ISOPHORONE
Ambient Water Quality Criteria
              Criteria and Standards  Division
              Office of Water Planning  and  Standards
              U.S. Environmental  Protection Agency
              Washington, D.C.

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                        CRITERION DOCUMENT

                            ISOPHORONE

CRITERIA

                           Aquatic Life

     The data base for freshwater aquatic life  is  insufficient  to

allow use of the Guidelines.  The following  recommendation is

inferred from toxicity data for saltwater organisms.

     For isophorone the criterion to protect freshwater aquatic

life as derived using the Guidelines is 2,100 y.g/1  as  a 24-hour

average and the concentration should not exceed  4,700  ug/1 at  any

time.

     For isophorone the criterion to protect saltwater aquatic

life as derived using the Guidelines is 97 ug/1  as  a  24-hour
                                                           i
average and the concentration should not exceed  220 ug/1 at  any

time.

                           Human Health

     For the protection of human health from the toxic properties

of isophorone ingested through the consumption  of  water and  fish,

the criterion is 460 ug/1.

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                          ISOPHORONE



Introduction



     Isophorone is an industrial chemical synthesized from



acetone -and used commercially as a solvent or cosolvent



for finishes, lacquers, polyvinyl and nitro cellulose resins,



pesticides, herbicides, fats, oils, and gums.  It is also



used as a chemical feedstock for the synthesis of 3,5 xylenol,



2,3,5-trimethyl-cyclohexanol, and 3,5-dimethylaniline.



     Isophorone is an unsaturated, cyclic ketone or aliphatic
                                                          o


enone produced commercially by passing acetone over calcium



oxide, calcium hydroxide, calcium carbide or mixtures of
                                                         t


these at 350°C and 1 atomosphere of pressure (Mark, et al.



1963).  It is also prepared by heating acetone with aqueous,



alkali metal hydroxide at approximately 150°C under pressure



(Mark, et al. 1963).  Blackford  (1975) has estimated isophorone



production at a level of 28 million pounds for 1973.



     Isophorone (^-isophorone) has the chemical name 3,5,5-



trimethyl-2-cyclohexen-l-one, and is also known as trimethyl



cyclohexanone or isoacetophorone  (Rohm and Haas,-1971).



Although isophorone is normally produced as the y-isomer,



it may exist also as a  ^-isomer having the chemical name



3,5,5-trimethyl-3-cyclohexen-l-one (Schering Ag. 1972).



The technical or industrial grade of isophorone normally



contains 3.0 percent or less of the  ^-isomer, causing a



slight deviation in the melting and boiling points reported



for pure isophorone (c*-isomer)  (Schering Ag. 1972; Rohm



and Haas, 1971) .
                              A-l

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     The pure compound  ( £T-isophorone) is a water-white



liquid which exhibits low volatility, possesses a camphor



or peppermint-like odor, and turns yellow upon standing



(Schering Ag. 1972; Browning, 1965; Patty, 1962; Sax, 1975).



It has the empirical formula CqH140 and a molecular weight



of 138.21.  The physical properties include: melting point,



-8.1°C; boiling point,  215.2°C; vapor pressure, 0.31 Hg



at 20°C and 1 mm Hg g at 38°C; and a density of 0.9229 at



20°C (Mark, 1963; Sax,  1975; Browning, 1965).  The compound



is soluble in water up  to 1.2 gm/100 ml at 20°C and is readily



soluble in fats, oils,  and other hydrophobic substances



(Patty, 1962; Rohm and  Haas, 1971; Jacob, 1949).



     Isophorone is considered chemically stable (Patty,



1962).  At 150°C, however, it will form salts with sulfuric



acid and a tricyclic $~-, & -unsaturated ketone in the presence



of 60 percent aqueous sodium hydroxide (Marx, 1971).  Such



reactions may be of little significance since the conditions



required for their completion are generally not found in



tne environment.



     In aqueous solutions, isophorone forms three different



tricyclic diketodimers  when exposed to direct sunlight  (Jennings,



1965) .  The molecular weights of these compounds are double



that of isophorone and  the melting points range from 182



to 186.5°C.  Following  ultraviolet irradiation for one and



ten days, conversions to the dimer were 10 and 50 percent,



respectively (Craven, 1963).  In a similar study, irradiation



for 40 and 80 days resulted in dimer conversions of 76 and
                              A-2

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83 percent, respectively (Craven, 1962).  The significance
of these laboratory studies with respect to the stability
of isophorone in the environment is not known.
     The microbiological degradation of isophorone, measured
as percent biooxidation, was investigated by Price, et al.
(1974) in domestic waste water and synthetic saltwater using
a modification of the standard BOD test.  The observed biooxi-
dation levels of isophorone were 13, 47, and 42 percent
in the domestic waste water at 10, 15, and 20 days, respec-
tively.  The biooxidation in synthetic saltwater reached
only nine percent after 20 days incubation.
     Although isophorone has been reported in drinking water,
the Delaware River, and effluents of several industrial
facilities, little or no information is available regarding
bioconcentration, persistence, or fate of isophorone under
environmental conditions.  However, its broad application
as a solvent or cosolvent or chemical feedstock for industrial
and agricultural products clearly suggests that the potential
for both point source and non-point source water contamination
exists (39 FR 37195).
     Isophorone has been reported to be toxic to aquatic
life, particularly saltwater invertebrate species. Isopphorone
also has been shown to be toxic to experimental mammals
in acute, subacute, and chronic toxicity tests.
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                          REFERENCES

Browning, E. 1965. Toxicity and metabolism of industrial
solvents, Elsevier, New York.

Craven, E.G. 1962. Isophorone. Jour. Appl. Chem.  (London).
12: 120

Craven, E.G. 1963, Dimeric isophorone. Ger. 1, 143, 809.
(cl. 120) Br. Appl.

Jacob, M.B. 1949. The analytical chemistry of industrial
poisons, hazards, and solvents.  Interscience, New York.

Jennings, P.w. 1965. Photochemistry of isophorone, I.  Disser-
tation Abstr. 26: 698

Mark, K.F., et al. 1963. Kirk-Othmer Encyclopedia of Chemical
Technology. 2nd ed. John Wiley, New York.

Marx, J.N. 1971.  Interaction of 2, ^-unsaturated  ketones
with hydrogen halides. Addition vs. salt formation. Tetra.
Lett.  52: 4957.            .    '

Patty, F.A. 1962. ed. Industrial Hygiene and Toxicology.
2nd ed. John Wiley, New York.
                              A-4

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Price, K.S., et al. 1974. Brine shrimp bioassay and BOD



of petrochemicals. Jour. Water Pollut. Control Fed. 46: 63.







Rohm and Haas. 1971. The name, chemical identity, and composi-



tion of the innert ingredients for use in pesticide.







Sax, N.I. 1976. Dangerous Properties of Industrial Materials.



4th ed. Van Nostrand Reinhold Co., New York.







Schering, Ag. 1972. Isophorone. Specif. No. 276. Agric.



Chem. Div. Berlin, E. Germany.
                              A-5

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AQUATIC LIFE TOXICOLOGY*
                       FRESHWATER ORGANISMS
Introduction
     Static acute toxicity tests have been reported  for  isophorone
in the bluegill, Daphnia magna, and alga, Selenastrum  capricornu-
tum.  The 50 percent effect concentrations were  between  117,000
and 224,000 ug/1.  A bioconcentration test indicated negligible
uptake of isophorone.
Acute Toxicity
     The 96-hour LC50 for the bluegill  (224,000   g/1)  after
adjustment for test methods and species sensitivity  results  in  a
Final Fish Acute Value for isophorone of 31,000  y.g/1  (Table  1).
     Daphnia magna has been tested and  the 48-hour EC50  is 117,000
ug/1 (Table 2) which indicates little,  if any, difference  in
sensitivity with the bluegill.  The Final Invertebrate Acute Value
(4,700 ug/D also becomes the Final Acute Value  since  the  former
is lower than the comparable value for  fish.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life  [43  FR  21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order  to  better
understand the following discussion and recommendation.   The
following tables contain the appropriate 'data that were  found  in
the literature, and at the bottom of each table are  the  calcula-
tions for deriving various measures of toxicity as described  in
the Guidelines.
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Chronic Toxicity
                                (
     No chronic studies have been reported on  the effects  of

isophorone on freshwater organisms.

Plant Effects

     The 96-hour EC50 values for cell number production  and

inhibition of chlorophyll a by  the alga, Selenastrum capricornutum,

are 122,000 and 126,000, respectively (Table 3).  These  effect

concentrations are essentially  the same as for  the bluegill and

Daphnia magna.

Residues

     A 28-day exposure  (U.S. EPA, 1978) to 14C-isophorone

resulted in bioconcentration by the bluegill to 7 times  that  in

the water (Table 4).  The half  life of isophorone in the whole

body was one day.  Thin-layer chroraatography was used  to verify

the analytical results.
                             B-2

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CRITERION FORMULATION
                     Freshwater-Aquatic Life
Summary of Available Data
     The concentrations below have been rounded  to  two significant
figures.
     Final Fish Acute Value = 31,000 ug/1
     Final Invertebrate Acute Value =  4,700 ug/1
          Final Acute Value = 4,700 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value  = not available
     Final Plant Value = 120,000 ug/1
     Residue Limited Toxicant Concentration =  not available
          Final Chronic Value = 120,000 ug/1
          0.44 x Final Acute Value = 2,100 ug/1
     No freshwater criterion can be derived for  isophorone using
the Guidelines because no Final Chronic Value  for either fish or
invertebrate species or a good substitute for  either value is
available.
     Results obtained with isophorone  and saltwater organisms
indicate how a criterion may be estimated.
     For isophorone and saltwater organisms, 0.44 times the  Final
Acute Value is less than the Final Chronic Value derived from
results of an embryo-larval test with  the sheepshead minnow.
Therefore, it seems reasonable to estimate a criterion for iso-
phorone and freshwater organisms using 0.44 times the  Final.  Acute
Value.
     The maximum concentration of isophorone is  the Final Acute
Value of 4,700 ug/1 and the estimated  24-hour  average  concentra-
                             B-3

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tion is 0.44 times  the  Final ^Icute Value.   No  important adverse
effects on freshwater aquatic organisms  have been  reported to be
caused by concentrations  lower  than  the  24-hour average
concentration.
     CRITERION:   For  isophorone the  criterion  to protect fresh-
water aquatic life  as derived using  procedures  other than the
Guidelines is 2,100 ug/1  as a 24-hour  average  and  the concentra-
tion should not exceed  4,700 u.g/1 at any time.
                             B-4

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CO
I
Ul
                           Table   1    Freshwater fish acute values for isophorone (U S  EPA, 1978)


                                                                             Adjusted
                                     Bioaseay  Test      Time      LC50      LC50
             Organism                Method;.-   Cone.**   (hrs)     (ug/l>    lug/l>


             Bluegill.                   S        U        96      224,000    122,000
             Lepomis  macrochirus
             "  S = static

             ** U = unmeasured

                Geometric mean of adjusted  values = 122,000 ug/1           = 31,000 yg/1

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w
I
                           TaDle   2   Freshwater  invertebrate acute  values for isophorone (U.S. EPA, 1978)
            Organism
             Cladoceran.
             Daphnia magna
                        faioassay  Test      time
                        leu-ou*   Cone.**   1/irs)
                                             48
          Adjusted
LC50      LCbO
(uq/i)    luq/i)	
117.000   99.100
*  S = static

** U = unmeasured

   Geometric mean of adjusted  values = 99,100 wg/1
                                                                    99
                                                                           - 4.700 wg/1

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03
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                            Table   3   Freshwater plant effects  for  isophorone  (U  S.  EPA,  1978)


                                                     Concentration
              Organism                Effect         (ug/i)	


              Alga.                   EC50 96-hr        122,000
              Selenastrum             cell numbers
              capncomutum

              Alga,                   EC50 96-hr        126,000
              Selenastrum             chlorophyll a
              capricornutum                       ~
              Lowest plant value = 122,000

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I
00
                           Tatle   4.    Freshwater residues for isophorone (U.S. EPA. 1978)


                                                                            Time
             Organism                           Bioconcentration Factor      (days;



             Bluegill.                                     7                    28
             Leponus macrochirus

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                       SALTWATER ORGANISMS



Introduction



     As with freshwater organisms, most of the available data  for



the effects of isophorone on saltwater organisms result from



static tests with unmeasured concentrations.  An embryo-larval



test has been conducted with the sheepshead minnow.



Acute Toxicity



     The 96-hour LC50 for the sheepshead minnow (U.S.  EPA,  1978)



was determined to be between 166,000 and 295,000 ug/1  (Table 8).



No Final Fish Acute Value can be derived but  it would  be higher



than the equivalent value for invertebrate species  (220 ug/1)



which is derived-from an unadjusted 96-hour LC50 value of  12,900



 g/1 for the mysid shrimp, Mysidopsis bahia (Table  5).



Chronic Toxicity



     The chronic value for the sheepshead minnow obtained  from an



embryo-larval test (U.S. EPA, 1978) is 51,614 ug/1  (Table  6).  The



limits on this test were 74,000 to 144,000 ug/1 which  is about 0.5



of the LC50 range (Table 8).  The Final Fish  Chronic Value, and



the Final Chronic Value since no invertebrate species  has  been



tested, is 7,700 ug/1.



Plant Effects



     Chlorophyll a_ was inhibited and cell numbers were reduced by



50 percent after 96-hour exposures of the alga, Skeletonema



costatum (U.S. EPA, 1978), to isophorone concentrations of  110,000



and 105,000 ug/1, respectively (Table 7).
                             B-9

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CRITERION FORMULATION
                       Saltwater-Aquatic Life
Summary of Available Data
     The concentrations  below have  been rounded to two significant
figures.
     Final Fish Acute  Value = not available
     Final Invertebrate  Acute Value =  220  ug/1
          Final Acute  Value = 220 ug/1
     Final Fish Chronic  Value =  7,700  ug/1
     Final Invertebrate  Chronic  Value  = not  available
     Final Plant Value = 110,000 ug/1
     Residue Limited Toxicant Concentration  = not  available
          Final Chronic  Value =  7,700  ug/1
          0.44 x Final Acute  Value  = 97 ug/1
     The maximum concentration of isophorone is  the  Final  Acute
Value of 220 ug/1 and  the 24-hour average  concentration  is 0.44
times the Final Acute  Value,   No important adverse effects on
saltwater organisms have been reported  to  be caused  by concentra-
tions lower than the 24-hour  average concentration.
     CRITERION:  For isophorone  the criterion to protect saltwater
aquatic life as derived  using  the Guidelines is 97 ug/1 as a
24-hour average and the  concentration  should not exceed 220 ug/1
at any time.
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                          "aole  5   Marine invertebrate acute values  for Isophorone (U S  EPA, 1978)



                                                                            Adjusted

                                    Bioassay  Test      Time       ix:50      LCbO
            Or>ja-usm                Metiiog*   Cone. **    (nts)      (ug/1)     (uq/H



            Mysid shrimp,              S        U        96        12,900     10,926

            Mysidopsis bahia
            *  S - static


            ** U = unmeasured

                                                                    10 926
               Geometric mean of adjusted  values - 10,926  yg/1     =-+5—  - 220  Mg/1
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CO
(H
to
                           Tafcle  6    Marine fish chronic values for isophorone  (U S. EPA.  1978)


                                                              Chronic
                                                    Limits    Value
             organism                     Test*      tug/ij     fug/lfr
             Sheepshead minnow,           E-L       74,000-   51,614
             Cyprinodon variegatus                 144,000
             * E-L = embryo-larval

               Geometric mean of chronic values = 51,614 wg/1    51t6¥ = 7,700 pg/1
                                                                   o. /

               Lowest chronic value = 51,614 vg/1

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01
I
H-
U>
                            Table   7   Marine plant effects  for  isophoi^B  (U  S   EPA,  1978)
                                                     Concentration
              Organism                Effect         (aq/i)	
              Alga,                   EC50 96-hr         110,000
              Skeleconema costatum    chlorophyll a

              Alga,                   ECSO 96-hr         105,000
              SVeletonema costatum    cell number
              Lowest plant value =  105,000  Mg/1

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W
 I
                                Table  8.   Other marine data for isophorone (U S. EPA, 1978)



                                     Test                               Result
            - Organism                Duration  Effect                   (ug/ll



             Sheepshead minnow,        96 hrs   LC50                    >166,000
             Cyprinodon variegatus                 .                    <295,000

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                          ISOPHORONE




                          REFERENCES
U.S. EPA. 1978.  In-depth studies on health and environmental



impacts of selected water pollutants.  Contract No. 68-01-



4646.
                                B-15

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Mammalian Toxicology and Human Health Effects



Introduction



     Isophorone is a high-boiling colorless liquid of low



volatility with an odor resembling peppermint.  Its salient



physical properties are summarized in Table 1.  Isophorone is



an excellent solvent for many oils, fats, gums and natural



and synthetic resins (Rowe and Wolf, 1963), but it is used



mainly as a solvent for vinylic resins applied by roller



coating (Blackford, 1975).  Isophorone is also used as a sol-



vent for cellulose derivatives, lacquers, and pesticide for-



mulations, particularly anilide and carbomate herbicides.



Because of its structure, isophorone is useful as a chemical



intermediate, and is utilized in the synthesis of 3,5-



xylenol, 3,3,5- trimethyl cyclohexanol, and plant growth



retardants (Haruta, et al. 1974).



     Isophorone is prepared commercially by two methods, both



of which require acetone as a starting material (Rowe and



Wolf, 1963).  Acetone is passed over calcium oxide, hydrox-



ide, carbide, or mixtures of these at 350°C, or is heated at



200-250°C under pressure.  The isophorone is separated from



the resultant products by distillation.  Because less than



three companies manufacture isophorone, production figures



are not published by the U.S. Tariff Commission.  The produc-



tion of isophorone can, however, be estimated from acetone



consumption data.  In 1973, 35 million pounds of acetone were



consumed for isophorone production (Blackford, 1975).  Black-



ford estimated that, for every pound of Methyl Isobutyl



Ketone produced, 1.25 pounds of acetone are required.  This
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                           TABLE 1
              Physical Properties of Isophorone
        (EPA, 1979a; Union Carbide, 1968; NIOSH, 1978)
Empirical Formula
Molecular Weight
Freezing Point
Boiling Point (760 nun)
Specific Gravity (20/20°C)
Refractive Index nD(20°C)
Vapor Pressure  (25°C)
Air Saturation
Evaporation Rate (ether =1)
Water Solubility (weight % at 20°C)
Commercial Puritya (weight %)
Impurities:
  6 -isophorone
  mes itylene (1,3,5-1rimethyIbenzene)
  mesityl oxide (2-methyl-2 pertene-
    4-one)
  phorone (2,6-dimethyl-2,5-
    heptachiene-4-one)
  isoxylitones
  water
Structure
C9H140
138.21
215. 2°C
0.9229 g/cc
1.4781
0.44 mm
0.06%
200
1.2
96-98%
2-4%
trace
trace
trace
trace
trace
3,5,5-trimethyl-2-cyclo-
  hexene-1-one
 'Isophorone plus trimethylcyclohexenone
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corresponds to a yield of slightly above 90 percent.  Assum-
ing a 90 percent yield, and an acetone consumption  figure  of
35 million pounds/ the estimated 1973 production of  iso-
phorone was 28 million pounds.
     NIOSH (1978) estimates that more than 1.5 million work-
ers are exposed to isophorone.  In the industrial handling of
isophorone inhalation of the vapors  is the most likely mode
of contact, although skin and eye contact with the  liquid  may
also occur.  Because of the odor and taste of isophorone,  in-
gest ion is not expected unless by accident.  In the  environ-
ment, isophorone has been detected in a few samples  of drink-
ing water, but not in ambient air, soil, or food.
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                          EXPOSURE
Ingestiort from Water
     Isophorone has been detected in several  samples of
                                                         * j
drinking water (Table 2), but these identifications cannot be
used to imply a continuous occurrence.  The sources of the
isophorone contamination were not identified, but they would
appear to be of industrial origin.
     The Environmental Protection Agency has  quantified
levels .of isophorone  in finished drinking water  in the New
Orleans area (EPA, 1974a).  At the Carrollton Water Plant
(City of New Orleans), and at two water treatment sites  in
Jefferson Parish, the highest measured isophorone concentra-
tions were 1.5, 2.2 and 2.9 ug/1, respectively.
     The National Organics Reconnaissance Survey/ initiated
in 1974, was designed to provide an estimate  of  the nation-
wide distribution of organic compounds in drinking water
(EPA, 1975).  In a comprehensive organic analysis of the
finished drinking waters of ten cities, isophorone was
identified only in Cincinnati, at a level of  0.02 ug/1.  The
Cincinnati water source was categorized as being contaminated
with industrial discharges.  Isophorone was not  found in  the
waters of Miami (FL), Seattle (WA), Ottumwa (IA), Philadel-
phia (PA), Tucson (AR), New York (NY), Lawrence  (MA), Grand
Forks (ND), or Terrebonne Parish (LA).
     EPA also maintains an inventory of organic  compounds
that have been isolated and identified in drinking water  in
the United States (EPA, 1975).  Two hundred and  fifty-three
compounds were compiled from an extensive search of the
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                                                TABLE 2

                               Water Types Contaminated with Isophorone
   Finished
   Drinking
    Water
               Effluent from
River
Latex
Plant
Chemical
Plant
Tire
Plant
Concentration
Reference
o
i
01
                                       9.5 ug/1 highest concen-
                                       tration reported in a
                                       nationwide survey

                                       1.5-2.9 ug/1, treated
                                       river water, New Orleans
                                       area

                                       trace (<0.01 ppb),
                                       Delaware River
                                                      0.04 mg/1
                                                                                   EPA  (1975)
                                                                                  EPA  (1974)
                                                          Sheldon and Hites
                                                          (1978)

                                                          Shackelford and
                                                          Keith  (1976)

                                                          Jungclaus, et al.
                                                          (1976)

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chemical literature and  from EPA  reports  generated  from the
Agency's analytical activities.   Although the  compounds in-
cluded in the inventory  were based  upon an analysis of  only  a
few (unspecified) public water  supplies,  isophorone was
nevertheless detected  at concentrations as high  as  9.5  ug/1.
     In a primarily qualitative study, Sheldon and  Kites
(1978) recently  found  trace quantitites (<0.01 ppb) of  iso-
phorone in water samples from the Delaware River near a
highly industrialized  region.   Isophorone was  also  identified
as a contaminant (approximate concentration, 0.04 mg/1) in
the wastewater from a  tire manufacturing  plant (Jungclaus, et
al. 1976).  Shackelford  and Keith (1976)  have  reported  that
isophorone has been detected in the effluents  from  latex and
chemical plants  in Alabama, but no  levels were reported.
Ingestion from ,Foods
     No reports  have been published concerning the  possible
presence of isophorone in food.
     A bioconcentration  factor  (BCF)  relates the concentra-
tion of a chemical in  water to  the  concentration in aquatic
organisms, but BCF's are not available for the edible portion
of all four major groups of aquatic organisms  consumed  in the
United States.   Since  data indicate that  the BCF for lipid-
soluble compounds is proportional to  percent lipids, BCF's
can be 'adjusted  to edible portions  using  data  on percent
lipids and the amounts of various species consumed  by Ameri-
cans.  A recent  survey on fish  and  shellfish consumption in
the Uni'ted States (Cordle, et al. 1978) found  that  the  per
capita consumption is  18.7 g/day.  From the data on the nine-
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teen major species identified in the survey and data on  the
fat content of the edible portion of these species  (Sidweli,
et al. 1974), the relative consumption of the four  major
groups and the weighted average percent lipids for  each  group
can be calculated:
                              Consumption    Weighted Average
         Group                 (Percent)      Percent Lipids
Freshwater fishes                 12                4.8
Saltwater fishes                  61                2.3
Saltwater molluscs                 9                1.2
Saltwater decapods                18                1.2
Using the percentages for consumption and lipids  for each  of
these groups, the weighted average percent lipids is 2.3 for
consumed fish and shellfish.
                                                          i
     A measured steady-state bioconcentration factor of  7  was
obtained for isophorone using bluegills containing  about one
percent lipids (U.S. EPA, 1978).  An adjustment factor of
2.3/1.0 = 2.3 can be used to adjust the measured  BCF from  the
1.0 percent lipids of the bluegill to the 2.3 percent lipids
that is the weighted average for consumed fish and  shellfish.
Thus, the weighted average bioconcentration factor  for iso-
phorone and the edible portion of all aquatic organisms  con-
sumed by Americans is calculated to be 7 x 2.3 =  16.
Inhalation
     No iponitoring information is available on the  levels  of
isophorone in ambient air.
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Dermal

     No direct information  is available on  the  importance  of


dermal absorption  in total  human exposure to  isophorone.   It


has been demonstrated  that  isophorone can be  absorbed  across


the skin of rabbits  (see Acute, Sub-acute,  and  Chronic


Toxicity section).   For those humans exposed  only  to back-


ground levels of isophorone, however, dermal  absorption  is


not likely to be a significant route of entry.


                       PHARMACOKINETICS


Absorption


     No direct quantitative information is  available on  the


absorption of isophorone in animals or man.   The demonstrated


toxicity of isophorone by oral, inhalation  and  dermal  expo-


sures (Acute, Sub-acute, and Chronic Toxicity section) in-


dicates that it is capable  of passage across  epithelial


membranes.

Distribution
•«^MM^_BMMV^^M^M_^^MM^W>—A                      V

     The tissue distribution and accumulation of isophorone


has not been studied.


Metabolism and Excretion


     Isophorone appears to  undergo oxidation  at the 3-methyl


group following oral administration of 1 g/kg to rabbits


(Truhaut, et al. 1970).  This reaction, shown below, precedes


glucuronide conjugation and urinary elimination.


           CM
             i.    ^"^                 I .I"1       -.
                                                 COOH
                             C-8

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The complete reaction sequence for isophorone biotransforma-



tion has not been determined and no quantitative data on the



extent of glucuronic acid conjugation are available.



     Isophorone has been detected as a urinary metabolite of



3,5,5-trimethylcyclohexanone in rats and rabbits (Truhaut, et



al. 1973).  A large percentage of the metabolite was present



as a glucuronide conjugate.



                           EFFECTS



Acute, Sub-acute, and Chronic Toxicity



     Effects on Experimental Mammals:  The acute toxicology



of isophorone is summarized in Table 3.  Oral LDso values in



the area of 2 gm/kg body weight have been reported for  rats



and mice by several authors.



     The Union Carbide Corporation reported a single skin



penetration LD5Q value of 1.39 g/kg in rabbits in a 1975



technical data1 booklet.  Single skin penetration refers to a



24-hour covered skin contact with the isophorone, but no de-



tails regarding the number of animals exposed nor any other



aspects of the experimental protocol were presented.



     Smyth and Seaton (1940) reported that 750 ppm was  the



highest concentration of isophorone to which rats and guinea



pigs could be exposed for several hours with no symptoms



other than slight eye and nose irritation.  The symptoms ex-



hibited by the animals following exposures to higher concen-



trations included eye and nose irritation, lacrimation,



swelling of the nose, instability, respiratory difficulty or



irregularity, marked increase in intestinal peristalsis and



light sarcosis (Table 4).  Exposures lasting 12 hours or more
                             C-9

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resulted in increased heart rates.  Opacity of  the  cornea  or



corneal necrosis, as revealed by Fluorescin staining,  was



found in the guinea pigs  following exposures  to 840  ppm  iso-



phorone lasting four hours or more.  Corneal  effects were



never observed in the rats.
                             C-10

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                                                                TABLE  3

                                                     Acute Toxicology  of  Isophorone
Route Animal
Oral Rats
Rats
Rats
n Rats
i
»-•
t^
r^
Mice
Dermal Rabbits
Inhalation'3 Rats and
Guinea Pigs
Rats
Guinea Pigs
Rats
Number Treated
per dose level3 Dose
n.s. 1.87 gAg
5 2.10 gAg
5 2.12 gAg
n.s. 2.37 gAg
n.s. 2.00 gAg
n.s. 1.39 gAg
n.s. 750 ppm
n.s. 1B40 ppro
n.s. 4600
6 Air saturated
with isophorone
Duration Mortality
LD50
14 day LD5o
14 day LDjn
U>50
LD50
LD50
"several" No death or
hours serious symptoms
4 hrs. Caused death in
some animals
8 hrs. No deaths
8 hrs. One death
Reference
Union Carbide
(1975)
Smyth, et al.
(1969)
Smyth, et al.
(1970)
Bukhalovskii,
et al. (1976)
Bukhalovskii,
et al. (1976)
Union Carbide
(1975)
Smyth and Seaton
(1940)
Smyth and Seaton
(1940)
Smyth and Seaton
(1940)
Union Carbide
(1975)
an.s. = not specified.
b600 ppm is the maximum attainable concentration of Isophorone in air (see discussion on page  C-13 and  appendix).

-------
o
I
H
to
                 Symptoms  Resulting From Acute Exposure of. buinea Pigs to isbphoron'e Vapors9'"3
                                          (Smyth and Seatonj i§40)
Concentration in PPM
Symptoms
Maximum exposure period (minutes)
Nasal irritation (rub nose)
Eye irritation (blink)
Lacrimation
Nose swollen
Instability
Respiratory difficulty
Diarrhea
Light narcosis
First death
4 , 600
480
(1)
(1)
5
8
40
60
120
180
(2)
1,840
360
U)
(1)
is
20
50
120
180
200
(2)
1>370
480
(1)
(i)
20
30
80
180
240
255
(2)
880
720
(1)
(i)
71,
75
135
360
480
600
(2)
750
1,440
15
15
(2}
(2)
(2)
(2)
(2)
(2)
(2)
300
1,440
(2)
(2)
(2)
(2)
(2)
'(2)
(2)
M
(2)
       (1)  At very  start  of  Exposure.
       (2)  Not  observed within  maximum exposure period.
       aNumbers are time  in  minutes  for first animal to display symptom indicated.  Time required
         for similar effects to be displayed by rats was about 2/3 of that for guinea pigs.
       b600 ppm is  the maximum  attainable concentration of Isophorone in air (see discussion on
         page C-13  and appendix).

-------
     Eight hour inhalation exposures to 4600 ppm  isophorone



did not result in any deaths to guinea pigs, but  in rats  a



four hour exposure to 1840 ppm was the minimum lethal  level



(Smyth and Seaton, 1940).  When death occurred it was  usually



during the exposure period due to paralysis of the respira-



tory center (narcosis).  A few deaths were attributed  to  lung



irritation.



     It must be noted that Rowe and Wolf  (1963) have  indi-



cated that the isophorone vapor concentrations reported by



Smyth and Seaton in this study (1940), and those  in a  related



subacute study described subsequently (Smyth, et  al.  1941;



1942), could not have been attained under the conditions



employed.  Later investigation led to the conclusion  that the



material used in the Smyth studies was an impure  commercial



product containing appreciable amounts of material(s)  more



volatile than isophorone (Rowe and Wolf,  1963).   Smyth main-



tained vapor concentrations in a flow-through chamber  by



bubbling air through the solvent in a constant temperature



bath and diluting the vapor stream with pure air,  and  moni-



tored the concentrations with an interferometer.   Since the



concentration of vapors within the exposure chamber was



measured by means of an  interferometer calibrated against



pure isophorone, it was apparently assumed that the vapors



present in the chamber were isophorone.



     A calculation of the maximum attainable concentration of



isophorone in air at standard temperature and pressure, pre-



sented in the appendix, yields a value of approximately 600



ppm.  This calculation indicates that the allegation  of Rowe
                             C-13

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and Wolf is probably correct and  implies  that  the value of



the Smyth data is seriously compromised.



     The microscopic pathology of those animals  surviving



acute exposure by 14 days was almost never severe and was



essentially reversible  (Smyth and Seaton, 1940).  Pathologi-



cal findings were reported for 95 percent of the lungs



(general congestion; alveolar and bronchiolar  secretion, red



cell leakage and epithelial cell  desquamation;  secondary



pneumonia), 56 percent  of the kidneys  (cloudy  swelling, dila-



tion, granular detritis and hyaline casts in convoluted



tubules; dilation of Bowman's capsule; general  congestion),



30 percent of the hearts  (dilation of  coronary  vessels), 17



percent of the livers  (congestion; hemorrhages  into parenchy-



ma; cloudy swelling) and  10 percent of the spleens  (conges-



tion).  The typical hematologic response  to acute isophorone



intoxication was a temporary drop1 in red  cells  and hemo-



globin, with white cells  appearing to  be  unchanged.



     Union Carbide (1975) reported that a single eight hour



innalation exposure to  air saturated with isophorone  (calcu-



lated concentration approximately 600  ppm) killed one of six



rats.



     Iri 1942, Smyth and coworkers compared the  subacute in-



halation toxicity of isophorone in rats and guinea pigs.  The



mortality and pathological details of  this study were origi-



nally reported by Smyth (1941).   Groups of ten  rats and ten



quinen piqs were reportedly exposed to isophorone vapors at



concentrations ranging  from 25 to 500  ppm for  eight hrs/day,



five days a week for six  weeks, but the experimental  methods
                             C-14

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utilized were similar to those described for  the Smyth  and
Seaton (1940) study.  Since it appears that this experiment
was also conducted with impure material and that the  concen-
tration of the isophorone tested is not accurately known
(Rowe and Wolf, 1963), these results are also of limited   ,
value.  The dose-related effects produced by  the 25 to  500
ppm exposures are summarized in Table 5.  Although about  half
the animals exposed to isophorone at 500 ppm  died before  the
thirtieth exposure; no guinea pigs died from  exposures  at 100
ppm or less, and no rats died from inhalation of vapors at  50
ppm or less.
     When death resulted from subacute inhalation exposure  it
appeared to be due to a combination of kidney and lung
damage, although none of the surviving animals  showed any-
severe grade of injury to these organs (Smyth,  et al. 1941;
1942).  The microscopic picture of various  tissues from the
survivors was rather uniform, varying in degree with  the  con-
centration breathed.  The lungs were frequently injured,
showing primarily congestion and leakage of red blood cells
into alveoli.  Cloudy swelling with increased secretion and
dilation of Bowman's capsule was a common finding  in  the  kid-
ney, but the action of isophorone on the liver, heart and
spleen was negligible.  Guinea pigs exposed to  500 ppm showed
an increase in polymorphonuclear white cells  and a corres-
ponding fall in lymphocytes, but no other consistent  changes
in hematologic parameters were found.
                             C-15

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                                                              TABLE  5

                                             Subacute Inhalation Toxicity  of  Isophorone
                                                            (Smyth, 1941)
Animal
   Concentration3
       (ppro)          Hr/Day
                                                              Duration
                                                               (Days)
Mortalityb
           Details
I
h-
a\
Rats
male, Wistar,
90-120 g
Guinea Pigs
both sexes,
250-300 g
         25



         50


        100


        200




         25



        100


        200


        500
                                       8


                                       8


                                       8
                                                         42  (30  exposures,
                                                         5 days/wk  x  6  wks)
                                                42 (30 exposures,
                                                5 days/wk x 6 wks)

                                                42 (30 exposures,
                                                5 days/wk x 6 wks)

                                                42 (30 exposures,
                                                5 days/wk x 6 wks)
                                                         42  (30  exposures,
                                                         5 days/wk  x  6  wks)
                                                         42  (30  exposures,
                                                         5 days/wk  x  6  wks)

                                                         42  (30  exposures,
                                                         5 days/wk  x  6  wks)

                                                         42  (30  exposures,
                                                         5 days/wk  x  6  wks)
    0%



    0%


   20%


   10%




    0%



    0%


   25%


   40%
No apparent signs of toxicity
Evidence of lung and kidney
pathology

Evidence of lung, spleen and
kidney pathology

Evidence of lung, spleen and
kidney pathology} conjunctivitis
and nasal irritation} urine
albumin

No apparent signs of toxicity
Evidence of lung and kidney
pathology} weight loss

Evidence of lung and kidney
pathology} weight loss

Evidence of lung, kidney and
liver pathology; conjunctivitis
and nasal irritation; weight
loss; increase in polymorpho-
nuclear white cells with a cor-
responding fall in lymphocytes
aRowe and Wolf
  trations are
bPercentage of
(1963) have indicated that the isophorone used in this study was impure and that  the  reported  concen-
higher than actually present (see discussion on page C-13 and appendix).
animals dying; usually 10 animals were tested at each dosage.

-------
     Smyth (1941) indicated that during the course of  the

study, both control and exposed animals, especially  the

guinea pigs, were troubled with infections  (parasites,  intes-

tinal protozoa and bacteria).  Although the affected animals

were reportedly eliminated from consideration,  the signifi-

cance of the infection on the other animals is  difficult to

ascertain.

     Subacute (90 day) feeding studies on  isophorone in  rats

and dogs have also been conducted  (EPA, 1979a).

     In the rat study, CFE albino weanlings were  divided into

4 groups of 20 males and females each and  fed 0,  750,  1500 or

3000 ppm isophorone in the daily diet (EPA, 1979a).  Individ-

ual body weights, food and compound consumption were tabu-

lated weekly.  After four weeks and at 90  days, five rats/

sex/group were killed and blood was collected for hematologi-

cal and clinical chemistry determinations.  Urine was  col-

lected from an additional five males and five females  per
         t
group at the same time and was also comprehensively  analyzed.

The rats sacrificed after four weeks were  examined for gross

pathology only, but after 90 days  tissues  from  ten rats  of

each sex from the control and 3000 ppm groups were examined

histologically.  The livers and kidneys from  five rats/sex

from the 750 and 1500 ppm groups were also examined.

     Two rats died during the study, one in the control  group

and one in the 3000 ppm group, of  an unspecified  infection

unrelated to the administration of isophorone.  The  body

weights and food consumption were  not significantly  affected

at the end of the study by feeding isophorone although the
                             C-17

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body weight of the 3000 ppm male group was  significantly
depressed for several weeks during  the study.  There was  no
significant difference between  the  treated  and control  groups
regarding hematology, blood chemistry or urinalysis, and  no
pathological lesions were observerd by either gross or  micro-
scopic examination.
     In the dog study, four male and four female  beagles  were
fed isophorone for 90 days at doses of 0, 35, 75  and 150
mg/kg/day, in gelatin capsules  (food containing  isophorone
was refused).  The dogs were weighed weekly and  bled monthly
        »
for hematological blood chemistry evaluation, and  urine was
collected and analyzed on the same  schedule as the blood.
All the animals survived  the study  and were killed after  90
days and examined grossly.  Twenty-eight selected  tissues
from the control and high level (150 mg/kg) groups were ex-
amined histologically, as were  liver and kidney  specimens
from the intermediate exposure  groups.
     All dogs survived the study in excellent condition (EPA,
1979a).  Food consumption was within normal limits and  body
weight was not affected by treatment.
     The hematology, biochemical, and urinalyses  tests  indi-
cated a lack of untoward effect of  90 doses of isophorone.
All organs appeared normal at gross examination  and no  sig-
nificant changes in organ weight were produced with the
ingestion of isophorone.  There was no evidence  of any  de-
finitive signs of cellular change in any of the  tissues
examined.
                             C-18

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     Isophorone has been shown to be weakly  irritating  to  the



skin of rabbits, but its effect was stronger on  the  ocular



mucosa where it induced reversible irritation of  the conjunc-



tiva and corneal opacity (Truhaut, et al. 1972).   These  lat-



ter results are consistent with the moderate rabbit  eye  irri-



tation ratings for isophorone reported by Carpenter  and  Smyth



(1946) and Union Carbide (1963).



     Effects on Humans:  The most significant consequence  of



human exposure to low levels of isophorone vapor  is  irrita-



tion of mucosal membranes.  In this respect  isophorone  is



probably the most irritating of all ketonic  solvents.   Smyth



and Seaton (1940) reported that groups of 11 or  12 human



subjects exposed for a few minutes to measured concentrations



of 40, 85, 200 and 400 ppm isophorone in a small  room experi-



enced eye, nose and throat irritation, but it appears that



these exposure concentrations were higher than actually



present (see discussion on page C-13).  A few complaints of



nausea, headache, dizziness, faintness,  inebriation  and  a



feeling of suffocation resulted from inhalation  of isophorone



at 200 and 400 ppm in air.  However, the symptoms of irrita-



tion and narcotic action were less severe at concentrations



of 40 and 85 ppm.



     In a sensory threshold study, Silverman, et  al. (1946)



exposed humans to the vapors of several  industrial solvents



including isophorone.  Twelve unconditioned  subjects of  both



sexes were exposed to the vapors for 15 minute periods  in  a



1200 ft3 chamber.  They found that exposure  to 25 ppm iso-



phorone produced irritation of the eyes, nose, and throat,'
                             C-19

-------
and that isophorone vapors were  considered  by  the  subjects  to
be the most irritating of all  the ketonic solvents  tested.
The highest tolerable level  for  an  eight hour  isophorone  ex-
posure was judged to be  10 ppm by a majority of  the subjects.
It should be noted that  the  concentration of isophorone  in
the exposure chamber was calculated  (nominal)  rather than
measured analytically, so the  true  concentration may have
been different than reported  (NIOSH,  1978).
     Union Carbide (1963) indicated  that one-minute exposures
to 200 ppm isophorone are intolerable for humans.   A concen-
tration of 40 ppm was intolerable to  half of an  unspecified
number of human volunteers after four minutes.   Union Carbide
also noted that isophorone did not  cause allergic  contact
sensitization in any of  the  ten  human volunteers.
Synergism and/or Antagonism
     Smyth and coworkers (1969,  1970) have  examined the  joint
toxic action of isophorone with  26  industrial  liquid chemi-
cals based on acute LDso's from  oral  intubations of female
albino rats.  In the initial study  (Smyth,  et  al.  1969),
LDso's were determined for each  of  the  compounds alone and
for 1:1 (v/v) mixtures of the  compounds.  Based  on  the as-
sumption' of simple similar action,  isophorone  evidenced
greater than additive toxicity in combination  with  nine  com-
pounds and less than additive  toxicity  in combination with  17
compounds.  The significance of  the  interactions was deter-
mined by modifying the interactive  ratios (predicted/observed
LC50) so' that the distribution approximated normality.  Sig-
                             C-20

-------
nificant interaction was then defined as those ratios which



were beyond 1.96 standard deviations from the mean ratio.  By



this criterion, none of the mixtures containing  isophorone



deviated significantly from the assumption of simple similar



action.  In a subsequent study (Smyth, et al. 1970), equal



volume mixtures of isophorone and propylene oxide showed



markedly less than additive toxicity but equitoxic mixtures



showed slightly greater than additive toxicity.



Teratogenicity



     Isophorone has apparently not been tested for terato-



genicity.



Mutagenicity



     No mutagenicity data for isophorone were encountered  in



the published literature.



Carcinogenicity



     Isophorone has tentatively been selected for carcino-



genesis testing in rats and mice by gavage by the National



Cancer Institute (NCI, 1979).  Apparently, isophorone was



selected on the basis of its reported presence in municipal



water supplies, the large number of workers exposed  indus-



trially (>1,500,000), a projected increase in production



levels (>25 million pounds are currently being produced),  and



the existing paucity of epidemiological, animal  and  metabolic



information (Personal communication, 1979).
                             C-21

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                     CRITERION  FORMULATION
Existing Guidelines  and  Standards
     The current  eight-hour  time-weighted  average threshold
limit value  (TLV)  for  isophorone established  by  the  American
Conference of Governmental Industrial Hygienists (1977)  is  5
ppm  (~ 28 mg/m3).  The TLV was  lowered  from 25 ppm (<-*140
mg/m3) to 5 ppm in response  to  a June 1973 communication
from the Western  Electric Company  to the TLV  committee re-
garding fatigue and  malaise  among  workers  exposed to levels
of 5 to 8 ppm for  one  month  (Am. Conf.  Gov. Ind.  Hyg., 1974).
When isophorone levels in air were lowered to 1  to 4 ppm
(/^ 6-23 mg/m3) by  increasing exhaust ventilation,  no fur-
ther complaints were received.
     The current U.S.  Federal standard  for occupational expo-
sure to isophorone is  25 ppm (140  mg/m3) as an eight-hour
time-weighted average  concentration limit  in  the  air of the
working environment  (Occup.  Safety Health Admin.,  1974).
This standard is based on the TLV  adopted by  the  ACGIH in
1968, and is intended  to prevent irritative and  narcotic ef-
fects.  The National Institute  for Occupational  Safety and
Health (NIOSH) currently recommends a permissible  exposure
limit of 4 ppn (23 mg/m3) as a  TWA concentration  for up to
a 10-hour workshift, 40-hour work  week  (Natl.  Inst.  Occup.
Safety Health, 1978).  The NIOSH recommended  standard is es-
sentially based on the 1974  ACGIH  TLV documentation.
     Isophorone was exempted from  the requirement  of  a toler-
ance und?er the Federal Food, Drug  and Cosmetic Act when used
as an inert solvent or cosolvent in pesticide formulations
                             C-22

-------
before a crop emerges from the soil, and for post-emergence



use both on rice before the crop begins to head and on  sugar



and table beets (U.S. EPA, 1974b).



Current Levels of Exposure



     As detailed in the Exposure section of this  report,  only



limited monitoring data are available regarding levels  of



isophorone in water, and virtually no information is  avail-



able on ambient levels in air or food.  Since  there is  a  lack



of extensive monitoring data on isophorone levels in  drinking



water, it is difficult to predict the magnitude or extent of



human population exposure.



     Although isophorone has been detected at  levels  of less



than 3 ppt in several water samples, a maximum daily  intake



can be calculated from the highest reported level (9.5  y.g/1;



U.S. EPA, 1975) by assuming that 100 percent exposure comes



from the ingestion of water and fish and shellfish from con-



taminated waters.  Assuming:  (a) an average daily consump-



tion of 2 liters of water plus 18.7 grams fish/shellfish; (b)



a bioconcentration factor of 16 (U.S. EPA, 1979b); and  (c)



100 percent gastrointestinal absorption of the ingested iso-



phorone; then the daily intake of isophorone from water would



be 21.8 ug/day (9.5 y.g/1 x  [2 liters +  (16 x 0.0187)] x



1.0).



Special Groups at Risk



     Certain occupations (particularly  individuals who  are



exposed to isophorone as a solvent) have elevated levels  of



exposure relative to the general population.
                             C-23

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Basis and Derivation of Criterion .
     Based on the available data on the toxicological  effects
of isophorone absorption  in both man and experimental  ani-
mals, a calculated water  quality criterion  for  isophorone can
only be based upon a non-carcinogenic end point.  Water
quality criteria may therefore be derived from  the TLV,  acute
oral LDso values, or from subacute oral toxicity data  using
non-carcinogenic biological responses.  Criteria derivations
based on all three approaches are presented below.
     Criterion Based on TLV:  Stokinger and Woodward  (1958)
presented a method for calculating equivalent water quality
levels from TLV's.  Essentially, this method consists  of
deriving an acceptable daily intake (ADI) from  the TLV by
making assumptions on breathing rate, and respiratory  and
gastrointestinal absorption.  Stokinger and Woodward assumed
that the daily total pollutant uptake from  air  at the  TLV
concentration can be safely tolerated, and  that this safe
quantity of pollutant per day can-be similarly  tolerated via
oral exposure.  The ADI is then partitioned into permissible
amounts from drinking water and from other  sources.
     The International Commission on Radiological Protection
(1974) has estimated that the "reference man" breathes 7.6 m3
of air during eight-hours of "light activity."  Since  respi-
ratory absorption rates are unknown, 50 percent absorption of
inhaled'isophorone will be assumed.  In addition, the  five
day per week TLV may be converted to a seven day per week
equivalent to reflect the more continuous pattern of exposure
                              C-24

-------
via drinking water.  An ADI for man can be thus calculated

from the TLV by multiplying by these factors:

     28 mg/m^ x7.6m^x0.5x5 days/7days = 76 mg/day

Since es-timates of isophorone exposure from non-water sources

are not available, it will be assumed that total isophorone

exposure is attributable to the ingestion of drinking water

and fish and shellfish.  For the purpose of estimating a  cri-

terion it will be further assumed that the maximal daily  in-

take of water is 2 liters, that the consumption of fish/shell

fish amounts to 18.7 grams/day, and that the gastrointestinal

absorption of isophorone is 100 percent.  Also a bioconcentra

tion factor of 16 has been calculated for fish (U.S. EPA,

1979b).  A water quality criterion may then be calculated as:

            	76 mg/man	_,    ,.         \
            (21+ [16 x 0.0187]) x 1.0 ~ JJ mg/J-

     It should be noted that the TLV is based on the preven-

tion of the irritant effects of isophorone from inhalation

exposures, rather than on chronic effects.  Consequently, the

development of a criterion by this approach probably has

little validity in this case.

     Criterion Based on Acute Oral Toxicity Data:  McNamara

(1976) has suggested that data from acute exposures can be

used to estimate chronic no-effect levels for toxic responses

to chemical absorption.  Based on an extensive review of  the

literature comparing the results of acute and chronic toxicity

bioassays, McNamara noted that "for 95 percent of chemical

compounds...[on which data were available]...LD5Q/1000 will
                             C-25

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produce no effects  in  a  lifetime."  Using  this  approximation

for isophorone, and an average oral LD5Q value  of  2  g/kg

(Effects section),  the no-observable-effect  level  for  iso-

phorone in rats can be estimated at 2 mg/kg/day.   This value

may be converted  into  an ADI by applying an  appropriate uncer-

tainty factor to  account for species extrapolation and limita-

tions of the data.  Since the chronic no-effect dose is merely

an estimate based on observed relationships  between  acute and

chronic toxicity, an uncertainty factor of 1,000 is  recommended

(see Natl. Acad.  Sci., 1977, p. 804).  Thus,  the estimated  ADI

for man is ug/kg  or 140  ug/roan, assuming a 70 kg body  weight.

By assum ing that man  consumes 2 liters of water per day, that

man is additionally exposed daily to 18.7  grams of fish and

shellfish which bioaccumulate isophorone from water  by a factor

of 16, and that gastrointestinal absorption  is  100 percent,  the

corresponding no-adverse-effect level in water  can be  calcu-

lated as follows:

            	140 ug/day	 _  fi,    .,
            (21+  [16 x 0.0187]) x 1.0 ~  bl ug/1

Based on these calculations, the criterion for  isophorone

should not exceed 0.06 mg/1.

     Criterion Based on  Subacute Oral Data:  As summarized  in

the Effects section, no  significant effects  were produced in

beagle dogs by feeding isophorone in gelatin capsules  at

levels up to 150  mg/kg/day for 90 days (U.S. EPA,  1979a).   Due
                                   L
to the fact that  this  study did not involve  a truly  chronic ex-
                              C-26

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posure, the Natl. Acad. Sci. (1977) guidelines for establising


an acceptable daily intake for man are not directly applicable


McNamara (1976) has suggested, however, that subacute exposures

                                                           r
can be used to estimate chronic no-effect exposure levels.


     McNamara (1976) found that for 95 percent of chemical 'com-


pounds for which data were available, a three-month no-effect


dose/10 will yield a level which should produce no adverse ef-


fects in a lifetime.  By using this relationship, the chronic


no-effect dose for dogs is calculated to be:


                     150 ^ = 15 mg/kg


The application of an uncertainty factor of 1000 is suggested


to convert this value to an ADI (see Natl. Acad. Sci., 1977,


p. 804).  Therefore, an estimated ADI for man is 15 ug/kg or


1,050 ug/man, assuming a 70 kg body weight.  Consumption of 2


liters of water daily and of 18.7 grams of contaminated aquatic


organisms which have a bioconcentration factor of 16 would


result in, assuming 100 percent gastrointestional absorption of


isophorone, a maximum permissible concentration of 0.46 mg/1


for the ingested water:


            	1050 ug/dav	
            (21+  [16 x 0.0187]) x 1.0   *D/ ug/J-


     In conclusion, criterion levels for isophorone can be esti-


mated on the basis of a TLV (33 mg/1), acute oral toxicity data


(0.06 mq/1), and a 90-day feeding study in dogs (0.46 mg/1).
                             C-27

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         The most prudent approach  at  this  time  would  be  to



recommend only an interim criteria  level  pending the  results of



future research, including  the planned NCI  bioassay.   An  in-



terim criterion of  0.46 mg/1  could  be  recommended in  cases



where ambient water  is the  sole  source of exposure to  iso-



phorone, because the  basis  for this value is  a well defined



no-effect level derived from  a higher  vertebrate species  (dog)



subjected to subchronic oral  exposure.  Since current  levels



of isophorone in water are  usually  less than  3 v.g/1,  although



amounts as high as  9.5 ug/1 have been  reported,  an ample



margin of safety apparently exists.



     In summary, based on the use of subchronic  dog toxico-



logical data and an  uncertainty  factor of 1,000,  the  criterion



level of isophorone  corresponding to an acceptable daily  in-



take of 15 ug/kg/day,  is 0.46 mg/1.  Drinking water contrib-



utes 87 percent of  the assumed exposure while eating  contami-



nated fish products  accounts  for 13 percent.   The criterion



level can similarly  be expressed as 3.5 mg/1  if  exposure  is



assumed to be from  the consumption  of  fish  and shellfish  pro-



ducts alone.
                              C-28

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                          REFERENCES


ACGIH. 1974.  American Conference of Governmental Industrial
Hygienists:   Documentation of. the threshold limit values for
substances in workroom air.  Edition 3, 1971, Cincinnati, 2nd
printing, p. 327.


ACGIH. 1977.  American Conference of Governmental Industrial
Hygienists:   Threshold limit values for chemical substances
and physical agents in the workroom environment with intended
changes for 1977.  Cincinnati, Ohio.


Altman, P.L., and D.S. Dittmer. 1974.  Biology Data Book, 2nd
edition, Vol. 3, p. 1581.  Federation of American Societies
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Blackford, J.S. 1975.  Acetone.  Chemical Economics Handbook,
Stanford Research Institute, Menlo Park, California.


Buklalovski, A.A., and B.B. Shugeav. 1976.  Toxicity and
hygienic standardization of isophorone, dihydroisophorone,
and dimethylphenylcarbinol.  Prom-st. Sint. Kauch. p. 4.
                                                         r

Carpenter, C.P., and H.F. Smyth. 1946.  Chemical burns of the
rabbit cornea.  Arru I. CsthaLmol. 29: 1363.
                             C-29

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Cordle, F., et al. 1978.  Human exposure to poloychlorinated
biphenyls and polybrominated biphenyls.  Environ. Health
Perspectives 24: 157.

Haruta, H., et al. 1974.  New plant growth retardants.  II.
Syntheses and plant growth retardant activities of quaternary
ammonium compounds derived from  -lonone and isophorone.
Agric. Biol. Chem. 38: 417.

International Commission on Radiological Protection. 1974.
Report of the task group on reference man.  Pergamon Press,
New York.

Jungclaus, G.A., et al. 1976.  Identification of trace or-
ganic compounds in tire manufacturing plant waste waters.
Anal. Chem. 48: 1894.

McNamara. 1976.  Concepts in health evaluation of commercial
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National Academy of Science. 1977.  Drinking water and
health.  National Research Council, National Academy of
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                             C-30

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National Cancer Institute.  1979.  Chemicals on standard



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NIOSH. 1978.  National Institute for Occupational Safety and
                                        i


Health.  Criteria for a recommended standard...occupational



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OSHA. 1974.  Standards and documentation.  Occupational



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23540.






Personal Communications. 1979.  Enclosures provided by Sharon



Leeney, Secretary to the Assistant Coordinator for Environ-



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for chemical selection - isophorone, (2) "Minutes - chemical



selection working group", August 25, 1977, (3) "Minutes -



sixth meeting of the chemical selection subgroup of the



clearinghouse on environmental carcinogens", November 1,



1977.

                           «





Rowe, V.K., and M.A. Wolf. 1963.  Ketones.  In: Industrial



Hygiene and Toxicology.  P.A. Patty  (ed.) 2nd ed.  Inter-



science Publ. New York. 1764.
                             C-31

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Shackelford, W.M., and L.H. Keith. 1976.  Frequency  of



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626.








Sheldon, L.S., and R.A. Kites. 1978.  Organic  compounds  in



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Sidwell, V.D., et al. 1974.  Composition of the edible por-



tion of raw  (fresh or frozen) crustaceans, finfish,  and  mol-



lusks.  I.   Protein, fat, moisture, ash, carbohydrate, energy



value, and cholestrol.  Mar. Fisheries Review  36:  21.








Silverman, L., et al. 1946.  Further studies on sensory



response to  certain  industrial solvent vapors.  Jour. Ind.



Hyg. Toxicol. 28: 262.








Smyth, Jr.,  H.F. 1941.  Response of guinea pigs and  rats to



repeated inhalation  of the vapors of isophorone.   Mellon



Institute of  Industrial Research.  Report 4.








Smyth, Jr.,  H.F., and J. Seaton. 1940.  Acute  response of



guinea pigs  and rats to inhalation of the vapors of  iso-



phorone.  Jour. Ind. Hyg. Toxicol. 22: 477.








Smyth, Jr.,  H.F., et al. 1942.  Response to guinea pigs  and



rats to repeated inhalation vapors of mesityl  oxide  and  iso-



phorone.  Jour. Ind. Hyg. Toxicol. 24: 46.
                             C-32

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Smyth, Jr., H.F., et al.  1969.  Exploration of joint toxic



action:  Twenty-seven industrial chemicals intubated in rats



in all possible pairs.  Toxicol. Appl. Pharmacol. 14: 340.








Smyth, Jr., H.F., et al.  1970.  An exploration of joint toxic



action.  II.  Equitoxic vs. equivolume mixtures.  Toxicol.



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Stokinger, H.E., and R.L. Woodward. 1958.  Toxicologic



methods for establishing  drinking water standards.  Jour.



Amer. Water Works Assoc.  50: 515.








Truhaut, R., et al. 1970.  Metabolic study on an industrial



solvent, isophorone, in the rabbit.  C.R. Acad. Sci. Ser. D.



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Truhaut, R., et al. 1973.  Metabolic transformations of 3,5,



5-trimethylcyclohexanone (dihydroisophorone).  New metabolic



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Union Carbide. 1963.  Toxicology studies - isophorone, sum-



mary data sheet.  Union Carbide Corporation, Industrial



Medicine and Toxicology Department, New York.
                             C-33

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Union Carbide. 1975.  Ketones Technical Booklet  (F-41971A)/
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U.S. EPA. 1974a.  Draft analytical report:  New Orleans area
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U.S. EPA. 1974b.  Exemptions from the requirement of a toler-
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                                        i
U.S. EPA. 1979a.  U.S. Environmental Protection Agency, Pes-
ticides Tolerance Division internal memo from W.E. Parkin
(Toxicology Branch) to D.M. Baker (Pesticides Control Branch)
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Pesticides Programs.
                             C-34

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U.S. EPA. 1979b.  Personal Communication, Environ. Prot,
Agency, Duluth, Minnesota.
                             C-35

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                          Appendix



     Calculation of appropriate  isophorone  concentration ThT



saturated air.



     For a sample  of  ideal  gas,



                          PV  = nRT



where


                            P  = pressure



                            V  = volume



                            n  = number  of moles



                            R  = universal gas  constant



                            T  = absolute  temperature
     Since n = - - ,  the  ideal  gas  equation can be rearranged
               mw

as follows to calculate  the  approximate  number of grams of



compound contained  in  a  particular volume of gas at a speci-



fied temperature and pressure:



                          PV  -  -2-  RT
                               mw



                             _  PV(mw)

                           y     RT





     At 25°C, the  vapor  pressure of isophorone is 0.44mm.



Assuming a 1 liter  volume of air,
                      0.44mm   ,  ,..      ._„  ^,
                             x  1  liter x 138.21
                      760mm
                  g  =  	
                         0.082       :     x 2.98 «K
                    =  0.00327  g  =  3.27  mg
                              C-36

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     The approximate ppm equivalent concentration  of  iso-

phorone in saturated air can then be calculated from  the

relationship:

              (mg/1) (24,450 ml/mole)
                          mw            ppm

          (3.27 mg/1) (24,450 ml/mole)    __a
          	  138.21 g/mole	 =  578 ppm
                             C-37

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