LO6J
          United States
          Environmental Protection
          Agency
                                                      FINAL DRAFT
                                                      ECAO-CIN-G076
                                                      September, 1989
          Research  and
          Development
          HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
          FOR  N-HEXANE
          Prepared for
          OFFICE OF SOLID WASTE AND
          EMERGENCY RESPONSE
          Prepared by
         Environmental Criteria and Assessment Office
         Office  of  Health and Environmental  Assessment
         U.S.  Environmental Protection Agency
         Cincinnati, OH  45268

                      DRAFT: DO NOT CITE OR QUOTE
                              NOTICE

      This document 1s a preliminary draft.  It has not been formally released
__ by  the U.S. Environmental Protection Agency  and should not at this stage be
*-^ construed to represent  Agency policy.  It 1s being  circulated for comments
   on  Us technical accuracy and policy Implications.

                   U.S. Eiivixonusmital Protection Agency
                   Library, Room 2404  P»-211-A
                   401 M Street,  S.W.
                   Washington, DO   80460
CM
                                            1..V

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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
                                                                      Office files  are
                                                                     aquatic  life  and
                                                                        The  literature
                                                                      are   Included  1n
    Health and  Environmental  Effects Documents (HEEOs) 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
emergency  and   remedial   actions   under   the  Comprehensive  Environmental
Response,   Compensation  and   Liability   Act   (CERCLA).    Both   published
literature  and  Information  obtained  for   Agency  Program
evaluated  as   they pertain  to  potential   human   health,
environmental   effects  of  hazardous  waste  constituents.
searched  for   In  this  document  and  the  dates   searched
"Appendix: Literature Searched."  Literature  search material  Is  current  up
to 8  months  previous to the  final draft  date listed on  the  front  cover.
Final  draft  document  dates  {front  cover)   reflect  the date  the document  Is
sent to the Program Officer  (OSHER).

    Several quantitative  estimates  are  presented  provided  sufficient  data
are  available.   For   systemic   toxicants,   these  Include:  Reference  doses
(RfDs) for chronic and  subchronlc exposures  for both the  Inhalation and oral
exposures.  The  subchronlc  or  partial  lifetime  RfD, Is  an estimate  of  an
exposure  level  which would  not  be  expected  to  cause adverse  effects  when
exposure  occurs  during  a  limited time  Interval  I.e., for  an  Interval  which
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.  Instead,
a  carcinogenic  potency  factor,  or  q*   (U.S.   EPA,  1980)   Is   provided.
These  potency  estimates  are  derived for both  oral  and Inhalation exposures
where possible.  In addition, unit risk  estimates  for air  and drinking water
are presented  based on Inhalation and oral  data,  respectively.

    Reportable   quantities   (RQs)  based   on   both  chronic   toxlclty   and
carclnogenlclty are derived.  The RQ Is  used  to determine the  quantity of  a
hazardous  substance  for  which  notification Is  required   In  the event  of  a
release   as   specified   under   the  Comprehensive   Environmental   Response,
Compensation  and  Liability  Act  (CERCLA).    These  two RQs  (chronic  toxlclty
and carclnogenlclty)  represent  two  of  six  scores  developed (the remaining
four  reflect  1gnHab1l1ty, 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 In U.S. EPA,  1984  and 1986a,  respectively.

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                               EXECUTIVE SUMMARY

    n-Hexane  Is  a colorless,  volatile and  flammable  organic  liquid  with a
weak  paraffin  odor.   n-Hexane Is soluble  1n  most  polar and nonpolar organic
solvents  such as  ether,  acetone,  benzene  and chloroform  (Sax  and  Lewis,
1987;  Weast  et al.,  1988).   It  Is  only slightly soluble In water.  n-Hexane
Is  commercially  produced  by  the fractional distillation of  suitable  petro-
chemical  feedstocks  and  subsequent   purification  with  molecular  sieves.
n-Hexane  Is  used  as  a  gasoline  additive  and  as  a  solvent  for  numerous
products and processes (Dale and  Dreham, 1981).
    In  the  atmosphere,  hexane probably occurs  almost  entirely  In  the vapor
phase  (Elsenrelch  et al., 1981).   Apparently,  reaction with photochemically
produced  hydroxyl  radicals Is  the  primary degradation  pathway (half-life =
2.9 days)  (Atkinson, 1985).   Small  amounts  of n-hexane may  be removed  from
the atmosphere by rain  washout; however,  It  would  be expected  to  rapidly
revolatlllze.   Neither   the   reaction   with  ozone nor  direct  photochemical
degradation  are  expected to be   Important  removal  processes.   In  yater,
Important  fate and  transport processes  are  expected  to be  volatilization
(half-life, <3 hours from a  typical river), aerobic degradation  (Jamison  et
al.,  1976;  Patel  et  al.,  1980a,b)  and adsorption to sediment  and suspended
organic  matter.    Estimated   BCF values   suggest  that  bloconcentratlon  In
aquatic organisms  Is not  significant.  Oxidation, photolysis  and  hydrolysis
are not expected  to be   Important   fate  processes  In  water.   In soil.  It
appears that n-hexane undergoes  aerobic degradation  (Patel  et  al., 1980a,b).
n-Hexane  probably  volatilizes  rapidly  to  the  atmosphere;  however,   the
potential for  n-hexane  to strongly  adsorb  to sediment  and  suspended  matter
may attenuate the volatilization rate.
                                      1v

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    n-Hexane  Is  a  highly  volatile,  natural  component  of  crude  oil  and
natural gas.   It Is released  to the environment  from  anthropogenic sources
Including  wastewater  and  fugitive  emissions  from n-hexane's  manufacture,
formulation,  use and  transport.  Accidental  spills of  crude  and  finished
fuel  products  and  emissions   from  gasoline,  motor  vehicle  exhaust  and
Incinerators  also  release  n-hexane   to  the  atmosphere.   n-Hexane  was  also
detected 1n the air above and In leachate from waste landfills.
    The available monitoring data  suggest  that  the general  population  may be
exposed to  n-hexane primarily through Inhalation.   Minor  exposure  may occur
through  direct  contact  with   refined   petroleum  products.   Representative
n-hexane  concentrations  In  the ambient  and  occupational  atmospheres  are
summarized In Tables 3-1 and 3-2.
    Two studies of  the  effects  of  n-hexane on aquatic  organisms were located
In  the  literature.  The  48-hour  LC^  In  4- to  6-day-old  Daphnla  was  3.88
mg/a  (Bobra  et  al.,  1983).    n-Hexane  was  much  less  toxic   to  blue-green
algae,  with  14-day EC5Q  values  for  reduced  growth  ranging  from  17,000-
80,000  mg/l  {Stratton, 1987).   In  a  genotoxlclty  assay  conducted In  bean
plants, 7500  mg/i of n-hexane  was  found to  Inhibit mitosis and appeared to
Increase the  frequencies of abnormal  anaphases  and total  aberrations (Gomez-
Arroyo et al., 1986).
    n-Hexane  Is   absorbed  readily through the  lungs.   Respiratory  uptake
data  In humans  (Nomlyama  and  Nomlyama,  1974)  Indicate  that  =28% of  the
Inhaled n-hexane was absorbed  by the lungs following exposure to 87-122 ppm
for  4  hours.   Respiratory  retention  of  n-hexane  was  =5.6%.   Toxlclty
studies Indicate  that  n-hexane  Is  absorbed readily from the gastrointestinal
tract.  n-Hexane may be absorbed following  dermal  exposure,  but the rate and
extent of absorption 1s unknown.

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    Distribution  of  n-hexane  following  Inhalation  exposure  Is  rapid  and
widespread.   The  highest  concentration of n-hexane In rats following  Inhala-
tion  exposure was  detected  In the  sciatic  nerves (Bus et  al.,  1981).  The
highest  concentrations  of  radioactivity following  Inhalation  exposure  to
14C-n-hexane  In  rats  were detected  In  the liver  and  kidneys  (Bus  et al.,
1982).
    Following   absorption,  n-hexane  undergoes   extensive   metabolism  and
elimination.   n-Hexane Is hydroxylated by the  mixed  function oxldase system
with  the  formation  of hexanols (Kramer et al.,  1974).   The major metabolite
Is  2-hexanol.  n-Hexane  shares  a  common metabolic  pathway  with  methyl-n-
butylketone.   2-Hexanol  enters  the  metabolic  pathway  for  methyl-n-butyl-
ketone,  resulting  In  the  formation  of  2,5-hexanedlone,  the  neurotoxlc
metabolite  of  n-hexane  and  methyl-n-butylketone.   Urinary  metabolites  of
n-hexane  In  humans  Included  2,5-hexaned1one,  2-hexanol,  2,5-dlmethylfuran
and Y-valerolactone (Perbelllnl et al., 1980).
    Nomlyama  and  Nomlyama (1974) determined  that =80% of  absorbed n-hexane
was excreted  unchanged  In the  expired  air of  volunteers.   Following exposure
to  14C-n-hexane,  rats  excreted  radioactivity  In  the  urine and  expired  air
In  a  blphaslc  manner.   Of  the radioactivity  excreted  In the  expired  air,
18-40X  was  present  as  14C02.   n-Hexane  Is  excreted  In  the  urine  as
metabolites.
    The  neurotoxlclty  of n-hexane  has   been  demonstrated  1n  a  number  of
subchronlc  Inhalation  animal  studies.   Results  of  these studies  Indicate
that  n-hexane neurotoxlclty  Is characterized  by the development of  periph-
eral  neuropathy  (Rebert et al.,  1982;  Pryor  et al., 1982; Frontall  et  al.,
1981;   Takeuchl  et  al.,  1980; Cavender  et  al.,  1984;  Ono  et al.,  1982;
Schaumburg  and  Spencer,  1976).   Peripheral  nerve damage  Is  associated  with

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giant  axonal  swellings, axonal  degeneration,  hlndllmb drag and  weakness  of
the  forellmbs  and  hlndHmbs  1n  rats.   Behavioral  alterations  1n  rats
following  Inhalation exposure  to  n-hexane  have  been  reported (Rebert et al.,
1982;  Pryor  et  al.,  1982).   It  appears  that  continuous exposure  to  lower
concentrations  produces more  severe  effects than  Intermittent  exposure  to
higher  concentrations,  but  axonopathy  and  nerve  conduction alterations  of
rats have  occurred  at  Intermittent concentrations as  low as 200  ppm (Ono  et
al.,  1982).   Clinical  signs of  neuropathy  have been documented  In  humans
exposed to an average n-hexane  concentration of 650  ppm In the work environ-
ment  (Herskowltz et  al.,   1971).   Ruff  et  al.  (1981)  reported  peripheral
neuropathy 1n a  patient exposed to an  average  n-hexane concentration  of  325
ppm.
    Two  oral  studies  Indicate  that  the  effects  of  oral  exposure to >570
mg/kg/day  n-hexane  are  similar to those associated  with  Inhalation exposure
(Krasavage et al.,  1980; Ono et  al.,  1981).  Testlcular atrophy was observed
In rats  treated  by  gavage  at 4000 mg/kg/day for  120  days (Krasavage et al.,
1980).
    Data  were  not  located  regarding  the  carclnogenldty  of  n-hexane   to
animals or humans  exposed  by  any  route.   However,  NTP  (1989)  has  completed
an Inhalation study using mice.  The  development  of  a technical report  1s  In
progress.  No data  were  located  regarding  the mutagenkHy  of  n-hexane.
Harks  et  al.  (1980)  found  no  teratogenlc  effects   of  orally administered
n-hexane  (260-2200  mg/kg/day)   In  rats.   A  temporary decrease In  postnatal
growth occurred  In  pups born  to  rat  dams  exposed by  Inhalation  to  1000 ppm
on days 8-16  of  gestation (Bus  et al., 1979).
    A  subchronlc  Inhalation RfD of  0.4 mg/m3  and  a  chronic Inhalation RfD
of 4x!0~2  mg/ma were  derived   from  the LOAEL  of 200  ppm that  resulted  In

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neurotoxldty  In  the  subchronlc study  by  Ono et  al.  (1982).   A subchronlc
oral RfD  of  0.6 mg/kg/day and  a  chronic  oral RfD  of  6xlO~2 mg/kg/day were
derived  from the  LOAEl  of  570 mg/kg/day  that  resulted  In  decreased body
weight  gain  In the subchronlc  study  by Krasavage et al.  (1980).   Since no
data regarding  the cardnogenldty were  available, n-hexane was  placed In
Group  D,  not classifiable as  to  Us  cardnogenlclty  to humans.  An  RQ of
1000 for  chronic  exposure  was  derived  from  the  subchronlc  Inhalation  study
by Ono  et al. (1982)  that  resulted  In  axonopathy  1n  rats.

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                              TABLE OF CONTENTS
                                                                        Page

1.    INTRODUCTION	       1

     1.1.   STRUCTURE AND CAS NUMBER	       1
     1.2.   PHYSICAL AND CHEMICAL PROPERTIES	       1
     1.3.   PRODUCTION DATA	       2
     1.4.   USE DATA	       2
     1.5.   SUMMARY	       4

2.    ENVIRONMENTAL FATE AND TRANSPORT	       5

     2.1.   AIR	       5

            2.1.1.   Reaction with Hydroxyl  Radicals	       5
            2.1.2.   Reaction with Ozone	       5
            2.1.3.   Photolysis	       5
            2.1.4.   Physical Removal  Processes	       5

     2.2.   WATER	       5

            2.2.1.   Hydrolysis	       5
            2.2.2.   Oxidation	       5
            2.2.3.   Photolysis	       6
            2.2.4.   Mkroblal Degradation	       6
            2.2.5.   Bloconcentratlon	       6
            2.2.6.   Adsorption	       6
            2.2.7.   Volatilization	       7

     2.3.   SOIL	       7

            2.3.1.   Mlcroblal Degradation	       7
            2.3.2.   Adsorption	       7
            2.3.3,   Volatilization	       7

     2.4.   SUMMARY	       7

3.    EXPOSURE	       9

     3.1.   WATER	       9
     3.2.   FOOD	      10
     3.3.   INHALATION	      10
     3.4.   DERMAL	      13
     3.5.   OTHER	      13
     3.6.   SUMMARY	      13
                                      1x

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                           TABLE  OF  CONTENTS  (cent.)
                                                                        Page

4.   ENVIRONMENTAL TOXICOLOGY	     14

     4.1.   AQUATIC TOXICOLOGY	     14

            4,1.1.   Acute Toxic Effects on Fauna	     14
            4.1.2.   Chronic Effects on Fauna	     14
            4.1.3.   Effects on Flora	     14
            4.1.4.   Effects of Bacteria	     15

     4.2.   TERRESTRIAL TOXICOLOGY	     15

            4.2.1.   Effects on Fauna	     15
            4.2.2.   Effects on Flora	     15

     4.3.   FIELD STUDIES	     15
     4.4    AQUATIC RISK ASSESSMENT	     15
     4.5.   SUMMARY	     16

5.   PHARMACOKINETICS	       17

     5.1.   ABSORPTION	       17
     5.2.   DISTRIBUTION	       18
     5.3.   METABOLISM	       19
     5.4.   EXCRETION	       21
     5.5.   SUMMARY	       22

6.   EFFECTS	       24

     6.1.   SYSTEMIC TOXICITY	       24

            6.1.1    Inhalation Exposures	       24
            6.1.2.   Oral Exposures	       28
            6.1.3.   Other Relevant Information	       29

     6.2.   CARCINOGENICITY	       29

            6.2.1.   Inhalation	       29
            6.2.2    Oral	       29
            6.2.3.   Other Relevant Information	       29

     6.3.   HUTAGENICITY	       31
     6.4.   TERATOGENICITY	       31
     6.5.   OTHER REPRODUCTIVE  EFFECTS	       31
     6.6.   SUMMARY	       31

7.   EXISTING GUIDELINES AND STANDARDS	       33

     7.1.   HUMAN	       33
     7.2.   AQUATIC	       33

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                           TABLE OF CONTENTS (cont.)
                                                                        Page

8.   RISK ASSESSMENT	      34

     8.1.   CARCINOGENICITY	      34

            8.1.1.   Inhalation	      34
            8.1.2.   Oral	      34
            8.1.3.   Other Routes	      34
            8.1.4.   Weight of  Evidence	      34
            8.1.5.   Quantitative Risk Evidence	      34

     8.2.   SYSTEMIC TOXICITY	      34

            8.2.1.   Inhalation Exposure	      34
            8.2.2.   Oral Exposure	      36

9.   REPORTA8LE QUANTITIES	      39

     9.1.   BASED ON SYSTEMIC TOXICITY	      39
     9.2.   BASED ON CARCINOGENICITY	      39

10.  REFERENCES	      44

APPENDIX A	     A-l

APPENDIX B	     B-l

APPENDIX C	     C-l
                                      x1

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                                LIST OF TABLES
No.                                 Title                               Page
1-1   Current Domestic Manufacturers of n-Hexane	    3
3-1   Representative Concentrations of n-Hexane In A1r	   11
3-2   n-Hexane Concentrations In Ambient Air of Representative
      Occupations	     12
6-1   Acute Lethal  Toxldty of n-Hexane	     30
9-1   Toxlclty Summary for n-Hexane	     40
9-2   Inhalation Composite Scores for n-Hexane	     42
9-3   n-Hexane:  Minimum Effective Dose (MED) and Reportable
      Quant 1 ty {RQ)	     43

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                                       LIST  OF  ABBREVIATIONS
o
          AEL
          BCF
          BAER
          CAS
          CS
          F344
          FEL

          Koc
          Kow
LD50
LOAEL
NOAEL
ppb
ppbv
ppm
ppmv
RfD
RQ

RVd
RV
  e
STEL
THOD
TLV
TWA
UV
Adverse effect level
Bloconcentratlon factor
Bralnstem auditory-evoked response
Chemical Abstract Service
Composite score
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Fischer 344
Frank effect level
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 5054 of recipients
Lowest-observed-adverse-effect level
No-Observed-adverse-effect level
Parts per billion
Parts per billion volume
Parts per million
Parts per million volume
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Short-term exposed level
Theoretical oxygen demand
Threshold limit value
Time weighted average
Ultraviolet
                                               X111

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                              1.   INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    n-Hexane  is  also  known as  n-hexane,  hexyl  hydride and  Skellysolve 8
(Chemline,  1989;  SANSS,  1989).   The structure, CAS number, molecular weight
and empirical formula for n-hexane are as follows:
                                          a\    /
                                             CH2
                                                   CH
CAS Registry number:  100-54-3
Empirical formula:  C0H,«
Molecular weight:  86.18
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    n-Hexane  is  a  colorless,  flammable  liquid  with a  slightly  paraffinic
odor.   It  is soluble  in  most  organic  solvents  such  as  ether,  acetone,
benzene and chloroform  (Sax  and  Lewis,  1987;  Weast et al.,  1988).   Selected
physical properties are as follows:
       Melting point:
       Boi1 ing point:
       Density:
       Vapor pressure
         at 25eC:
       Hater solubility
         at 25'C:
       Log Kow:
       Flash point:
-95°C
696C
0.6603 g/ntf

151.5 mm Hg

9.5 mg/^
4.11
-22.7'C
Weast et al., 1988
Neast et al., 1988
Weast et al., 1988
MacKay and Shiu, 1981
MacKay and Shiu, 1981
Hansch and Leo, 1985
Sax and Lewis, 1987
5942H
     -1-
                  06/16/89

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       Air odor threshold:      130 ppm           Amoore and Hautala,  1983
       Nater odor threshold:    0.0064 ppm        Amoore and Hautala,  1983
       Conversion factor:       1  ppm = 3.52 mg/m3

1.3.   PRODUCTION DATA
    n-Hexane  is  produced  commercially  by  the  fractional  distillation  of
suitable hydrocarbon  feedstocks,  such  as  crude oil or  the  liquids  stripped
from  natural  gas.  Pure  n-hexane is commonly removed  from  branched  hexanes
and other  contaminants  by  molecular sieves or other  methodology (Dale  and
Dreham,  1981;  Sax  and  Lewis,  1987).   Current  domestic  manufacturers  are
given in Table 1-1.
    Domestic  production  volume  for  recent years is as  follows  (USITC,  1985,
1986, 1987, 1988):
            Year                   Production             Sales
                                       (in thousands of pounds)
            1987                     852,035              383,310
            1986                     379,247              209,399
            1985                     482,457              306,577
            1984                     469,511              306,924
1.4.   USE DATA
    Most commercially  produced  n-hexane  is used as a gasoline  additive  or a
solvent for vegetable  oils,  paints,  inks,  etc.,  and  for  polymerization  and
other chemical  reactions.   n-Hexane  is also used as a denaturant for alcohol
and 1n  low-temperature thermometers  (Dale and  Dreham,  1981;  Sax  and  Lewis,
1987).
5942H                                -2-                            06/16/89

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o
                                                TABLE  1-1
                               Current Domestic Manufacturers of n-Hexane*
               Manufacturer
               Ashland  Oil  Co.
               Exxon Corp.
               The Humphrey Chemical  Corp
               Hill  Petroleum Co.
               Independent  Refining Corp.
               Pennzoi1  Co.
               Phillips  Petroleum  Co.
               Salomon,  Inc.
               Shell Oil  Co.
               Texaco,  Inc.
               Unocal Corp.
               Vista Chemical  Co.
               Location
        Ashland,  KY
        Baytown,  TX
        North Haven,  CT
        Houston,  TX
        Winnie,  TX
        Shreveport, LA
        Borger and Sweeney, TX
        Houston,  TX
        Houston,  TX
        El  Dorado, KA
        Beaumont, TX; Lemont, IL
        Houston,  TX
               •Source:   SRI,  1988;  USITC, 1988
               5974H
-3-
06/02/89

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1.5.   SUHMARY
    n-Hexane  1s  a colorless,  volatile and  flammable  organic liquid  with a
weak paraffin  odor.   n-Hexane 1s soluble  1n most  polar  and nonpolar organic
solvents  such as  ether,  acetone,  benzene  and chloroform  (Sax and  Lewis,
1987; Weast  et a!.,  1988).   It  Is  only  slightly  soluble In water.   n-Hexane
Is  commercially  produced  by  the fractional distillation of  suitable  petro-
chemical  feedstocks  and  subsequent  purification  with  molecular  sieves.
n-Hexane  Is  used  as  a gasoline  additive and a  solvent  for  numerous products
and processes  (Dale and Dreham,  1981).
5942H                                -4-                            07/26/89

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                    2.  ENVIRONMENTAL FATE AND TRANSPORT
2.1.   AIR
    Based on  a vapor  pressure  of  151.5 mm  Hg  at  25°C  (Mackay and  Shiu,
1981),  n-hexane  likely  exists  almost  entirely  In  the  vapor phase  In  the
ambient atmosphere (Eisenreich et al., 1981)
2.1.1.   Reaction  with  Hydroxyl  Radicals.  The  estimated half-life  for  the
gas-phase  reaction  of  n-hexane  with   photochemically   produced   hydroxyl
radicals  in  the atmosphere is 2.9 days  at  25eC.   This value  is  based  on an
experimental  rate constant  of  5.55x10"'2  cm3/molecule-sec  and  an  average
atmospheric  hydroxyl   radical  concentration  of  5.0x10*  mol/cm3  (Atkinson,
1985).
2.1.2.   Reaction  with  Ozone.    n-Hexane  is probably  not  susceptible  to
atmospheric degradation by ozone (Atkinson,  1985;  U.S.  EPA, 1987).
2.1.3.   Photolysis.    n-Hexane  does  not  absorb  UV  light  in the  environ-
mentally significant  range (>290 nm)   (Silverstein and  Bassler,  1963).   Thus,
it probably does not  undergo photolytic  degradation  In  the troposphere.
2.1.4.   Physical  Removal   Processes.   The  limited  water   solubility   of
n-hexane, 9.5  mg/^ (MacKay  and  Shiu, 1981),  suggests  that rain  washout  may
occur.  However, it is not  expected  to  be a  significant fate  process,  since
rapid revolatilization to the atmosphere would occur.
2.2.   NATER
2.2.1.   Hydrolysis.   n-Hexane  is  not  expected  to  hydrolyze  under  environ-
mental  conditions,  since   it  contains   no  hydrolyzable   functional   groups
(Lyman et al., 1982)
2.2.2.   Oxidation.  Pertinent data  regarding the oxidation  of  n-hexane in
water were not located 1n the available  literature dted 1n Appendix A.
5942H
-5-
06/16/89

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2.2.3.    Photolysis.   n-Hexane  does  not  absorb UV  light  In  the  environ-
mentally significant range (>290 nm)  (Silversteln and Bassler,  1963).   Thus,
it probably does not undergo photolytic  degradation  in water.
2.2.4.    Microbial Degradation.  Using  microbiota  from groundwater  contami-
nated by a  gasoline spill,  n-hexane  (as a component of high-octane gasoline)
underwent  46%  aerobic  biodegradation  after  192   hours   (Jamison  et  al.,
1976).    Bacteria  obtained from  water  and raised using  methane as  the  sole
carbon  source  rapidly oxidized  n-hexane  to 2-hexanol and   2-hexanone  under
aerobic  conditions  
-------
2.2.7.   Volatilization.   Based  on  n-hexane's  water  solubility,  9.5
at  25°C (Mackay  and Shiu,  1981),  and  vapor  pressure,  151  mm  Hg at  25°C
(Mackay and Shiu,  1981),  a Henry's Law constant  of  1.81  atm-nr/molecule  at
25°C can be  calculated  (Lyman  et al.,  1982).   Using  the group method of Mine
and  Mookerjee  (1975),   a   value   of   1.69  atm  mVmolecule  at   25aC  is
obtained.   The   magnitude   of  these   estimates   suggests   extremely   rapid
volatilization of  n-hexane  from  water  to the atmosphere.   Using  the Henry's
Law  constants above,  the volatilization half-life  from  a  model  river 1  m
deep, flowing 1 m/sec, with a wind velocity  of 3 m/sec  is  2.4-2.7  hours.
2.3.   SOIL
2.3.1.   Microbial Degradation.   Bacteria  obtained  from  soil  and  enriched
using   methane  as  the  sole  carbon  source  rapidly   oxidized   n-hexane.
2-Hexanol was  formed from  n-hexane  at microorganism-specific  rates ranging
from  0.05-0.1  pmo1/hour/5.0 mg  enzyme.   n-Hexane was  converted  to 2-hexa-
none at rates between 0.02 and 0.03 nmol/hour (Patel  et al.,  1980a,b).
2.3.2.   Adsorption.    Using the  method  of  Lyman et al.  (1982),  a Koc  for
n-hexane is  calculated to  be  1250-4100  (see  Section  2.2.6).  These  values
suggest that  n-hexane  displays slight  to low mobility  In  soil (Swann et al..
1983).
2.3.3.   Volatilization.  The  vapor  pressure  of n-hexane, 151  mm  Hg at 25*C
(Mackay  and  Shiu,  1981),  suggests  that volatilization  from soil  to  the
atmosphere is an important fate process.
2.4.   SUMMARY
    In  the atmosphere,  n-hexane  probably occurs almost entirely In the vapor
phase (Eisenreich  et al., 1981).   Apparently, reaction with photochemically
5942H                                -7-                            06/16/89

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produced hydroxyl  radicals  is  the  primary degradation  pathway  (half-life *
2.9 days)  (Atkinson,  T985).   Small  amounts of n-hexane may  be  removed from
the atmosphere  by rain  washout;  however,  it  would be  expected to  rapidly
revolatilize.   Neither   the  reaction  with  ozone  nor  direct  photochemical
degradation  are   expected   to  be  important  removal   processes.   In  water,
important  fate  and  transport  processes  are  expected  to  be volatilization
(half-life,  <3 hours  from  a typical river), aerobic degradation (Jamison et
al.,  1976;  Patel   et  al.,  1980a,b)  and adsorption  to  sediment  and  suspended
organic  matter.    Estimated  BCF  values  suggest  that  bloconcentratlon  in
aquatic  organisms is  not significant.  Oxidation,  photolysis and hydrolysis
are not expected  to  be  important   fate  processes  In  water.   In  soil,  it
appears   that   n-hexane  undergoes   aerobic   degradation  (Patel   et  al.,
1980a,b).  n-Hexane probably volatilizes  rapidly  to the  atmosphere;  however,
the  potential  for  n-hexane  to strongly  adsorb  to  sediment and  suspended
matter may attenuate the volatilization rate.
5942H                                -8-                             06/16/89

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                                3.  EXPOSURE
    n-Hexane  is  a  highly  volatile,  natural  component of  crude  oil  and
natural  gas.    It  may  be  released  to  the   environment  from  anthropogenic
sources  Including wastewater  and  fugitive emissions from n-hexane's manufac-
ture,  formulation,  use and  transport.   Accidental  spills   of  crude  and
finished  fuel   products  and  emissions from  gasoline,  motor vehicle  exhaust
and Incinerators also release n-hexane to the atmosphere.
    The  National  Occupational  Exposure  Survey estimated that  354,754 workers
are  occupationally  exposed  to  n-hexane  (NIOSH, 1989).   Based  on  available
monitoring data,  the  general  population ts exposed  to  n-hexane  primarily by
inhalation.   Minor  exposure  may   result  from  direct   contact  with  refined
petroleum products.
3.1.   NATER
    n-Hexane  was  found  in eight  samples from  Lake Pontchartrain,  LA,  at a
mean  concentration  of  2.4  ^g/^   (McFall  et  al.,   1985).   At  an  offshore
oil  production  platform in  the Gulf of  Mexico,  the  n-hexane  concentration
near  an  underwater  gas vent  was  7520  ng/^  (Sauer,   1981).   n-Hexane  was
identified  as  a  component  of  process  water  <79  jig/^)  from  these  oil
production platforms.   It was  detected In wastewater from  the  processing of
shale oil  (Hawthorne  and Sievers, 1984).  n-Hexane was found  in the leachate
of  a  municipal  solid  waste  landfill  in Minnesota  at a concentration  of 900
yg/^  (Sabel   and Clark,  1984).   n-Hexane  was found  in  European  drinking
water  supplies  (Kool  et  al.,  1982).   n-Hexane entered  seawatcr   during  an
experimental   test mimicking  an  oil  spill  on  the  ocean (McDonald  et al.,
1984).
5942H                                -9-                            06/16/89

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              3.2.   FOOD
                  n-Hexane  is a  volatile  component  of  roasted  filberts (Kinlin  et al.,
              1972).
              3.3.   INHALATION
                  Representative  n-hexane  concentrations  in  the  ambient  atmosphere  are
              given   In   Table  3-1.    Based  on  these  monitoring  data,  typical  rural
              concentrations  in  the  ambient atmosphere  range  from =0-25  ppb.   Similarly,
              ambient   urban  concentrations   are   ^0-300   ppb.   The   average   ambient
              concentration  of n-hexane  for  measured sites  in  the United  States  (urban,
              rural,  suburban  and  remote) was  3.684  ppmv (Shah  and  Heyerdahl,  1988).
              Based  on  this  average  concentration  and  an  average  dally air  intake  by
              humans  of  20 m3/day, the  average  daily intake of  n-hexane  can  be estimated
              at  259 mg.   Using  the  median n-hexane  concentration  for  rural  (0.046 ppbv),
              urban  (1.690 ppbv),  and  suburban  (1.858  ppbv)  areas  (Shah  and  Heyerdahl,
              1988),  the  average  daily intakes for  each area  are  calculated to  be  3.24,
              119 and 131 mg,  respectively.
                  n-Hexane  was qualitatively  identified  in air  samples above  hazardous
              waste  sites  (LaRegina  et   al.,  1986)  and municipal  landfills  (Young  and
              Parker, 1984).   In a study of emissions from  a  landfill  simulator,  n-hexane
              was found  in  891 of the  samples tested (Vogt  and Walsh, 1985).  Sources for
              n-hexane emissions  over  Tokyo,  Japan,  were  as  follows:   vehicle  exhaust,
              26%;  gasoline   vapor,  19%;  petroleum  refining,   29.6%;  and  petrochemical
              plants,  15.4%  (Madden  et al., 1986).   n-Hexane  was  identified  1n emissions
              from  incinerator stacks and  coal combustion (Junk and Ford, 1981).
                  Representative concentrations of n-hexane  1n  ambient  air associated with
              occupational uses of this compound can be found in Table 3-2.

o
              5942H                                -10-                           06/16/89

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                                  TABLE  3-2

                   n-Hexane Concentrations in Ambient Air
                        of  Representative  Occupations
Occupation
            Concentration
                         Reference
Spray painting/spray gluing
Gasoline tank removal
  breathing zone
  upwind
  downwind
  in excavation
  above excavation

Petroleum industry
  outside operators
  transport drivers
  service attendants

Hood floor finishing
site
             0.1-1.3 ppm
0-86.1 ppm
0-0.61 ppm
0-1.96 ppm
0-339 ppm
0-11.1 ppm
             0.473 mg/m3
             1.019 mg/m3
             1.175 mg/m3

                  NS
                  Whitehead et al., 1984
                               Shamsky and Samimi,  1987
                               Shamsky and Samimi,  1987
                               Shamsky and Samimi,  1987
                               Shamsky and Samimi,  1987
                               Shamsky and Samimi,  1987
                  Rappaport et al.,  1987
                  Rappaport et al.,  1987
                  Rappaport et al.,  1987

                  Vannetten et al.,  1988
NS = Not stated
5956H
               -12-
                                  06/02/89

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3.4.   DERMAL
    Pertinent data  regarding  dermal  exposure to n-hexane were not located  In
the available literature cited  In Appendix A.
3.5.   OTHER
    n-Hexane  was  detected In  eight  of 12 samples  of  mothers'  milk  from the
cities of  Bayonne,  NJ,  Jersey City,  NJ,  Brldgevllle, PA, and Baton Rouge,  LA
(Pelllzzarl  et  al.,  1982).   It was  also  found  1n  the urine  of  workers  at
chemical,  plastic  boat, plastic  button,  paint and  shoe factories (GhlttoM
et al., 1987).
3.6.   SUMMARY
    n-Hexane  Is  a  highly  volatile,  natural  component  of  crude  oil  and
natural gas.   It  1s  released  to  the  environment  from  anthropogenic  sources
Including  wastewater  and  fugitive  emissions  from n-hexane's  manufacture,
formulation,  use  and transport.   Accidental  spills  of crude  and  finished
fuel  products and  emissions  from gasoline,  motor  vehicle  exhaust  and  Incin-
erators also  release  n-hexane  to  the atmosphere.   n-Hexane was  also  detected
In the air above and  1n leachate from waste  landfills.
    The available monitoring  data suggest  that  the general  population  may be
exposed to  n-hexane primarily  through Inhalation.   Minor  exposure may occur
through  direct   contact  with  refined petroleum products.   Representative
n-hexane  concentrations  In   the  ambient  and  occupational  atmospheres  are
summarized 1n Tables  3-1 and 3-2.
5942H                                -13-                           07/26/89

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                        4.   ENVIRONMENTAL TOXICOLOGY
4.J.   AQUATIC TOXICOLOGY
4.1.1.   Acute Toxic Effects on  Fauna.   A single test of the  acute  toxicity
of  n-hexane  to aquatic  fauna  was located  In  the  literature.  Groups  of 10
water fleas,  Daphnia magna.  aged 4-6  days,  were  exposed  to five  nominal
concentrations  of   n-hexane   (2-4   replicates/concentration)   under  static
conditions  at  21-25°C  (Bobra  et   al.,  1983).   Untreated  controls   were
included.  The 48-hour LC50 was 45 mmol/m3 (3.88 mq/f).
4.1.2.   Chronic Effects on Fauna.
    4.1.2.1.   TOXICITY  --  Pertinent data regarding the effects  of chronic
exposure of  aquatic fauna  to n-hexane  were  not   located  In  the  available
literature cited in Appendix A.
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION   --  Pertinent  data  regarding
the  bioaccumulation/bioconcentration  potential  of  n-hexane  in aquatic  fauna
were not located in the available literature cited in Appendix A.
4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY  —  The  toxicity  of n-hexane to blue-green algae  was
investigated  by  Stratton (1987).  Cultures  of   Anabaena  sp.,  A.  variabills.
A. cylindrica. A.  inaequalis  and  Nostoc  sp.  were each exposed to 10 nominal
concentrations  of   n-hexane  ranging   from 1.0-14%  (10,000-140,000 mg/^>  for
10-14 days under static  conditions at 25°C.  Five to  10  replicates were used
for  each exposure  concentration,  and the entire experiment  was  repeated 3-5
times.  Untreated controls were included  in this study.   Optical  density was
recorded  to  monitor the  growth of  algal  cultures.   The  EC*o   values  for
reduced  growth  ranged  from  1.71 (17,000  mg/^) In  A.   Inaequalis   to 8.0%
(80,000 mg/^)  in Nostoc  sp.

5942H                                 -14-                            06/16/89

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    4.1.3.2.   8IOCONCENTRATION  -- Pertinent  data  regarding  the bloconcen-
traUon  potential  of  n-hexane  In  aquatic  flora  were not  located  In  the
available literature cited In Appendix A.
4.1.4.   Effects  on  Bacteria.    Pertinent   data  regarding  the  effects   of
exposure of  aquatic bacteria to  n-hexane were not  located  In the available
literature cited  In Appendix A.
4.2.   TERRESTRIAL TOXICOLOGY
4.2.1.   Effects  on Fauna.   Pertinent  data  regarding  the effects  of exposure
of  terrestrial  fauna  to  n-hexane  were not   located  In  the available litera-
ture cited 1n Appendix A.
4.2.2.   Effects  on Flora.   The clastogenlc  effects  of  n-hexane were studied
using  the  broad  bean,  Vlcla  faba.  root  tip assay  (Gomez-Arroyo et  al.,
1986).  Root  tips were exposed  to  n-hexane  concentrations  of  0.1-1.OX (1000-
10,000  mg/i)  for  1-4  hours.   Untreated  controls were also  Included.   The
Incidences  of  abnormal   anaphases  and   total  aberrations  appeared  to  be
elevated  compared   with  controls   at   7500  mg/i,   although  statistical
analysis was  not  performed.   In  addition, n-hexane  at  this  concentration
Inhibited cell division.
4.3.   FIELD STUDIES
    Pertinent data  regarding the   effects of n-hexane  on  flora and  fauna In
the field were not located In the  available  literature cited 1n Appendix A.
4.4.   AQUATIC RISK ASSESSHENT
    The lack of an  adequate  quantity  of  pertinent data  regarding  the effects
of exposure of aquatic fauna and  flora  to n-hexane  prevented  the  development
of a  freshwater criterion (U.S.  EPA/OHRS, 1986).   Although studies  of  acute
toxldty have been conducted In daphnlds  and blue-green algae,  neither  study
5942H                                -15-                           07/26/89

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o
met  the  necessary  conditions  for  inclusion  in  this  calculation.    Data
required  to  derive  a  freshwater  criterion  include  acute  studies  with
representatives from eight families  of freshwater fauna, chronic  studies  in
three families of fish  and  invertebrates,  a  study  in  a freshwater plant and
a bioconcentration study.
    No  data  were  located regarding  the  effects of exposure  of  marine fauna
and  flora  to n-hexane.   Acute  studies  with  representatives   from  eight
families of  marine  fauna and  at least three  chronic  studies  and one biocon-
centration  study  with   marine  fauna  and   flora  are  needed  to  develop  a
saltwater criterion.
4.5.   SUMMARY
    Two studies of  the  effects  of n-hexane on aquatic organisms  were located
in  the  literature.   The  48-hour  LCio in  4-  to  6-day-old  Daphnia was  3.88
mg/^  (Bobra  et  al.,  1983).   n-Hexane  was  much  less  toxic to  blue-green
algae,  with   14-day  ECso values  for  reduced  growth  ranging  from  17,000-
80,000  mg/^   (Stratton,  1987).   In  a genotoxicity  assay conducted  in  bean
plants, 7500  mq/4 of  n-hexane  was found to inhibit  mitosis  and  appeared  to
increase  the  frequencies  of   abnormal   anaphases  and  total   aberrations
(Gomez-Arroyo et  al.,  1986).
              5942H                                -16-                           06/16/89

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                            5.   PHARMACOKINETICS
5.1.    ABSORPTION
    Nomiyama  and Nomiyama  (1974)  studied  the  respiratory  absorption  of
n-hexane  1n  10  human  subjects exposed  for 4  hours  at  concentrations  of
87-122  ppm.   A  respiratory uptake  into  the  bloodstream  of  =28X  of  the
Inhaled n-hexane was  determined from  the measurement of n-hexane  in  expired
air.    Respiratory  retention of n-hexane  was *5.6X,  and  reached  constant
levels after 2 hours of exposure.
    Baker and Rlckert  (1981)  studied  the absorption of n-hexane  (500,  1000,
3000  and  10,000 ppm)  in  Fischer  rats  exposed  head only by  inhalation.
n-Hexane was  absorbed  rapidly  with apparent  steady-state  levels  reached  in
blood  and  tissues   within  2   hours.    The   apparent  steady-state  n-hexane
concentrations in blood,  measured  after  a 6-hour exposure to  n-hexane,  were
1.3,  2.2. 8.4  and 21 ng/m^ at  500, 1000, 3000 and 10,000  ppm,   respectively.
    The  gastrointestinal   absorption  of  n-hexane   has  not  been  studied.
However,  the  neurotoxicity study  by  Krasavage et al.  (1980)  indicated  that
n-hexane  is  absorbed   readily  from  the  gastrointestinal   tract  of  rats.
Krasavage et  al. (1980)  administered  n-hexane (6.6,  13.2 and  46.2 mmol/kg)
to rats by  gavage   and  found   that  plasma  levels  of  2,5-hexanedione  (the
neurotoxic metabolite of n-hexane) correlated with n-hexane  exposure.
    The  percutaneous  absorption  of  n-hexane  has   not  been   investigated,
although severe  intoxication has been  reported In humans  exposed to n-hexane
by this route  of  exposure  (Nomiyama  and  Nomiyama,  1974).    It  has  been
suggested  that  cutaneous  absorption  of  n-hexane   1s more hazardous  than
inhalation of n-hexane (Nomiyama and Nomiyama, 1974).
5942H                                -17-                           06/16/89

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5.2.   DISTRIBUTION
    Bus  et  al.  (1981) examined  the tissue distribution  of n-hexane In male
F344 rats exposed  by Inhalation to  a  concentration  of 1000 ppm for 6 hours/
day for  1 or  5  days.   The highest  concentration of n-hexane was found In the
sciatic  nerve  (46  ^g/g  wet  weight  after   1  day).  The  concentrations  of
n-hexane found  In  liver,  kidney and brain after  a  6-hour exposure for 1 day
were 1.23,  5.80 and  3.00  yg/g wet  weight, respectively.   The concentration
In  the  blood was  0.50  tig/ml.   The  concentrations   In  these  tissues  were
lower after 5 days of exposure than  after 1 day.
    The  tissue  distribution of  n-hexane In  female  albino rats exposed for
2-10 hours  to  =50,000  ppm vapor  has  been examined  (Bohlen et al.,  1973).
Tissue saturation  of  n-hexane  In blood, brain, adrenals,  kidneys  and  spleen
was attained  within 4-5 hours.  Tissue  saturation of  n-hexane  In the liver
was not  reached  even after 10 hours of  exposure.  The lack of saturation of
n-hexane In  the liver was attributed  to n-hexane-lnduced I1p1d accumulation
within this organ.
    The  disposition  of  radioactivity In male F344 rats  after  single Inhala-
tion exposures  for  6 hours to  500, 1000, 3000  or  10,000  ppm (l,2-14C)-n-
hexane was  studied  by Bus et al.  (1982).  Seventy-two hours after exposure,
radioactivity was   distributed  widely,  with  highest  levels  In  the  liver,
kidneys and sciatic nerve.
    Bus  et   al.   (1979)   Investigated   the  distribution  of  n-hexane  after
pregnant rats were  exposed  by  Inhalation to  1000  ppm  for 6 hours/day  during
gestation.   The  highest  concentration  of  n-hexane was  found  In  the  kidney
(6.33   yg/mi),    followed   by   the   liver    (0.85    vg/mi),   blood   (0.45
        and   brain   (0.04   iig/mi).    The  sciatic  nerve  was  not  analyzed.
5942H                                -18-                           07/26/89

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Levels  of  n-hexane  In  the  fetuses  were  comparable  with  those  found  In
maternal blood.  The plasma half-life  for  n-hexane was =60 minutes.
5.3.   METABOLISH
    The metabolism  of  n-hexane In guinea  pigs  following a single  1ntraper1-
toneal Injection of  250 mg/kg n-hexane was Investigated by DIVIncenzo et al.
(1976).   The  two  major  serum  metabolites of  n-hexane  were 2,5-hexaned1one
and  5-hydroxy-2-hexanone.  In  humans,  2,5-hexanedlone was  the main urinary
metabolite  Identified  {Perbelllnl et  al.,  1980);  other  metabolites Included
2-hexanol,  2,5-d1methylfuran  and  y-valerolactone.    Kramer et  al.  (1974)
demonstrated  that  n-hexane  was  hydroxylated  by the mixed  function oxldase
system of mice to produce hexanols.  The major metabolite was 2-hexanol.
    The  metabolism  of  n-hexane   In  F344  rats  following  a   single  6-hour
inhalation  exposure  was  studied  by  Baker  and  Rlckert  (1981).   The highest
concentrations  of  2,5-hexanedlone,  the  neurotoxlc  metabolite  of  n-hexane,
following  exposure  to  1000  ppm n-hexane  were  found  In   the  blood   (6.1
      ,  kidneys   (55   yg/g),   sciatic  nerve   (25   jig/g)  and   brain   (19
          Other   metabolites   Identified   Included   methyl-n-butylketone,
2,5-dlmethylfuran, 2-hexanol and  1-hexanol.
    DIVIncenzo et al.  (1976)  and  Perbelllnl  et  al.  (1981) suggested a common
metabolic scheme  for n-hexane  and methyl-n-butylketone.   Figure  5-1 depicts
a proposed metabolic scheme  for n-hexane  based  on  metabolic  studies of these
chemicals.   n-Hexane Is  hydroxylated  primarily to 2-hexanol,  which  1n  turn
enters  the  metabolic   pathway  for  methyl-n-butylketone, resulting In  the
formation  of  2,5-hexanedlone,  the  neurotoxlc  metabolite  of  n-hexane  and
methyl-n-butylketone.
5942H                                -19-                           07/26/89

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                              n-HEXRNE
                              E-HEXRNOL*
               2,5-HEXRNEDIOL         S-HEXflNONE
                                    (•ethyl-n-butyl let tone)
                       5-HYDROXY-2-HEXPNONE
                   a-oxidalion
                dec*rboxy 1 at Ion
                   oxidation
                lactonization
              y-VRLEROLRCTONE*
                      oxldktion
                       tyclization
                2,5-DinETHYLFURflN*
                          2,5-HEXRNEDIONE*
    *Found In workers' urine
5942 H
           FIGURE  5-1
     Metabolism of n-Hexane
Source:   Perbellini et al., 1981

              -20-
06/16/89

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5.4.   EXCRETION
    Nomlyama  and  Nomlyama  (1974)   studied   the   excretion  of  n-hexane  In
volunteers exposed  for  4 hours to 87-122  ppm n-hexane vapor.   Approximately
80% of absorbed n-hexane was excreted unchanged In the expired air.
    The  disposition  of  (1,2-14C)-n-hexane   in   F344  rats  after  a  6-hour
exposure  to  500, 1000,  3000  or  10,000  ppm  was  Investigated  by  Bus  et  al.
(1982).   The  elimination of  radioactivity was followed  for 72 hours  after
exposure.  The disposition of  radioactivity  was dose-dependent,  with  12,  24,
38 and 6254 of  the acquired  body burden  excreted  as n-hexane by the lung with
Increasing exposure concentration.   Of  the body burden of radioactivity,  38,
31,  27  and 18%  was recovered  as  expired  14C02  and 35,  40, 31  and  18%  was
recovered  In   the   urine  with   Increasing   n-hexane  concentration.    The
elimination  curve   for  exhaled  n-hexane  was  blphaslc.   The  Initial  rapid
phase, which  was observed In  the first 4-6  hours after  exposure, accounted
for  >90% of  the total  recovered  14C-n-hexane.   Excretion of  14C-n-hexane
was  essentially  complete  by   48   hours  after   exposure.    The   estimated
half-lives for the  alpha  (0.8-1.4 hours) and  beta (4.4-10.9  hours) excretion
phases were  similar  at  all exposure  concentrations.   Urinary  excretion  of
radioactivity  was  also blphaslc,  with  >90J4  of  the  total recovered  urinary
radioactivity  collected   In  the  first  24 hours  after exposure.   Estimated
half-lives of  the alpha-phase were  similar for the 1000,  3000  and  10,000  ppm
groups  (6.9-7.6  hours),  but  the half-life  for  the 500  ppm group was  12.7
hours.  The difference  may have  been  due  to altered  tissue distribution  at
the low exposure level.   Half-lives  for the  beta  phase were not calculated.
Excretion  of  14CQ?  was  85-96%  complete  1n  the  first  24  hours  after
exposure.   2,5-Hexanedlone  was  the main  urinary metabolite  Identified  In
humans  (Perbelllnl  et  al.,  1980).   Other  metabolites   Included  2-hexanol,
2,5-dlmethylfuran and y-valerolactone.

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          5.5.   SUMMARY
              n-Hexane  Is  absorbed  readily  through  the  lungs.   Respiratory  uptake
          data  In  humans   (Nomlyama  and  Nomlyama,  1974)  Indicate  that  =28% of  the
          Inhaled n-hexane  was  absorbed by the  lungs  following  exposure to 87-122 ppm
          for  4  hours.   Respiratory  retention  of  n-hexane  was  =5.6%.   Toxlclty
          studies Indicate  that  n-hexane  Is  absorbed readily from the gastrointestinal
          tract.  n-Hexane  may  be  absorbed following dermal  exposure, but the rate and
          extent of absorption  1s unknown.
              Distribution  of  n-hexane  following   Inhalation  exposure  Is  rapid  and
          widespread.   The   highest   concentration   of   n-hexane  In  rats  following
          inhalation  exposure was  detected  In  the  sciatic nerves  (Bus  et  a!.,  1981).
          The highest  concentrations  of radioactivity following  Inhalation  exposure to
          1*C-n-hexane  In rats  were  detected  In  the liver  and  kidneys (Bus et  al.,
          1982).
              Following   absorption,   n-hexane  undergoes   extensive  metabolism  and
          elimination.  n-Hexane 1s  hydroxylated by  the mixed  function oxldase  system
          with  the  formation  of hoxanols  (Kramer et  al.,  1974).   The major metabolite
          Is  2-hexanol.   n-Hexane  shares a  common  metabolic  pathway  with  methyl-n-
          butylketone.   2-Hexanol  enters the  metabolic  pathway  for  methyl-n-butyl-
          ketone,  resulting  In  the   formation  of  2,5-hexaned1one,  the  neurotoxlc
          metabolite  of  n-hexane  and  methyl-n-butylketone.  Urinary   metabolites  of
          n-hexane  In  humans  Included  2,5-hexanedlone,  2-hexanol,  2,5-d1methylfuran
          and y-valerolactone (Perbelllnl et al., 1980).
              Nomlyama  and  Nomlyama   (1974)  determined  that =80%  of  absorbed  n-hexane
          was excreted unchanged In the expired air  of volunteers.  Following exposure
          to  14C-n-hexane,  rats excreted  radioactivity  1n  the  urine and  expired  air
o
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In  a  blphaslc  manner.   Of  the  radioactivity  excreted  In the  expired  air,
18-40%  was  present  as  J4C02.    n-Hexane  Is  excreted  In  the  urine  as
metabolites.
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                                  6.   EFFECTS
6.1.   SYSTEMIC TOXICITY
6.1.1.   Inhalation Exposures.
    6.1.1.1.   SUBCHRONIC  —  Rebert  et  al.  (1982)  examined  the  electro-
physiological  correlates  of  n-hexane neurotoxlclty  In  groups of  6-15  male
Frats  exposed by  Inhalation to  either  1000  ppm  n-hexane,  24 hours/day,  5
days/week  for  11   weeks  or  10-mlnute  exposures  to  24,000  or  48,000  ppm
n-hexane 6  or 12  times/day,  5  days/week for  22 weeks.   The fifth  component
of  the BAER,  a  reflection  of activity In the region of the lateral  lemnlscus
or  Inferior  colUculus,  Increased In  latency  and  decreased In amplitude  In
rats exposed  continuously  to 1000  ppm n-hexane,  compared  with  controls.   The
latency of  the  compound  action potential of the ventral  caudal nerve  of the
tall  was  also  increased.    The  amplitude  of  the  fifth  BAER  component  was
decreased In  rats  exposed  Intermittently to 48,000 ppm  n-hexane but  not  to
24,000 ppm.   The  results of  this  study  Indicate  that  Intermittent adminis-
tration of  n-hexane had  little  effect on neurophyslologlcal  parameters until
exposure frequencies were Increased.
    In a  similar   study,  15 male  F344  rats exposed continuously (24  hours/
day)  to  1000 ppm  n-hexane  5  days/week  for  11  weeks  exhibited  a  marked
decrease  1n   hlndUmb   grip  strength  and   a  reduction   In multlsensory
conditioned avoidance response  compared  with controls (Pryor  et al.,  1982).
Transient  decreases  In  undlfferentlated motor  activity  and  forellmb  grip
strength were also  seen.    Continuous  exposure  to  1000  ppm  n-hexane  also
Inhibited weight gain,  which became  significant after  3 weeks of  exposure.
Forellmb grip strength  was  affected  slightly by  Intermittent  exposure  to
24,000 or  48,000  ppm n-hexane,  6, 12 or  24  times/day,  5 days/week  for  18
weeks.  Degeneration  of the sciatic  nerves  was  seen only  In rats exposed

5942H                                -24-                           07/26/89

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continuously  to  1000  ppm  n-hexane.   The  data   show  that  the  neurotoxic
effects of  Intermittent  exposure  of rats to high  concentrations  of n-hexane
are less severe than those after continuous exposure to lower concentrations.
    Groups  of  6-9 male  Sprague-Dawley  rats were  exposed  by  Inhalation  to
several treatment schedules of  n-hexane:   5000 ppm, 9 hours/day,  5 days/week
for 14 weeks; 2500 ppm,  10 hours/day, 6  days/week  for 30 weeks;  1500  ppm,  9
hours/day,  5  days/week  for  14  weeks and  500  ppm, 9 hours/day,  5 days/week
for 30 weeks (Frontali  et al.,  1981).  Peripheral   neuropathy  occurred  in the
rats  following exposure  to  5000  ppm and  2500 ppm  n-hexane.   Alterations
consisted of  giant   axonal  degeneration  affecting the  lateral,   medial  and
ventral  branches  of  the   tibial   nerves  supplying  calf  muscles.    Both
paranodal and  internodal   swellings  of  the  axons were seen.   Rats  exposed  to
1500  or  500   ppm  did  not  show  any  signs  of neuropathy.    A  significant
decrease  in  weight  gain  was  seen  in  rats  treated  with  5000  and 500 ppm
n-hexane.
    The neurotoxicity of  n-hexane  was studied in groups of  seven  male  Hi star
rats  following inhalation exposure  to  0 or  3000  ppm, 12  hours/day,  for  16
weeks  (Takeuchi   et  al.,  1980).    Decreased  body weight  occurred  in  the
exposed  rats   after  8   weeks  of   exposure.    Signs  of  clinical  neuropathy
(unsteady and  waddling gait) were  apparent after   10 weeks  of exposure.   Two
rats  died 1  and  3 days  before  the  end of  the 16-week exposure.   By  the end
of  16  weeks,  two  of the  remaining  five  rats  exhibited  foot  drop,  while all
five  rats  had  muscular  atrophy  in  the  legs.    Motor  and  mixed  nerve
conduction velocities,  as measured In the tall, were  significantly less than
those of  the   controls after  exposure for  4 weeks,  and  gradually decreased
after 8 weeks.   A prolongation in  the distal  latency of  peripheral  nerves
was  seen  after  4   weeks  of  exposure.    Histologlcal  examination  of the

5942H                                -25-                           06/16/89

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gastrocnetnlus and  soleus  muscles,  the dorsal  trunk of the tall nerve and  the
tlblal  nerve  was  performed In  two  of the n-hexane-treated rats.  The  tlblal
nerve  and the  dorsal  trunk  of the  tall nerve  showed  remarkable paranodal
swellings  In  the  myellnated  nerve  fibers.   Many  denervated neuromuscular
junctions were  observed  \n the muscle  of the n-hexane group.  Muscle  fibers
were severely Impaired.
    Cavender  et al.  (1984) studied the  toxlclty  of  n-hexane In groups of 15
male  and 15  female  F344  rats.   The  rats were  exposed  to 0,  3000,  6500 or
10,000  ppm  n-hexane vapors,  6 hours/day, 5  days/week,  for  13 weeks.   Mean
body  weight   gain  was significantly  decreased  1n males  In  the  10,000  ppm
group.   Necropsy analysis  of  these  rats also  Indicated a depression In brain
weights.   No  adverse  effect  of  n-hexane on  the brain or  body  weights  of
female  rats  was  found.    No  hlstopathologlcal  lesions  were  present  In  the
sciatic  and  tlblal nerves of  treated rats.   However, In  teased  nerve fiber
preparations, axonopathy  was  observed  In the tlblal nerve  1n  4/5 male rats
from the  10,000 ppm group and 1/5  males from the 6500 ppm group.  Axonopathy
was not  detected  1n  female rats.   No adverse testlcular effects  were noted.
The  authors   concluded    that  neurotoxlclty   resulting  from  Intermittent
exposure to n-hexane Is less severe than  continuous exposure.
    Ono  et al.  (1982) evaluated  the  neurotoxlclty of n-hexane In groups of
eight male Wlstar  rats exposed by  Inhalation  to  0,  200  or  500 ppm n-hexane,
12 hours/day, 7 days/week  for  24  weeks.  Motor nerve conduction velocity and
the  distal  latency  of  the  peripheral  nerve were  measured  In  the  ventral
trunk  of the tall nerve.   n-Hexane  treatment  did not  significantly  affect
the body weights   of  the  rats.  Nerve  conduction velocities  were decreased
slightly  In rats  treated with 200  ppm  n-hexane  after  20 weeks of exposure.
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A  marked  decrease  In  nerve  conduction  velocities  and  a  prolongation  of
distal  latencies  occurred 1n  rats  from the 500  ppm group after  8  weeks  of
exposure.   Degeneration  of  the  myelln  sheaths  and axons was  demonstrated
upon examination of the raveled tall nerves 1n all exposed groups.
    Schaumburg  and   Spencer   (1976)   examined  the  neurotoxlc   effects  of
continuous  exposure   of  rats  to  n-hexane.  Eight  Sprague-Dawley rats  were
exposed  to  400-600 ppm n-hexane  for 162 days.   Clinical  signs of neuropathy
developed  In rats after 45 days  of  exposure.   Further exposure resulted In a
progressive,   symmetrical,   distal   hlndUmb   weakness   with   foot-drop.
Axonopathy was also seen.
    Herskowltz et  al. (1971) reported neuropathy In  three cabinet finishers
exposed  to   an average air  concentration  of  650 ppm n-hexane.   The workers
were also  exposed  to  n-hexane  by  oral  and  dermal routes.   Symptoms Including
headache,  abdominal   cramps,   burning  sensation  of  the  face,  bilateral
foot-drop gait, bilateral wrist drop and numbness and weakness of the distal
extremities  developed 2-4 months  after the beginning of  exposure, fibrilla-
tion  potentials  were observed  In the small muscles  of the hands and  feet.
Scattered groups of small angulated  fibers  In  the anterior tlblal muscle and
sural  nerves were noted  from biopsy  findings.   Microscopic  examination  of
the motor  end  plates revealed axons  with  an  Increased number  of neurofHa-
ments with  abnormal  membranous structures, and  clumping  and  degeneration  of
mitochondria with dense bodies.   Swelling  of  the terminal axons  was present
In the motor end plates.  The  health  of  the patients Improved after  exposure
to n-hexane stopped.
    Ruff et  al.  (1981) reported  peripheral neuropathy 1n a  patient exposed
occupationally for several years  to an average  n-hexane concentration of 325
ppm.


5942H                                -27-                           07/26/89

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    6.1.1.2.    CHRONIC — Pertinent  data  regarding the toxicity of  n-hexane
following chronic  inhalation exposure  in  laboratory  animals  or  humans were
not located  in the available literature cited in Appendis A.
6.1.2.   Oral  Exposure.
    6.1.2.1.    SUBCHRONIC  —  Krasavage  et  al.   (1980)   Investigated  the
neurotoxic effects  of n-hexane  (997. purity) in rats  after oral  administra-
tion.   Groups of  five adult  male  COBS  rats  were administered  570  mg/kg
n-hexane by gavage,  5 days/week for 90 days  or  1140 or 4000 mg/kg doses for
120 days.  Controls  were  treated on the same schedule  with distilled water.
Treated  rats  had  reduced  food consumption and reduced  body weights  compared
with  controls.   Clinical  (hindlimb  weakness) and  histological  evidence  of
neuropathy was  seen  in  rats treated  with  a dose  level  of  4000  mg/kg/day.
Histological   changes  consisted  of  multifocal  axonal  swellings,  adaxonal
myelin   infolding  and  paranodal  myelin  retraction.    The  lower  doses  of
n-hexane did  not  produce evidence  of neuropathy.   Histological  examination
of  testicular tissue  revealed  atrophy of the  germinal  epithelium following
administration of 4000 mg/kg/day n-hexane.
    Ono  et  al.  (1981) described  the  neurotoxicity of n-hexane  after oral
administration.   n-Hexane was  diluted  in olive  oil and  administered orally
to  male Wistar  rats  <5-7/group)  daily  for 8  weeks.  Mixtures  of  0.4 m^
n-hexane  plus  0.6  m/ olive  oil  (=770 mg/kg/day)  were  administered  for
the  first  4   weeks.   For  weeks  5 and 6, the rats  were  administered 0.6 m^
n-hexane  (=1155   mg/kg/day)   and  for  weeks  7   and  8,    the   rats  were
administered  1.2  ml  n-hexane  (=2310  mg/kg/day).   Conduction  velocities
of the peripheral nerve were  measured  in  the tail.  No  changes  were seen in
the  body weights  of n-hexane-treated  rats.   Motor nerve conduction  velocity
was  significantly  less  in  treated  rats than in  controls  at  8  weeks  of
5942H                                -28-                            06/16/89

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administration.   Mixed  nerve conduction  velocity  (distal  portion) decreased
after  4  weeks,   while  mixed  nerve  conduction  velocity  (proximal  portion)
decreased after 6 weeks.
    6.1.2.2.   CHRONIC  —  Pertinent data regarding the  toxlclty  of  n-hexane
following chronic oral  exposure  were not located In the available literature
cited  1n Appendix A.
6.1.3.   Other  Relevant Information.   Table 6-1  summarizes  the  results  of
acute  lethal  exposure  to n-hexane  derived  from  a  limited  number  of studies.
The oral  LD5Q data  Indicate  that 14-day-old rats are more  sensitive  to the
acute  toxlclty of n-hexane when compared with young and old adult rats.
    Hewitt  et al.  (1980)  examined the acute hepatotoxlclty  and  nephrotoxl-
clty of  n-hexane  In male Sprague-Dawley  rats following  a  single  gavage dose
of  1292  mg/kg of  n-hexane solublllzed  In  corn oil; controls  received corn
oil  alone.    n-Hexane   treatment  did  not  produce  liver  or  kidney  Injury.
However,  when  administered  along  with  chloroform,  n-hexane  potentiated
chloroform-Induced hepatotoxlclty and nephrotoxlclty In rats.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.    Pertinent   data  regarding  the  carclnogenlclty   of
n-hexane  following   Inhalation  exposure  were  not  located  In  the  available
literature  cited  In  Appendix A.   NTP  (1989)  has  completed  an  Inhalation
bloassay  of  n-hexane  using mice.   The  technical  report  1s  being  peer
reviewed for fInallzatlon.
6.2.2.   Oral.   Pertinent  data  regarding  the   carclnogenlclty of  n-hexane
following oral  exposure were not  located In the available  literature  cited
In Appendix A.
6.2.3.    Other Relevant Information.   Other  relevant Information  regarding
the carclnogenlclty of  n-hexane were  not  located  1n  the  available literature
cited  In Appendix A.

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                                  TABLE  6-1
                      Acute  Lethal  Toxlcity of  n-Hexane
Species
Mouse
Rat
Route
Inhalation
oral
Results
LCLO 120 g/m3
LD,0 15,800 mg/kga
LD50 32,340 mg/kg"
LD50 28,710 mg/kgc
314-day-old rats (16-50 g)
"Young adult rats (80-160 g)
'Older adult rats (300-470 g)
Reference
NIOSH, 1989
Kimura et al., 1971
Kimura et al., 1971
Kimura et al., 1971
5974H
                       -30-
                                     06/15/89

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6.3.   MUTAGENICITY
    Pertinent  data  regarding  the  mutagenldty of n-hexane  were not located
In the available literature cited  In Appendix A.
6.4.   TERATOGENICITY
    Bus  et  al. (1979) examined  the perinatal toxldty  of  n-hexane 1n rats.
Groups of 7-9  pregnant F344  rats were  exposed by Inhalation to 0 or 1000 ppm
of 99%  n-hexane for 6 hours/day on  days  8-12 {7 rats),  days 12-16 (9 rats),
or days  8-16 (8 rats) of gestation. No  significant  changes In fetal resorp-
tlons, body  weights or visible anomalies  were noted  with any of the n-hexane
exposure  regimens  compared with  controls.   No  significant  Increases  In  the
Incidence  of  soft  tissue or  skeletal  anomalies were  seen.   The  postnatal
growth  of pups born  to  dams  exposed  to 1000 ppm  n-hexane on  days  8-16 of
gestation was  depressed  up to  3 weeks  of birth.   However, the litter weights
of the treated pups returned to control values by 7 weeks.
    Marks  et  al.  (1980) determined  that  n-hexane  was  not  teratogenlc  1n
mice.   Pregnant  CD-I  mice were administered  n-hexane  once dally  by  gavage
with  the  following  doses:   260 mg/kg/day (13  mice),  660 mg/kg/day (6 mice),
1320  mg/kg/day  (6  mice)  and  2200  mg/kg/day  (14  mice)  on  days  6-15  of
gestation.   One  of  14 dams  treated  with 2200 mg/kg/day  n-hexane  died.   The
Incidence of malformed mouse fetuses was  not significantly  different between
treated mice and control  mice  .
6.5.   OTHER REPRODUCTIVE EFFECTS
    Pertinent  data  regarding other  reproductive  effects  of  n-hexane were  not
located In the available literature cited In Appendix A.
6.6.   SUMMARY
    The  neurotoxlclty of  n-hexane  has   been  demonstrated  In  a  number  of
subchronlc  Inhalation animal  studies.   Results of  these   studies  Indicate


5942H                                -31-                           07/26/89

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that  n-hexane  neurotoxicity   is  characterized   by   the  development   of
peripheral  neuropathy '(Rebert et  al.,  1982;  Pryor et al.,  1982;  Frontali  et
al., 1981;  Takeuchl  et  al.,  1980; Cavender et al.,  1984;  Ono  et al.,  1982;
Schaumburg  and  Spencer,  1976).    Peripheral  nerve damage  is associated  with
giant axonal  swellings,  axonal  degeneration,  hindlimb  drag  and weakness  of
the  forelimbs  and  hindlimbs   in  rats.    Behavioral   alterations   in  rats
following inhalation exposure to n-hexane  have been reported 570  mg/kg/day
n-hexane are  similar to  those  associated  with inhalation exposure  (Krasavage
et  al.,  1980;  Ono et al.,  1981).   Testicular atrophy  was observed  in  rats
treated by gavage at 4000 mg/kg/day for  120 days  (Krasavage et  al.,  1980).
    Data were  not   located  regarding   the cardnogenicity  of  n-hexane  to
animals or  humans  exposed  by any route.   No  data were  located  regarding the
mutagenicity  of n-hexane.   Marks  et al. (1980) found no teratogenic  effects
of  orally  administered  n-hexane  (260-2200 mg/kg/day)  in  rats.  A  temporary
decrease in  postnatal growth occurred  in  pups  born to  rat dams exposed  by
inhalation to 1000 ppm on days  8-16 of gestation  (Bus et al., 1979).


5942H                                -32-                           06/16/89

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                    7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUMAN
    The  ACGIH  (1988)   recommended  TWA-TLV  for  n-hexane  is  50  ppm  <180
mg/m3).   ACGIH  (1988)  does  not  recommend  a  STEL for  n-hexane.   These
recommendations  are based  largely on  the  inhalation   and  oral   studies  in
animals  that  associate peripheral  neuropathy with exposure  to the compound
(ACGIH,  1986).   OSHA  (1989)  lists  transitional  limits  for n-hexane  of  500
ppm  (1800 mg/m3)  and  final  rule  limits  of  50  ppro  (180  mg/m3),  identical
to  the ACGIH  (1988) recommendation.  NIOSH  (1977)  recommended 100  ppm (350
mg/m3) as a workplace environmental TWA limit for n-hexane.
7.2.   AQUATIC
    Guidelines  and  standards  for  the  protection  of  aquatic  life  from
exposure  to n-hexane  were  not located  in  the  available  literature  cited  in
Appendix A.
5942H                                -33-                            06/16/89

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                             8.  RISK ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.    Pertinent   data   regarding   the   carcinogenicity  of
n-hexane to animals or humans following  inhalation exposure were  not  located
in the available literature cited in Appendix A.
8.1.2.   Oral.   Pertinent  data  regarding  the carcinogenicity  of  n-hexane  to
animals or humans  following  oral  exposure were not  located in  the available
literature cited in Appendix A.
8.1.3.   Other  Routes.   Pertinent  data  regarding  the  cardnogenicity  of
n-hexane  following  other  routes  of  exposure   were   not  located  in  the
available literature cited in Appendix A.
8.1.4.   Weight of Evidence.  The lack of data regarding  the  carcinogenicity
of n-hexane  in  humans  or animals is the basis for assigning n-hexane  to U.S.
EPA Group D —  not classifiable as to human  carcinogenicity, using the U.S.
EPA <1986b> guidelines.
8.1.5.   Quantitative Risk Estimates.   The  lack  of  positive  carcinogenicity
data for n-hexane precludes quantitative estimation of  carcinogenic risk.
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    8.2.1.1.    LESS THAN  LIFETIME  EXPOSURES  
-------
exposed  to 2500  ppm  for 10  hours/day,  6 days/week  for  30  weeks  (rec #3).
Takeuchl   et   al.   (1980)   reported  clinical  signs  of  neuropathy,  nerve
conduction changes and  decreased  body weight In rats exposed to 3000 ppm for
12  hours/day  for 16 weeks  (rec  #5).   Cavender et al.  (1984) exposed rats 6
hours/day, 5  days/week  to  3000,  6500  or  10,000  ppm  for  13  weeks (rec #6 and
7).   Decreased brain  weight  and  decreased  body weight were  noted  at 10,000
ppm.   Axonopathy was  observed at  both   the  6500  and 10,000 ppm  concentra-
tions.   This  treatment regimen   had  no  effect  on  the  hlstopathology  of
kidneys,  spleen,  liver  and testes, Indicating  that  peripheral  neuropathy Is
the  critical  effect  of  exposure  to n-hexane.   Schaumburg and Spencer (1976)
reported  neuropathy In  rats exposed continuously  to  400-600 ppm for 162 days
(rec  #10).   Axonopathy  and  nerve conduction  alterations  were observed  In
rats  (rec  #1) exposed  to 200  ppm  for  12  hours/day,  7 days/week for 24 weeks
(Ono  et  al.,   1982).  Because  gross Impairment of neurological  function  was
observed  by  Rebert et  al.  (1982)  and Pryor et al.  (1982) at  1000  ppm,  by
Takeuchl  et  al.  (1980) at  3000  ppm and  by Schaumburg and  Spencer  (1976)  at
400  ppm,  these studies define FELs but  do not define  LOAELs for  peripheral
neuropathy.   The  results  from  several   studies,  such  as   Frontall  et  al.
(1981) and  Cavender  et al.  (1984), Indicate that axonopathy resulting from
intermittent  exposure to n-hexane  Is   less severe when compared with  contin-
uous  Inhalation  exposure.   Also,  axonopathy  appears  later after Intermittent
exposure.   However,  Ono   et  al.  (1982)   demonstrated   that  Intermittent
exposure of rats  to n-hexane  at  concentrations  as  low as  200 ppm can  produce
axonopathy  and  nerve   conduction   alterations.   HerskowHz  et  al.   (1971)
reported  neuropathy  In  humans   exposed  to  n-hexane  1n   an  occupational
setting.   Symptoms  developed  2-4  months  after  exposure began.  The  average
concentration  of n-hexane In  the air  was  650 ppm.   However,  the workers were
also exposed orally and dermally  to n-hexane.
5942H
-35-
07/26/89

-------
    The  LOAEL  of 200  ppm  (expanded to a  continuous  exposure of  100  ppm or
352  mg/m3)  reported  by  Ono  et  al.   (1982)   can  be  used  to  calculate  a
subchronlc  Inhalation RfD  for  a  vapor  that   causes  systemic  effects.   As
demonstrated by  Baker and  Rlckert (1981),  steady  state  In  rats  Is reached
within  ?  hours  during  exposure;  therefore,  equilibrium  conditions  had
probably  been  established  during  the  12-hour  exposure periods  In  the study
by Ono et  al.  (1982).   In  the  absence  of data  to the contrary.  It Is assumed
that  the  ratio of  the  blood/gas partition coefficient  1n animals  to  humans
Is   1.    The  human   equivalent  concentration  Is   therefore   352  mg/m3.
Applying  an  uncertainty factor  of 1000  (10  to extrapolate  from  animals to
humans,  10 to  estimate  a  NOAEL  from  a  LOAEL  and  10 to  protect  sensitive
Individuals) results  In  an  RfD  for subchronlc  Inhalation  exposures  of 0.352
mg/m3,  which  rounds  to  0.4  mg/m3.   Confidence  In  this  RfD Is  medium.
Ono   et   al.   (1982)   provided  hlstologlcal   and  functional  evidence  for
neuropathy.  The  hlstopathology  of other   organs  was  not  examined.   The
chronic neurotoxldty of n-hexane has not been  studied.
    8.2.1.2.  CHRONIC  EXPOSURES  -- No  data regarding  the  chronic  effects of
n-hexane  are  available.   An  RfD  for  chronic  Inhalation  exposure can  be
derived  from  the subchronlc RfD of 0.352 mg/m3 based on  the 24-week  study
In rats  (Ono  et al.,  1982).   Application  of an uncertainty  factor  of  10 to
extrapolate from  subchronlc  exposure results  In an RfD for  chronic Inhala-
tion   exposures  of  0.0352    mg/m3,    which   rounds  to  4xlO~2   mg/m3.
Confidence In the RfD Is medium  (see Section 8.2.1.1).
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS  THAN  LIFETIME  EXPOSURES  — Groups of five  rats  were
administered 570  mg/kg/day  n-hexane  by gavage 5 days/week  for 90 days or
1140  or  4000  mg/kg/day n-hexane  for   120  days  (Krasavage et  al.,  1980).

5942H                                -36-                           07/26/89

-------
Peripheral  neuropathy,  paralysis and  testlcular  atrophy  were  observed  1n
rats  (rec  #2)  treated with 4000  mg/kg/day  n-hexane.   Signs of neuropathy  or
testlcular  atrophy were not  seen In rats  exposed  to  570 or 1140 mg/kg/day.
Significant  decreases  In  body  weight  gain  were seen  at  these  two   dose
levels.   Because  paralysis  represents  a  gross  Impairment  of  neurological
function,  the 4000 mg/kg/day  dosage  1s considered a PEL rather than a LOAEL.
    Decreased  nerve  conduction  velocities  were  observed  In rats  (rec  #3)
following  oral   administration  of  770-2310 mg/kg/day  n-hexane  dally  for  8
weeks  (Ono  et al.,  1981).   n-Hexane (770 mg/kg/day) was administered for the
first  4 weeks.   The  rats  were administered 1155 mg/kg/day for weeks 5 and  6,
and 2310 mg/kg/day for weeks  7  and 8.
    The lowest dose  administered  1n  the  oral studies,  570 mg/kg/day (rec #1)
reported by Krasavage et  al.  (1980), Is  a LOAEL because the body weight gain
of  the  rats  treated  with  this  dose   was   significantly  depressed.   The
decreased  body weight gain appeared to  be  associated  with  clinical signs  of
neuropathy  at  higher  doses.   The LOAEL  can  be used   to  derive  a subchronlc
oral  RfO  of  0.57 mg/kg/day  (rounded  to  0.6  mg/kg/tJay) by dividing  by  an
uncertainty factor of 1000 (10  to extrapolate  from animals  to humans, 10 for
the use of a  LOAEL and 10 to protect  sensitive Individuals).  Confidence  1n
this RfD Is low.   For risk assessment  1t would be desirable to have a strong
data base  that  defines both  a  LOAEL and a  NOAEL  and  contains corroborative
studies.  The data  reported by Krasavage et al.  (1980)  were part of a broad
study  that  evaluated  the  relative  neurotoxlclty of  n-hexane,  methyl-n-
butylketone, and  their metabolites.  In  addition,  the chronic neurotoxlclty
of n-hexane following oral exposure has not been studied.
5942H                                -37-                           07/26/89

-------
     8.2.2.2.    CHRONIC  EXPOSURES  —  Studies  of  chronic  oral  exposure  to
 n-hexane  were  not available.   A chronic oral RfD of  0.057  mg/kg/day  (rounded
 to  6xlO~2 mg/kg/day)  for  n-hexane  can  be derived  by dividing the  subchro-
 n1c  oral  RfD  by  an additional uncertainty  factor  of 10 to extrapolate  from
 subchronlc exposure.  Confidence  In  this RfD  1s  low  (see  Section 8.2.2.1).
5942H
-38-
07/26/89

-------
                           9.   REPORTABLE QUANTITIES
9.1.   BASED ON SYSTEHIC TOXICITY
    The  toxldty  of n-hexane  was discussed  In  Chapter 6  and dose-response
data  considered  for  CS derivation  are  summarized  In  Table 9-1.   Since  no
chronic  toxlclty  data  are available, subchronlc  data were  considered.   Both
Inhalation and oral  studies  Indicate that neuropathy 1s  the critical  effect
of  n-hexane  toxlclty.   In addition,  decreased  body  weight  gain  Is  often
associated with  the neurotoxldty.  Takeuchl  et  al. (1980) also  found  that
2/7  rats died after 15 weeks  of  treatment  with  3000  ppm  for  12 hours/day.
The  occupational  study  by Herskowltz et al.  (1971), In  which  neuropathy was
reported  In workers who experienced  Inhalation, oral and  dermal exposure,  1s
not  Included In Table 9-1.
    Besides  typical  signs of  n-hexane  neuropathy,  Krasavage  et  al.  (1980)
found  testlcular  atrophy  In   rats  administered  4000  mg/kg/day  n-hexane  by
gavage,  5 days/week for 120 days.
    Table 9-2  presents  CSs and  RQs  derived  for  the lowest  human equivalent
dosages  associated  with each  of the effects  summarized  In Table  9-1.   The
highest  CS  calculated,  13,  associated  with  neuropathy  In  rats  exposed  by
Inhalation (Ono  et  al.,  1982),  was selected  as  most  representative of  the
chronic  toxlclty of n-hexane.  The  CS of 13  and  Us corresponding RQ of  1000
are presented In Table 9-3.
9.2.   BASED ON CARCINOGENICITY
    No data were located  regarding  the carclnogenlclty of n-hexane In  humans
or  animals,  and  the  compound  was  placed 1n  EPA  Group  D.  Hazard ranking
based on  carclnogenlclty  Is not  possible for EPA Group D substances;  there-
fore, an RQ based  on  carclnogenlclty  cannot be assigned.   NTP  (1989)  has
recently completed an Inhalation  bloassay of  n-hexane using  mice.   The  final
technical report  1s  1n preparation.

5942H                                -39-                           09/26/89

-------
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5942H
                -42-
07/26/89

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                                  TABLE  9-3
                                  n-Hexane
          Minimum  Effective  Dose  (MED) and Reportable Quantity  (RQ)

Route:            inhalation
Species:          rat
Dose3:            270 mg/day
Duration:         24 weeks
Effect:           axonopathy, nerve conduction alterations
RVd:              1.85
RVe:              7
CS:               13
RQ:               1000
Reference:        Ono et al., 1982
'Equivalent Human Dose
5974H                                -43-                           06/15/89

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5942H                                -54-                           09/26/89

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Sexton,  K.  and H. Westberg.   1980.   Ambient hydrocarbon  and  ozone measure-
ments  downwind   of   a   large  automotive  painting  plant.   Environ.  Scl.
Techno!.  14: 329-332.

Shah,  J.J.   and  E.K. Heyerdahl.   1988.   National  ambient  volatile  organic
compounds (VOCs) data base update.  EPA/600/3-88/010a.  p. 34, 57.

Shamsky,  S.  and  B.  Samlml.   1987.   Organic  vapors at  underground gasoline
tank removal sites.  Appl. Ind. Hyg.  2: 242-245.

Sllversteln, R.M.  and C.G. Bassler.  1963.   Spectrometrlc Identification  of
organic compounds, 2nd ed.  John Wiley and Sons, Inc., New York, NY.  p. 155.

SRI  (Stanford  Research  Institute).   1988.   1988  Directory  of  Chemical
Producers, United States of America. SRI International,  p. 682.

Stratton, 6.W.   1987.  Toxic  effects of  organic  solvents on  the  growth  of
blue-green algae.  Bull. Environ. Contam. Toxlcol.   38(6): 1012-1019.

Swann, R.L., D.A. Laskowskl,  P.J.  McCall,  K.  Vander Kuy and H.J. Dlshburger.
1983.  A  rapid  method  for the  estimation  of  the environmental  parameters
octanol/water  partition  coefficient, soil  sorptlon constant,  water   to  air
ratio and water solubility.  Res. Rev.  85: 17-28.

Takeuchl,  Y.,   Y.  Ono,  N.  Hlsanga,  3.   Kotoh  and  Y.  Suglura.   1980.   A
comparative  study  on the neurotoxlclty  of n-pentane,  n-hexane  and  n-heptane
1n the rat.   Br. J. Ind. Med.   37: 241-247.


5942H                                -55-                           09/26/89

-------
U.S.  EPA.   1980.   Guidelines  and Methodology  used  1n  the  Preparation  of
Health  Effect  Assessment  Chapters   of  the  Consent  Decree  Water  Criteria
Ooxuments.   Federal Register 45(231): 79347-79357.

U.S.  EPA.   1984.   Methodology and Guidelines  for  Ranking  Chemicals  Based on
ChronU  Tox1c1ty  Data.   Prepared  by  the Office of  Health  and Environmental
Assessment,  Environmental  Criteria and  Assessment  Office,  Cincinnati,  OH for
the Office of Emergency and Remedial Response, Washington, DC.

U.S.   EPA.    1986a.    Methodology   for   Evaluating  Reportable   Quantity
Adjustments  Pursuant  to   CERCLA  Section  102.   Prepared  by  the  Carcinogen
Assessment Group,  Office  of Health and  Environmental Assessment, Washington,
DC for the Office of Emergency and Remedial Response, Washington, OC.

U.S.  EPA.   19865.   Guidelines  for  Carcinogen   Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

U.S.  EPA.   1987.   Graphical   Exposure Modeling  System  (GEMS).   Fate  of
Atmospheric   Pollutants   (FAP),   Office  of   Toxic   Substances,   U.S.   EPA,
Washington, DC.

U.S.  EPA/OWRS  (Environmental  Protection Agency/Office  of  Water  Regulation
and  Standards).   1986.   Guidelines  for Deriving  Numerical  National  Water
Quality  Criteria  for  the  Protection of Aquatic  Organisms  and Their  Uses.
Washington, DC.  NTIS PB85-227049/XAB.
5942H                                -56-                           09/26/89

-------
Uno,  I.,  S.  Wakamatsu, R.A. Wadden, S.  Konno  and H.  Koshlo.  1986.  Evalua-
tion of hydrocarbon reactivity In urban air.  Atmos. Environ.  19: 1283-1293.

USITC  (United  States  International  Trade Commission).    1985.   Synthetic
Organic Chemicals  United States  Production and  Sales,  1984.  USITC Publica-
tion 1745.  US11C. Washington, DC.  p. 16, 19,  21.

USITC  (United  States  International  Trade Commission).    T986.   Synthetic
Organic Chemicals  United States  Production and  Sales,  1985.  USITC Publlca-
tlon 1892.  USITC, Washington, DC.  p. 20, 23,  25.

USITC  (United  States  International  Trade Commission).    1987.   Synthetic
Organic Chemicals  United States  Production and  Sales,  1986.  USITC Publica-
tion 2009.  USITC, Washington, DC.  p. 19, 21,  23.

USITC  (United  States  International  Trade Commission).    1988.   Synthetic
Organic Chemicals  United States  Production and  Sales,  1987.  USITC Publica-
tion 2118.  USITC, Washington, DC.  p. 2-3, 2-5,  2-7.

Vannetten,  C.,  C.  ShlrtUffe  and  J.  Svec.    1988.   Formaldehyde  release
characteristics  from   a   Swedish   floor   finish.   Bull.   Environ.   Contam.
Toxlcol.   40: 672-677.

Vogt, W.G. and  J.J. Walsh.  1985.  Volatile organic compounds  In gases  from
landfill  simulators.  In: Proc.  APCA Annu. Meet.   6: 1-17.
5942H                                -57-                           09/26/89

-------
Madden,  R.A.,  I.  Uno  and  S.  Hakamatsu.   1986.   Source discrimination  of
short-term hydrocarbon  samples  measured aloft.  Environ.  Scl.  Techno!.   20:
473-483.

Weast.  R.C.,  M.J. Astle  and  W.H.  Beyer.   1988.   CRC Handbook  of  Chemistry
and Physics, 69th ed.  CRC Press, Inc., Boca Raton, FL.  p. C-303.

WhHehead,  L.W.,  6.L.  Ball,  L.J.  Fine and  G.O.   Langolf.   1984.   Solvent
vapor  exposures   In  both  spray  painting  and spray  glueing,  and  associated
operations.  Am.   Ind. Hyg. Assoc. J.  45:  767-772.

Young,  P.  and  A.  Parker.   1984.   Vapors,  odors,  and toxic gases  from  land-
fills.  In: ASTM Spec. Tech. Publ.  851: 24-41.
5942H                                -58-                           09/26/89

-------
                                  APPENDIX A

    This  HEED   Is  based  on  data   Identified  by  computerized   literature

searches of the  following:

                   CHEMLINE
                   TSCATS
                   CASR online (U.S.  EPA Chemical Activities Status Report)
                   TOXLINE
                   TOXLIT
                   TOXLIT 65
                   RTECS
                   OHM TADS
                   STORET
                   SRC Environmental  Fate Data Bases
                   SANSS
                   AQUIRE
                   TSCAPP
                   NTIS
                   Federal Register
                   CAS ONLINE (Chemistry and Aquatic)
                   HSDB


These  searches  were  conducted  In  May  1989,  and  the  following  secondary

sources were reviewed:
       ACGIH  (American  Conference  of  Governmental  Industrial  Hyglenlsts).
       1986.   Documentation  of  the  Threshold Limit  Values and  Biological
       Exposure Indices.  5th ed.  Cincinnati, OH.

       ACGIH  (American  Conference  cf  Governmental  Industrial  Hyglenlsts).
       1987.   TLVs:  Threshold  Limit  Values  for  Chemical Substances  In  the
       Work   Environment   adopted  by   ACGIH  with   Intended   Changes   for
       1987-1988.  Cincinnati, OH.  114 p.

       Clayton,  G.D.  and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
       Hygiene and Toxicology.   3rd rev.  ed.   Vol.  2A.  3ohn Wiley and Sons,
       NY.  2878 p.

       Clayton,  G.D.  and  F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
       Hygiene and Toxicology.   3rd rev.  ed.   Vol.  28.  John Wiley and Sons,
       NY.  2879-3816 p.

       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.  3817-5112 p.
5942H                                A-l                            07/26/89

-------
       Grayson,  M.  and D.  Eckroth,  Ed.   1978-84.   K1rk-0thmer Encyclopedia
       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.,  MA.  575 p.

       IARC  (International  Agency for Research on  Cancer).   IARC Monographs
       on the  Evaluation  of Carcinogenic  Risk  of  Chemicals to Humans.  IARC,
       Lyons, France: WHO.

       Jaber,  H.M.,  W.R.  Mabey,  A.T.  Lieu,  T.W.  Chou  and  H.L.  Johnson.
       1984.    Data   acquisition   for   environmental   transport  and   fate
       screening  for  compounds  of  Interest  to  the  Office  of  Solid  Waste.
       EPA-600/6-84-010.   (NTIS  P884-243906)  Menlo  Park,   CA:  SRI  Inter-
       national.

       NIP  (National  Toxicology  Program).   1987.   Toxicology  Research  and
       Testing Program.  Chemicals on Standard Protocol.   Management  Status.

       Ouellette,  R.P.  and  J.A.  King.   1977.    Chemical  Week  Pesticide
       Register.  McGraw-Hill  Book Co.,  NY.

       Sax,  I.N.   1984.  Dangerous  Properties of  Industrial  Materials.   6th
       edition.  Van Nostrand Relnhold Co., NY.

       SRI  (Stanford  Research  Institute).    1987.    Directory  of  Chemical
       Producers.  Stanford, CA.

       U.S.  EPA.  1986.   Report  on Status  Report  In   the  Special  Review
       Program,   Registration   Standards   Program  and   the   Data   Call   In
       Programs.   Registration  Standards and  the  Data  Call   In  Programs.
       Office of Pesticide Programs, Washington, DC.

       USITC   (United   States   International   Trade   Commission).    1986.
       Synthetic  Organic  Chemicals.   U.S. Production  and  Sales,  1985,  USITC
       Publication 1892.  Washington, DC.

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

       Worthing,  C.R.  and  S.B.  Walker,  Ed.   1983.   The Pesticide  Manual.
       British Crop Protection Council.   695 p.

       Wlndholz,  M.  Ed.   1983.  The Merck Index.   10th ed.   Merck  and  Co.,
       Inc., Rahway,  NJ.
5942H                                A-2                            07/26/89

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     In  addition,  approximately  30 compendia  of  aquatic  toxicity  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,  h.W.  and M.T. Fin ley.   1980.   Handbook  of Acute Toxicity of
        Chemicals  to  Fish  and Aquatic Invertebrates.   Summaries of  Toxicity
        Tests  Conducted  at  Columbia National  Fisheries  Research Laboratory.
        1965-1978.   United  States  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.

        Pimental, 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.
5942H                                A-3                              5/3/89

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                                 APPENDIX C
           DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO n-HEXANE
C.I.   DISCUSSION
      Dose/duration-response  graphs  for  inhalation  and  oral  exposure  to
n-hexane  generated  by  the  method  of  Crockett  et  al.  (1985)  using  the
computer  software  by Durkin  and  Meylan <1988)  developed  under  contract  to
ECAO-Cincinnati  are  presented in  Figures  C-l,  C-2,  C-3,  C-4 and  C-5.  Data
used  to  generate  these  graphs  are  presented  in  Section  C.2.  In  the
generation of  these figures  all  responses are  classified as adverse  (FEL,
AEL or  LOAEL)  or non-adverse (NOEL or  NOAEL)  for plotting.    For  inhalation
exposure  the ordinate  expresses   concentration  in  either of two  ways.   In
Figures C-l  the  experimental  concentration expressed  as mg/m3  was  multiplied
by  the  time  parameters  of  the  exposure protocol   (e.g.,  hours/day  and
days/week) and is presented as expanded  experimental concentration  [expanded
exp cone  (mg/m3)].   In  Figure  C-2, the expanded experimental concentration
was multiplied by the cube root of the ratio of the  animal :human body weight
to  adjust for  species  differences  in  basal  metabolic  rate  (Mantel  and
Schneiderman,  1975)  to  estimate  an equivalent human or  scaled concentration
[scaled  cone  (mg/m3)].   For oral  exposure,   the ordinate  expresses dosage
as  human  equivalent  dose.   The animal  dosage  in  mg/kg/day is multiplied  by
the cube  root of  the  ratio  of  the animal :human  body weight to  adjust for
species  differences  1n  basal  metabolic  rate  (Mantel  and  Schneiderman,
1975).   The  result  is  then  multiplied  by 70 kg,  the  reference  human body
weight, to express the human  equivalent dose as mg/day for a 70 kg human.
    The Boundary for Adverse Effects  (solid  line)  is  drawn  by Identifying
the lowest adverse  effect  dose  or concentration  at  the  shortest duration of
6107H
C-l
06/16/89

-------
 n
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                                                        rs
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                                                	,_. uf>
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                                                              Fie
          e.ei
(Inhalation Exposure)
                  0.1
HUMAN EQUIU DURATION (fraction  lifcspan)
         '  ENVELOP METHOD
                                            FIGURE C-1

                 Dose/Duration-Response  Graph  for  Inhalation  Exposure  to  n-Hexane,
                       Expanded Experimental Concentration (Envelop Method)

           Key:   F » FEL
                  A - AEL
                  I = LOAEL
                  n - NOAEL
                  N - NOEL

           Solid Line « Adverse Effects Boundary
           Dotted Line - No Adverse Effects Boundary
           6107H
                                                 C-2
                                                                                06/19/89

-------
I
9
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                               A6

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                             I     l   j
    e.ei

   n Exposure)
                                               0.1
                             HUNAN EQUIU DURATION  (fraction  lifospan)
                                       ' ENVELOP  NCTHOD
                                          FIGURE C-2

               Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
                             Scaled Concentration (Envelop Method)
          Key:
          F
          A
          L
          n
          N
FEL
AEL
LOAEL
NOAEL
NOEL
          Solid  Line  «  Adverse  Effects  Boundary
          Dotted Line - No  Adverse  Effects  Boundary
          6107H
                                        C-3
                                                         06/19/89

-------
o
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                                  I    1   1
                                                    A6
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          B.B1
< I nh«» I * t i on Exposure )
                                                4-
                                                              Fie
                                               B.l
                             HUMAN EQUIU DURATION  (fraction lifcspan)
                                   CEMSORED DATA HETHOD
                                          FIGURE  C-3

              Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
                    Expanded Experimental Concentration (Censored Method)
         Key:
               F
               A
               L
               n
               N
FEL
AEL
LOAEL
NOAEL
NOEL
         Solid  Line * Adverse  Effects  Boundary
         Dotted  Line - No Adverse  Effects  Boundary
        6107H
                                             C-4
                                                                            06/19/89

-------
r
               leeee
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                                   ft?
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                                   rs
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                                                                       Fie
                    8.81
         C InhAl at i 011 Exposure >
                               8.1
             HUMAN EQUIU DURATION (fraction I if(span)
                   CENSORED DATA METHOD
                   Key:
                                                    FIGURE C-4

                         Dose/Duration-Response Graph  for  Inhalation Exposure to n-Hexane,
                                      Scaled Concentration (Censored Method)
F
A
L
n
N
FEL
AEL
LOAEL
NOAEL
NOEL
                   Solid Line = Adverse Effects Boundary
                   Dotted Line = No Adverse Effects Boundary
                   6107H
                              C-5
                                                                                       06/19/89

-------
    1088800 r
 15
 r
5
M
a
e
u
186000 • r
      10000~ r
       1800 -t-
           0.801
(Oral Exposure)
                              0.01                     8.1
                         HUNAN EQUIU DURATION (fraction
                                 '   ENVELOP HETHOD
         Key:
                                     FIGURE  C-5

             Dose/Duration-Response Graph for Oral Exposure to n-Hexane,
                                  Envelop Method

           F * FEL
           A * AEL
           L » LOAEL
         Solid Line = Adverse  Effects  Boundary
         6107H
                                         C-6
06/19/89

-------
exposure at which  an  adverse effect  occurred.  From  this  point an  infinite
line is  extended  upward, parallel to  the  dose  axis.  The starting  point is
then connected  to the  lowest  adverse effect dose  or  concentration at  the
next  longer  duration  of  exposure   that   has  an   adverse  effect  dose  or
concentration equal  to or  lower  than  the previous  one.    This  process  is
continued  to  the  lowest adverse  effect dose  or  concentration.   From  this
point a  line  is  extended to the right,  parallel to  the duration  axis.   The
Region of Adverse Effects lies  above  the Adverse Effects Boundary.
    Using the envelope  method,  the Boundary for No  Adverse Effects  (dashed
line)  is  drawn  by   identifying  the  highest  no  adverse  effects  dose  or
concentration.  From  this point,  a  line parallel  to the duration  axis  Is
extended  to the  dose or  concentration axis.   The   starting  point  is  then
connected to the next lower  or  equal  no adverse  effect  dose  or  concentration
at  a  longer  duration  of  exposure.   When  this  process  can  no  longer  be
continued, a  line  is  dropped parallel  to the dose or concentration  axis to
the duration  axis.   The  No  Adverse Effects Region lies  below  the  No Adverse
Effects Boundary.  At  either end of  the graph between the Adverse Effects
and  No  Adverse  Effects  Boundaries  are  Regions of  Ambiguity.   The  area (If
any) resulting  from  intersection  of  the   Adverse   Effects  and  No  Adverse
Effects Boundaries is defined as the  Region of Contradiction.
    In the censored data method, all  no adverse  effect points located  in the
Region of  Contradiction are dropped  from   consideration  and the No Adverse
Effect Boundary 1s redrawn so that 1t does  not  intersect the Adverse Effects
Boundary and  no  Region of Contradiction Is generated. This method  results in
the most conservative definition of the No  Adverse  Effects Region.
6107H
C-7
06/19/89

-------
    Figures C-l and  C-2  present dose/duration-response graphs for Inhalation
exposure drawn by the envelope method.  Figure C-1 presents  results  using an
expanded  experimental   concentration.    The   Adverse  Effects  Boundary  is
defined  by  several  experimental  points  (rec #1,  2  and  9)   associated  with
peripheral  neuropathy  (Ono et  al.,  1982;  Rebert et  al., 1982;  Pryor  et al.
1982)  in  rats.   Record  #1  <0no et al.,   1982)  served as  the basis for the
determination  of the  RfD  for  subchronic  and  chronic  inhalation  exposure.
The No Adverse Effects Boundary is defined by two points  (rec #4  and  8)  also
associated  with  peripheral  neuropathy  (Frontal 1 et  al.,  1981;  Cavender et
al.,   1984).   The   rather  small   Region  of  Contradiction   reflects   the
possibility that Wistar  rats  are more sensitive than  Sprague-Dawley  rats to
n-hexane.   When  the   graphs   are  redrawn  to  eliminate   the   Region  of
Contradiction  (Figures C-  3 and C-4), the No Adverse Effects Boundary Is now
defined  by  only  one  NOAEL for  peripheral  neuropathy in  rats  (Cavender et
al.. 1984; rec #8).
    Figures C-2  and  C-4  present  the graph  redrawn  so that  the data are
expressed as  scaled  concentration.   Scaling produced the same Adverse and No
Adverse  Effects   Boundary  as  drawn  by   using   an   expanded  experimental
concentration.
    Figure  C-5 presents  the  dose/duration-response  graph  generated   by the
envelope method for  oral exposure.  The  Adverse Effects  Boundary 1s  defined
by  lethality  data in  mice (rec #4) and  rats  (rec #5), and  AEL  (rec  #3) for
peripheral  neuropathy in rats  and a LOAEL (rec #1) for decreased body weight
gain in rats (Krasavage  et  al..  1980).   Since no oral study defined  a  NOAEL
or  NOEL,  the  No  Adverse  Effects Boundary could not be drawn.  The LOAEL  (rec
#1) served  as  the basis  for determining  the  RfD for  subchronic  and  chronic
oral exposure.

6107H                                C-8                            06/19/89

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C.2.   DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS

C.2.1.   INHALATION EXPOSURE
Chemical Name:
CAS Number:
Document Title:
Document Number:
Document Date   :
Document Type   :
n-Hexane
110-54-3
Health and Environmental
pending
pending
HEED
            Effects Document on n-Hexane
RECORD
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Inhalation
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose: 352.000
Duration Exposure: 20.0 weeks
Duration Observation: 24.0 weeks
                          8
                          NR
                          NEURP
                          PNS
                          6
                  Comment:     Doses: 200 or 500 ppm. Motor nerve conduct.
                               veloc. (MCV) was slightly dec. at 200 ppm.
                               MCV was markedly dec. at the highest dose
                               after 8 wk.  Axonal degeneration was also
                               noted.

                  Citation:    Ono et al., 1982
RECORD #2:



Species:
Sex:
Effect:
Route :
Rats
Male
AEL
Inhalation
Dose: 2517.000
Duration Exposure: 18.0 weeks
Duration Observation: 18.0 weeks

                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          15
                          NR
                          NEURP
                          PNS
                          6
                  Comment:     Doses: 24,000 and 48,000 ppm,10 min expos. 6
                               or 12 times/d,5 h/d. Forelimb grip strength
                               decreased.  Brainstem auditory-evoked resp.
                               was decreased at the highest dose.

                  Citation:    Rebert et al., 1982; Pryor et al., 1982
6107H
                   C-9
                                      06/19/89

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RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Inhalation
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose: 3147.000
Duration Exposure: 30.0 weeks
Duration Observation: 30.0 weeks
                          6
                          NR
                          NEURP
                          PNS
                          6
                  Comment:      Doses and duration:  500 ppm,9  h/d,  5 d/wk,  30
                               wk;  1500 ppm 9 hr/d,  5 d/wk,  14 wk;  2500 ppm,
                               10 hr/d, 5 d/wk,  30  wk; EDOO  ppm,  9 hr/d,  5
                               d/wk, 14 wk.  Peripheral  neuropathy was  ob-
                               served at 2500 and 5000 ppm concentrations.

                  Citation:     Frontali et al.,  1981
RECORD #4:

Species: Rats
Sex: Male
Effect: NOAEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 629.000
Duration Exposure: 30
Duration Observation:
6
NR
NEURP
PNS
6
.0 weeks
30.0 weeks

                  Comment:      See previous record for doses and durations.
                               Rats sxpcsed to  500 and 1500 ppm doses did
                               not show signs of neuropathy. Decreases In
                               weight gain were seen in rats at 500 and 5000
                               ppm, but not at other cone.

                  Citation:    Frontali et al., 1981
RECORD #5:








Species: Rats
Sex: Male
Effect: FEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 5287.000
Duration Exposure: 16
Duration Observation:

7
NR NR
NEURP WGTDC
PNS BODY
7 4

.0 weeks
16.0 weeks

7
NR
DEATH
NS
10
                  Comment:     Dose: 3000 ppm, 12 hr/d for 16 wks. Dec. body
                               wt., muscular atrophy, foot drop, nerve con-
                               duct veloc. changes and axonal degen. were ob-
                               served.  Two rats died by end of 16 wk. expo.

                  Citation:    Takeuchi et al., 1980
6107H
                   C-10
                                     06/19/89

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RECORD #6:
RECORD #7:
Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Inhalation
Dose: 6294.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
15
NR
WGTDC
BRAIN
6
15
NR
NGTDC
BODY
4
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                  Comment:     Doses: 3000, 6500 or 10,000 ppm 6 hr/d, 5 d/
                               wk.  Decreases In brain weight and body weight
                               observed only in male rats at 10,000 ppm.

                  Citation:    Cavender et al., 1984
Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Inhalation
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose: 4091.000
Duration Exposure: 13.0 weeks
Duration Observation:  13.0 weeks
                          15
                          NR
                          NEURP
                          PNS
                          6
                  Comment:     Doses same as previous record. Axonopathy was
                               observed In male rats rats exposed to 6500 ppm
                               (1/5 rats) and 10,000 ppm (4/5 rats).  Female
                               rats did not show any signs of axonopathy
                               after expos.

                  Citation:    Cavender et al., 1984
RECORD #8:



Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Inhalation
Dose: 1888.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks

                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          15
                          NR
                          NEURP
                          PNS
                          6
                  Comment:     See previous records.  No effects at 3000 ppm.

                  Citation:    Cavender et al.,  1984
6107H
                   C-11
                                     06/16/89

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RECORD #9:
RECORD #11
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Inhalation
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  SUe of Effect:
                  Severity Effect:
Dose: 2518.000
Duration Exposure: 11.0  Weeks
Duration Observation: 11.0 Weeks
                          15
                          NR
                          NEURP
                          PNS
                          7
                  Comment:     Dose: 1000 ppm, 24 hr/d, 5 d/wk.  Alterations
                               1n bralnstem auditory-evoked resp.  and de-
                               creases In hlndllmb strength,  avoidance resp.,
                               body weight gain and motor activity observed.

                  Citation:    Rebert et al., 1982; Pryor et  al..  1982
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
N.S.
PEL
Inhalation
Dose: 1410.000
Duration Exposure: 162.0 days
Duration Observation: 162.0 days
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          8
                          NR
                          NEURP
                          PNS
                          8
                  Comment:     Range: 400-600 ppm continuously.  Unsteady,
                               waddling gait devel.  In rats after  45 days
                               Further expos, resulted 1n a progressive,
                               distal hlndllmb weakness with foctdrop.
                               Axonopathy also seen.

                  Citation:    Schaumburg and Spencer, 1976.
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Inhalation
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose: 1762.000
Duration Exposure:  9.0 days
Duration Observation:  9.0 days
                          9
                          NR
                          TERAS
                          FETUS
                          8
                  Comment:     Rats were exposed to 1000 ppm for  6 hr/d  on
                               days 8-12(7rats), days 12-16(9 rats),  or  days
                               8-16 (8rats) of gestation.

                  Citation:    Bus et al., 1979
6107H
                   C-12
                                     07/26/89

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C.2.2.   ORAL EXPSOSURE
RECORD #1
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Gavage
Dose: 407.000
Duration Exposure: 90.0 days
Duration Observation: 90.0 days
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          5
                          NR
                          NEURP
                          PNS
                          7
                                    5
                                    NR
                                    ATROP
                                    TESTE
                                    6
                  Comment:     Doses: 570 mg/kg/d 5 d/wk for 90 d, 1140 mg/
                               kg/d 5 d/w 4000 mg/kg/d 5 d/wk 120 days.
                               Decreased body weight gain at all doses.

                  Citation:    Krasavage et al.,  1980
RECORD #2:



Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Gavage
Dose: 2857.000
Duration Exposure: 120.0 days
Duration Observation: 120 days

                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          5
                          NR
                          NEURP
                          PNS
                          7
                                    5
                                    NR
                                    ATROP
                                    TESTE
                                    6
                  Comment:     See previous record. Hindiimb weakness, axonal
                               swelling, myelin retraction; testicular
                               atrophy at 4000 rng/kg/day, 5 days/week for 120
                               days.

                  Citation:    Krasavage et al., 1980
Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Oral.(NOS)
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose: 770.000
Duration Exposure: 8.0 weeks
Duration Observation: 8.0 weeks
                          7
                          NR
                          NEURP
                          PNS
                          6
                  Comment:     Doses: 770 mg/kg/d for 1st 4 wks, 1155 mg/kg/d
                               for wks 5 and 6, and 2310 mg/kg/d for wks 7 and
                               8.  Motor and mixed nerve conduction velocities
                               were decreased. No hlstopathology was
                               performed.

                  Citation:    Ono et al., 1981
6107H
                   C-13
                                     06/16/89

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RECORD #4:
Species:
Sex:
Effect:
Route:
Mice
Female
PEL
Gavage
                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
Dose:  2200.000
Duration Exposure: 10.0 days
Duration Observation: 10.0 days
                          14
                          NR
                          DEATH
                          NS
                          10
                  Comment:     Doses: 260 mg/kg/d (13 mice),  660 mg/kg/d <6
                               mice), 1320 mg/kg/d (6 mice)  and 2200 mg/kg/d
                               (14 mice) on days 6-15 of gestation.  One of 14
                               dams died. No teratogenic effects were found.

                  Citation:    Marks et al., 1980
RECORD #5:



Species:
Sex:
Effect:
Route:
Rats
NS
FEL
Oral.(NOS)
Dose: 15800.000
Duration Exposure: 1
Duration Observation


.0 days
: 1.0 days

                  Number Exposed:
                  Number Responses:
                  Type of Effect:
                  Site of Effect:
                  Severity Effect:
                          NR
                          NR
                          DEATH
                          NS
                          10
                  Comment:     LD5Q of 15800 mg/kg/d for 14-day-old rats.
                               LDso of 32340 mg/kg/d for young adult rats.
                               LD50 of 28710 mg/kg/d for older adult rats.
                               Symptoms of acute toxlclty was not reported.

                  Citation:    Kimura et al.. 1971
6107H
                   C-14
                                      06/16/89

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