)j'r
P/EPA
        00k
               United States
               Environmental Protection
               Agency
                                         FINAL DRAFT
                                         ECAO-CIN-6068
                                         Hay, 1990
Research and
Development
             HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
             FOR  2-HEXANONE
               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                         DRAFT: DO NOT CITE OR QUOTE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.

                           HEADQUARTERS LIBRARY
                           ENVIRONMENTAL PROTECTION AGENCY
                           WASHINGTON, D.C. 20460

-------
                                  DISCLAIMER

    This report  Is  an external draft  for  review purposes only and  does  not
constitute  Agency  policy.   Mention  of  trade names  or  commercial  products
does not constitute endorsement or recommendation for  use.
                                      11

-------
                                    PREFACE
    Health and  Environmental  Effects Documents (HEEDs) are  prepared  for  the
Office of  Solid  Waste and Emergency Response  (OSWER).  This  document series
1s  Intended  to support  listings  under  the  Resource Conservation and Recovery
Act  (RCRA)  as  well as  to provide health-related  limits and  goals  for  emer-
gency  and  remedial actions  under  the Comprehensive  Environmental  Response,
Compensation  and  Liability  Act  (CERCLA).   Both  published  literature  and
Information  obtained  for  Agency Program Office  files are evaluated  as  they
pertain to potential  human health, aquatic  life  and environmental  effects of
hazardous  waste  constituents.   The  literature searched for  In  this document
and  the  dates  searched  are  Included  In  "Appendix:  Literature  Searched."
Literature search  material  Is  current up  to 8 months previous  to  the  final
draft  date  listed  on the front  cover.   Final  draft document  dates  (front
cover) reflect the date the document Is sent to the Program Officer  (OSWER).

    Several  quantitative  estimates  are  presented  provided  sufficient  data
are available.   For systemic toxicants,  these  Include Reference doses (RfDs)
for  chronic  and  subchronlc  exposures  for  both  the  Inhalation  and  oral
exposures.   The  subchronlc  or  partial  lifetime  RfD  Is  an  estimate of  an
exposure  level   that  would not  be  expected  to  cause  adverse effects  when
exposure occurs  during a  limited  time  Interval  I.e.,  for an  Interval  that
does  not  constitute  a  significant  portion  of the  llfespan.   This  type  of
exposure estimate  has not been  extensively used,  or rigorously defined  as
previous risk assessment  efforts have  focused  primarily on  lifetime exposure
scenarios.   Animal data  used  for  subchronlc estimates  generally  reflect
exposure durations  of  30-90  days.   The general  methodology for  estimating
subchronlc RfOs  Is  the  same as  traditionally  employed for  chronic  estimates,
except that  subchronlc data are utilized when available.

    In the case  of  suspected  carcinogens,  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.   An RfD may also  be  derived  for  the noncarclno-
genlc health effects of compounds that  are  also carcinogenic.
    Reportable quantities  (RQs)  based  on both chronic toxldty and  carclno-
genldty are derived.  The RQ  1s  used  to determine  the quantity of  a hazard-
ous substance  for  which  notification  1s  required  In the event of
as  specified  under  the  Comprehensive  Environmental Response,
and Liability  Act  (CERCLA).   These  two RQs  (chronic  toxldty
genlclty) represent  two  of  six scores  developed (the  remaining
IgnUabllHy,   reactivity,  aquatic toxldty,  and  acute mammalian  toxldty).
Chemical-specific RQs reflect  the lowest of  these six  primary  criteria.   The
methodology for  chronic  toxldty and  cancer based  RQs  are defined  In  U.S.
EPA, 1984 and  1986c,  respectively.
   a release
Compensation
and cardno-
four reflect
                                      111

-------
                               EXECUTIVE SUMMARY

    2-Hexanone Is  known  by  the  synonyms  butyl  methyl  ketone, methyl  butyl
ketone and propyl acetone (Hawley, 1981; Wlndholz,  1983).   It  Is  a colorless
liquid that  1s  soluble  1n  alcohol  and ether  and  slightly soluble  In  water
(Wlndholz, 1983).  Production data for 2-hexanone are limited.  In 1977,  the
Tennessee Eastman  Company manufactured between  1  and  10  million pounds  of
2-hexanone .{U.S.  EPA,   1977).    However,  the   1988  Directory  of  Chemical
Producers (SRI,  1988) and  the U.S.  International  Trade  Commission  (US1TC,
1988)  do not have   listings  for  2-hexanone,  suggesting that   1t  Is  not
currently manufactured on an Industrial scale  In  the United  States  for  use
as an end-product.  Current  Import figures are  not  available.   2-Hexanone Is
used  as  a medium-evaporating  solvent for  nitrocellulose, acrylates,  vinyl
and alkyd coatings (Papa  and Sherman, 1981).
    2-Hexanone appears to be readily  degradable  1n air, water and  soil;  It
Is not likely  to be  a persistent environmental  contaminant.   If  released to
the atmosphere 2-hexanone Is expected to  exist 1n  the  vapor  phase  where It
will  degrade  by  reaction with sunlight-formed  HO  radical.   Based  upon  an
experimentally determined rate constant  (WalUngton  and  Kurylo,  1987),  the
half-life for  this  reaction has  been  estimated to  be -2.4 days  for  typical
atmospheric  conditions.   If  released  to the  aquatic  environment,  2-hexanone
may  degrade  by  blodegradatlon  or be  physically removed  by  volatilization.
2-Hexanone  appears  to   be   readily  biodegradable  based  upon results  from
limited  blodegradatlon screening  studies  (Babeu  and Valshnav,  1987;  Valshnav
et al.,  1987;  Shelton and  Tledje,  1984).   Volatilization half-lives of  -12
hours  and  5.7  days  can  be  estimated   for  a  shallow  model   river  and
environmental  pond,   respectively  (Thomas,   1982;   U.S.  EPA,  1986a).   If
                                      Iv

-------
released   to   soil,    2-hexanone   may   be   susceptible   to   significant
blodegradatlon  based   on  analogy  to  the  blodegradatlon  screening  studies
noted  above.   Although  significant   leaching  Is  possible,  concurrent  bio-
degradation may  decrease  the  potential  Importance of  leaching.   2-Hexanone
1s  used  as  a medium-evaporating  solvent  (Papa  and Sherman,  1981)  and  Is
expected to undergo significant evaporation  from dry surfaces.
    2-Hexanone  can be  released  to   the  aquatic  environment  by  wastewater
streams generated  at  various  fossil-fuel  processing and chemical  manufactur-
ing sites and by leaching from hazardous  waste  sites  and municipal landfills
(HSDB,  1989;  Brown  and  Donnelly,  1988;  Myers,  1983).  This  compound  Is
released to the atmosphere by  evaporation from  Us  use  as  a  solvent (Graedel
et  al.,  1986).   2-Hexanone  occurs  naturally.    It  has been  detected  as  a
volatile  component of blue-  cheese,  nectarines,  raw  chicken  breast  and
poultry  manure   (Day  and Anderson,   1965;  Takeoka et  al.,  1988;  Grey  and
Shrlmpton,  1967; Yasuhara, 1987).  The  general  population may be  exposed  to
2-hexanone through Ingestlon  of  natural  and  processed foods  (In which  H
occurs naturally)  and through  Inhalation  of vapors from commercial coatings
containing 2-hexanone as  a  solvent   (HDSB,  1989).    Insufficient  monitoring
data  are  available to  estimate average  human  dally  Intakes  of  2-hexanone
using food, Inhalation or  drinking water.
    The  96-hour   LC     and   EC5Q   for  the   fathead  minnow,   Plmephales
prgmelas.  exposed  to   2-hexanone  under  flowthrough  conditions  was 428  mg/S.
(Gelger et al.,  1986).  The  ED™  for scud, Gammarus.  mea'sured  as the  loss
of  an  escape response  when  organisms   experienced  a  mechanical stimulus
delivered by  hand  to  either  lateral  surface  when exposed to  2-hexanone  was
420 mg/a.

-------
    The  EC™ for  mixed mlcroblal  cultures, measured  as  the  concentration
of 2-hexanone that  would reduce the maximum observed blodegradatlon  rate by
50%,  was  5510  mg/i  (0.055  M)  (Valshnav,  1986).   Tests  assessing  the
efficacy  of  2-hexanone  as  a  repellent  for the  bee,  Apis  florea.  revealed
that  bees  exposed  to  concentrations  of 2-hexanone  from 62.5 and 4dOO  mg/i
resulted  In  64.0 and  82.6% repelled, respectively  (Gupta and Mohla,  1986;
Gupta, 1987).
    2-Hexanone 1s absorbed  readily from  the  GI  tract, the respiratory tract,
and through  the  skin.   Respiratory uptake  data  In humans (DIVIncenzo  et  al.,
1978) Indicate that -75-92% of Inhaled 2-hexanone was absorbed by the lungs
and  respiratory  mucosa  following  exposure  to  10-100 ppm for  4-7.5  hours.
Approximately 65-68%  of 2-hexanone vapor  was absorbed  by the lungs  of  dogs
exposed  to  50-100  ppm 2-hexanone  for  6 hours.   2-Hexanone  can  also  be
absorbed  readily through  the  skin.   A dermal  absorption  rate  of   4.8-8.0
iig/mln'Hnf2  was  determined  In  humans  from   the  analysis  of  excretion
data  (DIVIncenzo et al., 1978).
    Although     distribution     of    radioactivity     from   administered
(l-i«C)-2-hexanone  appears   to  be   rapid   and  widespread,  the   highest
concentrations of radioactivity following  oral  administration of  2-hexanone
In rats were detected 1n the liver  and blood (DIVIncenzo  et al., 1977).
    Following  absorption,   2-hexanone  undergoes  extensive  metabolism   and
elimination.  2-Hexanone 1s metabolized  by hepatic  cytochrome P-450 oxldases
with  the formation of  5-hydroxy-2-hexanone and  2,5-hexanedlone  (DIVIncenzo
et  al.,  1977;   Courl  et   al.,  1978).    The  metabolism  of  2-hexanone  to
2,5-hexanedlone  Is  regarded as  metabolic activation, since there  1s evidence
that  2,5-hexanedlone  mediates the neurotoxlclty  and testlcular toxUlty  of
2-hexanone.  2,5-Hexaned1ol  1s formed by  the  oxidation  of  2-hexanol or  by
the  reduction  of  5>hydroxy-2-hexanone.    Urinary  metabolites of  2-hexanone
                                      v1

-------
Include     2,5-hexanedlone,      2-hexanol,      5-hydroxy-2-hexanone      and
2,5-d1methylfuran.   2-Hexanol,  -5-hydroxy-2-hexanone,  and  2,5-d1methylfuran
are excreted as glucuronldes.
    Rats administered  14C-2-hexanone  by gavage excreted  44% of the  dose  1n
the  breath  as  14C02  (38%)  and  2-hexanone (6%)  (DIVIncenzo et al.,  1977).
Forty  and  1.4%  of  the dose was excreted  1n the  urine  and feces,  respec-
tively.  About 14% remained  In the carcass 48  hours  after  dosing.
    Humans  Ingesting  0.1  mg/kg   of  (1-14C)-2-hexanone excreted  40%  of  the
dose  In  the  breath  as 14CO  and 26%  In urine  (DIVIncenzo et al.,  1978).
Excretion of 2-hexanone Is less complete 1n humans than In rats.
    Acute Inhalation exposure of  animals  or humans  to  high  concentrations  of
2-hexanone vapor  causes an almost Immediate  Irritation to  the  eyes and  nose
(Schrenk  et  al.,  1936).    In   guinea  pigs,  exposure  to  6500-20,000   ppm
resulted 1n ataxla, narcosis and  death  (Schrenk et  al., 1936).   The cause  of
death  In  guinea pigs  was  attributed  to narcosis.  Congestion  of  the lungs,
kidneys and liver was  found  during autopsy examination.   In humans, exposure
to 1000 ppm  for a few minutes resulted In moderate ocular  and  nasal  Irrita-
tion (Schrenk et al..  1936).
    Results of  subchronlc  Inhalation  animal studies  Indicate that  2-hexanone
neurotoxlclty  1s  characterized  by the  development  of peripheral  neuropathy
(Mendell et al..  1974;  Spencer  et al., 1975;  Salda et al.,  1976;  Johnson  et
al.,  1977).   Neuropathologlcal  features  of peripheral nerve damage  Include
giant  axonal  swellings and  axonal degeneration.  Peripheral nerve  damage  Is
associated with hlndllmb drag and weakness of the forellmbs and hlndllmbs  In
rats,  monkeys  and  cats.   Electrodlagnostk  studies reveal   accompanying
abnormalities In EMG and MNCV (Johnson et  al., 1977; Duckett et  al., 1979).
    Behavioral  studies  revealed  alterations  In  rats   exposed   to   levels
associated with  hlstopathologlcal evidence of peripheral  neuropathy (Johnson
                                      vll

-------
et al.,  1977).   Intermittent exposure  to 50  ppm,  the lowest  concentration
tested 1n animal  Inhalation  studies,  was  associated with decreased MNCV  and
extensive  nerve  demyellnatlon  1n  rats   (Duckett  et  al.,  1979).   Clinical
signs of neuropathy have  been  documented  In humans exposed  to  2-hexanone In
the work environment at concentrations as low  as  9.2-36.0 ppm (Allen  et al.,
1975).
    Several oral  gavage and drinking water studies  Indicate  that  the  effects
of oral  exposure  to  2-Hexanone  are similar  to  those associated with  Inhala-
tion  exposure (Krasavage  et al.,  1979,  1980;  Homan and  Maronpot, 1978;
Abdel-Rahman  et  al.,  1978).   Generally,  large doses  were  administered  to
produce  the typical neurological  syndrome.  In  one  study, testlcular  atrophy
was  observed   In  rats  treated  by gavage  at  600 mg/kg/day for  10 weeks
(Krasavage et  al.,  1980).  The  oral  studies  were  not performed at  dosages
sufficiently low to Identify thresholds  for  neuropathy.
    Data were not  located  regarding  the cardnogenldty of 2-hexanone  to
animals  or humans exposed  by  any route.   No data were located  regarding  the
mutagenlclty of 2-hexanone  In prokaryotk or  eukaryotlc test systems.  In  a
teratogenldty study using pregnant rats, a decrease In maternal  weight gain
was  observed  at  1000  or  2000  ppm 2-hexanone  for 6 hours/day  throughout
gestation  (Peters  et  al.,  1981).   A  reduction In  the number and weight  of
live  offspring was  detected In  rats  exposed  to 2000  ppm 2-hexanone.  Post-
natal behavioral  changes were observed In  both  the 1000 and 2000 ppm groups.
    These  results  were corroborated  by  Tyl   et  al.  (1987)  who  found  a
decrease In maternal  weights in  mice  and rats only  after  exposure  to 3000
ppm of 2-hexanone during  days  6-15 of gestation.    Evidence  of  developmental
toxlclty  was  only observed In the  group  exposed  to 3000 ppm and  was  limited
                                     vlll

-------
to  Increased  Incidence  of dead  fetuses  (only  seen  In mice),  reduced  fetal
body weight  per  Utter,  and  reductions  In  skeletal  ossification  (mice  and
rats).   There was  no  evidence  of a dose-dependent Increase  In  developmental
toxldty,  nor any  evidence of any  type  of treatment-related effect, at  300
or 1000 ppm 1n either  species.
    2-Hexanone was  assigned  to  U.S.  EPA  Group  0:  not  classifiable as  to
carclnogenldty  to  humans because  of  a lack  of  cancer  data  In animals  or
humans  for any route  of exposure.   Therefore, neither estimates  of  carcino-
genic potency nor RQ derivation based on  cancer were  possible.
    Subchronlc Inhalation  and  oral  data confirm  that peripheral  neuropathy
1s  the critical  effect  of  exposure to  2-hexanone,  and  several  studies
Identify FELs associated with  gross  Impairment of neurological  function  such
as paralysis  or  hlndllmb  footdrag.   NOAELs for this effect  were  not  Identi-
fied and  studies  that may have  defined  LOAELs were  Insufficiently  reported
to  serve  as   the  basis  for RfD  derivation.   Therefore,  RfO values were  not
derived for subchronlc or  chronic Inhalation  or oral  exposure.
    An  RQ  of 100  was  derived  for 2-hexanone  based  on  neuropathy  In  rats
exposed Intermittently to  100 ppm In the  air  (Johnson  et  al.f 1977,  1979).
                                      1x

-------
                             TABLE OF CONTENTS
                                                                       Page
1.  INTRODUCTION	     1

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

2.  ENVIRONMENTAL FATE AND TRANSPORT	     4

    2.1.    AIR	     4
    2.2.    WATER	     4

           2.2.1.   Hydrolysis	     4
           2.2.2.   M1crob1al Degradation 	     4
           2.2.3.   Volatilization	     5
           2.2.4.   Adsorption	     5
           2.2.5.   B1oconcentrat1on	     5

    2.3.    SOIL	     5

           2.3.1.   Mlcrobtal Degradation 	     5
           2.3.2.   Adsorption/Leaching 	     5
           2.3.3.   Evaporation 	     6

    2.4.    SUMMARY	     6

3.  EXPOSURE	     8

    3.1.    WATER	     8
    3.2.    FOOD	     9
    3.3.    INHALATION	     9
    3.4.    DERMAL	     9
    3.5.    SUMMARY	    10

4.  ENVIRONMENTAL TOXICOLOGY	    11

    4.1.    AQUATIC TOXICOLOGY 	    11

           4.1.1.   Acute Toxic Effects on Fauna	    11
           4.1.2.   Chronic Effects on Fauna	    11
           4.1.3.   Effects on Flora	    12
           4.1.4.   Effects on Bacteria 	    12

    4.2.    TERRESTRIAL TOXICOLOGY 	    12

           4.2.1.   Effects on Fauna	    12
           4.2.2.   Effects on Flora	    12

-------
                         TABLE OF  CONTENTS  (cont.)
                                                                       Page
    4.3.    FIELD STUDIES	   12
    4.4.    AQUATIC RISK ASSESSMENT	   13
    4.5.    SUMMARY	   13

5.  PHARMACOKINETCS	   15

    5.1.    ABSORPTION	   15
    5.2.    DISTRIBUTION	   1&
    5.3.    METABOLISM	   17
    5.4.    EXCRETION	   20
    5.5.    SUMMARY	   21

6.  EFFECTS	   23

    6.1.    SYSTEMIC TOXICITY	   23

           6.1.1.   Inhalation Exposure 	   23
           6.1.2.   Oral Exposure	   27
           6.1.3.   Other Relevant Information	   29

    6.2.    CARCINOGENICITY	   31

           6.2.1.   Inhalation	   31
           6.2.2.   Oral	   31
           6,2.3.   Other Relevant Information	   31

    6.3.    MUTAGENICITY	   31
    6.4.    DEVELOPMENTAL TOXICITY 	   31
    6.5.    OTHER REPRODUCTIVE EFFECTS 	   34
    6.6.    SUMMARY	   34

7.  EXISTING GUIDELINES AND STANDARDS 	   37

    7.1.    HUMAN	   37
    7.2.    AQUATIC	   37

8.  RISK ASSESSMENT	   38

    8.1.    CARCINOGENICI1Y	   38

           8.1.1.   Inhalation	   38
           8.1.2.   Oral	   38
           8.1.3.   Other Routes	   38
           8.1.4.   Weight of Evidence	   38
           8.1.5.   Quantitative Risk Estimates 	   38

    8.2.    SYSTEMIC TOXICITY	   38

           8.2.1.   Inhalation Exposure 	   38
           8.2.2.   Oral Exposure	   40
                                     xl

-------
                          TABLE  OF  CONTENTS  (cent.).
                                                                        Page
 9.  REPORTABLE QUANTITIES 	   43
     9.1.   BASED ON SYSTEMIC TOXICITY
     9.2.   BASED ON CARCINOGENICITY .
10.  REFERENCES.
APPENDIX A: LITERATURE SEARCHED	
APPENDIX B: SUMMARY TABLE FOR 2-HEXANONE 	
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
            2-HEXANONE 	 .
43
47

49

61
64

65

-------
No.
6-1
9-1
9-2
9-3
                       LIST OF  TABLES
                          Title
Page
Acute Lethal Toxldty of  2-Hexanone	   30
loxUHy Summary for 2-Hexanone	   44
Composite Scores for 2-Hexanone  	   46
2-Hexanone: Minimum Effective Dose  (MED)  and  Reportable
Quantity (RQ)	   48

-------
                             LIST  OF  ABBREVIATIONS
BCF
BOD
BTU
CNS
CS
DNA
"50

E050
EEG
EHG
F344
FEL
GI
GMAV
GMCV
 ow
LC50
LOAEL
MNCV
ppb
ppm
Bloconcentratlon factor
Biological oxygen demand
British thermal unit
Central nervous system
Composite Score
Deoxyrlbonuclelc add
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Effective dose to 50% of recipients
Electroencephalograms
Electromyography
Fischer 344
Frank effect level
Gastrointestinal
Genus mean acute value
Genus mean chronic value
Soil sorptlon coefficient standardized
with respect to organic carbon
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
Lowest-observed-adverse-effec.t level
Motor nerve conduction velocities
Parts per billion
Parts per million
                                      xlv

-------
RfD
RNA
RQ
RVd
RVe
STEL
TLV
TWA
MS
 LIST  OF  ABBREVIATIONS  (cont.)

Reference dose
Rlbonucleic acid
Reportable quantity
Dose-rating value
Effect-rating value
Short-term exposed level
Threshold limit value
Time-weighted average
Water solubility
                                      xv

-------
                               1 .   INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    2-Hexanone  Is  also  known  by   the  synonyms butyl  methyl ketone,  methyl
butyl ketone and  propyl  acetone (Hawley, 1981; Wlndholz,  1983).   The  struc-
ture, molecular weight,  empirical  formula  and CAS number  for  2-hexanone  are
as follows:
Molecular weight:  100.16
Empirical formula:  C,H,,,0
                     o i c
CAS Registry number:  591-78-6
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    2-Hexanone  Is  a colorless  liquid  that  Is  soluble In alcohol  and  ether
(Wlndholz, 1983).  Selected physical properties are as follows:
    Melting point:
    Boiling point:
    Specific gravity:
    Vapor pressure:
      at 25°C
    Hater solubility:
      at 25°C
    Log Kow:
    Flash point:
    Odor threshold (air):
    Conversion factors:
    (air at 20°C)
-55.8°C
127.5°C
0.8125 (20/20'C)
11.6 mm Hg

16,000 ppm

1.38
28°C (open cup)
0.28-0.35 mg/m3
1  mg/m3=0.24 ppm
1  ppm=4.16 mg/m3
Papa and Sherman, 1981
Papa and Sherman, 1981
Papa and Sherman, 1981
Engineering Sciences
Data Unit, 1975
Erlchsen, 1952
Hansch and Leo, 1985
Papa and Sherman, 1981
Verschueren, 1983
2-Hexanone 1s flammable and considered a  moderate  fire  risk  {Hawley,  1981)
0183d
      -1-
                  06/12/89

-------
Ketones  such  as 2-hexanone  undergo addition,  redox  and condensation  reac-
tions forming alcohols, ketals,  acids and amines (Papa and Sherman,  1981).
1.3.   PRODUCTION DATA
    The  available  production  data  for  2-hexanone  are  very  limited.   The
public  portion  of  the U.S.  EPA  TSCA  Production  File for  1977  lists  the
following producers of 2-hexanone (U.S.  EPA,  1977):
         Polak's Frutal Works (Mlddleton,  NY)
            Manufacturer: production range confidential
         Tennessee Eastman Company {Klngsport,  TN)
            Manufacturer: production range of 1-10 million Ibs,
         Roure Bertrand DuPont, Inc. (Teaneck,  NJ)
            Importer: production range of  <1000 Ibs.
The  1988  Directory  of  Chemical  Producers  (SRI, 1988)  and the U.S.  Inter-
national Trade Commission  (USITC,  1988) do  not  have  listings  for  2-hexanone,
suggesting that  It  Is  not currently manufactured on an  Industrial  scale for
use as an end-product.  This  compound  may  be  Imported  Into the United States
but current  Import  figures are not available.   The  1987  OPD  Chemical Buyers
Directory lists  Chemcentral Corp.,  Chemical  Dynamics  Corp.,  Davos  Chemical
Corp. and Penta Manufacturing Company as suppliers of 2-hexanone (CMR, 1986).
    2-Hexanone  can  be  prepared by  reacting  1-hexene with l,4-benzoqu1none
(Flnley,  1982)  or by  reacting acetyl  chloride  with butylmagneslum  chloride
(Morettl, 1978).
1.4.   USE DATA
    2-Hexanone  is  used as  a  medium-evaporating  solvent  for  nitrocellulose,
acrylates, vinyl and alkyd coatings (Papa and Sherman,  1981).
1.5.   SUMMARY
    2-Hexanone  1s  known  by  the synonyms  butyl  methyl  ketone, methyl  butyl
ketone and propyl acetone (Hawley,  1981; VMndholz,  1983).   It Is  a colorless
0183d
-2-
06/12/89

-------
             liquid that  1s  soluble In  alcohol  and ether -and  slightly  soluble In water
             (Wlndholz,  1983).   Production data for 2-hexanone are limited.  In  1977,  the
             Tennessee Eastman  Company  manufactured between  1  and 10 million pounds  of
             2-hexanone   (U.S.   EPA,  1977).   However,  the  1988  Directory  of  Chemical
             Producers  (SRI,   1988)  and the  USITC  (1988)  do  not   have  listings   for
             2-hexanone,   suggesting  that   H   Is   not  currently  manufactured  on   an
             Industrial  scale  In  the United  States for  use  as  an end-product.   Current
             Import   figures   are   not   available.    2-Hexanone   Is   used   as    a
             medium-evaporating solvent  for  nitrocellulose,  acrylates,   vinyl  and alkyd
             coatings (Papa and Sherman,  1981).
ft
             0183d                               -3-                              06/12/89

-------
                     2.   ENVIRONMENTAL FATE  AND TRANSPORT
2.1.   AIR
    Based upon Us relatively high vapor pressure of  11.6  mm Hg at 25°C (see
Section 1.2.), 2-hexanone  1s  expected to exist almost entirely  In the  vapor
phase  In  the ambient  atmosphere  (Elsenrelch  et  al.,  1981).  The  dominant
degradation process 1n ambient air 1s  probably reaction  with sunlight-formed
HO  radical.   Based  upon   an  experimentally  determined  rate  constant  of
6.64xlO~lz  cma/mol-sec  at  23°C  (Wellington  and   Kurylo,   1987)   and  an
average  atmospheric  HO   radical  concentration  of   5x10    molecules/cm3,
the half-life for this reaction can be estimated to  be -2.4 days.
    In terms of  environmental  contaminants,  2-hexanone has  a relatively high
water  solubility of  16,000 ppm  at  25°C (see  Section  1.2.),  suggesting that
physical   removal   from   air  by   wet  deposition    (washout   by   rainfall,
dissolution In clouds, etc.) 1s possible.
2.2.   WATER
2.2.1.   Hydrolysis.   Experimental   hydrolysis   data  regarding   2-hexanone
were  not  located.   However,  ketones  are generally resistant to environmental
hydrolysis  (Harris,  1982);  therefore,  hydrolysis  of  2-hexanone  In  the
aquatic environment Is not expected to be Important.
2.2.2.   MUroblal  Degradation.    2-Hexanone  appears  to  be  readily  bio-
degradable  based upon results from  limited  blodegradatlon screening studies
(Babeu and  Valshnav,  1987; Valshnav  et al.,  1987; Shelton and Tledje, 1984).
Using  an acclimated mixed culture Inocula  and  the  standard  BOD  technique,
2-hexanone  was  found to have  a  BOO  of 5.22 over a  5-day  Inoculation period
(Babeu  and Valshnav,  1987;  Valshnav et  al., 1987).   2-Hexanone  was  also
found  to  be susceptible to blodegradatlon under  anaerobic  conditions.   In a
study  using  an  anaerobic  digester   sludge  Inocula,  conversion  to  >75%  of

0183d                               -4-                              06/12/89

-------
theoretical  methane  production  was  observed  during  an  8-week  Incubation
period (Shelton and Tledje, 1984).
2.2.3.   Volatilization.  Based upon  a  water  solubility of 16,000  ppm and a
vapor pressure  of 11.6 mm Hg at  25°C  (see  Section  1.2.),  the  Henry's  Law
constant  for  2-hexanone  can be  estimated to  be  9.56x10"'  atm-m'/mol.   A
Henry's  Law  constant of  this magnitude  Indicates  that volatilization  from
environmental waters  may  have some significance,  but 1s probably  not rapid
(Thomas,  1982).   Using  a  model river  estimation  method (Thomas,  1982),  the
volatilization half-life of  2-hexanone  from a river 1  m deep  flowing 1 m/sec
with  a  wind  velocity of   3  m/sec   can  be estimated  to be  -12  hours.   The
volatilization half-life from a model environmental pond can  be estimated to
be -5.7 days (U.S. EPA,  1986a).
2.2.4.   Adsorption.  The  relatively high  water  solubility  (In  comparison
with   other   environmental   contaminants)   of   2-hexanone   suggests   that
partitioning from the water  column  to sediment  and  suspended  material  should
not be significant.
2.2.5.   Bloconcentratlon.   Experimental  BCFs  for  2-hexanone  In  fish were
not located.  A  BCF  of  6.6  can be  calculated using a log K    value of  1.38
(Hansch and Leo,  1985)  and the following  equation  (Bysshe, 1982):  log BCF .
0.76   log  K     -   0.23.    This   calculated  BCF   value  Indicates   that
bloconcentratlon In aquatic organisms 1s probably  not  Important.
2.3.   SOIL
2.3.1.   Mlcroblal Degradation.  Data specific  to  the mlcroblal  degradation
of 2-hexanone  in soil were  not  located In the literature dted  In Appendix
A.  However, based upon the  limited blodegradatlon  screening  tests discussed
In Section 2.2.2., 2-hexanone may be readily biodegradable  1n soil.
2.3.2.   Adsorption/Leaching.  Data  specific  to the  leaching  of  2-hexanone
In soil  were  not located  In the  literature cited  In Appendix A.  A  K    of
0183d
-5-
05/23/90

-------
•21  can be  estimated using  a WS  of 16,000  ppm and  the  following equation
 {Lyman,  1982):   log  KQ(,  =  3.64-0.55  log  WS.   This  estimated  KQC  value
 Indicates   very  high   soil   mobility   (Swann  et   al.,   1983).   Although
 significant  leaching Is  possible,  concurrent blodegradatlon may decrease the
 potential  Importance of  leaching.
 2.3.3.   Evaporation.   2-Hexanone  can  be  expected  to evaporate  relatively
 rapidly  from dry surfaces.   It  1s used as  a medium-evaporating solvent for
 nitrocellulose,  acrylates,  vinyl   and  alkyd  coatings  (Papa  and  Sherman,
 1981).   In  an  evaporation  rate test  pertinent to solvents used  for coatings,
 2-hexanone  was found  to have an  evaporation half-life of  -0.9 hours (Park
 and  Hofmann, 1932).
 2.4.   SUMMARY
     2-Hexanone  appears  to  be  readily  degradable  In  air,  water  and soil;
 therefore,  It   Is not  likely  to  be  a  persistent  environmental contaminant.
 If  released to the  atmosphere, 2-hexanone  is expected to exist In the vapor
 phase  where 1t  will degrade  by  reaction  with sunlight-formed  MO radical.
 Based  upon  an  experimentally  determined   rate  constant   (Walllngton  and
 Kurylo,  1987),  the  half-life for  this reaction has been estimated to be -2.4
 days   for   typical   atmospheric  conditions.    If  released   to   the  aquatic
 environment,   2-hexanone  may  degrade  by  blodegradatlon  or  be  physically
 removed  by volatilization.   2-Hexanone appears to  be readily  biodegradable
 based  upon results  from limited blodegradatlon screening studies (Babeu and
 Valshnav,  1987;  Valshnav et  al.,  1987;  Shelton and Tledje, 1984).  Volatili-
 zation  half-lives  of -12  hours  and  5.7 days  can  be  estimated for a shallow
 model  river and  environmental pond,  respectively (Thomas,  1982;  U.S. EPA,
 1986a).   If released to  soil,  2-hexanone may  be  susceptible to  significant
 blodegradatlon  based  on  analogy  to  the  blodegradatlon  screening  studies
 0183d
-6-
06/12/89

-------
noted  above.    Although  significant   leaching   Is  possible,   concurrent
blodegradatlon   may   decrease   the   potential    Importance   of   leaching.
2-Hexanone 1s used as a  medium-evaporating solvent (Papa and  Sherman,  1981)
and Is expected to undergo significant evaporation from dry  surfaces.
0183d
-7-
06/12/89

-------
                                 3.   EXPOSURE

    2-Hexanone  occurs  as  a  natural  product.   It has  been  detected  as  a
volatile  component   of   blue  cheese,  nectarines,  raw  chicken  breast  and
poultry  manure  (Day  and  Anderson,  1965;  Takeoka et  al.,  1988;  Grey  and
Shrlmpton,  1967;  Yasuhara,  1987).   Hence,   the  general  population  may  be
exposed  to  2-hexanone  through IngesUon of natural  and processed  foods  (1n
which 1t  occurs naturally)  and  through  Inhalation of vapors  from  commercial
coatings containing 2-hexanone as a  solvent (HOSB, 1989).
    Another possible  source of  exposure to 2-hexanone  Is  through  Inhalation
during Its manufacture,  formulation Into products  and use  as  an evaporatlng-
medlum solvent  (HSDB,  1989).   The National Occupational Exposure  Survey  has
estimated that  810  U.S.  workers  are potentially  exposed to  2-hexanone  based
upon surveys conducted between 1981  and  1983 (NIOSH,  1988).
3.1.   WATER
    2-Hexanone  Is  released to the aquatic environment  by  various  wastewater
emissions.  It  has  been found  In  process  water  from jm situ  coal  gasifica-
tion In  Gillette, HY  (7  ppm),  in the aqueous  condensate from low-BTU gasifi-
cation of rosebud coal  in  Morgantown, WV  (202 ppm),  and 1n retort water from
Jjl  situ  oil  shale processing at Rock Springs,  WY (53 ppm) (HSDB,  1989).   It
has  also been  detected  in one  of  63  wastewater effluents  and  22  Intake
waters  from a wide range  of  chemical  manufacturing areas  across  the  United
States (HSDB, 1989).
    2-Hexanone  can  also be  released  to groundwater  by leaching  from  waste
sites.   Leachates  collected  from  municipal   landfills  have  been found  to
contain  2-hexanone  at  levels of 0.148  ppm  (Brown  and Donnelly,  1988).   A
0183d
-8-
06/12/89

-------
concentration  ranging  from  not  detected- to 0.38  ppm was  Identified 1n  a
leachate discharge to a  ditch  near an abandoned  landfill  In  Tybouts  Corner,
OE  (HSDB,  1989).   2-Hexanone was  detected at a  concentration  of 87  ppb  1n
the  Blscayne  Aquifer  (groundwater)  In  Oade County,  FL,  1n   1982   In  the
vicinity of an inactive  waste drum recycling  site (Myers,  1983).  An  average
concentration  of  7135 ppb  (maximum  of  14,000 ppb)  was   found  In two  well
water  samples  at  an unauthorized  hazardous waste  disposal site  1n  Lang
township, NJ (HSDB,  1989).   In 1984,  2-hexanone was  detected  In  3 of  11  well
waters at an abandoned landfill  1n Tybouts Corner, DE (HSDB,  1989).
3.2.   FOOD
    2-Hexanone has  been  qualitatively  detected  as  a volatile  component  of
tree-ripened nectarines  (Takeoka  et  al., 1988),  raw chicken breast  muscle
(Grey  and  Shrlmpton, 1967), mountain cheese (Dumont  and  Adda,   1978),  blue
cheese (Day and Anderson, 1965) and roasted filberts (Klnlln et  al.,  1972).
3.3.   INHALATION
    2-Hexanone Is  released  to  the atmosphere by  evaporation  from Us  use  as
a  solvent   (Graedel  et  al.,  1986).  The primary  environmental  release  of
manufactured ketones  (such  as 2-hexanone)  Is  reported to  be evaporation from
solvent  uses  (Lande  et  al., 1976).   2-Hexanone 1s  also  reported to  occur  In
tobacco  smoke  (Graedel et al., 1986).
    2-Hexanone  has  been qualitatively   detected  In  air   samples from  the
southern Black Forest  1n southwest Germany and in  suburban  air  samples from
Tubingen, West Germany (Juttner, 1986).
3.4.   DERMAL
    Pertinent  monitoring data  regarding the dermal  exposure of 2-hexanone
were  not located In  the  available  literature as cited in Appendix A.
0183d
-9-
06/12/89

-------
J.5.   SUMMARY
    2-Hexanone  can  be  released  to  the  aquatic  environment  by  wastewater
streams generated at various  fossil-fuel  processing  and  chemical manufactur-
ing sites and by  leaching  from  hazardous  waste  sites and municipal landfills
(HSD8,  1989;  Brown  and  Donnelly,   1988;  Myers,  1983).  This  compound  Is
released to the atmosphere by evaporation  from  Us  use  as a  solvent (Graedel
et  a!.,  1986).   2-Hexanone   occurs  naturally.    It  has   been  detected as  a
volatile  component   of   blue  cheese,   nectarines,   raw   chicken  breast  and
poultry  manure  (Day  and  Anderson,  1965;  Takeoka  et  al.,   1988;  Grey  and
Shrlmpton, 1967;  Yasuhara, 1987).   The general  population may be  exposed to
2-hexanone  through  1ngest1on of  natural   and  processed   foods  (1n which  It
occurs naturally) and  through Inhalation  of vapors  from commercial  coatings
containing  2-hexanone  as  a  solvent  (HDSB,  1989).   Insufficient  monitoring
data  are  available  to  estimate average  human   dally  Intakes  of  2-hexanone
through food,  Inhalation or drinking water.
0183d
-10-
05/23/90

-------
                         4.  ENVIRONMENTAL TOXICOLOGY
4.1.   AQUATIC TOXICOLOGY
4.1.1.   Acute Toxic  Effects on  Fauna.   Gelger et  al.  (1986)  assessed  the
acute  toxlclty  of  2-hexanone  to  the fathead  minnow,  Plmephales  promelas,
under  flowthrough  conditions at 25°C.  Minnows  used 1n the  test  were 26-37
days  old.   Concentrations  of 2-hexanone  In  test solutions  were analytically
verified.   Investigators  reported  a  96-hour   LC5_  and  EC,Q  of  428  mg/i.
Confidence limits to this estimate could not be calculated.
    Elliott and McElwee  (1988)  assessed the anaesthetic  action of  2-hexanone
In  the  scud,  Gammarus.   Test organisms were transferred  In  groups  of  six to
400-2000  ml  of   test   solution.   Their  responses  were  observed  until  a
steady  state  was  achieved.   The  endpolnt  used  to determine  the  ED_   was
the  loss  of  an  escape response  when  organisms   experienced  a  mechanical
stimulus  delivered by  hand   to either lateral  surface.  The  Investigators
reported an ED,-0 of 420 mg/i (4.23 mmol/l).
4.1.2.   Chronic Effects on Fauna.
    4.1.2.1.   TOXICITY -- Pertinent  data regarding the effects of chronic
exposure  of  aquatic fauna  to  2-hexanone were  not located  In  the  available
literature cited 1n Appendix A.
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION — Experimentally   generated
BCFs  for 2-hexanone  in  fish were  not located  In the  available  literature
cited  In appendix  A.   A BCF of 6.6  was  calculated using the  log  K   value
of  1.38  (see Chapter  2)  and the following equation  (Lyman et al.,  1982):
log  BCF =  0.76  log KQW  - 0.23.  This  BCF indicates  that  bloconcentration
in  fish  Is not significant.
0183d
-11-
05/08/89

-------
4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY — Pertinent  data  regarding  the  toxic  effects  of
exposure of  aquatic flora  to  2-hexanone were  not  located  In  the available
literature cited 1n Appendix A.
    4.1.3.2.   BIOCONCENTRATION — Pertinent  data  regarding  the  bloconcen-
tratlon  potential  of  2-hexanone  In  aquatic  flora  were  not located  In the
available literature cited In Appendix A.
4.1.4.   Effects on  Bacteria.   Valshnav  (1986)  manometrlcally  assessed the
ability  of  2-hexanone  to  Inhibit  the  blodegradatlon  of  2-hexanone  by
acclimated  mixed mlcroblal  cultures.   Assays  were  conducted  on  a  Warburg
apparatus at  30°C  over a  75-mlnute  exposure period.   The  ECrg,  the concen-
tration  of  2-hexanone  that would reduce  the  maximum observed blodegradatlon
rate by 5054, was 5510 mg/l (0.055 mol/l).
4.2.   TERRESTRIAL TOXICOLOGY
4.2.1.   Effects on  Fauna.   Gupta and Hohla  (1986)  assessed  the efficacy of
2-hexanone  as  a bee repellent.   The  number of bees  In  the  control and test
area  of  an  olfactometer  were  counted  at  1-minute Intervals for  5  minutes
before  application  of 2-hexanone  at  0.0625  and  0.5  g/8..   These  levels
repelled 64.1  and 81.854 of  the bees  In  the test area versus control.  Subse-
quently, Gupta  (1987)  assessed  the  efficacy of 2-hexanone as a repellent for
the  bee,  Aj)1s  f 1 j)rea.  Average  repellency  ranged  from 64.0% at  62.5 mg/st
to 82.654 at 4000 mg/l.
4.2.2.   Effects  on   Flora.    Pertinent  data  regarding   the   effects  of
exposure  of   terrestrial  flora  to  2-hexanone  were  not  located  in  the
available literature cited In Appendix A.
4.3.   FIELD STUDIES
    Pertinent  data  regarding the  effects of 2-hexanone on flora and fauna In
the field were  not  located 1n the available literature cited 1n Appendix A.
0183d
-12-
06/12/89

-------
4.4.   AQUATIC RISK ASSESSMENT
    The lack  of  pertinent  data regarding the effects  of  exposure of aquatic
fauna  and  flora  to 2-hexanone  precluded  the  development  of a  freshwater
criterion (Figure  4-1).   Development of a  freshwater  criterion  requires the
results of acute  assays  with a salmonld  fish species,  a  nonsalmonld fish or
amphibian,  planktonlc and benthlc  crustaceans,  an  Insect,  a nonarthropod and
nonchordate species  and  an  Insect or  species  from a  phylum  not previously
represented.   The  development of  a  freshwater  criterion also  requires  data
from  chronic  toxlclty tests  with two  species  of  fauna  and one  species  of
algae or vascular plant and at least one bloconcentratlon study.
    The lack  of  pertinent  data regarding the effects  of  exposure of aquatic
fauna  and  flora  to  2-hexanone  precludes  the  development of  a  saltwater
criterion.   Development of a  saltwater  criterion  will  require  the generation
of data In all of the required categories.
4.5.   SUMMARY
                                      for   the  fathead  minnow,   Plmephales
promelas. exposed  to  2-hexanone  under  flowthrough  conditions was  428  mg/a
The   96-hour   LC5Q  and   EC™
(Gelger  et  al.t 1986).   The  ED,-n for  scud,  Gammarus.  measured as  the loss
of  an  escape  response  when  organisms  experienced a  mechanical  stimulus
delivered by  hand  to either  lateral  surface when exposed  to  2-hexanone was
420 mg/1.
    The  EC™  for  mixed mlcroblal  cultures, measured  as  the  concentration
of 2-hexanone that  would  reduce the maximum  observed blodegradatlon rate by
50%,  was  5510  mg/S,  (0.055  H)  (Valshnav,  1986).   Tests  assessing  the
efficacy  of  2-hexanone as  a  repellent  for  the  bee.  Apis  florea,  revealed
that  bees exposed  to  concentrations  of  62.5  and  4000  mg/i  of  2-hexanone
resulted  In  64.0 and  82.6% repelled,  respectively  (Gupta and  Hohla,  1986;
Gupta, 1987).
0183d
                                -13-
06/13/89

-------
Fami ly
«l
Chordate (Salmoriid-f ish)
tt£
Chordate (warmwater fish)
#3
Choi-date (fish or amphibian)
«4
Crustacean (planktonic)
#5
Crustacean (bent hie)
#£
Insect an
*7
non-ftrthropod /-Chordate
KG
New Insect an or phylum
represent at ive
#3
al gae
#10
Vascular plant
•Nft=Not flva liable, »LCS. and
Pimephales prornelas

BMflV
Nfl
4£Bb
Nft
Nft
Nft
Nft
Nft
Nfl
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
ECi o in mg/L
TEST TYPE
SMCV«
Nft
Nft
Nft
Nft
Nft
Nft
Nft
Nft
NO
Ntt
for the fathead

BCF-
Nft
NA
Nft
Nft
Nft
Nft
Nft
Nft
Nfl
Nft
minnow,
                                  FIGURE 4-1
    Organization Chart  for  Listing  GMAVs,  GHCVs and BCFs  Required  to Derive
Numerical Water  Quality  Criteria  to  Protect  Freshwater  Aquatic  Life  from
Exposure to 2-Hexanone
Source:  U.S. EPA/OWRS, 1986
0183d
-14-
05/08/89

-------
                             5.  PHARMACOKINETICS
5.1.   ABSORPTION
    2-Hexanone 1s absorbed readily by  the  lungs,  by  the SI  tract and through
the skin  1n  humans  and animals.  A study  In which three  healthy male humans
were exposed  for  4  hours to 100 ppm 2-hexanone or for  7.5  hours  to  10  or  50
ppm  2-hexanone  Indicated,  by  the  difference  between  concentrations  1n
Inhaled and  exhaled air, that  75-92%  of the  Inhaled  2-hexanone  is  absorbed
by  the  respiratory  mucosa  and lungs (DWincenzo  et  al.,  1978).   Exposure  to
10 and  50 ppm for 7.5  hours  resulted  In 2-hexanone concentrations of 1.4 and
9.3  ppm  1n   expired   air,   respectively.   An  average   2-hexanone  breath
concentration  of  22 ppm was achieved  following  exposure  to  100 ppm  for  4
hours.
    Steady  state  appears  to have  been achieved within  the first  hour.   A
serum  concentration  of  1.2  iig/mi  2-hexanone  was  obtained  following  a
4-hour  exposure   to  100 ppm.   2-Hexanone was  not  detectable  in the  serum
after exposure to 10 or 50  ppm.   In  similar  experiments,  D1V1ncenzo et al.
(1978)  determined that  -65-68%  of  2-hexanone vapor was absorbed  by the lungs
of  four young male  beagle  dogs  that were exposed to  50 or 100 ppm 2-hexanone
for  6  hours.  Steady state  appears  to have  been reached within  the first  2
hours of exposure.
    DIVIncenzo et al.  (1977) examined  the  absorption of 2-hexanone following
a  single  gavage  dose of 20  or 200 mg/kg  14C-labeled  2-hexanone  in  corn oil
to  young  adult male  CD rats.  2-Hexanone was  absorbed rapidly  from the  GI
tract.   Serum 2-hexanone  concentration peaked  at  38  ng/ma within  2  hours
of  treatment  at  200  mg/kg.   Of  the  administered   dose  of  radioactivity,
38-42%  was  excreted as  C0?,  while 2.2-6% was  excreted unchanged in expired
air.  Over  a 48-hour period, 35-40% was excreted in urine, and  0.8-1.4% was
recovered in  feces.   From 13.6-17.6% was  retained In  the body,  primarily in
0183d
-15-
06/12/89

-------
the blood and  liver.   Total  recovery ranged from  97-99%  of  the administered
dose of radioactivity.
    Humans  also absorb  2-hexanone  from  the  GI  tract  readily.   Two  male
humans  that were  given  a  single  oral  dose  of   0.1  mg/kg  14C-2-hexanone
eliminated   29.0-50%   of  the   radioactivity   In   the  breath   as   14C02.
Expiration  of   14CQp   reached   a   peak   4  hours  after  treatment:   Urinary
excretion accounted for  25.0-27.6% of  the  radio-activity.   Overall  recovery
of 14C was 65.8% (OlVlncenzo et al., 1978).
    The  skin  1s  also an  effective  route  of absorption  for  2-hexanone  1n
humans.   On the  basis  of  excretion  data,  an  absorption  rate  of  4.8-&.0
ug/m1n~lcnf2  has  been  estimated  1n  humans  (D1V1ncenzo  et  al.,   1978).
The  average amount of 14C-2-hexanone  absorbed  through  the  human skin  was
21.4   mg.    In  male  beagle   dogs  exposed  dermally   to   14C-2-hexanone,
excretion data  Indicated that  the  rate  of  dermal absorption  plateaued at <20
minutes, then  rose markedly  over  the next  40 minutes.   The 8-hour cumulative
excretion accounted for  16.8%  of  a dose of unspecified magnitude  (OlVlncenzo
et al., 1978).
5.2.   DISTRIBUTION
    Forty-eight"   hours     after    rats    were     orally    administered
{l-14C)-2-hexanone  (200  mg/kg)  the highest concentrations  of radioactivity
were  found  1n  the   liver  and  blood  (DIVIncenzo  et  al.,   1977).   Without
providing   data,   the   Investigators   also  stated   that   distribution  of
radioactivity  was  widespread.   DIVIncenzo  et  al.   (1976)  determined  a serum
half-life   of   2-hexanone   In   guinea  pigs  to   be   78   minutes  following
1ntraper1toneal  administration of  450  mg/kg  2-hexanone  In  corn  oil.   The
clearance  time  of  2-hexanone  1n  the   serum  was   6  hours.   The amount  of
2-hexanone  equivalents in  the  blood  compartment at 1  hour  after  dosing was
1.4% of the  administered dose,  Indicating extensive distribution.
0183d
-16-
06/12/89

-------
    Abdel-Rahman  et  al.  (1976)  determined  a  peak  blood  level  of  650
jig/ml,  achieved  within  30   mlrvutes,   In  adult  male  Wlstar  rats  treated
1ntraper1toneal1y with  -460  mg/kg  2-hexanone.   The half-life for  the rapid
Initial phase of elimination  from  blood  was  10  minutes, followed by a slower
phase  of  elimination  with a  7-hour  half-life.   A  similar  serum elimination
time of 6  hours  for 2-hexanone  was determined In rats after oral administra-
tion of 200 mg/kg  (DlVlncenzo et al.,  1977),  although the peak serum concen-
tration was only 38 vg/ma.
    DlVlncenzo  et  al.  (1977) studied  the  subcellular  distribution  of radio-
activity  In  the  liver,  kidney  and  brain   of  rats  <24  hours  after  oral
treatment  with  200 mg/kg  of (l-14C)-2-hexanone.   Tissue  fractions examined
Included  the  acid-soluble   fraction,  DNA,  RNA,  crude  llpld fraction  and
original  homogenate.   Subcellular   distributions  of radioactivity  In liver,
kidney  and  brain were similar  among  the  tissues.   Radioactive incorporation
into  llplds and protein reached a peak  at 8  hours  and remained  unchanged or
decreased at 24 hours.
5.3.   METABOLISM
    The metabolism of  (l-14C)-2-hexanone  has been  studied  following gavage
administration  of  a  20 or  200 mg/kg  dose  to  rats (DlVlncenzo al.  1977).
Thirty-eight  percent  of  the administered dose  was  identified  as  14CO? in
the  breath.   Radioactive  metabolites  of  2-hexanone  in  the  serum included
2-hexanol,  5-hydroxy-2-hexanone and  2,5-hexanedione.  Metabolites detected
in  the  urine   included  2-hexanol,  5-hydroxy-2-hexanone,  2,5-hexaned1one,
2,5-d1methylfuran, y-valerolactone, norleuclne and urea.
    DlVlncenzo  et  al.  (1978)  exposed  three male  volunteers to 2-hexanone for
4  hours  (100 ppm)  or  7.5 hours (10  or  50 ppm).  Exposure  to 100  ppm for 4
hours  produced  an  average 2-hexanone concentration  in  the  expired  air of 22
0183d
-17-
06/12/89

-------
ppm;  exposures  to  10  and  50  ppm  for  7.5  hours  produced  mean  breath
concentrations  of  1.4  and   9.3  ppm,   respectively.    2,5-Hexanedlone,  a
neurotoxlc and testlcular  toxic metabolite,  was still detected  1n  the serum
after exposure to  50  and 100 ppm of 2-hexanone up  to  3  hours after cessaton
of the exposure.
    The metabolism of 2-hexanone  In guinea pigs  following a  single  Intra-
perltoneal Injection  of  450 mg/kg 2-hexanone was  Investigated  by DIVIncenzo
et al. (1976).  The principal  serum  metabolite  of  2-hexanone was 2,5-hexane-
dlone.   5-Hydroxy-2-hexanone  and  2-hexanol  were  also   Identified   In  the
serum.  Courl  et   al.  (1978)  detected 2-hexanol  and  2,5-hexanedlone  In  the
blood and urine of  guinea  pigs  treated with  114 mg/kg  2-hexanone  by  the
Intraperltoneal route.   Abdel-Rahman  et  al.  (1976)  detected  2-hexanol  and
2,5-hexanedlone 1n the blood  of rats and guinea  pigs  following Intraperlto-
neal  Injection of  2-hexanone.  Rats and  guinea pigs  were  administered  ~213
and  356  mg/kg  2-hexanone, respectively.   Abdel-Rahman et  al.  (1976)  were
unable to  detect  2,5-hexanedlone In the  blood  of  rats  exposed continuously
by Inhalation to 400 ppm 2-hexanone for <60 days.
    There  Is  some  evidence for  the  Involvement of hepatic  cytochrome P-450
In  the  u-1 oxidation  of 2-hexanone to 5-hydroxy-2-hexanone  and 2,5-hexane-
dlone  (Courl  et  al., 1978;  DIVIncenzo et  al.,  1977).   DIVIncenzo  et  al.
(1977) reported that  pretreatment of  rats  with 35 mg/kg  SKF 525A.  a  mixed-
function  oxldase  Inhibitor,  markedly Increased the respiratory excretion of
14CO? and decreased urinary radioactivity (DIVIncenzo  et al., 1977).
    Figure 5-1 depicts a proposed metabolic scheme  for  2-hexanone based  upon
the  studies   of  DIVIncenzo  et  al.  (1977,  1978).    2-Hexanone can  undergo
metabolism  by  several   pathways,   such  as   reduction,   a-ox1dat1on,   «-l
oxidation, decarboxylatlon and transamlnatlon.    One  step of the metabolism
of 2-hexanone  Involves the reduction of the carbonyl group  to  the secondary
0183d
-18-
12/07/89

-------
*!
•5!
£""

S
i
2
*.
c
*H3H3iH3iH3330H
1 Illl
HO 00
•*U*PI*« -tX
«»n»»i«»-" •» \
iMHmMi tuwir
"If II
x-j I!
=S ,| || ^
U * * ^M * J*
* ^s*s^ y



j \
4 *


1
H
|
f

i
,h
P
i*
«
ww





•i
i
H
e
u
T











f
i
* •
«• w


I


— I






0 OH
H 1
HOCCHjCHjCHCH,
l-Hr«rnr pmt«Ml< «cl<
1 tK«Mll>«llM»

V ,
4m
k
s
|
j
I
f *
S -




1CCHCCH(CHCH*
|-*«Ur»lKlMM

1
II
I*.
I*
4
• «i
• <
i!
•
                                                                    O)

                                                                    o
                                                                    c
                                                                    

                                                                     I
                                                                    O   i—

                                                                        *
      s
      *"
      u
      !-
      _*J
        I)
                                                                ac   *-   01
                                                                2   &>   u
                                                                    19   3

                                                                    i   5
      II  I
       O T

       €1
      sti a
£
                                                                    4)


                                                                    O
                                                                    Q.
                                                                    O
                         «-\-^  *
0183d
                       -19-
05/08/89

-------
alcohol 2-hexanol.   Another  Involves  the  oxidation of  the u-1  carbon  atom
to  form  the  hydroxyketone,  5-hydroxy-2-hexanone.   The  hydroxyketone  1s
further  oxidized  to  2,5-hexaned1one.   Presumably,   the   expired  14CO?  1s
produced  by   the   a-ox1dat1on   of   (l-14C)-2-hexanone  to  a-ketohexanoate,
followed  by   decarboxylatlon   to  14CO~  and   1-Pentanal.   Alternatively,
14CO_   could   be   formed   from  the  decarboxylatlon   of  2-keto-5-hydroxy
hexanolc  acid  that  results  from   the  oxidation  of  5-hydroxy-2-hexanone.
14C-Norleudne  can   be   formed   from   the  a-ox1dat1on  of  (l-14C)-2-hexa-
none  to  a-ketohexanoate,  which  In  turn   can   undergo transamlnation.   As
shown  In  Figure 5-1,  the  formation of 2,5-hexaned1one, -y-valerolactone and
the cyclic metabolite,  2,5-d1methylfuran,  proceeds  from 5-hyroxy-2-hexanone.
2-Hexanol, 5-hydroxy-2-hexanone and  2,5-d1methylfuran  are  excreted  as glucu-
ronldes.  Metabolism of  2-hexanone to  CO-  Is  considered a  detoxification
pathway,  whereas  the formation of  2,5-hexanedlone, a  neurotoxlc  metabolite.
Is regarded as metabolic activation.
5.4.   EXCRETION
    Two   volunteers  who  Ingested  a   single  oral   dose  of  0.1   mg/kg
14C-2-hexanone  excreted  -4054   of  the  total dose  as  14CO_  In  the  breath
(OlVlncenzo  et al.t  .1978).   Levels  of respiratory  14CO-  peaked  within  4
hours and declined  gradually within  3-5 days.   Excretion of radioactivity In
the  urine within 8 days accounted  for 26.3% of the administered  dose. The
feces  were  not assayed  for  radioactivity.   The overall recovery of  14C was
65.8%.
    Rats  administered 14C-2~hexanone  (20  or 200 mg/kg)  by gavage excreted
44%   of   the   dose   In  their  breath  as   14CO   (38%)  and   as  unchanged
2-hexanone (6%)  (OlVlncenzo  et  al.,  1977).   Urinary excretion  of  radioactiv-
ity represented 40% of  the  total  dose,  while elimination of radioactivity In
0183d                               -20-                             06/12/89

-------
the  feces  was  1.4%.   After 48 hours,  14% of the dose  remained  1n  the body,
whereas 8% remained after  6 days.   The experiments  performed with humans and
rats   Indicate   that   radioactivity   derived   from  (l-14C)-2-hexanone  was
excreted more completely by rats (DIVIncenzo et al., 1977, 1978).
5.5.   SUMMARY
    2-Hexanone 1s absorbed readily  from  the  GI  tract,  the respiratory tract,
and  through  the  skin.   Respiratory  uptake data  In  humans (DIVIncenzo et al.,
1978)  Indicate that  -75-92%  of Inhaled 2-hexanone  was  absorbed  by  the lungs
and  respiratory  mucosa  following  exposure  to  10-100  ppm  for  4-7.5  hours.
Approximately 65-68%  of 2-hexanone vapor  was  absorbed by the lungs  of dogs
exposed to  50  or 100  ppm  2-hexanone  for  6 hours.  A  dermal  absorption rate
of  4.8-8.0  ng/m1n~1cm~2  was  determined  In  humans   from   the  analysis  of
excretion data (DIVIncenzo et al., 1978).
    Although     distribution     of    radioactivity     from    administered
(1-14C)-2-hexanone  appears   to  be   rapid   and   widespread,   the  highest
concentrations of  radioactivity  following oral  administration of 2-hexanone
1n rats were detected In the liver and blood (DIVIncenzo et  al.,  1977).
    Following  absorption,  2-hexanone  undergoes  extensive  metabolism  and
elimination.  2-Hexanone  Is metabolized  by hepatic  cytochrome P-450 oxldases
with  the  formation of  5-hydroxy-2-hexanone and  2,5-hexaned1one (DIVIncenzo
et  al.,  1977;  Courl  et al.,   1978).    The  metabolism  of  2-hexanone  to
2,5-hexanedlone  Is regarded as metabolic  activation,  since  there Is evidence
that  2,5-hexanone mediates   the  neurotoxlclty  and  testlcular   toxlclty  of
2-hexanone.  2,5-Hexanedlol  Is formed  by the oxidation  of  2-hexanol  or  by
the  reduction  of  5-hydroxy-2-hexanone.    Urinary  metabolites of  2-hexanone
Include  2,5-hexaned1one,  2-hexanol,  5-hydroxy-2-hexanone and  2,5-dlmethyl-
furan.  2-Hexanol,  5-hydroxy-2-hexanone,  and 2.5-dlmethylfuran  are excreted
as glucuronldes.
0183d
-21-
12/07/89

-------
    Rats administered  1«C-2-hexanone  by gavage excreted  44% of the dose  In
the breath  as  l«C02  (38%) and  2-hexanone (6%)  (DIVIncenzo et al..  1977).
Forty  and  1.4%  of  the dose  was excreted  1n the  urine  and feces,  respec-
tively.  About 14% remained 1n the carcass  48  hours  after  dosing.
    Humans  Ingesting  0.1   mg/kg  of  (l-14C)-2-hexanone excreted  40% of  the
dose  In  the  breath  as «C02  and 26%  1n  urine  (DIVIncenzo et al.,  1978).
Excretion of 2-hexanone 1s less complete In humans than In rats.
0183d
-22-
12/07/89

-------
                                 6.  EFFECTS
6.1.   SYSTEMIC TOXICITY
6.1.1.   Inhalation Exposure.
    6.1.1.1.   SUBCHRONIC -- Spencer et al.  (1975)  exposed  six rats to 1300
ppm 2-hexanone, 6 hours/day, 5 days/week  for  4  months.   Three rats served as
controls.  During each  exposure,  the rats exhibited slight narcosis after  4
hours  and  loss of  coordination  after  5.5  hours.   Exposed rats  had a  slow
progressive weight loss beginning on the  73rd day  of  exposure.   In addition,
exposed rats developed a pronounced  hindUmb  foot  drop  between  the third  and
fourth  months  of  exposure  to  2-hexanone.   Some  of  the  exposed rats  also
exhibited  severe  proximal   hlndllmb  and  forellmb  weakness.   Peripheral  and
central  nerve  fiber  damage was   prominent.   Pathological  alterations  In
peripheral  nerves  Included axonal  dilatation along with fiber swelling  and
paranodal myelln retraction.  Axonal degeneration  was observed  In peripheral
nerves, spinal cord, medulla oblongata and cerebellum.
    Mendel 1 et al.  (1974)  evaluated the neurotoxlc effects of  2-hexanone In
rats and cats.  Four  Sprague-Dawley  rats  and  four  domestic  cats were exposed
to  2-hexanone, 24 hours/day, 7 days/week  for  12 weeks.   The  Initial  exposure
concentration  of  600  ppm  was adjusted  to 400 ppm at  an unspecified  time
because of weight loss  in  the exposed  groups.   Pair-fed animals were used as
controls.   Routine  recording of  the electrical activity of  various  muscles
Including  suprasplnatus,  triceps,   extensor  carpi,  deep  digital  flexors,
paraspinals, quadriceps, hamstring,  gastrocnemius  and anterior  tiblaUs  were
performed  by   EHG.   Signs   of  clinical weakness,  such   as  dragging of  hind
limbs,  developed  in  exposed animals at 5-8 weeks  (for  cats)  and  11-12  weeks
(for  rats).   Pathological  changes  in  exposed  cats,   as  revealed  by  EMG
findings,  consisted  of  abnormal  Insertlonal activity  with  positive  waves,
0183d
-23-
05/08/89

-------
which developed  between  4 and  6  weeks.   Fibrillation potentials  In muscles
at rest were  evident  between 9 and 10 weeks.   A  decrease  In the velocity of
ulnar nerve conduction occurred In cats between  7  and  9 weeks.   All muscles
examined displayed  these  EMG changes.  H1stopatholog1cal  examination  of the
sciatic nerves  of exposed animals  revealed a  peripheral  neuropathy charac-
terized by focal  swelling of  the  axon along the nerve fiber, accumulation of
neurofllaments  and  thinning  of  the  myelln  sheath  In  the  area of  axonal
swelling and denudation of myelln 1n both species.
    Signs of neuropathy were  reported  In  groups of  12 rats that were exposed
continuously  to  2-hexanone  at 225 ppm  for  <66  days or  400  ppm  for  <42 days
(Salda et al., 1976).  Paralysis  developed  1n  the rats  exposed to 225 ppm at
66 days and  1n  the  rats  exposed  to 400 ppm at  42 days.   Serial  sacrifice of
the  rats  for hlstopathologlcal  examination of  the sciatic  nerves  revealed
that  the  earliest changes were the accumulation  of neurofllaments,  followed
by axonal swelling and thinning of  the  myelln  sheath and eventual denudation
of myelln.
    Muscular weakness and sciatic nerve  axonal  hypertrophy and degeneration,
along with  myelln breakdown, were  observed In  nine rats  exposed  to 200 ppm
2-hexanone,  8 hours/day, 5  days/week  for  6 weeks  (Duckett et  al.,  1974).
There  were  four  control  rats;   sex  and  strain  of the rats  and method  of
measurement  of  exposure   levels were  not specified.   Duckett et  al.  (1979)
reported  an  effect of  2-hexanone  on sciatic  nerve conduction  velocity  In
rats, but at  a  lower  concentration.   Forty  Wlstar white rats were exposed to
50  ppm 2-hexanone  for  6 months,  8 hours/day,   5 days/week.  A  decrease  In
MNCV  In  the  exposed group was observed.  Demyellnatlon  of the sciatic nerve
was  present  in  32 of  the rats, with  2  of  the  rats  also  showing evidence of
axonal  hypertrophy.   According  to  the  authors,  the  observed  extensive
0183d
-24-
05/08/89

-------
demyell nation  and  minimal  axonal  changes  differ  from  the  observations  In
previous  studies  of  2-hexanone-1nduced   neuropathy,  which  have  described
axonal pathology as the primary lesion with secondary demyellnation.
    Johnson  et  al.   (1977)   Investigated   the  behavioral  and  neurological
effects of  2-hexanone 1n  rats  and monkeys.  Groups  of  10 albino  male rats
(Sprague-Dawley) and  8 male  monkeys  (Hacaca  fasdcularls) were exposed  to
2-hexanone at  0, 100 or  1000 ppm  for  6 hours/day,  5  days/week.   Exposure  to
1000 ppm was terminated after  25 weeks, when  rats and monkeys demonstrated a
bilateral  neuropathy manifested as  a hlndUmb  drag.  Five  of  the  monkeys
were  subjected  to  hlstopathologlcal  examination;  three  were  maintained
without  subsequent exposure  to  evaluate  the  reversibility of  the effects.
Exposure  to  100  ppm was  terminated  after  29  weeks  (rats)   or  41  weeks
(monkeys), when (presumably) the exposed animals  exhibited hlndllmb drag.
    The  animals were subjected   to  several  neurological  tests,  Including
recording of maximum MNCV of the  sciatic,  tibia!  and  ulnar nerves, absolute
refractory  period   of  these   nerves  and muscle  action  potentials.   In
addition,  EEG  and  visual  evoked potentials were  recorded  from  monkeys,  and
exposed rats  (number In   each  group  not  specified) were trained  so that the
Investigators  could  evaluate the effects  of 2-hexanone on  operant  behavior.
Behavior after exposure was compared with pretreatment performance.
    A  statistically  significant  (p<0.05)  concentration-  and duration-related
depression  In  MNCV were  observed  In the sciatic,  tibia!  and  ulnar  nerves  of
the  exposed monkeys  and   rats.  Also, a  reduction  In  evoked muscle  action
potentials  was  reported  that reached  statistical   significance  1n monkeys  at
1000  ppm.   Rats exposed  to  1000  ppm  2-hexanone  displayed  Impaired  operant
behavior  after 2  weeks.   Exposure to 100 ppm 2-hexanone  had  no  effect  on
operant behavior.   An Increase  In the latency of visual  evoked potentials
was  observed  In monkeys   following 4  months of exposure to  1000 ppm.   There
0183d
-25-
12/07/89

-------
were  no  effects  on  absolute  refractory  time  or  EE6.   The  three  monkeys
exposed  previously  to  1000  ppm  and  then  maintained  to  evaluate  recovery
exhibited no change In  sciatic, tibia!  HNCV  during  the first 2 months of the
recovery  period.   Complete  recovery  of the  HNCV  occurred  over  the  next
4-month  period.   Animals  (species not  stated)  exposed to  100  ppm exhibited
complete recovery of sclatlctlblal HNCV 1n 2 months.
    Johnson  et al.  (1979)   reported  no  effect  on  gross  hlstopathology  In
liver,  spleen,  kidney,  adrenal or brain  tissues In rats  or  monkeys  exposed
to  100  or  1000  ppm  for 29 or  41  weeks,   respectively.   Neuropathologlcal
examination  of the sciatic  nerves  from rats and  monkeys  In  the 1000  ppm
group  showed axonal  swelling  and myelln thinning.   Honkeys exposed  to  100
ppm showed  an  Increase  In nonmyellnated fibers  and  endoneural  collagen,  and
a decrease  In  large fibers.
    Five  male  rats  exposed  by Inhalation to  700 ppm 2-hexanone, 72 hours/
week  for  11   weeks  showed   a  reduction  In  weight  gain  with depletion  of
adipose  tissue and marked atrophy of the hlndllmb  musculature  (Katz  et  al.,
1980).   The  rats were exposed  for  two  20-hour  periods  and two  16-hour
periods  during the  work week.  A control group  of  five  rats was  exposed  to
conditioned air.   A  significant   depression  In  testlcular  weight was  also
observed.   Clinical  chemistry  and hematologlcal values  were  similar  among
exposed  and control  rats  except   for  a significant  reduction In the  total
white  blood cell  counts of treated  rats.   Signs  of  neuropathy were  also
evident as  early as the second week of exposure.
    Allen et al.  (1975)  reported  an  outbreak  of  neuropathy In humans  exposed
to  2-hexanone  In an  occupational setting.   Screening  procedures  (question-
naire,  EHG and  nerve  conduction   tests)  Identified 86  Individuals  affected
with toxic  neuropathy among  1157  workers  In  a  fabric-printing plant  In which
2-hexanone  was used as  a  solvent.  The  clinical  syndrome was presented as  an
0183d
-26-
12/07/89

-------
Insidious  distal  motor  and  sensory  disorder   with  minimal   reflex  loss.
Severely affected  Individuals  also  exhibited  moderate  weight loss.  The time
course  of  the  outbreak correlated  with  exposure  to  2-hexanone,  which  had
been  Introduced  as a new  solvent  ~7 months  earlier.   Further   Investigation
revealed  that  symptoms  developed   In  one  worker  after  only  5 weeks  of
exposure.  Levels  of  2-hexanone  associated  with  the outbreak were determined
to  be  9.2-36.0  ppm.   Several  other  chemicals   were   present   In  "trace"
amounts.  An  Investigation  of  dally work  habits  of the  employees  revealed
that  at  least  some  of the  workers were  subjected  to  dermal  as well  as
Inhalation exposure.  The  condition  of  the  workers Improved upon elimination
of 2-hexanone from the work environment.
    6.1.1.2.   CHRONIC — Pertinent  data  regarding  the  toxlclty  of  2-hexa-
none  following  chronic   Inhalation  exposure In laboratory  animals  or  humans
were not located In the available literature cited  In Appendix A.
6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC -- Krasavage  et   al.   (1980)    Investigated   the
neurotoxlc effects  of 2-hexanone (-96% purity)  1n rats  after  oral  adminis-
tration.  Groups  of  five  adult  male COBS  rats were  administered 0 or  600
mg/kg/day neat  2-hexanone  by gavage, 5 days/week  until  pronounced hind-limb
drag  was  observed.   Controls  were  treated  on  the  same  schedule   with
distilled water.   Exposure  to  2-hexanone  was  terminated  at  10  weeks  because
of  hlndllmb  drag.  Treated  rats had  reduced food consumption  and  reduced
body weights compared with  controls.  Hlstopathologlcal  examination revealed
giant axonal neuropathy  and testlcular atrophy.
    Homan and  Maronpot  (1978)  reported  that 1000 mg/kg/day  of  2-hexanone
administered  to  female  Wlstar  rats  In  their  drinking  water  for 120  days
produced  muscle  weakness   and  atrophy   and  peripheral  neuropathy.    Other
0183d
-27-
12/07/89

-------
effects Included a  reduction In both  food and water  consumption,  decreased
rate of body weight gain and Increased relative kidney weight.
    Abdel-Rahman et. al.  (1978) examined  the  effects  of  2-hexanone,  adminis-
tered  In  drinking  water,  on  water consumption,  body weight,  puplllomotor
activity and  locomotor  activity In guinea  pigs.   H1stopatholog1cal  examina-
tion was not  performed.   Groups of five  English  short hair  guinea  pigs (sex
not  reported)  were  administered   2-hexanone  In  their  drinking  water  at
concentrations  of  0.1  or  0.25% for 24  weeks.   On  the  basis of an  average
dally water  consumption  of 60  mi/day  and an  average body weight of  -0.6 kg
after 8 weeks  of  treatment (body weights were  recorded  only through  the 8th
week of treatment),  dosages were  -0,  100 and  250  mg/kg/day.  Exposed guinea
pigs gained weight  more  rapidly than  controls.   Locomotor  activity,  measured
only  In  guinea pigs at  the 0.25%  level  at  8 weeks, was  marginally  (p<0.1)
depressed.   Pupillary  response was decreased  to  about  the same degree  In
both  exposed  groups  (0.57 mm  at  0.1%  and  0.6 mm  at 0.25%) compared with
controls  (1.06  mm).  Statistical  analysis  was  not performed,   lo  determine
the  time  to  onset,  the  experiment was  repeated  at  the  0.25%  level.   De-
creased pupillary  response was  observed within the first  week  of treatment,
compared with  controls  (p<0.001),  and  decreased progressively throughout the
5 weeks of exposure.
    A  significant  reduction 1n body weight  was observed  at all  dose levels
In  male  rats that  were  administered  2-hexanone  at  concentrations of  0.25,
0.5  and  1.0%  In  the  drinking water  for  10-13  months  (Krasavage  et al.,
1979).   Assuming  an  average   water   Intake  of   0.14  8,/kg/day  (U.S.  EPA,
1986b), the  estimated doses are  350, 700  and 1400 mg/kg/day.   The  authors
reported  that  morphologic changes  observed were  similar  for those of  other
reports for this chemical.
0183d
-28-
12/07/89

-------
    6.1.2.2.   CHRONIC — Perlnent  data  regarding  the toxlclty  of  2-hexa-
none  following  chronic  oral  exposure  were  not  located  In  the  available
literature dted 1n Appendix A.
6.1.3.   Other  Relevant  Information.   Table  6-1  summarizes  the results  of
the acute lethal exposure to 2-hexanone derived  from several  animal studies.
The  oral  LD5Q  data  Indicate   that  rats   and  mice  are  nearly  equally
sensitive  to  the  acute  toxldty  of  2-hexanone.   The dermal  LD5Q  data  In
rabbits suggest that absorption occurs readily by this route.
    Schrenk et  al.  (1936)  examined  the  acute  toxlclty  of  2-hexanone  In
guinea pigs following  exposure to 2-hexanone vapors at concentrations  of  0,
1000,  2300, 6500  or 20000  ppm for  <810 minutes.   Nasal  Irritation occurred
within  the first  minute  at  all  levels   of  exposure.   Eye  Irritation  and
lacrlmatlon occurred  In all  groups within  30  minutes.   Incoordlnatlon  was
observed at 5-10 minutes at 20,000 ppm, at 20-30  minutes  at  6500 ppm and  at
90 minutes  at  2300 ppm.   Narcosis was observed  at 20-30  minutes at 2000  ppm
and at 90-120 minutes  at 6500 ppm.  Dyspnea  and  gasping  were  noted at 30-60
minutes  at 20,000  ppm  and  at  240-540  minutes  at 6500  ppm.   Guinea  pigs
exhibited narcosis after a 20- to 30-mlnute exposure to 20,000 ppm vapor.
    Lethality occurred  at  20,000 ppm at  70 minutes and  at 6500 ppm at  540
minutes.  Apparently, death was  due to narcosis  rather than to Irritation of
the  lungs.   Autopsy  examination  of  animals  that  died during  exposure
revealed slight congestion of  the brain,  and  moderately marked  congestion  of
the  lungs,  kidneys and  liver.   No  gross  pathology  was  observed  in guinea
pigs  exposed  to 2200 ppm  vapor  for 90 and  270  minutes,  or to  1000  ppm  for
810  minutes.   Volunteers exposed  for  a  few  minutes  to  1000  ppm  2-hexanone
vapor experienced moderate eye and nasal  Irritation.
    Specht  et  al.  (1940)  reported acute  toxlclty  of 2-hexanone   In guinea
pigs.   Ten female  guinea  pigs  exposed by Inhalation  to  6000  ppm  for  <525

0183d                               -29-                             12/07/89

-------
                                  TABLE 6-1

                     Acute Lethal Toxlclty of 2-Hexanone
Species
Rat
House
Rat
Route
oral
oral
Inhalation
Result
L050 2590
LD50 2430
8000 pptn
mg/kg
mg/kg
lethal to
Reference
NIOSH,
NIQSH,
NIOSH,
1989
1989
1989
                               6/6 1n 4 hours

Rat            Inhalation      4000 ppm lethal  to
                               0/6 In 4 hours

Guinea pig     Inhalation      6000 ppm lethal  to all
                               animals by 9 hours

Rabbit         dermal          1050 4800 mg/kg
                      Smyth  et  al.,  1954
                      Specht  et  al..  1940
                      NIOSH,  1989
0183d
-30-
06/12/89

-------
minutes displayed  symptoms  of narcosis, depressed body  temperature,  reduced
heart  and  respiratory  rate,  loss  of  cornea!   reflex  and  eye  and  upper
respiratory tract  Irritation.   Seven  guinea  pigs died  between  100 and  525
minutes.  Spencer  and  Schaumberg  (1977) observed clinical, gross and  micro-
scopic evidence of neuropathy In 11  young, adult  Sprague-Dawley  rats  exposed
continuously by Inhalation to 600 ppm  2-hexanone  for  3.5 days.   Sixteen age-
and weight-matched rats served as  controls.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.    Pertinent  data  regarding  the  cardnogenUHy  of  2-
hexanone  following Inhalation  exposure were  not located  1n  the  available
literature cited 1n Appendix A.
6.2.2.   Oral.  Pertinent  data  regarding the  carclnogenlcHy  of  2-hexanone
following oral  exposure were not located 1n  the available literature  cited
In Appendix A.
6.2.3.   Other  Relevant Information.   Other  relevant Information  regarding
the   carclnogenUlty   of  2-hexanone   were  not   located  1n   the   available
literature cited 1n Appendix A.
6.3.   HUTAGENICITY
    Pertinent data regarding  the mutagenUHy  of  2-hexanone were not  located
In the available literature cited 1n Appendix  A.
6.4.   DEVELOPMENTAL TOXICITY
    There are  relatively few data  regarding  the capacity  for 2-hexanone  to
produce developmental  toxlclty.   Peters et al.  (1981)  examined the  effects
of  2-hexanone  on  postnatal  development  and  behavior  In  rats   following
chronic Inhalation exposure.   Groups  of 25 pregnant  F344  rats  were  exposed
to  500,  1000  or 2000  ppm  2-hexanone for 6  hours/day throughout the  21  days
of  gestation.  Control groups  were  established  for  each of  the  exposed
groups.   Rats  In  the  2000 ppm group  were  pair-fed  since exposure at  this

0183d                               -31-                             05/23/90

-------
concentration was  associated  with a reduction  In  maternal  food consumption.
Behavioral,  neurological,  liver   function,   clinical   pathological,   organ
weight and  h1stopatholog1cal  evaluations  of the offspring were performed at
various  times  until  the offspring  were  20  months  old.   Behavioral  tests
Included  righting  reflex,  Inclined  screen  performance, food  maze  behavior,
open-field  behavior,  activity  wheel   behavior,  endurance  swim  test  and
avoidance conditioning.
    2-Hexanone exposure  reduced maternal  weight gain  by  10  and 14%  at  the
1000  and  2000 ppm  levels,  respectively.   Exposure  to  2000 ppm  resulted In
muscular  Incoordlnatlon and weakness by exposure day  20.   Reduced number  and
weight of  live offspring were reported at 2000  ppm.  These effects  were  not
reported  1n  the  500 ppm group,  which  --  because of problems  1n  the experi-
ment  — was  terminated before  the offspring were 3 weeks of age.   There were
no  consistent  treatment-related  alterations  1n survival,  organ weights  or
hlstopathologlcal  appearance  of  several  major  organs  and tissues.   Organs
examined  were   adrenals,   brain,  heart,  kidney,   liver,   lung,   ovaries,
pituitary,  pancreas,  prostate,   seminal  vesicles,  spleen,  testls,  thymus,
thyroid and  uterus.   PentobarbHal-lnduced sleeping time  (evaluated only In
offspring of  the 2000 ppm group)  was  Increased In  prenatally exposed males
and decreased In prenatally exposed females.
    Alterations  1n several of  the  behavioral  tests (Inclined screen,  food
maze  behavior, open field,  activity wheel) were detected  following  exposure
to  1000  and  2000  ppm of  2-hexanone.   The  results of  some  of the  tests
suggest  that  2-hexanone  exposure  Is  associated with hyperactlvlty  In young
but not  In  aged  rats.   Further,  the authors  noted that exposure  of  pregnant
rats  caused  a lifelong  dose-dependent  reduction  In  the growth  of  male  and
female offspring.

0183d                               -32-                             12/07/89

-------
    Using Inhalation chambers,  Tyl  et  al.  (1987) exposed  pregnant  F344 rats
and CD-I mice to the 2-hexanone  vapors.  The  exposures  occurred on gestation
days 6  through  15  and  at concentrations of 0,  300, 1000  or  3000  ppm.   Rats
were sacrificed on gestatlonal day  21  and  mice  on gestatlonal day 18.   There
was no  evidence of a treatment-related  effect  at 300 or  1000  ppm  In  either
mice or rats.
    Rats  exposed   to  3000 ppm,  observed  through gestation  day 15,  demon-
strated maternal toxidty (decreased  body  weight, reduced  body weight  gain,
and decreased food consumption).  These  effects  were  directly related  to the
exposure  and returned   to normal during the  postexposure  period  {gestation
days 15-21).   At  the time of  the scheduled sacrifice,  dams  exposed  to 3000
ppm  had  a   statistically  significant   Increase   In  relative kidney  weight;
there were no other treatment-related findings.
    Alterations In developmental  parameters In  rat  fetuses that demonstrated
statistically  significant effects  were   limited  to a  reduction  In  fetal
weight  and  a reduction  1n  skeletal ossification.   These effects were only
seen In the  group  exposed to  3000 ppm.  There were no statistically signifi-
cant changes In the external,  visceral, skeletal or total  malformations  In
any of the exposed groups relative to the controls.
    Similarly,  mice  were found  to  have  maternal toxidty after  exposure  to
3000 ppm, specifically,  the death of three pregnant  dams  on gestation day 6.
At  the  time of  the  scheduled  sacrifice,  observations  of  maternal  toxidty
were limited to dams exposed  to 3000  ppm.  These  animals had  statistically
significant  Increases  In abs.olute and  relative  liver weight;  there were  no
other treatment-related findings.
    Relative to the  controls,  developmental  toxidty In mice was  limited  to
groups  exposed  to  3000 ppm.    This  Included  statistically  significant
Increases In the number  of dead  fetuses, significant  reduction  In fetal body
0183d                               -33-                             12/07/89

-------
weight  per  litter  and  reductions  In  skeletal  ossification.   As with  the
exposed  rats,  there  were  no  statistically  significant  changes  In  the
external, visceral,  skeletal  or  total  malformations  1n  any of  the  exposed
groups relative to the controls.
6.5.   OTHER REPRODUCTIVE EFFECTS
    As  noted  In  Sections  6.1.1.1.  and  6.1.2.1.,  respectively,  following
Inhalation exposure  to  the  2-hexanone (700 ppm, 72  hours/week  for 11  weeks)
Katz  et  al.   (1980)  observed  a  significant  depression In  testlcular  weight
and Krasavage  et  al. (1980) found  that  exposure by  gavage (600 mg/kg/day,  5
days/week for  up  to  11  weeks)  produced  a testlcular  atrophy.  Similar  to the
neuropathy,  the  production  of  the  2,5-hexaned1one metabolite  appears  to be
an  Integral feature of the biochemical mechanism leading to the effect.
    The  testlcular effects  have been  evaluated  by  directly administering the
2,5-hexanedlone  to   test  animals.   The  mechanism  of  action for  the  effect
appears  to  be an alteration  of the biochemistry  (principally  llpld  metabo-
lism)  of the  testls  (Gillies  et  al.,  1981;  Boekelhelde,  1987).   Another
ramification  of  exposure appears  to  be attributable  to  a  direct  action on
the Sertol!  cells (Chapln et  al.,  1982) by  Inducing  a  biochemical dysfunc-
tion  of  the  systems  associated  with  mlcrotubule  assembly  {Boekelhelde,
1987).   Further,  this effect  1s  dependent  on the dose rate and  1s Indepen-
dent  of  the  total dose  (Boekelhelde and Eveleth,  1988).   Curiously,  this Is
the  direct  opposite of  the  dynamics  associated  with  the 2,5-hexaned1one
Induced  Injury of the nervous system (Krasavage et al., 1980).
6.6.   SUMMARY
    Acute Inhalation  exposure  of  animals or  humans  to  high concentrations of
2-hexanone vapor  causes  an  almost  Immediate  Irritation to  the  eyes and nose
(Schrenk  et  al.,  1936).   In  guinea   pigs,  exposure  to  6500-20,000  ppm


0183d                               -34-                             12/07/89

-------
resulted In ataxla, narcosis and death  {Schrenk  et  al.,  1936).   The cause of
death  In  guinea  pigs  was attributed  to narcosis.  Congestion of  the lungs,
kidneys and liver was found  during  autopsy  examination.   In humans, exposure
to  1000  ppm  for   a  few  minutes  resulted  In   moderate  ocular  and  nasal
Irritation (Schrenk et al.,  1936).
    Results of subchronlc Inhalation  animal  studies  Indicate that  2-hexanone
neurotoxlclty  Is  characterized by  the  development  of peripheral  neuropathy
(Mendell et al.,  1974;  Spencer et al., 1975; Salda et al.,  1976;  Johnson et
al.,  1977).   Neuropathologlcal features of  peripheral  nerve damage  Include
giant  axonal  swellings  and  axonal  degeneration.   Peripheral  nerve  damage Is
associated with hlndUmb drag  and weakness  of the forellmbs  and  hlndllmbs In
rats,  monkeys  and  cats.    Electrodlagnostk   studies   reveal   accompanying
abnormalities  1n EHG  and MNCV  (Johnson et al.,  1977; Duckett et al.. 1979).
A  marked  depression  In testlcular  weight  was   noted  by  one  Investigator
(Katz, 1980).
    Behavioral studies  revealed  alterations  In  rats exposed  to  levels  asso-
ciated with  hlstopathologlcal  evidence of peripheral neuropathy (Johnson et
al.,  1977).    Intermittent   exposure  to  50 ppm, the  lowest concentration
tested In  animal  Inhalation  studies,  was  associated with decreased MNCV  and
extensive  nerve  demyellnatlon  In  rats (Duckett  et al.,  1979).    Clinical
signs  of neuropathy have been  documented  In humans exposed  to 2-hexanone In
the work environment at concentrations  as low as  9.2-36.0 ppm (Allen  et al.,
1975).
    Several oral  gavage and  drinking  water  studies  Indicate  that the  effects
of  oral  exposure  to  2-Hexanone  are  similar   to  those   associated  with
Inhalation exposure (Krasavage et al.,  1979, 1980; Homan and  Haronpot,  1978;
Abdel-Rahman  et  al.,   1978).  Generally,  large   doses were administered  to


0183d                               -35-                         .    12/07/89

-------
produce the typical neurological  syndrome.   In  one study, testlcular atrophy
was  observed   In   rats  treated  by  gavage  at  600  mg/kg/day  for   10  weeks
(Krasavage  et  al., 1980).   The  oral  studies  were not performed  at dosages
sufficiently low to Identify thresholds for neuropathy.
    Testlcular effects  have  been studied  1n greater  detail  by administering
2,5-hexanedlone directly  to  test  animals.   Alterations are  observed  In  the
biochemistry  of  Upld metabolism  and  mlcrotubule assembly  (Gillies  et  al.,
1981;  Boekelhelde, 1987).   These  effects  appear  to  be dependent on the dose
rate and are Independent of the total dose (Boekelhelde and Eveleth, 1988).
    Data  were not  located  regarding  the carclnogenlcHy  of  2-hexanone  to
animals or  humans  exposed by any  route.   No data were located regarding  the
mutagenldty of 2-hexanone In  prokaryotlc or eukaryotlc  test  systems.   In a
teratogenldty study  1n  pregnant  rats,  a decrease  In maternal weight  gain
was  observed   at   1000  or 2000  ppm  2-hexanone  for  6 hours/day  throughout
gestation  (Peters  et  al., 1981).   A  reduction  In the number  and  weight  of
live offspring was detected  1n  rats  exposed to  2000  ppm 2-hexanone.   Post-
natal behavioral changes were observed In both  the 1000 and 2000 ppm groups.
    These  results  were  corroborated  by  Tyl   et  al.  (1987)  who  found  a
decrease  In maternal  weights  1n mice and rats  only after  exposure  to  3000
ppm of  2-hexanone  during  days  6-15 of gestation.   Evidence  of developmental
toxlclty was  only  observed In  the group  exposed  to  3000  ppm and was limited
to  Increased  Incidence of dead  fetuses  (only  seen In mice),  reduced  fetal
body weight per  litter,  and reductions  In  skeletal ossification  (mice  and
rats).  There  was  no  evidence  of  a  dose-dependent Increase  In developmental
toxlclty, at 300 or 1000 ppm In either species.
0183d                               -36-                             12/07/89

-------
                     7.   EXISTING  GUIDELINES  AND  STANDARDS
7.1.   HUMAN
    The current ACGIH (1988) recommended TWA-TLV  for  2-hexanone 1s 5 ppm (20
mg/m3).   ACGIH  (1988)  does  not   recommend  a  STEL  for  2-hexanone.   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  2-hexanone  of  100
ppm  (410  mg/m3)  and  final  rule  limits of  5 ppm  (20  mg/m3),  Identical  to
the ACGIH (1988) recommendation.
7.2.   AQUATIC
    Guidelines  and  standards   to  protect   aquatic   life   from  exposure  to
2-hexanone were not located 1n the available literature  cited In Appendix A.
0183d                               -37-                             09/11/89

-------
                              8.   RISK  ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.   Pertinent   data   regarding  the  carclnogenlclty   of
2-hexanone  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  carclnogenlclty of  2-hexanone
to  animals  or  humans  following  oral  exposure  were  not   located  1n  the
available literature cited In Appendix A.
8.1.3.   Other  Routes.    Pertinent data  regarding  the  carclnogenlcUy   of
2-hexanone  following other   routes  of  exposure  were  not   located  In  the
available literature dted In Appendix A.
8.1.4.   Weight  of  Evidence.   The lack  of  data regarding  the carclnogenlc-
lty of  2-hexanone  1n  humans  or  animals  Is  the basis for assigning 2-hexanone
to  U.S.  EPA Group  D  --  not classifiable as  to  human  carclnogenlclty,  using
the U.S. EPA (1986c) classification scheme.
8.1.5.   Quantitative Risk  Estimates.   The lack of positive  carclnogenlclty
data  for 2-hexanone precludes quantitative estimation of carcinogenic risk.
8.2.   SYSTEMIC TOXICITY
8-.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME  EXPOSURE  (SUBCHRONIC)  --  Several  studies
have  demonstrated  the development  of  peripheral  neuropathy in rats,  cats  and
monkeys  following  Inhalation exposure  to  2-hexanone  (Mendell et  al.,  1974;
Spencer  et al.,  19-75;  Salda et  al.,  1976;  Spencer  and  Schaumberg,  1977;
Johnson  et al.,  1977,  1979;  Ouckett  et  al.,  1974,  1979).   CNS  effects,
progressive weight  loss and  a pronounced  hlndllmb foot drop were  noted In
rats  (Rec.  #3) exposed  to 1300 ppm 2-hexanone,  6  hours/day,  5 days/week  for
4  months   (Spencer  et al.,  1975).  Mendell  et  al. (1974)  reported  altered


0183d                               -38-                             12/07/89

-------
electrical actlvHy of muscles,  hlndllmb  drag  and  hlstopathologlcal  evidence
of severe  neuropathy  In  cats  (Rec.  #5)  and rats  (Rec. #4)  exposed  continu-
ously to  400 ppm.  Salda  et al.  (1976)  reported  paralysis In  rats  exposed
continuously to  400  ppm  for 42  days or  to  225  ppm for 66  days  (Rec.  #15).
Johnson et  al.  (1977)  exposed rats  and  monkeys  6 hours/day, 5  days/week  to
1000 ppm for 25  weeks or to  100  ppm for  29 weeks (rats, Rec. #2) or  41  weeks
(monkeys, Rec. #1), when exposures  were  terminated because  hlndllmb  drag  was
evident.  MNCV  1n the  sciatic,  tlblal  and ulnar nerves were decreased  In  a
generally concentration- and duration-related  manner.   Exposure to  1000  ppm
6 hours/day  5  days/week  for  25 weeks had  no effect  on  the  hlstopathologlcal
morphology  of  liver,  spleen,  kidney, adrenal  or  brain  tissues  In  rats  or
monkeys,  Indicating  that  peripheral neuropathy  Is  the  critical  effect  of
repeated  exposure to  lower  levels  of 2-hexanone.    Because  gross  Impairment
of neurological  function was observed by Spencer et al.  (1975)  at  1300 ppm,
by Mendell  et  al. (1974)  at 400 ppm, by  Salda et  al.   (1976) at  2?5  and  400
ppm  and  by  Johnson et  al.  (1977)  at 1000 and  100 ppm, these studies define
FELs but do not define  LOAELs for peripheral neuropathy.
    Duckett et al. (1979)  reported  a reduction In  MNCV, along with  extensive
demyellnatlon of  the sciatic nerve.  In  rats  subjected  to  50 ppm ?-hexanone 8
hours/day, 5 days/week for 6 months  (Rec.  #8).  The  data  were available only
In  an  abstract,  however,  and  were  reported  In  Insufficient  detail   to
determine whether  the observed effects  define  a PEL or a  LOAEL.  Therefore,
1t Is Inappropriate to  use  this study as the basis  of an RfO.
    Allen et al.  (1975) reported an  outbreak of  neuropathy  In humans exposed
to 2-hexanone  In an  occupational setting.  The  clinical  symptoms correlated
with  exposure  to  2-hexanone  on  a   time  course basis;   2-hexanone was Intro-
duced as  a  new solvent  ~7  months  before  symptoms  were  reported.  Concentra-
tions of  9.2-36.0 ppm were quantified In  the  workroom  atmosphere.   However,
0183d                                -39-                             09/11/89

-------
U  appears  that  some  of  the  workers  also  had  skin  contact with  liquid
2-hexanone,  so  that both  dermal  and  Inhalation  exposure may  have  been  In-
volved.  Trace amounts  of other  chemicals were also  present  In the workroom
air.   These  data  are  not  appropriate  for  deriving an  RfD  for  Inhalation
exposure because  a threshold  for  neuropathy  1n  humans was  not  Identified,
the workers were  exposed simultaneously  to  a number of  chemicals  and mixed
routes  of  exposure were  Involved.   The data  are  sufficient,  however,  to
suggest  that  neuropathy  In  humans  may  occur  at  or  below  levels  associated
with neuropathy In  laboratory animals.
    The available data,  therefore, are  insufficient  for derivation  of  an RfD
for subchronlc  Inhalation exposure  to 2-hexanone.  It  is  recommended  that a
well-designed  Inhalation  study  be  performed  with   groups  of rats  exposed
continuously  to  2-hexanone  at   concentrations  <50  ppm.    Because  of  the
Insidious and  progressive nature of  the  neurologic  syndrome  associated with
this  chemical,  the study  duration  should  be at  least  6 months.   Several
behavioral and neurological variables should be evaluated.
    8.2.1.2.   CHRONIC  EXPOSURE  ~ No  data  regarding the  chronic  Inhalation
effects  of  2-hexanone  are  available.    In  the absence  of  sufficient  sub-
chronic  data,  an RfD  cannot be  derived for  chronic Inhalation  exposure to
2-hexanone.
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS  THAN LIFETIME  EXPOSURE  — In a  90-day gavage  study,  5
rats   (Rec.   #4)  were  administered  600  mg/kg/day  2-hexanone, 5  days/week
(Krasavage  et  a!., 1980).   Peripheral  neuropathy,  paralysis, decrease  in
weight   gain   and  testicular  atrophy  were  observed.   Because  paralysis
represents  a  gross  Impairment  of  neurologic function,  the  600  mg/kg/day
dosage  1s  considered a  PEL  rather  than  a LOAEL.   Homan  and  Haronpot  (1978)


0183d                               -40-                             09/11/89

-------
reported  that  1000  mg/kg/day  of  2-hexanone  administered  to  rats  1n  their
drinking  water  for  120  days   produced  muscle  weakness  and  atrophy  and
peripheral neuropathy  (Rec.  #2).  This study  was available only  as a  brief
abstract.
    Abdel-Rahman  et al.  (1978)  treated  groups  of  five  guinea  pigs  with
2-hexanone  In  their  drinking  water  at   doses  of  100  (Rec.  #3)  and  250
mg/kg/day.   Decreased   locomotor  activity  was noted  at  the  250  mg/kg/day
level at  8 weeks.   Pupillary response  was  decreased at  both  dosage levels.
In  addition,  a  significant  Increase  1n  body weight was  observed at  both
dosages.  This  study was  too limited  In scope  (hlstopathologlcal examination
was not performed),  however,  to be considered for  RfO derivation.
    Krasavage et  al. (1979)  administered  2-hexanone to rats at  doses  of 350
mg/kg/day  (Rec. #1), 700 mg/kg/day and 1400 mg/kg/day in the  drinking  water
for  10-13  months.   A  significant  reduction In body weight occurred at  all
dose levels.  Typical  cllncal signs of  neuropathy were noted  in  rats exposed
at  the  two  highest doses.   All  treated  groups  of  rats  exhibited morpho-
logical signs typical  for  the compound.  This  study  was  available  only  in an
abstract,  however,  and was too  briefly reported  to evaluate  the  effects at
the lowest dosage; hence, the study cannot serve as  the basis  of  an RfO.
    The  available  subchronic  oral  data,  while  demonstrating  that  neuro-
logical effects are  the  critical effects of  oral  exposure to  2-hexanone,  are
insufficient to  serve  at the basis  for quantitative risk  assessment.   Oral
studies designed  to evaluate peripheral neuropathy  In  rats at  dosages  <350
mg/kg/day  should  be initiated.   Because  of  the insidious and  progressive
nature of  the  neurologic  syndrome,  exposures should continue  for  at least  6
months.
0183d                               -41-                             09/11/89

-------
                8.2.2.2.   CHRONIC  EXPOSURE — Studies  of  chronic  oral  exposure  to
            2-hexanone  were  not  available.   In  the  absence of  sufficient  subchronk
™*         data, an RfD cannot be derived for  chronic  oral exposure to  2-hexanone.
            0183d                               -42-                             09/11/89

-------
                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The toxiclty of  2-hexanone was discussed 1n Chapter  6  and dose-response
data  considered  for  CS  derivation are  summarized  In  Table 9-1.   Since  no
chronic  toxldty  data  are available,  subchronlc  data  were  considered.   A
finding  common to  both  the   Inhalation  and oral  studies  [except for  the
developmental  toxldty  study  by Peters et  al.,  1981)] 1s  peripheral  neuro-
pathy,  which  was  frequently   accompanied by muscular  weakness,  paralysis,
hlndllmb  drag  and  hlstopathologlcal  evidence of  axonal  degeneration.   The
occupational study  by Allen et al. (1975),  1n which  neuropathy was reported
1n  workers  who  experienced  both   Inhalation  and  dermal  exposure,  1s  not
Included  In  Table  9-1.  In the study by Peters et  al.  (1981),  exposure  to
1000  and  2000  ppm of  2-hexanone  (6 hours/day through  gestation)  produced  a
10 and  14% weight  loss,  respectively.  In addition, at 1000 ppm there  was  a
decrease  In  body  weights and  behavioral  effects  In male offspring; at 2000
ppm there  was  a  decrease 1n the number of live pups, a decrease In the body
weights of all  offspring and behavioral alterations.
    Besides  typical  signs  of  2-hexanone-1nduced neuropathy,  Krasavage  et al.
(1980)  found  testlcular  atrophy  and  a  decrease  In  weight  gain In  rats
administered 600  mg/kg/day 2-hexanone  by gavage,  5  days/week for  90  days.
In  a  24-week  drinking  water  study  limited  to  evaluation  of  reflexes  and
behavior  In  guinea pigs, 100 mg/kg/day  resulted 1n  Impaired pupillary  reflex
(Abdel-Rahman et al., 1978).
    Table  9-2  presents  CSs and RQs  derived  for  the  lowest  human equivalent
dosages associated with  each  of the effects compiled  1n  Table 9-1.  Because
of  the  Insidious  and progressive  nature of  the  syndrome, neuropathy  was
assigned  an  RV   of  8.   The   fetotoxlc  effects  reported by  Peters et  al.


0183d                               -43-                             09/11/89

-------

41
kl
C
O)
k.
0>
Ol
ce





Ol
VI
e
o
Q.
VI
Ol
Of



IB — •
••* Ol >i
C v> (O
Ot O 'O
*- o, "s.
n> Di
^ C J4
»- IB V.
3 E Dl
5"ii
•O 41 — •
Ol vi >t
E 052
i_ ea tJ
o -v
i^ ^ O)
vi IB M
c 1\
1^ *- p*
,ssf
&
o
c
rt)
K
o»
* £
s 1
^k X
*• u.
0>
>,
^*
5 2"
M *"'
2 =
•^ o.
•N, •—
4> (O
r- (J Ol
O «- ••*
»- Irt IB
^Z ^^^^
Ol fi W
> Q-
Ol
Ol *••
IV Mf
1- "O Ol
A) S _i-
w o "^
,.jj
M
(9 — •
i_
• (9
5S
X
5


•«•».
VI C
Ol >-
^~ IB
U t_
Ol -»J
0.00




01
3
0
de
in
91

k. »
Ol •
kl ^
C fO
Ol
a.—
(/> Ol

ex
0
k.
•o
a*
g
<*» >t
£
i«
w a.
*— o
^ k.
C 3
— o*
z c




^
»
o
^

u
o
**0
O
*.
01 >a vi
* '"S
m in c
CM O
n - E
U1 >l
»»•*• (O ^*
•o
e < k.
Q. VI O
a. k. «fc.
o 3-
O £ «
CO (U
•- «« x


ee
Z



k.
m
•a
U1
cr>
C5


c
o

11



— ;
••^
^3 TO
c
41 --»
Z &
•»
^™» w%
n >>
E n
•vo w
6 P— 01
01 - X
m >>
•£> (0 CM
— ~v
VI k,
E t- O
0.3 *.
a, o
^r .K
O Ol
0 * 0>
*c\» X


ae
Z



k.
nj
A
in
CO
O

^>


ce
i
ot
3
Dl
,
(/> Ol
•>»•—
•" X
n> >o
k. 0
c
o

. 
o»
tt
1_
•O >s
£
.p 4-»
la
•— o
*O k.
C 3
~- Ol
X C




•o
O
CO
CM


U
«o
in
J3


• X
"•• I/I
n >»
•53 «,
gr^-S
s,;8
hO <4 
E u 0
o. a ».
ex o
£ .M
O Ol
0» 01
* oj X


oe
z



b.


«•


PC
Z





ce
•*»
^^
10
u
c
o

IB

IB
»•*
S S !£ * S
01 C7> 91 ^J » *•« • ^ Cfl
I — r— i — OJ^^OIP-'ra ^*
(*• p»
-* . ^> . . C9I C9i -" -
^** *i«* * Or* Of— 41 vi •
OIF- Ol*- 101— vi v» &-*••
^tf IB J£ ^ ^1 05 C " O> C »9l W C3 Ol IB
Ju <*- f«r«.f*r«»-*>GD ^-*
«J 3^-f ro^J O *— 91 O^~9l IQ9* at*-*
0) C3OI C/»Ol I-SIB^ <•)«•— «•— 0.0)
1
C
• O Ol ->-•
in kl 3> I ' ' ^«-* Ol
VI ^-O V ^ OljC£C
01 oivi k. cz c: *- C 3 — — O>0t«-Xk.
JC U 41 C 41 f f .Xl^tlOO.
ra ot-uoc iBXt-vi
SC X «• • > -Ol D>»-
>v ot^-1* >i >t >«k.k. u.
f VIOVI .COI fO> £U- VI lOk. (Ok. » CLV a*u a. u us ^*
30 ai — n •— >> o o o -— 01 « iof w,a k..a b.vi^-* k.£
VI3 UklE k.4rf 3E 3E 3VIVI Cl
341 O>3OI IBIB Olf- 0>>- 41 O Ol 4) u_
zc o-o-o eko. z»- z— z--*- QO



•o •a -o 13
CM en -o CM en -^ en
p— in o en 91 * » -^» v> -*^ vt f) E 4i
«>t ^~>>i WIO «>i «>> E Nvi— Ol
SIB NfQVi EVVI ElOvi 6t V.T9J< "s. •« .* Ol 0 E *•
o> M. •** ~* 5"~- nOioicnoiE*'- k.o
E m ot Dim c E-o Emoi E>nai r-o
4)E2 * XX to M enu-vi
9i * X • E CM >ivd o> o« tool o>>
^.>« in>» ^en «^- >*»— eo 01 «r >» 10
S5* CM -S ** 215 v i>5 ^ 2-5* "X '"'•S '
•X.k. — «>v k. vik. "Xk. "X,k. l/lvi EVOI
EVIO VIO Ek.O EvlO EviO Ek.j< CXvi>
a. t, u- E i- *- Q. a «- a.k, 0 Ofu
O 41 O OtCMVOlO 41 O Ol e CM •— O 41
CM CD X tneox CMCMX •— »o X r-iex !-• r— .— f— IB vi
• X
X X i=
r^. i*- .
ae ce ae 91 en >c ae
z z z Al Al en z



k, k. k. k. U k. k.
IO ra B  ID » Q. >> >«Oktae en
Z X Oi (/lot OIU«-Z u.
X -V 'X.*— V«— Js. X
*J *• *- X **X Ckivi*-> •«••
re IB O B 
-------


01
u
c
01
k
01
Ik
o>
Of







0)
VI
c
o
a.
a>
CC

ro —
*• 01 >|

a> O -a
•— o "s.

ss ^
^ Ol —
Ol VI >»
E<§€
O *N.
•k <— Ol
"i ro it
G &*^
£5 E.




a>
k
3

O

X






>.
~
h,
3
a.


01 19
i— U 01
U «* -to*
^ VI ra
f >•-"•
Ol A V)
» Q.

ai
01 -w
k 'O 01
01 O —
5-3

•w
k
• ro
e *>
z in
X
Ol



V.
VI C
a *-
w"*



flj
•5
o
ee

o
CO
0) r—
01 -
ro •

ro r—
vi ro
k •*•*
M 01

r
>> •o

ro vi
k k re
ro ro Ol
O.r— k
=J U
• U O) C
>l— •O —
f •• ">
** vi - o*
(O o) >»
B.-i-' J= •"
0 O..C
k - O Ol
3 I/I k *-
ai •- <-• a>
Z vi ro X



^

en
r—



OM
*


X.
VI

VI
01
>» X
ra


Ol

"x o


§OJ
Ol
10 *


X
10
I




4-*
ID
Ol
C




n

o


in




K

,


Ol
ro
Q. »
11

01

^
o>

"w
o
e co ai »» en
ro t** r** ix) c
^ 5? S,2 |1
roo oe«ra» Sv>
a. p • > • vi
cc •— >— re ^ pjro
§O co 01 ra vi iq (\j
w r- -o ra CM TJ
ro en A ** k •*< . c
z x r- « at M ai ora
>t Ol ^> ^c
jc ^^ ro 01
o> o. 2^
<- • o o a,
u k X r- Z
vi *- ^01 — g *

E *^ ** ^^ ^3

• c k 01 ™ 2
»t ro ••-»>> ^ ^
•= *•? ^ * 5^
<-«vi kOi'-i > •=•"
ro vi ro E ra i 2
cvoi •— k a. >» E
oc •-•-«> -o ^-g
alo "o. a. = JQ a"
5$ C?^ £ C |ft.
1 -^
3 01
f. Ol k
f 01
O <-> Ik
•O Ta T> . f 0)

r-» i0 iA O oj
: f;
5* vi a
$ - Ol
•* e e

0 S S "" *^
C3 ^^ ^^ JO S
i a a-
~ k a e 5S"
Ok k e 4i O re <£
CMO) Ol Q. -~> O tk OCTI
ro ra X »— — ji k e *• .«» o
oik koixi «e >, . a.
ji -o -o oi en k 2, a x
«•» » C r- ^ _- 01
o> e e *- < 01 >*
e *- *- *r O -C vtvi u
CM X •— *• k >» *"
§vi X «n a o> =
>, PkCVk Ik Q£ 0
rO • O • O O S e k
^t> QlkOlk ^S ^
** u_ M K
s «" 5
*" k O "*""
c< 5 |1 '
Z Z Z 3 S »i c
u 3 ro o
01 "x £
f o> " o
S f E A

01 Ol 01 >> V VI
« •••••«-• f> >, •
5 ro 10 ^ i^ E
X X 01 o
"2 k T3 k
e ^ c  Of ^ *j fO
n 10 co E M ex

o o o o g u 01
ik e -~
i/i — • ^~ ^ i o ja
k eft k r»* ^9 en


r- » Ol -O ,— .
ro « " >. - 0. «
E Q. § E ' °~ Q-
^ LU ^ r- ra LU
ra • CM vi »
ce ^> 01 • ^-i ra (/>
£ — "" . o o ~
I O> •*• ?O C <->
••s. Ol C.C^GOO|lk.C


2 « el>. ^ ^ -^ -5 5 *
•M -r- --• J 3 O c ^ •*- O "O
to aact^fd E ^o , c ^t  n ^^-M c (Q o
1 l < ^ ^ *"" I* «t)  4* c* o '*-' * i-
Ct. Ck. C=L. •<*-* u^'^vr i_ u
-- O> ^ d> ^- (U ny c (Q-^JQ O> C-M

"vS x.jrx.3 u n tu 
-------
                                            41
                                            u-
                                            V
0>
c
e
                              X
                              a>
                         CM    k
                          '    O
                              o
                              u
                              o
                              f
                              o
                              u

                                            ft
                                            4rf
                                            3
                                            O
                        •B

                       ^-« (
                        air
                          I
                        e >
                        o
                                                            re

                                                            *•
                                                            OI
at •—   f •—
D>     m
IB  >   ee   *
                                                            at i—    v>
                                                            — » CD        >- •
                                                     2     g
                                                     1     s
                                                     •o
                                                     e
                       •e
                        c
                        IB
                                                      Q.

                                                      O
                                                                    	
                                                                    o at   •—
                                                                     .
                                                            •O O>   (BO)
                                                            
                                                                       .
                                                             u "4-    wi *»    a.
                                                             01 u-    OJ IB    E
                                                            Q o   i— a.  i— i
                                                                   ^n     en
                                                                   OJ     CO
                                                                   •*•     en
                                                     fr*     M     O
0183d
                           -46-
                                       09/11/89

-------
(1981)  were  also  assigned  an  R\L  of  8.    The  Impaired  pupillary  reflex
                                   6
reported In  guinea  pigs  (Abdel-Rahman et a!.,  1978)  was assigned an  RVg  of
7.   The highest  CS  calculated,   22.4  associated  with  neuropathy  In  rats
exposed by  Inhalation (Johnson  et al.p  1977,  1979), was  selected  as  most
stringently representing the chronic toxldty of  2-hexanone.  The  CS of  22.4
and Us corresponding RQ of 100 are presented In Table 9-3.
9.2.   BASED ON CARCINOGENICITY
    No  data  were  located  regarding  the  carclnogenlclty of  2-hexanone  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;
therefore,  an RQ based on carclnogenlclty cannot be  assigned.
0183d                               -47-                             09/11/89

-------
                                   TABLE  9-3
                                  2-HEXANONE
           Minimum Effective  Dose (MED) and Reportable  Quantity  (RQ)
Route:
Species:
Dose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
Inhalation
rat
23.3
29 weeks
peripheral neuropathy and hlndllmb drag
3.3
8
26.7
100
Johnson et a!., 1977, 1979
'Equivalent human dose
0183d
            -48-
09/11/89

-------
                               10.  REFERENCES

Abdel-Rahman,  M.S., L.B. Hetland  and  D.  Courl.   1976.  Toxldty and  metabo-
lism of methyl n-butyl ketone.   Am.  Ind.  Hyg.  Assoc.  J.   37(2):  95-102.

Abdel-Rahman,  M.S.,  J.J.  Saladln,  C.E.  Bohman  and  0.  Courl.   1978.   The
effect of  2-hexanone  and 2-hexanone metabolUes  on puplllomotor actllty and
growth.  Am. Ind. Hyg. Assoc.  J.   39(2):  94-99.

AC6IH  (American  Conference of  Governmental  Industrial  Hyg1en1sts).   1986.
Documentation  of the Threshold Limit Values and  Biological  Exposure  Indices,
5th ed.  Cincinnati, OH.  p.  378-379.

ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).   1988.
Threshold Limit Values and Blologlal Exposure  Indices  for 1988-1989.   p.  26.

Allen,  N., J.R.  Mendell,  O.J.   BUlmaler,  R.E.  Fontaine  and  J.   O'Neill.
1975.   Toxic  polyneuropathy  due  to  methyl n-butyl  ketone.   An  Industrial
outbreak.  Arch.  Neurol.  32(4):  209-218.

Babeu,  L.   and  D.D.  Valshnav.    1987.   Prediction of  blodegradabllHy for
selected organic  chemicals.  J.  Ind. Mlcrob.  2:  107-115.

Boekelhelde,  K.    1987.   2,5-Hexanedlone   alters   mlcrotubule  assembly.
Toxlcol. Appl. Pharmacol.  88: 370-382.
0183d                               -49-                             09/11/89

-------
Boekelhelde, K. and  3.  Eveleth.   1988.   The rate of  2,5-hexaned1one  Intoxi-
cation,  not total  dose,  determines  the  extent  of   testlcular  Injury  and
altered  mlcrotubule  assembly  In the  rat.   Toxlcol.  Appl. Pharmacol.   94:
76-83.

Brown, K.W. and K.C.  Donnelly.   1988.   An estimation  of  the  risk associated
with  the  organic  constituents  of  hazardous  and  municipal  waste  landfill
leachates.  Haz. Mast. Haz. Water.  5:  1-30.

Bysshe,  S.E.    1982.    Bloconcentratlon  factor  1n  aquatic  organisms.   In.:
Handbook of Chemical Property Estimation Methods, W.J.  Lyman, W.F.  Reehl  and
D.H. Rosenblatt, Ed.  McGraw-Hill Book  Co.,  NY.  p.  5-1 to 5-13.

Chapln,  R.E.,  R.M.  Norton,  J.A.  Popp  and J.S.  Bus.   1982.  The effects  of
2,5-hexaned1one on  reproductive  hormones  and testlcular  activities   1n  the
F-344 rat.  Toxlcol. Appl. Pharmacol.   62:  262-272.

CMR  (Chemical  Marketing Reporter).  1986.   1987 OPD  Chemical  Buyers  Direc-
tory, 74th Annual  ed.  Schnell Publishing Co., NY.  p. 401.

Courl, D.,  M.S.  Abdel-Rahman and L.B.  Hetland,   1978.   Blotransformatlon  of
n-hexane and methyl  n-butyl ketone In  guinea pigs  and mice.   Am.  Ind.  Hyg.
Assoc. J.  39(4):  295-300.
0183d                               -50-                             09/11/89

-------
Crockett,  P.W.,  B.  KlUan,  K.S.  Crump  and  R.B.  Howe.   1985.   Descriptive
Methods  for  Using  Data from  Dissimilar  Experiments  to Locate  a  No-Adverse-
Toxic-Effects Region in the Dose-Duration Plane.   Prepared by  K.S.  Crump and
Company,  Inc.  under Contract No.  68-01-6807  for  the  Environmental  Criteria
and Assessment Office,  Cincinnati, OH.

Day, E.A.  and O.F. Anderson.   1965.   Gas  chromatographlc and  mass  spectral
Identification of  natural  components of the  aroma fraction of blue  cheese.
3. Agrlc. Food Chem.  13:  2-4.

D1  Vlncenzo,  G.D., C.J. Kaplan  and  J.  Dedlnas.   1976.   Characterization  of
the metabolites of  methyl n-butyl  ketone, methyl  Iso-butyl ketone and methyl
ethyl  ketone  1n   guinea  pig  serum  and their  clearance.   Toxlcol.  Appl.
Pharmacol.  36: 511-522.

DIVIncenzo,   G.D.,  M.L.  Hamilton,   C.J.   Kaplan  and  J.  Dedlnas.    1977.
Metabolic  fate and disposition  of 14C-labeled  methyl  n-butyl  ketone  In  the
rat.  Toxlcol. Appl. Pharmacol.   41(3):  547-560.

DIVIncenzo,  G.D.,   M.L.  Hamilton,  C.J.  Kaplan,  H.J.  Krasavage  and  J.L.
O'Donoghue.   1978.   Studies on  the respiratory uptake and excretion  and  the
skin absorption of  methyl n-butyl  ketone In humans and dogs.   Toxlcol.  Appl.
Pharmacol.  44(3):  593-604.

Duckett,  S.,  N.   Williams  and  S.  Francis.    1974.   Peripheral   neuropathy
associated with  Inhalation of  methyl butyl  ketone.   Experlentla.   30(11):
1283-1284.
0183d
-51-
09/11/89

-------
Duckett, S.,  L.J.  Streletz,  R.A.  Chambers,  M.  Auroux  and P.  Galle.   1979.
50  ppm  MnBk   (methyl  n-butyl   ketone)   subcllnlcal   neuropathy  In  rats.
Experlentla.  35(10): 1365-1367.

Dumont, 3.P.  and  J.  Adda.  1978.   Occurrence  of sesqulterpenes  In  mountain
cheese volatlles.   J. Agrlc. Food Chem.   26:  364-367.

Durkln, P.  and W.  Meylan.   1988.   Users Guide  for  D2PLOT:  A  Program  for
Dose/Duration  Graphs.    Prepared  by  Chemical  Hazard  Assessment  Division,
Syracuse Research Corporation under Contract No.  68-C8-0004  for the  Environ-
mental Criteria and Assessment Office, Cincinnati, OH.

Elsenrelch,  S.J.,  B.B. Looney  and O.J.  Thornton.   1981.  Airborne  organic
contaminants  1n the  Great  Lakes  ecosystem.   Environ.  Scl.   Technol.   15:
30-38.

Elliott, 3.R.  and  A.A. McElwee.   1988.   Observations  concerning  the  nature
of sites of anaesthetic action In Gammarus.  Br. J.  Anaesth.   60(7):  817-824.

Engineering  Sciences Data  Unit.   1975.  Vapour  pressures  and  critical  points
of pure  substances.   VI.   C3-C15 aliphatic  ketones.   Eng.  Scl.  Data  Item.
75025.  p.  1, 2, 8, 9.

Erlchsen,   L.V.   1952.    The  solubility   of  homologous  series  of  organic
compounds.   Naturwlssenschaften.   39:  41-42.
0183d                               -52-                             09/11/89

-------
Flnley,  K.T.   1982.   Qulnones.   In,:  K1rk-0thmer  Encyclopedia  of  Chemical
Technology, 3rd  ed,,  M.  Grayson  and D. Eckroth,  Ed.   John Wiley  and  Sons,
Inc., NY.  19: 572-573, 580, 606.

Gelger,  O.L.,  S.H. Polrler,  L.T. Brooke  and D.J.  Call,  Ed.   1986.   Acute
Toxldtles  of  organic  chemicals  to fathead  minnows  (Plmephales  promelas).
Vol.  III.   Center  for Lake  Superior  Environmental  Studies,  University  of
Wisconsin-Superior.  ISBN 0-9614968-2-7.   22 p.

Gillies, P.3., R.H.  Norton, T.S.   Baker  and J.S. Bus.  1981.  Altered  llpld
metabolism  In  2,5-hexanedlone Induced  testlcular  atrophy  and  peripheral
neuropathy 1n the rat.  Toxlcol. Appl.  Pharmacol.  59:  293-299.

Graedel, T.E.,  D.T.  Hawkins and  L.D.  Claxton.  1986.  Atmospheric  Chemical
Compounds: Sources, Occurrence  and Sloassay.   Academic  Press,  Inc.,  Orlando,
FL.  p. 265.

Grey,  T.C.  and D.H.  Shrlmpton.   1967.   Volatile  components  of  raw  chicken
breast muscle.  Br. Poultry Sc1.  8:  23-33.

Gupta, M.  1987.  Olfactory response of  Apis  florea  F.  to  aliphatic  straight
chain ketones.  J. Anlm. Morphol.  Physlol.   34{l-2):  117-129.

Gupta,  M.  and  R.S  Mohla.   1986.    Aliphatic   straight-chain   ketones   as
potential bee repellents.   Chem. Ind. (London).  0(9):  327-328.
0183d                               -53-                             09/11/89

-------
Hansch, C.  and A.J.  Leo.   1985.   Hedchem Project.   Issue  No. 26.   Pomona
College, Claremont, CA.

Harris, J.C.   1982.   Rate  of  hydrolysis,   in: Handbook of Chemical  Property
Estimation  Methods,  W.J.  Lyman,  W.F.   Reehl  and   O.H.   Rosenblatt,   Ed.
McGraw-Hill Book Co., NY.  p.  7-2 to 7-9.

Hawley,  G.G.   1981.   The Condensed  Chemical  Dictionary,   10th  ed.   Van
Nostrand Relnhold Co., NY.   p. 672.

Homan,  E.D.  and  R.R.   Maronpot.   1978.    Neurotoxlc  evaluation  of  some
aliphatic ketones.  Toxlcol. Appl. Pharmacol.   45:  312.

HSOB (Hazardous Substances  Data Bank).   1989.   On-line February 14, 1989.

Johnson,  B.L., 3.V.  Setzer,  T.R.  Lewis  and WK.  Anger.   1977.   Effects  of
methyl  n-butyl ketone  on  behavior and  the nervous  system.   Am.  Ind.  Hyg.
Assoc. J.  38(11): 567-579.

Johnson,  B.L., H.K. Anger, J.V.  Setzer,   D.W.  Lynch  and T.R.  Lewis.   1979.
Neurobehavloral effects  of methyl  N-butul  ketone and  methyl  N-amyl ketone In
rats  and  monkeys:  A summary  of  NIOSH Investigation.   J.  Environ.  Pathol.
Toxlcol.  2(5): 113-132.

Juttner, F.  1986.   Analysis  of  organic compounds  (VOC)  In the forest air of
southern Black Forest.  Chemosphere.  15:  985-992.
0183d                               -54-                             09/11/89

-------
Katz,  G.V.,  3.L.  O'Donoghue,  G.D.  01  Vlncenzo  and  C.3.  Terhaar.   1980.
Comparative neurotoxlclty  and metabolism of ethyl n-butyl ketone  and  methyl
n-butyl ketone In rats.  Toxlcol.  Appl.  Pharmacol.  52(1): 153*158.

K1nl1n, T.E.,  R.  Muralldhara,  A.O.  PHtet, A.  Sanderson and  3.P.  Halradt.
1972.  Volatile  components  In roasted filberts.   3.  Agrlc.  Food  Chem.   20:
1021-1028.

Krasavage, H.3.,  J.L.  O'Donoghue  and   C.3.  Terhaar.   1979.   Oral  chronic
toxlclty  of  methyl-n-propyl  ketone, methyl   n-butyl  ketone  and  hexane  In
rat.  Toxlcol. Appl. Pharmacol.  (Part 2):  A205.

Krasavage, W.J.,  3.L.  O'Donoghue,  G.D.  D1  Vlncenzo and  C.3.  Terhaar.   1980.
The  relative   neurotoxlclty   of  methyl-n-butyl  ketone,  n-hexane  and  their
metabolites.   Toxlcol. Appl.  Pharmacol.   52(3): 433-441.

Lande,  S.S.,   P.R.  Durkln,  D.H.   Christopher,  P.H.  Howard  and  3.  Saxena.
1976.   Investigation  of  selected   potential  environmental   contaminants:
Ketonlc  solvents.   U.S.  EPA,  Office  of Toxic  Substances,  Washington,  DC.
EPA 560/2-76-003.  p.  292.

Lyman,  W.3.    1982.   Adsorption coefficients  for soil  and  sediments.   In:
Handbook of Chemical Property  Estimation Methods, H.3.  Lyman,  W.F.  Reehl  and
D.H. Rosenblatt, Ed.  McGraw-Hill  Book Co.,  NY.  p.  4-1  to 4-11.

Lyman, H.3.,  W.F.  Reehl  and  O.H.  Rosenblatt.   1982.   Handbook of  Chemical
Property  Estimation  Methods.    Environmental  Behavior  of  Organic  Compounds.
McGraw-Hill Book Co.,  New York, NY.  p.  5-5.

0183d                               -55-                             09/11/89

-------
Mantel,  N.  and  M.A.   Schnelderman.    1975.   Estimating  "safe"  levels,  a
hazardous undertaking.  Cancer Res.  35: 1379-1386.

Mendell, J.R.,  K.  Salda, M.F.  Ganansia  et al.  1974.   Toxic  polyneuropathy
produced by methyl N-butyl ketone.  Science.  185(4153): 787-789.

Morettl,  T.A.   1978.   Acetic  acid  derivatives   (acetyl  chloride).    In:
Klrk-Othmer Encyclopedia  of  Chemical  Technology,  3rd ed., M.  Grayson and D.
Eckroth, Ed.  John Wiley and Sons, Inc., NY.  1:  162-163, 166-167.

Myers,  V.B.   1983.   Remedial  activities  at  the  Miami  drum  site,  Florida.
Natl. Conf. Manage.  Uncontrolled Hazard. Waste Site.  p. 354-357.

NIOSH   (National  Institute  for  Occupational  Safety  and  Health).   1988.
National Occupational  Exposure  Survey  (NOES).   Computer  database  printout.
5-10-88.  p. 53.

NIOSH  (National  Institute  for  Occupational  Safety  and Health).  1989.   RTECS
(Registry  of   Toxic   Effects   of  Chemical   Substances).    2-Hexanone,   CAS
Registry No. 591-78-6.  Online.

OSHA  (Occupational  Safety and Health Administration).   1989.  29  CFR  Part
1910.  A1r  Contaminants; Final Rule.  p. 2940.

Papa, A.J. and  P.O.  Sherman, Jr.  1981.   Ketones.   In,:  Klrk-Othmer  Encyclo-
pedia of Chemical  Technology,  3rd ed.,  M. Grayson and  D.  Eckroth,  Ed.   John
Wiley and Sons, Inc., New York.  13: 894-897,  934-935, 940-941.


0183d                               -56-                             09/11/89

-------
Park,  J.G.  and H.E.  Hofmann.   1932.  Aliphatic  ketones as  solvents.   Ind.
Eng. Chem.  24: 132-134.

Peters,  M.A.,  P.M.  Hudson and  R.L.  D1xon.   1981.   Effect  totlgestatlonal
exposure  to methyl N-butyl  ketone  has  on  postnatal  development  and behavior.
Ecotoxlcol. Environ. Saf.  5:  291-306.

Salda,  K.,  J.R.  Wendell  and  H.S.  Weiss.   1976.   Peripheral  nerve  changes
Induced  by  methyl n-butyl  ketone  and  potentlatlon  by methyl  ethyl  ketone.
J. Neuro. Exper. Neurol.  35(3): 207-225.

Schrenk,  H.H.,  H.P.  Yant  and  F.A.  Patty.   1936.   Acute Response  of  Guinea
Pigs  to  Vapors   of  Some  New  Commercial  Organic  Compounds.   X.  Hexanone
(Methyl   Butyl   Ketone}.   Public   Health   Report,   Vol.   51    p. 624-631.
NIOSH/00129658.

Shelton,  D.R.   and  J.H.  Tledje.    1984.    General  method  for  determining
anaerobic blodegradatlon potential.  Appl. Environ.  Mlcroblol.  47: 850-857.

Smyth, H.F., C.P.  Carpenter, C. Well and  U.C.  Pozzanl.  1954.  Range Finding
Tox1c1ty Data.   List V.  AMA Arch.  Ind. Hyg. Occup.  Med.  10: 61-68.

Specht, H., J.W.  Miller, P.3. Valaer and  R.R.  Sayers.   1940.   Acute Response
of Guinea Pigs to the  Inhalation of  Ketone  Vapors.   Federal  Security Agency,
U.S.  Public  Health  Service,  Washington,  DC.   National Institute  of  Health
Bull. No. 176.
0183d                               -57-                             09/11/89

-------
Spencer,  P.S.  and H.H.  Schaumburg.  1977.   Ultrastructural  studies  of  the
dying-back process.  IV. Differential vulnerability of PNS  and  CNS fibers In
experimental  central-peripheral  distal  axonopathles.   J.  Neuropathol  Exp.
Neurol.  36(2): 300-320.

Spencer,  P.S.,  H.H.   Schaumburg,   R.L.  Raleigh  and  C.J.  Terhaar.   1975.
Nervous  system  degeneration  produced   by  the  Industrial  solvent  methyl
n-butyl ketone.  Arch. Neurol.  32: 219-222.

SRI  (Stanford  Research  Institute).   1988.   1988  Directory  of  Chemical
Producers: United States of America.  SRI International,  Henlo Park, CA.

Swann,  R.L.,  D.A.  Laskowskl,  P.3.  McCall,  K. VanderKuy  and H.3.  Dlshburger.
1983.   A  rapid  method  for  the   estimation  of  the  environment  parameters
octanol/water  partition coefficient, soil  sorptlon  constant,  water  to  air
ratio and water solubility.  Res. Rev.  85: 17-28.

Takeoka,  G.R., R.A.  Flath,  H.  Guntert  and  W.  Jennings.  1988.   Nectarine
volatlles:  Vacuum steam distillation versus  headspace  sampling.   J.  Agrlc.
Food Chem.  36: 553-560.

Thomas,  R.G.   1982.   Volatilization from water.   Irr.  Handbook  of Chemical
Property Estimation Methods, W.O.  Lyman, W.F. Reehl  and  D.H.  Rosenblatt,  Ed.
McGraw-Hill Book Co., NY.  p. 15-1  to 15-34.

Tyl,  R.H.,  K.A.  France, L.C.  Fisher,  et al.   1987.   Developmental toxlclty
of  Inhaled  methyl Isobutyl ketone  In  Fisher 344 rats and  CD-I  mice.   Fund.
Appl. Toxlcol.  8: 310-327.

0183d                                -58-                             09/11/89

-------
U.S.  EPA.   1977.   Computer  print-out  of  non-confidential  production  data
from  the  TSCA  Production  File  for  1977.    U.S.  Environmental  Protection
Agency, Washington, DC.

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

U.S. EPA.   1984.   Methodology and Guidelines for Ranking  Chemicals  Based  on
Chronic  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.  Exams II Computer  Simulation.   Athens, GA.

U.S.  EPA.   1986b.  Reference  Values for  Risk Assessment.  Prepared  by the
Office  of  Health  and  Environmental  Assessment,  Environmental  Criteria  and
Assessment Office, Cincinnati, OH for  the Office of Solid Waste,  Washington,
DC.

U.S.  EPA.   1986c.   Guidelines   for  Carcinogen  Risk  Assessment.   Federal
Register.  51: 33992-34003.

U.S.  EPA/OWRS (Office  of  Water   Regulations  and Standards).   1986.   Guide-
lines for  Deriving Numerical  National  Water  Quality Criteria for  the Protec-
tion  of  Aquatic  Organisms  and Their Uses.   U.S. EPA,  Washington,  DC.  N1IS
PB85-227049/XAB.  p. 22-58, 98.

0183d                               -59-                             09/11/89

-------
USITC  (U.S.  International  Trade  Commission).    1988.    Synthetic   Organic
Chemicals.  U.S. Production and Sales.   USITC Pub!.  2118,  Washington,  DC.

Valshnav, D.D.  1986.  Chemical  structure-blodegradatlon  Inhibition and  fish
acute  toxldty  relationships   for  narcotic  Industrial  chemicals.    Toxic.
Assess.  1(2): 227-240.

Valshnav, D.D., R.S. Boethllng  and  L.  Babeu.  1987.   Quantitative  structure-
blodegradabUHy  relationships  for alcohols,  ketones  and  allcycllc  com-
pounds.  Chemosphere.  16: 695-703.

Verscheuren,  K.   1983.    Handbook  of   Environmental  Data  Organic  Chemicals,
2nd ed.  Van Nostrand Relnhold Co.,  New York. p.  320.

Walllngton,  T.J.  and  M.J.   Kurylo.    1987.   Flash  photolysis   resonance
fluorescence  Investigation  of  the  gas-phase reactions of  OH  radicals  with  a
series of aliphatic  ketones over the   temperature range 240-440  K.  J.  Phys.
Chem.  91: 5050-5054.

Wlndholz, H.,  Ed.   1983.   The Merck Index,  10th ed.   Merck  and  Co.,  Rahway,
NJ.  p. 866.

Yasuhara, A.   1987.   Identification of volatile compounds 1n  poultry manure
by gas chromatography-mass spectrometry.  3. Chromatogr.   387: 371-378.
0183d                               -60-                             09/11/89

-------
                                  APPENDIX A

                             LITERATURE SEARCHED



    This  HEED  Is  based  on  data  Identified  by  computerized  literature

searches of the following:

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


These  searches  were  conducted  In  Hay,   1988,  and  the following  secondary

sources were reviewed:
    ACGIH  (American  Conference of Governmental  Industrial  Hyg1en1sts).
    1986.  Documentation  of  the  Threshold  Limit Values  and  Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH  (American  Conference of Governmental  Industrial  Hyglenlsts).
    1987.  TLVs:  Threshold  Limit  Values for Chemical Substances  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.   John  Wiley  and
    Sons, NY.  2878 p.

    Clayton,  G.D. and   F.E.  Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd  rev.  ed., Vol.  28.   John  Wiley  and
    Sons, NY.  p. 2879-3816.
0183d                               -61-                             09/11/89

-------
    Clayton,   G.O.  and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
    Hygiene and  Toxicology,  3rd  rev.  ed.,  Vol.  2C.    John  Wiley  and
    Sons,  NY.   p.  3817-5112.

    Grayson,  M. and  D. Eckroth,  Ed.   1978-1984.  K1rk-0thmer  Encyclo-
    pedia  of  Chemical Technology, 3rd ed.  John  Wiley and  Sons,  NY.   23
    Volumes.

    Hamilton,  A. and H.L. Hardy.  1974.   Industrial Toxicology,  3rd  ed.
    Publishing Sciences Group, Inc.,  Littleton,  MA.   575  p.

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

    Jaber, H.M.,  W.R.  Mabey,  A.T.  L1eu,  T.W.   Chou and H.L.  Johnson.
    1984.    Data  acquisition   for  environmental  transport   and   fate
    screening  for compounds  of Interest  to  the Office  of  Solid Haste.
    EPA  600/6-84-010.    NTIS  PB84-243906.    SRI  International,   Menlo
    Park,  CA.

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

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

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

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

    U.S.  EPA.   1986.  Report  on Status  Report  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   (U.S.  International  Trade  Commission).    1986.   Synthetic
    Organic Chemicals.   U.S.  Production  and Sales, 1985, USITC  Publ.
    1892,  Washington, DC.

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

    Wlndholz,  M.t Ed.  1983.   The Merck  Index,  10th  ed.   Merck and Co.,
    Inc.,  Rahway,  NJ.

    Worthing,  C.R.  and S.B.  Walker,  Ed.   1983.  The Pesticide  Manual.
    British Crop Protection Council.   695 p.
0183d                               -62-                             09/11/89

-------
    In addition,  approximately 30  compendia of  aquatic  toxlclty data  were

reviewed, Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality  Criteria
    Data  Book.   Volume  3.   Effects  of  Chemicals  on   Aquatic  Life.
    Selected  Data  from the Literature  through  1968.  Prepared  for  the
    U.S. EPA under Contract No. 68-01-0007.  Washington,  DC.

    Johnson,  W.W.  and H.T. Flnley.   1980.   Handbook of  Acute  Toxlclty
    of  Chemicals  to  F1sh and  Aquatic   Invertebrates.   Summaries  of
    Toxlclty  Tests  Conducted  at  Columbia  National Fisheries  Research
    Laboratory.   1965-1978.    U.S.  Dept.  Interior, Fish  and  Wildlife
    Serv. Res. Publ. 137,  Washington, DC.

    HcKee, J.E. and  H.W.  Wolf.  1963.  Water Quality Criteria.  2nd  ed.
    Prepared  for  the  Resources   Agency  of  California,  State  Water
    Quality Control Board.  Publ.  No. 3-A.

    Plmental, D.  1971.   Ecological  Effects  of  Pesticides on Non-Target
    Species.  Prepared for the U.S.  EPA, Washington, DC.   PB-26960S.

    Schneider, B.A.   1979.  Toxicology  Handbook.   Mammalian  and Aquatic
    Data.  Book 1:  Toxicology  Data.   Office  of  Pesticide  Programs, U.S.
    EPA, Washington, OC.  EPA 540/9-79-003.  NTIS PB 80-196876.
0183d                               -63-                             09/11/89

-------
                                  APPENDIX B



                         Summary Table for 2-Hexanone
                    Species    Exposure    Effect    RfD or q-j*    Reference
Inhalation Exposure
Subchronlc ID
Chronic ID
Cardnogenlclty 10
Oral Exposure
Subchronic 10
Chronic ID
Cardnogenlclty ID
REPORTABLE QUANTITIES
Based on Chronic Toxlclty:
Based on Cardnogenlclty:

ID ID
ID ID
ID ID

ID ID
ID ID
ID ID

100
ID

ND ID
NO ID
ND ID

ND ID
ND ID
ND ID

Johnson
et al.,
1977, 1979
ID
ID - Insufficient data; ND = not derived
0183d
-64-
09/11/89

-------
                                  APPENDIX C
           DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 2-HEXANONE
C.I.   DISCUSSION
    Dose/duration-response  graphs  for   Inhalation   and   oral   exposure  to
2-hexanone  generated  by  the  method  of  Crockett et  al.  (1985)  using  the
computer  software  by  Durkln  and Meylan  (1988)  developed under contract  to
ECAO-C1nclnnat1  are  presented  In  Figures  C-l,  C-2 and  C-3.   Data  used  to
generate  these  graphs are  presented  1n  Section  C.2.   In the  generation  of
these figures,  all  responses are  classified  as  adverse  (FEL,  AEL  or LOAEL)
or  nonadverse  (NOEL  or  NOAEL)  for  plotting.   For  Inhalation exposure  the
ordlnate  expresses  concentration 1n either of  two ways.   In Figure  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/ma)].   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
Schnelderman, 1975)  to  estimate an equivalent human  or  scaled  concentration
[scaled  cone  (mg/m3).  For  oral exposure  the  ordlnate 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  In  basal metabolic  rate  (Mantel  and Schnelderman, 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
exposure  at  which  an adverse  effect  occurred.   From  this  point an  Infinite


0183d                               -65-                             09/11/89

-------
    imeee
     imee•-
i
6
hi
          e.aeei
(Inhalation Exposure)
                   e.eei             9.01              e.i
                    HUMAN EQUIU DURATION (fraction  lifespan)
                               ENVELOP HtTMOt
 Key:
F . FEl
L « LOAEL
N - NOAEL
 Solid line * Adverse Effects Boundary
 Dashed line « No Adverse Effects Boundary
                                   FIGURE  C-l

      Dose/Duration Response Graph for Inhalation Exposure to 2-Hexanone,
                      Expanded Experimental Concentration
0183d
                             -66-
09/11/89

-------
      18008
 E
 V
 o
 w

 V
          9.8991
on  Exposure>
                   e.eei             e.ei              e.i
                    HUMAN EQUIO  DURATION  (fraction lifespan)
                               EWELOP  rETHOI>
 Key:
F » FEL
L « LOAEL
N - NOEL
 Solid  line  -  Adverse Effects Boundary
 Dashed line « No Adverse Effects Boundary
                                    FIGURE C-2

       Dose/Duration Response Graph  for  Inhalation Exposure to 2-Hexanone,
                               Scaled Concentration
 0183d
                              -67-
09/11/89

-------
 •«


 »
 W
 VI
 o
 e
 1

      10000~ ~
           8.8081
<0i*»l Exposure)
                                                             T2
                                                          F4
                                                                            LI
                                         I •  I 1 I 1
                                                                 4-
                    e.eei             e.ei              0.1

                     HUMAN EQUIU DURATION (fraction lifespan)

                               ENVELOP HFTHOD
 Key:
F . FEL

L - LOAEL
 Solid line « Adverse  Effects Boundary
 Dashed line = No Adverse  Effects Boundary
                                   FIGURE C-3


      Dose/Duration Response Graph  for  Inhalation  Exposure to 2-Hexanone,

                                Envelope  Method
0183d
                             -68-
09/11/89

-------
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 concen-
tration 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
1s  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 concen-
tration.   From  this  point a  line  parallel  to  the duration axis  1s  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
1s 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  ends  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 It  does  not  Intersect the  adverse effects
boundary and  no  region of contradiction  1s  generated.  This method results
in the most conservative definition of the no-adverse effects  region.
    Figures C-l  and  C-2  present  dose/duration-response graphs for Inhalation
exposure drawn by the envelope method.   Figure  C-l  presents  results  using  an
expanded  experimental  concentration.   The adverse  effects   boundary  1s

0183d                               -69-                             09/11/89

-------
defined  by  several  experimental  points  (Recs.  #1,  5,  8)  associated  with
peripheral neuropathy  (Johnson et  al., 1977,  1979;  Hendell  et al.,  1974;
Duckett  et  al.,  1979)   In  the rat,  cat  and monkey.   The adverse  effects
boundary also Includes studies that reported  eye and  upper  respiratory tract
Irritation  (Rec.  #12) and  mortality  (Rec.  #13)   In  acutely exposed  guinea
pigs  (Schrenk  et  al.,.  1936;  Specht  et  al.,  1940).   The  only  nonadverse
effect  point  {Rec.  #16)  was  a  NOEL  for  lethality  1n  rats (Smyth et  al.,
1954).
    Figure C-2  presents  the graph redrawn so that  the  data  are expressed as
scaled  concentration.  Scaling excluded from the  adverse effects  boundary a
PEL for  peripheral neuropathy  In  cats  (Rec.  #5) but Included a PEL (Rec. #6)
for  neuropathy  In  rats   (Duckett  et  al.,  1974)   and a  PEL  (Rec. #10)  for
mortality In rats (Smyth et al., 1954).
    Figure  C-3  presents  the  dose/duration-response  graph  generated  by  the
envelope method for  oral  exposure.   The adverse effects  boundary  Is  defined
by  lethality  data  In guinea pigs  (Rec. #8)  and mice (Rec.  #7) and  a LOAEL
(Rec.  #3)  for  Impaired  pupillary  response  1n  guinea  pigs   (NIOSH,  1979;
Abdel-Rahman et al.,  1978).  There  were no nonadverse points to plot;  there-
fore, only an adverse effects region and a region  of ambiguity are defined.
C.2.    DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Inhalation Exposure
Chemical Name:    2-Hexanone
CAS Number:       591-78-6
Document Title:   Health and Environmental Effects  Document on 2-Hexanone
Document Number:  pending
Document Date:    pending
Document Type:    HEED
0183d                               -70-                             09/11/89

-------
RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Monkeys
Male
PEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
73.0
41.0 weeks.
41.0 weeks
Number Exposed:     8
Number Responses:   NR
Type of Effect:     NEURP
Site of Effect:     PNS
Severity Effect:    8

TOO ppm (410 mg/m3), range: 100 or 1000 ppm 6 hours/day,
5 days/week; decreased motor nerve conduction velocity,  hind-
limb drag.

Johnson et al., 1977, 1979
RECORD #2: Species: Rats
Sex: Male
Effect: FEL



Dose: 73.0
Duration Exposure: 29.0 weeks
Duration Observation: 29.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10
NR
NEURP
PNS
8





Comment:       100 ppm (410 mg/m3}, range:  100 or  1000 ppm 6 hours/day,
               5 days/week; decreased motor nerve  conduction velocity,  hind-
               limb drag.                   *

Citation:      Johnson et al., 1977, 1979
RECORD #3: Species: Rats
Sex: NR
Effect: FEL
Route: Inhalat.1
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:



on
6
NR
NEURP
PNS
8
Dose:
Duration
Duration

6
NR
NEURP
CNS
8

Exposure:
Observation:

6
NR
MGTDC
BODY
3
951.0
4.0 months
4.0 months






Comment:       1300 ppm (5325 mg/m3) 6 hours/day,  5 days/week;  hlndllmb
               drop, PNS and CNS nerve fiber damage, loss  of body weight,

Citation:      Spencer et al., 1975
0183d
                     -71-
                                           09/11/89

-------
RECORD #4:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
FEL
Inhalation
Dose:
Duration Exposure:
Duration Observation:
1639.0
12.0 weeks
12.0 weeks
Number Exposed:     4
Number Responses:   NR
Type of Effect:     NEURP
SHe of Effect:     PNS
Severity Effect:    8

400 ppm (1639 mg/m3) continuous;  hlndllmb drag and giant
axonal swelling.

Mendell et al., 1974
RECORD #5: Species: Cats
Sex: NR
Effect: FEL



Dose: 1639.0
Duration Exposure: 12.0 weeks
Duration Observation: 12.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
4
NR
NEURP
PNS
8





Comment:       400 ppm (1639 mg/m3); hlndllmb drag,  axonal  swelling,
               altered EMG.

Citation:      Wendell et al., 1974
RECORD #6:



Species:
Sex:
Effect:
Route:
Rats
NR
FEL
Inhalation
Dose:
Duration
Duration


Exposure:
Observation:

195.0
6.0 weeks
6.0 weeks

Comment:


Citation;
Number Exposed:     9
Number Responses:   NR
Type of Effect:     NEURP
Site of Effect:     PNS
Severity Effect:    8

200 ppm (819 mg/m3} 8 hours/day,  5 days/week;  peripheral
neuropathy (hlndllmb drag), axonal degeneration.

Duckett et al., 1974
0183d
                     -72-
                                           09/11/89

-------
RECORD #7;
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
LOAEL
Inhalation
Dose:                  1639.0
Duration Exposure:     6.0 weeks
Duration Observation:  6.0 weeks
Number Exposed:     12
Number Responses:   NR
Type of Effect:     NEURP
Site of Effect:     PNS
Severity Effect:    7

400 ppm (1639 mg/m3) continuous; paralysis, axonal
degeneration, demyellnatlon.

Salda et al.t 1976
RECORD #8: Species: Rats
Sex: NR
Effect: PEL
Route: Inhalat
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:



Ion
40
NR
NEURP
PNS
8
Dose: 49.0
Duration Exposure: 6.0 months
Duration Observation: 6.0 months






Comment:       50 ppm (205 mg/m3) 8 hours/day, 5 days/week;  decreased motor
               nerve conduction velocity, 32/40 rats had demyellnatlon of
               sciatic nerve, 2/40 had axonal degeneration.

Citation:      Ouckett et a!., 1979
RECORD #9: Species: Rats
Sex: Hale
Effect: PEL
«
Dose:
Duration Exposure:
Duration Observation:
1229.0
11.0 weeks
11.0 weeks
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
15
NR
NEURP
PNS
8
15 15
NR NR
WGTDC WGTDC
TESTE BODY
4 4


Comment:
Citation:
700 ppm (2868 mg/ma) 72 hours/168 hours; decreased body
weight gain, depletion of adipose tissue and atrophy of hind-
limb musculature.  A significant depression In testlcular
weight was noted.

Katz et al., 1980
0183d
                     -73-
                                           09/11/89

-------
RECORD #10:

Comment:
Citation:
RECORD #11:

Species: Rats Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed: 6
Number Responses: 6
Type of Effect: DEATH
SHe of Effect: BODY
Severity Effect: 10
8000 ppm (32,772 mg/m3) for 4 hours; lethal to 6/6.
Smyth et al . , 1954
Species: Guinea pigs Dose:
Sex: NR Duration Exposure:
Effect: PEL Duration Observation:
Route: Inhalation
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
5462.0
1.0 days
1.0 days



24579.0
3.0 days
3.0 days

Comment:       6000 ppm (24579 mg/m3); lethal to all animals by 72 hours
               of exposure.

Citation:      Specht, 1940
RECORD #12: Species: Guinea
Sex: NR
Effect: LOAEL
pigs


Dose:
Duration Exposure:
Duration Observation:
4097.0
0.6 days
0.6 days
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
NR
NR
IRRIT
EYE
9
NR
NR
IRRIT
NASAL
9





Comment:       1000 ppm (4097 mg/m3) for up to 810 minutes (range 1000,
               2300, 6500 or 20,000 ppm); nasal and ocular Irritation;
               mortality at 6500 ppm.

Citation:      Schrenk et al., 1936
0183d
-74-
09/11/89

-------
RECORD #13:
Comment:
Citation:
RECORD #14:

Comment:
Citation:
RECORD #15:

Species: Guinea pigs Dose: 8909.0
Sex: NR Duration Exposure: 0.4 days
Effect: PEL Duration Observation: 0.4 days
Route: Inhalation
Number Exposed: 10
Number Responses: 7
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
6000 ppm (24,579 mg/m3) up to 525 minutes.
Specht et al., 1940
Species: Rats Dose: 2458.0
Sex: NR Duration Exposure: 9.0 days
Effect: LOAEL Duration Observation: 9.0 days
Route: Inhalation
Number Exposed: 11
Number Responses: NR
Type of Effect: NEURP
SHe of Effect: PNS
Severity Effect: 8
600 ppm (2458 mg/m3) continuous; neuropathologlcal
Spencer and Schaumberg, 1977
Species: Rats Dose: 922.0
Sex: NR Duration Exposure: 66.0 days
Effect: FEL Duration Observation: 66.0 days
Route: Inhalation
Number Exposed: 12
Number Responses: NR
Type of Effect: NEURP
SHe of Effect: PNS
Severity Effect: 8
Comment:       225 ppm (922 mg/m3) continuous;  paralysis,  axonal
               degeneration, demyellnatlon.

Citation:      Salda et al., 1976
0183d
-75-
09/11/89

-------
RECORD #16:
Species:
Sex:
Effect:
Route:
Rats
NR
NOEL
Inhalation
Dose:                  2731.0
Duration Exposure:     1.0 days
Duration Observation:  1.0 days
Comment:

Citation:
Number Exposed:     6
Number Responses:   0
Type of Effect:     DEATH
SHe of Effect:     BODY
Severity Effect:    10

4000 ppm (16386 mg/m3) for 4 hours; no lethality,

Smyth et al., 1954
Oral Exposure
Chemical Name:
CAS Number:
Document Title:
Number:
Document Date:
Document Type:
   2-Hexanone
   591-78-6
   Health and Environmental
   pending
   pending
   HEED
                 Effects Document on 2-Hexanone
RECORD #1:



Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Water
Dose:
Duration
Duration


Exposure:
Observation:

350.0
10.0 months
10.0 months

Comment:
Citation:
Number Exposed:     NR       NR
Number Responses:   NR       NR
Type of Effect:     NEURP    WGTDC
Site of Effect:     PNS      BODY
Severity Effect:    8        3

0.25% (range: 0.25, 0.5, 1.0%); 350, 700 and 1400 mg/kg/day.
Decreased body weight at all doses.  Signs of neuropathy at
the two highest dose levels, morphologic changes at all  doses

Krasavage et al., 1979
0183d
                     -76-
                                           09/11/89

-------
RECORD #2:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Water
Dose:                  1000.0
Duration Exposure:     120.0-days
Duration Observation:  120.0 days
               Number Exposed:      NR
               Number Responses:    NR
               Type of Effect:      NEURP
               Site of Effect:      PNS
               Severity Effect:     8
Comment:
Citation:
RECORD #3:
1000 mg/kg/day; continuous for 120 days; muscle weakness and
atrophy, neuropathology.
Homan and
Species:
Sex:
Effect:
Route:
Maronpot (1978)
Guinea pigs
NR
LOAEL
Water

Dose:
Duration Exposure:
Duration Observation:

100.0
24.0 weeks
24.0 weeks
Number Exposed:     5        5
Number Responses:   NR       NR
Type of Effect:     FUNP     WGTIN
Site of Effect:     EYE      BODY
Severity Effect:    7        3

0.1% (range: 0.1, 0.25%, doses 100,  250 mg/kg/day)  estimated
from data provided; Impaired pupillary response,  altered
locomotor activity measured only at  0.25%.

Abdel-Rahman et al. (1978)
RECORD #4:



Species:
Sex:
Effect:
Route:
Rats
Male
FEL
Gavage
Dose:
Duration
Duration


Exposure:
Observation:

429.0
90.0 days
90.0 days

Comment:
Citation;
5
NR
NEURP
PNS
8
5
NR
ATROP
TESTE
4
5
NR
MGTOC
BODY
4
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
600 ppm (2458 mg/m3); 5 days/week;  severe hlndleg footdrop,
paralysis, and decrease In weight gain,  and testlcular
atrophy were reported.

Krasavage et al., 1980
0183d
                     -77-
                                           09/11/89

-------
RECORD #5:
Comment:
Citation:
RECORD #6:
Comment:
Citation:
RECORD #7:
Comment:
Citation:
Species: Rats Dose: 2590.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SUe of Effect: NR
Severity Effect: 10
1050 value, details not provided.
Smyth et a!., 1954
Species: Mice Dose: 2430.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: MR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 10
LDgo value, details not provided.
NIOSH, 1989
Species: Mice Dose: 1000.0
Sex: NR Duration Exposure: 1.0 days
Effect: PEL Duration Observation: 1.0 days
Route: Oral (NOS)
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
SUe of Effect: NR
Severity Effect: 10
I.DLO value, details not provided.
NIOSH, 1979
0183d
-78-
09/11/89

-------
RECORD #8:     Species:    Guinea pigs       Dose:-                  914.0
               Sex:       NR                Duration Exposure:      1.0 days
               Effect:    PEL               Duration Observation:  1.0 days
               Route:     Oral (NOS)

               Number Exposed:     NR
               Number Responses:   NR
               Type of Effect:     DEATH
               Site of Effect:     NR
               Severity Effect:    10

Comment:       LQ|_Q value, details not provided.

Citation:      NIOSH, 1979
NR = Not reported
0183d                               -79-                             09/11/89

-------
         UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

                       WASHINGTON. D.C  20460
                           MAYI°
SUBJECT:  Health and Environmental Effects Document
          for 2-Hexaaon*
                                                          OF
                                                      AND DEVELOPMENT
FROM:     William H. Farland, Ph.D.
          Director
          Office of Health and Environmental
            Assessment (RD-689)

TO:       Matthew Straus
          Chief, Waste Characterization Branch
            Office of Solid Waste  (WH-562B)

        I am forwarding copies of the Health and Environmental
Effects Document for 2-H«x*non« (ECAO-Cin-G068).

        The HEEDs support, listings under RCRA, as well as, provide
health-related limits and goals for emergency and remedial
actions under CERCLA.  These documents represent scientific
summaries of the pertinent available data on the environmental
fate and mammalian and aquatic toxicity of each chemical at an
extramural effort of about $10K.  The attached document has been
reviewed within OHEA, by staff in OPP and OTS, and by two
external scientists.
                                                 •
        Should you wish to see any of the files related to the
development of the HEEDs, please call Chris DeRosa at FTS:
6B4-7531.

Attachment

-------
                             DATE:
                      ROUTE SLIP

         K. Bruneske  (OS-305)
         M. Callahan  (RD-689)
         P. Durkin (SRC)
         R. Hardesty  (RD-689)
         B. Hostage (OS-210)
         S. Irene (OS-33-)
         E. HcNamara  (PM-
         J. Moore (RD-689)
         M. Pfaff (RD-689)
         C. Ris (RD-689)
         R. Rubenstein  (OS-330)
         R. Scarberry (OS-330)
         C. Zamuda (OS-240)
.

-------