UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 187
White Spirit
(Stoddard Solvent)
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.
First draft prepared by Dr P.B. Larsen, Institute of Toxicology,
National Food Agency of Demark, Soborg, Denmark
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 1996
The International Programme on Chemical Safety (IPCS),
established in 1980, is a joint venture of the United Nations
Environment Programme (UNEP), the International Labour Organisation
(ILO), and the World Health Organization (WHO). The overall objectives
of the IPCS are to establish the scientific basis for assessment of
the risk to human health and the environment from exposure to
chemicals, through international peer-review processes, as a
prerequisite for the promotion of chemical safety, and to provide
technical assistance in strengthening national capacities for the
sound management of chemicals.
The Inter-Organization Programme for the Sound Management of
Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
Agriculture Organization of the United Nations, WHO, the United
Nations Industrial Development Organization and the Organisation for
Economic Co-operation and Development (Participating Organizations),
following recommendations made by the 1992 UN Conference on
Environment and Development to strengthen cooperation and increase
coordination in the field of chemical safety. The purpose of the IOMC
is to promote coordination of the policies and activities pursued by
the Participating Organizations, jointly or separately, to achieve the
sound management of chemicals in relation to human health and the
environment.
WHO Library Cataloguing in Publication Data
White spirit.
(Environmental health criteria ; 187)
1.Solvents - adverse effects 2.Solvents - toxicity
3. Environmental exposure I.Series
ISBN 92 4 157187 X (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR WHITE SPIRIT
Preamble
1. SUMMARY
1.1. Properties of white spirit
1.2. Uses and sources of exposure
1.2.1. Production
1.2.2. Uses and emission into the environment
1.3. Environmental transport, distribution and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism
1.6. Effects on laboratory animals and in vitro systems
1.7. Effects on humans
1.8. Effects on other organisms in the laboratory and field
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS
2.1. Identity
2.1.1. Technical specifications
2.1.2. Chemical composition
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Production
3.3. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.2. Transformation
4.2.1. Biodegradation
4.2.2. Abiotic degradation
4.2.3. Bioaccumulation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.1.3. Soil
5.1.4. Waste sites
5.2. General population exposure
5.3. Occupational exposure
5.3.1. Considerations concerning vapour exposure
5.3.2. Exposure levels
5.3.3. Exposure limit values
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption
6.1.1. Inhalation
6.1.1.1 Human exposure
6.1.1.2 Related hydrocarbon exposure in animals
6.1.2. Dermal exposure
6.1.3. Oral exposure
6.2. Distribution
6.2.1. Human exposure
6.2.2. Animal exposure
6.2.3. Exposure to related hydrocarbons
6.3. Metabolic transformation
6.4. Elimination and excretion
7. EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Inhalation
7.1.1.1 White spirit
7.1.1.2 Exposure to related hydrocarbons
7.1.2. Oral exposure
7.1.3. Dermal exposure
7.1.4. Aspiration
7.2. Short-term and long-term exposure
7.2.1. Inhalation
7.2.1.1 White spirit
7.2.1.2 Exposure to related hydrocarbons
7.2.2. Dermal exposure
7.2.2.1 White spirit
7.2.2.2 Exposure to related hydrocarbons
7.3. Irritation; sensitization
7.3.1. Skin irritation
7.3.1.1 White spirit
7.3.1.2 Exposure to related hydrocarbons
7.3.2. Eye irritation
7.3.3. Respiratory irritation
7.3.4. Sensitizing properties
7.4. Other effects
7.4.1. Nephrotoxicity
7.4.2. Neurotoxicity
7.4.2.1 Behavioural effects
7.4.2.2 Neurophysiological and neuromorpho-
logical effects
7.4.2.3 Neurochemical effects
7.4.3. Biochemical effects
7.4.3.1 White spirit
7.4.3.2 Exposure to related hydrocarbons
7.5. Reproductive toxicity, embryotoxicity and teratogenicity
7.6. Genotoxicity
7.6.1. Bacterial assays
7.6.2. Yeast assay
7.6.3. In vitro mammalian cell assays
7.6.4. In vivo mammalian assays
7.7. Carcinogenicity
7.7.1. White spirit
7.7.2. Related refinery streams
8. EFFECTS ON HUMANS
8.1. Single exposure
8.1.1. Inhalation, controlled exposure
8.1.1.1 Irritation
8.1.1.2 CNS effects
8.1.1.3 Neurobehavioural effects
8.1.1.4 Odour
8.1.2. Inhalation, accidental exposure
8.1.3. Oral exposure
8.1.4. Dermal exposure
8.2. Short-term and long-term exposures
8.2.1. Effects on the nervous system
8.2.1.1 Symptoms and clinical picture
8.2.1.2 Neurological findings
8.2.1.3 Neuropsychological findings
8.2.1.4 Epidemiological studies
8.2.1.5 Comments and uncertainties concerning
the epidemiological studies
8.2.1.6 Prognosis and follow-up
8.2.2. Effects on skin
8.2.3. Effects on kidneys
8.2.4. Effects on liver, blood and bone marrow
8.2.5. Haematological and biochemical effects
8.3. Reproductive toxicity
8.4. Carcinogenicity
8.4.1. Epidemiological studies with painters
8.5. Genotoxicity
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Laboratory experiments
9.1.1. Microorganisms
9.1.2. Aquatic organisms
9.1.3. Terrestrial organisms
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Evaluation of effects on the environment
11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
12. FURTHER RESEARCH
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
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Criteria monographs, readers are requested to communicate any errors
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A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Case postale
356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).
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This publication was made possible by grant number 5 U01
ES02617-15 from the National Institute of Environmental Health
Sciences, National Institutes of Health, USA.
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR WHITE SPIRIT
Members
Dr D. Anderson, British Industry Biological Research Association
(BIBRA) Toxicology International, Carshalton, Surrey, United
Kingdom
Mrs P. Barker, Health and Safety Executive, Magdalen House, Bootle,
United Kingdom
Dr R.S. Chhabra, Division of Intramural Research, National Institute
of Environmental Health Sciences, Research Triangle Park, North
Carolina, USA
Dr Ih Chu, Environmental and Occupational Toxicology Division,
Environmental Health Centre, Tunney's Pasture, Ottawa, Canada
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom (Chairman)
Dr O. Ladefoged, Institute of Toxicology, National Food Agency of
Denmark, Sœborg, Denmark
Dr P.B. Larsen, Institute of Toxicology, National Food Agency of
Denmark, Sœborg, Denmark (Rapporteur)
Dr P. œrbaek, Department of Occupational Health, University Hospital,
Malmo, Sweden
Dr C.K. Seng, Department of Community, Occupational and Family
Medicine, National University Hospital, National University of
Singapore, Singapore
Representatives of other Organizations
Dr P. Montuschi, Institute of Pharmacology, Faculty of Medicine and
Surgery, Catholic University of the Sacred Heart, Rome, Italy
(Representing the International Union of Pharmacology)
Dr D.E. Owen, Conseil Européen des Fédérations de l'Industrie Chimique
(CEFIC), Brussels, Belgium
Secretariat
Dr P.G. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland (Secretary)
Mr J.D. Wilbourn, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
ENVIRONMENTAL HEALTH CRITERIA FOR WHITE SPIRIT
A WHO Task Group on Environmental Health Criteria for White
Spirit met at BIBRA Toxicology International, Carshalton, United
Kingdom, from 13 to 17 November 1995. Dr P.G. Jenkins, IPCS, welcomed
the participants on behalf of Dr M. Mercier, Director, IPCS, and the
three IPCS cooperating organizations (UNEP/ILO/WHO). The Group
reviewed and revised the draft monograph and made an evaluation of the
risks for human health and the environment from exposure to white
spirit.
The first draft of the monograph was prepared by Dr P.B. Larsen,
National Food Agency of Denmark, Ministry of Health, Sœborg, Denmark.
He also prepared the second draft, incorporating comments received
following circulation of the first draft to the IPCS contact points
for Environmental Health Criteria monographs.
Dr P.G. Jenkins, IPCS, was responsible for both the overall
scientific content and the technical editing.
The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.
ABBREVIATIONS
AEP auditory evoked potential
CBF cerebral blood flow
CNS central nervous system
CT computerized tomography
EEG electroencephalography
EMG electromyography
ENG electroneurography
FID flame ionization detector
GC gas chromatography
IR infrared
LAWS low aromatic white spirit
LEI lifetime exposure intensity
MS mass spectrometry
MTE mild toxic encephalopathy
NCV nerve conduction velocity
OR odds ratio
PEG pneumoencephalography
POS psycho-organic syndrome
RR relative risk
TLV threshold limit value
TST temperature sensitivity
VER visual evoked response
VTR vibration threshold
1. SUMMARY
1.1 Properties of white spirit
White spirit is a clear colourless solvent with very low water
solubility and a characteristic odour (odour threshold: 0.5-5 mg/m3).
The most common variety of white spirit is a mixture of saturated
aliphatic and alicyclic C7-C12 hydrocarbons with a content of 15-20%
(by weight) of aromatic C7-C12 hydrocarbons and a boiling range of
130-230°C. The C9-C11 hydrocarbons (aliphatics, alicyclics and
aromatics) are most abundant, constituting > 80% (by weight) of the
total. This ordinary white spirit is designated white spirit, type
1, regular grade, as three different types and three different
grades exist. The type refers to whether the solvent has been
subjected to hydrodesulfurization (removal of sulfur) alone (type 1),
solvent extraction (type 2) or hydrogenation (type 3). The
hydrodesulfurized type contains less than 25% aromatic hydrocarbons,
the solvent-extracted less than 5%, and the hydrogenated less than 1%.
Each type comprises three different grades: low flash grade (flash
point: 21-30°C; initial boiling point: 130-144°C), regular grade
(flash point: 31-54°C; initial boiling point: 145-174°C), and high
flash grade (flash point: > 55°C; initial boiling point:
175-200°C). The grade is determined by the crude oil used as the
starting material and the conditions of distillation. Type 0 white
spirit is defined as a distillation fraction with no further
treatment, consisting predominantly of saturated C9-C12 hydrocarbons
with a boiling range of 140-220°C. The low flash grade possesses the
highest vapour pressure of approximately 1.4 kPa (10.5 mmHg) at 20°C.
A USA variety of type 1 is called Stoddard solvent and is a
petroleum distillate defined according to its boiling range of
149-204°C and the absence of rancid or objectionable odours.
1.2 Uses and sources of exposure
1.2.1 Production
The various types and grades of white spirit are produced from
straight-run naphtha and straight-run kerosene, which are refinery
streams obtained from the distillation of crude oil. These fractions
are subjected to fractional distillation into appropriate boiling
ranges and to different kind of treatments (referred to in section
1.1) to obtain the desired type of white spirit. The composition of
the solvents may vary due to variation in the composition of the crude
oil and also because of the differences in refinery processing. White
spirit may, therefore, have changed over time because of changes in
manufacturing processes. Quantitative data are not available, but
there is a trend towards increased use of low aromatic white spirit in
Europe.
1.2.2 Uses and emission into the environment
White spirit is used mainly in paints and varnishes, in cleaning
products and as a degreasing and extraction solvent. Details of the
solvents used in paints are not available, but white spirit is a
common component of the solvent in a wide variety of paints. It is
also used by both amateur and professional painters as a diluent. The
proportion of the total solvent represented by white spirit varies
between paints. Estimates of white spirit as a percentage of total
paint solvents are approximately 45% for Europe and 25% for the USA.
White spirit may be present as a minor constituent of water-based
paints.
Although exact figures of white spirit consumption in the paint
industry are not available, the following figures of the consumption
of aliphatic and aromatic hydrocarbons give some impression of the
usage of white spirit, as it constitutes a large part of the total
hydrocarbons (Table 1).
Table 1. Solvent consumption in the paint industry
(in thousands of tonnes)
Europe USA
1987 1985
Aliphatic hydrocarbons 695 433
Aromatic hydrocarbons 435 572
Other solvents, e.g., alcohols, ketones,
glycol ethers, esters 470 935
Total solvent consumption 1600 1940
In 1985 the annual sale of white spirit in the USA was
7.17 × 105 tonnes, and consumption in 1986 in western Europe amounted
to 7.5 × 105 tonnes.
The major part of the manufactured white spirit is released to
the environment and largely partitions to the atmosphere.
1.3 Environmental transport, distribution and transformation
The environmental transport and transformation of white spirit
constituents will depend on the physico-chemical and biological
properties of the constituents. The lower molecular weight alkanes
and aromatics tend to volatilize and undergo photodegradation in the
atmosphere. The higher molecular weight alkanes and cycloalkanes tend
to be sorbed to organic matter in soil or water. Biodegradation is
expected to be the primary fate of white spirit in soil and water.
Biodegradation of C7 to C12 hydrocarbons is expected to be
significant under environmental conditions favourable to microbial
oxidation. Ready biodegradability has been demonstrated in laboratory
tests using sewage sludge. The low water solubility and moderate
vapour pressure of white spirit suggest that volatilization and
subsequent photooxidation are important for abiotic degradation.
Reported octanol/water partition coefficients (log Pow) of 3.5 to 6.4
indicate a moderate potential for bioaccumulation. However, the
degradability and lowered bioavailability following sorption would
reduce the likelihood of bioconcentration in the field.
1.4 Environmental levels and human exposure
There are few data on white spirit in air, water or soil.
Monitoring at a site contaminated with spilt white spirit (Stoddard
solvent) revealed soil levels of up to 3600 mg/kg and deep soil water
levels of up to 500 mg/litre. Biodegradation led to a 90% reduction
in soil concentration over a 4-month period following remediation.
Humans are predominately exposed to white spirit through the
inhalation of vapour. The general population is exposed during the
domestic use of paints and lacquers containing white spirit. Mean
exposure concentrations during amateur painting have not been
estimated but would be expected to be similar to those encountered by
professionals. Exposure concentrations for humans in recently painted
rooms would be expected to be lower, but no estimated values are
available. Occupationally exposed humans would be exposed to similar
concentrations during house painting. Spray-painting could lead to
higher exposures and exposure to aerosols. An 8-h average exposure
level of 150-240 mg/m3 has been estimated for painters in ventilated
rooms. Peak concentrations in closed or poorly ventilated rooms may
be as high as 6200 mg/m3, particularly at high temperatures.
Vehicle washers using products containing white spirit showed
measured time-weighted average (TWA) exposures ranging from 5 to
465 mg/m3 for automobiles and 45 to 805 mg/m3 for heavy vehicles.
TWA measurements of between 90 and 210 mg/m3 were made in dry
cleaning plants using white spirit (Stoddard solvent). The highest
reported exposure concentration was for workers in airline hangars,
with a short-term value of up to 8860 mg/m3.
1.5 Kinetics and metabolism
White spirit vapour is readily absorbed by inhalation. In humans
59% of the aliphatic and alicyclic hydrocarbons and 70% of the
aromatic hydrocarbons were absorbed at a white spirit vapour level of
1000 mg/m3. The hydrocarbons are distributed from blood to other
tissues, and a human fat:blood partition coefficient of 47 has been
calculated. White spirit is widely distributed throughout the body in
humans. Experiments performed with single hydrocarbon exposure to
rats revealed higher brain:blood partition ratios for aliphatics and
alicyclics than for aromatic hydrocarbons.
White spirit is eliminated from the blood in a biphasic manner
after exposure. After an initial and very short distribution phase
with rapid elimination from the blood, a long phase with a
considerably slower elimination (half-life of about 46 h) follows.
Thus, white spirit has been detected in blood 66 h after a single
inhalation exposure. The half-life in adipose tissue has been
estimated to be 46-48 h.
Only sparse data on elimination and metabolism of white spirit
exist, but urinary excretion of metabolites and elimination of parent
compounds through expiration have been demonstrated in humans.
1.6 Effects on laboratory animals and in vitro systems
White spirit possesses low acute toxicity for mammals. Thus an
LC50 for rats was not achieved with 8-h exposure to 8200 mg/m3
(1400 ppm). In a group of four cats, all were killed at 10 000 mg/m3
(vapour and aerosols). The general signs were irritation, loss of
coordination, tremor and clonic spasms. No mortality was found after
oral administration (gavage) of 5000 mg/kg to rats. In rabbits loss
of appetite and hypoactivity followed a single dermal exposure of
2000-3000 mg/kg, and death occurred in 1 out of 16 exposed animals.
In skin irritation tests white spirit was determined to be a
slight to moderate irritant.
In short- and long-term toxicity studies on white spirit, the
central nervous system (CNS), respiratory system, liver and kidney
were generally found to be the target of white spirit toxicity.
Irritation of the respiratory tract has been observed following
inhalation exposure, and histopathological signs from irritation have
been observed in rats exposed nose-only to 4-h exposures for 4 days at
214 mg/m3.
Guinea-pigs were the most sensitive of five species tested with
long-term exposure. There was increased mortality following 90 days
of continuous exposure to levels of 363 mg/m3 or more. During
postmortem examinations pulmonary irritation was found.
Rats exposed to 4800 mg/m3, 8 h daily, for 26 weeks exhibited
reduced nerve conduction velocity in the tail axon. Neurobehavioural
tests indicated only mild effects and only immediately after a daily
exposure.
Rats exposed to 2290 and 4580 mg/m3, 6 h daily, for 3 weeks or 6
months were found to develop increases in the levels of catecholamines
and serotonin in the brain and reduced protein content in synaptosomes
isolated from the animals. No effects were noted in neurobehavioural
tests.
Neurophysiological recordings have shown changes in sensory
evoked potentials in the brain of rats measured 2 months after a
6-month period of exposure to either 2339 or 4679 mg/m3 (400 or
800 ppm) of dearomatized white spirit. Three weeks of exposure to
this solvent also resulted in increased levels of reactive oxygen
species in brain tissue from the rats.
In several inhalation studies, male rats developed the so-called
"alpha2-microglobulin nephropathy".
Repeated dermal exposure of rabbits caused reduction in weight
gain and liver toxicity at dose levels of 2000 mg/kg, given 3 times
weekly for 4 weeks.
There have been three developmental toxicity studies, all of
which reported essentially negative findings. However, insufficient
data are available for a comprehensive assessment.
White spirit was not found to be genotoxic in assays using
Salmonella typhimurium and Saccharomyces cerevisiae, a mouse
lymphoma mutation assay, mouse and rat bone marrow cytogenic tests,
and rodent (rat and mouse) dominant lethal tests.
No carcinogenicity studies have been performed with experimental
animals exposed to white spirit. Related heavier and lighter refinery
distillation streams such as kerosene, straight-run and light
straight-run naphtha have induced skin tumours in mice after 80 weeks
of skin application.
1.7 Effects on humans
The odour threshold of white spirit is quite low, and vapours can
be detected at levels of 0.5-5 mg/m3. Tolerance of the odour may be
developed.
Eye irritation has been reported in connection with acute
exposure down to a level of 600 mg/m3 (100 ppm). At higher levels
respiratory irritation and more pronounced eye irritation occur.
Acute CNS symptoms such as headache, "drunkenness", dizziness and
fatigue have been reported in several cases of occupational exposure.
Controlled 7-h exposure to levels of 600 mg/m3 or more resulted
in impaired balance during walking and to an increased reaction time.
Exposure to 4000 mg/m3 for 50 min resulted in impaired performance in
tests for perceptual speed and short-term memory.
One case of cyanosis, apnoea and cardiac arrest after excessive
inhalation exposure during painting has been reported.
Ingestion of white spirit has been reported to produce
gastrointestinal irritation with pain, vomiting and diarrhoea.
Lesions of the mucous membranes in the oesophagus and the
gastrointestinal tract followed the oral exposure.
Owing to its low viscosity and low surface tension, white spirit
poses a risk of aspiration into the lungs following oral exposure. A
few ml of solvent aspirated into the lungs are able to produce serious
bronchopneumonia and 10-30 ml may be fatal.
Prolonged dermal exposure to white spirit, e.g., resulting from
wearing clothes that have been soaked or moistened by white spirit for
hours, may produce irritation and dermatitis.
Single cases of acute toxicity to the kidney, liver and bone
marrow have been reported following exposure to white spirit at high
levels. However, owing to lack of details and the sporadic nature of
the reportings, the relevance of these findings is unclear.
There have been few reports concerning the haematological or
biochemical effects of white spirit. However, clinical studies reveal
decreased erythrocyte, leukocyte and platelet counts, and increased
mean corpuscular volume in exposed workers. Similar haematological
changes have been observed in animal studies. There are no consistent
serum biochemical changes; reduced aspartate aminotransferase and
lactate dehydrogenase activity and elevated creatinine kinase activity
have been observed.
Numerous epidemiological studies have been performed involving
painters with long-term exposure to white spirit. Increased incidence
of complaints of memory impairment, fatigue, impaired concentration,
irritability, dizziness, headache, anxiety and apathy have been
demonstrated in several cross-sectional studies. Studies including
neuropsychological tests have shown impaired ability in performing
some of the tests. In some studies an overall reduction in cognitive
functioning was noted to a degree that corresponded to a diagnosis of
chronic toxic encephalopathy (see section 8.2.1). In a few studies a
dose-response relationship was established. This was the case in a
comprehensive study in which painters predominantly exposed to white
spirit were compared with non-exposed bricklayers. Painters with low
solvent exposure were comparable to non-exposed bricklayers with
regard to neuropsychological test results. However, the prevalence of
impaired functioning increased with increasing exposure in the groups
of painters with medium and high exposure.
Similar complaints and neuropsychological test results, although
more severe, were reported from clinical studies in which painters
predominantly exposed to white spirit had been referred to
occupational medical clinics for detailed examinations because of
health complaints and suspected chronic toxic encephalopathy due to
the long-term solvent exposure.
In case-control studies, increased odds ratios for the award of
disability pension because of mental disturbances were found for
painters compared to other occupational groups not exposed to white
spirit or other solvents.
Several case-control studies have shown a high risk of
glomerulonephritis among painters. Even though cross-sectional
studies using early markers of nephropathy were inconclusive, they are
consistent with the hypothesis that painters have an increased risk of
glomerulonephritis and renal dysfunction.
Several minor studies concerning reproductive effects in humans
have been undertaken. In one of the most extensive studies,
reproductive parameters were compared between members of a union for
painters and members of a union for electricians. No firm conclusion
in this or in the other studies could be drawn as no significant
differences occurred. Nevertheless, there is a suggestion that
parental exposure to solvents may have an untoward effect on the
offspring. However, there is no adequately reported information
directly related to white spirit.
Few epidemiological studies of cancer in humans exposed solely to
white spirit are available. Increased risks of respiratory,
pancreatic and kidney cancer have been reported in three studies on
dry cleaners where white spirit was the predominant cleaning solvent.
For painters, an occupational group widely exposed to white spirit,
evidence has been found of increased cancer risks, particularly in the
lung and bladder.
There was no increase in sister-chromatid exchange in a group of
painters with long-term solvent exposure. However, there were some
small increases in cytogenetic damage in a small number of humans
exposed mainly to petroleum vapours.
1.8 Effects on other organisms in the laboratory and field
Few studies on the toxicity of white spirit to organisms other
than laboratory mammals have been reported.
Reports of inhibitory effects on growth of the fungus
Aspergillus niger have been made, although concentrations of the
white spirit in the growth medium were difficult to assess. No
effects were found on mycorrhizal fungi in a single study. Increased
oxygen uptake by excised plant root tips has been reported; the
significance of this finding is doubtful for actual exposure in the
field.
The few studies on the aquatic toxicity of white spirit and
related hydrocarbon mixtures indicate moderate toxicity to freshwater
and marine organisms. The toxicity is probably due to the dissolved
fraction and leads to 96-h LC50 values of the order of 0.5 to
5.0 mg/litre.
These results are likely to overestimate the effects of white
spirit in the field, given its volatility and lowered bioavailability
following sorption to soil/sediment.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
Appraisal
White spirit is a petrochemical solvent containing mainly C7
to C12 aliphatic, alicyclic and aromatic hydrocarbons with a
boiling range of 130-220°C. Different qualities exist and are
defined according to different kinds of treatment (hydro-
desulfurization, solvent extraction and hydrogenation) or
according to their boiling range or flash-point. The ordinary and
most widely used quality of white spirit contains 80-85% (by weight)
aliphatic and alicyclic alkanes and 15-20% (by weight) aromatic
hydrocarbons. This quality is denoted as white spirit type 1 in
Europe and Stoddard solvent in the USA.
2.1 Identity
White spirit is a mixture of saturated aliphatic and alicyclic
C7-C12 hydrocarbons with a maximum content of 25% of C7-C12 alkyl
aromatic hydrocarbons (Henriksen, 1980).
Molecular formulae: CnH2n+2 ( n-alkanes and isoalkanes)
CnH2n (cycloalkanes)a
CnH2n-6 (aromatics), n>6
Relative molecular 150 (approximate average value)
mass: 92-170 (for single constituents)
(CEFIC, 1989)
Common synonyms: Lacknafta (Sweden); Lakkibensiini (Finland);
Mineral Spirit; Mineral Turpentine; Mineralsk
Terpentin (Denmark); Mineralterpentin
(Sweden); Petroleum Spirits; Solvent Naphtha;
Stoddard Solvent; Terpentin (Denmark);
Testbenzin (Germany), Turpentine Substitute
(Henriksen, 1977; Hass & Prior, 1986; IARC,
1989a).
Common trade name: B.A.S.; C.A.S.; Clairsol; Dilutine; Exxsol;
Halpasol; Hydrosol; Indusol; Sane;
Kristalloel; Laws; Ragia; Solfina; Sangajol;
Shellsol; Solfina; Solnap; Solvesso;
Spezialbenzin; Spirdane; Spraysol; Stoddard
Solvent; Supersol; Terpentina; Tetrasol;
Thersol; Varnolene; Varsol; W.S.; White
Spirit (CEFIC, 1989; IARC, 1989a).
a Aliphatic alkanes are also known as "paraffins", while
"naphthenes" is a commonly used term for cycloalkanes.
CAS registry number: 8052-41-3 (Stoddard solvent);
64742-82-1 (white spirit type 1);
64741-92-0 (white spirit type 2);
64742-48-9 (white spirit type 3);
64742-88-7 (white spirit type 0)
(CEFIC, 1989)
EINECS number: 232-489-3 (Stoddard solvent);
265-185-4 (white spirit type 1);
265-095-5 (white spirit type 2);
265-150-3 (white spirit type 3);
265-191-7 (white spirit type 0)
(CEFIC, 1989)
2.1.1 Technical specifications
The content of white spirit can vary, because of differences in
the raw material (crude oil) and in the production processes. The
different kinds of white spirit are defined according to physico-
chemical properties rather than exact chemical composition. The
specifications for white spirit in different countries are listed in
Table 2.
White spirit is a complex mixture containing mainly C7-C12
hydrocarbons with a boiling range of 130-220°C. The various types are
produced as distillation fractions from naphtha and kerosene
components of crude petroleum. The composition of the various types
of white spirit depends on the production process.
Type Description Aromatics Benzene
(% by weight) (% by weight)
1 hydrodesulfurized < 25 < 0.1
2 solvent extracted < 5 < 0.02
3 hydrogenated (hydrotreated) < 1 < 0.002
White spirit types 1, 2 and 3 are defined as follows (CEFIC,
1989):
Type 1: Naphtha (petroleum), hydrodesulfurized heavy
A complex combination of hydrocarbons obtained from a
catalytic hydrodesulfurization process. It consists of
hydrocarbons having carbon numbers predominantly in the 7-12
range and boiling in the range of approximately 90 to 230°C
(194 to 446°F).
Table 2. Specifications for white spirit in selected countries and internationally (from: IARC, 1989a)
Country, product and Distillation Flash-point Kauri-butanol Sulfur content Colour Aromatic content
specification reference IBP/FBPa (°C) (°C) value (min/max) (% by weight) (Saybolt) (% by volume)
Germany
Testbenzine (white spirit) 130 min/ 21 min - - +20 max (Hazen -
(DIN 51632) 220 max colour number)
United Kingdom
Mineral solvent (white spirit, approx. 130/ above 32 - - not darker than < 25
type A) (BS 245: 1976) 220 max standard colour
solution
Mineral solvent (white spirit, approx. 130/ above 32 - - not darker than 25-50
type B) (BS 245: 1976) 220 max standard colour
solution
USA
Mineral spirit type 1 - regular 149 min/ 38 min 29/45 -c +25 min -
(Stoddard solution) 208 max
(ASTM D235-83)b
International standard
Mineral solvent for paint (technically identical to BS 245: 1976)
- white spirit, etc. (ISO 1250)
a IBP = initial boiling point; FBP = final boiling point
b Also includes specifications for high flash-point (60 °C min), odourless (Kauri-butanol value, 29 max) and low dry-point (185 max)
types of mineral spirit
c Bromine number, max 5
Type 2: Naphtha (petroleum), solvent-refined heavy
A complex combination of hydrocarbons obtained as the
raffinate from a solvent extraction process. It consists
predominantly of aliphatic hydrocarbons having carbon
numbers predominantly in the 7-12 range and boiling in the
range of approximately 90 to 230°C (194 to 446°F).
Type 3: Naphtha (petroleum), hydrotreated heavy
A complex combination of hydrocarbons obtained by treating a
petroleum fraction with hydrogen in the presence of a
catalyst. It consists of hydrocarbons having carbon numbers
predominantly in the 6-13 range and boiling in the range of
approximately 65 to 230°C (149 to 446°F).
The naphtha and kerosene fractions from crude petroleum are first
subjected to hydrodesulfurization, followed by fractional distillation
into the appropriate boiling ranges. In the case of type 3 white
spirit, hydrogenation (treatment with hydrogen over a catalyst, also
termed hydrotreatment) is carried out on the fraction of hydro-
desulfurized white spirit. The sequence of fractionation and hydro-
genation may be reversed.
Hydrogenation converts the unsaturated aromatics into saturated
cycloalkanes. Consequently, hydrogenated white spirit contains
straight- and branched-chain aliphatics ( n- and iso-alkanes), a
relatively large fraction of cycloalkanes (naphthenes) and practically
no aromatics.
White spirit that has not been treated beyond the process of
distillation is termed straight-run white spirit (type 0). Stoddard
solvent is a USA term for white spirit which corresponds to a type 1,
hydrodesulfurized solvent. Types 1, 2 and 3 are further divided into
three technical grades which are defined by flash point (see also
section 2.2).
- "low flash" white spirit, flash point 21-30°C
boiling point 130-144°C
- "regular flash" white spirit flash point 31-54°C
boiling point 145-174°C
- "high flash" white spirit flash point > 55°C
boiling point 175-200°C
2.1.2 Chemical composition
The chemical composition of white spirit depends on the type
and grade (for the distinction between different grades see section
2.2). However, the traditional white spirit type 1, regular grade has
a complex but a well-defined chemical content. Tables 3 and 4 present
overall results from analytical analysis of white spirit type 1,
regular grade from different parts of the world.
Table 3. Content of aliphatic and cyclic alkanes in white spirit
Molecular size North European white spirita USA white spirit (Stoddard solvent)b
alkanes monocyclic alkanes dicyclic alkanes alkanes monocyclic alkanes dicyclic alkanes
(% w/w)c (% w/w) (% w/w) (% v/v) (% v/v) (% v/v)
C6 - 0.01 - - - -
C7 0.10 (0.064) 0.17 - - 2.4 -
C8 0.88 (0.58) 1.4 - 0.9 4.3 -
C9 10 (7.4) 8.7 1.7 9.5 5.0 2.7
C10 17 (11) 11 3.5 21 8.4 4.7
C11 8.4 (4.0) 3.8 3.2 13 5.0 3.2
C12 0.58 (0.58) 0.65 0.46 3.4 1.0 1.0
C6-C12 37 (23) 26 8.9 48 26 12
C6-C12 total alkanes total alkanes 85%
72% specified
(+ 12% unspecified)
a Varnolene (boiling range: 162-198 °C), white spirit from the Danish market (Henriksen, 1980)
b Stoddard solvent (boiling range: 152-194 °C), white spirit from the USA market (Carpenter et al., 1975a)
c The values in parentheses indicate the percentage by weight of n-alkanes
Table 4. Aromatic content of white spirit
Molecular Substance Northern Russiab USAc
size Europea (% w/w) (% v/v)
(% w/w)
C6 benzene 0.001 0 0.1
C7 toluene 0.005 0.20 0.4
C8 ethylbenzene 0.2 0.25
o-xylene 0.34 1.2
m-xylene 0.49 2.4
p-xylene 0.22 0.54
total C8 aromatic hydrocarbons 1.3 4.4 1.4
C9 n-propylbenzene 0.97 0.29
isopropylbenzene (cumene) 0.21 0.14
1-methyl-2-ethylbenzene 0.60 0.44
1-methyl-3-ethylbenzene 1.2 1.4
1-methyl-4-ethylbenzene 0.66 0.72
1,2,3-trimethylbenzene (henimellitene) 0.62 0.08
1,2,4-trimethylbenzene (pseudocumene) 2.1 2.5
1,3,5-trimethylbenzene (mesitylene) 0.83 1.6
trans-1-propenylbenzene 0.40 -
total C9 aromatic hydrocarbons 7.6 7.1 7.6
C10 n-butylbenzene 0.97 0.29
isobutylbenzene 0.37 0.44
sec-butylbenzene - 0.08
tert-butylbenzene - 0.25
1-methyl-2-isopropylbenzene (o-cymene) 0.06 0.07
1-methyl-3-isopropylbenzene (m-cymene) 0.47 0.29
1-methyl-4-isopropylbenzene (p-cymene) 0.62 0.70
1,2-diethylbenzene 0.13 -
1,3-diethylbenzene 0.25 0.10
1,4-diethylbenzene 0.13 -
1,2-dimethyl-3-ethylbenzene 0.08 0.06
1,2-dimethyl-4-ethylbenzene 0.25 0.15
1,3-dimethyl-2-ethylbenzene - 0.07
1,3-dimethyl-4-ethylbenzene 0.26 0.15
1,3-dimethyl-5-ethylbenzene 0.38 0.37
1,4-dimethyl-2-ethylbenzene 0.28 0.14
1,2,3,4-tetramethylbenzene (prebnitene) 0.16 0.08
1,2,3,5-tetramethylbenzene (isodurene) 0.14 0.12
Table 4. (Con't)
Molecular Substance Northern Russiab USAc
size Europea (% w/w) (% v/v)
(% w/w)
C10 1,2,4,5-tetramethylbenzene (durene) 0.34 0.08
tetralin 0.08 -
total C10 aromatic hydrocarbons 5.2 4.0 3.7
C11 total C11 aromatic hydrocarbons 1.2 - 0.9
C12 total C12 aromatic hydrocarbons 0.12 - 0.1
- indans + tetralins 0.5
C6-C12 total aromatic hydrocarbons 15.4 15.4 14.7
a Varnolene (boiling range: 162-198°C), white spirit from the Danish market
(Henriksen, 1980)
b White spirit (boiling range: 165-200°C) from the Russian market
(Leont'ev et al., 1974). The values were originally given as percentage by
weight of the total aromatic fraction but were transformed to percentage by
weight of total hydrocarbon fraction by Henriksen (1980)
c White spirit (Stoddard solvent; boiling range: 152-194°C) from the USA market
(Carpenter et al., 1975a)
Tables 3 and 4 show that saturated aliphatic and cyclic
hydrocarbons constitute about 85% of the content of white spirit and
aromatic hydrocarbons about 15% (by weight). Nearly all the
hydrocarbons are in the C7-C12 range. The C9-C11 fractions of
aliphatic and alicyclic hydrocarbons predominate with a total content
of 67-73% of the products, of which half is made up by the C10
fraction. The aromatic fraction is dominated by C9 and C10
isomers, amounting to 7.1-7.6% and 3.7-5.2% of the total content,
respectively.
Henriksen (1980) detected a total of 208 different substances
(87.5% of the content, 12.5% not specified as single compounds) when
analysing a northern European (Danish) white spirit type 1, regular
grade (Varnolene). For a high-flash white spirit (Varsol HF) almost
the same aliphatic/aromatic hydrocarbon distribution was found, but
the dominant fractions were substances with higher relative molecular
mass ( n-decane, n-undecane, n-dodecane and n-tridecane).
For low-flash solvents, higher contents of the more volatile low
molecular weight hydrocarbons are expected. In de-aromatized
solvents, the content of aromatic hydrocarbons has been reduced either
by solvent extraction (removal) or by hydrogenation (catalytic
conversion). The hydrogenated solvents have a higher content of
cycloalkanes as a result of the conversion of aromatic hydrocarbons
(CEFIC, 1989).
It is important to bear in mind that the composition of white
spirit may have changed over the years. Firstly, the content may vary
because of different origins of the crude oil used for the production.
Secondly, the refinery processes that determine the content of the
final products may have undergone changes over the years (see section
3.2).
2.2 Physical and chemical properties
White spirit is a clear, colourless, non-viscous solvent with a
characteristic odour. For each of the three types of white spirit
there exist three different technical grades of white spirit (CEFIC,
1989):
- Low-flash grade
- Regular grade
- High-flash grade
Physical properties of the three different grades are given in Table 5.
The n-octanol/water partition coefficient (log Pow) for white
spirit (17% v/v aromatics) was determined by reverse-phase HPLC to
range from 3.5 to 6.4, indicating a moderate potential for
bioaccumulation (Coveney, 1985).
2.3 Conversion factors
1 ppm white spirit = 5.25-6.0 mg/m3
1 mg/m3 = 0.17-0.19 ppm
(based on the ppm-mg/m3 relationship given in Table 8)
2.4 Analytical methods
Different ways of sampling and different analytical methods may
be utilized for the measurement of white spirit vapour in air.
Trapping of vapour on charcoal tubes is a widely used technique for
the sampling of volatile hydrocarbons, and this method is recommended
by NIOSH for the measurement of the time-weighted average exposure for
naphthas in the occupational environment (NIOSH, 1984).
Table 5. Physical properties of white spirit
Low flash Regular High flash
Initial boiling point (IBP) (°C)a 130-144 145-174 175-200
Final boiling point (°C)a IBP+21,
max. 220
Average relative molecular massa 140 150 160
Relative density (15°C)b 0.765 0.780 0.795
Flash point (°C)a 21-30 31-54 > 55
Vapour pressure (kPa, 20°C)b 1.4 0.6 0.1
Volatility (n-butyl acetate=1)b 0.47 0.15 0.04
Autoignition temperature (°C)b 240 240 230
Explosion limits
(% by volume in air)b 0.6-6.5 0.6-6.5 0.6-8
Vapour density (air=1)c 4.5-5 4.5-5 4.5-5
Refractive index (at 20°C)c 1.41-1.44 1.41-1.44 1.41-1.44
Viscosity (cps, 25°C)c 0.74-1.65 0.74-1.65 0.74-1.65
Solubility
(% by weight in water)c < 0.1 < 0.1 < 0.1
Kauri-butanol valuec 29-33 29-33 29-33
Aniline point (°C)c 60-75 60-75 60-75
Reactivityc react with strong oxidizing agents
Odour threshold (mg/m3)d - 0.5-5 4
a CEFIC (1989); b FDKI (1986); c IARC (1989a);
d Carpenter et al. (1975a,b)
Sampling of air for the measurements of instantaneous
occupational concentrations (e.g., peak concentrations) or
concentrations in expired air (alveolar air) may be performed by the
use of gas pipettes or flexible bags (Aastrand et al., 1975; Cohr &
Stokholm, 1979b).
Analytical measurements in air may be conducted by directly
reading infrared (IR) instruments, which yield quantitative results
for total content of hydrocarbons (Lundberg, 1987). Qualitative
results can be obtained by gas chromatographic (GC) separation of the
sample and detection by flame ionization (FID) or mass spectrometry
(MS) (Aastrand et al., 1975; Carpenter, 1975a,b; Cohr & Stokholm,
1979b; NIOSH, 1984).
Einarsson et al. (1990) have proposed a computerized GC-MS method
for the measurement of white spirit vapour in workplace air and for
the calculation of the hygienic effect from the single hydrocarbon
components.
Various analytical methods are summarized in Table 6.
Table 6. Analytical methods for determining white spirit
Medium Sampling Analytical Range Detection limit Reference
method (recommended or used)
Air charcoal tube, extraction with GC-MS - - Einarsson et al. (1990)
carbon disulfide
Air charcoal tube, extraction with GC-FID 100-2000 mg/m3 - NIOSH (1984)
carbon disulfide approx. 0.5-10 mg/sample
Air charcoal/silica gel, extraction GC-FID - 0.4 µg/sample McDermott (1975)
with hexane
Air gas-tight syringe GC-FID - 0.5 µg/sample Carpenter (1975a)
Air gas-tight syringe GC-FID - 0.025 µg/sample Carpenter et al. (1975b)
Air direct measurement IR - approx. 1 mg/m3 Lundberg (1987)
Alveolar air gas pipette GC-FID 280-1500 mg/m3 - Aastrand et al. (1975)
Blood headspace of sample GC-FID 1-4 mg/kg - Aastrand et al. (1975)
Fat vapours from heated sample GC-FID 10-40 mg/kg - Pedersen et al. (1984)
trapped on charcoal and
extracted with 1,2-dichloroethane
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
White spirit does not occur naturally. However the single
chemical substances in white spirit are present in crude oil.
3.2 Production
An overview of the production of the different types of white
spirit is given in Fig. 1 (IARC, 1989a).
White spirit type 1 (the traditional white spirit) with a content
of up to 25% of aromatics is produced from straight-run naphtha and
straight-run kerosene, which are refinery process streams obtained
from the distillation of crude oil. These fractions are subjected to
fractional distillation into the appropriate boiling ranges of white
spirit (130-220°C). A hydrodesulfurization process (removal of
sulfur) is carried out either before or after the fractional
distillation.
White spirit type 2 is produced by solvent extraction of the
kerosene and naphtha fractions followed by a fractional distillation.
The extraction process for removal of the aromatic hydrocarbons can be
undertaken with sulfolane, sulfur dioxide, or N-methylpyrollidone.
Hydrodesulfurization may occur (CEFIC, 1989; IARC, 1989a).
To obtain white spirit type 3, the ordinary type 1 white spirit
is subjected to hydrogenation (treatment with hydrogen over a
catalyst). The hydrogenation converts the aromatics into saturated
alicyclic hydrocarbons. The hydrogenation process may be performed
before the fractional distillation.
In 1985, the total amount of the various white spirit solvents
produced in the USA was 922 000 tonnes. This was made up of odourless
white spirit (236 000 tonnes), Stoddard solvent (324 000 tonnes) and
140 Flash solvent (362 000 tonnes) (IARC, 1989a).
3.3 Uses
White spirit is used as an extraction solvent, as a cleaning
solvent, as a degreasing solvent, and as a solvent in aerosols,
paints, wood preservatives, asphalt products, lacquers and varnishes.
In western Europe about 60% of the total white spirit consumption is
used in paints, lacquers and varnishes; white spirit is the most
widely used solvent in the paint industry (IARC, 1989a; CEC, 1990).
About 45% of the white spirit sold in the USA in 1985 was used in the
paint and coating industry. The total amount sold was 717 000 tonnes
of white spirit (IARC, 1989a).
In some countries white spirit in paint has been replaced by
other kinds of solvents in recent years. In Denmark the professional
use of paint containing white spirit has been regulated.
A trend towards higher consumption of hydrogenated white spirit
can be seen from the consumption pattern in Europe (Table 7).
Table 7. Consumption of white spirit in western Europe in thousands
of tonnes (IARC, 1989a)
Type 1972 1986
Type 1 (hydrodesulfurized) 670 540
Type 2 (solvent extracted) 30 40
Type 3 (hydrogenated) 50 120
Total 750 700
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
White spirit (Stoddard solvent) may be released to the
environment during its use as a solvent in dry-cleaning plants or as
an industrial degreasing agent (ATSDR, 1993). It may also enter water
or soil as a result of storage leaks (Schmitt et al., 1991) or spills
during use or transportation (ATSDR, 1993).
There are few data specific to the transport and transformation
of Stoddard solvent in the soil/groundwater systems. However, the
environmental transport and transformation of white spirit (Stoddard
solvent) constituents will depend on the physico-chemical and
biological properties of the constituents. Some constituents dissolve
more quickly in percolating groundwater and are sorbed less strongly
onto soils, thus being transported more rapidly, and may or may not be
susceptible to degradation (USAF, 1989).
4.1 Transport and distribution between media
The lower molecular weight alkanes and aromatics tend to
volatilize and undergo photodegradation in the atmosphere. The higher
molecular weight alkanes and cycloalkanes tend to be sorbed to organic
matter in soil or water. The lower molecular weight alkanes may also
be sorbed in to organic matter if volatilization is not rapid (ATSDR,
1993). Jones & McGugan (1978) studied the evaporation of white spirit
from a shallow pool (1 m2 in area) and a waste site (0.5 m deep;
1 m2 in area). The more volatile components evaporated rapidly from
the pool, volatilization decreasing over the first 10 to 20 min. The
linear release rate for the less volatile components was 0.29 kg/m2
per h. The initial release rate from the waste site was much higher
than from the pool; however, the rate in the waste site had fallen to
less than that of the pool within 3 h. The subsequent release rate
was 0.105 kg/m2 per h based on nonane.
The primary pathway of concern from the soil/groundwater system
is the contamination of groundwater resulting from large spills of
white spirit (Stoddard solvent) or leaking underground storage tanks.
The vapour from leaked or spilled solvent may diffuse through soil.
Spills of white spirit would result in the evaporative loss of the
more highly volatile components; the fraction remaining in the soil
would be expected to be relatively mobile and moderately persistent.
In deep soil and groundwater the persistence may be higher. The
downward migration of weathered surface spills and subsurface
discharges represent a potential threat to underlying groundwater.
Large surface spills or subsurface discharges may result in a separate
organic phase on the surface of the groundwater. Migration of the
organic phase may be very different from that of the groundwater
itself (USAF, 1989).
Schmitt et al. (1991) reported soil and soil water contamination
by white spirit from underground storage tanks. The highest
concentrations in the soil (3500 mg/kg) and in soil water
(500 mg/litre) were found immediately below the site of the tanks.
4.2 Transformation
4.2.1 Biodegradation
Biodegradation is expected to be the primary fate process for
white spirit (Stoddard solvent) in soil and water. The rate and
extent of biodegradation are dependent on the ambient temperature, the
presence of a sufficient number of microorganisms capable of
metabolizing the hydrocarbons and the concentration of white spirit in
or on the soil or water (ATSDR, 1993).
Biodegradation of C7 to C12 hydrocarbons is expected to be
significant under environmental conditions favourable to microbial
oxidation. Naturally occurring hydrocarbon-degrading microorganisms
have been isolated from polluted soil and, to a lesser extent,
non-polluted soil (USAF, 1989).
Stone & Watkinson (1982) conducted two tests for ready
biodegradability of low aromatic white spirit (no details of
composition given) using OECD test guidelines 301B and 301D. The
formula of the white spirit was considered as C10H22 (relative
molecular mass, 142), leading to a theoretical oxygen demand of 3.49
mg oxygen per mg and a theoretical carbon dioxide evolution of 3.10 mg
CO2 per mg. The white spirit was degraded by 55-63% in the Stum test
(guideline 301B) and 12-13% in the closed bottle test (guideline
301D). Neither test was ideally suited to the white spirit. The
Strum test results were probably conservative, owing to the volatility
of the test substance. Low dispersion-limiting organism-substrate
interaction was considered to be the cause of the low result in the
Closed Bottle test. White spirit was considered to be readily
degradable.
Schmitt et al. (1991) studied the bioremediation of a site
contaminated with white spirit (Stoddard solvent) (up to 3500 mg/kg
soil) from an underground storage facility. The authors reported 99%
removal of white spirit by biological treatment to a concentration
below the limit of detection within 4 months.
4.2.2 Abiotic degradation
The low water solubility and moderate vapour pressure of white
spirit (Stoddard solvent) suggest that volatilization and subsequent
photooxidation are important processes for abiotic degradation in the
atmosphere (USAF, 1989).
4.2.3 Bioaccumulation
The octanol/water partition coefficient (log Pow) of white
spirit (17% v/v aromatics) has been found to be 3.5 to 6.4 (section
2.2). This indicates a moderate potential for bioaccumulation by
organisms from water and a likelihood of partitioning to fat within
organisms. The sorption to soil/sediment in the environment will tend
to reduce bioavailability and, therefore, uptake of white spirit
components. There are no studies quantifying bioconcentration factors
for white spirit. No information is available on the bioconcentration
of white spirit directly. However, organisms have been found to
accumulate the hydrocarbons present in fuel oils, some of which occur
in white spirit (ATSDR, 1993).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
The detection of white spirit (Stoddard solvent) in soil and
water requires collection of a representative field sample and
laboratory analysis for the specific major components. However, the
relative concentrations of the white spirit constituents will vary
with time and distance from the site of initial contamination.
Therefore, there are few data specifically related to environmental
levels.
5.1.1 Air
White spirit is not monitored in air as a hydrocarbon mixture,
but its volatile components (low molecular weight alkanes and
aromatics) are monitored (ATSDR, 1993).
5.1.2 Water
There is little information regarding the levels of white spirit
as a hydrocarbon mixture in surface or groundwater. Many monitoring
studies have revealed the hydrocarbon constituents of white spirit;
however, it is unclear whether these resulted from white spirit
release or that of any other hydrocarbon mixture or compound (ATSDR,
1993). Schmitt et al. (1991) measured white spirit levels in soil
water at a site contaminated by underground storage tanks in 1987. A
concentration of 500 mg/litre was detected immediately below the site
of the tanks, but the contamination was localized and no solvent had
migrated off-site.
5.1.3 Soil
There have been few monitoring studies for white spirit as a
hydrocarbon mixture in soil (ATSDR, 1993). Schmitt et al. (1991)
monitored a site contaminated with white spirit from underground
storage tanks and found levels of up to 3500 mg/kg in the immediate
vicinity of the storage tanks. However, the lateral extent of soil
contamination was rather limited. Levels of up to 2200 mg/kg were
measured in the vicinity of the underground pipes which connected the
tanks to a former dry-cleaning facility.
5.1.4 Waste sites
White spirit has been identified in at least 7 of the 1300
hazardous waste sites on the US EPA National Priorities List (NPL).
However, it is not known whether there have been releases to the
environment from these sites (ATSDR, 1993).
5.2 General population exposure
A major part of the manufactured white spirit is released to the
air, owing to its extended use as a solvent and as the volatile
ingredient in paints, varnishes and lacquers. Henriksen (1977)
estimated that, out of a total consumption in Denmark of
236 000 tonnes in 1975, more than 15 000 tonnes (> 63% of the
consumption) might have been emitted into the atmosphere.
The general population may be regularly exposed to white spirit,
because of its extensive use in lacquers, paints and cleaning
solvents. People who do home maintenance work or a lot of hobby work
may be particularly exposed via inhalation of vapour or skin contact
with the solvent. Exposure peak concentrations can be very high if
there is a lack of occupational protection equipment, inadequate
ventilation or little attention towards the possible danger of
chemical exposure. However, the total life exposure from these
activities will usually be much lower than for people occupationally
exposed to white spirit. Section 5.3 includes descriptions of some
situations in which exposure levels of white spirit have been measured
during painting.
5.3 Occupational exposure
5.3.1 Considerations concerning vapour exposure
The components of white spirit do not all have the same
volatility, and so white spirit vapour does not have the same
composition as the solvent. Both the gaseous phase and the liquid
phase change during volatilization because of rapid evaporation of the
most volatile components and slower evaporation of the less volatile
ones. An exception to this is flash evaporation from a hot surface in
which the total liquid phase is evaporated instantaneously. Thus the
evaporation rate and the composition of the gaseous phase depend on
temperature, air pressure, diffusion and convection properties.
Aerosols formed during work will increase the surface area of the
liquid and increase the evaporation rate (Hass & Prior, 1986).
5.3.2 Exposure levels
Cohr & Stokholm (1979b) investigated the working conditions of
14 house painters during 19 days of work. Air samples from the
inhalation zone collected on charcoal tubes revealed a geometric mean
exposure level of 929 mg/m3 white spirit vapour. The paint work was
mainly done by rolling or spraying. In 24 out of 30 samples the
levels exceeded 600 mg/m3. Short-term peak exposures estimated from
air samples collected on gas pipettes while paint was being sprayed
showed a geometric mean of 4038 mg/m3 (95-100% of the total organic
volatile compounds was estimated to be white spirit).
Hansen (1988) measured the exposure level in the inhalation zone
during paint work done by brush in six different but realistic
everyday scenarios. The conditions varied with respect to the painted
area, ventilation, room volume, temperature, etc. The white spirit
vapour levels in the different scenarios ranged from 270 to
6140 mg/m3.
Riala et al. (1984) measured the exposure resulting from indoor
house painting at 92 work situations in 18 different buildings. They
found that the exposure from alkyd paint (white spirit content of
30-50%) varied greatly depending on the actual situation. Thus the
exposure level correlated with the amount of paint used (i.e. treated
surface area), the volume of the room and the ventilation rate. An
average exposure level of 1260 mg/m3 (210 ppm) was found from
painting of large surfaces (21 samples), while an average value of
210 mg/m3 (35 ppm) was found from painting of small surfaces
(14 samples). From these measurements and from questionnaires
answered by 231 painters, it was estimated that the yearly inhalation
dose in the 1960s and early 1970s for an average painter amounted to
0.53 kg of white spirit, corresponding to a daily 8-h continuous level
of 240 mg/m3 (40 ppm). However, painters working after 1977 were
found to have been exposed to a somewhat lower yearly level of 0.32 kg
of white spirit, corresponding to a daily 8-h level of 150 mg/m3
(25 ppm).
Gill et al. (1991a) investigated the concentration of white
spirit vapour in the breathing zone of one person engaged in domestic
painting in 25 inside and 6 outside different painting scenarios. Two
paint products were applied by brush and contained white spirit
concentrations of 23.5% and 32%. Time-weighted average exposure
levels of 18-136 mg/m3 (3.1-23.7 ppm) and 37-372 mg/m3
(6.4-65.1 ppm) were measured for the outdoor and the indoor scenarios.
Car washers using spray liquid containing white spirit were
exposed to time-weighted average levels ranging from 5 to 465 mg white
spirit/m3 during the washing of automobiles and from 45 to 805 mg/m3
during the washing of heavy vehicles. The study covered a total of 11
washes, and 97 charcoal air samples from 27 workers were analysed.
Both ordinary white spirit (type 1; boiling range 145-200°C) and
high-flash white spirit (boiling range: 185-200°C) were used (Niemelä
et al., 1987).
Oberg (1968) measured the level of white spirit (Stoddard
solvent) at 30 different dry-cleaning plants in Detroit City. The
cleaning plants utilized Stoddard solvent 105, -120 or -140
(respective flash points of 40°C, 49°C and 60°C). Peak exposures of
1500-4500 mg/m3 (250-750 ppm) were measured during the cleaning cycle
at the plants using the most volatile solvent, while peak exposures at
plants using Stoddard solvent -140 never exceeded 1200 mg/m3
(200 ppm). The 8-h average exposures on ordinary working days were
calculated to be 210 mg/m3 (35 ppm), 150 mg/m3 (25 ppm) and
90 mg/m3 (15 ppm) in plants using Stoddard solvent 105, -120, or
-140, respectively.
NIOSH has made several surveys of white spirit (Stoddard
solvent/mineral spirit) in various occupational environments. The
following levels have been determined in samples taken in the
breathing zone of workers: maintenance painters, 33-761 mg/m3 (NIOSH,
1973); workers in airline hangars, 363-8860 mg/m3 (NIOSH, 1975a);
workers inn screen cleaning processes, 137-385 mg/m3 (NIOSH, 1975b);
workers at a washing machine for automobile parts, 43-594 mg/m3
(NIOSH, 1975c); manufacture of catapult cylinders, 2615 mg/m3
(spraying solvent), and up to 275 mg/m3 for painting operations
(NIOSH, 1975d); ski boots finishing, 345-451 mg/m3 (NIOSH, 1975e);
telephone cable assembly, 79-244 mg/m3 (NIOSH, 1980).
5.3.3 Exposure limit values
Threshold limit values (TLV) for white spirit (Stoddard solvent)
in various countries are given in Table 8.
Table 8. Occupational exposure limits for white spirit
Country Threshold Limit Value
(time-weighted average)
(mg/m3) (ppm)
Australiaa 790 -
Belgiuma 525 100
Canadab 525 100
Denmarkc 145 25
Netherlandsb 575 100
Norwayd, (< 22% aromatics) 275 50
(> 22% aromatics) 120 25
Swedena, (petroleum spirit) 300 50
United Kingdome 575 100
(short term, 15 min) 720 125
USA (ACGIH)a 525 100
a ILO (1991)
b IRPTC (1991)
c Directorate of National Labour Inspection Service (1994)
d Norwegian Labour Inspection Service (1991)
e UK Health and Safety Executive (1994)
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
Appraisal
Since white spirit is a mixture of many chemicals, the study
of the toxicokinetics is complex. Generally speaking, the relative
percentage of the single compounds and their different physical and
chemical properties greatly affect the toxicokinetics of white
spirit. White spirit is readily absorbed following inhalation
exposure. The inhalation absorption of white spirit depends on
several factors including concentration in the inspired air, blood
partition coefficient, pulmonary ventilation and pulmonary blood
flow. White spirit is widely distributed throughout the body in
humans. Studies in rats indicate that white spirit is distributed
in brain, kidney, liver and fat. Aromatic components are generally
more soluble in blood than aliphatic and alicyclic hydrocarbon
components. Biotransformation of white spirit occurs, although no
adequate information on white spirit metabolism is available. White
spirit is mainly excreted in urine and partly in expired air.
6.1 Absorption
6.1.1 Inhalation
6.1.1.1 Human exposure
Aastrand et al. (1975) showed that white spirit is readily
absorbed by inhalation. Human volunteers were exposed for 30 min
during rest or during exercise to 1250 and 2500 mg/m3 of white spirit
(boiling range, 150-200°C; 83% aliphatics and alicyclics, 17%
aromatics). At the end of the exposure period the concentration of
aliphatics and aromatics in alveolar air was found to be about 25% and
15%, respectively, of the concentration in the inspired air. With
exposure during exercise (load of 50 watts, corresponding to light
work), the pulmonary ventilation tripled and the concentrations of the
aliphatics and the aromatics in the alveolar air increased to about
50% and 20%, respectively, of the concentrations in the inspired air.
However, the total amount of retained vapour was considerably
increased because of the three-fold rise in pulmonary ventilation.
Measurements of the concentrations in venous and arterial blood were
found to reflect the exposure level quite well. Thus the amount in
blood doubled as the exposure level doubled. Exposure to 1250 mg/m3
during hard exercise (load of 150 watts) resulted in a seven-fold rise
in pulmonary ventilation, an increase in aliphatics in venous blood
from 1.3 mg/kg (rest level) to 5.4 mg/kg, and an increase in aromatics
from 0.2 to 2.6 mg/kg. The total uptake over a period of 30 min was
measured in one subject during exposure to 1000, 1250, 1500 and
2000 mg/m3 white spirit vapour. Of the total amount of the inspired
aliphatic fraction, 59% was retained at the lowest and 46% at the
highest level. The uptake of the aromatics was found to be 70% at
the lowest level and 58% at the highest. (The quantitative
analytical determinations were carried out on n-decane and
1,2,4-trimethylbenzene as markers for the aliphatic and the aromatic
fractions, respectively).
Similar experiments and findings were reported by Stokholm & Cohr
(1979b) in a study including 21 human volunteers. They noted rapid
changes in the concentration of white spirit (17% aromatic
hydrocarbons) in alveolar air if the exposure concentration or the
pulmonary ventilation changed. Steady state in alveolar air was
obtained after 20 min of exposure at rest and after 1´ h during work.
The aromatic fraction reached steady state in alveolar air earlier
than the aliphatic fraction. In nine students exposed to 204, 600,
1200 and 2400 mg/m3 (34, 100, 200 and 400 ppm) (corresponding to
aliphatic/aromatic levels (in mg/m3) of 172/36, 508/104, 990/203 and
1934/398), the alveolar air at steady state contained 31.6-33.6% of
the aliphatic exposure levels while the alveolar contents of aromatics
were 8.2-11.5% of the aromatic exposure levels. Thus, no great
differences were seen in retention at the different exposure levels.
After 7 h of exposure to the above-mentioned levels the concentrations
in blood of aliphatics/aromatics were found to be 0.74/0.12,
2.30/0.40, 4.07/0.91 and 9.07/2.01 mg/litre, respectively. Steady
state in blood was not achieved in these experiments. (The aliphatic
fraction was analysed by gas chromatography as a "total aliphatic
fraction", whereas the aromatic fraction was calculated on the basis
of analytical determination of 1,2,4-trimethylbenzene, which was
chosen to represent the aromatic fraction).
A minor accumulation of white spirit in blood was found after
5 days of exposure (6 h/day) to 600 mg/m3 (100 ppm) of white spirit
(99% aliphatics). The mean concentration of white spirit in blood
of seven volunteers increased from 2.00 mg/litre on day 1 to
2.54 mg/litre on day 5 (Pedersen et al., 1984).
Pedersen & Cohr (1984a) exposed 12 volunteers to a vapour
concentration of 600 mg/m3 (100 ppm) of three different types of
white spirit for 6 h. For two of the solvents, the concentration in
blood at the end of the exposure reached mean values of 3.1 and
3.2 mg/litre. These solvents consisted of 57% aliphatics, 25%
alicyclics plus 17.9% aromatics, and 52% aliphatics plus 47.9%
alicyclics, respectively. A significantly (p < 0.001) lower mean
value of 2.3 mg/litre was obtained after exposure to the third solvent
containing 98.9% aliphatic alkanes (38.7% C11 isomers and 44.4% C12
isomers) and 1.1% cycloalkanes.
Pedersen et al. (1987) exposed eight volunteers to 600 mg/m3
(100 ppm) of white spirit (98.9% aliphatic alkanes (83.1% C11-C12
isomers) and 1.09% cycloalkanes) for 3 h and seven volunteers to
600 mg/m3, 6 h/day for 5 days. The total amount of white spirit
absorbed in blood was calculated to be 392 ± 38 mg after 3 h of
exposure and 3464 ± 329 mg after 5 lots 6 h of exposure.
Gill et al. (1991b) reported an uptake of 55-60% in four
volunteers exposed to 575 mg/m3 (100 ppm) during periods of about
4 h. The uptake for each person was determined 4-6 times throughout
the exposure period and was calculated as the percentage reduction in
the white spirit concentration between the inspired and the expired
air. At the end of the exposure period, the level of white spirit in
the blood of the four volunteers was 1.37-1.60 mg/litre. (The white
spirit, Carless 100F, was reported to be a typical white spirit).
6.1.1.2 Related hydrocarbon exposure in animals
Dahl et al. (1988) examined the uptake of 19 different C3-C9
hydrocarbons in nose-only exposure experiments with rats. The uptake
was determined by measuring the vapour concentration in the inlet and
outlet airstreams. The uptakes for rats exposed to 100 ppm of each of
the C7 to C9 hydrocarbons are listed in Table 9.
Table 9. Uptake of inhaled hydrocarbon vapour
(in nmol×kg-1×min-1×ppm-1)
C7 C8
n-heptane 4.5 n-octane 6.6
2,3-dimethylpentane 4.1 2,3,4-trimethylpentane 5.0
tetramethylbutane 1.8
C9
n-nonane 9.2
1,2,4-trimethylbenzene 13.6
The animals were pre-exposed for 1 h before measurement of uptake
in a 10-min period. Each value is the mean value for two sets of
experiments each with two rats exposed 5 times (i.e. 2 × (2 × 5)
determinations). The heptane value was only based on 2 × 5
determinations.
The values from Table 9 fit into the overall pattern of C3-C9
hydrocarbon exposures: a) highly volatile hydrocarbons are less well
absorbed than less volatile ones; b) unsaturated hydrocarbons (i.e.
alkenes and aromatics) are absorbed to a greater extent than saturated
ones; c) branched hydrocarbons are less well absorbed than linear
ones; d) for the n-alkane series, uptake increases with increasing
molecular size. In experiments at exposure levels in the range of
1-5000 ppm it was noted that no saturation of uptake occurred in the
1-100 ppm range for any of the substances. To achieve uptake
saturation for most of the substances it was necessary to use exposure
levels of 1000 or 5000 ppm (Dahl et al., 1988).
6.1.2 Dermal exposure
No quantitative data are available with respect to absorption of
white spirit through human skin.
In rats dermal absorption in the tail was observed after exposure
to three different kinds of white spirit (Verkkala et al., 1984). A
skin area of 12 cm2 was exposed for 3 h (dose not specified). Five
animals were used for each experiment. The total absorbed doses of
the three products were: A) 260 ± 80 mg; B) 210 ± 40 mg; and C)
240 ± 20 mg. The three kinds of white spirit consisted of: A: 60.0%
aliphatics, 39.7% alicyclics and 0.3% aromatics; B: 61.0% aliphatics,
27.3% alicyclics and 11.7% aromatics; C: 83% aliphatics alicyclics
(31.8% C11-C13 isomers) and 17% aromatics.
From in vitro experiments performed with rat skin it was
concluded that skin permeation for a variety of hydrocarbons
correlates directly with the water solubility of the substances
(Tsuruta, 1982). Thus it was found that the more water-soluble
aromatic compounds were absorbed through skin to a considerably
greater extent than the less water-soluble aliphatic compounds. The
penetration of o-xylene was 800 times higher than that of octane.
6.1.3 Oral exposure
There are no quantitative data available on the extent of
gastrointestinal absorption following ingestion of white spirit.
6.2 Distribution
6.2.1 Human exposure
The in vitro Cblood/Cair partition coefficient for white spirit
(17% aromatics) was determined to be 23 for the aliphatic fraction and
87 for the aromatic fraction (incubation for 2 h at 37°C) (Cohr &
Stokholm, 1979a).
In the study by Aastrand et al. (1975), the in vivo blood/air
partition coefficients never exceeded 10 with respect to the aliphatic
fraction or 50 with respect to the aromatic fraction (calculated by
Hass & Prior, 1986). (It should be noted, however, that these
in vivo calculations were based on data where equilibrium between
the concentrations in alveolar air and in blood was not achieved).
Distribution of white spirit to adipose tissue has been
demonstrated by Pedersen et al. (1984, 1987). Seven volunteers were
exposed to 600 mg/m3 (100 ppm) of white spirit (99% aliphatics)
6 h/day for 5 days. The concentration of white spirit was determined
in biopsies from adipose tissue, in venous blood and in alveolar air
immediately after each exposure and up to 66 h after the last
exposure. The level of white spirit in adipose tissue gradually rose
(after the last exposure on day 5) to a value of 41 mg/kg fat, but had
declined to 32 mg/kg fat 66 h later. From a mathematical fit using a
three-compartment model and the data from blood and fat measurements,
a fat:blood partition coefficient of 47 was calculated. The
redistribution phase was estimated to be 20 h and the half-life of
white spirit in adipose tissue was calculated to be 46-48 h. From
these data white spirit maximum and minimum steady-state fat
concentrations of 55 and 35 mg/kg, respectively, were calculated in
the case of occupational exposure to 600 mg/m3 (100 ppm) (maximum
level: Friday afternoon; minimum level: Monday morning). Finally,
steady-state maximum and steady-state minimum brain concentrations of
5 and 0.6 mg/kg, respectively, were estimated.
6.2.2 Animal exposure
Lam et al. (1992) exposed rats to 0, 2290 or 4580 mg/m3 (0,
400 or 800 ppm) of white spirit (20% v/v aromatics) for 6 h/day,
5 days/week, for 3 weeks. The total aromatic hydrocarbon fraction
concentration in the brain at the high exposure level was about twice
the concentration at 2290 mg/m3 (1.54 and 0.73 mg/kg), whereas the
concentration in brain of the total aliphatic fraction at 4580 mg/m3
exceeded the 2290 mg/m3 level by more than three times (8.65 and
2.39 mg/kg). The authors concluded that accumulation may occur during
long-term exposure to high levels of aliphatic hydrocarbons.
6.2.3 Exposure to related hydrocarbons
Experiments conducted with exposure to different single
hydrocarbons have shed light on the differences in distribution
pattern between aliphatic, alicyclic and aromatic hydrocarbons.
Zahlsen et al. (1990) exposed Sprague-Dawley rats to 1000 ppm of
one of three C9 compounds ( n-nonane, 1,2,4-trimethylbenzene and
1,2,4-trimethylcyclohexane) for 12 h daily during 14 days. The
concentrations of the three compounds in blood, brain and fat were
measured during the period. From these measurements brain/blood and
fat/blood partition coefficients (concentration ratios) were
calculated (see Table 10). (An approximate blood/air partition
coefficient is 4.3 for n-nonane, 3.3 for 1,2,4-trimethylcyclohexane
and 14.3 for 1,2,4-trimethylbenzene, when the concentration in blood
on day 1 is divided by the vapour concentration in air).
The remarkably high distribution of n-nonane and 1,2,4-tri-
methylcyclohexane to the brain is probably due to differences in
biological affinity and solubility or to different metabolic rates
in the tissues.
Eide (1990) exposed rats to nine different C8-C12 hydrocarbons
at 100 ppm, 12 h each day for 3 days. After the last exposure, blood
and brain samples were immediately taken for analysis. Table 11 shows
that while the aliphatic content in blood increased together with
increasing molecular size from n-octane to n-dodecane the
concentration in brain only increased from n-octane to n-decane
and thereafter declined from n-decane to n-dodecane.
When the aliphatic, alicyclic and aromatic hydrocarbons were
compared, it was noted that although the aromatics produced the
highest concentrations in blood they were found in the lowest
concentration in brain. For the alicyclic and aliphatic hydrocarbons,
lower values in blood and remarkably higher values in brain were
detected, especially for the alicyclic hydrocarbons.
Similar studies made by Zahlsen et al. (1992), using 15 different
C6 to C10 hydrocarbons, confirmed the above findings of differences
in distribution between aliphatic, alicyclic and aromatic hydro-
carbons. In these studies concentrations were determined in the
blood, brain, liver, kidney and fat on days 1, 2 and 3 of exposure and
following 12 h of recovery after the last exposure (Table 12).
For the n-alkanes it was noted that accumulation in fat
occurred during the 3-day exposure period. For the aromatic
substances the content in fat peaked on day one and was remarkably
reduced after the next two days of exposure. Overall, the alicyclics
were most extensively distributed from blood to other tissues.
6.3 Metabolic transformation
Very little is known about the metabolic fate of white spirit,
since metabolic studies have most frequently been conducted with
single hydrocarbons and not with hydrocarbon mixtures. Consequently
it is difficult to predict the extent of the metabolic conversion of
single components in a mixture because several factors may influence
the metabolism, e.g., substrate saturation of the metabolizing
enzymes, competition phenomena and enhancement or inhibition of enzyme
systems.
Table 10. Brain/blood and fat/blood partition coefficientsa
Compound Concentration ratio Blood concentrationb
brain/blood µmol/litre
n-nonane 11.4 90
1,2,4-trimethylcyclohexane 11.4 60
1,2,4-trimethylbenzene 2.0 280
fat/blood µmol/litre
n-nonane 113 90
1,2,4-trimethylcyclohexane 135 60
1,2,4-trimethylbenzene 63 280
a The partition coefficients were calculated after a 12-h daily
exposure to 1000 ppm on day 14 of the exposure period.
b The blood concentrations have been read from the graphs made by
Zahlsen et al. (1990).
Table 11. Concentrations of C8-C12 hydrocarbons in blood and brain
of rats (µmol/kg)
Substance Brain Blood
Aliphatics
n-octane 25.2 3.6
n-nonane 54.5 4.1
n-decane 60.2 6.8
n-undecane 47.7 13.7
n-dodecane 12.5 17.4
Alicyclics
1,2-dimethylcyclohexane 83.9 6.2
1,2,4-trimethylcyclohexane 84.9 6.9
Aromatics
1,2-dimethylbenzene 28.6 10.3
1,2,4-trimethylbenzene 36.5 17.1
Concentrations were determined for each substance after the animals
had been exposed to 100 ppm of the substances 12 h daily for 3 days.
Table 12. Distribution of C8-C10 hydrocarbons in rat tissuea
n-octane 1,2-dimethylcyclohexane o-xylene
n-nonane 1,2,4-trimethylcyclohexane 1,2,4-trimethylbenzene
n-decane tert-butylcyclohexane tert-butylbenzene
Blood 3.6 6.2 10.3
4.1 6.9 17.1
6.8 12.9 15.5
Brain 25.2 83.9 28.6
54.5 84.9 36.5
60.2 60.2 38.7
Liver 8.4 78.0 22.4
13.0 42.4 35.4
45.9 21.9 47.0
Kidney 41.9 162.2 (20.8) 95.2
45.2 349.7 (43.3) 103.6
77.7 261.5 (84.4) 256.6 (27.9)
Fat 697 (308) 1640 (730) 1228 (71)
1022 (577) 1476 (647) 1070 (120)
1230 (952) 1363 (825) 1171 (320)
a Concentration are given in µmol/kg (mean value from four animals).
The animals were exposed to 100 ppm of the substances 12 h daily
for 3 days. Values in parentheses are from animals that had a 12-h
recovery period after the last exposure.
The aliphatic hydrocarbons are known to undergo oxidative
conversion, catalysed by monooxygenases, to alcohols. The cytochrome
P-450-dependent monooxygenases, located mainly in the endoplasmatic
reticulum of liver cells, are responsible for this first metabolic
transition.
For n-alkanes with a carbon chain length of 7 or less, the
predominant oxidation to alcohol occurs at the penultimate carbon
(omega-1 oxidation) resulting in secondary mono- or dialcohols. For
the higher n-alkanes, only oxidation at the terminal carbon has been
observed (omega-oxidation). Branched isomers of the alkanes are
mainly oxidized at the omega or omega-1 position yielding either
secondary or tertiary alcohols (Scheline, 1978; Sipes & Gandolfi,
1986).
The monocyclic and polycyclic alkanes (such as cyclohexane and
decalin) are mainly oxidized at the CH2-groups in the ring structure
(Longacre, 1987).
After this primary conversion, conjugation of the hydroxy group
to glucuronic acid or sulfate may occur. For some substances further
oxidation to aldehyde/ketone or carboxylic acid by other enzyme
systems takes place. Thus 2,5-hexanedione and octanoic acids can be
obtained from 2,5-hexanediol and isomers of 1-octanol. The fatty
acids formed from the n-alkanes can be degraded by ß-oxidation
(Sipes & Gandolfi, 1986; Low et al., 1987; Graham et al., 1987).
The first step of alkylbenzene metabolism is generally oxidation
to alcohol at the alkyl moiety in the molecule by the cytochrome P-450
enzyme system. To a lesser extent, direct hydroxylation of the
aromatic structure occurs. The hydroxy group is then conjugated to
glucuronic acid or sulfate, or is oxidized further to ketone/aldehyde
or carboxylic acid, which may then be conjugated to glucuronic acid,
sulfate or glycine (Antti-Poika et al., 1987; Riihimäki & Hänninen,
1987; Engström et al., 1987; Lee, 1987; Laham, 1987; Longacre, 1987).
During oxidation of benzene and naphthalene (or other
polyaromatic hydrocarbons), intermediary arene oxides (epoxides) may
be formed by cytochrome P-450. During further hydration and
oxidation, the aromatic nature of the ring or the ring structure
itself may be broken. In the case of benzene, the very reactive
benzoquinones can be formed (Snyder, 1987; Franklin, 1987).
6.4 Elimination and excretion
Absorbed white spirit vapour is to some extent eliminated by the
lungs. Stokholm & Cohr (1979b) measured the concentration of
aliphatics and aromatics in the alveolar air of six volunteers during
and after 7 h of exposure to either 300 or 600 mg/m3 (50 or 100 ppm)
white spirit (17% aromatics). Ten minutes after exposure had ceased,
the expiratory concentration levels of aliphatics and aromatics were
found to be about 12% of the initial exposure level for both
fractions. Sixteen hours later, the levels in expiratory air had
fallen to 2% (aliphatics) and 4% (aromatics) of the initial exposure
level.
Pedersen et al. (1987) measured the concentration of white spirit
in blood after a single 3-h exposure and repeated daily 6-h exposures
to 600 mg/m3 (100 ppm) white spirit (99% aliphatics, 1% cyclic
aliphatics). After exposure had stopped there was a short phase with
rapid elimination from blood resulting from distribution to other
tissues. This phase was followed by a long phase with a rather slow
elimination and a half-life of 46 h (see Fig. 2). The half-life of
white spirit in adipose tissue was calculated to be 46-48 h (see also
the description in section 6.2).
Gill et al. (1991b) found that white spirit was rapidly cleared
from the blood stream in four volunteers. White spirit levels of
1.37-1.60 mg/litre blood were reached after 4 h exposure to 575 mg/m3
(100 ppm). Forty minutes after the exposure had stopped, the level in
the blood had declined below the detection limit of 0.5 mg/litre.
(The white spirit used, Carless 100F, was reported to be a typical
white spirit).
Pfäffli et al. (1985) analysed urine from car washers exposed to
white spirit containing 11% aromatics (the exposure levels were
determined and described by Niemelä et al. (1987), see section 5.3).
The authors found that the amount of dimethylbenzoic acid isomers in
the urine was linearly related to the exposure. These acids are known
to be formed by the oxidation of trimethylbenzenes, which in this case
were present in white spirit to the extent of approximately 1%.
Most of the information concerning the elimination and excretion
of aliphatic and aromatic hydrocarbons has derived from studies
involving exposure to single substances. These studies indicate that
the aromatics are mainly excreted in the urine as metabolites. More
than 80% of the absorbed amount of toluene, xylene, ethylbenzene,
1,2,4-trimethylbenzene and tetralin has been found as metabolites in
urine. Lower aromatics with high vapour pressure (and low blood/air
partition coefficient) are, to a small extent, excreted unchanged in
expired air. Thus about 5% of the absorbed amount of xylene was found
to be expired in humans and about 9% of absorbed ethylbenzene was
found to be expired in the rat. With exposure to higher aromatics,
such as 1-methyl-4-isopropylbenzene, the amount excreted in expired
air seems to be minute (Antti-Poika et al., 1987; Riihimäki &
Hänninen, 1987; Engström et al., 1987; Laham, 1987; Longacre, 1987;
Lee, 1987).
There are very few quantitative data for aliphatics and cyclic
aliphatics concerning the different elimination routes. Because of
higher vapour pressure and lower blood/air partition coefficient, the
lower aliphatics and cyclic aliphatics are eliminated in expired air
to a greater extent than the aromatics. Thus 25-35% of absorbed
cyclohexane and 15% of absorbed methylcyclohexane has been found
in expired air from rabbits. In addition, n-hexane and
2,2,4-trimethylpentane are reported to be eliminated by exhalation.
The greater part of the absorbed amount of the aliphatic compounds is
excreted as metabolites in the urine, but volatile metabolites may be
expired to some extent (Longacre, 1987; Graham et al., 1987; Low et
al., 1987).
7. EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 Inhalation
7.1.1.1 White spirit
The acute toxicity of white spirit in inhalation studies is
summarized in Table 13.
Table 13. Acute toxicity of white spirit in inhalation studies
Species Sex Exposure Effects Reference
Rat male/ > 14 000 mg/m3, restlessness, Coombs et al.
female 4 h no deaths (1977)
Rat male 8200 mg/m3, LCLOW Carpenter et
8 h al. (1975a)
Rat male 10 000 mg/m3 LCLOW Carpenter et
(aerosols), 8 h al. (1975b)
Rat male/ 5500 mg/m3, no deaths, API (1987a)
female 4 h languid behaviour
Cat 10 000 mg/m3, LC100 tremor, clonic Carpenter et
7.5 h convulsions al. (1975a)
Dog 8000 mg/m3, 8 h tremor, clonic Carpenter et
spasms, irritation al. (1975a)
Because of low acute toxicity, LC50 values for rats exposed to
white spirit could not be determined (Carpenter et al., 1975a,b; API,
1987a). Groups of 15-16 male Harlan-Wistar rats (age approximately 5
weeks) were exposed for 8 h to 2400 mg/m3 (420 ppm), 4600 mg/m3
(800 ppm) and 8200 mg/m3 (1400 ppm) of white spirit (Stoddard
solvent) (48% aliphatics, 38% cyclic aliphatics, 14% aromatics) and to
10 000 mg/m3, 5000 mg/m3, 2500 mg/m3, 1250 mg/m3 and 500 mg/m3
of a dearomatized white spirit (140° Flash Aliphatic Solvent: a "high
flash" white spirit which has a flash point of 60°C (140°F) and which
contains 61% aliphatics, 36% cyclic aliphatics, 3% aromatics). Out of
15 rats one died following high exposure to Stoddard solvent. Symptoms
such as slight loss of coordination, eye irritation and bloody exudate
from the nostrils were reported. Rats exposed to Stoddard solvent
(2400 mg/m3) did not show any sign of toxicity during exposure or
during the 14 days of follow-up. There were two deaths among the 16
animals exposed to 10 000 mg/m3 of 140° Flash Aliphatic Solvent
(owing to condensation a vapour concentration of 2900 mg/m3 was
measured). Animals exposed to this level exhibited slight loss of
coordination and irritation of the skin. At 500 mg/m3 (270 mg/m3
measured) no toxic effects were noted (Carpenter et al., 1975a,b).
In another acute inhalation study, five Sprague-Dawley rats of
each sex were exposed to 5500 mg/m3 of white spirit (Stoddard
solvent) vapour (boiling range, 160-199°C; 14.5% aromatics) for 4 h.
All animals survived; clinical signs included languid behaviour and
squinted eyes (API, 1987a).
Four cats exposed to 10 000 mg/m3 (1700 ppm) of white spirit
(Stoddard solvent) died during the 7.5 h of exposure. The animals
developed decreased reactivity to light, tremor and clonic
convulsions. A dog exposed to 8000 mg/m3 (1400 ppm) of Stoddard
solvent for 8 h suffered from eye irritation, increased salivation,
tremors and clonic spasms. At 4000 mg/m3 (700 ppm) no sign of
toxicity was noted (Carpenter, 1975a).
Four cats exposed to 10 000 mg/m3 (combination of vapours and
aerosols) of 140° Flash Aliphatic Solvent did not show any sign of
poisoning, but a dog exposed to 1700 mg/m3 for 8 h exhibited
lacrimation (Carpenter et al., 1975b).
7.1.1.2 Exposure to related hydrocarbons
Ten female Harlan-Wistar rats were exposed for 8 h to an aerosol
concentration (droplet size < 1 µm) of 8700 mg/m3 of High Aromatic
Solvent (96% of C9-C11 aromatic hydrocarbons), which contained, in
general, the same aromatic hydrocarbons as white spirit. Progressive
signs of distress developed: nasal and ocular irritation, salivation,
redness of extremities, loss of coordination, prostration, tremor,
convulsions and anaesthesia. Two animals died but the others recovered
during the following 4 days. Exposure to vapour at a calculated level
of 6300 mg/m3 (2000 mg/m3 measured) did not induce any adverse
effect (Carpenter et al., 1977a).
Carpenter et al. (1977b) estimated a 4-h LC50 value of
5300 mg/m3 (969 ppm) as a result of studies on Harlan-Wistar rats
exposed to High Naphthenic Solvent (boiling range, 157-183°C; 29%
aliphatics, 70% cyclic aliphatics, 1% aromatics). The toxic signs
were nasal irritation, salivation, loss of coordination, tonic
convulsions, tremors and death. The lowest exposure level with lethal
outcome was 3600 mg/m3 (650 ppm).
Inhalation studies involving various fractions of hydrocarbons
have been conducted by Hine & Zuidema (1970). Groups of Long-Evans
male rats were exposed for 4 h to 10 different hydrocarbon test
samples. Six samples contained aliphatic and alicyclic alkanes
covering the range from C6 to C14, and four samples contained
aromatic hydrocarbons in the C8-C14 range. Among the aliphatic and
alicyclic samples, the sample containing C9-C10 alkanes was the most
toxic, the LC50 value being 2000-2600 ppm. The LC50 for the aromatic
C8 sample was found to be 6350 ppm. LC50 values for the other
aromatic samples were not obtained because of the lack of lethal
effect of saturated or nearly saturated vapour.
Nilsen et al. (1988) estimated a LC50 value of 23 400 mg/m3
(4467 ppm) for n-nonane in an inhalation study with male
Sprague-Dawley rats. Ataxia, general and focal seizures and spasms
were observed. Pulmonary oedema and liver congestion were found in
the dead animals. At an exposure level of 23 400 mg/m3 remarkable
loss of Purkinje cells in the cerebellum was found in six surviving
animals, in contrast to the situation in four animals dying from the
exposure. No sedative or narcotic effects were observed. Eight hours
of exposure to n-decane, n-undecane, n-dodecane and n-tridecane
at vapour saturation level (7950 mg/m3 (1369 ppm), 2820 mg/m3
(442 ppm), 990 mg/m3 (142 ppm) and 310 mg/m3 (41 ppm)) did not cause
lethal or adverse behavioural effects.
7.1.2 Oral exposure
No deaths and no toxic signs were reported following acute oral
dosing of male and female rats with 1, 2, 4 or 8 mg/kg body weight of
low aromatic white spirit (17% aromatics; boiling range, 157-198°C)
(Coombs et al., 1977).
Five Sprague-Dawley rats of each sex were administered 5.0 g/kg
of white spirit (Stoddard solvent; 14.5% aromatics) by oral gavage. No
deaths occurred during the 14 days of observation. Hypoactivity and
ataxia were noted in five animals (API, 1986a).
7.1.3 Dermal exposure
Four New Zealand White rabbits of each sex were exposed for 24 h
with a bandage containing doses of 2.0 or 3.0 g/kg body weight of
white spirit (Stoddard solvent) (14.5% aromatics). The exposed area,
which measured about 10% of the body surface, was shaved before
exposure and the skin of two animals in each dose group was abraded.
All animals exhibited loss of appetite and hypoactivity on the first
day after exposure. At the lowest dose level thickening and redness
of the skin developed. One low-dose female with skin abrasion died
three days after exposure (API, 1986a).
Hine & Zuidema (1970) tested rabbits with 10 different fractions
of C6-C14 hydrocarbons by dermal application. Three animals per
group and exposures of 2 and 5 ml/kg for 4 h were used. Exposure to
5 ml/kg of four aromatic samples covering the C8-C14 range all
resulted in one death. Exposure to six solvents consisting of
aliphatic and cyclic aliphatic alkanes did not cause lethal effects,
except exposure to 5 ml/kg of a C11-C12 solvent, which caused one
death.
7.1.4 Aspiration
Aspiration to the lung of non-viscous hydrocarbon solvent
resulted in deaths in a series of animal experiments in which a
wide range of single hydrocarbons were tested. In these tests
anaesthetized male Wistar rats (2-5 animals per group) were
manipulated to aspirate 0.2 ml of a solvent consisting of alkanes (C6
to C14), cycloalkanes (C5 to C12), aromatics (C6 to C18) or
various mixtures of hydrocarbons (gasoline, oil of turpentine, dry
cleaning solvent, kerosene, diesel oil). Rapid death (within a few
seconds) due to asphyxia was produced by the most volatile
hydrocarbons, whereas slower death (over a period of several hours)
due to pulmonary oedema, bleeding and respiratory distress was caused
by the least volatile solvents (Gerarde & Linden, 1963).
7.2 Short-term and long-term exposure
7.2.1 Inhalation
7.2.1.1 White spirit
In short- and long-term inhalation toxicity studies on white
spirits, the respiratory system, haematopoietic system, liver and
kidney were generally the toxicity targets.
Rector et al. (1966) exposed Long-Evans and Sprague-Dawley
rats (14-18 animals of both sexes in each group), guinea-pigs
(14-59 animals per group), New Zealand albino rabbits (3-5 animals per
group), squirrel monkeys (3 animals per group) and beagle dogs
(2 animals per group) for 90 days to continuous levels of white spirit
(boiling range, 140-190°C; 80-86% aliphatics and cyclic alkanes, 1%
alkenes, 13-19% aromatics). Nine different exposure levels in the
range of 114-1271 mg/m3 were used. A significant increase in
mortality was seen in guinea-pigs at exposure levels of 363 mg/m3 or
more. No increased mortality was found in the other animal species.
No signs of toxicity during the exposure were noted, except for
occasional slight diarrhoea and nasal discharge in guinea-pigs. At
autopsy, irritation and congestion of the lung were commonly observed
in all species. The severity of lung irritation appeared to be
dose-related and congestion in general appeared in animals exposed to
1271 mg/m3. Histopathological examination of the liver revealed mild
to moderate vacuolar changes of the hepatic cells in guinea-pigs
exposed to 363 mg/m3 or more. However, no clear dose-related trend
was found. Occasional changes in leukocyte counts in dogs, rabbits
and guinea-pigs were not judged to exceed normal variations. No
significant exposure-related effects were observed with respect to
weight gain, pathology, or haematological and biochemical parameters.
Jenkins et al. (1971) exposed guinea-pigs to white spirit
(19-20% aromatics; 892 mg/m3) for 90 days and found similar effects
in the liver to those reported by Rector et al. (1966).
Carpenter et al. (1975a) exposed groups of 25 male Harlan-Wistar
rats and 4 beagle dogs to white spirit (Stoddard solvent) vapour at
levels of 0 mg/m3, 480 mg/m3 (84 ppm), 1100 mg/m3 (190 ppm) and
1900 mg/m3 (330 ppm) (boiling range, 152-194°C; 47.7% aliphatics,
37.6% cyclic aliphatics, 14.7% aromatics) for a period of 13 weeks
(6 h/day, 5 days/week). Histopathological lesions of the kidneys and
dilated tubules were found in 6 out of 9 and 3 out of 9 rats exposed
to 1900 and 1100 mg/m3, respectively. These lesions were also noted
in rats killed after only 8 weeks of exposure. Significant, although
not dose-related, changes in haematological values were thought to be
mainly a consequence of the deviant values found in the control group.
No differences were found in weight gain. In dogs no changes were
observed with respect to body and organ weights, haematological and
clinical chemical values or histopathological parameters.
In a similar study with rats and dogs and with considerably lower
exposure levels of dearomatized white spirit vapour (140° Flash
Aliphatic Solvent; 0 mg/m3, 49 mg/m3 (7.8 ppm), 100 mg/m3 (16 ppm)
and 230 mg/m3 (37 ppm)), slight tubular degeneration was noted in 14
out of 35 rats (control plus exposed animals). However, this was not
considered to be due to exposure. There were no other effects on
either rats or dogs, and no exposure-related changes in haematological
or clinical chemical parameters were found (Carpenter et al., 1975b).
Riley et al. (1984) exposed a group of six female rats to white
spirit vapour at a mean concentration level of 214 mg/m3 (boiling
range, 150-195°C; 61% aliphatics, 20% cyclic aliphatics, 19%
aromatics; exposure duration, 4 h/day for 4 consecutive days).
Histological examination of the respiratory tract revealed the
presence of inflammatory cell infiltrate in the nasal cavity, trachea
and larynx, loss of cilia, hyperplasia of mucosa cells and basal
cells, and squamous cell metaplasia.
Blair et al. (1979) conducted an inhalation toxicity study on Low
Aromatic White Spirit (LAWS) in Wistar male and female rats. Groups
of 18 males and 18 females were exposed to LAWS vapour (7500, 4000 and
2000 mg/m3) for 6 h, 5 days/week, for 13 weeks. Body weight, food
and water consumption and clinical observations were recorded every
week. At the end of the study, organ weight, blood chemistry and
haematology parameters and complete histopathological evaluations were
performed. No clinical signs and toxicity were observed except that
the high-dose groups were slightly lethargic when examined 30 min
after cessation of exposure. One exposure to LAWS caused low-grade
anaemia and mild degenerative changes in the kidneys of males at all
exposure levels. In female rats there were dose-related increases in
the liver weight of exposed animals. However, there were no
histopathological lesions observed in the livers of treated animals.
In the kidneys, hyaline droplets were found most frequently in the
proximal tubular epithelium of the outer cortex.
Oestergaard et al. (1993) exposed groups of 30 young (3 months
old) and groups of 14 old (15 months old) male rats to vapour
concentrations of 0, 2290 and 4580 mg/m3 (0, 400 and 800 ppm) of
white spirit (boiling range, 148-200°C; 20 v/v% aromatics). After
exposure for 6 months (6 h/day, 5 days/week) and a follow-up period
without exposure of 4 months, the animals were killed. The animals
showed signs of discomfort during exposure, especially during the
initial exposure period. Mucosal irritation, bloody discharge from
the nose and lacrimation were present. Narcotic effects were
gradually reduced. Although the body weights of the high-dose group
were reduced, this difference disappeared during the follow-up period.
At both exposure levels the rats had a significantly higher water
consumption than controls (only the group of young rats were
monitored). Clinical chemical parameters of the urine were
unaffected, but significant increases were found for plasma urea and
creatinine levels at both exposure levels. Serum alanine
aminotransferase activity was significantly reduced. No macroscopic
or histopathological changes were found at sacrifice, and no
differences in the kidney tubules were noted between exposed and
unexposed rats.
7.2.1.2 Exposure to related hydrocarbons
Nau et al. (1966) exposed groups of 18-38 rats (strain not
specified) to the vapour of a C9-C10 aromatic solvent (boiling
range, 155-200°C; 26 mole% aliphatics plus cyclic aliphatics, 42 mole%
C9 aromatics, 29 mole% C10 aromatics, 3 mole% C11 aromatics) for
18 h/day, 7 days/week for a maximum of 150 days (the C9-C10 aromatic
fraction is by far the most abundant aromatic fraction in white spirit
type 1, which may contain about 15% of these isomers, see section
2.1.2). The exposure levels used were 50, 200, 616 and 1000 ppm.
After the first day at 1000 ppm of exposure the rats developed
congestive changes in the lungs and liver, enlarged spleen and
haemorrhagic kidneys. After day 8, a significant fall in white blood
cell count and a shift in the polymorphonuclear-lymphocyte ratio was
observed. At 616 ppm similar effects were found in connection with
reduced weight gain after a total of 135 days of exposure. Fatty
changes in the liver, stimulation of bone marrow activity, and
haemorrhages around the nose and mouth were further reported at this
level. After 2 months, 70% of a subgroup of rats was affected by
bilateral cataract. A group of rats exposed to 200 ppm for 8 h/day,
5 days/week, for 18 weeks did not show any significant changes in
haematological values, weight gain, bone marrow activity or lens
opacity. Groups of three rhesus monkeys exposed to the vapour at
50 ppm and 200 ppm for 7 h/day, 5 days/week, for 18 weeks developed
changes in haematological parameters with a decrease in white blood
cell count, increase in haematocrit readings and a shift in the
polymorphonuclear-lymphocyte ratio. At 200 ppm, the animals appeared
sedated and "groggy" during exposure.
7.2.2 Dermal exposure
7.2.2.1 White spirit
The shaved intact skin (15 × 20 cm) of groups of 10 New Zealand
White rabbits was exposed to doses of 200, 1000, and 2000 mg/kg of
white spirit (Stoddard solvent). Exposure was carried out using
occlusion bandage for a duration of 6 h and was given 3 times weekly
for 4 weeks. At the highest dose level, there was a significant
reduction in weight gain in both sexes, whereas only the female body
weight gain was reduced at 1000 mg/kg. Changes in haematological
parameters noted at 2000 mg/kg were judged not to be treatment-
related. At 2000 mg/kg, female rabbits developed liver lesions
characterized as white streaks or foci with granular surface (API,
1986b).
7.2.2.2 Exposure to related hydrocarbons
Nau et al. (1966) exposed male C3H mice dermally to 0.10-0.15 g
of a C9-C10 aromatic solvent (for composition see section 7.2.1)
3 times a week for up to 50 weeks. The total dose per mouse was
calculated to be 10.6 g. Increased incidences of histopathological
findings were observed in the exposed group compared to controls.
These consisted of inflammatory reactions, hyperkeratosis and
ulcerations of the skin, inflammatory reactions and focal haemorrhages
of the lung, amyloidosis of the spleen, necrosis of the liver,
cortical scarring and sclerosis of the kidneys. Exposure to
n-decane (total dose 16.3 g per mouse) induced increased incidences
of fibrosis of dermis, pigmentation and ulceration of the skin, and
haemorrhage, pigmentation and inflammation of the kidneys and lungs.
However these responses were judged to be less severe than those found
after exposure to C9-C10 aromatics.
7.3 Irritation; sensitization
Appraisal
White spirit (Stoddard solvent) is judged to be a slight to
severe skin irritant, depending on the duration of exposure and the
animal species used.
7.3.1 Skin irritation
7.3.1.1 White spirit
Guillot et al. (1982) compared three different guidelines for the
testing of irritating properties of 56 chemicals (Official French
guidelines for testing cosmetics, Guidelines from the Association
Française de Normalisation, and OECD guidelines). White spirit
(specified as white spirit, dilutine 5) was judged to be "moderately
irritant" according to the first mentioned guideline, while a
"slightly irritant" score was obtained using the two other sets of
guidelines. In all three tests, a quantity of 0.5 ml was used and an
occlusive dressing was applied. Exposure duration was 23 h for the
first method mentioned and 4 h for the other two methods.
In a test for primary dermal irritation, 0.5 ml of Stoddard
solvent (14.5% aromatics) was applied to the shaved (abraded and
nonabraded) skin of six male New Zealand White rabbits. The exposed
area was covered with an occlusive dressing for 24 h. The exposure
caused moderate to severe erythema and oedema according to the Draize
test after 24 h of skin contact. After 72 h, a primary dermal
irritation index of 4.5 was calculated (API, 1986a).
In a skin irritation test with New Zealand White rabbits exposed
to white spirit (Stoddard solvent), Nethercott et al. (1980) found
only minor signs of irritation and hence calculated an index of 1.55.
The application site was covered with gauze and an elastic bandage for
a duration of 24 h.
Application of 200, 1000 and 2000 mg/kg of white spirit (Stoddard
solvent) to the shaved intact skin (15 × 20 cm2) of 10 New Zealand
White rabbits 3 times a week for 4 weeks resulted in a dose-related
increase in irritation response (Draize testing). Following the
application, the test site was occluded for 6 h with a gauze pad and a
sheet of polyethylene. "Moderate irritation" was observed at the
lowest dose level and "severe irritation" at the highest dose level
(API, 1986b).
Semi-occluded application of undiluted 0.5 ml of Low Aromatic
White Spirits (LAWS 15/20A) to the clipped dorsum (6 cm2) of six New
Zealand white rabbits for 4 h caused moderate irritation and slight
oedema. One inflammatory response had regressed 14 days after the
application (Gardener, 1989).
Anderson et al. (1986) compared the irritating properties of
14 organic solvents in relation to the responses obtained when using
1% and 2% sodium lauryl sulfate aqueous solutions as positive
reference solutions. An area of 1 cm2 of shaved skin on the flanks
of 10 Dunkin Hartley guinea-pigs was exposed to 10 µl of each solvent
3 times daily for 3 days. White spirit and trichloroethylene were
found to be the most potent irritants among the solvents, giving
similar results to the 2% sodium lauryl sulfate solution. The
validation included scoring for macroscopic response, dermal thickness
and the amount of affected dermal cells.
7.3.1.2 Exposure to related hydrocarbons
Hine & Zuidema (1970) tested 10 hydrocarbon solvents (covering
the overall range of C8-C16 hydrocarbons), each containing a narrow
range of components. They found that four aromatic solvents (covering
the range C8-C14) were moderate irritants (according to the Draize
test) after 24 h of skin contact in rabbits (six animals/group with
both intact and abraded application sites). A similar response was
found for a solvent containing C9-C10 aliphatic and alicyclic
alkanes, whereas other alkane solvents containing hydrocarbons outside
the C9-C10 range produced only slight responses. A C13-C16 solvent
was a minimal irritant.
Hoekstra & Phillips (1963) conducted studies with different kinds
of mineral oils and certain purified substances. Guinea-pigs were
dermally exposed by spraying 0.6 ml solvent every second day for a
total of four exposures. In contrast to the above-mentioned study
performed by Hine & Zuidema (1970), the authors found that maximum
skin damage resulted from C14 to C19 alkanes. Purified n-dodecane
and n-tetradecane (which may be present in high amounts in
high-flash white spirits) resulted in score 5 (8 was the highest
irritation score). Effects from lower hydrocarbons were thought to be
caused mainly by defatting and not to be due to directly irritating
properties.
Ingram et al. (1993) studied the effects of a hydrogenated white
spirit/naphtha (boiling range, 134-217°C; 86.8% aliphatic and
cycloaliphatic hydrocarbons; 12.9% aromatics) after application to the
skin of a group of 20 mice three times per week for up to 4 weeks.
From day 7 to day 14 signs of skin irritation, including skin
thickening, cracking and patchy hair loss, were apparent. Microscopic
observations showed epidermal necrosis after 4 days (one day after the
second treatment). From day 7 epidermal necrosis, ulceration, eschar
formation, vesiculation and epidermal hyperplasia were observed,
indicating repeated cycles of necrosis and healing.
7.3.2 Eye irritation
No or only very slight irritation occurred after the application
of 0.1 ml of white spirit (Stoddard solvent; 14.5% aromatics) to the
eyes of six rabbits. One hour after application one of the rabbits
showed mild injection and swelling of the conjunctiva. However, these
signs of irritative response disappeared after 24 h (API, 1986a).
These findings were in agreement with studies conducted by Hine &
Zuidema (1970), who tested various fractions of hydrocarbons in the
C6-C16 range. They found moderate irritative responses in rabbit
eyes exposed to aromatic samples (C8-C11), but minimal responses
after exposure to aliphatic and alicyclic alkanes.
Dogs exposed to a vapour level of 1700 mg/m3 of 140° Flash
Aliphatic Solvent developed signs of eye irritation and lacrimation
(Carpenter et al., 1975b). Eye irritation was also observed in other
experimental animal inhalation studies but usually at higher
concentrations (see section 7.1.1).
7.3.3 Respiratory irritation
Carpenter et al. (1975a) used respiratory depression in mice as
an index of irritative response in the upper respiratory tract. Three
of six male Swiss-Webster mice developed a decline in respiratory
rate (below 50% of the normal rate) during 1 min of exposure to
10 000 mg/m3 (1700 ppm vapour and aerosols) of white spirit (Stoddard
solvent; 15% aromatics). A similar decrease in respiratory rate did
not occur at 4400 mg/m3 (770 ppm).
Exposure to mice of either 350 mg/m3 (56 ppm vapour) or
1200 mg/m3 (vapour plus aerosol) of dearomatized white spirit
(140° Flash Aliphatic Solvent) did not induce respiratory tract
irritation or change in respiratory rate (Carpenter et al., 1975b).
Exposure to an aerosol level of 3200 mg/m3 of "High Aromatic Solvent"
induced a reduction in respiratory rate of more than 50% (Carpenter et
al., 1977a).
7.3.4 Sensitizing properties
White spirit (Stoddard solvent containing 14.5% aromatics) was
found not to be sensitizing in a Buehler test. A 75% (by volume)
solution of white spirit (Stoddard solvent) in a vehicle of paraffin
oil used for the three sensitizing doses was found to induce mild to
moderate irritation. A 25% (by volume) solution was used as a
challenge dose (API, 1986a).
7.4 Other effects
7.4.1 Nephrotoxicity
Phillips & Egan (1984) exposed groups of 35 male and 35 female
Sprague-Dawley rats to the vapour of either dearomatized white spirit
(boiling range, 155-193°C; 58% aliphatics, 42% cyclic aliphatics,
< 0.5% aromatics) or of C10-C11 isoparaffinic hydrocarbon solvent
(boiling range, 156-176°C; 100% isoalkanes mainly in the C10-C11
range). Exposure levels were measured to be 1970 and 5610 mg/m3 for
dearomatized white spirit and 1910 and 5620 mg/m3 for isoparaffinic
hydrocarbon solvent. The exposure period was set at 6 h/day,
5 days/week, for 12 weeks. No deaths occurred and only occasionally
decreased weight gain was noted during exposure of male animals
exposed at the high levels. The male rat kidney was found to be the
main target organ. After 4, 8 and 12 weeks, significant increases in
absolute and relative kidney weights were found in all exposed groups,
but were most striking at the high exposure levels. Histopathological
examination revealed the presence of regenerative epithelium in the
cortex and dilated tubules filled with proteinaceous casts in the
corticomedullary areas of the kidney. The changes were focal in
nature, covering 5-10% of the tubules. These observations were
identical to the effects found when the authors reexamined the kidney
slides from the white spirit study performed by Carpenter et al.
(1975a).
Phillips & Cockrell (1984) more closely examined the renal
effects of white spirit exposure. Sprague-Dawley and Fisher rats were
placed in three groups of 50 animals of each sex per strain. One
group of each strain was exposed to 0, 570 and 4580 mg/m3 (0, 100 and
800 ppm) of white spirit (Stoddard solvent; boiling range, 156-204°C;
55% aliphatics, 27% cyclic aliphatics and 18% aromatics) for 6 h/day,
5 days/week, for 8 weeks. Exposure affected kidney function slightly
in male rats. At the end of the exposure period, dose-related
increases in urine volume (and decreased osmolality) and increased
urinary content of glucose and protein were found. A marked increase
in the number of epithelial cells in the urine was also observed.
Male Fischer rats were more significantly affected than male
Sprague-Dawley rats. The structural changes in the kidneys were
identical to those described in the study of Phillips & Egan (1984)
and were found in animals killed after 4 weeks of exposure. In a
similar study with Fischer rats exposed to C10-C11 isoparaffinic
solvent (boiling range, 156-176°C; mainly C10-C11 aliphatics) at 1830
and 5480 mg/m3 (300 and 900 ppm), electron microscopy of the kidneys
disclosed electron-dense phagolysosomes corresponding to "hyalin
droplets" in the epithelial cells of the proximal convoluted tubules.
This was observed in male rats killed on day 5 of exposure or later.
A group of rats with a recovery period of 4 weeks after exposure
regained normal kidney function, but recovery from the structural
changes in the proximal convoluted tubules and at the corticomedullary
junction was not complete.
Lam et al. (1994) exposed male rats to dearomatized white spirit
(boiling range, 148-200°C; 20% aromatics) vapour concentrations of
0, 2290 or 4580 mg/m3 (0, 400 or 800 ppm). The kidney weights and
the relative kidney weights of the rats exposed to white spirit were
increased compared to the control. In the case of the relative kidney
weight, the changes were dose-dependent.
Carpenter et al. (1977b) found similar histopathological changes
in kidneys of male Harlan-Wistar rats exposed 6 h/day, 5 days/week,
for 13 weeks to levels of 0, 610, 2100 and 5500 mg/m3 (0, 110, 380
and 1000 ppm) of High Naphthenic Solvent (boiling range, 157-183°C;
29% aliphatics, 70% cyclic aliphatics, 1% aromatics).
In a study involving exposure to High Aromatic Solvent, (boiling
range, 184-206°C; > 96% aromatics mainly C9-C11) using levels of
0, 100, 220 and 380 mg/m3 (0, 17, 38 and 66 ppm) and the above-
mentioned duration, slight kidney tubule regeneration appeared in a
dose-related manner (Carpenter et al., 1977a).
Viau et al. (1984) found after 9.5 months of exposure of male
Sprague-Dawley rats (8 h/day, 5 days/week) to 6500 mg/m3 of a
white-spirit-like solvent (99% C10-C12 aliphatics) a significant
decrease (p < 0.001) in urine osmolality. After 10 months of
exposure the animals were dosed with ammonium chloride 2 mmol/kg. The
net acid excretion was determined and found to be significantly
reduced (p < 0.001). Elevated activity of urinary lactate
dehydrogenase was further noted as an indication of distal tubular
dysfunction.
Much research effort has been devoted to elucidating the
nephrotoxic effects of volatile hydrocarbons. Studies with, for
instance, n-decalin, 2,2,4-trimethylpentane, and unleaded gasoline
have revealed similar effects to those described above (Gaworski et
al., 1985; Short et al., 1987; Olson et al., 1987). The effects have
been found to be species- and sex-specific, since they have only been
observed in male rats. More detailed examination of the development
of the pathological events has been performed. In the early phase
after exposure to even very low levels of hydrocarbons (e.g.,
0.04 mg gasoline/kg per day or 28 mg/m3 (5 ppm) of decalin),
lysosomal accumulation of crystalloid protein droplets (hyaline
droplets) occurs in the epithelial cells of the renal proximal
convoluted tubules. Individual cells undergo cytolysis, detach from
the base membrane, and slough into the lumen of the nephron. In
severe cases this may lead to granular casts at the junction of the
thin loop of Henle. Furthermore, the loss of cells at the proximal
convoluted tubules leads to restorative increased cell proliferation
and hyperplasia. The male rat specific protein alpha2-microglobulin
has been observed to accumulate in protein droplets, and the hindered
catabolism of this protein (by coupling to specific hydrocarbons) is
thought to be a crucial point in the initiation of the nephrotoxic
response (Swenberg et al., 1989). However, in an assessment by the US
Environmental Protection Agency (US EPA, 1991) it was concluded that
if a chemical induces alpha2-microglobulin accumulation in male rats,
the associated nephropathy is not used as an end-point for determining
non-carcinogenic hazard.
7.4.2 Neurotoxicity
7.4.2.1 Behavioural effects
Kulig (1989) found minor behavioural changes in male Wistar rats
(8 per group) exposed to white spirit vapour levels of 0, 1200, 2400
and 4800 mg/m3 (0, 200, 400 and 800 ppm) (boiling range, 158-193°C;
44% aliphatics, 36% cyclic aliphatics, 18% aromatics) 8 h/day for
three consecutive days. Before the exposure the rats were trained to
react to a light stimulus on either of two panels and to depress a
lever at the illuminated site to get access to water. Immediately
after the first day of exposure the latency time from stimulus to
reaction was significantly increased in an exposure-related manner.
However, on day 3 the differences in response between the exposed
groups and the control group had almost disappeared. Measurement of
spontaneous activity and motor coordination did not show any
differences between the groups. In a similar study lasting 26 weeks,
the tests were performed at least 10 h after the daily exposure had
ceased. No differences in performance were seen compared to controls
during the 26 weeks of exposure. In week 17, however, the test was
done immediately after the end of the daily exposure and the exposed
groups now had a poorer performance (increased response time)
indicating that an acute effect was still demonstrable. Behavioural
tests designed to measure changes in activity, coordination, grip
strength and discrimination performance did not reveal significant
differences compared to control rats. Measurements of tail nerve
conduction velocity showed significant lower conduction velocities in
rats exposed to 4800 mg/m3.
Oestergaard et al. (1993) examined the behavioural effects of
6 months of white spirit inhalation in adult and old rats. Groups of
male Wistar rats were exposed to 0, 2290 and 4580 mg/m3 (0, 400 and
800 ppm) of white spirit (boiling range, 148-200°C; 80% aliphatic and
cycloaliphatic hydrocarbons, 20% aromatics) 6 h/day, 5 days/week, for
6 months. Neurobehavioural tests were performed after an exposure-
free period of 2 months. No changes were found compared to control
groups with respect to general functional behaviour or performance in
cognitive tests (passive avoidance, eight-arm radial maze, and Morris
maze). The study was performed with groups (36 rats in each group) of
young rats (aged 3 months at the start of exposure) and with groups
(14 rats in each group) of old rats (15 months old at the start of
exposure). No differences were seen between the age groups except in
the case of motor activity, young rats being more active.
Similar behavioural tests were conducted with male Wistar rats
after a recovery period of two months after exposure to 0, 2339 and
4679 mg/m3 (0, 400 and 800 ppm) of white spirit type 3 (boiling
range, 145-200°C; < 0.4% aromatics) 6 h/day, 5 days/weeks, for
6 months. Decreased motor activity during the dark periods was noted,
compared to controls, but no exposure-related effects were noted in
the other behavioural tests (Lund et al., 1996).
7.4.2.2 Neurophysiological and neuromorphological effects
In the above-mentioned study, sensory evoked potentials were
recorded in 8-10 rats from each exposure group after the 2 months of
recovery. The recordings of flash evoked potential, somatosensory
evoked potential and auditory evoked potential all revealed
exposure-related increases in the amplitudes of the early-latency
peaks of the sensory evoked potentials. It was concluded that
exposure to dearomatized white spirit induced long-lasting and
possibly irreversible effects in the nervous system of the rat (Lund
et al., 1996).
Different neurophysiological and morphological changes were found
in the rat tail after percutaneous exposure to different qualities of
white spirit. An area of 12 cm2 on the tail of five male Wistar rats
per group was treated with three different kinds of white spirit 3
h/day, 5 days/week, for 6 weeks. The solvent (dose not specified) was
pipetted onto cotton wool and a occlusive dressing was made around the
tail. The solvents differed mainly in aromatic content (low content
of 0.3% in solvent A) and in the content of n-nonane (low content of
1.9% in solvent C).
A B C
Boiling range (°C) 150-200 152-182 180-230
Aromatics (% by weight) 0.3 11.7 17
n-Nonane (% by weight) 11.3 13.3 1.9a
n-Decane (% by weight) 7.6 10.0 9.1a
a n-alkane plus isomers
Motor conduction velocity in the tail was unchanged after the
exposures, when compared to controls. However, the recorded
electrophysiological response from exposure group A exhibited the
polyphasic nature of the amplitude, the duration being significantly
(p < 0.01) longer than that recorded from the controls. Exposure to
solvent B yielded a significant (p < 0.05) protraction of the
recorded motor response, while no significant effects were noted after
exposure to solvent C. Morphological analysis of the tail nerve
revealed axon swelling and widening of the nodes of Ranvier in animals
exposed to solvents A and B. Demyelinated foci were found in the
axons from animals exposed to solvent C (Verkkala et al., 1983, 1984).
7.4.2.3 Neurochemical effects
Savolainen & Pfäffli (1982) measured enzyme activity in the brain
of male Wistar rats exposed 6 h daily, 5 days/week for 4-17 weeks to
575, 2875 and 5750 mg/m3 (100, 500 and 1000 ppm) white spirit vapour
(boiling range, 152-182°C; 61% aliphatics, 27.3% cyclic aliphatics,
11.7% aromatics). After 8 weeks, a dose-dependent decrease in the
cerebellar succinate dehydrogenase activity was measured and after
12 weeks creatine kinase activity had increased. The latter finding
was assumed to be due to glial cell proliferation as an increase
in the specific activity in the glial cell fraction was not
demonstrated. Furthermore, white spirit was suggested to affect
muscle cell membranes, as sialic acid and uronic acid contents had
decreased in proportion to phospholipids or total membrane protein.
Exposure to 575 mg/m3 for 17 weeks was found to be a virtual
no-effect level.
Edelfors & Ravn-Jonsen (1985, 1992) examined calcium uptake,
ATP-ase activity and membrane fluidity in rat brain synaptosomes. It
was found that calcium uptake in rat brain synaptosomes was affected
after short-term exposure (18 h) to white spirit at 3000 and
6000 mg/m3 (500 and 1000 ppm) (quality of the solvent not specified).
Synaptosome preparations from rats exposed to 3000 mg/m3 showed an
increased calcium uptake compared to control rats, while after
exposure to 6000 mg/m3 the calcium uptake was reduced. Calcium
uptake is known to be affected by anaesthetics altering membrane
fluidity (Edelfors & Ravn-Jonsen, 1985). Ca++/Mg++-ATPase activity
in rat synaptosomes membranes was reduced after 20 min of in vitro
exposure of the preparations to buffers containing a dearomatized
white spirit at 12-50% of the saturation concentration. Membrane
fluidity determined by fluorescence polarization was slightly reduced
due to the exposure (Edelfors & Ravn-Jonsen, 1992).
Lam et al. (1992) found dose-related increases in the contents of
the neurotransmitters noradrenaline, dopamine and 5-hydroxytryptamine
in the whole brain after vapour exposure of male Wistar rats. Groups
of five animals were exposed 6 h/day, 5 days/week, for 3 weeks to
white spirit (boiling range, 148-200°C; 20% aromatics) vapour
concentrations of 0, 2290 or 4580 mg/m3 (0, 400 or 800 ppm). In a
long-term exposure study with an exposure period of 6 months and a
recovery period of 4 months, modified regional neurotransmitter
(noradrenaline, dopamine, 5-hydroxytryptamine) concentrations were
demonstrated. Furthermore, in this study whole brain dopamine and
5-hydroxytryptamine contents were increased. These results indicated
that 6 months of exposure irreversibly affected neurotransmitter
concentrations (Oestergaard et al., 1993).
In another 3-week study involving exposure to 0, 2339 or
4679 mg/m3 (0, 400 or 800 ppm) white spirit (boiling range,
148-200°C; 20% aromatics), the yield of synaptosomal protein per g
brain tissue was reduced (Lam et al., 1995). This finding was
repeated when the exposure was extended to 6 months followed by a
4-month exposure-free period (Lam et al., 1995). It was suggested
that the exposure caused a reduced number of neuronal interconnections
(or a reduced nerve terminal protein content) and that this was
possibly compensated for by the increased neurotransmitter contents
also found in this study. The increased 5-hydroxytryptamine
concentrations were maintained by increased re-uptake rate and storage
capacity. The weight of the brain and the brain protein content were
not affected by the exposure.
Lam et al. (1994) measured the formation of reactive oxygen
species, the level of reduced glutathione, and the activity of
glutamine synthetase in subcellular fractions (P2 fractions) of brain
tissue taken from rats immediately after 3 weeks of in vivo
exposure to dearomatized white spirit vapour (boiling range,
145-200°C; < 0.4% aromatics). The animals (10 male Wistar rats in
each group) were exposed to 0, 2339 or 4679 mg/m3 (0, 400 or 800 ppm)
6 h/day, 7 days/week, for 3 weeks. Dose-related increased levels of
reduced glutathione (GSH) were found in the P2 fractions from the
hemisphere, and an increased rate of generation of reactive oxygen
species was found in hippocampal P2 fractions taken from rats exposed
to 4679 mg/m3 (glutamine synthetase activities were not significantly
affected). Both findings were interpreted as reflecting oxidative
stress in the brain and were comparable to findings reported in other
studies in which similar experiments were conducted with neurotoxic
aromatic solvents.
Bondy et al. (1995) performed a similar study in which groups
of 5- or 14-month-old male Wistar rats were exposed to 0, 2290 or
4580 mg/m3 (0, 400 or 800 ppm) of white spirit (boiling range,
150-220°C; 14-20% aromatics) 6 h/day, 7 days/week, for 3 weeks.
Glutathione concentrations were unchanged in the P2 fractions isolated
from the frontal cortex and hippocampus, indicating no sign of
pro-oxidant events. In the hippocampus, P2 glutamine synthetase
activities were elevated in young (exposed at both concentrations) and
in old rats (exposure to the high dose). From this it was suggested
that glial activation was taking place.
7.4.3 Biochemical effects
7.4.3.1 White spirit
In the above-mentioned study by Lam et al. (1994), dearomatized
white spirit depressed liver P2 glutamine synthetase activity and the
rate of generation of reactive species in the P2 fraction of kidney
when rats were exposed to 4580 mg/m3. These findings suggest an
induction of oxidative stress in these two organs.
Bondy et al. (1995) documented depressed levels of glutathione
and depressed activity of glutamine synthetase in the P2 fraction
of the kidney and liver. In the kidney the levels were only
significantly affected in the groups of aged rats, indicating a higher
degree of vulnerability than in the young rats. The findings were
interpreted as increased pro-oxidant events occurring in both liver
and kidney in rats exposed to white spirit.
7.4.3.2 Exposure to related hydrocarbons
n-Nonane (which together with n-decane is the most abundant
chemical substance in white spirit, with approximately 10% content of
each) has been found to affect liver function in rats. Female albino
rats dosed intraperitoneally with n-octane or n-nonane (1.0 ml/kg)
daily for 2 or 7 days developed a significant increase in relative
liver weight and decreased activities of aniline hydroxylase,
aminopyrine- N-demethylase and glucose-6-phosphatase. Phenobarbital-
induced sleeping time was prolonged, indicating a decrease in the
activity of metabolizing enzymes in the liver (Khan & Pandya, 1980).
In another similar study, there were increased levels of alkaline
phosphatase activity in the liver, spleen and bone marrow, together
with decreased levels in kidneys. No such changes were found in brain
tissue. A significantly elevated level of activity in the spleen
persisted for at least 42 days after one intraperitoneal dose of
n-nonane or n-octane (1.0 ml/kg) (Pandya & Khan, 1982).
Pyykkö et al. (1987) observed significant increases in the
activities of liver cytochrome P-450, cytochrome P-450-dependent
monooxygenases and NADPH-cytochrome c reductase in Sprague-Dawley
rats one day after intraperitoneal dosing with single isomers of C8
and C9 aromatics (5 mmol/kg). A more complex response was seen in
the lungs, because of reduction in cytochrome P-450 activity and
increases or reductions in the activity of different monooxygenases.
7.5 Reproductive toxicity, embryotoxicity and teratogenicity
Appraisal
The studies in this section yielded essentially negative results,
but details were insufficient to make a comprehensive assessment.
Female rats (26 and 27 animals per group) were exposed to 0, 600
and 2400 mg/m3 (0, 100 and 400 ppm) white spirit (Stoddard solvent;
boiling range, 157-204°C; 43% aliphatics, 33% cyclic aliphatics, 24%
aromatics) for 6 h a day on days 6 to 15 of gestation. No maternal
toxicity was observed and there were no differences in litter size or
average fetal weight between the groups. An increased incidence of
pups with skeletal variations was observed in the exposed groups. The
details of the skeletal variations were not reported. In each exposed
group one litter contained pups with at least one unusual skeletal
variation. However, these effects were considered to be expressions
of retarded growth and not malformations (API, 1983).
Signs of maternal toxicity (decreased weight gain and eye
irritation) were found when pregnant Wistar rats were exposed for 6 h
daily to 5700 mg/m3 (950 ppm) of white spirit on day 3 to day 20
of gestation. The average fetal body weight was reduced by 14%
(p < 0.001) and an increased incidence of delayed ossification and
increased number of fetuses with extra ribs were noted. The effects
were thought primarily to be a result of maternal toxicity (Jakobsen
et al., 1986).
In another study in which pregnant rats were exposed to white
spirit at 600 and 1800 mg/m3 (100 and 300 ppm) 6 h/day from day 6 to
day 15 of gestation, no treatment-related effects were found with
respect to implantation, number of live fetuses, fetal resorption,
fetal size, sex distribution, or in soft tissue (Biodynamics, 1979;
Phillips & Egan, 1981).
7.6 Genotoxicity
Appraisal
The overall conclusion from the tests conducted with white spirit
for genotoxicity is that there is no genotoxic potential. Only one in
vitro assay yielded a positive result at a cytotoxic level.
A summary of assays for determining mutagenicity and related
end-points is given in Table 14.
Table 14. Genotoxicity studies
System Dosea Response Reference
(+S9/-S9)
Bacterial assays
Salmonella typhimurium 0.001-5 µg/plate negative/negative API (1984a)
strain TA98, TA100, TA1535,
TA1537, TA1538; +/- rat 3.38-25 µl/ml
liver S9; plate and
suspension assays
Salmonella typhimurium 0.0001-100 negative/negative Gochet et
strain TA98, TA100, TA1500, µg/plate al. (1984)
TA1535, TA1537, TA1538
Yeast
Saccharomyces cerevisiae 0.001-5 µg/plate negative/negative API (1984a)
D4; +/- rat liver S9; plate
and suspension assays 3.38-25 µl/ml
Mammalian in vitro cell assay
L5178Y TK+/- mouse 0.5-100 µg/ml negative/negative API (1984a)
lymphoma mutation assay;
+/- rat liver S9
L5178Y TK+/- mouse 12.5-100 µg/ml positiveb/positiveb API (1987b)
lymphoma mutation assay; 12.5-60 µg/ml
+/- rat liver S9
Human lymphocytes, 20-50 µl negative Gochet et
sister-chromatid exchange al. (1984)
Table 14. (Con't)
System Dosea Response Reference
(+S9/-S9)
Mammalian in vivo assay
Rat bone marrow cytogenetic 0.087, 0.289 and negative API (1984a)
test (Sprague-Dawley 0.868 mg/kg per day
CD rats) i.p. for either a
single day or 5 days
Micronucleus test 0.01, 0.05, 0.1 ml negative Gochet et
(BALB/c mice) i.p., or 50 g/m3 al. (1984)
inhalation
Rodent dominant lethal 100, 300 ppm inhalation negative Phillips &
test (rats) 6 h/day, 5 days/week Egan (1981)
for 8 weeks
Rodent dominant lethal 780 mg/kg s.c. as negative API (1984b)
test (Swiss-Webster mice) one single dose
Rodent dominant lethal 780 mg/kg i.p. as negative API (1984b)
test (Long-Evans rats) one single dose
a i.p. = intraperitoneal; s.c. = subcutaneous
b more than 50% increase in mutation frequency only at cell toxic concentrations
7.6.1 Bacterial assays
Assays with Salmonella typhimurium TA98, TA100, TA1535, TA1537
and TA1538 elicited no mutagenic effects. Plate and suspension assays
were conducted with white spirit (Stoddard solvent; boiling range,
157-204°C; 19% aromatics), both with and without microsomal metabolic
activation, at dose levels of 0.001-5 µg/plate and 3.38-25 µl/ml (API,
1984a).
Gochet et al. (1984) performed similar tests with white spirit
containing 15% aromatics and obtained negative results.
7.6.2 Yeast assay
The same concentrations as used for the bacterial assays
(described in section 7.6.1) elicited no mutagenic response in
Saccharomyces cerevisiae D4 in assays with and without metabolic
activation (API, 1984a).
7.6.3 In vitro mammalian cell assays
White spirit (Stoddard solvent; boiling range, 157-204°C; 19%
aromatics) was found to be non-mutagenic in a L5178Y TK+/- mouse
lymphoma assay, with and without metabolic activation, when used in
the dose range 0.005-0.1 µl/ml (API, 1984a).
However, white spirit (Stoddard solvent; boiling range,
161-199°C; 14.5% aromatics) was judged to be positive in an assay
both with and without metabolic activation (API, 1987b). In the
concentration range 0.0125-0.1 µl/ml, more than a 50% increase in
mutation rate was noted at 0.03-0.06 µl/ml (more than a 50% increase
in mutation rate was validated as a positive mutagenic response).
These levels, however, led to relative cell growth of 12-66% compared
to negative controls. Most toxic responses were seen in assays
without metabolic activation.
No significant increase in chromosomal abnormalities (breaks,
gaps, fragments and chromosome rearrangement) were noted in the bone
marrow of Sprague-Dawley rats after a single intraperitoneal exposure
or after daily intraperitoneal exposure for 5 days to white spirit
(Stoddard solvent; boiling range, 157-204°C; 19% aromatics). Dose
levels of 0.087, 0.289 and 0.868 ml/kg were used (API, 1984a).
No induction of sister-chromatid exchange (SCE) in human
lymphocytes was observed after incubation in culture medium containing
0, 20 and 50 µl white spirit (15% aromatics) (Gochet et al., 1984).
7.6.4 In vivo mammalian assays
Gochet et al. (1984) found no cytogenic damage in a micronucleus
test conducted with BALB/c mice. Intraperitoneal injections of 0.1,
0.05 and 0.01 ml of white spirit (initial boiling point, 160°C; 15%
aromatics) were given to 10 animals each, while inhalation of 50 g/m3
for 5 lots of 5 min (each exposure period was separated by 5 min
without exposure) was performed with five mice.
In a rodent dominant lethal test, male rats were exposed to 600
and 1200 mg/m3 (100 and 300 ppm) of white spirit 6 h/day, 5 days per
week, for 8 weeks. No effects on implantation rates, implantation
efficiency or fetal deaths were observed (Phillips & Egan, 1981).
A similar lack of mutagenic effect on male germ cells was
observed in dominant lethal tests with mice and rats dosed
subcutaneously or intraperitoneally with 1 ml/kg of white spirit
(Stoddard solvent) or 140 Aliphatic Solvent (API, 1984b).
7.7 Carcinogenicity
7.7.1 White spirit
No experimental animal data has been reported concerning the
carcinogenic properties of white spirit.
The carcinogenic properties of petrochemical products are usually
ascribed to the content of benzene or polyaromatic hydrocarbons (PAH),
especially benzo[ a]pyrene. In white spirit, however, these
constituents are only present in very minute amounts.
7.7.2 Related refinery streams
In a series of experiments, Blackburn et al. (1986) tested a
number of (undiluted) samples derived from the refining of crude oil.
In each experiment, groups of 50 male C3H/Hej mice, 6-8 weeks old,
were given twice weekly applications of 50 mg of the samples on shaven
interscapular skin for 80 weeks or until a papilloma larger than
1 mm3 appeared. Skin tumour incidence (histologically unspecified)
was evaluated in mice surviving at the time at which one-half of the
tumour-bearing animals had developed a tumour (or at 60 weeks,
whichever came first). The controls consisted of seven groups of
50 mice treated similarly with toluene and four groups of 50 mice that
were only shaven. Three skin tumours were seen in the toluene-treated
controls and none in the others. In the group treated with light
straight-run naphtha (boiling range, 49-177°C), 11 out of 44 mice
developed skin tumours, the average latent period being 85 weeks. Of
two groups treated with straight-run kerosene (boiling range,
177-288°C), 9 out of 30 and 4 out of 27 mice developed skin tumours,
the average latent period being 70 and 62 weeks, respectively.
8. EFFECTS ON HUMANS
8.1 Single exposure
8.1.1 Inhalation, controlled exposure
8.1.1.1 Irritation
a) White spirit
Carpenter et al. (1975a) reported eye irritation and lacrimation
in six volunteers after 15 min exposure to white spirit (Stoddard
solvent; 48% aliphatics, 38% cyclic aliphatics, 14% aromatics) at a
vapour concentration of 2700 mg/m3. At 850 mg/m3, only one person
reported slight eye irritation. No irritation was detected at
140 mg/m3.
Hastings et al. (1984) found an increase in subjective reportings
of mild irritation symptoms during a 30-min exposure of 25 volunteers
to a white spirit (Stoddard solvent) vapour concentration of
600 mg/m3 (35% aliphatics; 40% cyclic aliphatics; 25% aromatics).
Irritation of the nose was experienced by 31% (15% in a control group)
and eye irritation by 36% (24% in the control group). No changes in
the rates of eye-blinking, swallowing or breathing were noted.
Stokholm & Cohr (1979a,c) exposed nine volunteers (students) to
0, 204, 600, 1200 and 2400 mg/m3 (0, 34, 100, 200 and 400 ppm) and
six students and nine painters to 0, 300 and 600 mg/m3 (0, 50 and
100 ppm) for a duration of 7 h to white spirit vapour (17% aromatics).
The reporting of eye irritation was the most sensitive measure of
effect. There was a significant dose-response relationship in the
house painter group and in one group of students exposed up to
2400 mg/m3; there was a higher sensitivity in the house painters.
Among students, a dose-related increase in irritation of the nose was
noted from 600 to 2400 mg/m3.
b) Exposure to related hydrocarbons
Volunteers exposed for 15 min to vapours of "High aromatic
solvent" (> 99% aromatics, comparable with the aromatic fraction
in white spirit; boiling range, 184-206°C), at a concentration of
190 mg/m3, experienced mild irritation of the throat, eyes and nose.
At 410 mg/m3, the ocular and nasal irritation were described as
burning and stinging (Carpenter et al., 1977a).
8.1.1.2 CNS effects
In the study of Carpenter et al. (1975a) (see section 8.1.1.1),
slight dizziness was reported in two out of six volunteers exposed to
white spirit (Stoddard solvent) vapour at 2700 mg/m3 for 15 min.
Cohr et al. (1980), in a study using white spirit with an
aromatic content of 17% (see Stokholm & Cohr (1979c) section 8.1.1.1),
found dose-related increased incidences of headache, tiredness and
giddiness among nine students exposed up to 2400 mg/m3 (400 ppm).
There was increased reporting of headache in a group of nine painters
at 600 mg/m3 (100 ppm) (original report by Stokholm & Cohr, 1979c).
8.1.1.3 Neurobehavioural effects
Gamberale et al. (1975) did not find any influence on performance
in neurobehavioural tests conducted for the evaluation of perceptual
speed, reaction time, short-term memory, numerical ability and manual
dexterity among 14 volunteers exposed for 30 min to white spirit
vapour at 0, 625, 1250, 1875 and 2500 mg/m3 (17% aromatic
hydrocarbons, 83% aliphatic and cycloaliphatic hydrocarbons).
However, with exposure to 4000 mg/m3 for 50 min, significantly
impaired performance was seen in the tests for perceptual speed and
short-term memory. At this level the white spirit concentration in
alveolar air corresponded to the concentration found in exposure of
the volunteers to 2500 mg/m3 during light exercise.
Cohr et al. (1980) found altered vestibular-cerebellar reflex (in
Romberg test and in a walking performance test with closed eyes) after
nine students were exposed for 7 h to white spirit (17% aromatics) at
exposure levels of 600, 1200 and 2400 mg/m3 (100, 200 and 400 ppm).
Nine painters were not affected at 600 mg/m3 (highest level for this
group). Short-term memory (verbal learning and memory test) was
significantly impaired in the group of house painters at 300 mg/m3
(50 ppm) while no impairment was noticed among students at levels
up to 2400 mg/m3 (also reported by Stokholm et al., 1979) (for
description of neuropsychological test methods, see section 8.2.1.3).
8.1.1.4 Odour
Carpenter et al. (1975a,b) found an odour threshold level in the
range of 0.5-5 mg/m3 (0.09-0.9 ppm) for white spirit (Stoddard
solvent) and around 4 mg/m3 (0.6 ppm) for "140° Flash Aliphatic
Solvent" (3% aromatics). The odour experiments were performed with
panels of six volunteers. Olfactory fatigue (decreased sense of
smell) was reported during exposure to Stoddard solvent using a panel
of 50 volunteers, Hastings et al. (1984) determined the odour
threshold level for Stoddard solvent to be 2 mg/m3.
A pure aromatic solvent "High Aromatic Solvent" comparable to the
aromatic fraction in white spirit was found to have an odour threshold
level of approximately 0.4 mg/m3 (0.07 ppm) (Carpenter et al.,
1977a).
8.1.2 Inhalation, accidental exposure
Niehrenberg et al. (1991) reported a near-fatal case of poisoning
involving a 42-year-old woman who after several hours of painting in a
closed room developed chest pain, cyanosis, apnoea and cardiac arrest
with ventricular fibrillation. During hospitalization, pulmonary
oedema, haemolytic anaemia and metabolic abnormalities were observed.
The exposure from the white spirit in the lacquer and paint she was
using was estimated to be very high because of the lack of
ventilation.
Atkinson et al. (1989) reported a case in which a 60-year-old man
developed malaise with headache, anorexia and coughing after one hour
of painting in an unventilated bathroom using a white-spirit-
containing paint. Because of loss of coordination he fell and was
admitted to the hospital. During the following days at the hospital
bone marrow suppression and liver cell damage were verified.
8.1.3 Oral exposure
Ingestion of white spirit has resulted in gastrointestinal
irritation including vomiting, diarrhoea and gastrointestinal pain.
Severe lesions and ulcerations in the mucous membranes of the
oesophagus and the gastrointestinal tract have been reported after
ingestion of about 500 ml white spirit (Paris et al., 1978).
As in the case of kerosene and other petroleum solvents with low
viscosity, the severity of symptoms after ingestion of white spirit
depends on whether the solvent is aspirated into the lungs.
Aspiration can cause serious bronchopneumonia, which may be fatal
within 24 h. A dose of 30 ml aspirated into the lung may be fatal
(McDermott, 1975). Other reports describing the aspiration hazard
of petroleum distillates indicate that oral doses as low as 10 ml
can be fatal and aspiration of a volume of 1-2 ml may produce
bronchopneumonia (Velvart, 1981; Rumack & Lovejoy, 1986).
8.1.4 Dermal exposure
From several series of patch testing with humans, it was found
that petroleum solvents with boiling ranges below approximately 270°C
were primary irritants (Klauder & Brill, 1947). Petroleum solvents
with boiling ranges above this seemed less irritating. Increased
content of cyclic aliphatics or aromatic hydrocarbons increased the
irritant action of the solvent. Thus increased irritancy was assumed
to be connected with the increased solvency and defatting action of
the solvent.
Nethercott et al. (1980) reported five cases of ulcerative and
erythematous lesions of the genitals and the buttocks in workers
wearing clean coveralls which were still moist after dry-cleaning with
white spirit (Stoddard solvent). In the report six further cases of
cutaneous irritation (vesicle formation, crusting, erythema and
desquamation) following skin contact with Stoddard solvent were
mentioned.
Tagami & Ogino (1973) reported four cases in which children
developed dermatitis after wearing kerosene-soaked clothing. In a
laboratory test, 0.1 g of an 85% kerosene solution applied under
occlusional dressing for 24 h to 34 volunteers resulted in positive
skin reactions in all subjects. The most common reactions were
assessed as faint diffuse erythema and swollen clear erythema. No
reactions were noted when a 40% kerosene solution was used.
8.2 Short-term and long-term exposures
This section includes human data from occupationally exposed
people. The studies have been selected according to the following
criteria concerning exposure:
* studies that have actual measurements for white spirit;
* studies with description of white spirit exposure;
* studies where white spirit exposure is highly anticipated because
of the occupation (e.g., house painters);
* studies referring to mixed hydrocarbon exposure combined with
additional data relating to white spirit exposure.
Studies with combined exposure to several chemicals have not been
included if the white spirit exposure was found to be of only minor
importance. Studies indicating exposure to "organic solvent" or
"solvent" without further information have not been included.
8.2.1 Effects on the nervous system
White spirit belongs to the broad category of organic solvents
that have created debate with respect to their neurotoxicity. In
1985, WHO and the Nordic Council of Ministers appointed a working
group with the aim of setting diagnostic criteria and evaluating
methods. The working group found that the symptoms and the
neurological and psychological deficits occurring after long-term
solvent exposure were quite non-specific (WHO/NCM, 1985). Therefore,
the clinical diagnosis on an individual basis had to be based on an
overall assessment of the occupational history, the clinical status,
the results of some neurological and psychological tests, and the
evaluation of the role of other factors of possible etiological
importance. The following criteria for identification and
classification of neurological and psychological deficits were
proposed:
a) Organic affective syndrome in which clinical manifestations
consist of depression, irritability, and loss of interest in
daily activities. There is no reduced CNS function (judged from
the evaluation of neuropsychological test methods).
b) Mild chronic toxic encephalopathy. Clinical manifestations are
fatigue, mood disturbances, and memory and concentration
problems. CNS function is impaired with respect to psychomotor
function (speed, attention, dexterity); short-term memory
impairment and other abnormalities are commonly noted.
c) Severe chronic toxic encephalopathy. This covers loss of
intellectual abilities of sufficient severity to interfere with
social or occupational functioning: memory impairment, impairment
in abstract thinking, impaired judgement, other disturbances of
cortical function, personality change. More pronounced and
pervasive CNS functional deficits and some neurophysiological and
neuroradiological test abnormalities.
It was emphasized that overlap exists between the different very
broad categories and that they do not necessarily represent stages
through which individuals have to pass to reach the most severe
end-point (WHO/NCM, 1985).
At another WHO meeting in 1988 (WHO, 1989), the diagnosis of
solvent-related organic brain syndrome was supplemented according to
the "Diagnostic and Statistical Manual of Mental Disorders", DSM-III-R
(American Psychiatric Association, 1987). Thus the organic brain
syndrome was found to have features in common with the definitions of
mild syndrome of dementia, mild organic affective syndrome or mild
organic personality syndrome. The organic brain syndrome is
characterized by a general cognitive impairment and changes in mood
and personality. Symptoms and signs of these changes vary in their
relative severity from case to case. Usually the changes are mild.
The above-mentioned classification of mental disorders may help
when reading literature in which many other terms such as chronic
painter's syndrome, chronic organic brain syndrome, organic solvent
disease, psycho-organic syndrome, psycho-organic neuropathy,
pre-senile dementia, and dementia have been used to describe the
neurotoxic responsesa.
The term dementia, in particular, has created some confusion,
because dementia may be used in two different contexts, which must be
clearly distinguished. Firstly, it is used to describe a specific
a In the description of studies reviewed in this chapter, the terms
employed in the original research reports will be used.
entity of diseases such as pre-senile and senile dementia, Alzheimer
disease, or other very serious diseases characterized by progressive
and widespread brain degeneration. Secondly, it is used in a broader
sense to describe a clinical syndrome of impairment of intellectual
capacity, memory and personality but without impairment of
consciousness. The origin of this syndrome may be more benign
diseases or exposure to some toxic substances. The term dementia is
often used to describe a syndrome resulting from chronic organic
solvent exposure, particularly in literature from the Nordic countries
(CEC/DME, 1990; Arlien-Soeborg, 1992a).
8.2.1.1 Symptoms and clinical picture
Different kinds of neurotoxic effects are described in the
sections 8.2.1.2 to 8.2.1.5. In this section, however, an overall and
more general clinical picture from human exposure to white spirit will
be presented.
In the report from the WHO/Nordic Council of Ministers meeting,
Arlien-Soeborg (1985) summarized the clinical effects from long-term
exposure to organic solvents. Most experience has been obtained from
the monitoring of painters. This group has been very extensively
studied because of high occupational exposure to organic solvent since
the introduction of alkyd paint. Thus painters constitute an
occupational group that to a great extent and in several countries
(e.g., the Nordic countries) has been predominantly exposed to white
spirit.
The painters most often complained about the following acute
symptoms: irritation of eyes, nose and throat; reduced sense of taste;
nausea; loss of appetite; headache; feeling of drunkenness; dizziness;
fatigue (Lajer, 1976; Elofsson et al., 1980; Hane & Hogstedt, 1980;
Seppäläinen & Lindström, 1982; Lindström & Wickström, 1983;
Arlien-Soeborg, 1985; Cherry, 1985; Valciukas et al., 1985; Oerbaek et
al., 1985; Linz et al., 1986; Fidler et al., 1987; Askergren et al.,
1988; van Vliet et al., 1989a).
Often these symptoms disappeared during exposure-free periods in
weekends or holidays, but over the years these symptom-free periods
got shorter and a chronic syndrome state developed. Arlien-Soeborg
(1985) reported the following chronic symptoms in a group of 50 house
painters: memory impairment, forgetfulness, excessive fatigue,
weariness, inability to concentrate, irritability, low frustration
tolerance, headache, dizziness, apathy, lack of initiative, anxiety,
nervousness, depressions, low spirits, bursts of perspiration, alcohol
intolerance, abdominal pains, diarrhoea, nausea, impotence, reduced
libido, blurred vision.
Several of these symptoms have also been described by others,
although in most cases the distinction between the acute and the
chronic states has not been made.
In severe chronic cases, fatigue and impairment of learning
ability, concentration, memory and initiative may change the
personality of the affected person in such a way that a normal working
life as well as normal family life may be impossible. In several
cases it has been described how these adverse effects resulted in
change of occupation or in the awarding of a disability pension
(Agrell et al., 1980; Bruhn et al., 1981; Gregersen et al., 1987;
Gregersen, 1988). A positive association between the awarding of
disability pensions due to neuropsychological disorders and long-term
solvent exposure as a painter (mainly exposure to white spirit) has
been demonstrated in epidemiological studies reported by Axelson et
al. (1976a), Mikkelsen (1980), Lindström et al. (1984) and Brackbill
et al. (1990).
8.2.1.2 Neurological findings
This section comprises the reports from a) neurophysiological and
b) clinical neurological examinations of workers exposed to white
spirit. Most of the studies have been performed with few but selected
subjects (often patients), and a reference group was not usually
present.
a) Neurophysiological and neuroimaging examinations
The neurophysiological examinations described in this section can
be divided into the following groups:
i) electrophysiological examination of the brain
electroencephalography (EEG)
auditory evoked potentials (AEP)
cerebral blood flow measurement (CBF)
ii) neuroimaging examination of the brain
pneumoencephalography (PEG)
computerized tomography (CT)
iii) electrophysiological examination of the peripheral nerve
system
nerve conduction velocity measurement (NCV)
nerve action potential amplitudes (NAP)
electromyography (EMG)
For further description of these methods the reader is referred
to Valciukas (1991) and Arlien-Soeborg (1992b).
An overview and descriptions of the studies using these
techniques with people exposed to white spirit are given in Table 15.
Table 15. Neurophysiological examination of patients with previous exposure to white spirita
Reference/Neurophysiological Groups studied Exposure Results
examinations
Axelson et al. (1976b) 10 patients (house painters) aliphatic and aromatic 6 painters were found to have
Electroencephalography suffering from chronic hydrocarbons including white pathological EEG recordings
psycho-organic syndrome (POS). spirit; exposure for 20-45 years
Gregersen et al. (1978) 35 retired house painters suffering several years (typically cerebral or cortical atrophy in
Computerized tomography, from organic cerebral syndrome > 20 years) of exposure to paint 17 of 18 examined painters
Pneumoencephalography solvents, mainly white spirit
Arlien-Soeborg et al. (1979)b 50 patients (house painters) with exposed mainly to white spirit EEG: slightly or moderately
Electroencephalography, signs of chronic brain syndrome (paint solvent); Mexp. 27 years abnormal in 9 of 46 patients;
Computerized tomography, CT: brain atrophy identified in
Pneumoencephalography 19 out of 38 examined; PEG: brain
atrophy identified in 12 of
12 examined
Gyldensted et al. (1980)b 51 patients (house painters) with exposed mainly to white spirit; 27 cases of cerebral atrophy in
Computerized tomography suspected chronic organ solvent Mexp. 26.7 years the group of painters; atrophic
intoxication; 38 referents patients had been exposed for
longer duration than painters
without atrophy
Arlien-Soeborg et al. (1981)b 57 out of 113 patients (house mixed solvent exposure; house brain atrophy was judged to occur
Computerized tomography and car painters) suffering from painters mainly exposed to white in 28 (49%) of the patients
or Pneumoencephalography suspected chronic encephalopathy spirit; Mexp. 25.3 years
Table 15. (Con't)
Reference/Neurophysiological Groups studied Exposure Results
examinations
Arlien-Soeborg et al. (1982) 9 house painters with intellectual mainly exposure to white spirit reduced (p < 0.05) CBF in the
Cerebral blood flow impairment and suspected chronic (paint solvent); Mexp. 22 years; group of painters (36.8 ml/100 g
solvent intoxication; only subjects no recent exposure before the per min) compared to the controls
with no or very slight cerebral CBF examination (45.4 ml/100 g per min)
atrophy (observed by CT examination
were included;
11 unexposed controls
Flodin et al. (1984) 28 patients with POS; 20 patients mixed solvent exposure; Mexp. in the neurophysiological
Electroencephalography, with early stages of POS; POS group: 24 years; Mexp. early examination, pathological results
Electromyography, 28 patients without POS; POS was stage POS group: 21 years; were found in 61% of the POS
Nerve conduction velocity diagnosed on the basis of neuro- Mexp. non-POS group: 16 years; group; in 25% of the early stage
psychiatric test performance and exposure to white spirit POS group, and in 32% of the
the occurence of relevant occurred at frequencies of non-POS group
symptoms 24%, 41% and 21% (percentage of
all exposures) in the respective
groups
Gregersen et al. (1987) 21 painters diagnosed with paint solvent exposure; slight to moderate abnormal
Electroencephalography chronic toxic encephalopathy Mexp. 25.5 years findings were noted in 6 out
Computerized tomography of 16 EEG-examined patients;
Pneumoencephalography 4 out of 5 examined by PEG or
CT exhibited cerebral atrophy
to a varying degree
Table 15. (Con't)
Reference/Neurophysiological Groups studied Exposure Results
examinations
Berstad et al. (1989) 26 patients referred to a neuro- mixed solvent exposure; 17 patients (9 painters) were,
Computerized tomography logical department with suspected Mexp. 23.9 years for 17 patients according to medical examination
Electroencephalography organic solvent syndrome with a confirmed diagnosis of and neuropsychological tests,
Electromyography organic solvent syndrome diagnosed with organic solvent
syndrome; EEC: abnormal findings
in 5/17 cases; CT: atrophy in
2/17 cases; EMG and other
neurological examinations revealed
5 cases (2 painters) of
polyneuropathy
a Mexp. = mean exposure period; EEG = electroencephalography; CT = computerized tomography; PEG = pneumoencephalography;
CBF = cerebral blood flow; NCV = nerve conduction velocity; POS = psycho-organic syndrome
b These studies are made on the basis of more or less the same background population but reviewed at different times.
For most of the subjects included in the reports in Table 15,
exposure has been estimated indirectly. The estimates are usually
based on historical exposure data, i.e. working materials, methods,
conditions, ventilation and use of protective equipment. The estimates
of exposure are consequently imprecise and this makes it more
difficult to establish any relationship with the chosen outcomes of
the studies.
A common feature of these studies is that they were conducted in
connection with other clinical examinations of workers (patients) and
that the patients were highly suspected or known to suffer from toxic
encephalopathy.
Although the degree of dementia in a group of painters with
cerebral atrophy (n=27) was found to be more severe than the degree of
dementia in a group of painters without atrophy (n=24), no significant
difference in the frequency of dementia was observed between the two
groups (85% and 71%, respectively) (Gyldensted et al., 1980).
In the study by Arlien-Soeborg et al. (1981), oto-neurological
testing was performed but the abnormal pattern of nystagmus found in
62 of the painters could not be correlated with brain atrophy found in
28 painters.
Neurophysiological examinations have also been used in several of
the epidemiological studies (Tables 16 and 17) (Elofsson et al., 1980;
Seppäläinen & Lindström, 1982; Oerbaek et al., 1985; Linz et al.,
1986; Askergren et al., 1988; Mikkelsen et al., 1988; Triebig et al.,
1988). In these studies the neurophysiological examinations have been
performed as a screening tool among active and generally healthy
workers. Therefore, the extent of pathological findings would be
expected to be less than in the examinations previously mentioned in
this section. However, some effects were found in these epi-
demiological studies. Alteration in peripheral nerve functioning
was observed by Eloffson et al. (1980), Linz et al. (1986) and
Askergren et al. (1988), while some changes in cerebral parameters
were observed by Oerbaek et al. (1985) and Mikkelsen et al. (1988).
b) Oto-neurological performance tests
Vestibular and vestibulo-oculomotor tests measure CNS function in
connection with body balance and eye movements. These functions are
vulnerable to various types of CNS intoxication and CNS disease. With
respect to solvent toxicity, the monitoring of body sway in standing
position (e.g., Romberg's test) and nystagmus (repetitive eye
movements) from vestibular response to different challenges (change in
body position or irrigation of the ear with cold or warm water) are
sensitive methods for detecting abnormal function (Arlien-Soeborg,
1992b).
Arlien-Soeborg et al. (1981) performed some routine vestibular
examinations as a part of the study described in Table 15. The
following parameters were recorded: spontaneous nystagmus, positional
nystagmus, differential-caloric nystagmus and optokinetic nystagmus.
Abnormal findings occurred in 58 of the 113 patients (house and car
painters) in the differential-caloric test and four further abnormal
findings were detected in the other tests. However, no correlation
was established between these results and findings of cerebral atrophy
or intellectual impairment (evaluated in neuropsychological testing),
or duration of exposure.
Ödkvist et al. (1987) studied solvent-exposed workers who had
been referred to a department for occupational medicine. Of the
31 workers (mainly painters), 16 were diagnosed with confirmed
psycho-organic syndrome (POS), 7 with suspected POS, and 8 without
POS. The 16 plus 7 workers had been exposed for an average of 27 and
21 years, respectively, mainly to aliphatic and aromatic hydrocarbons
(including white spirit). The workers were subjected to a battery of
nine audiological and nine vestibular tests. All three groups
showed abnormal findings in two of the audiological tests (test for
interrupted speech discrimination and test for cortical response to
frequency glides). In the vestibular test battery, considerable
abnormal performance was observed in seven of the nine tests. The
groups with confirmed or suspected POS were most affected, especially
in electronystagmography, coordination test, Romberg's test, saccade
test and visual suppression test. Thus, overall performance was found
to be correlated with the degree of POS. More complex and polysynaptic
functions were affected to a higher degree than more simplistic
functions or simple reflexes.
Ledin et al. (1989) subjected nine patients (mainly painters)
diagnosed with psycho-organic syndrome to a similar audiological/
vestibular test battery. Compared to 50 unexposed controls, the
painters (mean exposure period 21 years) exhibited significantly
increased body sway area in Romberg's test (both with eyes open and
with eyes closed). In the visual suppression test, significantly
impaired ability to suppress vestibular nystagmus was recorded in the
exposed group. The authors found that testing for postural
equilibrium control as a part of the examination of the cerebral
function might be a suitable indicator for solvent-induced CNS
lesions.
8.2.1.3 Neuropsychological findings
The clinical diagnostic neuropsychological examination of a
person is the most comprehensive and most fully developed form of
neuropsychological evaluation. The individual diagnostic examination
consists of information from three sources: clinical interview,
behavioural observation and psychometric testing.
a) Clinical interview. This interview concerns the history of
subjective symptoms and their development, functioning in work, family
and leisure time, prior performance level, and concurrent
psychological functions and signs of brain dysfunction. In some
situations the interview may be substituted by a questionnaire.
b) Behavioural observation. To the trained neuropsychologist,
behavioural observation is a very important source of information
which allows evaluation beyond the limitations of a formal testing
procedure. The observation is extended to the testing situation,
observing coping and compensation strategies while dealing with the
tests.
c) Psychometric testing. These tests may be regarded as an extension
of behavioural observation, presenting intellectual tasks in a
standardized way. Most neuropsychological tests are designed with
the aim of studying a certain intellectual function in relative
isolation and ruling out, as far as possible, other variables.
Furthermore, the tests are standardized to gain a higher degree of
objectivity, sensitivity, specificity, reproducibility and intra-/
interpersonal comparability (Soerensen, 1992).
The individual diagnosis based on medical and psychological
interviews and testing may indicate encephalopathy but not cause. It
must be followed by an extensive medical and neurological work-up to
exclude other causes of brain dysfunction before solvent exposure can
be considered the cause.
A working group appointed by WHO and the Nordic Council of
Ministers evaluated the many different neuropsychological test methods
(WHO/NCM, 1985). From these tests a core test battery for clinical
testing was proposed as useful for evaluating solvent-induced CNS
effects:
Cognitive verbal ability
Vocabulary (power test)
Psychomotor function
Simple reaction time
Santa Ana dexterity test
Finger-tapping test
Perceptual speed
Digit symbol substitution (WAIS - Weschler Adult
Intelligence Scale)
Short-term memory
Benton retention test
Digit span (WAIS)
Mood
Profile of mood states (POMS)
These tests were chosen because they are standardized and widely
used, and they are of known empirical value in solvent neurotoxicity
testing. At another WHO meeting in 1989, the test proposals were
divided into obligatory and strongly recommended tests, and additional
tests were included. The Trail Making A and B test and the Block
Design test were put forward as obligatory tests and the Aiming test
as a strongly recommended test (WHO, 1989).
The test for cognitive verbal ability is considered to be
unaffected by slight brain disruption and is therefore used for the
estimation of pre-exposure ability and pre-exposure intellectual
level. Testing for perceptual speed and psychomotor function,
however, are judged to be rather sensitive tests for determining
solvent-induced CNS effects. For further description of these tests,
their performance and interpretation of test results, the reader is
referred to WHO/NCM (1985), Valciukas (1991) and Soerensen (1992).
The findings from neuropsychological testing of workers and
patients with known or suspected mental impairment due to white spirit
or mixed solvent exposure are reported below. Findings from
epidemiological studies performed mainly with healthy workers are
reported in section 8.2.1.4.
Arlien-Soeborg et al. (1979) found 39 out of 50 painters to be
intellectually impaired on the basis of the results from a
neuropsychological test battery. More than half of the patients
showed impaired performance with respect to sentence repetition (53%),
paired associates (learning) (60%), digit span (62%) and visual
gestalts (memory) (64%). The painters had been referred to an
occupational medical clinic because of suspected chronic brain
syndrome. (Data concerning exposure and neurological examinations are
given in Table 15).
In the study by Arlien-Soeborg et al. (1981) (mentioned in
sections 8.2.1.2 a and b and in Table 15), neuropsychological testing
(using the test battery mentioned above) was performed with 81 out
of a total of 113 painters. Of these, 57 were judged to be
intellectually impaired. However, no correlation was found with
impaired vestibular functioning, which was observed in 52 of the 113
painters.
Flodin et al. (1984) diagnosed 33 people with psycho-organic
syndrome (POS), 27 with early stage POS, and 68 with non-POS on the
basis of answers from a questionnaire on psychiatric symptoms
and/or scorings in a Swedish neuropsychological test battery
(neuropsychological testing performed with 91 persons). All were
patients who were examined after they had been referred to an
occupational medical clinic because of the presence of subjective
symptoms in connection with organic solvent exposure. It was
concluded that POS only occurred after 9 years or more of exposure,
while early stages of POS (some subjective symptoms but not
necessarily associated with reduced mental performance) may develop
after only 3 years of exposure (for information on exposure see
Table 15).
Gade et al. (1988) retested two groups of 10 people 2 years after
a first neuropsychological testing had been performed. All were
diagnosed in the first test with solvent-induced toxic encephalopathy
and half of them were further diagnosed by CT scanning with cerebral
atrophy. The patients were mainly occupied as house painters and had
been exposed to solvents for an average period of 24 years. In the
first testing no comparisons were made to appropriate controls, but,
on retesting, matching was conducted with two groups of 10 patients
selected from an overall control group of 120 patients recruited from
different hospital wards. In the neuropsychological retest, which
included nine tests evaluating intelligence, cognitive functioning and
psychomotor performance, significantly lower scores were obtained by
the group without atrophy. However, when regression analysis was made
and differences in age, educational level, and verbal intelligence
were accounted for, no clear differences in the test performances
persisted compared to the controls. The authors emphasized the
necessity of using proper controls to avoid misclassification with
respect to toxic encephalopathy.
8.2.1.4 Epidemiological studies
The epidemiological studies on workers exposed to white spirit
are listed in Tables 16 and 17. The studies are grouped in the two
tables according to the exposure information. Table 16 includes those
studies in which exposure was predominantly to white spirit, i.e. the
exposure has been verified in the text or the study group is an
occupational group known to be predominantly exposed to white spirit,
e.g., house painters. Table 17 includes studies in which the white
spirit exposure is not defined with the same degree of certainty or is
part of a more complex exposure. It should be noted that the column
labelled "results" has been mainly used to describe positive findings
from the studies. Accordingly, no reporting in this column indicates
negative or inconclusive results from the testing/examinations.
8.2.1.5 Comments and uncertainties concerning the epidemiological
studies
It is not possible to interpret and evaluate the studies in
Tables 16 and 17 without referring to questions and problems that have
been raised in connection with these studies. In sections 8.2.1.2 and
8.2.1.3, aspects concerning different views of the relevance,
performance and interpretation of the neuropsychological and
neurological tests have been briefly mentioned. These aspects and
problems concerning sensitivity may be even more apparent when the
tests and examinations are conducted with active workers, where the
Table 16. Epidemiological studies on workers exposed to white spirita
Reference/type of studyb Groups studied Exposurec Results
Blume et al. (1975); 52 house painters Paint solvents, mainly The performance of painters was significantly worse in
Hane et al. (1977) 52 unexposed white spirit and aromatic tests for figure classification and psychomotor
Cross-sectional study industrial workers hydrocarbons; coordination. Compared to a standard scale,
Neuropsychological test Mexp. 14.2 years significantly reduced scores were further noted in
battery (10 tests memory tests and simple reaction-time tests.
representing a range of
different mental functions)
Hane & Högstedt (1980) 232 solvent exposed Mixed solvent exposure; Significantly more symptoms in the exposed group (in
Cross-sectional study workers (104 painters, house and car painters the answers from 18 out of 24 questions): Fatigue,
Mailed questionnaire 29 car painters, most heavily exposed; paraesthesia, bad memory, impaired concentration,
concerning symptoms and 99 metalworkers), house painters exposed depression, irritability, chest pain and reduced
daily performance 173 unexposed approximately 70% of the libido were the most prominent symptoms; housepainters
electricians and working hours, mainly to and car painters were most affected, and a positive
postmen white spirit, toluene correlation was found between increasing number of
and xylene symptoms and age (exposure).
Mikkelsen (1980) 2601 painters and 1790 Painters mainly exposed A relative risk (RR) of 3.4 (p < 0.05) was calculated
Historical follow-up study bricklayers who were to white spirit (about for painters for being awarded disability pensions
Disability pension, awarded disability 75% of the total solvent because of presenile dementia (without specific cause
information from register pensions exposure) indication) compared to bricklayers; a RR of 3.3
files (p < 0.05) was found when using Copenhagen men
as referents.
Seppäläinen & Lindström 72 house painters Mexp. 20.2 years; average Significantly more painters reported of nausea,
(1982) Cross-sectional study 77 reinforcement exposure to white spirit feelings of drunkenness, mucous membrane irritation,
Questionnaire workers was estimated to be 40 paraesthesia, vertigo and impaired sense of smell;
Neurophysiological ppm during working hours no notable group differences were found in EEG and
examinations (EEG, NCV) NCV measurements.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Lindström & Wickström 219 house painters Mexp. 22 years with an Among painters there were significantly increased
(1983) Cross-sectional study 229 reinforcement estimated average level of prevalences of acute symptoms such as nausea, runny
Questionnaire 8 workers white spirit of 40 ppm noses and malaise. Significantly poorer performance
neuropsychological tests during working hours; in 4 tests. Short-term visual memory and simple
determining intelligence exposure indices made for reaction time were most affected functions. For these
and psychomotor performance total life-time exposure functions a slight correlation between performance
and average exposure levels and total exposure/exposure level was demonstrated.
Cherry et al. (1985) 1) 236 painters Mixed solvent exposure; 1) Painters significantly more often reported of
Cross-sectional study 128 non-exposed average levels of white tingling in hands and feet, depression, difficulties
1) Questionnaires joiners spirit were under two in concentration and increased irritability.
2) Neurological examination 2) 44 painters working conditions 2) Significantly impaired scoring in 10 out of 14 test
(nerve conduction 44 non-exposed measured to be 125 and parameters. After rematching with other controls and
measurements); 9 joiners 578 mg/m3; Mexp. allowance for a lower preceding intellectual level of
neuropsychological tests 11.7 years (n=44) the painters, no significant differences were noted.
determining intelligence No effect on peripheral nerve function was observed.
and psychomotor function
Fidler et al. (1987) 101 construction Mixed solvent exposure. Among painters, dose-related increase in symptoms such
Cross-sectional study painters; 31 dry wall Exposure indices were as dizziness, nausea, fatigue, feeling of drunkenness
Questionnaire tapers (the control calculated on the basis of and mood tensions. Impaired performance in one
Neuropsychological tests group was not used in duration of exposure (years psychomotor performance test and one short-term memory
(8 tests for intellectual the evaluation because as a painter), type of work, test were associated with the exposure during the
functions and psychomotor of pronounced frequency of exposure, latest year. Because signs of mental impairment did
performance) differences compared amount of solvent used, not form a consistent pattern the findings in the
to the painter group) exposure during the study were judged to be in accordance with the WHO
latest year, etc. Mexp. definition of the mildest form of chronic solvent
18 years. toxicity.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Baker et al. (1988) 186 construction Information about intensity Unadjusted as well as adjusted* prevalence rates of
Cross-sectional study painters and duration were symptoms such as forgetfulness, lassitude,
Questionnaire combined and different disorientation, dysphoria and numbness of fingers and
Neuropsychological test exposure indices were toes increased significantly with increasing LEI.
battery (9 tests determining calculated. Stratification Significant dose (LEI)-response relationship was also
verbal ability, psychomotor to 6 subgroups according found for five mood parameters and in the symbol-digit
performance and memory) to the index of lifetime test. When stratifying according to exposure duration
exposure intensity (LEI). without accounting for the exposure intensity the
Median exposure period: neuropsychological parameters were affected to a
12 years. minor degree.
Mikkelsen et al. (1988) 85 painters White spirit was estimated The following odds ratios (OR) for painters compared
Cross-sectional study 85 bricklayers to account for about 75% of to bricklayers were found for the development of
Neuropsychological test the total solvent exposure. dementia (the presence and degree of dementia
battery (13 tests for Mexp. 32.5 years with an evaluated from the overall performance in the test
intellectual functions and average daily solvent battery): high exp.: OR= 5.0 (p < 0.05); medium
psychomotor performance) consumption of 1.3 l/d = exp.: OR= 3.6 (p < 0.05); low exp.: OR= 1.1. Only a
Neurological tests (motor 41.4 (l/d)years. Solvent weak correlation was found between exposure and
performance, coordination, exposure was graded performance in specific neurological tests. However a
reflexes, sensitivity) according to the cumulative strong correlation was found between exposure levels
Neurophysiological solvent consumption. Low and the total number of abnormal scores. In CT
examination (CT) exp.: < 15 (l/d) years scanning, exposure and dose relationship for
(n=22); medium exp.: 15-30 differences were noted in 3 out of 11 different
(l/d)years (n=29); high parameters. An average no-observed-effect level of
exp.: > 30 (l/d)years 40 ppm for 13 years was estimated (possible
* Adjustments were made by regression analysis to account for the factors age, race, education, social status and alcohol habits.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
(n=33). Average exposure confounders were identified and taken into
level (all painters) was account).
estimated to be 40 ppm. 21
painters had been exposed
during the latest week
before examination.
Gubéran et al. (1989) 1916 painters Paint solvents. No further A relative risk (RR) of 1.8 (not significant) was
Historical follow-up study 1948 electricians specific data with regard calculated for the painters compared to the
Disability pension, Both groups were to the solvent exposure. electricians for receiving disability pension because
information from register awarded disability of neuropsychiatric diseases.
files pensions
Bove et al. (1989) 93 construction Mixed solvent exposure. The vibration thresholds were significantly higher in
Cross-sectional study painters Mexp. 18 years. Different the older painters than in the comparable controls.
Vibration thresholds and 105 unexposed exposure indices were The painter group had a significant excess of high-
temperature sensitivity controls calculated on the basis of level temperature sensitivity compared to controls.
intensity and duration of Among painters, there was a positive association
exposure. between vibration threshold and exposure level and
cumulative exposure over the past year.
Bazylewicz-Walczak et al. 226 exposed rubber Solely white spirit exposure The performance of the exposed groups (as a total),
(1990) Cross-sectional study footwear industry from gluing. Mexp. about compared to the controls, was significantly worse with
Neuropsychological test workers; 102 non- 500 mg/m3 in the last 13 regard to 4 of the 7 tests for intellectual
battery (7 tests for exposed hosiery years. The two groups were functioning and with regard to 3 of the 5 tests for
intellectual functions and plant workers divided into three sub- psychomotor performance. The affected variables were:
5 test for psychomotor groups with respect to age. correctness of perception and reproduction of visual
performance) Further the exposed subjects material, projection of spatial relationships,
were divided according to concentration, speed of reactions to single and
exposure duration complex light stimuli, and manual dexterity. Variables
I: 5-10 years (n=51); such as simple and complex reaction time and
II: 11-15 years (n=103); coordination were found to deteriorate with duration
III: 16-30 years (n=72). of exposure.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Bolla et al. (1990); 187 workers selected Mainly exposure from Significant dose-related response in test for
Bleecker et al. (1991) from two paint aromatic hydrocarbons vibration threshold and in 5 test parameters for
Cross-sectional study manufacturing plants (toluene, xylene) and sustained attention and concentration. The effects
Questionnaires aliphatic hydrocarbons. were judged to be subclinical. No differences between
Neuropsychiatric evaluation No unexposed controls Average lifetime exposures the exposure groups were observed regarding symptoms
Vibration threshold test estimated to be 2, 7, 12 typically related to the "painter's syndrome".
Neuropsychological test and 18 ppm (as total
battery (13 tests for hydrocarbons) for 4 sub-
intellectual functions and groups of workers (n = 44
psychomotor performance) in each group). Mexp.
15-16 years for the
four groups.
Brackbill et al. (1990) 3565 people receiving Painters was selected OR = 1.42 (p < 0.05) for painters for getting
Cross-sectional study disability pensions as a group highly disability pension because of chronic
Disability pension because of chronic exposed to solvents. neuropsychiatric diseases compared to unexposed
information from register neuropsychiatric bricklayers.
files conditions;
83 245 people receiving
disability pensions
because of other
reasons not mental
4291 painters and
1641 bricklayers were
included in the
two groups
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Demers et al. (1991) 28 solvent-exposed Mixed solvent exposure. Dizziness experienced by 82% and syncopal episodes
Cross-sectional study painters 76% of the painters during work by 11% of the painters. Vibration tests
Subjective symptoms 20 nonexposed reported white spirit were performed with a "Vibrometer" on the index
Vibration perception boilermakers exposure. 42% of the fingers and the big toes to assess peripheral nerve
threshold test painters were solvent functioning. The tests demonstrated significantly
exposed more than 50% reduced vibration perception thresholds compared to
of the working time. the control group.
Mexp. 30 years.
Spurgeon et al. (1990, Study group 1: Study 1: Mainly exposed In both studies significantly impaired performance was
1992); Cross-sectional study 90 brush painters to white spirit. Estimated observed in the symbol-digit substitution test for the
Questionnaire concerning 90 unexposed age- average level of 50 ppm exposed groups. In study 2, the performance of workers
symptomatology and matched controls for 2 days a week. exposed for more than 10 years was worse in paired
psychiatric state Study group 2: Study 2: Exposure more associate learning test. After accounting for other
Neuropsychological test 144 solvent-exposed diverse because of the possible influences on performance, significant effect
battery for intellectual brush painters, spray inclusion of several from exposure remained only for the subgroups exposed
functions and perceptual painters, printers and different occupations. for more than 30 years.
speed others Both groups divided into It was concluded that the investigation provided some
144 unexposed age- four subgroups of exposure evidence for effects on cognitive functioning after
matched controls duration: < 10 years; long-term solvent exposure.
10-20 years; 21-30 years;
> 30 years.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Hooisma et al. (1993a) 47 young painters Cumulative solvent No consistent group differences were found between
Cross-sectional study (30-40 years old) consumptions of young and young and old painters and their age-matched controls.
Neuropsychological test 45 older painters older painters were 11.5 For young painters the test scores for immediate
battery (8 WHO core tests (55-72 years old) (l/d)years and 23.1 (l/d) memory were related to nonprotected spray painting in
and 14 computerized tests) 53 young controls years, respectively, with the last 5 years and the time spent in painting during
(30-40 years old) daily average consumptions the last 5 years. For the older painters the test
43 older controls of 0.8 and 0.7 l/d. scores for visuo-motor performance and memory were
(55-72 years old) related to the time spent in painting during the last
5 years and the total number of prenarcotic episodes,
respectively. However, these isolated findings were
found to be inconsistent.
Hooisma et al. (1993b) 120 young painters Paint solvent exposure. Younger and older painters experienced significantly
Cross-sectional study (30-40 years old) Individual data collected more complaints in 21/43 and 18/43 questions
Questionnaire containing 169 young controls on: total hours of painting concerning symptoms. In no cases did the controls
43 questions regarding (30-40 years old) or spray-painting, hours experience significantly more complaints. The two
subjective symptoms and 127 older painters of non-protected spray- exposed groups had more complaints concerning core
9 questions regarding (55-72 years old) painting, numbers of symptoms in relation to solvent exposure such as
personality 157 older controls prenarcotic episodes. fatigability, bad memory and impaired concentration.
(55-72 years old) The symptoms appeared to be related to periods of
heavy exposure rather than to other exposure
measures. No significant differences were observed in
questions concerning personality.
Table 16 (Con't)
Reference/type of studyb Groups studied Exposurec Results
Bolla et al. (1995); 144 workers from two At both plants aliphatic The performance of the exposed group was worse in 14
Ford et al. (1991) paint manufacturing hydrocarbon mixtures out of 15 test parameters. Significantly impaired
Cross-sectional study plants (from same (white spirits), toluene performance was noted in 5 tests for motor function
Neuropsychological exposure group as and xylene were the three and manual dexterity. In 10 out of the 15 tests there
test battery Bolla et al. (1990) most widely used solvents. was a positive trend between impaired performance and
and Bleecker et al. Cumulative hydrocarbon duration of exposure (for 3 tests p < 0.05). The
(1991)) exposure: 180 ppm x years scorings were adjusted for the cofactors age,
and 97 ppm x years at the vocabulary and race.
52 unexposed two plants. Lifetime-
workers weighted average exposure
were 11.7 ppm and 7.6 ppm,
respectively.
a This table includes those studies in which exposure was predominantly to white spirit, i.e. the exposure has been verified in the text
or the study group is an occupational group known to be predominantly exposed to white spirit.
b AEP = auditory evoked potential; CBF = cerebral blood flow; CT = computerized tomography; EEG: electroencephalography;
EMG = electromyography; ENG = electroneurography; NCV = nerve conduction velocity; VER = visual evoked responses
c Mexp.: mean exposure period
Table 17. Epidemiological studies on workers exposed to white spirita
Reference/type of studyb Groups studied Exposurec Results
Lindström (1973) 42 solvent exposed Mixed solvent exposure, The performance of the exposed groups was
Cross-sectional study workers (including 11 including paint solvents. significantly worse in all of 5 psychomotor
Neuropsychological testing spray-painters) with Mexp. 6 years for both functioning tests, in 3 out of 4 tests for vigilance
for intelligence, symptoms of suspected groups. and manual dexterity, and in 1 out of 3 intelligence
personality, psychomotor solvent poisoning, tests. The performance of the subgroup of workers
function, vigilance and 126 solvent exposed with suspected poisoning was significantly worse than
dexterity workers (including 40 that of the other exposed workers.
spraypainters)
50 unexposed controls
Axelson et al. (1976a) 151 persons awarded Selected occupations with A relative risk of 1.8 (p < 0.05) was calculated
Case-control study pensions because of solvent exposure: painters, for solvent-exposed workers for being awarded
Data collected from chronic nonspecific varnishers and carpet- disability pension because of chronic neuropsychiatric
disability pension neuropsychiatric layers. Main exposure: disorders compared to workers without solvent
register files disorders white spirit and other exposure.
248 persons awarded aliphatic and aromatic
pensions because of solvents.
other, non-mental Mexp. 14.2 years.
causes
Lajer (1976) 44 solvent exposed Paint solvents, including Significantly increased number of painters with
Cross-sectional study painters white spirit. Exposed symptoms. Painters suffered from 4.1 symptoms per
Questionnaire 38 unexposed for 1-45 years. Exposed person, electricians 0.9. The painters more often
concerning symptoms electricians on the day of questioning. complained of eye irritation, reduced sense of taste
and appetite, headache, nausea, vertigo, fatigue,
and of sensations of intoxication.
Table 17. (Con't)
Reference/type of studyb Groups studied Exposurec Results
Elofsson et al. (1980) 80 spray painters Mixed solvent exposure. Higher frequency of neurological and psychiatric
Cross-sectional study 2 × 80 referents from Levels of about 100 mg/m3 symptoms and complaints in the group of painters.
Medical and psychiatric electronic industry were measured. Exposure Further significantly impaired performance in tests
examinations ranked according to years concerning simple reaction time, manual dexterity,
Neurological examinations and intensity of exposure. perceptual speed and memory. Reduced nerve conduction
(EEG, VER, NCV, CT) (Exposure-free period of velocity and lowered nerve action potentials were
Neuropsychological test 18-24 h before the found. Correlation between degree of exposure and
battery (18 tests - examinations). extent of effects was not demonstrated (exposure was
representing a range of highly correlated to age, and age to some degree to
different mental performance).
functioning)
Lindström (1980) 56 solvent exposed Mixed solvent exposure. Significantly reduced scoring of the exposed group in
Cross-sectional study workers (26 painters) Main exposures: paint 6 out of 14 test parameters. Most pronounced was
Neuropsychological testing diagnosed with solvent solvent (n=21), aromatic decline in visuomotor performances (symmetry drawing,
(11 tests for intelligence induced occupational and aliphatic hydrocarbons Mira test) and decreased freedom from distractibility
and psychomotor disease (n=13), halogenated (digit span). In 2 tests significant correlation was
functioning) 43 unexposed hydrocarbons (n=21). found between the reduced score and exposure duration.
construction workers Exposure graded roughly No correlation to exposure level was found.
into low (n=3), intermediate
(n=26) and high (n=27)
exposure levels. Mexp. 9.1
years
Olson (1982) 47 solvent exposed Mixed solvent exposure. Significantly impaired performance of the exposed
Cross-sectional study workers from the paint Mexp. 24.1 years (n=38). workers in tests determining simple reaction time and
Questionnaire industry Mexp. 4.3 years (n=9, but perceptual speed. The performance of the exposed
Neuropsychological tests 47 unexposed workers more heavily exposed). workers was worse in the afternoon compared to the
(4 tests performed before 18 definitely exposed to morning test. The performance of the most heavily
and after a working day) white spirit at a mean exposed was worse than that of long-term exposed
level of 44 mg/m3. workers, indicating that symptoms were mainly due to
acute solvent exposure.
Table 17. (Con't)
Reference/type of studyb Groups studied Exposurec Results
Lindström et al. (1984) 374 construction Painters and carpet- An odds ratio of 5.5 (p < 0.05) was calculated for
Case-control study workers awarded layers were chosen as solvent-exposed workers for being awarded disability
Disability pension, data pensions because of selected occupations with pension because of neurosis (a diagnostic group
from register file neuropsychiatric solvent exposure. No including neurosis, persona pathologica, psychosomatic
disorders specific exposure disease, nervositas) compared to workers not exposed
374 construction information. to solvents.
workers awarded
pension because of
other reasons
Valciukas et al. (1985) 55 shipyard Wide variety of solvents The painters were significantly impaired in 2 out of
Cross-sectional study painters including white spirit. 95% the 3 neuropsychological tests. Significantly
Questionnaire 55 non-exposed of the painters exposed increased prevalence of acute symptoms in painters.
3 neuropsychological tests controls > 10 years. The painters No differences were found in chronic symptoms.
for perceptual functions divided into 5 subgroups No correlation was found between duration of exposure
according to exposure and test scores or symptoms.
duration.
Oerbaek et al. (1985) 50 solvent exposed Mixed solvent exposure. Significantly higher scores in the solvent-exposed
Cross-sectional study workers from the Exposure indices were group in 15 of the 60 questioned symptoms. Subjects
Clinical examination painting industry calculated on the basis of with the higher exposure indices were the most
Questionnaire of 60 50 unexposed sugar intensity and duration of affected. Significant changes in EEG measurements and
symptoms refinery workers exposure. Mexp. 18 years. decrease in regional cerebral bloodflow was observed
Neuropsychological test One group of 4 subjects in the exposed group. Further, an overall tendency
battery (9 tests for had only been exposed towards impaired performance in the neuropsychological
intellectual functions and to white spirit. testing was noted in the exposed group. Analysis of
psychomotor performance) individual test scores recalled that 7 of the exposed
Neurophysiological workers had pathological brain dysfunction.
examination (EEG, CBF, NCV)
Table 17. (Con't)
Reference/type of studyb Groups studied Exposurec Results
Linz et al. (1986) 15 solvent exposed Mixed solvent exposure The group of painters had an increased prevalence of
Cross-sectional study industrial painters from paint solvent. neurasthenic symptoms, most frequently memory loss
Questionnaire referred to an Mexp. 8.8 years. and personality change. Psychological tests disclosed
Neuropsychological test occupational health No-one exposed during poor short-term memory, difficulties in learning, and
battery clinic. 30 workers with the last 2 months an array of neuropsychological deficits. In 21 out of
Neurophysiological no or minor exposure to before examination. 30 test parameters painters scored lower than the
examinations (CT, EEG, EMG, solvents. normal average level. Neurophysiological examinations
NCV) (EMG + NCV) revealed peripheral neuropathy in 5 out of
7 painters.
Askergren et al. (1988) 39 house painters Group I and II exposed to Groups II and III more often reported of symptoms such
Cross-sectional study (group I) solvent-based paint for as impaired memory, sore throat and gastrointestinal
Questionnaire 40 house painters 22% and 42% of the total problems (group III had a significantly higher alcohol
Neurophysiological (group II) painting time in the latest consumption than groups I and II). Group II displayed
examinations (ENG, AEP, 44 bricklayers year, and to water-based signs of peripheral nervous system impairment (altered
vibration threshold) (group III) paint for 72% and 57% of ENG measures).
the time. Mexp: 22.3 years Furthermore, proteinuria and altered haematological
(group I) and 21.2 years parameters were found in both painter groups.
(group II). Very low Overall, only mild effects of mixed exposure from
exposure levels were solvent-based and water-based paints were found.
measured.
Triebig et al. (1988) 86 house painters Mixed solvent exposures A significantly higher degree of "change in
Cross-sectional study 39 matched controls from paint solvents. personality" was registered in one test in the painter
Questionnaire Measurements of daily group. Impaired short-term memory was found in a
Neurophysiological exposure level on different highly exposed painter subgroup. No other noteworthy
examinations (CT, EEG, NCV) paint solvents (white observations were made in other tests or examinations.
Neuropsychological test spirit not included in the
battery assessing measurements). Exposure
intellectual functions indices were calculated
on the basis of time spent
Table 17. (Con't)
Reference/type of studyb Groups studied Exposurec Results
each day by painting with
solvent-based paints.
Mexp. 24 years.
van Vliet et al. (1989a) 379 solvent-exposed Mixed solvent exposure. RR = 1.7-3.5 (p < 0.05) for the exposed group with
Cross-sectional study workers (painters, Exposure indices were respect to prenarcotic symptoms such as nausea,
Questionnaire (questions carpet-layers and calculated on the basis shortness of breath and loss of appetite. The presence
about solvent exposure, road-markers) of either exposure of the prenarcotic symptoms was correlated to the
prenarcotic (acute) and 443 workers not intensity or duration. intensity of exposure but not to exposure duration.
neurasthenic (chronic) exposed to solvents Only weak association between the occurrence of
symptoms) neurasthenic symptoms and solvent exposure.
van Vliet et al. (1989b); 252 persons awarded Approximately 46% in each An OR (corrected for relevant confounders) of 2.3
van Vliet et al. (1990) disability pensions group exposed to solvents (P < 0.05) was found for association between solvent
Case-control study because of mental (painters, carpet-layers, exposure and pension due to neurotic disorders (based
Questionnaire concerning disorder and road-markers). on 76 exposed cases). The OR was not significantly
solvent exposure 822 workers chosen Painters exposed to C8-C11 increased for the association between exposure and
randomly as control alkanes and C7-C10 other mental disturbances, single or combined.
All subjects were aromatics. However, among painters a significant dose-response
members of either the Exposure indices were association was found (disability pension vs.
painter or the calculated on the basis increasing exposure intensity). Only a weak
construction worker of exposure intensity association was found with exposure duration.
organization or duration. Mexp. Increased OR of 1.7 and 2.6 were found for painters
(cases) 20.6 years. who had worked with paint rolling or spraying for more
Mexp. (controls) than one day each week.
15.6 years.
Table 17. (Con't)
Reference/type of studyb Groups studied Exposurec Results
Spurgeon et al. (1994) 110 paint-makers from Many different paint No effects on cognitive functions or mental health
Glass et al. (1994) two paint production solvents used. White spirit were found in the group of paint-makers.
Cross-sectional study plants use largely reduced since
Neuropsychological test 110 age-matched 1976 and 1982 at the two
battery controls plants. Exposure
Questionnaire concerning individually described in
mental health status relation to mean ppm level
and to the cumulative dose
ppm x year. 26 workers
exposed to mean levels above
40 ppm and 25 workers
exposed to more than
600 ppm x years.
a This table includes studies in which the white spirit exposure is not defined with the same degree of certainty as in
Table 16 or is part of a more complex exposure.
b AEP = auditory evoked potential; CBF = cerebral blood flow; CT = computerized tomography; EEG = electroencephalography;
EMG = electromyography; ENG = electroneurography; NCV = nerve conduction velocity; VER = visual evoked responses
c Mexp.: mean exposure period
so-called "healthy worker effect" may be expected to dilute effects
from exposure and thus tend to bias the results towards a
no-observable effect. On the other hand, an overestimation of the
neurotoxicity of white spirit may result from case-studies if a
primary connection between adverse effects and exposure to white
spirit is made without consideration being given to other potential
causal factors.
In a report from the Commission of the European Communities on
long-term neurotoxic effects in painters, one of the major limitations
was found to be the lack of exact knowledge about exposure levels and
the nature of exposure (CEC, 1990). Although white spirit is the most
frequently used paint solvent, additional solvents such as other
aliphatic or aromatic hydrocarbon thinners, glycol ethers, secondary
and tertiary alcohols, esters and ketones are also used in
considerable amounts. Furthermore, painters may be exposed to various
kinds of dust. Dust from old paint layers may contain lead because of
the previous use of lead-containing colour pigments.
However, some of the studies mentioned in Table 16 contain more
specific exposure information (duration and exposure levels) with
respect to white spirit (Seppäläinen & Lindström, 1982; Lindström &
Wickström, 1983; Mikkelsen et al., 1988; Spurgeon et al., 1990, 1992;
Bazylewicz-Walczak et al., 1990). In these studies, together with the
studies by Blume et al. (1975) and Hane et al. (1977), the most
predominant solvent exposure is to white spirit.
Mikkelsen et al. (1988) critically reviewed the literature and
presented several items that could bias the studies. The "healthy
worker effect" may be present in all cross-sectional studies conducted
with active workers. Recent solvent exposure, which has occurred to
a varying degree in most of the studies, makes it impossible to
determine whether impaired performance in neuropsychological testing
was caused by acute or chronic effects on the CNS. Thus, acute
effects caused by recent solvent exposure may lead to an
overestimation of the chronic effects on the one hand, or
alternatively they may mask an underlying chronic dose-response
relationship.
In several studies, the absence of any observed toxicity
resulting from chronic exposure may be due to the relatively low
exposure levels in the study groups. Further attention should be paid
to the fact that the occupational level of solvent vapour has been
reduced in the past decade. Another factor is a short exposure
period, since an exposure period of 10 years or more is, according to
some authors, considered to be a minimum for induction of chronic CNS
effects. To overcome some of these problems, it was concluded that
the likelihood of observing positive findings would increase if the
workers were consistently divided into different graded exposure
groups.
Another crucial point mentioned by Mikkelsen et al. (1988) is the
selection of a proper control group. The intellectual level in this
group should ideally match the pre-exposure intellectual level in the
group of interest, e.g., painters. Although very careful selection
and matching have been made according to possible cofactors such as
age and educational, cultural and social backgrounds, and no overt
differences exist in life-style or in use of drugs or alcohol, this
still does not guarantee that the individuals from the control group
and the group of interest were comparable with respect to the
pre-exposure intellectual level. However, if some of the above-
mentioned covariates can be identified, it may be possible to
compensate for the influence from them by the use of statistical
methods such as multiple regression analysis. Pre-exposure
intellectual level could also be validated if previous military
intelligence tests were made available or by the use of "hold tests",
which are intelligence tests for abilities that are thought not to be
influenced by solvent toxicity or minor brain dysfunctions (e.g.,
tests for cognitive verbal ability, see section 8.2.1.3).
Thus, Mikkelsen et al. (1988) concluded that hidden differences
may very well occur between unexposed and exposed groups due to the
difficulties in overcoming these problems. However, false dose-
response relationships are very unlikely to occur when the workers
have been stratified according to different exposure groups, and
therefore a positive dose-response association should be taken as very
strong evidence for real differences between groups.
Dose-response relationships for different end-points have been
demonstrated in some of the studies shown in Tables 16 and 17. In
these studies, exposure was graded into different subgroups (Mikkelsen
et al., 1988; Bazylewicz-Walczak et al., 1990; Bleecker et al., 1991;
Bolla et al., 1995) or individual exposure indices were estimated
(Fidler et al., 1987; van Vliet et al., 1989a,b).
8.2.1.6 Prognosis and follow-up
Agrell et al. (1980) made a 5-year follow-up on the population
(52 house painters and 52 unexposed controls) described by Blume et
al. (1975) and Hane et al. (1977) (Table 16). Of the 52 age-matched
pairs, 42 answered a mailed questionnaire concerning subjective
symptoms. After the 5-year period there was a significant increase in
the symptoms reported by the painters with respect to irritability,
impaired memory and depression, whereas the symptoms reported by the
controls had not changed. Four of the painters had changed occupation
to non-exposed jobs and 11 painters were receiving disability pension.
Bruhn et al. (1981) performed a 2-year follow-up study on 26 of
the 50 patients (previously occupied as house painters) who were
initially examined by Arlien-Soeborg et al. (1979) (Table 15). After
the 2-year follow-up period, most of the subjective symptoms were
present to a similar degree. However, considerable improvements were
noted with respect to headache, dizziness, and irritability. On a
group basis, no significant changes were noted after re-examination
for neurological status, neuropsychological impairment (a battery of
seven tests) and cerebral atrophy (CT scanning). At the individual
level, the performance of two patients was significantly worse in the
neuropsychological tests, and in two patients cerebral atrophy had
progressed. At the time of the follow-up, 16 patients received
disability pensions and two patients were recommended for this.
Lauritsen et al. (1985) re-examined 69 out of 77 solvent-exposed
workers (41 of these were painters) after a 3-year follow-up period.
In exposed workers without encephalopathy, the number of symptoms was
found to have diminished while patients with diagnosed toxic
encephalopathy showed unchanged conditions or slight deterioration
(all workers were questioned about 12 different symptoms). No
significant difference was found in intellectual functioning following
neuropsychological retesting (battery of five tests). Of the 69
workers, 29 were still occupationally active (type of work not
specified), but 42 received disability pension and/or other
compensation because of work-related sequelae.
In a 5-year follow-up study, Gregersen et al. (1987) described
the social consequences for 21 painters who had been diagnosed with
chronic toxic encephalopathy. The diagnosis was based on detailed
clinical examinations, including interviews about exposure (levels and
duration) and subjective symptoms, neuropsychological testing, and
neurological and neurophysiological examinations. At the time of
diagnosis all the painters had given up their job and five years later
11 worked in other jobs while 10 were receiving the highest disability
pension. Clear differences were noted between those who were still
working and those who were awarded a pension. The former group were
considerably younger, had a history of lower exposure and were less
impaired in their intellectual functioning.
Edling et al. (1990) examined 102 out of 111 solvent-exposed
workers after a follow-up period of 6.7 years. All the workers
(of whom 71 were painters) were at the time of the initial examination
referred to a medical clinic. Forty-six were at that time diagnosed
as having mild toxic encephalopathy (MTE, defined as neuropsychiatric
symptoms plus mental impairment as shown by neuropsychological
testing) while 65 subjects exhibited the neuropsychiatric symptoms but
without additional mental impairment. The two groups were comparable
with respect to age (mean age 56 and 53 years, respectively) and
exposure duration (26 and 23 years, respectively). At the time of
follow-up, more people in the MTE group had stopped working
(74 compared with 35%) and were receiving disability or early
retirement pensions. At re-examination the MTE group had deteriorated
with respect to depression, concentration difficulties and lack of
initiative, while improvements were seen in the non-MTE group. In a
neuropsychological test battery, the differences in performance
between the two groups persisted from the initial to the follow-up
examination. The only deterioration noted was poorer performance of
the MTE group in two hold-tests (tests in which performance is not
supposed to be affected by solvent exposure). In a reclassification
of these workers, 12 from the MTE group were diagnosed as belonging to
the non-MTE group, while three from the non-MTE group were diagnosed
as having MTE. As an explanation for this, the authors suggested that
acute effects from exposure just prior to the initial examination
could have led to some workers being incorrectly assigned to the MTE
group. It was concluded that solvent-induced effects on the CNS
persist even after exposure had ceased. However, people with
neuropsychiatric symptoms but without impairment of mental function
may in many cases recover after removal from exposure. (The authors
found that some bias was possible because of the lower frequency of
employment in the MTE group).
Oerbaek et al. (1986) and Oerbaek & Lindgren (1988) conducted a
follow-up study with 32 workers (25 painters) previously diagnosed
with solvent-induced chronic toxic encephalopathy. After 21-88
months without exposure, the workers were retested with the
neuropsychological tests conducted at the time of the diagnosis.
Significant improvement was seen in a test for visual perception
whereas impairment was found in tests for verbal memory and simple
reaction time. Improvement was reported in subjective symptoms,
especially with respect to irritability, headache and dizziness,
whereas impairment was noted with respect to short-term memory,
peripheral sensory perception and anxiety. In conclusion, impaired
intellectual function was judged to be permanently affected, since no
firm conclusion could be drawn with respect to overall improvement/
impairment in the exposure-free period.
The overall picture of the follow-up studies is that symptoms
improve, particularly in younger subjects having normal test results,
but are still partially present after cessation of exposure. The
abnormal neuropsychological findings remain unchanged, thus suggesting
that the brain disorder is neither fully nor partially reversible.
8.2.2 Effects on skin
From a questionnaire study it appears that white spirit (18%
aromatics) may give rise to skin disorders of the hands consisting
of dry and rough skin surface with small fissures. This was
reported by 11% in a group of 148 people with dermal exposure to
white spirit, compared to 4% in an unexposed group of 71 people. A
dose-response relationship was observed, since heavily exposed workers
(exposure > 4 h/day) more often reported these effects (Björn et al.,
1983).
Among 98 American railroad workers suffering from occupational
dermatitis, a connection between the disease and the use of kerosene
and white spirit was found in 10 cases. Six of these cases were
identified by the use of patch testing in combination with exposure
data, while four cases were identified solely on the basis of the
history of exposure (Kaplan & Zeligman, 1962).
8.2.3 Effects on kidneys
There have been few human studies on the nephrotoxicity of white
spirit. However, there have been several studies and case reports on
renal disease and dysfunction among workers exposed to paints and
mixed solvents.
Table 18 shows a series of case reports of glomerulonephritis
with exposure to white spirits and paint solvents.
Ravnskov (1978) reported eight cases in which exposure to organic
paint solvent was apparently involved in the development of post-
streptococcal glomerulonephritis. In three of the cases the
exposure had lasted for a long time (occupational exposure), whereas
for the remaining five patients it was of shorter duration (exposure
from home painting). In all cases the subjects had suffered from
respiratory tract infections around the time of the exposure. The
glomerulonephritis and the nephrotic syndrome developed within one day
to a few weeks after exposure/infection.
In an evaluation of case-studies concerning the development of
glomerulonephritis after solvent exposure, Churchill et al. (1983)
reported one case in which white spirit was involved. In an
additional 16 cases the exposures were from other related hydrocarbon
mixtures. The actual case described in more detail by D'Apice et al.
(1978) involved a pair of 16-year-old identical twin sisters who
within a period of 6 weeks developed Goodpasture's Syndrome (syndrome
with acute antibody-mediated glomerulonephritis). One sister
developed the syndrome after 5 days at a job in which she sprayed
ball-bearings with white spirit. The other sister developed this very
serious syndrome after selling petrol (gasoline) for 2 weeks. The
author assumed that hydrocarbon exposure may in some cases be a
cofactor in the development of the syndrome.
Daniell et al. (1988) reported the case of a 29-year-old man who
developed renal failure after one year of floor cleaning with white
spirit (Stoddard solvent) (often for 6 h each day without using any
kind of protective equipment). Renal biopsy revealed diffuse
glomerulonephritis and focal necrosis. Findings from radioimmunoassay
for antibodies towards anti-glomerular basement membrane (anti-BGM)
were strongly positive. The patient often experienced a feeling of
getting "high" during the working day.
Table 18. Case series of glomerulonephritis and exposure to white spirit and paint solvent
Exposure Subjects Ages Diagnosisa Reference
Males Females Total
Paint solvents 5 0 5 19, 21, 22 Goodpasture's syndrome Beirne & Brennan (1972)
jet fuel 1 0 1 28, 32, 44 Rapidly progressive GN
Stoddard solvent 1 0 1 29 Anti-GBM nephritis Daniell et al. (1988)
Paint solvent 1 0 1 59 Subacute GN von Scheele et al. (1976)
Paint solvent 7 1 8 10, 10, 15, 36, Post-streptococcal GN Ravnskov (1978)
41, 45, 51, 55 Nephrotic syndrome
White spirit 0 1 1 16 Goodpasture's syndrome D'Apice et al. (1978)
a GN = glumerolunephritis
Harrington et al. (1989) studied 50 cases of biopsy-proven
glomerulonephritis and 50 community-based healthy referents matched
for age, sex, place of residence and socio-economic and ethnic
groupings. Fifteen of the cases had a history of workplace exposure
to paints and varnishes compared to 11 of the controls (OR:1.4).
Yaqoob et al. (1992) assessed the exposure history of 55
patients with end-stage renal failure due to biopsy-proven primary
glomerulonephritis. The 55 patients were divided into two groups
based on duration and intensity of exposure. The intensity of
exposure was divided as follows:
1. heavy intensity (factor of 2): e.g., occupational house painting
indoors; industrial spray painting without protection; carpet
cleaning and floor-covering agents; production of paint and glue;
2. moderate intensity (factor of 1): e.g., non-occupational house
painting indoors; spray-painting with protection devices;
industrial degreasing of metal; printing work, dry cleaning;
3. low intensity (factor of 0.5): e.g., outdoor painting, motor
repairs (Bell et al., 1985).
Those with heavy exposure were shown to have higher serum creatinine
despite similar degrees of proteinuria and proportion of
hypertensives. This suggests that those with greater hydrocarbon
exposure had more advanced disease. The authors further compared the
hydrocarbon exposure score of the 55 patients with 55 normal controls
matched for age, sex, social class and residential status. The
hydrocarbon exposure score was significantly higher among the
patients. When compared to a third control group of 45 patients with
end-stage renal failure secondary to other diseases, the hydrocarbon
exposure scores were again significantly higher in the patients with
primary glomerulonephritis.
In another case-referent study (Porro et al., 1992), 60 patients
with primary glomerulonephritis were compared with 120 controls
matched by sex and age. Intensity of solvent exposure was evaluated
using criteria similar to those of Yaqoob et al. (1992). The OR was
5.42 (95% CI 2.01-14.59) in the high exposure group and 2.12 (95% CI
0.81-5.57) in the lower exposure group. A test for linear trend was
statistically significant.
While the evidence for solvent-induced glomerulonephritis in
humans is at best circumstantial, the hypothesis remains credible and
consistent with current concepts of immunologically mediated
glomerular diseases. Alterations in the glomerular basement membrane
by solvents may render them antigenic. Alternatively, impairment of
the immune system by solvents may suppress self-recognition and permit
antibody production against unaltered tissue components (Wilson &
Dixon, 1986; Yamamoto & Wilson, 1987).
Most of the studies using biomarkers of nephrotoxicity involved
mixed solvent exposure. In only one study (Lauwerys et al., 1985) was
white spirit specifically mentioned. However, studies on painters and
paint manufacturing workers will be of relevance in this report.
In a review article Lauwerys et al. (1985) reported the results
of an unpublished study on 33 workers in the metallurgical industry.
The workers had been exposed to an estimated mean white spirit vapour
concentration of 93.6 mg/m3 (15.6 ppm) for an average of 8.5 years.
However, no indication of altered kidney function was found from
measurements of urinary ß2-microglobulin, retinol-binding protein and
albumin. Similar examinations performed on 43 car painters mainly
exposed to white spirit and toluene (exposure duration, 6-36 years;
average levels of 43.8 mg/m3 (7.3 ppm) white spirit and 7.9 mg/m3
(2.1 ppm) toluene) yielded negative results as well.
The most extensive study on paint manufacturing workers was
conducted by Normand et al. (1990); 420 workers were studied. The
exposure consisted of a complex mixture with 124 mg/m3 (33 ppm) of
toluene and concentrations of other organic solvents less than 10% of
the threshold limit value (time-weighted average). The potential
influence of lead and cadmium pigments was assessed through biological
monitoring. Exposed groups had higher mean microalbuminuria as well
as higher prevalence of elevated microalbuminuria. Similar results
were found in 40 paint manufacturing workers by Askergren et al.
(1981).
In studies by Ng et al. (1990) and Franchini et al. (1983) on
45 paint manufacturing workers and 118 painters, respectively, no
difference in the albumin excretion was found but the range was higher
in the exposed groups.
Hotz et al. (1989) used a similar hydrocarbon exposure score to
Yaqoob et al. (1992) on a group of 148 workers. The results suggest
that N-acetyl-glucosaminidase activity and erythrocyturia is
associated with hydrocarbon exposure.
Yaqoob et al. (1993a,b) evaluated the glomerular and tubular
markers of 112 paint sprayers with exposure to paint-based mixtures
of hydrocarbons. They had significantly higher prevalence of
elevated serum creatinine, abnormal urinary total protein, and
N-acetyl-glucosaminidase, gamma-glutaryl transferase and
leucine-aminopeptidase excretion.
Stevenson et al. (1995) found higher levels of serum laminin and
soluble E-selectin in a group of 111 workers exposed to paint-based
hydrocarbons. Serum laminin is a basement membrane turnover marker
and E-selectin an endothelial activation marker. These elevations
suggest alterations to the basement membranes and overlying vascular
endothelial cells resulting in auto-antibody production.
The long-term significance of these early markers of
nephrotoxicity has often been questioned. However, the elevation of
these markers lends support to the hypothesis that painters are at
higher risk of developing nephropathy, presumably from hydrocarbon
exposure.
8.2.4 Effects on liver, blood and bone marrow
Braunstein & Schenectady (1940) reported a case in which a
previously healthy 26-year-old man developed swelling of the liver and
jaundice. The man worked at a dry cleaning factory and had been
exposed to white spirit (Stoddard solvent) for a period of 3 months
(heavy skin and inhalation exposure). In addition to the liver
effects, symptoms and diseases, such as muscular weakness, dermatitis
of the hands, anaemia, gastrointestinal disorders, blood in the
stools, albuminuria and glucosuria, were described. After
hospitalization and removal from exposure, complete recovery took
place.
In another case a 41-year-old man working as a heavy equipment
mechanic was exposed frequently for 16 years to white spirit (Stoddard
solvent). He developed diffuse petechia, anaemia and depression
of all cellular components of the bone marrow. The patient died
11 months later, the diagnosis being aplastic anaemia (Prager &
Peters, 1970). Other cases in which white spirit (Stoddard solvent)
was considered the cause of lethal or non-lethal aplastic anaemia have
been described (Kegels, 1958; Scott et al., 1959).
Liver damage, revealed by histological findings (steatosis and
fibrosis) and by elevated serum transferase activity, was recorded in
13 out of 156 patients who were admitted to hospital because of
suspected long-term solvent intoxication. No other factors (e.g.,
alcohol abuse, exposure to known hepatotoxic agents such as
pesticides, drugs) could explain the findings. Ten of the 13 patients
were house painters and had for a period of 6-39 years been exposed to
vapour from paint solvents. Liver biopsies were repeated after 4-37
months in three of the workers. The histological findings were
unchanged, although the workers had stopped working with solvents
(Doessing et al., 1983).
8.2.5 Haematological and biochemical effects
Appraisal
There have been few reports on the haematological and
biochemical effects of white spirit. However, clinical studies have
revealed decreased erythrocyte, leukocyte and platelet counts, and
increased mean corpuscular volume in exposed workers. Similar
haematological changes have been observed in animal studies. There
are no consistent serum biochemical changes; reduced aspartate
aminotransferase and lactate dehydrogenase activities and elevated
creatinine kinase activity have been observed.
Hane et al. (1977) determined a significantly lower mean
concentration of haemoglobin in a solvent-exposed group (n=52)
compared to controls (n=52) (Table 16). Sedimentation rate and serum
transaminase activities were unaffected.
In a cross-sectional study, Elofsson et al. (1980) determined
haematological parameters in 80 spray painters (Table 17). The group
mean values were all within normal limits. Compared to two reference
groups, however, significantly higher values were found in the exposed
group with respect to haemoglobin, haematocrit, erythrocyte numbers
and alkaline phosphatase activities.
Oerbaek et al. (1985) carried out measurements of haematological
and biochemical parameters in a group of 50 solvent-exposed workers
from the painting industry and in a reference group (Table 17).
Significant differences were found for several parameters
(lowered platelet counts, altered leukocyte differential counts,
reduced lactate dehydrogenase activity and increased aspartate
aminotransferase activity). However, no consistency was found in
these differences as an exposure-effect relationship could not be
demonstrated. The authors concluded that significant alterations in
haematological and biochemical parameters may only occur with exposure
to very high levels of organic solvents.
Pedersen & Rasmussen (1982) analysed 21 haematological and
biochemical parameters in 122 male patients referred to a medical
clinic because of a suspected solvent poisoning syndrome. From a
detailed description of exposure, white spirit turned out to be one of
the dominant agents for 55 construction painters and 18 printers. The
only significantly affected parameters were lowered leukocyte counts,
lowered serum creatinine level and, in recently exposed workers,
increased serum creatine kinase activity. These findings were not
considered to be substantial enough to provide evidence for some
solvent-induced effects, basically due to the limitations of the
comparison of exposed hospital out-patients with a control group of
non-exposed hospital in-patients. In an earlier study, Pedersen et
al. (1980) found an increase in the serum creatine kinase activity in
a group of 69 solvent-exposed workers. This increase was assumed to
be an early sign of solvent-induced myopathy.
In a clinical study, seven volunteers (students) were exposed to
600 mg/m3 (100 ppm) of white spirit (99% aliphatic alkanes), 6 h/day
for 5 days. After the exposures the serum creatine kinase activity
had increased to 76% above the pre-exposure level, and serum follicle
stimulating hormone (FSH) had significantly decreased to 9% below the
initial level. No changes were found in plasma immunoglobulins
(Pedersen & Cohr, 1984b).
Beving et al. (1983) determined the level of platelets in the
blood from 12 car painters exposed to solvents (mainly white spirit
and methyl- n-butyl-ketone) and organic isocyanates. The mean
level of platelets was significantly reduced compared to that of
50 unexposed subjects (150 × 109 and 220 × 109 platelets/litre,
respectively), while the serotonin uptake rate in the platelets was
significantly increased.
Beving et al. (1988) examined the fatty acid composition in
platelets from 12 workers exposed to paint solvents (consisting of 70%
white spirit and 30% aromatic hydrocarbons and various acid esters).
A minor but significant shift towards a higher proportion of saturated
fatty acids and a lower proportion of unsaturated fatty acids in the
phospholipid fraction of the platelets was found in the exposed group,
compared to a group of 12 subjects. The authors suggested that this
may reflect similar changes in other membranes, e.g., in the CNS
neurons.
Significantly decreased erythrocyte count and increased
erythrocyte volume, compared to controls, were observed in a group of
17 car repair painters (as well as in a group of 28 car mechanics)
frequently exposed to white spirit and other paint solvents (Beving et
al., 1991).
8.3 Reproductive toxicity
Appraisal
There have been several reports on the effect of solvents on
reproductive function. However, no distinction has generally been
made between the types of solvent, as to whether they are
chlorinated hydrocarbons or oxygenated solvents. It should be noted
that low molecular weight glycol ethers have been used in solvents
which are developmental and reproductive toxins. It is not always
clear which solvents are used or the extent of exposure.
Using questionnaires Holmberg & Nurminen (1980) examined
occupational exposure of 120 case mothers who had given birth to
children with congenital CNS defects (anencephaly, hydrocephaly, spina
bifida, microcephaly and other anomalies) and of 120 referent mothers
who had normal children. Case mothers were found to be more
frequently exposed to organic solvents during the first trimester of
the pregnancy than referent mothers (rate ratio estimate RR = 5.5,
p < 0.025). A total of 12 case mothers had been exposed to solvents
and four of these to white spirit (two in combination with other
solvents).
In a study by Peters et al. (1981), 92 cases of brain tumour in
children less than 10 years old were compared with 92 matched controls
for parental occupational history. A relative risk of 2.8 (p=0.02)
was calculated for fathers being exposed to solvents and a relative
risk of 7.0 (p=0.04) was found for exposure to paint solvents in
particular (seven case fathers and one referent father).
In a similar study concerning 948 children with cancer (282 cases
of tumours), an increased odds ratio of 5.00 (p < 0.05) was
calculated for the connection between brain tumour of the child and
the father's occupation as a painter (based on seven cases with the
father employed as a painter) (Hemminki et al., 1981). Similar
findings were also reported in a study by Olsen (1983), who emphasized
that until further data were available the relationship between
childhood brain tumour and paternal occupation as a painter should be
considered purely hypothetical.
In another case-control study, 388 mothers of children born with
oral clefts were matched to 388 mothers of children without anomalies.
By interviewing the mothers about their occupational and domestic work
and chemical exposure during the pregnancy it was found that 14 of the
cases, as opposed to 4 of the controls (p < 0.05), had been exposed
to organic solvents in the first trimester. Ten of the cases had been
exposed to hydrocarbon products of the white spirit type (six of these
as the only exposure). Two of the referents had been exposed to this
kind of solvent. The women were only considered as exposed if their
average exposure level was estimated to exceed one third of the
current threshold limit value (TLV) for the solvent, or if the
exposure data indicated peak levels reaching or exceeding the TLV
(Holmberg et al., 1982).
Mikkelsen et al. (1983) collected reproduction data by combining
data registers from trade unions and public register files concerning
birth, death and cancer. The study included 11 543 men from the
painters union and 21 421 men from the electrician union. No
differences were found between the groups with respect to reproductive
parameters such as the risk of having children with congenital
malformations, the female/male sex-ratio and infant mortality. Minor
(not significant) differences were observed with respect to slightly
reduced birth weight and size of the children of the painters, and a
slightly increased frequency of childhood cancer. However no firm
conclusions could be drawn from these findings.
Similar trends towards lowered birth weight and/or birth body
length of children whose fathers worked as spray-painters/construction
painters were reported by Daniell & Vaughan (1988) and Höglund et al.
(1992).
A questionnaire study concerning the rate of infertility
included 3251 male painters and 1397 male construction workers in
the Copenhagen district. Infertility was defined as having been
involuntarily childless for a period of at least 2 years. A
significantly increased infertility rate was detected among the
painters aged 21-40 years compared to the group of construction
workers. No such differences were found in the older groups
(age: 41-60 years). The authors noted that for the group of painters
with increased infertility the period in which they desired to have
children coincided with the period in which organic solvents were most
intensively used in alkyd paints (Bjerrehuus & Detlefsen, 1986).
Heidam (1984) observed an increased odds ratio (OR: 2.9; 95%
CI: 1.0-8.8) of spontaneous abortion among 76 women occupied as
painters compared to controls (women working as shop assistants or
packers within the same county). The study was performed with mailed
questionnaires and covered all women working as painters and women in
nine other selected occupations in a population of 430 000. The
questionnaire included the entire reproductive history of the women
before May 1980. At the calculation of the odds ratios the values
were adjusted with respect to the number of pregnancies in the group,
with respect to the pregnancy order, and to the woman's age using a
logistic regression model. The elevated OR for painters (and for
factory workers as well) could not be associated to any single agent.
The association between solvent exposure and spontaneous abortion
was examined in an interview study with 1926 women of whom
approximately one-third had experienced spontaneous abortion during
the first 20 weeks of gestation. The women were questioned about
solvent exposure (different types of solvents, exposure duration
during pregnancy and exposure intensity). From 15 cases and 12
controls exposed to paint thinner a crude odds ratio (OR) of 2.3
(95% CI: 1.0-5.1) was calculated. An adjusted OR of 1.8 (CI: 1.1-3.0)
was calculated from a total of 75 cases and controls exposed to
aliphatic solvents (mainly from paints and paint thinner). In the
latter OR, allowance (by logistic regression) was made for different
confounding factors (maternal age, race, education, previous fetal
loss, smoking, working hours per week). No positive relationship was
found between duration of exposure and the OR (Windham et al., 1991).
Overall, there is a suggestion that parental exposure to solvents
may have an untoward effect on the offspring.
8.4 Carcinogenicity
Appraisal
Several epidemiological studies of cancer in workers with
potential exposure to white spirit, e.g., painters, metal
machinists, construction workers and dry cleaners, are available.
Increased relative risks for certain cancers (e.g., lung, kidney,
prostate, Hodgkin's lymphoma) have been observed, but the studies
are insufficient to demonstrate causal association with exposure to
white spirits.
Twenty-five patients suffering from Hodgkin disease were matched
with 50 reference workers and interviewed about occupation and
chemical exposure. Exposure was defined as handling organic solvents
every working day for at least 1 year within the preceding 10-year
period. Twelve (48%) patients with Hodgkin disease and six referents
(12%) were occupationally exposed with a relative risk of 6.6
(p = 0.0005). These 18 subjects had been exposed for a median period
of 8 years. Two of the patients had been exposed to white spirit
(together with other solvents) while another three (painters) had been
exposed to paint solvents (not further specified) (Olsson & Brandt,
1980).
Hardell et al. (1984) performed a matched case-control study
including 102 cases of primary liver carcinoma (83 hepatocellular
carcinomas, 15 cholangiocellular carcinomas, 3 haemangiosarcomas, and
one unspecified liver sarcoma) and 204 controls. Exposure data was
obtained from questionnaires sent to close relatives of the cases and
controls. The exposure to organic solvent of 22.4% of the cases and
13.5% of the controls was "high-grade" (more than one week of
continuous exposure or more than one month of repeated brief
exposures). In the exposed group a risk ratio of 2.1 (p < 0.05) was
calculated for hepatocellular carcinoma. The most common exposures
were to solvents such as thinners, turpentine and white spirit. (The
ratio was calculated without accounting for alcohol consumption, which
in itself gave rise to an increased relative risk for hepatocellular
carcinoma of 4.2).
In a case-control study, Siemiatycki et al. (1987) examined the
association between cancer of many sites and exposure to 12
petroleum-derived liquids including white spirit. In all, 3726 cancer
patients were interviewed about occupation and exposure history. Of
these, 739 had been exposed to white spirit primarily in their work as
construction painters (20.8%), mechanics and repairmen (19.6%), or
working with metal machining equipment (5.4%). Among these, 92 cases
of squamous-cell lung cancer and 100 cases of prostate cancer were
identified. A grading of exposure into four groups, according to
intensity and duration of exposure, was made, and relative risks were
calculated, allowing for any possible cofactor (factors which were
calculated to affect the risk estimate by more than 10% in a
confounder analysis). With respect to squamous-cell lung cancer and
prostate cancer, the relative risk increased with increasing exposure,
and for the highest exposure group relative risks of 1.7
(90% CI: 1.2-3.3) and 1.8 (90% CI: 1.3-2.6) were calculated for the
two cancer forms. For Hodgkin's lymphoma a relative risk of 2.0
(90% CI: 1.0-4.1) was calculated on the basis of 12 cases with
long-term (> 20 years) exposure. There was no increased risk for
cancers of the bladder, kidney, stomach, colon, rectosigmoid colon or
rectum, or for non-Hodgkin's lymphoma. Analysis of the association
between job titles and cancer only revealed positive associations for
metal machinists (relative risk = 2) and for construction workers
(relative risk = 1.4), occupations in which white spirit was found
to be used extensively. (Relative risk for a specific cancer was
calculated using the patients having cancers at other sites as
controls).
Several studies have been performed with laundry and dry cleaning
workers exposed to perchloroethylene and/or white spirit (Stoddard
solvent). These studies reported increased risk of cancer of the
kidney, lung and pancreas (Duh & Asal, 1984; Brown & Kaplan, 1987;
Petrone et al., 1987). Stoddard solvent was extensively used as the
cleaning solvent (> 50% of the solvent consumption), especially in
the Oklahoma studies (Duh & Asal, 1984; Petrone et al., 1987).
In the study by Duh & Asal (1984) an elevated standardized
mortality odds ratio of 1.7 (37 deaths, p < 0.05) was found for lung
cancer and a ratio of 3.8 (7 deaths, p < 0.05) for kidney cancer.
Petrone et al. (1987) conducted a cohort-mortality study with 4000
dry-cleaning workers and found an increased proportionate mortality
ratio for respiratory cancer of 1.42 (44 deaths, p < 0.05) and for
pancreatic cancer of 1.96 (12 deaths, p < 0.05). Similar results
were obtained for the subset of workers (about 60% of the cohort)
solely exposed to white spirit (Stoddard solvent).
Nakamura (1985) studied causes of death among 1711 laundry and
dry-cleaning workers in Japan and found non-significantly elevated
standardized proportional mortality ratios (SPMR) of 1.4 (16 deaths)
for respiratory cancer and 2.5 (2 deaths) for kidney cancer in women
(but not for these sites in men). Significantly elevated ratios were
seen for cancer of the bone in women (SPMR 10; 5 deaths) and for
cancer of the small intestine in men (SPMR 1.7; 18 deaths). Petroleum
solvents such as white spirit (Stoddard solvent) and naphtha were the
most widely used (in about 65% of cases) of the cleaning solvents.
In an aircraft maintenance facility, no statistically significant
risks of non-Hodgkin's lymphoma or multiple myeloma were seen among
small groups of workers exposed to white spirit (Stoddard solvent)
(Spirtas et al., 1991).
8.4.1 Epidemiological studies with painters
The International Agency for Research on Cancer has evaluated in
detail epidemiological cancer studies on painters or workers in the
paint manufacturing industry (IARC, 1989b). No further description of
these studies will therefore be given in this monograph. In the
overall IARC evaluation, it was found that the larger cohort studies,
in particular, indicated a consistent excess of all cancers (about 20%
above the respective national averages) and a consistent excess of
lung cancers (about 40% above the national averages). Less consistent
but increased risks were noted for cancers of the oesophagus, stomach
and bladder. Some studies reported excess leukaemia and cancers of
the buccal cavity and larynx.
Gubéran et al. (1989) (not included in the IARC evaluation, see
Table 16) found higher incidences of cancer among 1916 painters than
those expected for the region of Geneva. Significantly increased
incidences were observed with respect to lung cancer (n = 40;
SIR = 147; 90% CI: 111-191), cancer of the gall bladder (n = 3;
SIR = 375; 90% CI: 102-969), testis cancer (n = 5, SIR = 313; 90%
CI: 123-657) and bladder cancer (n = 13; SIR = 171; 90% CI: 101-272).
In a case-control study based on 19 904 male patients in the New
Zealand Cancer Registry, Bethwaite et al. (1990) identified three
cancer sites associated with occupation as a painter. Increased
odds ratios were calculated for bladder tumours (OR: 1.52; 95%
CI: 1.00-2.31), kidney and other urothelial tumours (OR: 1.45; 95%
CI: 0.85-2.50) and multiple myeloma (OR: 1.95; 95% CI: 1.05-3.65). In
the calculation of the OR values for each cancer site, the remaining
registrants for the other cancer sites served as controls.
8.5 Genotoxicity
Sixteen tank cleaners exposed to the vapours of white spirit,
xylene and petrol (gasoline) were examined for chromosomal aberrations
in bone marrow cells and in peripheral lymphocytes and for micronuclei
in erythropoietic bone marrow cells. Significantly elevated values
compared to unexposed controls were found with respect to chromosome
aberration in peripheral blood lymphocytes and with respect to
micronuclei in polychromatic erythrocytes and erythroblasts. A
dose-response relationship was noted between a high and a low exposure
group, but the high exposure group (n = 9) contained eight smokers.
Differences were still present when all the smokers from the group of
tank cleaners (n = 10) were compared with smokers from the referent
group. The cleaners had a median exposure period of 7 years and the
hydrocarbon exposure level had in some cases been measured as
100-300 ppm. There was a high degree of dermal contact with the
hydrocarbon solvents, as well as exposure to liquids containing heavy
metals (Högstedt et al., 1981).
Kelsey et al. (1988, 1989) did not find any correlation between
sister chromatid exchange (SCE) frequency in peripheral blood
lymphocytes and cumulative lifetime (chronic) solvent exposure in a
group of 106 painters. Elevated SCE frequency was noted in recently
(acutely) exposed and currently smoking painters, whereas the SCE
frequencies in recently exposed not currently smoking painters were
comparable to non-smoking controls.
Nylander & Berg (1991) tested the mutagenicity of urine from
32 road tanker drivers handling petrol, diesel, paraffin and white
spirit. No difference in mutagenicity was found compared to 33 office
workers serving as referents. Mutagenicity was tested in the
Salmonella/microsome system using strain TA98 and TA100.
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
Appraisal
There have been very few studies on the toxicity of white
spirit to organisms in the environment. LC50 values in the order
of 0.5 to 5 mg/litre have been reported for aquatic organisms either
for white spirit or for related hydrocarbon mixtures. There are
difficulties in obtaining meaningful results from such tests with
volatile materials. It is likely that exposure in the general
environment will be low, given the volatility of many of the
components of white spirit and sorption to soil/sediment. Since
information on general environmental concentrations of white spirit
is unavailable, it is not possible to assess the risk of white
spirit exposure to organisms.
9.1 Laboratory experiments
9.1.1 Microorganisms
Persidsky & Wilde (1956) studied the effect of white spirit
(Stoddard solvent) (1123 litres/ha, 100 gallons/acre) on the growth of
Aspergillus niger. The exposure reduced the number of colonies per
membrane by 49%. The nitrification capacity and carbon dioxide
evolution were reduced by 88% and 79%, respectively. The growth of
Aspergillus, over a 5-day incubation period, as measured by the
average weight of the mycelium, was reduced by 30 to 40%. The effect
of Stoddard solvent on the growth and development of symbiotic
mycorrhizal fungi was studied in sand cultures using Pinus
radiata. The application did not significantly affect the weights
of total seedlings, tops or roots.
9.1.2 Aquatic organisms
Dennis et al. (1979) exposed the water flea (Daphnia magna) and
two species of fish, the fathead minnow (Pimephales promelas) and
bluegill (Lepomis macrochirus), to heavy aromatic naphtha (boiling
point, 168-274°C; hydrocarbons C8-C11) under static conditions at
20°C. On the basis of preliminary bioassays, the 48-h LC50 for the
daphnids was estimated to fall within the range of 0.42-2.3 mg/litre,
and the 96-h LC50 values were estimated to fall within the ranges of
4.2-20.8 and 2.1-4.2 mg/litre for the two fish species, respectively.
Adema (1985) tested the toxicity of white spirit (C7-C11;
alkanes 53%; ratio of iso to normal alkanes, 1.3; cycloalkanes
27%; aromatics 20%) to two marine crustaceans, the brown shrimp
(Crangon crangon) and the gammarid Chaetogammarius marinus. Three
different test methods were used in closed or open systems to give a
total of five tests (two closed, three open) for the gammarid and
three tests (one closed, two open) for the shrimp. The different
methodologies for the preparation and extraction of the test medium
and different chamber design meant that, in some cases, surface films
or droplets of undissolved white spirit components were present. As
expected, test methods providing opportunity for evaporation of white
spirit and those with lower extraction efficiency for chemical
analysis produced 96-h LC50 estimates higher than those for other
methods. The 96-h LC50 values for closed systems with high
efficiency extraction ranged from 2.5 to 4.5 mg/litre, whereas those
for open systems ranged from 10 to 40 mg/litre (both based on dosed
amounts). The average LC50 for closed systems based on measured
amounts was 0.53 mg/litre. In open containers without renewal of test
solutions, the concentrations of all components of the white spirit
fell to undetectable levels within 96 h. Comparison of tests with and
without renewal in open systems showed that the majority of animals
killed were affected at an early stage of exposure. Results were the
same regardless of the presence or absence of surface film or
droplets, suggesting that the dissolved component was responsible for
the toxicity. The authors suggested C9-C11 aromatics and alkanes as
the most likely white spirit components to contribute to toxicity.
9.1.3 Terrestrial organisms
Voigt (1953) studied the effect of white spirit (Stoddard
solvent; 1123 litres/ha, 100 gallons/acre) on the oxygen uptake of
excised root tips of the plant seedlings of jack pine, red pine, white
pine and black locust. Oxygen uptake (µl/h per mg dry weight) was
increased by 38.5, 7.6, 18.8 and 19% for the four plant species,
respectively.
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
All the constituents of white spirit are readily absorbed into
the blood stream following inhalation of the vapour. White spirit is
also dermally absorbed. Absorbed white spirit is widely distributed
throughout the body. It passes through the blood-brain barrier.
Quantitative distribution figures are available for some constituents
showing preferential partitioning into fat for both aliphatics and
aromatics. However, residues of white spirit constituents remaining
in the body following short- or long-term exposure are likely to
concentrate in fat.
There is no information on the brain concentration of white
spirit constituents in humans. In rats, the ratio of aliphatic to
aromatic concentrations in the brain following 3 weeks of exposure
increased with dose. Insufficient information is currently available
to enable extrapolation from animal studies to humans on distribution
of components.
Adequate information is not available on the metabolic breakdown
of white spirit. However, metabolism studies have been reported for
some of the single constituents. The main metabolic pathway for both
aliphatic and aromatic compounds is by oxidation. Some metabolites
are then conjugated prior to excretion. The half-life for white
spirit elimination from fat has been estimated to be 46 h. The
majority of excretion is via the urine, with a minor proportion
through exhaled air.
Residual white spirit from the high acute exposure of amateur
painters will be lost within a few days. Regular occupational
exposure will lead to accumulation in fat.
White spirit has low acute toxicity by the inhalation, dermal and
oral routes. Central nervous system depression following acute
exposure may lead to lack of coordination and extended response time.
Dizziness and tiredness were reported following a 7-h exposure to
600 mg/m3 (100 ppm). Exposure to very high concentrations of white
spirit in enclosed spaces can lead to narcotic effects and loss of
consciousness. Chest pain, cyanosis, apnoea and cardiac arrest have
been reported. White spirit may cause serious lung damage after oral
ingestion because of aspiration of the solvent into the lungs.
White spirit is a slight to moderate irritant to skin in humans.
Prolonged or repeated exposure can lead to severe irritant dermatitis
due to defatting. Slight irritation of the eye, nose and throat has
been reported in humans at a white spirit vapour concentration of
600 mg/m3 (100 ppm).
Nervous system effects have been reported following repeated
exposure of rats by inhalation; these include slight neurobehavioural
effects, increased levels of brain dopamine, noradrenaline and
serotonin, and changes in sensory evoked brain potentials. Other
reported effects include mild anaemia, change in liver weight, and
"alpha2-microglobulin nephropathy". The interpretation of
neurobehavioural effects after acute exposure to white spirit is
difficult and only one study is available; a lowest-observed-effect
level (LOEL) of 1200 mg/m3 was indicated for an acute narcotic effect
in rats. No-observed-adverse-effect level (NOAEL) and lowest-
observed-adverse-effect level (LOAEL) values in laboratory animals are
given in Table 19.
Table 19. No-observed-adverse-effect levels and lowest-observed-
adverse-effect levels from animal studies
Route Effects Exposure NOAEL/LOAEL
Dermal systemic (weight gain, 200 mg/kg NOAEL
haematological) occlusion 6 h
3 times
weekly for
4 weeks
Inhalation kidney function/structure 600 mg/m3 LOAEL
8-13 weeks
Inhalation liver weight 2000 mg/m3 LOAEL
13 weeks
Inhalation biochemical effects in 575 mg/m3 LOAEL
brain, glial cell 17 weeks
proliferation
Inhalation neurotransmitters 2290 mg/m3 LOAEL
26 weeks
Inhalation motor activity, 2339 mg/m3 LOAEL
evoked potentials 26 weeks
There have been no reproduction studies, and the developmental
toxicity studies in animals are inadequate to evaluate these
end-points.
The weight of evidence indicates that white spirit is not
genotoxic.
There have been no white spirit carcinogenicity studies on
laboratory animals.
Many epidemiological studies on occupationally exposed humans
have identified symptoms of central nervous system effects of solvent
exposure, predominantly to white spirit. These have ranged from
dizziness and headache to impaired capability in performing
neuropsychological tests. In severe cases, chronic toxic
encephalopathy has been diagnosed. The prevalence of impaired
functioning increased with increasing exposure duration in studies
comparing painters with control groups from other building trades.
Details of symptoms and case studies are given in chapter 8 and the
summary in section 1.7.
Estimates of occupational exposure in epidemiological studies
have been based on historical exposure indications, i.e. working
materials, methods, conditions, ventilation and use of protective
equipment. Such imprecise estimates of exposure make it difficult to
establish exposure-effect relationships for the subjects studied.
There are few reported measurements of occupational exposure
concentrations of white spirit for painters in epidemiological
studies. Therefore, estimates have been made from measurements in
other studies. There is general agreement that brush and roller
application of alkyd paints leads to an average white spirit
concentration of around 600 mg/m3 (100 ppm). Given that painters are
estimated to spend around 40% of their time applying alkyd paints
(as opposed to applying water-based paints or preparing surfaces), an
estimated average daily 8-h exposure to 240 mg/m3 (40 ppm) has been
used in studies. Without ventilation, exposure can peak at much
higher levels of between 1800 and 6000 mg/m3 (300 and 1000 ppm).
Similar average and peak exposures have been reported in other
industries, such as dry cleaning, where Stoddard solvent is used.
On the basis of these average exposure levels and results of
neuropsychological tests (see section 8 for details), an attempt has
been made to model exposure/effect of white spirit on house painters.
This leads to the suggestion that exposure to an average of 240 mg/m3
(40 ppm) white spirit for more than 13 years could lead to chronic
central nervous system effects. However, considerable reservations
apply to this estimate. The Task Group could not estimate a
no-observed-adverse-effect level for occupational exposure to white
spirit based on the studies available. The frequent occurrence of
neuropsychological signs among workers in house painting implicates
white spirit in the development of "chronic toxic encephalopathy".
Case-control studies and studies on early markers of nephro-
toxicity are conflicting and the long-term significance of these
markers has been questioned. However, they suggest that painters have
a higher risk of primary glomerulonephritis and renal dysfunction.
It is not possible to evaluate reproductive toxicity and
carcinogenicity end-points for humans, since there are no adequate
studies directly relating to white spirit exposure.
10.2 Evaluation of effects on the environment
There are no measurable concentrations of white spirit in the
environment except following spills. However, the constituent
compounds would be expected to partition largely to the atmosphere.
Less volatile constituents partition to soil and sediment, where
lowered bioavailability reduces uptake by organisms. White spirit is
readily biodegradable under aerobic conditions. Octanol/water
partition coefficients ranging from 3.5 to 6.4 indicate moderate
potential for bioaccumulation. No studies have measured
bioconcentration factors; however, because of the reported fate
studies, these would be expected to be low in the field. The few
toxicity studies available show moderate toxicity to aquatic
organisms.
11. RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
a) In order to reduce exposure concentrations for the general public
and the occupationally exposed, paints based on white spirit
should not be used in inadequately ventilated areas.
b) All practicable methods should be used to minimize exposure of
indoor painters to white spirit. Greater use should be made of
water-based and other paints.
12. FURTHER RESEARCH
a) Comparative studies should be made of different types of white
spirit to elucidate differences in the toxicity of components
(aliphatics, aromatics, etc).
b) Reproductive and developmental toxicity studies need to be
carried out on animals.
c) Assessment of dermal absorption needs further research.
d) Further study is needed to model the kinetics and metabolism of
white spirit.
e) Clarification is needed on the relationship between acute and
long-term neurotoxicological effects in humans.
f) Research is needed on neurotoxicological mechanisms in order to
evaluate animal-to-human extrapolation.
g) Rodent carcinogenicity studies are needed.
h) If a suitable population exposed to white spirit could be
identified, longitudinal studies should be conducted.
i) Further studies are needed to establish a no-observed-adverse-
effect level for occupationally exposed humans. Validation of
modelling studies is recommended.
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
IPCS (1982) made an evaluation of petroleum solvents
(special-boiling-point solvents, white spirit and high-boiling-point
aromatic solvents). In this evaluation attention was drawn to acute
CNS effects (narcosis) from accidental inhalation of very high vapour
concentrations and to general non-specific symptoms (feelings of
ill-health) from excessive chronic exposure. In addition it was noted
that solvents containing benzene or n-hexane may have specific
chronic effects.
In 1986 the Nordic Expert Group for Documentation of Occupational
Exposure Limits concluded in its evaluation that the critical effects
of white spirit are irritation of the eyes and mucous membranes and
acute and chronic CNS effects. It was also noted that the risk of
developing chronic toxic encephalopathy following long-term exposure
should be taken into consideration (Hass & Prior, 1986).
The International Agency for Research on Cancer evaluated some
petroleum solvents, including white spirit, in 1989 and found these
solvents not classifiable with respect to their carcinogenicity to
humans (IARC group 3). There was inadequate evidence for
carcinogenicity in humans and no experimental animal data on white
spirit were available (IARC, 1989a).
In their report "Organic Solvents and the Central Nervous
System", the World Health Organization and Nordic Council of Ministers
(WHO/NCM, 1985) concluded: "Clinical, epidemiological and experimental
data indicate that long-term exposure to organic solvents may cause
adverse effects in the central and peripheral nervous system." ...
"The principal central nervous system disorders caused by long-term
solvent exposure can be classified in two categories: the organic
affective syndrome, consisting mainly of different psychiatric
symptoms, and chronic toxic encephalopathy." ... "In view of the
potential severity of the disorder and the uncertainty regarding the
reversibility of some neurological and psychological deficits and
their impact on social life, adequate preventive action should be
taken to reduce solvent exposure whether at the workplace or in
relation to leisure use."
The Commission of the European Communities and the Danish
Ministry of the Environment in 1990 organized an international
conference on organic solvents and the nervous system. In the
conference report it was concluded: "Occupational exposure to organic
solvents in concentration levels at workplaces in the last 30 years
imply a risk of central nervous system deficits."..."All longitudinal
studies show a uniform indication of increased risk of being awarded
an early disability pension due to neuropsychiatric disorders,
although the individual diagnosis might vary from registry to
registry. Thus, a marked association between occupational exposure
and neuropsychiatric disorders is established." (CEC/DME, 1990;
Arlien-Soeborg et al., 1992).
In 1994 the European Union agreed to classify a large number of
petroleum-derived substances with regard to carcinogenicity and risk
from lung aspiration (other toxicological effects were not evaluated).
The five EINECS numbers for white spirit were included in different
petrochemical groups, owing to differences in refinery treatment.
They were (with the exception of white spirit type 0) classified as
carcinogenic category 2, with the risk phrase R45 (may cause cancer)
attached. However, this classification need not apply if it can be
shown that the substances contain less than 0.1% (by weight) benzene.
In addition, all the white spirit solvents were, owing to the
aspiration risk, classified as harmful (Xn), with the risk phrase R22
(harmful if swallowed) attached (European Commission, 1994). This
risk phrase may, in the near future, be replaced by a new phrase R65
(harmful: may cause lung damage if swallowed) (European Commission,
1995).
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RESUME
1. Propriétés du white spirit
Le white spirit est un solvant incolore et limpide, très peu
soluble dans l'eau et d'odeur caractéristique (seuil olfactif:
0,5-5 mg/m3). Sa variété la plus courante consiste en un mélange
d'hydrocarbures aliphatiques et alicycliques saturés en C7-C12, avec
une une teneur de 15-20% (en poids) en hydrocarbures aromatiques en
C7-C12 et un intervalle d'ébullition de 130-230°C. La majeure
partie du mélange (au moins 80% en poids) est constituée d'hydrocarbures
aliphatiques, alicycliques et aromatiques en C9-C11. Ce white
spirit ordinaire est désigné par l'expression white spirit,
type 1, qualité ordinaire et il en existe trois autres types et
qualités. Selon que le produit a été soumis uniquement à une
hydrodésulfuration (élimination du soufre), à une extraction par
solvant ou à une hydrogénation, on a respectivement affaire au type 1,
2 ou 3. Le type 1 (hydrodésulfuré) contient moins de 25%
d'hydrocarbures aromatiques, le type 2 (extrait par solvant), moins de
5% et le type 3 (déshydrogéné), moins de 1%. Il existe trois qualités
pour chaque type: la qualité à bas point d'éclair (point d'éclair:
21-30°C; point d'ébullition initial: 130-144°C), la qualité ordinaire
(point d'éclair: 31-54°C, point d'ébullition initial: 145-174°C) et la
qualité à haut point d'éclair (point d'éclair: > 55°C; point
d'ébullition initial: 175-200°C). La qualité est déterminée par le
brut de départ et les conditions de distillation. Le white spirit de
type 0 est défini comme la fraction de distillation sans traitement
ultérieur, qui contient essentiellement des hydrocabures saturés en
C9-C12 et dont l'intervalle d'ébullition est de 140-220°C. C'est le
produit à bas point d'éclair qui possède la tension de vapeur la plus
élevée, soit environ 1,4 kPa (10,5 mmHg) à 20°C.
Il existe aux Etats-Unis une variété de type 1 appelée "Stoddard
solvent". C'est un produit de distillation défini par son intervalle
d'ébullition de 149-204°C et l'absence d'odeur désagréable, rance en
particulier.
2. Usages et sources d'exposition
2.1 Production
Le white spirit de différents types et qualités est obtenu à
partir de naphta ou de kérosène de première distillation qui sont des
produits de raffinerie provenant de la distillation du brut. Ces
produits sont soumis à une distillation fractionnée qui donne les
fractions correspondant aux intervalles d'ébullition voulus, fractions
qui subissent ensuite différents traitements (indiqués à la section
1.1) pour aboutir au type de white spirit désiré. La composition des
solvants dépend de la composition du brut de départ et des procédés de
raffinage utilisés. Il est donc possible que le white spirit ait
changé au cours du temps en fonction de l'évolution des procédés de
fabrication. Malgré l'absence de données quantitatives, la tendance
qui se dégage en Europe est celle d'une utlilisation accrue du white
spirit à faible teneur en hydrocarbures aromatiques.
2.2 Usages et émissions dans l'environnement
Le white spirit est principalement utilisé pour la confection
de peintures et de vernis, de produits de nettoyage et plus
particulièrement de dégraissage, ou encore comme solvant d'extraction.
On n'a pas de précisions sur les solvants utilisés dans les peintures,
mais on sait que le white spirit entre dans la composition d'un grand
nombre d'entre elles. De nombreux peintres amateurs ou professionnels
l'utilisent également pour diluer leur peinture. La proportion de
white spirit dans le solvant utilisé pour la peinture varie selon la
peinture. On estime que cette proportion va de 45% environ en Europe
à 25% aux Etats-Unis. Du white spirit peut également être présent en
petites quantités dans la peinture à l'eau.
Les chiffres de la consommation de white spirit dans l'industrie
des peintures ne sont pas connus avec exactitude mais on peut
néanmoins donner les chiffres suivants, relatifs à la consommation
d'hydrocarbures aliphatiques et aromatiques, qui permettent de se
faire une idée de l'utilisation du white spirit, puisque celui-ci
représente une part importante du volume total des hydrocarbures
consommés.
En 1985, les ventes annuelles de white spirit aux Etats-Unis ont
totalisé 7,17 × 105 tonnes et sa consommation en Europe occidentale
s'est montée à 7,5 × 105 tonnes l'année suivante.
La majeure partie du white spirit produit aboutit dans
l'environnement et, pour une large part, dans l'atmosphère.
Tableau 1. Consommation de solvants par l'industrie des peintures
(en milliers de tonnes)
Europe 1987 USA 1985
Hydrocarbures aliphatiques 695 433
Hydrocarbures aromatiques 435 572
Autres solvants: alcools, cétones, éthers du 470 935
glycol, esters
Consommation totale de solvants 1600 1940
3. Transport, distribution et transformation dans l'environnement
Le transport et la transformation des constituants du white
spirit dans l'environnement dépendent de leurs propriétés
physico-chimiques et biologiques. Les alcanes et les hydrocarbures
aromatiques inférieurs ont tendance à se volatiliser et à subir une
photodécomposition dans l'atmosphère. Les alcanes et les cycloalcanes
ont tendance à s'adsorber sur les matières organiques présentes dans
le sol ou dans l'eau. Dans des conditions environnementales
favorables à une oxydation microbienne, la biodégradation des
hydrocarbures en C7 à C12 est vraisemblablement importante. Des
essais en laboratoire sur des boues d'égout ont montré que ces
composés étaient facilement biodégradables. La faible solubilité dans
l'eau et la tension de vapeur modérée du white spirit donnent à penser
que la volatisation et la photooxydation qui lui fait suite jouent un
rôle important dans la dégradation abiotique de ses constituants. A
en juger par la valeur du coefficient de partage entre l'octanol et
l'eau (log Pow), qui est comprise entre 3,5 et 6,4, le potentiel de
bioaccumulation paraît modéré. D'ailleurs, la biodégradabilité et la
moindre biodisponibilité que présentent ces hydrocarbures une fois
adsorbés, réduisent encore la probabilité de bioconcentration dans le
milieu naturel.
4. Concentrations dans l'environnement et exposition humaine
On a peu de données sur la présence du white spirit dans l'air,
l'eau et le sol. Un contrôle effectué sur un site contaminé par des
déversemments de white spirit (solvant de Stoddard) a révélé que le
sol en contenait jusqu'à 3600 mg/kg avec, dans les eaux souterraines
profondes, des valeurs pouvant atteindre 500 mg/litre. Quatre mois
après la prise de mesures pour lutter contre cette pollution, la
biodégradation avait réduit de 90% la pollution du sol.
L'exposition humaine est principalement due à l'inhalation de
vapeurs et, dans le cas de la population générale, elle se produit
lors de l'utilisation, dans le cadre des activités domestiques, de
peintures ou de vernis contenant du white spirit. On n'a pas évalué la
concentration à laquelle sont exposées les personnes qui font des
travaux de peinture en amateurs, mais elle devrait être du même ordre
que pour les professionnels. Dans les pièces récemment peintes,
l'exposition humaine est vraisemblablement plus faible, mais on ne
dispose d'aucune estimation à ce sujet. La peinture au pistolet
devrait entraîner une exposition plus importante, notamment du fait de
la formation d'aérosols. On estime que des peintres travaillant
dans des pièces ventilées sont exposés à des concentrations de
150-240 mg/m3, en moyenne calculée sur 8 h. Dans un local fermé ou
mal ventilé, les concentrations peuvent atteindre 6200 mg/m3, en
particulier lorsque la température est élevée.
Pour les laveurs de voitures qui utilisent des produits contenant
du white spirit, on estime que l'exposition pondérée par rapport au
temps (MPT) est de 5 à 465 mg/m3 dans le cas des automobiles et de 45
à 805 mg/m3 dans le cas des poids lourds. Dans des ateliers de
nettoyage à sec ou l'on utilisait le solvant de Stoddard, on a mesuré
des concentrations (en MPT) de 90 à 210 mg/m3. L'exposition la plus
forte a été relevée chez des ouvriers travaillant dans des hangars
d'aviation, avec des valeurs pouvant atteindre 8860 mg/m3 sur un bref
intervalle de temps.
5. Cinétique et métabolisme
Une fois inhalé, le white spirit est facilement absorbé. On a
constaté que chez l'homme, 59% des hydrocarbures aliphatiques et
alicycliques et 70% des hydrocarbures aromatiques étaient absorbés
lorsque la concentration des vapeurs de white spirit était de
1000 mg/m3. Les hydrocarbures passent du sang dans les autres tissus
et on a calculé que le coefficient de partage entre les graisses et le
sang était de 47. Des expériences au cours desquelles des rats
avaient subi une unique exposition à des hydrocarbures ont révélé que
le coefficient de partage entre le sang et le cerveau était plus élevé
pour les hydrocarbures aliphatiques et alicycliques que pour les
hydrocarbures aromatiques.
Après exposition, le white spirit s'élimine du sang selon un
processus biphasique. A une phase initiale très brève caractérisée
par la distribution du mélange et son élimination du sang, succède une
phase durant laquelle l'élimination est beaucoup plus lente (demi-vie
d'environ 46 h). C'est ainsi que l'on a pu déceler la présence de
white spirit dans le sang 66 h après une seule inhalation. On estime
que la demi-vie du white spirit dans les tissus adipeux est de
46-48 h.
On ne dispose que de données fragmentaires sur le métabolisme du
white spirit et son élimination. Toutefois, on a mis en évidence, chez
l'homme, l'excrétion des métabolites par la voie urinaire et celle du
composé initial par la voie respiratoire.
6. Effets sur les animaux de laboratoire et les systèmes d'épreuve
in vitro
Le white spirit ne présente qu'une faible toxicité aiguë pour les
mammifères. Par exemple, la CL50 n'a pas été atteinte chez des rats
en 8 h d'exposition à 8200 mg/m3, soit l'équivalent de 1400 ppm. Par
contre, dans un groupe de quatre chats, la mortalité a été totale
après exposition à une concentration de 10 000 mg/m3 (vapeurs et
aérosol). Les signes généraux d'intoxication observés consistaient en
irritation, perte de la coordination, tremblements et spasmes
cloniques. Aucune mortalité n'a été enregistrée parmi des rats qui
avaient reçu par gavage 5000 mg/kg de white spirit. Chez des lapins,
on a noté une perte d'appétit et une hypoactivité après une seule
exposition à 2000-3000 mg/kg par la voie cutanée. La mortalité a été
de 1 animal sur 16.
Les tests cutanés montrent que le white spirit est légèrement à
modérément irritant.
Les études toxicologiques à court et à long terme révèlent qu'en
général, le système nerveux central, l'appareil respiratoire, le foie
et les reins sont les organes cibles de l'action toxique du white
spirit.
Après exposition par la voie respiratoire, on a observé une
irritation des voies respiratoires et des rats qui avaient été exposés
uniquement par le nez à du white spirit 4 h par jour pendant 4 jours à
214 mg/m3, ont présenté des signes histologiques d'irritation. Lors
de tests d'exposition de longue durée sur cinq espèces différentes, ce
sont les cobayes qui se sont révélés être l'espèce la plus sensible.
Après 90 jours d'exposition à des concentrations de 363 mg/m3 ou
davantage, on a noté une augmentation de la mortalité. L'examen
post-mortem a mis en évidence une irritation pulmonaire.
Chez des rats exposés 8 h par jour pendant 26 semaines à une
concentration de 4800 mg/m3, on a constaté une réduction de la
vitesse de conduction nerveuse au niveau de l'axone des nerfs de la
queue. Selon les épreuves neurocomportementales, les effets sont
bénins et ne s'observent qu'immédiatement après une exposition
quotidienne.
Des rats qui avaient été exposés tous les jours pendant 6 h et
durant 3 semaines ou 6 mois à des concentrations respectivement égales
à 2290 et à 4580 mg/m3 de white spirit, ont présenté une augmentation
des catécholamines et de la sérotonine cérébrales et on a constaté,
après isolement, que les synaptosomes avaient une moindre teneur en
protéines. Les épreuves neurocomportementales n'ont pas mis d'effets
en évidence.
Sur le plan neurophysiologique, l'enregistrement des potentiels
évoqués cérébraux a révélé des modifications chez des rats qui avaient
été soumis 2 mois auparavant à une période d'exposition de 6 mois à
des concentrations de white spirit désaromatisé respectivement égales
à 2339 ou 4679 mg/m3 (400 ou 800 ppm). Une exposition de 3 semaines
à ce même solvant a eu pour résultat d'accroître la teneur des tissus
cérébraux en espèces oxygénées réactives.
Lors de plusieurs épreuves d'exposition par inhalation, on a
observé, chez des rats mâles, une néphropathie dite à "alpha2-
microglobulines".
L'exposition répétée de lapins à du white spirit par la voie
cutanée (3 fois par semaine pendant 4 semaines) a provoqué une
diminution du gain de poids et des effets hépatotoxiques à la dose de
de 2000 mg/kg .
On a effectué trois études sur la toxicité du white spirit pour
le développement, qui toutes n'ont donné que des résultats négatifs.
Les données ne sont toutefois pas suffisantes pour que l'on puisse
procéder à une évaluation complète.
Un certain nombre d'épreuves de génotoxicité (tests sur
Salmonella typhimurium et Saccharomyces cerevisiae, test de
mutation sur lymphome murin, tests cytogénétiques sur moelle osseuse
de rat, tests de léthalité dominante sur souris et rats) ont donné des
résultats négatifs.
Aucune étude de cancérogénicité n'a été réalisée sur des animaux
de laboratoire exposés à du white spirit. Des fractions légères ou
lourdes résultant de la distillation du brut et voisines du white
spirit, comme le kérosène ou le naphta lourd ou léger de distillation
directe, ont provoqué la formation de tumeurs cutanées chez des souris
au bout de de 80 semaines d'application sur la peau.
7. Effets sur l'homme
Le seuil olfactif du white spirit est assez bas et on peut
déceler la présence de vapeurs à des concentrations de 0,5-5 mg/m3.
Une tolérance à l'odeur peut apparaître.
On a signalé des cas irritation oculaire lors d'une exposition à
du white spirit à la concentration de 600 mg/m3 (100 ppm). A
concentration plus élevée, on note une irritation des voies
respiratoires et une irritation oculaire plus intense. Dans plusieurs
cas d'exposition professionnelle, on a constaté des symptômes
neurologiques centraux tels que céphalées, ivresse, étourdissements et
sensation de fatigue.
Une exposition contrôlée de 7 h à des concentrations égales ou
supérieures à 600 mg/m3 a entraîné une perturbation de l'équilibre
pendant la marche et une augmentation du temps de réaction. Une
exposition de 50 min à une concentration de 4000 mg/m3 a provoqué une
diminution de la performance dans les tests de vitesse de perception
et une détérioration de la mémoire à court terme.
Il y a eu un cas de cyanose avec apnée et arrêt cardiaque chez un
sujet qui avait inhalé une quantité excessive de white spirit en
appliquant de la peinture.
On a également signalé des cas d'irritation gastro-intestinale
avec douleurs, vomissements et diarrhées après ingestion de white
spirit. Cette exposition par la voie orale a d'ailleurs entraîné des
lésions au niveau des voies digestives et notamment des lésions de la
muqueuse oesophagienne.
Comme le white spirit présente une faible viscosité et une faible
tension superficielle, il y a un risque d'aspiration pulmonaire en cas
d'ingestion. Quelques ml de solvant qui pénètrent dans les poumons
suffisent à provoquer une grave pneumopathie qui peut être fatale si
la quantité aspirée atteint 10 à 30 ml.
Une exposition cutanée prolongée au white spirit telle qu'il
peut s'en produire lorsque des vêtements imbibés de white spirit sont
portés pendant plusieurs heures, peut provoquer une irritation et une
dermatite.
On a signalé des cas de néphro-, hépato- et médullo-toxicité
après exposition à de fortes concentrations de white spirit.
Toutefois, en l'absence de détails précis sur ces cas et du fait de
leur caractère sporadique, on ne peut guère en apprécier la portée.
Il y a peu de rapports qui fassent état d'effets hématologiques
et biochimiques. Toutefois, les études cliniques révèlent une
diminution du nombre des érythrocytes, des leucocytes et des
plaquettes ainsi qu'une augmentation du VGM chez les travaillleurs
exposés. Des anomalies hématologiques analogues ont été observées
chez l'animal. On a observé occasionnellement une réduction de
l'activité de l'aspartate-aminotransférase et de la lactate-
déshydrogénase ainsi qu'une augmentation de celle de la créatinine-
kinase, mais ces modifications biochimiques ne sont pas toujours
présentes.
De nombreuses études biochimiques ont été effectuées sur des
peintres exposés pendant de longues durées à du white spirit. Un
certain nombre d'études transversales ont révélé un accroissement des
symptômes subjectifs tels que pertes de mémoire, fatigue, difficulté à
se concentrer, irritabilité, étourdissements, céphalées, anxiété et
apathie. Certains tests neuropsychologiques ont mis en évidence une
baisse de la performance. D'autres études ont momtré qu'il pouvait y
avoir un affaiblissement général des fonctions cognitives
correspondant à un diagnostic d'encéphalopathie toxique chronique
(voir la section 8.2.1). Dans quelques études, il a été possible
d'établir une relation dose-réponse. C'est le cas, en particulier,
d'une étude très complète sur des peintres essentiellement exposés à
du white spirit et que l'on a comparés à des poseurs de briques. Les
peintres peu exposés aux solvants se sont révélés comparables aux
poseurs de briques non exposés en ce qui concerne les résultats des
tests neuropsychologiques. En revanche, chez les peintres moyennement
à fortement exposés, la prévalence des résultats neuropsychologiques
médiocres augmentait avec l'exposition.
Des symptômes analogues et des résultats neuropsychologiques
voisins, encore que moins bons, ont été relevés lors d'études
cliniques effectuées sur des peintres hospitalisés en vue d'examens
approfondis à la recherche d'une éventuelle encéphalopathie toxique
chronique attribuable à une exposition prolongée à du white spirit.
Lors d'études cas-témoins, on a constaté que l'odds ratio relatif
à l'attribution d'une pension d'invalidité pour cause de troubles
mentaux, était plus élevé chez les peintres que chez les autres corps
de métiers non exposés à du white spirit ou à d'autres solvants.
Plusieurs études cas-témoins montrent qu'il y a un risque élevé
de glomérulonéphrite chez les peintres. Même si les études
transversales utilisant des marqueurs précoces de néphropathie n'ont
pas permis de conclusions définitives, elles corroborent l'hypothèse
selon laquelle les peintres présentent un risque accru de
glomérulonéphrite et d'insuffisance rénale.
Un certain nombre d'études ont été consacrées aux effets du white
spirit sur la fonction de reproduction humaine. Dans l'une des plus
complètes de ces études, on a comparé les paramètres génésiques d'un
groupe de peintres à ceux d'un groupe d'électriciens. Ni cette étude,
ni d'autres d'ailleurs, n'ont débouché sur des conclusions certaines
car aucune différence significative n'a été relevée. Néanmoins, il a
été avancé que l'exposition des parents à des solvants pourrait avoir
des effets nocifs sur leur progéniture. Quoi qu'il en soit, on n'a
pas eu connaissance de données qui mettent directement en cause le
white spirit.
Il n'y a guère d'études qui soient consacrées uniquement à la
cancérogénicité du white spirit pour l'homme. Trois études portant
sur des employés d'ateliers de nettoyage à sec où l'on utilisait
surtout du white spirit comme solvant ont mis en évidence un
accroissement du risque de cancers des voies respiratoires, du
pancréas et du rein. Chez les peintres, un corps de métier largement
exposé au white spirit, on est fondé à penser qu'il y a un risque
accru de cancers, notamment de cancer du poumon et de la vessie.
Chez un groupe de peintres longtemps exposés à divers solvants,
on n' a pas observé d'échanges entre chromatides soeurs. En revanche,
chez un petit nombre de personnes exposées à des vapeurs de pétrole,
on a constaté une légère augmentation des lésions cytogénétiques.
8. Effets sur les autres êtres vivants au laboratoire et dans
leur milieu naturel
Peu d'études ont été consacrées à la toxicité du white spirit
pour des organismes autres que les mammifères de laboratoire.
On possèdeles résultats d'études sur l'effet inhibiteur que le
white spirit exercerait sur la croissance du champignon Aspergillus
niger, mais il est difficile de déterminer quelle a pu être la
concentration de white spirit dans le milieu de croissance. En ce qui
concerne les autres champignons, il n'existe qu'une seule étude,
consacrée à des champignons mycorhiziens et dont les résultats sont
négatifs. On a observé une augmentation de la fixation d'oxygène par
des racines dont les extrémités avaient été excisées, mais il est
douteux que cette observation puisse être révélatrice de l'exposition
effective dans le milieu naturel.
Les quelques études consacrées à la toxicité du white spirit et
autres mélanges d'hydrocarbures sur la faune et la flore aquatiques,
indiquent que ces produits ne sont que modérément toxiques pour les
organismes marins ou dulçaquicoles. Les effets toxiques sont
probablement attribuables à la fraction dissoute. La valeur de la
CL50 à 96 h est comprise entre 0,5 et 5,0 mg/litre.
Ces résultats surestiment probablement les effets toxiques du
white spirit dans l'environnement, compte tenu de sa volatilité et de
sa moindre biodisponibilité après sorption sur les particules du sol
ou sur les sédiments.
RESUMEN
1. Propiedades de la trementina mineral
La trementina mineral es un disolvente incoloro claro que posee
una muy baja hidrosolubilidad y un olor característico (umbral
olfatario: 0,5-5 mg/m3). La variedad más corriente consiste en una
mezcla de hidrocarburos C7-C12 saturados alifáticos y alicíclicos
con un contenido de 15%-20% (en peso) de hidrocarburos C7-C12
aromáticos y un margen de ebullición de 130-230°C. Los hidrocarburos
C9-C11 (alifáticos, alicíclicos y aromáticos) son los más
abundantes, y representan como mínimo el 80% (en peso) del total.
Esta variedad ordinaria recibe el nombre de trementina mineral tipo
1, calidad media, dado que hay tres tipos distintos y tres niveles
de calidad. El tipo indica si el disolvente ha sido sometido a
hidrodesulfuración (eliminación del azufre) únicamente (tipo 1), a
extracción con solventes (tipo 2) o a hidrogenación (tipo 3). El tipo
hidrodesulfurado contiene menos de un 25% de hidrocarburos aromáticos,
el extraído con solventes menos del 5%, y el hidrogenado menos del 1%.
De cada tipo hay tres niveles de calidad en cuanto a inflamabilidad:
calidad baja (punto de inflamación: 21-30°C; punto de ebullición
inicial: 130-144°C), calidad media (punto de inflamación: 31-54°C;
punto de ebullición inicial: 145-174°C) y calidad alta (punto de
inflamación: > 55°C; punto de ebullición inicial: 175-200°C). La
calidad depende del petróleo crudo utilizado como material de partida
y de las condiciones de destilación. La trementina mineral de tipo 0
corresponde a una fracción de destilación no sometida a tratamiento
ulterior, constituida predominantemente por hidrocarburos C9-C12
saturados con un margen de ebullición de 140-220°C. Los productos de
calidad inflamatoria baja poseen la máxima presión de vapor,
aproximadamente 1,4 kPa (10,5 mmHg) a 20°C.
Una variedad del tipo 1 producida en los Estados Unidos es el
denominado disolvente Stoddard, consistente en un destilado de
petróleo que se caracteriza por un margen de ebullición de 149-204°C y
por la ausencia de olores rancios o desagradables.
2. Usos y fuentes de exposición
2.1 Producción
Los diversos tipos y calidades de trementina mineral se obtienen
a partir de nafta de primera destilación y queroseno de primera
destilación, que son efluentes de refinería generados por la
destilación del crudo. Estas fracciones son sometidas a destilación
fraccionada en márgenes de ebullición apropiados y a diferentes tipos
de tratamiento (mencionados en la sección 1.1) para obtener el tipo de
trementina mineral deseado. La composición de los disolventes depende
de la composición del crudo y de las diferencias de procesamiento en
la refinería. La trementina mineral, así pues, puede haber
experimentado cambios con el tiempo, de resultas de la evolución del
proceso de fabricación. Aunque no se dispone de datos cuantitativos,
se observa en Europa una tendencia a utilizar cada vez más trementinas
minerales poco aromáticas.
2.2 Usos y emisión al medio ambiente
La trementina mineral se utiliza sobre todo en pinturas y
barnices, para limpiar productos y como disolvente desengrasante y de
extracción. No se dispone de datos precisos sobre los disolventes
usados en las pinturas, pero la trementina mineral es un componente
corriente del disolvente de muchas de ellas. También la utilizan como
diluyente pintores aficionados y profesionales. La proporción del
disolvente total correspondiente a la trementina mineral varía según
la pintura. Se estima que el porcentaje de trementina mineral
respecto a la cantidad total de disolvente de la pintura es de
aproximadamente un 45% en Europa y un 25% en los Estados Unidos. Las
pinturas de acuarela contienen a veces una pequeña cantidad de
trementina mineral.
Aunque no se dispone de cifras exactas sobre el consumo de
trementina mineral en la industria de la pintura, las siguientes
cifras sobre el consumo de hidrocarburos alifáticos y aromáticos
permiten hacerse una idea del uso de trementina mineral, toda vez que
ésta constituye una gran parte del total de hidrocarburos.
En 1985 la venta de trementina mineral en los Estados Unidos se
elevó a 7,17 × 105 toneladas, y en 1986 el consumo en la Europa
occidental ascendió a 7,5 × 105 toneladas.
La mayor parte de la trementina mineral fabricada se libera al
medio ambiente y se reparte sobre todo por la atmósfera.
3. Transporte, distribución y transformación en el medio ambiente
El transporte y la transformación medioambientales de los
componentes de la trementina mineral dependen de sus propiedades
fisicoquímicas y biológicas. Los alcanos y los productos aromáticos
de menor peso molecular tienden a volatilizarse y a fotodegradarse en
la atmósfera. Los alcanos y cicloalcanos de mayor peso molecular
suelen verse sorbidos por la materia orgánica del suelo o el agua. Se
considera que el principal destino de la trementina en el suelo y el
agua es la biodegradación, y se supone que la biodegradación de los
hidrocarburos C7 a C12 es importante cuando las condiciones
ambientales son favorables a la oxidación microbiana. Se ha
demostrado una rápida biodegradabilidad en pruebas de laboratorio
realizadas con fangos de alcantarillado. La baja hidrosolubilidad y
la moderada presión de vapor de la trementina mineral llevan a pensar
que la volatilización y posterior fotooxidación son importantes para
la degradación abiótica. Los coeficientes de reparto octanol/agua
(log Pow) notificados, entre 3,5 y 6,4, indican un moderado potencial
de bioacumulación. No obstante, la degradabilidad y la menor
biodisponibilidad tras la sorción reducirían las probabilidades de
bioconcentración en el terreno.
Cuadro 1. Consumo de disolventes en la industria de pinturas
(en miles de toneladas)
Europa EE.UU
1987 1985
Hidrocarburos alifáticos 695 433
Hidrocarburos aromáticos 435 572
Otros disolventes, p. ej. alcoholes, acetonas, 470 935
glicoléteres, ésteres
Consumo total de disolventes 1600 1940
4. Niveles ambientales y exposición humana
Son pocos los datos disponibles sobre la presencia de trementina
mineral en el aire, el agua o el suelo. La vigilancia de una zona
contaminada por un derrame de trementina mineral (disolvente de
Stoddard) reveló niveles de hasta 3600 mg/kg en el suelo, y de hasta
500 mg/litro en aguas del suelo profundo. La biodegradación determinó
una reducción del 90% de la concentración del producto en el suelo a
lo largo de un periodo de cuatro meses después de la reparación.
La forma predominante de exposición humana a la trementina
mineral es la inhalación de vapor. La población general se ve
expuesta durante el uso doméstico de pinturas y lacas. No se han
calculado las concentraciones medias a que se exponen los pintores
aficionados, pero cabe pensar que son parecidas a las que se producen
en el caso de los profesionales. La exposición humana en habitaciones
recién pintadas debe de ser menor, pero no se dispone de valores
estimados. Las personas en contacto ocupacional con el producto
estarían expuestas a concentraciones similares a las que se dan
durante la pintura de viviendas. La pintura con pistola podría
acompañarse de exposiciones más altas y de exposición a aerosoles. Se
ha estimado que en un intervalo de 8 horas la concentración a que
están expuestos los pintores en habitaciones ventiladas es como
promedio de 150-240 mg/m3. Las concentraciones máximas en
habitaciones cerradas o poco ventiladas pueden ser de hasta
6200 mg/m3, sobre todo cuando la temperatura es elevada.
En sistemas de lavado de vehículos que usan productos con
trementina mineral se han detectado exposiciones promedio ponderadas
por el tiempo comprendidas entre 5 y 465 mg/m3 para los automóviles,
y entre 45 y 805 mg/m3 para los vehículos pesados. En instalaciones
de lavado en seco que utilizaban trementina mineral (disolvente de
Stoddard) se hallaron valores de entre 90 y 210 mg/m3 de ese mismo
parámetro. La mayor concentración de exposición notificada es la
hallada en el entorno de trabajadores de hangares de líneas aéreas,
con valores a corto plazo de hasta 8860 mg/m3.
5. Cinética y metabolismo
El vapor de trementina mineral es absorbido fácilmente por
inhalación. En el hombre, a una concentración de vapor de trementina
de 1000 mg/m3 se detectó una absorción de un 59% de los hidrocarburos
alifáticos y alicíclicos, y del 70% de los hidrocarburos aromáticos.
Los hidrocarburos pasan de la sangre a otros tejidos, y se ha
calculado un coeficiente de reparto grasa/sangre de 47 en el hombre.
La trementina mineral se distribuye ampliamente por todo el organismo
en el ser humano. Experimentos realizados con ratas expuestas a un
solo tipo de hidrocarburo pusieron de manifiesto unos cocientes de
reparto cerebro/sangre mayores para los hidrocarburos alifáticos y
alicíclicos que para los aromáticos.
La trementina mineral presente en la sangre se elimina de forma
bifásica tras la exposición. A una primera y muy breve fase de
distribución con eliminación rápida sigue una fase larga de
eliminación considerablemente más lenta (semivida de aproximadamente
46 horas). Así, se ha detectado trementina mineral en la sangre 66
horas después de una sola exposición por inhalación. Se ha estimado
que la semivida en el tejido adiposo es de 46-48 horas.
Se dispone sólo de datos dispersos sobre la eliminación y el
metabolismo de la trementina mineral, pero se ha demostrado en el
hombre la excreción urinaria de metabolitos y la eliminación de
compuestos emparentados a través de la espiración.
6. Efectos en animales de laboratorio y en sistemas in vitro
La toxicidad aguda de la trementina mineral para los mamíferos es
baja. Así, con una exposición de 8 horas a 8200 mg/m3 (1400 ppm) no
se alcanzó la CL50 en la rata. En un estudio realizado con un grupo
de cuatro gatos, todos ellos murieron al ser sometidos a 10 000 mg/m3
(vapor y aerosoles), tras sufrir como signos generales irritación,
pérdida de coordinación, temblor y espasmos clónicos. En la rata, no
hubo mortalidad tras la administración oral (con sonda) de 5000 mg/kg.
En conejos se observó pérdida de apetito e hipoactividad tras una
exposición cutánea única de 2000-3000 mg/kg, y 1 de los 16 animales
expuestos murió.
Pruebas de irritación cutánea revelaron que la trementina mineral
es un irritante entre leve y moderado.
En estudios de toxicidad a corto y a largo plazo, la trementina
mineral tuvo por lo general efectos tóxicos en el sistema nervioso
central (SNC), el sistema respiratorio, el hígado y el riñón.
Se ha observado irritación de las vías respiratorias tras la
exposición por inhalación, y se han observado signos histopatológicos
de irritación en ratas expuestas únicamente por vía nasal a 214 mg/m3
en sesiones de 4 horas durante 4 días.
El cobayo fue la más sensible de las cinco especies sometidas a
exposición a largo plazo. Se observó un aumento de la mortalidad tras
90 días de exposición continua a niveles de 363 mg/m3 o superiores.
Las necropsias pusieron de manifiesto signos de irritación pulmonar.
En ratas expuestas durante 8 horas diarias a 4800 mg/m3 durante
26 semanas se halló una disminución de la velocidad de conducción
nerviosa en el axón de la cola. Las pruebas neurocomportamentales
revelaron únicamente efectos leves, y sólo inmediatamente después de
la exposición diaria.
En ratas expuestas 6 horas diarias a concentraciones de entre
2290 y 4580 mg/m3 durante 3 semanas o 6 meses se observaron niveles
elevados de catecolaminas y serotonina en el cerebro y una disminución
del contenido proteico de sinaptosomas aislados de los animales. Las
pruebas neurocomportamentales no pusieron de manifiesto efecto alguno.
Estudios neurofisiológicos han revelado cambios en los
potenciales evocados sensoriales del cerebro de ratas al cabo de 2
meses de terminado un periodo de 6 meses de exposición a 2339 ó
4679 mg/m3 (400 ó 800 ppm) de trementina mineral desaromatizada. Una
exposición de 3 semanas a este disolvente dio lugar también a un
aumento de la concentración de las formas reactivas de oxígeno en el
tejido cerebral de ratas.
En varios estudios de inhalación, ratas macho desarrollaron la
llamada nefropatía asociada a "alpha2-microglobulina".
En el conejo, la exposición cutánea reiterada frenó el aumento
ponderal y causó toxicidad hepática a concentraciones de 2000 mg/kg
aplicadas 3 veces a la semana durante 4 semanas.
Se han efectuado tres estudios sobre la toxicidad para el
desarrollo, en todos los cuales se han notificado resultados
prácticamente negativos. No obstante, los datos disponibles son
insuficientes para hacer una evaluación detallada.
La trementina mineral no tuvo efectos genotóxicos en pruebas
efectuadas con Salmonella typhimurium y Saccharomyces cerevisiae,
en una prueba de mutación con células de linfoma de ratón, en pruebas
citogénicas con médula ósea de ratón y de rata, y en ensayos de
dominancia letal en roedores (rata y ratón).
No se han realizado estudios de carcinogenicidad con animales de
experimentación expuestos a trementina mineral. Efluentes de
destilación de refinería emparentados, más pesados y más ligeros,
tales como el queroseno, la nafta de primera destilación y la nafta de
primera destilación ligera, han inducido la aparición de tumores de
piel en ratones después de 80 semanas de aplicación cutánea.
7. Efectos en el hombre
El umbral olfatorio de la trementina mineral es muy bajo,
pudiéndose detectar vapores del producto a concentraciones de
0,5-5 mg/m3. Puede aparecer tolerancia olfativa.
Se ha informado de la aparición de irritación ocular como
resultado de la exposición aguda a partir de niveles de 600 mg/m3
(100 ppm). Concentraciones superiores dan lugar a irritación
respiratoria y a una más pronunciada irritación ocular. En varios
casos de exposición laboral se han notificado síntomas agudos del SNC
tales como cefalea, ebriedad, vértigo y fatiga.
Una exposición controlada de 7 horas a concentraciones de
600 mg/m3 o superiores provocó trastornos del equilibrio durante la
deambulación y un aumento del tiempo de reacción. La exposición a
4000 mg/m3 durante 50 minutos causó una disminución del rendimiento
en diversas pruebas de determinación de la velocidad de percepción y
de la memoria reciente.
Se ha notificado un caso de cianosis, apnea y paro cardiaco tras
una exposición excesiva por inhalación durante trabajos de pintura.
Se ha señalado que la ingestión de trementina mineral provoca
irritación gastrointestinal acompañada de dolor, vómitos y diarrea.
La exposición oral causó lesiones en las mucosas del esófago y del
tubo digestivo.
La exposición oral a la trementina mineral acarrea un riesgo de
aspiración pulmonar, debido a la baja viscosidad y la baja tensión
superficial del producto. Unos cuantos mililitros de disolvente
aspirados en los pulmones pueden dar lugar a una bronconeumonía grave,
y una cantidad equivalente a 10-30 ml puede ser mortal.
La exposición cutánea prolongada a trementina mineral, por
ejemplo por llevar ropa impregnada o humedecida por el producto
durante horas, puede ocasionar irritación y dermatitis.
Se han notificado casos aislados de toxicidad aguda para el
riñón, el hígado y la médula ósea tras la exposición a altas
concentraciones del producto. No obstante, dado que los datos al
respecto son escasos y esporádicos, es difícil discernir la verdadera
importancia de esas observaciones.
Hay unos cuantos estudios sobre los efectos hematológicos o
bioquímicos de la trementina mineral. No obstante, los estudios
clínicos muestran una disminución del recuento de eritrocitos,
leucocitos y plaquetas, y un aumento del volumen corpuscular medio en
trabajadores expuestos. Se han detectado cambios hematológicos
análogos en animales. No se han observado cambios bioquímicos
coherentes en el suero, pero sí una disminución de las actividades
aspartato aminotransferasa y lactato deshidrogenasa, así como un
aumento de la actividad creatininacinasa.
Se han llevado a cabo numerosos estudios epidemiológicos en
pintores expuestos a trementina mineral de forma prolongada. Varios
estudios transversales han puesto de manifiesto una mayor incidencia
de síntomas de pérdida de memoria, fatiga, problemas de concentración,
irritabilidad, vértigo, cefalea, ansiedad y apatía. Pruebas
neuropsicológicas realizadas como parte de diversos estudios han
revelado una disminución de la capacidad para realizar algunas de las
tareas. En algunos estudios se observó una reducción global de las
funciones cognitivas, que por su magnitud correspondía a un
diagnóstico de encefalopatía tóxica crónica (véase la sección 8.2.1).
En unos cuantos estudios se estableció una relación dosis-respuesta.
Así ocurrió en un estudio amplio en que se procedió a comparar a
pintores expuestos predominantemente a trementina mineral con
albañiles no expuestos. Los pintores que habían sufrido una
exposición baja al disolvente obtuvieron resultados similares a los de
los albañiles no expuestos en las pruebas neuropsicológicas. No
obstante, la frecuencia de trastornos de las funciones cognitivas
aumentó paralelamente al incremento de la exposición en los grupos de
pintores sometidos a exposiciones medias y altas.
Se ha informado de síntomas y de resultados de pruebas
neuropsicológicas parecidos, si bien más graves, en estudios clínicos
realizados en pintores expuestos predominantemente a trementina
mineral y derivados a dispensarios de medicina del trabajo para que se
les examinara a fondo en vista de sus síntomas, compatibles con una
presunta encefalopatía tóxica crónica por exposición prolongada a
disolventes.
En diversos estudios de casos y testigos se halló que el riesgo
relativo aproximado de concesión de una pensión de invalidez por
trastornos mentales era mayor en el caso de los pintores que en el de
otros grupos profesionales no expuestos a trementina mineral u otros
disolventes.
Varios estudios de casos y testigos han puesto de manifiesto un
elevado riesgo de glomerulonefritis entre los pintores. Aunque no
concluyentes, los estudios transversales realizados mediante
marcadores precoces de la nefropatía son compatibles con la hipótesis
de que los pintores corren un riesgo mayor del habitual de padecer
glomerulonefritis y disfunción renal.
Se han llevado a cabo varios estudios secundarios sobre los
efectos reproductivos en el hombre. En uno de los más importantes se
procedió a comparar el valor de los parámetros reproductivos entre los
miembros de un sindicato de pintores y los de un sindicato de
electricistas. Ni en éste ni en los otros estudios se pudo llegar a
conclusiones firmes, ya que no se observaron diferencias
significativas. Hay con todo algún indicio de que la exposición a
disolventes puede tener efectos indeseables en la descendencia. No
obstante, carecemos de datos directamente relacionados con la
trementina mineral y presentados de forma adecuada.
Son pocos los estudios epidemiológicos realizados sobre el cáncer
en personas expuestas únicamente a trementina mineral. Se ha
informado de un aumento del riesgo de cáncer respiratorio, pancreático
y renal en tres estudios realizados entre personal de establecimientos
de limpieza en seco que utilizaban sobre todo trementina mineral como
disolvente de limpieza. En cuanto a los pintores, grupo profesional
muy expuesto a ese producto, hay pruebas de que padecen un mayor
riesgo de cáncer, sobre todo de pulmón y de vejiga.
No se produjo ningún aumento del intercambio de cromátides
hermanas en un grupo de pintores expuestos de forma prolongada al
disolvente. No obstante, se hallaron algunos aumentos leves de las
lesiones citogenéticas en un reducido número de personas expuestas
sobre todo a vapores de petróleo.
8. Efectos en otros organismos en el laboratorio y en el terreno
Hay pocos estudios sobre la toxicidad de la trementina mineral
para organismos distintos de los mamíferos de laboratorio.
Se ha informado de efectos inhibitorios sobre el crecimiento del
hongo Aspergillus niger, si bien resultó difícil evaluar las
concentraciones de trementina mineral en el medio de cultivo. En un
único estudio realizado con micorriza no se observó ningún efecto. Se
ha informado de un aumento de la captación de oxígeno por puntas de
raíz de plantas extirpadas, pero el significado de este hallazgo por
lo que se refiere a la verdadera exposición en el terreno es incierto.
Los pocos estudios realizados sobre la toxicidad acuática de la
trementina mineral y de las mezclas de hidrocarburos relacionadas
muestran una moderada toxicidad para los organismos de agua dulce y de
mar. La toxicidad se debe probablemente a la fracción disuelta y
se manifiesta en una CL50 a las 96 horas del orden de 0,5 a
5,0 mg/litro.
Estos resultados probablemente sobrestiman los efectos de la
trementina mineral en el terreno, habida cuenta de su volatilidad y de
su menor biodisponibilidad tras su sorción por el suelo y el sedimento.