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

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    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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    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


         2.1. 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


         3.1. Natural occurrence
         3.2. Production
         3.3. Uses


         4.1. Transport and distribution between media
         4.2. Transformation
               4.2.1. Biodegradation
               4.2.2. Abiotic degradation
               4.2.3. Bioaccumulation


         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


         6.1. Absorption
               6.1.1. Inhalation
                 Human exposure
                 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


         7.1. Single exposure
               7.1.1. Inhalation
                 White spirit
                 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
                 White spirit
                 Exposure to related hydrocarbons
               7.2.2. Dermal exposure
                 White spirit
                 Exposure to related hydrocarbons
         7.3. Irritation; sensitization
               7.3.1. Skin irritation
                 White spirit
                 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
                 Behavioural effects
                 Neurophysiological and neuromorpho-
                                  logical effects

                 Neurochemical effects
               7.4.3. Biochemical effects
                 White spirit
                 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


         8.1. Single exposure
               8.1.1. Inhalation, controlled exposure
                 CNS effects
                 Neurobehavioural effects
               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
                 Symptoms and clinical picture
                 Neurological findings
                 Neuropsychological findings
                 Epidemiological studies
                 Comments and uncertainties concerning
                                  the epidemiological studies
                 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


         9.1. Laboratory experiments
               9.1.1. Microorganisms
               9.1.2. Aquatic organisms
               9.1.3. Terrestrial organisms


         10.1. Evaluation of human health risks
         10.2. Evaluation of effects on the environment








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    International Register of Potentially Toxic Chemicals, Case postale
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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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    FIGURE 1

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    Dr D. Anderson, British Industry Biological Research Association
         (BIBRA) Toxicology International, Carshalton, Surrey, United

    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


    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


         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

         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.


    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

    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

         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

         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

         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

         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

         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.



          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,

    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,

    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)

    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

    Mineral solvent (white spirit,     approx. 130/    above 32            -                  -         not darker than           25-50
     type B) (BS 245: 1976)            220 max                                                          standard colour

    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,

         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

    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,

    -    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

      (% 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

         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

    3.1  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

         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).

    FIGURE 2

         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


         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

         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).


    5.1  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

    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)



          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  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).  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

    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

         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

    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

    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

    1,2-dimethylcyclohexane            83.9                  6.2
    1,2,4-trimethylcyclohexane         84.9                  6.9

    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

         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,

         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

         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).

    FIGURE 3

         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).


    7.1  Single exposure

    7.1.1  Inhalation  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).  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

    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  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.  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  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).  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


          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  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.  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

         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.

         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

         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  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).  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).  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  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.  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


          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


          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

    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


    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

    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)

    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,

         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.


    8.1  Single exposure

    8.1.1  Inhalation, controlled exposure  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).  CNS effects

         In the study of Carpenter et al. (1975a) (see section,
    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,
    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).  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  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.,

    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

         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

         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

    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).  Symptoms and clinical picture

         Different kinds of neurotoxic effects are described in the
    sections to  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

         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).  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

    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

           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

    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

    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

    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

    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

    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

         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,

         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.  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

    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

          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)
              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

         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 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

         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.  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.  Comments and uncertainties concerning the epidemiological

         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 and, 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,

    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.
                                  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.

    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).

    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

    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.

    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.

    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

         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

         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

         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).  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.,

         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.

         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

    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

         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


          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

         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


          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

         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.

         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


          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,

         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

         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.



          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,


    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

    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

         The weight of evidence indicates that white spirit is not

         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


    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.


    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.


         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,


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    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

    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

         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

         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

         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-

         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

         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

         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.


    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

         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

         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.

    See Also:
       Toxicological Abbreviations
       White spirit (HSG 103, 1996)