INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 65
BUTANOLS: FOUR ISOMERS
- 1-Butanol
- 2-Butanol
- tert-Butanol
- Isobutanol
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
World Health Orgnization
Geneva, 1987
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
Organization. The main objective of the IPCS is to carry out and
disseminate evaluations of the effects of chemicals on human health
and the quality of the environment. Supporting activities include
the development of epidemiological, experimental laboratory, and
risk-assessment methods that could produce internationally
comparable results, and the development of manpower in the field of
toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
chemicals.
ISBN 92 4 154265 9
The World Health Organization welcomes requests for permission
to reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made
to the text, plans for new editions, and reprints and translations
already available.
(c) World Health Organization 1987
Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved.
The designations employed and the presentation of the material
in this publication do not imply the expression of any opinion
whatsoever on the part of the Secretariat of the World Health
Organization concerning the legal status of any country, territory,
city or area or of its authorities, or concerning the delimitation
of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the
names of proprietary products are distinguished by initial capital
letters.
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR BUTANOLS - FOUR ISOMERS:
1-BUTANOL, 2-BUTANOL, tert-BUTANOL, ISOBUTANOL
INTRODUCTION
1-BUTANOL
2-BUTANOL
tert-BUTANOL
ISOBUTANOL
REFERENCES
WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR
BUTANOLS - FOUR ISOMERS: 1-BUTANOL, 2-BUTANOL, tert-BUTANOL,
ISOBUTANOL
Members
Dr B.B. Chatterjee, Calcutta, India
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
Experimental Station, Abbots Ripton, Huntingdon, United Kingdom
(Rapporteur)
Dr R. Drew, Department of Clinical Pharmacology, Flinders
University of South Australia, Bedford Park, South Australia,
Australia (Chairman)
Dr M.-S. Galina Avilova, Institute of Occupational Hygiene and
Professional Diseases, Moscow, USSR
Dr A.A.E. Massoud, Department of Community, Environmental and
Occupational Medicine, Faculty of Medicine, Ain-Shams
University, Abbasia, Cairo, Egypt (Vice-Chairman)
Dr A.N. Mohammed, University of Calabar, Calabar, Nigeria
Dr C.P. Sadarangani, Bader Al Mulla and Brothers, Safat, Kuwait
Secretariat
Ms B. Bender, International Register of Potentially Toxic
Chemicals, United Nations Environment Programme, Geneva,
Switzerland
Dr K.W. Jager, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland (Secretary)
Ms F. Ouane, International Register of Potentially Toxic Chemicals,
United Nations Environment Programme, Geneva, Switzerland
NOTE TO READERS OF THE CRITERIA DOCUMENTS
Every effort has been made to present information in the
criteria documents as accurately as possible without unduly
delaying their publication. In the interest of all users of the
environmental health criteria documents, readers are kindly
requested to communicate any errors that may have occurred to the
Manager of the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland, in order that they may be
included in corrigenda, which will appear in subsequent volumes.
* * *
Detailed data profiles and legal files can be obtained from the
International Register of Potentially Toxic Chemicals, Palais des
Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 -
985850).
ENVIRONMENTAL HEALTH CRITERIA FOR BUTANOLS - FOUR ISOMERS:
1-BUTANOL, 2-BUTANOL, tert-BUTANOL, ISOBUTANOL
A WHO Task Group on Environmental Health Criteria for Butanols
met in Geneva from 11 to 15 November 1985. Dr K.W. Jager opened
the meeting on behalf of the Director-General. The Task Group
reviewed and revised the draft criteria document and made an
evaluation of the health risks of exposure to butanols.
The first draft of this document was partially based on
information contained in Toxicology Data Sheets made available by
the Health, Safety and Environment Division of Shell Internationale
Petroleum Maatschappij B.V., and on information obtained by a
search of data bases by IRPTC. Additional information supplied by
IPCS Participating Institutions was added to the second draft.
The efforts of all who helped in the preparation and
finalization of the document are gratefully acknowledged.
* * *
Partial financial support for the publication of this criteria
document was kindly provided by the United States Department of
Health and Human Services, through a contract from the National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina, USA - a WHO Collaborating Centre for Environmental
Health Effects. The United Kingdom Department of Health and Social
Security generously covered the costs of printing.
INTRODUCTION
The butanol isomers occur naturally as products of fermentation
and are also synthesized from petrochemicals. They are used widely
as solvents and intermediates in chemical industries. Human
exposure to high concentrations of the butanol isomers will be
primarily occupational while exposure to low concentrations will be
mainly through foods in which they occur naturally or as flavouring
agents. Apart from slight differences in the boiling point and
water solubility, the physical properties of the isomers are
similar.
With only minor differences between isomers, the toxicity for
aquatic organisms of all four butanols is low and none of the
compounds shows any capacity for bioaccumulation. Apart from
tert-butanol, all isomers are readily biodegradable and would be
expected to be fully oxidised by microorganisms within a few days.
The tert-butanol is metabolized more slowly and would be degraded
within a few weeks. The likely background concentrations of all
butanol isomers would not have any impact on the aquatic
environment.
In animals, the butanols are readily absorbed through the lungs
and gastrointestinal tract. 1-Butanol, 2-butanol, and isobutanol
are primarily metabolized by alcohol dehydrogenase and are rapidly
eliminated from the blood. tert-Butanol is not a substrate for
alcohol dehydrogenase and its elimination is slower than that of
the other isomers. On the basis of oral LD50 values in the rat,
the butanols can be classified as being slightly or practically
non-toxic. In large amounts, all isomers have the ability to
induce signs of alcoholic intoxication in both animals and man.
Data regarding other biological effects in man and animals cannot
be easily compared and symptoms and effects are covered in the
separate sections for each isomer.
On the basis of the available data, the Task Group did not
expect any adverse effects from occupational exposure under
conditions of good manufacturing practice.
The Task Group considered that the available data were
inadequate to give guidelines for the setting of occupational
exposure limits for any of the butanol isomers.
The effects of long-term exposure to low concentrations of the
butanols could not be judged because of lack of information. The
Task Group recommended that relevant studies should be conducted so
that this could be achieved.
ENVIRONMENTAL HEALTH CRITERIA
FOR
1-BUTANOL
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR 1-BUTANOL
1. SUMMARY
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
2.2 Physical and chemical properties
2.3 Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6. KINETICS AND METABOLISM
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Aquatic organisms
7.2 Terrestrial organisms
7.3 Microorganisms
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
8.1.1 Acute toxicity
8.1.1.1 Signs of intoxication
8.2 Skin, eye, and respiratory tract irritation
8.2.1 Skin irritation
8.2.2 Eye irritation
8.2.3 Respiratory tract irritation
8.3 Repeated and continuous exposure
8.3.1 Inhalation studies
8.3.2 Other routes of administration
8.4 Mutagenicity
8.5 Carcinogenicity
8.6 Reproduction, embryotoxicity, and teratogenicity
8.7 Special studies
9. EFFECTS ON MAN
9.1 Toxicity
9.1.1 Eye irritation
9.1.2 Case reports of occupational exposure
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
10.1.1 Exposure levels
10.1.2 Toxic effects
10.2 Evaluation of effects on the environment
10.2.1 Exposure levels
10.2.2 Toxic effects
10.3 Conclusions
11. RECOMMENDATIONS
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
1. SUMMARY
1-Butanol is a flammable colourless liquid with a rancid sweet
odour. It has a boiling point of 118 °C, a water solubility of 77
g/litre and its 1-octanol/water partition coefficient is 0.88. Its
vapour is 2.6 times denser than air. It occurs naturally as a
product of fermentation of carbohydrates. 1-Butanol is also
synthesized from petrochemicals and is widely used as an organic
solvent and as an intermediate in the manufacture of other organic
chemicals. Human exposure is mainly occupational. Exposure of the
general population will be mainly through its natural occurrence in
foods and beverages, and its use as a flavouring agent. Exposure
may also result from industrial emissions. 1-Butanol is readily
biodegradeable and does not bioaccumulate. It is not directly
toxic for aquatic animals and practically non-toxic for algae.
However, some protozoa are slightly sensitive to 1-butanol and it
should be managed in the environment as a slightly toxic compound.
It poses an indirect hazard for the aquatic environment because it
is readily biodegraded and this may lead to oxygen depletion.
In animals, 1-butanol is readily absorbed through the skin,
lungs, and gastrointestinal tract. It is rapidly metabolized by
alcohol dehydrogenase to the corresponding acid, via the aldehyde,
and to carbon dioxide, which is the major metabolite. The rat oral
LD50 for 1-butanol ranges from 0.7 to 2.1 g/kg body weight. It is,
therefore, slightly toxic according to the classification of Hodge
& Sterner. It is markedly irritating to the eyes, and moderately
irritating to the skin. The primary effects from exposure to
vapour for short periods are various degrees of irritation of the
mucous membranes, and central nervous system depression. Its
potency for intoxication is approximately 6 times that of ethanol.
A variety of investigations have indicated the non-specific
membrane effects of 1-butanol. Effects of repeated inhalation
exposure in animals include pathological changes in the lungs,
degenerative lesions in the liver and kidneys, and narcosis.
However, it is not possible to determine a no-observed-adverse-
effect level on the basis of the animal studies available. 1-
Butanol has been found to be non-mutagenic. Adequate data are not
available on its carcinogenicity, teratogenicity, or effects on
reproduction.
The most likely acute effects of 1-butanol in man are alcoholic
intoxication and narcosis. Signs of excessive exposure may include
irritation of the eyes, nose, throat, and skin, headache, and
drowsiness. Vertigo has been reported under conditions of severe
and prolonged exposure to vapour mixtures of 1-butanol and
isobutanol. However, in this study, it was not possible to
attribute the vertigo to a single cause. It has been reported that
exposure to 1-butanol may affect hearing and also light adaptation
of the eye.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
Chemical structure: CH3-CH2-CH2-CH2OH
Chemical formula: C4H10O
Primary constituent: 1-butanol
Common synonyms: 1-butyl alcohol, butanol-1, normal-butyl
alcohol, 1-hydroxy butane, normal-propyl
carbinol, butyric alcohol, NBA, butan-1-
ol, butyl alcohol
CAS registry number: 71-36-3
2.2. Physical and Chemical Properties
Some physical and chemical properties of 1-butanol are listed
in Table 1.
Table 1. Physical and chemical properties of 1-butanol
-------------------------------------------------------------------
(at 20 °C and 101.3 kPa, unless otherwise stated)
Physical state colourless liquid
Odour rancid sweet
Odour threshold approximately 3.078 mg/m3
Relative molecular mass 74.12
Density (kg/m3) 809 - 811
Boiling point 118 °C
Freezing point -89 °C
Viscosity (mPa x s) 2.96
Vapour density (air = 1) 2.55
Vapour pressure (kPa) 0.56
Flashpoint (°C) 33
Autoignition temperature 345 °C
Explosion limits in air (v/v) lower = 1.4%
upper = 11.2%
Solubility (% weight) in water, 7.7; miscible with
ethyl alcohol, ether, and
other organic solvents
n-octanol/water partition coefficient 0.88
Conversion factors 1 ppm = 3.078 mg/m3
1 mg/m3 = 0.325 ppm
-------------------------------------------------------------------
2.3. Analytical Methods
NIOSH Method No. S66(321) has been recommended for the
determination of 1-butanol. It involves drawing a known volume of
air through charcoal to trap the organic vapours present
(recommended sample is 10 litres at a rate of 0.2 litre/min). The
analyte is desorbed with carbon disulfide containing 1% 2-propanol.
The sample is separated by injection into a gas chromatograph
equipped with a flame ionization detector and the area of the
resulting peak is determined and compared with standards (NIOSH,
1977).
A gas-chromatographic separation and determination method for
1-, sec-, and tert-butanols, with a sensitivity of 1 mg/m3 was
reported by Abbasov et al. (1971).
Testing methods for the butanols (ASTM D304-58) are described
in ASTM (1977).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
1-Butanol is used as an ingredient in perfumes and flavours
(Mellan, 1950), and for the extraction of: hop, lipid-free protein
from egg yolk (Meslar & White, 1978), natural flavouring materials
and vegetable oils, perfumes (Mellan, 1950), phenols, and
oligosaccharides from plant tissue (Sodini & Canella, 1977), and
as a solvent in removing pigments from moist curd leaf protein
concentrate (Bray & Humphries, 1978). 1-Butanol is also used as:
an extractant in the manufacture of antibiotics, hormones, and
vitamins (Mellan, 1950; Doolittle, 1954; Yamazaki & Kato, 1978),
and of rhenium (Gukosyan et al., 1979); a solvent for paints,
coatings, natural resins, gums, synthetic resins, dyes, alkaloids,
and camphor (Mellan, 1950; Doolittle, 1954); a cleanser for moulded
contact lenses (Mizatani et al., 1978); an intermediate in the
manufacture of butyl acetate, dibutyl phthalate, and dibutyl
sebacate (Mellan, 1950; Doolittle, 1954) as well as of the esters
of herbicides (e.g., 2,4-D, 2,4,5-T) (Monich, 1968). Other
miscellaneous applications of 1-butanol are as a swelling agent in
textiles, as a component of brake fluids, cleaning formulations,
degreasers (Monich, 1968; Sitanov et al., 1979), and repellents
(Zaikina et al., 1978); and as a component of ore floation agents
(Monich, 1968), of protective coatings for glass objects (Artigas
Gimenez et al., 1979) and of wood-treating systems (Amundsen et
al., 1979). Mixed with xylene, it is used to produce a glass
substitute that can be used for sunglasses, safety glasses, windows
for airplanes and others (Ferri, 1979). 1-Butanol is also used as
an additive to increase the fineness of ground cement (Tavlinova &
Dovyborova, 1979) and as a solvent in the purification of
polyolefins (Takeuchi et al., 1978). It may be liberated during
photographic processing operations.
A further use of 1-butanol is as a flavouring agent in butter,
cream, fruit, liquor, rum, and whiskey. Other foods in which it is
used include: beverages (12 mg/litre maximum), ice cream and ices
(7 mg/kg maximum), candy (34 mg/kg maximum), baked goods (32 mg/kg
maximum), cordials (1 mg/litre maximum), and cream (4 mg/kg
maximum) (Hall & Oser, 1965).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
A high rate of degradation of 1-butanol has been found in a
wide range of test methods. The data in Table 2 suggest a high
proportion of the total oxygen required for its complete oxidation
is taken up within a few hours and degradation would be complete
within a few days. Its biodegradation in surface waters may
present a hazard in terms of oxygen depletion.
At a concentration of 20 mg/litre, butanol gives a strong
unpleasant odour to drinking-water. The odour threshold is 1
mg/litre (Nazarenko, 1969).
No data are available on distribution in soil, sediments, or
air.
Table 2. Biodegradation data for 1-butanol
------------------------------------------------------------------------
activated 36% of ThOD removed in 24 h by Gerhold & Malaney
sludge unadapted municipal sludge (1966)
44% of ThOD removed in 23 h by McKinney & Jeris
adapted sludge (1955)
biodegradation rate in adapted sludge Pitter (1976)
at 20 °C, 84.0 mg COD/g per h
5d BOD 68% of ThOD in fresh water Price et al. (1974)
45% of ThOD in synthetic sea water Price et al. (1974)
5d BOD 33% of ThOD (AFNOR Test) Dore et al. (1974)
66% of ThOD (APHA Test) Bridie et al. (1979b)
anaerobic degraded by acetate-enriched methane Chou et al. (1978a,b)
digestion culture after adaptation, 100% of ThOD
removed at 100 mg/1itre per day after
4 days of adaptation; 98% of ThOD
removed at 80 mg/1itre in anaerobic
upflow filters (hydraulic residence
time 2 - 10 days) after 52 days of
adaptation
---------------------------------------------------------------------------
ThOD = theoretical oxygen demand - the calculated amount of oxygen needed
for complete oxidation to water and
carbon dioxide.
COD = chemical oxygen demand - measures the chemically oxidizable
matter present.
BOD = biochemical oxygen demand - a simple bioassay measuring the
potential deoxygenating effect of
biologically oxidizable matter present
in an effluent.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
1-Butanol and other congeners occur naturally as a result of
carbohydrate fermentation in a number of alcoholic beverages
including beer (Bonte, 1979), grape brandies (Schreier et al.,
1979), apple brandies (Woidich et al., 1978), wine (Bikvaloi &
Pasztor, 1977; Bonte, 1978), and whisky (Pastel & Adam, 1978). It
has been detected in the volatiles of the following products: hops
(Tressl et al., 1978), jack fruit (Swords et al., 1978), heat-
treated milks (Juddou et al., 1978), muskmelon (Yabumoto et al.,
1978), cheese (Dumont & Adda, 1978), southern pea seed (Fisher et
al., 1979), and cooked rice (Yajima et al., 1978). 1-Butanol is
also formed during deep frying of corn oil, cottonseed oil,
trilinolein, and triolein (Chang et al., 1978). The production or,
in some cases, use of the following substances may result in
exposure to 1-butanol: artificial leather, butyl esters, rubber
cement, dyes, fruit essences, lacquers, motion picture and
photographic films, raincoats, perfumes, pyroxylin plastics, rayon,
safety glass, shellac varnish, and waterproofed cloth (Tabershaw et
al., 1944; Cogan & Grant, 1945; Sterner et al., 1949; Mellan, 1950;
Doolittle, 1954). It has also been detected by gas chromatographic
methods in waste gases obtained during the boiling and drying of
oil (Novokonskaya et al., 1978), and it is released from polyvinyl
chloride linoleum plasticized with poly(dibutyl maleate)
(Moshlakova et al., 1976) and from hardened parquet lacquer
(Dmitriev & Michahikin, 1979).
Whilst testing the air of mobile homes for the presence of
organic chemicals, 1-butanol was found with a frequency of 47%; the
mean concentration was 5 ppb and the range 0.07 - 26 ppb (Connor et
al., 1985).
An industrial emission study indicated that 616 tonnes of 1-
butanol were released into the air, over 1 year, in The Netherlands
(Anon, 1983).
6. KINETICS AND METABOLISM
1-Butanol is readily absorbed through the lungs, skin, and
intestinal tract (Sander, 1933; Theorell & Bonnichsen, 1951; Winer,
1958; Merritt & Tomkins, 1959; Wartburg et al., 1964) and is
primarily eliminated after metabolism by alcohol and aldehyde
dehydrogenases.
It has been shown that 1-butanol disappeared rapidly from the
blood of rats. After an oral dose of 2000 mg/kg body weight, the
maximum blood-alcohol concentration was 500 mg/litre after 2 h.
The concentration dropped to 150 mg/litre after 4 h and only 0.03%
of the dose was excreted in the urine after 8 h (Gaillard &
Derache, 1965).
In a study on rabbits, it was stated that aliphatic alcohols
appeared to be metabolized and eliminated from the body by:
(a) oxidation and elimination of the products (acids,
aldehydes, ketones, and carbon dioxide) in the urine and
expired air;
(b) conjugation as glucuronide or sulfate and elimination of
the products in the urine; and
(c) elimination of the unchanged alcohol in the expired air or
urine.
In the case of 1-butanol, though no specific numbers concerning
the expired air were given, it was found to oxidize to the
corresponding acid via the aldehyde, and to carbon dioxide (CO2);
1.8% of the alcohol was excreted conjugated with glucuronic acid
within 24 h (Kamil et al., 1953).
According to DiVincenzo & Hamilton (1979), rats dosed, by
gavage, with 450 mg 1-butanol/kg body weight excreted 83.3% of the
dose as carbon dioxide (CO2), at 24 h. Less than 1% was eliminated
in the faeces, 4.4% was excreted in the urine, and 12.3% remained
in the carcass. Similar excretion patterns were observed at 45 and
4.5 mg/kg body weight. About 75% of 1-butanol excreted in the
urine was in the form of o-sulfate (44%) or o-glucuronide (30%).
1-Butanol was absorbed through the skin of dogs at a rate of 8.8
µg/min per cm2; dogs exposed by inhalation to 1-butanol vapour at
53.9 mg/m3 (50 ppm) over 6 h absorbed about 55% of the inhaled
vapour. When administered orally to rats, 14C-labelled butanol was
found in the liver, kidneys, small intestine, and lungs, 1 h after
administration. A decrease in the radioactivity was observed in
the organs 4 h later. During the first 3 days, 95% of 14C was
excreted from the body; however, only 2.8% of 14C was eliminated in
the urine and faeces combined (Rumyanstev et al., 1975).
When administered intraperitoneally (ip) to rats in a single
dose, 1-butanol accumulated in the brain nuclei and liver nuclei
and, at a slower rate and reaching a lower maximum concentration,
in mitochondria (Mikheev et al., 1977).
Excretion of 1-butanol in the breath and urine of rabbits
following an oral dose of 2 ml/kg body weight was less than 0.5%
of the dose administered in each case (Patty, 1982). In a 1-month
study, 1-butanol, administered 5 times/week to mice at 0.1 - 0.5 of
the LD50, showed cumulative properties (Rumyanstev, 1976). The
elimination of 1-butanol from the perfusate of isolated rat liver
was a zero-order process above the concentration of 0.8 mmol and a
first-order process below this concentration (Auty & Branch, 1976).
In an in vitro study using rat liver slices, it was reported
that 1-butanol was oxidised by alcohol dehydrogenase. At the
concentration of 1-butanol tested (25 µl/500 mg liver per 2 ml
incubate), CO2 production was decreased by approximately 60% and
the lactate/pyruvate ratio in the medium was increased ten fold
(Forsander, 1967).
The in vitro metabolism of 1-butanol by rat hepatic microsomes
has been studied by Teschke et al. (1974) and Cederbaum et al.
(1978, 1979). The first authors showed that hepatic microsomes
catalysed the oxidation of 1-butanol to its aldehyde by means of a
reaction requiring molecular oxygen and NADPH. This reaction was
inhibited by carbon monoxide. A direct demonstration of the role
of hydrogen peroxide (H202) in the cytochrome P-450-mediated
pathway stems from the observation that reagent H2O2 added to
microsomal preparations stimulated the oxidation of butanol
(Cederbaum et al., 1978). Indirect evidence was provided by the
observation that azide, which prevents the decomposition of H2O2 by
catalase, actually stimulated the oxidation of 1-butanol.
Thiourea, a compound that reacts with hydroxyl radicals, inhibited
NADPH-dependent microsomal oxidation of 1-butanol to a similar
extent, in both the absence and presence of the catalase inhibitor
azide (Cederbaum et al., 1979). Achrem et al. (1978) showed that
the hydroxyl ion from butanol interacted with the Fe of haem in
cytochrome P-450.
Twelve human volunteers were exposed for 2 h to 1-butanol at
300 or 600 mg/m3 in inspired air during rest and during exercise
(50, 100, or 150 w) on a bicycle ergometer. At the highest dose
level, the difference between levels in inspired and expired air
indicated an uptake of 47% 1-butanol at rest, and 37, 40, and 41%
at 50, 100, and 150 w, respectively. After 30 min exposure to 300
or 600 mg/m3, the 1-butanol concentrations in the arterial blood
were 0.3 and 0.5 mg/litre, respectively. The combination of an
apparently high uptake and low concentrations in arterial blood is
probably because 1-butanol is dissolved in the water of the dead
space mucous membranes (Astrand et al., 1976).
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1. Aquatic Organisms
Toxicity data for aquatic organisms are given in Table 3.
Table 3. Table of acute toxicity data for fresh-water organisms
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Fish
Fresh-water species
Creek chub 1900 - 2300 24-h LC50 Gillette et al. (1952)
(Semotitus
atromaculatus)
Golden orfe 1200 48-h LC50 Juhnke & Lüdemann
(Leuciscus idus (1978)
melanotus)
Goldfish 1900 24-h LC50 Bridié et al. (1979a)
(Carassius auratus)
Fathead minnow 1730 - 1910 96-h LC50 Mattson et al. (1976)
(Pimapheles promelas) Veith et al. (1981,
1983)
Bleak 2250 - 2400 96-h LC50 Linden et al. (1979)
(Alburnus alburnus) Bengtsson et al. (1984)
Amphibia
Tadpole 2820 threshold for Münch (1972)
( Rana sp.) narcosis
Invertebrates
Fresh-water species
Water flea 1880 24-h EC50 immobilization Bringmann & Kuehn
(Daphnia magna) (1982)
Harpacticoid copepod 1900 - 2300 96-h LC50 Mattson et al. (1976)
(Nitocra spinipes) Bengtsson et al. (1984)
Marine species
Brine shrimp 2950 24-h LC50 Price et al. (1974)
(Artemia salina) 2600 excystment Smith & Siegel (1975)
inhibited
------------------------------------------------------------------------------------------
Table 3. (contd.)
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Algae (fresh-water)
Green algae
(Scenedesmus 875 8-day no- total biomass Bringmann & Kuehn
quadricauda) observed- (1978a)
adverse-
effect level
Chlorella 8500 EC50 Jones (1971)
pyrenoidosa I chlorophyll
content
Blue-green algae
(Microcystis 100 8-day no- total biomass Bringmann & Kuehn
aeruginosa) observed- (1978a)
adverse-
effect level
------------------------------------------------------------------------------------------
LC50 data for 5 species of fish range from 1000 to 2400
mg/litre and for 3 species of aquatic invertebrates from 1880 to
2950 mg/litre. These concentrations are unlikely to be achieved in
the field except locally after accidental spills or through
effluence from industrial sites; even under these conditions, the
high levels of contamination would not last long. Fresh-water
algae are very resistant to the toxic effects of 1-butanol at
realistic exposures.
Hill et al. (1981) looked at effects of 1-butanol on goldfish
with a conditioned reflex of avoiding light followed by electric
shock. The fish were housed in a tank separated into 2
compartments by a metal plate with a hole big enough for the fish
to swim through. Training involved a 10-s light pulse followed by
a 20-s shock to one side of the tank. Experimental concentrations
of 1-butanol (2.5 - 15 mmol) were applied to the tanks and fish
were exposed to step-wise increases (2.5 mmol) in concentration
with approximately 1.5 h between each step (a 15 mmol concentration
of 1-butanol is 58% of the 24 h LC50 for this species). Two
responses were scored; "avoidance", defined as the fish leaving the
test side of the tank during the light stimulus and before the
shock, and "escape", defined as leaving during the 20-s shock.
With each step up to 10 mmol butanol, there was a transitory
reduction in avoidance. At 10 mmol or higher concentrations, there
was also a fall in escape response. Recovery to control scores
after first exposure to 10 mmol butanol was slow and incomplete
after 2 h. 1-Butanol at 15 mmol, achieved either step-wise or by
single application, led to a dramatic and non-recoverable fall in
both avoidance and escape to approximately 20% of control values.
Escape and avoidance success was correlated with brain levels of
butanol. Final concentrations of butanol in the fish brain were
75% of those expected, assuming complete equilibrium with tank
water. This compares with 90% for ethanol in the same species.
Measuring of brain butanol over a longer period indicated that
butanol was metabolized by the goldfish in a similar way to ethanol
(Hill et al., 1980). The concentrations of the alcohol that
produced effects in these studies are high compared with likely
exposure levels in natural waters.
7.2. Terrestrial Organisms
Seed germination in lettuce (Lactuca sativa) was inhibited by
50% at a concentration of 1-butanol of 390 mg/litre (Reynolds,
1977). Seed germination in cucumber (Cucumis sativus) was
inhibited at 2500 mg/litre (Smith & Siegal (1975). 1-Butanol had
an antisenescence effects on the leaves of oat seedlings (Avena
sativa). It both maintained chlorophyll levels and prevented
proteolysis in the dark (Satler & Thimann, 1980). There are no
relevant data on terrestrial animals; however, as for terrestrial
plants, significant exposure to butanol is unlikely.
7.3. Microorganisms
Some toxicity data for microorganisms are given in Table 4.
It would be highly unlikely that bacteria would be affected by
1-butanol in the field. Protozoans are more susceptible than
bacteria, but only transitory effects on protozoan populations are
likely from spills and effluent since the experimental no-observed-
adverse-effect levels are high.
1-Butanol at a concentration of 20 mg/litre in water reduced
nitrification; a concentration of 5 mg/litre was the no-observed-
adverse-effect level for nitrification (Nazarenko, 1969). 1-
Butanol does not bioaccumulate (Chiou et al., 1977).
Table 4. Toxicity data for microorganisms
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Protozoa
Uronema parduczi 8 20-h no-observed-adverse- total Bringmann &
(ciliate) effect level biomass Kuehn (1981)
Chilomonas paramaecium 28 48-h no-observed-adverse- total Bringmann &
(flagellate) effect level biomass Kuehn (1981)
Entosiphon sulcatum 55 72-h no-observed-adverse- total Bringmann &
(flagellate) effect level biomass Kuehn (1981)
------------------------------------------------------------------------------------------
Table 4. (contd.)
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Bacteria
Pseudomonas putida 650 16-h no-observed-adverse- total Bringmann &
effect level biomass Kuehn (1976)
Bacillus subtilis 1258 EC50 spore germination Yasuda-Yasaki
et al. (1978)
7400 no inhibition of Chou et al.
degradation by methane (1978)
culture on acetate
substrate
------------------------------------------------------------------------------------------
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single Exposure
8.1.1. Acute toxicity
Some acute toxicity data for experimental animals are given in
Table 5.
Table 5. Acute toxicity data for experimental animals
-------------------------------------------------------------------
Species Route LD50 LD100 Reference
(g/kg body (g/kg body
weight) weight)
-------------------------------------------------------------------
Rabbit dermal 5.3 - Patty (1982)
Rabbit dermal 4.2 - Egorov (1972)
Rabbit dermal - 7.5 Patty (1963)
Hamster oral 1.2 - Dubina & Maksimov (1976)
(0.6-2.3)a
Mouse oral 2.68 - Rumyanstev et al. (1979)
Rabbit oral 3.4 - Münch & Schwartze (1925)
Rabbit oral 3.5 - Münch (1972)
Rat oral 2.1 - Jenner et al. (1964)
Rat oral 0.8-2.0 - Purchase (1969)
Rat oral 0.7 - NIOSH (1977a)
Rat oral - 4.4 Smyth et al. (1951)
Mouse ip 0.1-0.3 - Maickel & McFadden (1979)
Rat ip 1.0 - Lendle (1928)
Rat ip 0.2 - Macht (1920)
Rat ip - 1.0 Browning (1965)
Cat iv - 0.24 Macht (1920)
Mouse sc - 5.0 Patty (1982)
-------------------------------------------------------------------
a 95% confidence limits for this study.
Rats survived inhalation exposure to 1-butanol at 24 624 mg/m3
(8000 ppm) for 4 h (Smyth et al., 1951). Mice did not show any
evidence of toxicity when exposed to 1-butanol at 5078.7 mg/m3 (650
ppm) for 7 h, but exposure to 20 314.8 mg/m3 (6600 ppm) produced
signs of marked central nervous system (CNS) depression (narcosis
after approximately 2 h) with lethality after 3 h (Patty, 1982).
Male Swiss mice (10 per group) were exposed by inhalation for
4 h to 1-butanol at 1446.7, 1686.7, 2597.8, or 2970.2 mg/m3 (470,
548, 844, or 965 ppm). Following this exposure, the animals were
tested in a "behavioural despair" swimming test. Compared with
controls, a dose-related decrease in the duration of immobility
measured over a 3-min period was observed (de Ceaurriz et al.,
1982).
8.1.1.1 Signs of intoxication
The acute toxicity of 1-butanol (Table 5) is moderate in
several animal species, and is mainly associated with effects on
the CNS. Injection (ip) of 1-butanol in rats induced behavioural
effects of intoxication (pronounced ataxia) that were virtually
identical to those of ethanol, but the intoxicating potency of
1-butanol was approximately 6 times higher (McCreery & Hunt, 1978).
Similarly, after ip administration in mice, 1-butanol was 6 times
more potent than ethanol in inducing narcosis (Browning, 1965).
The performance in a simple functional test of rats treated with a
non-toxic single oral dose of 1-butanol (0.0163 mol/kg body weight)
was studied by Wallgren (1960). Rat performance decreased soon
after treatment, but recovery was rapid (Wallgren, 1960). In
rabbits, the oral administration of 2.1 - 2.44 g 1-butanol/kg body
weight caused deep and rapid narcosis; in mice, the narcotic dose
by ip injection was 0.76 ml/kg body weight (compared with 4.5 for
ethanol) and 20.31 mg/m3 (6.6 ppm) by inhalation (Browning, 1965).
In conscious rabbits, the effects of 1-butanol on circulatory
variables was investigated in double blind studies. 1-Butanol did
not produce any significant effect at an intravenous (iv) dosage of
0.008 g/kg body weight. Doses of 0.1 g/kg body weight and
particularly of 0.33 g/kg resulted in a transitory decrease in
the heart rate and the systolic and especially diastolic blood
pressures. Butanol anaesthetized rats and mice at 15.7 and 15.3
mg/litre, respectively; the anaesthesia transiently lowered the
blood levels of erythrocytes and haemoglobin. The animals that
died during the treatment showed lung haemorrhages and hyperaemia
of other parenchymatous organs. The minimum concentration of
1-butanol disturbing conditioned reflexes was 65 mg/m3 (Rumyanstev
et al., 1979). In acute studies, when 1-butanol was administered
by the oral or ip route, post-mortem findings included marked
hyperaemia of the liver, congestion of several organs in animals
that died early, and degenerative signs becoming visible in the
liver and kidneys of the rats dying after 5 days. Haemorrhagic
areas in the lungs and blood changes were also noted. In the
kidney, hyperaemia and cloudy swelling with cast formation in the
cortex were seen, the only signs of necrosis were in the medulla
(Smyth & Smyth, 1928; Purchase, 1969; Maickel & McFadden, 1979).
In normothermic dogs, the mean lethal dose for 1-butanol,
administered iv, was 1.26 g/kg body weight and, at a constant
infusion rate, the blood alcohol level increased almost linearly
with time (McGregor et al., 1964).
8.2. Skin, Eye, and Respiratory Tract Irritation
8.2.1. Skin irritation
In a 24-h patch test, application of 405 or 500 mg 1-butanol to
the skin of rabbits resulted in moderate irritation (US DHEW,
1978).
8.2.2. Eye irritation
Instillation of 1.62 mg and 20 mg 1-butanol into rabbit eyes
resulted in severe irritation after 72 h and 24 h, respectively (US
DHEW, 1978).
1-Butanol is an irritant of mucous membranes, especially of the
eye and, in man, it causes an unusual form of keratitis (section
9.1.2).
Instillation of 0.005 ml undiluted 1-butanol or an excess of
40% solution in propylene glycol in the rabbit eye caused severe
corneal irritation. A 15% solution in propylene glycol caused
minor corneal injury (Patty, 1982).
8.2.3. Respiratory tract irritation
On the basis of the effects of 1-butanol on the respiratory
rate in male Swiss OF1 mice, de Ceaurriz et al. (1981) predicted
that exposure to a concentration of 40.01 mg/m3 (13 ppm) in air
would have only a minimal or no effect on man, a concentration of
390.9 mg/m3 (127 ppm) would be uncomfortable, but tolerable, and
3909 mg/m3 (1268 ppm) would be intolerable.
8.3. Repeated and Continuous Exposure
8.3.1. Inhalation studies
Inhalation studies on the effects of 1-butanol on experimental
animals are summarized in Table 6.
According to Rumyantsev et al. (1976), the no-observed-adverse-
effect level of 1-butanol can be set at 0.09 mg/m3 (0.03 ppm) for
both the rat and the mouse under conditions of long-term continuous
exposure.
When 3 groups of 3 guinea-pigs were exposed to 1-butanol in air
at 307.8 mg/litre (100 ppm), 4 h per day, for 64 days, the number
of red blood cells and relative and absolute lymphocyte counts were
decreased. Haemorrhagic areas were observed in the lungs of the
exposed animals. There were also early degenerative lesions in the
liver, as well as cortical and tubular degeneration in the kidneys
(Smyth & Smyth, 1928).
Five white mice were exposed to a concentration of 24.3 mg
1-butanol/litre of air (24 624 mg/m3) for a total exposure time of
130 h (number of h per day not specified). Although the exposed
animals were narcotized repeatedly, they gained in weight and
survived the exposures. Reversible fatty changes were observed in
the livers of the mice (Weese, 1928).
Table 6. Inhalation effects on experimental animals
---------------------------------------------------------------------------------------------------------
Species Dose Duration Effects Reference
---------------------------------------------------------------------------------------------------------
Mouse 24624 mg/m3 repeated exposure narcosis; no deaths; reversible fatty Weese (1928)
(8000 ppm) for several days infiltrations of the liver and the kidneys
Guinea- 307.8 mg/m3 64 days, 4 h/day degenerative lesions in liver, kidney, and lung Smyth & Smyth
pig (100 ppm) (1928)
Rat 218 mg/m3 5 h/day, 6 days/ during the first 2 months, a decrease in O2 Savelev et al.
(71 ppm) week for 6 months consumption and delay in the restoration of (1975)
normal body temperature after cooling; during
the next 4 months of long-term exposure, an
increase in O2 consumption and a return to
normal body temperature after cooling was noted
Rat and 6.8 and 4 months decreased sleeping time; stimulated blood Rumyanstev et
mouse 40.9 mg/m3 continuously cholinesterase; disturbances of reflexes and al. (1979)
(2.2 and neuromuscular sensitivity of the nervous
13.3 ppm) system; increased thyroid activity and
secretion of thyroxine; increases in
eosinophile leukocytes in blood after injection
of adreno-corticotrophin (ACTH)
Rat 0.09 and 92 days after 4 weeks at 21.8 mg/m3, the amount of RNA Baikov &
21.8 mg/m3 continuously and DNA in blood decreased; there was increased Khachaturyan
(0.03 and leukocyte luminescence, increased diastase (1973)
7.1 ppm) activity, decreased catalase activity,
increased penetration of butanol across blood-
tissue barriers in testis, spleen, and thyroid;
no effects were observed at 0.09 mg/m3
Mouse 13.6 and 30 days decreased sleeping time Kolesnikov
40.01 mg/m3 continuously (1975)
(2.1 and
13 ppm)
Rabbit -- prolonged mild bronchial irritation with some enlargement Browning (1965)
exposure of bronchial lymphnodes
---------------------------------------------------------------------------------------------------------
8.3.2. Other routes of administration
The neuropharmacological effects of 1-butanol were investigated
in 31 male Sprague Dawley rats weighing between 200 - 400 g.
1-Butanol was administered iv to the rats at concentrations of
6.7 - 8.1 mmol/kg body weight. Within 20 - 60 s of the iv
administration, the rats lost their righting reflexes.
Nonconvulsive epileptoid activity was noted in the
electroencephalographic tracing compared with the tracing prior to
the 1-butanol administration (Marcus et al., 1976).
DiVincenzo & Hamilton (1979) applied 1-14C-1-butanol to the
skin of 2 male beagle dogs and observed an absorption rate of 8.8
µg/min per cm2. Application of 42 - 55 ml/kg per day for 1 - 4
consecutive days to the skin of rabbits resulted in 100% mortality.
However, repeated applications of 20 ml/kg per day for 30 days over
a period of 6 weeks did not produce any fatalities (Patty, 1982).
According to Cater et al. (1977), the daily oral administration
of approximately 500 mg 1-butanol/kg body weight dissolved in corn
oil, for 4 days, did not affect the testicular tissues of rats.
1-Butanol caused a significant dose-dependent decrease in rat
liver contents of thiamine, riboflavin, pyrixodine, niacin, and
pantothenic acid, after daily oral administration of 1 or 2 ml/kg
body weight for 7 days (Shehata & Saad, 1978). Oral administration
of butanol (1 or 2 ml/kg of a 10% aqueous solution) for 7 days to
rats significantly increased the cerebral GABA levels in the
hemispheres (Saad, 1976).
The influence of 1-butanol on the metabolic status of some rat
organs and on the rabbit circulation was studied by Geppert et al.
(1976). Rats received 1-butanol im at a dose of 0.1 g/kg body
weight per day for 50 days. The metabolic status of some organs
was examined and compared with that in control rats that had
received NaCl solution (9 g/litre) in an equivalent volume (double
blind studies). The tissue levels of metabolites of the adenylic
acid-creatine phosphate system, glycogen, glucose, and lactate did
not differ significantly between the groups. In the liver, the
tissue levels of glycogen, free creatine, and total creatine were
significantly elevated in rats that had received 1-butanol.
A group of 30 male Wistar rats was exposed to 1-butanol in the
drinking-water (69 g/litre), which also contained sucrose (250
g/litre). A control group of equal size was used for comparison.
Electron microscopic studies that were carried out after 5, 9, and
13 weeks demonstrated that, within 5 weeks, 1-butanol at this
dose level gave rise to the formation of irregularly shaped
megamitochondria in liver cells. It was speculated that this was
an adaptive process (Wakabayashi et al., 1984). Ethanol and
1-propanol, both at 320 g/litre, produced similar effects under the
same test conditions.
8.4. Mutagenicity
1-Butanol was found not to be mutagenic in the Ames Salmonella/
microsome test (McCann et al., 1975). It inhibited the initiation
of a new cycle of DNA replication in E. coli but permitted the
completion of DNA replication initiated before the addition of
1-butanol to the medium (Patty, 1982). In spite of the fact that
the lymphocytes of alcoholic patients exhibit higher incidences of
exchange-type aberrations of the chromosome and the chromatid type
compared with controls, several alcohols tested including 1-butanol
do not produce any effects on the chromosomes of human lymphocytes
in culture (Obe et al., 1977). Obe & Ristow (1977) showed that
1-butanol does not affect sister chromatid exchange in Chinese
hamster cells in vitro. In the same cell system, ethanol was also
found to be inactive, but acetaldehyde induced sister chromatid
exchanges; butyric aldehyde was not tested.
1-Butanol was negative in a sister chromatid exchange test
using avian embryos (Bloom, 1981).
8.5. Carcinogenicity
Although two long-term studies on rats have been recorded by
the US National Cancer Institute, both of these studies were
inadequate, by present standards, for the assessment of the
carcinogenicity of the substance. No adequate data on
carcinogenicity are available.
8.6. Reproduction, Embryotoxicity, and Teratogenicity
No relevant data on the effects of 1-butanol on reproduction,
embryotoxicity, and teratogenicity have yet been published. An
inhalation teratology study with 1-butanol is in progress in the
USA (US EPA, personal communication, 1985).
8.7. Special Studies
Various investigations have indicated that 1-butanol exerts
non-specific effects on biological membranes. Evidence of
reversible functional derangement of cell membranes by 1-butanol
was provided by Stark et al. (1983) and Shopsis & Sathe (1984).
The first group of authors was also able to demonstrate
cytotoxicity in cultured corneal endothelial and hepatoma cells.
The interaction of 1-butanol with rat liver microsome membranes
was studied by Birkett (1974) using a microsome-bound fluorescent
probe. 1-Butanol decreased the fluorescent binding to the
microsomal membrane, possibly because of a changed net charge on
the membrane. 1-Butanol increased the fluidity of Chinese hamster
cell plasma membranes (as measured by fluorescence polarization) at
concentrations that inhibited cell adhesion (Juliano & Gagalang,
1979). Moreover, 1-butanol reduced manganese binding to
phosphatidylserine or cardiolipin vesicles to the same extent
(Puskin & Martin, 1978). These authors also reported that
1-butanol increased cholestane mobility in phosphatidylserine
vesicles, thus indicating a more fluid bilayer.
1-Butanol inhibited several rat microsomal metabolic activities
in vitro including ethoxycumarin deethylation (Aitio, 1977) and
the activity of aldrin epoxidase (Wolff, 1978). A sex difference
in the spectral interaction of 1-butanol with liver microsomes from
adult mice has been reported by Van den Berg et al. (1979a). In
males, a profound reverse type I spectrum was elicited, whereas
only a small spectral change of irregular shape was apparent in
females. No sex difference was found in immature animals.
1-Butanol also interfered with both type II (aniline) and type I
(ethylmorphine) binding in mouse liver microsomes. The apparent
dissociation constant of 1-butanol for type I binding was 30 mmol
(Van den Berg et al., 1979b).
Prostaglandin biosynthesis requires the presence of a hydroxyl
radical. 1-Butanol was shown to be a hydroxyl radical scavenger
and, therefore, an inhibitor of the biosynthesis of prostaglandins.
A test system containing microsomes was prepared from bovine
vesicular glands. In the presence of epinephrine, incorporation of
14C-eicosa-8,11,14-trienoic acid into prostaglandins was 16.4% for
prostaglandin E and 23.4% for prostaglandin F. When 0.025 ml of
1-butanol was added to this incubation system, the amounts
incorporated were 7.8% and 9.1%, respectively (Panganamala et al.,
1976). In another study using isolated perfused rat lung, the
infusion of low concentrations of 1-butanol (0.002 - 0.2 mmol)
resulted in maximum release of prostaglandins into the venous
effluent at the lowest concentration tested. However, there was a
gradual decrease in the prostaglandin output as the concentration
of the alcohol increased (Thomas et al., 1980).
Adult male Swiss Cox mice (20 - 25 per group) were dosed orally
by intubation with 1-butanol in distilled water at levels of 0.5,
1.0, or 2.0 g/kg body weight in one single dose. This caused a
dose-related hypothermia and impairment of rotarod performance.
Repetitive doses, at 24 to 72-h intervals did not lead to the
development of tolerance in relation to these effects (Maickel &
Nash, 1985).
1-Butanol caused relaxation of the canine basilar artery,
whereas linear alcohols with fewer carbon atoms above a threshold
of 10-2 mol caused contraction (De Felice et al., 1976).
1-Butanol, applied to the lateral olfactory tract of the guinea-pig
as a dilute suspension (0.1 - 0.2 mmol), blocked the nerve impulse
(Hesketh et all., 1978). The compound also inhibited the
contraction of the CaCl2-depolarized guinea-pig ileum (Yashuda et
al., 1976) and prolonged frog miniature end-plate currents (Ashford
& Wann, 1979).
1-butanol can potentiate the toxicity of carbon tetrachloride
(Cornish & Adefuin, 1967) in Sprague Dawley rats.
9. EFFECTS ON MAN
9.1. Toxicity
The most important effects of 1-butanol inhalation are symptoms
of alcohol intoxication and narcosis (Smyth, 1956).
Following exposure to 1-butanol vapours, the signs of poisoning
in human beings, may include irritation of the nose, throat, and
eyes, the formation of translucent vacuoles in the superficial
layers of the cornea, headache, vertigo, and drowsiness. Defatting
of the skin leading to contact dermatitis involving the fingers and
hands may also occur, as with other solvents.
9.1.1. Eye irritation
Tabershaw et al. (1944) reported that exposure to levels of
more than 153.9 mg/m3 (50 ppm) resulted in irritation of the eyes.
However, results of a 10-year study revealed few or no complaints
of irritation among workers exposed to an average 1-butanol
concentration of 307.8 mg/m3 (100 ppm) (Sterner et al., 1949).
9.1.2. Case reports of occupational exposure
In a raincoat manufacturing plant, the solvent used for the
cementing process was 1-butanol, to which various amounts of
diacetone alcohol and denatured alcohol were added. Of the 35
employees working in the department, 28 were found to have from 10
to 1000 vacuoles in the corneal epithelium. The affected workers
complained of epiphora and burning and itching of the eyes.
Swelling of the eyelids and occasional redness of the eyes were
also observed. The symptoms were more severe on awakening in the
morning than during the day. When the patients were away from
work, the corneal changes were considerably improved and resolved
completely in 10 days (Cogan & Grant, 1945). The authors presumed
that these symptoms were caused by 1-butanol, but stated that the
other components might also be responsible for the symptomatology.
The physical condition of workers exposed to 1-butanol was
followed for 10 years. At the beginning of the study, when the
concentration of 1-butanol was 615.2 mg/m3 (200 ppm) or more,
corneal inflammation was occasionally observed. The symptoms
included a burning sensation that could continue for several days
after cessation of exposure, blurring of the vision, lachrymation,
and photophobia. These symptoms began in the middle of the working
week and became more severe towards the end of the week. In
addition, the mean erythrocyte count was slightly decreased. Later
in the study, after the average concentration was reduced to 307.6
mg/m3 (100 ppm), no systemic effects were observed. Complaints of
irritation of the eyes or disagreeable odour were rare at this
concentration (Sterner et al., 1949).
Velazquez et al. (1969) reported that prolonged exposure (3 -
11 years) to 1-butanol in a cellulose acetate ribbon factory had
caused hearing loss in 9 out of 11 exposed workers. Following this
finding, the 1-butanol level in the working atmosphere was found to
be 246.2 mg/m3 (80 ppm). However, this level may not be
representative of the past exposure.
Seitz (1972) reported 7 case histories, which occurred between
1965 and 1971, concerning workers who had been exposed to 1-butanol
and isobutanol in a non-ventilated photographic laboratory. They
handled the alcohols under intense and hot light without any
precautions. Exposure levels were not quantified but must have
been excessive, exposure time ranged from 1 1/2 months to 2 years.
Two workers had transient vertigo, 3 severe Meniere-like vertigo
with nausea, vomiting and/or headache. In one of these cases,
hearing was also perturbed. Two workers did not have any signs or
symptoms. For ACGIH (1980), the last two papers were the reason for
the reduction of the TLV from 307.8 to 153.9 mg/m3 (100 ppm to 50
ppm).
Several papers concerning clinical observations on workers
exposed to mixtures of solvents including 1-butanol have been
published (Kalekin & Brichenko, 1972; Petrova & Vishnevskii, 1972;
Sanatina, 1973; Shalaby et al., 1973; Kudrewicz Hubicka et al.,
1978; Zaikov & Bobey, 1978). Pathological observations included
effects on the central nervous system, liver, respiration, blood
composition, and complications during pregnancy. However, it is
not possible to judge whether these effects were due to exposure to
1-butanol.
Baikov & Khachaturyan (1973) recommended the maximum
permissible concentration of 1-butanol in ambient air to be set at
a level of about 0.09 mg/m3 (0.03 ppm), as a result of studies with
18 volunteers exposed to 1-butanol vapour at levels of between 0.3
and 15 mg/m3. Five concentrations of 1-butanol vapour were tested.
At 1.2 mg/m3, 1-butanol changed the light sensitivity of the dark-
adapted eye and the electrical activity in the brain. At 1 mg/m3,
these parameters were unaffected.
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of Human Health Risks
10.1.1. Exposure levels
General population levels of exposure to 1-butanol through food
and beverages are not available. Occupational levels of exposure
to 1-butanol are limited and inadequate.
10.1.2. Toxic effects
1-Butanol is readily absorbed through the skin, lungs, and
gastrointestinal tract. In animals, 1-butanol is rapidly
metabolized by alcohol dehydrogenase to the corresponding acid, via
the aldehyde, and to carbon dioxide, which is the major metabolite.
The rat oral LD50 for 1-butanol ranges from 0.7 to 2.1 g/kg body
weight; it is, therefore, slightly toxic according to the
classification of Hodge & Sterner. It is markedly irritating to
the eyes and moderately irritating to the skin. The primary
effects from exposure to vapour for short periods are various
levels of irritation of the mucous membranes and central nervous
system depression. Its potency for intoxication is approximately 6
times that of ethanol. A variety of investigations have indicated
non-specific membrane effects of 1-butanol. Effects of repeated
inhalation exposure in animals include pathological changes in the
lungs, degenerative lesions in the liver and kidneys, and narcosis.
However, from the animal studies available, it is not possible to
determine a no-observed-adverse-effect level. 1-Butanol has been
found to be non-mutagenic. No adequate data are available on
carcinogenicity, teratogenicity, or effects on reproduction.
In man, 1-butanol, in the liquid or vapour phase, can cause
moderate skin irritation and severe eye irritation manifested as
a burning sensation, lachrymation, blurring of vision, and
photophobia. Ingestion of the liquid or inhalation of the vapour
may result in headache, drowsiness, and narcosis. The occurrence
of vertigo under conditions of severe and prolonged exposure to
vapour mixtures of 1-butanol and isobutanol has been reported.
From this study, it was not possible to attribute the vertigo to a
single cause. The symptoms were reversible when exposure ceased.
The minimal information available suggests that occupational
human exposure to air concentrations below 307.8 mg/m3 (100 ppm) is
not associated with any adverse symptoms. However, studies on
human volunteers indicate that the light-sensitivity of dark-
adapted eyes and electrical activity of the brain may be influenced
by air concentrations as low as 0.092 mg/m3 (0.03 ppm).
10.2. Evaluation of Effects on the Environment
10.2.1. Exposure levels
No quantitative data on levels in the general environment are
available but, because 1-butanol is readily biodegradable,
substantial concentrations are only likely to occur locally in the
case of major spillages.
10.2.2. Toxic effects
At background concentrations likely to occur in the
environment, 1-butanol is not directly toxic for fish, amphibia, or
crustacea and is practically non-toxic for algae. Some protozoa
are slightly sensitive to 1-butanol.
1-Butanol should be managed in the environment as a slightly
toxic compound. It poses an indirect hazard for the aquatic
environment, because it is readily biodegradable, which may lead to
oxygen depletion.
10.3. Conclusions
1. On the available data, the Task Group was unable to make an
assessment of the health risks of 1-butanol for the general
population; however, it was considered unlikely to pose a
serious hazard under normal exposure conditions.
2. The Task Group was of the opinion that sufficient data were not
available to establish guidelines for setting occupational
exposure limits. There are reports of adverse effects
resulting from occupational overexposure to levels above 307.8
mg/m3 (100 ppm); therefore, and in line with good manufacturing
practice, exposure to 1-butanol should be minimized.
3. The ecotoxicological data available indicate that the impact of
background concentrations of 1-butanol on the aquatic
environment can be expected to be minimal.
11. RECOMMENDATIONS
1. The Task Group noted that, from the animal studies available,
it was not possible to determine a no-observed-adverse-effect
level. Relevant studies should be conducted so that this can
be achieved.
2. Information on residue and emission levels is desirable.
3. Epidemiological studies, including precise exposure data, would
assist in a better assessment of the occupational hazard of
1-butanol.
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
In 1974, the Council of Europe established an acceptable daily
intake (ADI) of 1 mg/kg body weight for butan-1-ol.
More recently (Council of Europe, 1981), specific limits of
30 mg butan-1-ol/kg in beverages and food have been established.
The Food Additives and Contaminants Committee (UK MAFF, 1978)
recommended that residues in food do not exceed 30 mg/kg and
required the results of a 90-day oral toxicity study in the rat
within two years.
Butan-1-ol was evaluated by the EEC Scientific Committee for
Food in 1980. The Committee agreed on the following evaluation:
The available toxicological data relate to metabolism
and short-term oral studies in rats. No long-term oral
studies are available. The Committee was therefore unable
to establish an ADI. Residues occur in food from use as
extraction and carrier solvent as well as from natural
occurrence, but adequate residue data are not available.
The Committee considers the use of this compound
temporarily acceptable as an extraction solvent provided
the residues are limited to 30 mg/kg food. The Committee
requires the provision of an adequate 90-day oral study in
rats as well as information on residue levels by 1983
(CEC, 1981).
At their 23rd meeting, the Joint FAO/WHO Expert Committee on
Food Additives (JECFA) reviewed the data on 1-butanol. They
concluded that:
"There was a lack of data on the effects of long-term
oral exposure to 1-butanol. There were some results of
studies on workers exposed for periods of up to 11 years
to known vapour concentrations, but these were inadequate
for setting an ADI for man. The evaluation of this
compound was not possible on the basis of the data
available. New specifications were prepared, but no
toxicological monograph" (WHO, 1980).
ENVIRONMENTAL HEALTH CRITERIA
FOR
2-BUTANOL
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR 2-BUTANOL
1. SUMMARY
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
2.2 Physical and chemical properties
2.3 Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6. KINETICS AND METABOLISM
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Aquatic organisms
7.2 Terrestrial organisms
7.3 Microorganisms
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
8.1.1 Acute toxicity
8.1.2 Signs of intoxication
8.2 Skin and eye irritation
8.3 Short-term exposures
8.4 Long-term exposures
8.5 Reproduction, embryotoxicity, and teratogenicity
8.6 Mutagenicity
8.7 Carcinogenicity
8.8 Special studies
9. EFFECTS ON MAN
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
10.1.1 Exposure levels
10.1.2 Toxic effects
10.2 Evaluation of effects on the environment
10.2.1 Exposure levels
10.2.2 Toxic effects
10.3 Conclusions
11. RECOMMENDATIONS
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
1. SUMMARY
2-Butanol is a flammable colourless liquid with a
characteristic sweet odour. It has a boiling point of 98.5 °C, a
water solubility of 12.5%, and an n-octanol/water partition
coefficient of 0.61. Its vapour is 2.6 times denser than air.
2-Butanol occurs naturally as a product of fermentation of
carbohydrates. It is used for the extraction of fish meal to
produce fish protein concentrate, for the production of fruit
essences, and as a flavouring agent in food. Human exposure to
2-butanol is mainly occupational. The general population is
exposed through its natural occurrence in food and beverages and
its use as a flavouring agent. Exposure may also result through
industrial emissions.
2-Butanol is readily biodegradeable by bacteria and does not
bioaccumulate. It is not toxic for aquatic animals, algae,
protozoa, or bacteria. 2-Butanol should be managed in the
environment as a slightly toxic compound. It poses an indirect
hazard for the aquatic environment, because it is readily
biodegraded, which may lead to oxygen depletion.
In animals, 2-butanol is absorbed through the lungs and
gastrointestinal tract. No information is available regarding
dermal absorption. Approximately 97% of the dose of 2-butanol in
animals is converted by alcohol dehydrogenase to the corresponding
ketone, which is either excreted in the breath and urine or further
metabolized. The rat oral LD50 for 2-butanol is 6.5 g/kg body
weight; it is, therefore, practically non-toxic, according to the
classification of Hodge & Sterner. The acute toxic effects are
ataxia and narcosis. Its potency for intoxication is approximately
4 times that of ethanol. 2-Butanol is irritating to the eyes and
non-irritating to the skin. From the animal studies available, it
is not possible to determine a no-observed-adverse-effect level.
No adequate data are available on mutagenicity, carcinogenicity,
teratogenicity, or effects on reproduction.
In man, the most likely acute effect of 2-butanol is alcoholic
intoxication. No published data are available concerning other
effects in man.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
Chemical structure: OH
|
CH3-CH-CH2-CH3
Chemical formula: C4H10O
Primary constituent: 2-butanol
Common synonyms: sec-butyl alcohol, secondary butyl
alcohol, butylene hydrate, 2-hydroxy
butane, methyl ethyl carbinol,
butan-2-ol, sec-butanol, SBA,
2-hydroxybutane, CCS 301
CAS registry number: 78-92-2
2.2. Physical and Chemical Properties
Physical and chemical properties of 2-butanol are given in
Table 1.
Table 1. Physical and chemical properties of 2-butanol
-------------------------------------------------------------------
(at 20 °C and 101.3 kPa, unless otherwise stated)
Physical state colourless liquid
Odour characteristic sweet odour
Odour threshold approximately 7.69 mg/m3
(2.5 ppm)
Relative molecular mass 74.12
Density (kg/m3) 806 - 808
Boiling point (°C) initial 98.5 (min)
dry point 100.5 (max)
Freezing point (°C) -115
Viscosity (mPa x s) 3.54
Vapour density (air = 1) 2.55
Vapour pressure (kPa) 1.66
Flashpoint (°C) 23
Autoignition temperature (°C) 406
Explosion limits in air (%) (v/v) lower = 1.7
upper = 9.0
Solubility (% weight) in water, 12.5; miscible with
ethyl alcohol and ether
n-octanol/water partition 0.61
coefficient
Conversion factors 1 mg/m3 = 0.325 ppm
1 ppm = 3.078 mg/m3
-------------------------------------------------------------------
2.3. Analytical Methods
2-Butanol is usually determined quantitatively using gas
chromatography (Abbasov et al., 1971; Bartha et al., 1978; Beaud &
Ramuz, 1978).
NIOSH (1977b) Method No S53 (353) has been recommended. It
involves drawing a known volume of air through charcoal to trap the
organic vapours present (recommended sample is 10 litres at a rate
of 0.2 litre/min). The analyte is desorbed with carbon disulfide
containing 1% 2-propanol. The sample is separated by injection
into a gas chromatograph equipped with a flame ionization detector
and the area of the resulting peak is determined and compared with
standards.
Testing methods for the butanols (ASTM D304-58) are described
in ASTM (1977).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
The principal use of 2-butanol is as a chemical intermediate
for conversion into methyl ethyl ketone, a solvent with a fairly
high boiling point (Monich, 1968).
2-Butanol is used for the extraction of fish meal to produce
fish protein concentrate. It is also used for the preparation of
fruit essence and as a flavouring agent in food (Federal Register,
1977). Very recently, 2-butanol has proved to be useful as a
debittering agent for protein hydrolysates (Latasidis & Sïpberg,
1978).
2-butanol is used, to some extent, as a solvent for lacquers,
enamels, vegetable oils, gums, and natural resins; it is also used
in hydraulic brake fluids, industrial cleaning compounds, polishes,
and penetrating oils, and in the preparation of ore-flotation
agents and perfumes (Patty, 1963).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
A high rate of degradation of 2-butanol has been seen in a wide
range of test methods. The data in Table 2 suggest that a high
proportion of the total oxygen required for its complete oxidation
is used within a few hours, and degradation would be complete
within a few days. Its biodegradation in surface waters may
present a hazard in terms of oxygen depletion.
No data are available on distribution in soil, sediments, or
air.
Biodegradation data are given in Table 2.
Table 2. Some biodegradation data for 2-butanol
------------------------------------------------------------------------------
5d BOD 33% of ThOD (AFNOR) Dore et al. (1974)
83% of ThOD (APHA) Bridié et al. (1979)b
activated sludge 9.3% of ThOD removed in 24 h by Gerhold & Malaney
unadapted municipal sludge (1966)
58% of ThOD removed in 23 h by McKinny & Jeris (1955)
adapted sludge
biodegradation rate in adapted Pitter (1976)
sludge at 20 °C, 55.0 mg COD g
per h
anaerobic digestion degraded by acetate-enriched Chou et al. (1978)
methane culture after adaptation;
100% of ThOD removed at 342 mg/
litre after 14 days of adaptation
93% of ThOD removed at 110 mg/ Chou et al. (1977)
litre in anaerobic upflow filters
(hydraulic residence time 2 - 10
days) after 52 days of adaptation
bioaccumulation 2-butanol does not bioaccumulate Chiou et al. (1977)
------------------------------------------------------------------------------
ThOD = theoretical oxygen demand - the calculated amount of oxygen needed
for complete oxidation to water and carbon
dioxide.
COD = chemical oxygen demand - measures the chemically oxidizable matter
present.
BOD = biochemical oxygen demand - a simple bioassay measuring the potential
deoxygenating effect of biologically
oxidizable matter present in an effluent.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
A residue of between 10 and 70 mg 2-butanol/kg has been
reported to remain in the dry fish protein concentrate following
extraction with this solvent.
2-Butanol has been found in a number of alcoholic beverages
including beer (Bonte et al., 1978), wine (Bikvalvi & Pasztor,
1977; Bonte, 1978), apple brandies (Woidich et al., 1978), and
grape brandies (Bonte et al., 1978; Schreier et al., 1979);
2-butanol has also been detected in volatiles of cheese (Dumont &
Adda, 1978), southern pea seeds (Fischer et al., 1979), and virgin
oil (Olias Jimbnez et al., 1978).
An industrial emission study indicated that 33 tonnes of
2-butanol were released into the air of the Netherlands over a
period of 1 year (Anon, 1983).
6. KINETICS AND METABOLISM
In rabbits, 2-butanol was oxidized to methyl ethyl ketone,
which could be detected in the expired air, and also conjugated to
form 2-butyl glucuronide, which could be isolated from the urine
(Williams, 1969). 2,3-Butanediol and 3-hydroxy-2-butanone were the
main metabolites of 2-butanol found in the blood of rats given 2.2
ml 2-butanol/kg body weight (Dietz, 1980).
Male rabbits were given 2 ml 2-butanol/kg body weight orally,
and venous blood samples were analysed after 1, 2, 3, 4, 5, and
10 h. The concentration of 2-butanol peaked within an hour at
about 1 g/litre and disappeared to a trace after 10 h. Unchanged
2-butanol was excreted to the extent of 3.3% of the dose in the
breath and 2.6% in the urine. Methyl ethyl ketone, a metabolite,
was detected in the blood and reached a maximum level after 6 h; it
was excreted in amounts equivalent to 22.3% of the dose in the
breath and 4% in the urine (Saito, 1975).
Dietz et al. (1981) developed a pharmacokinetic model to
describe the biotransformation of 2-butanol and its metabolites
2-butanone, 3-hydroxy-2-butanone, and 2,3-butanediol (Fig. 1A).
Male Sprague Dawley rats were given 2-butanol (2.2 ml/kg body
weight, orally) after an overnight fast; blood concentrations of 2-
butanol and its metabolites were estimated at various times up to
30 h. Concentrations of 2-butanol reached a maximum (0.59 g/litre)
within 2 h and declined to less than 0.05 g/litre after 16 h. As
the blood concentration of 2-butanol fell, the concentrations of 2-
butanone, 3-hydroxy-2-butanone, and 2,3-butanediol rose to maximum
levels of 0.78, 0.04, and 0.21 g/litre at 8, 12, and 18 h,
respectively. Approximately 97% of the 2-butanol dose was
converted 2-butanone by alcohol dehydrogenase; the calculated
clearance constant for 2-butanol was 0.40 ml/min. In separate
studies, the individual metabolites were administered to rats in
order to calculate their clearance constants.
2-Butanol exhibited an apparent blood elimination half-life of
2.5 h in rats treated orally with 2.2 ml/kg body weight. With
decline in blood-alcohol concentration (maximum level 800 mg/litre,
1 h after administration), there was a rise in 2-butanone levels
with 430 mg/litre detected at 1 h and a maximum of 1050 mg/litre
detected 4 h after administration of the alcohol (Traiger &
Bruckner, 1976).
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1. Aquatic Organisms
Some toxicity data for 2-butanol in aquatic organisms are given
in Table 3. Only two LC50 values are available for fish, and these
indicate low toxicity for these species. The toxicity of 2-butanol
for aquatic invertebrates is equally low.
Table 3. Toxicity data of 2-butanol for aquatic organisms
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Fish
Fresh-water species
Golden orfe 3520 48-h LC50 Juhnke & Lüdemann (1978)
(Leuciscus idus
melanotus)
Goldfish 4300 24-h LC50 Bridié et al. (1979a)
(Carassius auratus)
Invertebrates
Fresh-water species
Water flea 2300 24-h EC50 immobilization Bringmann & Kuehn (1982)
(Daphnia magna)
Marine species
Brine shrimp 3800 EC50 excystment Smith & Siegel (1975)
(Artemia salina)
Algae
Green algae
(Scenedesmus 95 8-day no- total biomass Bringmann & Kuehn
quadricauda) observed- (1978a)
adverse-
effect level
Chlorella 8900 EC50 Jones (1971)
pyrenoidosa chlorophyll
content
------------------------------------------------------------------------------------------
7.2. Terrestrial Organisms
An EC50 of 650 mg/litre was reported by Reynolds (1977) for
seed germination in lettuce (Lactuca sativa). Inhibition of seed
germination in cucumber (Cucumis sativus) was observed at 50 375 mg
2-butanol/litre (Smith & Siegel, 1975). There are no relevant data
for terrestrial animals, but, as in the case of terrestrial plants,
significant exposure to 2-butanol is unlikely.
7.3. Microorganisms
Some toxicity data for microorganisms are given in Table 4.
The toxicity of 2-butanol for both protozoa and bacteria is very
low.
Table 4. Toxicity of 2-butanol for microorganisms
------------------------------------------------------------------------------------------
Species Concentration Parameter Comments Reference
(mg/litre)
------------------------------------------------------------------------------------------
Protozoa
Uronema parduczi 1416 20-h no-observed- total Bringmann & Kuehn
(ciliate) adverse-effect level biomass (1981)
Chilomonas paramaecium 745 48-h no-observed- total Bringmann & Kuehn
(flagellate) adverse-effect level biomass (1981)
Entosiphon sulcatum 1282 72-h no-observed- total Bringmann & Kuehn
(flagellate) adverse-effect level biomass (1981)
Bacteria
Pseudomonas putida 500 16-h no-observed- total Bringmann & Kuehn
adverse-effect level biomass (1976)
Bacillus subtilis 1630 EC50 spore germination Yasuda-Yasaki et
al. (1978)
------------------------------------------------------------------------------------------
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1. Single Exposure
8.1.1. Acute toxicity
Acute toxicity data for 2-butanol are given in Table 5.
2-Butanol shows low acute toxicity in rodents.
Table 5. Acute toxicity of 2-butanol
-------------------------------------------------------
Species Route of LD50 (g/kg Reference
administration body weight)
-------------------------------------------------------
Rat oral 6.5 US DHEW (1978)
Rabbit oral 4.9 Münch (1972)
Mouse intraperitoneal 0.8 US DHEW (1978)
-------------------------------------------------------
Six male albino rats were exposed to 2-butanol vapour at 48.5
mg/litre (16 000 ppm) for 4 h. Within 14 days, 5 of the 6 rats
died (Smyth et al., 1954).
8.1.2. Signs of intoxication
Signs of intoxication due to 2-butanol exposure include
restlessness, ataxia, prostration, and narcosis (Patty, 1963).
The effects of a moderate non-toxic oral dose of 2-butanol
(0.0163 mol/kg body weight) was studied in rats using a simple
functional test by Wallgren (1960). The intoxicating effect of
2-butanol, compared with that of ethanol (taken equal to 1), was
4.4 on an equimolar basis. Recovery after the treatment was slow.
The livers of mice that died 1 - 3 days following a single
intraperitoneal (ip) dose of 2-butanol showed an abnormal brownish
coloration in the peripheral areas, the livers of those that died
after 4 - 6 days were uniformally dark brown in colour (Maickel &
McFadden, 1979).
8.2. Skin and Eye Irritation
2-Butanol is practically not irritant to the skin of the
rabbit, but it is irritant to the rabbit eye (Smyth et al., 1954).
8.3. Short-Term Exposures
White mice (15 - 20 g) were repeatedly exposed to 2-butanol
vapour at 16.2 mg/litre (5330 ppm) for a total of 117 h. Although
the mice were narcotized, they survived.
Six groups of 2 mice each were exposed to 2-butanol vapour at
5 mg/litre (1650 ppm). After 420 min, no signs of intoxication
were observed. When increasing concentrations were used with
decreasing durations of exposure, ataxia, prostration, and deep
narcosis occurred. The time necessary to induce these symptoms
was inversely proportional to the level of exposure. At a
concentration of 10 mg/litre (3300 ppm), ataxia occurred in 51 -
100 min, prostration in 120 - 180 min, and narcosis in 300 min. At
a concentration of 60 mg/litre (19 800 ppm), these signs appeared
in 7 - 8 min, 12 - 20 min, and 40 min, respectively. No deaths
were observed in this study (Starrek, 1938, cited in Patty, 1982).
The neurophysiological effects induced by 2-butanol were
investigated in 31 male Sprague Dawley rats (200 - 400 g).
2-Butanol was administered intravenously (iv) to the rats at a
concentration of 8.1 mmoles/kg body weight. Within 20 - 60 seconds
of the iv administration, the rats lost righting reflexes. Some
changes were also noticed in the electroencephalographic tracings
compared with the tracings prior to the alcohol administration
(Marcus et al., 1976).
8.4. Long-Term Exposures
No long-term exposure studies are available.
8.5. Reproduction, Embryotoxicity, and Teratogenicity
No relevant data on reproduction, embryotoxicity, or
teratogenicity have yet been published. However, an inhalation
teratology study with 2-butanol is in progress in the USA (US EPA,
personal communication, 1985).
8.6. Mutagenicity
2-Butanol did not show any mutagenic activity in the yeast
Schizosaccharomyces pombe in both the presence and absence of
mouse liver microsomes (Abbondandolo et al., 1980).
8.7. Carcinogenicity
No carcinogenicity studies are available.
8.8. Special Studies
The effects of 2-butanol on cell survival were studied in the
yeast S. pombe and in V-79 Chinese hamster cells by Abbondandolo
et al. (1980). At 5% concentration, 2-butanol decreased the
survival of suspended yeast cells, but did not have any effect on
monolayer cultures of V-79 cells.
2-Butanol inhibited the contraction of the depolarized guinea-
pig ileum induced by calcium chloride (CaCl2) (Yashuda et al.,
1976).
2-Butanol can potentiate the toxicity of carbon tetrachloride
(CCl4) (Cornish & Adefuin, 1967). This potentiation may be due to
the metabolite 2,3-butanediol, which also has this effect (Traiger
& Bruckner, 1976; Dietz & Traiger, 1979).
Inhalation exposure of rats to 2-butanol (1539 mg/m3 (500 ppm)
for 5 days) resulted in a 47% increase in the cytochrome P-450
levels of kidney microsomes. A maximal increase of 33% in liver
microsomal cytochrome P-450 content was seen after inhalation of
2-butanol at 6156 mg/m3 (2000 ppm) for 3 days. This treatment led
to a 77% increase in the formation of the preneurotoxic metabolite
2-hexanol from 1-hexane by liver microsomes (Aarstad et al., in
press).
Rats receiving a single oral dose of 2-butanol at 2.2 ml/kg
body weight were sacrificed 16, 20, or 40 h after dosing. A 50 -
97% increase in microsomal acetanilide hydroxylase activity was
found. At 40 h, liver cells showed a marked proliferation of
smooth endoplasmic reticulum. This stimulation of the drug-
metabolizing system may explain, to a certain extent, the
potentiation of CCl4 hepatoxicity by 2-butanol (Traiger et al.,
1975).
9. EFFECTS ON MAN
Excessive exposure may result in headache, dizziness,
drowsiness, and narcosis (Muir, 1977). No adverse systemic effects
due to exposure to 2-butanol have been reported in man (Patty,
1982).
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of Human Health Risks
10.1.1. Exposure levels
Levels of exposure of the general population to 2-butanol
through food and beverages, and occupational exposure levels are
not available.
10.1.2. Toxic effects
In animals, 2-butanol is absorbed through the lungs and
gastrointestinal tract. No information is available regarding
dermal absorption. Approximately 97% of the dose of 2-butanol in
animals is converted by alcohol dehydrogenase to the corresponding
ketone, which is either excreted in the breath and urine or further
metabolized. The rat acute oral LD50 for 2-butanol is 6.5 g/kg
body weight; it is, therefore, practically non-toxic according to
the classification of Hodge & Sterner. The toxic effects from
acute exposure are ataxia and narcosis. The potency of 2-butanol
for intoxication is approximately 4 times that of ethanol. It is
irritating to the eyes and non-irritating to the skin. From the
animal studies available, it is not possible to determine a no-
observed-adverse-effect level. No adequate data are available on
mutagenicity, carcinogenicity, teratogenicity, or effects on
reproduction.
In man, the most likely acute effect of 2-butanol is alcoholic
intoxication. No published data are available concerning other
effects on man.
10.2. Evaluation of Effects on the Environment
10.2.1. Exposure levels
No quantitative data relating to levels of 2-butanol in the
general environment are available, but, because it is readily
biodegradable, substantial concentrations are only likely to occur
locally in the case of major spillage.
10.2.2. Toxic effects
At the background concentrations likely to occur in the
environment, 2-butanol is not toxic for aquatic animals, algae,
protozoa, or bacteria, and it should be managed in the environment
as a slightly toxic compound. It poses an indirect hazard for the
aquatic environment, because it is readily biodegradable, which may
lead to oxygen depletion.
10.3. Conclusions
1. The Task Group was unable to make an assessment of the health
risks of 2-butanol for the general population on the basis of
available data. However, it was considered that 2-butanol was
unlikely to pose a serious hazard, under normal exposure
conditions.
2. The Task Group was of the opinion that available data are not
sufficient to establish guidelines for setting occupational
exposure limits. In line with good manufacturing practice,
exposure to 2-butanol should be minimized.
3. The ecotoxicological data available indicate that the impact of
background concentrations of 2-butanol on the aquatic
environment can be expected to be minimal.
11. RECOMMENDATIONS
The Task Group recommended that:
1. As it was not possible to determine a no-observed-adverse-
effect level on the basis of available animal studies, relevant
studies should be conducted so that this could be achieved.
2. Information on residue and emission levels is desirable.
3. Epidemiological studies including precise exposure data would
assist in an assessment of the occupational hazards from
2-butanol.
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
The Food Additives and Contaminants Committee (UK MAFF, 1978)
recommended that residues of butan-2-ol in food should not exceed
30 mg/kg and required the results of a 90-day oral toxicity study
in the rat within 2 years.
This compound could not be included in lists 1 or 2 by the
Council of Europe and it was included in list 3A (Council of
Europe, 1981).
At their 23rd meeting, the Joint FAO/WHO Expert Committee on
Food Additives (JECFA) reviewed the data on 2-butanol. They
concluded that "The evaluation of this compound was not possible on
the basis of the data available. New specifications were prepared,
but no toxicological monograph" (WHO, 1980).
ENVIRONMENTAL HEALTH CRITERIA
FOR
tert-BUTANOL
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR tert-BUTANOL
1. SUMMARY
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1 Identity
2.2 Physical and chemical properties
2.3 Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6. KINETICS AND METABOLISM
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Aquatic organisms
7.2 Terrestrial organisms
7.3 Microorganisms
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
8.1.1 Acute toxicity
8.1.2 Signs of intoxication
8.2 Skin and eye irritation
8.3 Short-term exposures
8.4 Reproduction, embyrotoxicity, and teratogenicity
8.5 Mutagenicity
8.6 Carcinogenicity
8.7 Special studies
9. EFFECTS ON MAN
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
10.1.1 Exposure levels
10.1.2 Toxic effects
10.2 Evaluation of effects on the environment
10.2.1 Exposure levels
10.2.2 Toxic effects
10.3 Conclusions
11. RECOMMENDATIONS
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
1. SUMMARY
tert-Butanol is a colourless liquid or white crystalline solid
with a camphor-like odour. It has a melting point of 25 °C, a
boiling point of 81.5 - 83 °C, is freely soluble in water, and its
n-octanol/water partition coefficient is 0.37. Its vapour is 2.6
times denser than air. It is used primarily as a solvent, a
dehydrating agent, and as an intermediate in the manufacture of
other chemicals. It is also used as a denaturant for alcohols.
Human exposure will be mainly occupational. Data on exposure of
the general population are not available, but it may result from
industrial emissions. tert-Butanol is inherently biodegradable and
does not bioaccumulate. At ambient levels, it is not toxic for
fish, amphibia, crustacea, algae, or bacteria.
In animals, tert-butanol is absorbed through the lungs and
gastrointestinal tract; no information is available on dermal
absorption. tert-Butanol is not a substrate for alcohol
dehydrogenase and is slowly metabolized by mammals. Up to 24% of
the dose is eliminated in the urine as the glucuronide, and up to
10% of the dose can be excreted in the breath and urine as acetone
or carbon dioxide. The rat oral LD50 is 3.5 g/kg body weight; it
is, therefore, slightly toxic according to the classification of
Hodge & Sterner. The primary acute effects observed in animals are
signs of alcoholic intoxication. Its potency for intoxication is
approximately 1.5 times that of ethanol. Animal data regarding
skin and eye irritation are not available. tert-Butanol produces
physical dependance in animals and post-natal effects in offspring
exposed in utero. Data concerning the pathological effects of
repeated exposure of animals are not available. From the animal
studies available, it is not possible to determine a no-observed-
adverse-effect level. tert-Butanol has been found not to be
mutagenic. Adequate data are not available on carcinogenicity,
teratogenicity, or effects on reproduction.
In man, tert-butanol is a mild irritant to the skin. No other
effects on man have been reported, and there have been no reports
of poisonings.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS
2.1. Identity
Chemical structure:
CH3
|
CH3 - C - CH3
|
OH
Chemical formula: C4H10O
Primary constituent: tert-butanol
Common synonyms: 2-methyl-2-propanol, tert-butyl
alcohol, tertiary butanol, t.
butanol, trimethyl carbinol, TBA,
TMA, t. butyl hydroxide, NCL-C55
367, trimethyl methanol
Cas registry number: 75-65-0
2.2. Physical and Chemical Properties
Some physical and chemical data for tert-butanol are given in
Table 1.
Table 1. Physical and chemical data for tert-butanol
-----------------------------------------------------------------------------
(at 20 °C and 101.3 kPa, unless otherwise stated)
Physical state solid (crystals)
Odour camphor-like
Odour threshold approximately 144.7 mg/m3(47 ppm)
Relative molecular mass 74.12
Density (kg/m3) 779 - 782 at 26 °C
Boiling point (°C) initial 81.5 (min.); dry point 83.0 (max.)
Melting point 25 °C
Viscosity (mPa x s) 3.3 at 30 °C
Vapour density (air = 1) 2.55
Vapour pressure (mm Hg) 31 (at 25 °C, 42; at 30 °C, 56)
Flashpoint (°C, TOC) 16
(°C, TCC) 4
Autoignition temperature 470 °C
Explosion limits in air (v/v %) lower 2.35; upper 8.0
Solubility soluble in water; miscible with ethyl
alcohol, ether; also soluble in ketones,
esters, aromatic and aliphatic hydrocarbons
n-octanol/water partition 0.37
coefficient
Conversion factors: 1 mg/m3 = 0.325 ppm
1 ppm = 3.078 mg/m3
-----------------------------------------------------------------------------
2.3. Analytical Methods
Testing methods for the butanols (ASTM D304-58) are described
in ASTM (1977).
It is known that several alcohols, including tert-butanol,
give colour reactions with aldehyde in the presence of sulfuric
acid (Patty, 1963). NIOSH (1977b) describes several methods.
AOAC has finalized the method for detecting tert-butanol in
distilled liquors (AOAC, 1975).
tert-Butanol has been determined in the air of industrial
premises by Abbasov et al. (1971) using a gas chromatographic
method and by Zamarakhina (1973) using a photometric method, and in
blood by Wood & Laverty (1976).
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
The primary use of tert-butanol is as a solvent. It is also
used as a dehydrating agent, in the extraction of drugs, in the
manufacture of perfumes (particularly in the preparation of
artificial musk), in the recrystallization of chemicals, and as a
chemical intermediate (e.g., in the manufacture of tert-butyl
chloride and in the manufacture of tert-butyl phenol). It is an
approved denaturant for ethyl alcohol and for several other
alcohols. Catalytic dehydration of tert-butanol is carried out to
obtain isobutylene, and it has been patented for use as a gasoline
antiknock agent.
Moreover, it is used in the purification of polyolefins, for
the separation of solids from coal liquids and as blowing agent for
the manufacture of imide group-containing foams from copolymers of
methacrylonitrile and methacrylic acid (Patty, 1963; Monich, 1968;
Sherman, 1978).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
No data are available on the distribution of tert-butanol in
soil, sediments, or air.
In short-term tests, there was little degradation but over a
longer period of about one month, most of the material was fully
degraded. Therefore, tert-butanol is inherently rather than
readily biodegradable. Some biodegradation data for tert-butanol
are given in Table 2.
tert-Butanol does not bioaccumulate (Chiou et al., 1977).
Table 2. Biodegradation data for tert-butanol
---------------------------------------------------------------------------
5d BOD 0% of ThOD (AFNOR) Dore et al. (1974)
1% of ThOD (APHA) Bridié et al. (1979b)
30d BOD 0% of ThOD (closed-bottle Gerike & Fischer (1979)
test, conventional)
0% of ThOD (closed-bottle Gerike & Fischer (1979)
test, preadaptation)
MITI test 0% of ThOD removed after Gerike & Fischer (1979)
14 days (BOD14: 7% of ThOD)
OECD screening 29% of ThOD removed after Gerike & Fischer (1979)
test 19 days; no pre-adaptation
Sturm test 32% of ThOD removed, but no Gerike & Fischer (1979)
production of CO2
AFNOR T90-302 80% of ThOD removed after Gerike & Fischer (1979)
test 28 days
93% of ThOD removed after Gerike & Fischer (1979)
42 days
Zahn-Wellens 96% of ThOD removed after Gerike & Fischer (1979)
test 6 days
Couple-units test 33% of ThOD removed after Gerike & Fischer (1979)
(conventional) 42 days adaptation
Square-wave 69% of ThOD removed after Gerike & Fischer (1979)
feeding 30 days adaptation
Activated 0.8% of ThOD removed in 24 h Gerhold & Malaney
sludge by unadapted municipal sludge (1966)
2% of ThOD removed in 23 h by McKinney & Jeris (1955)
adapted sludge
---------------------------------------------------------------------------
Table 2. (contd.)
---------------------------------------------------------------------------
98% of ThOD removed in 5 days Pitter (1976)
by adapted sludge;
biodegradation rate at 20 °C
0.03/h
Anaerobic 73% of ThOD removed at Chou et al. (1978)
digestion 400 mg/litre in anaerobic
up-flow filters (hydraulic
residence time 2 - 10 days)
after 52 days of adaptation
---------------------------------------------------------------------------
ThOD = theoretical oxygen demand - the calculated amount of oxygen
needed for complete oxidation to
water and carbon dioxide.
COD = chemical oxygen demand - measures the chemically oxidizable
matter present.
BOD = biochemical oxygen demand - a simple bioassay measuring the
potential deoxygenating effect of
biologically oxidizable matter
present in an effluent.
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
An industrial emmission study indicated that 207 tonnes of
tert-butanol were released into the air in the Netherlands over a
period of 1 year (Anon, 1983).
No other data are available.
6. KINETICS AND METABOLISM
tert-Butanol is not a substrate for alcohol dehydrogenase
(Derache, 1970; Cederbaum et al., 1983) and is slowly metabolized
by mammals (Williams, 1969; Derache, 1970; Beaugé et al., 1981).
Possible routes of metabolism are direct conjugation of the
hydroxyl group with glucuronic acid and oxidation of one or more of
the alkyl substituents. Following treatment with tert-butanol,
24% of the dose was detected as the glucuronide conjugate in the
urine of rabbits (Kamil et al., 1953) and increased acetone
excretion has been observed in the breath and urine of rats treated
with tert-butanol (Baker et al., 1982; Yojay et al., 1982).
After a single oral dose of tert-butanol (25 mmol/kg), blood
concentrations in female Wistar rats declined slowly from 13.2 ±
0.5 mmol at 2 h to 11.4 ± 0.3 mmol at 20 h (Beaugé et al., 1981).
In rats maintained on a liquid diet containing 20 ml tert-
butanol/litre for 20 days, the blood level 30 min after withdrawal
of the diet of 20 mmol declined to 5 mmol in 8 h. By comparison,
blood levels of ethanol of 45 mmol (achieved by a liquid diet of
87 ml ethanol/litre for 20 days) were reduced to zero within 4.5 h
(Wood & Laverty, 1979). In female Sprague Dawley rats given single
oral doses of either ethanol (5.0 g/kg body weight) or tert-
butanol (1.2 g/kg body weight), the rates of elimination were 10.7
± 0.5 and 0.7 ± 0.1 mmol/kg per h, respectively (Thurman et al.,
1980).
Following an oral dose of 2 g tert-butanol/kg body weight to
rats, a maximum blood level of 1240 mg/litre (124 mg%) was reached
in 2 h; this decreased very slowly to 1200 mg/litre (120 mg%) after
4 h and to 1100 mg/litre (110 mg%) after 8 h; only about 1% of
the dose was excreted in the urine (Gaillard & Derache, 1965).
tert-Butanol was found in the blood of rabbits 70 h after oral
administration of 2 ml/kg body weight (Saito, 1975).
In Long-Evans rats treated with tert-butanol (1 g/kg body
weight, route not specified), the rate of disappearance of tert-
butanol from the blood was apparently of first order with a half
life of 9.1 h (Baker et al., 1982). Using 14C- and 13C-
tert-butanol, the same authors investigated the metabolism of
tert-butanol to form acetone. It was found that following
administration of tert-butanol (0.75 - 2 g/kg body weight),
approximately 0.5 - 9.5% of the dose was excreted as acetone in
the urine and breath. The total production of acetone varied
considerably between animals given the same dose, and, as a
result, no correlation between dose and acetone excretion could
be established. Evidence was also obtained indicating that carbon
dioxide (CO2) was a metabolic product of tert-butanol. The
conversion of tert-butanol (possibly via acetone) was not
quantified. Yojay et al. (1982) provided evidence that, in rats
treated intraperitoneally with tert-butanol at 1 or 2 mg/kg body
weight, blood levels of acetone were approximately proportional to
the dose of tert-butanol. In support of the in vivo metabolic
conversion of tert-butanol to acetone, Cederbaum & Cohen (1980)
and Cederbaum et al. (1983) demonstrated the metabolism of
tert-butanol to formaldehyde and acetone in an in vitro system
consisting of rat liver microsomes and a hydroxyl radical
generating system.
Investigations on the induction of tert-butanol metabolism
have been conducted by Baker et al. (1982), Thurman et al. (1980),
and McComb & Goldstein (1979). In rats, Baker et al. (1982) were
unable to demonstrate increased conversion of tert-butanol to
acetone in animals in which the hepatic mixed-function oxidase
activity had been induced by prior phenobarbital treatment.
Thurman et al. (1980) studied the effects on tert-butanol
elimination in rats of pre-treatment (oral) with 5.7% (w/v)
tert-butanol every 8 h, for either 1 or 2.5 days. After the
pre-treatment, animals were given tert-butanol to raise their blood
levels to between 1250 and 1500 mg/litre. The rates of elimination
were very similar, but there was a suggestion of slightly faster
elimination following pre-treatment. The investigators concluded
that, unlike ethanol pre-treatment, which induces its own
metabolism, tert-butanol pre-treatment had little or no effect on
the subsequent rate of tert-butanol elimination in the rat.
In contrast to the results obtained in rats, it appears that
tert-butanol elimination in mice can be substantially increased by
pre-treatment with tert-butanol. Male Swiss Webster mice were
given an ip loading dose of 6.8 mmol tert-butanol/kg body weight
and then exposed to various vapour concentrations of tert-butanol
for 24 h. It was found that 15 min after the 24-h inhalation
period, blood- tert-butanol levels were linearly related to the
vapour concentrations. Blood levels ranged from 3 to 14 mmol with
increasing vapour concentrations of 30 - 100 µmol/litre air (McComb
& Goldstein, 1979). It was also found that the rate of elimination
of blood- tert-butanol was significantly increased by inhalation.
In mice, after a single ip injection of 8.1 mmol tert-butanol/kg
body weight, initial blood levels of 8 mmol took 8 - 9 h for
elimination (blood- tert-butanol half-life was approximately 5 h).
However, after 3 days, inhalation at a vapour concentration to give
levels of 8 mmol/litre blood, tert-butanol disappeared within 3 h
of removal of mice from the inhalation chamber (half-life of tert-
butanol in blood was approximately 1.5 h) (McComb & Goldstein,
1979).
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
<