TECHNICAL REPORT DATA
                            ffteme irtd Instructions on the rtvtrte btfort completing)
1. R6PORT NO.
  EPA/60Q/8-89/093
             3. RECIPIENT'S ACCESSION NO
                PB90-142456/AS
4. TITLE ANDSUmTLE
  Updated  Health Effects Assessment for Methyl Ethyl

  Ketone
                                                           S. REPORT DATE
             t. PERFORMING ORGANIZATION CODE
 . AUTHOR(S)
                                                           I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
                                                           10. PROGRAM ELEMENT NO.
                                                           11. CONTRACT7GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
 Environmental Criteria  and Assessment Office
 Office of Research and  Development
 U.S. Environmental Protection Agency
 Cincinnati. OH   45268	
             13. TYPE OF REPORT AND PERIOD COVERED
             14. SPONSORING AGENCY CODE
                EPA/600/22
15 SUPPLEMENTARY NOTES
16. ABSTRACT
   This report  summarizes and evaluates information  relevant to a preliminary  interim
 assessment of  adverse health effects associated  with  specific chemicals or compounds.
 The Office of  Emergency and Remedial Response  (Superfund) uses these documents  in
 preparing cost-benefit analyses under Executive  Order J2991 for decision-making under
 CERCLA.  All estimates of acceptable intakes and carcinogenic potency presented in
 this document  should  be considered as preliminary and reflect limited resources
 allocated to this  project.  The intent in these  assessments is to suggest acceptable
 exposure levels whenever sufficient data are available.   The interim values presented
 reflect the relative  degree of hazard associated with exposure or risk to the
 chemical(s) addressed.  Whenever possible, two categories of values have been
 estimated for  systemic toxicants (toxicants for  which cancer is not the endpoint of
 concern).  The first, RfD$ or subchronic reference  dose, is an estimate of an exposure
 level that would not  be expected to cause adverse effects when exposure occurs  during
 a limited time interval.  The RfD is an estimate of an exposure level that would not
 be expected to cause  adverse effects when exposure  occurs for a significant portion
 of the lifespan.   For compounds for which there  is  sufficient .evidence of
 carcinogenicity, qi*s have been computed, if appropriate, based on oral and
 inhalation data if available.
                               KEY WORDS AND DOCUMENT ANALYSIS
                 DESCRIPTORS
                                              b.IDENTIFIERS/OPEN ENDED TERMS
                           C. COSATI Field/Croup
 •. DISTRIBUTION STATEMENT

  Public
19. SECURITY CLASS (Thu Report I

  Unclassified
                           21. NO. OF PAGES
                                              20. SECURITY CLASS
                                                Unclassified
                           22. PRICE
IP4 Pan* 2220.1 (IU*. 4-77)   PHCVIOUI COITION i* OMOkKTK

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                                            EPA/600/8-89/093
                                            February, 1989
          HEALTH EFFECTS ASSESSMENT
           FOR METHYL ETHYL KETONE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
     OFFICE OF RESEARCH AND DEVELOPMENT
    U.S. ENVIRONMENTAL PROTECTION AGENCY
            CINCINNATI,  OH  45268

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                                  DISCLAIMER

    This  document  has  been  reviewed  In  accordance with  the  U.S.  Environ-
mental  Protection  Agency's   peer   and administrative  review  policies  and
approved  for  publication.   Mention of  trade names  or commercial  products
does not constitute endorsement or  recommendation for use.
                                      11

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                                    PREFACE
    This report  summarizes  and evaluates Information relevant  to  a prelimi-
nary  Interim  assessment  of adverse  health effects  associated with  methyl
ethyl ketone.   All  estimates  of acceptable Intakes and  carcinogenic  potency
presented 1n  this  document  should be  considered  as preliminary and  reflect
limited  resources   allocated   to  this  project.    Pertinent  toxlcologlc  and
environmental  data  were located  through  on-Hne  literature searches  of  the
TOXLINE, CANCERLINE  and the CHEMFATE/OATALOG data  bases.  The  basic  litera-
ture  searched supporting  this  document  1s  current up to  May,  1985.   Secon-
dary sources of  Information have  also  been  relied  upon  In the  preparation of
this  report and represent  large-scale health assessment  efforts that  entail
extensive  peer   and Agency  review.    The  following  Office  of  Health  and
Environmental  Assessment (OHEA) sources have been  extensively utilized:

    U.S.  EPA.   1983.    Reportable  Quantity  Document   for   2-Butanone
    (Methyl  Ethyl   Ketone).   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.    1985a.   Health and  Environmental  Effects Profile  for
    Methyl Ethyl Ketone.  Prepared by  the Office  of Health and  Environ-
    mental  Assessment,  Environmental  Criteria and Assessment  Office,
    Cincinnati,   OH  for  the   Office   of   Solid   Waste   and  Emergency
    Response,  Washington,  DC.

    The Intent  In these assessments 1s  to suggest  acceptable exposure  levels
for   noncardnogens  and  risk cancer   potency   estimates  for  carcinogens
whenever sufficient  data were  available.   Values  were not derived  or  larger
uncertainty factors  were employed  when  the  variable data  were limited  in
scope   tending   to   generate   conservative  (I.e.,   protective)   estimates.
Nevertheless,  the  Interim  values  presented reflect  the relative  degree  of
hazard or risk associated with  exposure to the  chemical(s) addressed.

    Whenever  possible,  two  categories  of  values  have  been   estimated  for
systemic  toxicants   (toxicants for  which  cancer  is  not  the  endpoint  of
concern).  The  first,  RfD$  (formerly  AIS)  or  subchronic  reference dose,  1s
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  lifespan).
This  type of  exposure  estimate has not been extensively  used,  or  rigorously
defined, as  previous risk  assessment efforts have been  primarily  directed
towards  exposures  from  toxicants in  ambient  air  or water  where  lifetime
exposure  is  assumed.    Animal   data   used  for   RFD§   estimates   generally
include exposures with  durations  of  30-90  days.   Subchronic human data  are
rarely available.   Reported exposures  are usually  from  chronic occupational
exposure  situations  or  from   reports  of acute accidental exposure.   These
values  are   developed   for   both   Inhalation   (RfDgj)   and   oral
exposures.
                                      111

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                                   ABSTRACT
    In  order  to  place the  risk assessment  evaluation  In  proper  context,
refer  to  the preface  of  this  document.   The  preface outlines  limitations
applicable to all documents of  this  series as well  as  the appropriate Inter-
pretation and use of the quantitative estimates  presented.

    A number of  subchronlc Inhalation studies using  experimental  animals  are
available, which  suggest  threshold  exposure  levels for liver  damage,  neuro-
logical Impairment  and fetotoxldty.  An RfDg  of  3.0  mg/day was based on  a
NOAEL of  235 ppm from a subchronlc  Inhalation  study and  was  verified by  the
U.S. EPA  (1985b).   No  chronic exposure data and no  oral  data were available;
however,  an  RfD$o  of  32  mg/day,  an RfD$i  of   64  mg/day and  an RfDj of  6
mg/day  were  estimated based   on   the  subchronlc  Inhalation  data.   These
estimates should be reviewed when adequate chronic  data  become available.   A
CS  of  9.6 was  calculated for  methyl  ethyl  ketone  based on  decreased  body
weight gain In rats exposed by Inhalation.

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                               ACKNOWLEDGEMENTS
   .The  Initial  draft  of  this  report  was  prepared  by. Syracuse  Research
Corporation under  Contract No.  68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen Ball  was the Project
Officer.  The final documents  In this  series  were  prepared  for the Office of
Emergency and Remedial Response,  Washington, DC.

    Scientists from  the  following  U.S. EPA offices  provided  review  comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment  Group
         Office of A1r Quality  Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by the following:

    Judith Olsen and Erma Durden
    Environmental Criteria and  Assessment Office
    Cincinnati, OH

Technical  support  services  for   the   document  series  was  provided  by  the
following:

    Bette Zwayer, Pat Daunt, Karen  Mann and Jacky Bohanon
    Environmental Criteria and  Assessment Office
    Cincinnati, OH
                                      v1

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                         TABLE OF  CONTENTS

1.
2.


3.










4.




5.
6.







ENVIRONMENTAL CHEMISTRY AND FATE. 	 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL .... 	
2.2 INHALATION 	 ..........
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	 . .
3.1. SUBCHRONIC 	 ..............
3.1.1. Oral 	 	 	
3.1.2. Inhalation. 	 .........
3.2. CHRONIC 	 	 	 	 	
3.2.1. Oral. 	 	 	 	
3.2.2. Inhalation 	
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. ...................
3.3.2. Inhalation. ................
3:4. TOXICANT INTERACTIONS 	 	
CARCINOGENICITY 	
4.1. HUMAN DATA 	 	 	 	
4.2. BIOASSAYS 	
4.3. OTHER RELEVANT DATA 	 	
4.4. WEIGHT OF EVIDENCE 	
REGULATORY STANDARDS AND CRITERIA 	
RISK ASSESSMENT 	
6.1. SUBCHRONIC REFERENCE DOSE (RfDs) 	
6.1.1. Oral (RfDso) 	
6.1.2. Inhalation (RfDSi) 	
6.2. REFERENCE DOSE (RfD). ..... 	
6.2.1. Oral (RfD0) 	
6.2.2. Inhalation (RfDi) 	
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 4
4
. . . 4
4
. . . 6
. . . 6
6
. . . 6
. . . 6
. . . 6
. . . 8
9
. . . 9
. . . 9
. . . 9
. . . 9
. . . 11
. . . 12
. . . 12
. . . 12
12
, , . 13
... 13
... 14
6.3.   CARCINOGENIC POTENCY (q-|*) ................    14

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                           TABLE  OF  CONTENTS  (cont.)
                                                                        Page
 7.  REFERENCES	   15
APPENDIX:  Summary Table for Methyl Ethyl Ketone	   21

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                            LIST  OF ABBREVIATIONS

ADI            .         Acceptable dally Intake
CAS                     Chemical Abstract Service
CS                      Composite score
Koc                     Soil sorptlon  coefficient
Kow                     Log octanol/water partition coefficient
LOAEL                   Lowest-observed-adverse-effect level
MED                     Minimum effective dose
NOAEL                   No-observed-adverse-effect  level
ppm                     Parts  per million
RfD                     Reference dose
RfDi                    Inhalation reference dose
RfDn,                    Oral reference dose
RFD$                    Subchronlc reference dose
RFD$i                   Subchronlc Inhalation reference dose
                        Subchronlc oral reference dose
                        Dose-rating value
RVe                     Effect-rating  value
STEL                    Short-term exposure limit
TLV                     Threshold limit value
TWA                     Time-weighted  average
                                      1x

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                     1.   ENVIRONMENTAL CHEMISTRY AND FATE

    The relevant  physical  and  chemical properties and environmental  fate  of
methyl ethyl ketone (CAS No.  78-93-3)  are summarized below.

Chemical class:                aliphatic  ketone
Molecular weight:              72.1                     Verschueren,  1983
Vapor pressure at 20°C:         77.5  mm Hg              Verschueren,  1983
Water solubility at 20°C:      268 g/8,                 Papa  and Sherman, 1981
Log Kow:                       0.29                     Hansch and Leo, 1985
Koc:                           4.5-50  (estimated)      U.S.  EPA, 1985a
Bloconcentratlon factor         0.5-1 (estimated)       U.S.  EPA, 1985a
Half-life 1n air:              14-15 hours             Graedel, 1978;
                                                       U.S.  EPA, 1985a
        1n water:              few days                U.S.  EPA, 1985a

    The primary  removal  mechanism  for atmospheric  methyl ethyl  ketone will
be direct photolysis (U.S. EPA, 1985a).   Detection  of  methyl  ethyl  ketone  In
rain, cloudwater  and airborne  partlculate matter  suggests that small  amounts
of  this compound  may  also  be removed  from  the atmosphere  by wet  and  dry
deposition (U.S. EPA, 1985a).
    In  water,  methyl  ethyl ketone  1s  expected to be  removed  by evaporation
(half-life  of  3-12  days)  and   blodegradatlon   (half-life  >3  days)  (NLM,
1987).   Direct photolysis near  water surfaces  may also be  possible  (U.S.
EPA,  1985a).   Bloconcentratlon   In  aquatic   organisms   and  adsorption  to
sediments are not expected to be Important fate processes (U.S. EPA, 1985a).
0003H                               -1-                              03/01/89

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    The half-life of methyl  ethyl  ketone  1n soil  could not be located In the
literature  searched.   By  analogy  to  aquatic  media,  the  dominant  fate
processes 1n soil are expected  to  be  volatilization and blodegradatlon (NLM,
1987;  U.S.  EPA,  1985a).  Methyl ethyl  ketone residue  may  be susceptible to
significant leaching  (NLM,  1987; U.S.  EPA,  1985a).  It has  been speculated
that the half-life of methyl  ethyl  ketone In soil would be on the order of a
few days.
0003H                               -2-                              03/01/89

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           2.  ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1.   ORAL
    Quantitative data on the  oral  absorption of  methyl ethyl  ketone  are  not
available,  but   absorption   from   the  gastrointestinal  (GI)  tract  can   be
Inferred   from    systemic    toxic   effects   observed   after   acute  oral
administration  (Lande et al., 1976).  In male  rats,  the peak  blood  level  of
methyl ethyl  ketone  (0.95  rag/ml)  was reached  within 4 hours  following oral
administration  of  a 1690  mg/kg dose of  the  compound  1n water,  Indicating
rapid absorption  from  the  GI tract (D1etz  et  al.,  1981; D1etz  and  Tralger,
1979).
2.2.   INHALATION
    PerbelUnl  et  al.  (1984)  reported a mean  blood  concentration of  methyl
ethyl  ketone  of   2630+2450  yg/1  (range:  842-9573  yg/l)  1n   workers
exposed to  methyl  ethyl  ketone and several  other  compounds and that  70% of
the  Inhaled methyl  ethyl  ketone  was  retained 1n the  alveolar space.   The
environmental concentration correlated  significantly with the  alveolar con-
centration  of methyl ethyl  ketone, which  1n  turn   correlated  significantly
with blood  levels.  At the end  of  an  8-hour  work  shift, the urine  of  workers
exposed to  a  mean  concentration of methyl  ethyl  ketone In  the air  of  10H67
vg/2,  contained   a  mean   concentration  of  487+277   ^g/a   (PerbelUnl   et
al.,  1984).  Mlyasaka  et  al.  (1982) reported  that the  urinary  levels  of
methyl ethyl  ketone  rose rapidly  during the first 2 hours  of  an 8-hour work
shift 1n  occupatlonally  exposed workers and  the  levels correlated with  the
measured  levels  1n the air.   Therefore, pulmonary absorption  of methyl ethyl
ketone appears to occur rapidly during occupational exposure.
0003H                               -3-                              11/22/88

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                3.   TOXICITY  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
3.1.   SUBCHRONIC
3.1.1.   Oral.   Pertinent  data  regarding  the  effects  of  oral  exposure  to
methyl ethyl  ketone on  humans  or experimental  animals were not  located  In
the available literature.
3.1.2.   Inhalation.   The subchronlc   Inhalation  studies  on  methyl  ethyl
ketone are  summarized  In  Table  3-1.   Cavender et  al. (1983)  exposed  both
sexes  of  Fischer 344  rats to  methyl  ethyl  ketone  at  concentrations of  0,
1250,  2500  or  5000 ppm (0, 3687,  7373  or  14,746 mg/m3),  6  hours/day,  5
days/week for 90 days.   There were no  treatment-related  effects at the  1250
ppm  level;  SGPT  activity 1n  female rats was  elevated at  the  2500 ppm level.
At  the 5000 ppm level,  effects were more  severe:   these  Included depressed
mean  body  weight;  slight   but   significant  Increases   In   liver  weight,
I1ver-to-body weight  ratio,   and  I1ver-to-bra1n weight ratio;  significantly
decreased SGPT  activity; and  Increased alkaline phosphatase,  potassium and
glucose values 1n treated females.
    Exposure  of  Wlstar  rats   to  methyl  ethyl  ketone at a  level of  0 or 200
ppm  (0  or  590  mg/m3),  12  hours/day,   7  days/week  for  24 weeks  reportedly
resulted  In  slight  neurological  effects  of  unknown   biologic  significance
measurable  only  at 4  months of  treatment (Takeuchl et  al.,  1983),  but  In
another study using rats exposed  to 1125  ppm  (3318 mg/m3) continuously for
5  months  did not  result 1n  neuropathy,  as  Indicated  by  absence  of paral-
ysis  (Salda et   al.,  1976).   In  both   studies,  only a single  toxlcological
endpoint was  examined,  such  as  motor nerve conduction  velocity,  mixed nerve
conduction  velocities,  or  distal  motor  latency (Takeuchl  et  al.,  1983)  or
paralysis (Salda et al., 1976).
0003H                               -4-                              11/21/88

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    LaBelle and  Brleger  (1955) observed  no  effects of exposure  to  0  or 235
ppm (0  or  693 mg/m3) of methyl  ethyl  ketone, 7 hours/day,  5  days/week, for
12 weeks, on  growth,  hematologlcal  or pathological parameters  of a  group of
25 rats.  Although the growth  of  the  rats In the exposed group was less than
the controls,  no  statistical  analysis   was  provided.   Information  on the
specific  organs   evaluated  pathologically  was  not  provided.    Guinea  pigs
presumably exposed to the same  level  exhibited  no  adverse effects on growth,
hematology or  hlstopathology  from the treatment.   Similarly,  exposure to 0,
125, 250, 500  or  1000 ppm of the compound for 30  days  had  no  effect on rats
and guinea pigs  (Mellon  Institute,  1950); however, details  of  exposure were
not provided.
3.2.   CHRONIC
3.2.1.    Oral.   Pertinent  data  regarding  the  chronic  oral  toxlclty  of
methyl   ethyl  ketone  to  humans  or experimental  animals were not  located In
the available  literature.
3.2.2.    Inhalation.    Pertinent  data   regarding   the   chronic   Inhalation
toxlclty of methyl  ethyl ketone  to  humans  or experimental  animals  were not
located In the available literature.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE  EFFECTS
3.3.1.    Oral.  Pertinent data  regarding  the teratogenlclty of methyl  ethyl
ketone  following oral   administration  were  not  located  In   the  available
literature.
3.3.2.    Inhalation.   Schwetz  et  al.  (1974)  exposed groups  of  21-47  preg-
nant Sprague-Dawley  rats  to methyl  ethyl  ketone by  Inhalation at  levels of
0,  1000  or  3000  ppm (0, 2949  or 8848 mg/m3) for  7  hours/day on days  6-15
of  gestation.   There was  no maternal  toxlclty at  either   exposure  level.
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Somewhat decreased  fetal  body  measurements  (body  weight  and  crown-to-rump
length) were seen at the lower  but not  at  the  higher  exposure level.   At  the
1000  ppm  level,  there  was  a  significant  Increase  In  the  percentage  of
Utters  having  at  least  one  fetus  with  a  skeletal  abnormality;  however,
there was no significant Increase 1n gross,  soft-tissue or  specific  skeletal
anomalies.   At the  3000  ppm level,  a significant  Increase  In  Utters  having
fetuses with gross  external  anomalies  or Internal  soft-tissue  anomalies  was
seen.   Schwetz  et al.   (1974)  concluded that  methyl  ethyl  ketone was  feto-
toxlc and  potentially  teratogenlc,  but not  maternotoxlc  to rats  exposed  at
levels of 1000 or 3000  ppm during  days  6-15 of  gestation.
    Deacon  et al.  (1981)  conducted an  experiment  to clarify the  results  of
the study reported by Schwetz et al. (1974).   Groups  of  25  pregnant  Sprague-
Dawley  rats were  exposed to methyl  ethyl  ketone by Inhalation at levels  of
400,  1000  or  3000 ppm  (1180, 2949 or  8848 mg/m3), 7 hours/day on days  6-15
of  gestation.   A  control  group  of  35 pregnant  rats was  maintained.   No
maternal effects  of  toxldty  were  noted at  the  two  lower concentrations  and
only  a  decrease   In  body  weight gain  of  the  dams  was  reported at  the  high
exposure level.   Five  fetuses  among  all the  groups,  Including  controls,  had
at  least one  malformation  upon  examination  for  external   and soft  tissue
malformation.    Details  of  these  malformations  are  discussed  In U.S.  EPA
(1985a).   Deacon  et al.  (1981)  concluded  that  methyl  ethyl ketone was  not
teratogenlc 1n  rats, because of  the low  Incidence and the  distribution  of
the  malformations  observed  1n  the pups.  Fetotoxldty  was, however,  mani-
fested  as  an  Increased Incidence of extra  ribs and  of  delayed ossification
In the cervical centra  at the high exposure level only.
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3.4.   TOXICANT INTERACTIONS
    Combined  exposure  to  TOO  ppm of  n-hexane  and  200  ppm of  methyl  ethyl
ketone  for  24 weeks  resulted  1n neurotoxk  effects (defined as  changes  In
motor nerve  conduction  velocity, distal motor  latency and mixed  nerve con-
duction velocities)  In  rats  that were not observed  when  either  chemical was
tested by Itself (Takeuchl et  al.,  1983).  Methyl  ethyl  ketone has also been
shown to  potentiate  the  effect  of  n-hexane on  the alveolar epithelium  of
rats  exposed  to the  mixture  for 8  hours/day for <89  days  (Schnoy  et al.,
1982).  Although  lesions  were  not  demonstrable by  light  microscopy,  ultra-
structural examination revealed  the  presence  of  fatty  deposits  1n  Type I and
II pneumocyte cells.
    Hewitt et  al.   (1983,  1986)  found that  methyl ethyl  ketone potentiated
the  ftepatotoxlc  action  of  chloroform  In  rats.  In  the  earlier study,  a
significant  positive  correlation was  shown  between  the carbon  chain  length
of  ketones   and  the  severity   of  the  potentiated  chloroform-Induced  liver
damage.    In  the later  study,   1t  was determined  that choleotasls  resulted
from  potentlatlon  of  chloroform-Induced  alterations  1n  canallcular  membrane
permeability.
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                              4.  CARCINOGENICITY
4.1.   HUMAN DATA
    Pertinent data  regarding  the carcinogenic effects of  exposure  to methyl
ethyl ketone on humans were not 'located In the available literature.
4.2.   BIOASSAYS
    Pertinent data  regarding  the carcinogenic effects of  oral  or  Inhalation
exposure to methyl  ethyl  ketone  on experimental animals were  not  located In
the available literature.  No  tumors were observed  on  the  skin of  mice after
dermal application  of  50 mg  of  methyl  ethyl  ketone twice weekly  for  1  year
(U.S. EPA, 1985a).  Methyl ethyl ketone  1s  not  scheduled  for  carcinogenldty
testing by the National Toxicology  Program (NTP, 1987).
4.3.   OTHER RELEVANT DATA
    Methyl ethyl  ketone  was  negative   for  reverse mutation  when   tested  In
Salmonella typhlmurlum strains TA98, TA100, TA1535  or  TA1537  with  or  without
metabolic activation  (Florin  et al.,  1980;  Douglas  et  al.t   1980).   Methyl
ethyl ketone  has  been shown,   however,  to be  a strong  Inducer  of  aneuploldy
in  the dlploid  061.M  strain  of Saccharomyces  cerevlslae (Zlmmermann  et  al.,
1985).   When  Ineffective  low levels  of  methyl ethyl  ketone were  combined
with  Ineffective  low  levels of nocodazole,  another Inducer of  aneuploldy In
this  system,  significantly elevated  levels  of aneuploldy  resulted  (Mayer and
Coin, 1987).
4.4.   WEIGHT OF EVIDENCE
    Methyl ethyl  ketone  has not  been tested  for cardnogenlclty by the  oral
or  Inhalation  routes.   No tumors  were  observed 1n the only  dermal exposure
study as seen 1n  Section  4.2.  (U.S.  EPA,  1985a).   IARC has not evaluated the
risk  to  humans  associated with  oral  or Inhalation exposure  to  methyl ethyl
0003H                               -9-                              03/01/89

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ketone.   Because of lack of evidence, methyl ethyl ketone 1s classified as a
U.S.   EPA  Group   0   chemical;   that   1s,   not   classifiable  as  to  human
cardnogenldty.
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                     5.  REGULATORY STANDARDS AND CRITERIA

    ACGIH  (1986a)  set  a TLV-TWA  of  200  ppm  (590 mg/m3) and  a STEL of  300
ppm  (885  mg/m3)  for methyl  ethyl  ketone; the  basis  for these  standards  Is
the minimization of  eye and  nose  Irritation,  and systemic  toxic effects  are
not expected to develop at  this exposure level  (ACGIH,  19865).
    The NIOSH  (1978) recommendation and   OSHA (1985)  PEL  for  methyl  ethyl
ketone are both 200 ppm (590  mg/m3).
    ACGIH  (1986b)  summarized  the  occupational  standards and  their year  of
establishment 1n other countries as follows: 200 ppm  1n West  Germany (1974);
150  ppm  1n Sweden  (1974);  100 ppm  1n  East Germany  (1973);  and 100 ppm  in
USSR (1966), Yugoslavia (1971) and Hungary (1974).
0003H                               -11-                             11/21/88

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                              6.  RISK ASSESSMENT
6.1.   SUBCHRONIC REFERENCE DOSE (RfDg)
6.1.1.   Oral  (RfD.J.   The  lack  of  subchronlc  oral  toxlclty  data  pre-
                   wU
eludes the  derivation  of  an  RfDSQ for  subchronlc  exposure to  methyl  ethyl
ketone based  on oral  data.   U.S.  EPA  (1985a) derived  a  chronic  oral  RfOQ
of 3 mg/day based on the subchronlc rat  Inhalation  study reported by LaBelle
and BMeger  (1955).   Derivation of  the  RfD  will  follow 1n Sections  6.1.2.
and 6.2.1.   Therefore,  1t  would  be  appropriate to  use the  subchronlc  rat
NOAEL of 46 mg/kg/day, adjusted  for oral  route by multiplying  the Inhalation
NOAEL by an  absorption factor of  0.5, as  the basis for an  RfDSQ  for  methyl
ethyl  ketone.  Applying an uncertainty factor  of 100  (10 for both Inter- and
Intraspecles  variability)  to  the  rat  NOAEL  of  235   ppm  (693  mg/m3),  con-
verted to  46  mg/kg/day,  results 1n an RfDSQ of 0.5 mg/kg/day or  32 mg/day.
Medium confidence 1s  placed 1n the RfD-Q  as discussed  In Section  6.2.1.
6.1.2.   Inhalation  (RfOSI).    As  reported   In   Section   3.1.2.,   several
subchronlc  Inhalation  studies  have been  performed with  methyl ethyl ketone.
Two of  these studies  were considered not  useful  for risk  assessment:   the
study by  Salda et al.  (1976) 1n  which  only one toxlcologlcal  endpoint  was
evaluated  and  the   study  by  Mellon  Institute  (1950)  1n  which  complete
exposure data were not  available and  a short  duration of  exposure (30 days)
was used.
    A NOAEL  of  235  ppm  (693  mg/m3)  for  methyl  ethyl  ketone 1n  rats  can  be
Identified  from  the  LaBelle  and BMeger  (1955) study.  For Identifying  the
toxic  threshold  for methyl  ethyl  ketone,  the studies by  Cavender  et  al.
(1983) and Takeuchl  et al. (1983)  are useful, as  both  also define  a  NOAEL.
NOAELs of  2500  ppm (7373  mg/m3)  for  Increased SGPT activity  In female  rats
(Cavender  et  al.,   1983)  and   200  ppm   (590  mg/m3)  for  temporary  slight
neurological  effects of unknown  biological  significance  1n  rats  (Takeuchl  et

0003H                               -12-                              03/01/89

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al., 1983)  were Identified  from  these  studies.  According  to the  analysis
provided by  the U.S.  EPA  (1985a,b),  the  NOAEL  from the LaBelle and  BMeger
(1955)   study  provides  the  lowest and most  protective  dose and Is  therefore
the  study  of  choice  for  deriving  the  RfD-.   Additionally,  methyl  ethyl
ketone   was also tested for  teratogenUHy  (Schwetz  et  al.,  1974;  Deacon  et
al., 1981)  and  the  observed  LOAEL, estimated to  be   130.5  mg/kg/day  for
fetotoxlclty  from  the Schwetz  et al.  (1974)  study (U.S.  EPA, 1985b),  was
higher   than the NOAEL estimated from  the  data of LaBelle and  Brleger  (1955).
The  NOAEL  of 235  ppm  (693 mg/m3) from the  rat subchronlc Inhalation  study
(LaBelle  and  Brleger,   1955)  converts   to  92  mg/kg/day   by  expanding  to
continuous exposure  and  using 0.223  mVday as a  reference  Inhalation  rate
for  rats  and  a reference  body weight for rats of  0.35 kg as  follows:   693
mg/m3  x (7/24  hours/day)  x  (5/7 days/week)  x 0.223  mVday/0.35  kg  =  92
mg/kg/day.  Applying  an  uncertainty  factor  of  100  (10 for  both  Intra- and
Interspedes  extrapolation),  results 1n  an  RfOSI  of  0.9 mg/kg/day  or  64
mg/day   for  a 70 kg  man.  Confidence 1n  this  RfDST  is medium as  discussed
1n Section 6.2.1.
6.2.   REFERENCE DOSE (RfD)
6.2.1.    Oral  (RfDQ).  U.S.  EPA  (1985a)  derived a  chronic RfD  of 3 mg/day
for methyl ethyl ketone  from the  rat  subchronlc  Inhalation study  reported by
LaBelle  and  Brleger  (1955).  The  NOAEL of  235 ppm (693 mg/m3) converts  to
46  mg/kg/day  by using the methodology  presented  1n Section 6.1.2.  and  also
using  an absorption  factor  of  0.5  to  extrapolate  from Inhalation  to  oral
exposure.  Applying  an uncertainty  factor  of  1000  (10 for  both  Intra- and
Interspedes  variability  and 10  to  extrapolate from  subchronlc  to  chronic
data),   results  In  the chronic RfD_  of  0.05 mg/kg/day  or  3  mg/day  for  a 70
kg  man.  This  value  Is  verified and available  on  IRIS (U.S.  EPA,  1985b).
0003H                               -13-                             03/01/89

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Confidence In  the  study was rated  medium because only 25  rats  were  exposed
to only one dose and  the control  group  was  not characterized.   The data base
was  given a  medium  rating  because  four  other  studies  support  the  NOAEL.
Therefore, confidence 1n the RfD was rated medium (U.S.  EPA, 1985b).
6.2.2.   Inhalation  (RfD.).    Using  the  methodology  discussed  In   Section
6.1.2. and  applying an additional  uncertainty factor  of  10 to  expand from
subchronlc to  chronic exposure  to  the  RfDSI  of  0.9 mg/kg/day or 64  mg/day
results  In  a  chronic RfD,  of  0.09  mg/kg/day  or   6  mg/day.   This  chronic
RfD,  was  derived  for Interim  purposes  only and the Issue  of  the Inhalation
RfD for methyl ethyl ketone Is  pending verification  by  the  RfD  Workgroup.
    A  CS  of  9.6 was derived by  the U.S.  EPA  (1985a) based  on  the decreased
weight gain effects  reported  1n the LaBelle and  Brleger (1955)  study  at  235
ppm  (693  mg/m3).    Discussion  and  details  of  the  derivation  are  presented
1n  the  U.S.  EPA (1985a) document.   The human MED of 110  mg/day  corresponds
to  an RV.  of  2.4  and the  effects  of  decreased bo.dy  weight  warranted  an
RV& of 4, resulting 1n a CS of  9.6.
6.3.   CARCINOGENIC POTENCY (q^)
    Methyl ethyl ketone  Is classified  as  a U.S.  EPA Group  D  chemical; that
1s, not classifiable as to  human  cardnogenlcHy  because of lack  of  evidence
for cardnogenlcHy.
    The lack  of carclnogenldty data  precludes the   derivation of  a  carcino-
genic potency for  exposure  to methyl ethyl ketone.
0003H                               -14-                             03/01/89

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                                7.   REFERENCES

ACGIH  (American  Conference of  Governmental  Industrial  Hyg1en1sts).   1986a.
Threshold Limit  Values  for Chemical  Substances  1n  the Workroom  Environment
adopted by ACGIH.  Cincinnati,  OH.   p. 24.

ACGIH  (American  Conference of  Governmental  Industrial  Hyg1en1sts).   1986b.
Methyl  Ethyl  Ketone.   Documentation of  the  Threshold  Limit  Values  and
Biological Exposure Indices,  5th ed.   p.  395.

Cavender, F.L., H.W. Casey, H.  Salem,  J.A. Swenberg and  E.J.  Garalla.   1983.
A  90-day vapor  Inhalation toxldty  study of  methyl  ethyl  ketone.   Fund.
Appl. Toxlcol.  3(4):  264-270.

Deacon, H.M., M.D. Pliny,   J.A.  John,  et  al.  1981.  Embryotox1c1ty  and feto-
toxlclty of  Inhaled methyl ethyl  ketone  In rats;  Toxlcol. Appl. Pharmacol.
59(3): 620-622.  (Cited  1n U.S. EPA,  1985a)

Dletz,  F.K.  and  G.J. Tralger.   1979.  Potent1at1on of carbon  tetrachloride
hepatotoxldty  1n  rats  by   a  metabolite  of   2-butanone:   2,3-Butanediol.
Toxicology.  14(3): 209-215.   (Cited  1n U.S.  EPA, 1985a)

Dletz,  F.K.,  M.  Rodrlguez-Glaxola,   G.J.  Tralger,  V.J.  Stella  and  K.J.
Hlmmelsteln.   1981.   Pharmacok1net1cs of  2-butanol  and  Us  metabolites  In
the  rat.   J. Pharmacoklnet.  Blopharm.   9(5): 553-576.   (Cited In  U.S.  EPA,
1985a)
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Qouglas,  G.R., E.R. Nestmann,  J.L.  Belts,  et  al.   1980.  Mutagenic activity
In pulp mill effluents.  Water Chlorlnatlon: Environ. Impact Health Eff.  3:
865-880.   (CHed  In U.S.  EPA,  1985a)

Florin, I.,  L.  Rutberg,  M.  Curvall  and  C.R.   Enzell.   1980.   Screening of
tobacco smoke constituents for  mutagenlclty  using  the Ames  test.   Toxicology.
15: 219-232.  (CHed 1n U.S.  EPA,  1985a)

Graedel,  I.E.  1978.  Chemical Compounds In the Atmosphere.  Academic Press,
NY.  p. 187.

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

HewHt, W.R.,  E.M. Brown  and  G.L.  Plaa.   1983.    Relationship  between  the
carbon skeleton  length of ketonlc  solvents  and potentlatlon of  chloroform-
Induced  hepatotoxlclty  In  rats.   Toxlcol. Lett.   16(3-4):  297-304.    (CA
98:22111146)

Hewitt, L.A., P. Ayotte  and  G.L.  Plaa.   1986.   Modifications 1n  rat hepato-
bHlary function  following treatment with  acetone,  2-butanone,  2-hexanone,
mlrex,  or   chlordecone  and  subsequently  exposed  to  chloroform.  Toxlcol.
Appl.  Pharmacol.    83(3):  465-473.   (Taken  from MEDLINE  Database File 154 on
Dialog, Accession No.  86209163)

LaBelle,  C.W. and  H. Brleger.  1955.  Vapour toxlclty of a  composite solvent
and  Us principal  components.   Arch. Ind.  Health.   12:  623-627.   (CHed In
U.S. EPA,  1985a)

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Lande,  S.S.,  P.R.  Durkin,  D.H.  Christopher,  P.H.  Howard  and  J.  Saxena.
1976.   Investigation  of   selected   potential   environmental   contaminants:
Ketonlc solvents.   Prepared  under  Contract No.  68-01-3100.  Office  of  Toxic
Substances, U.S. EPA,  Washington,  DC.   EPA 560/2-76-003.

Mayer, V.W. and C.J.  Go1n.  1985.  Effects  of  chemical combinations  on  the
Induction  of  aneuploldy  In  Saccharomyces  cerevlslae.   Mutat.  Res.   187(1):
21-30.   (Taken   from  MEOLINE  Database  File  154  on  Dialog,  Accession  No.
87090136)

Mellon  Institute.   1950.   Methyl  Ethyl  Ketone,  Report  14-33,  unpublished,
Union Carbide Corporation.   (Cited  1n  U.S.  EPA,  1985a)

Mlyasaka,  M., M.  Kumal, A, Koizumi,  et al.   1982.  Biological  monitoring of
occupational  exposure  to  methyl  ethyl  ketone  by  means  of  urlnalysls  for
methyl  ethyl  ketone  Itself.   Int.  Arch.  Occup.  Environ.  Health.   50(2):
131-137.  (Cited 1n U.S.  EPA, 1985a)

NIOSH  (National  Institute  for  Occupational  Safety   and  Health).   1978.
Criteria  for   a  Recommended  Standard...Occupational  Exposure  to  Ketones,
U.S.  DHEH,  PHS,  CDC.   Cincinnati,  OH.   Publ.  No. 78-173.   (Cited  In  U.S.
EPA, 1985a)

NLM  (National  Library  of  Medicine).   1987.   Hazardous  Substance  Data  Base.
Report No. 99.  On-Llne.
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NTP (National Toxicology Program).  1987.  Management  status  report  produced
from NTP  Chemtrack System.   Data received  up to  01/09/87.   NTP,  Research
Triangle Park, NC.

OSHA (Occupational  Safety  and Health  Administration).   1985.  OSHA  Occupa-
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Papa,  A.J. and  P.O. Sherman,  Jr.   1981.  Ketones.  ln_:  K1rk-0thmer  Encyclo-
pedia  of  Chemical  Technology, Vol. 13,  3rd  ed.,  M. Grayson and  D.  Eckroth,
Ed.  John Wiley and Sons,  Inc.,  New York.   p. 894-941.   (Cited In U.S.  EPA,
1985a)

PerbelUnl,   L.,  F. Brugnone, P.  Mozzo, V.  Cocheo and  D.  Caretta.   1984.
Methyl   ethyl  ketone  exposure In  Industrial workers:  Uptake and kinetics.
Int. Arch. Occup.  Environ.  Health.  54(1): 73-81.   (CUed 1n  U.S.  EPA,  1985a)

Salda,   K.,  J.R. Mendel!  and H.S.  Weiss.   1976.   Peripheral  nerve  changes
Induced by  methyl  n-butyl  ketone and potentlatlon by  methyl ethyl  ketone.
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Schnoy,  N.,   R.  Schmidt,  A.  AHendlrch  and  A.M.  Wagner.   1982.    Ultra-
structural alteration  of  the alveolar  epithelium  after exposure  to  organic
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Schwetz,  B.A.,  8.K.J.  Leong  and P.J.  Gehrlng.    1974.   Embryo- and  feto-
toxldty  of  Inhaled   carbon   tetrachlorlde,  1 ,l-d1chloroethane  and  methyl
ethyl  ketone 1n  rats.   Toxlcol.  Appl.  Pharmacol.   28(3): 452-464.


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Takeuchl, Y.,  Y.  Ono,  N. Hlsanaga,  et  al.   1983.  An experimental  study  of
the combined effects of  n-hexane  and methyl ethyl ketone.   Br.  3.  Ind.  Med.
40(2): 199-203.

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

U.S.  EPA.   1983.   Reportable  Quantity Document for 2-Butanone  (Methyl  ethyl
ketone).   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.   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.   1985a.  Health and  Environmental Effects Profile  for  Methyl  Ethyl
Ketone.   Prepared by  the  Office  of  Health  and Environmental  Assessment,
Environmental  Criteria and  Assessment Office,  Cincinnati, OH for  the  Office
of Solid Waste and Emergency Response, Washington, DC.

U.S.  EPA.   1985b.   Integrated Risk  Information  Systems (IRIS).   Reference
dose  (RfD)  for oral  exposure for  methyl  ethyl  ketone.   On-line  (Verification
date  7/8/85.)   Office  of Health  and  Environmental  Assessment,  Environmental
Criteria and Assessment Office, Cincinnati,  OH.


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Verschueren, K.  1983.  Handbook of  Environmental  Data  on  Organic  Chemistry,
2nd ed.  Van Nostrand Reynold Co., NY.   p.  850-852.

Zlmmermann, F.K.,  V.W.  Mayer, I.  Scheel  and  M.A.  Resnlck.   1985.   Acetone,
methyl  ethyl  ketone,  ethyl   acetate,  acetonUMle and  other polar  aprotlc
solvents  are   strong  Inducers  of  aneuploldy  1n  Saccharomyces  cerevlslae.
Mutat.  Res.   149(3):  339-351.   (Taken  from MEDLINE  Database  File  154  on
Dialog, Accession No. 85188025)
0003H                               -20-                             11/21/88

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