed that a 25% solution was
associated wHh severe skin Irritation and possible sensltlzatlon 1n human
patch tests.
Cyclohexylamlne Is widely recognized as a weak sympathomlmetlc agent
(Classen et al., 1968; Rosenblum and Rosenblum, 1968; Weschler et a!.,
1969). Classen and Marquardt (1969, 1972) found cardiovascular effects,
Including blood pressure changes and either a positive chronotroplc effect
or a reflex bradycardla, after acute oral or Intravenous administration of
cyclohexylamlne. These Investigators also observed that cyclohexylamlne can
aggravate eplnepherlne-lnduced cardiac necrosis In presensltlzed rats.
These effects were not observed after repeated exposure (Rosenblum and
Rosenblum, 1968; Schmahl, 1973). In humans, Elchelbaum et al. (1974)
observed that cyclohexylamlne had a weak pressor effect on arterial blood
pressure.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carcinogenic potency of
cyclohexylamlne after Inhalation exposure could not be located 1n the
available literature as cited In Appendix A.
6.2.2. Oral. Pertinent data regarding the carclnogenldty of oral cyclo-
hexylamlne 1n humans could not be located In the available literature as
dted 1n Appendix A.
Price et al. (1970) reviewed the oncogenlclty of cyclohexylamlne In
laboratory animals. They reported a study with 0, 0.15, 1.5 or 15 mg/kg/day
cyclohexylamlne sulfate of unspecified purity administered In the diet to
groups of 25 male and 25 female Sprague-Oawley rats for 2 years (see Section
6.1.2.2.). At the end of the 2-year period, eight males and nine females
were alive 1n the high concentration group. The only neoplasm reported was
0064d -30- 09/30/87
-------
a grade 2 invasive transitional-cell carcinoma 1n the urinary bladder of one
of the surviving males. Since spontaneous bladder tumors are rare In
untreated rats, Price et al. (1970) considered their findings to be signifi-
cant. In a second study (Price et al., 1970), groups of 35 male and 45
female Wlstar rats received diets containing a 10:1 mixture of cyclamate/
saccharin at concentrations that provided dosages of 500, 1120 or 2500 mg/kg
bw for 2 years. Urine tests revealed that many of the rats were able to
convert cyclamate to cyclohexylamlne. Starting at the 79th week, 50% of the
treated survivors In each group received dally dietary supplements of
cyclohexylam1ne«HCl that provided free base at 25, 56 or 125 mg/kg/day.
Of 25 high concentration males and 35 high concentration females who were at
risk for tumor development, 7 males and 1 female had bladder tumors. Three
of the tumors appeared In rats that had received supplemental cyclohexyl-
amlne (125 mg/kg/day) and five appeared In rats with no supplement.
In a critical review of these studies, Bopp et al. (1986) commented
that, In subsequent pathological analyses, the number of tumors observed In
rats treated with a cyclamate:sacchar1n mixture (at 2500 mg/kg/day) supple-
mented with 125 mg/kg/day cyclohexylamlne had Increased to 12. The tumors
were described as nonmetastatlc and nonlnflltratlng. In addition, epithe-
lial hyperplasla was observed In the bladders of 6 controls and 18 high
concentration rats. Pathology revealed renal calcification In six rats that
had tumors, and the bladder of one high concentration rat was Infected with
the parasite, Tr1chosomo1des crasslcauda. which has been associated with
carclnogenesls; however, the occurrences of calcification and bladder
parasites were not restricted to rats that had tumors, so that the etiology
of the tumors remained obscure.
0064d -31- 06/12/87
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Several other animal bloassays Involving chronic oral cyclohexylamlne
exposure were discussed In Section 6.1.2.2. Gaunt et al. (1976) adminis-
tered 600, 2000 or 6000 ppm cyclohexylam1ne»HCl to groups of 48 Wlstar
rats/sex for 2 years. In 27 tissues analyzed hlstologlcally, most tumors
were found either In the controls alone or with similar frequencies 1n both
controls and treated rats. In a 2-year mouse study by Hardy et al. (1976),
dietary cyclohexylam1ne»HCl was administered at 300, 1000 or 3000 ppm to
groups of 48 male and 50 female ASH-CS1 mice for 80 weeks. The Investi-
gators found no statistically significant differences In tumor Incidence In
any of 24 tissue sites examined and no Incidence of urinary bladder
neoplasla 1n any treatment group. Oser et al. (1976) fed diets containing
cyclohexylam1ne-HC1 that provided cyclohexylamlne at 15, 50, 100 or 150
mg/kg/day to groups of 30 FDRL rats/sex (parental generation) 1n a multi-
generation study. No treatment-related Increases 1n neoplasms were observed
In any tissue studied, and no bladder neoplasms occurred at any concentra-
tion level. In lifetime studies conducted by Kroes et al. (1977), three
generations of Swiss mice were treated orally with 0.5X dietary cyclohexyl-
amlne from cyclohexylamlne sulfate. Each group consisted of 50 male and 50
female mice. H1stolog1cal examination suggested no Increased tumor Inci-
dence 1n any of the treated groups. No cyclohexylamlne-treated mice had a
bladder tumor. Similarly, Schmahl (1973) found no bladder tumors In Wlstar
rats fed 0.4% cyclohexylamlne for 2 years, and no Indication of any treat-
ment-related neoplasms. As part of a larger toxldty study, groups of two
beagle dogs/sex were administered 0.15, 1.5 or 15 mg/kg/day cyclohexylamlne
sulfate for 4 years, after which the doses were Increased to 50, 100 or 150
mg/kg/day for an additional 6 years (Industrial B1o-Test Laboratories,
1981). Cyclohexylamlne had no effect on the development of tumors 1n any
tissue analyzed.
0064d -32- 09/30/87
-------
6.2.3. Other Relevant Information. Pertinent data regarding other
relevant Information on the tumor1gen1c1ty of cyclohexylamlne could not be
located 1n the available literature as cited In Appendix A.
6.3. MUTAGENICITY
Studies regarding the mutagenlc effects of cyclohexylamlne are described
In Table 6-1.
Cyclohexylamlne was found to be negative In several reverse mutation
assays using Salmonella typh1mur1um as Indicator organism (McCann, 1976;
Herbold, 1981; Mortelmans et al., 1986), with or without metabolic activa-
tion (I.e. liver S-9 mix). In fluctuation tests with five prokaryotlc
strains, cyclohexylamlne was only slightly genotoxlc to Escher1ch1a coll at
cytotoxlc concentrations (Voogd et al., 1973). Fluck et al. (1976) showed
that 50 yl of cyclohexylamlne did not result In differential zones of
Inhibition 1n repair proficient vs. repair deficient strains of E_^ coll. and
Legator et al. (1982) observed that cyclohexylamlne was not mutagenlc toward
S. typhlmurlum. and only weakly mutagenlc against Serratla marcescens 1n a
mouse host-mediated assay. Styles and Penman (1985) found that parenterally
administered cyclohexylamlne Induced somatic mutations In pigment cells of
mouse embryos; however, the method of Injection was probably Inappropriate
for 1_n utero exposure (Bopp et al., 1986).
Tests for chromosomal aberrations after cyclohexylamlne treatment have
yielded mixed results. Several Investigators (Green et al., 1970; Stoltz et
al., 1970; Legator et al., 1969; Turner and Hutchlnson, 1974; van Went-de
Vrles et al., 1975) reported structural aberrations, especially gaps and
breaks, 1n mammalian somatic cell chromosomes after treatment. Brewen et
al. (1971) and Dick et al. (1974) found no similar effects In rat and human
cell cultures. Legator et al. (1969) observed spermatogonla chromosomal
0064d -33- 12/09/87
-------
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aberrations In rats treated IntraperHoneally, but Machemer and Lorke (1976)
reported no effects 1n the germ cells of Chinese hamsters treated orally
with higher doses. Very high doses of cyclohexylamlne produced a small
Increase 1n sister chromatld exchanges In a human lymphocyte culture (Wolff,
1983).
A majority of studies (Green et al.t 1972; Epstein et al., 1972;
Machemer and Lorke, 1975; Lorke and Machemer, 1974; Chauhan et al., 1975)
failed to detect true dominant-lethal effects In rodents administered cyclo-
hexylamlne orally or parenterally. In one study by Green et al. (1972),
toxic levels of cyclohexylamlne only Increased prelmplantatlon loss, which
Is not considered a reliable Indicator of dominant-lethal mutatlonal
effects. A second study on the same mating pairs revealed that 35% of the
eggs removed from females mated with treated males were not dividing, which
suggested a lack of fertilization as the cause of the prelmplantatlon loss.
Petersen et al. (1972) observed that treatment of male mice with a total
parenteral dose of 500 mg/kg/day resulted In significant Increases In
postlmplantatlon losses; however, the fertility rate 1n these studies was
abnormally low, and the number of live embryos was not reduced by either
cyclohexylamlne or the positive control (TEM), despite the Increases In
postlmplantatlon losses. The validity of the data of Peterson et al. (1972)
are therefore questionable.
6.4. TERATOGENICITY
Lorke and Machemer (1983) administered by gavage 0, 10, 30 or 100
mg/kg/day cyclohexylamlne from cyclohexylam1ne«HCl In dem1neral1zed water
to groups of 25 mated female Wlstar rats and 25 mated female NMI mice from
day 6-15 of gestation. The dams were sacrificed on days 18 and 20 of gesta-
tion, and the number of Implantations, dead and live fetuses, resorptlons
0064d -37- 12/09/87
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and runts were measured. The Investigators also recorded the Utter weights
and average fetus weight/Utter and the average placenta! weight/Utter, and
examined 1/3 of the fetuses for visceral malformations and 2/3 for skeletal
malformations. The only effects observed 1n either species were decreased
body weight gain 1n the high-dose rat dams and decreased fetal and placental
weights 1n the offspring of high-dose rats.
As reported 1n an abstract, Kennedy et al. (1969) administered 1.5 or 15
mg/kg/day cyclohexylamlne sulfate 1n a series of reproductive experiments In
female rats and rabbits and assessed reproductive signs of toxlclty. In one
experiment, cyclohexylamlne was administered during the period of organo-
genesls (days not specified). In a second experiment, female rats received
the compound from day 15 of gestation through weaning of the Utter.
Results of both experiments revealed no consistent differences between
controls and treated animals 1n any reproductive parameter, and there was no
evidence of soft tissue or skeletal malformations 1n either treated
group. In a teratology experiment, the frequency of resorptlons 1n rabbits
appeared to be greater In treated groups than 1n controls.
6.5. OTHER REPRODUCTIVE EFFECTS
Oser et al. (1976) studied groups of 30 FDRL rats/sex fed diets contain-
ing cyclohexylam1ne»HCl that provided cyclohexylamlne at 0, 15, 50, 100 or
150 mg/kg/day. The FQ generation was bred six times, with 1-week rest
periods between the weaning of each Utter. In addition, the Investigators
conducted muH1generation reproduction studies with 15 treated rats selected
from the first Utters of each generation and 15 pairs of treated males of
each generation mated to 15 untreated females. Of 15 treated females
producing a second Utter, 7 were delivered by Caesarian section on day 20
for examination of possible teratogenlc effects, and the remaining 8
0064d -38- 12/09/87
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delivered their litters naturally. Oser et al, (1976) found that dam
weights at first mating were reduced significantly from control levels at
SO, 100 and 150 mg/kg/day as a result of decreased food consumption. The
fertility Index appeared to be reduced slightly at 150 mg/kg/day 1n the
fourth and fifth matlngs of FQ rats. The number of live births/Utter was
decreased by >10X in the 100 and 150 mg/kg/day groups when data were
combined across generations. The rate of pup growth was also slightly
diminished at the two highest dose levels, but, after culling of the Utters
at 4 days, offspring mortality was negligible. Because almost every mating
resulted In the birth of a live Utter, cyclohexylamlne treatment at even
the highest dosages had no consistent effects on fertility, gestation or
Implantation. Finally, examination of fetuses from the second Utters of
each of the F, to F. generations (50-100 fetuses/Htter/generatlon)
revealed no treatment-related differences In soft tissue or skeletal
anomalies.
Subsequent covarlance analysis of these data by Bopp et al. (1986)
Indicated that the effects of 150 mg/kg/day cyclohexylamlne on fetal body
weights and litter size were due primarily to maternal body weight
decrements.
In a 6-generat1on study conducted by Kroes et al. (1977), 25 F male
and 50 female Swiss mice were mated to produce FI and F , generations.
Subsequent to these matlngs, five new generations, each derived from two to
three separate matlngs of the previous generation, were produced. Genera-
tions FI , F-, F3a, F and F&a were used 1n 4-month toxldty
studies, generations F_. , F. , F.. and Fc. were used 1n perinatal
2b 3c 4b 5b
studies, generation F,. was used 1n both perinatal and teratogenldty
studies, and generations FQ, F-. and F. were used in a long-term
0064d -39- 06/12/87
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toxlclty study (see Section 6.1.2.2.). In the 4-month studies, Kroes et al.
(1977) exposed 30 females and 15 males to 0.5% dietary cyclohexylamlne from
cyclohexylamlne sulfate, measured body weights and performed limited macro-
scopic and hlstologlcal examination after sacrifice. Pregnancy rates were
not affected adversely In any generation, but the mean numbers of llveborn
fetuses and the day 20 survival rates were reduced 1n all generations
relative to controls. Day 5 and day 20 mean offspring body weights were
also reduced In most groups of offspring. No unusual tissue pathology was
observed 1n sections of the kidneys, liver or urinary bladder.
In the perinatal studies, Kroes et al. (1977) measured the numbers of
Implantation sites, live fetuses, resorptlons and mean fetal weights of the
offspring of dams sacrificed on day 20 of gestation. Cyclohexylamlne treat-
ment (0.5X) significantly decreased the mean number of Implantation sites In
all generations except F,.. Kroes et al. (1977) did not discuss maternal
DD
toxlclty 1n either the perinatal or 4-month studies. Treatment signifi-
cantly reduced weight gain 1n a 21-month study (see Section 6.1.2.2.), but
1t was unclear whether the effects occurred Immediately. Finally, Kroes et
al. (1977) Indicated that cyclohexylamlne-exposed fetuses showed a "tendency"
to delayed ossification, although no supporting data were provided.
Long-term bloassays using dietary cyclohexylamlne 1n rats (Gaunt et al.,
1976) and mice (Hardy et al., 1976) were discussed In Section 6.1.2.2.
Two-year administration of 6000 ppm cyclohexylam1ne«HCl 1n Wlstar rats was
associated with significantly elevated Incidences of bilateral testlcular
atrophy and tubular calcium deposits, and treatment with 2000 ppm resulted
1n Increased numbers of tubules with few or no spermatlds (Gaunt et al.,
1976). Based upon protein deprivation studies, which Indicated that
testlcular damage occurs only under extreme dietary conditions, the
Investigators did not consider their results an artifact of reduced food
0064d -40- 09/30/87
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Intake; however. Hardy et al. (1976) observed no testlcular effects In
ASH-CS1 mice given <3000 ppm dietary cyclohexylam1ne»HCl for 80 weeks.
In short-terra studies (Gaunt et al., 1974; Mason and Thompson, 1977;
Ceilings and Klrkby, 1974; Brune et al., 1978; James et al., 1981) described
In Section 6.1.2.1., testlcular effects 1n rats were clearly observed with
diets that provided cyclohexylamlne at >200 mg/kg/day. Brune et al. (1978)
and Colllngs and Klrkby (1974) reported that diets that provided 100 to -175
mg/kg/day had no effect on the testes, although conclusions from the latter
study may be limited because of small sample sizes. Dogs treated repeatedly
with oral cyclohexylamlne at -240 mg/kg/day for 9 weeks had decreased sperm
counts and Increases In the number of abnormal spermatozoa, but no decreases
In relative testlcular weights (James et al., 1981). Gaunt et al. (1974)
found that decreases In germ cell numbers occurred at lower levels than
Impairments In reproductive performance.
Studies of dominant-lethal effects In cyclohexylamlne-treated male
rodents were discussed In Section 6.3. In general, the compound does not
appear to Impair Implantation In females mated with treated males.
6.6. SUMMARY
There are no pertinent data regarding the chronic or subchronlc Inhala-
tion toxldty of cyclohexylamlne 1n experimental animals. Ep1dem1o1og1cal
or occupational exposure data could not be located In the available litera-
ture as cited 1n Appendix A.
Results of subchronlc feeding studies (Gaunt et al., 1974; Colllngs and
Klrkby, 1974; Mason and Thompson, 1977; James et al., 1981; Brune et al.,
1978) have suggested that testlcular damage 1s the major treatment-related
effect of dietary cyclohexylamlne. Findings 1n rats after administration of
0064d -41- 09/30/87
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200 mg/kg/day Included tubular atrophy, reductions In sperm count, sperm
motllHy and numbers of early and late spermatlds, Impaired spermatogenesls,
and a decrease 1n testlcular weights. Reproductive performance was not
Impaired, however, by administration of a diet containing 6000 ppm cyclo-
hexylamlne-HCl for 10 months (Gaunt et al., 1974). James et al. (1981)
found similar effects on the spermatozoa of dogs treated for 9 weeks at -240
mg/kg/day. No clearly Identifiable toxic effects were found with adminis-
tration of <200 mg/kg/day (Ceilings and Klrkby, 1974; Mason and Thompson,
1977; Brune et al., 1978).
Besides testlcular effects, the only other major consistent finding 1n
these subchronlc studies Involved Inhibition of body weight gain, usually
accompanied by decreases In food Intake. In separate paired feeding
studies, Gaunt et al. (1974) demonstrated that weight gain Inhibition was
probably a result of an altered metabolic state, and therefore secondary to
cyclohexylamlne treatment.
Lifetime administration of 600, 2000 and 6000 ppm cyclohexylam1ne«HCl
to male and female Wlstar rats resulted In concentration-related Inhibitions
of body weight gain and food and water consumption statistically significant
at >600 ppm (Gaunt et al., 1976). Longevity was Increased by treatment.
The concentration of 6000 ppm was associated with severe testlcular atrophy
and Increased calcium deposits In testlcular tubules. At 2000 ppm (82
mg/kg/day), males had slight testlcular effects consisting of an Increase In
the number of tubules with few or no spermatlds. Based on dted literature,
Gaunt et al. (1976) stated that the extent of tubular damage observed at
6000 ppm could not have resulted from the decreased food consumption. In
addition to this effect, females treated with 6000 ppm had transient
reductions In hemoglobin and PCV; both sexes given 6000 ppm had decreases In
0064d -42- 06/12/87
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neutrophll counts, Increases In lymphocyte numbers and Increases In foamy
pulmonary macrophages, and both 2000 and 6000 ppm females had Increased
relative thyroid weights.
Hardy et al. (1976) treated groups of 48-50 ASH-CS1 mice of both sexes
with 300, 1000 or 3000 ppm cyclohexylam1ne-HCl orally for 80 weeks. The
Investigators collected blood samples, measured body and organ weights and
food and water consumptions, and performed comprehensive hlstopathologles on
24 tissues. The only treatment-related effects were hepatic. Hales exposed
to >1000 ppm had Increases In foamy hepatic macrophages. and high concentra-
tion females had a significant Increase 1n cell vacuolatlon and nuclear
polyploldy.
Oser et al. (1976) conducted 24-month oral toxldty studies on groups of
30 FDRL rats administered cyclohexylamlne-HCl In a diet that provided
dosages of 15, 50, 100 or 150 mg/kg/day cyclohexylamlne; the rats were also
bred for mult1generat1onal studies. Starting at 50 (female) and 100 (male)
mg/kg/day, treated rats showed Inhibition of body weight gain. Further
analysis revealed that these effects were a result of decreased food
consumption. Incidences of testlcular atrophy and bladder hyperplasla were
significantly elevated In the groups exposed to 50 and 150 mg/kg/day.
although reproductive performance In affected males (fertility Index) was
not significantly affected. Oser et al. (1976) did not consider the results
as biologically significant. When data were analyzed across generations,
the number of live births/Utter was reduced at 150 mg/kg/day, and the rate
of pup growth was decreased slightly at the highest two concentrations.
Covarlance analysis suggested that the offspring effects were secondary to
decrements In maternal weight gain (Bopp et al., 1986).
0064d -43- 06/12/87
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In another multlgeneratlonal experiment, Kroes et al. (1977) studied the
long-term toxldty of 0.5X dietary cyclohexylamlne from cyclohexylamlne
sulfate In groups of 50 Swiss SPF mice of both sexes. Twenty-one-month
experiments were conducted 1n three generations of mice. The only reported
effect was a decrement 1n body weight gain not accompanied by decreases In
food Intake. In reproductive (4-month and perinatal) studies, Kroes et al.
(1977) observed that treatment was associated with decreased numbers of
Hveborn fetuses, reduced survival rates and lower numbers of Implantations.
Other lifetime bloassays (Price et al., 1970; Schmahl, 1973; Industrial
_&1o-Test Laboratories, 1981) have not found significant nonneoplastlc toxic
effects of oral cyclohexylamlne administration 1n rats and dogs, other than
Inhibitions In weight gain. Although Kroes et al. (1977) reported a
tendency toward delayed ossification In mouse fetuses prenatally exposed to
cyclohexylamlne, they provided no supporting data. Other researchers
(Kennedy et al., 1969; Oser et al., 1976; Lorke and Machemer, 1983) found no
evidence of teratogenldty 1n fetuses of orally exposed animals.
LDcQ values after oral exposure 1n rats range from 156-614 mg/kg (NAS,
1968; Smyth et al., 1969; Tanaka et al., 1973), and 7 hours of Inhalation
exposure to 1200 ppm (4867 mg/m3) was fatal to all tested rats (Uatrous
and Schulz, 1950). Acute exposure In humans was associated with nausea,
drowsiness and skin Irritation (Hallette and von Haam, 1952; Watrous and
Schulz, 1950). Cyclohexylamlne was a weak sympathomlmetlc agent after acute
exposure (Classen et al., 1968), but Us pressor effects were not observed
after repeated exposures (Rosenblum and Rosenblum, 1968; Schmahl, 1973).
Only one animal bloassay (Price et al., 1970) found evidence of a
tumorlgenlc potential for cyclohexylamlne. These Investigators reported a
study with 0.15, 1.5 or 15 mg/kg/day cyclohexylamlne sulfate administered In
the diet to groups of 25 male and 25 female Sprague-Dawley rats for 2 years.
0064d -44- 09/30/87
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Among eight high concentration males and nine high concentration females
surviving to the end of the study, one male had an Invasive bladder carci-
noma, which 1s an unusual tumor 1n rats. In a subsequent study,
administration of a 10:1 cyclamate/saccharln mixture 1n the diet at 2500
mg/kg/day, supplemented with 125 mg/kg/day cyclohexylam1ne»HCl, resulted
1n an Increased Incidence of nonmetastatlc and nonlnvaslve bladder
paplllomas. The results of the Price et al. (1970) study are questionable
because calcification found 1n the kidneys of six rats may have contributed
to the observed Incidence. Also, several more recent bloassays using larger
numbers of animals failed to note any treatment-related differences 1n the
Incidence of any tumor type, and did not find a single Incidence of bladder
tumors (Schmaehl, 1973; Gaunt et al., 1976; Hardy et al., 1976; Oser et al.,
1976; Kroes et al.. 1977).
Cyclohexylamlne was nonmutagenlc, or only weakly mutagenlc, 1n various
mutation assays with prokaryotlc organisms (McCann, 1976; Herbold, 1981;
Mortelmans et al.. 1986; Voogd et al., 1973; Legator et al., 1982). In both
somatic cell and germ cell chromosomal aberration assays, cyclohexylamlne
yielded mixed results (Green et al., 1970; Legator et al., 1969; Turner and
Hutchlnson, 1974; Dick et al., 1974; Machemer and Lorke, 1976). Results do
not appear to depend on dosage. Most studies (Epstein et al., 1972; Lorke
and Machemer, 1974; Machemer and Lorke, 1975; Chauhan et al., 1975) reported
negative results In dominant-lethal assays. In two assays (Green et al.,
1972; Epstein et al., 1972) In which questionable or positive findings were
reported, either postlmplantatlon loss was not studied or experimental
design made Interpretation difficult.
0064d -45- 09/30/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
The ACGIH (1986a) recommended a TWA-TLV of 10 ppm (-40 mg/m8) for
human Industrial exposure to cyclohexylamlne. This recommendation was based
upon the possibility of toxic and Irritant effects at higher concentrations,
and the possibility that continued exposure may lead to carcinogenic,
mutagenlc and teratogenlc effects. The TWA-TLV was formally adopted by the
ACGIH (1986b).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of cyclohexylamlne could not be located In the available litera-
ture as dted 1n Appendix A.
0064d -46- 06/12/87
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6. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carcinogenic potential
of cyclohexylamlne after Inhalation exposure could not be located 1n the
available literature as cited In Appendix A.
8.1.2. Oral. There were no epidemiclogical or occupational data 1n the
available literature regarding the oncogenldty of cyclohexylamlne by the
oral route.
Only one animal bloassay found evidence of a tumorlgenie potential for
cyclohexylamlne. Price et al. (1970) reported a dietary study with cyclo-
hexylamlne sulfate that provided cyclohexylamlne at dosages of 0.15, 1.5 or
15 mg/kg/day to groups of 25 male and 25 female Sprague-Dawley rats for 2
years. Among eight high concentration males and nine high concentration
females surviving to the end of the study, one male had an Invasive bladder
carcinoma. In a subsequent study, administration of a 10:1 cyclamate/
saccharin mixture, supplemented with 125 mg/kg/day cyc!ohexylam1ne«HCl,
resulted In an Increased Incidence of nonmetastatlc and nonlnvaslve bladder
paplllomas. The results of the Price et al. (1970) study are questionable
because calcification, found 1n the kidneys of six rats, may have contrib-
uted to the observed Incidence; also, several more recent bloassays using
larger numbers of animals and much larger dosages failed to note any
treatment-related differences 1n the Incidence of any tumor type and did not
find a single Incidence of bladder tumors In rats (Schmaehl, 1973; Gaunt et
al., 1976; Oser et al., 1976; Kroes et al., 1977) or mice (Hardy et al.,
1976).
0064d -47- 06/12/87
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8.1.3. Other Routes. Pertinent data regarding the oncogenlclty of cyclo-
hexylamlne by routes other than oral or Inhalatlonal exposure could not be
located 1n the available literature as cited In Appendix A.
8.1.4. Weight of Evidence. Although the 2-year rat study reported by
Price et al. (1970) suggested a possible association of cyclohexylamlne with
a bladder tumor response, whereas a more recent study using larger numbers
of rats and much higher dosages (Gaunt et al., 1976) found no association of
cyclohexylamlne with any tumor type. Other evidence supporting a lack of
association of cyclohexylamlne with tumors 1n rats Include the multlgenera-
tlon study by Oser et al. (1976) and the 2-year study by Schmahl (1973).
The 2-year mouse study by Hardy et al. (1976) 1s sufficient evidence for
lack of carc1nogen1dty 1n this species. Support for noncarc1nogen1c1ty In
mice Is provided by the lifetime multlgeneratlon study by Kroes et al.
(1977).
If the results reported by Price et al. (1970) are regarded as spurious,
the animal studies collectively provide a large body of evidence for
noncardnogenldty 1n animals. To date, no specific guideline has been
developed on what Is considered a rare tumor frequency 1n rodents and how
that applies to expected frequency of cancer In man 1n that site (or other
sides). Accordingly, H 1s judged that the one responding male with a
carcinoma of the bladder may, or may not, be associated with cyclohexylamlne
exposure; what seems more clear are the negative results In the other
studies under conditions which should have produced cancer If
cyclohexylamlne were to be a carcinogen. No data are available regarding
carc1nogen1c1ty 1n humans. Using the guidelines provided by U.S. EPA
(1986b), cyclohexylamlne Is most appropriately assigned to EPA Group E
(although a Group D classification 1s debatable), evidence of
noncardnogenldty for humans.
0064d -48- 12/14/87
-------
8.1.5. Quantitative Risk Estimates. The available data are not appro-
priate for estimating the carcinogenic risk of human exposure to cyclohexyl-
amlne. Rather, RfOs for systemic toxldty will be calculated (Sections
8.2.2.1. and 8.2.2.2.).
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the Inhalation
toxldty of cyclohexylamlne after subchronlc or chronic exposure could not
be located 1n the available literature as cited In Appendix A.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Results of
subchronlc feeding studies (Gaunt et al.. 1974; ColHngs and Klrkby, 1974;
Mason and Thompson, 1977; James et al., 1981; Brune et al., 1978) have
suggested that testlcular damage 1s the major treatment-related effect of
dietary cyclohexylamlne. Findings 1n rats after administration of 200
mg/kg/day Included tubular atrophy, reductions In sperm count, motllUy and
numbers of early and late spermatlds, Impaired spermatogenesls and decrease
In testlcular weights. Reproductive performance was not Impaired by feeding
a diet containing 6000 ppm for 10 months (Gaunt et al., 1974). James et al.
(1981) found similar effects In dogs treated for 9 weeks at an estimated TWA
dosage of 240 mg/kg/day. Clearly Identifiable toxic effects on the testes
were not found with administration of <200 mg/kg/day (Colllngs and Klrkby,
1974; Mason and Thompson, 1977; Brune et al., 1978).
Besides testlcular effects, the only other major consistent finding 1n
these studies Involved Inhibition In body weight gain, sometimes accompanied
by decreases 1n food Intake. In separate paired feeding studies. Gaunt et
al. (1974) demonstrated that weight gain Inhibition was probably a result of
0064d -49- 12/14/87
-------
Increased metabolic rate. In two of the rat studies (Gaunt et al., 1974;
Mason and Thompson, 1977), the dietary level of 2000 ppm cyclohexyl-
am1ne*HCl was associated with Inhibition 1n weight gain but no other
measurable effect. Brune et al. (1978) reported decreases In weight gain
that were statistically significant at a diet providing >200 mg/kg/day but
not <100 mg/kg/day cyclohexylamlne base. NOAELs based on testlcular effects
and decreased rate of body weight gain 1n male Sprague-Dawley rats are 100
mg/kg/day cyclohexylamlne 1n the 90-day study by Brune et al. (1978), 0.06%
cyclohexylam1ne«HCl In the diet of male Wlstar and Sprague-Dawley rats 1n
the 90-day study by Mason and Thompson (1971) and 600 ppm cyclohexyla-
m1ne*HCl 1n the diet of Wlstar rats of both sexes In the 90-day study by
Gaunt et al. (1974). Gaunt et al. (1974) measured food Intake and body
weights, and estimated Intakes of cydohexylam1ne*HC1 at 41, 143 and 468
mg/kg/day at 600, 2000 and 6000 ppm, respectively. When these dosages are
multiplied by 99.17/135.63, the ratio of the molecular weight of cyclohexyl-
am1ne/cyclohexy1am1ne hydrochlorlde, dosages of cyclohexylamlne of 30, 105
and 342 mg/kg/day are estimated. The Intermediate dosage, 105 mg/kg/day,
was associated with reduced testlcular weight and reduced rate of body
weight gain attributed at least 1n part to altered basal metabolic rate.
The NOAEL of 30 mg/kg/day, therefore, appears to be the most appropriate
basis for an RfO for subchronlc oral exposure. Division by an uncertainty
factor of 100, 10 to extrapolate from animals to humans and 10 to protect
sensitive Individuals, results In an RfD of 0.3 mg/kg/day or 21 mg/day for a
70 kg human.
Confidence In the subchronlc oral RfD Is high because the key study
(Gaunt et al., 1974) Identified NOAELs for reduced body weight and testlcu-
lar effects, which are the critical effects of cyclohexylamlne. The
0064d -50- 12/14/87
-------
developmental and reproductive toxldty of cyclohexylamlne have been
adequately Investigated.
8.2.2.2. CHRONIC EXPOSURES — Two-year dietary administration of 600,
2000 and 6000 ppm cyclohexylamlne.HC1 to male and female Ulstar rats
resulted In concentration-related Inhibitions of body weight gain and food
and water consumption (Gaunt et al., 1976). At the lowest dietary con-
centration, terminal body weights were reduced -7% 1n males and ~11X In
females; food consumption was <2% of controls. Longevity was Increased by
treatment. The concentration of 6000 ppm was associated with severe testlc-
ular atrophy and Increased calcium deposits In testlcular tubules. At 2000
ppm (82 mg/kg/day), males had slight testlcular effects consisting of an
Increase In the number of tubules with few or no spermatlds. Based on cited
literature, Gaunt et al. (1976) stated that the extent of tubular damage
observed at 6000 ppm could not have resulted from the decreased food con-
sumption. In addition to this effect, females treated with 6000 ppm had
transient reductions In hemoglobin and PCV; both sexes given 6000 ppm had
decreases In neutrophll counts, Increases 1n lymphocyte numbers, and
Increases In foamy pulmonary macrophages; and both 2000 and 6000 ppm females
had Increased relative thyroid weights.
Hardy et al. (1976) treated groups of 48-50 ASH-CS1 mice of both sexes
with 300, 1000 or 3000 ppm cyclohexylam1ne«HCl orally for 80 weeks. The
Investigators collected blood samples, measured body and organ weights and
food and water consumptions, and performed comprehensive hlstopathologles on
24 tissues. The only treatment-related effects were hepatic. Males exposed
to 1000 (but not 3000) ppm had Increases 1n foamy hepatic macrophages, and
high concentration females had a significant Increase In cell vacuolatlon
and nuclear polyploldy.
0064d -51- 12/14/87
-------
Oser et al. (1976) conducted 24-month toxldty studies on groups of 30
FDRL rats fed diets containing cyclohexylam1ne»HCl that provided cyclo-
hexylamlne at 15, 50, 100 or 150 mg/kg/day; the rats were also bred for
mult1generat1onal studies. Starting at 50 (female) and 100 (male) mg/kg/
day, treated rats had statistically significant Inhibitions of body weight
gain. Further analysis revealed that these effects were a result of
decreased food consumption. Incidences of testlcular atrophy and bladder
hyperplasla were elevated significantly 1n the groups exposed to 50 and 150
mg/kg/day; the fertility Index appeared to be reduced slightly at 150
mg/kg/day. When data were analyzed across generations, the number of live
births/Utter was Inversely proportional to concentration, and the rate of
pup growth was slightly decreased at the two highest concentrations.
CovaHance analysis suggested that the effects on pup growth were secondary
to decrements 1n maternal weight gain (Bopp et al., 1986).
In another multlgeneratlonal study, Kroes et al. (1977) studied the
long-term toxldty of 0.5X dietary cyclohexylamlne from cyclohexylamlne
sulfate In groups of 50 Swiss SPF mice of both sexes. Twenty-one-month
experiments were conducted In three generations of mice. The only reported
effect was a decrement 1n body weight gain not accompanied by decreases In
food Intake. In reproductive (4-month and perinatal) studies, Kroes et al.
(1977) observed that treatment was associated with decreased numbers of
llveborn fetuses, reduced survival rates and lower numbers of Implantations.
Other lifetime bloassays (Price et al., 1970; Schmahl, 1973; Industrial
B1o-Test Laboratories, 1981) have found no significant toxic effects of oral
cyclohexylamlne administration to rats and dogs, other than Inhibitions In
weight gain. Although Kroes et al. (1977) reported a tendency toward
delayed ossification In mouse fetuses exposed prenatally to cyclohexylamlne,
0064d -52- 12/14/87
-------
they provided no supporting data. Other researchers (Kennedy et al., 1969;
Oser et al., 1976; Lorke and Machemer, 1983) found no evidence of terato-
genldty 1n fetuses of orally-exposed animals.
The results of the long-term studies suggest that rats are more sensi-
tive than mice to the testlcular and reduced weight gain effects of cyclo-
hexylamlne exposure. Effects on body weight occur at dietary concentrations
lower than those associated with testlcular effects. In the Gaunt et al.
(1976) study, reduced body weights were observed at 600 ppm cyclohexyl-
am1ne*HCl, the lowest level tested. Although terminal body weights were
reduced only 7% 1n males and 11X 1n females (p<0.01), the effect could not
be attributed to reduced food consumption. The Investigators estimated
equivalent dosages of cyclohexylam1ne*HCl at 600 ppm of 24 and 35
mg/kg/day In males and females, respectively. These values correspond to
dosages of cyclohexylamlne of 18 and 26 mg/kg/day, respectively. Oser et
al. (1976) also observed reduced body weight gain 1n rats at >15 mg/kg/day
cyclohexylamlne from cyclohexylam1ne«HCl, but the effect was not
statistically significant until 50 mg/kg/day, the next higher dosage.
Therefore, the body weight changes observed at the lowest doses In both the
studies are considered marginal and not adverse. In the Gaunt et al. (1976)
study male rats exposed to doses of >2000 ppm cyclohexylamlne showed
dose-related testlcular degeneration. The RfD Work Group on September 17,
1987 considered the 2000 ppm as LOAEL and 600 ppm as the NOAEL for
testlcular damage. The most appropriate approach, therefore, Is to base
derivation of an RfD for chronic oral exposure on the NOAEL of 18 mg/kg/day
1n male rats In the Gaunt et al. (1976) study. Application of an
uncertainty factor of 100, 10 to extrapolate from animals to humans and 10
to protect unusually sensitive Individuals, results In an RfD for chronic
0064d -53- 12/14/87
-------
oral exposure to cyclohexylamlne of 0.2 mg/kg/day or 13 mg/day for a 70 kg
human. This RfD was verified on September 17, 1987.
Confidence 1n the RfO Is high. The subchronlc study (Gaunt et al.,
1974) and another long-term rat study (Oser et al., 1976) Indicate that the
cyclohexylamlne dosage of 18 mg/kg/day probably approximates the NOAEL for
these effects. The carclnogenlcHy, developmental and reproductive toxldty
of cyclohexylamlne have been adequately Investigated.
0064d -54- 12/14/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
There were no subchronlc or chronic toxlclty data In the available
literature regarding Inhalation exposure to cyclohexylamlne. Toxic effects
after oral exposure were discussed 1n Chapter 6, and a summary of major
findings for lifetime exposure and reproductive studies Is provided In Table
9-1. Since all the researchers listed 1n Table 9-1 administered cyclohexyl-
amlne as the hydrochlorlde or sulfate salt, exposure concentrations were
first adjusted to the equivalent free base levels when this conversion was
not performed by the Investigators. Subchronlc data were not Included In
Table 9-1 because, with the exception of results from ColUngs and Klrkby
(1974), effects observed 1n the short-term studies were seen at the same or
lower doses 1n chronic testing. In the Colllngs and Klrkby (1974) study, a
dietary level of 2.5% cyclohexylam1ne-HCl produced death 1n all rats
within 5 days. Because this finding Is clearly an acute effect, It Is not
appropriate to Include In RQ derivation.
Calculation of CSs for the various toxic effects Is provided In Table
9-2. For any given effect, a CS was calculated only from the data yielding
the lowest equivalent human dosage. From the data summarized 1n Table 9-1,
the most severe toxic effect occurring at any dietary concentration was
fetotoxlclty (Oser et al., 1976; Kroes et al., 1977). Although It was
unclear from the Kroes et al. (1977) study If the fetal and Implantation
effects were secondary to maternal toxldty, neither study provided convinc-
ing evidence for teratogenldty. Therefore, the appropriate RV for both
studies 1s 8. Since the equivalent human dose In the Oser et al. (1976)
study was lower, It 1s appropriate to derive a CS based upon the female data
from this study. The dietary concentration of 150 mg/kg/day cyclohexylamlne
0064d -55- 12/14/87
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was converted to an equivalent human dose of 18.2 mg/kg/day after multipli-
cation by the cube root of the body weight ratio of rats (0.125 kg) to man
(70 kg). The equivalent human dose for a 70 kg human 1s 1274 mg/day, for an
RVrf of 1.0. When multiplied by the RVe, a CS of 8.0 1s obtained. This
CS corresponds to an RQ of 1000 (Table 9-3).
9.2. BASED ON CARCINOGENICITY
The available data regarding oral carcinogenic bloassays of cyclohexyl-
amlne 1n experimental animals were described In Chapter 6. Based on the
satisfactory negative results for carclnogenlclty In animal bloassays, 1t Is
recommended (see Section 8.1.4.) that cyclohexylamlne be considered an EPA
Group E compound. No cancer-based hazard ranking or cancer RQ can be
determined for Group E compounds.
0064d -58- 12/14/87
-------
TABLE 9-3
CYCLOHEXYLAMINE
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 1274 mg/day
Effect: fetotoxldty
Reference: Oser et al., 1976
RVd: 1.0
RVe: 8
Composite Score: 8.0
RQ: 1000
*Equ1valent human dose
0064d -59- 12/14/87
-------
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IARC (International Agency for Research on Cancer). 1980. IARC Monographs
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0064d -66- 12/14/87
-------
Hachemer, L. and D. Lorke. 1975. Experiences with dominant lethal test In
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NAS (National Academy of Sciences). 1968. National Research Council Ad Hoc
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0064d -73- 12/14/87
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0064d -74- 12/14/87
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s 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 1n 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 Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances 1n
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati. OH. Ill 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.
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.
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Grayson, M. and -D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, 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.
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 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
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.
0064d -76- 12/14/87
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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 Toxlclty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, 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.
U.S. Environmental Protection Agency
Region 5, Library (PH2J)
77 West Jackson Boulevard, 12th Fto*
Chicago, IL 60604-3590
0064d -77- 12/14/87
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