ISOPHORONE Ambient Water Quality Criteria Criteria and Standards Division Office of Water Planning and Standards U.S. Environmental Protection Agency Washington, D.C. ------- 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. ------- 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 ------- 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 ------- 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. A-3 ------- 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 ------- 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 ------- 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. B-l ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 03 I -J 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 ------- I 00 Tatle 4. Freshwater residues for isophorone (U.S. EPA. 1978) Time Organism Bioconcentration Factor (days; Bluegill. 7 28 Leponus macrochirus ------- 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 ------- 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. B-10 ------- "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 OJ I ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 C-l ------- 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 C-2 ------- 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. C-3 ------- 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 C-4 ------- 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) ------- 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- C-6 ------- 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. C-7 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 ------- 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 for Experimental Biology, Bethesda, Maryland. 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 ------- 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 and industrial chemicals. In: Advances in Modern Toxi- cology, Vol. 1, Part 1. New Concepts in Safety Evaluation (Mehlman, M.A., et al. eds.). John Wiley and Sons, New York. p. 455. National Academy of Science. 1977. Drinking water and health. National Research Council, National Academy of Sciences, Washington, D.C. p. 939. C-30 ------- National Cancer Institute. 1979. Chemicals on standard protocol. National Cancer Institute, Carcinogenesis Testing Program. NIOSH. 1978. National Institute for Occupational Safety and i Health. Criteria for a recommended standard...occupational exposure to ketones. DHEW (NIOSH) Publication No. 78-173. p. 243. OSHA. 1974. Standards and documentation. Occupational Safety and Health Administration. Federal Register. 39: 23540. Personal Communications. 1979. Enclosures provided by Sharon Leeney, Secretary to the Assistant Coordinator for Environ- mental Cancer, NCI (Dr. Thomas Cameron): (1) Summary of data 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 ------- Shackelford, W.M., and L.H. Keith. 1976. Frequency of organic compounds identified in water. U.S. EPA. 600/4-76-062. U.S. Environ. Prot. Agency, Athens, GA. p. 626. Sheldon, L.S., and R.A. Kites. 1978. Organic compounds in Delaware River. Environ. Sci. Technol. 12: 1188. 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 ------- 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. Appl. Pharmacol. 17: 498. 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. 271: 1333. Truhaut, R., et al. 1972. Toxicity of an industrial solvent, isophorone. Irritating effect on the skin and mucous mem- branes. Jour. Eur. Toxicol. 5: 31. Truhaut, R., et al. 1973. Metabolic transformations of 3,5, 5-trimethylcyclohexanone (dihydroisophorone). New metabolic pathway dismutation. C.R. Acad. Sci. Ser. D. 276: 2223. Union Carbide. 1963. Toxicology studies - isophorone, sum- mary data sheet. Union Carbide Corporation, Industrial Medicine and Toxicology Department, New York. C-33 ------- Union Carbide. 1975. Ketones Technical Booklet (F-41971A)/ Union Carbide Corporation, Chemical and Plastics Division, New York. U.S. EPA. 1974a. Draft analytical report: New Orleans area water supply study. Region IV, Surveillance and Analysis Division, Lower Mississippi River Facility. U.S. EPA. 1974b. Exemptions from the requirement of a toler- ance. Isophorone. Fed. Regist. 39: 37195. U.S. Environ. Prot. Agency, Washington, D.C. U.S. EPA. 1975. Preliminary assessment of suspected carcino- gens in drinking water: Report to Congress. U.S. Environ. Prot. Agency, Washington, D.C. U.S. EPA. 1978. In-depth studies on health and environmental impacts of selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-4646. 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) regarding Pesticide Petition No. 2F1224. May 11, 1972. Pro- vided by David Ritter, Office of Toxic Substances, Office of Pesticides Programs. C-34 ------- U.S. EPA. 1979b. Personal Communication, Environ. Prot, Agency, Duluth, Minnesota. C-35 ------- 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 ------- 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 ------- |