-------
                      The results of a study on the reactivities of forty-




five solvents, which was sponsored by the National Paint, Varnish, and Lacquer




Association, are summarized in Table 17.  The smog chamber measurements used




mixtures of 4 ppm organic solvent and 2 ppm nitric oxide.  Each of the solvents




was rated from 1 to 3 for every measured parameter; Table 17 defines the




rating system.  With the exception of mesityl oxide (a branched chain olefin




as well as a ketone), none of the ketones exceeded an average rating of 2.0.




The ketones had low eye irritation and formaldehyde production ratings.  While




branched chain ketones were generally higher than straight chain ketones in




oxidant production, they were similarly rated in NO  production.  Four ketones




(acetone, MEK, methyl isopropyl ketone, and cyclohexanone) had an average




rating of 1.2 or less.




                      Smog production consists of a rather complex sequence




of free-radical reactions, which involve inorganic and organic substrates.




Several excellent reviews detail the proposed free-radical chain reactions and




their contributions (Hecht e_t _al. , 1974; Altshuller and Bufalini, 1965, 1971).




While there exists some experimental evidence on how the ketones participate




in smog generation, much of the reasoning is based on ketone photolysis in




oxygen-free atmospheres.  While their relative contribution to overall smog




generation has not been established, it is  thought to be minor.




                      Ketones can participate in the photochemical smog cycle




as free-radical chain initiators.  Alkyl radicals, such as those generated in




the Norrish "Type I" reaction of excited ketones, are known initiators




(Haagen-Smit  and Wayne, 1968; Laity, 1973).  The photooxidation of acetone




and 2-methyl-2-butene mixtures supports this supposition.  The olefin disappears
                                      35

-------
Table 17.   Summary of Photochemical  Reactivity of Forty-Five Solvents
            (Levy jit^ al., 1973)
Oxi-
NO, dant
Solvents
Ketones
Acetone
Cyclohexanone
Diacetone alcohol
Dlisobutyl ketone
Di-ii-propyl ketone
Isophorone
Mesityl oxide
Methyl tert-butyl ketone
Methyl isobutyl ketone
Methyl ii-butyl ketone
Methyl ethyl ketone
Methyl n-propyl ketone
All other Solvents
Benzene
trans-2-Butene
tert-Butylbenzene
Cumene
Cyclohexane
£-Cymene
Diethylamlne
2-Ethoxyenthanol
Ethylbenzene
Ethylene
Isobutyl acetate
Isopropyl alcohol
Mesltylene
Methyl benzoate
N-Methyl pyrrolidone
a-Methylstyrene
Mineral spirits 7.5% ar.
14.6% ar.
15.0% ar.
16.0% ar.
19.8% ar.
53. n ar.
2-Nltropropane
n-Octane
92% n-Octane/8% m-Xylene
80% n-Octane/20% ra-Xylene
50% n-Octane/50% m-Xylene
Phenyl acetate
Styrene
Tetrahydrofuran
Toluene
Triethylamine
m-Xylene

Reactivity Category

3 High reactivity
2 intermediate reactivity
1 low reactivity
C-tUx Max

1
1
2
2
2
2
3
3
2
2
2
1

1
3
2
2
2
3
1
2
2
3
1
1
3
1
2
3
2
2
2
2
2
3
1
1
2
2
3
1
2
2
2
1
3
N02
t-Max,
min
0-100
101-200
201-360

1
1
3
3
2
3
3
3
2
2
1
1

1
3
1
2
1
2
1
3
2
3
1
1
3
1
3
3
2
2
2
2
3
3
1
1
2
3
3
1
2
3
2
1
2






Eye
Re-
sponse

1
1
1
1
1
1
2
1
1
1
1
1

1
2
1
2
1
1
1
1
2
2
1
1
2
1
1
3
1
1
1
1
1
2
1
1
1
1
2
1
3
2
2
1
2
Oxidant
Max,
ppm
0.57-0.85
0.29-0.56
0-0.28
formal-
de-
hyde

1
1
1
1
1
1
2
1
2
1
1
1

1
2
1
1
1
1
1
1
1
3
1
1
2
1
1
3
1
1
1
1
1
1
1
1
1
1
1
1
2
1
1
1
1
E.I.
seca

0-60
61-160
161-360
Aver-
aged,
Rating

1
1
1.7
1.7
1.5
1.7
2.5
2
1.7
1.5
1.2
1.0

1
2.5
1.2
1.7
1.2
1.7
1
1.7
1.7
2.7
1
1
2.5
1
1.7
3
1.5
1.5
1.5
1.5
1.7
2.2
1
1
1.5
1.7
2.2
1
2.2
2
1.7
1
2
Formal-
dehyde,
POTl
1.0-1.6
0.5-1.0
0-0.5
                Eye response.
                                       36

-------
more rapidly from the ketone-olefin mixture (Altshuller and Bufalini, 1971).

Results are summarized in Table 18.

        Table  18.  Photooxidation  of  Acetone  (A)  and  2-Methyl-2-butene  (MB)
                  in Air  Mixtures by Sunlight  Fluorescent  Lamps
                  (From Altshuller and Bufalini,  1971)
Initial
Concentrations In ppn
Acetone

10
5
10
20
2-Methyl-2-butene

0
10
10
10
60
A
12.4
10.2
11.4
12.2
Amount Reacted
During Irradiation
Percent at given tiaes
MB

2.3
4.5
7.S
120
A MB
23.3
22.4 7.0
23.8 8.6
23.6 17.6
(ninutft$)
180
A MB
31.9
34.7 11.3
32.4 15.8
33.5 28.7
Products at
180 »in. in ppn
Formaldehyde

2.88
0.93
1.8
3.84
Total Oxidant

0.352
0.29
0.49
0.84
                      The acyl radicals produced in the Norrish "Type I"

fragmentation can react with oxygen and nitrogen dioxide to yield peroxyacyl

nitrates.  Evidence supporting this scheme has been published by Laity et al.

(1973).  The irradiation of diethyl ketone and of jt-butyl ethyl ketone in smog

chambers yielded high concentrations (18 and 27 ppb, respectively) of peroxy-

propionyl nitrate and 36 and 23 ppb, respectively, of peroxyacetyl nitrate.

The data suggest the following reaction scheme:


                 [C2H5COR]*	•	>•  C2H5CO' + R-

                      where R = C2H5 or jz-Ct+Hg

                  C2H5CO + 02  	>  C2H5C002-

                  C2H5C002' + N02  	>-  C2H5C002N02


                      Laity et al. (1973)  have suggested that olefins produced

by the Norrish "Type II" reaction would also participate in the conversion of

NO to NO £ and in the build-up of ozone and aldehyde.  In support of their sug-

gestion, they cite the slower reaction of  cyclohexanone in smog chambers than

other ketones with a-hydrogens.  Cyclohexanone does not fragment by a "Type II"

reaction because of its stereochemistry.
                                     37

-------
                      The abstraction of ketonic a-hydrogen atoms, such as ob-




served in the free-radical oxidations (see Tables 12 and 14), can also be




important in smog generation.  When MIBK is irradiated in air without nitrogen




oxides, ketone disappearance is less rapid and acetone production is low (Laity




ej; jj_. , 1973).  This is excellent evidence that products formed through the




inorganic reaction cycle are important to the ketone degradation.  Since ozone




and peroxide react relatively slowly with ketones, radical reactions in which




the inorganic radicals are the hydrogen abstractors are suggested.




            5.   Other Chemistry




                 Although ketone chemistry includes a wide number of reactions,




few of them are important either to their consumption or their environmental




degradation.  Table 19 lists many of the possible reactions.
                                      38

-------
Table  19.  Miscellaneous Ketone Chemistry  (From Lurie, 1966;  Cram and Hammond,

            1964; Roberts and Caserio, 1965;  Royals,  1961; House,  1965)
            Ketone forming reactions





            1.  From acyl derivatives



                    (a)  From  acyl derivatives
   A1C1;



  r othe

Lewis acid
                         RCOX + CH2=CHR 	r-	->• RCOCH=CHR + HX
                                 '      or other
                    (b)   Grignard  reactions




                         RjCOX + R2MgX - — - - > RjCORp  + MgX2






                    (c)   Carboxylic acid condensation





                         RjCOjH +  R2C02H
                                                            R2COR2
             2.  Acetylene hydration
                                       Liq. NH3
                    (a)  HCeCH +  NaNH2 	»• HC=C~Na+ + NH3
                    (b)  HCsCNa +  RX ——	•> HCsCR + NaX





                    (c)  HCsCR + H20 	——	* CH3COR


                                       HgSO,,
            3.  Olefin ozonation
                                             RjR2CO + R2RitCO
            Ketone reactions
            4.  Catalytic hydrogenation over supported metals  (such as Raney nickel)


                                                       OH
                         C2H5COCH3 + H2 — -* C2H5CHCH3
                                          39

-------
Table 19.   (cont'd)
        5.   Hydride transfer

                (a)  Front metal hydrides (such as LiAlH^ and
     C2H5COCH3 + MH
                                                  OM
                                                  I
                                              C2H5CHCH3
                (b)  From aluminum isopropoxide (Meerwein, Ponndorf , Verley Reaction)
     3C2H5COCH3 + A1[OCH(CH3)2]3
                                                          ^[C2H5(CH3)CHO] 3A1

                                                               + (CH3)2CO
        6.  Reductive dimerization (M = sodium, potassium, magnesium)

                                                   HO OH
2R,R2CO + M
                                         Arid
                                                RiR2C-CRiR2
        7.  Reduction to saturated carbon (Wolf-Kishner Reaction)
      O + H2NNH2 _)
                                                       H20
        8.  Halogenation
                (a)  R!R2CO + PC15
 (b)  RiRgCO + SF^
                                             RjR2CF2
        9.  Condensation reactions

                 (a)  Claisen condensation


                     CH3CH2COCH3 + C2H5C02C2H5
                                              40
                                                             Major

                                                        CH3COCH(CH3)COC2Hs

                                                             Minor

-------
Table 19.   (cont'd)
                  (b)  Reformatsky Reaction (X - halogen)
C2H6COCH3 + XCH2C02C2H5
                           Zn
                                                                       OH

                                                                       I
                                                                   C2H5CCH2C02C2H5


                                                                       CH3
                  (c)  With alkyl halides (carbonyl  oxygen vs.  a -  carbon reactivity)


                                   Base
                       C2H5COCH3
                                   H+ Base
                    C2H5COCH2e
                       C2H5COCH20 + CH3X
                          -> C2H5COCH2CH3


                                Major


                                   OCH3

                                  /

                           + C2H5C=CH2


                                Minor
          10.  With isocyanides
                  RN=C: + C2H5COCH3 + CH3C02H
          11.  With alkidene phosphorines
                                    0 CH3

                                    II I
                               -»• RNHC-C-OCOCH3


                                      C2H5
                  R3PCH2 + C2H5COCH3
                            CH3


                        C2H5OCH2 + R3PO
                                             41

-------
Table 19.   (cont'd)
        12.  With diaifoMthane







                CH2N2 + C2H5COCH3 	>•





                                         + n-C3H7COCH3 + C2H5COC2H5







        13.  With acetylene



                                                                       OH

                        Base                                           I
                                                              HT
                HC=CH ^	HCsCO + C2H5COCH3 	*  —	>• C2H5CC5CH


                       H+ Base                                         '
                                                                       CH3
        14.  With aromatics
                                           A2

-------
II.   Environmental Exposure Factors




     A.    Production Consumption




          1.   Quantity Produced




               Of the selected ketones, quantitative data on production,




sales, imports and exports are available for only seven:  MEK; MIBK; dia-




cetone alcohol; cyclohexanone; acetophenone; benzophenone; and acetone.




Although acetone is not being considered in this study, its production




data are of interest since it is a precursor of several other ketones




including MIBK, diacetone alcohol, mesityl oxide and isophorone.




               Table 20 reports production and sales figures for the




seven ketones listed above; Table 21 summarizes their import and export




data.  The quantities in Table 20 refer only to U.S. production and sales.




Net import and export of MEK and MIBK have a negligible effect  on the market




availability (USTC, 1971).  Import and export of cyclohexanone, acetophenone




and benzophenone were generally negligible (USITC, Annual b).  A majority of




the cyclohexanone is produced for captive consumption (SRI, 1973, 1974, 1975).




               In 1968, seven ketones accounted for approximately 98% of




the aliphatic ketones produced (excluding acetone and cyclohexanone).  The




seven were  rated by the U.S. International Trade Commission (formerly U.S.




Tariff Commission) in the following order of decreasing production:  MEK;




MIBK; diacetone alcohol; mesityl oxide; diisobutyl ketone; isophorone; and




methyl isoamyl ketone (USTC, 1971).  The USTC (1971) accounted  for the remain-




ing 2% primarily as ethyl amyl ketone;  trimethylnonanone;  2,4-pentanedione




(acetylacetone); and 2,5-hexanedione (acetonylacetone).  Smaller amounts of




methyl amyl ketone and diethyl ketone were also reported.
                                     43

-------
                                                           M   ft    -H
                                                                                  9^   O   *O
                                                                                  lA   O   CM
                                                                                  ^   C1   •*


 c
 o
13
 0)
 4-1
 O
 0)
rH
 (U
en

M-4
 O

 CO
 
-------
 CD  n)
 (0  3
 C  C
-a H
 CU H
 jj to
 o p
 0)
rH  .«
 Q) rH
4-1

 O
 o


w
o
o
o
                                                                         o
                                                                         o
      o
      o
      o
 C  r-»
 cfl  ON
 D.
 B
     0
     O
(N


 Q)
                                            O
                                            0
                                to
                                •o


                                o
                                D.
                                c
                                a
                                IB
                                •3
                                O
                                •C
                                                45
-------
                Although production figures are not available for ketones

other than those listed in Table 20, the 1973 production of three ketones

(diacetone alcohol; isophorone; and mesityl oxide) can be estimated from acetone

consumption data (see Table 22).  Blackford (1975) estimated that each pound of

MIBK produced required 1.25 pounds of acetone; this corresponds to a yield of

slightly above 90%.  The production of the other three ketones Was calculated

with the 90% yield estimate.  The estimated diacetone alcohol production (43

million pounds) is about 20% lower than the reported sales (51 million pounds) ,

and the MIBK estimation of 210 million pounds is 55 million pounds higher than

the USITC figures  (Table 20).  While the values for isophorone and mesityl

oxide might be poor estimates,  they do place a perspective on their commercial

importance.
       Table  22.   Estimated Production  of  Four Ketones  Derived
                  From Acetone  in  1973
                  (From Blackford,  1975)

                                         In Millions  of Pounds
Ketone
Methyl isobutyl ketone
Diacetone alcohol
Isophorone
Mesityl oxide
Acetone Consumed
for Production
263
48
35
27
Estimated
Ketone Production
210
43
28
22
 (a) Approximately 90% yield from acetone is assumed.
                                    46
-------
                                                              I

           2.    Producers,  Major Distributors,  Importers,  Sources  of
                Imports and Production Sites

                The producers and production site locations for  the selected

ketones are listed in Table 23.   The distribution of plant locations  is

illustrated in Figure 6.  Table 24 summarizes major producers of these ketones

for the years 1965 to 1973.

                Table 23 also lists plant capacities for three ketones:  MEK;

MIBK; and cyclohexanone.  The capacities are quite flexible.  Two plants,

which manufacture MEK by butane oxidation (Celanese Corp.  and Union Carbide

Corp.), can adjust process conditions in order to produce MEK or acetic acid.

Two other plants  (Shell Chemical Co. and Enjay Chemical Co.) can produce

either acetone or MEK (Stanford Research Institute  (SRI),  1972a).  The MIBK

facilities can be adjusted to produce the related acetone derivative, methyl

isoamyl ketone (Oosterhof, 1967).  The data on cyclohexanone in Table 23

do not include a plant  (Monsanto Company at Luling, La.) having a 25  million

pound capacity for cyclohexanol  (captive and merchant; synthesis via phenol

reduction)(SRI, 1974).  This plant could be used for production of cyclo-

hexanone .

                Construction of additional plant facilities for MEK will

increase its capacity by 320 million pounds in 1977.  Shell Chemical Co.

anticipates the completion of a 230 million pound plant in Norco, La., by

late 1977  (Chemical Marketing Reporter  (CMR), 1975c).  Exxon Chemical Co.

will expand production  at its Linden, N.J., plant from 210 to 300 million

pounds; a major part of this expansion is expected on stream early in 1977

(Anon., 1975a).  Universal Oil Products has also reported increasing capacity

for benzophenone at its East Rutherford, N.J., plant (CMR,-1975d).
                                    47
-------
Table  23.    Majjor  Producers,  Production  Sites,  and  Annual  Production  Capacities
                   of  the  Selected Ketones   (From SRI,  1974,   1975)
                                   Producer
                                                                                      Capacity In millions
                                                                                            o f pound s
                                                                                         1974       1975
 Diethyl ketone
                            Ace to Chemical  Co., Inc.
                             Roehr Chemical Co., Inc.
                             (subsidiary)
                            Hexagon Laboratories, Inc.
                            Union Carbide Corp.

                            E.I. Dupont deNemours & Co.
                                    Long Island City, NY
                                    Bronx,  NY
                                    Institute  and
                                     So. Charleston, WV
                                    Deepwater, NJ  and Bronx, NY
 Di-n-propyl ketotiu



 Diisobutyl ketone


 Methyl ethyl ketone
Aceto  Chemical Co., Inc.
 Roehr Chemical Co., Inc.
 (subsidiary)

Union  Carbide Corp.
 Chemical & Plastics Div.

Atlantic Richfield Co.
 ARCO  Chemical Co., Div.
Celanese Corp.
 Celanese Chem. Co., Div.
Dart Industries
 Aztec Chems.
Dixie  Chemical Co.
Eastman Kodak Co.
Exxon  Corporation
 Exxon Chem. Co., Div.
Shell  Chemical Co.
                            Union Carbide Corp.
Long  Island City, NY
Institute and
So. Charleston, WV
Channelview, TX

Pampa, TX
Elyria, OH
Bayport, TX
Kingsport, TH
Bayway , NJ
Deer Park, TX

Martinez, CA
Norco, LA

Brownsville, TX
Total


50

115
	
n.a.
n.a.
210
100

	
50

75
600


64

115
n.a.
3
n .a.
200
100

n .a.
50

60
592



Dehydrogenation of
sec-butyl alcohol
Butane oxidation
Butadiene by-product


Dehydrogenation of
s_e_c- butyl alcohol

Dehydtogenation of
sec-butyl alcohol
Butane oxidat ion

 Methyl £-propyl  ketone
                            Union Carbide Corp.
                             Chemical & Plastics Div.
                                                                 Institute and
                                                                  So.  Charleston, W
 Methyl n-butyl ketone


 Methyl isobutyl ketone
 Methyl  n-arayl ketone
 ELastToan Kodak Co.
 Eastman Chemical Products, Inc.

 Eastman Kodak Co.
 Eastman Chemical Products, Inc.
 Exxon Corporation
 Exxon Chemical Co.,  Div.
 Shell Chemical Co.
 Industrial  Chemical  Div.

 Union Carbide Corp.
 Chemical &  Plastics  Div.
                             Eastman Kodak Co.
                             Eastman Chemical Products, Inc.
                             Lachet Chemical, Inc.
                             Union Carbide Corp.
                             Chemical & Plastics Div.
Kingsport,  TN


Kingsport,  TN

Bayway,  NJ

Deer Park,  TX
Dominguez,  CA

Institute and
 So. Charleston, WV
               Total
                                     Kingsport, TN
                                     Chicago Heights,  IL
                                                                 Institute and
                                                                  So.  Charleston,  WV
                                                                                           30 <2&r

                                                                                           35 (40)C
                                                                                           80 (80)
                                                                                           35 (16)c
30

40
80
35
                                                                                           240 (246)C  250
 Methyl n-hexyl ketone


 Ethyl n-butyl ketone
 Union Camp Corp.
  Harchem Div.
                             Union Carbide Corp.
                              Chemical & Plastics Div.
                                     Dover,  OH
                                                                 Institute and
                                                                  So.  Charleston,  WV
 Mesityl  oxide
                             Shell Chemical Co.
                              Industrial Chen. Div
                             Union Carbide Corp.
                              Chemical & Plastics Div.
                                                                 Deer Park, TX
                                                                 Dominguez, CA
                                                                 Insititue and
                                                                  So.  Charleston,
 Diacetone alcohol
                             Shell Chemical Co.
                              Industrial Chem. Div.
                             Union Carbide Corp.

                             Celanese Corp.
                                     Deer Park, TX
                                     Dominguez, CA
                                     Institute and
                                      So. Charleston, WV
                                     Pampa,  TX
                                                                 48
-------
Table  23.     (cont'd)
                                                                                                  Capacity  in mil] ions
                                                                                                       of  Pounds
                                                                                                     1974      197S
    ^rianone                    Shell  Chemical  Co.
                                  Base  Chemicals                        Martinez, CA

   3-Methylcyilonexanone         Frank  Enterprises                       Columbus, OH

   Oyi. lohexanone                 All led Chemical Corp.                                ,
                                  Plastic  Div.                           Hopewell, VA
                                 Celanese  Corp.
                                  Celanese Chem. Co.  Div.
                                 Dow  Badisrhe Co.
                                 El Paso Natural Gas  Co.
                                  El  Paso  Products  Co.
                                 Monsant o  Co.
                                  Monsanto Textiles Co.
                                 Nipro, Inc.
                                 Rohm 4 Haas Co,
                                  Rohm  & Haas Kentucky,  Inc.
                                 Union  Carbide  Corporation
                                  Chemical & Plastics Div.
                                 I'nion Carbide Corporation
                                  CehraUal  & Plastics  Div.                Institute and
                                                                          So. Charleston, WV

                       ;         Eastman Kodak Co.
                                  Eastman Chemical  Products,  Inc.         Kingsport, TN
                                 linion Carbide Corp.
                                  Chemicals & Plastics Div.               Institute and
                                                                          So  Charleston, WV

   U!,vl atnyl ketone             Givaudan Corp.                           Clifton,  NJ
                                 Shell Chemical  Co.
                                  Industrial Chem.  Div.                   Martinez, CA


                                 Mackenzie  Chem.  Works,  Inc.              Central  Islip,  NY
                                 Union Carbide Corp.
                                  ChemicaJ s & Plast ics Div.               Institute and
                                                                          So. Charleston, WV


                                 Union -Carbide Corp.
                       tone)      Chemicals & Plastics Div.               Institute and
                                                                          So. Charleston, WV

                                 Clark Oil 6, Refining Co.
                                  Clark Chemical Corp.                   Blue Island,  IL
                                 Civaudan Corp.
                                  Chemical  Div.                           Clifton,  NJ
                                 Union Carbide Corp.
                                  Chemical & Plastics DIV.                Bound  Brook,  NJ
                                                      f
                                 Allied Chemical  Corp.
                                  Plastics Div                           Frankforrt, PA
                                 Skolly Oil Co.                           El  Dorado, KS
                                 Universal Oil Products Co.
                                  Chemical & Plastics Group
                                  Chemical Div                           East Rutherford,  NJ

                                 Aceto ChemicaJ Co ,  Im.                 Calstadt, NJ
                                 &A> Corp., Chemical  Div.                 Linden,  NJ
                                 Givaudan Corp.                          Clifton,  NJ
                                 Norda Inc.                              Boontin,  NJ
                                 Orbics Products                         Newark,  NJ
                                 Parke, Davis & Ci .                      Detroit,  MI
                                 Universal Oi1 Prodm ts Co.
                                  Chemical  Div                           E.  Rutherford,  NJ
                                 N'evUle-Synthese ^rganics,  Inc.          NevilJe  Island, PA
Bay City TX
Free-port, TX
Odessa, TX?
Penasacola, ,FI
Augusta, GA
Louisville, KYe
raft, LAE
100
250
64
500
150
40
71)
100
250
64
500
150
40
_70
Cyclohexane oxidation
Cyclohexane oxidat ion
Cyclohexane oxidation
Cyciohexjne oxidation
Cyclchexane oxidation
Cy< lohexane oxidat ion
Cyclohexane oxidation
    a.   Exxon Chemical Company plans to expand capacity to 300 million pounds per year.   Expected  completion  date  is early  19/7
        (Anon.,  1975)

    b.   Shell Chemical Company is reportedly constructing a 230 million pound plant In Norco,  LA to  be  completed  in late  1977.
        (Chemical Marketing Reporter, 1975c)

    c.   Chemical Marketing Reporter, 1975a

    d    Captive  and merchant

    e.   Captive

    f.   Technical grade
                                                                      49
-------
CO
 o
 4-1
 CO
 (U
 e
 o
 4-1
 0)
TJ
 OJ
 U
 (U
4-1
 O
 0)
 O

 •a
 o
 (-1





>s
.C
•P  Q>
•H
a
Diisopropyl
ketone
Di-n-propyl
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                Major ketone distributors are listed in Table 25.   Countries




from which the aliphatic ketones (other than acetone) are imported include




West Germany, Japan, Belgium, France, and the United Kingdom (USTC, 1971).




           3.   Production Methods and Processes




                This section reviews the five most important methods used in




production of the selected ketones:  alcohol dehydrogenation (MEK and other




linear ketones); hydrocarbon oxidation (MEK, cyclohexanone and acetophenone);




phenol reduction (cyclohexanone); cumene oxidation (acetone and acetophenone);




and acetone  condensation and subsequent reactions (MIBK, diacetone alcohol,




mesityl oxide,  diisobutyl ketone, isophorone, and trimethylnonanone).  The




chemistry of these processes is described in Table 8 (see page 19).




                The most important method for producing the straight chain




ketones is by dehydrogenating the corresponding alcohols, which are obtained




by hydrating olefins  (Lurie, 1966; SRI, 1974, 1975).  Alcohol oxidation




processes yield water,'which must be removed-from the product.  Since, at




best, the water by-product requires an expensive distillation and, at worst,




the ketone-water azeotrope cannot be separated, the  dehydrogenation process




is preferred.




                The sec-butyl alcohol dehydration to MEK is representative.




In the U.S., the vapor phase dehydrogenation is preferred over the liquid




phase reaction.  Its  advantages over the liquid phase processes are higher




conversion and  better process control  (Sittig, 1968).  Figure 7 describes




the process  flow.   The components consist of a preheater, a vapor phase




reaction  chamber, and a purification system.  The catalyst is a supported
                                    56
-------
           Table  25.     Major  Distributors   of  the  Selected  Ketones
                               (From  CMR,   1975f)
tUfiTHYL KgTONE
\c et <• CheinK a I  Co. ,  Inc.
Cotuav Products to.
Hexagon Laboratories,  Inc.
toeltr Chemii-al  Division

DlibOBLrYi.  KMQNh
                                                                               METHYL
                                                                                              KETONE
Arasco Division Union  Oil
Ash land Chemical  Co.,  Industrial Chemicals & Solvents Division
OPS Chemical  Co
..hemisphere  ( or p.
Dynamic ChemiLal  Products.,  Inc.
Eastman C'hem u-a I  Products ,  Inc.
McKesson IhomicaL Co.
Stnmos Oil  ;,  Chemical  Co.
Suburban Chemical Co.
rranswurliJ < l,cmi<'dls,  Inc.
c'-i ion Car b ide  Corp.
A. I.I).  Chemir al  Co. ,  Inc.
Al 11 t-d  Cm on i ,11  Corp. ,  Specialty  Chemical Division
Amore Cbi-ra)' als,  Inc.
imsco Division Union  Oil
\rnst !  Solvent^ l  Chemicals  Co.
Arco Chemical Co.
Ashlaiid rhetnurfl  Co.,  Industrial  Chemicals  &  Solvents
Atlanta Chemical  Co.,  Inc.
Buff,i]" Solvents  & Chemicals  Corp.
( PS ( hemical  ynamac Chemical Products, Inc .
Eastman Chemical Products, Inc.
Exxon Chemical Co., U.S.A.
Fallek Chemical Corp.
Gage Product* Co.
Hoosier Solvents * Chemicals Corp.

Howe t> > rench
International Chtnical Corp.
Intsel Corp.
Hallinckrodt  Chemical Works
McKesson  Chemical  Co.
Morgan Chenn cals,  Inc .
Philipp Brothers Chemicals , Inc.
Riches-Nelson,  Inc
SRS, Inc.
Shell Chemical  Co.
Stanalchem, Inc .
Stinnes Oil & Chemical Co.
Suburban  Chemical  Co.
Tar Residuals,  Jnc
Texas Solvents  6. Chemicals Co.
Thompson-Hayward  Chemical  Co.
Trans world Chemi c a Is ,  Inc .
Union Carbide Corp. ,  Chemicals and  Plastics

METHYL ISOAMYL  KETONE
Amsco Division  Union Oil
Ashland Chemical  Co . ,  Industrial  Chemicals  &  Solvents  Division
Eastnan Chemical  Products , Inc -
McKesson  l hemical  Co.
Suburban  Chemi t a 1  Co.
Thompson-Hayward  Chemical  Co .
Traneworld Chemicals,  Inc.
Union Carbide Corp.,  Chemicals and  Plastics

       n-HEXYL  KLTONE
Glvaudan Corp.

MbSITYL OXIDE
A.I.D. Chemical Co.,  Inc.
Exxon Chemical  Co.,  U.S.A.
Shell Chemical  Co.
                                                                              D1ACETONL Al .C OHOL
                                                                              Aceto Chemical Co.
                                                                              Amsco Division Union
                                                                              Ashland Chemical  Co.
                                                                              Celanest: Chemical Co
                                                                              McKesson Chemii al Co
                                                                              Shell Chemical Co.
                                                                              Suburban Chemital to
                                                                              Tr«n«world Chemicals
                    Tnc
                     Oil
                    ,  Industrial  Chemicals  & Solvents Division
                      Inc
Union Carbide Corp. ,  Chemicals  and Plastics
-------
         Table   25.   (cont'd)      Major  Distributors  of  the  Selected Ketones
CYCLQHEXANONE

A.I.D.  Chemical Co., Inc.
Allegheny  Solvents & Chemicals  Co.
Allied  Chemical Corp., Plastics Division
Arnsto Division Union Oil
Amsco Solvents & Cnemicals Co.
Ashland Chemical Co., Industrial Chemicals & Solvents  Division
Atlanta Chenuc al Co., Inc.
Celanesc Chi-mical Co.
Chemisphere  Corp.
Columbia Nitiogen Corp./Nipro,  Inc.
Delta Solvents & Chemicals Co.
Dynamic Chemical Product s, Inc.
FaJlek  Chemical Corp.
Hoosler Solvents & Chemicals Corp.
Howe &  French
McKesson Chemical Co.
Olilo Solvents & Chemical* Co.
Vhilipp Brothers Chemicals, Inc.
htdiialcliem,  Tnc.
Suburban Chemical Co.
l'obc?y Chemical Co.
Transworld Chemicals, Inc.

ISOPHORONE

Aceto Chemical Co.,  Inc.
Amsco Division Union Oil
Ashland Chemical Co., Industrial Chemicals and Solvents  Division
JPS Chemica'  Co.
Exxon Chemical Co.,  U.S.A.
Intrrnat lonal Chemical Co .
McKesson Chemical Co.
Ohio Solvents £. Chemicals Co.
Stinnes Oij  & Chemical Co.
Suburban C,h :rucal Co.
Ihompson-Havward Chemical Co.
Union Ca^-bldu Corp., Chemicals and Plastics

ACETf LACETON>

Acetu Chemical Co.,  Inc.
Howard Hjll & Co.
Henlev .^ Co   Inc.
Lonz."   inc.
Mackenzie  Chemical  Works, Inc.
Wec.tco Chemic als,  Inc .
Aceto Chemical Co., Inc.
Araynco,  Inc.
Research  Organic/Inorganic Chemical Corp.

ACETOPHENONE
Allied Chemical  Corp., Plastics Division
Chemical Dynamics  Corp.
Clark Chemical  Corp.
C.ivaudan Corp.
Trueger Chemical Co.
Union Carbide Corp.,  Chemicals and Plastics

BENZOPHENONE
Conray Products Co.
Fabtex Corp.
Givaudan Corp.
 ICD Chemicals,  Inc.
Norda,  Inc.
 Orbis Products  Corp.
 Parke,  Davie &  Co.,  Chemical Marketing
 Universal  Oil Products Co., Chemical  Division
                                                              58
-------
                      l alcohol
                          » Prfheatet
                                             Solvent
                                                      Hydrogen
                                                     Methyl
                                                     ethyl
                                                     ketone
                                               T
                                              Alcohol
                                             to recovery
Figure  7.   Methyl Ethyl  Ketone From Secondary Butyl Alcohol By
            Dehydrogenation (From Faith  et al., 1965)

    (Reprinted with permission from Interscience Publishers)
                              Nitrogen
'-(l
Unreactel
hydrocarbons


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- — '—L2 	 ^.

-
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J
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Other
organics
Figure  8.   Methyl Ethyl Ketone From  Butane by Liquid-Phase
            Oxidation  (From Faith e_t  _al. ,  1965)

     (Reprinted with  permission from  Interscience  Publishers)
                                  59
-------
metal oxide, usually zinc oxide, although other catalysts, such as magnesium

oxide, copper oxide, beryllium oxide and chromium oxide have been used

(Austin, 1974; Faith £t al. , 1965).  The preferred reaction conditions are

the approximate temperature range 400 to 500°C, with a mean residence time

of 2 to 8 seconds (Faith et_ jal. , 1965; Sittig, 1968; Austin, 1974).  Operating

pressures are described as atmospheric.  The reported alcohol conversion to

MEK is from 75 to 85%.  In the purification system, the reactor vapors are
                                           •
cooled in a brine cooled condenser.  The uncondensed gases are scrubbed,

usually with see-butanol, to remove entrained MEK and sec-butanol; the latter

is then recycled.   The condensed fraction is distilled and fractionated

(Austin, 1974; Sittig, 1968; Faith £t ail. , 1965).

                A liquid phase  dehydrogenation is reportedly used  for MEK

production  in Europe.  The conditions are 300°F at atmospheric pressure using

Raney nickel or copper chromite as catalyst.  MEK and hydrogen are driven

off as soon as they form  (Austin,  1974;  Faith £t _al., 1965).

                Liquid phase oxidation of the corresponding hydrocarbons can

be used for the manufacture of  eyelohexanone from cyclohexane; acetophenone

from  ethyl  benzene; and MEK from n-butane  (Austin,  1974;  Faith £t  al.,  1963;

Dorsky ej^ aL. , 1963).  Conditions must be carefully  controlled to  prevent

competing reactions.  For  example, by varying the conditions,  acetic acid

can be the  major product  in butane oxidation  (Faith  et_ _al. , 1965).   The cyclo-

hexane and  butane oxidations are similar.  Figure 8  outlines the  process flow

chart for the liquid  phase butane  oxidation.  The hydrocarbon  is  oxidized  at

ca. 125°C in a solution containing a  cobalt or manganese  salt as  catalyst.

Glacial acetic acid and water  have been  reported as  solvents  (Dorsky et al. ,

1963; Faith et al., 1965).  With either  solvent, an  acid  resistant reactor
                                    60
-------
must be used.  The pressure is generally maintained at about 30 psig in



order to keep the hydrocarbon in solution (Dorsky et al., 1963; Faith



e_t jal. , 1965).  Reaction time is reported as 1.5 hours (Dorsky e± _al. , 1963).



               Hydrogenation of phenol in a heterogeneous process is the



major method for cyclohexanone production.  Phenol reduction can be performed



either in liquid or gas phase.  Figure 9 shows the typical process flow.  The



reactor temperature is held at 75° to 150°C.  While at the lower temperatures



phenol conversion is low, at higher temperatures selectivity is poor.  The



catalyst is either palladium, or some other metal of the palladium group,



dispersed on an inert support (1 to 10% by weight).  The solid catalyst is



usually held within perforated tubes at the bottom of the hydrogenator.



The gas consists of hydrogen and nitrogen, generally in a ratio of 85/15 at



15 to 75 psig.  Conversion of almost 96% and a yield of almost 95% is re-



ported (Sittig, 1968).



               The cumene hydroperoxide process yields phenol, acetone  (0.6



pounds per pound of phenol produced) and acetophenone (0.05 pounds per pound of



phenol produced) (Lederman and Poffenberger, 1968; Dorsky et^ _a!L. , 1963).  The



process flow is shown in Figure 10.  An emulsified solution of cumene in aqueous



sodium carbonate (pH 8.5 to 10.5) and air is fed into a reactor maintained at



160 to 260°F at a pressure slightly above atmospheric.  About 30% conversion



to cumene hydroperoxide  [C,HC(CH_)^O^H] is reached after three  to four hours.
                          b ~>    J 2. 2.


Unreacted cumene is removed by steam or vacuum stripping.  The remaining cumene



hydroperoxide (approximately 80% concentration) is fed to dilute acid (usually



5 to  25% sulfuric acid at 120-150°F).  The resulting mixture is phase separated.



The oil layer contains acetophenone and a-methyl styrene in addition to phenol,
                                     61
-------
                                                  Solvent
                                                                  Inert g»ws
                                                                 —• -"• Cyclohexanone
Figure  9.   Cyclohexanone By  The Catalytic Hydrogenation of Phenol
                 (From Sittig,  1968)
       Alkali
    Cumene
    Air
Water

 \
                     Dilute
                  Recycle cumene
                 Acetone
                              '
                                              Mcthylslyiene
                                                             Phenol
                                                             Acetophenone
Figure 10.  Acetone and  Acetophenone  By Cumene  Oxidation
              (From Lederman and Poffenberger,  1968)
    (Reprinted  with permission from  Interscience Publishers)
                                   Acid
                                             *-Water
                                                    Methyl
                                                   isobutyl
                                                    ketone
 Figure  11.   Methyl  Isobutyl Ketone From Acetone  (Via Diacetone
              Alcohol and Mesityl Oxide)  (From Faith  ej: al. ,  19650
    (Reprinted  with  permission from Interscience Publishers)
                                62
-------
acetone and unreacted cumene.   These organics are separated by distillation




(Lederman and Poffenberger, 1968).




                MIBK is the most important ketone produced by acetone con-




densation.   The flow sheet for its preparation and that of its intermediates,




diacetone alcohol and mesityl oxide, is shown in Figure 11.  Acetone is




dimerized to diacetone alcohol by a liquid phase reaction at 0 to 20°C over




a fixed bed, alkaline catalyst (Austin, 1974; Faith et. al. , 1963).  Reaction




times of approximately 6 seconds are reported for a tubular reactor operation




(Sittig, 1968).  Diacetone alcohol is then dehydrated in the presence of




a weak acid at 100 to 120°C to mesityl oxide.  The mesityl oxide is then




hydrogenated at mild temperatures (120 to 165°C) over nickel or copper




catalyst (Austin, 1974; Faith £t jil., 1965; Sittig, 1968).




                Isophorone and diisobutyl ketone are products of triacetone




alcohol.  The acetone trimer is a by-product in the diacetone alcohol pro-




duction  (Oosterhof, 1967), or under modified reaction conditions it is ob-




tained as the major product (Lurie, 1966; Sittig, 1968).




           4.   Market Prices




                Table 26 reports ketone prices for the years 1970-1975.




The price of MEK has been steadily decreasing since 1958.  Its price per




pound has decreased as follows: 12.5<: from 1958 to 1967; 11.5c from 1968




to 1969; 10.5? in 1970; IOC in 1971; and 80 in 1973  (SRI,  1972b;  CMR,




1974a).  Since 1958, MIBK price has remained constant in the range of 13.0




to 14.5
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According to the Chemical Economics Handbook (SRI, 1973), cyclohexanone




price was 31<: per pound (delivered) from 1959 to 1967, but it was reduced




in 1968 to 18<: per pound (delivered) in order to compete with isophorone as




a coating solvent.  Since growth was less than expected, the price was in-




creased in May 1973 to 19.5
-------
restricts branched chain ketones like MIBK to a greater  extent  than  MEK




and other straight chain ketones.   The coatings market has  met  the regu-




latory action by removing branched chain ketones and reformulating with




straight chain ketones,  reformulating with other solvent systems, and




moving toward newer technologies.   The overall historical effect  has been




moderate growth for MEK (Kline,  1975; SRI, 1972a; CMR,  1975a).




                     The Occupational Safety and Health  Administration




(OSHA) has recently initiated new occupational standards for MEK and six




other ketones:  methyl n-propyl ketone; methyl n-hexyl ketone,  ethyl n-




butyl ketone; MIBK; cyclohexanone; and mesityl oxide (Anon. 1975c,  1975e,




1975f).  The new standards set an "action level" at one-half the maximum




permissible exposure limit.  The provisions of the occupational standards




are discussed in "Regulations"  (pages 286-287).  These standards, if they




come into effect, could weaken the market position for MEK, as well as the




other solvents presently exempt from some air pollution controls.  It also




might result in further weakening of the solvent based coatings share of




the coating market.




                     The occupational health problems in vinyl chloride




plants might create some losses in PVC resin manufacture (Anon., 1975d).




Since  formulation of PVC coatings is an important outlet for MEK as well



as other ketones  (see Major Uses, pages  72-80),  reduction  in PVC resin, manu-




facture  could in turn weaken the MEK market demand.  However, if the PVC




market is replaced by other resins that use ketones, the net effect for




MEK would not be significant.




                     Goldstein  (1975) has suggested that increased costs in




petroleum feedstock might  improve the market position of cellulosic products,
                                  66
-------
If this prediction is accurate,  it represents a positive influence in the




MEK market.   MEK as well as other ketones are common solvents for cellulosics




(see Major Uses, pages 72-80).




                b.   Methyl Isobutyl Ketone




                     The demand for branched chain ketones,  including MIBK,




is declining as the result of air pollution regulations based on Los Angeles




Rule 66 (Oosterhof, 1967; CMR, 1975a).  The Chemical Marketing Reporter




(1975a) stated that while MIBK production is on the decline, the sales have




not been drastically reduced.  Historical demand for MIBK (1963 to 1973)  has




dropped at 1% per year.  The Chemical Marketing Reporter (1975a) has pro-




jected decline through 1975 at 5% per year; 125 million pounds in 1979 down




from 161 million pounds in 1975.




                c.   Cyclohexanone




                     The nylon market accounts for some 95% of the cyclo-




hexanone produced  (SRI, 1973).  The currently expanding nylon market is




reportedly straining feedstock capacity  (Greek, 1975).  At currently pre-




dicted expansion, demand is expected to exceed existing and proposed feed-




stock capacity by 1977.




                     About 5% of the cyclohexanone produced is used as a




solvent.  Since it is exempt from restrictions on photochemically active




solvents, it has been used as a replacement for restricted solvents, such




as isophorone.  However, the Chemical Economics Handbook (SRI, 1973) re-




ported that its growth in the solvent market was less than expected.




According to the Chemical Economics Handbook, the reasons for the slower




market growth included slower than expected promulgation of the Los Angeles
                                  67
-------
Rule 66 type air pollution regulations in the areas with a high demand for




cyclic ketones and increased recycling capabilities in the coating plants.




The recent OSHA decision placing cyclohexanone under "action level" stan-




dards could weaken its present strength as a replacement for the photochem-




ically reactive solvents.  This, along with the expected, tight supply could




reduce cyclohexanone's share of the coating solvent market.




                d.   Other Ketones




                     While branched chain ketones have been losing strength




in the solvent market, straight chain ketones have in general been gaining




(CMR, 1974a, 1975a).  The straight chain ketones have been used to replace




both branched chain ketones and other photochemically reactive solvents




(CMR, 1974a, 1975a; Levy, 1973).  However, methyl n-butyl ketone failed to




be a suitable substitute for MIBK since it was found to cause nerve damage




(CMR, 1975a) (see p. 261).  Demand for acetophenone in solvent systems and




for other uses is not expected to appreciably change  (CMR, 1975b).
                                  68
-------
     B.    Uses




          1.    Major Uses




               Table 27 lists the major uses of the selected ketones.  Table




28 summarizes estimates of consumption in 1973 for MEK, MIBK, and cyclohex-




anone.  Some elucidation is also given for the uses of diacetone alcohol,




mesityl oxide, isophorone, acetophenone, and benzophenone.  Consumption of




the eight ketones totaled approximately 1.5 billion pounds.  Only qualitative




information is available on the consumption of the remaining ketones.  But




the literature does suggest that large proportions of diacetone alcohol, iso-




phorone and mesityl oxide are consumed as solvents (USTC, 1971).  It also




appears that non-solvent uses consume most of the acetophenone and benzophenone




production (Browning, 1965; Dorsky j_t aJ_. , 1963; Anon., 1975a; van den Dool,




1964).




               a.   Chemical Intermediates




                    The cyclohexanone used as a chemical intermediate




accounts for approximately 95% of its total production.  The products, adipic




acid  and E-caprolactam, are used in the manufacture of nylon 66 and nylon 6,




respectively  (SRI, 1973; Kralovec and Louderback, 1965).




                    Synthesis of the peroxide and the oxime of MEK accounted




for approximately 1% of consumption (USTC, 1969, 1971).  While the oxime is




used  as an anti-skimming agent in surface coatings (USTC, 1971), the peroxide




is important as a radical polymerization initiator (USTC, 1969; Noble, 1974).




               b.   Solvents




                    Solvents can be divided into two rather broad areas:




those used in coatings and allied formulations (inks, adhesives, etc.) and




those used for selective extraction.  For use in coatings, the solvent must





                                     69
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           Table 27.   Major Uses of the Selected Ketones
        Use

Application solvent:

    Coatings
       Cellulosic, vinylic
       and acrylic resins
   Ketones
All aliphatic
ketones and
acetophenone
 References
Hagemeyer, 1952
Lurie, 1966
Browning, 1965
USTC, 1971
Dorsky, 1963
Dean, 1968, 1972a,
      1972c
    Coatings
       Alkyd, epoxy and
       other natural and
       synthetic resins
All aliphatic
ketones and
acetophenone
Dean, 1970, 1972b
Blount, 1975
Lurie, 1966
    Adhesives
MEK, MIBK
Blomquist, 1963
Selective extraction:

    Lube oil/wax refining
MEK, MIBK,
diisobutyl ketone
Tuttle, 1968
Lurie, 1966
    Rare metal refining
MIBK, diisobutyl
ketone, mesityl
oxide
 Seaborg,  1963
 Nielsen,  1966
 Taylor, 1969
 Silvernail  and
 McCoy, 1969
 Chemical  intermediate:

    Product
        e-caprolactam
        Adipic  acid
 Cy clohexanone
 SRI,  1973
 Kralovec and
 Louderback, 1965
        Methyl ethyl ketoxime    MEK
        Methyl ethyl peroxide    MEK
                        USTC,  1971
                        USTC,  1969
                                  70
-------
 CO
^r
r^~
01
!   1
             ~~-   o    o
 c
 CO

en
 B
 O
o\
 c
 o
 O
 0)
 G
 O
 I
 to
 C
 O
CJ
 w
w
oo
CN
 CO
H
                                                                                                         i-     <
                                                                                                        C C  H w
                                                                                                  • 13 60     H
                                                                                                     01  O  O  G i
                                                                   71
-------
dissolve or disperse a material into a form suitable for application,  and




after application the solvent must evaporate.   Primary consumption of  the




ketonic solvents occurs through their use in the coatings industry.   In




selective extractions, the solvent dissolves a substrate from a mixture in




order to separate and purify one or more of the components.   Ketones are con-




sumed in moderate quantities for extraction purposes, e.g.  for rare metal




refining and for lube oil/wax refining (Wyart and Dante, 1969; von Fisher




and Bobalek, 1964; Tuttle, 1968).




                c.   Coating Formulations




                     Surface coatings are applied to impart protection,




special properties and decoration.  Coatings consist of films formed from




natural or synthetic resins, which are usually combined with pigments




and other additives to control drying or provide special qualities.  Sol-




vents are used to prepare a form in which the coating can be suitably




applied.  The solvent must disperse the coating materials and yield a




solution with a viscosity suitable for application.  After application, it




must evaporate at a rate capable of yielding the correct finish  (SRI, 1971;




Donnel, 1967; Higgins, 1964; von Fisher and Bobalek, 1964; and Friedberg,




1965).  The ketones are particularly good solvents  for  coating formulations.




They have greater solvent strength than other oxygenated solvents of similar




boiling points, and they have the required viscosity characteristics.  Be-




cause they have excellent capacity for being diluted with the relatively




cheap hydrocarbon solvents, they have an important  economic advantage over




other classes of active solvents, such as the esters  (Martens, 1968; Wyart




and Dante, 1969).
                                    72
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                The ketones are generally recognized as especially good




solvents for vinylic, cellulosic and acrylic resins (Lurie,  1966; USTC,




1971; Klug, 1964; Donnel, 1967).  Ketones generally comprise about 25%




of the total weight of coating formulations (see Table 29).   The active




solvent concentration can go as high as 40% in some formulations




(von Fisher and Bobalek, 1964).  While coatings for spray application are




formulated with the low boiling, low molecular weight ketones, brush




application requires formulation with the higher boiling, higher molecular




weight, and more expensive ketones (Martens, 1968).  Ketones have also




been mentioned as solvents for alkyd, epoxy, and other resins (Blount,




1975; Hughes _et _al. , 1975).




                     While the coatings industry consumed an estimated




800 million pounds of ketones worth 70 million dollars in 1970, oxygenated




solvent consumption was estimated at 1850 million pounds (valued at 185




million dollars) (SRI, 1971).  Estimates of acetone consumed as a coating




solvent ranged from 200 to 350 million pounds  (USTC, 1971; CMR, 1974b;




Blackford, 1975).  It is concluded that acetone and MEK account for roughly




two-thirds of the ketones consumed and MIBK about one-sixth.  The bulk of




the remaining ketonic solvents  consists  of  cyclohexanone, mesityl  oxide,




isophorone and diacetone alcohol, which were consumed in more or less




similar quantities  (see Table 22, page 46  and Table 28).




                     Hughes et al. (1975) have published a conflicting




estimate of solvent consumption by the paint industry for 1972.  While




their dollar estimate is not significantly different, their estimated
                                   73
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quantities are lower:  total solvent, 2930 million pounds; oxygenated
solvents, 930 million pounds; and ketones, 350 million pounds.  The
ketones used were estimated as follows (in millions of pounds):  acetone,
136; MEK, 145; MIBK, 60; and all other ketones, 11.

       Table 29.  Composition of a Typical Coating Formulation:
                           White Vinyl Aircraft Enamel
                             (From Gaynes et al., 1967)
                                              Percentage
                 Material                     by weight
               Film formers
                Titanium dioxide                 I6-8
                Santicizer 160                    3.0
                Amber lack 292X                   41.7
                VAGH                              7 . 7
                Guaiacol                         <0 • 3-
                KRZ  (Vanderbilt)                  0*6
                Total                            69.9
               Solvents
                Cyclohexanone                     1 • 5
                Isophorone                        4 . 9
                Methyl  isobutyl ketone           19.1
                Toluol                            4.6
                Total Solvent                    30.1
                                    74
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                  The end use of ketonic solvents in coatings can only be

  qualitatively estimated from resin consumption data.  Surface coating data

  for 1970 is listed in Table 30.  The criteria for industrial use is that the


              Table  30.   Consumption of  Surface  Coatings  in 1970
                          (From SRI,  1971)
Total Surface Coatings
Trade Sales
  House
    Water based
    Solvent based
  Miscellaneous
    Automotive refinishing
    Traffic paint
    Other

Industrial
    Automotive
    Wood furniture and fixtures
    Metal containers
    Metal furniture and fixtures
    Appliances
    Machinery and equipment
    Paper film and foil
    Sheet, strip and coil
    Factory finished wood
    Transportation (non-automotive)
    Electrical insulation
    Other

Maintenance finishes
    Exterior
    Interior
    Marine

Millions
of gallons
820
425
380
230
150
45
20
15
10
395
40
50
40
25
20
25
25
15
15
15
10
50
65
35
20
10
Value in
millions^ of
dollars
2,760
1,530
1,360
755
605
170
110
30
30
1,230
130
110
110
85
80
75
75
65
45
45
40
150
225
125
65
35
                                        75
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coating was applied in a factory (SRI,  1971,  von Fisher  and  Bobalek,  1964).




Consumption in automobile refinishing plants, which apply  coatings  just as




in manufacturing plants, is classified  as trade sales.   Although trade sales




accounted for somewhat more than one-half of  the total  coatings  market, it




is estimated that they consumed only a  relatively small percentage  of the




ketones.  Of the total 425 million gallons of trade sales  paint, 230 million




gallons were water-based house paints,  which  were not formulated with ketones




(Dean, 1972a, 1972b; Donnel, 1967).  The remaining trade sale paints con-




sisted of 150 million gallons of solvent-based house paint and 45 million




gallons of miscellaneous paints, which  consisted mainly of automobile re-




finishing and traffic paints (SRI, 1971).




                     Table 31 summarizes trade sales data for alkyd and




acrylic coatings.  Alkyd coatings are generally thinned with the less




expensive hydrocarbon solvent.  Some formulations, such as for spray appli-




cations, do contain some low boiling ketones to impart quick drying (Dean,




1972b; Donnel, 1967).  Since this is not necessary in the house paints, it




is concluded that  the majority  (ca. 139 million gallons) of the total solvent-




based house paint  (ca.  150 million gallons)  consumed only a small quantity




of the ketones.  The automobile refinishing  and traffic paints, which do




require quick drying, will contain some ketone.  Overall, it is concluded




that ketonic solvents are not heavily consumed in trade sale, paints,  and"




that the trade sale paints which most  likely contain ketones are predom-




inantly specialty  paints and not usually consumer items.
                                    76
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   Table 31.  Consumption of Selected Surface Coatings in Trade Sales
                   Alkyd Coatings Consumption in 1971
                           (from Dean, 1972b)


                                                   Amount in
           Type                                 millions of gallons

         House paint                                 139
         Automobile refinishing paint                 12
         Traffic paints                               10
         Miscellaneous paints                          4
           Solvent Based Acrylic Coatings Consumption in 1971
                            (from Dean, 1972a)
                                                   Amount in
           Type                                 millions of gallons
         Automobile refinishing  paint                  6
         Other formulations                             2
                     Table 32 describes the industrial consumption of acrylic,

cellulosic, and vinylic coatings; these are thought to consume most of the

ketones (USTC, 1971; SRI, 1972a).  Alkyd coatings, which are sometimes form-

ulated with ketones , are also included.  Acrylic coatings are important as

automobile top coats and for other metal coatings; cellulosic resins are

heavily favored for wood and paper; and vinylic resins are important as

metal coatings and also in textile coatings.  Altogether, these coatings

are fairly evenly divided over the industrial sectors, and it would seem then

that ketonic solvents are also fairly evenly divided within the coatings

industry.

                d.   Adhesives

                     The solvent action in adhesive application is similar

to that in coatings.  The solvent must disperse the adhesive binder to a

spreadable form and must evaporate after application.  The binder can consist
                                    77
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     Table  32.    Consumption of Selected  Industrial Surface Coatings
Acrylic Coatings  (fro« Dean, 1972a)

                                         Amount  in
Type                                millions of  gallons

Automobile topcoat  finishes                 18.0
Coil coatings                               4.5
Appliance coatings                           3.5
Other coatings (a)                           7.0

Total                                      33.0
Cellulosic Coatings  (from Dean, 1968)

                                         Amount in
Type                                millions of gallons

For nitrocellulose and
cellulose acetate-butyrate
  Wood furniture finishes                   29
  Factory finished Wood                     6
  Paper, film and foil                     15
  Miscellaneous coatings (b)                 8
For ethyl cellulose  and other
cellulose derivatives                       	5_
Total                                      63
Vinylic Coatings Consumption in  1971  (from Dean, 1972b)

                                         Amount in
Type                                 millions of gallons

PVC resin solution
   Can and closure containers                18
   Maintenance and marine                    6
   Miscellaneous metals (c)                  9
   Other (d)                                J_
Total                                       40
                                   Amount  of  PVC  consumed
 Type  of PVC Dispersion             in millions of pounds

 Plastisols in paint-like
 coatings  for metal surfaces               12.5
 Organosols in paint-like
 coatings  for metal surfaces                5.5
 Other plastisols and organosols (e)      440.0
 Total                                   458.0
 (a)   Includes metal containers, metal furniture,  transportation other than automotive and  factory finished wood.

 (b)   Includes cans, machinery, automotive and metal  finishes.

 (c)   Includes automobiles, appliance' equipment and machinery, electric wire and furniture.

 (d)   Includes film and foil, magnetic tape,  paper and wood.

 (e)   Most used  in molding and textile coating.
                                                   78
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Table  32.    (cont'd)
            AcryJic Coatings (from Dean, 1972a)
                                                                       Coatings
        Type                                                     (millions of gallons)
        Product Finishes                                                      145
          Wood furniture and fixture finishes (f)                   40
          Machinery and equipment enamels (g)                       22
          Metal furniture finishes                                 20
          Auto, truck and bus finishes (h)                         12
          Metal container finishes  (i)                            10
          Appliance finishes (j)                                    5
          Insulating varnishes (k)                                  3
          Coil, sheet and strip coatings (1)                         3
          Prefinished wood primers                                  3
          Toy, sporting good, gym and baby
          equipment finishes                                        2
          Other industrial product finishes (m)

        Maintenance Finishes                                                   35
          Exterior coatings                                        18
          Interior coatings                                        12
          Marine  coatings                                           5
           Total                                                               180
          (f)  Includes nitrocellulose  lacquers plasticized with alkyd resins.
          (g)  Includes  farm equipment,  construction equipment, earth moving equipment, electrical
              machinery,  stationary machinery and machine tools.
          (h)  Includes auto engine enamels  and chassis enamels for buses and trucks.
          (i)  Includes drum enamels and coatings for  the exterior of metal cans.
          (j)  Includes major and  minor appliances plus air conditioning and heating equipment.
          (k)  For electrical insulation applications  (excludes polyester coatings).
          (1)  All prefinished metal coil coatings are included.
          (m)  Includes coatings for railroad equipment, aircraft, miscellaneous transportation
              vehicles, paper and paperboard, flexible packaging materials (such as film and foil),
              hardware, silk screens,  cable, leather, and other miscellaneous applications.  Tinting
              color  vehicles are  also  included.
                                                        79
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of natural gum, rubber or synthetic resin.   Some of  the more important




adhesives using ketonic solvents are based on phenol-epoxy resins,  phenol-




butyral resins and cellulose acetate-butyrate resins,  all of which are  used




for metal bonding.  These are used in aircraft dopes,  for automotive manu-




facturing, and joining tubular metal (e.g., bicycles and refrigerator cooling




coils).  Other systems include rubber-based adhesives  used in masking tape




and as can sealers and butadiene-acrylonitrile/vinyl chloride systems for




leather binding (Blomquist, 1963).




                e.   Extractive Solvents




                     From 6 to 10% of the ketonic solvents are consumed in




refining rare metals and dewaxing lube oil.  The refining processes take




advantage of the ketones capability to dissolve or not to dissolve some com-




ponents of a mixture.  The ketones used for lube oil/wax refining include




MEK,  MIBK, and diisobutyl ketone  (USTC, 1971; Tuttle,  1968).  Ketones employed




for rare metal extraction include 2,4-pentanedione,  MIBK, diisobutyl ketone,




and mesityl oxide  (Lurie, 1966; Browning,  1965; USTC, 1971).




                     The flow sheet for a  typical oil/wax refining operation




is shown in Figure 12.   In this operation, the  feedstock and solvent are




heated to approximately  125°F.  The ratio  of the solvent to  feedstock is  in




the range of  2.2  to  3.2.  Since the solvent will selectively dissolve the




oil,  the wax  can  be  crystallized  and collected  by a rotary vacuum  filter




maintained at  17  to  20°F.  Oil content of  the wax cake  is further  reduced




by washing with cold,  oil-lean solvent.  Solvent is separated from the




processed wax  cake and from oil by  distillation.  In a  typical operation,




7500  barrels  of heavy  paraffin distillate  is processed  daily with  an annual
                                     80
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yield of 200 million pounds of wax and one million barrels of lubricating

and other oils.   Solvent loss in the process is estimated at 0.1% of the

feed  (Tuttle,  1968;  Nelson, 1968; SRI, 1972a).
                         Rotary
                         vacuum
                          filter
                 Ketone
                                                         Ketone
Receiver

 Settler
        IKetone
  fa—nc,.   ,
          Flash  *- Ketone
          drum .-«-.
                                                             Ketone
                                                              Stripper
            feed
                 Stripper
                 •*— Steam
                                                                    -Oil
                                                                  ->-Wax
          o Pump
         (If) Exchanger
         (H) Heater
         (1?) Refrigeration
       Figure 12.  Flow Plan For  Solvent  Dewaxing
                   (From Tuttle,  1968)
       (Reprinted with permission from  Interscience Publishers)

                      Rare metal  refining utilizes the partitioning of metal

 complexes between ketonic and aqueous  phases.   The process consists  of  pre-

 paring the appropriate metal ion complexes in aqueous solution followed by

 liquid/liquid extraction with the  ketonic solvent.  A typical example of this

 procedure is the separation of tantalum  and niobium from ores containing the

 two metals as well as titanium,  zirconium, iron, manganese and other metals.

 The fluorides of tantalum and niobium  can be selectively extracted from the

 aqueous phase into MIBK.  While  tantalum will partition into the MIBK at mod-

 erate acidity, niobium requires  higher acidities.  The metals can be isolated

 either by first extracting tantalum at low pH and then extracting niobium at

 high pH with fresh solvent, or by  extracting both metals at high pH  and then

 partitioning the niobium out of  the organic phase with a fresh, low  pH  aqueous

 phase (Taylor, 1969).
                                     81
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                     The ketonic extraction procedure  is  used  for  refining




the actinides (Seaborg, 1963;  Silvernail and McCory, 1969),  including




actinium, thorium, uranium,  plutonium,  zirconium,  hafnium (Nielsen,  1966),




tantalum, and niobium (Taylor, 1969).




                     In summary, ketonic solvents  are  consumed primarily




in the industrial coatings industry.   Other solvent uses  include lube  oil




dewaxing and chemical extraction processes.  Since industrial  uses are per-




vasive, the distribution of the industries using ketones  in coatings and




other solvent applications probably follows urbanization  throughout  the U.S.




           2.   Minor Uses




                Table 33 lists the minor uses of the selected  ketones.  Most




are either as chemical intermediates or as solvents.  Some are closely re-




lated to their major uses; their classification as minor  uses  was based on




the relatively small amounts consumed.   Minor solvent  formulation uses




include:  inks (MEK, MIBK, methyl isoamyl ketone,  mesityl oxide, diacetone




alcohol, cyclohexanone, and 2,5-hexanedione); pesticides  (MIBK, diacetone




alcohol, and cyclohexanone); and wood stains (MEK, MIBK,  diisobutyl ketone,




diacetone alcohol, and 2,5-hexanedione).




                     Selective extraction with ketones is used in the




pharmaceutical industry, tall oil refining industry, and for the laboratory




extraction and analysis of aqueous metals  (MIBK, diisobutyl ketone,  mesityl




oxide).  Other minor uses taking advantage of the ketonic solvent power in-




clude the cleaning and degreasing of leather, metal, and wool  (MEK, MIBK,




cyclohexanone, and methylcyclohexanone) and  the formulation of paint, varnish,




and rust removers  (MEK, diacetone alcohol, and mesityl oxide).
                                   82
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   Table  33.    Minor Uses of  Ketones
     Ketone
Acetophenone
2,4-Pentanedione
 2,5-Hexanedione
Benzophenone


Cyclohexanane
Diacetone alcohol
 Diisobutyl ketone
 Ethyl amyl ketone

 Ethyl butyl ketone


 Isophorone
Intermediate in the syntheses of
Pharmaceuticals, resins, corrosion
inhibitors, rubber chemicals, dye-
stuffs, and flavor and fragrance
materials.

Intermediate in the syntheses of
acetylacetone peroxide, other
1,3-diketones,  1,3,5-triketones,
pyrroles,  pyrazoles,  isoxazoles,
quinolines.
Preparation of metal chelates for
use as driers in coatings.
Preparation of dental materials.
Color photography developing.
Gasoline additives.

Intermediate in the synthesis of
perfume ingredients and other
materials.
Preparation of chelates.
Tanning agent.
Solvent for inks.
Solvent for wood stains.
Gasoline additives.

Flavor and fragrance  ingredient.
Drier in U.V. inks.

Solvent to inks and pesticides.
For cleaning and degreasing metals
and leathers.
In paint removers.
As a spotting and relustering agent.
Solvent for textile dying.
Sludge solvent in oil for piston-
type aircraft lubrication.

Component  in castor-oil based
hydralic fluids.
Solvent for Inks, pesticides
and woodstains.
In paint and rust removers.
As a viscosity  index  improver
for lube oils.

Solvent for extracting
Pharmaceuticals.
Laboratory reagent for  analysis
of aqueous metals.
Solvent for wood stains.
In rubber  for milled  crepe rubber.
Intermediate for the  syntheses  of
dyes,  inhibitors, Pharmaceuticals
and insecticides.

As flavor  and fragrance additive.

Intermediate in the synthesis of
organic products.

In synthesis of 3,5-xylenol.
In synthesis of plant growth
retardants.
   References

Dorsfcy et al., 1963
Browning, 1965
Anon., 1975a
Opdyke, 1973/74


Lurie, 1966
Ream, 1952
Freeman, 1964

Freeman, 1964

Shell Internationale, 1963

Lurie,  1966
Reynolds, 1952
Bruno, 1968
Peacock, 1969
Shell  Internationale, 1963

Opdyke, 1973/74
Van den Dool, 1964

Bruno, 1968
Browning, 1965
 S.R.I.,  1973
 Kralovec and
 Louderback, 1965

 USTC,  1971
 Lurie,  1966
 Bruno,  1968
 Peacock, 1969
 Rector,  1952
Lurie,  1966
Blackwood, 1969
Skougstad, 1970

Peacock,  1969
Browning,  1965
 Opdyke,  1973/74

 Browning,  1965
 Leston,  1971
 Haruta,  1974
-------
Table  33.    (cont'd)
                         Ketone
                                                      Uses
                                                                                    References
                      Methy1-
                      cyclohexanone

                      Methyl ethyl
                      ketone
In varnish and rust removers.
                                       Browning,  1965
                      Methyl  isoamyl
                      ketone
Intermediate in the synthesis          Lurie,  1966
of methyl isopropenyl ketone, sec-
butylamine, 1,3-diketones.
As a solvent for inks                  Bruno,  1968
and wood stains.                       Peacock,  1969
In paint removers.                      Downing,  1967
As a dye solvent.                       Hagetneyer,  1952
In degreasing woolens.
In manufacture of  artificial leathers.
As an extractant in hardwood pulping.   S.R.I.,  1972
Laboratory solvent.                    Browning,  1965
In Pharmaceuticals and cosmetics.
Stabilizer for methylene chloride.     Beckers,  1975

Solvent for inks.                       Bruno,  1968
                      Methyl  isobutyl
                      ketone
Solvent for pesticides in wood stains  Lurie,  1966
                      Methyl nj-amyl
                      ketone
                                           and inks.
                                           For cleaning and degreasing metals.
                                           Intermediate in the synthesis of
                                           imldazoles and acetal ethers.
                                           Denaturant for ethanol.
                                           Extractant for tetracycline
                                           salts.
                                           Laboratory reagent for the analysis
                                           of aqueous metals.
                                       Browning,  1965
                                       Peacock,  1969
                                       Bruno,  1968

                                       Pentz and Lescisin, 1965
                                       Blackwood, 1969

                                       Skougstad, 1970
As a fragrance and flavor ingredient.  Rector, 1952
                      Mesityl Oxide         Solvent  for  inks.                      Bruno, 1968
                                            In paint and varnish removers.         Downing, 1967
                                            In stain removers.
                                            Synthesis of lube  oil  additives        Lurie, 1966
                                            and plastlcizers.
                                            As a carburetor cleaner.
                                                            84
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                Several of the ketones are either used as flavor and fragrance




materials (methyl ii-amyl ketone, methyl n_-hexyl ketone, ethyl butyl ketone,




ethyl arayl ketone, acetophenone, and benzophenone) or to synthesize such




materials (acetophenone, 2,4-pentanedione and 2,5-hexanedione).




           3.   Discontinued Uses




                At the present time, branched chain ketones are declining as




solvents for coatings and allied formulations.  The decline results from




nationwide adoption of air pollution regulations based on Los Angeles Air




Pollution Control District's Rule 66.  This decline is discussed in more




detail in Market Trends (see page 65 ).  Substitution of methyl ii-butyl




ketone for MIBK as a coating solvent was started but has ceased, since it




was found to cause nerve damage (CMR, 1975a).




                The use of MEK in the manufacture of terephthalic acid from




xylene at the Mobil Chemical Company plant at Beaumont, Texas (Towle et al.,




1968; CMR, 1974a) has been discontinued for economic reasons.  This market




was estimated to consume 41 million pounds of MEK in 1970 (SRI, 1972a), and




30 million pounds in 1973 (CMR, 1974a).




                Acetophenone was reportedly used during World War II as




an intermediate for styrene production.  This manufacturing process is not




now competitive (Dorsky _£t _al., 1963).  Use of acetophenone as a sedative




has ceased because of its narcotic effect  (Merck Index, 1952; Browning, 1965).




           4.   Projected or Proposed Uses




                The available literature provided no suggestions for new




solvent uses or for replacement of other solvent systems with ketonic




systems.  The information on replacing branched chain ketones with linear




ketones is discussed in Market Trends, p.  65.
                                   85
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                The use of cyclohexanones  as  intermediates  in  catechol




synthesis has been proposed (Anon.,  1975b).




           5.   Possible Alternatives to Use




                a.   Solvent For Formulating  Coatings




                     Since ketonic solvents are consumed in greatest quantities




in formulating industrial coating systems, one possible means  of  reducing their




consumption is to eliminate some non-essential coatings.  Industrial coatings




are applied to wood, metal, paper, textiles,  and other surfaces for protection,




decoration, and imparting other useful properties.   The coating film will pre-




vent the rusting or corroding of metal surfaces and the rotting of wood.




Textile coatings enhance durability and value; they are often used to sim-




ulate more expensive materials (Higgins, 1964).  Paper coatings also give




decoration, durability, and special properties.  Coatings provide pack-




aging materials with a barrier against water, oxygen, carbon dioxide,




hydrogen sulfide, greases, fats, oils, and miscellaneous chemicals.  Some




printing methods require that the paper be coated (Whitney ej^ jl. , 1967).




It is judged that the vast majority of coating uses could not be eliminated




without accepting some economic penalty.




                     The electroplating of metal surfaces is a possible




alternative to surface coatings formed by resin films.  Since the process




requires that the object being coated conduct a charge, it is limited to




metals.  Insufficient data was available to compare the cost or durability




of the plated and film coatings.  Electroplating does create potential occu-




pational health and environmental problems, such as the difficult procedure




of removing metal ions from waste-water discharges (Lowenheim, 1965).




                     Other alternatives include the removal or reduction




of solvent used in the coating formulation.  As the result of air pollution





                                    86
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 control regulations on the branched chain ketonic solvents, the coatings

 industry has already started to use alternatives.  This section reviews

 the  following alternatives:  reformulated solvent systems; high solids

 (organosols and plastisols); water based coatings; and powder coatings.

                      (1)  Reformulation

                          Solvent reformulation consists of replacing the

 active component  (ketone) in the solvent with an alternative.  The re-

 formulated blend  must possess  similar solution characteristics (resin

 solubility, viscosity, etc.) and evaporation characteristics to the

 original  solvent.  The branched chain ketones  (e.g., MIBK and isophorone)

 have been replaced by straight chain ketones  (e.g., MEK and cyclohexanone)

 (SRI, 1973; CMR,  1975a).  Esters are the primary alternatives for formu-

 lating a ketone-free solvent  (Klug, 1964; Wyart and Dante, 1969), but

 reformulation with esters results in a more costly solvent.  Kline  (1975)

 suggests  that reformulating with conforming solvents will not be the trend;

 in part,  this is  due to  the expense of the new solvent blend  (Martens,

 1968; Levy, 1973).  Table 34  illustrates the cost differences between re-

 formulation and the original  solvent.  Another disadvantage to reformu-

 lating is that new, more stringent air pollution regulations and new occu-

 pational  standards could require another reformulation.  Levy  (1973) also

 noted that a reformulated solvent might release more pounds of reactive

 solvent even though it complies with standards.
                Table 34.  Comparison of Costs  for  Reformulating
	a Solvent  Blend (From Levy,  1973)	
	Solvent	Re f ormula t ion	
Methyl ethyl ketone         14%           Methyl ethyl ketone         68%
Toluene                     80%           Toluene                     10%
2-Nitropropane               6%           Butyl acetate               22%
Cost                  $0.52/gal           cost                  $0.94/gal
Reactivity                0.34a           Reactivity                0.13a

o
   Weighted reactivity by proportions of the compounds in the formula.
                                    87
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                     (2)  High Solids and Powder Coatings




                          High solids formulations are dispersions  of very




fine resin particles mixed in the plasticizers,  pigments and other  compounds to




yield a semi-liquid form.   These can be either plastisols,  which are formu-




lated without solvent, or organosols, which contain some active solvents (in-




cluding ketones) and hydrocarbon diluent (Dean,  1972c).  High solids disper-




sions can be formulated with vinylic, polyester, or polyurethane resins and




can be used to coat textiles or metal surfaces (Kline, 1975).  Kline (1975)




notes that the high solids systems have energy advantages over the  conven-




tional solvent systems and latex coatings.




                          Zimmt (1974) notes some disadvantages caused by




occupational safeguards.  Some high solids formulations use monomers (e.g.,




styrene and acrylate esters) as part of the liquid matrix, which are some-




times volatile and toxic.  High solids coatings require radiation curing




with either electron beam or ultraviolet irradiation.  Since electron beams




can create X-rays, heavy shielding is necessary or shielding is necessary to




prevent eye damage when U.V. irradiation is used.  In addition, the U.V.




irradiation could generate some ozone and initiate photochemical smog pro-




duction within the plant.




                          Powder coatings, which  are  formulated without




solvent,  are limited in application to metallic surfaces.  Kline (1975)




reports that only two techniques which have been  developed have reached




commercial acceptance:  fluidized bed process and electrostatic spraying.




In the fluidized bed process, the object to be coated  is preheated above




the melting point of the coating ingredients and  then  immersed in a  sus-




pension of the  coating materials maintained by an upward air flow.   Two






                                    88
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disadvantages of this technique are that the minimum coating thickness is




more than 5 mills and the film might be uneven.   In electrostatic spraying,




the powder is given an electric charge at the nozzle of the spray gun and




the object to be coated is grounded.  The coating is more evenly distributed




and can be applied thinner (3-4 mills) than that applied by the fluidized




bed process.




                          Powder coatings have reportedly met very limited




success for automobile topcoatings.  The technique is efficient for single




color in a production line but poor if successive runs in a production




line require different colors (Kline, 1975).  Thus, its potential as an




alternative is limited.




                      (3)  Water-Based Coatings




                          The water-based coatings are reportedly the




fastest growing segment of the industrial coatings market (Kline, 1975;




Spence and Haynie, 1972).  The resins formulated into water-based coatings




include polyvinyl acetate and acrylics  (Dean, 1972a,b,c).  While the form-




ulated solvent consists of at least 80% water, the remaining blend can in-




clude organic solvents.  Glycols are the favored solvent (Ruhm, 1970),




whereas ketones are poor solvents  (May, 1973).  The film properties from




these formulations are reportedly equal to or superior to solvent-based




coatings.




                          The water-based coatings can be applied by several




methods:  dip, flow or curtain coating; electrostatic, hot airless or steam




spray; roll or coil coating; or electrodeposition  (Kline, 1975).  Spence and




Haynie (1972), report that the spraying techniques are the most common currently
                                   89
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used.   However, it is electrodeposition that is  expected  to become  the  dom-




inant method.   Kline (1975)  estimates that 200 electrodeposition tanks  now




exist in the U.S.




                          The usual technique has been to charge the metal




object to be coated as the anode.  The coating deposits uniformly to a




maximum thickness of 1.0 to 1.5 mills (Spence and Haynie, 1972).  Kline




(1975) reports that PPG Industries is developing a cathode technique which




is superior to the anodic procedure.




                          Electrodeposition requires a high capital in-




vestment.  While the average cost is estimated between $100,000 and $250,000,




costs go as high as $1.5 to $2.0 million for equipment for automotive body




coating  (Kline, 1975; Spence and Haynie, 1972).   However, operating costs are




reportedly lower, paint wastes are less, and curing time is shorter than




for other application techniques (Kline, 1975).




                          The major uses of electrodeposition in order of




decreasing importance are for the automotive industry, appliances, electrical




equipment, metal furniture, and  steel products.  An impediment to its growth




is the present  inability of electrodeposition to topcoat automobiles.  It




is now used only for undercoatings, but technology is reportedly being de-




veloped  to extend the techniques to topcoats as well.  According to Spence




and Haynie  (1972),  the  industry  must develop paints formulated with conduc-




tive  solids for success in this  application.




                b.   Other Solvent Uses




                     The function  of solvents in adhesive  formulations is




similar  to that in  coatings.  Just as in  coatings, it is possible to re-




formulate a solvent blend  (Blomquist, 1963).
                                   90
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                     The only solvent-free process listed for adhesives is




the "hot-melt" or '"fusible" system (Blomquist, 1963).   The system uses ad-




hesives which can be softened by heating and applied while heat softened.




The disadvantage of this system is that the adhesive remains heat sensitive,




so the applications are limited to systems which are not heated above the




critical temperatures.




                     Other solvent systems can be used in place of those




based on ketones for extraction purposes.   For example, benzene-toluene




or benzene-ethylene dichloride solvent systems can be used for lube oil




dewaxing (Tuttle, 1968).
                                   91
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      C.    Environmental Contamination Potential




           1.    General




                The sources of the selected ketones in the environment  are




not well defined.   It is known that they are formed naturally,  are emitted




from industrial uses, and occur as a product of man's activity; but the




relative importance of the sources of each ketone cannot be established with




the evidence at hand.  There is not sufficient information to estimate  the




total human exposure to these ketones.




                Most of the selected ketones are naturally occurring.  The




straight chain ketones are frequently found in foods, where they are impor-




tant components in natural flavoring.  Man's food processing can increase




their concentration.  They are also produced in biological degradation of




organic wastes by soil and water organisms.  Man affects their production




from organic wastes by the amounts of wastes disposed and the disposal tech-




niques.  The ketones are produced in air by the photooxidation of branched




chain olefins.  The hydrocarbons emitted from motor vehicles and from sta-




tionary sources include these branched  chain olefin precursors.




                Most information available on the  direct release of ketones




to the environment is related to ketonic vapors.   The major sources of




these emissions are  the evaporation of  ketonic solvents from surface coatings




and allied industrial uses, vehicle emissions, losses from their production,




and other  sources  (Spiller, 1973; Hoffman, 1970; Danielson, 1967).  The




relative contributions  from each source is expected to vary for every ketone.




For MEK, the evaporation of coating solvents is apparently the dominant source.
                                    92
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On the order of 300 million pounds of MEK are evaporated from industrial




surface coating solutions annually, and a large percentage is apparently




vented to the atmosphere without treatment to control its release.  For




other ketones, vehicle emissions could be a sizable contributor, if not,




in fact, the major source.  For example, the mesityl oxide released to the




atmosphere with automobile exhaust is expected to be quite significant com-




pared to the release of evaporated solvents from industrial coatings.  While




mesityl oxide is produced in about the same concentration as MEK in auto-




mobile exhaust, it is consumed in formulating coating solvents about one




order of magnitude less than MEK.  Also, it is expected that evaporated




mesityl oxide will be reduced by a greater percentage than evaporated MEK




prior to release of the solvent vapors to the atmosphere  (see page 285).




The major source of acetophenone emissions, according to  Imasheva  (1966),




is from the cumene hydroperoxide process which produces phenol, acetone,




and acetophenone as the major products.




            2.   From Production




                 There is not much published data on environmental contamination




 from ketone production.  The only data available in the literature was limi-




 ted to discussions of total organic carbon in waste water discharges (Sittig,



 1974).




                 The processes by which the ketones are manufactured usually




 have closed reactor systems.  The linear ketones are usually prepared by




 dehydrogenation of the corresponding alcohols;  some MEK and cyclohexanone are




 produced by partial oxidation of the corresponding alkanes; some  cyclohexanone




 is manufactured by phenol reduction; and most of the branched chain ketones are
                                     93
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products of acetone (see Production,  page 56).   The potential for contam-




ination arises from the incomplete condensation of ketonic vapors or their




incomplete scrubbing from reaction gases prior to venting to the atmosphere;




from fugitive emissions; from material transfers; and from accidental spil-




lage.  Water pollution potential arises if water is used as the scrubbing




solvent.  This potential is minimized when wash water is recycled or non-




aqueous scrubbing solvents are used.   Sludge and solid waste disposal by




methods other than incineration is also a potential source of release to the




environment  (see Disposal, page  106).




           3.   From Transport and Storage




                Ketone emissions to the atmosphere during transport and




storage can  result from  accidental spillage, vapor losses during transfer




operations,  and venting  losses from tanks.  The  annual amounts  lost are un-




known.




                Dowd  (1974) surveyed potential losses of  solvent  from




storage and  filling operations in paint and resin manufacture.  He  reported




that 41%  of  all solvent  storage tanks over 5,000 gallon capacity  did not




control venting losses.   Controlled tanks, in general, were  equipped with




conservation vents.




                Dowd  (1974) calculated  the solvent  losses  during  filling




operations  (see Table  35).  These losses  are proportional on a  weight basis




to the product of the  vapor pressure and  molecular weight.   According to




Dowd,  the filling losses are  not  controllable.   Based on  his estimates,




typical ketone filling losses were calculated to range around 0.3  to 0.4




pounds/100 gallons of  ketone.  On a weight basis, the loss will be  on the




order  of  50  pounds per million pounds.  Evaporation  losses will occur during




each tank filling.





                                    94
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      Table 35 .   Filling Losses  For Selected Solvents  at  20°C
                       (From Dowd,  1974)
Solvent
Vapor Pressure,   Molecular Weight
  at 20°C(mm)  	>(g)
                                                            Filling Loss
                                                            Q.b/100 gal)
Acetone
Ethyl acetate
Toluene
Mineral Spirits
.,, ,-- -T-. ^ ...."--- —
186
74
22
2(est)
..j 	 - "»•*- •• 	 - '•" -— • — — • —
58
88
92
160(est)
0.494
0.299
0.0927
0.0147
            4.    From Use

                 Evaporation of solvents from industrial surface coatings and

 related uses (e.g., printing inks and adhesives)  release more of the selected

 ketones to the environment than all other uses.   Virtually all solvents from

 coatings are evaporated.  To prevent the ketonic  vapors from reaching the

 environment, it is necessary to first collect the organic vapors and subse-

 quently remove and ultimately dispose of the ketones (see Current Controls,

 page 110).  In comparison, the ketone loss in processing solvents (e..g. , lube

 oil dewaxing)  is reported at ca.  1% (Tuttle, 1968) for each extraction.

                 The solvent losses during the formulation of the coating

 solutions are considered to be small (DiGiacomo,  1973; Dowd, 1974).   Losses

 are attributed to fugitive emissions.  Solvents evaporating during the resin

 cooking and thinning are collected by hoods and either incinerated or removed

 with activated carbon.

                 Specific information on the quantities of ketones lost to

 the atmosphere in actual operations is not available, but there does exist

 some information on the total emissions (Hoffman, 1970; Danielson, 1967;

 Bersowitz et_ al., 1973) and the potential emissions (Hughes £t al.,  1975).

 Hughes et al.  (1975) have estimated the quantity  of solvent evaporated from

 industrial coatings other than automobile and architectural painting.  The
                                    95
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   predicted solvent evaporation values, which are summarized in Table 36 are

   estimates for weight of ketone lost per unit produced.  They do not take into

   account any emissions control technology.
      Table 36 .   Predicted Ketonic Solvent Evaporated from Some
                 Industrial Coatings (From Hughes  et^ _al. ,  1975)

                                                            Emissions factor
                                                               for ketones
Product catagory	Product	(g.  ketone/unit produced)

Paper and paperboard                                                	

Fabric treatment                                                    	

Sheet, strip and coil             Metal Cans                        2.657
                                  Duct work                         8650.0
                                  Fencing                           4119
                                  Wood paneling                     3.83
                                  Canopies and awnings              4325
                                  Screening                         3.83
                                  Metal doors (excluding            175.1
                                     garage doors)
                                  Gutters                           8650

Major appliances                  Refrigerators                     120
                                  Driers                            45.2
                                  Washers                           33.7
                                  Enameled plumbing                  	
                                    fixtures

Wood furniture                    Bedroom furniture                 3.7

Metal furniture                   Filing cabinets                   8650
                    Some perspective of the potential amount of ketone released

    to the atmosphere can be developed by inspecting the industrial surface

    coating operations and the required controls over organic content of ambient

    air and emissions.  With solvent based coating solutions, the operations

    proceed through a production line which can be separated into three phases:
                                       96
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application of the coating solution; a flash-off period during which the




solvent can evaporate at ambient temperature; and baking (National Paint and




Coatings Association, 1975; Feldstein, 1974).  The weights of solvent




evaporated in each phase are not known.  However, it is known that some




residual solvent (7 to 10%) can remain after the baking (Gadomski et al.,




1974).




                Throughout the production line, atmospheric ketones must be




maintained at a low enough concentration to conform to insurance standards




and occupational health requirements  (Baskin e_t _al. , 1971).  This can be




achieved by flushing with air and/or  removing solvent vapors through ven-




tilation hoods  (see Current Controls, page 110).




                The amount by which the ketone  concentration is reduced before




release to the  atmosphere will be controlled to some extent by the air pollu-




tion  regulations of each state.  For  most states, the regulations are similar




to Los Angeles  County's Rule 66  (see  Regulations, page 285).  In general, re-




lease of non-complying solvents  (photoreactive  solvents such as blends con-




taining MIBK  or diacetone alcohol) will require control.  However, complying




solvents need not be reduced except for those emitted from paint bake ovens




(Feldstein, 1974; National Paint and  Coatings Association, 1975).  Under Rule 66,




the reduction in solvent emissions  is specified as 85%.  Since most  of the




coatings industry uses incineration to control  emissions  (National Paint and




Coatings Association, 1975), the ketone is destroyed rather than collected




for disposal  elsewhere (see Current Controls, page 110).




                It is assumed that, in general, the surface coatings industry




will  release  solvent vapors to the atmosphere with minimal control required




by law.  Thus,  emissions of solvents  blended with MEK, other linear, non-




phot ochemically reactive ketones, and some of the branched chain ketones






                                    97
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might only be controlled when they originate from the paint bake ovens.

Branched chain ketones (e.g., MIBK), which are formulated into non-com-

plying solvents and require reduction of all emissions,  are less likely

to be released to the atmosphere than the ketones in complying solvents.

           5.   From Disposal

                Most of the waste ketones are generated from coating

operations.  According to industry sources  (National Paint and Coatings

Association, 1975), the ketones annually consumed by coating and allied

industrial uses  (e.g., adhesives)  are neither recycled nor collected for

disposal, but are directly incinerated or released to the atmosphere.

The  controls over these emissions  are discussed in the section on environ-

mental contamination potential from use, p. 95.

                 The information on other ketone wastes was insufficient

for  estimating the amounts disposed or the  methods of disposal.  There  is

some monitoring  data on ketones in waste-water streams and landfill leachate

 (see Table  44, page  126).

                 Potential environmental contamination from disposal methods

is included  in the discussion on  the recommended methods  of disposal  (see

page 106).   While potential  losses from incineration are  considered neg-

 ligible  (Besselievre,  1969),  the  potential  exists for air and water contam-

 ination from disposal in sewage  or into  landfills  (Abrams je_t _al. ,  1975).

            6.    Potential Inadvertent Production in  Other Industrial
                 Processes as  a By-Product

                 Inadvertent  ketone production results from incomplete hydro-

 carbon  oxidation, fermentation processes, and their  release from natural

 substances  during processing.  This  section will discuss  ketone production
                                    98
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from fuel burning,  particularly in auto emissions,  but  excludes  ketone




production in food by biochemical processes such as fermentation.   The




latter will be discussed in the following section.




                Small quantities of ketones are produced by the  partial




oxidation of petroleum fuels.  Some quantitative data has been reported




on the ketones in automotive emissions, but no information was found on




ketone emissions from stationary sources.  Ketone concentration in auto-




motive emissions varies with the engine running conditions and fuel; their




concentrations range from less than detectable quantities up to 1-2 ppm




(Rose, 1962; Bellar and Sigsby, 1970; Seizinger and Dimitriades, 1972).




The ketones  (excluding acetone) and maximum concentrations reported are:




MEK, 1.0 ppm; mesityl oxide, 1.5 ppm; 3-methyl-3-buten-2-one (methyl iso-




butenyl ketone), 0.8 ppm; methyl propyl  (or isopropyl) ketone, 0.8 ppm; and




acetophenone, 0.4 ppm (Seizenger and Dimitriades, 1972).  Annual automotive




hydrocarbon  emissions have been estimated at 27.3 million tons (Council on




Environmental Quality, 1974) with typical hydrocarbon concentrations of




900 ppm  (American Chemical Society, 1969).  While the ketones are relatively




minor  components in automotive exhaust emissions, the quantity emitted might




be a significant contribution to their ambient atmospheric concentration.  For




example, if  it is assumed that any one ketone occurs at an average concen-




tration of 0.1 ppm, and total hydrocarbon concentration is approximately




1000 ppm, then annual ketone emission would be on the order of 5 million




pounds.  This production would be only a moderate contribution to the poten-




tial contamination from use of MEK, but could be a substantial contribution




for the other ketones, such as mesityl oxide or methyl propyl ketone.
                                    99
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                The syntheses of acetaldehyde and acetic acid appear to be




the only major chemical processes which would yield significant amounts of




ketonic products among those listed in Austin's (1974) survey of the 100




leading organic chemicals.  In the controlled oxidation of commercial n-




butane (95% n-butane, 2.5% isobutane and 2.5% pentane), conditions can be




modified so that the major product is acetaldehyde, acetic acid, or MEK




(Austin, 1974; Faith et_ _al. , 1965) (see Production, page 56 ).  While the




acetaldehyde production uses a vapor phase oxidation  (ca. 100 psi and 700°C),




acetic acid is produced by liquid phase oxidation  (ca. 350°C and 800 psi)




with cobalt or manganese acetates as the usual catalyst for both (Austin,




1974; Faith ej: al., 1965).  In acetaldehyde production, Austin  (1974) reported




the product mixture includes acetone (4%) and mixed solvent  (12%).  In acetic




acid production, Faith et al. (1963) included ketones in miscellaneous organic




by-products (8% of the product mixture).  Other processes are also used for




acetaldehyde and acetic acid production which do not produce side-streams of




ketone.




                The ketones have been observed in  effluents  of  coal gasi-




fication plants (Kavan and Basyrova, 1967, 1968) and  kraft paper mills




(Bethge and Ehrenborg, 1967).  Small quantities of MEK, methyl  isopropyl




ketone, methyl n-propyl ketone,  and diethyl ketone have been detected.




           7.   Potential  Inadvertent Production in the  Environment




                The ketones are  minor constituents of a wide number of




foods.  In some cases, man influences their concentration by fermentation




processes, heat treatment, and other commercial processing (Chang, 1966).
                                    100
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Since ketones are important components of the food flavors, some of the com-




pounds (e.g., acetophenone, methyl nonyl ketone, methyl heptyl ketone) are




important additives (Chang, 1966; Hamann and Guenther, 1966).  Table 37




summarizes some of the lower molecular weight ketones observed in food stuffs.




The information available in the literature is not sufficient for estimating




the amount of ketones ingested in the diet.




                Diacetone alcohol and mesityl oxide have been observed in




foodstuffs exposed to,acetone.  They formed in meat carcasses which had been




exposed,  to freshly painted surfaces where acetone was a component of the




paint solvent.  They were also found in vegetables and seeds, from which oil




had been extracted with acetone  (Fore e^ al. , 1975; Patterson and Rhodes,




1967; Pearce £t ad. , 1967).




                Ketones are intermediate products in the biodegradation of




organic  compounds.  Man influences biological ketone production by waste




disposal methods.  MEK and acetone have been identified as products of the




activated sludge treatment of sewage  (Malaney and Gerhold, 1962; Abrams




et al.,  1975) and as components  of the leachate from solid waste (Borrows




and Rowe, 1975; Abrams ejt al. , 1975).  Borrows and Rowe have measured  fairly




high  concentrations of acetone in year old landfill leachate  (ca. 0.60 g/£).




It is possible that the resulting acetone can subsequently yield condensation




productions,  such as diacetone alcohol.  Diacetone alcohol has been identified




as a minor  component (2.9 mg/£)  in a landfill leachate, but no information




was given concerning its source  (Alford, 1975).  The information at hand




is not sufficient to allow a reasonable estimate of the potential inad-




vertent  production of the ketones from waste disposal.
                                     101
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Table 37.  Ketones Observed in Foodstuffs
Ketone
Methyl ethyl ketone
















Methyl n-propyl ketone














Methyl ri-butyj ketone




Methyl isobutyl ketone
Methyl n-amyl ketone











CoMBodity Concentration
Cheeiei

(Swiss cheese) 0.3 ppm
Milk 0.077-0.079 ppm
Cream 0.154-0.177 ppm
Milk fat 8 ppm
Roasted bar ley
Bread
Honey
Chicken
Corn silage
Oranges

Black tea
Rum
Tobacco

Cheeses


(Swiss cheese) 0.98 ppm
Evaporated milk
Milk 0.007-0.026 ppm
Cream 0.025-0.045 ppm
Bananas
White bread
Soybeans
Potato chips
Toasted oats

Tobacco

White bread
Toasted oats

Milk 0.007-0.011 ppm
Cream 0.017-0.018 ppm
Oranges
Cheeses

(Swiss cheese) 0.45 ppm
Evaporated milk
Butter
Milk
Cream 0.004-0.007 ppm
Milk fat 16 ppm
White bread
Soybeans 1 ppm
Peaches
Orange juice
Reference
Rakanlahl et al., 1965;
Harper et al. , 1962;
Langler et ~~al . , 1967
Wong and Patton, 1962
Wong and Patton (1962)
Lawrence and Hawke, 1963
Collins, 1971
Wick et al., 1964
Cremer and Riedmann, 1964
Minor et al. , 1965
Morgan and Pereira, 1962
Schultz e^ al. , 1964;
Dlnsmore and Nagy, 1971
lamanlshi, 196')
FenarollI et al , 1965
Chackraborty and
Weybrew, 1963
Nakanishi et al , 1965;
Harper £t al. , 1962;
Harvey and Walker, 1960;
Langler et^ a±. , 1967
Muck et al. , 1963
Wong and P.itton, 1962
Wong and Patton, 1962
Issenberg and Wick, 1963
Wick et al , 1964
Fujimaki et al , 1965
Mookherjee et al., 1965
Hrdllcka and J.micek,
1964
Chackraborty and
Weybrew, 1963
Wick et al. , 1964
Hrdllcka and lannuk,
1964
Wong and Patton, 1962
Wong and Patton, 1962
Schultz e^ a_l , 1964
Nakanishi et al., 1965;
Harvey and Walter , 1960;
Langler et al. , 1967
Muck et _a_l , 1 963
Winter e_t al^. , 1963
Wong and Patton, 1962
Wong and Patton, 1962
Lawrence and Hawke, 1963
Wick et a_K , 1964
Fujimaki e_t a^. , 1965
Broderick e^ al. , 1966
Dinsmore and Nagy, 1971
                                   102
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                Ketones are minor constituents in photochemical smog




(Altshuller, 1966; Altshuller and Bufalini,  1965, 1971; Haagen-Smit and




Wayne, 1968).  They are thought to be formed in photooxidative reactions




of branched chain olefins with ozone.  MEK,  for example, is formed as a




product in ozonation of 2-methyl-l-butene (Altshuller and Bufalini, 1971).
                                       103
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      D.    Current Handling Practices  and Control Technology




           1.    Special Handling in Use




                The Occupational Health and Safety Administration (OSHA)  is  in




the process of establishing regulatory control over the industrial use of the




ketones (see Current Regulations - OSHA, p. 286).  Practices  which have pre-




viously been recommendations will become legal requirements (Manufacturing




Chemists Association, 1961, 1962).  The OSHA standards on ketones seek occu-




pational protection against inhalation and dermal contact and prevention of




fire or explosion (OSHA, 1975d).




                The OSHA standards do not consider respirators an adequate




substitute for reducing ambient concentrations of ketones.  If the engineering




and work practice controls cannot reduce concentrations below the permissible




levels (see Table 105, p. 287)> the concentration must be reduced to the lowest




feasible level, and workers must then wear an appropriate respiratory device.




                Plant locations where the ketone vapors are present have




been designated as Class I, Group D, under the National Electrical Code




(NEC).  This requires that all electrical wiring and electrical equipment




(e.g., lighting, relays, motors,  controls and switches) must be explosion-




proof or otherwise conform to the NEC Article 500  (MCA, 1961, 1962).




                In case of spills, all potential sources of ignition must be




eliminated, the area must be ventilated, and the spill cleaned up immediately.




                If a worker's clothing becomes wet with any of the ketones




designated as flammable liquids  (see p.  286), the worker must immediately




remove them until they have dried.
                                   104
-------
           2.    Methods for Transport and Storage




                Since the ketones are combustible,  transport and storage




techniques must provide protection against fire and explosion hazards.




Methods are often regulated by federal,  state,  and  local agencies.   The U.S.




Department of Transportation (DOT) lists some of the ketones as flammable




liquids (e.g., MEK and MIBK) but not other ketones  (e.g., diacetone alcohol)




(United Parcel Service, 1973).   State and local agencies enforce intrastate




transportation and storage regulations.   These are  often adopted from model




codes of the National Fire Protection Association (MCA, 1961, 1962; NFPA,




1974, 1975).




                The ketones can be transported in tank cars, tank trucks,




metal barrels or drums (55 gallon), metal cans and  polyethylene bottles (up




to 10 gallons maximum), and glass bottles (up to 1  gallon maximum)  (NFPA, 1975;




United Parcel Service, 1973; MCA, 1961,  1962).   In  interstate shipments, con-




tainers and vehicles must be placarded and conform to the requirements of the




DOT.  These are detailed in the MCA1s Chemical Safety Data Sheets  (MCA, 1961,




1962).




                In loading and unloading containers or tankers, precautions




must be taken against fire hazards.  This includes  grounding metal drums or




tankers, using spark resistant tools, and designation of dock areas as Class I




hazardous locations as defined by the National Electric Code (MCA,  1961,




1962; NFPA, 1975).




                Storage tanks should be outside of  any building.  NFPA (1974)




suggests that underground tanks should be located at least one foot from




existing building foundations and supports, and at  least three feet from the
                                    105
-------
nearest line of adjoining property that might be built  upon.   Tanks  should




not receive any of the load from a building foundation.   Above-ground tanks




should be in remote areas at least 25 feet from any important building.   Above-




ground tanks should be diked in case of rupture, and vented or equipped  with




pressure relieving devices (MCA, 1961, 1962).




                NFPA (1975) suggests that outside or detached storage is pre-




ferred to indoor storage.  Indoor storage should be in a standard flammable




liquid storage room or cabinet.  The ketones should be segregated from oxidizing




material.  Containers should be protected against physical damage.  The area




should be kept cool and well vented, and should be equipped with automatic




sprinklers or some adequate extinguishing system.  Storage rooms should be




pitched to trapped floor drains  (MCA, 1961, 1962; NFPA, 1974, 1975).




           3.   Disposal Methods




                The favored disposal method for the selected ketones is in-




cineration (MCA, 1961, 1962; Besselievre, 1969).  Combustion efficiency is




better than 99.99% (Abrams £t  al., 1975).




                Disposal through  conventional sewage systems should not be




used  for disposal of large quantities of the ketones, but  could be acceptable




for small quantities.  Discharge  of  large quantities into  a  sanitary sewer




creates the hazard of an explosion  (United Parcel Service, 1973; MCA, 1961,




1962).  If the discharge is diluted  with large  quantities  of water, the




explosion danger is eliminated.   Activated sludge will effectively degrade




some  of the selected ketones.   The efficiency of activated sludge is given




as:  'MEK, 90%, and acetophenone,  90% (Abrams et^ al., 1975).  However, Gaudy




et al.  (1963) observed that under the conditions for activated sludge treatment
                                   106
-------
in a sewage treatment plant, MEK is very resistant to sludge biodegradation

and would evaporate to the atmosphere more rapidly than it would' biodegrade.

                If the selected ketones are land disposed, they can either

evaporate to the atmosphere or migrate with leachate (Abrams _ejt aJL. , 1975;

Garland and Mosher, 1975).  While soil bacteria will degrade ketones in a

period estimated at 1 to 2 months, Abrams et al_. (1975) note that if high

industrial waste loadings are present, the biodegradation rate could be

slowed.  They concluded that if land disposed, large quantities of the

ketones are a contamination threat.

                The MCA (1961, 1962) recommends that, prior to their dis-

posal, metal containers which formerly contained acetone or MEK should be

drained and then steamed.

           4.   Accident Procedures

                The emergency response to accidental spillage of the selected

ketones is principally concerned with the prevention or the suppression of

fire  (NFPA, 1975; United Parcel Service, 1973).  The United Parcel Service

(1973) suggests the following procedure for spills of the water soluble

ketones:

      Personnel:

        Wear protective clothing and for high concentrations wear gas mask.
        Wash skin and eyes thoroughly if contacted.  Remove and wash con-
        taminated clothing.

      Vehicle or Facility:    '

        Hose down with water.  Dry with commercial, non-organic drying
        agent.
        Do not allow waste liquid to enter sewer system.
                                  107
-------
For the water insoluble ketones,  the response is modified as  follows:

      Vehicle or Facility:

        Rinse area of spill with alcohol and then with plenty of water.
        Repeat until all of the chemical has been removed.  Dry with
        commercial, non-organic drying agent.  Do not allow waste liquid
        to enter sewer system.

                Table 38 summarizes the hazard ratings and fire fighting

information for selected ketones.  Fire fighters working in the vicinity

of the ketones should wear full protective gear, including a respiratory

device (NFPA, 1975).  The NFPA system rates health, flammability, and

reactivity on a scale from 0 to 4, with zero being the safest category.

All ketones received a reactivity rating of zero, which NFPA defines as,

"materials which are normally stable even under fire exposure conditions and

which are not reactive with water.  Normal fire fighting procedures may be

used."  The ketones range in health ratings  from 1 to 3.  These ratings are

defined as follows:

      3    Materials extremely hazardous to  health, but areas may be entered
           with extreme  care.  Full protective clothing, including self-
           contained breathing apparatus, rubber gloves, boots and bands
           around  legs,  arms  and waist  should be provided.  No skin surface
           should  be exposed.

      2    Materials hazardous to health, but areas may be entered freely
           with self-contained breathing apparatus.

       1    Materials only slightly hazardous to health.  It may be desirable
           to wear self-contained breathing  apparatus.

The  ketones  received flammability ratings of 2  or  3.  These  are defined as:

       3    Liquids which can  be  ignited under almost  all normal temperature
           conditions.   Water may be ineffective on  these  liquids because of
           their  low flash points.  Solids which form coarse dusts, solids in
           shredded or  fibrous form that create  flash fires, solids that burn
           rapidly, usually because they contain their  own oxygen, and any
           material that ignites  spontaneously  at  normal temperatures in air.

      2    Liquids which must be moderately  heated before  ignition will occur
           and  solids  that readily give off  flammable vapors.  Water spray may
           be used to  extinguish  the fire because  the material  can be cooled to
           below  its flash point.


                                   108
-------
      Table 38.   Accidental Spill  Response  Information
                        (From NFPA,  1975)
Ketone
Acetophenone
Acetone
Cyclohexanone
Ethyl butyl
ketone
Health a
1
1
1
1
Hazard Identification
a
Flatnmability
2
3
2
2
a
Reactivity
0
0
0
0
Fire
Fighting b
Phases
3
1
2
3
Methyl ethyl
  ketone

Isophorone

Methyl isobutyl
  ketone

Mesityl oxide
2

2
2

3
0

0
3

3
    For definition of the numerical rating, see the text.

    Fire Fighting Phases:

       1.    Use dry chemical, "alcohol" foam, or carbon dioxide; water
             may be ineffective, but water should be used to keep fire-
             exposed containers cool.  If a leak or spill has not ig-
             nited, use water spray to disperse the vapors and to protect
             men attempting to stop a leak.  Water spray may be used to
             flush spills away from exposures and to dilute spills to
             nonflammable mixtures.

       2.    Use water spray, dry chemical, "alcohol" foam, or carbon
             dioxide.  Use water to keep fire-exposed containers cool.
             If a leak or spill has not ignited, use water spray to
             disperse the vapors and to protect men attempting to stop
             a leak.  Water spray may be used to flush spills away from
             exposures and to dilute spills to nonflammable mixtures.

       3.    Use water spray, dry chemical, foam, or carbon dioxide.
             Use water to keep fire-exposed containers cool.  If a leak
             or spill has not ignited, use water spray to disperse the
             vapors and to provide protection for men attempting to stop
             a leak.  Water spray may be used to flush spills away from
             exposures.
                                     109
-------
           5.    Current Controls




                Control of the ketonic solvents emitted from industrial




coatings has been well developed.   The control technology consists of two




stages: collection of the effluent gases,  and removal of ketones and other




solvents.




                The most often used methods for removing solvent vapors from




the effluent air are incineration and carbon adsorption (Danielson, 1967;




Baskin et_ _al. , 1971; Mattia, 1970).  Scrubbing the organic vapors is not




efficient and is usually used as a first stage, before adsorption or in-




cineration  (Cooper, 1969; Mattia, 1970).  With carbon adsorption the




collected solvent could be either recycled or degraded  (Cooper, 1969;




Mattia, 1970).  The economics upon which the choice of air pollution tech-




nology is based depend in part upon the capital and operating costs, value




of recovered solvent, and future plant expansion.




                Ketones, as well as other organic solvents, can be oxi-




dized by direct or catalytic incineration.  In either process, the amount




of organic  emissions that are eliminated depends upon the incineration




temperature (Danielson, 1967; Gadomski ert jiiL. , 1974).   Table 39 compares




the removal efficiency for the  catalytic and direct flame combustion of




organic vapors emitted from metal  decorating industry sources.  The direct




flame  afterburners reduced organic gases somewhat more  than the catalytic




incinerator (Danielson, 1967; Gadomski e^t al. , 1974).   Baskin et^ al.  (1971)




noted  that  the catalytic incinerator has an economic advantage over direct




flame  units.  A  typical catalytic  incineration system is illustrated in




Figure 13.
                                  110
-------
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                                                               111
-------
                               ALL-METAL
                          CATALYST El EMENTS
                                                 FRESH MAKLUP AIR
                 PREHEAT BURNER
                         FROM SOLVENT
                         EVAPORATION ZONE
                                                         SUPPLY FAN
                                                Of-CONTAMINATED)
                                                AIR RETURN TO OVEN


      Figure 13.   Typical  Catalytic Combustion System for  Paint  Bake  Oven
                                (Baskin _et _al. , 1971)

           (Reprinted with permission  from UOP  Air  Correction Division)

                In the  adsorption technique for removing solvent  vapors,


the methods using  activated  carbon are predominant  (Cooper, 1969).  In the


most commonly used systems,  two adsorbing vessels are used (Cooper, 1969;


Mattia, 1970).  While one  vessel is in use, the carbon in  the  other vessel


is being regenerated.   Carbon adsorption systems using moving-bed or  fluidized


bed designs have also been reported (Cooper, 1969).  The carbon  can be re-


generated either with steam  or with hot air.  Figures 14   and  15  chart the


flow of two modifications  of the ZORBCIN process for regenerating spent


carbon with hot air.  In the former  the collected organics are  incinerated,


while in the latter they  are recycled.

                                           EXHAUST TO ATMOSPHERE
      CONTAMINATED
      AIR STREAM
                AIR
               FILTER
                         X1X7
                             ADSORBER NO. I
                             ADSORBER NO. 2
                                 SLOWDOWN STREAM
              REGENERATING
                  FAN
      CONTAMINATED
          AIR FAN
   REGEN.t
AIR COOLER!
                                                              EXHAUST
                                                            TO ATMOSPHERE
                                                HEAT INTER-
                                                  CHANGER
                            COOLING
                             WATER
MAKE-UP
   - -    •  a i
                  AIR
 INCINERATOR  I INCINERATOR
      FAN  !
         NAT GAS
      Figure  14.   ZORBCIN Process For Purifying Contaminated Air  Streams

                   (From Mattia, 1970)  (Reprinted with permission from
                  the American  Institute  of  Chemical Engineers)

                                  112
-------
                                         EXHAUST TO ATMOSPHERE
                         NO. I  PRIMARY
                           ADSORBER
             rH>"*
VAPOR-LADEN
         AIR
        FILTER
                                            U-|	»•
VAPOR-LADEN
  AIR FAN
                  i ,
                         NO. 2 PRIMARY
                           ADSORBER
                                                                EXHAUST TO ATMOSPHERE
                                                 t
                                                   REGEN.
                                                   AIR HEATER
1
                        RFGFNFAN
                        REGEN. FAN
                                                               SECONDARY
                                                                ADSORBER
                                                           STM
                                       COOLING WATER
                                                                                  CON-
                                                                                  DENSER
                                                                              WEAK WATER
                                                                                 TANK
            Figure  15.
                        Cascade  Adsorber  Process  For Recovering Solvents From
                        Dilute Vapor-Laden  Air  Streams
                         (From Mattia, 1970)   (Reprinted with  permission  from

                        the  American Institute  of  Chemical  Engineers)
                      The four most  popular  methods  for  the  application  of  industrial


      coatings are dipping,  flow coating,  coil or  roller coating,  and  spray (Baskin


      et al. ,  1971;  Hughes e_t al. , 1975).  Canopy  hoods  are  suitable for removing any


      organic  vapors emitted  from the  first  three  methods.  With spraying techniques,


      overspray can  run  from  30 to 90% (Baskin e^  al., 1971),  so more  sophisticated
                                           113
-------
equipment is required.  The spraying  techniques  require  a ventilated spray

booth enclosure to prevent the accumulation  of explosive or toxic  concentra-

tions of the organic vapors (Baskin e^ _al.,  1971; Hughes et^ _al.,  1975).

               Designs of spray booths are illustrated in Figures  16 (dry

baffle); 17 (paint arrester or filter pad);  and  18  (water spray  curtain).  The

booths are designed to remove particulates as well  as to collect  the organic

vapors.  The dry baffle and filter pad systems will only remove  particulates;

the water-curtain system will remove  solvent vapors as well (Baskin et al. ,

1971).  The booths are ventilated at  velocities  from 2.8 to 4.3  meters per

minute per square meter of booth opening, with a minimum average velocity over

the face of the booth during spray operation of  not less than 0.5 meter/second

(Hughes et. al. , 1975).
  Figure  16.   Dry Baffle Spray Booth
              (Hughes e^ ail. ,  1975)
                Figure 17. Filter Pad or Paint
                  Arrestor Spray Booth
                       (Hughes ejt al. , 1975)

                                         WATER
                                       RECIRCUIATING
                                         PUMP  |
                                            MAKI- -UP
                                            WATER
                   Figure 18.
Water-Wash Spray Booth
(Hughes .et al. , 1975)
      114
-------
                Paint bake ovens are built to standards set for fire and ex-

plosion prevention.  The vapor levels must not exceed the lower explosive

limits (LEL) of the organic vapor (Danielson, 1967; Baskin et^ ad. , 1971).  The

amount of air needed for dilution is computed with a factor of safety from

4 to 12.   Other requirements of the oven are that the vapor concentration must

be less than the level of toxicity during loading or unloading (Baskin et al.,

1971).

                Paint ovens can be designed for batch operation (Figure 19)

or continuous operation (Figure 20).   They are designed with bottom ventillation,

since the organic solvents are generally heavier than air (Danielson, 1967).
      Figure 19.   An Indirectly Heated,  Gas-Fired,  Recirculating,
                  Batch-Type  Paint-Baking  Oven
                  (From Danielson,  1967)
                                     115
-------
             CONTAMINATED
             GAS EXHAUST
CURTAIN
AIR
     Figure 20.  A Direct-Heated, Gas-Fired,  Recirculating, Continuous
                 Paint-Baking Oven (Zone 1  is 4 ft wide; Zone  2,  5 ft
                 4 inches wide; Zone 3, 4 ft  wide)
                 (From Danielson, 1967)
                                     116
-------
      E.    Monitoring and Analysis




           1.    Analytical Methods




                Gas chromatography  (g.c.)  is  currently the most well developed




technique for analyzing trace quantities of ketones (Analytical Quality Control,




1972; Webb £t al.,  1973).  Flame ionization detection (FID) is the most sen-




sitive detection technique now available for  the selected ketones (Webb et




al., 1973; Fishbein, 1972).  Coatings based on silicone polymers and glycols,




especially carbowax and DECS, are the most frequently used packing materials




in the columns (Analabs, 1974; Fishbein, 1972).   While peak assignment in




the past was based upon relative retention time, gas chromatographic-mass




spectral  (g.c.-m.s.) instrumentation is now commonly used to confirm the




assignments (Webb et al,, 1973).




                The organization of g.c. data has been simplified by the




Kovats Retention Index System for tabulating relative retention times  (Caroff




ejt _al. , 1966; Anderson, 1968).  The relative  retention time RT  is the ratio




of RT  (retention time of the sample) •» RT  (retention time of a reference




hydrocarbon).  The system is quite useful for standardizing analytical pro-




cedures between laboratories which are performing quality control, monitoring




or surveillance (Anderson, 1968).  Anderson (1968) has noted the following




sources of error in determining the Kovats Retention Indices:  instrumentation




(from changes in carrier gas flow and column temperature); stationary phase




degradation, especially by oxidation; adsorption on the stationary phase,




especially when the polarity between the stationary phase and the sample is




high; non-linear response caused by changes in gas flow and column temperature;




and overlapping peaks.  Indices based on hexane are tabulated for selected




ketones in Table 40.





                                     117
-------
         Table 40.
Kovats Retention Indices For Selected Ketones

(From Anderson, 1968)
           DC-401
           Column
  DECS
 Column
Apiezon L
 Column
   Thermal
   Conductivity
   Detector
   (T.C.)
Response Factor
   Flame
   lonization
   Detector
     (F.I.D.)
Response Factor
Acetone
Methyl ethyl ketone
Methyl propyl ketone
Methyl isoamyl
ketone
Methyl isobutyl
ketone
Mesityl oxide
Cy c loh exan one
Diisobutyl ketone
Methyl heptyl ketone
Isophorone
Methyl nonyl ketone
466 ± 29
560 ± 9
640 ± 29
698 ± 10
714 ± 17
792 ± 15
894 ± 11
961 ± 15
1076 ± 12
1121 ± 3
1276 ± 7
1053 ± 29
1127 ± 14
1203 ± 14
1343 ± 14
1217 ± 14
1382 ± 14
1757 ± 14
1430 ± 25
1590 ± 25
2110 ± 28
1813 ± 29
472 ± 20
553 ± 15
648 ± 16
704 ± 37
692 ± 14
776 ± 29
898 ± 16
945 ± 8
1059 ± 7
1124 ± 1
1263 ± 6
0.87
0.70
1.49
1.47
0.72
1.87
.70
1.20
0.65
0.77
1.18
2.10
0.98
1.33
1.27
0.78
1.86
0.97
1.07
0.60
0.86
1.14
                    Chromatographic Conditions

(1)  Columns:  1)  10'  x 1/8" s.s.-10% DC-401 on 60-80 mesh Gas-Pak WAB
             2)  6'  x 1/4" copper-30% DECS on 60-80 mesh Gas-Pak WAB
             3)  10'  x 1/8" s.s.-10% Apiezon L on 60-80 mesh Gas-Pak WAB

(2)  Column temperature 150°C

(3)  Carrier gas:  Helium with a flow rate of 50 ml/min measured with a
                  soap bubble flow meter.

(4)  T.C.  Detector:   Operating temperature 225°C
                    Filament current 150 ma.

(5)  F.I.D. Detector:  H  flow rate 20 ml/min.
                      Air flow rate 40 ml/min.
                      Operating temperature 250°C

(6)  Sample size: 0.1-0.5 ul

(7)  Recorder chart speed:  0.5, 1.0, 2.0 inches per minute
                             118
-------
                Table 41 lists some g.c.  analyses reported for the selected




ketones.  The sample pretreatment is the critical factor in the analyses.




At the minimum, the pretreatment must remove interferences and quantitatively




transfer the ketones either to air or to a suitable organic solvent (e.g. ,




freon or chloroform).  For example, auto emissions have large quantities of




hydrocarbons whose retention times are of the same order as the ketones.  The




carbonyls have been successfully isolated from the hydrocarbons by the use




of cutter columns  (Bellar and Sigsby, 1970) and by preparation of carbonyl




derivatives  (such as the dinitrophenylhydrazones and bisulfites) (Ellis et




al. , 1965; Barber and Lodge, 1963).  The sensitivity of the analysis depends




on the  ability of the technique to concentrate the ketones from large samples




(Analytical  Quality Control, 1972; Webb «at aJL. , 1973; Bellar and Lichtenberg,




1974).




                Air samples containing ketones can be collected and pretreated




in the  field or collected in Tedlar bags and pretreated in the laboratory.




Schuetzle et al.  (1975) noted that polyethylene, Saran, and Mylar are not




suitable because of leakage.  However, only a slight loss of MIBK occurred




after 45 hour  storage in a Tedlar bag (see Figure 21).  Air samples can be




concentrated and pretreated by cold trapping  (Ellis et al., 1965) , by ad-




sorption  (Mueller and Miller, 1974; Jenkins, 1973, 1974; Bellar and Sigsby,




1970),  by collection in solvents  (Ellison and Wallbank, 1974), and by pre-




paring  derivatives  (Rails, 1960; Barber and Lodge, 1963; Soukup e£ jl. , 1964;




Jones and Monroe, 1965; Dinsmore and Nagy, 1971).  While the preparation of




derivatives  (especially the dinitrophenylhydrazones) is an excellent method




for isolating  carbonyls, the technique does not quantitatively collect the




ketones.  Selective adsorption can isolate carbonyls with excellent results,




but requires rather sophisticated instrumentation (Bellar and Sigsby, 1970).





                                      119
-------
            Table 41.   Analysis  of  the Selected  Ketones  by  Gas  Chromatography
                                                                                            Sensitivity
                                                                                            or Limits
Reference
Coruin (1969)

Smoyer et al. (1971)

Bellar and Sigsby (1970)
Selzinger and Dimitriades
(1972)
Ellis et al. (1965)



Jenkins e_t al. (1973, 1974)


White e_t al. (1970)
Cooper et al.. (1971)

Mueller and Miller (1974)

Grob and Grob (1971)

Bumham et al. (1972)




Kuuata et al. (1974)

AutLern et al. (1975)

Keith ( 19 74)
Ellison et al. (1974)

l)i os more and Nagy (1971)




Zlatkib and Liebich (1971)
Zlatkis e^ aK (1973)
Fore et al. (1975)


Type of Sample
Sea water

Air

Automotive
emissions

Automotive
emissions


Air


Air (occupational
surveillance)

Air (occupational

Air

Drinking water




Air

Waste water


Waste water
Waste water and
waste sludges
Liquid (orange
juice)



Liquid (urine)

Solid (oil seeds)


Isolation and Concentration Detection
Sampled the headspace gases

Sampled in stainless steel
tubes
Isolated ketones from hydro-
carbons by a cutter column ;
backflush to analytical column
Isolated ketones from hydro-
carbons by scrubbing through
a 1% NaHS03 train. Thermal
regeneration of ketones.
Concentration by adsorption
on Chromosorb 102, backflush
to analytical column
Concentration by adsorption
on activated carbon, de-
sorption by CS_
Concentration by adsorption
sorption by CS_
Concentration on cigarette
filter charcoal
Concentration on XAD-2 or
XAD-T resin



Concentration on Tenax G,

Freon extraction and
concentration

and concentration
Steam distillation and
partition into cyclohexanone
Stripping with N. stream,
collection as 2,3-dinitro-
pheny Ihydrazone derivative.
Regeneration of carbonyl by
flash thermal method
Strip with N_ stream,
collected on Tenax C.C.
Direct elution (with
water) onto analytical
co 1 umn
GC
(FID)
GC-MS
(FID)
GC
(FID)

GC
(1C)


GC-MS
(FID)

GC
(FID)

GC

GC
(FID)
GC-MS
(FID)



GC
(FID)
GC-MS
(FID)

GC— MS
(FID)
GC-IR
(FID)
GC-MS
(FID)



GC-MS
(FID)
GC
(FID)

Compounds Studied of Detection Remarks
Acetone and methyl <5 Mg/&
ethyl ketone
Acetone and methyl ppm
ethyl ketone
Acetone, methyl ethyl 0.05 ppm Cutter column [1,2,3-
ketone > and mesityl tris (cyanoethoxy) pro-
oxide pane ] holds oxygenates
Acetone and methyl 5 ppm Scrubbing does not
ethyl ketone quantitatively remove
higher molecular weight
ketones
Cyclohexanone Emission, 5 Measured rate of emis-
<1 x 10 sion rather than con-
g/cm^ sec centration
Methyl ethyl ketone <20 ppm Better than 90%
recovery

Methyl ethyl ketone <25 ppm About 60% recovery for

Ace tophenone 1
'

Methyl isobutyl ketone Better
than 1
ppb for i
neutral
organlcs
ppb level

Acetophenone 1.1 ng 87.9 4 2,2% recovery o£
samples spiked 0.013-
11.0 mg/H
and ace tophenone
Methyl isobutyl ketone 1 ml Poor recovery (38% at
0.5 mg/fc; 51% at 20 rag/
Acetone, methyl ethyl
ketone, C-5 ketones



MEK, methyl n-propyl ketone
and methyl n-amyl ketone
Mesityl oxide and diacetone
alcohol 2 ppm

GC- Gas chromatography
MS- Mass spectroraetry
TC- Thermal conductivity detection
FID- Flame ionization detection
IR- Infrared spectrometry
                                                        120
-------
                   600
                      0  5  10  Ib  A)  P1!  10
Figure 21.   The Effect of Storage Time on Sample Recovery from Tedlar Bags
                             (From Schuetzle ejt al. , 1975)
(Reprinted with permission from the Air Pollution Control Association)

                 Since water is  not a  suitable  solvent  for  g.c.  analysis,

 aqueous ketones must be transferred to  another phase.   Techniques  used  with

 aqueous samples include headspace sampling  (Corwin, 1969),  liquid-liquid

 extraction  (Austern et_  al. , 1975; Keith,  1974),  distillation or stripping

 with an inert  carrier gas  stream  (Ellison and  Wallbank,  1974;  Dinsmore  and

 Nagy,  1971; Webb £it auL. , 1973), and adsorption (Burnham £t al. , 1972).   Head-

 space  sampling is  quite convenient in the absence of interferences.   Ex-

 traction  techniques for the lower molecular weight ketones are limited  by

 their  water solubilities  (Webb  et_ al. ,  1973;  Ellison and Wallbank,  1974).

 Their  solubility also limits  the  quantitative  transfer by  gas  stripping

 techniques.   Bellar and Lichtenberg  (1974)  found that  only 20% of  MEK (10 ml

 sample at 100 ug/£) was removed by a  300  m£ purge with N.  (20  m£/min) com-

 pared  to  quantitative stripping of identically sized samples of methylene

 chloride,  chloroform, and  benzene.   The concentration  of low molecular  weight

 ketones on  synthetic resins has given excellent detection  limits and recovery

 (Burnham  et _al. , 1972).

                 Table 42 lists  analytical methods other than ga,s chromato-

 graphy.   Most  of the listed techniques  are primarily useful for occupational
                                     121
-------
I
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Acetone, MEK and
MIBK are three
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tude less sensi-
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with Cyclohexanone No interference
hydroxy- and methyl from acylic
sulfonlc Cyclohexanone ketones.
CJ
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-------
health surveillance or as screening tests.   Since the infrared technique can




measure airborne ketone without a sample collection, it is quite useful for




field analysis and monitoring in the absence of interferences (Wilks, 1973).




The MIRAN portable infrared gas analyzer is equipped to measure ambient air




at a single wavelength.  The system has a variable cell pathlength, a scale




expandable from 1 x 20 x, and a variable wavelength setting.  Table 43 sum-




marizes the settings to be used for analyses of the selected ketones and the




minimum detection for each (Wilks, 1973).
                                        123
-------
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-------
           2.    Current  Monitoring




                No organized monitoring of  the ketones  in air,  water,  or




soil has been reported in the available literature.   Recent reports on their




observation in the environment have usually been on  grab samples.   Table  44




summarizes recent studies which have reported ketones in the environment.




Except for the study by Corwin (1969) ,  the  ketones were identified among




several organic components within the sample and not quantified.




                While Corwin (1969) observed variations in ketone  concentra-




tion (MEK and acetone) between the two  sampling locations (one  each in the




Straits of Florida and the Mediterranean Sea) and between depths  of sample




collection at each location (see Figure 22), he offers no explanation of  the




data other than to suggest that the variations could be related to the biota.




                Except for the two studies  reporting ketones in drinking




water (Anon., 1972; Abrams Q ai^. , 1975), the remaining ketone  samples were




from industrial waste streams.  The contamination sources for the ketones that




were detected in drinking water were not identified.




                The apparent minor interest in data  on ambient  environmental




ketone concentrations is perhaps attributed in part  to the knowledge that they




are present in small quantities in food and throughout the environment, and




that analysis of the low concentrations is  rather costly.  While the ketones




do participate in photochemical smog production, at  their ambient  concentra-




tions their contributions are relatively minor when  compared to other hydro-




carbons such as olefins and aldehydes (Altshuller, 1966; Altshuller and Bufalini,



1971).
                                      125
-------
                                CJD
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                                                                             126
-------
    [j|=  METHYL  ETHYL  KETONE Ug/L

     A=  BUTYRALDEHYDE yg/L

     O =  ACETONE yg/L
  = METHYL ETHYL  KETONE
O= ACETONE  yg/L
                           40     50
                                  -•"-O
                                                 1200 J
        a)  Sampled at the Straits of
                   Florida
   b)   Sampled at the Eastern
           Mediterranean
Figure 22.  Distribution, by Depth, of Volatile Organic Compounds in Sea Water
            (Corwin, 1969)

            (Reprinted with permission from the Bulletin of Marine  Science)
                                     12'
-------
III.   Health and Environmental Effects




      A.    Environmental Effects




           1,   Persistence




                a.    Biological Degradation,  Organisms,  and Products




                     The biological occurrence of aliphatic methyl ketones




(see Forney and Markovetz, 1971) coupled with the fact that significant




accumulation of these compounds in the biosphere has not been noted, indicates




that a recycling of these organic molecules is occurring.  The experimental




evidence substantiating the rapid removal of ketonic compounds in the environ-




ment is meager.  The reported studies have mainly considered the degradation




and degradation mechanisms in pure cultures of microorganisms.  A number of




these studies have been oriented towards understanding the mechanism of




ri-alkane oxidation by microorganisms where methyl ketones are intermediate




products.  For example, butanone, pentanone, and hexanone were reported to be




produced from the respective alkanes by Mycobacterium smegmatis (Lukins and




Foster, 1963).




                     The bulk of the fate-related information available in




the literature is for saturated aliphatic ketones (generally C  - C  ).  A




few alicyclic ketones have also been studied for their susceptibility to bio-




degradation.  It was further noted from the literature that although micro-




organisms from a variety of sources (soil, water, activated sludge, etc), have




been used in degradation studies; quite often the conditions simulate only




the aqueous environment.  The salient features of the reported studies on




microbial breakdown of ketones are summarized in Table 45.
                                     129
-------
Table  45.  Summary of  the Studies  Dealing  with  Biodegradability of  Ketones
          RejerericK



     Levine and Krampitz (1952)
     Mills and Stack (1954)
     Caudy et al (1963)
     I.ukins and Foster (1963)
     Marion and Malaney (1963)
     Buzzell et al (1968)

Concentration
le*t Cheaical Ueaj
Acetone 2 g/ liter




Acetone 50-1000 ppro
Diethyl ketone
Methyl isobutyl ketone
Methyl n-amyl ketone
Methyl phenyl ketone
Acetone 1 g/liter
Butanone as COD




Methyl n-alkyl 0.2%
kttunet. (C -C ) v/v
2,4-Pentadlone
4-Heptanone
Acetophenone
(c3 - c9)
3 -ethyl 2-butjnone
2-Tridecanone

Acetone 10 mg/1
2- Butanone

Source of
MlCrOOTMDlMM
Corynebacterium £p.
enriched from soil



Bon-flocculent seed
developed from settled
sewage


Sewage feed





Pure cultures of
Hycobacterium
Corynebacterium sp.
isolated from alkane

AlcaUgengs
faecalls (a member
of the activated
sludge flora)

Sewage seed

Env Ir oiwen tal
Uaad During of the
the T«at Teat .
Aqueous 60 min.
(representing
high cell con-
centration)

Aqueous 1C days




Activated 8 hours
sludge eystetr
(using synthetic
waste containing
ketones as the
organic carbon)
Aqueous 30 min.
(representing
high cell con-
centration)

Aqueous IfiR - ]<)2
high cell con-
centration)


Aqueous -0 day1'

Criteria
Cheaical
Alteration
Oxvgen
uptake
determined
ia.mometr J-
tally
Riological
oxygen
demand


COD
measure-
ments



Oxygen
uptake in
harburg
resplro-
meter.
Oxygen
Warburg
rtin'.tant
volume
meter
Ox.gt-n
utillzu-
     Lowerv et al (1968)
     Perrv (1968)
     Buzzell et al  (1969)
     Morris and Trudgill (1971)
      Murray et al (1976)
     Metabolism by photogynthetic ba^cterii
      51«g«l (1954); 81^*1 and
      S.lth (1955); !!•»*! (1957)
Methyl n-alkyl ketones
(C.-C,)
A 7
4-Methyl-2-pentanone
4-Heptanone
Cyclohexenone
«3-C8>

Acetone
2-Butanone



Cyclohexanone

Cyclohexanone






2 -Butanone
sria
Acetone




0.05 ml Stock cultures
ketone/20 ml Of yeast - Candida
growth medium lipolytic.B. G. pvil/-
cherrima, Candida
ap T13. Rhodotorula
glutinia
4-2 mM Brevihacterium
sp. isolated from soil
2-methylbuLane

180 mg/1 Freeze dried sludge
as carbon



Not stated Nocardia globerula
CL1 isolated by soil
hexane as the carbon
source
0.1% (v/v) Nocardia sp. isolated
In growth by soil enrichment with
0.5 uM in carbon source
respiration
studies


Mycobacterlum
vaccat

15-30 \M 9cock culture* of
ftwriM pboto*TBthatic b*c-
Mtabollc teriuB
0.2X Aorias fjl^ti»«*
frtwth
Aqueous 23 days f.rovtt,




Aqueous 90 itiJn. CxvBtn
(representing uptake in
high cell con- Warburg
centration) resplrc-
n.eter
Activated L2 hourf, Oxygen
sludge uptake in
system Warburg ,
soluble
carbon
Aqueous Not Oxyfcen
high cell con- Warburg
centration) manoireter
Aqueous 7 dayb Growth,
(representing for ox>gen

metric and
polaro-
^raphic
technique

Up to 6 Aqueous Conv«raiac
hour* to cellu-
lar inter-
14C-«**av

                                                         130
-------
                     The available  information  has  been  organized  into




three sections:   (1)  pure culture studies,  (2)  mixed  culture studies, and




(3) activated sludge systems.   The information  pertinent to each of  these




categories is reviewed below.




                     (1)  Biodegradation by Pure Cultures of Microorganisms




                          Pure culture studies  dealing with the metabolism




of ketones by heterotrophic (those bacteria which use organic  carbon for




growth) and photosynthetic bacteria (utilizing  light as  the source of energy),




and fungi have been reported.   The heterotrophic microorganisms are perhaps




of major significance in removal of organic contaminants from the environment,




and, therefore, these studies will receive more emphasis.




                          (a)  Biodegradation by Heterotrophic Bacteria




                               (i)  Methyl n-alkyl ketones




                                    Isolation of the bacteria capable of




metabolizing methyl n-alkyl ketones has been reported by a number of re-




searchers.  Among the various ketones, acetone has been investigated most




extensively.  As early as 1923, Supniewski (1923) reported that Bacillius




pyocyaneous would grow in a medium containing 0.23% acetone, and that it




produced acetic and formic acids as end products of growth.  Levine and




Krampitz (1952) failed to isolate an acetone oxidizing organism from soil




using an enrichment medium consisting solely of inorganic salts and acetone.




Upon supplementing the enrichment medium with yeast extract, a Corynebacterium




sp. was isolated, which was able to oxidize acetone.   The ability of the
                                     131
-------
organism to oxidize acetone was an adaptive process,  and required growth of the




organism in the presence of acetone.   Lukins and Foster (1963)  reported isolation of




4 bacterial strains (tentatively named as MB,-, MB ,  MA  and MC )  from soil and




mud, which were able to use 2-butanone as a carbon source.   No information




regarding the rate of growth and/or the rapidity of  the breakdown by the




isolated organisms was revealed in this study.  Pure cultures of  Alcaligenes




faecalis, an organism which has been identified as a member of the activated




sludge flora, were reported to be able to oxidize acetone and heptanone after




a lag period of about 5 days (Marion and Malaney, 1963).  Under similar conditions,




other methyl n-alkyl ketones tested (2-butanone, 3-methyl-2-butanone, 2-pentanone,




2-octanone and 2-nonanone) appeared to be resistant to oxidation (Figure  23).




The interpretation of the experimental data is complicated by the fact that




the cells consumed oxygen in the absence of the test chemical at high rates.




The presence of the endogenous oxidizable substrate may have prevented the




adaptive synthesis of the enzymes responsible for the breakdown of ketones.




An inhibition of the adaptive synthesis of the acetone oxidizing system in




Corynebacterium sp. by increase in the concentration of yeast extract in the




medium has been noted by Levine and Krampitz  (1952).  The problem of inter-




preting the  data  (Marion and Malaney, 1963) is further magnified due to




possible changes in the endogenous oxygen uptake due to the presence of the




added ketones.
                                       132
-------
   H
    CM
   O
          900
          800
          /OO
          600	
3-Methyl-2-butonone

I'll
  2-Penlcnone
           100
             0   24  48  72  96  120  144 168   0  24 48  72  96  120  144  IC8  102
                          LENGTH  OF  WARBURG RUN, HR



       Figure 23.  Oxidation  of ketones by Alcaligenes faecalis.

                   (Marion &  Malaney,  1963)


             (Reprinted with permission from Water Pollution Control Federation)


                                     Methyl n-alkyl ketones have been  reported


to be involved  in  alkane oxidation by microorganisms (Forney and Markovetz,


1971; Lukins and Foster,  1963).   From this, it appears likely that  the  cells


grown on alkanes might be simultaneously adapted to grow and/or oxidize corres-


ponding methyl  ketones.   A number of studies have been reported which deal with


the metabolism  of  methyl ketones  by alkane utilizing microorganisms.  Lukins


and Foster  (1963)  reported that  the strains of Mycobacteria (M. smegmatis  422,


M. rhodochrous  382,  and  M. fortuitum 389), when grown at the expense  of alkanes,


were also able  to  grow on acetone,  2-butanone, and 2-pentanone as a sole source
                                      133
-------
    of  carbon.   In comparable  tests, none of the  organisms  grew on  3-pentanone,
    2,4-pentadione,  2-hexanone,  2-,3-  or 4-heptanone,  or  2-octanone.  In  general,
    the short-chain ketones  supported  more  rapid  and  abundant  growth  (implying
    rapid breakdown)  than  the  long chain ketones.   Studies  of  oxygen  uptake with
    propane grown  cells of M.  smegmatis, and a Corynebacterium sp.  revealed
    that the cells were  able to  rapidly oxidize all the methyl ketones  tested,
    even those that would  not  support  growth  (Table 46).  The  methyl  ketones  with
    increasing chain lengths were oxidized  at  decreasing  rates.
Table 46.  Oxidation of ketones by organisms known to grow at the expense of alkanes
          (Lukins and Foster, 1963)
               Substrate
                                        Oxygen uptake in 30 min.
                                          M. smeg-
                                         matis 422
 OS15*
                                          yliters
          None	13
          Acetone	244
          2-Butanone	196
          2-Pentanone	180
          3-Pentanone	176
          2,4-Pentandione  	  92
          2-Hexanone	217
          3-Heptanone	98
          4-Heptanone	108
          2-Octanone	116
          2-Undecanone	89
          2-Tridecanone  	 109
          Acetophenone	52
yliters
   14
  325
  266
  183
   78
   52
   78
           * A Corvnebacterium sp.  isolated  from propane  enrichment  cultures.
                                         134
-------
                                    In a similar  study,  Perry (1968)  found

that C, - C0 alkane grown cells of Brevibacterium strain JOBS were able to
      1    o
oxidize C  - C0 n-alkyl methyl ketones  (Table 47).   None of the ketones except
         3    8 —
acetone, however, were able  to support  growth of  the organisms.  The suscept-

ibility to oxidation  in general,  increased with an increase in the chain

length of the ketones tested.  This  is  contrary to the findings of Lukin  and

Foster  (1963), with Mycobacterium sp.  (see above).
 Table 47.  Oxidation of ii-Methyl Ketones  by Brevibacterium Strain JOB5 Cells
            Grown on Paraffinic Hydrocarbons3 (Perry,  1968)
Respirometer

Acetone
Butanone
Pentanone
Hexanone
Heptanone
Octanone
Grovth substrate
Methane
10
56
48
25
88
98
Ethane
2
26
36
17
63
75
Propane
21
39
25
9
99
83
Butane
13
85
80
208
204
90
Pentane
59
91
66
73
150
114
Hfxane
1
3
23
Jl
97
67
Heptane
0
9
22
60
77
87
Octane
0
14
17
20
47
75
    a Total ^liters 0 uptake in 90 minutes.
                                      135
-------
                                    Information on the pathways of breakdown



of ketones in microbial systems is meager.   Short chain methyl n-alkyl ketones



have received considerably more attention than other compounds.  Supniewski



(1923) notes that Bacillus pyocyaneus grown on acetone as the sole carbon



source, produced acetic and formic acids as end products.  From the ability



of acetone grown cells of a soil Corynebacterium to oxidize acetol (1-hydroxy-



propan-2-one) and acetaldehyde, Levine and Krampitz (1952) concluded that



these compounds may be intermediates in the pathway of acetone oxidation.



The author proposed that the oxidation of acetone gives rise to acetol, which



undergoes cleavage to yield acetaldehyde and a one-carbon unit as follows:
           CH3C-CH3    	»•   CH3COCH2OH  	>-   CH3CHO + Cl


              0


           acetone                 acetol             acetaldehyde
                                    Oxidation was further confirmed by the


                                 14
results of the studies utilizing   C-carbonyl labelled acetone.  Acetol was



also isolated and characterized as an oxidation product of acetone by Myco-



bacterium smegmatis (Lukins and Foster, 1963).  Presumptive evidence was also



obtained for the formation of a corresponding hydroxy-substituted intermediate



(suspected to be l-hydroxy-2-butanone) during the bacterial oxidation of



butanone.  Ethyl acetate and ethanol were reported to be intermediates in



2-butanone catabolism by a soil Nocardia (referred to as LSU 169) (Eubanks,



1973) .   It was proposed that  the bacterium  converted  2-butanone to ethyl-



acetate which was subsequently hydrolyzed to  ethanol  and acetate.



                                    The first report of the isolation and



characterization of an oxidative intermediate from the metabolism of any methyl
                                      136
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ketone other than acetone was provided by Forney and his coworkers (Forney

et. al. , 1967; Forney and Markovetz, 1968).  In the culture fluid of a

Pseudomonas multivorans incubated with 2-tridecanone, the authors identified

2-tridecanol, 1-undecanol, 1-decanol and undecanoic acid.  In subsequent

studies, a new intermediate,  undecyl acetate,  was identified.   Based on their

findings, the authors proposed the pathways illustrated in Figure 24, for the

oxidation of 2-tridecanone; the pathway provides for conversion of the substrate

to acetate, a common central metabolite in cellular metabolism.
                       2-Tridecanone

                   CH3-(CH2)9-CH2-C-CH3
                                  I"
                                  0
                       Undecyl Acetate

                   CH3-(CH2)9-CH2-0-C-CH3
                   2-Tridecanol
              CH Q—
                               H
      1-Undecanol
   CH3-(CH2)9-CH2-OH
                                    it
                                    0
                             \/
 Acetate
 CH3-COOH
    Undecanoic Acid

   CH3-(CH2)9- COOH
   Via g-oxidation,
   Tricarboxylic Acid
   and Glyoxalate Cycles
Via Tricarboxylic Acid
and Glyoxalate Cycles
       Figure  24.  Proposed Pathway for Complete Degradation of 2-Tridecanone
                  by  Two Aerobic Pseudomonads  (Forney and Markovetz,  1968)

                                    Although the pathway of breakdown of methyl

n-alkyl ketones has been investigated in some depth in pure cultures of micro-

organisms, nothing is known about the environmental fate and the pathways of

breakdown in  the environment.

                                     137
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                               (ii)  Cyclohexanone

                                    Norris and Trudgill (1971)  reported

that Nocardia globerula enriched on cyclohexanol was able to oxidize cyclo-

hexanone at rates very similar to that for cyclohexanol.   Each  mole of

cyclohexanone was oxidized with the consumption of 1.65 mole of oxygen.  Theor-

etically, 8 moles of oxygen are needed for complete oxidation of one mole of

cyclohexanone.  This suggests accumulation of a less oxidized intermediate.

Alternatively, some of the cyclohexanone carbon may be converted to cellular

constituents and may not be completely oxidized.  Studies with subcellular

systems led the authors to propose the following pathway for cyclohexanol/

cyclohexanone oxidation (Figure 25).

                                        0
                                    Cyclohexanone
                                               e-Caprolactone
 Cell
 Metabolism
                  B-oxidation
          Figure 25.
                                    Adipic acid
Reaction Sequence for the Oxidation of
Cyclohexanone by Nocardia globerula CLl^
(Modified from Norris and Trudgill, 1971)
                                                6-Hydroxycaproi
                                                      acid
                                     138
-------
                                        A species of Nocardia,  which used




cyclohexanone as sole source of carbon for growth, was isolated from soil by




Murray and coworkers (1974).  Non-proliferating cells of this organism were




able to rapidly oxidize cyclohexanone.  Cyclohexane-grown cells exhibited no




growth on the related compound, cyclohexane-l,2-dione.  Gas chromatographic




analysis of the supernatant from cultures growing on cyclohexanone revealed




that a possible intermediate in the degradation was 2-hydroxycyclohexan-l-one.




This is a different mechanism than the one proposed by Norris and Trudgill




(1971), which involved the formation of a lactone (Figure 25).




                           (b)  Biotransformation Catalyzed by Photosynthetic




                               Bacteria




                               Many photosynthetic bacteria are able to




metabolize organic  substrates photosynthetically, and also aerobically in




darkness.  A number of researchers have investigated the metabolism of acetone by




photosynthetic microorganisms.  The reported studies have, however, been




oriented  towards understanding the mechanism of substrate assimilation in




relation  to bacterial photosynthesis, rather than the environmental fate of




methyl ketones.  Moreover,  it is unclear  at the present time as to what role,




if  any, photosynthetic microorganisms play in the breakdown of organic con-




taminants in the environment.  Photosynthetic bacteria  are generally found




in  places where oxygen is  deficient, but  light is not a limiting  factor.




Such  areas are sediments of ponds, estuarine sediments, narrow banks in the




lakes, and open ocean where oxygen has been depleted and there is still a




low light intensity.  It is likely that in these environmental mediums, photo-




synthetic bacteria  may have some role in metabolizing ketones.
                                      139
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                               Siegel (1954) reported the photosynthetic

conversion of acetone to acetate by the photosynthetic bacterium Rhodo-

pseudomonas gelatinosa grown in light in the presence of acetone.  Seigel

and Smith (1955) later investigated the dark aerobic metabolism of acetone

by R.. gelatinosa and found that acetone underwent direct carboxylation with

CO- to form acetoacetate, which is the precursor of acetate.  These investi-

gations further indicated that the same metabolic pathway is followed in

the dark aerobic metabolism of acetone as in its photosynthetic metabolism,

and that energy must be provided at discrete points in the pathways.  The

available energy is used for the carboxylation of acetone to form acetoacetate,

or for assimilation of acetate, a low molecular weight cellular intermediate,

into cell material.  On the basis of their  experimental  findings, Siegel and

coworkers proposed the following pathway  (Figure  26) for metabolism of

acetone in the photosynthetic bacterium.  Other ketones  could perhaps also

be attacked by photosynthetic bacteria; however, no experimental data is

available at the present time to support  this possibility.
                                               CELL
                                             MATERIAL
                      ACETONE + CO,
                                [ENERGY]-
                      LIGHT; O,
                                             AcO
      Figure  26.  Photosynthetic and Aerobic Metabolism of Acetone  in
                 R.  gelatinosa  (Siegel, 1957)

         (Reprinted with permission from The American Society of Biological
             Chemists, Inc.)
                                     140
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                              (c)   Biodegradation of  Ketones  by Fungi
                                   Hopkins and  Chibnall (1932)  established  that
Aspergillus versicolor, which grew on long-chain  paraffins, also grew on
related methyl ketones.  Lowery and coworkers (1968) surveyed  several species
of yeasts for  their  ability to utilize various ketones  as growth substrates.
The  authors found that several species of  genus Candida were able to utilize
some of the methyl ketones  tested  (Table 48).  It was concluded  that 2-hexanone
and  2-heptanone were most  readily  utilized.  The  data further  indicated that
shifting the  position of the carbonyl groups, methyl substitution, cycliza-
tion,  unsaturation,  and the introduction of a second carbonyl  group all
rendered these ketones unsuitable  for growth.
Table 48.   Growth  of Yeasts on  Individual Ketone Substrates   (Lowery  et al,  1968)
Microorganisms
2
Substrate Candida
lipolytica
(8661)
Candida
pulcherrima
(Merck)
Candida Rhodotorula glutinis
ap. T 13 	
(U. of Cal) C145 H)
2-Butarione
2-Pentanone
3~Pentanone
4-Methyl-2-pentanone
2-Hexanone
Cyclohexanone
2-Heptanone
4-Heptanone
2-Undecanone
                     2 +
                     2 +
        No growth (-); trace of growth (^); growth (2 +); good growth (3 +); and abundant growth (4 +).
        None of the yeasts tested grew on the following ketones:  acetone, 2,3-pentanedione, 2,4-pentane-
        dione, 3~methyl-2~pentanone, 5-methyl-2-hexanone, 5-hexene^2-one, 3-heptanone, 3-methyl-2-hepta-
        none, 2,3-heptanedione, 2-octanone, 2-nonanone, 2-decanone and pinacolone.
        Candida brumptii, Candida gulllenaondll and Candida sp. T 16 were not able to utilize any of the
        above ketones as growth substrate.
                                         141
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                     (2)   Biodegradation by  Mixed Cultures




                          Relatively little  information is  available con-




cerning the biodegradability of ketones in the presence of  mixed cultures




of microorganisms.  Mills and Stack (1954) have reported the results of  a




10-day BOD test with methyl n-alkyl ketones.  These investigators inoculated




the dilution bottles with dispersed seed (non-flocculent growth, see




Heukelekian, 1949), developed from settled sewage and acclimated to an organic




mixture that approximated their company's  plant process effluent.  The sim-




ulated process effluent was also used as the dilution water in this study;




the BOD equivalent for the ketones were calculated from the difference be-




tween the BOD of the process effluent, and the process effluent plus ketone.




A shortcoming of  this  approach is  that  the  presence  of  ketones  may  cause




considerable change in the oxidation of the process effluent chemicals; and in




that case, the subtraction of  the BOD of the process effluent will not rep-




resent the oxygen used for biodegradation of the ketones.




                          As shown in Table  49, the ketones investigated




(acetone, 2-butanone, methyl isobutyl ketone, methyl n.-amyl ketone, and




acetophenone) were susceptible to oxidation.  The 10 day BOD test was greatest




for acetone, the  oxygen depletion decreased with an  increase in  chain length.




A comparison of the amount of  oxygen consumed per mole  of  substrate with the




calculated theoretical oxygen  demand revealed that the  test ketones were not




completely mineralized.  However, a low oxygen to substrate ratio could also




be expected if part of ketonic carbon was assimilated by the cell and converted




to cell constituents and intermediates which are less oxidized  than the terminal




oxidation product - CO .  Data  is not available to distinguish between the




two explanations.
                                     142
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       Table 49.   Results of a 10-Day BOD Test With Ketones
                   (Mills and Stack, 1954)
Substrate
Acetone
Die thy 1 ketone
Methyl isobutyl
ppm Oxygen
Depletion in 10 days
(Substrate Concn. ,
1000 ppm)
Equivalents ,
Mole of
Observed
1030 2.17
820 2. 7
ketone 600 1.9
Methyl n-amyl ketone 360 1.8
Moles of Oxygen/
Substrate
Theoretical (for
Complete Oxidation)
4
7
8.5
10
 (2-heptanone)

Methyl phenyl ketone
 (Ace t ophenone)
240
5.25
9.5
                          In a 20 day BOD test, Buzzell and coworkers (1968)

found that both acetone and methyl ethyl ketone (2-butanone) were extensively

oxidized (Figure 27).  Nitrification was not detected until the 12th day of

the study, suggesting little error in the oxygen uptake data due to non-

carbonaceous oxygen consumption.  The results of the chemical oxygen demand

and total organic carbon in the same samples closely corroborated the results

of the oxygen utilization data.  The increase in microbial population

concurrent with the oxidation of ketones further supports the view that the

test ketones were metabolized by microorganisms.
                                     143
-------
     25 -
Figure 27.  Results of a 20-Day Biodegradability Test With
            Acetone and Methyl Ethyl Ketone  (Buzzell et^ al.,  1968)


   (Reprinted with permission from Manufacturing Chemists
       Association, Inc.)
                             144
-------
                     (3)   Biodegradation in Activated Sludge System




                          In an effort to investigate the kinetics of volatile




substrate removal in activated sludge systems,  Gaudi et al.  (1963) employed




acetone and butanone as model substrates.  In an activated sludge system,




a volatile organic substrate is removed by dual mechanisms - physical strip-




ping and biological metabolism.  The rate of biological removal of ketones




was determined in a Warburg apparatus.  At the substrate concentration and




temperature employed in the study, the authors confirmed that the losses due




to physical stripping were not a serious concern in the Warburg apparatus,




and that the removal would truly reflect the biological metabolism.  The




rates of loss due to physical stripping were separately determined and the




two kinetic constants were integrated to obtain a combined kinetic equation.





                          Mixed liquor taken from the activated sludge system




developed from a sewage seed and synthetic waste containing ketones served as




the biological material in the Warburg study.  The loss of ketones was followed




by determining COD at various intervals.  The results of this study are de-




picted in Table 50.   Nearly 40-60% loss of ketones was noted after 8 hours.




Unfortunately, the experiments were terminated at 8 hours (perhaps due to




depletion of all the oxygen) and, therefore, it is unclear if complete removal




of these compounds would have occurred.  The rate of loss of the ketones was




reported to be a zero-order kinetic process (with acetone, however, the data




could also be fitted to first-order kinetics).   The uptake of oxygen linked




to the oxidation of ketones, and the increase in biological solids in the




system (apparently at the expense of the ketones), provide further support




for the susceptibility of these compounds to microbial attack.
                                     145
-------
Table  50.  Biological  Removal of Ketones in Warburg Apparatus  (Gaudi et_ al,  1963)





Substrate
Acetone
Butanone





Substrate
Concentration
mg/1
as COD
1000
1000



Biological Velocity
Constant*

First Order Zero Order
Kinetics Kinetics
hr-l mg/t/hr
0.0261-0.0329 50-60
62.5-110





Biological
Solids in
8 Hours
nig/liter
66-125
Lower than
initial
concentration
-63




Oxygen Uptake/
mg solids**
0.0356-0.0942
0.0307-0.0397



  * Where the data could be fitted to both first and zero order kinetics, both velocity constants are given.




  ** Accumulated oxygen uptake in two hours (units unclear) divided by initial solids concentration (mgs).
                            Buzzell et_ al.  (1969)  studied  the  biodegradability




of  acetone and  2-butanone in a Warburg respirometer, and parallel shake  culture




studies under conditions which simulated  slug loading of an  activated  sludge




process.  Standardized activated sludge culture, which had been preserved by




freeze drying and rejuvenated prior to use,  was used to  inoculate the  flasks.




The mixed liquor  volatile suspended solids  (MLVSS) at the  start were 2500 mg/&;
                                        146
-------
£
2
  I - < 60
      20
                              88% A
                    D-..
                  567
                  TIME - hr
                        8 9 X)  11  12
                                         61—
1°
      100


     I
     I 80
                                             <60
                                          -  < 40
                                              20
 \
.  \
'••. \
 v\
                                                                     851 A
                                                                      ••-A
                                                                         3 S
                  667
                  TIME - hr
                                                                8  9  10 II 12
    Figure 28.   Behavior of Acetone and  2-Butanone in the Activated
                Sludge Environment  (Buzzell  at al., 1969)
                   Warburg Respirometer  Studies
                   0:  Oxygen utilization
                   A:  Percentage of  the initial soluble carbon remaining
                   Parallel Shake Culture  Studies

                   C:  Soluble organic carbon removal
                   D:  Changes in dehydrogenase enzyme activity


        (Reprinted  with permission from Manufacturing Chemists
            Association,  Inc.)
                                   147
-------
the organic chemical was at 180 mg/H as carbon.   The  authors  measured oxygen




utilization and soluble carbon removal to assess the  biodegradability of  the




ketonic compounds, and dehydrogenase activity (enzyme system responsible  for




oxidizing unspecified organic compounds in the cell)  to determine the adverse




effect of the test material on the biological agent.




                          The results of this study are confusing and hard to




interpret.  Since 85-88% of the soluble carbon remained in the Warburg flask,




as compared with 27-35% in the open flasks, it appears likely that the compounds




were removed from the open unit predominantly by evaporation.  Alternatively,




the lower level of carbon removal and coupled oxygen uptake in Warburg could




be due to limited availability of oxygen in the system.  These possibilities




cannot be distinguished from the data available.  From the Warburg data,  it can




be calculated that moles of oxygen  consumed per mole of acetone and 2-butanone




are, respectively, 4.11 and 4.9.  Theoretical oxygen demand/mole of substrate is




calculated to be 4 moles for acetone, and 5.5. moles for butanone.  These




findings  suggest that the soluble carbon removed in the Warburg study




(12-15%)  was completely mineralized by microbial action.
                                      148
-------
                     (4)  Probable Environmental Fate of Ketones




                          In studying biodegradation of ketones, researchers




have frequently utilized pure cultures of microorganisms.  The pure culture




studies in general reveal very little about the environmental fate of a




chemical.  In that respect, they have very limited application.  However, upon




considering a number of points such as the relative ease by which an organism




can be isolated which metabolizes the chemical, how extensively and rapidly




the chemical is degraded by the isolated organism, whether acclimation is




required for degradation to occur, some insight into the environmental fate of




the chemical can be achieved.  In this section, an attempt has been made to




infer from the reported studies, the probable fate of ketones under environ-




mental conditions.




                          The projected environmental fate of ketones is sum-




marized in Table 51.   As can be seen, information is available for most methyl




ii-alky 1 ketones, some methyl substituted ketones  (4-methyl-2-pentanone, 3-




methyl butanone), and certain alicyclic ketones.  Other  commercially important




branched chain ketones  (e.g., diisopropyl, diisobutyl, methyl isobutyl, methyl




isoamyl, trimethyl nonanone, mesityl oxide, and diacetone alcohol) have not been




investigated for their  susceptibility to microbial attack.




                          The available data suggests that most methyl n-




alkyl ketones are susceptible to microbial degradation.  Lower  chain ketones




appear more easily attacked.  Methyl substitution (branching),  unsaturation,




and introduction of a second carbonyl group tend to make the resulting compound




harder to degrade.  Alicyclic ketones (e.g., cyclohexanone) appear to be also
                                     149
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 Table 51.   Biodegradability of Ketonic Solvents -  Summary of Information

                                                         Probable Fate
         Compounds Tested             Type of Test             In the Environment

         2-Butanone                   P, AS, M                    + +
         J-Methylbutanone                  P                       +
         2-Pentanone                      P                      + +
         3-Pentanone                      P                       +
         4-Methyl-2-pentanone             P, M                      +
         2,4-Pentadione                    P                       +
         2-Hexanone                      P                      + +
         2-Heptanone                    P, M                     + +
         3-Heptanone                      P                      + 4.
         4-Heptanone                      P                       +
         2-Octanone                      P                       +
         Cyclohexanone                    P                      + 4,
         Acetophenone                   P, M                      +
         P:  Pure culture
         M:  Mixed culture
         AS:  Activated sludge system
         + +:  Extensive degradation
         +:   Minor transformation
         +:   Uncertain

attacked fairly easily by  microorganisms  and degraded to  cellular intermediates.

In general,  it appears unlikely that ketonic solvents will accumulate  in aquatic

or soil  environment to a  considerable extent.   However,  it is possible that

because  of  their extremely volatile nature,  they may escape from soil  and/or

water  and reside predominantly in the atmospheric environment, where little

biodegradation generally  takes place.   Therefore, their  ultimate environmental

fate will be dependent not only on their  susceptibility  to microbial attack,

but also on the rate  of exchange between  environmental media, mobility in a

particular environment, and  photochemical and chemical breakdown in the atmos-

phere.  Furthermore,  the  media in which ketonic solvents are initially released

 (Section II-C, p.  92  ) will have a considerable effect  on the overall  fate of
 these  chemicals.   For example, if they  are discharged  into sewage  treatment

 plants where biological  activity is  very high, a  substantial quantity  may be

 biodegraded, and loss due to volatility may be small.
                                        150
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                b.    Chemical Degradation in the Environment




                     Information on the chemical degradation  of the ketones




is reviewed in Section I-B-2,3 (see pages 24-38).   The ketones are stable to




the usual environmental oxidants and are not degraded by hydrolysis.  Some of




the ketones produced by condensation of acetone (e.g., mesityl oxide and




diacetone alcohol), could fragment back to acetone in environments of slightly




acidic or alkaline conditions.  The ketones which are the subject of this study




will also be photochemically degraded to a significant extent (the branch chain




ketones are somewhat more susceptible).  The overall persistence of ketones  in




the environment will thus be dependent to a significant extent on their chemical




and photochemical breakdown.
                                     151
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            2.   Environmental Transport - Volatility, Leaching, and
                Downward Movement

                No  experimental data has been reported concerning the trans-

 port  and mobility of  ketonic solvents in the environment.  The information

 presented below has been derived largely from the physical and chemical

'properties of  these compounds.

                The vapor  pressure  of a chemical determines, to a great extent,

 the magnitude  of  loss of that compound to the atmosphere.  The high vapor

 pressure of ketones (see Table 4),  suggests that these compounds are volatile

 enough to enter and distribute through the atmosphere.   The  low molecular

 weight ketones (e.g., methyl ethyl  ketone, methyl propyl ketone, etc.) will

 be lost much more rapidly  than higher molecular weight ketones.

                Organic chemicals are gradually  lost from aqueous solution by

 codistillinp with water;  the rate of  loss by  this mechanism  is dependent upon

 the compounds  vapor pressure, water solubility,  and adsorption properties

 (Kenaga, 1972).  Mackay and Wolkoff (1973) have  developed an equation  (see

 Table  52 ) for predicting the  evaporation  rate  of slightly soluble  organic

 compounds from water.  Using this approach,  the half-lives for evaporation

 of ketonic solvents from aqueous  solutions have been calculated  and are pre-

 sented in Table 52.   In general, it  appears  that ketones will not  be  rapidly

 lost to the atmosphere from aqueous solutions;  this may  be attributed  to

 their relatively  high water solubility.

                 The recent studies  of Billing et^ _al. (1975)  have raised

 some question concerning the validity of  the  approach advanced by Mackay and
                                      152
-------
Wolkoff (1973) for calculation of evaporation half-lives for chemicals.




Billing et al. (1975) found a discrepancy between experimentally determined




half-lives of certain low molecular weight chlorinated hydrocarbons and values




calculated according to the equation developed by Mackay and Wolkoff  (1973).




The authors noted that the experimental values were always much higher than




calculated values; furthermore, the seven-fold variation in the calculated




values between the compounds predicted to evaporate the most slowly (half-




life, 0.34 min) and the most rapidly (half-life, 2.3 min) was not reflected




in the experimental values (evaporation half-life range, 21-27 min).  In view




of this information, it is suggested that the calculated evaporation  half-




lives be treated as only rough approximations, and be used only to draw




general conclusions about the evaporation losses of ketonic solvents.
                                   153
-------
Table 52.   Rate of Evaporation of Ketones From Aqueous Solutions
            (calculated according to Mackay and Wolkoff, 1973)
Ketone
Methyl ethyl ketone
Methyl propyl ketone
Methyl isobutyl ketone
Methyl n_-amyl ketone
Ethyl butyl ketone
Diisobutyl ketone
Mesityl oxide
Cyclohexanone
For Comparison
Benzene
DDT
Vapor Calculated Evaporation
Pressure Half Life at
mm Hg at 20° C*
20°C (Hours)
70
27
15
2
4
1
8
2
95.2 (25°C)
lxlO~7 (25°C)
138
48
33
49
24.5
9.1
92.7
331.2
0.62
88.8








(25°C)
(25°C)
     Data on molecular weight, vapor pressure and solubility obtained  from
 Tables 2,  3 and 4 were  used in these  calculations..

   at less than  saturation  concentrations  in  a square meter  of water  undergoing
   constant  mixing.
 Method of calculation  (Mackay  and Wolkoff, 1973)
                                      12.48    L  P,
                           T  (days)  =
                                                 W
                                               is
                                            P.
                                             is
                                           M.
 T    = half life of a chemical  present  at  less  than saturation
 L    = depth of water;  it is convenient to consider depth of 1 meter
                                  3
       (i.e.,  a total volume of 1m )
 P    = partial pressure of water (23.76 mm of Hg at 25°C)
 C.   = solubility of compound in water  in  mg/1
  is
                                          2
 E   = evaporation rate of water (2740  g/m /day, used by Mackay and Wolkoff, 1973)
 P   = vapor pressure of the compound
  is
 M.
molecular weight of the compound

                            154
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                In view of their relatively high water solubility, it appears




 likely  that the ketones lost  to the atmosphere due to volatilization, and




 codistillation with water, will be washed out of the atmosphere with rain.




 Thus, ketones may reside  for  extended periods of time in water, and some




 cycling between air and water is likely.




                Volatilization of chemicals from soil and other surfaces




 depends upon the vapor pressure of the chemical as modified  by the adsorptive




 interactions with the surface (Spencer and Cliath, 1975).  Since  ketones are




 very water soluble, they  will more likely be contained in soil water and,




 thus, significant evaporation losses of ketones from soil may occur.  The




 high water solubility will allow the ketones to migrate through soil and




 eventually make their way to  ground water.  In general, the  physical




 properties of ketones indicate that they should be fairly mobile  in the




 environment.




           3.    Bioaccumulation




                Bioaccumulation (also  referred  to  as bioconcentration)  refers




to concentration of a compound by an  organism from the  surrounding environment




by various processes,  including absorption,  adsorption,  ingestion, etc.   Ex-




perimental data concerning bioaccumulation potential  of ketones  is not  avail-




able in the literature.   For synthetic compounds,  accumulation in organisms




generally depends on equilibrium between fat (in the  organisms)  and water




solubility.   Since most ketonic solvents are fairly water  soluble, it  appears




unlikely that they will bioaccumulate  in significant  quantities  in food chain




organisms.  Furthermore,  methyl ketones  are known  to  be rapidly  attacked  by
                                     155
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microorganisms; and, therefore,  they are not likely to be around to be




taken up by the organisms.




                In many instances, octanol-water partition coefficients have




provided useful information regarding bioconcentration potential of chemicals.




Neely et al. (1974) have reported a linear relationship between octanol-water




partition coefficient and bioconcentration of chemicals in trout muscle.  Using




the equation of the straight-line of best fit, derived by Neely and coworkers,




we have calculated the bioconcentration factor for those ketones for which




octanol-water partition coefficient is available from the literature (Leo et




al. , 1971).  The calculated bioconcentration potential of ketones is shown




in Table 53.   Since the partition coefficient for the ketones fall outside




the range of the partition coefficients represented in the straight line of




best fit, less confidence must be placed  on these predictions.  From the cal-




culated values, it appears that ketones in  general do not have high biocon-




centration  potentials.  Of some concern may be the long chain methyl ketones,




such as 2-hexanone, or alicyclic ketones, such as acetophenone.  However, since




these as well  as other ketones will be susceptible to metabolism and excretion




from the organism  (unlike the compounds studied by Neely et al. } 1974),  the




actual  bioconcentration  factor  for  the  ketones may be lower than calculated




from  the method  of  Neely et^ al.  (1974) .




            4.   Biomagnification




                Biomagnification  indicates  concentration of a compound through




the consumption of  lower organisms by higher food  chain  organisms with a net




increase in tissue  concentration  (Isensee e_t _al. ,  1973).  No experimental data
                                      156
-------
      Table 53.  Bioconcentration Potential of Ketones in Fish
                 (Calculated according to the Regression equation
                  of Neely et: al. , 1974)

                              Log Octanol-Water
  Ketone                    Partition Coefficient            Calculated Bioconcen-
                                     25°C*                      tration Factor
2-Butanone
2-Hexanone
Cyclohexanone
1-Hexen- 5- one
Acetophenone
0.26 - 0.29
1.38
0.81
1.02
1.58
1.84 - 1.91
7.447
3.65
4.753
5.57
     *
      Data  obtained  from Leo et al. , 1971
regarding biomagnification potential of ketones is available in the literature.

               To some extent,  the water solubility of ketones could be help-

ful in providing an approximate idea of their biomagnification potential.

Metcalf and Lu (1973) have reported a relationship between water solubility

and ecological magnification of 16 organic compounds which the authors eval-

uated in their model aquatic ecosystem.  They obtained a regression equation

for the line fitted by the method of least square.  This relationship has

been used here to predict the biomagnification potential of ketones from their

water solubility.  The results shown in Table 54 indicate that hardly any bio-

magnification of ketones in fish should be expected.  Certain branched ketones

and higher chain length ketones may be of some concern because of  their rela-

tively low water solubility and, hence, somewhat  greater predicted ecological

magnification potential (range between 6-8).  In  general, however,  it  is unlikely

that ketones will bimagnify to a significant extent in  the  food  chain  organisms.
                                     157
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Table 54.   Calculated Ecological Magnification of Ketones  in Metcalf's
           Model Aquatic Ecosystem (see Metcalf and Lu,  1973)


                                                        Calculated Ecological
                                                        Magnification (fish)
                            Log Water Solubility,        , concn.  in fish
Ketone
Die thy 1 ketone
Diisopropyl ketone
Diisobutyl ketone
Methyl ethyl ketone
Methyl n-propyl ketone
Methyl n-butyl ketone
Methyl isobutyl ketone
Methyl n-amyl ketone
Methyl isoamyl ketone
Methyl n-hexyl ketone
Ethyl ji-butyl ketone
Ethyl n-amyl ketone
Mesityl oxide
Diacetone alcohol
Ace tony lace tone
Cyclohexanone
Methylcyclohexanone
Isophorone
Acet ophenone
ppb at 20°C
7.531
8.22
5.699
8.428
7.633
7.214
7.278
7.161
6.732
5.954
7.633
7.415
7.447
—
7.491
7.398

7.07918
6.74
concn. in water
0.0
0.0
8.79
0.0
0.0
0.0
0.0
>1
1.98
6.08
0.0
0.0
0.0
0.0
0.0
0.0

>1
1.95
                       Method of Calculation:

      The regression equation for the straight line plotted from
      the relationship between water solubility and ecological
      magnification in model aquatic ecosystem (Metcalf and Lu,
      1973) is:
                     y = 7.205 - 1.595 x

               where y = log water solubility

                     x = log ecological magnification  (fish)
                               158
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      B.    Biology




           1.    Absorption




                Previous reviews (Browning,  1965;  Rowe  and Wolf,  1963)  have




used the ability of certain ketones to cause systemic toxic effects as  an




indicator of absorption by various routes of administration.  While this




approach is probably valid for the ketonic solvents,  it is not particularly




illuminating because there is no way to distinguish between toxic potency and




the rate of absorption.  As detailed in later sections, almost all of the




ketones can be lethal on oral, dermal, and inhalation exposures;  thus,  ab-




sorption, by these routes, may be assumed.




                Little direct quantitative information is available on the




absorption of ketonic solvents.  Only Haggard and coworkers (1945) determined




ketone blood levels.  This work, however, involved a series of intraperitoneal




injections to rats in an attempt to determine comparative toxicities of




three amyl ketones.  While offering useful data on ketone elimination  (dis-




cussed in the appropriate sections below), no attempt was made to study ab-




sorption kinetics.  in one instance in which a rat was injected with methyl




isopropyl ketone  (1 g/Kg), the  first measurement  of  ketone  blood  levels  taken




one hour after dosing was about 83 mg ketone/100 ml of blood and rapidly declined




thereafter  (see Figure 34, p.181).  This pattern  is indicative of relatively




rapid absorption from the injection site.




                The dermal absorption of methyl ethyl ketone on normal and




hydrated skin surfaces using ketone in expired air as an index of absorption




has been examined by Wurster and Munies (1965).   Using human subjects,  considerable




variation was found between individuals in both the steady-state concentration
                                     159
-------
of methyl ethyl ketone in expired air (2.54 - 13.00 yg/£) and in the time re-

quired to reach the steady-state level (9-42 minutes).   No correlation was

found between these two values.  As indicated in Figure 29 ,  hydration of the

stratum corneum caused a marked increase in both the peak and steady-state

concentrations of methyl ethyl ketone in expired air.  The decline in methyl

ethyl ketone concentration from the peak value in hydrated skin is probably

due to dehydration of the skin by the ketone.  However, the higher steady-state

value for hydrated skin suggests that the dehydration effect is only partial

and that the water level in the hydrated skin remains above normal at least for

the three hour experimental period (Wurster and Munies, 1965).  Other ketones

were not tested.
     to
     R
             0)  !_
             o <
            S-g   30
               a
                           30
60
90     120
Time( min.)
150
210
       Figure/29.   Expired air data showing the influence of moisture on the
                   percutaneous absorption of methyl ethyl ketone.  KEY: 0,
                   normal skin; •,  hydrated skin.  (Wurster and Munies, 1965)
                                     160
-------
                The level of glucuronic acid in plasma has been suggested




as a means of following the absorption of cyclohexanone after oral admin-




istration to rabbits (Deichmann and Dierker, 1946).   As will be discussed in




a later section (see p. 175), glucuronide conjugation is a common route in the




elimination of many ketones and an increase in glucuronic acid levels - after




acid hydrolysis of the conjugate - can be used as an index of ketone exposure




(e.g., Treon ej; aJ.. , 1943a or b).  However, the results of Deichmann and Dierker




(1946) indicate that this method may not be quantitatively reliable.  At a




dose of 760 mg/kg, maximum absorption occurred after two hours with a peak plasma




glucuronide level of 15 mg/100 ml.  At double this dose, peak absorption apparently




occurred after seven hours with a peak plasma glucuronide level of 120 mg/ml.




At a dose of 2840 mg/kg which was lethal in twenty-six hours, however, plasma




levels peaked at only  43 mg/100 ml between three and five hours.  In that




urine glucuronide levels continued to remain high throughout the twenty-four




hour observation period thus indicating that extensive absorption did occur,




the low plasma glucuronide levels found with the high dose cast doubt on the




suitability of this method for determining quantitative levels of ketone ab-




sorption.
                                      161
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           2.    Metabolism


                a.    Reduction Reactions


                     A variety of in vivo and in vitro investigations indicate


that ketone reduction to the corresponding secondary alcohol may be a major


route in ketone metabolism especially for the aliphatic and alicyclic ketonic


solvents.  Thus far, only three enzymes have been identified which catalyze this


reaction (alcohol dehydrogenase, aromatic aldehyde-ketone reductase, and a, (3-


unsaturated ketone reductase), although additional enzymes may well be involved.


                     Alcohol dehydrogenase, which is well known for its role


in the conversion of acetaldehyde to ethanol, has been shown to catalyze the


reduction of certain ketones to the corresponding alcohols.  The reaction, which


is reversible and requires nicotinamide adenine dinucleotide (NADH/NAD ), may


be written          Q                          QH


                    II               - 	.   I           +
                  R-C-R' + NADH + "  (      ' R-CH-R1 + NAD

Winer  (1958), using NADH levels to assay enzymatic activity, found that a


variety  of aldehydes and alcohols would serve as substrates for horse liver


dehydrogenase.  In addition, cyclohexanone but not methyl ethyl ketone or


acetone  was reduced.  Under equivalent  incubation conditions, the initial rate


of  cyclohexanone reduction was only one-sixth that of acetaldehyde.   In the


reverse  reaction, however, the initial  oxidation rate of cyclohexanol was equal


to  ethanol while an unspecified methylcyclohexanol was oxidized only  80% as

                           &                                          _ ^
rapidly  as ethanol.  The Km for cyclohexanone was found to be 1.9 x 10  M  (as

                   -4                                _3
opposed  to 2.1  x 10  M  for acetaldehyde) and 1.3 x 10  M for cyclohexanol


(compared to 5.3 x 10   M for ethanol).
 *  The  substrate  concentration which  gives  a  reaction velocity  equal  to  one-half

   the  maximum velocity.
                                      162
-------
                     The more detailed results of Merritt  and Tomkins  (1959)

indicate that horse liver  alcohol dehydrogenase is able to reduce certain

alicyclic  ketones but that the enEyme is  quite sensitive  to ring modification

(see Table 55).
        Table 55.  Substrate Specificity  of Horse Liver  Alcohol Dehydrogenase
                   (modified from Merritt and Tomkins, 1959)
                    Vi Moles Substrate                         y Moles Substrate
                    Metabolized/E280/                         Metabolized/E?80/
Ketones
Acetaldehyde
Acetone
Methyl ethyl ketone
Cyclohexanone
2-Methylcyclohexanone
3-Methylcyclohexanone
4-Methylcyclohexanone
Cyclopentanone
Cycloheptanone
minute
68.2
0.0
0.0
8.52
3.86
3.05
6.84
0.0
3.52
Corresponding Alcohol*
Ethanol
sec-Propanol
sec-Butanol
Cyclohexanol
2-Methylcyclohexanol
3-Methylcyclohexanol
4-Methylcyclohexanol
Cyclopentanol
Cycloheptanol
minute
9.74
0.0
3.49
13.4
1.19
2.1
13.1
0.0
6.54
                                                  — 3             — 4
  * Ketones and aldehydes tested at concentrations of ]. 0 x 10 M, NADH 1.0 x 10  M,
    phosphate buffer, pH 7.2,  1.0 x 10 M.
                                        -3             -4
    Alcohols tested at concentrations of 1.0 x 10 M, NADH 1.0 x  10 M, NaOE-glycine

    buffer, pH 9.5, 1.0 x 10  M.
                      As in the study by Winer  (1958),  the oxidation of cyclo-

hexanol proceeds  at  about the same rate as ethanol oxidation, while the reverse

reaction - the reduction of cyclohexanone - is  only one-eighth  as rapid as  that

of  acetaldehyde.   In studying the  kinetics of the cyclohexanone reaction, Merritt
                                      163
-------
                                                               _3
and Tomkins (1959) calculated a Km for cyclohexanol of 1.6 x 10  M - very
                                             _3
close to that noted by Winer (1958), 1.3 x 10  M.  For cyclohexanone reduction,

however, Merritt and Tomkins (1959) found that the Km was dependent on cyclo-

hexanone concentration showing negative cooperativety.  At concentrations below

  -3                     -4                           -3
10  M the Km was 5.0 x 10  M but increased to 7.6 x 10  M at higher concentra-

tions .

                    Methylation of the cyclohexanone ring causes a marked drop

in reactivity.  Elliott and coworkers (1969) found that the rates of oxidation

and Km values varied markedly with both the position of the methyl group in

the ring and  the steric configuration of  the methyl group (see Table 56).
Table 56.  Michaelis  Constant and Relative Rates of Reduction  of Ketones
            (Elliott et  al.,  1969)


(±)-2-Methylcyclohexanone
(+) - 2-Ke thy Icy c lohexanone
(- ) -2-Methy Icy clohexanone
(±) -3-Methylcyclohexanone
(+)-3-Methylcyclohexanone
(-) -3-Methylcyclohexanone
A- Me thy Icy clohexanone
Cyclohexanone
Km
(molar) 11 „
1.79 x 10 "
1.03 x 10
2.12 x 10
1.44 x 10
1.19 x 10 \
1.48 x 10 \
1.88 x 10
2.3 x 10
Relative
Rates£
1.1
3.6
0.4
57.6
1.1
68.1
40.3
100.0
  11  Km values  were  obtained from Lineweaver  and Burke  plots.
  E,  Oxidation  rates of  ketones were  compared with cyclohexanone  at  the same
    concentration
                                      164
-------
Although the results of Elliott and coworkers (1969) confirm the decreased



reactivity of methylcyclohexanone and the stereospecific nature of the de-



crease, no concentration effect on cyclohexanone Km was noted.



                    The relative specificity for ring size is also apparent



from Table 55.  An increase in one carbon (cycloheptanone) reduces activity



by about 50% and a decrease in one carbon (cyclopentanone) abolishes activity.



The inability of acetone or methyl ethyl ketone to act as substrates for horse



liver alcohol dehydrogenase indicates that a ring configuration may be necessary



for ketone reduction.  The moderate activity of sec-butanol does, of course,



indicate that some alcohols analogous to the acyclic ketones may bind to the



enzyme, but the inability of acetone to inhibit cyclohexanone reduction  [detailed



data not given by Merritt and Tomkins (1959)] suggests that the binding site



for the cyclic compounds may be different from that of the acyclics.



                    The thermodynamics of cyclohexanone reduction by horse



liver alcohol dehydrogenase approximates that of acetaldehyde reduction.  The



K   (aldehyde or ketone + NADH + H /alcohol + NAD ) for acetaldehyde reduction


           -12
is 8.6 x 10    giving an oxidation-reduction potential, E  ', of -0.280 volt;

                                                      _g

cyclohexanone reduction has an average K   of 5.5 x 10   with a E  ' of -0.200
                                    6   eq                       o


volt  (Merritt and Tomkins, 1959).  While cyclohexanone reduction is somewhat



less  thermodynamically favorable than that of acetaldehyde, the similar E  '



values do indicate that horse liver alcohol dehydrogenase could play a signifi-



cant  role in the in vivo reduction of cyclohexanone and perhaps other related



alicyclic ketones.  Yeast alcohol dehydrogenase, however, does not catalyze



this  reduction for any of the above alicyclic ketones or the oxidation of the



corresponding alcohols (Merritt and Tomkins, 1959; Winer, 1958).




                                    165
-------
                     An enzyme which will catalyze the reduction of certain

aliphatic, alicyclic ketones and at least one acyclic aliphatic ketone has

been partially purified from rabbit kidney cortex tissue (Gulp and McMahon,

1968).  The enzyme, referred to as aromatic A-K reductase, was also found

in the kidney cortex of rats and hogs as well as in rabbit liver but not in

heart, lung, or smooth muscle tissue.  Like alcohol dehydrogenase, aromatic

A-K reductase is associated with the cytosol.  However, unlike alcohol re-

ductase, the reaction is irreversible, requires NADPH rather than NADH, and

shows different substrate specificity (see Table 57).
      Table  57-   Substrate Specificity of Aromatic A-K Reductase
                 (Modified from Gulp and McMahon, 1968)

                                                  NADPH oxidized
      Substrate*	(u Moles/min/mg protein)

      Acetaldehyde                                       0**
      Acetone                                            0
      Diethyl  ketone                                    24
      Cyclopentanone                                     3
      Cyclohexanone                                    452
    # Acetophenone                                      42
      p-Chloroacetophenone                             280
      p-Nitroacetophenone                              635
      Benzaldehyde                                     433
    # p-Ilethoxybenzaldehyde                            284
    // p-Chlorobenzaldehyde                             1283
    # p-Nitrobenzaldehyde                              1277


                                                      _T                   -4
      *   Substrates  tested  at concentrations  of  1 x 10    M,  NADPH 1.6 x 10   M,
          sodium  phosphate buffer  0.1 M and enzyme (0.05  to 5.0 mg protein/
          3 mSl) ,  at pH 7.0 and temperature  of  25°C.   Reaction assayed or NADPH
          oxidation determined as  A O.D./t  at  340 nm.

      **  Also no activity when NADH was  substituted for NADPH

      #   Corresponding alcohols used  to  test  for reversibility  of reaction using
          both NAD+ and NADP+
                                     166
-------
As indicated in Table 57, the apparent irreversibility of  the reduction




is based on tests with the alcohol analogues of acetophenone and three




substituted benzaldehydes.  These tests were conducted at pH 10 using




either NADP  or NAD .  For the aldehyde analogues, semicarbazide was added




to the reaction mixture to bind any aldehyde formed, thus facilitating




oxidation.  No aldehyde oxidation was noted.




                     That the enzyme is not alcohol dehydrogenase is




apparent in the failure of acetaldehyde to serve as a substrate with




either NADPH or NADH.  The reduction of cyclopentanone, acetophenone, and




diethyl ketone in addition to cyclohexanone  suggests  that aromatic  A-K




reductase  could be involved  in the metabolism  of a variety  of ketonic




solvents resistant to degradation by alcohol dehydrogenase.  Further studies on




the  substrate specificity of aromatic A-K reductase,  however, have  not been en-




countered,  although  this may have been the enzyme involved  in the reduction




of acetophenone noted by Maylin and Anders  (1969) in  rat liver  post-micro-




somal supernatant.




                     Another NADPH-linked ketone reductase  has  been purified




from the cytosol  fraction of dog erythrocytes  and human liver.  This enzyme,




however, is specific for a,g-unsaturated ketones.  Of the ketonic solvents




under review, the enzyme has been shown to reduce 3-buten-2-one (Km of 7.8 x




10   M in erythrocyte enzyme  and 2.8 x 10~ M  in liver  enzyme), but not methyl




ethyl ketone or 2-cyclohexen-l-one.  NADPH consumption and  substrate reduction




showed an  approximate 1:1 ratio suggesting that either the  keto group or the




carbon-carbon double bond, but not both, was reduced  (Frazer et al., 1967).
                                      167
-------
                    Thus, three enzymes have been specifically identified in

ketone reduction - alcohol dehydrogenase, aromatic A-K reductase, and a,B-

unsaturated ketone reductase - all associated with the cytosol.  This is

consistent with the results of Leibman (1971), who examined the in vitro metab-

olism of various ketones in complete cytosol and microsomal fractions, rather

than partially purified enzyme preparations, and found that ketone reduction

occurred almost exclusively in the cytosol.  Similar to the tissue distribution

of aromatic A-K reductase noted by Gulp and McMahon (1968), Leibman (1971) found

that acetophenone reduction occurred primarily in the liver and kidney, to a

lesser extent in the heart and lung, and not at all in the brain cytosol of

rabbits (see Table 58).
     Table 58:  Acetophenone Reduction in Various Rabbit Tissue Cytosols
                                     (Leibman, 1971)

     Organ                               Initial rate of NADPH oxidation
     	(nmol/min/100 mg tissue)
     Liver                                              138
     Kidney                                              96
     Heart                                               30
     Lung                                                30
     Brain                                                0
                    However, Leibman  (1971) also found that both NADPH and

NADH could serve as reducing agents for acetone, methyl ethyl ketone, or

acetophenone  (see Table  59).
                                     168
-------
    Table  59.  Oxidation of Pyridine Nucleotides in Rabbit Liver Cytosol
               in  the Presence of Ketones   (Leibman,  1971)
                   Concentration
Initial Rate of Oxidation
Ketone of Ketone
Acetone 1 M
Methyl ethyl ketone 50 mM
Acetophenone 8 mM
None -
Nucleotide
NADPH
NADH
NADPH
NADH
NADPH
NADH
NADPH
NADH
(nmol/min/ 100 mg_liver)
283
296
157
173
278
25
8
<5
These results suggest at least two mechanisms for ketone reduction:   one de-

pendent on NADPH which reduces both aromatic and aliphatic ketones and the other

dependent on NADH which reduces aliphatics with equal facility but is less able

to reduce aromatic ketones.   These NADPH and NADP dependent reductions may

reflect the activity of a number of different cytosol enzymes rather than just

the NADH-dependent alcohol dehydrogenase and NADPH-dependent aromatic A-K

reductase discussed above.  This seems probable in that neither of these

enzymes could catalyze the reduction of acetone, and alcohol dehydrogenase

did not reduce methyl ethyl ketone (Merritt and Tomkins, 1959 - see Table 55;

Gulp and McMahon, 1968 - see Table 57).  Nevertheless, it is also possible

that the higher concentrations of acetone and methyl ethyl ketone used by
                                    169
-------
Leibman (1971) facilitated ketone reduction by alcohol dehydrogenase, aromatic



A-K reductase or other enzymes in the cytosol.  However, at least one enzyme



in addition to alcohol dehydrogenase and aromatic A-K reductase is implicated



by the reversibility of NADPH- and NADH-mediated acetophenone reduction (see



Table 60).





     Table 60.  Reversibility of Acetophenone Reduction in Rabbit Liver

                Cytosol (Leibman, 1971)



                                                          Initial rate of
Substrate
(8 x 10~3M)
Acetophenone
1-Phenylethanol
Nucleotide
(2 x 10~4M)
NADPH
NADH
NADP
NAD
oxidation or
(nmol/min/100
320
128
320
152
reduction
mg liver)


 In  this  instance,  the  substrate and nucleotide  concentrations  are similar  to


                                              -3                            -4
 those  used by  Gulp and McMahon  (1968)  [  1 x  10  M  for  substrate and  1.6 x  10  M



 for nucleotide] who found  that  aromatic  A-K  reductase  could not catalyze the



 oxidation of 1-phenylethanol  to acetophenone.



                     The  reversibility  of ketone reduction noted by Leibman



 (1971) for acetophenone  and by  Merritt and Tomkins (1959) for  many horse liver



 alcohol dehydrogenase  reactions is also  indicated  by in vivo studies of secon-



 dary alcohol metabolism.   Haggard and  coworkers (1945)  have noted the rapid



 and extensive  conversion of three amyl alcohols (pentan-3-ol,  pentan-2-ol, and



 3-methyl butan-2-ol) to  the corresponding ketones  (diethyl, methyl n-propyl,  and
                                      170
-------
methyl isopropyl, respectively) after intraperitoneal injection of rats with




these alcohols.  In a similar experiment administering a variety of secondary




alcohols to rabbits by intubation, Kamil and coworkers (1953) found that the




following alcohols were converted to ketones to some extent:  DL-butan-2-ol to




methyl ethyl ketone, hexan-2-ol to methyl ketone (presumably methyl ri-butyl




ketone), and 4-methylpentan-2-ol to methyl isobutyl ketone.  However, contrary




to the results of Haggard and coworkers  (1945), pentan-2-ol and pentan-3-ol were




not oxidized.  Whether this is attributable to the differences in route of




administration or species exposed cannot be determined from the available data.




                     As evidenced by the information thus  far presented, a variety




of ketones are converted to the corresponding  secondary alcohols prior to elimi-




nation.  The various reductions are  catalyzed by one of at least three enzymes




which are associated with the cytosol,  occur primarily in  the liver and kid-




neys, and require NADPH or NADH.  While  some of the individual reactions may be




irreversible in pure enzyme preparation, ketone/alcohol conversion seems to




be reversible  in vivo.  Most  information available  on the  rate  of  such- re-




ductions in vitro  (see Table  55,  57, and 59) suggests that compounds  containing




aromatic or cyclohexyl rings  are much more readily reduced than low molecular




weight acyclic aliphatic ketones.  This  is consistent with in. vivo studies




on various mammals  indicating that the  following aliphatic and cyclohexyl




ketones are reduced to corresponding alcohols  in appreciable amounts  prior to




conjugation:   acetophenone, 47% (Smith £t _al. , 1954a); benzophenone,  50%




(Robinson, 1958); cyclohexanone, 51-80%  (Elliott _et _al., 1959); 2-, 3-, and




4-methylcyclohexanone, 72-80% (Elliott et_ al. , 1965); and  2-, 3-, and 4-




tert-butylcyclohexanone, 76.5-80% (Cheo  e_t al. , 1967) [see Table 64,  p. 185 for
                                      171
-------
details of these studies].   However, it should also be noted that the metabolism




of higher acyclic aliphatic ketones has received relatively little attention.




Kamil and associates (1953) have noted that 45.2% of methyl _n-amyl ketone is




apparently reduced to heptan-2-ol after oral administration to rabbits.   Thus,




the enzymatic apparatus may well exist for the reduction of at least some




aliphatic ketones.  The predominance of reduction in the metabolism of a par-




ticular ketone seems related to the degree of glucuronide or sulfate conjuga-




tion with subsequent urinary elimination.  Quantitative aspects of this process




are discussed in the section on elimination (see p. 184) while the general




pattern of ketone conjugation is discussed in part (d) of this section (see




p. 175).




               b.   Oxidation




                    Perhaps the most important ketone oxidation reaction is




the conversion of methyl n-butyl ketone  to 2,5-hexanedione.  As discussed in




Section III-D-3  (p. 266),  this dione may be the neurotoxic agent associated




with the neuropathogenic properties of both methyl n-butyl ketone and n-hexane.




This conversion  seems to proceed by hydroxylation of the  Y  carbon forming




5-hydroxy-2-hexanone.  This, in turn, is either reduced to 2,5-hexanediol or




further oxidized to 2,5-hexanedione.  This latter metabolite appears to pre-




dominate in  the  serum and  could be  reduced to 5-hydroxy-2-hexanone, but is




not significantly converted to the  diol.  Both methyl isobutyl ketone and




methyl ethyl ketone undergo corresponding oxidative/reductive metabolic con-




version  (DiVincenzo jit; al. , 1976).  These findings are  consistent with those




of Abdel-Rahman  and coworkers  (1975) showing  that  rats, guinea pigs, and rabbits




exposed  to methyl n-butyl  ketone vapor excrete 2-hexanol  and 2,5-hexanediol in




the urine principally as 0-glucuronides.




                                      172
-------
                    Alicyclic ketone oxidation has been long recognized.   Adipic
acid, excreted in the urine, has been cited as a minor metabolite of cyclohexanone
after intraperitoneal injection of both mice (Filippi, 1914) and guinea pigs
(Frey, 1939).  In addition, Boyland and Chasseau (1970) have found that cyclo-
hexanone, injected intraperitoneally into rats, lowers liver glutathione levels.
Since cyclohexanone does not have an activated double bond and does not undergo
glutathione conjugation _in vitro, these investigators have speculated that cyclo-
hexanone may be oxidized to cyclohex-2-en-l-one prior to conjugation.  Both
oxidation reactions for cyclohexanone are diagrammed below.
                                    Cyclohexanone
                                  0
                   cyclohex-2-en-l-one
                                                \
                                                   \
                   Glutathione
    COOH
    CH2
    CH2
    CH2
    CH2
    COOH
Adipic Acid
                                     173
-------
The cyclohex-2-en-l-one reaction is apparently a simple dehydrogenation.

Adipic acid formation, however, would require at least one intermediate, the

identity of which has neither been determined nor proposed.

                    Isophorone also appears to undergo oxidation of the 3-

methyl group after oral administration of  1 g/kg to  rabbits.   This reaction,

shown below, precedes glucuronide conjugation and urinary elimination.
                                               y^      TT r< s- I        I  "COOH
The pathway of this reaction and the structure of the glucuronide conjugate

formed have not yet been identified (Truhaut et_ _al. , 1970).


                 c.    Miscellaneous  Reactions

                      Lewin  (1907),  in  subcutaneous  injections  of  rabbits with
                                                              /TTT     r\   (""H
mesityl  oxide  and phorone  [a  linear isomer of  isophorone,      j3    ,,    (3   ],
                                                           CH3-C=CH-C-CH=C-CH3

has  proposed  that these ketones are converted  to disulfide compounds.   The proposed

metabolite of  mesityl oxide involves  the linking of two such sulfur substituted

molecules of  mesityl  oxide  by  disulfide bridges  to give:

                   CH3   S - S      CH3
                                               CH3

                =  CH  \S  -  S/ \CH  =  C
 Additional studies supporting the formation of this proposed metabolite have

 not been encountered.


                                     174
-------
                d.    Conjugation Reactions

                     Many of the ketonic solvents have been shown to undergo

conjugation with glucuronic acid, sulfate, or glutathione prior to renal

excretion.   Glucuronic acid conjugation may proceed via either ketone reduc-

tion to the corresponding secondary alcohol or ketone oxidation to a carboxylic

acid derivative.  The formation of sulfuric acid esters (ethereal sulfates)

by sulfate conjugation probably occurs exclusively through secondary alcohol

formation.  Glutathione conjugation, with subsequent tnercapturic acid for-

mation, seems restricted to the alicyclic ketones and does not involve alcohol

or carboxylic acid formation.  This general outline of ketone conjugation

reactions is summarized in Figure 30.
 Carboxylic  acid
    derivative
 Glucuronide
me th oxi da t i on
 [isophorone]
Ketone
                    Glucuronic
                       acid
                                                         Glutathione
                [alicylic
                   ketones]
                                              reduction
               Secondary Alcohol
                                                  SOi
                                             w
Mercapturic
    acid
              Sulfuric acid ester
           Figure 30,   Overview of Ketone Conjugation Reactions
                                          major
                                          route
                                      175
-------
                    Of the conjugation routes given in Figure 30, glucuronic

acid formation is by far the most common.  Although conjugation does not seem

to be a quantitatively significant pathway in the elimination of most acyclic

aliphatic ketones (see Section III-B-3, Elimination, p. 184), Neubauer .(1901)

as indicated in Table 61, has demonstrated that many of these ketones cause an

increase in urinary glucuronic acid levels after oral administration to rabbits.
         Table 61.  Ketones Causing Increases in Glucuronic Acid
                    Urinary Excretion After Oral Administration
                    to Rabbits (Neubauer, 1901)
         Ketone                                   Dose (g/kg)

    Methyl ethyl                                   0.96
    Methyl n-propyl                                1.40 (in 2 doses)
    Methyl isopropyl                               1.37 (in 2 doses)
    Diethyl                                        1.03
    Methyl n-butyl                                 1.06
    Methyl tert-butyl                              1.01
    Ethyl n-propyl                                 1.02
    Ethyl isopropyl                                0.85
    Methyl n-hexyl                                 1.35
    Mesityl  oxide                                  1.33 (in 3 doses)
 In  addition,  Saneyoshi  (1911)  has  isolated  a  glucuronide  of  2-butanol  from

 the urine  of  rabbits which had received  2-3 grams  of methyl  ethyl  ketone (2-

 butanone)  in  the  diet,   However, the  only acyclic  aliphatic  ketone which has

 been shown to undergo extensive glucuronide conjugation is methyl  n-hexyl

 ketone  (42% of dose) after oral administration  to  rabbits (Kamil et^ al., 1953;

 see Table  64, p.  185).

                                    176
-------
                     All alleyclic ketones, however, are conjugated to a




marked degree, primarily as glucuronides.  Indirect evidence of cyclohexanone




and methylcyclohexanone conjugation is presented by Deichmann and Thomas (1943)




who noted that oral administration of these ketones to rabbits resulted in




greatly increased glucuronic acid levels and slightly depressed inorganic




sulfate levels in the urine.  Treon and coworkers (1943 a & b) have noted similar




results after both oral and inhalation exposures to these ketones.  The in-




creased glucuronic acid levels in urine parallel similar increases in plasma




and serum glucuronic acid after oral administration of cyclohexanone to rats




(Deichmann and Dierker, 1946).




                     Since these early investigations, the conjugation products




of the alicyclic ketones have been isolated and identified.  Cyclohexanone




is conjugated primarily as the glucuronide of cyclohexanol (Elliott et al.,




1959) , although small amounts of the sulfuric acid  ester and 2-hydroxycyclo-




hexylmercapturic acid and its sulfate ester are also formed.  Similar patterns




are followed by both cyclopentanone and  cycloheptanone  (James and Waring,  1971).




Methylcyclohexanones (Elliott et al., 1965) and tert-butylcyclohexanones  (Cheo




e^. _al., 1967) are also conjugated as glucuronides and sulfuric acid esters of




the corresponding alkyl cyclohexanols, but no indication of mercapturic acid




formation was found.  In that glutathione derivatives of the unsubstituted




alicyclics occur in only trace amounts (James and Waring, 1971) and the analy-




tical technique used by Elliott and coworkers (1965) and Cheo and coworkers  (1967)




has a recovery of ±5% (Stekol, 1936), small quantities of methylcyclohexyl-




mercapturic acid may have gone undetected.
                                        177
-------
                     Aromatic ketones undergo similar conjugation reactions.




Acetophenone is conjugated primarily as methyl phenyl carbaryl glucuronide,




although conjugation with glycine to form ii-benzoylylione  (hippuric acid) via




benzoic acid also occurs (Smith ej; jil^. , 1954a; Thierfelder and Klenk,  1924b).




In addition, a small amount of acetophenone is conjugated with sulfate  (Smith




j^t _al. , 1954a).  Mercapturic acid formation, however, has not been noted.




Benzophenone undergoes glucuronic acid, but not sulfuric acid, conjugation




as benzhydrol.  This is in contrast  to £-hydroxybenzophenone which is  directly




conjugated with glucuronic acid at the free hydroxyl group  (Robinson,  1958).




                     Since these conjugation reactions  are  closely associated




with ketone elimination, the quantitative aspects  and experimental details  of




the above studies are discussed in the following section  (p. 184).
                                        178
-------
            3.  Excretion/Elimination

                a.   Elimination as Free Ketone

                     Although most of the ketones examined seem able to under-

go reduction reaction, many acyclic ketones seem to be  eliminated  unchanged

in expired air and urine.   In fact, many of the ketonic solvents are normal

constituents of  human urine.  This was first suggested  by Tsao  and Pfeiffer

(1957)  who found traces  of  methyl ethyl ketone in urine of healthy adults.

Zlatkis and coworkers (1973) subsequently found a variety of acyclic ketones

in normal urine  along with  a few additional acyclic ketones and cyclohexanone

in the  urine of  individuals with diabetes mellitus  (see Table  62).  Three  of

these  ketones — methyl  ethyl, methyl ri-propyl, and di-n-propyl — are  considered

key  components in the profile of normal urine  (Zlatkis  _e_t _al. ,  1973).


       Table  62.   Ketone  Components  of Normal Human Urine and the
                   Urine of  Individuals with Diabetes Mellitus (After
                   Zlatkis ^t ail. , 1973)
                                                     Urln* of Individuals
                                      PTMCHC in          with Diabetea
               Ketone                 Normal Human Urine        Mellitus

           Solvents

             Acetone                         "*"                 ^"
             Methyl ethyl Ketone                +                 +
             Methyl ii-propyl Ketone             +                 +
             Methyl isobutyl Ketone             +                 +
             Methyl ji-amyl Ketone               +                 +
             Methyl ti-heptyl Ketone             +                 +
             Ethyl ri-propyl Ketone              +                 +
             Ethyl n-butyl Ketone               -                 +
             Dipropyl Ketone                   +                 +
             Ethyl ri-amyl Ketone                +                 +
             Mesityl oxide (tentatively)          +
             Cyclohexanone                    -                 +

           Other Ketones

             3-methyl-2-butanone                +                 +
             2,3-butanedione                   +                 +
             3-methyl-2-pentanone               +                 +
             5-methyl-3-hexanone                +
             3-penten-2-one                   +                 +
             6-methyl- 3-heptanone               +                 +
             3-methyl cyclopentanone            +                 +
             3-hydroxy-2-butanone               -                 +
                                         179
-------
                   In acute exposures  to the acyclic ketones, elimination  of




unchanged ketones in the expired air may also be  a major  route of elimination.




This is, perhaps, to be expected, since many of these  ketones have  low boiling




points and high vapor pressures (Williams,  1959).




                   In studying the rate of  elimination of three  amyl  alcohols




injected intraperitoneally into rats at doses of  1 g/kg,  Haggard and  coworkers




(1945) found that most of the alcohol  was rapidly converted to the  corresponding




ketone and subsequently eliminated as  ketone in the expired air  and,  to  a




much lesser extent, in the urine (see  Figures 31-33).   In addition, approximately




100% of an intraperitoneal injection of methyl isopropyl  ketone  was eliminated




within 25 hours in the expired air and urine (see Figure  34).
                                     180
-------
         U    5   10   ID  20   25  30  35   40





10 "g 50

OD
c
c.
s
c °- -m



|







••



lA
\

\
\
1 X1 \
^
J

\^L
\












\ K
\
"\
\
i i
Pentanol
130 mg Alcoh
Alcohol \ "I""1
f 1 «|>i"-,l
K'"0"" { ul-











\

'^V
p-\.








1
2
il Given
Asr 2 / mil
.> 1 my
An lib .' me.
3 li mq













J


0 'j 10 15 20 ^5 30 3b 4
Fimelhr )

Figure 31.  Concentrations  of  pentanol-3
 and diethyl ketone  in blood and loss by
 elimination in expired  air and  urine
 after administration of 1  g/kg.   Lower
 curves, alcohol; higher curves,  ketone.
Figure 32.  Concentrations  of pentanol-
 2 and methyl n-propyl  ketone in blood
 and loss by elimination  in expired
 air and urine after  administration of
 1 g/kg of the alcohol.   Curve A,
 alcohol; K, ketone.
                           1	1   I
                      3 - Methyl Butanol - 2
                      196ms Alcohol Given
                   Elimin.ition
 18   90 |	
                              30  35  40
Figure  33.   Concentrations of 3-methyl
 butanol-2  and methyl isopropyl ketone
 in blood and loss by elimination in
 expired air and urine after adminis-
 tration of 1 g/kg of the alcohol.
 Curve  A, alcohol; K, ketone.
                                                            10  15  20   2b  30  3')  40
Figure  34.   Rate of metabolism of methyl
  isopropyl  ketone in the rat as
  determined from elimination in
  expired  air and urine and disap-
  pearance from the blood.
                 Figures 31-34 from Haggard  and  coworkerp, 1945.
-------
The kinetics of elimination presented in these figures are rather complex.




In the simplest case where only methyl isopropyl ketone is administered (Figure




34),ketone plasma levels reflect first order elimination (with a half-




life of about 5.28 hours) up to fifteen hours after injection.  After fifteen




hours, the amount of ketone eliminated relative to the concentration in the




blood increased and the half-life dropped to under four hours.  This pattern




might be explained in terms of the respiratory depressant effect of methyl




isopropyl ketone.  As the ketone blood level falls below about 12 mg per 100 ml




blood at fifteen hours after injection, the respiratory rate may increase and




thus result in a proportionately greater elimination of the ketone in expired air.




However, since quantitative data on the effect of ketone blood levels and




respiratory rate is not presented, the above explanation is speculative.




Whatever the actual cause, similar patterns are presented in Figures 31-33 for




ketone elimination after all alcohols have been eliminated from the blood.




Based on these figures, it would appear that methyl n-propyl ketone and




methyl isopropyl ketone are eliminated at about the same rate  (half-life




under 4 hours) while diethy1 ketone is eliminated somewhat more slowly




 (half-life over  5 hours).




                    DiVincenzo et al.  (1976) determined serum half-lives and




 clearance  times  in guinea pigs for methyl jn-butyl ketone, methyl isobutyl




ketone, methyl ethyl ketone, 2-hexanol, 5-hydroxy-2-hexanone,  2,5-hexanedione




 and  2,5-hexanediol.  Clearance times  after  a single i.p. dose  of 450 mg/kg




 dissolved  in 25% corn oil were as follows:  2,5-hexanedione was  almost  three




 times as  long  as for MBK and MIBK and twice as  long for 2,5-hexanediol  and




 5-hydroxy-2-hexanone.   Clearance time for methyl ethyl ketone was  twice  as
                                    182
-------
   long as that for methyl _n-butyl ketone.

                       Schwarz (1898) found that varying amounts of methyl

   ethyl ketone, methyl n-propyl ketone, and diethyl ketone were eliminated in

   the expired air of dogs in a twenty-four hour period after oral administration

   (see Table 63).


   Table 63.  Elimination of Ketones in the Expired Air of Dogs 24 Hours After
              Oral Administration (Schwarz, 1898)



Ketone
Methyl
ethyl -
Ketone
Methyl
propyl -
Ketone
Diethyl




Expt.
No.
1


2
1


2
1

2

Body Weight
of Dogs in
Grains
4350


3600
3300


3950
3000

3170


Mg Ketone
per Dose
1723


1216
1181


1505
996

346

Mg Ketone
per 1 kg
Body Weight
396


338
358


381
332

109


Mg Ketone
Eliminated
522


402
250


408 1
88

-
% of Ketone
Eliminated
in Expired
Air
30.3%


33.1%
21. 2%


27.1%
8.8%

-
- Translated from Schwarz, 1898, p.  190



    The amount of diethyl ketone eliminated after 24 hours is less than would be

    expected from the results of Haggard and coworkers (1945).   Again, insufficient

    data is presented to account for the apparent discrepancy which may or may

    not indicate quantitative species specific differences in routes of ketone

    elimination.
                                       183
-------
                b.  Elimination as Conjugation Products




                    The other major route of ketone elimination is conjugation




with subsequent excretion of the conjugate in the urine.  As mentioned




previously, this is a major mode of elimination for the aromatic and alicyclic




ketones and for at least one acyclic aliphatic ketone  (methyl n-amyl ketone).




The primary studies supporting this conclusion are summarized in Table 64.




In addition, Truhaut and coworkers (1970) have reported that isophorone is




eliminated in the urine as a glucuronide.  Quantitative data on the extent




of glucuronic conjugation, however, is not available.




                    It should be emphasized that none  of the investigations




summarized in Table 64 are balance studies —  i.e.,  no attempt  is made to  recover




100% of th'e<,dose, and to determine alternate, routes of elimination or -patterns




of tissue distribution and storage.  The  recovery of  over ninety percent  of




dose for  both an unspecified mixture of methylcyclohexanones and for  (+)  3-




tert-butylcyclohexanone is fortuitous, indicating only that these ketones are




eliminated almost  exclusively as  conjugates in the  urine.  The recovery of




around  50% of the  dose for most of the other ketones  severely limits  the




utility of these  studies  in assessing total patterns  of ketone elimination.




                    A comparison  of Table 64 with Table 55  (p. 163) will  show




that jin vitro  studies on  ketone reduction do not correlate with the observed




in viyo conjugation of  the alicyclic ketones.  The  order  of alicyclic ketone




reduction in vitro is cyclohexanone > methylcyclohexanones  - cycloheptanone  >»




cyclopentanone.   The  order of ketone conjugation ^n vivo, however,  appears to




be methylcyclohexanones > cyclohexanone  - cycloheptanone  >  cyclopentanone.
                                    184
-------
               Table  64.    Ketone  Conjugation  and Renal  Excretion  in Rabbits
                              Route of                  Duration
                            Administration 	  Dpse	of Test
                                                                            ol Doae  Eliminated  -  (range)
                                                                 Sulphate   Mercapturic
                                                    Glucuronide    Ester       Acid       Other
Methyl n-amyl  Chinchilla       Intubation     950 mg/kg    24 hrs
ketone         Rabbits (3)
              3 kg each
                                                                              n.d.     Small amount     41%+      Kami 1 e_l al,,
                                                                                      of unchanged                195 3
                                                                                      ketone in
                                                                                      urine
Cyclopent-
a n one
Rabbits,
female,
Wi^tar strain,
200-250 g (3)
               Rabbits,
               teniale ,
               Wistar strain,
               .'00-250 e  (3)
                              Intubation      193 mg/kg    24 hrs
  47%          2%       trace
(39-5H)       (0-5)
Sulfur-con-    51.5%+
taming metab-
olite
    25%
 (2 2-2 7)
                              Intubation      186 mg/kg    24 hrs        51-86%        n.d.      trac
               Habbiis,
               young (2)
                              Intubation      890 mgAg    4 days       45-50%
                              Intubation      248 rag/kg    18 hrs
                                                                      66%
                                                                    (51-86)
                                                                                      No tie
                                                                                      ketone
                                                                                      urine
lames anil
Wai ing, 1^71
               Rabb its ,
               voung (2)
                              Intubation      560 nig/kg   3 dayb
    2-Meth,'l-
    cyclo-
                              Incubation
                ntubation      516 mg/kg    24 hrs



                              572 rag/kg    24 hrs



                              60/ mg/kg    24 hrs
  72.3%        0.9%
(53.4-92.6)  (0.0-2.6)
                                                                      73-6%        2.2%
                                                                    (4^.8-89.7)  CO.5-4.0)
                                                                      80 .1%        ] . 1%
                                                                    (74.7-85 9)  CO.0-3.2)
                                                mg/kg
                                                                      76.5%     "negligible"   0
                                                                     (71-82)
                                             b45 mg/kg   24 hrs        91.5%      "negligible"   0
i- tert-
but>lcyc lo-
hexannnt
^,-clohf ptjnoru- iUr-Sj cs ,
^Lstar strain,
20') K-250 g (3)
\cistophenune ihlnchilla
Rabbles (3)
3 kg each
Rabbits
Benzophenone Rabbits (3)
555 mg/kg 24 hrs
Intubation 190 mg/kg 24 hrs
Intubation 450 mg/kg 24 hrs
Intra- 2 g per n.s.
peritoneal animal
injection
Intubation 364 mg/kg 24 hrs
80.0%
(74-87)
602
(58-86;
47%
(40-55)
48.8%
50%
(46-61)
"negligible" 0 80%
14?, ,raie StjJ 1 ur-co/j- 73;
(12-15) Laming metab-
olite
1 .0%
(1.01
3% n.d. 5CU
n.d. n.d 48.8'-t il
0 n.d. 50% R<
n.s. = not specified
n.d. - not determined
                                                                  185
-------
The significant degree of cyclopentanone conjugation in vivo again suggests




that additional enzymes are involved in ketone metabolism or that the




activities of -the -enzymes studied"in vitro were considerably'altered during




isolation.




                   Data on the rate of elimination of the ketones which




undergo extensive conjugation are limited to measurements of-glucurenic-acid




and inorganic sulfates (as percent of total sulfates) in twenty-four urine




samples of rabbits receiving oral doses of cyclohexanone and methylcyclo-




hexanone.  This information is summarized in Table 65 .  A rise in glucuronic




acid and a decrease in the percent of inorganic sulfates indicate increased




excretion of  the ketones as glucuronides and sulfuric acid esters, respectively.




(Deichmann and Thomas, 1943; Treon £t al., 1943a).  As Table 65 indicates,




glucuronic acid and sulfate levels return to normal one to two days after




ingestion of  both ketones with methylcyclohexanone apparently eliminated




somewhat more rapidly.




                   In a subsequent study, Deichmann and Dierker  (1946)




followed the  glucuronic acid levels in hourly  samples of plasma and urine  of




rabbits over  a twenty-four hour period after the oral administration of




cyclohexanone at  750 mg/kg, 1518 rag/kg, and 2840 mg/kg, using one rabbit at




each dose level.  At the lower dose, which approximates those of Table  65,




both plasma and urine glucuronic acid levels peaked after two hours  (15 mg




glucuronic acid/100 ml plasma), dropped rapidly between two and four hours,




and returned  to normal after twenty-four hours.  At the intermediate dose,




plasma glucuronic acid peaked after seven hours to over ten times the




concentration of  the lower dose (1518 mg glucuronic acid/100 ml plasma)
                                      186
-------
   Table  65.  Excretion of  Glucuronic Acids and Sulfates  in 24 Hour
               Urine  Samples of Rabbits  Following Oral Administration
               of Cyclohexanone and Methylcyclohexanone*
 Days After
  Dose
   1
   2
   3
   A
Cyclohexanone
 % Inorganic
  Sulfates
           Glucuronic
             acid(mg)
       [Dose]

   890  mg/kg (1)

38.4           858
            2,632
30.8
71.1
92.7
               76
               81
      890 mg/kg (1)
58.3
62.5
90.1
89.2
947
60
75
80
2,133
1,090
78
49
mg/kg (2)
1,246
100
30
                                Days After
                                 Dose
Methylcyclohexanone

                   Glucuronic
                     acid(rag)

              [Dose]

            560 mg/kg (1)
Inorganic
Sulfates
                                                                   75.0
                                                                   S.4.4
                                                                   94.2
                                                               2,133
                                                                 306
                                                                  81
                                                                     522 mg/kg (2)
                                                    80
                                                    90
                                                    85
                                                              944
                                                              160
               Normal Daily Excretion of Glucuronic Acid in Rabbits, 35.2  mg±24.8 [S.D.]  (2)
               Normal % Urinary Sulfates As  Inorganic  SuJfates, Approximately 85% (1)
 *   Isomer(s)  not  specified
(1)  Treon, et  al. ,  1943a
                  (2) Deichmann and Thomas,  1943
                                        187
-------
and then decreased gradually,  returning to normal after twenty-four hours.


Urinary glucuronides, however, remained elevated after twenty-four hours.


This would suggest that  cyclohexanone is eliminated relatively  rapidly


from the blood  and deposited in the body, while urinary elimination  takes


place gradually over a more prolonged period.  The animal  receiving  the


highest dose  died after  twenty-six hours and eliminated about 50% less


cyclohexanone/unit dose  than the rabbit given the intermediate dose.   This


may indicate  that acute  cyclohexanone poisoning has an inhibitory effect


on  cyclohexanone elimination.   However, because so  few animals were  used


in  this study,  no  firm conclusions are possible.


                     Although oral administration  is  the most commonly used


method  of  exposure  in metabolism studies of  ketones,  Treon and coworkers


 (1943b) have  shown  a direct relationship between  the  concentration of


methylcyclohexanone in air and  the degree  of sulfate  and  glucuronide


 conjugation in rabbits (see Figure 35).




,, _
< E
O "3J
1 1
= |
•i "•"
_>• E

0 0
6 3
It





3000
2800
2600
2400
2200
2000

1800

1600
1400

1200

1000
800
600
400
200
n




-
_

_

-
_

_

-
—
-
-
-




















i

Mathylcydohaxanofie
-
-
-
-













1 1

-

~
-

-

"
~
-
-
-
1 ' 1 111 -L
                                           s _
                                           1*
                                           Is
                                           ȣ
                                           ::<)?
                                           o _
                                           II
vu

80
70
60
50
40
30
20
10
0

M*thytcyctoh»xanone
~~
-
-
-
-
-
-


-







1







1 1
-






1 1
-
-
-
-
-
-
1 III
         300 600  900 1200 1500 1800 2100 2400 2700 3000 3300

                    P.P.M lnhal«tx>n
                                                   300  600  900  1200 1500 1800 2100 2400 2700 3000 3300

                                                              P.P.M Inhalation
       Figure 35 .   Influence  of Methylcyclohexanone Inhalation  on  Glucuronic
                    Acid  (A) and Sulfate Elimination (B) in Rabbit  Urine

                    (Treon et  al.,  1943b)
                                      188
-------
A similar relationship for cyclohexanone exposures was not demonstrated.  How-




ever, inhalation of cyclohexanone did have the general effect of increasing




glucuronic acid and decreasing inorganic sulfate elimination in rabbit urine.




          4.   Transport, Distribution, and Storage




               No direct information is available on any of these aspects of




ketone biology.  Of course, certain deductions can be made based on infor-




mation presented above — e-g-> methyl ethyl ketone can be absorbed through




the skin and transported to the lungs, presumably by the circulatory system,




where the ketone is then eliminated in expired air.




               As described previously (see Section I-A-2, Physical Properties,




p. 4), all of the ketonic solvents under review are extremely soluble  in




organic solvents, but the water solubility of the acyclic aliphatic ketones




decreases with increasing molecular weight.  Nelson and Hoff  (1968) have  found




that the partition coefficients (mineral oil vs. Na.SO  saturated aqueous




solution) increase going from acetone  (0.345), to methyl ethyl ketone  (3.21), to




methyl n-butyl ketone (20.7).  Mesityl oxide, which is very slightly soluble




in water, but readily soluble in organic solvents, does seem  to be stored  in




guinea pigs in that repeated inhalation exposures to subanesthetic concentra-




tions leads to death from narcosis  (Smyth et^ _aJL. , 1942).  Jeppsson  (1975)  has




recently evaluated the effect of lipophilicity on ketone toxicity and  concluded




that highly lipophilic compounds may be less toxic because they are preferentially




sequestered in lipid components and do not reach receptor sites.  Thus, lipid




storage, for at least some water-insoluble ketones, does seem likely.
                                     189
-------
     C.    Human Toxicity




          In an occupational environment,  workers are most likely to  be exposed




to the ketonic solvents dermally or by inhalation.   The ketone vapors enter




the body through the mucous membranes of the nose,  eyes, and respiratory tract.




Skin contact with the solvent leads to ready absorption of some ketones due to




their high lipid solubility.  The volatility of these compounds has some influence




on dermal absorption, with rapid evaporation limiting actual absorption.




Voluntary ingestion of the ketones is uncommon.




          The ketone vapors are generally found to be irritating to the eyes




and nose at relatively low concentrations and, therefore, allow sufficient warning




of exposure, thus limiting the danger of gross overexposure.  However, for some




of the solvents, these  'warning signs' and irritations do wear off to some extent,




and limited tolerance to the vapors can be acquired during the work week; how-




ever, this tolerance is lost over the weekend and must be reacquired  (Vernot




at al., 1971; Elkins, 1959).  Rowe and Wolf  (1963) state that lower concentrations




of the vapors may not cause discomfort, but  can cause impairment of judgement




and thereby create a secondary hazard.  Such an effect has been noted by




Nakaaki  (1974), who found  that methyl ethyl  ketone altered estimates  of time




periods at vapor concentrations causing only minor eye  and throat  irritation.




The solvent vapors are  also known to produce headache,  nausea with vomiting,



dizziness, and drowsiness  to some degree.  At higher concentrations,  the vapors





are narcotic  (see Section  III-D, Toxicity -  Birds and Mammals, p.  204).




          Skin contact  with liquid solvent or vapor may  lead  to dermatitis.




The skin  chaps due to  the  defatting activity and lipid  solubility  of  the ketones




 (Rowe and Wolf,  1963;  Smyth at al., 1949).   Occupational dermal exposures  are




usually concurrent with inhalation of vapors;  therefore,  any  physiological




effects other  than dermatitis may be due to  the combined exposures.






                                      190
-------
          1.   Acute Exposure:  Occupational and Related Contact




               The majority of the ketonic solvents have not resulted in




industrial incidents and injuries in their usage.




               Smith and Mayers (1944) report additional cases in which in-




halation and dermal exposures to methyl ethyl ketone have occurred in raincoat




factories using methyl ethyl ketone (MEK) as a solvent.  In one instance, the




air concentrations of MEK ranged from 300 ppm to 600 ppm, and additional con-




tact was made because the workers tended to wash their hands in the solvent.




As a result of this exposure, several workers developed disabling dermatoses




and/or numbness of the fingers and arms.  One worker also complained of numbness




in the legs.  Smith and Mayers (1944) note that exposure of the face and other




bare skin to vapors of MEK is enough to develop dermatitis if proper venti-




lation is not employed.




               In the other incidents reported by Smith and Mayers  (1944), the




employees were exposed to a mixture of acetone and MEK, with concentrations of




MEK ranging from 398 to 561 ppm and of acetone from 330 to 495 ppm.  The com-




bined effect of these two ketones led to gastric complaints, headaches, and




fainting in two girls who were involved in brushing waterproofing materials,




which were dissolved in the solvents, onto raincoats.




               One other incident involving methyl ethyl ketone (MEK) was




reported by Smyth (1956).  An eye injury resulted from exposure to MEK vapor;




however, the injury was believed to have been caused by an impurity and not




the solvent itself.
                                      191
-------
               Elkins (1959)  reported headache,  nausea,  and respiratory




irritation in workers exposed to methyl isobutyl ketone  at a level of




approximately 100 ppm.   These symptoms were alleviated by installation of




a better ventilation system which lowered concentration  to about 20 ppm.




               Specht and coworkers (1940)  found that dermal exposures to




mesityl oxide caused considerable irritation.   During their experiments on




animals, several laboratory workers complained of irritation of their hands




even though they were wearing latex gloves.




               One other ketonic solvent is reported to  cause some gastritis




in humans.  Acetophenone, also known as hypnone, was used in the treatment




of mental patients in the 19th century to sedate and induce sleep.  The




acetophenone was only of secondary importance as a sedative (Mairet and




Comberbale, 1886), and at therapeutic levels, this ketone caused a burning




sensation in the stomachs of some patients.




          2.   Chronic Exposures:  Epidemiology of Peripheral Neuropathy




               Clinical, histopathological, and electrophysiological evidence




indicate  that methyl n-butyl ketone produces a peripheral neuropathy in chroni-




cally exposed humans.  In addition, 2,5-hexanedione, the principal body metabo-




lite of MBK, the related alkane n-hexane, and the alcohol 2,5-hexanediol, each




produce similar peripheral neuropathies in chronically exposed animals.  The




pathology which underlies this peripheral neuropathy is concurrent axonal de-




generation  of the distal regions of vulnerable nerve fibers sited in both the




peripheral  and central nervous systems.  This type of pathology has been termed




"dying-back" or "central and peripheral distal axonopathy"  (Spencer and Schaumburg,




1976c-e).   Certain compounds — lead salts, acrylamide,  organophosphates, thallium
                                     192
-------
salts — are only poisonous when gross overexposure occurs (Fullerton, 1969).




Acrylamide, t ri- or tho- cresy 1 phosphates, n-hexane,  and certain nutritional




disorders have all been found to cause a "dying-back" disease where a distal




degeneration of nerve fibers occurs (Herskowitz £t_ _al. , 1971; Schaumburg et




al. , 1974; Krishnamurti jaj; _al. , 1972; Cavanagh, 1964),  In the dying-back poly-




neuropathies, clinical signs of weakness occur bilaterally in distal regions




of the legs and then proximally (Spencer and Schaumburg, 1974b).   In the peri-




pheral nervous system, nerve fiber degeneration commences in tibial nerve




branches supplying the calf muscles and, in the central nervous system, in the




distal regions of long nerve tracts located in the spinal cord, medulla oblongata,




and cerebellum (Spencer and Schaumburg, 1976d, 1976e).  Histological findings




include axonal swellings with masses of neurofilaments, an increased number




of mitochondria, myelin degeneration, and the presence of abnormal axonal or-




ganelles  (Spencer and Schaumburg, 1974b).




               A peripheral neuropathy similar to that described above has




resulted  from the practice of "huffing" (Prockop &t ad., 1974).  "Huffing"




of organic solvents is accomplished by inhaling vapors from solvent-soaked rags.




No direct oral use or prolonged cutaneous contact with the liquid occurs.




Severe cases of "huffing" neuropathy have been reported in seven men in Florida




who had been using a commercially available lacquer thinner consisting of 11




compounds.  At this writing, Prockup has not indicated what component or




components are suspected as being neurotoxins.  The lacquer thinner contained




the following substances:
                                      193
-------
               n-hexane                 0.5% (a known neurotoxin,  see Schaumburg
                                              and Spencer,  1976)
               acetone                 12.7%
               isopropyl acetate        1.2%
               isopropyl alcohol        0.5%
               isobutyl acetate        12.6%
               toluene                  3.9%
               isobutyl alcohol         3.5%
               isobutyrate              0.5%
               xylene                  43.6%
               methyl amyl ketone      15.5%
               2-nitropropane           5.8%

Tison and coworkers (1976) have stated that methyl amyl ketone, earlier suspected

as the offending agent in "Buffer's" neuropathy (Means et_ a\^. , 1975) does not pro-

duce neuropathy in chronically exposed rats and chickens.  Experimental neuropathy

was produced by chronic exposure to the lacquer thinner.

               In mid-August, 1973, an employee in the print department at an Ohio

vinyl-coated fabrics plant was diagnosed as suffering from a peripheral neuropathy

of suspicious origin  (Gilchrist £t ad., 1974; Billmaier et al_. , 1974; Craft, 1974;

Allen _et: _al. , 1975).  The patient complained of having been weak since May.  His

clinical symptoms included:  bilateral weakness of the wrist extensors and flexors,

and the finger extensors, flexors and  abductors; a foot drop, bilateral atrophy of

the interosseous muscles; and absence  of ankle deep  tendon reflexes.  Results of

an electromyogram (EMG) confirmed the  diagnosis  (Gilchrist £t al_. ,  1974).  According

to the patient described  above,  five other  employees  in  the  print department of

this plant were suffering from similar symptoms.  Subsequently health officials

performed EMG's on over 1,100 employees throughout the plant.

               Data from  this survey have been summarized by both Gilchrist  and

associates  (1974) and Billmaier  and coworkers  (1974).  Gilchrist  and associates

(1974) report  that  45 cases  of peripheral neuropathy which could  not be attributed

to non-occupational causes  (e.g. , diabetes) were found.  Thirty-five of these

cases appeared in print department workers.  This is  similar to the report by

Billmaier and  coworkers  (1974) which included information in cases  of neuropathy

which could have been caused by  diabetes or isoniazid therapy  (see  Table 66).

                                     194
-------
 Table 66.   Ill vs.  Not 111 Employees,  in Print  Department  and  Non-Print  Departments,
            Showing  Job Categories  in the Print  Department  (Billmaier  e_t  al. ,  1974)

Group

Non-Print Departments
Print Department (Total)
Operatorst
Helperst
Foremen
Service Helpers
Not Known
Total, All Departments

111
*
30
38t
27
10

1

68
Not
111

954
135
42
49
21
15
8
1089

Total

984
173
69
59
21
16
8
1157
        *
        Includes 18 persons with diabetes or other condition which can cause
        or  contribute  to neuropathy.
        tlncludes one person with diabetes, and one person on isoniazid therapy.
        •^Significant at p <  .001 using the chi-square test.
               Investigation of the plant revealed that methyl n-butyl
ketone  (MBK) was introduced to the printing department in August, 1972, as
a substitute for methyl isobutyl ketone (MIBK) in a solvent mixture with
methyl  ethyl ketone  (MEK).  By December 1972, MBK had completely replaced
MIBK and at this time the first symptoms of neuropathy were occurring in
the workers (see Figure 36).

               Due to the predominance of cases of neuropathy in workers in
the print department, chemical analysis of the vapors in the printing area
were conducted.  Contamination levels of MIBK, methyl methacrylate, n-hexane,
toluene, xylene,  methyl alcohol,  acetone,  and mineral spirits were very small
(Billmaier et al. ,  1974).   The MEK and MBK levels, high in all areas, are
given in Table  67.   Although there is considerable variability in concentrations
of the chemicals,  the back of  the  printer  had quite high vapor levels.

                                     195
-------
Figure 36.
u -
9 -
8

5 -
3 -

1
0

i i „ i


























































    Aug  Sep  Oct  Nov   Dec  Jan  Feb  Mar  Apr  May  Jun  Jul  Aug  Sep  Oct
            1972                            1973

   * Month of Onset for 7 Cases Unknown

Thirty-eight  Peripheral Neuropathy Cases, by Month  of Onset* in
Ohio Factory  Workers, December  1972 - September  1973
(Gilchrist _et _al. ,  1974)
Table 67.   Results of Area Atmospheric Sampling  for Methyl Ethyl Ketone*
            (MEK)  and Methyl Butyl  Ketone**  (MBK)  in Parts Per Million
            (Billmaier e^ _al. ,  1974)
            Data is listed from lowest to highest  result obtained for each
            solvent at each work location.
Front
of Printer
MEK MBK
104
109
124
162
220
453
565
570
670
: 331
2
2
4
5
5
9
11
19
21
9
.3
.6
.1
.1
.8
.7
.5
.8
.7
.2
Back
of Printer
MEK MBK
85
265
401
440
603
608
725
750
763
516
2.
3.
9.
9.
21.
23.
48.
49.
156.
36.
5
0
0
8
7
9
6
9
0
0
Wind-up
Area
MEK MBK
39
44
47
49
127
143
250
289
338
147
1
2
2
2
5
6
7
9
17
6
.0
.0
.0
.6
.9
.0
.9
.8
.5
. J
       *
       Threshold Limit Value, MEK = 200 parts per million
       *
       Threshold Limit. Value, MBK = JOO Darts per million

                                     196
-------
               In addition to the presence of high  amounts  of  vapors,  poor

working practices such as: (1) eating  in  the work  area,  (2) washing hands with

the solvent, and (3) using solvent soaked rags to  clean  equipment were  noted

(Billmaier eJL a.1. , 1974).  These practices, as well as  working overtime,

increased the risk of disease (Gilchrist ej^ al.,  1974).

               In September, 1973,  the department was closed for installation

of improved ventilation   and removal  of  MBK from  the production areas.

Improved working practices were instituted before reopening the printing

department.  Since that  time no new cases of peripheral neuropathy have been

reported  (Gilchrist e^t aJL. , 1974), and once removed  from the work environment,

those affected by the disease have  improved greatly (Allen  et al., 1975) .

The recovery pattern of  workers who had  developed neuropathy is presented

in Figure  37.
                    Sep   Oct   Nov   Dec   Jan
                                            Ftt>   M»r   Apr   M«y
       Figure 37.   Rates of Recovery After Exposures Ceased, With Points
                   Representing Total Scores of Clinical and EMG Findings
                              (Allen et al., 1975)


                                      197
-------
               The apparent rash of cases of neuropathy reported in Ohio tend




to indicate that a change in production was responsible;  over the past several




years, the only change of that sort was the introduction of MBK into the work




environment.  A similar plant on the West Goast which has not used MBK has




reported no incidents of disease (Craft, 1974).  Craft (1974) has reported




two isolated cases of peripheral neuropathy following occupational MBK exposure




in Connecticut and Iowa.  The information presented here, in conjunction with




animal studies (see Section III-D-3), indicates that MBK exposure causes a toxic




peripheral neuropathy in humans.
                                      198
-------
          3.    Controlled Studies


               Few studies on the toxicity of ketonic solvents to humans have


been conducted.  The primary route of absorption utilized in these studies is


inhalation (see Table 68), though some tests on skin sensitization have been


reported.


               a.   Inhalation


                    Early investigators have determined intolerable or


objectionable vapor levels for several of the ketones — methyl ethyl ketone


(Patty et. al., 1935) , methyl n-propyl ketone (Yant ^t al. , 1936) , methyl n-butyl


ketone (Schrenk et^ _al. , 1936).  In these three ketones the objectionable levels


for a few minutes of exposure were 1000 ppm or greater.  Specht and coworkers


(1940) exposed subjects to lower concentrations and found that 150 ppm of methyl


n-propyl ketone vapor caused eye, nose, and throat irritation.


                    Nelson and coworkers  (1943) performed controlled vapor


exposure tests on several solvents including methyl ethyl ketone and cyclohexanone.


The same group of investigators conducted further studies of a similar experimental


design of five other ketones — methyl isobutyl ketone, diisobutyl ketone, di-


acetone alcohol, mesityl oxide, and  isophorone — a few years later  (Silverman


et al., 1946).   Ten to twelve individuals (male and female) were exposed  to


solvent vapors at varying concentrations  for three to five minute periods  in  a

       3
1200  ft  chamber.  After exposure, each person was asked to classify the  effect


of the solvent vapor on the eyes, nose, and throat as causing either:  (1)  no


reaction, (2)  slight irritation, or  (3) strong irritation.  The odor,  if  any, was


classified as  definite, moderate, strong, or overpowering.  Then each  person  was


asked if he  felt he could work in the atmosphere for a full eight hours.
                                      199
-------
   Table  68.  Human Inhalation -  Exposure Levels  and Physiological Effects
Ketone
                    Level of Exposure (ppm)
                                                    Effects  & Comments
                                                                           Reference
Methyl ethyl ketone
Methyl n-propyl ketone
Methyl n-butyl ketone
Methyl Isobutyl ketone
Diisobutyl ketone
2,5-Hexanedione
Ulacctonc alcohol
Mesityl oxide
Cyclohexanone
Isophorone
100
200
300
1000
150
1300
1500
1000
100
>100
>200
>50
50
100
NS
100
25
50
50
75
25
Throat irritation
Eye irritation
Objectionable - highest
bearable level for
8 hr. day - 200 ppm
Almost intolerable
(short exposure)
Eyes, nose, throat
irritation
Objectionable to eyes
and nose
Markedly irritating
to nose and eyes
Objectionable, strongly
irritating to eyes and nose
Headache, nausea
Threshold for detection
of odor
Objectionable, highest
bearable level for
8 hr. day - 100 ppm
Objectionable, highest
bearable level for
8 hr . day - 25 ppm
Eyes and nose irritation
Dizziness, headache,
lacrlmatlon, intolerable
level
Irritation of mucous
membranes
Objectionable, highest
bearable level for an
8 hr. day - 50 ppm
Eye irritation
Objectionable, highest
bearable level for an
8 hr. day - 25 ppm
Eye irritation
Objectionable, highest
bearable level for an
8 hr. day - 25 ppm
Objectionable, highest
bearable level for an
Nelson et al. ,
1943
Patty et al. ,
1935
Specht et al . ,
1940 ~
Yant et al. ,
1936
Schrenk et al. ,
1936
Elkins, 1959
Shell Chemical
Corp., 1957a
Silverman et al.,
1946
Silverman et al. ,
1946
Carpenter et al. ,
1953
Browning, 1965
Silverman ct a] . ,
1946
Silverman et al.,
1946
Nelson et aj^. ,
1943
Silverman et al.,
1946
                                                      8 hr. day - 10 ppm
                                           200
-------
                    As indicated in Table 68, the isophorone vapors were




considered the most irritating of all the ketonic solvents, with the highest




level tolerable for an eight hour work day at 10 ppm (Silverman et al., 1946).




Three others were given a 25 ppm limit as the highest tolerable — cyclohexanone




(Nelson e_t _al., 1943), diisobutyl ketone and mesityl oxide (Silverman et al. ,




1946).




                    Due to the design of these experiments, primarily sub-




jective judgments on the vapor effects could be obtained since the exposures




were only for a few minutes.  The effects of general tolerance, decreased




sensitivity of mucous membranes, or hypersensitivity could not be measured.  At




best the data presented can only give a rough idea of the irritation of these




compounds.




                    Carpenter and associates (1953) exposed humans to longer




periods of vapor exposures to verify the data presented by Silverman and co-




workers (1946) on diisobutyl ketone.  Initially Carpenter and coworkers (1953)




exposed two men, 25 and 32 years old, to 50 ppm for a three hour period in  a




6% foot cube where the air was drawn in at approximately 900 £/minute.  At  the




beginning the men noted a slight irritation of eyes and nose.  The vapor could




be smelled and tasted throughout the exposure period.  However, no appreciable




discomfort was experienced.  Ten days later these two men and one additional




man were exposed to 100 ppm for three hours; these men all agreed that  the  100




ppm exposure level would be unsatisfactory over an eight hour day.  At  this




exposure level, slight lacrimation, dizziness, and headache were noted in




addition to initial irritation  (Carpenter et al., 1953).
                                      201
-------
                    Imasheva (1966) studied the effects of acetophenone




inhalation in a group of 18 "practically healthy" people from age 18 to 20.  For




each individual a threshold of olfactory sensation was determined.  The most




sensitive person had a threshold at 0.202 ppb acetophenone.  For the majority




(14) of those tested, 0.404 ppb was the average threshold.




                    Three subjects were also tested for light sensitivity




during exposure to acetophenone vapor.  The threshold for decrease in light




sensitivity was determined to be 0.202 ppb (Imasheva, 1966).




                    Dobrinskiy (1966) had determined the same threshold levels




in fifteen individuals exposed to  cyclohexanone vapors.  With this ketone  the




threshold for olfactory sensation  occurs at 53.2 ppb.  The three persons in-




volved in light studies suffered a decrease in sensitivity at a threshold




concentration of 29.3 ppb  (Dobrinskiy, 1966).




                    Dobrinskiy (1966) also studied the effects of cyclohexanone




on brain activity in six human subjects.  In this part of  the experiment the




subject was at relative rest during the exposure and then  tested  for conditional




reflex and for reinforced  rhythm with a flickering light.  The threshold limit




for effects of cyclohexanone on rhythm reinforcement as determined by  electro-




encephalogram  (EEC) was 22.4 ppb.  In conditioned reflex,  the threshold con-




centration was 14.9 ppb.   On the basis of this information Dobrinskiy  (1966)




concluded that 9.9 ppb cyclohexanone should be the maximum permissible con-




centration for single exposure.




                    The variance in allowable vapor exposure determined in




these studies  is due to the difference 'in the: criteria of  the investigators




Nelson and coworkers  (1943) were concerned with  determining the maximum con-




centrations of the chemical in workroom air which could be tolerated for eight







                                      202
-------
hours, whereas the work on cyclohexanone by Dobrinskiy (1966)  and acetophenone




by Imasheva (1966) was more concerned with what levels actually caused some




measurable effect.




                    The odor threshold of diacetone alcohol in water or room




temperature, determined by using nine individuals, was found to range from




5.63 to 269 ppm with a mean of 44.12 ppm at room temperature (Lillard and




Powers, 1975).




                    Methyl ethyl ketone, at vapor concentrations of 90 to




270 ppm for exposure periods of 0.5 to 4 hours, has been shown to affect estimates




of time passage in both men and women.  In men, time estimates were shortened,




while in women, an increased variability in estimates of 5, 10, and 30 second




time periods was found (Nakaaki, 1974).   As noted earlier in this section,




this type of exposure could create a secondary hazard in occupational situations.




               b.    Dermal




                    Ethyl ri-amyl ketone and acetophenone were tested at a




concentration of 2% in petrolatum on human skin.  No irritation resulted from




a 48 hour closed patch test in 25 subjects exposed to ethyl n-amyl ketone




(Kligman, 1972) or a similar group exposed to acetophenone (Kligman, 1971).




Further tests did not indicate any sensitization had occurred in either case.




Katz (1946), however, has called acetophenone a common skin irritant.
                                    203
-------
      D.    Toxicity - Birds and Mammals




           1.    Acute Toxicity




                a.    Acute Oral Toxicity




                     Numerous studies have been conducted on the acute




oral toxicity of the ketonic solvents.  Some of the essential experimental




details and basic lethality data from these studies are summarized in




Table 69.   Most of this information comes from the work of Smyth, Carpenter,




and coworkers at the Mellon Institute.  Where two references are given for




a single entry — e.g, methyl n-propyl ketone — the first refers to a




relatively detailed but unpublished Mellon Institute report, while the




latter refers to summaries of these reports periodically published in




range-finding toxicity data lists.  Direct references to Mellon Institute




cite unpublished summary data sheets or monthly reports from that institution.




Because the same general methodology was followed in all of these studies,




an evaluation of the comparative toxicities of the ketones is somewhat




facilitated.




                     As Smyth and coworkers have emphasized repeatedly,




these studies are designed only to estimate comparative hazards  (Smyth and




Carpenter,  1948; Smyth £t _al., 1954 and 1962).  The results are most  often




expressed as 14 day  LD  ' s ±  1." 96 standard deviations.  These results are




usually based on four to six  dose levels of the compounds administered to




groups of six to ten animals.  Mortality is noted over the ensuing fourteen




days, and the statistical methods of  Thompson  (1947) and Weil (1952)  are




used in estimating the LD   ' s  (Smyth  et^ jl., 1962).
                                      204
-------
Table 69.   Acute Oral Toxicity of Various Ketones:  Single Dose by Intubation
Chemical
Saturated Aliphatic*
if Carbons
3 Acetone
4 Methyl ethyl
ketone


5 Methyl n-
propyl
ketone
Diethyl
ketone
6 Methyl n-butyl
ketone
Methyl iso-
butyl ketone

7 Methyl n-amyl
ketone
Methyl iso-
amyl ketone
Ethyl n-butyl
ketone
8 Ethyl n-amyl
Ethyl sec-
amyl ketone
9 Dilsobutyl
ketone
12 Isobutyl
heptyl
ketone
Other Saturated
2,4-Pentane -
dione


2 , 5-Hexane-
dione
Diacetone
alcohol
Dilution and
Vehicle

n.s
10% dispersion in
1% "Tergitol" 7**
n.s.
n. s.
10% dilution in
corn oil
n.s.
n.s.
n.s .
20% in 1% "Tergitol" 7
20% in 1% "Tergitol" 7
undiluted
20% in 1% "Tergitol" 7
n.s.
n.s.
20% in 1% "Tergitol" 7
207. in 17. "Tergitol" 7

107. in water
5% in water
n.s.
n.s.
10% in water
*
Orfaniaa

Rats, F,
C-W (4-5)
Rats, M, Sh
Rats
Rats, F,
C-W (4-5)
Rats, M,
C-W (5-6)
Rats, M,
C-W (3-4)
Rats, M,
C-W (3-4)
Rats, M
Rats, F,
C-W (3-4)
Rats, F,
C-W (3-4)
Rats, M,
CFN (5-6)
Rats, M,W
Rats
Rats
Guinea Pigs
Mice
Rats, M,W
Rats, M,W

Rats, M,W
Rats, M,W
(3-4)
Rabbits
Rats, M,
W (3-4)
Rats, M,
NuBbar
Treated
per Dose
Level

n.s.
10
n.s.
5
5
5
5
n.s .
n.s.
n.s .
5
n.s.
n.s.
n.s .
n.s.
n.s.
10
10

10
10
n.s.
n.s.
n.s.
Doee
<*Ag)

10.7
(7.3-14.1)
3.98*
(3.94-4.01)
3.3
5.53
(4.50-6.82)
3.73*
(2.68-5.21)
2.14
(1.54-2.99)
2.59
(2.11-3.18)
4.57
2.08
(1.91-2.27)
1.67
(1.48-1.88)
3.48#
(2.12-5.66)
2.1 fit
(2.56-2.98)
>5
3.5
2.5
3.8
5.75
(4.69-7.06)
8.74
(7.18-9.99)

1.05
0.97*
(0.90-1.05)
0.94
(0.84-1.07)
2.7
4.0
Mortality
Data

14 day LD,_
(tl.96 S.DT)
14 day LD
(il.96 S.D.)
Lethal
14 day LD
(±1.96 S.DT)
14 day LD
(±1.96 S.fi.)
14 day LD
(±1.96 S.D.)
14 day LD
(±1.96 S.B.)
LD50
14 day LD -
(±1.96 S.T) )
14 day LD
(±1.96 S.B.)
14 day LD
(±1.96 S.B")
14 day LD
(±1.96 S.DT)
LD50
§
14 day LD
(±1.96 S,n"
14 day LD
(±1.96 S.B.

14 day LD5Q
14 day LD
(±1.96 S.D
14 day LD,n
(±1.96 S.B?
14 day LD5Q
14 day LDJO
Reference

Smyth Pt
al_. , 1962
Carpenter,
1949
Shell Chemical
Corp., 1959
Smyth et. al. ,
1962
Carpenter ,
1954
(Smyth et
al. , 1962)
Smyth et
al., 1954
Smytb e^t
al. , 1954
Union Carbide,
1968
Mellon Institute
,953
1
Smyth t^t a^. ,
1962
Carpenter, 1957
(Smyth et al. ,
1962
Carpenter, 1948d
(Smyth et al.,
1949)
Shelanski, 1973
Shell Chemical
Corp., 1958
Carpenter, 1948b
(Smyth et al. ,
1949)
Carpenter, 1948c
(Smyth et al. ,
1949)

Smyth, 1941a
(Smyth S
Carpenter,
1944)
Smyth, 1945
Mellon Institute
1955
Smyth S.
Carpenter, 1944
Smyth, 1946a
                                      205
-------
Table  69.    (cont'd)
           Chemical
                           Dilution and
                             Vehicle
                                                       Organism
Number
Treated
per Dose
Level
 Dose
(g/kg)
Mortality
  Data
                                                                                                            Reference
Unsaturated Aliphatics
Methyl iso-
propenyl
ketone

Mesityl oxide




Alicyclics & Aromatics
Cyclohexanone












Methycyclo-
hexanone


Isophorone





Acetophenone
















Benzophenone

n.s.
n.s.

20% in 1% "Tergitol" 7
20% in 1% "Tergitol" 7




undiluted



n.s.
undiluted


undiluted

n.s.


undiluted



n.s.

undiluted

n.s.

n.s.


20% in 1% "Tergitol" 7


undiluted

propylene glycol

corn oil
n.s.

n.s.

undiluted

n.s.

Rats
Guinea Pigs

Rats, M,W
(3-4)
Guinea Pigs




Rats, M,W
(3-4)


Rats, F
Mice


Rabbits,
"young"
Mice


Rabbits
"young"


Rats

Rats, F,W

Rats, F,W

Rats


Rats, M,W
(3-4)

Rats, M,W
(3-4)
Rats, F

Rats, F
Rats, M/F,
0-M
Rabbits

Rats, F,W

Rats

n.s.
n.s.

10
10




5



n.s.
n.s.


3




5



n. s.

5

5

n.s.


10


n.s.

n.s.

n.s.
10
(SM.SF)
n.s.

5

n.s.

0.18
(0.06-0.25)

1.12
(0.99-1.28)
1.00




1.54*
(1.14-2.08)


1.34
1.4


1.6-1.9

2 78


1.25-5.0



1.87

2.10

2.12

3.0


0.9
(0.81-1.00)

2.20
(1.59-3.10)
1.07

5.20
3.200
(2.460-4.160)
1.76
(1.67-1.85)
2.55

>10

LD50
Lethal
range
14 day LD
(±1.96 S.D.)
Lethal to
6 animals
within 14
days

14 day LD
(±1.96 S.3V)


14 day LD5Q
LD
:>u

LDioo

24 hour
LD,.,
50
LD
all animals
died in
14-90 min.
LD50

14 day LD

14 day LD5Q

14 day LD


14 day LD
(±1.96 S.D:)

14 day LD
(tl.96 S.BV)
14 day LD.n

14 day LD,0
14 day LD

14 day LD,n
(±1.96 S.B:)
14 day LD

LD50

Rowe &
Wolf, 1963

Mellon Insti-
tute, 1952
Carpenter ,
1941



Nycum et al. ,
1967 ~
(Smyth et al. ,
1969a)
" "
Novogoro-
dova et al. ,
1967
Treon et al. ,
1943a
Caujolle t,
Cauiolle,
1965
Treon et al . ,
1943a


Union Carbide,
1968
Smyth et al . ,
1969b
Smyth et al. ,
1970
Smych £.
Carpenter,
1944
Smyth, 1946b
(Smyth et
_§!., 1949)
Mellon Insti-
tute, 1956
Mellon Insti-
tute, 1956

Jenner et 
-------
                       Dose-response information is available on nine of the

   ketonic solvents under review and is summarized in Table 70.   All of these

   ketones appear to have a relatively low LD-.QQ to LDQ ratio.   For methyl

   ethyl ketone and ethyl n-butyl ketone,  the LD1QQ/LD  is only  two.  The

   highest LD nf,/LDn is four, given by both methyl n-propyl ketone and cyclo-

   hexanone.   Given these narrow ranges between complete and zero lethality,

   it is not surprising that four of these ketones — ethyl n-butyl ketone,

   diisobutyl ketone, mesityl oxide, and acetophenone — do not  show consistent

   positive correlations between dose and mortality.


Table  70 :  Per Cent Mortality in Rats After Intubation With Various Ketonic Solvents
              (see Table     for reference and experimental details)

Kctone
ttarMlity
100%
90%
80%
70%
60Z
50%
40%
30%
20%
10%
01

s.o.)

Methyl ethyl
Ketone
6.3
5.0


3.98





3.1*
3.98
(3.H-4.01)
Dove of Ketone in |/kf
Methyl n-propyl
Ketone
7.95



3.98





2.00
3.73
(2.M-5.21)
Methyl isoamyl
Ketone


5.84



2.92



1 1.**
3.44
(2.12-5.**)
Ithyl n-butyl
Ketone
3.98
2.52






3.16

2.00
2.7*
(2.S*-J.M>
Dil»o butyl
Ketone


7.95
5.0



3.98
6.3


5.75
(4.S9-7.0.)
2,4-Pentanedione

1.58



1.26


1.0


0.5
0.97
(0.90-1.05)
Mesttyl ojcl
-------
onset of narcosis is inversely proportional to the dose.   The duration of

narcosis in these exposures is relatively prolonged, lasting from seven to

fifteen hours (Treon £_t ai., 1943a).   This is similar to the activity of methyl

ethyl ketone, which at levels above the LD   (- 4 g/kg) caused narcosis for as

long as fifteen hours in surviving rats (Carpenter, 1949).  In fatal exposures,

death usually occurs within forty-eight hours of dosing.   As with the onset of

narcosis, death usually occurs more rapidly at higher doses.  Detailed data on

methyl ethyl ketone in Table 71 illustrates this pattern.

   Table 71.  Response of Rats to Single Intubations of Methyl Ethyl Ketone
                            (from Carpenter, 1949)


 Dose            Mortality          Number of Dying on Specified Day After Dosing
(g/kg)       (# dying/// exposed)    Day 0       Day 1       Day 2       Day 6


 3.16              0/10
 3.98              6/10                14                       1
 5.0               9/10                261
 6.3              10/10                3            7


Only with trimethylnonanone is delayed death noted.  With this ketone, death

usually does not occur until seventy-two hours after dosing  (Carpenter,

1948c).

                      Gross pathological findings  are also quite similar  in

ketone intoxication.  Congestion or hemorrhage of  the  lungs,  congestion  of

the  liver and intestines,  as well as discoloration of  the liver, kidney,  and

spleen are  most often noted.  In addition, methyl n-propyl ketone has  caused

surface burns on the  liver where contact with the stomach occurred  (Carpenter,

1954), and  ethyl sec-amyl ketone has caused local irritation  of the  gastric

mucosa in rats, guinea pigs, and mice  (Shell Chemical  Corp.,  1958).
                                       208
-------
                     As is evident in Table 69,  the commercially  significant

ketonic solvents have a relatively narrow range of acute oral  toxicity.

Fourteen  day  LD  's range from about 1 g/kg  for 2 ,4-pentanedione,  mesityl

oxide, and  acetophenone to  about 10 g/kg for acetone and trimethylnonanone.

Only methyl isopropenyl ketone (LDSO 0.18 g/kg  to rats) falls  outside of

these  limits.   Further, the confidence limits of the LD   estimates given

in Table  69 sometime approach a factor of two  [e.g. - methyl ri-propyl ketone,

LDcn  (+ 1.96  S.D.)  of 3.73  (2.68-5.21) g/kg], making precise comparisons of
  50  ~
toxicity  among the various  ketones difficult.   However, in  terms of relative

toxicity, the ketones do seem to fall into  three basic groups:   those with 14  day

LD   's near or below 1 g/kg, those with LD   's  between 1 and 5 g/kg, and those

with  LD   ' s above 5 g/kg.   Using this rather arbitrary classification, a semi-

quantitative comparison of  the acute oral toxicity of the various ketones  is

offered in Table 72.


     Table  72.   Relative  Acute Oral  Toxicity of  the Ketonic Solvents
                           (based  on  data from Table 69)
    more
    toxic
    less
    toxic
     Relatively High
       Toxicity (1)

Methyl Isopropenyl ketone
2,4-Pentanedione
Acetophenone
Mesityl oxide
Methylcyclohexanone
                                        Medium Toxicity (2)
Cyclohexanone
Methyl n-amyl ketone
Isophorone
Methyl isobutyl ketone
Methyl n.-butyl ketone
2,5-hexanedione
Ethyl n-butyl ketone
Methyl isoamyl ketone
Methyl n-propyl ketone
Methyl ethyl ketone
Diacetone alcohol
Relatively Low
   Toxicity (3)

Ethyl n-amyl ketone
Diisobutyl ketone
Trimethylnonanone
Acetone
            (1)  14 day LD   approximately 1 g/kg or below
            (2)  14 day LD^ 1-5 g/kg
            (3)  14 day LD   generally above 5 g/kg
                                       209
-------
While this type of classification may well do the least violence to the avail-




able data, it is not particularly satisfying.  However, before more detailed




comparisons can be made, some of the experimental parameters which may affect




estimates of ketone toxicity should be appreciated.  Information is available




on four of these parameters:  the vehicle used in administering the ketone, and




the sex, species, and age of the animal used.




                     Of all the factors affecting the oral toxicity of a given




ketone, the vehicle used in administering the ketone seems to be the most




important.  This is particularly evident in  the studies on acetophenone summarized




in Table 69.  For female rats, the LD  ' s varied from 1.07 g/kg using propylene




glycol as the vehicle to 5.20 g/kg using corn oil  (Mellon Institute, 1956).  Un-




diluted acetophenone has an intermediate LD   , 2.25 g/kg, for female rats  (Smyth




e_t _al. , 1969b).  Similar variations are seen in male rats of the same strain




and age, with undiluted acetophenone having  a 14 day LD   of 2.20  g/kg but  a




20% dispersion of acetophenone in 1% "Tergitol" 7 being about twice as toxic —




14 day LD   of 0.9  g/kg  (Mellon Institute, 1956; Smyth, 1946b).  The toxicity




of acetone is also  influenced by the vehicle used.  Rats -- presumably of  the




same  sex  and strain — yielded an LDj.. of 12.2  (8.0 -  18.8) g/kg with undiluted




acetone and a LD   of 9.15  (8.9 - 9.9) g/kg  with 50% acetone in water  (Mellon




Institute,  1965; data not summarized in Table 69).  Although comparable data  is




not available for the other ketones, it seems reasonable to assume that the




vehicle has a significant effect on oral ketone toxicity by influencing the




amount absorbed  and/or  rate of absorption.




                     Although rats have been most  often used in acute oral toxicity




studies,  tests have also been conducted using rabbits, mice and guinea pigs.




Consequently, LD   values are available on rats and at least one of these  other






                                       210
-------
animals for ethyl sec-amyl ketone, 2,4-pentanedione, methyl isopropenyl" ketone




mesityl oxide, cyclohexanone, and acetophenone (see Table 69).  For most of




these ketones, the LD _ values are extremely close.  The greatest apparent




difference in species response is found with ethyl sec-amyl ketone (guinea pig




LD   of 2.5 g/kg, rat 3.5 g/kg, mice 3.8 g/kg).  However, these values are well




within the limits of variation often noted in testing different groups of rats —




e.g., acetophenone and methyl ethyl ketone.  Thus, none of these common laboratory




mammals seem particularly sensitive to ketone ingestion.  This has been




specifically noted by Novogorodova and coworkers (1967) who, while providing no




experimental details, state that rats and rabbits are no less susceptible than




mice to oral doses of cyclohexanone.




                    The effect of age on the susceptibility to ketone poisoning




has been examined for methyl ethyl ketone using Sprague-Dawley rats of three




age groups: 14 days old (16-50 g), young adult (80-160 g), and older adult




(300-470 g).  The acute oral LD   's (with 95% confidence limits) for these




groups were 2.5  (2.0-3.2) g/kg, 2.9 (2.3-3.5) g/kg, and 2.7 (2.1-3.5) g/kg,




respectively.  These results indicate that methyl ethyl ketone is isotoxic in




all  three age groups (Kimura et_ al., 1971).  No additional information is avail-




able on the effect of age on ketone toxicity.




                    The effects of  sex on the response to the oral administration




of ketones is unclear.  Information is available on the responses of both




male and female  rats to methyl ethyl ketone, methyl isobutyl  ketone, and aceto-




phenone  (see Table 69 for details).  Based on  the LD   values given, males seem




more sensitive to methyl ethyl ketone and less sensitive to methyl isobutyl




ketone than do female rats.  However, the vehicles used in the female methyl
                                       211
-------
ethyl ketone study and male methyl isobutyl ketone  study are not  specified.   For



acetophenone, the undiluted ketone has about the same LD   values for both male



(2.2 g/kg) and female (1.76 g/kg)  rats.  Consequently, the apparent  difference



in the responses of males and females to methyl ethyl ketone and  methyl isobutyl



ketone may possibly be attributable to differences  in the vehicles used.



                      Thus, of the four experimental parameters on which some



information is available, the type of vehicle used  seems to have  a marked effect



on estimates of ketone oral toxicity.  The type of  common laboratory mammal (rat,



mouse, rabbit, or guinea pig) used seems to have no pronounced effect.  The



influences of age and sex on susceptibility to ketone intoxication is less



clear.  The limited information available does not  indicate that sex and age



have pronounced effects in the response of rats.



                      Given these limitations, certain patterns do seem evident



in the acute oral toxicities of the ketonic solvents.  Rowe and Wolf  (1963)



have stated that ketone toxicity generally increases with increasing molecular



weight.   This does seem to apply to the acute oral toxicities of the straight



chain methyl ketones with three to seven carbons.  However, the reverse relation-



ship seems apparent in the acute oral  toxicities of ethyl and isobutyl ketones



of five to twelve carbons.  Both of these patterns are illustrated in Figure  38.



                      In an attempt to make this comparison as reliable as possible,



the LD,-n  values given by Smyth, Carpenter and associates are used when available



in Figure 38.  Only the LD   value for ethyl sec-amyl ketone is from  another
                          jU                 	


source — i.e., Shell Chemical Corporation, 1958.  The choice of  the  LD   value



for methyl ethyl ketone used in Figure 38, 5.53 g/kg  (Smyth e^t _al. , 1962), is



arbitrary.   The value given by Carpenter  (1949), 3.98 g/kg, could be  used with



equal justification.





                                       212
-------
                     If the ketones  in Figure 38 are  considered as a single


series, a  roughly parabolic relationship between acute  oral toxicity  and


molecular  weight is apparent.  This is similar to  the patterns noted  for a


series of  alicyclic ketones  (Caujolle and Caujolle,  1965)  and acyclic aliphatic


ketones  (Jeppsson, 1975) on intraperitoneal and intravenous injections  (see


Figure 40, p.  244).




                        KEY:  No. Carbons   Methyl Ketones    Ethyl or Isobutyl Ketones


                                                                 Diethyl ketone

                                                                 Ethyl n-butyl ketone
                                                                 Ethyl sec-amyl ketone
                                                                 Diisobutyl ketone
                                                                 Isobutyl heptyl ketone
3
4
15 —




10 -
LD
(±1.96 S.D.)
g/k


-
c __
_
5
6
8
9
12
\
\
\
\
-L \
\
\I
'\ y
\] T
Acetone
Methyl ethyl ketone
Methyl n-propyl ketone D
Methyl n-butyl ketone
Methyl n-amyl ketone E
-— F
Cl
D
I



1 j x'
xx

/'"


                      1   2    3   4   5   6   7    6   9 ' 12

                                    Number of Carbons/Molecule
 Figure 38.
Relationship  Between Number of  Carbons per Molecule  and Acute Oral
LD50's With Rats for Straight Chain Methyl Ketones  ( 	) and
Ethyl or  Isobutyl Ketones  ( 	  )  (See Table 69  for sources of
data and  experimental details.)
                                      213
-------
               b.   Acute Dermal Toxicity




                    As indicated in Table 73, many of the ketonic solvents




have been tested for acute dermal toxicity.   As with oral toxicity,  most of




the studies have been conducted by Smyth, Carpenter,  and coworkers at the




Mellon Institute.  The basic techniques used in these studies is the one-day




cuff method.  This involves clipping the fur from the entire trunk of male




albino New Zealand rabbits.  The ketone is then applied to the skin and a




sheet of impervious plastic film (or cuff) is used to keep the dose in con-




tact with the skin.  After twenty-four hours, during which time the rabbit




is immobilized, the cuff is removed and any remaining ketone washed away.




Mortality is observed for the ensuing fourteen days and the LD   is calculated




as discussed under acute oral toxicity (Smyth et al., 1962).  An older method —




which has been used only with diones, mesityl oxide, and acetophenone — en-




tails exposing guinea pigs over a four-day period using a poultice to retain




the chemical.  This procedure, however,  tends to underestimate the toxicity of




the chemical because much of the dose is absorbed by the saturated pad and does




not come into contact with the skin  (Smyth and Carpenter, 1948).




                    Occasionally, other  methods have been used to estimate the




dermal toxicity of ketones but, based on the data available for cyclohexanone




and acetophenone,  the results of such studies cannot be reliably compared with




those described above.   For instance, Treon and coworkers  (1943a) applied




30 ml and 55 ml of cyclohexanone in  5 ml portions at 20 minute intervals to




the skin of rabbits.  Twenty minutes after the last application, the skin




was washed with  soap and water.  Consequently, the cyclohexanone was in  con-




tact with the skin for under four hours.  The rabbits receiving the smaller
                                      214
-------
Table 73.  Acute Dermal Toxicity of Ketones

Simple
Saturated Aliphatics
Methyl ethyl ketone
Methyl n-propyl
ketone
Diethyl ketone
Methyl n-butyl
ketone
Methyl isobutyl
ketone
Methyl n-amyl
ketone
Methyl -Lsoamyl
ketone
Ethyl ci-butyl
ketone
Ethyl n-amyl
ketone
Diisobutyl ketone
Isobutyl heptyl
ketone
Other Saturated Ali-
phatics
2,4-Pentanedione
2 , 5-Hexanedione
Diacetone alcohol
Unsaturated Aliphatlcs
Methyl isopropenyl
ketone
Mesltyl oxide
AlicycUc & Aromatic
Cyclohexanone
Kethylcyclohexanone
Isophorone
Acetophenone
Benzopheaone
Organism

Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit

Rabbit
Guinea Pig
Guinea Pig
Rabbit

Rabbit
Guinea Pig
Mice

Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Rabbit
Guinea Pig
Rabbit
Number
Exposed per
Dose Level

4
3-10
4
4
4
4
4
4
6
n.s.
6
9-10

n.s.
n.s.
6
n.s.

6
6-10
10

4
n.s.
n.s.
n.s.
5-10
n.s.
6
n.s.
Dose
(g/kg)

8.1
10.2
6.5
(2.9-14.4)
16.2
4.85
(3.44-6.80)
16.0
10.3
(7.6-13.9)
8.8
(6.0-13.1)
16.3
>5
16.2
9.0
(7.7-10.6)

4.85
1.0
6.4
13.6
(12.8-14.6)

0.20
(0.06-0.66)
1.9
0.43

0.948
(0.596-1.54)
10.2-23.0
4.9-7.2
1.39
6.17
(5.19-7.36)
16.3
(11.1-2.42)
20.5
3.5
(2.0-6.2)
Mortality

U L°50
U LD50
14 day LD
(tl.96 S.BT)
14 day LD50
14 day LD
('1.96 S,fl")
no mortality
over 14 days
14 day U>
(11.96 S.O")
14 day LD
(11.96 S.B")
no mortality
over 14 days
-50
14 day LD50
14 day LD
(11.96 S.DT)

approximate
LD50
no deaths
14 day LD5Q
14 day LD
(11.96 S.DT)

14 day LD
(11.96 S.BV)
14 day LD5Q
All dead in
3-9 hours

14 day LD
(11.96 S.BV)
Lethal range
Lethal range
LD50
14 day LD
(11.96 S.DT)
14 day LD
(11.96 S.3V)
No lethality
over 14 days
LD50
Reference

Smyth ex al. .
1962
Carpenter,
1949
Carpenter,
1954
(Smyth et al ,
1962)
Smyth el ri. ,
1954
Smyth et al. ,
1954
Mellon Insti-
tute, 1953
Smyth et al. ,
1962
Carpenter,
1957 ;
(Smyth et al ,
1962)
Carpenter,
1948a
(Smyth et al. ,
1949)
Shelanski,
1973
Carpenter ,
1948b
(Smyth et al. ,
1949)
Carpenter,
1948c
(Smyth et al. ,
1949)

Smyth, 1945 '
Smyth, 1941a
Smyth and
Carpenter ,
1944
Smyth, 1946a
(Smyth and
Carpenter ,
1944)

Smyth et al. ,
1951"
Carpenter ,
1941
Shell Chemical
Corp., 1957b

Nycum et al. ,
1967
(Smyth et al.,
1967)
Treon et al. ,
1943a
Treon et al. ,
1943a
Union Car-
bide, 1968
Smyth, 1946b
Mellon Insti-
tute, 1956
Smyth and
Carpenter,
1944
Opdyke, 1973
                     215
-------
portion — which amounted to 10.9 g/kg — became slightly anesthetized but




survived.  The other rabbit — which received a dose of 23.1 g/kg — died




after three hours and forty-five minutes.  Thus, the lethal range was esti-




mated at 10.2 - 23.0 g/kg.  The LD   value estimated by Nycum and coworkers




(1967) is about ten-fold lower than the non-lethal dose in the above exposure.




Nycum and coworkers (1967), however, used the standard one-day cuff technique




in which the animal was exposed to the cyclohexanone over a twenty-four hour




period.  This longer exposure period probably accounts for the much lower




estimate of lethal dose.




                       Variations in exposure technique also seem to account for




the various estimates of acetophenone dermal toxicity.  The lack of mortality




with guinea pigs at 20.5 g/kg  (Smyth and Carpenter, 1944) is probably due  to




the use  of the poultice in retaining the dose.  As discussed previously,  this




technique is thought to give lower estimates of toxicity than the one day  cuff




method  (Smyth and Carpenter, 1948).  This is apparently true with acetophenone




in that  the standard one-day cuff method yielded a 14-day LD   of 16.3 g/kg.




In the  third study which gave  an even lower LD   estimate of 6.17 g/kg,  Smyth




 (1946b)  applied varying doses  of acetophenone to rabbit skin by  gentle rubbing.




Smyth  (1946b) states that  this method generally yields an LD   about  twice that of




the cuff method.  Thus, an LD  _  of 3.08  g/kg was estimated  as being  comparable to




an LD    using the cuff method.   This value, however,  is not in agreement with the




actual  cuff LD   of 16.3  g/kg  (Mellon Institute, 1956).  Assuming that no




extraneous factors are involved, this discrepancy seems to  support the conclusion




that results based on different  exposure techniques cannot  be compared with
                                         216
-------
satisfactory reliability.   Thus,  in Table 73,  the data on benzophenone  (Opdyke,




1973), ethyl n-amyl ketone (Shelanski,  1973),  and isophorone (Union Carbide,  1968)




are of limited use in estimations of comparative toxicity.  This is particularly




true for the estimates of Shelanski (1973) and Opdyke (1973),  neither of which




present any procedural details.




                       Methyl isobutyl ketone and ethyl n-butyl ketone  are clearly




among the least toxic on dermal application.  These ketones are apparently absorbed




slowly — if at all — and are not lethal to rabbits at the highest dose level




which can be administered by the cuff technique.  Details in the ethyl _n-butyl




ketone exposure indicate that this ketone caused neither skin irritation nor




weight loss in exposed animals (Mellon Institute, 1953; Carpenter, 1948a).




Diisobutyl ketone is also poorly absorbed and has a calculated LD   near the




maximum dose level, 16.2 g/kg.




                       Diacetone alcohol and acetophenone also have 14-day LD




values above 10 g/kg by the standard cuff method.  However, these ketones differ




from the above group in terms of skin irritation.  Diacetone alcohol causes erythema




and shallow scaling in rabbits at doses near the LD   (Smyth, 1946a).  Aceto-




phenone, which is even less toxic in 14 day mortality studies, causes severe skin




necrosis which is typical of the more highly toxic ketones.  In addition, aceto-




phenone caused severe kidney damage (Smyth, 1946a).




                       Most of the other ketones on which data are available seem to




be both toxic and corrosive at doses below 10 g/kg.  Mesityl oxide is the most




extensively studied of this group.  In guinea pigs, doses from 1.85 to 3.98




g/kg caused rapid deaths in most animals and subcutaneous edema at the




application site.  Gross pathological observations included mottled liver, pale







                                        217
-------
spleen and kidneys, as well as congestion of the stomach and intestines (Car-




penter, 1941).  The LD   calculated for guinea pigs (1.9 g/kg)  is well below




the 5.13 g/kg LD   for rabbits (Mellon Institute, 1952).  In that the guinea




pig poultice exposures presumably underestimate toxicity, these results could




be interpreted as indicating that guinea pigs are more susceptible than rabbits




to dermal applications of mesityl oxide.  Mice, at least, do seem to be the most




susceptible animal tested.  On applications of only 0.43 g/kg, the skin became




markedly irritated in a few minutes and narcosis was induced within fifteen




minutes followed by death in three to nine hours (Shell Chemical Corp., 1957b).




Methyl ethyl ketone, methyl n-propyl ketone, and methyl isoamyl ketone seem to




have effects similar to those of mesityl oxide.  Pathological findings for these




ketones show involvement of the liver and kidneys along with erythema and




narcosis of the skin.  In addition, congestion and hemorrhage of the lungs were




noted for both methyl isoamyl ketone and methyl _n-propyl ketone  (Carpenter, 1949,




1954, and 1957).  Of these relatively toxic ketones, 2,4-pentanedione is somewhat




exceptional in that it caused no local  skin irritation  (Smyth, 1941a).




                       As in oral exposure, delayed death is noted only for tri-




methylnonanone.  At the highest dose tested, 12.9  g/kg, which was lethal to nine




of  ten exposed rabbits, death was delayed for up to ten  days after exposure.




While most animals developed erythema,  necrosis  of the  skin was  seen  only




occasionally.  Also unlike any of the other ketones on  which data are available,




trimethyInonanone  caused persistent diarrhea  (Carpenter, 1948c).




                       No further details are available  on  any of the ketones




listed in Table  73.  As evident from the above  discussion,  LD    values do not




seem to be good  indicators of the type  of acute  toxic  response to the dermal




application of a given ketone.  Consequently, a  listing  of  relative toxicity




based on these values does not seem warranted.





                                        218
-------
               c.   Acute Inhalation Toxicity




                    By far the greatest amount of information on the acute




toxicity of ketones comes from inhalation studies.  As in oral exposures, most




of the ketones under review cause narcosis, over a relatively short period




of time, which may progress to respiratory arrest during the exposure period.




Generally, those animals which survive the exposure period seem to recover




rapidly from narcosis and suffer no permanent adverse effects.  In a few




instances, animals die after the exposure period.  These deaths are usually




attributed to lung irritation which may include severe congestion and/or




hemorrhage.




                    However, such broad generalizations on acute inhalation




toxicity are only of qualitative validity.  Although certain basic response




patterns are apparent, the specific types of responses may vary markedly in




magnitude.  For example, some ketones cause rapid and severe irritation to the




respiratory tract while others cause only mild irritation even on prolonged




exposures.  Further, the quantity, quality, and consistency of the information




available on the individual ketones varies greatly.  Methyl ethyl ketone and




cyclohexanone have been extensively studied by a number of investigators who




provide detailed data on dose-response relationships, pathology, and mechanisms,




of action but use differing methods of exposure and criteria of response.  At




the other extreme, only a rough approximation of the lethal range is available




for acetophenone.
                                      219
-------
                     Because of the many common features and yet significant




diversity found in the available information on the acute inhalation toxicity




of ketones, a somewhat different approach will be adopted in the presentation




of this data.  First, the general methodology used by the various investigators




will be compared.  Secondly, the common aspects of ketone intoxication will be




detailed.  This will be followed by capsule summaries of the data available




for the individual ketones.  Lastly, the relative activities of the various




ketones will be discussed within the limitations of the available data.




                      (i)    Methodology




                            Almost all of the information on the acute inhalation




toxicity of ketones comes from three groups of investigators: Smyth and coworkers




(references beginning with Smyth, Carpenter, Nycum, and Mellon Institute); Patty




and coworkers  (Patty et. al. , 1935; Schrenk jit al. , 1936; Yant e_t al. , 1936) ;




and Specht and coworkers  (1938 and 1940).  Most acute inhalation tests have




been conducted on either  rats or guinea pigs and have involved exposure to a .known




concentration  of ketone vapor over a specified period of time.  In the studies




by Smyth and coworkers, the vapor concentrations  are nominal — i.e. , they are




prepared by  diluting  a known concentrated vapor using a proportioning pump, but




the actual vapor concentration to which the animals are exposed is not analytically




determined.  The other two groups of investigators do analytically determine




the levels of  ketone  vapor in the exposure chambers.  Occasionally,  Smyth and




coworkers  also expose animals to "saturated" or "concentrated" vapors generated




either by heating the ketone to 170°C  (with the consequent  possibility of




partial  oxidation) or by  using a fog-nebulizer.   In either  case, such exposures
                                      220
-------
serve only as rough indications of hazard (Carpenter et al.,  1949).   Because
the concentration of vapor generated will vary widely with the vapor pressure
of the ketone and because actual concentrations are not monitored,  the results
from "saturated" or "concentrated" vapor exposures are not comparable with the
results from known concentration exposures.
                           These three groups of investigators also differ in the
type of data presented.  Smyth and coworkers attempt to subject animals to
exposures that will cause no lethality, fractional lethality, and total lethality
by varying either the concentration or the exposure period.   Consequently,
standard dose-response relationships are often presented.  Information on
pathology and response patterns from any given exposure, however, is often
quite limited.  Specht and coworkers (1940)  and Patty and coworkers present
similar data along with information on time-response and relatively detailed gross
pathology.
                    (ii)   General Patterns in Ketone Vapor Intoxication
                           The primary response to the inhalation of ketone vapors
is progressive narcosis.  This involves a loss of corneal, auditory, and equili-
bratory reflexes as well as a general depression of vital signs such as heart
rate, respiratory rate, and body temperature.  These qualitative similarities were
noted by Specht and coworkers  (1940) who exposed guinea pigs to the ketones listed
below:
               *Acetone                      *Methyl isobutyl ketone
                Methyl ethyl ketone           2,5-Hexanedione
               *Methyl n-propyl ketone       *Mesityl oxide
               *Methyl n-butyl ketone         Cyclohexanone
               *Methyl n-amyl ketone
                Methyl ii-hexyl ketone

                                       221
-------
For the compounds marked with an asterisk (*) ,  common pathological findings




were also given.  The most frequently noted pathological finding is congestion




and mild hemorrhage in the lungs.  Congestion is also common in the kidneys,




spleen, adrenals, and brain, and is attributed to the effects of ketones on




the vasomotor center.  Selective action by ketones is evident in distention




of the renal tubules (Specht _et al. , 1940).




                   (iii)    Capsule Summaries




                            METHYL ETHYL KETONE




                            The acute inhalation toxicity of methyl ethyl




ketone is typical of most of the acyclic aliphatic ketones under review.




Mortality data  from acute exposures to rats, mice, and guinea pigs are summarized




in Table 74.  Patty and coworkers  (1935) noted the following response sequence




in guinea pigs  exposed to concentrations of  33,000 ppm and 100,000 ppm:




irritation of the eyes and nose, lacrimation, incoordination, narcosis, respira-




tory distress,  and death.  In addition, opacity of the cornea developed after




30 minutes at the higher  concentrations.  A  similar pattern is detailed by




Specht and coworkers  (1940) who  also noted marked salivation as an initial response




to 25,000 ppm.   Exposures of 10,000 ppm x 13.5 hours are not fatal to guinea




pigs but narcosis is induced after about four hours.  At 3,300 ppm, Patty and




coworkers  (1935) noted neither irritant nor  narcotic effects during an exposure




period of 13.5  hours.  The narcosis induced  by exposures to 10,000 - 50,000




ppm over periods of 4-14  hours was accompanied by progressive dose-related




decreases in respiratory  rate, heart rate, and body temperature  (Specht et al. ,




1940).  In non-fatal exposures which caused  unconsciousness, narcosis often




persisted for several hours after  exposure  (Patty et al. , 1935).
                                      222
-------
Table 74.  Acute Inhalation Toxicity of Methyl Ethyl Ketone

Organism
Rats, Female,
Sherman, young






Rats, Female,
Sherman, young



Rats, Female,
Sherman

Mice

Guinea Pig
Guinea Pig



Guinea Pig y
mixed strain,
4UO-oOOg





Number
Exposed
6

6
6
6
6
6
6
6
6
6


[6]


10
10
5
6

6
6
iO







Concentration
(ppm, v/v)
1000

2000
2000
2000
2000
4000
8000
4000
8000
16000


Saturated
vapor

8000
8000
8000
10000

33000
100000
25000

25000
25000




Duration
(hours)
8

2
4
8
2
2
2
8
8
8


0.5
1
2
4
8
8
=15

=3.3-4.3
=0.75-0.92
3

4.5
5.4





Mortality
0/6

0/6
1/6
5/6
0/6
4/6
6/6
0/6
3/6
6/6


1/6
5/6
6/6
1/10
6/10
0/5
no fatality
noted
fatal
fatal
1/10
(Cumulative
deaths)
5/10
7/10
10/10 b-/ 42
hrs. after
exDOOurc


Reference
Mellon Institute,
1945






Mellon Institute,
1950
[partially summ-
arized in Smyth
et al. , 1962]
Mellon Institute,
1949

Carpenter, 1949

Carpenter, 1949
Patty et al. ,
1935


Specnt et al. ,
1940






                                223
-------
                              Only Patty and coworkers (1935)  have described gross




pathology in methyl ethyl ketone exposures.   In addition to the previously noted




corneal opacity at 100,000 ppm, fatally exposed animals had moderate to marked




congestion of the lungs, liver, and kidneys, as well as mild congestion of the




brain.  These findings were also noted in animals that survived narcosis but were




sacrificed immediately after exposure.  However, these pathological findings were




absent in animals that survived narcosis and were sacrificed eight days after




exposure (Patty e_t al. , 1935) .




                              Death from acute methyl ethyl ketone inhalation can




be attributed to either lung irritation or narcosis.  Patty and coworkers (1935)




concluded that narcosis was the primary factor because all of the guinea pigs




which survived narcosis eventually recovered.  However, in comparable exposures,




Specht and coworkers  (1940) note that some animals survived narcosis and did




not die until 24-48 hours after exposure.  In these animals, death was probably




due to lung congestion.




                              Little detailed information is available on the




rat and mice exposures.  In terms of lethal response, both rats and mice are




apparently much more  susceptible than guinea pigs to methyl ethyl ketone inhalation.




This  greater tolerance  of guinea pigs as opposed to rats holds true for most of  the




ketones under review.   The marked differences in the results from Mellon Institute




 (1945) and Mellon  Institute  (1950) have been attributed to variations in the




samples of methyl  ethyl ketone  used in  these two tests  (Mellon Institute, 1950).
                                        224
-------
                              METHYL n-PROPYL KETQNE

                              This ketone  seems  to  be  about twice as toxic

as methyl ethyl ketone on acute inhalation but has  about the same pharmacological

affects.  A summary of acute inhalatioii  exposures  to rats and guinea pigs is

given in Table 75 and again demonstrates the  greater susceptibility of rats.  As

with methyl ethyl ketone, acute exposure to guinea pigs caused irritation of the

nose and eyes, lacrimation, incoordination, narcosis,  respiratory distress, and

death.  With methyl ii-propyl ketone, all of these  symptoms were caused at 13,000

ppm x 5 hours and all but death at 5,000 ppm  x  - 6 hours.  None of these effects

were produced during a 13.5 hour  exposure to  1500  ppm  (Yant e_t a_l., 1936).  Nar-

cosis was accompanied by dose dependent  decreases  in respiration, heart rate, and

body temperature  (Specht ejt^ a.1.,  1940).   In some animals, narcosis persisted for

several hours after exposure  (Yant et  al., 1936).


         Table 75.  Acute Inhalation Toxicity of Methyl n-Propyl Ketone
       Organism
Number
Exposed
Concentration
 (ppm, v/v)
Duration
(hours)
Mortality
                                                                      Reference
	 . — • — • 	 " 	
Rats, Car-
worth-Wistar
4-5 weeks,
90-120g

Guinea pigs,
Female ,
400-600g



Guinea pigs


6




10





6


2000
4000


Saturated vapor
[21,000 ppm]**
10,000





5,000
13,000
50,000
4
4


0.5
1.0
9





13.5
5
0.8
1/6
6/6


0/6
6/6
4/10
during
exposure,
survivors
die 48 hrs
after exposure
not fatal
fatal
fatal
Carpenter,
1954
(Smyth et
al. , 1962)

Specht et
al., 1940




Yant et al.,
1936

                                          225
-------
                              Specht and coworkers (1940)  noted congestion and




emphysema of the lungs and kidney along with distention of the renal tubules as




the primary pathological effects.  Also noted was slight congestion of the liver




and adrenals, but no changes in the heart, stomach, and pancreas.   Congestion




was attributed to the vasomotor effect of the ketone.   Similar pathology was




also noted by Yant and coworkers (1936), who again found that animals subjected




to exposures which probably caused initial pathological damage showed no signs




of pathology 4-8 days after exposure.  Congestion and pinpoint hemorrhage of the




lungs were also noted in fatally exposed rats (Carpenter,  1954).




                              As with methyl ethyl ketone, death during exposure




is probably due to narcosis, while death in animals surviving the exposure period




is due to lung irritation (Yant et. _al. , 1936; Specht _et _al. , 1940).




                              DIETHYL KETONE




                              Few data are available on this ketone.  An




exposure  to 8000 ppm x 4 hours killed  four of six Carworth-Wistar rats and exposure




to "concentrated" vapors was lethal to some rats after fifteen minutes  (Smyth et




al.,  1954).




                              METHYL n-BUTYL KETONE




                              Information on the acute inhalation toxicity of




methyl n-butyl ketone gives no indication of its chronic neuropathological effects.




As indicated in Table 76, this ketone is about twice as toxic as methyl n-propyl




ketone to both guinea pigs and rats.   Except for the difference in  potency, the




pathological  response of guinea  pigs  is identical  to that  of methyl n-propyl




ketone.
                                         226
-------
      Table  76.  Acute  Inhalation  Toxicity  of Methyl n-Butyl  Ketone
Number Concentration Duration
Organism Exposed (pp«,v/v) (hours) Hortality Reference
Rats, sex
n.s, , Car-
worth-Wistar
90-120g




Guinea pigs,
female, mixed
strains,
400-600g




Guinea pig


6
6


6



10






10
6


4,000
8,000


Cone . vapor
(<5000 ppm)


6,000






12,000
2,300
6,500
20,000
4
4


0.5
>0.5


6.6


8.8



•>2 hr.
13.5
9.0
1.2
0/6
6/6


0/6
lethal to
some ani-
mals
2/10
(cumulative
mortality)
7/10
10/10 by
72 hrs after
exposure
Lethal
No deaths
Lethal
Lethal
Smyth et
a_l. , 1954






Specht et
al., 1940






Schrenck et
al. , 1936

                              METHYL ISOBUTYL KETONE




                              As indicated in Table 77,  this ketone seems to be




about twice as toxic to rats as the n-butyl isomer assuming equal sensitivity




between the two strains of rats.  Although the pathological effects of this




ketone are very similar to those of the n-butyl isomer,  differences are noted in




the narcotic response.  While the methyl n-butyl ketone  caused decreases in




respiratory rate and heart rate, methyl isobutyl ketone  caused initial marked




depression in these values followed by slight signs of recovery.  This indicates




that methyl isobutyl ketone has not only a narcotic effect but also a marked




irritating effect on the nasal mucosa which caused rapid reflex inhibition of




respiration (Specht et al., 1940).
                                       227
-------
         Table 77.  Acute  Inhalation  Toxicity of Methyl Isobutyl Ketone
            Organism
Number
Exposed
Concentration
  (pp»,v/v)
Duration
(hours)
Mortality   Reference
iats, sex,
i.s>. , Sher-
nan, 100-150g

lice
Juinea pigs,
remale


6

n.s .
10


2,000
4,000
Saturated vapor
20,000
1,000
10,000
16,300
25,000-30,000
4
4
0.25
0.5
0.5
23
4
3.3
0.75
0/6
6/6
0/6
6/6
Lethal
No deaths
Lethal to
most ani-
mals
9/10 died
(1.3-3.3
hours)
Lethal to
most ani-
mals
Mellon
Institute,
1953
Smyth et al. ,
1951
Shell Chemical
Corp., 1957a
Specht, 1938


                                METHYL n-AMYL KETONE

                                A summary  of  the acute inhalation toxicity  of this

ketone is  given in Table  78.   This ketone seems to have  about the same  toxicity to

rats as methyl isobutyl ketone.  It is,  however, markedly more toxic  than either

of the methyl butyl ketones to guinea pigs  in terms of  the time required  to

induce narcosis and death.   Its irritant and pathological properties  are  similar

to methyl  n-butyl ketone  (Specht e_t al., 1940) .


            Table 78.  Acute Inhalation Toxicity of Methyl n-Amyl Ketone
          Organsim
                        Number
                        Exposed
           Concentration   Duration
           (ppm, v/v)     (hours)
                         Mortality
                                      Reference
Rats, sex,
n.s. , Car-
uorth-Wistar
4-5 weeks,
90-120g


Guinea pigs,
Female, mixed
strain, 400-
600g
6
6


6


10
10


2,000
4,000


concentrated
vapor

2,000
5,000


4
4


0.5
1.0
2.0
15
2-4.7


0/6
6/6


0/6
2/6
5/6
No deaths
Lethal


Mellon
Institute,
1958

Smyth et
aU , T%2

Specht et
aU , 1940


                                          223
-------
                              METHYL ISOAMYL KETONE




                              The acute inhalation toxicity of this ketone has




been examined only on rats (Carworth Farms-Nelson).  Exposures to 1000 ppm x 4




hours caused only poor coordination.  Twice this concentration resulted in




narcosis after two hours but did not result in any deaths.  An exposure to 4000




ppm x 3 hours was lethal to all of the six rats tested.  Inhalation of "concentrated"




vapor (-6,000-10,000 ppm) resulted in narcosis in thirty minutes and convulsive




breathing during and after the exposure period.  Two of the twelve exposed




animals died, both of which had capillary breakdown of the lungs (Carpenter, 1957).




                              ETHYL n-BUTYL KETONE




                              Sherman rats exposed to 2000 ppm x 4 hours became




anesthetized but did not die.  Twice this concentration over the same period




resulted in the deaths of all six exposed rats  (Carpenter, 1948a).




                              METHYL n-HEXYL KETONE




                              Because of its very low vapor pressure, Specht and




coworkers (1940) exposed guinea pigs only to the highest concentration obtainable,




1300 ppm.  This concentration did not prove lethal over a 14 hour exposure period




but did cause typical signs of ketone intoxication including coma after twelve




hours and progressive decreases in respiratory  rate, heart rate, and body




temperature.  While the  latter two parameters showed gradual declines typical




of narcotic response, respiration showed an initial sharp decrease characteristic




of exposure to irritant vapors.  Because of the low concentration which causes




coma, Specht and coworkers  (1940) have concluded  that this ketone has as great,




or a greater, depressant effect than other straight chain methyl ketones.
                                        229
-------
                              ETHYL sec-AMYL KETONE




                              Air saturated with this ketone at 25°C  (=3000 ppm)




caused irritation of the eyes and respiratory tract of both rats and  mice.   Three




of six mice died as a result of the exposure.  Saturated air at 35°C  (-6000 ppm)




caused death in all six exposed mice and four of six exposed rats.  Both species




showed normal signs of ketone intoxication: uncoordination, respiratory distress,




and narcosis (Shell Chemical Corporation, 1958).




                              DIISOBUTYL KETONE




                              Carpenter and coworkers (1953) have demonstrated




both sex and strain differences in the response of rats to this ketone.  In




exposures to 2000 ppm x 8 hours, seven of twelve female Sherman rats  died.   How-




ever, in identical exposures, male Sherman rats as well as male and female Carworth




Farm Wistar rats showed no lethality.  Smyth and Carpenter (1941) indicated that




guinea pigs are less susceptible to this ketone than rats.




                              TRIMETHYLNONANONE




                              "Saturated" vapor (probably less than 700 ppm) of




this ketone killed two of six rats in an eight hour exposure causing  marked




congestion of the lungs (Carpenter, 1948c).




                              2,4-PENTANEDIONE




                              Two of six rats exposed to  2000 ppm x 2 hours died




within twenty-four hours.  Four hours exposure  to  the same concentration caused




death in four of six rats within two hours after exposure.  A concentration of




1000 ppm x  1 hour was not fatal but  did  cause  anesthesia  and slight irritation
                                        230
-------
of the eyes and nose (Smyth, 1945).  Exposures to saturated vapor at 25°C killed




no rats in half an hour but caused death in all rats after a one hour exposure.




All deaths occurred during anesthesia.  Only slight irritation of the lungs was




noted (Smyth, 1941a).




                              2,5-HEXANEDIONE




                              Because of its low vapor pressure, 2,5-hexanedione




has only been tested under "saturated" conditions.  Specht and coworkers (1940)




were able to generate a concentration of 400 ppm at room temperature.  Guinea pigs




evidenced only slight transient signs of irritation and a moderate drop in




respiratory rate - but no significant changes in heart rate or body temperature -




during a 12.5 hour exposure period.




                              Smyth and Carpenter  (1944) found that exposure to




"saturated" vapor for one hour caused no deaths in six male Wistar rats.  Exposures




for greater than one hour caused death in some animals.




                              DIACETONE ALCOHOL




                              Like the diones, diacetone alcohol seems to be only




a mild irritant.  Male Sherman rats exposed to 1500 ppm x 8 hours suffered no




lethality and showed only minor signs of irritation to the eyes and nose (Smyth,




1946a).




                              METHYL  ISOPROPENYL KETONE




                              This unsaturated ketone is clearly the most toxic




ketone in acute inhalation exposures.  A concentration of 125 ppm x 4 hours was




lethal to five of six exposed rats.   Saturated vapor killed six exposed rats




after a two minute exposure period (Smyth et_ al.,  1951).  In non-lethal exposures
                                        231
-------
(524 ppm x 1.5 hours),  this ketone is very irritating to the eyes and nose of




rats.  Cyanosis and convulsions were noted in rats dying during exposure to




2910 ppm x a few minutes.  Animals dying after the exposure period suffered from




severe respiratory irritation (Dow Chemical, unpublished data).




                              MESITYL OXIDE




                              Summaries of acute inhalation exposures to mesityl




oxide with resulting mortalities are given in Table 79.   Details on the acute







           Table 79.  Acute Inhalation Toxicity of Mesityl Oxide

Organism
' Rats, male,
Wistar, 90-
120g
and
Guinea pigs,
males and
females,
250-300g
Guinea pJgs,
female,
mixed
strains,
400-600g
Number
Exposed
n. s.

n.s.
20
n.s .
n.s.
n.s.
n. s.
10




Concentration
(ppm, v/v)
500

1,000
2,500
13,000



5,000




Duration
(hours)
8

8
8
O.J66
0.25
0.5
1.0
5.4

7.0



Mortality Reference
30% mortality I Smyth et al.,
during exposure 1942
68% mortality
1007, mortality
no mortality
16% mortality
20% mortality
100% mortality
,
f
3/10 dead, all } Specht et. al.,
comatose ! 1940
6/10 dead
10/10 by 5 hrs j
after exposure
 inhalation toxicity of mesityl oxide presented by Specht and coworkers  (1940)




 indicate that this compound is, in some respects, atypical of most other ketone'S.




 The response sequence in guinea pigs was characterized by irritation of the mucous




 membranes, muscular weakness and incoordination, narcosis, cyanosis, and death.




 As with most other ketones, narcosis was characterized by a steady decline in




 body  temperature, the magnitude of which was proportional to vapor concentration.




 However, as indicated in Figure 39, the respiratory rate at lower concentrations




 showed a marked  tendency to return to normal.  At concentrations of 5,000 ppm




 (0.5%) and 10,000 ppm  (1.0%), the heart rate remained normal or slightly elevated
                                      232
-------
during the hour of exposure.  This lack of depression indicated some stimulatory

pharmacological effect in addition to narcosis.  Although pathological findings
 Figure 39;
Three-dimensional Graph of Respiratory Rate During Exposures to
0.23, 0.5, and 1.0 per cent Mesityl Oxide Vapor (Specht e_t al., 1940)
were  similar to methyl ii-propyl ketone,  the bodies of  guinea pigs  dying during

exposure were described as having  a  "rather vile  smell"  not noted  with  other  ketones.

The bodies of these animals became rigid prior  to death  and were found  to  be  dis-

tended with gas and fluid in  the alimentary canal (Specht _e_t_ _al. ,  1940).

                              No unusual odor was noted  by Smyth and  coworkers

 (1942) in exposures to rats and guinea pigs.  All deaths occurred  during exposure

due to narcosis accompanied by moderate  lung irritation.
                                     233
-------
                              CYCLOHEXANONE




                              Acute inhalation exposures to cyclohexanone




are summarized in Table 80.   Because of  its low vapor  pressure,  this  ketone  was






              Table 80:  Acute Inhalation Toxicity of Cyclohexanone
Number Concentration Duration
Organism Exposed (ppm, v/v) (hours) Mortality ., Reference
Rats, sex,
n. s. , Car-
worth-Wistar
4-5 weeks,
90-120g






6



6


[6]


6



Guinea pigs,
female, mixed
stock, 400-600g

6

10



2,000



4,000


2,639
(2131-3268)

Saturated vapor



4,000



4



4


4


0.5

>0.5

7.6



1/6, anes-
thesia after
2-5 hours

6/6, anes-
thesia after
J-5 hours
LC.j0 for 4
hr. exposure
Nycum et
al. ,"1967







(±1.96 S.D.)
0/6

death in some
animals
3/10 died
four hours
after ex-
posure



_J
__|
Specht et
al. , 1940

1
tested only at 4000 ppm by Specht and coworkers (1940).   Like most ketones,




cyclohexanone caused narcosis and a progressive decrease in body temperature




during exposure.  Respiratory rate showed a rapid initial decrease characteristic




of the reflex effect of irritation to the nasal mucosa.   This was followed by




a more gradual decline as narcosis progressed.   Heart rate, however,  initially




increased and did not fall below normal until about one  hour after exposure.




This is somewhat similar to the effect of mesityl oxide  at 5000 ppm and indicates




that narcosis is not the only marked pharmacological effect of cyclohexanone.




Corneal opacity developed in all exposed animals one day after exposure.   Specht
                                     234
-------
and coworkers (1940) also noted that recovery from narcosis was unusually slow.




Complete recovery, including the reversal of corneal opacity, took several weeks.




                              The results with rats indicate that, as with most




ketones, rats are more susceptible than guinea pigs.  Fatally exposed rats had




unusually dark red liver, kidneys, and blood (Nycum £t al., 1967).




                              METHYLCYCLOHEXANONE




                              Rabbits and cats exposed to 2500 ppm x 1 hour




experienced respiratory irregularities, poor coordination, and sleepiness but




not death.  Respiratory irritation, incoordination, and prostration were seen




in rats, mice, and guinea pigs exposed to 3,500 ppm x 30 minutes  (Flury and




Klimmer, 1938).




                              ISOPHORONE




                              Smyth  (1941b)  and Smyth and Seaton  (1940) have




noted  typical signs of ketone poisoning in  rats and guinea  pigs exposed to




750 ppm -  4600 ppm over  several  hours.  Deaths in both studies were  attributed




to respiratory paralysis or lung irritation.  Rowe and Wolf (1963) have indicated




that  the samples  used  in these studies contained  significant amounts of im-




purities more volatile  than isophorone.   Thus, the summaries of these studies,




given  in Table 81, may have  limited value.







             Table  81.  Acute Inhalation  Toxicity  of Isophoronp
Organism Number Concentration Duration Mortality Reference
Exposed (ppn, v/v) (hour*)
Rats and
Guinea pigs




Rats


Guinea pigs
n.s.





n.s.


n.s.
750 ppm


>750 ppm


1840


4600
several
hours

several
hours

4


8
no death
or serious
symptoms
causes
death in
some animals
caused death
in some
animals
no deaths

Smyth,
1941b




Smyth and
Seaton,
1940

                                       235
-------
                              ACETOPHENQNE




                              Exposure to a mist of acetophenone (-4,400-5,000




ppm) was not lethal to any of six rats over a two hour period but killed six of




six after four hours exposure.  Death was attributed to anesthesia.   Lungs,




kidneys, and liver were congested in fatally exposed animals (Smyth,  1946b).






                   (iv)   Comparative Acute Inhalation Toxicity




                          As should be apparent from the preceding capsule




summaries, valid comparisons of acute inhalation toxicity among the ketones are




limited by a number of factors.  First, the amount and type of information on




the different ketones varies greatly.  Secondly, the purity of the ketones used




in the various studies was not accurately determined.  There are indications




that unspecified impurities may have affected toxicity estimates on at least




two ketones — methyl ethyl ketone and isophorone.  The importance of impurities




in other  studies cannot be determined.  Further, in comparing the studies using




rats, the importance of sex and strain differences is also speculative.  Definite




sex and strain differences seem evident for diisobutyl ketone (Carpenter et al.,




1953).  Because most ketones  seem to act in about  the same way,  it seems




plausible that sex and strain differences may influence the  results in studies




on other  ketones.




                          Estimates of vapor concentrations  which cause varying




degrees of  response over  specified exposure periods have been made for seven  of




the ketones under  review  and  are summarized in  Table  82.  These  estimates are




based on  the  studies described in the  capsule summaries.  The values  for




maximum concentration  for several hours without serious disturbance seem to




accurately  reflect the relative acute  inhalation toxicities  of  these  ketones.
                                     236
-------
 a
 o
•H
 a
 C
 o
 en

 o
•H
-rl
a,

 to
 0)
 a
•H
 3
O
 o

 0)

 3
 to
 o

 B1
 to
 •U

 O

 01
 <4-l

 M-l
 0)
 4-J

 3
 CM

 00
 •s
 H














(T,
G
CX

*""
•^

>
s
Keton:
o
U!
a.
0)
d
H

O
W
1_(
3
O
CX
a)
ot
c















c
o
1-J
o

CX
o
en


>. 0!
•H H
tfl X
dl O


>-,

D C
O 4-J

•H


•— t X CiJ
>-, -I-1 C
-C 3 O
3 ° QJ



"-* :>>. QJ
x: a o
dj i qj


_,
"i ^c
.d iH C
I ill




f~H at

X .>, o
QJ 4J OJ

/


'
Ketone
Single exposures

cx
a.

o
o


e
cx
ex
o
o
o
CO

e
CX
cx
o
o
LA


J
1
1



,
1




1














Kills in a few-
minutes
E
cx
cx

o
o

A
E
cx

o
o
o


E
cx
ex
o
o
cQ

E
CX
cx
0 O
o o
o o
-, T-H

4J m
a- 
-------
Mesityl oxide is the most toxic of this group.   With the exception of the other

acyclic unsaturated ketone, methyl isopropenyl ketone,  mesityl oxide is the

most toxic ketone under review.

                          The straight chain, methyl ketones seem to increase in

acute inhalation toxicity with increasing molecular weight.  This pattern has

been noted by Specht and coworkers (1940) , who showed a positive relationship

between oil over water partition coefficients and the narcotic effectiveness for

these ketones as indicated in Table 83.   The value of C is  defined as the con-

centration of vapor necessary to induce coma over a standard time interval

relative to acetone where 1/C equals one.  These values are based on the previously

discussed study of the effect of several ketones in guinea pigs.  Similar patterns

are not apparent for the branched chain or cyclic ketones.

                          Because the information in this  section is relatively

diffuse, Table 84 is presented summarizing the oral, dermal, and inhalation

exposures to the ketonic solvents.
     Table 83.  Narcotic Effectiveness Compared to Oil Over Water Partition
       Coefficients  for Various Ketones (modified from Specht et al., 1940)

Ketone




Acetone
Methyl ethyl
Methyl propyl
Methyl n-butyl
Me thy 1 n-afliy !
Methyl n-hexy i
•lethvl isobutyl
Methyl isobutenyl
2 ,5-Hexanedione
Cyclohexanone
Narcotic ef tec tlveness
(Relative)
to Acetone
1/C


1.0
3.9
It. 2
9.8
11.8
19.5
5.26
8.29
3.87
4.15



Olive 01 I


0.11
1.87
16.58
26.52
42.16
59.00
20.640
4.550
0.056
24.090
Parti t ion coc

Cot tonsecJ
oil


0. 16
1. 70
9.04
18. 32
26.90
W.50
24.000
4.670
0.050
10. 410
t i 1C lep.ts , oil

l.ard
>uL


0 16
2. 39
7.66
8.95
18.29
17.00
	
	
	
	
over water

ue
-------
Table 84.   Summary  of Acute  Oral,  Dermal, and Inhalation Toxicity Data of
             Various  Ketonic Solvents


Compound
Simple Saturated
Ke tones
4 carbons
Methyl ethyl keton



5 carbons
Methyl n-propyl
ketone
Diethyl ketone

6 carbons
Methyl a-butyl
ketone


Methyl isobutyl
ketone

1 carbons
Methyl n-amyl
ketone
Methyl Isoamyl
ketone
Ethyl butyl ketone

8 carbons
Methyl n-hexyl
ketone
Ei-hyl n-amyl ko-
tonc
9 carbons
Q-Liiobvit"! ketone


It carbons.
LsnbutyL liuptyl
ketone
Other Saturated
5 carbons
2,4-Pentanedione

6 carbons
2,5-Hexanedione

Unsaturated
5 urbons
Methylisopropenyl
6 carbons
""1. sityl oxLde

Alicy die and
Aliphatic
6 carbons
Cyclohexanone
ketone
7 carbons
Mothylcyclo-
hexanone ketone
9 caroons
Isophorone ketone
8 carbons
Acetophenone
ketone



Oral LD^o
Rats (rag/kg)



3.98 (3.94-4.01)
[M]
5.53 (4.50-6.82)
[F]

3.73(2.68-5.21}
[M]
2.14(1.54-2.29)
[M]

2.59(2.11-3.18)
[M]


4.57 [M]
2.08(1.91-2.27)
[F]

1.67(1.48-1.88)
[F]
3.48(2.12-5.66)
[M]
2.76(2.56-2.98)
[M]

n.d.a.

>5|n.s.l not lethal
3.5


5.75(4.69-7.06)
[MJ

8.74(7.18-9.99)
[M]


0.97(0.90-1.05)
[M]

2.7
4.0

0.18 In. s.]

1.12(0.99-1.28)
[M]


1.54(1.14-2.08)
[M]

1.0-1.25**


2.1J[F]

0.90(0.81-1.00)
[M]
2.22(1.59-3.10)
[HI
2.55[F]

Dermal LD^y
Male rabbits (g/kg)



8.1




6.5(2.9-14.4)

16.2


4.85(3.44-6.80)



16.0 not lethal



10.3(7.6-13.9)

8.8(6.0-13.1)

16.3 not_ lethal


n.d.a.

»5 not lethal
n.d.a.


16.2


9.0(7.7-10,6)



4.85


6.4
13.6(12.8-14.6)

0.2(0.06-0.66)

5.13(3.64-7.21)



0.948(0. 596-1. 54) +
10.2-23+

4.9-7.2


1.39

3.08*

16 3 (U. 1-24.2)*
I
1
Inhalation Exposure
ppm K duration In h
(lethality data in pa
Rats



8000 x 8, (3/6)




2000 x 4 (1/16)

8000 x 4 (4/6)


8000 x 4 (6/6)



4000 x 4 (6/6)



4000 x 4 (6/6)

4000 x 3 (6/6)

4000 x 4 (6/6)


n.d.a.

n.d.a.
6000 x 8 (4/6)


2500 x 4 (3/6)


•700 x 8 (2/6)



2000 x 2 (2/6)
2000 x 4 (4/6)

1700 x >1 (lethal)
1500 x 8 not lethal

125 x 4 (5/6)

500 x 8 (30X)



2000 x 4 (1/16)


3500 x 0.5 not
lethal

1840 x 4 (lethal)

n.d.a.

n.d.a.


s
rs .
rentheBls)
Guinea Pig



33,000 x 3.8
(lethal)



10,000 x 9
(4/10)
n.d.a.


6,000 x 6.6
(2/10)
12,000 x 2
(lethal)
10,000 X 4
(lethal)


5,000 x 3.3.
(lethal)
n.d.a.

n.d.a.


1300 x 12 iFJ
not letha!
n.d.a.
n.d.a


2,500 x 8
(2/4)

n d.a.




n.d.a.

400 x 12.5
not lethal
n.d a.

n.d.a.

5000 x 5.4
(3/10)


4000 x 7 6
(3/10)

3500 x 0_._i
prostration
but not lethal
4600 x 8_
not lethal
n.d.a.




               Key.  ** - rabbits

                   + - see text for discussion of conflicting data

                   n.s. - not specified
                   n.d.a. - no data available
                                            239
-------
                 d.    Acute Parenteral Toxicity
                       The acute  toxicity of  the ketonic  solvents on  parenteral
administration has  received relatively little attention.   Table 85  summarizes
most  of  the available information.   While most of these studies use intra-
peritoneal injections, the rather disparate results  for mesityl oxide and
acetophenone would  seem to indicate that  these studies  are not readily com-
parable  to one another.  However, studies by a single group of investigators
on  a  related series of ketones  may give reliable indications of relative
toxicity.   Of the studies in  Table 85, this would include the work of Haggard
and coworkers (1945) on the amyl ketones,  as well as the studies  by Caujolle
and coworkers (Caujolle and Roux, 1954; Caujolle 
-------
                    In the study by Haggard and coworkers (1945), rats were

given repeated intraperitoneal injections of three amyl ketones - methyl n-

propyl ketone, methyl isopropyl ketone, and diethyl ketone.  These injections

were given in decreasing amounts until respiratory failure occurred, at which

time ketone venous blood levels were determined.  This type of repeated dosing

was used in an attempt to achieve equilibrium between blood and tissue ketone

levels at the time of death.  Assuming a coefficient of distribution between

blood and tissue of 0.8, the concentration of ketone present in the animal's

body which would cause death by respiratory failure could then be calculated.

This value was termed the "basic lethal amount."  The basic lethal amounts

and venous blood levels at respiratory failure for the three amyl ketones are

given in Table 86.
        Table 86.  Comparative Toxicities of Amyl Ketones Administered
                   Intraperitoneally to Rats (Haggard et al^., 1945)


                                            Concentration in

Ketone
Methyl nr-propyl
Diethyl
Methyl isopropyl

Amount Administered
(g/kg)
2.53
2.79
2.98
Venous Blood at
Respiratory Failure
(mg/100 mA)
156
155
127
Basic Lethal
Amount
(g/kg)
1.25
1.25
1.02
The presumed advantage of using the basic lethal amount rather than the amount

administered as an index of toxicity is that the basic lethal amount should be

consistent for any given chemical, regardless of the route of administration,

providing that blood/tissue equilibrium is reached.  Using this criterion,
                                   241
-------
methyl isopropyl ketone would be considered the most, rather than the least,




toxic of the amyl ketones, while methyl n-propyl ketone and diethyl ketone




would be equitoxic.  Because blood levels are not available in any of the




other studies on ketone toxicity and because Haggard and coworkers (1945)




did not use other routes of administration, the validity of this system for




comparing ketone toxicity cannot be evaluated.




                     The work of Caujolle and coworkers (Caujolle and Roux,




(1954; Caujolle et^ al . , 1953), summarized in Table 85, clearly indicates




that the methylcyclohexanones are about twice as toxic as cyclohexanone on




intravenous injection to dogs.  While toxicity tests by other routes of ad-




ministration do not use individual methyl cyclohexanone isomers, these results




are in agreement with the relative dermal - but not oral - toxicity of cyclo-




hexanone and methylcyclohexanone noted by Treon and coworkers (1943a) .




                     Two studies, not summarized in Table  85, have noted




strikingly similar hyperbolic relationships between toxicity and molecular




weight for two different groups of ketones on parenteral administration.




Caujolle and Caujolle  (1965) determined  the toxicity of a  series of alicyclic




ketones from four  to fifteen carbons by  intraperitoneal injections to mice




and rats.  The results with both species were similar.  In  assessing toxicity




by a  variety of criteria - including minimum lethal  dose,  24 hour LD   and




LD    , as well as  maximum non- lethal dose  - the  toxicity consistently in-




creased going from four to eight carbons and decreased going from eight  to




fifteen carbons.   Jeppsson  (1975)  found  a  nearly identical pattern  for the




toxicity of a series of acyclic aliphatic ketones on intravenous injection  to




mice  using AD     (anesthetic dose) as well as LD   and LD    as  indices  of
 toxicity.   These  results  are  summarized  in  Table  87.
                                    242
-------
           Table 87.   Anesthetic (AD100)  and Toxic Doses (LD50 and LD100)  of
                      Some Ketones After  Intravenous Administration to Mice.
                      LD50 was Estimated  in 60 Animals/Compound and AD100  and
                      LD100 in About 10 Animals/Compound.  Confidence Limits
                      are Given at P = 0.05 (Jeppsson, 1975)
Ketones
     AD 100
 mol x 10 3/kg
    LD50
mol x 10~3/kg
    LD100
mol x 10 3/kg
3-Pentanone
4-Heptanone
5-Nonanone
6-Undecanone
7-Tridecanone
8-Pentadecanone
9 - Hep t ade c an one
 4.54 (3.92-5.17)
 1.32 (1.16-1.47)
 0.83 (0.70-0.96)
 1.19 (1.02-1.37)
 9.51 (7.45-11.56)
13.40 (10.56-16.25)
28.52 (26.26-30.78)
5.97 (5.47-6.47)

0.97 (0.93-1.05)
0.69 (0.64-0.73)

5.29 (5.03-5.56)
13.34 (12.03-14.65)
 2.37 (2.11-2.63)
 1.83 (1.64-2.02)
 2.13 (1.92-2.35)
17.70 (10.52-24.89)
50.31 (48.64-51.97)
39.46 (36.57-42.35)
     The similarity between the patterns noted by Jeppsson  (1975) and Caujolle  and
     Caujolle  (1965) is illustrated in Figure 40, which compares the LD..   value
     to the number of carbons for each series of ketones.
                           This  pattern is  not unlike that suggested in   Figure  38 (p. 213)
      for  the  oral toxicity of acyclic aliphatic ketones.   Jeppsson  (1975)  has ex-
      plained  this parabolic relationship between  the number of carbons  and toxicity
      both in  terms of  lipophilicity  and  increasing  molecular size.   Given a homolo-
      gous series of  compounds,  the oil/water partition coefficient  will increase
      with the addition of methylene  groups.  Thus,  starting with the lowest mole-
      cular weight compound, toxicity will  initially increase with molecular weight,
      because  of increased ability to reach and  interact with lipid receptor sites.
                                        243
-------
             50 -
             40-
 LD100       30 -
(mM/kg)
             20-
             10-
                     * Alicyclic Ketones
                  Acyclic
                    Ketones
                                         8     9    10    11    12   13   14   15   16   17
                                            Number of Carbon
         Figure 40.   Relationship Between Molecular Weight and LD   's For a
                     Series of Alicyclic Ketones (Caujolle and Caujolle, 1965)
                     and Acyclic Ketones (Jeppsson, 1975)
                                      244
-------
However, increased lipophilicity past an optimum point will result in the

rapid sequestering of the compound in fat tissue, preventing interaction

with receptor sites.  Further, increasing molecular size will eventually

counteract, increasing lipophilicity and resulting in slower passage through

lipid membranes.

                    Serum ornithine carbamyl transferase (OCX) has been

used as an index of the hepatotoxic effects of acetone, methyl ethyl ketone,

and methyl isobutyl ketone on intraperitoneal injection to male guinea pigs

(DiVincenzo and Krasavage, 1974).  Because most of this enzyme is present in

the liver, increased enzyme activity in the serum is indicative of liver cell

rupture.  The effects of these ketones on OCT serum is presented in Table 88.

Lethality was noted only at the highest doses of methyl ethyl ketone and

methyl isobutyl ketone (see Table 85, p. 240).
Table 88.  Effects of Acetone, Methyl Ethyl Ketone, and Methyl Isobutyl Ketone
           on Serum Ornithine Carbamyl Transferase in Guinea Pigs (DiVincenzo
           and Krasavage, 1974)
       Ketone
Dose (g/kg)
                                                    Mean  OCT Activity  (Range)
                                                      in  International Units
Control
Acetone

Methyl ethyl ketone


Methyl isobutyl ketone


1.5
3.0
0.75
1.5
2.0
0.5
1.0
2.02
1.1
2.3
1.5
4.5
10.8
4.0
6.4
_^ — 	 • — •> 	
(0-8.9)







                                   245
-------
Acetone and methyl isobutyl ketone caused neither changes in OCT levels nor




liver damage at the levels tested.  Methyl ethyl ketone, however, resulted in




slightly elevated OCT levels at 2.0 g/kg and obvious lipid deposition in the




liver at 1.5 g/kg and 2.0 g/kg, but actual tissue damage was not noted at any




dose level.  This is consistent with the results from other exposure routes




indicating that the liver is not a primary target in ketone intoxication.
                                    246
-------
                  e.   Primary Skin Irritation

                       Primary skin irritation  caused by  the ketones has

been  evaluated by the  uncovered application of  the chemical to  the clipped

intact skin  of a rabbit's belly.   Either undiluted solvents or  dilutions

of  10, 1, 0.1, and  0.01 percent in 0.01 ml are  applied  to five  rabbit bellies

and the skin response  is graded 24 hours after  application.   The ten-point

grading system used by Smyth and Carpenter in their Range Finding lists

(1944, 1948a,  b, c, 1949, 1954, 1957,  1962) as  first  presented  in 1944  is

based on the degree of capillary injection, erythema,  and edema and/or  necrosis

of  the skin  which occurs in  24 hours  (see Table 89).
             Table 89.   Grading System for Primary Skin Irritation
                                 (After  Smyth et  al., 1949)
        Grade                           inaction

          1    None from undiluted material.

          2    Trace of capillary injection from undiluted material.

          3    Strong capillary injection from undiluted material.

          4    Slight erythema from undiluted material.

          5    Strong erythema from undiluted material.

          6    Necrosis from undiluted material; 10 percent solution causes
               reaction no more severe than edema.

          7    One percent solution causes no more  severe reaction  than edema.

          8    0.1 percent solution causes no more  severe reaction  than edema.

          9    0.01 percent solution causes no more severe reaction than edema.

         10    Dilution smaller than a 0.01 percent solution.
                                         247
-------
                           The ketonic solvents  as a.  group  are not  severe skin
  irritants  when  applied uncovered to the  clipped belly of rabbits.   Test
  results  are presented in Table 90 below.   The volatile nature of  the solvents
  leads to fairly rapid evaporation and in several cases - i.e., methyl  n-
  propyl ketone,  methyl n-butyl ketone, methyl isoamyl  ketone,  diacetone alcohol,
  and cyclohexanone -  no skin irritation was found after the  24 hour test period.
  In no case did  edema or necrosis occur.
               Table 90.   Primary Skin Irritation of Ketonic  Solvents
                                                in Rabbits
     Ketone
Methyl  ethyl ketone

Methyl  n~propyl ketone
D.iethyl ketone
Methyl  n-butyl ketone
Methyl  isobutyl ketone
Methyl  n-amyl ketone
Methyl  Isoamyl ketone

Ethyl n-butyl ketone

Disobutyl ketone

Isobutyl heptyl ketone

Other Saturated
2,4-pentanedione
Diacetone alcohol
Unsaturated
Mesityl oxide
Alicyclic and Aliphatic
Cyclohexanone
Isophorone
Acetophenone
           Nature of Irritation
Trace  of capillary injection in two of five
animals tested
No irritation; solvent evaporates  too quickly
Trace  of capillary injection from  undiluted solvent
No irritation from undiluted solvent
Trace  of irritation
Slight erythema from undiluted material
No irritation from undiluted solvent
Trace of capillary injection in two of five
animals
Erythema in one of five and marked capillary
injection in two of five animals tested
Erythema in two of five and minimal capillary
injury in three of five
Trace irritation, erythema
No irritation from undiluted solvent

Slight capillary injection

No irritation from the undiluted solvent
Mild irritation with slight erythema
Slight erythema from undiluted solvent
    Reference

Carpenter, 1949
Carpenter, 1954
Smyth et_ al., 1954
Smyth  e_t al. , 1951
Union Carbide, 1968
Mellon Institute, 1958
Carpenter, 1957
Smyth et^ al. , 1962
Carpenter, 1948a
Smyth et_ al., 1949
Carpenter, 1948b

Carpenter, 1948c
Mellon Institute, 1955a
Mellon Institute, 1955b

Mellon Institute, 1952

Nycum et^ al. , 1967
Truhaut e^ al., 1972
Mellon Institute, 1956
                                               248
-------
                           f.    Eye  Irritation


                                 Carpenter and Smyth  (1946) have studied the severity

       of  chemical  burns of  the  eyes  caused by application of  various  solvents

       including some ketones.   The  test  utilized  normal  albino rabbits.  Undiluted

       single  instillations  of varying amounts (0.005, 0.02, 0.10  and  0.5 ml) or

       dilutions of  5,  10, 15 and 40  percent  in 0.5 ml quantities were  directly

       applied  into  the  conjunctival  sac  of both eyes  and  allowed one minute  of

       direct contact before the  eyelids  were  released.   The eye injury  was assessed

       18 to 24  hours after  administration in  both  eyes,  one of  which was  stained

      with  fluoreacein.   The  system  of scoring the injury  and  the grading of the

      injury are given in Table  91A  and  B.
               Table  91.
(A)  System For Numerical Scoring of  Injury  to the Rabbit
     Eye  24 Hours  After Application  of a  Material (B)  Grades
     of Injury  Employed For  Rating the Relative Damage Pro-
     duced  By Chemicals in the Eye

                       (Carpenter and Smyth,  1946)
                                                      B
In>rv_Grade                    Definition

    1     0.5 nl undiluted gives injury of 0 to 1.0 points

    2     0.5 nl undiluted gives Injury of over 1.0 up to 5.0 points

    3     0.1 ml undiluted gives Injury of up to 5 0 points (0.5 ml
          gives over 5.0)

    4     0.02 ml undiluted gives injury of up to 5.0 points (0.1 ml
          gives over 5.0)

    5     0.005 ml undiluted gives injury of up to 5.0 points (0.02
          ml gives over 5.0)

    6     Excess of 40 percent solution gives injury of up to 5 0
          points (0.005 ml gives over 5.0)

    7      Excess of 15 points solution gives injury  of up to 5.0 points
          (40 percent gives over 5.0)

    8      Excess of 5 percent solution gives injury  of up to 5.0 points
          (15 percent gives over 5.0)


    9      Excess of 1 percent solution gives Injury  of up to 5.0 points
          (5 percent gives over  5.0)
   10
          Excess of 1 perc«nt solution gives Injury of over 5.0 points.
                                Syaptoa Visible Before Ploursscein Staining

                                 Cornea dull

                                 Cornea opaque, less than half of area

                                 Cornea opaque, more than half of area

                                 Keratoconus

                                 Iritis, slight internal congestion

                                 Iritis, marked Internal congestion




                                Symptom Visible After Floureacein Staining

                                (If necrosis is diffuse assign points
                                corresponding to half observed area.)

                                 Necrosis on less than 5 percent of cornea

                                 Necrosis on 5 to 12 percent

                                 Necrosis on 13 to 37 percent

                                 Necrosis on 38 to 62 percent

                                 Necrosis on 63 to 87 percent

                                 Necrosis on 88 to 100 percent

                                   Total
Points   Maximum




  2

  4

  f>        6

          6

  1

  2        2
                                                                                                        _6

                                                                                                        20
                                                  249
-------
                     The results  of  the  rabbit  eye  irritation  tests have been




reported in the Range Finding lists  by Smyth and coworkers  (1946,  1948, 1949,




1954, 1962, 1969).   These data are compiled in  Table 92 .




                     The majority of ketonic solvents cause from a trace to  a




moderate degree of eye injury according  to the  Carpenter and Smyth (1946)




guidelines.  Truhaut and coworkers (1972)  have  modified this scoring  system




and report effects on individual  portions  of the eye; these workers found




isophorone to be a moderate irritant to  the mucous  membrane of the eye by




producing conjunctivitis as well  as causing some corneal opacity which was




curable.  These results concur with the  moderate rating given  by Carpenter and




Smyth (1946) (see Table 92 ).




                     Only one ketone tested caused  a more severe injury, a




grade eight injury.  Application  of a 15 percent solution of acetophenone to




the rabbit's eye gives a score of over 5.0 points on the 20 point  scale in




Table 91.
                                     250
-------
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                                                                        251
-------
          2.    Subacute and Chronic Toxicity




               a.   Subacute and Chronic Oral Toxicity




                    Subacute or chronic oral toxicity data are available on




only four of the ketones under review.  This information is summarized in




Table 93.  None of the exposures described in this table proved fatal to any




of the animals tested.  Some kidney damage is evident in exposures to diacetone




alcohol, methyl n-amyl ketone, and acetophenone.  This is consistent with the




observation made by Specht and coworkers (1940) in acute inhalation exposures -




i.e., ketones may have a selective action on the kidneys.  However, not too




much can be made of this observation because, in most cases, damage is indi-




cated only by a slight rise in kidney weight relative to total body weight.




The studies of Hagan and coworkers (1967), Smyth (1946b), and Novogorodova and




coworkers (1967) apparently involved rather detailed pathological investigations.




None of these studies report pathological changes in the kidneys.




                    Novogorodova and coworkers  (1967) did note apparent liver




damage  and adverse central nervous system effects in rats attributable to




cyclohexanone exposure over a  six month period.  Male rats exposed  to several




concentrations - 0.01 mg/kg, 0.05 mg/kg, and 5  mg/kg - were tested  for reflex




activities in response to light stimuli.  The 0.05 mg/kg/day  group  demonstrated




a retarded response reinforcement, an  increased latency  period in response to




light,  and an increased number of conditioned response failures.  In the




5 mg/kg/day dosage group, these changes were aggravated  to the point where




3 of  the 5 rats  in the group stopped  functioning within  2 weeks.  Their
                                    252
-------
             Table   93.    Subacute  and  Chronic  Oral Toxicity  of  Ketones
Chemical
Mod* of
                                                                               Dur-
                                                                      DOM (••/ at loo
                                                                       hj/digr) OfrTf Mortality
                                         Details
SATURATED ALIPHATICS

Diacetone alcohol
                                     Rats, 10 at      In drinking water     10    30    no deaths
                                     each dose level
                                                                           40    30    no deaths
                                         "no effect"
                                                                                                  cloudy swelling of kidney
                                                                                                  tubules in one rat
                                                                      Mellon  institute,
                                                                      1955b
                                                                      (similar data
                                                                      reported in  Sroyth
                                                                      and Carpenter, 1948)
Methyl  n-arayl ketone
 Cyclohexanone
                                     Rats, CFE strain  Intubation, in oil   100     14    no deaths
                                     5 female(85-95g)
                                     t, 5 male(95-115g)
                                     per dose level                       500     14    no deaths
                                      same as above     as  above
                                      same as above     as  above
                                      except 15 of
                                      each sex used
                                      per dose level
                                                                          100     72    no deaths
                                                                          500     72    no deaths

                                                                           20     91    no deaths
                                                                          100    91    no deaths
                                                                          200    91    no deaths
                                         increase in liver weight
                                         relative to total body
                                         weight at both dose  levels
                                         in males only

                                         increase in liver weight  in
                                         males noted only at  higher
                                         dose along with increased
                                         number of cells excreted  in
                                         urine

                                         no effects noted
                                          increase in relative  kidney
                                          weight in males
                                          increase number of cells
                                          excreted in urine in  both
                                          males and females
                                          increased relative liver
                                          weights in males and  females,
                                          increased kidney weights in
                                          males
                                          increased number of cells
                                          excreted in urine in  both
                                          males and females
                                                                                                                               Gaunt tt al. ,  1972
                                      Rats, male,
                                                       intubation
                                                                          0.01  180    no deaths
                                                                          0.05  180    no deaths
                                                                                                   no effect noted
                                                                                                   slight  changes in con-
                                                                                                   ditioned  reflex activity
                                                                      Novogorodova ej:  al
                                                                      1967
                                                                          5.0   180   no deaths
                                                                          280    25   no  deaths
                                          marked changes  in con-
                                          ditioned reflex activity
                                          degenerative morpholo-
                                          gical changes of nervous
                                          system, liver,  stomach,
                                          and spleen
                                          [see text for details]
                                          no changes in weight gain
                                          and general condj tion
                                          decline in work capacity
                                          on 25th day
Acetophenone Rats, 5 male in diet
and 5 female
per exposure
group
1, 6, 5. 30 no deaths questionable increase in
25 liver and kidney weights
definite increased liver
weight relative to total
body weight - questionable
increase in kidney weight
[see text for details]
Smyth, 1946b
                                      Kats, Weaning     in diet
                                      Osborne-Mendel
                                      10 male and
                                      10 female
                                                                        1000    119    no deaths
                                                                                                   no effect
                                                                                                                               Hagan
                                                                                                                                        al. , 1967
                                                                253
-------
autopsies reveal degenerative liver changes, hyperemia of the mucous membranes




of the stomach and plethora in the spleen.  Liver function tests were performed




on 4 rats who received 0.05 rag/kg cyclohexanone for six months and the only




change noted was a stable reduction in serum albumin, a parameter which is




often effected in liver disease  (Novogorodova _et^ al^,, 1967).




                    Cyclohexanone at levels of 1% in the diet has also been




shown to slightly inhibit weight gain in  first generation male and female




mice over exposure periods of 110 days.   However, second generation mice show




no growth retardation  (Gondry, 1973).
                                    254
-------
               b.    Subacute and Chronic Inhalation Toxicity




                    Chronic inhalation exposures to various ketones which




do not induce peripheral neuropathy are summarized in Table 94.   It will be




noted that adverse effects, when induced, are qualitatively similar to acute




inhalation exposures.




                    Methyl isobutyl ketone, while not showing any unequivocal




peripheral neuropathic activity, did cause narcosis in rats during multiple




six hour exposure periods to 1500 ppm.  In addition, kidney damage was indi-




cated in rats by increased organ weights, toxic nephrosis of the proximal




tubules, and progressive hyaline droplet degeneration (MacEwen £_t _al. , 1971;




MacKenzie et al., 1971; and Vernot et al., 1971).




                    Carpenter and coworkers (1953) also noted statistically




significant increases in kidney weights in male and female rats in multiple




exposures to diisobutyl ketone at concentrations of 250 ppm and above.  As in




acute exposures, female Sherman rats were much more susceptible in repeated ex-




posures to high concentrations (1650 ppm) of this ketone.  Further, the increased




liver and kidney weights in female, but not male, rats at 250 ppm indicate that




this increased susceptibility also occurs in chronic exposures (Carpenter et al.,




1953).




                    The unsaturated aliphatic ketones, methyl isopropenyl ketone




and mesityl oxide, also show signs of kidney damage over prolonged exposures.




As might be expected from acute inhalation studies, methyl isopropenyl ketone is




the more toxic and rats are more susceptible than guinea pigs.  In subacute




exposures (30 ppm x 7 hrs/day x 20 exposures), lung irritation and leucocytosis
                                     255
-------
Table 94.   Subacute  and Chronic  Inhalation  Toxicity of  Various Ketones
                       Cone.   Hr/ DuraUo
                     (ppm, v/v)  Day  in Days
^™«™s
Hats, 25 (60 expo- to exposure
sures , 5
day/wk x 7
wk)
Rats, Snerman, 125, 250, n.s. 30 no deaths
15 male & 15 500, and
female per 1000
dose level
Guinea pigs ,
mixed-strain,
10 male per
dose level

occurred after expo-
10 (one death each)
and period 9 (three
deaths)
Rats, young 1,500 6 <100 no deaths
adult, 6 (contamin- [5day/week
ated with for up to
0.9% MBK) 3 months]
r.re, ICE, 40 102 24 14 no drat^s
Oogs , beagles , 8
^onk^vs, rtt-MiH, 4 200 24 1/t no deatUe
"* 200 24 14 no deaths
Monkeys, 100 24 90 no deaths
rhesus, 2 (260 torr)
of 68% 0
and 32% N2
Rat-, , Wistar, as above 24 90 no deaths
80
Pusobutyl keiont- Rat;,, Sherman, 125 7 42 no deaths
15 of each sex (30 exposures,
per exposure 5days/wk x 6
level weeks )
250 " " " no deaths
500 " " " no deaths
920 " " " no deaths
1650 " " " all 15 females and
2 ot 15 males dieu
during 1st exposure
Guinea pigs, 125 " " " no deaths
mixed strain,
males, 10 250 " " " no deaths

from controls in growth, 1955
hematologi cal or patho-
logical examinations
No significant histopatho- Mellon Institute,
logical changes in lung, 1950
liver , or kidney
No statistically signifj-
In body, liver, or kidney
weigh L<;

acute lethal data. This is
posures . ]
Slight narcosis during Spencer et ,1 1 . , 1975
exposure Spencer, J 975
Normal weight gain
No ^iigns of neurological
dis function
Mln ini£il but consistent
distal axonal changes
wi thout. actual nerve
fiber degeneration
No -,ij>ns of toxic response ila< Ti,on cl >iJ . , 1971
at either dose level vc rnol et nl . 19/1
MacKenzie, 1971
Increased kidney weights
Int ceased kidney and
liver weights, t ox i c
nephrosi'i in proximal
tubules ol kidney
No 'significant variation
No effect on totr.il body
weight gain
Increased liver and kidney
WO 1 gll t S
Kidney pathology pro-
gressive hyaline droplet
No liver pathology
No effects noted Carpenter ^ al , 195 J
Increased liver and kidney
wejghts in females
Decreased liver weights in
males
Increased liver and kidney
weights in males and females
During 1st and 2nd exposure
only , males exhlbi ted in coor-
dination. Surviving males
had increased liver and kidney
we i gh t s
louer liver weights
                                    256
-------
Table  94.     (cont'd)
                                   Cone.    Hr/    Duration
                                                in Day
                                                             Mortality
Chemical
UNSATURATED AJ-1PHA1ICS
Met hy I isopropeny 1 ketone






CYCLl C AROMATICS
and AL1PHATICS
Cyclohexanone

Me thylcyclohexanone

Rat 15

and rabbits
Guinea pigs "


Wistar, 90-
120 g, 10
animals per
exposure
8rou<> 100
250
500
Guinea pigs, 50
both sexes ,
250-300 g,
10 animals
per exposure
group 2 50
500
Rat> 300
Rabbits 25

Rabbits , 190
young, 4
per expo-
sure
group
309
773
1414
3082
Monkey, 608
rhesus,
1 animal
Rabbits, 182
young, 4
per expo-
sure
group
514
1139

7 up to 140
exposures)

(20 ex-
posures)


(30 ex-
posures)
" 14
(10 ex-
posures)
8
(42 ex-
posures)
14
(10 ex-
posures)
2 30
4 189

6 70
(50 ex-
posures ,
5days/wk
x 10 wks)
6
6
6 21
(15 ex-
posures ,
5days/wk
x 3 wks)
6 70
(50 ex-
posures ,
5days/wk
x 10 wks)
6 70
(50 ex-
posures ,
5daye/wk
X 10 wka)
6
6 21
(15 ex-
posures.

slight increase


no increase
no ncrease

9/10 died due to
exposure
no deaths
no deaths
no deaths
2/10 died due to
exposure
no deaths
no deaths

no deaths
no deaths
no deaths
2/4 died
no deaths
no deaths
no deatht,
no deaths

LeucoLytosJs Dow Chemical,
tubular injury
Irritation of nose and eyes

Lungs severely affected
Some changes in kidney and spleen
Weight loss
Irritation of nose and eyes
Depressed grovth
Irritation of nose and eyes


Smyth ,~1941c
I.fucocytosis and hypertrophyl Ito, 19t>9
of liver , kidney, and spleen
Anemia and Leukopenia

No signs of toxicity Treon et al. , 1943b
Very slight conjunctival
congestion
gestion and salivation
Slight lethargy
Con junc Lival c. ongest ion and
irritation
Light narcosis, labored breathing,
incoordination, salivation, con-
junctival congestion and irritation
Slight conjunctival con-
gestion (see text)
No signs of toxicity Treon et al. , 1943b
Slight conjunctival con-
gestion
Lethargy, slight salivation and
lacrimation , con junctival
congestion
                                                x 10 wk«)
                                                                             Lethargy, salivation, lacrimatIon,
                                                                             conjunctival congestion and
                                                                             irritation
                                                         257
-------
                 Table  94.,   (cont'd)
                                      Cone.   Hr/  Durst ton
ChemiL al Animal (ppni, v/v) Day Days
liophorunt; Rci:-, male, 25 8 42
Wit,Lar, 90- (30 ex-
1"?0 g posures ,
5day&/wk
x 6 wks)
50

100 " "

200 " "
500 " " "
Guinea pigs , 25 8 42
both sexes, (30 ex-
250-300 g posures,
5days/wk
x 6 wks)
too " "

200 8

500 8 " "

Mortality
no deaths




no deaths

2/10 died

1/9 died
5/10 died





no deaths

2/9 died

4/10 died

Details
No apparent signs of toxic i ty




Evidence of lung ari< kidney path-
ology
evidence of lung, spleen, and kidney
pathology

ii ir

pp g y



Evidence of lung and kidney path-
ology
Evidence of lung and kidney path-
ology
Evidence of lung , kidney , and liver
pathology
                                                                                                                    Smyth et jil. , 1942 and
                                                                                                                    Smyth," 194lb
Aci'tophenone           Ratb ,  male,     .143     24        70       no  deaths         No apparent  ->)pis of toxicity           Imasheva, 1966
                      60-70  g,  15   (0.007  mg/
                      per exposure     m^)
                      gioup

                                     1.43     24        70       no  deatlis         Variable changes in choiinesterase
                                   (0.07 mg/                                     activity, decrease in alblumin to a-
                                      mj                                        globulin rat ic>, and dystrophy of
                                                                                liver
                                                                    258
-------
seem to be the primary responses.   However,  in chronic exposures  (15 ppm x




7 hrs/day x up to 100 exposures),  lung irritation is apparently not  severe,




but slight kidney injury is indicated by increased organ weight and  pathological




changes in the kidney tubules (Dow Chemical, unpublished data).




                     Smyth and coworkers (1942) compared the subacute inhala-




tion toxicity of mesityl oxide and isophorone.  Pathological details of these




studies are given by Smyth (1941 b and c).   Unlike acute exposures in which




mesityl oxide is more toxic, isophorone caused greater pathological  damage




and mortality in comparable subacute exposures.  Death from isophorone exposure




was due primarily to kidney and lung damage.  Lungs showed congestion and




hemorrhage typical of ketone exposure.  Kidney pathology included congestion,




cloudy swelling, degeneration, and necrosis of the epithelial vessels of the




renal tubules.  Mesityl oxide, however, caused much less severe lung irritation




and cloudy swelling of the kidneys.  Lethality patterns were also quite different




for these two ketones.  Mesityl oxide caused no deaths in multiple exposures




under 500 ppm.  This may indicate that mesityl oxide caused death by accumu-




lating to anesthetic concentrations with repeated exposure.  Isophorone, how-




ever, causes a gradual decrease in mortality in multiple exposures to decreasing




concentrations.  This pattern is indicative of cumulative toxic effects (Smyth




eit al. , 1942).




                     Comparable details are not available in the remaining




studies summarized in Table 94 .  Some liver damage seems apparent in rats after




70 day continuous exposure to 1.43 ppm acetophenone but no kidney pathology




was noted.  Cholinesterase activity was observed in 5 of the 15 rats in each
                                     259
-------
group and changes were observed, though not consistent ones;  in three rats the




cholinesterase activity decreased 22% and in one rat the activity increased




by 45%.  Total blood protein and albumin levels were also measured in 5 rats




of each group.  It was found that in the 1.43 ppm group, there was a distinct




decrease in albumin/globulin ratio even though the total protein stayed the




same (Imasheva, 1966).




                     In multiple exposures to cyclohexanone and methylcyclo-




hexanone, Treon and coworkers (1943b) noted effects in rabbits typical of




acute inhalation toxicity.  Even though narcosis was unusually protracted in




acute exposures to guinea pigs  (Specht et_ jil. , 1940), no obvious cumulative




effects were noted in these repeated exposures to rabbits.  In the one monkey




exposed to cyclohexanone  (608 ppm x 6 hrs/day x 50 exposures), severe injuries




of the lungs, liver, kidneys, and heart muscle were associated with a chronic




pulmonary infection (Treon ejt _al. , 1943b).




                    Recently, Tison and coworkers (1976) have found that rats




and chickens exposed to 650 ppm methyl ri-amyl ketone continuously for 1000 hours




failed to develop a peripheral  neuropathy.




          3.   Peripheral Neuropathy




               The recent outbreak of cases  of peripheral neuropathy in workers




occupationally exposed  to methyl n-butyl ketone  (see Section  III-C, p. 192) has




led  to long-term experimental exposures of  rats,  cats,  dogs and  chickens.   The




clinical and histological evidence indicates that methyl ri-butyl ketone  (MBK) and




2,5-hexanedione, a metabolite of MBK  (see  Section III-B, p. 174), both produce  a




peripheral neuropathy known  as  "dying-back"  disease (Spencer  and Schaumburg,  1974b).




Although the mechanism  of action of  these  ketones has  not been  determined,  several




theories on  the  action  of other chemicals  causing this  neuropathy have been pub-




lished;  a detailed discussion of these  is  presented by  Spencer  and  Schaumburg (1974a,
                                         260
-------
                Many of the studies published on MBK-induced neuropathy involve




inhalation exposure.  The results of these are presented in Table 95.




                Duckett and his associates (1974a, b) have found both clinical




and histological signs of neuropathy in nine rats exposed to 200 ppm (by volume)




MBK for eight hours a day, five days a week, for six weeks.  The rats experienced




muscular weakness in all limbs lasting a few hours after each experimental




period.  After the six weeks exposure, the rats were killed and their sciatic




nerves examined histologically.  The examination revealed axonal swelling,




beading, and degeneration as seen in secondary myelin breakdown.




                In addition to this study, Duckett and coworkers (1974a, b)




exposed eight rats to a mixture of 200 ppm MBK and 2000 ppm methyl ethyl




ketone (MEK) for the same time periods.   Three of the rats died; the cause




of death was not reported.  Results of this combined exposure were similar




to those after exposure to 200 ppm MBK.  However, these rats required a full




day, rather than a few hours, to recover from one exposure period (Duckett




etal. , 1974b).




                Recently, Saida and coworkers (1976) exposed three dozen rats,




each weighing 160-180 g, continuously  to either MBK at 225 ppm, MEK at 1125 ppm




or the combination of MBK:MEK at 225:1125 ppm.  On the basis of clinical findings




of "paralysis," no neuropathy was detected in the animals exposed to MBK alone




or to MEK alone after 55 days in each  case, but neuropathy was found after 25




days in animals exposed to a mixture of these compounds.  They suggested that




there is a marked potentiation of peripheral neurotoxicity when animals are




exposed to a combination of methyl ethyl ketone and methyl butyl ketone in a




ratio of 1 to 5.  Saida et al. (1976) also exposed another group of rats to




MBK at a level of 400 ppm continuously 24 hours per day.  These animals developed




clinical evidence of neuropathy after 42 days, but pathological evidence of






                                   261
-------
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                                                               262
-------
neuropathy was present after only 28 days of exposure.   Spencer and Schaumburg




(1976a) exposed a colony of cats to a variety of ketones.  Eighteen animals re-




ceived twice daily subcutaneous injections containing 150 mg/kg of either un-




diluted commercial grade MIBK, MBK, MEK, a 9:1 mixture of MEK and M1BK respec-




tively or a 9:1 mixture of MEK and MBK, 5 days a week for up to 8% months.  Four




additional cats received twice daily injections of an equivalent volume of saline,




5 days a week for up to 5 months.  It was noted that narcosis and excessive sali-




vation commonly commenced shortly after injection.  Abcess formation and skin




ulceration were seen in several animals.  Generalized weakness and death occurred




in ten animals treated with MEK or MEK/MBK mixtures.  Two animals treated with




MBK alone died.  MIBK was tolerated well.  Neurological dysfunction was detected




in cats intoxicated with MBK alone.  Peripheral neuropathy developed after eight




to ten weeks of intoxication and animals went on to display a severe hindlimb




footdrop.  By 16 weeks they were unable to walk and dragged themselves with




weakened forelimbs.  These animals displayed neuropathological evidence of




dying-back disease in the central and peripheral nervous systems.  Animals in-




toxicated with the 9:1 mixture of MEK and MBK displayed no clinical dysfunction




but there was some pathological evidence of nerve damage.  MEK produced no clinical




or pathological evidence of neuropathy.  MIBK or 9:1 mixtures of MEK and MIBK pro-




duced no clinical evidence of neuropathy.




               A similarly designed experiment exposing rats to vapors of




100 ppm or 330 pptn MBK for six hours a day, five days a week, for five months




failed to reveal signs of neuropathy (Raleigh e^ al., 1975).  At the time of




the preliminary report, Raleigh and coworkers (1975) had not completed the




histological examinations.  However, the findings of Duckett and his asso-




ciates (1974a, b) would indicate that some clinical signs should have appeared






                                     263
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in animals exposed to 330 ppm methyl n-butyl ketone  over  a  five month period.




Differences in sex and strain of animal as  well as methodology  (e.g., vapor




penetrating system) may be responsible for  some of this discrepancy; however,




no details of these factors were given.




               Experiments with rats exposed to higher concentrations of MBK




have resulted in peripheral neuropathy.  Coordinated studies  by McDonough




(1974) and Spencer and Schaumburg (1975a) reveal that exposure  of  six rats




to 1300 ppm MBK for six hours a day, five days a week, for  four months  has




led to peripheral neuropathy.  In addition, six rats were exposed  to  com-




mercial grade methyl isobutyl ketone (MIBK) at 1500  ppm for up  to  five  months;




three animals served as controls (Spencer et al., 1975)  [Commercial grade




MIBK is known to contain MBK as an impurity.  Spencer and his associates




(1973) had indicated that as much as three percent MBK was  in the  MIBK




used in the experiment.  Spencer (personal communication, 1975)  reported




that the actual percentage of MBK contamination was  closer  to 0,9  percent].




               The MBK exposures led to slight narcosis by  the fourth hour




and some loss of coordination after five and one-half hours of exposure.




The rats gained weight slowly, and beginning on the 73rd day of exposure,




progressively lost weight.  The animals suffered progressive weakness of both




hind  feet  after three to four months of exposure, and the most severely im-




paired exhibited some forelimb weakness  (Spencer and  Schaumburg, 1975a; Spencer




et al., 1975).




               The histopathological findings  reveal  consistent patterns of




abnormality in the central and peripheral  systems after MBK exposure.  Peri-




pheral nerve degeneration was predominant  in the intramuscular and distal




portions of the nerve, with a secondary degeneration  of the myelin sheath.







                                     264
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Abnormal axonal swellings located in the degenerating nerve fibers were  com-




prised of masses of neurofilaments (Spencer and Schaumburg, 1975a; Spencer et




al. , 1975).




               The rats exposed to 1500 ppm MIBK vapor showed only slight




narcosis during the exposure period, normal weight gain,  and no neurological




signs after five months exposure (Spencer et^ al_. , 1975).   Histological




examination revealed only minor neurological changes with no apparent




nerve fiber degeneration.  Due to the small percentage of MBK in the com-




mercial grade MIBK, further studies on the pure compound are being  conducted




to determine any possible neurotoxicity (Spencer, personal communication,




1975).




               Further rat studies are reported by Mendell (1974) and Mendell




and coworkers (1974).  These studies were designed to approximate the period of




occupational exposure in the Ohio case studies (see Section III-C-2, p.  193).




Initially, four Sprague Dawley rats were exposed to 600 ppm MBK continuously




for 60 or more days.  This level was lowered during the experiment  to alleviate




some complications due to weight loss and lethargy.  The rats began  to show




clinical weakness in 11 to 12 weeks.  Pathology revealed swollen axons with




increased numbers of neurofilaments and degeneration of the myelin  sheath




at the axonal swellings - results similar to those found by Spencer  and




coworkers (1975), cited above.




               Additional studies involving the same continuous exposure




schedule were conducted with chickens and cats (Mendell, 1974; Mendell et al.,




1974).  The chickens were initially exposed to 200 ppm MBK and the  cats to 600




ppm; both of these levels also were cut to 100 and 400 ppm, respectively, in




order to limit the range of toxic responses.  The chickens showed clinical






                                     265
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symptoms at 35 days; they were unable to stand upright.   The cats were dragging




their hind limbs beginning at weeks five through eight and later experienced




forelimb weakness.  Pathological findings were similar to those in the rats.




Electromyograms (EMG) were conducted periodically on the cats and the first




changes were noted after four to six weeks of exposure.   The irregular EMG




patterns were similar to those found in humans suffering from neuropathy




(Mendell et. _al. , 1974).




               Cats exposed to either 100 ppm or 330 ppm MBK vapors for six




hours a day, five days a week, for five months failed to show clinical signs




of neuropathy  (Raleigh et_ ai. , 1975).  Only minimal histological changes were




seen in the nervous tissue of the cats exposed at the 330 ppm level.  Con-




sidering the different dosage schedules, the results of the cat exposures




by Raleigh and associates (1975) and Mendell and coworkers  (1974) are not




necessarily incompatible.




               A few studies  conducted by subcutaneous injection of the




ketonic solvents are reported for both methyl _n-butyl ketone  (MBK) and 2,5-




hexanedione (see Table 96).




               Raleigh and coworkers (1975) induced peripheral neuropathy




in cats receiving subcutaneous injections of 150 mg/kg/day  for five days a




week over a two month period.  Dogs, dosed on a similar schedule for  two to




four months, also showed symptoms of peripheral neuropathy.   Experiments on




guinea pigs given repeated topical applications of MBK did  not produce clinical




signs of neuropathy  (Raleigh  ej; aJL. , 1975).  Neither dosage level nor details




on application methods were  specified in this preliminary report.




                In this same  series of neuropathy studies, Raleigh and co-




workers  (1975)  found signs of peripheral neuropathy in rats receiving 2,5-




hexanedione subcutaneously or orally.  The oral doses were  administered as





                                     266
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Table  96.   Subacute and  Chronic  Toxicity  of MBK and 2,5-Hexanedione by Subcutaneous
            Injection
                 Laboratory Animal     Dosage Schedule      nonage Levels
   2, 5-hexnnedione      Rats             Daily, five days/     340 MR/k^/day    Development of peripheral n*ruo- Raleigh et al. , 1975
                                week for 19 weeks                pathv

                 Rats, Six, Sprague-    Daily, five days/     0. i ril        Clinical sit^ns of dysfunction;   ^penrer and SchaumburK
                 ^wley           week (a) for H      f>.? -t 00.4 ml    pathological sljtns of peripheral I975b,c
                                weeks plus (h) For    (230 to 140 mp;/   neiirooathv
                                6 to 10 weeks       kp,/dav

   Methyls-butyl ketone  Cats             2>. d^ily , five djys/   ^on mp/V^/iiny    Procured peripheral neuropathy   Raleigli e^ aj. , 19~/5
   (MBK)                          week, 2-4 ninths      total

                 DORS             2x dailv, five d«vs/   ^0 n«/kp/dav    Produced neriph^r^J nt-uropaEhv   "         "
                                week, 2-4 months      total
25 ml  of  a 0.5 percent solution of 2,5-hexanedione,  or 520 mg/kg/day  for

approximately two months.   The subcutaneous  injections were  given at  a rate

of 340 mg/kg/day, five days per week for  19  weeks.

                Detailed  reports on the subcutaneous  injection of 2,5-

hexanedione in six 400 gram Sprague-Dawley  rats are  presented by Spencer and

Schaumburg (1975b, c).   These rats were injected with 0.1 ml of the dione

five days a week for  13  weeks plus 0.2 ml or 0.4 ml  (~ 230 or 340 mg/kg/day)

for six weeks.   A symmetrical weakness of hind limbs and feet, characterized

by a waddling gait, occurred in some animals.  The  rats were examined weekly

and sacrificed on or  before the appearance  of clinical signs.  All animals

exhibited pathological changes indicative of "dying-back" disease regardless

of the presence  of clinical symptoms.

                Nerve  fiber degeneration was  most apparent at the distal portions

of nerves with proximal  nerve fiber presentation.   Abnormalities included

axonal swellings which were comprised of  masses of  neurofilaments as  well as

areas  of demyelination.   Additional pathological findings were similar to those


                                      267
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seen in animals exposed to methyl _n-butyl ketone (Spencer and Schaumburg 1975b,  c).



Spencer and Schaumburg (1976b)  studied the clinical and neuropathologic effects  on  rats



(six in each group) of drinking 0.5% solutions of various ketones  administered for  thre



months.  These compounds included 2,5-hexanedione, 2,5-hexanediol, 2,4-hexanedione,



2,3-hexanediol, 1,6-hexanedione and 3,5-heptanedione.   2,4-Hexanedione was administered



for one month and the animals were only examined clinically.   Weight loss and clinical
                                                                           f


peripheral neuropathy developed in rats drinking 2,5-hexanedione,  2,5-hexanediol.



Neuropathological changes were found in vulnerable areas of the central and peripheral



nervous systems.  No abnormalities were found in the other experimental animals.



           4.   Sensitization, Repeated Doses



                No sensitizing effects have been reported in the ketones.



As indicated in Section IIl-C-3-d  (p. 203), skin sensitization tests for ethyl n-



amyl ketone and acetophenone were  carried out on human volunteers; the ketones



produced no sensitization  (Kligman, 1971 and 1972).



           5.   Teratogenicity



                Little work has been done on the teratology or embryotoxicity



of ketonic solvents.  Griggs and coworkers  (1971) and Weller and  Griggs  (1973)



have reported  on  the effect of cyclohexanone vapors on chick embryos.  One



other  ketone,  methyl ethyl ketone  (MEK) has been studied  for effects on  rat



embryos and  fetuses  (Schweta et_ _al. ,  1974).



                Griggs  and his associates  (1971) exposed  groups of eggs  to


unspecified  concentrations of  cyclohexanone vapors  for  three or six hours



prior  to incubation.  Other  groups were  incubated  for  96  hours at 37°C before



exposures  of  three,  six,  or  twelve hours.   After  13 days, the embryos were



examined for  abnormalities.  Examinations  revealed  normal head, beak,  toes,



eyes,  feathers, and  extra-embryonic membranes.  Macroscopically,  hearts  and



brains were  normal.  Livers  from the  experimental  group were darker  than the



controls.  The groups exposed  prior  to incubation weighed significantly  less



than their controls.  The embryos  exposed  for  three hours post incubation dif-



 fered  significantly  in  both weight and percent  mortality.



                                       268
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               Some of the chick embryos in all groups were allowed to hatch.




Those exposed for three or six hours pre-incubation and six or twelve hours




post-incubation were normal in appearance and behavior, although the percent




mortality for these groups was 20 to 50 percent, as compared to 10-20 per-




cent for controls.




               The chicks from both groups exposed three hours post-incubation




were unable to walk properly or maintain posture.  Their only apparent physical




abnormality was inwardly curled toes.  Weller and Griggs (1973), discussing




the same studies, indicate that the chicks appeared normal at birth and




developed locomotor difficulties within a few hours.  Both Griggs and co-




workers (1971) and Weller and Griggs (1973) indicate that cyclohexanone has




a functional, rather than morphological, teratogenic effect which may be due




to an upper motor neuron lesion.  Weller and Griggs (1973) suggest that the




lesion might be localized at the neuromuscular junction.  These investigators




indicate further studies utilizing mammalian embryos are in progress.




               Experiments conducted by Schwetz and his coworkers (1974)




involved exposing adult female Sprague-Dawley  (Spartan) rats to methyl ethyl




ketone (MEK) at nominal concentrations of 1000 ppm and 3000 ppm.  Pregnant




rats were exposed for seven hours per day on days 6 through 15 of the gestation




period.  None of the litters were totally resorbed,- and 'the resorbtion rate




was not altered by exposure to MEK.  Fetal body measurements in the 1000 ppm




group were decreased somewhat, though no such  change was seen in the 3000 ppm




group.  Although no significant increase in specific gross, soft tissue, or skeletal




anomalies was found at 1000 ppm, a significant increase in exposed litters having




fetuses with skeletal abnormalities was found.  At 3000 ppm, a significant pro-




portion of the litters had fetuses with gross external anomalies or internal




soft tissue anomalies (see Table 97).  Exposure to either level of methyl ethyl




ketone had no apparent effect on the mother rats.





                                     269
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Table 97.   Effect of Inhaled  MEK on the  Incidence of  Fetal Anomalies Among

             Rat Litters3 (Schwetz j2t _al. ,  1974)


                                                            Methyl ethyl ketone

                   Solvent Concentration (ppn)              Control    1000	3000

                   Number of litters examined               43       23          21

                   % of litters affected (No. of litters)

                   Gross                               (0)       (0)       19 (4)b'c

                   Skeletal

                   Skull anomalies                       12 (5)     23 (5)         (0)
                    (delayed ossification)
Lumbar ribs or spurs
Vertebral anomalies
Sternebral anomalies
(bipartite; delayed ossification
Total skeletal
Soft tissue
Subcutaneous edema
Dilated ureters
Total soft tissue
24
21
(a) 61
(b) 11
58

33
12
51
(10)
(9)
(14)
(2)
(25)

(14)
(5)
(22)
27
18
65
95

9
30
70
(6)
(4)
(15)
(21)b

(2)
(4)
(16)
38
33
43
81

48
24
76
(8)
(7)
(9)b
(17)

(10)
(5)
(16)
                   a Administered by inhalation seven hours a day on days 6-15 of gestation.

                   b Incidence significantly different from control by the Fisher Exact
                     Probability test, p < 0.05

                   c Two brachygnathous and two acaudate fetuses.

                   * Data from the two control groups were combined for statistical comparison
                     with the exposed animals in all categories except Sternebral anomalies
                     (delayed ossification)



                  Schwetz and  his associates (1974) concluded that at 1000 and


3000 ppm exposure levels, MEK is  embryotoxic,  fetotoxic,  and potentially  tera-


togenic.   No  further  studies by these workers  on MEK teratogenicity  are in


progress (Schwetz, personal communication,  1975).


            6.    Mutagenicity


                  No information is  available  on  the  potential mutagenicity  of


the ketonic solvents  in birds and mammals.


            7.    Carcinogenicity


                  Most of the  ketonic solvents  have not been tested for car-


cinogenicity.   Methyl ethyl ketone applied  twice weekly  to the skin  of mice
                                           270
-------
at 50 rag per application caused no tumors over a one  year exposure  period




(Morton £t al., 1965).




                Pathological examinations in chronic  toxicity studies (see




Section III-D-2, p. 252) also'revealed no  tumors.




           8.   Behavioral Effects




                No behavioral effects of the ketonic  solvents have  been re-




ported in birds and mammals.  The effects on social insects are discussed in




Section III-E-1 (p. 273) of  this report.




           9.   Possible Synergisms




                Little work on the possible synergisms of ketonic solvents




has been reported.  The joint toxic action of acetophenone and isophorone has




been studied by Smyth and associates (1969b, 1970).  In these experiments,




each compound was tested with others in both equitoxic and equivolume mixtures.




                When acetophenone is mixed with either tetrachloroethylene,




formalin, or carbon tetrachloride on a 1:1 by volume basis, a more-than-additive




degree of toxicity results.   Isophorone was not found to have greater than




a random "more-than-additive" or "less-than-additive" effect (Smyth et al., 1969b)




                Smyth and coworkers (1970) utilized equitoxic mixtures in which




the volumes of the two compounds were directly proportional to their re-




spective rat oral LD   values.  The comparison of equivolume to equitoxic




mixtures showed that the combination of isophorone and propylene oxide yielded




a great difference in predicted-to-observed LD  's.  The adjusted ratios were




calculated as follows:  where the predicted (P) to observed (0) ratio was




greater than 1, the adjusted ratio was (P/0) -1; where the P/0 <1,  the ad- .-•




justed ratio was 1- (0/P):  In the above mentioned case,1 the equitoxic adjusted
                                      271
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ratio was 0.16 and the equivolume adjusted ratio was -1.46.   Acetophenone



combinations were not as widely divergent (Smyth e_t^ a^. ,  1970).



                The synergistic effects of acetophenone combined with other-



compounds has been indicated'by Ryazanov (1968).  Ryazanov suggests a formula



for calculating concentration effect levels as follows:





                      X = ^  +^  +^ •"
                          m..   m    m.,




where: (1) X is the unknown total concentration



       (2) a,b,c are substances whose concentrations are to be determined



       (3) M.. , m , m  ... are their respective maximum permissible


                     concentrations for isolated action.



The combination of acetophenone with any of the following - acetone, benzene,



phenol - should not exceed an X value of 1.5  (Ryazanov, 1968).



           10.  Cataract Formation



                Guinea pigs  subcutaneously and  topically administered cyclo-



hexanone developed bilateral cataracts  (Rengstorff et_ _al., 1971).  Rengstorff



et al. (1971)  report unpublished work by Callahan on 28 albino guinea pigs  of



both  sexes from 9 to 18 weeks in age, weighing  385 to 650 grams.   The solvent



was dropped on a three-inch  clipped dorsal surface of the guinea pig or  injected



subcutaneously for three times a week for three weeks.  The animals were ex-



amined initially after  60 to 90 days and then every 30 days over a total of



six months.   The results of  these studies are in Table 98.  Cutaneous admin-



istration of  (0.5 ml) caused bilateral  cataracts in 25 percent of  those  dosed.



Subcutaneously induced  effects were not  as prevalent.
                                      272
-------
 Table 98.  Cataracts Found in  Guinea Pigs After  Cutaneous and  Subcutaneous
            Application of Cyclohexanone  (Rengstorff et al.,  1971)
                    Route

                Cutaneous
                  (0.5 ml)
                Subcutaneous
                  1:1 Solvent:
                  (0.05 ml)
Saline
                  I Solvent in saline
                  (0.05 ml)
                                             Cataractous Responses

                                                Cyclohexanone

                                                         Month

                                             Animal   2  3  4 5
                 1
                 2
                 3
                4-12
                                              1-4
                 5
                 6
                 7-16
o o  o o  X
o o  o o  X
  O  O X  X
  No effect

    25%

  No effect
   X  X  x  x
   o  o  o  x
  No effect

    12%
             0 - Indicates no defect in lens.

             x - Indicates isolated vacuolated area in periphery of lens.

             X - Indicates extensive vacuolated areas involving the entire periphery
                of lens.


      E.    Toxicity - Lower Animals

            1.    Insect Alarm Pheromones

                 In recent  years, certain  naturally occurring  ketones have

been identified as insect  alarm pheromones,  chemicals  capable of eliciting

definitive  distress reactions in certain  social insects.  Although the ketone

pheromones  are species specific for the type  of response  generated at a  given

concentration, the same  ketone  may serve  as pheromone  for several different

species.  In any given group,  alarm behavior  is induced only  when the parti-

cular ketone or a very close stereochemical analogue is present in sufficient

quantity  (Amoore e£ a!L. , 1969).   Table 99 lists some of the ketones commonly

found as pheromones,

                                         273
-------
     Table  99.   Ketonic Solvents as  Alarm Pheromones  in Social Insects
     Ketone/Alarm Pheromone

     2-Heptanone
     (Methyl n-amyl ketone)
     Methyl heptenone
     4-Methyl-2-hexanone
     4-Methyl-3-heptanone
     6-Methyl-3-octanone

     3-Octanone
     (Ethyl n-amyl ketone)

     3-Nonanone
     (Ethyl n-hexyl ketone)

     Propyl Isobutyl ketone
Insect

Apis mellifera
Atta sp.
  Atta texana
Irldomyrmex pruinosus
(Roger)

Iridomyrmex sp.
Tapinoma sesile (say)

Dolichoderus clark
(Wheeler)

Atta sp.
  Atta texana
Pogomyrmex sp.
  Pogomyrmex bad!us

Crematogaster sp.

Crematogaster sp.
Myrmica brevinodis
 Crematogaster sp.
Reference

Shearer and Boch, 1965
Blum £t al., 1968
Moser e^ al., 1968
Amoore e_t  al. , 1969
Blum £t al. , 1963

Cavill and Hinterberger, 1960
Wilson and Pavan, 1959

Cavill and Hinterberger,
1962

Blum et al., 1968
Moser e_t al. , 1968
McGurk e± al. , 1966
Blum ^t al., 1971

Crewe et. al. , 1972

Crewe and Blum, 1970
Crewe and Blum, 1970

Crewe et al. , 1972
 Tapinoma sessile (say)    Wilson and Pavan, 1959
                  Blum and coworkers  (1966)  compared  the activities  of the  2-

alkanones in  releasing alarm behavior in Iridomyrmex pruinosus, an ant species

that  utilizes 2-heptanone  (methyl rv-amyl ketone) as an alarm pheromone.   They

tested ketones of varying  carbon chain length for alarm releasing  activity in

this  species  of ant  and rated them  according to strength of alarm  response (see

Table 100, p. 275).   Blum  and coworkers (1966) found that  the greatest alarm

releasing activity occurred  in the  C& to Cg  ketones, especially the straight

chain molecules structurally similar to 2-heptanone.  Little or no activity

occurred in response to exposure to the C  and C  compounds, which are highly

volatile, or  in the  lighter  molecular weight ketones (C <  10).
                                          274
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Table  100.   The Activity of  Ketones  as  Releasers of  Alarm for Iridomyrmex
               pruinosus  (Blum  et  al.,  1966)
                        Compound

                        2-Propanone

                        2-Butanone                            0
                        2,3-Butadione                         0
                        3-Buten-2-one                         0

                        2-Pentanone                            2
                        3-Pentanone                            °
                        2,4-Pentadione                        2
                        Methyl cyclopropyl ketone              1
                        3-Methyl-2-butanone                   1
                        3-Methyl-3-buten-2-one                 0
                        Cyclopentanone                        0

                        2-Hexanone                            3
                        2,5-Hexanedione                       3
                        5-Hexen-2-one                         3
                        4-Methyl-2-pentanone                   1
                        4-Methyl-3-penten-2-one                1
                        4-Methyl-4-hydroxy-2-pentanone         1
                        3,3-Dimethyl-2-butanone                0
                        Cyclohexanone                         0

                        2-Heptanone                           5
                        3-Heptanone                           4
                        4-Heptanone                           4
                        4-Methyl-2-hexanone                   2
                        5-Methyl-2-hexanone                   2
                        5-Methyl-3-hexen-2-one                 3
                        2,4-Dimethyl-3-pentanone              2

                        2-Octanone                            4
                        3-Octanone                            3
                        2,3-Octadione                         2
                        2-Methyl-4-heptanone                   3
                        5-Methyl-4-hepten-2-one                2
                        5-Methyl-5-hepten-2-one                2
                        6-Methyl-5-hepten-2-one                4
                        Acetophenone                          2
                        Cyclooctanone                         0

                        2-Nonanone                            U
                        5-Nonanone                            2
                        2,6-Dimethyl-4-heptanone              1
                        6,6-Dimethyl-3-heptanone              4
                        Phenyl ethyl ketone                   2
                        Isophorone                            0

                        2-Decanone                            2
                        Phenyl ii-propyl ketone                 1
                        Cyclodecanone                         0

                        2-Un dec an one                          0

                        2-Dodecanone                          0
                        Phenyl n-amyl ketone                   0
                        Cyclodociecanone                       0

                        2-1'ridccsnonc                         0
                                              275
-------
                Similar pheromone activity ratings have been  compiled for

other insects - Pogomyrmex badius (Blum et_ al. ,  1971), the honey bee (Apis sp.)

(Boch and Shearer, 1971), and the ant Atta texana  (Moser £t al., 1968).   These

studies reveal that the position of the carbonyl grouping on  the chain,  as well

as the positioning of methyl group branching,  affects  the relative activities

of the compound.  If the carbonyl grouping is  located  centrally on the chain

(Blum ejt _al., 1966) or has branching  groups  nearby (Boch  and  Shearer, 1971),

the relative activity is lessened.

                Data in Table 101 indicate various stereochemical  properties

of compounds which influence their ability to  act  as surrogate alarm pheromones

for Iridomyrmex pruinosus.  The width and height as well  as  linear length of

the molecule appear to be instrumental in determining the pheromone activity

of the compounds.  As seen  in Table  101,  ri-butyl acetate,  which most closely

matches the  insect's true pheromone,  2-heptanone,  in these  three areas, has a

high activity rating  (5).   Two  other  compounds,  2-ethoxyethyl acetate and

2-octanone,  both have width and height identical to those of 2-heptanone,

though their lengths are  somewhat  longer.  Both of these compounds have ac-

tivity ratings of  four.   On the other hand,  2-hexanone,  with a length less than

that of 2-heptanone but identical  in  width  and height, has  even less activity  -

three.  The  chemical n-heptaldehyde,  which  is similar to 2-heptanone only  in

height, has  the lowest  activity rating.

   Table 101.  Physical Properties, Linear Dimensions, and Activity Ratings
               of Compounds Evaluated as  Alarm Pheromones For !_._
                                  (Blum,  1969)


Compound
2-Hexanone
Cyclohexanone
2-Heptanone
Cycloheptanone
n-Hept aldehyde
4-Methyl-2-hexanone
n-Butyl acetate
2-Ethoxyethyl acetate
2-Octanone
Cyclooctanone

Molecular
Height
100
98
114
112
114
114
116
132
128
126
Boiling Point
ro
(at 760 mm HK)
126
156
151
178
115
139
126
156
173
200°
Linear
length
A
9.8
7.1
11.1
7.3
11.7
9.2
11.0
12.3
12.4
7.4
Dimensions
Width
A
4.9
6.1
4.9
6.6
4.2
5.9
5.0
4.9
4.9
6.6
Height
A
3.6
4.7
3.6
5.0
3.6
5.0
3.7
3.6
3.6
5.1
Activ:
Ratii
3
1
5
1
1
2
5
4
4
1
     ' Natural alarm substance

      713 aim Hg

      A rating of one denotes least active and five aost active
                                      276
-------
                Amoore and associates  (1969) have also found that little

variation in structure is tolerated before  the  alarm activity decreases.   The

structural  changes  are correlated with activity ratings for 2-heptanone  and

several other  compounds in Figure 41.
                  Structural        Alarm
            stereochemical formulas  activity
     Structural          Alarm
stereochemical formulas     activity
                   2-OCTANONE
                   3-HEPTANONE
                                                 n-BUIYl ACETATE
                   2-ttNTANONf
                                                  7-BROMOOCTANE
       Figure 41A (left).  Ketones.  Many ketones related to  2-heptanone were
            tested for alarm-releasing activity on Iridomyrmex pruinosus.
            Nevertheless, only  a  rather limited amount of-variation in molecular
            size and shape proved compatible with alarm activity.
       Figure 41B (right).  Nonketones.  Provided that they bear a close
            resemblance to the  molecular shape and polar location of 2-heptanone,
            a remarkable variety  of  unrelated chemicals were  found to mimic
            its pheromone action.   (Amoore et £l., 1969)
       (Reprinted with permission from the American Association for the
            Advancement of Science)
                                        277
-------
                Further  studies on alarm pheromones have been  conducted to



determine the concentration of ketones necessary to elicit  the behavioral



response.  Wilson  and  associates (1969) have developed  a mathematical model



for determining the  threshold concentrations of pheromone  activity.  This



formulation depends  on the emission rate of the compound,  the  diffusion co-



efficient of the compound in air, and the distance involved,  as well as the



time factor.



                Moser  and coworkers (1968) have determined the threshold con-



centrations of a series  of ketones in Atta texana, an  ant, and have shown that



the nature of the  response is concentration dependent.   The ketone 4-methyl-3-



heptanone, the alarm pheromone of this species, elicits alarm behavior at


  -5    3
10   cm  saturated air.   [Moser and associates  (1968)  arrived at the ketone



concentrations by  serially diluting a saturated sample at 250°C and injecting



the appropriate amount via syringe into  a 6 £  container which housed the ants.]


                                          —ft    ^
At the  lowest  concentration employed  (10  cm , in this case), the worker ants



detected  the  chemical; at higher concentrations they seemed attracted by the



vapors.   Considerably increased concentrations  (10~   for 4-methy1-3-heptanone)



led to  workers running around with mandibles  open,  challenging other workers.



Peak alarm activity lasted for  45 to  75  seconds,  and after about three minutes



,"i~ M~\ i :.,.  ft. lu.i.I'l.-tj  to r.o;inal.  No other ketone .:uuld  t;li».it alari'i response at



-'j-. I' .1  '--•'••  c us. tni LC' i  i on , bt.r. several, .suo.h a^  ->uiij, t j.\c.-ue, 3-nep can one, 3-



>;i-i j-:soae ,t A -.in.'! hy i - i-hexanone,  and ri-iTu?thy 1-j-hepiai'iona.,  reso.1 ted  la alarm at

   - '    'i
i'-!   >- :  ^-.-I'-i: :n.A:' ru  •• f-oi!Cf-:iLrat ir.ns.   OrhrT'-:  • i-jt.i d  [stt.le  r. i- no respon.if



 1 " '• ''•"•  iT ;" i ''•.") ^f"  f ritj wofkr')  ^n r ^ (Mf SPT ft" a1    IQnh';
-------
                 The possibility of the alarm pheromones  serving as toxicants

in the social insects has  been studied by  Saslavasky and coworkers (1973)  in

the oriental hornet Vespa  orientalls and by Quraishi and Thorsteinson  (1965) in

immature  stages of Aedes aegypti.  The latter investigators found that 1 pi/ml

concentrations of 2-heptanone and 4-heptanorie applied  to the food supply of

A., aegypti  larvae and pupae caused a low degree of mortality (0-10%) .   Quraishi

and Thorsteinson (1965) have also reported that 2-heptanone had a reversible

anesthetic  effect on the larvae, but not on the pupae,  of the insect.

                 Several compounds, including the ketones 3-nonanone  and cyclo-

hexanone, were tested as alarm pheromones  and toxins in the oriental hornet

(Saslavasky et al., 1973).  Studies indicate considerable variation  in response

to the ketones by different age groups and types of colonies of hornets (see

Table 102 below).  As can  be seen, the only commercially important solvent


     Table  102.   Response  of  Colonies and  Groups of Imagines  Towards
                  Ketones     (After Saslavasky  ej; _al. , 1973)
Cvclopentanone
Cyc lohexanone
i-Oc tauorie
3-"onanone
2-Methy] -3-hexanone
6-Methyl~5-hepte-n-2-one
2 -Methyl- 3-nonanone
0
i
2
4
3
It
0
A
A
B
E
A
A
A
n A o c
0 A u C
? A n K
n A o F
2 A n n
4 A 2 A
2 A n A
(>
0
n
2
2
2
0
.
f
I)
<
n
A
A
     Alarm behaviors are expressed as follows:

     0 = nonresponse,   1 = wuak response,  2 = reasonable response, 3 = strong response,   4 - very strong response

     Mortality is expressed as follow^:

     A = 0 percent, B = 25 percent,C = 25-50 percent, n *= 50-75 percent, F = 75-100 percent

     Spreading and feeding with ketones caused convulsion and death (0.5-S minutes)
                                        279
-------
tested here,  cyclohexanone,  does not elicit much alarm behavior, although it does

cause some mortality in the younger groups of imagines - a combination of workers,

males and young queens.  Saslavasky and coworkers (1973) also note that the

larvae and pupae of the hornet are subject to higher mortality from exposure

to the ketones as are the same developmental stages in the yellow-fever mos-

quito A., aegypti (Quraishi and Thorsteinson, 1965) .

           2.   Other Toxic Effects

                The 96 hour LD   of methyl ethyl ketone to mosquito fish

(Gambusia _affinia) is given as 5.6 g/£ (Wallen jet al. , 1957).  Buzzell and co-

workers  (1968) report that a 96 hour exposure to 10 g/£ of this ketone results

in no mortality to bluegill fingerlings (Lepomis macrochirus).

                Crisp and coworkers  (1967) have demonstrated that four ketones -

acetone, methyl ethyl ketone, diethyl ketone, and cyclohexanone - induce nar-

cosis in barnacle larvae.  In this study, thermodynamic activities rather than

concentrations are used in describing the exposure conditions.  The threshold

narcotic response is defined as loss of forward movement while  the appendages

of the larvae are still active.  The results for the  four ketones are summarized

in Table 103.
      Table 103.  Thermodynamic Activities of Various Ketones Producing
                  Threshold Narcosis in the Nauplius Larvae of the
                  Barnacle, Elminius modestus (Crisp et al., 1967)
                                                           Average
              Ketone                               Thermodynamic Activity
                  t                                             -2
          Acetone                                       1.9 x 10
          Methyl ethyl ketone                           2.0 x 10
          Diethyl ketone                                3.55 x 10~2
          Cyclohexanone                                 2.05 x 10


        = Balanus balanoides larvae used


                                      280
-------
                A pattern of decreasing potency  -  indicated  by  increasing


thermodynamic activity - with increasing chain length was  noted not  only for


the acyclic ketones summarized in Table 103,  but also for  homologous series of


aliphatic hydrocarbons, halogenated hydrocarbons,  alcohols nitriles, and ethers.


      F.    Toxicity - Plants


           No studies have been encountered concerning the effects of any of


the ketonic solvents on plants.


      G.    Toxicity - Microorganisms


           As discussed previously (see p. 128), certain microorganisms have


been shown to degrade various ketonic solvents.   Relatively little,  however,


is known about the toxic effects of ketones on microorganisms.   Using a mixed


microbial culture, Buzzell and coworkers  (1968)  state that the mean tolerance


levels for methyl ethyl ketone and acetone are 14 g/£ and 24 g/£, respectively.


As indicated in Figure 42, Egyud (1967) has shown that a variety of ketones,


including many ketonic solvents, have only a mild and apparently transient


inhibitory effect on the growth of Escherichia coli at ketone concentrations

         _3
of 1 x 10  M.  Only methyl vinyl ketone has any pronounced inhibitory effect.


Mesityl oxide, a structurally related unsaturated ketone of some commercial im-


portance, is no more toxic than most of the saturated ketones.


           Some of the ketonic solvents have been shown to have mild to marked


stimulatory effects on the germination rate of uredospores of Puccinia gaminis,


a fungus which causes stem rust in wheat  (French, 1961).  This has been demon-


strated by placing dilutions of various ketones in the annulus of a Conway


diffusion cell and floating uredospores on a phosphate buffer in the inner com-


partment.  After incubation at 16°C for ninety minutes, the extent of germi-


nation was determined.  The degree of germination was then compared to a


standard stimulator and relative activity ratings assigned (see Table 104).



                                      281
-------
            150 —i
            100 —4
             50 H
                                                    150 -i
                         I''Ir~nI
                         1         2        3

                          Timelhr.)
                                                    100 -\
50 H
                                                                  Timelhr )
            150 -,
            100 H
            50 H
                                                    150 -i
                                                    100 H
                                                  a
                                                 O
                                                     50 H
                          Timelhr.)
Figure 42.  The Effect of Ketones on the Proliferation  of  £.  coll.   -  The assay
   contained 0.25 ml of bacterial suspension,  4.0 ml  of M-9-glucose media,  0.5 ml
   of the inhibitor (1 x 10~2M) and water  to bring  up the  final volume to 5.0 ml.
   In the control, the inhibitor was replaced  with  water.  The final concentration
   of the inhibitor was 1 x 10"3M. The amount  of bacterium was 2.8 x 108 cells/ml.
   The reaction mixture was incubated at 37°C  under aerobic conditions.

(a) 0	0 control,  A	A acetone,FJ—[_J methyl-ethyl ketone, *——• 2-pentanone,
           k	—A 2-hexanone.
(b) 0	0 control,  A	6 2-octanone,l  I—T~j 2-nonanone, ••	•# 2-decanone,
           k	A 2-undecanone.
(c) 0	0 control,  A	A 2-dodecanone ,[^]—|	] 2-tridecanone , •-	• methyl-
           isohutyl ketone, i	^ methyl-vinyl ketone.
(d) 0	O control,  A	A mesityl oxide,|J|—Qjacetophenone, •	• 2-acetvlfuran,
           i	A cyclopropyl-methy1 ketone.

                                     (Egyud, 1967)
                                     282
-------
            Table 104.  Stimulatory  Activity of  Some  Ketones  on
                       Uredospore Germination (French,  1961)


            Ketone                        Dilution        Rating*

       Methyl ethyl ketone                 10~3              27
       Methyl n-propyl ketone              10_o              ^
       Methyl isopropyl ketone             10_3             ^^
       Diethyl ketone                      10~3              93
       Methyl n-butyl ketone               10__^              87
       Methyl n-amyl ketone                ^®-L             ^^
       Dipropyl ketone                     10~6             100
       Methyl ja-hexyl ketone               10 o'             150
       Mesityl oxide                       10"                69


* Rating: >80 = highly stimulatory; 20-80 = stimulatory; 0-20 = inactive


In comparing these results with a variety of other ketones,  aldehydes, alcohols,

and hydrocarbons, French (1961) has concluded that this stimulatory effect is

non-specific in terms of chemical reactivity, and probably attributable to the

ketones  (or other compounds) serving as substrates for enzyme systems in the

fungal spores.
                                       283
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IV.    Regulations and Standards




      A.    Current Regulations




           I.   Food, Drug, Pesticide Authorities




                Several of the ketonic solvents are covered under food




additive regulations and are regarded as safe food additives.  Those in-




cluded are methyl ethyl ketone, methyl n-propyl ketone, methyl n-amyl ketone,




ethyl butyl ketone, dipropyl ketone, methyl isobutyl ketone, ethyl amyl ketone,




methyl hexyl ketone, methyl heptyl ketone, methyl nonyl ketone, acetophenone,




and benzophenone  (FDC Law Reporter, 1975).




           2.   Air and Water Acts




                Rule 66 of the Los Angeles Air Pollution Control District




limits the industrial emission of solvents.  When an organic solvent is.




exposed  to baking, heat-curing, heat-polymerizing, or  flame contact, no more




than  15  pounds per day may be  emitted.  When no baking, heat-polymerizing, or




flame contact occurs, the emission of photochemically  reactive solvents is




limited  to 40 Ibs per day, but there is no limit imposed on non-photochemically




reactive solvents.  A photochemically reactive solvent is  one which contains




either:  (1)  5% or more by volume of olefinic compounds; (2) 8% or more by




volume of aromatic compounds with 8 or more carbon atoms,  except ethyl benzene;




 (3) 20%  or more  of ethyl benzene, branched ketones, trichloroethylene, or




toluene; or  (4) a total of 20% or more of a mixture or blend from the preceding




classes  of compounds.  Whenever a compound has a structure which meets the




specification of more than one class, it is always assigned to the class with




the least allowable percentage (Feldstein, 1974).
                                      285
-------
                Rule 66.1 extends the control over emissions to architectural

coatings and Rule 66.2 to disposal of solvent wastes (Feldstein, 1974).   Rule

66C limits total organic emissions (photochemically reactive and non-photo-

chemically reactive) to 3000 Ib/day or 450 Ibs in any one hour (Feldstein, 1974)

                Regulation 3 of the San Francisco Bay Area Air Pollution

Control District differs from Rule 66.  The most important difference in terms

of the regulations of the ketonic emissions is that the branched chain ketones

are exempted.  However, isophorone and mesityl oxide (as olefins) and aceto-

phenone  (as a substituted aromatic) are designated as reactive.  The basic

requirement of Regulation 3 is to limit emissions of organic compounds to less

than 50 ppm.  If over 50 ppm are emitted, the operation is not in violation,

provided  one of the following conditions can be met:

                1.   A complying material is being used  (no reactive organic
                     compounds and no heat applied.

                2.   There are less than 5%  reactives in the emission.

                3.   There are less than 10  Ibs/day reactive organic com-
                     pounds in the emission  or less than 20 Ibs/day total
                     organic compounds in the emission.

                4.   The reactive compounds  have been reduced  by 85% overall.

            3.   Other EPA Authority - None

            4.   OSHA

                The Occupational Safety and  Health Administration (OSHA) has

listed permissible levels in workroom air for several of the ketonic solvents.

Those included are  listed in Table 105.

                On May 8, 1975, OSHA released proposed standards for six of

the ketonic solvents  (OSHA, 1975d).  These proposed regulations for methyl

ethyl ketone, methyl n-propyl ketone, methyl isobutyl ketone,  methyl n-amyl
                                       286
-------
ketone,  ethyl n-butyl ketone,  and cyclohexanone cover  the permissible work-

room air concentrations (see  Table 105),  respiratory protection  devices, and

hazardous location classifications as well as fire hazard and  type of liquid

classifications.   Cyclohexanone is classified as a combustible liquid; the

others  would be  considered  as flammable  liquids  (OSHA, 1975c).   Initially,

public  hearings  were set  for  August 5 with June 20,  1975, as the deadline  for

interested persons to submit  written data, views and arguments.   However,  due

to  many requests for extension of the comment period,  a new deadline was set

for July 21, with hearings  set back to  September 3,  1975  (OSHA,  1975a).  Some

of  the  controversy is centering on the  permissible  levels in workroom air.   The

proposed regulations establish certain  mandatory procedures for the employer,

should  any employee be exposed to one half the airborne concentrations based

on  a  time-weighted average.  On August  29, 1975, OSHA (1975b)  issued a request

for comments on  the inflationary impact of the proposed standards; such  infor-

mation  will be  considered after the oral testimony  is  heard in September.

Inflationary impact statements will be  prepared and  further hearings will  be

held  after their release  (OSHA, 1975b).

      Table 105.   OSHA Standards For Ketones in Workroom Air  (OSHA, 1974)
                      Keto
                   Saturated aliphatics

                      Methyl ethyl ketone            200    590

                      Methyl ri-propyl ketone           200    700

                      Methyl a-butyl kecone           100    410

                      Methyl isobuty] ketone           100    410

                      Methyl n-amyl ketone            100    465

                      Ethyl .n-butyl ketone            50    230

                      Diisobutyl ketone              50    290

                   OtherSaturated

                      Diacetone alcohol              50    240

                   Unsaturated aliphatics

                      Mesityl oxide                25    100

                   Alicyclic and Aliphatic

                      Cyclohexanone                50    200

                      Isophorone                  25    140




                   a.  Parts c-t vapor or gas per million parts of contaminated air bv volume
                      at  25 '- ,-mc1 7^ -rm HE pressure.

                   b.  Approximate milLiKraxns o* particular per cubic meter of air.


                                          287
-------
           5.    DOT


                Transportation of classified liquids is controlled by ICC


regulations which have been described in Section II-D-2, p. 104.


           6.    Other Federal


                None


           7.    States, Counties


                None


           8.    Foreign Countries


                Foreign countries have adopted food regulations and per-


missible workroom air levels for some of the ketones.  The Council of Europe


(1970) lists ethyl n-amyl ketone as a temporarily admissible artificial


flavoring substance; it has also listed acetophenone with an admissible


daily intake of 1 mg/kg.  Permissible workroom levels in other countries for

three of the solvents are given in Table 106.


     Table 106.   Permissible Workroom Air Levels  of Ketonic Solvents:
                         Foreign Countries    (Winell,  1975)
USA
OSHAa 1974
mg/m3
590
• 700
200
BRDb
1974
mg/m3
590
700
200
DDRC
1973
mg/m3
300
	
_ __
Sweden
1975
mg/m3
440
	
___
USSR
1972
mg/m3
200
200
10
   Ketone


   Methyl ethyl ketone


   Methyl ri-propyl ketone  700

   Cyclohexanone
   3 OSHA - Occupational Safety and Health Administration



     BRD - Federal Republic of Germany


   r*
     DDR - German Democratic Republic
                                      288
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      B.    Consensus and Similar Standards




           1.   TLV




                Threshold Limit Values (TLV's)  have been published for several




of the ketones (see Table 107).




                Two ketone TLV's have been changed in the 1974 listing pre-




pared by the American Conference of Governmental Industrial Hygienists (ACGIH).




That for diisobutyl ketone was lowered from a 50 ppm limit to a 25 ppm value




upon reevaluation of data presented by Silverman and coworkers (1946), in




which these workers found some eye irritation at 50 ppm exposure.  The TLV




for isophorone was lowered from 10 ppm to 5 ppm due to a June, 1973, commun-




ication to the TLV committee regarding fatigue and general illness in workers




exposed to levels of 5 to 8 ppm isophorone (Ware, 1973).




           2.   Public Exposure Limits




                None
                                     289
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Table 107.   Threshold Limit Values For Workroom Conditions For 1974









           Ketone                                 ppm      mg/m3




      Simple Saturated




           Methyl ethyl ketone                    200      590




           Methyl n.-propyl ketone                 200      700




           Methyl n-butyl ketone                  100      410




           Methyl isobutyl ketone                 100      410




           Methyl n-amyl ketone                   100      465




           Methyl isoairyl ketone                  100      475




           Ethyl n-butyl ketone                     50      230




           Diisobutyl ketone*                       25      150




      Other Saturated




           Diacetone alcohol                        50      240




      Unsaturated




           Mesityl oxide                            25       100




      Alicyclic and Aliphatic




           Cyclohexanone                            50       200




           Isophorone*                               5        25








      *1974 Revision
                                 290
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                            Summary and Conclusions



      This study examines the potential environmental impact of ketonic


solvents with the exception of acetone.  Most of the selected ketones fit


into two major classifications:   (1) straight-chain ketones, including


methyl ethyl ketone (MEK), cyclohexanone, diethyl ketone,  methyl n-propyl


ketone, methyl n-butyl ketone, ethyl n-butyl ketone, 2,5-hexanedione


(acetonylacetone), and 2,4-pentanedione (acetylacetone),  and (2) branched-


chain ketones which are manufactured from acetone, including methyl iso-


butyl ketone (MIBK), mesityl oxide, diacetone alcohol, trimethylnonanone,


and diisobutyl ketone.  These categories dominate both ketone production


and consumption in solvent formulations.  Acetophenone is the most impor-


tant of the remaining ketones.  Others which were considered include


diisopropyl ketone, methylcyclohexanone, and benzophenone.


      Annual production for the selected ketones in 1973 was estimated at

                              *
approximately 1.5 billion pounds.  Most of the production was consumed in


industry either as a solvent or as a chemical intermediate; a relatively


small proportion of the ketones are formulated into consumer products.


Relatively few ketones dominate the market.  The three major ketones in order


of decreasing production importance are cyclohexanone  (638 million pounds),


MEK (505 million pounds), and MIBK  (155 million pounds).   Some 95% of cyclo-


hexanone is consumed in the production of adipic acid and e-caprolactam for


nylon manufacture.  Most of the remainder (32 million pounds) is consumed


as a solvent.  MEK (ca. 400 million pounds) and MIBK (ca.  101 million pounds)


are principally consumed in solvent blending.  Other ketones (in order of


importance as solvents) are diacetone alcohol, isophorone, mesityl oxide,
                                    291
-------
and acetophenone.   They are also chiefly consumed by industry.   A large




proportion of the aromatic ketones and high molecular weight,  straight-




chain ketones are used as flavor and fragrance additives or for inter-




mediates in their production.




      Ketonic solvents are consumed in greatest quantities in formulating




coatings and allied products (such as inks and adhesives).  Most of the




solvents are consumed in industrial coatings (e.g., for automobiles, wood




products, and metal products).   This includes from 60 to 70% of total MEK




and MIBK consumption.  Less important solvent uses include lube oil dewaxing




(about 5 to 10% of MEK); rare metal refining (branched chain ketones in-




cluding about 5 to 10% of MIBK); pesticide formulations (including aerosol




formulation); degreasers; paint, varnish, and rust removers; and solvents




for other industrial processing.




      The environmental release of the manufactured ketones primarily




originates from the evaporation of solvent during drying of industrial




coatings and allied industrial uses  (e.g., inks and adhesives).  Only a




minor fraction of these evaporated ketones are recycled.  The majority are




either discharged to the atmosphere  or disposed by other means  (usually




incineration).  The release of evaporated ketonic solvents to the atmosphere




is reduced to some extent  as the  result of complying with air pollution




regulations, which are usually  similar to Los Angeles Air Pollution Control




District's Rule 66.  It requires  reduction of evaporated  solvents prior to




their release to the atmosphere,  if  they contain in excess of 20% of photo-




chemically reactive  (branched-chain) ketones and 5% of olefins  (mesityl oxide




and isophorone are olefins), and  all solvents emitted from baking ovens.
                                     292
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Except when exposed to heat, straight-chain ketones are  exempt  from




requirements to reduce emissions.   Specific information  on ketones dis-




charged into the atmosphere was not available.




     Other origins of atmospheric ketones include fugitive emissions from




manufacture, transport, handling,  and use.   These losses do not appear to




be as important as the losses from solvent  evaporation.   Losses in tank




filling are estimated at 50 pounds of ketone lost per million gallons for




each filling.  Losses from storage are unknown, although it is  known that




some 40% of the ketone storage tanks do not control venting losses.




     Some of the selected ketones occur naturally in food and are produced




as an intermediate in biological oxidation of organic wastes.  For example,




the linear methyl ketones are intermediate products in the biological deg-




radation of the corresponding alkanes.  The straight chain ketones are commonly




observed in foods in concentrations from the ppb to ppm level.   As mentioned




above, some ketones are added to food to improve flavor and fragrance.




     The selected ketones are also produced by partial oxidation of ali-




phatic hydrocarbons.  Automobile exhaust contains low concentrations of some




ketones, including MEK, methyl n-propyl (and isopropyl)  ketone, and mesityl




oxide.  Concentrations as high as 1.5 ppm have been observed.  However,




the average concentration is unknown.  Automobile exhaust is not considered




likely to be a major source of MEK, but could be important as a source of




less heavily consumed commercial ketones such as methyl ri-propyl ketone and




mesityl oxide.   Ketones could also be produced by atmospheric oxidation of




hydrocarbons.  It has been observed that olefins in the photochemical smog




cycle will yield ketones, probably by ozonization.
                                    293
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      Most of the selected ketones are chemically  stable  to  the normal




environmental conditions.   With the exception of mesityl  oxide, the  ketones




are stable to oxygen at ambient conditions;  mesityl oxide forms a highly




reactive peroxide.  The ketones are biodegradable  in soil and water.   The




lower chain length ketones appear to be the most  susceptible.  The intro-




duction of chain branching, unsaturation, a second carbonyl  group or cycli-




zation appears to increase resistance to biodegradation.   Atmospheric ketones




degrade by photochemical processes.  They are minor participants  in photo-




chemical smog production.   Their contribution to smog production increases




with the introduction of chain branching or unsaturation.




      Ketones appear to migrate readily within the environment and readily




move between the media  (air, water, soil).  The low molecular weight ketones




are relatively water soluble and volatile.  They are usually observed as com-




ponents of surface waters  and possibly originate from natural sources.  There




is little monitoring information available on the selected ketones in soil




or air.  From the physical properties, it is evident that ketones in soil as




well as in water will volatilize,  and atmospheric ketones will be washed out




with rainfall.  Ketones in the soil will probably migrate with surface and




ground water.




      In acute exposure,  all of the ketonic  solvents seem to act as physical




toxicants  causing narcosis with central nervous system depression.  At suf-




ficiently high doses, some selective  renal toxicity may be induced.  Although




two of the ketones  are  neurotoxic, renal toxicity seems to be the most common




effect of the majority  of  ketonic  solvents during chronic exposures.




      The most commercially significant ketonic solvents also seem to be the




least toxic.  Methyl ethyl ketone  is  reported to have no adverse effect on





                                        294
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guinea pigs after inhalation exposures  of  235  ppm x  7 hr/day x  60 exposures




over 84 days.   Similarily,  hypobaric exposures to methyl  isobutyl ketone  at




100 ppm x 24 hr/day x 90 days had no effect on monkeys  or dogs. Under  the




same exposure conditions, however, some kidney pathology  has been noted in




rats.  Cyclohexanone is somewhat exceptional in that adverse chronic effects




do not include kidney damage.  In oral administration to  rats  for  180 days,




0.01 mg/kg/day had no effect and 0.05 mg/kg/day caused a  slight decrease in




stimulus response.  Only at 5 mg/kg/day were degenerative morphological




changes noted in the nervous system, liver, stomach and spleen.  In inhal-




ation, cyclohexanone seems to have a no effect level similar to methyl ethyl




ketone:  190 ppm cyclohexanone x 6 hr/day x 50 exposures  over  70 days caused




no apparent adverse effects in rabbits.




      Most of the remaining ketonic solvents cause chronic effects similar




to methyl  isobutyl ketone, but at markedly lower concentrations.  Diacetone




alcohol has been shown to cause cloudy swelling of the kidney  tubules in rats




on oral administration of 40 mg/kg/day x 30 days, but no effect at 10 mg/kg/




day  over the same period.  Oral administration of acetophenone at 25 mg/kg/day




x 30 days  to rats caused slight increases in liver and kidney weights, but




morphological damage was not demonstrated.  In inhalation, acetophenone




reportedly has no apparent toxic effect on exposures of  .143 ppm x 24 hrs/day




x 70 days.  However, at 1.43 ppm, dystrophy of the liver and changes in blood




protein fractions as well as plasma cholinesterase activity have been noted.




The  two most common unsaturated ketones, mesityl oxide and isophorone, seem




to differ  significantly in mode of action.  Exposures of  500 ppm mesityl oxide




x 8  hr/day x 10 exposures over 14 days caused death in rats and guinea pigs.
                                       295
-------
In that lower concentrations caused no adverse effects,  death was  attrib-




uted to the accumulation of mesityl oxide to anesthetic  levels  with con-




sequent circulatory and respiratory depression as in acute exposures.




Isophorone, at concentrations of 100 ppm - 500 ppm x 8 hr/day x 30 exposures




or 42 days, caused fractional mortality in rats and guinea pigs roughly




proportional to the concentration.   Here, death was attributed to  cumu-




lative toxic damage of the kidneys  and lungs.  Over an exposure period of




8 hr/day x 5 days/week x 6 weeks, mesityl oxide and isophorone, at concen-




trations of 50 ppm and 25 ppm respectively, caused no apparent adverse effects.




     Recently, considerable attention has been focused on the peripheral and




central neuropathic properties of methyl n-butyl ketone  and its metabolite




2,5-hexanedione.  In chronic subcutaneous exposures, both of these compounds




seem to have about the same neuropathic potency and should be regarded as




occupational hazards.  The ability of methyl n-butyl ketone to cause periph-




eral neuropathy in man during occupational exposure has  been clearly




documented in epidemiological surveys.  The threshold level for chronic




exposure to man is unknown.  However, methyl ni-butyl ketone exposures of 100 ppm




x 6 hrs/day x 5 days/week x 5 months  do not cause peripheral neuropathy in cats




and rats.  A lower limit to methyl n-butyl ketone induced neuropathy is further




suggested by the presence of this ketone in milk and cream at levels of




0.007 - 0.011 ppm and 0.017 - 0.018 ppm, respectively.  Nonetheless, neither of




these neurotoxic ketones are normal constituents of human urine.  The re-




maining ketonic solvents have not been shown to be neurotoxic on chronic




exposures, although  only commercial grades of methyl isobutyl ketone, containing




a small amount of methyl n-butyl ketone, have been specifically screened and




found not  to produce unequivocal evidence of nerve fiber damage.
                                     296
-------
     Little information is available on the teratogenic potential of ketones.




Cyclohexanone has been shown to cause motor disturbances in new hatched chickens,




but morphological teratisms have not been noted.   The results of mammalian studies




should be available in the near future.  Methyl ethyl ketone at environmentally




unrealistic concentrations (1,000 - 3,000 ppm) may be teratogenic to rats.




     The carcinogenic or mutagenic potential of the ketonic solvents cannot be




evaluated from the available data.  On dermal exposure, methyl ethyl ketone did




not cause carcinogenicity in mice when applied at 50 mg/mouse x twice weekly x




1 year.




     Based on the available data, the potential for adverse effects from ketone




exposure at reasonable environmental levels does not seem high.  Both the neuro-




pathic effects of methyl _n-butyl ketone and the renal toxicity of the more




common ketonic solvents seem to have threshold levels above environmental con-




centrations.  However, the long term effects of these compounds have not been




well characterized:  most of the available information concerns exposures of




under  180 days.  In addition, other neurotoxic substances producing.a rather similar




pattern of nervous system disease  (acrylamide, carbon disulphide, cresyl  phosphates,




metal  salts) are also present in the environment in low levels.  Further, in-




formation on mutagenicity, carcinogenicity, and teratogenicity is scant.  Never-




theless, most of the ketonic solvents  are normal constituents of food products




and have been monitored in human urine.  Because of the apparent inverse  re-




lationship between toxicity and commercial importance, the ranking of hazard




potential among the various ketones has not been attempted.  For instance,




although MEK overwhelmingly dominates  the ketonic solvent emissions, this




compound appears to be among the least hazardous ketones.  For the remaining




ketones, the greater proportion of environmental contamination is probably not




attributable to solvent use.





                                     297
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                                      330
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing/
REPORT NO. 2
EPA-560/2-76-003
TITLE AND SUBTITLE
Investigation of Selected Potential Environmental
Contaminants: Ketonic Solvents
Sheldon S. Lande, Patrick R. Durkin, Deborah
H. Christopher, Philip H. Howard, Jitendra Saxena
PERFORMING ORGANIZATION NAME AND ADDRESS
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Merrill Lane, University Heights
Syracuse, NY 13210
12 SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
3. RECIPIENT'S ACCESSIONHMO.
5. REPORT DATE
April 1976
6. PERFORMING ORGANIZATION CODE
8. PERFORMING ORGANIZATION REPORT NO
TR 76-500
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
EPA 68-01-3100
13. TYPE OF REPORT AND PERIOD COVERED
Final Technical Report
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
           This report reviews the potential environmental  hazard  from the commercial
 use of ketonic solvents with the exception of  acetone.   Three  ketones - cyclo-
 hexanone, methyl ethyl ketone, and methyl isobutyl  ketone  -  dominate the market.
 Other commercial ketonic solvents include diacetone alcohol, isophorone, mesityl
 oxide, and acetophenone.   Information on physical and  chemical properties, production
 methods and quantities, commercial uses and factors affecting  environmental con-
 tamination, as well as information related to  health and biological effects,  are
 reviewed.

' 7- KEY WORDS AND DOCUMENT ANALYSIS
•»• DESCRIPTORS
cyclohexanone ketonic solvents
methyl ethyl ketone ketones
methyl isobutyl ketone
diacetone alcohol
isophorone
mesityl oxide
methyl n-butyl ketone
I8. DISTRIBUTION STATEMENT ' "
Document is available to public through the
National Technical Information Service,
Sorinefield. Virginia 22151
b.lDENTIFIERS/OPEN ENDED TERMS

19. SECURITY CLASS (THis Report >
20. SECURITY CLASS (This page)
c, COSATI I'lelcl/Group

21. NO. OF PAGbS
330
22. PRICE
EPA Form 2220-1 (9-73)
                                          33(D
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