cyeLOHEXANONE

1. ehemical and Physical Data

1.1 Synonyms

Chem. Absií. Services Reg. No.: 108-94-1Chem. Abstr. Name: Cyclohexanone

IUP AC Systematic Name: Cyclohexyl ketone

Synonym: Ketohexamethylene; pimelic ketone; pimelin ketone

1.2 Structural and molecular fonnulae and molecular weight

CsH1QO

o

Ó MoL. wt: 98.14

1.3 Chemical and physical properties of the pure substance

(a) Description: Colourless liquid with peppermint and acetone odour (Krasavage et

al., 1982; Windholz, 1983)

(b) Boilng-POint: 155.6°C; 47°C at 15 mm Hg (Weast, 1985)

(c) Melting-POint: -16.4°C (Weast, 1985)

(d) Density: 0.948 at 20°C/4°C (Weast, 1985)

(e) Spectroscopy data: N uclear magnetic resonance, inrared and ultraviolet spectral

data have been reported (Sadtler Research Laboratories, 1980; Pouchert, 1981,

1983, 1985).

(j Solubility: Miscible with most organic solvents. Soluble in ethanol, diethyl ether,.

benzene, chloroform and other common organic solvents; soluble in water (150g/l at 10°C, 50 g/l at 30°C) (Kasavage et al., 1982; Windholz, 1983; Weast, 1985)

(g) Volatility: Vapour pressure: 5.2 mm Hg at 25°C (Kasavage et al., 1982)(h) Refractive index 1.4507 at 20°C (Weast, 1985)

(i) Flash-point: 44°C (closed-cup; Krasavage et aL., 1982)

-157-

158 IAC MONOGRAHS VOLUME 47

(¡) Conversion factor: mg/m3 = 4.0 x ppm1

1.4 Technical products and impurities

Trade Names: Anon; Anone; Hexanon; Hytrol 0; Nadone; SextoneCyclohexanone is available in various grades of purity (98% min, ~ 99.8% ). Impunties

reported include formic acid (up to 0.05%) and water (up to 0.2%; Fisher & Van Peppen,1979; Riedel-de Haën, 1984; Eastman Kodak Co., 1985; Aldrich Chemical Co., Inc., 1988).

2. Production, Use, Occurrence and Analysis

2.1 Production and use

(a) Production

Cyclohexanone is produced commercially in several major ways. One widely used pro-cess yields cyclohexanol and cyc1ohexanone by the cåtalytic oxidation of cyclohexane. Thecyclohexanol/cyclohexanone product mixure, also called KA oil, is further reacted to pro-duce adipic acid and hexamethylene diamine, intermediates in the manufacture of nylon 66.Pure cyc1ohexanone can be produced in high yields by this process either by distilation or bycatalytic dehydrogenation of the cyclohexanol (Considine, 1974).

Another important and veiy efficient process is based on the hydrogenation of phenoL.The cyclohexanone produced is further reacted to produce cyclohexanone oxie, an inter-

mediate which then can undergo a Beckmann rearrangement to yield caprolactam (seeIARC, 1986; Considine, 1974; Fisher & Van Peppen, 1979), the importnt intermediate for .

nylon 6 (see IARC, 1979).

Cyclohexanone production and consumption are determined by the demand for rawmaterials for nylon. Other uses are minor and have little effect on overall production.

ln 1979, approxiately 318 () tonnes of cyclohexanone were produced in the USA(Mannsvile Chemical Products Corp., 1979). The US International Trade Commission(1985, 1986, 1987) reported production of approxiately 360 00 tonnes each year in 1984 and1985 and 40 () tonnes in 1986.

Production of cyclohexanone elsewhere in the world has not been documented.

(b) Use

Cyc1ohexanone is used predominantly (about 95% of production in the USA) for thesythesis of raw materials used in the production of nylon. The remainder is used as a chemi-cal intermediate in other processes, as an additive or as a high-boiling, slow-diyg solvent.

lCalculated from: mg/m3 = (molecular weightl24.45) x ppm, asuming standard temperature (25°C) and pres-

sure (760 mm Hg)

CYCLDHEXAONE 159

Cyclohexanone is used as a solvent in insecticides, woo stains, paint and varnish removers,spot removers, cellulosics, and natural and sythetic resins and lacquers. Additive uses in-clude detergents, degreasing of metals, mould release agent for paints or varnishes, levellingagent in dyeing and delusterig silk, and lube oil additive, especially for aircraft piston-tyeengines. Cyclohexanone is also used as a monomer in the sythesis of cyclohexanone resins,polyvyl chloride and its copolymers (see IARC, 1979), and methacrylate ester polymers

(International Technical Information Institute, 1979; Hawley, 1981; Windholz, 1983; Sittig,

1985; American Chemical Society, 1987).

(c) Regulatory status and guidelines

Occupational expsure limits for cyclohexanone in 28 countries or regions are pres-ented in Thble 1.

Table t. Occupational exposure limits for cyclohexanonea

Country or region Year Concentrationb InterpretationC(mg/m3)

Australia 1984 200 1WAAustria 1985 200 1WABelgium 1984 200 1WAB\llgaria 1984 10 1WAChina 1985 50 1WACommission of the Europen 1986 200 1WA

Communities 100 MaxmumCzehoslovakia 1985 200 Average

400 MaxmumDenmark 1988 100 1WAFinland 1987 200 1WA

250 STEL (15 min)France 1986 100 1WAGermany, Federal Republic of 1988 200 1WAHungary 1985 20 1WA

40 1WAIndonesia 1985 200 1WA1 taly 1984 200 1WAJapan 1988 100 1WAMexico 1985 200 1WANetherlands 1986 200 1WANorway 1981 100 1WAPoland 1984 20 1WARumania 1984 100 Average

200 MaxmumSweden 1984 S 100 1WA

S 200 STEL (15 min)Switzrland 1985 100 1WA'Tiwan 1985 200 1WAUK 1987 100 1WA

400 STEL (10 min)

160 IAC MONOGRAHS VOLUME 47

Table 1 (contd)

USAdOSHANIOSHACGIH

USSRVenezuelaYugoslavia

Year Concentrationb InterpretationC(mg/m3)

1983 200 1WA1983 100 1WA1988 S 100 1WA1986 10 Ceiling1985 200 1WA1985 200 1WA

Country or region

llrom Direktoratet for Arbeidstilsyet (1981); US Occupational Safety and Health Administration

(1983); International Labour Office (1984); Areidsinspectie (1986); Commission of the Europen Com-munities (1986); Institut National de Recherche et de Sécurité (1986); Cook (1987); Health and SafetyExecutive (1987); National Swedish Bord of Ocupational Safety and Health (1987); -iõsuojeluhalltus(1987); American Conference of Governmental Industrial Hygienists (1988); Arjdstilsyet (1988);Deutsche Forshungsgemeinshaft (1988)bS, skin notationCTA, 8-h time-weighted average; STEL, short-term expure limitdQSHA, Occupational Safety and Health Administration; NIOSH, National Institute for Ocupation-al Safety and Health; ACGIH, American Conference of Governmental Industrial Hygienists

2.2 Occurrence

(a) lVaturaloccurrence

Cyclohexanone is not known to ocur as a natural product.

(b) Occupationa expsure

On the basis of a US National Occupational Expsure survey, the National Institute forOccupational Safety and Health (1983) estimated that 336 20 workers were potentially ex-posed to cyclohexanone in the USA in 1981-83.

Mean time-weighted average (I A) concentrations of 6-28 ppm (24112 mg/m3; per-

sonal samples) and 2.8-23.4 ppm (11-94 mg/m3; area samples) cyclohexanone were detectedin a screen-priting plant (Samimi, 1982). Personal8-h 1W A air concentrations of cyclohex-

anone ranging from 0.4 to 1.1 ppm (1.6-.4 mg/m3) with a mean of 0.7 ppm (2.8 mg/m3) andarea samples containing 0.1-2.0 ppm (0.4-8.0 mg/m3) were reported in a plant that producedpaper and viyl wall coverigs (Ordin et aL., 1986).

(c) Air

Few data are available on ambient air concentrations of cyclohexanone. Its presencewas reported in the air of one house near an offset priting offiCe, but the concentration wasnot given (Verhoeff et al., 1987).

CYCLOHEXAONE 161

2.3 ADalysis

Cyclohexanone is readily analysed by collecting vapours in air samples by adsorption onchromosorb, desorption with carbn disulfide and determination by gas chromatographywith flame-ioniztion detection. The detection limit was 0.8 ng (equivalent to 0.05 ppm; 0.2

mg/m3) for a 10-1 sample (Elskamp, 1979). Another air sampling method involved extraction

of cyclohexanone in distiled water, condensation with fudural in an alkaline medium, acidi-fication with sulfuric acid and colorietric determination at 550 nm (Domanski, 1977).

An electrometric or colorietric titration method, whieh can be used when no othercarbnyl compound is present, is based on the reaction of cyclohexanone with hydroxylaminehydrochloride to form the oxie and hydrogen chloride (Fisher & Van Peppen, 1979).

3. Biological Data Relevant to the Evaluation of

earcinogenic Risk to Humans

3.1 CarciDogenicity studies iD animaIs

Oral administration

Mouse: Groups of 52, 52 and 47 male and 52, 50 and 50 female B6C3F 1 mice, seven toeight weeks old, were given 0,650 or 13 () mgll (ppm) cyclohexanone (96% pure) in thedrikig-water for 104 weeks. A further group of 41 female mice received 25 () mg/l (max-

mum tolerated dose) cyclohexanone over the same period. Survval in the respective groupswas 88%, 90% and 70% in males and 86%, 85%,40% and 15% in females. The incidences ofliver-cell adenomas or carcinomas (only combined figures reported) were 16/52,25/51 and13/46 in males and 3/52,6/50,3/50 and 2/41 in females, respectively. The incidence in low-dose males was statistically significant (p = 0.041, adjusted for differences in mortality). lnfemale mice, a statistically significant increase (p = 0.036; life-table method) in the inci-dence of malignant lymphomas and leukaemia was observed in the low-dose group: 8/52controls, 17/50 at 6500 ppm, 4/50 at 13 00 ppm and 0/41 at 25 () ppm (Lijinsky & Kovatch,1986).

Rat: Groups of 52 male and 52 female Fischer 344 rats, seven to eight weeks old, re-ceived 0, 3300 or 650 mg/l (ppm; maxmum tolerated dose) cyclohexanone (96% pure) in thedriking-water for 104 weeks. A slight decrease in survval was observed in high-dose fe-males but was not statistically significant. Dose-related reductions in boy weight were ob-served in treated groups. A signifiCant increase (p = 0.03) in the incidence of adrenal corticaladenomas was observed in low-dose males (controls, 1/52; low-dose, 7/52; high-dose, 1/51).The incidences of thyroid follcular-cell adenomas-crcinomas (reported in combination)were 1/52, 0/51 and 6/51 (p = 0.053) in control, low-dose and high-dose males, respectively.No difference in the incidence of liver tumours was observed between treated and controlgroups (Lijinsky & Kovatch, 1986).

162 !AC MONOGRAHS VOLUME 47

3.2 Other relevant data

(a) Exprimental systems

(i) Absorption, distribution, exretion and metabolismCyc1ohexanone is metabolized in rats, rabbits and dogs to cyclohexanol, which is conju-

gated with glucuronic acid and excreted mainly in urie; veiy little cyclohexanone or freecyclohexanol is found in urie (Ellott et al., 1959; Martis et al., 1980; Greener et al., 1982).Cyc1ohexanone did not accumulate in the boy (Martis et al., 1980).

(ii) Toxic effects

The acute oral LDso for cyclohexanone has been reported to be 2.07 and 2.11 g/kg bw inmale and female mice, respectively, and 1.80 g/kg bw in male and female rats. The intraperi-

toneal LDso has been reported to be 1.23 g/kg bw in male mice, 1.13 g/kg bw in male rats, 1.54g/kg bw in male rabbits and 0.93 g/kg bw in male guinea-pigs. Oral and intraperitoneal ad-

ministration of cyclohexanone caused narcosis, and death due to central nervous system de-pression and respiratoiy arrest. Autopsy revealed peritoneal and intestinal congestion inmice, suggesting an irtant effect (Gupta et al., 1979).

Cyclohexanone did not induce ski allergy in the guinea-pig maxiztion test (Brozeet al., 1988). Application of 0.2 ml undiluted cyclohexanone to the shaved back of rabbits for24 h induced marked irtation, which totally disappeared only six days later. Instilation of99, 80 or 40% cyclohexanone in cottonseed oil caused eye irtation in rabbits. No significant

difference was observed in the pentobarbital sleeping-time test in mice that received 120 or250 mg/kg bw cyclohexanone intraperitoneally on three consecutive days, suggesting no ma-jor effect of the compound on hepatic drug metabolizing enzyes (Gupta et al., 1979). Theseenzyes were not induced by cyclohexanone in beagle dogs (Martis et al., 1980). .

Groups of miee received 407000 mgll (ppm) cyclohexanone in the drikig-waterfor 13 weeks; one-third of the females and two-thirds of the males in the highest-dose groupdied durig treatment. One male in the group receivig 34 00 mgll died; the other animaishad 15-24% depression of bo weight gain, depending on sex. With 47 00 mgll, focllivernecrosis and hyperplasia in the thymus were observed in some animais. Pathological changesat lower doses were minimal (Ljinsky & Kovatch, 1986).

Expsure of rabbits by inhalation to about 1200 mg/m3 cyclohexanone for 6 h per day

on five days per week for three weeks and to 120556 mg/m3 for ten weeks induced narco-sis, loss of cordination and death (2/4 animais) only in the highest expsure group; slightconjunctival irtation was seen at doses of 120300 mg/m3. No toxic effect was observedwith expsure to 750 mg/m3 (freon et al., 1943).

Intravenous administration of about 280 mg/kg bw per day cyclohexanone to beagledogs for 18-21 days produced a monbund condition and central nervous system effects andliver and kidney toxicity. No significant change in bo weight was observed (Koeferl et ti.,1981).

Intravenous administration of 50 or 100 mg/kg bw cyc1ohexanone to rats for 28 consecu-tive days caused no significant ophthalmological or haematological toxicity or alterations inclinical chemistiy, gross pathology or histopathology (Greener et al., 1982).

CYCLOHEXAONE 163

Guinea-pigs and rabbits were administered 0.5 or 5 mglkg bw cyclohexanone intrave-nously or 0.5 ml percutaneously three times a week for three consecutive weeks; lenticularalterations (anterior subcpsular vacuoles) were observed in all groups of guinea-pigs butnot in rabbits (Greener & Youkiis, 1984).

Electrophysiological and neuropathological examination of rats receivig intraperito-

neal injections of 20 mglkg bw cyclohexanone twice daily on five days per week for up to 13weeks revealed no damage to the peripheral nervous system (perbellini et al., 1981).

(ii) Effects on reproduction an prenatal toxicity

Chick embiyos were expsed to cyclohexanone vapours (concentration unspecified) ei-ther for 3 or 6 h prior to incubation or for 3, 6 or 12 h after 96 h of incubation. Growth retarda-tion was noted in day-13 embiyos followig expsure for 3 or 6 h prior to or after incubation.ln sorne hatchings expsed after incubation, an abnormal gait was se en (Griggs et al., 1971).

Dietaiy administration of 1 % cyclohexanone to TB or NMRI mice for several genera-tions was reported to affect the vibilty and growth of firt-generation males and females.No such effect was seen in animais of the second generation (Gondiy, 1972). (Te WorkigGroup noted that the vibility of both control and treated animais was low.)

CFI mice received daily intraperitoneal injections of 50 mg/kg bw cyclohexanone for 28days; beginning on the tenth day of treatment and throughout the expsure period, femaleswere housed with an untreated male. On the last day of treatment, females were kiled andthe uterus examined for dead, resorbed and vible fetuses. No adverse effect was noted in

the seven expsed litters (Hall et al., 1974).

CD-1 mice were expsed by oral intubation to 0 (25 mice) or 80 (24 mice) mg/kg bwcyclohexanone per day on days 8-12 of gestation and the offsprig were evaluated for growth

and vibilty over the first three postnatal days. No treatment-related maternai or develop-mental effect was observed in this teratology sceening assay (Chernoff & Kavlock, 1983),nor were effects detected when the offsprig were observed until 250 days of age (Gray &Kavlock, 1984; Gray et al., 1986).

ln a similar study, groups of 28 ICR miee were expsed by oral intubation to 0 or 2200mg/kg bw cyclohexanone per day on days 8-12 of gestation. The treatment was lethal to 6/28females, but no maternai mortality was observed in the control group. Maternai weight gaindurig the treatment period was significantly reduced in the treated group, and two females

had completely resorbed litters. Pup weight at birh and on postnatal day 3 was significantlyreduced in the treated group, but litter size and vibilty were normal (Seidenberg et aL., 1986)

(iv) Genetic an related effectsCyclohexanone was not mutagenic to four strains (fA1535, TA1537, TA98 and TA1(0)

of Salmonella typhimurium in the presence or absence of an exogenous metabolic system in aplate incorpration assay (Haworth et al., 1983).

It was reported in an abstract (Aaron et al., 1985) that expsure of Chinese hamsterovaiy cells to cyclohexaone just as they were enterig the S-phase induced sister chromatidexchange and gene mutation in the absence, but not in the presence of an exogenous meta-

164 IAC MONOGRAHS VOLUME 47

bolic system. Under these conditions, no chromosomal aberration was induced in the pres-ence or absence of an exogenous metabolic system.

Cyclohexanone at 10-2, 10-3 and 10-4 M induced chromosomal aberrations in culturedhuman leucoes (Collin, 1971; Lederer et aL., 1971). It also produced an increase in thefrequency of chromosomal damage in human lymphoces both in terms of ploidy and struc-tural changes (Dshlovoi et al., 1981).

Chromosomal abnormalities were induced in bone-marrow cells of male rats (Rattusnorvegicus) 6, 24 and 48 h after subcutaneous injection of three doses each of 0.1,0.5 and 1.0g/kg bw cyclohexanone (maxum tolerated dose). Abnormalities increased with dose anddecreased with time, and consisted of chromatid gaps, breaks, centric fusions, centromericattenuation, chromatid exchanges and polyploidy (de Hondt et al., 1983).

(b) Humans

(i) Absorption, distribution, exretion an metabolismNo data were available to the Workig Group.

(ü) Toxic effects

Allergic contact dermatitis to a cyclohexanone resin (composition unspecified) was re-ported on patch testing of five patients with paint-related allergies (Bruze et al., 1988). Irr-tation of the eyes, nose and throat was described in a review in volunteers expsed to cyclo-hexanone (Krasavage et al., 1982).

ln 100 workers expsed by inhalation (3.7 mg/m3) and via ski contact (10-4 mg/cm2 onthe hands) durig the production of caprolactam to cyclohexanone, no difference in nervous

system function, bloo and respiration was reported relative to 49 controls. There was someindication of liver disorders among a subgroup of workers, 30-39 years old, with more thanfive years' expsure to cyclohexanone (Bereznyak, 1984).

(ii) Effects on fertilty and on pregnancy outcomesNo data were available to the Workig Group.

(iv) Genetic and related effectsNo data were available to the Workig Group.

3.3 Epidemiological studies or carcinogeDicity to humaDs

No data were available to the Workig Group.

4. Summary of Data Reported and Evaluation

4.1 Exposures

Cyclohexanone is a sythetic organic liquid used priariy as an intermediate in the

production of nylon. Other minor applications are as an intermediate, additive and solventin a variety of products. Occupational expsure levels have been measured in some indus-tries.

CYCLOHEXAONE 165

4.2 Experimental carcinogenicity data

Cyclohexanone was tested for carcinogenicity by oral administration in the drikig-

water in one strain of mice and one strain of rats. ln mice, there was a slight increase in theincidence of tumours that ocur commonly in this strain, only in animais given the low dose.ln rats, a slight increase in the incidence of adrenal cortical adenomas ocurred in malestreated with the low dose.

4.3 Human carcinogenicity data

No data were available to the Workig Group.

4.4 Other relevant data

No significant systemie toxicity was reported in humans or experiental animaIs. Nosignificant prenatal toxicity was observed in mice.

Cyclohexanone induced chromosomal aberrations and ploidy changes in cultured hu-man cells and in rats. It did not induce mutation in bacteri. (See Appendix 1.)

4.5 Evaluation 1

There is inadequate evidence for the carcinogenicity of cyclohexanone in experientalanimais.

No data were available from studies in humans on the carcinogenicity of cyclohexa-none.

Overall evaluation

Cyclohexanone is not classìfiable as to its carcinogenicity to huma (Group 3).

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