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                         DRAFT: DO NOT CITE OR*Q081t                v*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.


0064d                               -4-                              06/12/87

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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

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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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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.
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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


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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

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              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-
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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).
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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.

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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.
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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,
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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.

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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

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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

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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

-------
    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

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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

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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

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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

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    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

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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

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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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                                              ?   S   S   2   5   £
                                              CM   OB   9>   n   xi   r~
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                                41

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                                i
0064d
   -57-
                           12/H/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

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                                  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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Register.  51(185): 33992-34003.

U.S.  EPA.   1987.   Graphical  Exposure  Modeling  System  (GEMS).   Octanol-Water
Partition Coefficient (CLOGP)  and/or  Fate of  Atmospheric Pollutants  (FAP)
computer data  systems.  U.S.  EPA,  Research  Triangle Park, NC.

USITC  (U.S.  International  Trade  Commission).  1984.   Imports of  benzenold
chemicals  and  products 1983.   USITC Publ.  1548,  Washington, DC.  p.  14.
0064d                               -72-                             12/14/87

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van Hent-de VMes, G.F., J. Freudenthal, A.M. Hogendoorn, M.C.T.  Kragten  and
L.G. Gramberg.  1975.   ln_  vivo  chromosome-damaging  effect of  cyclohexylamlne
1n the Chinese hamster.   Food  Cosmet.  Toxlcol.   13(4):  415-418.

Verschueren, K.  1983.  Handbook of Environmental Data  on Organic Chemicals,
2nd ed.  Van Nostrand Relnhold Co..  NY.   p.  425.

Voogd, C.O., 3.J.  van der  Stel  and J.J. Jacobs.  1973.  [Onderzoek  op  muta-
gene working van natrlumcyclamaat,  natrlumsaccharlnaat  and  cyclohexylamlne.]
(Dutch)  Report 15/73 Chemo, Dutch State Institute  of  Public  Health.   (Cited
1n Cattanach, 1976)

Watrous, R.M.  and  H.N.  Schulz.  1950.   No  title provided.    Ind.  Ned.  Surg.
19: 317.  (Cited 1n ACGIH,  1986a)

Weast,  R.C.,  Ed.   1985.   CRC  Handbook  of  Chemistry  and  Physics, 66th  ed.
CRC Press, Inc., Boca Raton, FL.  p. D-159.

Wechsler, A.S., S.E.  Epstein  and A.  Gllck.   1969.   Mechanism of  the  sympa-
thomlmetlc  action  of cyclohexylamlne  and  hexylamlne,  release  of  catechol-
amlnes  from nerve endings.   J.  Pharmacol.  Exp.  Ther.   170:  62.   (Cited  1n
Bopp et al., 1986)

Wellens, H.   1982.  Comparison of  the  sensitivity  of  Brachydanlo  rerlo  and
Leuclscus  Idus  1n the  study  of the  toxldty  to fish  of chemical  compounds
and wastewaters.  Z.  Wasser Abwasser Forsch.  15(2): 49-52.
0064d                               -73-                             12/14/87

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Wlndholz, M.,  Ed.   1983.   The Merck  Index.  10th ed.  Merck and  Co.,  Inc.,
Rahway, N3.   p. 392.

Wolff, S.  1983.  Sister chromatld exchange as a test for mutagenlc carcino-
gens.  Ann.  NY Acad.  Scl.   407: 142-153.

Wotzka, J.,  B.  Glest  and  S. PfUzner.   1985.   Biochemical  degradabllHy  of
selected allcycllc  compounds.  Acta. Hydrochlm. Hydroblol.  13:  583-590.
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.
0064d                               -75-                             12/14/87

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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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