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    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


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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. 

FIGURE 1A

    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

7.1.  Aquatic Organisms

    The toxicity of  tert-butanol has been tested in very few 
organisms.  However, in the few studies performed, the toxicity of 
the compound has been very low. 

    Some toxicity data for aquatic organisms are given in Table 3. 

Table 3.  Toxicity of  tert-butanol for aquatic organisms
-------------------------------------------------------------------
Species           Concentration  Parameter  Comments     Reference
                  (mg/litre)
-------------------------------------------------------------------
Fish (acute)

Fresh-water species

Creek chub        3000 - 6000    24-h LC50               Gillette 
 (Semotitus                                               et al. 
 atromaculatus)                                           (1952)

Goldfish          > 5000         24-h LC50               Bridié  
 (Carassius                                               et al. 
 auratus)                                                 (1979a)

Invertebrates (acute)

Marine species

Brine shrimp      7800           EC50       excystment   Smith & 
 (Artemia salina)                                         Siegel 
                                                         (1975)

Algae

Fresh-water

Green algae
 Chlorella         24 200         EC50       chlorophyll  Jones 
 pyrenoidosa                                 content      (1971)
-------------------------------------------------------------------

7.2.  Terrestrial Organisms

    An EC50 of 90 800 mg/litre was reported for germination in 
cucumber  (Cucumis sativus) by Smith & Siegel (1975).  There are 
no relevant data for terrestrial animals.  However, significant 
terrestrial exposure to  tert-butanol is unlikely for either plants 
or animals. 

7.3.  Microorganisms

    One study has indicated that Nitrosomonas (nitrifying 
bacterium) shows a high tolerance for  tert-butanol;  tert-Butanol 
inhibits nitrifying activity at 39 400 mg/litre (Blok, 1981). 

    There was no inhibition of degradation by methane culture on 
acetate substrate at 7400 mg  tert-butanol/litre (Chou et al., 
1978). 
                                                              
8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1.  Single Exposure

8.1.1.  Acute toxicity

    Some acute toxicity data for animals are given in Table 4. 

Table 4.  Acute toxicity of  tert-butanol in animals
------------------------------------------------------
Species  Route of         LD50 (g/kg    Reference
         administration   body weight)
------------------------------------------------------
Rat      oral             3.5           US DHEW (1979)
Rabbit   oral             3.6           Münch (1972)
Mouse    intravenous      1.5           Patty (1982)
Mouse    intraperitoneal  0.9           US DHEW (1978)
------------------------------------------------------

8.1.2.  Signs of intoxication

    Animals exposed to the vapours of  tert-butanol may manifest 
the following signs of intoxication: restlessness, irritation of 
mucous membranes, ataxia, prostration, and narcosis (Patty, 1963). 

    The narcotic potency of  tert-butanol in rabbits is similar to 
that of other butanols (Münch, 1972).  After ip administration to 
mice, the LD50 was > 1000 mg/kg body weight at 30 min and 441 
mg/kg body weight at 7 days; gross post-mortem examination of the 
livers showed an abnormal dark coloration (Maickel & McFadden, 
1979).  In rabbits, an oral dose of 1.3 g  tert-butanol/kg body 
weight was shown to be the minimum narcotic dose (Münch & Schwartz, 
1925).  The minimum oral lethal dose in the rabbit was 6.0 ml/kg 
body weight (approximately 4.7 g/kg) (Patty, 1963).  Injection (ip) 
of  tert-butanol in rats induced a spectrum of intoxication 
virtually identical to that of ethanol, but its intoxicating 
potency was approximately 1.5 times that of ethanol (McCreery & 
Hunt, 1978). 

    Oral administration of a single dose of 24 mmol  tert-
butanol/kg body weight caused a temporary disturbance in the fat 
metabolism in the liver cells of female Wistar rats.  The authors 
suggest that this may be related to the stress induced by the 
administration of  tert-butanol, which is metabolized very slowly 
(Beaugé et al., 1981). 

8.2.  Skin and Eye Irritation

    No data are available on skin and eye irritation in animals. 

8.3.  Short-Term Exposures

    Physical dependence following  tert-butanol administration was 
investigated using 12 random-bred male albino rats.  A liquid diet 
containing 20 ml  tert-butanol/litre was given to the rats for 

4 - 20 days.  Docility and slight ataxia were observed in the rats 
during this period.  About 5 - 6 h after removal of the diet, 
withdrawal-signs such as muscular rigidity, stiff curled tails, 
abnormal gait, tremor, and irritability became apparant.  Four rats 
exhibited spontaneous forelimb convulsions.  Audiogenic convulsions 
were observed in 5 rats, and 3 of them died as a consequence.   tert-
Butanol was still detectable in the blood of the rats, 8 h after 
its withdrawal (Wood & Laverty, 1979). 

    In another study, 15 adult male Long Evans rats were exposed 
to 4 different protocols using various concentrations of  tert-
butanol in water as their only available fluid; 14 animals were 
used as controls.  At concentrations of 3.5 ml/litre, severe toxic 
reactions were found, including anorexia, self mutilation, and 
death.  When animals consumed at least 3 g  tert-butanol/kg body 
weight per day for 90 days, withdrawal symptoms were observed, 
independent of dosing conditions.  Such an intake occurred only 
when the concentration of  tert-butanol was 3% or greater (Grant 
& Samson, 1981).  In female Sprague Dawley rats,  tert-butanol 
administered by gastric intubation, every 8 h, for up to 6 days, 
was shown to produce physical dependence (Thurman et al., 1980). 

    An investigation was undertaken with 5 to 8-week-old male 
Swiss-Webster mice weighing 22 - 30 g.  A priming dose of 6.8 - 
10.1 µmol  tert-butanol/kg body weight (10% w/v in 0.9% saline) was 
administered ip to groups of 24 mice.  They were then exposed to 
vapour concentrations of between 50 and 80 µmol  tert-butanol/litre 
air for 24 h per day; concentrations below or above these limits 
either did not produce physical dependance or were initially too 
toxic.  Because it was found that continual exposure induced the 
elimination of  tert-butanol, exposure concentrations were 
increased daily, in order to maintain a steady blood- tert-butanol 
level of between 5 - 8.5 mmol.  Exposure lasted for 1, 3, 6, or 9 
days.  Withdrawal signs were noted after removing the mice from the 
inhalation exposure.  The intensity of the withdrawal reaction 
increased with the duration of inhalation and with the blood- tert-
butanol levels maintained during the intoxication period.  The 
withdrawal syndrome was qualitatively similar to that produced by 
ethanol.   tert-Butanol has been shown to be 4 - 5 times as potent 
as ethanol in producing physical dependence.  Thus, since it is 
also 4 - 5 times more lipid soluble than ethanol, McComb & 
Goldstein (1979) concluded that the dose of alcohol necessary to 
induce physical dependence was inversely proportional to its 
solubility. 

    In a study by Bellin & Edmonds (1976), physical dependence was 
induced in 12 male Sprague Dawley rats (350 - 500 g) and 10 female 
albino guinea-pigs (200 - 400 g) when given  tert-butanol ip 
(0.8 g/kg body weight as a 10% w/v solution) at 8-h intervals 
for 4 days.  Alteration of body temperature (decreased during 
intoxication and increased during withdrawal) was more pronounced 
in the rats than in the guinea-pigs.  However, these differences 
could be due to species or sex. 

    An impairment of avoidance behaviour was shown following short-
term ingestion of  tert-butanol in mice (number not stated).  
Experimental animals received a liquid diet containing  tert-
butanol at 12.5 ml/litre for 7 days and during this time ingested 
an average of 3.4 g  tert-butanol/kg body weight, per day.  One day 
after cessation of this diet, the animals were exposed to the 
avoidance training procedure.  Avoidance was much less in the 
treated group than in the controls (Snell & Harris, 1980). 

    Pregnant Swiss Webster mice (15 per group) were fed liquid 
diets containing  tert-butanol at concentrations of 0, 5.0, 7.5, 
or 10 g/litre from day 6 to day 20 of gestation.  In order to gain 
insight into the effects of maternal nutrition and behaviour on 
post-natal pup development, approximately half of the treated 
maternal animals were replaced, within 24 h of parturition, with 
untreated females, also recently delivered.   tert-Butanol was 
approximately 5 times more potent than the same dose of ethanol in 
producing developmental delay in post-parturition physiological, 
and psychomotor performance, scores.  At the higher concentrations, 
there were also significant postnatal maternal, nutritional, and 
behavioural factors affecting lactation and/or nesting behaviour, 
which influenced the development of pups exposed  in utero (Daniel 
& Evans, 1982). 

8.4.  Reproduction, Embryotoxicity, and Teratogenicity

    No relevant data on reproduction, embryotoxicity, or 
teratogenicity have yet been published.  In contrast to ethanol, 
 tert-butanol at concentrations of 1000 - 4000 mg/litre did not 
reduce the  in vitro fertilizing capacity of mouse spermatozoa 
(Anderson et al., 1982). 

    An inhalation teratology study is in progress in the USA (US 
EPA, personal communication, 1985). 

8.5.  Mutagenicity

    At a concentration of 1%,  tert-butanol was classified among 
the chemicals that had no apparent mutagenic effect on formation 
of antibiotic-resistant mutants in  Micrococcus aureus populations 
(Clark, 1953).   tert-Butanol was not mutagenic in  Neurospora 
 crassa (Dickey et al., 1949).  In short-term tests conducted by 
the National Toxicology Program (USA),  tert-butanol was negative 
in the Ames test ( Salmonella, +/-activation), mouse lymphoma, and 
 in vitro cytogenetics assays (US EPA, personal communication, 
1985). 

8.6.  Carcinogenicity

     tert-Butanol is currently being evaluated for carcinogenicity 
by the US National Cancer Institute using the standard bioassay 
protocol.  Groups composed of 50 male and 50 female B6C3F1 mice 
were exposed for 2 days per week, from week 9 to 104, to 0, 5000, 
10 000, or 20 000 mg  tert-butanol/litre drinking-water.  Groups 
comprising 50 male and 50 female Fischer 344 rats were exposed at 

the same rate to the same levels from weeks 7 to 104.  The 
treatment period has now been completed and histological 
examinations are in progress (IARC, 1984). 

    An inhalation carcinogenicity study has been initiated in the 
USA (US EPA, personal communication, 1985). 

8.7.  Special Studies

     tert-Butanol was investigated for its ability to deplete the 
cerebral calcium level.  An ip dose of 2 g/kg body weight was 
administered to male Sprague Dawley rats weighing between 150 and 
225 g.  The animals were sacrificed 30 min after the administration 
of the alcohol.  There was a significant decrease in cerebral 
calcium contents compared with that in the control animals (35 
mg/kg versus 55 mg/kg) (Ross, 1976). 

    In Sprague Dawley rats (190 - 250 g), ip administration of 
aqueous  tert-butanol (250 g/litre) was shown to increase carbon 
tetrachloride-induced hepatotoxicity, as evaluated by serum 
glutamate-pyruvate transaminase levels.  However, there was no 
depletion in hepatic glutathione or loss in body weight (Harris & 
Anders, 1980).   tert-Butanol can potentiate the toxicity of carbon 
tetrachloride in Sprague Dawley rats (Cornish & Adefuin, 1967). 

    The inhibition of the synthesis of ornithine decarboxylase 
(ODC) and tyrosine aminotransferase (TAT) by  tert-butanol was 
studied in partially-hepatectomized female rats (about 238 g) of 
mixed strains.  Immediately after partial hepatectomy, 15% (w/v) 
aqueous  tert-butanol (2.8 g/kg body weight) was given to 6 rats by 
gastric intubation.  In the liver, 4 h after partial hepatectomy, 
the ODC activity was decreased to 22% and the TAT activity to about 
52% of the activities in the control group.  In the kidney, 4 h 
after partial hepatectomy, the ODC activity was decreased to about 
31% of the activity in the control group.  In the brain,  tert-
butanol did not induce any significant changes in the ODC activity 
compared with that in the control group (Poso & Poso, 1980). 

    The presence of a hydroxy radical is needed for prostaglandin 
biosynthesis.   tert-Butanol was shown to be a hydroxyl radical 
scavenger and, therefore, an inhibitor of prostaglandin 
biosynthesis.  In the incubation system of microsomes, prepared 
from bovine vesicular glands containing epinephrine, the 14C 
incorporation as a percentage of total labelled prostaglandins E 
and F, respectively, was 16.4% and 23.4%.  When 0.025 ml of  tert-
butanol was added to this incubation system, the values were 15.5% 
and 13.8%, respectively.  Further increases in concentration 
resulted in decreased incorporation (Panganamala et al., 1976).  
In another study using isolated perfused rat lungs, the infusion of 
low concentrations of  tert-butanol (0.002 mmol - 0.2 mmol) resulted 
in the continuous output of prostaglandins into the venous 
effluent.  However, there was a gradual decrease in the 
prostaglandin output as the concentration of the alcohol increased 
(Thomas et al., 1980). 

    Cation flux across membranes has been investigated in a number 
of studies.   tert-Butanol inhibited, in a dose-dependent manner, 
the  in vitro contraction of depolarized guinea-pig ileum induced 
by calcium chloride (Yashuda et al., 1976) and at a 34 mmol 
concentration impaired the response of rat brain cortex slices to 
electrical stimulation, inhibiting the influx of sodium, but only 
weakly affecting potassium afflux (Wallgren et al., 1974).  
Wiesbrodt et al. (1973) studied the effects of  tert-butanol on 
the gastric mucosa of Heidenheim pouches in 4 unanaesthetized 
dogs.  They observed a decrease in the transmucosal potential and 
an increase in the net flux of Na+ ion into the lumen of the pouch 
at all concentrations tested (0.5 - 1.5 mol). 

    The effect of  tert-butanol, at 1 mmol concentration, on 
isolated rat mitochondria and lysosomes was studied by Sgaragli 
et al. (1975).  The alcohol did not affect lipid peroxidation and 
membrane stability as evaluated by the release of total protein 
acid phosphatase and glutamate dehydrogenase. 

     tert-Butanol decreased the  in vitro Km of phosphorilase  b for 
glucose-1-phosphate with saturating glycogen concentrations and 
markedly increased Vmax (Dreyfus et al., 1978).  Akhtem et al. 
(1978) studied the interaction between  tert-butanol and cytochrome 
P-450 from rat liver microsomes; they revealed spectral shifts 
indicating the formation of alcohol-cytochrome P-450 complexes.  
Sugiyama et al. (1976) found that  tert-butanol greatly enhanced 
the side chain cleavage activity of purified P-450. 

    A 15-min pre-session oral administration of  tert-butanol 
at 0.25 - 3 g/kg body weight to 4 trained male Long Evans rats 
produced a dose-related decrease in fixed-ratio responding at 
doses of 0.5 g/kg or more.   tert-Butanol was 1.6 times as potent as 
ethanol, in this respect.  The 1 g/kg dose decreased responding by 
about 20%, 15, 30, or 60 min after dosing (Witkin & Leander, 1982). 

     tert-Butanol produced a marked dose-dependent activation 
of locomotor activity in short-sleep mice, selectively bred for 
relative insensitivity to the hypnotic properties of ethanol.  In 
alcohol-sensitive long-sleep mice, the locomotor activity was 
depressed in a dose-dependent fashion.  Test doses were 0, 4, 5, 
or 6 g/kg body weight, administered intravenously in 0.9% saline 
(Dudek & Philips, 1983). 

    Twelve neonatal Long Evans rats were given  tert-butanol at 
doses of up to 2.69 g/kg body weight per day in a milk formula 
through a cannula, from postnatal days 4 to 7 (corresponding to 
the brain growth spurt).  At this point, they were transferred to 
a plain milk formula, for the next 11 days.  After sacrifice on day 
18, exposed animals showed significant decreases in absolute and 
relative brain weights and lower DNA levels in hind-brain samples 
in comparison with controls, indicating a certain degree of 
microcephaly (Grant & Samson, 1982). 

    No effects were found in the basal synaptosomal membrane 
fluidity or in the activity of Na+ + K+ ATPase in the brain of 
Sprague Dawley rats given a single oral dose of 1.85 g  tert-
butanol/kg body weight (Beaugé et al., 1984). 

9.  EFFECTS ON MAN

     tert-Butanol is slightly irritant to the skin.  When the 
compound was applied to the skin of 5 human volunteers, no reaction 
other than slight erythema and hyperaemia was observed (Oettel, 
1936).  However, Edwards & Edwards (1982), described an allergic 
skin reaction to  tert-butanol in a 58-year-old patient who used 
skin screen containing  tert-butanol.  A patch test was positive 
for  tert-butanol.  There are no other published reports of adverse 
effects or poisonings in man. 

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 through food and 
occupational exposure levels are not available. 

10.1.2.  Toxic effects

    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 irritiation are not available.   tert-Butanol produces 
physical dependance in animals and post-natal effects in offspring 
exposed  in utero.  Data on 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.  No 
adequate data are available on carcinogenicity, teratogenicity, or 
effects on reproduction. 

    In man,  tert-butanol is a mild irritant to the skin.  There 
have not been any reports of poisonings or any other effects in 
man. 

10.2.  Evaluation of Effects on the Environment

10.2.1.  Exposure levels

    No quantitative data relating to levels in the general 
environment are available, but, because  tert-butanol is inherently 
biodegradable, substantial concentrations are only likely to occur 
locally in the case of major spillage. 

10.2.2.  Toxic effects

     tert-Butanol is inherently biodegradable and is not toxic for 
fish, amphibia, crustacea, algae, or bacteria. 

10.3.  Conclusions

1.  On the available data, the Task Group was unable to make an 
    assessment of the health risks from  tert-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 available data are not 
    sufficient to establish guidelines for setting occupational 
    exposure limits.  In line with good manufacturing practice, 
    exposure to  tert-butanol should be minimized. 

3.  The ecotoxicological data available indicate that the impact of 
    background concentrations of  tert-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 hazards from 
     tert-butanol. 

12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    The Council of Europe has recently established (Council of 
Europe, 1981) a specific limit of 30 mg  tert-butanol/kg in candy 
in confectionery.   tert-Butanol was evaluated by the EEC 
Scientific Committee for Food in 1980.  The Committee agreed on the 
following evaluation: 

        "The available data are insufficient to establish an
    ADI.  Biochemically, this solvent will behave like other
    tertiary carbinols, which are generally not very reactive.  
    The residues in food are minimal and are not a hazard to 
    health.  The Committee considers the use of this compound 
    temporarily acceptable as an extraction solvent provided 
    residues from use as an extraction solvent in food as 
    consumed do not exceed 10 mg/kg food.  The provision of an 
    adequate 90-day feeding study in a rodent species is 
    required by 1983."








                   ENVIRONMENTAL HEALTH CRITERIA

                                FOR

                             ISOBUTANOL



CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR ISOBUTANOL

 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 exposures
          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

    Isobutanol (2 methyl propanol) is a inflammable colourless 
liquid with a sweet odour similar to that of amyl alcohol.  It 
has a boiling point of 108 °C, a water solubility of 8.7%, and 
its  n-octanol/water partition coefficient is 0.83.  Its vapour 
is 2.6 times denser than air.  It occurs naturally as a product of 
fermentation and is synthesized from petrochemicals.  It is used as 
an organic solvent, as a plasticizer, in the manufacture of 
isobutyl esters, in perfumes, and as a flavouring agent.  Human 
exposure is primarily occupational.  Exposure of the general 
population will mainly be from its natural occurrence in food and 
its use as a flavouring agent, but may also result from industrial 
emissions. 

    Isobutanol is readily biodegradable and does not bioaccumulate.  
It is not directly toxic for fish, crustacea, amphibia, or algae.  
Protozoa will tolerate levels of isobutanol likely to be found in 
the environment.  Isobutanol 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, isobutanol is absorbed through the skin, lungs, and 
gastrointestinal tract.  It is metabolized by alcohol dehydrogenase 
to isobutyric acid via the aldehyde and may enter the tricarboxylic 
acid cycle.  Small amounts of isobutanol are excreted unchanged 
(< 0.5% of the dose), or as the glucuronide (< 5% of the dose) 
in the urine.  In rabbits, metabolites found in the urine  include 
acetaldehyde, acetic acid, isobutylaldehyde, and isovaleric acid.  
Oral LD50 values (2.5 - 3.1 g/kg body weight) and the inhalation 
LC50 (19.2 g/m3) in rats classifies isobutanol as slightly toxic 
according to Hodge & Sterner.  The acute toxic effects are 
alcoholic intoxication and narcosis.  Isobutanol is severely 
irritating to the eyes and moderately irritating to the skin.  A 
group of rats given a solution of isobutanol (1 mol/litre) as their 
sole drinking liquid for 4 months did not show any adverse effects 
on the liver, while another group given a 2 mol/litre solution as 
their sole drinking liquid for 2 months showed reductions in fat, 
glycogen, RNA content, and overall size of the cells in the liver.  
Continuous inhalation exposure of rats to 3 mg/m3 for 4 months 
resulted in depression of leg withdrawal response to electrical 
stimulation, and minor changes in formed elements of the blood and 
serum enzymes.  The estimated no-observed-adverse-effect level was 
0.1 mg/m3.  In a lifetime carcinogenicity study, groups of rats 
received isobutanol subcutaneously (0.05 ml/kg, twice a week) or 
orally (0.2 ml/kg body weight twice a week).  The animals exhibited 
toxic liver damage ranging from steatosis to cirrhosis.  Animals 
showing malignant tumours totalled 8 in the subcutaneous group, 
3 in the oral group, and 0 in the control group.  The majority of 
treated animals also showed hyperplasia of blood-forming tissues. 

    From the animal studies available, it is not possible to 
determine a no-observed-adverse-effect level for long-term 
exposure.  No adequate data are available to assess the 
mutagenicity or teratogenicity of isobutanol or effects on 
reproduction. 

    The only reported observations in man relate to the production 
of vertigo under conditions of severe and prolonged exposure to 
vapour mixtures of isobutanol and 1-butanol.  Thus, it is not 
possible to attribute the vertigo to a single cause. 

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

Chemical structure:      CH3
                           \
                             CH-CH2OH
                            /
                         CH3

Chemical formula:        C4H10O

Primary constituent:     isobutanol

Common synonyms:         isobutyl alcohol, isopropylcarbinol,
                         2-methyl-1-propanol, 2-methylpropyl
                         alcohol, 1-hydroxymethylpropane,
                         2-methylpropan-1-ol, 1-propanol,-2-methyl,
                         fermentation butyl alcohol

CAS registry number:     78-83-1

2.2.  Physical and Chemical Properties

    Physical and chemical properties of isobutanol are given in 
Table 1. 

Table 1.  Physical and chemical properties of isobutanol
-----------------------------------------------------------------
            (at 20 °C and 101.3 kPa, unless otherwise stated)

Physical state                 colourless liquid                   
Odour                          sweet, similar to that of amyl      
                               alcohol, but weaker                 
Odour threshold                approximately 4.6 mg/m3 (1.5 ppm)   
Relative molecular mass        74.12                               
Density (kg/m3)                801-803                             
Boiling point (°C)             107.9                               
Freezing point (°C)            -108                                
Viscosity (cP)                 3.98                                
Vapour pressure (kPa)          1.17                                
                               12.2 at 25 °C                       
Vapour density (air = 1)       2.55                                
Flashpoint (°C)                27.8                                
Autoignition temperature (°C)  434                                 
Explosion limits air (% v/v)   lower = 1.7, upper = 10.9           
Solubility (% weight)          in water, 8.7; soluble in alcohol   
                               and ether                           
 n-octanol/water partition      0.83                               
coefficient                                                        
                                                    
 Conversion factors (25 °C)     1 mg/m3 = 0.324 ppm  
                               1 ppm  = 3.083 mg/m3 
-----------------------------------------------------------------

2.3.  Analytical Methods

    Testing methods for the butanols (ASTM D304-58) are described 
in ASTM (1977). 

    NIOSH (1977) Method No S64 (341) 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. 

    The Association for Official Analytical Chemists has published 
an Official Final Action for the assay of isobutanol in spirits, 
based on gas chromatographic analysis (AOAC methods, 1975). 

3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    The major use of isobutanol is in the manufacture of isobutyl 
acetate, which is employed in the lacquer industry.  Furthermore, 
isobutanol is used as a solvent in paint and varnish removers and 
in the manufacture of isobutyl esters, which serve as solvents, 
plasticizers, flavourings, and perfumes.  It is also used as a 
flavouring agent in butter, cola, fruit, liquor, rum, and whisky 
(Hall & Oser, 1965).  The average maximum levels at which it is 
used in the USA are listed in Table 2 (Hall & Oser, 1965). 

Table 2.  Average maximum use levels of isobutanol in the USA
-------------------------------------------------------------
Food in which used  Approximate average maximum level (mg/kg)
-------------------------------------------------------------
Beverages           17

Ice cream, ices     7

Candy               30

Baked goods         24
-------------------------------------------------------------

    Isobutanol is one of the three main alcohols in fusel oil, and 
is present in large amounts in some alcoholic beverages (Hedlund 
Kiessling, 1969). 

    Natural isobutanol is produced by the fermentation of 
carbohydrates.  Isobutanol is found in fruits:  cherry (Postel et 
al., 1975), raspberry and blackberry (McGlumphy, 1951; Nursten et 
al., 1967; Broderick, 1976), grape (Bober, 1963), and apple 
(Schreier et al., 1978).  It also occurs in beverages:  brandy 
(Postel et al., 1975), coffee (Walter & Weidemann, 1969), cider 
(Matthews et al., 1962; Kieser et al., 1964), and gin (Clutton & 
Evans, 1978).  Isobutanol has been identified in sundry other foods 
including cheddar cheese (Liebich et al., 1970), and hop oil 
(Lammers et al., 1968). 

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    No data are available on distribution in soil, sediments or 
air. 

    Isobutanol is readily biodegradable (Table 3).  It is degraded 
in significant amounts within a few hours, and degradation would be 
expected to be complete within a few days. 

Table 3.  Biodegradation of isobutanol
-------------------------------------------------------------------
5d BOD     64% of ThOD in fresh water        Price et al. (1974)

           46% of ThOD in synthetic          Price et al. (1974)
           seawater

5d BOD     16% of ThOD (APHA)                Bridié et al. (1979a)

           63% of ThOD after adaptation      Bridié et al. (1979a)
           (APHA)

Activated  32.5% of ThOD removed in 24 h by  Gerhold & Malaney
sludge     unadapted municipal sludge        (1966)
          
           44% of ThOD removed in 24 h by    McKinney & Jeris
           adapted sludge                    (1955)
-------------------------------------------------------------------
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.

    Nazarenko (1969) reports an oxygen requirement of approximately 
1.4 mg to oxidize 1 mg of isobutanol.  Isobutanol at a 
concentration of 20 mg/litre inhibits nitrification in water 
(Nazarenko, 1969). 

    Isobutanol does not bioaccumulate (Chiou et al., 1977). 

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    An industrial emission study indicated that 90 tonnes of 
isobutanol were released into the air over 1 year in the 
Netherlands (Anon, 1983).  Isobutanol produced naturally during the 
fermentation of carbohydrates can enter the environment by leaching 
from industrial waste landfills.  A concentration of 0.3 g/litre 
was found to be leaching from a 1-year-old landfill (US EPA, 1980). 

6.  KINETICS AND METABOLISM

    Isobutanol can be absorbed through the lungs and from the 
gastrointestinal tract (Browning, 1965). 

    Isobutanol (2 ml/kg body weight) was given to male rabbits by 
gavage, and blood levels of isobutanol were determined.  After 1 h, 
a maximum concentration of 0.5 g/litre was observed.  After 6 h, 
isobutanol was no longer detectable in the blood.  Less than 0.5% 
of the administered isobutanol was excreted unchanged in the breath 
or urine within 40 h (Saito, 1975). 

    Isobutanol can be metabolized to isobutyric acid and then 
proceed into the tricarboxylic acid cycle, possibly via succinate 
(Fig. 1B) (Saito, 1975).  The urinary metabolites resulting from 
repeated ingestion of isobutanol were also studied by Saito (1975).  
Isobutanol (2 ml/kg body weight) was administered by stomach tube 
to male rabbits.  The rabbits were then given water saturated with 
isobutanol instead of pure water to drink and the urinary 
metabolites were determined.  The length of time over which the 
urine was collected was not specified.  The urinary metabolites 
were acetaldehyde (80 mg), acetic acid (16 mg), isobutyraldehyde 
(10 mg), isovaleric acid (128 mg), and unmetabolized isobutanol (40 
mg).  The origin of urinary isovaleric acid was not discussed by 
the author.  Saito (1975) has proposed the scheme shown in Fig. 1B 
for the metabolism of isobutanol in rabbits. 

FIGURE 1B

    When Kamil et al. (1953) administered isobutanol (25 mmol 
total) by stomach tube to Chinchilla rabbits, 4.4% of the applied 
dose was excreted within 24 h, as the glucuronide.  After 
administration of 6 ml isobutanol to the stomach of rabbits (Kamil 
et al., 1953), no aldehydes or ketones were observed in the expired 
air within 6 h. 

    Gaillard & Derache (1965) reported that, following an oral dose 
of 2 g/kg body weight to rats, 0.27% was excreted in the urine 
within 8 h. 

    The oxidation of isobutanol and other lower alcohols by both 
rat liver homogenates and by the perfusion  in situ of rat liver 
was studied by Hedlund & Kiessling (1969).  The authors observed 
that the alcohols were oxidized at rates that decreased in the 
following order:  1-propanol, isobutanol, ethanol, and isoamyl 
alcohol.  Furthermore, from their studies with the alcohol 
dehydrogenase (ADH) inhibitor pyrazole, these authors concluded 
that all the alcohols studied must be oxidized by ADH in the same 
manner as ethanol in an NAD-mediated oxidation. 

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1.  Aquatic Organisms

    Some data on the toxicity of isobutanol for aquatic organisms 
are given in Table 4.  The high lethal concentrations (1000 - 4000 
mg/litre) for fish, amphibia, and crustacea indicate that, at 
background levels, isobutanol would not be disruptive for an 
aquatic ecosystem. 
Table 4.  Toxicity of isobutanol for aquatic organisms
------------------------------------------------------------------------------------------
Species           Concentration  Parameter             Comments        Reference
                  (mg/litre)               
------------------------------------------------------------------------------------------
Fish

Fresh-water species

Bleak             1000-3000      96-h LC50                             Lindén et al. 
 (Alburnus                                                              (1979)
 alburnus)

Golden orfe       1520           48-h LC50                             Juhnke & Lüdemann
 (Leuciscus                                                             (1978)
 idus melanotus)

Goldfish          2600           24-h LC50                             Bridié et al. 
 (Carassius                                                             (1979a)
 auratus)

Amphibia

Tadpole           4000                                 threshold for   Münch (1972)
 (Rana sp)                                              narcosis

Invertebrates

Fresh-water species

Water flea        1250           24-h EC50             immobilization  Bringmann & Kuehn
 (Daphnia magna)                                                        (1982)

Marine species

Brine shrimp      1400           24-h LC50                             Price et al. (1974)
 (Artemia salina)  3800           EC50                  excystment      Smith & Siegel 
                                                                       (1975)
------------------------------------------------------------------------------------------

Table 4.  (contd.)
------------------------------------------------------------------------------------------
Species           Concentration  Parameter             Comments        Reference
                  (mg/litre)               
------------------------------------------------------------------------------------------
Algae

Green algae

 Scenedesmus       350            8-day no-observed-    total biomass   Bringmann & Kuehn
 quadricauda                      adverse-effect level                  (1978a)

Blue-green algae

 (Microcystis      290            8-day no-observed-    total biomass   Bringmann & Kuehn
 aeruginosa)                      adverse-effect level                  (1978a)
------------------------------------------------------------------------------------------

7.2.  Terrestrial Organisms

    Toxicity studies in plants indicate that germination will not 
be affected by exposure to isobutanol at background levels.  An 
EC50 of 760 mg/litre was reported by Reynolds (1977) for seed 
germination in lettuce  (Lactuca sativa).  Smith & Siegel (1975) 
found an EC50 of 40 800 mg/litre for seed germination in cucumber 
 (Cucumis sativus). 

    There is no information on terrestrial animals, but exposure is 
unlikely to be significant, except locally after spills. 

7.3.  Microorganisms

    Some data on the toxicity of isobutanol for microorganisms are 
given in Table 5.  Available toxicity data on protozoa bacteria and 
algae suggest tolerance to exposure to isobutanol.  No-observed-
adverse-effect levels for various species ranged from 22 to 1180 
mg/litre).  Exposure to background levels of isobutanol should not 
be disruptive for the ecosystem. 


                                                     
Table 5.  Toxicity of isobutanol for microorganisms
------------------------------------------------------------------------------------------
Species                 Concentration  Parameter             Comments       Reference
                        (mg/litre)
------------------------------------------------------------------------------------------
Protozoa

 Chilomonas paramaecium  22             48-h no-observed-     total biomass  Bringmann & 
(flagellate)                           adverse-effect level                 Kuehn (1981)

 Uronema parduczi        169            20-h no-observed-     total biomass  Bringmann & 
(ciliate)                              adverse-effect level                 Kuehn (1981)

 Entosiphon sulcatum     296            72-h no-observed-     total biomass  Bringmann & 
(flagellate)                           adverse-effect level                 Kuehn (1981)

Bacteria

 Pseudomonas putida      280            16-h no-observed-     total biomass  Bringmann & 
                                       adverse-effect level                 Kuehn (1976)

 Bacillus subtilis       1180           EC50                  spore          Yasuda-Yasaki  
                                                             germination    et al. (1978)
------------------------------------------------------------------------------------------
8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1.  Single Exposures

8.1.1.  Acute toxicity

    The oral EC50 for narcosis in rabbits was 19 mmol isobutanol/kg 
body weight (Münch, 1972). 

    Acute toxicity data are given in Table 6. 

Table 6.  Acute toxicity of isobutanol
---------------------------------------------------------------------
Species  Route of        Parameter  Results           Reference
         administration
---------------------------------------------------------------------
Guinea-  inhalation      LC50       19 900 mg/m3      Kushneva et al.
pig                                                   (1983)
Mouse    inhalation      LC50       15 500 mg/m3      Kushneva et al.
                                                      (1983)
Rabbit   inhalation      LC50       26 250 mg/m3      Kushneva et al.
                                                      (1983)
Rat      inhalation      LCLoa      8000 mg/m3 (4 h)  US DHEW (1978)
Rat      inhalation      LC50       19 200 mg/m3      Kushneva et al.
                                                      (1983)
Cat      intravenous     LDLoa      0.018 g/kg        US DHEW (1978)
Rabbit   oral            LDLoa      3.75 g/kg         US DHEW (1978)
Rabbit   oral            LD50       41 mmol/kg        Münch (1972)
Mouse    oral            LD50       3.5 g/kg          Kushneva et al.
                                                      (1983)
Rat      oral            LD50       3.1 g/kg          Kushneva et al.
                                                      (1983)
Rat      oral            LD50       2.46 g/kg         US DHEW (1978)
Rabbit   skin            LD50       4.24 g/kg         US DHEW (1978)
---------------------------------------------------------------------
a Lo = lowest.

    After ip administration of isobutanol to mice, the LD50 
was > 1000 mg/kg at 30 min and 544 mg/kg at 7 days.  Gross post-
mortem examination of livers showed an abnormal dark coloration 
(Maickel & McFadden, 1979). 

    Smyth et al. (1954) reported 100% survival of rats exposed for 
2 h to saturated isobutanol vapour (approximately 49 248 mg/m3 or 
16 000 ppm) in air, but observed 2 deaths in a group of 6 rats when 
they were exposed for 4 h to a concentration of 24 624 mg/m3 (8000 
ppm) in air. 

8.1.2.  Signs of intoxication

    The toxic effects of isobutanol are mainly alcoholic 
intoxication and narcosis.  Stupor and loss of voluntary movements 
in animals can be considered signs of intoxication by the oral 
route (Münch, 1972).  Rats and rabbits were exposed, by inhalation, 
for a period of 4 h to various concentrations of isobutanol.  At a 

concentration of 15 700 mg/m3, there was irritation of the airways.  
Three days later, symptoms included central nervous depression, a 
decreased number of lymphocytes in bone marrow, a decreased blood-
lactate level, delay in elimination of bromophthalein from blood, 
and morphological changes including dystrophia of hepatocytes and 
olfactory neurons in the brain.  After exposure to 8000 mg/m3, 
symptoms were similar but less severe.  An isobutanol concentration 
of 1300 mg/m3 decreased bone marrow lymphocyte numbers.  A 
concentration of 100 mg/m3 only altered breathing frequency 
(Kushneva et al., 1983). 

8.2.  Skin and Eye Irritation

    Application of 500 mg isobutanol to the skin of rabbits for 
24 h was moderately irritating.  However, application of 2 mg to 
the rabbit eye caused severe irritation (US DHEW, 1978). 

8.3.  Short-Term Exposures

    Hillbom et al. (1974a,b) gave one group of 6 male Wister rats 
a 1 mol/litre solution of isobutanol as their sole drinking liquid 
for a period of 4 months.  Another group of 5 rats of the same 
species was given a 2 mol/litre solution of isobutanol as their 
sole drinking liquid for 2 months.  Both groups were provided an 
 ad libitum diet of ordinary laboratory food containing about 26% 
of calories as protein, 55% as carbohydrate, and 19% as fat.  At 
the end of the study, all animals were decapitated, and their 
livers examined.  No adverse effects were detected in the group 
given the 1 mol/litre solution, while the rats in the group given 
the 2 mol/litre solution showed a decrease in fat, glycogen, RNA, 
and overall size of the liver cells. 

    Oral administration of between 1/10 and 1/5 of the LD50 of 
isobutanol for 6 days/week over 1 month, did not result in any 
deaths in rats (Kushneva et al., 1983).  Continuous exposure of 
rats, by inhalation, to isobutanol at 3 mg/m3 over 4 months, 
caused an increased threshold for leg withdrawal response to 
electrical stimulation, and depression of haemoglobin content, 
erythrocyte count, and activities of cholinesterase and catalase 
in the blood.  The activities of alanine-amino transferase and 
aspartate amino transferase were elevated.  At 0.5 mg/m3, numbers 
of white cells and erythrocytes, haemogloglobin content, and 
cholinesterase activity were all decreased.  No effects were 
observed at 0.1 mg/m3 (Tsulaya et al., 1978). 

8.4.  Long-Term Exposures

    With the exception of a carcinogenicity study, no long-term 
studies have been reported. 

8.5.  Reproduction, Embryotoxicity, and Teratogenicity

    No relevant data are available on reproduction or 
embryotoxicity and no conclusions can therefore be drawn. 

8.6.  Mutagenicity

    The only reported study on mutagenicity is that of Hillscher et 
al. (1969) who demonstrated an increased rate of reverse mutation 
when  Escherichia coli CA 274 was treated with 0.7% isobutanol, 
without metabolic activation.  This study in itself is inadequate 
to assess the mutagenic potential of the compounds. 

8.7.  Carcinogenicity

    Two groups of 19 and 24 male and female Wistar rats (10 weeks 
old) were administered purified isobutanol.  Group one received 
0.2 ml/kg body weight, orally, twice weekly.  Group two received 
0.05 ml/kg, subcutaneously, twice weekly.  Two control groups (25 
rats each) received 1 ml of 0.9% sodium chloride twice weekly 
(controls for group one were dosed orally; controls for group two 
were dosed subcutaneously).  All rats were dosed until spontaneous 
death.  Test rats presented liver carcinomas and sarcomas, spleen 
sarcomas, stomach proventricular carcinomas, and myeoid leukaemia. 
Tumours of these types did not occur in the control groups (Table 
7).  In the exposed animals, toxic liver damage was found, ranging 
from steatosis and cell necrosis to fibrosis and cirrhosis.  In 
addition, most exposed animals had hyperplasia of blood-forming 
tissues.  The carcinogenic response was attributed to isobutanol 
(Gibel et al., 1974, 1975).  No statistical analysis of the data 
was performed. 

Table 7.  Summary of tumours in experimental animalsa
-------------------------------------------------------------------
Agent        Application      Number   Average   Malignant  Benign
             (twice weekly)   of       survival  tumour     tumour
                              animals  (days)
-------------------------------------------------------------------
Control      oral: 1 ml/kg    25       643       0          3
(0.9% NaCl)  body weight
solution)
             subcutaneous:    25       643       0          2
             1 ml/kg body
             weight

Isobutanol   oral: 0.2 ml/kg  19       495       3b         9
             body weight

             subcutaneous:    24       544       8c         3
             0.05 ml/kg
             body weight
-------------------------------------------------------------------
a Adapted from:  Gibel et al. (1975).
b Proventriculus carcinoma and liver cell carcinoma; proventriculus
  carcinoma and myeloid leukaemia; myeloid leukaemia.
c Proventriculus carcinoma (2); liver sarcoma (2); spleen sarcoma;
  mesothelioma; retroperitoneal sarcoma (2).

8.8.  Special Studies

    In 8 guinea-pigs, serum enzyme (SGOT, SGPT, GLDH) activities 
and triglyceride levels were measured 16 h after oral 
administration of 33.5 mg isobutanol/kg olive oil.  There was no 
statistically-significant difference between treated animals and 8 
olive-oil treated controls (Siegers et al., 1974). 

    Isobutanol can potentiate the hepatic toxicity of carbon 
tetrachloride (Cornish & Adefuin, 1967). 
                                                          
9.  EFFECTS ON MAN

    Isobutanol may be absorbed through the lungs and the 
gastrointestinal tract (Browning, 1965). 

    No data are available on the effects of isobutanol on the skin.  
However, as with other defatting solvents, isobutanol may cause 
erythematous skin lesions (Schwarz & Tulipan, 1939). 

    Immersion of the hands of 5 healthy male volunteers in a 
1:1 (v/v) mixture of  m-xylene and isobutanol, for 15 min at 
room temperature, caused only a mild and sometimes barely 
distinguishable erythema or a burning feeling.  Isobutanol (in a 
1:1 mixture with  m-xylene) dehydrated the skin and decreased the 
absorption of xylene.  However, when water was added as 8% of the 
mixture, this effect was reduced.  The dermal effects of isobutanol 
only and its absorption were not studied (Riihimaki, 1979). 

    Seitz (1972) reported 7 case histories, occurring between 
1965 and 1971, of 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 present any signs 
or symptoms. 

    Eye irritation, blurred vision, and transient corneal 
vacuolization have been decribed in another excessive (no 
measurements done) mixed exposure of workers to isobutanol and 
butyl acetate.  With adequate work room ventilation, it did not 
recur.  The author felt that the more irritant butyl acetate would 
be the main contributor to this effect (Büsing, 1952). 

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 isobutanol 
through food and beverages are not available and occupational 
exposure levels are limited and inadequate. 

10.1.2.  Toxic effects

    In animals, isobutanol is absorbed through the skin, lungs, 
and gastrointestinal tract.  Isobutanol is metabolized by alcohol 
dehydrogenase to isobutyric acid via the aldehyde and may enter the 
tricarboxylic acid cycle.  Small amounts of isobutanol are excreted 
unchanged (< 0.5% of the dose), or as the glucuronide (< 5% of 
the dose) in the urine.  In rabbits, metabolites found in the urine 
include acetaldehyde, acetic acid, isobutyraldehyde, and isovaleric 
acid.  Oral LD50 values (2.5 - 3.1 g/kg body weight) and inhalation 
LC50 (19.2 g/m3) in rats classify isobutanol as slightly toxic 
according to Hodge & Sterner.  The acute toxic effects are 
alcoholic intoxication and narcosis.  Isobutanol is severely 
irritating to the eyes and moderately irritating to the skin.  A 
group of rats given a 1 mol/litre solution of isobutanol as their 
sole drinking liquid for 4 months did not show any adverse effects 
in the liver; another group given a 2 mol/litre solution as their 
sole drinking liquid for 2 months showed a reduction in fat, 
glycogen, and RNA content, and in the overall size of the cells in 
the liver.  Continuous inhalation exposure of rats to 3 mg/m3 for 
4 months resulted in depression of leg withdrawal response to 
electrical stimulation, minor changes of formed elements of the 
blood and serum enzymes.  The estimated no-observed-adverse-effect 
level was 0.1 mg/m3. 

    In a lifetime carcinogenicity study, groups of rats received 
isobutanol subcutaneously (0.05 ml/kg body weight twice a week) or 
orally (0.2 ml/kg body weight twice a week).  The animals exhibited 
toxic liver damage ranging from steatosis to cirrhosis.  Numbers of 
animals showing malignant tumours totalled 8 in the subcutaneous 
group, 3 in the oral group, and 0 in the control group.  The 
majority of treated animals also showed hyperplasia of blood-
forming tissues. 

    Because of lack of mutagenicity studies, the Task Group could 
not determine whether isobutanol was a genetically active compound.  
The findings in the carcinogenicity study are a cause for concern.  
Because of methodological inadequacies and the manner of reporting 
the data, it was not possible to determine whether isobutanol 
should be regarded as an animal carcinogen.  Thus it is not 
possible to extrapolate from this study to possible long-term 
effects in man. 

    From the animal studies available, it is not possible to 
determine a no-observed-adverse-effect level for long-term 
exposure.  No adequate data are available to assess mutagenicity 
or teratogenicity of isobutanol or effects on reproduction. 

    Exposure of the general population to isobutanol through food 
and beverages is unlikely to lead to acute toxic effects.  The only 
reported observations in man relate to the production of vertigo 
under conditions of severe and prolonged exposure to vapour 
mixtures of isobutanol and 1-butanol.  From this study, it is 
not possible to attribute the vertigo to a single cause. 

10.2.  Evaluation of Effects on the Environment

10.2.1.  Exposure levels

    Little quantitative data relating to levels in the general 
environment are available, but, because isobutanol 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, isobutanol is not directly toxic for fish, amphibia, 
crustacea, or algae.  Protozoa will be tolerant to levels of 
isobutanol likely to be found in the environment. 

    Isobutanol should be managed in the environment as a slightly 
toxic compound.  It poses an indirect hazard to the aquatic 
environment, because it is readily biodegradable, which may lead to 
oxygen depletion. 

10.3.  Conclusions

1.  On the basis of available data, the Task Group considered it 
    unlikely that isobutanol would pose a serious acute health risk 
    to the general population under normal exposure conditions.  
    However, the Task Group was unable to make an assessment of the 
    long-term health risk of isobutanol for the general population.  
    It was concluded that the results of the carcinogenicity study 
    need verification by a bioassay of modern standards. 

2.  The Task Group considered that the data available were 
    inadequate to set an occupational exposure limit.  In line with 
    good manufacturing practice, exposure to isobutanol should be 
    minimized. 

3.  The ecotoxicological data available indicate that the impact of 
    background concentrations of isobutanol on the aquatic 
    environment can be expected to be minimal. 

11.  RECOMMENDATIONS

1.  The Task Group noted that, from the animal studies available, 
    it is not possible to determine a no-observed-adverse-effect 
    level.  Relevant studies should be conducted so that this can 
    be achieved. 

2.  The Task Group considered that adequate studies should be  
    conducted to assess the mutagenicity and carcinogenicity of 
    isobutanol.

3.  Epidemiological studies, including precise exposure data, would 
    assist in a better assessment of the occupational hazard of 
    isobutanol. 

4.  Additional information on environmental pathways (notably 
    emission and leaching) and residues are desirable. 

12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    The Council of Europe (1981) included isobutanol in the list 
of flavouring substances that can be added to foodstuffs without 
hazard to public health at a level of 25 mg/kg for beverages and 
food. 

    At their 23rd meeting, the Joint FAO/WHO Expert Committee on 
Food Additives (JECFA) reviewed the data on isobutanol.  They 
concluded that: 

        "The evaluation of this compound was not possible
    owing to the paucity of toxicological data.  New
    specifications were prepared, but no toxicological
    monograph" (WHO, 1980).

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(in Russian)


    See Also:
       Toxicological Abbreviations