isopropyl alcohol

JOURNAL OF APPLIED TOXICOLOGY. VOL. 15(6). 501-506 (1095)

Toxicology Update

Note: 1 he roxicology Update represents a brief review o f an often extensive literature base. Only some of the directly related references may be included

ISOPROPYL ALCOHOL

Synonyms: 2-Propanol; sec-propyl alcohol; propan-2-01: n-propan-2-01; di- methylcarbinol; isopropanol; petrohol; avantine; IPA. CAS no.: 67-63-0. Boiling point: 82.5"C @ 760 mmHg. Color: Colorless liquid. Conversion factor: 1 ppm = 0.4 mg m-?. DOT designation: Flammable/combust- ible material. Flammability: autoignition tempera- ture. 399°C: flash point. 11.7"C (closed CUP): LEL. 2.5%; UEL, 12.0%. Melting point: - 88.5"C. Molecular formula: C3Hx0. Molecular weight: 60.09. Odor: threshold. 90 nig m-.3; recognition. 4@200 ppm (98-490 mg m 3 ) ;

pleasant odor. Solubility: > 10% in water; log K,,, = 0.05; soluble in benzene. soluble > 10% in alcohol, ether and acetone, misciblc with chloroform and most organic solvents and insoluble in salt solution: log K,,,. = 0.34. Specific gravity: 0.7855 (water = 1). Vapor density: 2.08. Vapor pressure: 32.4 mmHg @ 20°C. Viscosity: 2.4 centipoise @ 20°C. (References: 1.2. )

Composition

Isopropyl alcohol (IPA) is prepared by an indirect hydration technique in which 4(MO% propylene isolated from refinery exhaust gases is rcactcd with sulfuric acid. Earlier, the IPA prep- aration process involved 88-93% sulfuric acid reacting with propylene gas at 25°C for a longcr duration. In a newer process. weak acid has replaced the strong acid and propylene gas is absorbed in 6OYO sulfuric acid at 85°C for a short reaction time.'

Uses

Isopropyl alcohol is used in: antifreeze mixtures; extraction of alkaloids; as solvent for gums, shellac. essential oils, creosote. resins; in quick-drying oils and inks: in denaturing alcohol; an antiseptic in hand lotions, after-shave lotions. cosmetics; in the manufacture of acetone, in liniments. pcrmancnt- wave preparations. pharmaceuticals. hair tonics; as a solvent in perfumes.

Table 1. Lethal dose values for isopropyl alcohol."

Species

Rabbit Rat Mouse Rabbit Mouse Rat Human Rabbit

Route of administration

Oral Oral Oral Skin lntraperitoneal Inhalation Ingestion Oral

'From Refs 2, 5 and 76.

Type Test concentration

LD,, 8.0 g kg ' LD,, 3600 rng kg ' LD,, 5045 rng kg '

LD,, 12,800 mg kg ' LD,, 4477 mg kg ' LD,, 12,000 ppm at 8 h

ED,, 2280 rng kg ' for the onset LD,, 248 g

of narcosis

oils and in extraction processes; as rubbing alcohol, which is 62-72% by volume isopropanol; and as an ingredient in liquid soaps and window cleaners. In addition, it is also used as a coating solvent, as a de-icing agent for liquid fuels, as a dehydrating agent, as a synthetic flavoring adjuvant and in non- alcoholic beverages, candy and baked goods. I.-'

Acute toxicity Isopropyl alcohol is toxic by oral, dermal and inhalation exposure. I t may produce greater central nervous system (CNS) depression compared to ethanol at comparable blood levels and it is considered to be 1.5---2.0 times more toxic than ethanol.' A toxic dose of rubbing alcohol (70% isopropanol) is about 1 ml kg but as little as 0.5 ml kg-' may cause symptoms. Adults have survive 1-1 ingestions.4 The acute toxicity data for various mammalian species are presented in Table 1.

Ingestion. The major effects following acute overexposure to isopropyl alcohol are gastritis, depression of the central nervous system with hypothermia and respiratory depression and hypoten- sion.s Other specific symptoms associated with ingestion may include nausea. vomiting, abdominal pain. hematemesis. CNS depression. areflexia. depressed respirations and oliguria followed by diuresis. The CNS effects associated with acute exposures may include dizziness. poor coordination.

headache and confusion, which may progress to stupor, coma and loss of deep tendon reflexes in serious cases. Nervous system depression often persists for 24 h.' Isopropyl alcohol intoxication has a rapid onset of action ( 3 M min), with peak effects within several hours. The pupils are generally miotic and nystagmus is usually p r ~ s e n t . ~ Iso- propyl alcohol ingestion can rapidly produce coma, but in non-fatal cases the coma rarely persists for more than 12 h.".' In alcoholics. IPA ('blue heav- en' due to the blue dye added for hospital use) toxicity has a clinical presentation of stupor' or a belligerent. uncooperative patient.'."' The plasma concentration associated with serious toxic symptoms in humans is 1500 p,g ml-l."

Some alcoholics prefer IPA to ethanol. Alcoholics who hide their addiction will present clinically as an encephalopa- thy.' Severc poisoning leads to deep coma. respiratory depression and hypo- tension.'* The oral lethal dose for adult, non-alcoholic humans is approximately 8 ounces (248 g) but alcoholics have a higher tolerance:13.'-' the hospital course of a 54-kg male that ingested 1 I of isopropanol is reported. The blood pressure dropped to 6010. the pulse was 108 and respiration was 16. The patient showed meiosis and loss of deep tendon reflexes. Within 1 h after instituting dialysis. the blood pressure rose to 84/ 40, the pulse dropped to 88 and the respiratory rate was 18. After 3 h on dialysis. the patient began to 'thrash about'.

Daily oral intake o f 2.6 or 6.4 mg kg I

CCC 02ML437Xi951060.50 I -Oh 0 199.5 by J o h n Wiley & Sons. Ltd. Reccvvett 13 December 1994

Acccpied 21 April I995

502 S. DHILLON AND R. VON BURG

of IPA by groups of eight men for 6 weeks had no effect on blood cells, serum or urine and produced no subjective symptoms." A daily dose of 16 ml of IPA was ingested by a human subject for 3 days without any discomfort. However, a dose of 25 ml led to acute symptoms.lh

Inhalation. Inhalation exposure of IPA may produce symptoms resembling those of acute ingestion exposure and may include nausea, vomiting, abdominal pain, hematemesis, CNS depression, areflexia, depressed respirations and oliguria followed by diuresis. A concentration of 400 pprn may cause slight irritation but is considered too low to cause CNS de~ress i0n . l~ It may cause exacerbation of symptoms owing to its irritant properties in persons with impaired pulmonary function, especi- ally those with obstructive airway diseases.h

Irritation of the mucous membranes, ataxia, prostration, deep CNS depression and death were the effects noted in experimental animals following exposure to high vapor concentrations of IPA.2

Eye contact. Application of a 70% solution of IPA to the rabbit eye caused mild transitory injury manifested by conjunctival redness, corneal opacity and iritis.IX Irrigation of rabbit eyes with 50% IPA solution for 3 min caused a reaction that graded 50 on a scale of 0-100. Ten healthy volunteers exposed to 400 pprn for 3-5 min had mild irritation of the eyes, nose and throat. At 800 ppm, most of the subjects considered the irritation to be 'uncomfortable'.

Skin contact. Isopropyl alcohol is not considered to be a dermal irritant' but in the neonate, cases of skin burns due to IPA have been reported.*" A fatality in a 4-year-old occurred when IPA was used subsequent to scalding with hot water.21 Instances of intoxication have also been reported in children receiving alcohol sponge baths for Adults with extensive skin lesions were similarly intoxicated,22 indicating that dermal absorption can significantly contribute to the overall systemic

Chronic toxicity

Ingestion. Human volunteers ingesting daily doses of 2.6 or 6.4 mg kg-' body wt. IPA for 6 weeks produced no subjective symptoms and showed no adverse effects on blood cells, serum or urine production." Oral administration of 0.5-10.0% IPA to rats in their drinking water for 27 weeks resulted in decreased body weight gain.

No other gross or microscopic abnor- malities of the brain, pituitary, lung, heart, liver, spleen, kidneys or adrenals were observed.lx The addition of 1.3 g kg-l body wt. IPA to the drinking water of three dogs for 1 h a day for 6 months led to no consistent pathological changes other than drunkenness 3-5 h after intake.I2

Inhalation. A health hazard evaluation at a printing company using a offset lithographic printing process measured exposure levels of 247-501 mg m-3 IPA in the personal breathing zone of the press operator. Reported symptoms included difficulty in concentration, dizziness, cough, chest pain and dry skin.2s

A continuous exposure of rats to 8.14 pprn of IPA for 86 days resulted in changes in reflex behavior, enlarged spleen, some evidence of liver parenchy- mal cell dystrophy and degenerative changes in cerebral motor cortex. Rats exposed to 0.24 pprn showed no ill effects.26

Eye contact. contact.

See acute toxicity: eye

Skin contact. Isopropyl alcohol is a defatting agent and can cause dermatitis on prolonged exposure. Persons with pre-existing skin disorders may be more susceptible to the effects of this agent.I7

Sensitization

There are a number of case reports of contact dermatitis associated with topical application of alcohols.'.27 Two patients with alcohol dermatitis and hypersensitivity to primary alcohols were tested for hypersensitivity to sec- ondary alcohols. Isopropyl alcohol produced an intense eczematous response in both patients.2x One patient with acquired sensitivity to isopropyl alcohol demonstrated cross-reactivity to buta- no1 and n-propanoL2' Severe allergic keratoconjunctivitis was reported to be due to an alcohol swab used to clean the eyes following a routine eye exam.3" Opacification and epithelial sloughing occurred in several patients following the application of a tonometer tip wiped with 70% isopropyl alcohol." A hospital laboratory assistant developed contact dermatitis from the use of dispos- able IPA pre-injection swabs and the allergic reaction was confirmed with patch testing.32

Target organ effects

The target organs likely to be affected following exposure to IPA are eyes, respiratory system, CNS, liver, kidney and skin. Isopropyl alcohol irritates the eyes, nose, throat, upper respiratory

tract and skin, produces a CNS depression and damages the liver and kidney. Cases of acute tubular necrosis, hepatic dysfunction, hemolytic anemia and myoglobinuria have been r e p ~ r t e d . ~ Rats given 2-5% IPA in their drinking water for 12 weeks showed a dose- dependent increase in liver, kidney and adrenal weight."

Absorption-metabolism-excretion

Isopropyl alcohol is rapidly absorbed in the intestine. About 80% of the orally administered dose is absorbed within 30 min. Complete absorption occurs within 2 h. Skin absorption is relatively small but can be significant and contribute to systemic toxicity. Studies indicate that IPA distributes to an apparent volume of 0.6-0.7 1 kg-L.h Distribution to the tissues is complete within about 2 h.4

Acute or chronic administration of IPA to rats caused a significant increase in hepatic cytochrome P-450 content as well as other enzyme systems. This increase in the P-450 content is believed to potentiate the toxicity of other compounds, such as CC14, by selectively enhancing its metabolism to an active metab~l i te . '~

Alcohol dehydrogenase oxidizes IPA to acetone but this metabolic process is considerably slower than with ethanol owing to the low affinity of the enzyme to IPA.s The lung and kidney will each excrete approximately 47% of the absorbed dose of IPA ~nchanged. ' .~ Acetone may be further metabolized to acetate, formate and finally carbon dioxide. Clinically insignificant excretion occurs into the stomach and ~ a l i v a . ~ In the neonate, the half-life for the elimination of IPA was 9.6 h;'s in a 2-month-old infant the half-life was reported to be 5.8 h." In adults, the apparent half-life of IPA ranged from 2.9 to 16.2 h. Alcoholics appear to have shorter half-lives, generally in the range 3 4 h.h.37 The apparent half-life of acetone was longer, with a range of 7 .6-26.2 h .3x

Acetonemia has been used to confirm the diagnosis of IPA intoxication but a number of case reports question the validity of this as~umption.'~~' OCCU- pational exposure to IPA was studied in 12 workers by testing environmental air, alveolar air, venous blood and urine during their work shift. Isopropyl alcohol in environmental air at concentrations between 7 and 645 mg m-3 was detected in alveolar air between 4 and 437 mg m-3 but was not detected in blood or urine. Acetone, a metabolite of IPA, was found in alveolar air, blood and urine. Alveolar and blood acetone concentrations were highly correlated with alveolar IPA concentration at any time during exposure. Acetone ranged

TOXICOLOGY UPDATE 503

between 0.76 and 15.6 mg I - ' in blood, between 4 and 92 p g I - ' in alveolar air and between 0.85 and 53.7 mg I-' in urine. Alveolar IPA uptake ranged between 0.03 and 6.8 mg min-l and was highly correlated with environmental IPA concentration. During the exposure, acetone eliminated by the lung ranged between 20 and 273 mg in 7 h and in urine between 0.3 and 9.6 mg in 7 h. Acetonuria was higher the next morning than at the end of exposure .'I'

The toxic effects of alcohols are apparently attributable to their denaturing action on soluble proteins and reduc- ing the surface-tension of ~ a t e r . ~ ' A number of studies indicate that IPA also has a facilitory action on the toxicity of other compounds. Facilitation has been noted in an IPA packaging plant where the workers became ill (hepatotoxicity) after accidental exposure to carbon t e t r a c h l ~ r i d e . ~ ~ . ~ ' Enhanced liver toxicity by IPA has also been noted in combination with 1,1,2- trichloroethane, chloroform, trichloro- ethylene and d i m e t h y l n i t r ~ s a m i n e . ~ ~ ~ '

Immunotoxicity

In mice, the incorporation of tritium- labeled thymidine was enhanced in con- canavalin A-stimulated murine spleen cells by acetone and isopropanol.'" In mice and rats, IPA inhibited the killing of tumor cells by natural killer effector cells."' See sensitization, for other effects.

Reproductive toxicity

lsopropyl alcohol was administered in drinking water in doses of 1.5, 1.4 and 1.3 g kg-I body wt. per day to parents and to two successive generation of rats, respectively. No adverse effects were observed on reproductive function, embryonic and postnatal develop- ment. The only effects noted were some retardation of growth early in life of first-generation rats. I'

Rats were exposed to IPA at 3500, 7000 and 10 000 pprn for 7 h a day on gestations days 1-19, No detectable teratogenic effects were observed at 3500 ppm. At the higher levels of exposure the dams showed a decrease in weight gain. The litters showed reduced fetal weights, there was an increase in the number of resorptions and there were significantly more malformations

In a two-generation reproductive study, Sprague-Dawley rats were gavaged with 0, 100, 500 or 1000 mg kg-' IPA for at least 10 weeks prior to mating, gestations and lactation. There was a statistically significant reduction in the mating index of the high-dosed P2 males but there was

no other evidence of treatment-related reproductive effects.'* Similarly, no teratogenic effects were seen with rabbits dosed with up to 480 mg kggl day-I for gestation days 6-18.''

Teratogenicity and developmental neurotoxicity were investigated in rats gavaged with IPA from gestation day 6 through to postnatal day 21. At the high-dose level tested (1200 mg kg-' day-!), maternal toxicity was not manifested and there were no significant findings in the pups with respect to behavioral tests, organ weights or path- ology that could be attributed to the IPA exposure.54 However, with inhalation exposures, levels of IPA that produced maternal toxicity (5000 ppm) produced congenital malformations in rats."

Neurotoxicit y

In an in vitro study, there was a correlation between hypnotic potency of aliphatic alcohols (including IPA) and their ability to disrupt the structure of the neuronal membrane.s6.'7 Lipo- philic chemicals can enter the brain more easily than ionic compounds and IPA enters the brain three times more effectively than water." Decreases in the resting membrane potential" and inhibition of membrane ATPase activity'" attributable to IPA have also been reported. This may account for the CNS depiessing effect of IPA. Rats exposed to 5000 pprn IIJA vapor for 90 days showed an increase in motor activity that was reversible after cessation of exposure.6' With respect to the peripheral nervous system, IPA has not been implicated in peripheral nerve injury except for a case of polyneuropathy reported in 1979.'' Teramoto et

found a decrease in the sensory conduction velocity of the caudal nerve of rats exposed to 8000 ppm for 8 h a day, 5 days a week for 20 weeks but the conduction velocity returned to normal after cessation of exposure. Dose-dependent changes in the monoamine content of different regions of the brain have also been reportedhJ but the significance of such changes remains unclear.

Ohashi et exposed guinea pigs to 400 pprn IPA for 24 consecutive hours and found mucociliary and mor- phological changes in the eustachian tube that were dose related and required up to 7 days to recover.

Genotoxicity

The Ames mutagenic assay with tester strains TA98, TA100, TA1525 and TA1537 of Salmonella typhimurium was negative both with and without S9 metabolic activation." Isopropyl alcohol also did not increase sister chroma- tid exchange frequencies in Chinese

hamster lung fibroblasts with or without metabolic a~t ivat ion. '~ However, a statistically significant increase of mitotic aberrations was reported in rat bone marrow after a 4-month exposure to 10.3 mg m-' IPA in air for 4 months."

Carcinogenicity

Evidence of carcinogenicity of IPA is considered inadequate in animals as well as humans. Groups of 3-month- old male C3H, ABC or C57BL mice were exposed to a concentration of 7700 mg m-3 IPA in air for 3-7 h a day, 5 days a week for a period of 5-8 months. Animals sacrificed at the age of 8-12 months did not show an increased incidence of lung tumors compared with that in controls." In an 18-month exposure study, CD-1 mice were exposed to target concentrations of 0, 500, 2500 or 5000 ppm for 6 h a day, 5 days a week. Animals exposed to the two higher levels increased body weight gain, increased relative liver weights, decreased relative brain weights, and showed seminal vesicle enlargement, ectasia of the seminal vesicles and renal tubular dilation. The no-observed- adverse-effect level (NOAEL) for non- carcinogenic effects from this study was 500 ppm. There was no increase in neoplasia or m ~ r t a l i t y . ~ "

Additionally, 3-month-old male C3H, A B C and C57BL mice were treated by subcutaneous injection with 0.025 ml of IPA once weekly for a period of 2 W O weeks, at which time the animals were sacrificed. No increased incidence of lung tumors was found.'"

However, IPA manufactured by the strong-acid process is considered to have adequate evidence for carcinogenicity in humans owing to the increased incidence of paranasal sinus cancers."

Epidemiology

Two epidemiological studies at IPA manufacturing plants using the strong- acid process reported an increased incidence of sinus and laryngeal cancers. The increased incidence was S 2 1 times greater than that expected in the general p ~ p u l a t i o n . ~ ' . ~ ~ ~ ~ ' It is unclear whether the increased cancer incidence in these studies is due to a chemical intermediate or some by-product rather than the IPA itself.74 No epidemiological data appear to be available for the weak-acid process manufacturers. I

Environmental fate

Isopropyl alcohol enters the environ- ment as emissions from manufacturing and its use as a solvent. It occurs naturally in plants and is released during the microbial degradation of biological wastes. Small quantities have been

504 S. DHILLON AND R. VON BURG

detected in grapefruit essence oil, roasted filbert nuts, pine logs and milk products.' Human exposure will be mainly from occupational atmospheres, use of consumer products, IPA-containing cosmetics and the diet. It has been estimated that ca. 50% of the isopropanol produced is released into the atmosphere.' In the atmosphere, IPA will photodegrade primarily by reaction with hydroxyl radicals with a half-life of one to several days. Rain-out is also a major source of removal from the atmosphere. Its contribution to the formation of smog is low.*

When spilled on soil, IPA can evapor- ate, biodegrade or leach into the ground owing to its high vapor pressure and low soil adsorption. A log K,,, value of 0.34 suggests that IPA will not bind to soils or sediments. Degradation rates in soil have not been determined but the material is readiIy biodegradable both aerobically and anaerobically.' If soil degradation is not rapid, it is apt to leach into the groundwater owing to its high water solubility. Isopropyl alcohol has been detected in the leach- ate from municipal landfills.2

When released into water, IPA will volatilize owing to its significant vapor pressure. The estimated half-life from water 1 m deep with a 1 m s-' current is ca. 5.4 days. Isopropyl alcohol may also biodegrade in surface water, although no data on its degradability in natural waters could be found. The fate of IPA in groundwater has also not been determined."

Environmental toxicity Ecotoxicity values for IPA in some selected species are given in Table 2. The low octanoliwater partition coef- ficient suggests that it will not biocon- centrate in fish.' A bioconcentration factor of 0.5 has been estimated for IPA.'

Regulatory status Worker exposure standards for IPA are presented in Table 3.

Pursuant to Section 8(d) of the Toxic Substances Control Act (TSCA), the EPA promulgated a model Health and Safety Data Reporting Rule. The Sec- tion 8(d) model rule requires manufacturers, importers and processors of listed chemical substances and mixtures to submit to the E P A copies and lists of unpublished health and safety studies. Isopropyl alcohol is included on this list [40 CFR 716.120 (7/1/88)].

Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use and exposure to the EPA, as cited in the preamble of 51 F R 41329 [40 CFR 712.30 (7/1/88)].

Table 2. Acute ecotoxicity values for various speciesa

Species LC5,/LD,, (mg I-') Comments

Carassius auratus (goldfish) Poecilia reticulata (guppies) Crangon crangon (brown shrimp) Pimephales promelas (fathead minnows)

Pimephales promelas (fathead minnows) Aedes aeg ypti (mosquito larvae) Daphnia magna (water flea)

> 5000 rng I - '

7060 ppm

1400 mg I - ' 1150 rng I-I 11 830 mg I 11 160 mg I - 1 11 130 rng I - ' 6.1-10.4 g I- '

25-120 mg I - 1

2.3 g I - '

Protozoans 0.1-4.9 g I

Scenedesmus 1800 mg I-' quadricauda (green algae) Microcystis 1000 mg I-' aeruginosa (blue- green algae)

"From Refs. 2, 5, 77 and 78.

24-h LD50

7-day L C , ~

48-h LC50 96-h L C ~ O

I - h LC50 (static) 24-h LC,, (static) 48-h LC,, (static) 96-h LC,,

4-h LC,, (static)

44-h EC,, (cell multiplication in hibition) Variable time; EC,, for cell multiplication inhibition Cell multiplication inhibition

Cell multiplication inhibition

Table 3, Permissible worker exposure levels and other regulatory stan- dardsa

OSHA: PEL 400 ppm STE L 500 ppm Ceiling 800 ppm IDLH 12 000 ppm

TLV 400 ppm STEL 500 ppm Ceiling Not applicable

ACGIH:

"From Refs 7, 9 and 80.

According to the Federal Insecticide Fungicide and Rodenticide Act (FIFRA) requirements, residues of IPA are exempt from the requirement of a tolerance when used as a solvent, co- solvent, stabilizer or inhibitor in accord- ance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest [40 CFR

Isopropyl alcohol is a food additive permitted for direct addition to food for human consumption, by the Food and Drug Administration (FDA), as long as: the quantity added to food does not exceed the amount reasonably

180.1001 (c)(7/1/88)].

required to accomplish its intended physical, nutritive or other technical effect in food; and when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient (21 CFR 172.515 (4/1/88)].

S. Dhillon and R. Von Burg? ICF Kaiser Engineers, 1800 Harrison Street, Oakland, CA 94612, USA

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TOXICOLOGY UPDATE 505

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