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. J. Kielhorn and Dr. G. Rosner, Fraunhofer
    Institute of Toxicology and Aerosol Research, Hanover, Germany

    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization

    World Health Organization
    Geneva, 1996

         The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme, the International
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    the effects of chemicals on human health and the quality of the
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    of the biological action of chemicals.

    WHO Library Cataloguing in Publication Data


    (Environmental health criteria ; 179)

    1.Morpholine  2.Solvents  3.Chemical industry
    4.Environmental exposure  I.Series

    ISBN 92 4 157179 9                 (NLM Classification: TP 247.5)
    ISSN 0250-863X

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         1.1. Physical and chemical properties
         1.2. Analytical methods
         1.3. Sources of human and environmental exposure
         1.4. Environmental transport, distribution and transformation
         1.5. Environmental levels and human exposure
         1.6. Kinetics and metabolism in laboratory animals and humans
         1.7. Effects on laboratory mammals and  in vitro test systems
         1.8. Effects on humans
         1.9. Effects on other organisms in the laboratory and field
         1.10. Evaluation of human health risks and effects on the
               1.10.1. Evaluation of effects on human health
               1.10.2. Evaluation of effects on the environment
         1.11. Conclusions and recommendations
               1.11.1. Recommendations for protection of human health
               1.11.2. Recommendations for protection of the environment
               1.11.3. Recommendations for further research


         2.1. Identity
               2.1.1. Technical product
               2.1.2. Impurities
         2.2. Physical and chemical properties
               2.2.1. Physical properties of morpholine
                 Storage of morpholine
               2.2.2. Chemical properties of morpholine
         2.3. Conversion factors for morpholine
         2.4. Analytical methods
               2.4.1. Determination of morpholine in air
               2.4.2. Determination of morpholine in water
               2.4.3. Determination of morpholine in soil and sediments
               2.4.4. Determination in biological and other material


         3.1. Natural occurrence
         3.2. Anthropogenic sources
               3.2.1. Production levels and processes
                 World producers
                 Production figures
                 Production processes

                 Losses to the environment during normal
                 Methods of transport
                 Accidental release
               3.2.2. Uses
                 Rubber chemicals
                 Anticorrosion agent
                 Waxes and polishes
                 Optical brighteners
                 Bactericides, fungicides and herbicides
                 Food additive applications


         4.1. Transport and distribution between media
               4.1.1. Volatilization
         4.2. Transformation
               4.2.1. Biodegradation
                 Batch biodegradation tests
                 Biodegradation in laboratory-scale
                                  wastewater treatment plants
               4.2.2. Abiotic degradation
                 Hydrolytic degradation
                 Photochemical degradation
                 Degradation by physico-chemical
               4.2.3. Bioaccumulation
         4.3. Interaction with other physical, chemical or biological
         4.4. Ultimate fate following use
               4.4.1. Fate of morpholine in various products
               4.4.2. Waste disposal


         5.1. Environmental levels
               5.1.1. Ambient air
               5.1.2. Water
                 River water
               5.1.3. Sediment
               5.1.4. Soil
               5.1.5. Terrestrial and aquatic organisms
         5.2. General population exposure
               5.2.1. Indoor air
               5.2.2. Drinking-water and food
               5.2.3. Tobacco
               5.2.4. Cosmetics and toiletry articles
               5.2.5. Rubber articles

         5.3. Occupational exposure during manufacture, formulation or
               5.3.1. Exposure to morpholine
               5.3.2. Exposure to  N-nitrosomorpholine


         6.1. Absorption
         6.2. Distribution
         6.3. Metabolic transformation
         6.4. Elimination and excretion
               6.4.1. Expired air
               6.4.2. Urine
               6.4.3. Faeces
         6.5. Retention and turnover


         7.1. Single exposure
               7.1.1. Oral
               7.1.2. Inhalation
               7.1.3. Dermal
               7.1.4. Intraperitoneal
         7.2. Short-term exposure
               7.2.1. Oral
               7.2.2. Inhalation
               7.2.3. Dermal
         7.3. Long-term exposure
               7.3.1. Oral
               7.3.2. Inhalation
               7.3.3. Dermal
         7.4. Skin and eye irritation; sensitization
               7.4.1. Eye irritation
               7.4.2. Skin irritation
               7.4.3. Sensitization
         7.5. Reproductive toxicity, embryotoxicity and teratogenicity
         7.6. Mutagenicity and related end-points
               7.6.1. Mutagenicity of morpholine
                 Mammalian cells  in vitro
                  In vivo studies in mammals
               7.6.2. Mutagenicity of morpholine in the presence of
                       nitrite and nitrate
               7.6.3. Mutagenicity of  N-Nitrosomorpholine
         7.7. Carcinogenicity
               7.7.1. Morpholine
                 Oral studies
                 Inhalation studies

               7.7.2. Morpholine and nitrite
                 Oral studies
               7.7.3. Carcinogenicity of  N-nitrosomorpholine
         7.8. Factors modifying toxicity; toxicity of metabolites
               7.8.1. Factors modifying toxicity
               7.8.2. Morpholine metabolites
         7.9. Mechanisms of toxicity - mode of action


         8.1. General population exposure
               8.1.1. Controlled human studies
                 Organoleptic effects
               8.1.2. Epidemiological studies
         8.2. Occupational exposure


         9.1. Laboratory experiments
               9.1.1. Microorganisms
                 Microorganisms in water
                 Microorganisms in soil
                 Pathogenic microorganisms
               9.1.2. Other aquatic organisms
                 Monocellular green algae
               9.1.3. Terrestrial organisms
         9.2. Field observations






         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication.  In the interest of all users of the Environmental Health
    Criteria monographs, readers are requested to communicate any errors
    that may have occurred to the Director of the International Programme
    on Chemical Safety, World Health Organization, Geneva, Switzerland, in
    order that they may be included in corrigenda.

                                  *     *     *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).

                                   *     *     *

         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, and by financial support
    from the European Commission.

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    FIGURE 1

    health or environmental effects of the agent because of greater
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    these rules are followed.



    Dr J. Kielhorn, Fraunhofer Institute of Toxicology and Aerosol
         Research, Hanover, Germany (Joint Rapporteur)

    Dr J.S. Knapp, Department of Microbiology, University of Leeds, Leeds,
         United Kingdom (Joint Rapporteur)

    Dr I. Linhart, Centre of Industrial Hygiene and Occupational Diseases,
         National Institute of Public Health, Prague, Czech Republic

    Dr U. Schiecke, Federal Environmental Agency, Berlin, Germany

    Dr J.A. Sokal, Institute of Occupational Medicine and Environmental
         Health, Sosnowiec, Poland (Chairman)

     Representatives of other organizations

    Dr P. Montuschi, Department of Pharmacology, Catholic University of
         the Sacred Heart, Rome, Italy (representing the International
         Union of Toxicology (Vice-Chairman)


    Mrs C. Partensky, International Agency for Research on Cancer, Lyon,

    Dr E. Smith, International Programme on Chemical Safety, World Health
         Organization, Geneva, Switzerland (Secretary)


         A WHO Task Group on Environmental Health Criteria for Morpholine
    met at the World Health Organization, Geneva, from 8 to 11 November
    1994.  Dr E.M. Smith, IPCS, welcomed the participants on behalf of Dr
    M. Mercier, Director of the IPCS, and on behalf of the heads of the
    three IPCS cooperating organizations (UNEP/ILO/WHO).  The Task Group
    reviewed and revised the draft monograph and made an evaluation of the
    risks for human health and the environment from exposure to

         The first draft of this monograph was prepared by Dr J. Kielhorn
    and Dr G. Rosner, Fraunhofer Institute of Toxicology and Aerosol
    Research, Hanover, Germany.  The second revised draft was prepared by
    Dr J. Kielhorn.  Dr E.M. Smith and Dr P.G. Jenkins, both members of
    the IPCS Central Unit, were responsible for the scientific content and
    technical editing, respectively.

         The efforts of all who helped in the preparation and finalization
    of the monograph are gratefully acknowledged.


    CHO       Chinese hamster ovary
    DOC       dissolved organic carbon
    FID       flame ionization detector
    FPD       flame photometric detector
    GC        gas chromatography
    HPLC      high-performance liquid chromatography
    IC        ion chromatography
    MLSS      mixed liquor suspended solids
    MS        mass spectrometry
    NMOR       N-nitrosomorpholine
    NO        nitrogen oxide
    NOAEL     no-observed-adverse-effect level
    NSD       nitrogen selective detector
    OECD      Organisation for Economic Co-operation and Development
    TEA       thermal energy analyser


    1.1  Physical and chemical properties

         Morpholine (1-oxa-4-azacyclohexane) is a colourless, oily,
    hygroscopic, volatile liquid with a characteristic amine ("fishy")
    odour. It is completely miscible with water, as well as with many
    organic solvents, but has limited solubility in alkaline aqueous
    solutions. It is a base, the pKa of the conjugated acid being 8.33. 
    Correspondingly, the octanol-water partition coefficient is pH-
    dependent (log Pow -2.55 at pH 7 and -0.84 at pH 10; 35°C).  The
    vapour pressure of aqueous solutions of morpholine is very close to
    that of water.

         Morpholine can undergo a variety of reactions.  It behaves
    chemically as a secondary amine.  Under environmental and
    physiological conditions, the proven animal carcinogen
     N-nitrosomorpholine (NMOR) is formed by reaction of solutions of
    nitrite or gaseous nitrogen oxides with dilute solutions of
    morpholine.  Nitrogen oxide (NO) levels may be of importance in
    nitrosation.  The conditions of nitrosation, in particular pH, play a
    significant role.

    1.2  Analytical methods

         Morpholine can be determined by gas chromatography (GC) with
    packed as well as capillary columns, high-performance liquid
    chromatography (HPLC) and ion chromatography (IC).  Detectors used
    include flame ionization detector (FID), flame photometric detector
    (FPD), nitrogen selective detector (NSD), and mass spectrometry (MS)
    and thermal energy analyser (TEA) for GC, and UV-detector and TEA for
    HPLC.  For the determination of trace amounts, derivatization is
    required.  The method of choice for sensitivity seems to be GC with
    TEA following the derivatization to NMOR (the detection limit is
    2-3 µg/kg in various matrices).  Low concentrations of morpholine in
    air can be determined by GC with NSD.

    1.3  Sources of human and environmental exposure

         It is estimated that around 25 000 tonnes of morpholine per year
    are produced industrially world-wide, but details of production from
    some countries are lacking.

         The main production process used appears to be the reaction of
    diethylene glycol with ammonia in the presence of hydrogen and

         Morpholine is an extremely versatile chemical but knowledge of
    its uses is incomplete. It is important as a chemical intermediate in
    the rubber industry, as a corrosion inhibitor, and in the synthesis of
    optical brighteners, crop protection agents, dyes and drugs. 

    Morpholine is used as a solvent for a large variety of organic
    materials, including resins, dyes and waxes.  It can be used as a
    catalyst.  Morpholine is still used in some countries in toiletry and
    cosmetic products. It is used in some countries in several direct and
    indirect food additive applications.

         Human and environmental exposure arises from both gaseous and
    aqueous emissions and directly from some of its uses, including, for
    example, its use in cosmetic formulations and waxes. The main
    emissions probably result from its manufacture and its use in the
    chemical industry (notably in production and use of rubber chemicals)
    and as an anti-corrosion agent.  Morpholine has been detected in a
    wide variety of foods and tobacco. It could be that this morpholine
    arises from the wax coatings on fruit or on packaging, but in some
    cases its origin is unknown.

    1.4  Environmental transport, distribution and transformation

         Morpholine is chemically stable in the biosphere although it is
    subject to chemical and biological nitrosation to NMOR.

         Morpholine is inherently biodegradable.  Under the conditions of
    model activated sludge plants, morpholine is biodegradable.  However,
    under non-adapted conditions there is probably no significant
    degradation of morpholine.  The mean solid retention time in activated
    sludge plants is of crucial importance and must be over 8 days if
    reliable morpholine degradation is to be achieved.

         There are inadequate data on the bioaccumulation of morpholine in
    aquatic and terrestrial organisms.  From the  n-octanol/water
    partition coefficient for morpholine (log Pow = -2.55 at pH7), no
    bioaccumulation would be expected.

         As morpholine is an important industrial chemical with a wide
    range of applications, the presence of the compound or its derivatives
    is to be expected in many industrial effluents.  Its use as a
    corrosion inhibitor in boiler water means that it will be found in
    boiler wastewater, including that from power plants using morpholine. 
    Its use in the manufacture of rubber additives results in an
    undefinable amount of morpholine being released into the hydrosphere
    or geosphere through tyre abrasion and disposal of used tyres.

         As a result of its use in waxes and polishes, morpholine is
    released into the environment through volatilization.  It is quickly
    adsorbed by moisture.  The main compartment for accumulation of
    morpholine is therefore the hydrosphere. The limited data suggest that
    morpholine does not accumulate in the hydrosphere.

         Incineration is the preferred method of disposal for undiluted
    morpholine, but nitrogen oxide emission controls may be required to
    meet environmental regulations. For aqueous effluents, activated
    sludge treatment is adequate, but only if the plant is carefully
    controlled (see above).

    1.5  Environmental levels and human exposure

         There are no data available on levels of morpholine in ambient
    and residential indoor air and in drinking-water. There are limited
    data on its occurrence in natural waters and no information on its
    occurrence in soil.

         Based on the available data, the main source of general
    population exposure to morpholine is food, which can be contaminated
    with morpholine through direct treatment of fruit with waxes
    containing morpholine for conservation purposes, through steam
    treatment during food processing, and by the use of packaging material
    containing morpholine.  However, quantitative data on food
    contamination by morpholine and NMOR are limited.  For example, in
    prepacked milk products, values ranged from 5 to 77 µg/kg morpholine
    and up to 3.3 µg/kg NMOR.  Morpholine content in various food samples
    (fish, meat, plant products, beverages) usually did not exceed
    1 mg/kg.  Higher levels (up to 71.1 mg/kg) were detected in citrus
    fruits in Japan.  A survey in Italy did not identify NMOR in a variety
    of foods at a detection limit of 0.3 µg/kg.  Existing data do not
    permit an estimation of the intake of morpholine and NMOR from food.

         Morpholine has been found in cigarette tobacco at a concentration
    of 0.3 mg/kg, and in snuff and chewing tobacco at concentrations up to
    4.0 mg/kg.  Levels of NMOR up to 0.7 mg/kg have been reported in the
    past in snuff. These were probably associated with the use of
    morpholine-containing waxes in packaging.

         NMOR has been detected in some toiletry and cosmetic products,
    e.g., shampoos and eye make-up, and in rubber articles, e.g. baby
    pacifiers and feeding bottle teats, at levels up to 3.5 mg/kg.

         Occupational exposure to morpholine may occur in several
    industries.  There are few data on exposure of workers to morpholine. 
    All reported values are below 3 mg/m3.  Occupational exposure to
    NMOR has been found in the rubber industry, where concentrations up to
    250 µg/m3 have been measured.

         The data currently available provide an indication of the
    potential for human exposure but do not allow a precise estimation of
    the levels of exposure of the general and occupational populations to
    morpholine and NMOR.

    1.6  Kinetics and metabolism in laboratory animals and humans

         Morpholine is absorbed after oral, dermal and inhalation
    exposure. In the rat following oral and intravenous administration,
    morpholine is rapidly distributed, the highest concentrations being
    found in the intestine and muscle.

         In the rabbit, following intravenous and inhalation exposure,
    morpholine is preferentially distributed to the kidneys, lower
    concentrations reaching the lung, liver and blood.

         Morpholine does not bind significantly to plasma proteins. 
    Plasma half-lives have been reported to be 115 (rat), 120 (hamster),
    and 300 min (guinea-pig).

         Morpholine is excreted mainly via the renal route, as the
    unchanged compound, in a variety of species.  One day after
    administration, 70-90% of morpholine was found in urine.
    Neutralization of morpholine enhances the rate of excretion of the
    compound. A small percentage of morpholine is excreted in expired air
    and faeces.

         Studies in rats, mice, hamster and rabbit indicate that
    morpholine is eliminated almost completely as the unmetabolized
    compound.  In the guinea-pig,  N-methylation followed by Noxidation
    can occur, with up to 20% of the administered dose being metabolized.
    In the presence of nitrite, morpholine can be converted to NMOR both
     in vitro and  in vivo.  Depending on the dose, 0-12% of morpholine
    administered to rats with nitrites may be nitrosated.

         Immunostimulation, involving macrophage activation, may increase
    the extent of nitrosation.

    1.7  Effects on laboratory mammals and  in vitro test systems

         The acute toxicity of morpholine after oral administration shows
    LD50 values of 1-1.9 g/kg body weight and 0.9 g/kg body weight in
    the rat and guinea-pig, respectively. Rats receiving neutralized
    morpholine (1 g/kg body weight) survived. After intraperitoneal
    administration, the LD50 was 0.4 g/kg body weight in the mouse and
    between 0.1 and 0.4 g/kg body weight in the rat.  After inhalation
    exposure, the LD50 was about 8 g/m3 in the rat and between 5 and
    7 g/m3 in the mouse.  The dermal LD50 was 0.5 ml/kg of undiluted
    morpholine in the rabbit.  The acute toxicity of morpholine is
    characterized by gastrointestinal haemorrhage and diarrhoea after oral
    exposure, and irritation and haemorrhage of the nose, mouth, eyes and
    lung after inhalation. In a 30-day gavage study on rats at doses of
    0.16 - 0.8 g/kg body weight, there were severe toxic effects and
    mortality at all dose levels. In the guinea-pig at doses of
    0.09 - 0.45 g/kg body weight there was also severe toxicity and
    mortality at all dose levels.

         After short-term inhalation exposure to morpholine (7.2 g/m3,
    4 h/day, 4 days and 1.63 g/m3, 4 h/day, 5 days/week, 30 days), 
    alterations in lung function have been reported in rats. Mortality
    rate in the rat ranged from 0 to 100% depending on exposure level
    (0.36-18.1 g/m3, 6 h/day, 9 days). Inhalation toxicity was dose-
    related with various degrees of local irritation (eyes, mouth, nose,
    lung) and haemorrhage at the higher exposure levels.  One study
    reported increased function of thyroid gland and another necrosis of
    liver and renal tubules after inhalation exposure.

         A 90-day study showed that morpholine administered orally
    (0.2-0.7 g/kg body weight per day) for 90 days may reduce body weight
    gain and renal function in the mouse. After 672 days of oral exposure
    to morpholine (0.28-0.5 g/kg body weight per day), forestomach
    epithelium hyperplasia was reported (mouse).

         In a 13-week inhalation study, morpholine (0.09-0.9 g/m3,
    6 h/day, 5 days/week) has been reported to cause dose-related lesions
    of nasal mucosa and pneumonia at the higher exposure levels (0.36 and
    0.9 mg/m3). No treatment-related changes to a number of parameters
    were observed at 0.09 g/m3; this concentration may be considered a
    no-observed-adverse-effect level (NOAEL) under the conditions of
    sub-chronic inhalation exposure.

         Morpholine in the undiluted and unneutralized form is highly
    irritant for the eye and skin, probably due to its alkaline
    properties.  Dilution and neutralization of its pH may significantly
    reduce its topical toxicity.  Morpholine (2%) did not induce
    sensitivity in the guinea-pig using the modified Buehler method.

         Morpholine did not induce mutations in bacteria or yeasts with
    and without metabolic activation (with one exception at a very high
    concentration).  It was negative in the host-mediated assay.

         Morpholine did not induce DNA-repair in primary rat hepatocytes
    and did not induce a significant increase in sister chromatid exchange
    in Chinese hamster ovary cells. Morpholine was considered to be weakly
    mutagenic in the L5178Y mouse lymphoma assay.  It increased type III
    foci in the BALB/3T3 malignant cell transformation assay, although
    neutralized morpholine did not.

         Morpholine caused neither point mutation nor chromosomal
    aberration in hamster embryos exposed  in utero.

         No increase in the incidence of tumours was seen in rats given up
    to 0.5 g/m3 morpholine by inhalation for 104 weeks nor in mice given
    1% morpholine oleate in their drinking-water for 96 weeks. In a long-
    term study on a group of 104 rats given 1000 mg morpholine/kg diet,
    there were three liver cell carcinoma, two lung and another

    angiosarcoma (unspecified) and two malignant glioma, whereas in a
    control group of 156 rats there were no tumours. With hamsters under
    the same conditions, no tumours were found.

         Morpholine given simultaneously with nitrite yields positive
    results in the host-mediated assay, probably due to the formation of
    NMOR.  Morpholine fed simultaneously with nitrite induced liver and
    lung tumours in rats and liver tumours in hamsters probably due to the
    endogenous formation of NMOR.  NMOR is mutagenic in bacteria and
    yeasts; weakly positive results were reported for sister chromatid
    exchange in CHO cells and for mutations in mouse lymphoma L5178Y
    cells.  NMOR is carcinogenic in mice, rats, hamsters and various
    fishes, producing liver and lung tumours in mice, liver, kidney and
    blood vessel tumours in rats, liver, upper digestive and respiratory
    tract tumours in hamsters, and liver tumours in fish.

    1.8  Effects on humans

         There have been no reports on incidents of acute poisoning or on
    the effects of short- or long-term exposure to morpholine by the
    general population.

         The phenomenon known as blue vision or glaucopsia, as well as
    some instances of skin and respiratory tract irritation, have been
    described in reports of occupational exposure to morpholine; however,
    no atmospheric concentrations of morpholine were given.  It was
    reported that the number of chromosomal aberrations in the lymphocytes
    of peripheral blood of workers exposed for 3-10 years to morpholine at
    concentrations of 0.54-0.93 mg/m3 did not differ significantly from

         Undiluted morpholine is strongly irritant to skin; a dilute
    solution (1 to 40) was mildly irritant.

         The potential carcinogenicity of morpholine in exposed human
    populations has not been investigated.

    1.9  Effects on other organisms in the laboratory and field

         Among the aquatic organisms tested, certain cyanobacteria
     (Microcystis) and unicellular green algae  (Scenedesmus) appear to
    be the most sensitive taxa as toxicity threshold values (criterion:
    inhibition of population growth) of 1.7 mg/litre for  Microcystis and
    4.1 mg/litre for  Scenedesmus have been reported (duration of
    exposure: 8 days).

         Aerobic bacteria like  Pseudomonas proved to be much more
    resistant: the 16-h toxicity threshold and the NOEC for population
    growth have been cited as 310 and 8700 mg/litre, respectively.

    However, 1000 mg/litre inhibited respiration and dehydrogenase
    activity (up to 20%) in activated sludge from industrial treatment

         Among aquatic protozoans tested so far, representatives of the
    genera  Entosiphon and  Chilomonas (with threshold values of 12 and
    18 mg/litre, respectively, for the inhibition of population growth)
    turned out to be the most sensitive.  The 24-h EC values
    (E=immobilisation) for  Daphnia were in the range of
    100-120 mg/litre.  The 48- to 96-h LC50 values reported for fish
    tested in fresh, brackish or seawater were > 180 mg/litre, rainbow
    trout being the most sensitive species.

         No data on long-term effects in aquatic invertebrates and
    vertebrates are available.  Information about the toxicity of
    morpholine in free-living soil organisms is almost entirely lacking,
    being restricted to a 3-day EC value of about 400 mg/litre given for
    germination inhibition in lettuce.

    1.10  Evaluation of human health risks and effects on the environment

    1.10.1  Evaluation of effects on human health

         The general population is primarily exposed to morpholine by
    consumption of contaminated food.  Contamination of tobacco and
    tobacco products, and cosmetic and toiletry articles and rubber
    products may also contribute to overall exposure.  Occupational
    exposure to morpholine occurs in many industries; the compound is
    absorbed by inhalation and skin absorption.  Data are inadequate to
    determine the degree of exposure of the general population. Data on
    occupational exposure to morpholine are also limited.

         Morpholine is not highly toxic under conditions of acute
    exposure. The LD50 after oral administration is 1-1.9 g/kg body
    weight in rats and 0.9 g/kg body weight in guinea-pigs. LC50 values
    of 7.8 mg/m3 (rats) and 4.9-6.9 g/m3 (mice) have been reported.

         In the conditions of short-term and long-term inhalation
    exposure, the critical effects appear to be irritation of the eyes and
    respiratory tract. A concentration of 90 mg/m3 may be considered the
    NOAEL in the conditions of the 13-week experiment in rats (6 h/day,
    5 days/week). In a long-term inhalation study (104 weeks), increased
    incidences of inflammation of the cornea, and inflammation and
    necrosis of the nasal cavity were observed in rats at 540 mg/m3. 
    Increased incidence of irritation of eyes and nose was also observed
    at 36 and 180 mg/m3.

         High exposures to morpholine causes severe damage to the liver
    and kidneys of rats and guinea-pigs. Fatty degeneration of the liver
    was reported in rats after feeding morpholine (0.5 g/kg body weight)
    daily for 56 days.  When administered morpholine oleic acid salt in

    the drinking-water at a dose of about 0.7 g/kg body weight per day for
    13 weeks, mice showed cloudy swelling of the kidney proximal tubules. 
    Decreased body weight gain was observed in female mice in the long-
    term (672 days) feeding experiment at dose levels between 0.05 and
    0.4 g morpholine (as oleic acid salt).

         At the reported levels of the present occupational and
    environmental exposures, morpholine does not seem to create any
    significant risk of systemic toxic effects. Local effects (irritation)
    of the eyes and respiratory tract may occur in non-controlled
    occupational and incidental exposures to high concentrations of
    airborne morpholine, and skin irritation may result from contact with
    liquid (even diluted) morpholine.

         Morpholine does not appear to be mutagenic or carcinogenic in
    animals. However, it can be easily nitrosated to form NMOR, which is
    mutagenic and carcinogenic in several species of experimental animals.
    Morpholine fed to rats sequentially with nitrite caused an increase in
    tumours, mostly hepatocellular carcinoma and sarcomas of the liver and
    lungs. It is therefore prudent to consider exposure to morpholine as
    increasing the carcinogenic risk in exposed populations.

    1.10.2  Evaluation of effects on the environment

         In view of the very restricted knowledge regarding environmental
    exposure, the lack of effect data relating to long-term exposure in
    water and to short- and long-term exposure in the terrestrial
    environment, a sound risk assessment cannot be carried out at present. 
    On the basis of the reported properties of morpholine, the available
    ecotoxicological information and the few data on environmental
    concentrations, certain conclusions can be drawn.

         The high water solubility of morpholine and its low volatility
    (under environmental conditions) make the hydrosphere the pre-dominant
    environmental sink.

         Morpholine is inherently biodegradable and, although degradation
    is slow, there are no data to suggest accumulation in the hydrosphere. 
    Bioaccumulation is unlikely.

         There are relatively few data on toxicity of morpholine to free-
    living organisms.  However, it seems unlikely that current levels of
    morpholine emission cause any significant damage to the wider
    environment.  Local effects, due for example to factory emissions or
    to morpholine release due to wear of tyres, remain to be evaluated.

         Contamination of some foods, e.g., fish, with morpholine may be
    due to environmental contamination, but this is uncertain.

         Conversion of morpholine to NMOR is the main cause of concern,
    especially with respect to vertebrate populations.  NMOR has been
    reported in industrial wastewater and in soil near a factory.  The
    presence of morpholine in water destined for processing to drinking-
    water is a cause for concern.

    1.11  Conclusions and recommendations

         Morpholine does not present a toxic risk to humans at the usual
    levels of exposure, but its conversion to the carcinogenic NMOR should
    be noted.

         There is no evidence at present levels of exposure that
    morpholine poses a substantial risk to biota in the environment.

    1.11.1  Recommendations for protection of human health

    a)   Human exposure to morpholine should be avoided as far as

    b)   Contamination of food through food packaging and food processing
         should be avoided.

    c)   Morpholine should not be used in rubber products intended for
         direct contact with humans.

    d)   Morpholine should not be used in toiletry or cosmetic

    e)   Industrial effluents should be rigorously treated to avoid entry
         of morpholine into drinking-water.

    f)   In the light of the formation of carcinogenic NMOR the present
         occupational exposure limits should be reconsidered.

    1.11.2  Recommendations for protection of the environment

         Spills and shock loads to effluent treatment plants should be

    1.11.3  Recommendations for further research

         Studies should be undertaken on the following topics:

    a)   reproductive toxicity in mammals;

    b)   long-term toxicity in mammals;

    c)   effect of exposure of mammals to low levels of morpholine with
         and without nitrite and nitrate;

    d)   transnitrosation by NMOR under  in vivo and  in vitro

    e)   biodegradation under anaerobic conditions, especially under
         nitrate-reducing conditions;

    f)   microbial catalysis of  N-nitrosation under realistic

    g)   environmental levels of morpholine in groundwater, soil and
         rivers used for drinking-water;

    h)   environmental levels of morpholine around morpholine-producing
         and -processing factories;

    i)   metabolism and toxicokinetics in humans as a part of the
         development of methods for biological monitoring of morpholine;

    j)   monitoring of morpholine and NMOR levels in food, drinking-water
         and indoor air;

    k)   data on occupational exposure should be collected and made


    2.1  Identity

    CAS/IUPAC name:                  Morpholine

    Chemical formula:                C4H9NO

    Chemical structure:              CHEMICAL STRUCTURE 1

    CAS registry number:             110-91-8

    EEC number:                      613-028-00-9

    EINECS number:                   2038151

    UN number:                       2054

    Synonyms:                        1-oxa-4-azacyclohexane
                                     diethylene oximide
                                     diethyleneimide oxide
                                     diethylene imidoxide

    Relative molecular mass:         87.12

    2.1.1  Technical product

         The compound is marketed under the name of "Morpholine".  It is
    distributed as an anhydrous liquid and as 40% and 88% solutions with
    water (Air Products and Chemicals, 1989).

    2.1.2  Impurities

         Morpholine is marketed as a product with approximately 99% purity
    (Cosmetic Ingredient Review, 1989; BUA, 1991).  The exact chemical
    nature of the impurities depends on the production process (see
    section  When produced from diethylene glycol,
    2-(2-aminoethoxy)ethanol is a by-product, which can be isolated and
    recycled (Heilen et al., 1989).  Reported impurities are
     N-ethylmorpholine and ethylenediamine (Heilen et al., 1989) and
    2-methoxy ethanol (BUA, 1991).

         During the production of morpholine from diethanolamine, it is
    possible that  N-hydroxyethylmorpholine may be formed (Cosmetic
    Ingredient Review, 1989).

         Impurities in cosmetic grade morpholine have been reported to
    include arsenic (up to 3 mg/kg) and lead (up to 20 mg/kg) (Estrin et
    al., 1982).  The Cosmetic Ingredient Review (1991a) lists morpholine
    as having insufficient data on impurities.

         Fajen et al. (1979) found 0.8 mg/kg  N-nitrosomorpholine (NMOR)
    in a morpholine charge used for the production of a vulcanization
    accelerator in a chemical factory in Ohio.  NMOR could not be detected
    (detection limit: 50 µg/kg) in morpholine stored under nitrogen in
    Germany (BUA, 1991).

    2.2  Physical and chemical properties

    2.2.1  Physical properties of morpholine

         Morpholine is a colourless, oily, hygroscopic, volatile liquid
    with a characteristic amine smell (Reinhardt & Brittelli, 1981). 
    Morpholine vapour is heavier than air and as a result, the vapour can
    travel a significant distance to a source of ignition and "flash

         It is completely miscible with water, soluble in the usual
    solvents and can itself be used as a solvent (Heilen et al., 1989). 
    It has a low solubility in alkaline aqueous solutions. 

         Morpholine is a strong base, the 0.01% (w/w) mixture having a
    pH of 9.4, and the 10% (w/w) mixture having a pH of 11.2 (Texaco,

         Some physical and chemical properties are presented in Table 1.  Storage of morpholine

         Morpholine can be stored for an unlimited time in iron or steel
    containers if protected from atmospheric moisture and carbon dioxide. 
    However, it is unstable in the presence of copper, zinc and their
    alloys and these metals should not be used in storage containers for
    morpholine (Heilen et al., 1989; Air Products and Chemicals, 1989).

    2.2.2  Chemical properties of morpholine

         Morpholine can undergo a diversity of reactions.  It is an amino
    ether; the ether function of the molecule is typically inert and most
    of the reactions involve the secondary amine group.

    Table 1.  Some physical and chemical properties of morpholine

    Melting point (°C)               -3.1a; -4.9b,c; -5d

    Boiling point (°C at 1013 hPa)   128.2a; 128.3c; 128.9b; 128-130d

    Flash point (°C) - Open cup      38b;
                     - Closed cup    35c; 31d

    Autoignition temperature (°C)    275a,d; 310c;

    Explosion limits in air          1.4-13.1 vol% d; 1.8-11 vol% e;
                                     1.8-15.2 vol% a

    Decomposition temperature        > 330°Cd; > 550°C
                                     (in steam cycles)a

    pKa (conjugated acid)            8.33 (25°C)f;
                                     8.36c (temperature not given)

    Vapour pressure (°C)             10   20   40   60   80    100   120
                    (kPa)            0.6  1.1  3.2  8.3  10.5  40.9  81.8

    Density g/cm3 (20°C)             0.994b; 0.999c; 1.00d; 1.007a

    log  n-octanol/water partition    -0.723 (free base; calculated)g
    coefficient (log Pow)            -1.08 (free base; calculated)h
                                     -0.66 (free base; calculated)i

    Solubility in water              completely miscible with watera

    Solubility in organic solvents   completely miscible with, for
                                     instance, methanol, ethanol, acetone,
                                     diethylether, benzene, toluene,

    Refractive index                 1.4537-1.4545 at 20°Ce

    Human olfactory threshold        0.036 (mg/m3)j

    a  Heilen et al. (1989); b  Brown (1966); c  Texaco (1986);
    d  BASF (1987); e  Cosmetic Ingredient Review (1989);
    f  Lide (1990); g  UBA (1990); h  Leo et al. (1971);
    i  Le Therizien et al. (1980); j  Hellman & Small (1974)

         It reacts with inorganic acids and acid gases such as CO2,
    H2S, or HCN to form morpholine salts.  This property is of use in
    the addition of morpholine as an anticorrosive in boiler systems
    (Brown, 1966).  Morpholine can react with oxidizing agents, undergo
    direct chlorination, and form complexes with metallic halides.  It
    reacts with carboxylic acids, anhydrides, chlorides and esters to form
    morpholides (Brown, 1966).  Alkyl morpholides are formed by reaction
    of morpholine with alkyl halides, dialkyl sulfates or trialkyl
    phosphates.  The  N-alkylmorpholides, particularly
     N-methylmorpholides, and  N-ethylmorpholides, are widely used as
    catalysts in the preparation of polyurethanes (Brown, 1966). 
    Morpholine reacts with formaldehyde to form  N-formyl-morpholine,
    which is used industrially as a selective solvent for the extraction
    of very pure aromatic compounds (Heilen et al., 1989).

         Morpholine reacts with fatty acids to form soaps which are used
    in household and automotive waxes and polishes.  Their principal
    advantage is that the morpholine evaporates at the same rate as water,
    leaving a water-resistant wax base (Mjos, 1978; Texaco, 1986). 
    Vulcanizing agents for the rubber industry are formed by the reaction
    of morpholine with sulfur and sulfur-containing compounds (Taylor &
    Son, 1982).

         Morpholine is flammable.  Violent reaction and fire may result
    when the product is mixed with oxidizing agents (Air Products and
    Chemicals, 1989).

          N-nitrosomorpholine (NMOR) can be formed by reaction of aqueous
    solutions of nitrite with morpholine or by reaction of gaseous
    nitrogen oxides in aqueous solutions of morpholine (see section 4.3).

    2.3  Conversion factors for morpholine

         1 mg/m3    = 0.276 ppm at 20°C and 1013 hPa
         1 ppm      = 3.62 mg/m3

    2.4  Analytical methods

         Methods suitable for measuring trace levels of morpholine include
    ion chromatography (IC), gas chromatography (GC) with packed as well
    as capillary columns, and high-performance liquid chromatography
    (HPLC), usually using reverse phase (RP) columns.

         The poor UV absorptivity of morpholine necessitates chemical
    derivatization to detect trace amounts.

         Detection methods include UV detectors (for HPLC) and flame
    ionisation detectors (FID, following GC), as well as thermal energy
    analysers (TEA).  Photochemical methods are used but are not specific
    for morpholine.

         An overview of the analytical methods for determining morpholine
    in various matrices is given in Table 2.

         For the detection of trace amounts of NMOR, GC or HPLC together
    with TEA has proved to be the method of choice.  The use of internal
    standards helps to distinguish NMOR in the sample from artifacts
    caused by nitrosation or transnitrosation during the work-up procedure
    (BUA,1991; ECETOC, 1991).

    2.4.1  Determination of morpholine in air

         Table 2 summarizes the available methods.

         Air samples can be collected and concentrated by passing through
    silica gel or an impinger containing dilute acid.  A 20-litre sample
    is recommended to reach concentrations between 7 and 210 mg/m3
    (NIOSH, 1977).  Bianchi & Muccioli (1978) collected air samples
    without absorption on a solvent and rapidly performed the GC.

         Sollenberg & Hansen (1987) described an isotachophoretic
    determination of morpholine using 10 mM potassium cacodylate (pH 6.5)
    as leading electrolyte, and 10 mM creatinine with 5 mM HCl as
    terminating electrolyte.  This method has been used primarily to
    measure  N-methylmorpholine in air samples from a polyurethane foam
    factory (Hansen et al., 1986).  Aarts et al. (1990) also used an
    isotachophoretic method for determining morpholine in rubber samples
    (see Table 2).

    2.4.2  Determination of morpholine in water

         The methods given in Table 2 (water) are suitable for the
    determination of morpholine in steam condensates or non-aqueous

    2.4.3  Determination of morpholine in soil and sediments

         A GC/MS method has been used to detect morpholine in sediment and
    soil (Spies et al., 1987).

    2.4.4  Determination in biological and other materials

         Morpholine has been determined in biological tissues and fluids
    using GC/FID (Tombropoulos, 1979).  Morpholine and some of its
    metabolites ( N-hydroxymorpholine,  N-methylmorpholine and
     N-methylmorpholine- N-oxide) could be separated using two
    complementary HPLCs, one using reversed-phase and the other
    ion-exchange chromatography (Sohn et al., 1982a).

         Morpholine has been determined in a number of foods and beverages
    as well as in tobacco, snuff and packaging material (see section
    5.2.2).  The methods used are summarized in Table 2.  Generally,
    morpholine is extracted from the samples using steam distillation
    followed by purification and derivatization.

        Table 2.  Methods for the analysis of morpholinea
    Matrix      Sample preparation                         Methodb           Detectorb    Detection        Recovery    References
                                                                                          limit            (%)

    Air         adsorption on silica gel,                  GC                FID          7 mg/m3c         100         NIOSH (1977)
                desorption with H2SO4,
                neutralization with NaOH

    Air         collected directly                         GC                FID          36 mg/m3         not given   Bianchi &
                                                                                                                       Muccioli (1978)

    Air         absorption in 1 N KOH (impinger);          GC                TEA          not given        not given   Fajen et al.
                extraction with dichloromethane                                                                        (1979)

    Air         adsorption on silica gel;                  HPLC              UV           not given        90-96       Simon & Lemacon
                derivatization to m-toluamides                               (235-255 nm)                              (1987)

    Air         absorption on silica gel,                  GC                NSD          0.03 mg/m3       93 ± 5%     BIA (1989)
                extraction with methanol
                + 2% KOH

    Water       derivatization to p-tosylamide,            GC                FID          70 ng/litre      45-67       Singer &
                acidification with HCl (pH 1),                                                                         Lijinsky (1976a)
                extraction with diethylether

    Water       addition of Cu(II), CS2 in                 UV/VIS            VIS          10 µg/litre      89          Karweik &
                chloroform and NH3/NH4Cl-buffer                              (434 nm)                                  Meyers (1979)

    Water,      with Ni(II); phosphate buffer              HPLC              UV           not given        95-100      Moriyasu et al.
    solutions                                                                (325 nm)d                                 (1984)

    Water       Cu(II); remainder; titrated                titration         Cu-ion-      lower            98          Hassan et al.
                with EDTA                                                    selective    mg range                     (1985)

    Table 2 (cont'd)
    Matrix      Sample preparation                         Methodb           Detectorb    Detection        Recovery    References
                                                                                          limit            (%)

    Water       derivatization with                        HPLC              VIS          < 10 µg/litrec   9-97        Koga &
                1,2-naphthoquinone-4-sulfonate,                              (436 nm)                                  Akiyama (1985)
                extraction with dichloromethane

    Water       derivatization to benzene-                 GC                FPD          < 2 ng           approx.100  Hamano et al.
                sulfonamide; extraction with                                                                           (1980)

    Steam       addition of KOH to pH > 10                 GC                FID          1 mg/litre       > 90        Malaiyandi et
    condensate                                                                                                         al. (1979)

    Steam       none                                       IC                CD           100 µg/litre     91-97       Gilbert et al.
    condensate                                                                                                         (1984)

    Steam       acidification with HCl; derivatization     HPLC              VIS          30 µg/litre      96          Lamarre et al.
    condensate  to dabsyl amide, addition of NaHCO3                          (456 nm)                                  (1989)

    Blood,      extraction with methanol; purificaction    GC                FID          < 4 mg/kgc       55-70       Tombropoulos
    tissue,     over picrate; neutralisation                                              (tissue)                     (1979)
    urine       with CaCO3                                                                < 21 mg/litrec

    Urine,      extraction with methanol homogenized       HPLCe             UV (196 nm)  not given        not given   Sohn et al.
    tissues     in KCl, phosphate buffer,                  a) RP                                                       (1982a)
                extraction with methane                    b) IC

    Food,       steam distillation; derivatization         GC/GC-MS          FID          200 µg/kg        45-67       Singer &
    drinks      to p-tosylamide                                                           (food)                       Lijinsky (1976a)
                                                                                          4 µg/litre

    Table 2 (cont'd)
    Matrix      Sample preparation                         Methodb           Detectorb    Detection        Recovery    References
                                                                                          limit            (%)
    Food        homogenization with HCl and                GC                FPD          10 µg/kg         89-100      Hamano et al.
                methanol; derivatization to benzene                                                                    (1981)
                sulfonamide; extraction with n-hexane

    Food,       addition of alkali; injection              GC                TEA          87 µg/litre      not given   Rounbehler &
    drinks      of the liquid sample                                                                                   Fine (1982)

    Citrus      steam distillation                         GC/GC-MS          FID          200 µg/kg        95;         Ohnishi et al.
    fruits                                                                                                 24-87f      (1983)

    Tobacco,    steam distillation; derivatization         GC/               FID          < 0.3 mg/kgc     50          Singer &
    smoke       to p-tosylamide                            GC-MS                                                       Lijinsky (1976b)

    Snuff,      extraction with water; filtration;         GC/               TEA          2 µg/kg          70-80       Brunnemann
    tobacco,    acidification; extraction with             GC-MS                                                       et al. (1982)
    packing     diethylether; nitrosation;
    material    extraction with dichloromethane

    Paper,      extraction with HCl; nitrosation with      GC                TEA          3 µg/kg          90          Hotchkiss &
    cardboard   NaNO2; extraction with dichloromethane                                                                 Vecchio (1983)

    Rubber      extraction/reextraction with               GC                PND          2 mg/kgc         not given   Lakritz &
    articles    dichloromethane/HCl                        HPLC                                                        Kimoto (1980)

    Rubber      air passed through powdered sample;        isotachophoresis  not given    not given        not given   Aarts et al.
    articles    trapped in dil. HCl                                                                                    (1990)
    a  adapted from BUA (1991); b  HPLC = high-performance liquid chromatography, UV = ultraviolet, GC = gas chromatography,
    FID = flame ionisation detector, IC = ion chromatography, CD = conductivity detector, TEA = thermal energy analyser,
    VIS = visible, FPD = flame photometric detection, PND = phosphorus nitrogen detector, NSD = nitrogen selective detector,
    RP = reversed phase; c  smallest measurable value (detection limit not given); d  measured as diethyldithiocarbamate;
    e  method used primarily for the separation of morpholine metabolites; f  removal efficiency of morpholine from peel

    3.1  Natural occurrence

         Morpholine is not known to occur naturally.

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes  World producers

    a)   Producers in USA (Chemical Marketing Reporter, 1989; 1990)

         -    Air Products and Chemicals
         -    BASF Co.
         -    Dow Chemical Co. (up to the end of 1990)
         -    Texaco Chemical Co.

    b)   Producers in western Europe (SRI, 1990)

         -    BASF AG, Ludwigshafen, Germany
         -    Chemische Werke Hüls AG, Marl, Germany (up to mid-1990)
         -    Texaco Ltd., Dyfed, Wales, United Kingdom

    c)   Producers in Japan (Japan Chemical Week, 1991)

         -    Koei Chemical
         -    Nippon Nyukazai
         -    Osaka Organic Chemical Ind.

    d)   Producers in other countries

         Morpholine is manufactured in India and in the Common-wealth of
    Independent States (CIS).  Production figures

         Between 1974 and 1981, USA production was stable at about
    11 000 tonnes/year (NRC, 1981). Two new plants were planned in the USA
    in the 1980s, namely BASF (with an estimated capacity of
    8200 tonnes/year) and Air Products and Chemicals (no capacity given).

         BASF reported that in 1988 it manufactured morpholine at Geismar,
    Louisiana, USA, as well as importing it from the parent plant in
    Germany.  The combined import/production volumes were about 30% of a
    9000 tonnes/year market, i.e. 2700 tonnes per year (Dynamac
    Corporation, 1988).  In Germany, about 12 000 tonnes were produced
    in 1988, around 75% being exported (BUA, 1991).  Production figures
    from other European countries are not available.  In Japan,

    1500-1600 tonnes/year is produced (Japan Chemical Week, 1991).  In
    India, 200-500 kg/day (60-150 tonnes per year) is manufactured
    (Subrahmanyam et al., 1983).  Production data from other countries are
    not available.

         It is estimated that elsewhere in the world around 1000 tonnes of
    morpholine are produced annually.  Production processes

         Three methods of producing morpholine have been described:

    a)   Reductive ammonation of diethylene glycol and hydrogen at a
         pressure of 30-400 × 105 Pa and temperature of 150-400°C.
         Possible catalysts include copper, nickel, cobalt, chromium,
         molybdenum, manganese, platinum, palladium, rhodium and
         ruthenium.  Morpholine is recovered by fractional distillation
         (Mjos, 1978).

    b)   Dehydration of diethanolamine with a strong acid such as oleum,
         concentrated sulfuric acid or concentrated hydrochloric acid. 
         The acid is neutralized by the addition of an alkali to give the
         free base of morpholine.  Morpholine is recovered by extraction
         using an organic solvent or concentrated aqueous alkali followed
         by distillation (Mjos, 1978).

    c)   Heating bis(chloroethyl)ether and anhydrous ammonia in a closed
         vessel to 50°C for 24 h.  After venting the excess ammonia, the
         product is filtered from ammonium chloride, and purified
         morpholine obtained by distillation (Mjos, 1978).

         BASF (Germany) uses method a in a continuous process in a closed
    system, and the Texaco Chemical Company also uses method  a. Hüls
    (Germany) produced morpholine up to 1990 using method  b (BUA, 1991).
    Air Products and Chemicals use a low-pressure process in their plant
    at Pace, Florida, USA (NRC, 1981).  Losses to the environment during normal production

         A USA study on atmospheric morpholine releases was conducted by
    Anderson (1983).  No direct measurements were taken, and estimates of
    morpholine emissions were based on analogy with emissions from
    ethylene oxide production.  Total annual emissions (process, storage
    and fugitive emissions) from the processing to rubber accelerators (at
    96 USA sites) and optical brighteners (at 128 USA sites) were
    estimated at 5100 kg/year.  Morpholine emission from miscellaneous
    uses were estimated at an additional 900 kg/year (Anderson, 1983).  Methods of transport

         Morpholine should be stored and transported in iron or steel
    containers (Air Products and Chemicals, 1989).  Accidental release

         There are no reports available on accidental releases of

    3.2.2  Uses

         Morpholine is an extremely versatile chemical.  It is most
    important as a chemical intermediate in the rubber industry, in
    corrosion control, and in the synthesis of a large number of drugs,
    crop protection agents, dyes and optical brighteners (Texaco, 1986;
    Heilen et al., 1989).  Morpholine is a solvent for a large variety of
    organic materials, including resins, dyes and waxes (Texaco, 1986). 
    It can be used as a catalyst.  Morpholine is still used in the USA in
    toiletry and cosmetic products at concentrations up to 5% (Cosmetic
    Ingredient Review, 1989).  It is permitted for use in the USA in
    several direct and indirect food additive applications.

         The use pattern, which varies from country to country, is shown
    in Table 3.

         Approximately 33% of USA-produced morpholine is used as
    intermediates for rubber accelerators and 25% as corrosion inhibitor
    in steam boiler systems (Mjos, 1978).  A high proportion  (25-50%) of
    the morpholine produced in Germany is used for optical brighteners in
    detergent formulations.  In Germany, morpholine-based vulcanization
    auxiliaries are either imported or have been replaced by other
    products.  The use of about half of the morpholine produced in Germany
    could not be identified (BUA, 1991).  Rubber chemicals

         Morpholine derivatives are used in rubber vulcanization,
    stabilization and the manufacture of special high-speed tyres. 
    Morpholine may be released during rubber processing (Mjos, 1978;
    Heilen et al., 1989; BUA, 1991).  Anticorrosion agent

         Morpholine has a volatility similar to water.  It is therefore
    widely used as a neutralizing amine in combating carbonic acid
    corrosion in condensate return lines in steam boiler systems as well
    as in aqueous hydraulic liquids and similar systems.

    Table 3.  Use pattern for morpholine (tonnes/year)

                                    USA (1981)a    Germany

    Rubber chemicals                4920 (40%)

    Corrosion inhibitors            3690 (30%)     small amounts

    Optical brighteners             615 (5%)       750-1500 (25-50%)

    Alkyl morpholines                              300-400 (10-13%)

    Waxes and polishes              615 (5%)       < 100 (< 3%)

    Diazotype/blueprints                           100 (3%)

    Miscellaneous/no information    2460 (20%)     < 900-1750 (30-60%)

    a  From: Mannsville Chemical Products (1981)
    b  From: BUA (1991)

         Morpholine vapours protect silver and other metals against
    corrosion and tarnish by acid fumes such as SO2 and H2S. 
    Corrosion of metal aerosol containers and valves can also be prevented
    by the use of low levels of morpholine (Texaco, 1986).  Morpholine is
    effective in hydraulic system fluids based on glycols, where various
    metals are in contact with the fluid at the same time (Brown, 1966). 
    Morpholine derivatives have been used as corrosion inhibitors in
    mineral lubricating oil, turbine oils, for protecting storage tanks,
    pipes and other devices used in handling petroleum distillates, and
    for inhibiting the corrosive action of grease-proof paper on steel and
    other metals (Texaco, 1986).  Waxes and polishes

         Salts of morpholine with long-chain fatty acids, such as oleic or
    stearic acid, have wax-like properties and are used as emulsifying
    agents in the formulation of water-resistant waxes and polishes for
    automobiles, floors, leather and furniture.  When the loosely-bound
    fatty acid-morpholine compound breaks down, the morpholine component
    evaporates at approximately the same rate as water, leaving a film
    highly resistant to water spotting and deterioration. Morpholine is
    typically present in concentrations up to 2% (Texaco, 1986).

         Morpholine is no longer employed in the production of waxes and
    polishes in Germany (BUA,1991).  Optical brighteners

         Optical brighteners are used in detergent formulations in the
    soap and detergent industry.  The diaminostilbene triazine type
    brightener with morpholine as a substituent on one of the triazine
    rings is particularly effective on cellulosics and is used in home
    laundry detergents because it is stable to chlorine bleaches (Texaco,
    1986).  Catalysts

         Morpholine derivatives such as  N-methylmorpholine and
     N-ethylmorpholine are used as catalysts for the production of
    polyurethane foams.  Pharmaceuticals

         Morpholine derivatives are used as analgesics and local
    anaesthetics (Texaco, 1986; Fisher, 1986; Rekka et al. 1990; Cusano &
    Luciano, 1993), antibiotics (Kleemann & Engel, 1982; Schröder et al.
    1982; BUA, 1991), antimycotics (Lauharanta, 1992; Reinel & Clarke,
    1992) and for plaque control in dentistry (Collaert et al., 1992a,b).  Bactericides, fungicides and herbicides

         Several morpholine derivatives, e.g., morpholinium salts of
    certain acylated sulfonamides, possess bactericidal activity. 
    Morpholine hydroperiodide has been used as a water disinfectant
    (Texaco, 1986).

         Morpholine fungicides are used for agricultural purposes (Mercer,
    1991), as foliar fungicides with protective and curative properties
    for the control of powdery mildew and rust (Brouwers et al., 1992;
    Leenheers et al. 1992), and as foliar fungicides for cereals
    (Ackermann et al., 1989).  Morpholine is also used in the preparation
    of herbicides that can be applied either to the soil before the weeds
    emerge or to the growing plants (Texaco, 1986).  Food additive applications

         USA Federal regulations permit the use of morpholine in several
    direct and indirect food additive applications (Cosmetic Ingredient
    Review, 1989).  Certain fatty acid salts of morpholine can be used as
    components of protective coatings applied to fruits and vegetables
    with the concentrations not allowed to exceed the level required to
    produce the intended effect (US FDA, 1988). Indirect food additive
    possibilities include the use of morpholine as a corrosion inhibitor
    for steel and or tinplate used in food containers (US FDA, 1984a), as
    a defoaming agent used in the manufacture of paper and paperboard for
    food-packaging materials (US FDA, 1984b), as a component of adhesives
    (US FDA, 1984c), and as a defoaming agent in animal glue used for

    packaging materials (US FDA, 1984d).  Morpholine is only allowed as a
    boiler-water additive in concentrations up to 36 mg/m3 (10 ppm), but
    is not permitted when the steam comes into contact with food, milk or
    milk products (US FDA, 1984e).

         In Germany, the use of morpholine in water-repellent food
    packaging material is forbidden (BUA, 1991).  Cosmetics

         Morpholine is used in the USA by the cosmetic industry.  Data
    submitted to the US Food and Drug Administration (US FDA) in 1981 and
    1986 (Cosmetic Ingredient Review, 1989) and in 1991 (Cosmetic
    Ingredient Review, 1991a) show that at least in the USA, morpholine is
    still used in cosmetic products.  In 1981, morpholine was used in 38
    cosmetic preparations, the majority (32) being mascara.  It is also
    used in eyeliner, eye shadow and skin care preparations.  Morpholine
    is listed by the Cosmetic Ingredient Review as an ingredient used in
    cosmetics, although there are insufficient data to substantiate safety
    (Cosmetic Ingredient Review, 1989,1991a).

         Morpholine is listed in Annex II of the EEC Cosmetics Directive. 
    Annex II lists compounds that must not be used in cosmetic
    formulations. In Germany, the use of morpholine in cosmetic
    preparations has been forbidden since 1985 (BUA, 1991) and in the EU
    since 1986 (EEC, 1990).

         Hydroxybenzomorpholine (HBM) is used as a colour additive for
    hair dyes or colorants.  In the FDA voluntary cosmetic registration
    programme, it is listed as a component of 46 products. 
    Isostearamidopropyl morpholine lactate (IML), an antistatic agent
    primarily used in hair conditioners and products, is present in five
    reported cosmetic items.  Quaternary morpholinium salts are given as
    possible ingredients in hair conditioners and deodorants in wave
    formulations (Mjos, 1978).  The presence of morpholine as an
    ingredient in shampoos has been reported (Spiegelhalder & Preussmann,
    1984).  However, a German survey in 1990 showed that morpholine was
    not present in shampoos in Germany (BUA, 1991).


    4.1  Transport and distribution between media

    4.1.1  Volatilization

         As morpholine is freely miscible with water, a Henry's constant
    cannot be reliably calculated.  However, estimates for this constant
    (BUA, 1991) have been published.  Donath et al. (1977) measured the
    distribution coefficient (between vapour and liquid phase) for
    morpholine as a function of temperature (50 to 130°C). They found that
    the rate of volatilization was dependent on the concentration of
    morpholine in the liquid phase. Extrapolation of their curve to 20°C
    for morpholine concentrations of 10-15 mg per litre gives a value of
    0.02, corresponding to a Henry constant value of 49 Pa.m3.mol-1. 
    Calculations from Bosholm (1983) give a value corresponding to
    244 Pa.m3.mol-1.

         According to the classification of Smith et al. (1980),
    morpholine belongs to the group of "moderately volatile" substances.

    4.2  Transformation

    4.2.1  Biodegradation

         Morpholine seems to be degraded only by a restricted range of
    microbes, mostly  Mycobacterium spp., which have specially adapted
    (acclimated) themselves to this substrate under specific conditions
    (Knapp et al., 1982; Cech et al., 1988; Knapp & Brown, 1988; Brown &
    Knapp, 1990).  Dmitrenko et al. (1985, 1987) identified an
     Arthobacter sp. capable of doing this.  Dmitrenko & Gvozdyak (1988)
    reported the isolation of morpholine-degrading mycobacteria and found
    that these organisms could utilize morpholine anaerobically with
    nitrate as a terminal electron acceptor.  Calamari et al. (1980) and
    Tölgyessy et al. (1986) both reported the resistance of morpholine to
    biodegradation.  In addition, Tanaka et al. (1968) and Subrahmanyam et
    al. (1983) both reported the failure of effluent treatment systems to
    degrade morpholine.

         Knapp & Brown (1988) isolated 13 morpholine-degrading bacterial
    strains of  Mycobacterium spp. in pure culture from their laboratory
    activated sludge plant (ASP).  They also found morpholine-degrading
    bacteria in samples from a number of other habitats, including
    activated sludge (from two sewage works), water from two rivers,
    compost, soil and leaf litter. In all cases, there was a lag period of
    10 to 20 days before degradation could be detected. The growth rate of
    these morpholine-degrading strains is slow not only on morpholine but
    also on other substrates.

         Swain et al. (1991) studied the catabolic pathway for morpholine
    when  Mycobacterium strain MorG was grown with morpholine as sole
    source of carbon and nitrogen.  The results indicated that morpholine
    is initially catabolized to 2-(2-aminoethoxy)acetate which can be
    oxidatively cleaved to give rise to glycolate and indirectly to
    ethanolamine.  Mazure (1993) showed that morpholine can be degraded by
    mixed cultures of gram-negative bacteria.  Two mixed cultures were
    studied, one containing 9 and the other 10 bacterial strains, mostly
    pseudomonads.  Interestingly, none of the individual strains was
    capable of sustained growth with morpholine as a sole carbon and
    nitrogen source.  The rate at which the two mixed cultures degraded
    morpholine was similar to that shown by  Mycobacterium aurum in a
    study by Cech et al. (1988).

         Emtiazi (1993) reported that several Gram-negative bacteria
    isolated as degraders of pyrrolidine and piperidine could oxidize
    morpholine but could not grow on it as the sole source of carbon and
    nitrogen.  However, at least one strain could utilize morpholine as a
    source of nitrogen if given succinate as a carbon source; the
    degradation of morpholine was slower than that shown by mycobacteria.  Batch biodegradation tests

         In several early studies all employing some form of biological
    oxygen demand (BOD) test with unadapted inocula, morpholine was found
    to be resistant to biodegradation (Swope & Kenna, 1950; Lamb &
    Jenkins, 1952; Mills & Stack, 1953).  However, Mills & Stack (1955) in
    a later study utilized an inoculum adapted (for 116 days) to the
    presence of morpholine and found that morpholine was degraded in a BOD
    test after 4 days.

         Strotmann et al. (1993) assessed the biodegradability of
    morpholine using a test similar to that of the modified OECD Screening
    Test (die-away test in an open system with low bacterial density)
    (OECD guideline 301 E; OECD, 1981a,b).  The inoculum used was taken
    from an industrial sewage plant.  As morpholine was regularly
    discharged into this treatment plant, the inoculum was regarded as
    adapted.  An unadapted inoculum was obtained from a laboratory-scale
    wastewater treatment plant operated with municipal wastewater.  The
    extent of degradation during the 28-day test (20°C incubation) was
    determined by following the decrease in dissolved organic carbon
    (DOC).  The results showed that morpholine was degraded by both
    adapted and unadapted inoculum.  The lag period before start of
    degradation was about 15 days for the adapted inoculum and 16 days for
    the unadapted.  The lag period given for the adapted cultures in this
    study was rather long, especially considering the result of the
    Zahn-Wellens test (below) carried out using the same inoculum. The
    degradation period was 5 to 7 days for both unadapted and adapted
    cultures. Under the conditions in this test, morpholine showed ready

    biodegradability.  The activated sludge concentration was about 30 mg
    mixed liquor suspended solids (MLSS) per litre.  Initial morpholine
    concentration was 36 mg/litre.

         A Zahn-Wellens Test (a test to estimate inherent
    biodegradability) according to OECD guideline 302 B (OECD, 1981a,b)
    was also performed by Strotmann et al. (1993).  The adapted and
    unadapted sludges were obtained as above, but the activated sludge
    concentration was higher (1 g MLSS/litre).  The concentration of
    morpholine was about 725 mg/litre resulting in an initial DOC of
    400 mg/litre; test duration was 31 days.  Results showed that the lag
    period with unadapted and adapted cultures was about 16-20 days and
    7 days, respectively.  In both cultures the extent of DOC removal was
    more than 90% (morpholine was therefore rated as "inherently
    biodegradable").  After the lag period, the maximum  biodegradation
    rates for adapted and unadapted activated sludges were
    6 g morpholine/kg MLSS per h and 3 g morpholine/kg MLSS per h,
    respectively.  In this test the use of an adapted inoculum
    significantly shortened the lag time.  The authors suggested that this
    effect, which was not observed in the modified OECD screening test,
    might be due to the higher inoculum concentration used in the
    Zahn-Wellens test.  Biodegradation in laboratory-scale wastewater treatment

         A laboratory-scale wastewater treatment plant operating with
    municipal wastewater was supplemented with 4.5 to
    5.0 mg morpholine/litre.  More than 99% of the ammonia could be
    eliminated by nitrification.  The total organic carbon (TOC)
    degradation ranged between 80 and 94%.  The time taken for the sludge
    to adapt to morpholine was 10 to 12 days.  The adapted sludge of this
    treatment plant was reported to be able to degrade morpholine for a
    period of more than one month to more than 90% (Strotmann et al.,

         In a die-away test (EEC, 1983), the kinetics of morpholine
    biodegradation in the above treatment plant were determined (Strotmann
    et al., 1993).  At 20 h after adding 40 mg morpholine per litre, 65%
    of the morpholine was degraded; after 25 h less than 10% of the added
    morpholine was still present.  In this adapted treatment plant, the
    degradation occurred without any lag period, the maximum degradation
    rate (3 g morpholine/kg MLSS per h) being reached after 18 h. 
    According to the authors, morpholine concentrations of 5 mg/litre in
    wastewater can be well degraded in an adapted wastewater treatment
    plant.  However, shock loading with high concentrations (35 mg/litre)
    can result in high concentrations of undegraded morpholine in the

         A model activated sludge plant capable of treating a simple
    industrial waste influent (pH 5.4-5.6) containing morpholine, acetate
    and salicylate and mineral salts was set up (Brown & Knapp, 1990). 
    The activated sludge was taken from the treatment plant of a
    morpholine-containing effluent from a large chemical factory.  It was
    found that when morpholine was absent from the influent, the ability
    of the activated sludge to degrade this compound was subsequently
    reduced.  This was shown by an increase in the lag period before
    morpholine degradation could be detected in a die-away test from over
    40 days, and was accounted for by a decline in the specific population
    of morpholine-degrading microorganisms.  The morpholine degradative
    phenotype was shown to be genetically unstable in several pure
    cultures of mycobacteria (Brown et al., 1990).

         Since morpholine-degraders have a low growth rate, they can only
    establish themselves in activated sludge if the Mean Solids Retention
    Time (sludge age) is relatively long.  Under semi-continuous
    conditions (800 mg morpholine/litre), a sludge age of 8 days was
    needed to achieve complete morpholine degradation (Cech & Chudoba,

         In their investigations into morpholine-degrading bacteria in
    river water from several different sites in Yorkshire, United Kingdom,
    over a 3-month period, Knapp & Whytell (1990) found, as a general
    trend, that the numbers of morpholine-degraders increased and die-away
    lag times decreased as water passed downstream.  This was probably
    related to the cumulative polluting effects of discharges of effluent
    to the rivers.  The number of morpholine-degraders found in this
    investigation agreed with similar studies from rivers in eastern
    England. Of the 58 die-away tests carried out on 29 water samples,
    only 3 (all from water classed as very clean) failed to reveal
    morpholine biodegradation, although in several sites the numbers were
    near the limits of detection (Knapp & Whytell, 1990).

    4.2.2  Abiotic degradation  Hydrolytic degradation

         Morpholine can thermally decompose at temperatures used in boiler
    steam cycles. Agarwala (1982) found that, at 316°C, morpholine
    decomposed in 12 h by 2-5% only, when used in boilers at 95 kg/cm2
    and 108 kg/cm2, the decomposition products being ammonia and
    carbonic acid products.  Under the conditions found in steam-water
    cycles in nuclear power plants (260°C and 4.55 MPa), ammonia,
    methylamine, ethylamine, ethanolamine and 2-(2-aminoethoxy)ethanol
    were identified as morpholine degradation products (Gilbert & Saheb,
    1987; Lamarre et al., 1989).

         Under normal field conditions, it is assumed that morpholine is
    stable.  However, no experimental data are available to confirm this.  Photochemical degradation

         Amines react rapidly with hydroxyl radicals, and the irradiation
    of amine-NOx mixtures in air results in the rapid conversion of NO
    to NO2 and in the formation of ozone, carbonyls and other products
    (Grosjean, 1991).  The rate constant for the degradation of morpholine
    in the atmosphere by hydroxyl radicals has not yet been measured
    experimentally.  Grosjean (1991) postulated a rate constant of
    2-10 × 10-11 cm3.mol-1.sec-1 and gave a tentative reaction
    scheme based on experimental data for dialkylamines.

         Using the method of Atkinson (1988), a half-life (for morpholine)
    of less than one day has been calculated (BUA, 1991).

         As morpholine shows no absorption in the UV spectrum
    (lambda > 260 nm), direct photochemical degradation in the atmosphere
    or in the hydrosphere is unlikely (BUA, 1991).  Degradation by physico-chemical processes

         Upon combustion in the presence of sufficient oxygen, carbon
    monoxide, carbon dioxide and nitrogen gases are produced.

         Combustion under oxygen-starved conditions can result in the
    production of carbon monoxide, hydrogen cyanide, nitriles, cyanic
    acid, isocyanates, cyanogens, nitrosamines, amides and carbamates
    (Air Products and Chemicals, 1989).

    4.2.3  Bioaccumulation

         There are no data on the bioaccumulation of morpholine in aquatic
    and terrestrial organisms.  However, as the  n-octanol/water
    partition coefficient for morpholine is log Pow = -2.55 (at pH 7),
    bioaccumulation is not expected (BUA, 1991).

    4.3  Interaction with other physical, chemical or biological factors

         Due to its carcinogenic properties the formation of NMOR from
    morpholine has to be taken into account when assessing health and
    environmental aspects of morpholine.  NMOR can be formed by reaction
    of aqueous solutions of nitrite with morpholine (Mirvish, 1975) or by
    reaction of gaseous nitrogen oxides, e.g., N2O3, N2O4, NOx
    in aqueous solutions of morpholine, even under normal environmental
    conditions (Challis & Kyrtopoulos, 1979; Mirvish et al., 1988;
    Schuster et al., 1990).  Nitrogen oxide (NO) levels may be higher than
    was previously thought (Cooney et al. 1992; Hibbs, 1992). The
    conditions of nitrosation, in particular the pH, plays a significant

         In aqueous solutions, the reaction is as follows:


         The rate of reaction of the nitrosation of morpholine by nitrite
    is greatest at a pH value of 3.4, where the rate constant is
    0.42 mol-2.s-1.  An increase in the pH value has been shown to
    result in a decrease in the rate of nitrosation with nitrite (Mirvish,
    1975; Archer et al., 1977), and the rate was almost zero at pH > 7
    (Archer et al., 1977).

         In contrast, nitrosation with gaseous nitrogen oxides (N2O3,
    N2O4, NOx) can take place over the whole pH range (Challis &
    Kyrtopoulos, 1979; Meiners et al., 1980).  Cooney et al. (1987) found
    that, under certain conditions, the yield of NMOR at pH 7 was ten
    times higher than at pH 2, but there was no further increase beyond
    this pH.

         Some nitrosamines, particularly alpha-nitrosamine aldehydes, are
    potent transnitrosation reagents and are capable of nitrosating
    morpholine at pH 7.9 (Loeppky et al., 1987).

         Numerous reaction accelerators are known, e.g., thiocyanate
    (Boyland et al., 1971), halides (Mirvish, 1975), formaldehyde (Archer
    et al., 1977) and nitrosophenols, e.g.,  p-nitroso- o-cresol (Davies
    et al., 1980).  Enhancement of the nitrosation of morpholine by
    nitrogen dioxide was reported in the presence of iodine (Challis &
    Outram, 1979), vanillin and related phenols (Cooney & Ross, 1987) and
    halides, particularly bromide (Cooney et al., 1987).

         In contrast, the following compounds have been reported to
    inhibit the nitrosation of morpholine almost completely: ascorbic acid
    (Lathia & Schellhöh, 1981; Leach et al., 1991); urea or ammonium
    sulfamate (Mirvish et al., 1972); gallic acid and sulfite (Mirvish,
    1975); L-cysteine and DL-methionine ( in vitro study under
    physiological conditions, Lathia & Edeler, 1989), catechol and
    4-hydroxychavicol (Shenoy & Choughuley, 1989); alpha-tocopherol
    (Norkus et al., 1986; Cooney et al., 1987; Schuster et al., 1990);
    sulfhydryl compounds such as cysteine, cysteamine, glutathione and
    thioglycolic acid, as well as extracts of onion and garlic juice

    (Shenoy & Choughuley, 1992). Vitamin C, glucose, mannitol, cabbage
    juice, orange juice, shiitake mushroom extract and saliva inhibited
    the nitrosation of morpholine  in vitro, but catechin, epicatechin
    and tea extract enhanced the same reaction (Ohnishi, 1984).  The
    inhibitory effect of Chinese tea on the formation of NMOR  in vitro
    and  in vivo has also been described (Wang & Wu, 1991).

         Several C-nitro compounds, in particular tetranitromethane, have
    been demonstrated to transnitrosate morpholine to form  NMOR (Fan et
    al., 1978).  C-nitro compounds are widely used in industry as
    pesticides, bactericides, colouring agents, drugs and perfumes.

         Singer (1980) described the transnitrosation of morpholine with
    nitrosamines and nitrosureas under acid conditions in the presence of
    thiocyanate.  These reactions are dependent on the pH value and steric
    and electronic factors, as well as on the basicity of the amines. In a
    model study, the nitrosation of morpholine by nitro-nitroso compounds,
    such as those found in fried bacon, was observed (Liu et al., 1988).

         NMOR can be formed  in vivo in humans and has been found in
    various tissues and fluids such as human saliva (Boyland et al., 1971;
    Wishnok & Tannenbaum, 1977) and human gastric juice (Ziebarth, 1973;
    1974; Sen & Baddoo, 1989; Yurchenko et al., 1990).  NMOR formation has
    been reported in rat lungs (Postlethwait & Mustafa, 1983), whole mice
    (Iqbal et al. 1980; Norkus et al. 1984), stomach (Furman & Rubenchik,
    1991), hepatocytes isolated from woodchucks  (Marmota monax) (Liu et
    al., 1992) and microorganisms (Archer et al., 1979; O'Donnell et al.,
    1988; Calmels et al., 1991a,b).  Bacterial catalysis of
     N-nitrosation of morpholine has been reported in a range of bacteria
    often isolated from the human gut or urinary tract infections (Suzuki
    & Mitsuoka, 1984; Calmels et al., 1987, 1988; Mackerness et al.,
    1989),  including the ubiquitous gut bacterium  Escherichia coli and
     Pseudomonas aeruginosa, which is also widespread in the aquatic
    environment.  Bacterial catalysis of  N-nitrosation of morpholine is
    heat labile and is optimal at neutral to slightly alkaline pH (Calmels
    et al., 1985; Leach et al., 1987).   N-nitrosation by bacteria is
    generally associated with the ability to reduce nitrate.  It appears
    that those that reduce nitrate to nitrogen or nitrogen oxides (e.g.,
     P. aeruginosa) can nitrosate at much greater rates than those (e.g.,
     E. coli) that only reduce nitrate to nitrite (Leach et al.,1987;
    Calmels et al., 1988).  There is considerable variation between
    strains of the same species.  Bacterial  N-nitrosation of morpholine
    has been shown to follow Michaelis-Menten kinetics (Calmels et al.,
    1985; Leach et al., 1987).   E. coli A10, for example, displays Km
    values of 7.4 mmol/litre for morpholine and 11.4 mmol/litre for sodium
    nitrite.  It has been shown that the rate of bacterial  N-nitrosation 
    of secondary amines is inversely related to the pKa of the amine
    (Calmels et al., 1985; Leach et al., 1987, 1991), with a linear
    relationship between log10 of the rate of nitrosation and pKa.
    Morpholine, having a relatively low pKa, is thus relatively
    susceptible to nitrosation compared, for example, to alkyl amines.

         It has been shown that ascorbate is capable of inhibiting
    nitrosation of morpholine by  P. aeruginosa (Leach et al., 1991). 
    Although most nitrosation studies have used whole bacteria, an enzyme
    catalyzing  N-nitrosation of morpholine has been isolated and
    purified from two denitrifying bacteria (Calmels at al., 1990).

    4.4  Ultimate fate following use

    4.4.1  Fate of morpholine in various products

         Morpholine is an important industrial chemical with a wide range
    of applications (see section 3.2.2) and therefore may be present in
    many industrial emissions.

         Its use as a corrosion inhibitor in boiler water means that
    morpholine and its decomposition products will be found in boiler
    wastewater, including water from power plants using morpholine.  In a
    study by McCain & Peck (1976), morpholine concentrations in the
    discharge streams of three Hawaiian power plants ranged from not
    detectable to 0.008 mg/litre, suggesting that the potential for human
    exposure is small.

         Its use in the manufacture of rubber additives results in an
    indefinable amount of morpholine being released into the hydrosphere
    or geosphere not only during manufacturing processes but also through
    tyre abrasion and disposal of used tyres.

         Morpholine is released during vulcanization processes using
    morpholine-containing accelerators such as  2-( N-morpholino-
    thio)benzothiazole (MBS) (Badura et al., 1989).  Some of the amine is
    released into the atmosphere and some is bound to the rubber.  Even
    the accelerator itself can contain free amine. The morpholine content
    of MBS is < 0.4% by weight.  This level can be higher if the
    accelerator is not stored properly and is exposed to heat or moisture
    (BUA, 1991).

         Aarts et al. (1990) detected free volatile morpholine at
    concentrations of between 70 (new) and 230 mg/kg (old) in samples of
    dithio-bis-morpholine (DTBM).  After extraction in water for one hour
    in an ultrasonic bath, ten times this amount was detected, i.e.
    960 mg/kg in newly made and 2750 mg/kg in stored DTBM.  These
    quantities of amine could be released during vulcanization.

         Optical brighteners adhere to clothes during the first wash but
    tend to be released into the wastewater in subsequent washings. 
    Although these substances are not themselves biologically degradable,
    they have been found to disappear from wastewater after a two-step
    biological treatment presumably due to the high rate of adsorption to
    the sludge particles (Jakobi et al., 1983).

         As mentioned in section 3.2.2, morpholine is released into the
    environment by volatilization through its use in waxes and polishes
    (Texaco, 1986).

    4.4.2  Waste disposal

         Controlled incineration is the preferred method of disposal
    (Sittig, 1985; Air Products and Chemicals, 1989).  The incinerator
    should be equipped with a scrubber or thermal unit.  Nitrogen oxide
    emissions should meet environmental regulations.


    5.1  Environmental levels

    5.1.1  Ambient air

         No data are available on levels of morpholine in ambient air.

    5.1.2  Water  River water

         Since mid-1990, the levels of morpholine in some rivers in North
    Rhine-Westphalia, Germany, have been monitored (BUA, 1991).  No
    morpholine could be detected at three different points in the River
    Rhine or in five of its tributaries (detection limit, 5 µg/litre).  No
    morpholine was found in samples of Tennessee freshwater (detection
    limit, 0.07 µg/litre) (Singer & Lijinsky, 1976a).  In 1979, 33 water
    samples were collected at 11 sites in Japan, but no morpholine could
    be detected (detection limit, 1-5 µg/litre) in any of the samples
    (Environment Agency Japan, 1980).  Wastewater

         There are no data on morpholine levels in wastewater.

         A single sample of wastewater from a tyre chemical factory in
    Ohio, USA was found to contain 3 µg NMOR/litre (Fajen et al., 1979).

         In England, samples were taken from the inlets and outlets of
    four sewage treatment plants (Richardson et al., 1980).  NMOR
    (100 µg/litre) was found only in the outlet of a cutting-fluid
    recovery plant.

    5.1.3  Sediment

         Spies et al. (1987) examined contaminated sediments in San
    Francisco Bay, USA and found several benzothiazoles, including
    2-(4-morpholinyl)-benzothiazole, which is present as an impurity in
    commercial 2-(morpholinothio)-benzothiazole used in motor tyres. The
    authors carried out weathering tests on this latter commercial
    substance and found that the morpholine impurity was environmentally
    stable.  They suggested that the 2-(4-morpholinyl)-benzothiazole found
    in the sediments (up to 0.36 mg/kg dry weight) was a result of
    accumulated street run-off. Morpholine itself could not be detected.

         In 1979, 33 bottom sediment samples were collected at 11 sites in
    Japan, but no morpholine could be detected (detection limit,
    0.01-0.5 mg/kg) in any of the samples (Environment Agency Japan,

    5.1.4  Soil

         There are no data on the presence of morpholine in soil.
    2-(4-Morpholinyl)-benzothiaozole (273 µg/kg dry weight) was detected
    1.6 km from a motorway in California, USA (Spies et al., 1987) (see
    also section 5.1.2).

         NMOR (4.4 mg/kg) was detected in a single sample of soil near to
    a tyre chemical factory in Ohio, USA (Fajen et al., 1979).

    5.1.5  Terrestrial and aquatic organisms

         Levels of morpholine found in single or small samples of fish are
    given in Table 6, but the sample numbers are too low to make an
    evaluation.  No other data are available.

    5.2  General population exposure

    5.2.1  Indoor air

         No data on indoor air exposure to morpholine are available.

         Analysis for NMOR in the air inside new cars showed levels of up
    to 2.5 µg/m3. Levels were 4 to 10 times lower when the air-venting
    system was working, indicating that NMOR exposure is limited to the
    first few minutes of each trip (Rounbehler et al., 1980).  During a
    simulation of conditions inside cars on a hot day, concentrations of
    up to 0.4 µg NMOR/m3 were measured at 60°C (Dropkin, 1985).

    5.2.2  Drinking-water and food

         There are no data on the morpholine content of drinking-water.

         Food can become contaminated with morpholine in several ways: 
    (a) through direct treatment of fruit with waxes containing morpholine
    for conservation purposes;  (b) by use of packaging material
    containing morpholine, and (c) through steam treatment during

         Ohnishi et al. (1983) found morpholine at concentrations of
    < 71.1 mg/kg in the peel of retail citrus fruits in Japan. In the
    pulp (flesh) of the fruits the level was much lower, being less than
    0.7 mg/kg (Table 4). Marmalade made from whole fruits contained
    concentrations of morpholine between 0.3 to 0.7 mg/kg. If the fruits
    were previously washed in washing-up liquid, morpholine concentrations
    were reduced, but only by 25%. Even if the fruit was boiled for
    20 minutes, a third to a quarter of the morpholine still remained. The
    morpholine removed by these processes could be detected quantitatively
    in the washing and boiling water (Ohnishi et al., 1983).

    Table 4.  Morpholine content of citrus fruits and marmalade from
              citrus fruitsa
    Sample                                         Number   Morpholine

    Orange (variety a)c             peel            12      
                                    fruit pulp       3       0.2-0.7

    Orange (variety b)c             peel             6       5.0-71.1
                                    fruit pulp       1       0.3

    Mandarine                       peel             2       16.1-18.0
                                    fruit pulp       1       n.d.

    Lemon                           peel             2       n.d.-5.2
                                    fruit pulp       1       n.d.

    Grapefruit                      peel             2       2.8-7.0
                                    fruit pulp       1       n.d.

    Marmalade from citrus fruits                     4       0.3-0.7

    a  adapted from Ohnishi et al. (1983)
    b  n.d. = not detectable (detection level 0.2 mg/kg),
       presumably fresh weight
    c  variety not specified

         Sen & Baddoo (1989) reported the morpholine and NMOR content of
    waxed and unwaxed apples of Canadian origin, obtained either direct
    from the packers or from retail sources.  Liquid wax spray is used as
    a protective coating on fruit and vegetables to reduce moisture loss
    and thereby extend the shelf-life of the product. Apple homogenates
    and liquid waxes were analysed for their morpholine contents
    (Table 5).  Although the concentrations of morpholine found in waxed
    apples were high, NMOR could not be found in any of the waxed or
    unwaxed samples. Low levels of morpholine in the unwaxed apples could
    be due to contamination during packing or transport.

         Singer & Lijinski (1976a) analysed a variety of foodstuffs for
    the presence of morpholine but the sample size was too small to draw
    any conclusions. The results are given in Table 6.  The sources of
    contamination with morpholine are in these cases not clear. The
    possibility of artifacts is unlikely according to the authors.

    Table 5.  Concentration of morpholine and NMOR (mg/kg) in samples of
              liquid waxes and waxed and unwaxed applesa
         Liquid wax            Unwaxed apples          Waxed apples
    NMOR    morpholine     NMOR      morpholine     NMOR    morpholine

    0.286      27 300       n.d.        n.d.         n.d.       4.3
    0.668      31 500       n.d.        0.118        n.d.       4.9
    0.138      24 400       n.d.        0.016        n.d.       6.3
    0.277      38 500       n.d.        0.041        n.d.       7.1
    0.152      22 500       n.d.        n.d.         n.d.       4.0
    0.585      33 300       n.d.        0.018        n.d.       7.7

    a  adapted from Sen & Baddoo (1989);  n.d. = not detected (detection
       limit: 0.005 mg/kg for morpholine, 0.0005 mg/kg for NMOR)

         Table 7 summarizes the results of investigations into the
    concentrations of morpholine and NMOR in prepacked milk products
    (Hoffmann et al., 1982). The values range from 5-77 µg/kg for
    morpholine and "not detectable" to 3.3 µg/kg for NMOR. Contamination
    of prepacked foodstuffs with morpholine might be explained by the use
    of morpholine in steam boiler systems for paper and cardboard

         Hotchkiss & Vecchio (1983) found morpholine concentrations of
    between 0.098 and 8.4 mg/kg (mean 0.38 mg/kg) in food packaging. A
    sample of flour nearest the wall of the paper bag contained 1.1 µg
    NMOR/kg. The bag itself contained 33.0 µg NMOR/kg. In an experimental
    72-h incubation at 100°C, between 1 and 2.3 µg NMOR/kg migrated from
    packaging material to various dry foods.

         Sen & Baddoo (1986) investigated the migration of NMOR out of
    waxed packaging material into margarine. Waxed wrappings and margarine
    samples taken 1 cm from the outer layer of the block contained NMOR
    (5-73 µg/kg and 0.5-1.4 µg/kg, respectively). NMOR was not detectable
    in those samples taken from the inside of the block.  Samples taken of
    margarine packed in aluminium backed wrappers, specially coated waxed
    papers or plastic containers were negative for NMOR (detection level,
    0.5 µg/kg).

         Aitzetmüller & Thiele (1982) found no NMOR in 20 margarine
    samples from different countries (detection limit, 0.5 µg/kg).

        Table 6.  Morpholine content in various food samplesa
    Food                   No. of    Concentration     References
                           samples   (mg/kg)b


    Fish sausage             5          n.d.           Hamano et al. (1981)
    Cod roe                  3          n.d.           Hamano et al. (1981)
    Codc                     -d         tracese        Singer & Lijinsky (1976a)
    Spotted troutc           1          6              Singer & Lijinsky (1976a)
    Smallmouth bassc         1          < 0.7          Singer & Lijinsky (1976a)
    Salmonc                  1          1              Singer & Lijinsky (1976a)
    Ocean perchc             -d         9.0            Singer & Lijinsky (1976a)
    Tuna (in tins)           -d         < 0.6          Singer & Lijinsky (1976a)


    Baked ham                5          0.2            Hamano et al. (1981)
    Baked ham                -d         0.5            Singer & Lijinsky (1976a)
    Frankfurter sausages     -d         0.4            Singer & Lijinsky (1976a)

    Plant products

    Spinach                  2          n.d.           Hamano et al. (1981)
    Miso (from soja)         2          n.d.           Hamano et al. (1981)


    Evaporated milk          -d         0.2            Singer & Lijinsky (1976a)
    Coffee                   -d         1.2            Singer & Lijinsky (1976a)
    Tea                      -d         tracesf        Singer & Lijinsky (1976a)
    Beer (in tins)           -d         0.4            Singer & Lijinsky (1976a)
    Beer (in bottles)        -d         < 0.2          Singer & Lijinsky (1976a)
    Wine                     -d         < 0.7          Singer & Lijinsky (1976a)

    a  adapted from BUA (1991)
    b  fresh weight except for tea and coffee (dry weight);
       n.d. = not detected (detection limit 0.01 mg/kg)
    c  frozen from Tennesee & Columbia rivers
    d  average from several samples; exact number not given
    e  < 0.3 mg/kg
    f  < 0.1 mg/kg dry weight
    Table 7.  Morpholine and NMOR content (mg/kg) in food products
              and their waxed containersa
    Sample                       Food                 Container
                           NMOR      morpholine   NMOR      morpholine

    Butter                 0.0032      0.058      0.0019      0.22

    Cream cheese           0.0009      0.077      n.d.        0.68

    Yoghurt                n.d.        0.038      n.d.        3.06

    Cottage cheese         0.0004      0.044      0.0054     17.2

    "Cheese" (semi-soft)
    Country of origin:
    Germany                0.0033      0.009      n.d.        0.026
    Denmark                0.0031      0.01       0.0016      0.025
    Austria                0.0007      0.005      0.0012      0.022
    USA                    0.0014      0.008      n.d.        0.132

    Gouda                  0.0016      0.035      n.d.        0.035

    Frozen peas            n.d.        0.026      0.0031      0.057
    and carrots

    a  adapted from Hoffmann et al. (1982); n.d. = not detected
       (detection limit for NMOR, 0.0002 mg/kg)

         Gavinelli et al. (1988), in a survey in Italy, found no NMOR in a
    variety of foodstuffs including canned beef, pork, poultry, cured
    meat, milk products, malt products, domestic Italian canned wines and
    beers. The limit of detection was 0.3 µg/kg. Similarly, Pensabene &
    Fiddler (1988) found no NMOR in samples of different USA fish-meat
    frankfurter sausages (limit of detection, 0.2 µg/kg). These authors
    assumed that the positive results in their earlier work were due to

         Groenen et al. (1987) found NMOR in cheese (2.8 µg/kg) and cured
    meat products (34 µg/kg) after addition of morpholine (10 mg/kg) in
    the alkaline pH range.

         Liu et al. (1988) suggested that the NMOR in fried bacon was
    formed by transnitrosation.

         USA Federal regulations permit the use of morpholine in several
    direct and indirect food additive applications (US FDA, 1984a,b,c,d,e;
    1988; see section 3.2.2). Although the US Food and Drug Administration

    allows morpholine to be used as a direct or indirect food additive, in
    1980 one of the biggest USA producers recommended its customers not to
    use morpholine in this way (Litton Bionetics, 1980).

    5.2.3  Tobacco

         Morpholine was found in unburned cigarette tobacco at a
    concentration of 0.3 mg/kg (Singer & Lijinsky, 1976b). In cigarette
    smoke condensate < 5 mg/kg was detected, equivalent to
    0.08 µg/cigarette. It has been established that an appreciable portion
    of the inhaled smoke is swallowed and retained in the stomach where
    nitrosation of ingested amines is known to occur (Sander & Bürkle,

         Brunnemann et al. (1982) analysed 10 popular snuff brands from
    the USA and Sweden for morpholine and volatile  N-nitrosamines (see
    Table 8). In the five USA brands, morpholine concentrations of between
    1.5 and 4.0 mg/kg were found; in the Swedish products, the
    concentrations were between 0.2 and 2.5 mg/kg. An analysis of the
    snuff containers that were made of waxed cardboard gave morpholine
    values of 0.17 to 4.74 mg/kg (USA) and 0.46 to 4.83 mg/kg (Swedish).
    The morpholine content in the snuff could have come through diffusion
    from the container made of waxed cardboard. Another possibility was
    contamination during the tobacco processing as suggested by the very
    high morpholine content (19.4 mg/kg) of a single sample of chewing
    tobacco, packaged in aluminium.  NMOR formed by nitrosation from
    morpholine was found in 5/5 of the USA and 2/5 of the Swedish snuff
    samples (Brunnemann et al., 1982).

         Brunnemann & Hoffmann (1991) reported that since 1981 they had
    routinely determined the concentrations of NMOR in a leading snuff
    brand in the USA with the aim of creating awareness of the fact that
    morpholine is a precursor of NMOR and must be removed. In eight
    commercial snuff brands analysed in 1986 (Hoffmann et al., 1987), only
    three were found with traces of NMOR (9-39 µg/kg). Brunnemann &
    Hoffmann (1991) noted that the decrease in the NMOR content (from
    about 700 µg/kg in 1981 to an undetectable level in 1990) is most
    probably due to modifications in packaging, since snuff products in
    the USA are now sold in plastic containers that have no wax coatings
    (Table 9).

         Österdahl & Slorach (1983) analysed snuff and chewing tobacco on
    the Swedish market for volatile  N-nitrosamines.  NMOR was found in
    9/30 samples in concentrations between 0.4 and 4.0 µg/kg (Swedish
    brands) but in none of the three USA brands. One of three chewing
    tobacco brands contained 0.8 µg morpholine/kg.

    Table 8.  Nitrosomorpholine and morpholine in snuff containersa

    Snuff brand        Snuff tobacco (µg/kg)b    Snuff container
                       NMOR       morpholine     NMOR         morpholine

    USA       I          24          2800           34           845
              II        690          1500           10           170
              III       690          4000          230          4740
              IV        630          3200            4            90
              V          31          2200            3           140

    Sweden    I          44           820            4          1750
              II       < 2d           200            3           460
              III      < 2d           780           13          4830
              IV         10           940           23          4290
              V        < 2d          2500        n.d.e          n.d.

    a  from Brunnemann et al. (1982)
    b  based on dry weight
    c  uncorrected for moisture; had previously contained snuff.
       Containers of USA I-III and Sweden I-IV were cardboard boxes
       with a metal lid, USA IV were plastic containers with individual
       snuff portions in porous paper bags; USA V was a plastic container;
       Sweden V were individual snuff portions in Al-bags.
    d  detection limit = 2 µg/kg
    e  n.d. = not determined

    Table 9.  NMOR in fine-cut snuff (on the basis of dry tobacco weight)a

     Year                    Yield (µg/kg)

     1981                         690
     1984                          29.4
     1984/85                      238
     1985                          29
     1986/87                     < 2b
     1987                          43
     1990                        < 2

    a  from Brunnemann & Hoffmann (1991)
    b  detection limit = 2 µg/kg

         A survey of smokeless tobacco products commercially available in
    1987-1988 showed that trace levels of NMOR were still found in some
    United Kingdom (mean 0.5 µg/kg) and Swedish (mean 1 µg/kg) oral
    tobacco products packed in waxed containers, but no NMOR was detected
    in Indian zarda or European nasal snuff (Tricker & Preussmann, 1991).

    5.2.4  Cosmetics and toiletry articles

         Morpholine is used in some countries in cosmetic products as a
    surfactant and emulsifier at concentrations up to 5% (Cosmetic
    Ingredient Review, 1989).

         Data submitted to the Food and Drug Administration (FDA) in 1981
    by cosmetic firms participating in the voluntary cosmetic registration
    programme indicated that morpholine was used in a total of 38 cosmetic
    products including eyeliner, eye shadow, mascara and skin care
    preparations (Cosmetic Ingredient Review, 1989). The greatest use of
    morpholine was in mascara (32 products). The reported concentration
    ranges of morpholine in these products were < 0.1% (4 products),
    > 0.1-1% (17 products) and > 1-5% (17 products).  Table 10
    summarizes data submitted to the FDA in 1986 showing that the greatest
    use of morpholine was in eye make-up removers, at concentrations of
    > 0.1-1% and > 1-5% (Cosmetic Ingredient Review, 1989). These data
    show that the ocular region and the skin around are the areas directly
    exposed to cosmetic products containing morpholine. The potential also
    exists for morpholine-containing products to come in contact with the
    conjunctiva and cornea. Additionally, it must be emphasized that these
    morpholine-containing products may be applied several times daily over
    the course of several years.  Due to lack of appropriate safety data,
    the Cosmetic Ingredient Review Expert Panel could not conclude that
    morpholine was safe for use in cosmetic products (Cosmetic Ingredient
    Review, 1989).

         Morpholine is listed in Annex II of the European Economic
    Community (EEC) Cosmetics Directive and therefore must not be used in
    cosmetic formulations (EEC, 1986). Investigations in 1988 and 1989 in
    the Federal Republic of Germany showed that no morpholine could be
    detected in toiletry articles (BUA, 1991).

         Data from a 1985 US Food and Drug Administration report given in
    Table 11 show that NMOR was found at concentrations between 48 and
    1240 µg/kg in seven mascara products (Cosmetic Ingredient Review,
    1989). It is not known whether the NMOR detected was formed in the
    cosmetics.  Table 11 also shows the results of an analysis of various
    toiletry articles in the Federal Republic of Germany prior to the EEC
    Directive in 1986. NMOR was detected in 18% of the products
    (Spiegelhalder & Preussman, 1984).

        Table 10.  Product formulation data for morpholinea
    Product                 Total no. of    Total no.     No. of product formulations
    category                formulations    containing    within estimated
                            in category     ingredient    concentration ranges

                                                           > 0-1%    > 1       > 1-5%

    Eye make-up                 77              29           11                    18

    Eye, face, or body        1264               2                      2
     preparations other
     than eye make-up

    1986 totals               1341              31           11         2          18

    a  US FDA (1986)

    5.2.5  Rubber articles

         NMOR was found in commercial samples of rubber chemicals at
    concentrations of 60-3500 µg/kg by Spiegelhalder & Preussmann (1982),
    who noted that the occurrence of nitrosamines was directly related to
    the use of corresponding vulcanization accelerators. The nitrosamines
    could be leached out by water, buffer solutions or milk but could not
    be completely removed even after boiling or treating with acid or
    alkaline solutions (Spiegelhalder & Preussmann, 1982).

         Several rubber articles which come into contact with skin or
    food, in particular baby bottle teats and pacifiers (dummies), were
    assayed for NMOR; 10 µg/kg migrated from a silicone rubber pacifier
    (1 out of 11 different samples; detection level, 1 µg/kg) after
    incubation for 24 h at 40°C (Spiegelhalder & Preussmann, 1982). Sen et
    al. (1984) found NMOR in 2 out of 10 brands of nipples and in one
    pacifier at concentrations of between 0.1 µg/kg (detection level) and
    86 µg/kg. The same authors found NMOR (5.7 µg/kg) in one plastic
    nipple shield, no NMOR being found in the other 41 samples of nipples
    and pacifiers (detection limit, 1 µg/kg) (Sen et al., 1985).

         Westin et al. (1987) tested 16 types of children's pacifiers and
    baby-bottle nipples on sale in Israel from nine different countries
    and found NMOR at levels of up to 2 µg/kg.

    Table 11.  N-nitrosomorpholine (NMOR) in toiletry articles and

    Productsa                No. of      No.             (µg/kg)
                             samples   positive
                                                   maximum    average

    Shampoos                    45        13         640         133

    Colour toners                7         -           -           -

    Hair conditioners           16         -           -           -

    Foam baths                   7         -           -           -

    Shower gels                  9         4         380         145

    Cream and oil baths          8         2         440           -

    Cosmetic bath additives      5         -           -           -

    Children's shampoos          5         1         230           -
    Children's bath and
     skin care products          8         6         360          80

    Body lotions and rubs        6         -           -           -

    Face tonics, cleaners,      29         -           -           -
     and masks

    Mascarab                     7         7        1240         306

    a  from Spiegelhalder & Preussmann (1984), with the exception of
    b  from CIR (1986)

         In a survey in Germany in 1990, no morpholine or NMOR was found
    in the rubber articles tested; these included balloons, baby
    dummies/teats, rubber gloves, condoms and rubber rings for bottling
    (BUA, 1991).

    5.3  Occupational exposure during manufacture, formulation or use

         A USA National Occupational Hazard Survey, conducted by NIOSH,
    detected worker exposure to morpholine in 283 different industries
    (NRC, 1981). In 1970, 501 283 workers were potentially exposed to the

    actual product, 22% were exposed to a product known to contain
    morpholine, and 74% were exposed to a generic product suspected to
    contain morpholine.

         Data from the USA National Occupational Exposure Survey (NOES) in
    1988 indicated that in a total of 30 industries and 8711 plants
    surveyed, 146 511 workers, including 44 839 women, were potentially
    exposed to morpholine in the workplace (NIOSH, 1988).

         Many countries recommend for morpholine an 8-h time-weighted
    average exposure limit of 70 mg/m3 (skin notation) and a 15-min
    short-term exposure limit (STEL) of 105 mg/m3 (ILO, 1991).

    5.3.1  Exposure to morpholine

         Only a few studies have been reported concerning the exposure of
    workers to morpholine.

         An analysis in Ontario, Canada of condensed steam samples in four
    hospitals and one food processing plant using corrosion inhibitors in
    the steam-generating plants gave mean values for morpholine of
    2.41 mg/litre in the hospitals (9 samples; range 2.1-2.9 mg/litre) and
    1.1 mg/litre in the factory (9 samples; range 0.6-1.8 mg/litre)
    (Malaiyandi et al., 1979).

         Fajen et al. (1979) found morpholine levels of 230 and
    42 µg/m3, respectively, in air samples from two out of four rubber
    industry factories; these two were a tyre factory and its chemical

         Taft & Stroman (1979) described an investigation into workers
    exposed to a number of chemicals in the drying and bagging departments
    of a tyre and rubber company manufacturing the rubber accelerator,
    4-morpholino-2-benzothiazolyl [(4-morphinyl-2-benzothiazole)]
    disulfide. This rubber accelerator is manu-factured by reacting
    morpholine with 2-mercaptobenzothiazole (MBT). With the exception of
    one personal sample showing 0.05 mg of morpholine/sample (0.4 ppm) at
    the level of detection, all other samples showed negative results.

         Occupational exposure to morpholine was measured in 15 factories
    of the chemical, plastic and rubber industries in Germany from 1980 to
    1990, and in no case was the German workplace exposure limit of
    70 mg/m3 reached. Of 35 measurements, 90% were below 0.26 mg/m3
    (BUA, 1991).

         Katosova et al. (1991) reported average levels of 0.54 to 0.93 mg
    morpholine/m3 with maximum concentrations of 0.73 to 2.14 mg/m3 in
    a morpholine production factory in the former-USSR.

    5.3.2  Exposure to N-nitrosomorpholine

         Occupational exposure to NMOR has been found in the rubber
    industry.  Table 12 gives a summary of the data published.

         Fajen et al. (1979) found NMOR in air samples from a tyre
    chemical factory and an aircraft tyre factory. In the chemical
    factory, NMOR was also found as an impurity in morpholine (0.8 mg/kg)
    and in bismorpholine carbamylsulfenamide (BMCS), a vulcanisation
    accelerator (0.4 to 0.7 mg/kg), as well as in wastewater
    (0.003 mg/kg), utility steam condensate (0.002 mg/kg), and dirt
    scrapings on a staircase (730 mg/kg). Outside the chemical plant, a
    soil sample contained 4.4 mg/kg (Fajen et al., 1979). It is possible
    that the NMOR in these samples was formed by the transnitrosation from
     N-nitrosodiphenylamine, also produced in the tyre chemical factory,
    together with morpholine present in the steam condensate (BUA, 1991).

         A survey was carried out by NIOSH and a tyre manufacturing
    company in 1979 into the levels of NMOR in four different work areas
    in the factory as well as personal exposure levels (Ringenburg &
    Fajen, 1980; London & Lee, 1987). Personal breathing-zone air samples
    ranged from 0.6 to 1.8 µg/m3 (mean 0.8 µg/m3), and workplace
    levels from 0.8 to 3.7 µg/m3.  In a survey at another tyre
    manufacturing company during the same year, nitrosamine levels were
    highest (1.62 µg/m3) during the extrusion process of racing tyre
    components (McGlothlin, 1980; McGlothlin & Wilcox, 1984). Exposure to
    NMOR in rubber press operator fumes was investigated by NIOSH in
    another company. The highest personal exposure to NMOR was
    0.063 µg/m3, and the highest area sample 0.038 µg/m3.

         In a factory producing rubber parts for automobile interiors, the
    highest level of NMOR (19 µg/m3) was found in the process sample
    taken directly above one of the extruder ovens. Other personal and
    process levels were in the range 0.1 to 1.4 µg NMOR/m3.

         Between 1980 and 1990, 775 samples of workplace air from 124
    factories in Germany involved in the production and fabrication of
    rubber articles were analysed for NMOR (BUA, 1991).  Of the samples,
    71% showed concentrations less than the guidance  value of 1 µg/m3
    (BUA, 1991).

         According to Spiegelhalder (1983) and Schuster et al. (1990),
    higher concentrations of NMOR are to be found in work areas where
    higher temperatures are required for fabrication/vulcanization. High
    levels of NMOR from storage areas probably result from continued
    emission of volatile NMOR.

         NMOR was not detected in the environment of a metal factory using
    metal-working fluids (Fadlallah et al., 1990).

        Table 12.  Occupational exposure to NMORa
    Production area             Country     Year        No. of monitoring  Type of        Concentration     Reference
                                                             places        monitoring     (µg/m3)b

    Tyre chemical factory       USA         1978              10           area           0.07-5.1          Fajen et al. (1979)

    Tyre manufacturer           USA         1978              20           area           0.6-27            Rounbehler & Fajen
                                                              12           area           0.08-8.5          (1983)
                                                               7           area           0.02-3.9
                                                               6           process        0.41-2.9
                                                               6           area           < 0.01-0.60
                                                               7           process        < 0.1-22.0
                                                               7           area           < 0.002-250
                                                               8           process        0.1-25

    Tyre manufacturer           USA         1979/             13           area           0.1-1.62          McGlothlin (1980),
                                            1980                                                            McGlothlin & Wilcox (1984)

    Tyre manufacturer           USA         1979/              4           area           0.85-3.7          Ringenburg & Fajen (1980);
                                            1980               6           personal       0.6-1.8           London & Lee (1987)

    Industrial rubber articles  USA         1978               4           area           0                 Fajen et al. (1979)

    Industrial rubber articles  USA         1980/             11           area           < 0.005-0.0376    Hollett et al. (1982)
                                            1981               7           personal       < 0.0096-0.0629

    Rubber articles for         USA         1982               4           area           0.8-19            Lee (1982)
     car outfitting                                           13           personal       0.4-1.2

    Rubber industry             Germany     1979/        20 monitoring     area and       0.1-17            Spiegelhalder &
                                            1981         points in 17      personal                         Preussmann (1982)

    Table 12 (cont'd)
    Production area             Country     Year        No. of monitoring  Type of        Concentration     Reference
                                                             places        monitoring     (µg/m3)b

    Rubber industry             Germany     1987             545           personalc      < 2.5 (73%),      TRGS (1989)
                                                                                          > 2.5 (27%)
                                                                                          max. 41

    Chemical industry           Germany     1987              22           not given      < 1 (91%)d        TRGS (1989)

    Leather industry            Germany     1987              50           not given      < 1 (100%)        TRGS (1989)

    Foundries                   Germany     not given        658           not given      < 1 (95%),        TRGS (1989)
                                                                                          > 1 (5%)
                                                                                          max. 2.1

    a  adapted from BUA (1991)
    b  the percentage of samples which had this given concentration is given in parentheses
    c  sum of all measured N-nitrosamines
    d  in 82% below the detection level (0.2 µg/m3)

    6.1  Absorption

         Toxicity experiments on rodents have shown that morpholine is
    absorbed after oral, dermal and inhalation exposure (see Table 13).

    6.2  Distribution

         Tanaka et al. (1978) determined the distribution of
    [14C]-labelled morpholine in male Wistar rats (3 animals/group,
    250-300 g) after oral (200 mg/kg) and intravenous injections
    (150 mg/kg).  The radioactivity was determined in the dried, powdered
    organs.  Large amounts were only found in muscle and intestine.  In
    rats sacrificed 2 h after oral administration of morpholine-HCl, 29%
    of the radioactivity was found in the intestine and 26% in the muscle. 
    Similarly, 2 h after intravenous injections, 19 and 27% of the dose
    was found in the intestine and muscle, respectively.

         Female New Zealand rabbits (number not given) were exposed to
    morpholine (905 mg/m3) for 5 h by nose-only inhalation
    (Tombropoulos, 1979). At the end of the exposure, the animals were
    sacrificed and the tissue and body fluids analysed.  Concentrations of
    morpholine were highest in urine (324 mg/litre) and kidney
    (118 mg/kg), the other tissues having concentrations below 40 mg/kg.

         Van Stee et al. (1981) injected six male New Zealand rabbits
    intravenously with 5 mmol [14C]-labelled morpholine/kg body weight
    (435 mg/kg).  The distribution of radioactivity after 30 min showed
    the highest concentrations in the renal medulla (36 mmol/kg) and
    cortex (15.4 mmol/kg), followed by lung (5.1 mmol/kg), liver
    (4.7 mmol/kg) and blood (2.3 mmol/litre).  Morpholine was not bound to
    serum proteins. 

    6.3  Metabolic transformation

         Morpholine is eliminated mainly in a non-metabolized form in the
    urine of the rat, mouse, hamster and rabbit (Griffiths, 1968; Tanaka
    et al., 1978; Van Stee et al., 1981; Sohn et al., 1982b).  However,
    Sohn et al. (1982b) reported that morpholine is metabolized by
     N-methylation followed by  N-oxidation in the guinea-pig.  After an
    intraperitoneal injection of 125 mg/kg [14C]-labelled morpholine in
    guinea-pigs, 20% of the radioactivity was found in the urine as
     N-methylmorpholine- N-oxide.  However, the morpholine ring can be
    cleaved in mammalian systems.  In several studies on the metabolism of
    morpholine derivatives in the rat, ring cleavage products have been
    noted (Tatsumi et al., 1975; Hecht & Young, 1981; Kamimura et al.,

        Table 13.  Single exposure toxicity data for morpholinea
    Species        No./sex        Dosage                        Results      Cause of death/symptoms         Reference


    Rat            5              1.05 g/kg body weight         LD50         n.g.                            Smyth et al. (1954)

    Rat            57             1.6 g/kg body weightb         LD50         gastrointestinal haemorrhage    Shea (1939)

    Rat            5 m + 5 f      1.9 g/kg body weight          LD50         dyspnoea, haemorrhagic          BASF (1967)

    Rat            7 m            1.0 g/kg body weight; pH 7    no deaths    n.g.                            Börzsönyi et al. (1981)

    Guinea-pig     33             0.9 g/kg body weightb         LD50         gastrointestinal                Shea (1939)
                                                                             haemorrhage, diarrhoea


    Rat (Wistar)   4 m            0.4 g/kg body weight          all died     n.g.                            Stewart & Farber (1973)

    Rat (Wistar)   4 m            0.1 g/kg body weight          lethal       n.g.                            Stewart & Farber (1973)
                                                                for 1/4

    Mouse          5 m + 5 f      0.4 g/kg body weight          LD50         irritation around               BASF (1967)
                                                                             injection area, dyspnoea


    Rat            5 m + 5 f      18.1 g/m3; 6 h                lethal       haemorrhage of nose, mouth      Hazleton (1981)
                                                                for 9/10     and eyes; spasms; tremors

    Rat            6              saturated atmosphere;c        all died     spasms; caustic burns           BASF (1967)
                                  5´ h                                       on nose and extremities

    Table 13 (cont'd)
    Species        No./sex        Dosage                        Results      Cause of death/symptoms         Reference

    Inhalation (contd)

    Rat            n.g./m         8.2 g/m3;                     LC50         n.g.                            Lam & Van Stee (1978)

    Rat            n.g./f         7.8 g/m3;                     LC50         n.g.                            Lam & Van Stee (1978)

    Rat            n.g.           65.2 g/m3; 8 h                lethal       irritation of nose,             Shea (1939)
                                                                             eyes; lung haemorrhage

    Rat            n.g.           43.4 g/m3; 8 h                lethal       n.g.                            Shea (1939)

    Mouse          n.g./f         6.9 g/m3;                     LC50         n.g.                            Lam & Van Stee (1978)

    Mouse          n.g./m         5.2 g/m3;                     LC50         n.g.                            Lam & Van Stee (1978)

    Mouse          n.g.           4.9 g/m3;                     LC50         n.g.                            Zaeva et al. (1968)


    Rabbit (New    n.g.           0.5 ml/kg body weight         LC50         n.g.                            Smyth et al. (1954)

    a  adapted from BUA (1991); n.g. = no details given
    b  morpholine diluted with 4 parts water; deaths within a week
    c  inhalation of a saturated atmosphere at 20°C formed by bubbling air through a 5-cm layer of morpholine
         In the presence of nitrite, morpholine can be converted to NMOR
    (see section 4.3). NMOR was found in the stomachs of rats that had
    been fed on diets containing morpholine and nitrite (Sander et al.,
    1968; Inui et al., 1979).

         Immunostimulation of rats by intraperitoneal treatment with
     E. coli lipopolysaccharide (LPS; 1 mg/kg) led to a large increase in
    urinary nitrate and urinary metabolites of NMOR when morpholine
    (80 µmol/kg) and L-arginine (400 µmol/kg) were injected
    intraperitoneally. The replacement of LPS with nitrate (330 µmol/kg
    intraperitoneal) did not increase urinary metabolites of NMOR (Leaf et
    al., 1991). This result is consistent with endogenous nitrosation of
    morpholine by nitrogen oxide (NO) from oxidation of the guanido group
    of arginine by induced NO synthase (Hibbs, 1992).

         Hecht & Morrison (1984) developed a method to monitor the
     in vivo formation of NMOR by measuring  N-nitroso
    (2-hydroxyethyl)glycine, its major urinary metabolite. The formation
    of NMOR was measured in F-344 rats over wide range of doses of
    morpholine (38.3-0.92 µmol) and sodium nitrite (191-4.8 µmol).
    According to estimates by the authors, 0.5 to 12% of the morpholine,
    depending on the dose, was nitrosated.

          In vitro nitrosation of morpholine has been reported.  NMOR was
    formed when morpholine was added to human saliva (Tannenbaum et al.,
    1978).  Additionally, a new type of metabolite  N-cyanomorpholine was
    identified in human saliva (Wishnok & Tannenbaum, 1976).

    6.4  Elimination and excretion

    6.4.1  Expired air

         Elimination of 14C from labelled morpholine (intraperitoneal
    injection) through expired air is minimal. In rats, experiments have
    shown that only about 0.5% of the dose of radioactively labelled
    morpholine is exhaled as 14CO2 (Sohn et al., 1982b). In rabbits
    0.0008% of the administered dose was 14CO2 (Van Stee et al.,

    6.4.2  Urine

         Elimination studies on male Wistar rats (200-350 g) were carried
    out by administering morpholine-HCl (500 mg/kg) or [14C]-labelled
    morpholine-HCl (200 mg/kg) orally and morpholine-HCl (250 mg/kg)
    intravenously.  In all cases, over 85% of the dose was excreted in
    urine within 24 h.  A further portion, up to 5%, was excreted during
    the next three days.  [14C]-morpholine palmitate was eliminated
    slightly more slowly, but the urinary excretion within 3 days
    following oral administration amounted to 90% of the dose (Tanaka et
    al., 1978).  Of the radioactive morpholine administered to rats,
    62-77.5% was excreted in the urine after 24 h (Griffiths, 1968; 

    Ohnishi, 1984).  Following intraperitoneal administration to rats,
    urinary excretion within 24 h was 87.8% of the dose (Maller &
    Heidelberger, 1957).  In the dog, 70-80% of the radioactive morpholine
    was excreted in the urine (Rhodes & Case, 1977).

         The time-course of urinary excretion of 14C by Sprague-Dawley
    rats, Syrian golden hamsters, and strain II guinea-pigs treated with
    [14C]-morpholine was compared by Sohn et al. (1982b).  Although in
    all three species over 80% was excreted in 3 days, the rate of urinary
    excretion within the first 6 h was greatest in the hamster and least
    in the guinea-pig.

         Van Stee et al. (1981) infused rabbits intravenously with
    [14C]-morpholine (5 mmol/kg) which had been neutralized with HCl. 
    After 4 h, 18.5% of the dose was excreted in the urine.  When the pH
    of the urine was lowered from 7.8-7.9 to 7.1-7.2 by administration of
    ammonium chloride (10 g/litre) in drinking-water prior to the
    injection, the urinary excretion more than doubled (to 43%).

         These data suggest that the urinary excretion of morpholine is
    enhanced by its neutralization with acid.

    6.4.3  Faeces

         Rats dosed orally or intravenously with morpholine hydrochloride
    excreted not more than 1.7% of the dose in the faeces (Griffiths,
    1968; Tanaka et al., 1978).  However, when dosed orally with
    morpholine palmitate (Tanaka et al., 1978, Ohnishi, 1984), up to 7%
    was excreted in faeces.

    6.5  Retention and turnover

         Plasma concentration-time curves of 14C after intraperitoneal
    injections of [14C]-morpholine (125 mg/kg in 0.9% NaCl) in Sprague-
    Dawley rats, Syrian golden hamsters, and strain II guinea-pigs
    declined biexponentially.  Whereas rates of first phase of elimination
    from plasma in rats and hamsters were similar (half-lives of 115 and
    120 min, respectively), the half-life in guinea-pigs was significantly
    longer (300 min) (Sohn et al., 1982b).


    7.1  Single exposure

         Table 13 summarizes the toxicity data on single exposure to

    7.1.1  Oral

         Oral administration of morpholine to rats resulted in LD50
    values of 1-2 g/kg body weight (Shea, 1939; Smyth et al., 1954; BASF,
    1967). Gastrointestinal and nasal haemorrhage were reported. In
    contrast, when morpholine was administered to seven male rats at a
    neutral pH, no deaths occurred with concentrations of 1 g/kg body
    weight (Börzsönyi et al., 1981).

         A study on guinea-pigs resulted in a LD50 of 0.9 g morpholine
    per kg body weight. Gastrointestinal and nasal haemorrhage were
    reported (Shea, 1939).

    7.1.2  Inhalation

         There have been reports of inhalation studies with morpholine on
    rats (Shea, 1939; BASF, 1967; International Labour Office, 1972;
    Lam & Van Stee, 1978; Hazleton, 1981) and mice (Zaeva et al., 1968;
    Lam & Van Stee, 1978).

         Exposure to morpholine at vapour saturation concentrations
    resulted in almost 100% lethality after 5.5 h (BASF, 1967).  It had
    irritating and corrosive properties.

         In studies with lower concentrations, Lam & Van Stee (1978)
    obtained LC50 values of 7.8 and 8.2 g/m3 for female and male rats,
    respectively, whereas other authors reported no deaths at three times
    this concentration (see Table 13).

         Reported LC50 values for mice are consistently in the range of
    5-7 g/m3 (see Table 13).

    7.1.3  Dermal

         Smyth et al. (1954) noted necrosis on the clipped skin of albino
    rabbits within 24 h of application of undiluted morpholine. Mortality
    within 14 days in New Zealand rabbits after penetration of morpholine
    into the skin gave an LD50 of 0.5 ml/kg body weight.

         Other reports are discussed in section 7.4.2.

    7.1.4  Intraperitoneal

         When morpholine was administered intraperitoneally to rats
    (Stewart & Farber, 1973) and mice (BASF, 1967), the LD50 was in the
    range 0.1-0.4 g/kg body weight for rats and 0.4 g/kg body weight for
    mice (see Table 13).

    7.2  Short-term exposure

         As with single-exposure, the effects of morpholine after short-
    term exposure depend on the method of exposure. The available data on
    short-term exposure are summarized in Table 14.

    7.2.1  Oral

         Rats and guinea-pigs were fed morpholine at concentrations of
    0.16-0.8 g/kg body weight and 0.09-0.45 g/kg body weight,
    respectively, by gavage for 30 days (Shea, 1939). At concentrations of
    half of the LD50, nearly all the animals died within 30 days, the
    principal symptoms being severe damage to the secreting tubules of the
    kidney, fatty degeneration of the liver and necrosis of the stomach
    glandular epithelium.

         Fatty degeneration (lipidosis) of the liver in rats was noted
    after feeding morpholine (0.5 g/kg body weight) daily for 56 days
    (Sander & Bürkle, 1969).

         Shibata et al. (1987a) carried out a 13-week toxicity study in
    B6C3F1 mice using morpholine as the fatty acid salt, morpholine
    oleic acid salt (MOAS), at dosage levels of 0%, 0.15%, 0.3%, 0.6%,
    1.25% and 2.5% MOAS in the drinking-water.  At the highest MOAS level,
    body weight gains were slightly reduced. Histopathological analysis
    showed cloudy swelling of the proximal tubules, but no other
    alterations were observed in the organs of either sex. Urinalysis
    showed increases in both specific gravity and plasma urea nitrogen in
    some dosage groups, suggesting a possible malfunctioning of the kidney
    (see Table 14).

    7.2.2  Inhalation

         In rats that died after 5 days repeated exposure to 65.2 g/m3,
    lung haemorrhage, severe damage to the secreting tubules of the
    kidney, and fatty degeneration of the liver were observed (Shea,

        Table 14.  Short-term exposure to morpholinea
    Species        No./sex        Dosage/concentration/         Mortality      Pathological, histopathological             Reference
                                  length of exposure                           or biochemical changes


    Rat            20             0.16 g/kg body weight per     8/20           beginning necrosis of liver, kidney         Shea (1939)
                                  day; 30 days; in 2 ml H2O                    and stomach mucous membrane

                   20             0.32 g/kg body weight per     8/20           necrosis of liver, kidney, stomach
                                  day; 30 days; in 2 ml H2O

                   20             0.8 g/kg body weight per      19/20          weight loss, lethargy, severe necrosis
                                  day; 30 days; in 2 ml H2O                    of liver, kidney, stomach

    Rat            7 f            0.5 g/kg body weight per                     sacrifice after 270 days, moderate          Sander & Bürkle
    (Sprague-                     day; 56 days                                 liver adipose degeneration                  (1969)

    Mouse          10 m + 10 f    0.15 and 0.3% MOAS; 91 days                  no significant changes                      Shibata et al.
    (B6C3F1)                      (0.07 or 0.14 g morpholine/                                                              (1987a)
                                  kg body weight per day)

                   10 m + 10 f    0.6% MOAS; 91 days                           m: increase in specific gravity of
                                  (ca. 0.2 g morpholine/kg                     urine; f: increase in blood urea
                                  body weight) per day

                   10 m + 10 f    1.25% MOAS; 91 days                          increase in specific gravity of
                                  (ca. 0.4 g morpholine/kg                     urine and blood urea
                                  body weight per day)

    Table 14 (cont'd)
    Species        No./sex        Dosage/concentration/         Mortality      Pathological, histopathological             Reference
                                  length of exposure                           or biochemical changes

                   10 m + 10 f    2.5% MOAS; 91 days                           reduced weight gain; increase in specific   Shibata et al.
                                  (ca. 0.7 g morpholine/kg                     gravity of urine and blood urea;            (1987a)
                                  body weight per day)                         increased relative kidney weight with
                                  swelling of proximal tubules

    Guinea-pig     20             0.09 g/kg body weight         3/20           slight alterations in liver, kidney         Shea (1939)
                                  per day; 30 days (syringe)

                   20             0.18 g/kg body weight         12/20          necrosis of liver, kidney, stomach
                                  per day; 30 days (syringe)

                   20             0.45 g/kg body weight         16/20          severe degeneration of liver, kidney,
                                  per day; 30 days (syringe)                   stomach


    Rat            n.g.           7.2 g/m3; 4 h/day; 4 days     n.g.           increased residual volume and               Takezawa &
                                  total lung capacity                                                                      Lam (1978)

    Rat            n.g.           65.2 g/m3; 34 h over 5 days   some deathsb   necrosis of liver and kidney tubules;       Shea (1939)
                                                                               lung irritation

    Rat            6-8 m          0.08 g/m3; 4 h/day; 8 days    no deaths      hypersecretion of thyroid gland,            Grodeckaja
                                                                               higher accumulation of 131I in the          & Karamzina
                                                                               thyroid gland                               (1973)

    Rat            5 m + 5 f      0.36 g/m3; 6 h/day; 9 days    0/10           red stains around nose and mouth;           Hazleton
                                                                               weight loss in females                      (1981)

                   5 m + 5 f      1.81 g/m3; 6 h/day; 9 days    2/10           irritation to nose and eyes; weight loss;   Hazleton
                                                                               decrease in spleen/brain weight ratios      (1981)

    Table 14 (cont'd)
    Species        No./sex        Dosage/concentration/         Mortality      Pathological, histopathological             Reference
                                  length of exposure                           or biochemical changes

                   5 m + 5 f      3.62 and 18.1 g/m3;           10/10          bleeding from eyes, nose and                Hazleton
                                  6 h/day; 9 days                              mouth                                       (1981)

    Rat            n.g.           1.63 g/m3; 4 h/day;           n.g.           reduced weight gain; increased residual     Takezawa &
                                  5 days/week; 30 days                         volume and total lung capacity              Lam (1978)

    Rat            20 m + 20 f    0.09 g/m3; 6 h/day;                          no significant differences in body          Conaway et al.
    (Sprague-                     5 days/week; 13 weeks                        weight, clinical chemistry, haematology     (1984b)
    Dawley)                                                                    or organ weight data; no nasal lesions

                   20 m + 20 f    0.36 g/m3; 6 h/day;                          in 2/20 females focal necrosis in
                                  5 days/week; 13 weeks                        nasal cavity

                   20 m + 20 f    0.9 g/m3; 6 h/day;                           lesions of nose and mouth; after 7
                                  5 days/week; 13 weeks                        weeks in 8 animals focal metaplasia
                                                                               and necrosis in nasal turbinates; after
                                                                               13 weeks, increased incidence and
                                                                               severity; pneumonia

    Rabbit         4 m            0.9 g/m3; 6 h/day;                           increased hydrolytic enzyme content         Tombropoulos
                                  5 days/week; 33 days                         in alveolar macrophages                     et al. (1983)

    a  adapted from BUA (1991); b.w. = body weight; n.g. = not given
    b  exact numbers not clear
         Rats inhaling morpholine at 3.62 or 18.1 g/m3 for 9 days, 6 h
    per day, died within the exposure period (Hazleton, 1981).  At lower
    concentrations (1.81 g/m3), weight loss and irritation to nose and
    eyes, as well as two deaths, were reported. The report concluded that
    the maximal tolerated dose for rats is about or just below 0.3 g/m3.

         Increased thyroid activity, shown as increased uptake of injected
    131I, was observed in male rats after exposure to 0.08 g
    morpholine/m3, 4 h/day, for 4 days (Grodeckaja & Karamzina, 1973).

         Takezawa & Lam (1978) reported an increase in lung weight,
    residual volume and total lung capacity in rats exposed to morpholine
    (7.2 g/m3, 4 h/day for 4 days or 1.63 g/m3 for 30 days).

         Tombropoulos et al. (1983) examined the induction of lysosomal
    enzymes by morpholine in rabbits.  Two acid hydrolases,
    alpha-mannosidase and acid phosphatase, were induced in the lung
    alveolar macrophages during the course of inhalation exposure
    (905 mg/m3, 250 ppm, 6 h/day, 5 days/week for a total of 33
    exposures).  The induction was also observed when macrophages were
    cultured in the presence of morpholine.

         Conaway et al. (1984b) exposed groups of 40 rats to morpholine
    (0, 0.09, 0.36 and 0.9 g/m3) for 7 and 13 weeks. Shallow, rapid
    breathing was noted in all groups except the controls. Lesions of the
    nasal septum, anterior cavities, nasoturbinates and maxilloturbinates
    were observed in the 0.36 and 0.9 g/m3 groups but not in the lowest
    exposure group.

         Lung sections of all rats killed after 7 weeks contained early
    lesions of chronic murine pneumonia. In the upper dosage group, these
    lesions had developed in severity by 13 weeks. There were no apparent
    treatment-related effects in any of the haematology, clinical
    chemistry or urinalysis data at weeks 7 or 13.

    7.2.3  Dermal

         Shea (1939) investigated the effects of single and repeated
    dermal application of morpholine on rabbits and guinea-pigs.  He found
    that whereas unneutralized, undiluted morpholine caused 100% lethality
    and even the diluted compound caused mortality and severe necrotic
    burns and inflammation, application of undiluted morpholine
    neutralized to pH 7 with sulfuric acid caused neither gross nor
    microscopic pathology of the skin with the exception that the dermis
    was thickened at the site of application.

         Undiluted morpholine applied for 5-15 min to rabbit skin led to
    severe necrosis (BASF, 1967).

         Data on short-term dermal exposure to morpholine are also
    discussed in section 7.4.2.

    7.3  Long-term exposure

         Table 15 summarizes the data on long-term exposure to morpholine.

    7.3.1  Oral

         Mice (10 males and 10 females/group) were given 0%, 0.25% or 1.0%
    MOAS in their drinking-water for 96 weeks and then given normal tap
    water for a further 8 weeks (Shibata et al., 1987b). During the study,
    the physical appearance and general behaviour did not appear to be
    affected by treatment. Decreased body weight gain was noted at 1% MOAS
    (both sexes) and at 0.25% MOAS (females). Gross pathological and
    extensive biochemical examinations did not reveal treatment-related
    effects. The incidence of hyperplasia in forestomach epithelium of
    males in the 1% group was statistically higher than in the controls,
    but otherwise no significant increase in the incidence of non-
    neoplastic and neoplastic lesions could be found.

    7.3.2  Inhalation

         Migukina (1973) reported increased nervous system activity and
    increases in haemoglobin and peripheral red blood cell counts in rats
    and guinea-pigs exposed to morpholine (0.008 and 0.07 g/m3) for 4
    months.  An increase in the chromosomal aberrations of the bone marrow
    cells was also noted (see section 7.6). This study was deficient with
    respect to the description of study methods.

         Harbison et al. (1989) carried out an extensive long-term
    exposure inhalation study. Groups of 70 rats of each sex were exposed
    to morpholine (0, 0.036, 0.181, 0.543 g/m3) 6 h per day, 5 days per
    week, for 104 weeks, with an interim sacrifice at week 53. Levels of
    nitrates and nitrites in the drinking-water were reported to be
    < 0.1 mg/litre and 0.01 mg/litre, respectively. Survival, body weight
    gain, organ weight and haematology and clinical chemistry data were
    normal in exposed groups, compared to the controls.  In-life clinical
    examinations revealed increased incidences of inflammation of the
    cornea, inflammation and squamous metaplasia of the turbinate
    epithelium, and necrosis of the turbinate bones in the nasal cavity of
    both male and female rats. No increase in the incidence of neoplasms
    was found.  Only tissues from the respiratory tract and eyes were
    examined histologically in the case of the mid- and low-dose groups.

    7.3.3  Dermal

         No data are available on long-term dermal exposure to morpholine.

        Table 15.  Long-term exposure to morpholinea
    Species        No./sex   Dosage/concentration,                   Effect                                            Reference
                             length of exposure


    Mouse          50 m      0.25% MOAS; 672 days (ca. 0.05-0.14 g   no significant changes                            Shibata et al.
    (B6C3F1)b                morpholine/kg body weight per day)                                                        (1987b)

                   50 f      0.25% MOAS; 672 days (ca. 0.07-0.17 g   decreased body weight gain
                             morpholine/kg body weight per day)

                   50 m      1% MOAS; 672 days (ca. 0.28-0.5 g       decreased body weight gain; increase in blood
                             morpholine/kg body weight per day)      urea nitrogen; hyperplasia in forestomach

                   50 f      1% MOAS; 672 days (ca. 0.21-0.57 g      decreased body weight gain
                             morpholine/kg body weight per day)


    Rat            84 m      0.008 g/m3; 34 h within 5 days;         reversible changes in haemogram, kidney,          Migukina (1973)
                             16 weeks                                liver, lung, spleen, myocardium

                   84 m      0.07 g/m3; 4 h/day;                     changes in haemogram, liver, kidney
                             5 days/week; 16 weeks                   lung, spleen, myocardium

    Rat            20        1.09 g/m3; 6 h/day;                     no significant increase in spinal cord            Savolainen &
                             5 days/week; 15 weeks                   axonal succinate dehydrogenase activity; no       Rosenberg (1983)
                                                                     significant alteration of enzyme activity in
                                                                     muscle; morpholine concentration in brain
                                                                     increased with length of exposure

    Table 15 (cont'd)
    Species        No./sex   Dosage/concentration,                   Effect                                            Reference
                             length of exposure

    Rat            70 m +    0.036 and 0.18 g/m3; 6 h/day;           increased incidence of irritation around          Harbison et al.
    (Sprague-      70 f      5 days/week; 104 weeksc                 eyes and nose                                     (1989)
                   70 m +    0.54 g/m3; 6 h/day;                     local necrosis around eyes and nose;
                   70 f      5 days/week; 104 weeksc                 kerativitis

    Guinea-pig     24        0.008 g/m3; 4 h/day;                    swollen lymph nodes of the spleen                 Migukina (1973)
                             5 days/week; 16 weeks

                   24        0.07 g/m3; 4 h/day;                     swollen alveoli; atrophy of lymph vessels in
                             5 days/week; 16 weeks                   lung and spleen; increase in haemoglobin and
                                                                     erythrocyte number, decrease in leucocytes

    a  adapted from BUA (1991); b.w. = body weight
    b  MOAS: morpholine administered as oleic acid salt in drinking-water; in brackets, the daily intake of morpholine
       calculated from MOAS intake
    c  10 m + 10 f killed at 53 weeks
    7.4  Skin and eye irritation; sensitization

    7.4.1.  Eye irritation

         Eye injury in rabbits was tested by Smyth et al. (1954), who
    reported severe eye burns with 0.5 ml of a 1% solution. BASF (1967)
    reported that 1 drop of undiluted morpholine in rabbit eyes, repeated
    once after 5 min, caused oedema, opacity, staphyloma and corrosion of
    the eye mucous membranes within 24 h.

         A solution of morpholine (0.02 mol/litre) neutralized with HCl
    had no injurious effect on the eyes of rabbits when applied
    continuously for 10 min after removal of the corneal epithelium to
    facilitate penetration. Similarly, the irritative reaction of 10-20%
    aqueous morpholine was reduced on neutralization (Grant, 1974).

         In-life clinical examinations in rats exposed to up to
    0.54 g/m3 (150 ppm) morpholine revealed increased incidences in
    inflammation of the cornea at week 103 of the study (Harbison et al.,
    1989).  Findings included keratitis, oedema, abrasion, scarring, and
    ulceration with or without neovascularization and corneal epithelial
    hyperplasia. A high incidence of retinal degeneration was observed,
    primarily in female animals, which was probably an age-related light-
    induced retinal degeneration.

         Albino rabbits, three of each sex, were treated with a mascara
    composite containing 1% morpholine; 0.1 ml of the cosmetic was
    instilled into one eye of each rabbit daily for 14 days. Before the
    application each day, the eye was evaluated for ocular irritation. A
    slight redness of the conjunctiva was noted throughout the duration of
    the study but this cleared within 24 h of the last treatment. A sodium
    fluorescein dye test performed at the conclusion of the study
    indicated no abnormalities of the cornea or its iris membranes
    (Cosmetic Ingredient Review, 1989).

    7.4.2  Skin irritation

         In rabbits treated with aqueous solutions of 2, 20, 40 and 60%
    morpholine, the skin reactions were evaluated after 0.5, 24, 48 and
    72 h (Lodén et al., 1985).  A 2% solution of morpholine caused skin
    irritation after 72 h, whereas 40% and 60% solutions immediately
    caused reddening of the skin.

         Wang & Suskind (1988) measured the irritant potential of
    morpholine by applying 0.1 g mixture (0.1, 0.5, 2, 5 and 10%
    morpholine in petrolatum) to guinea-pig skin for 24 h. Observations
    were made 1, 24 and 48 h after removal of the test materials, and no
    noticeable effects were found.

         A mascara composite containing 1% morpholine was applied to
    normal and abraded skin of six albino rabbits (Cosmetic Ingredient
    Review, 1989). At the end of the 14-day treatment period, no dermal
    toxicity or irritation was observed.

    7.4.3  Sensitization

         Sensitization studies (modified Buehler) on guinea-pig skin using
    2% morpholine in petrolatum gave negative results (Wang & Suskind,
    1988). In an  in vitro study into the biochemical causes of
    sensitization, it was found that morpholine as a hapten did not react
    with the amino acids glycine, lysine and cystine, as did related
    compounds which showed sensitizing reactions (Wang & Tabor, 1988).

    7.5  Reproductive toxicity, embryotoxicity and teratogenicity

         No adequate studies on reproductive toxicity, embryotoxicity or
    teratogenicity have been reported.

    7.6  Mutagenicity and related end-points

    7.6.1  Mutagenicity of morpholine

         Table 16 summarizes the short-term mutagenicity tests on
    morpholine.  Bacteria

         No mutagenic response was observed in plate tests with strains of
     Salmonella typhimurium, either with or without metabolic activator,
    exposed to morpholine at up to 10 µl/plate (approximately 10 mg/plate)
    (Texaco, 1979a; Haworth et al., 1983), whereas a 99.8% purity sample
    did induce weak mutagenic responses in  S. typhimurium TA100 and
     Escherichia coli WP2  uvr A at the unusually high dose level of
    50 mg/plate (Glatt & Oesch, 1981). The activity in strain TA100 did
    not require S9 mix and is, therefore, unlikely to have been due to
    0.2% contamination by NMOR (see below).

         In mouse peritoneal cavity host-mediated assays with
     S. typhimurium TA1530 and TA1930, no increase in the proportion of
    mutants was observed following the oral administration of morpholine
    (Braun et al., 1977; Edwards et al., 1979). These groups served as
    controls in a study of nitrosation (see below).  Yeast

         No gene conversion was induced in  Saccharomyces cerevisiae D4
    by morpholine concentrations up to 10 µg/litre per plate.  Toxicity
    was observed at the highest concentration (Texaco, 1979a).

        Table 16.  Short-term in vitro microbial mutagenicity assays with morpholinea
    Test organisms           Strain              Analyzed     Metabolic   Dosage range           Result with/     Reference
                                                 purity (%)   activityb                          without S9-mix

    Salmonella typhimurium   TA98/100/1535/1537  not given       RA       0.109-10.9 mg/plate       -/-           Haworth et al. (1983)

    S. typhimurium           TA98/100/1535/1537  not given       RA       0.005-10 µl/plate         -/-           Texaco (1979a)

    Saccharomyces            D4                  not given       RA       0.005-10 µl/platec        -/-           Texaco (1979a)

    S. typhimurium           TA98/1535/1537      99.8            RA       0.0158-50 mg/plate        -/-           Glatt & Oesch (1981)

    S. typhimurium           TA100               99.8            RA       0.0158-50 mg/plate        (+)/(+)d      Glatt & Oesch (1981)

    Escherichia coli         WP2 uvrA            99.8            RA       0.0158-50 mg/plate        (+)d/-        Glatt & Oesch (1981)

    S. typhimurium           TA1950              99              HM1      1450-2900 µmol/kg         -             Braun et al. (1977)

    S. typhimurium           TA1530              not given       HM2      4 mg/kg body weight       -             Edwards et al. (1979)

    a  adapted from BUA (1991)
    b  RA = Arochlor-induced rat liver-S9; HM1 = Host-mediated assay NMRI-mice; HM2 = Host-mediated assay CD-1 mice
    c  toxic at 10 µl/plate for strain Salmonella typhimurium TA1538 and Saccharomyces cerevisiae D4
    d  (+) = positive only at the 50 mg/plate dose  Mammalian cells in vitro

         When tested over the range 0.625-1.25 µl/ml (approximately
    0.625-1.25 mg/ml) morpholine induced small increases in the fraction 
    of tk mutants in mouse lymphoma L5178Y cells.  No exogenous metabolic
    activation system was required for this weak activity (Texaco, 1979b;
    Conaway et al., 1982a,b).

         Morpholine induced no DNA-repair in the primary cultures of rat
    hepatocytes (0.1-100 µg/ml) (Conaway et al., 1984a).

         Morpholine induced small increases in the frequency of SCEs in
    Chinese hamster ovary (CHO) cells. No exogenous metabolic activation
    system was required for this activity, which was observed at
    concentrations of 50 and 100 nl/ml (approximately 50 and 100 µg/ml) in
    the absence of S9 mix (Litton Bionetics, 1980).

         Morpholine increased the numbers of type III foci in the
    Balb/C3T3 cell transformation assay tested at different dosages
    (0.001-0.3 µl/ml), corresponding to 78-52% survival in the
    cytotoxicity test (Texaco, 1979b, Litton Bionetics, 1979a,b; Conaway
    et al., 1982a,b).

         In another study of  in vitro transformation of Balb/3T3 cells
    with and without metabolic activation, the morpholine in the culture
    medium was neutralized before testing (Litton Bionetics, 1982). No
    significant increases were induced in transformed foci over the tested
    concentration ranges (0.015 to 1.400 µl/ml in the non-activation
    assay; 0.0175-0.7 µl/ml in the activation assay). Morpholine was
    therefore considered as being inactive in this test.  In vivo studies in mammals

         Inui et al. (1979) administered a dosage of 500 mg morpholine 
    per kg body weight to female Syrian hamsters on the 11th or 12th day
    of pregnancy. The embryos were removed 24 h later and embryo cells
    examined.  For detection of induced mutations, embryo cells were
    cultured in normal medium for 72 h and then transferred to a medium
    containing 8-azaguanine (10 or 20 mg per litre) or ouabain (1 mM). No
    chromosomal aberrations, micro-nucleus formation, or 8-azaguanine- or
    ouabain-resistant mutations were found.

         Migukina (1973) reported an increase in the number of chromosomal
    aberrations, particularly "fragmentations", in bone marrow cells of
    rats and guinea-pigs exposed for 4 months to 8 or 70 mg
    morpholine/m3 (see also section 7.3.2). However, there were
    deficiencies in the study report (BUA, 1991).

    7.6.2  Mutagenicity of morpholine in the presence of nitrite and

         Although morpholine has given negative responses in a number of
    mutagenicity assays, there is concern for its ability to be nitrosated
    readily to form NMOR (see section 4.3).

         Two mouse peritoneal cavity host-mediated assays with
     S. typhimurium have been performed. In one, with strain TA1530,
    different morpholine doses were administered orally to mice
    simultaneously with a standard sodium nitrite dose of 120 mg/kg. The
    mixtures were adjusted to pH 3.4. Significant increases in the  mutant
    fraction were observed with morpholine doses of 4-40 mg/kg, the full
    range tested (Edwards et al., 1979). In the other assay, with strain
    TA1950, equimolar mixtures of morpholine and sodium nitrite (1450 or
    2900 µmol/kg, approximately 125 or 250 mg/kg) were administered orally
    to mice (pH 7.0). Significant increases in the mutant fraction were
    observed at both dose levels. When the nitrite was administered to the
    mice 10 min before the morpholine treatment, no mutagenic response was
    induced (Braun et al., 1977).

         Mutations were found in  S. typhimurium TA1535 used to test the
    urine of OF1 mice after morpholine (250 mg/kg body weight) had been
    administered in the presence of nitrate (2000 mg/kg). Lower levels of
    nitrate (333 and 666 mg/kg) caused no mutations (Perez et al., 1990).

    7.6.3  Mutagenicity of N-nitrosomorpholine

         NMOR is mutagenic to  S. typhimurium TA100 in the presence of S9
    mix at dose levels above 2000 µg/plate.  In yeast, it induced forward
    mutation and aneuploidy, but not mitotic recombination. In cultured
    mammalian cells, conflicting results were obtained in unscheduled DNA
    synthesis (UDS) assays in fibroblasts, while weakly positive results
    were reported for sister-chromatid exchange (SCE) in CHO cells, for tk
    locus mutation in mouse lymphoma L5178Y cells, and for enhanced colony
    growth of BHK cells in soft agar. NMOR was negative in an  in vitro
    cytogenetic assay using RL1 (rat liver cell line) cells (IARC, 1978;
    NRC, 1981).

    7.7  Carcinogenicity

         Carcinogenicity studies have been carried out with morpholine
    alone, as well as in the presence of nitrite, to investigate the
    possible formation and effect of NMOR.

    7.7.1  Morpholine  Oral studies

         Greenblatt et al. (1971) treated 40 Swiss mice (20 male and
    20 female) with 6.33 g morpholine/kg food (estimated dosage, 0.9 g/kg

    body weight per day for 28 weeks. The control group consisted of
    80 mice of each sex. After a further 12 weeks of observation the
    surviving animals were sacrificed. No increase in the lung tumour rate
    (0.1 adenoma/mouse) was found compared to the controls
    (0.18 adenoma/mouse). It should be noted that the duration of exposure
    in this study was shorter than that normally used in a well-designed
    long-term carcinogenicity study.

         Multi-generation oral studies were performed on Sprague-Dawley
    rats fed 5, 50 or 1000 mg/kg morpholine, together with various dietary
    concentrations of sodium nitrite (0, 5, 50 or 1000 mg/kg diet)
    (Newberne & Shank, 1973; Shank & Newberne, 1976). From the day of
    conception, the pregnant animals were given 0 or 1000 mg morpholine/kg
    feed. The F1 and F2 generations were fed likewise for the length
    of the experiment. The estimated dosage for the young animals was
    10 mg/day and for mature animals 20 mg/day. The average life-span was
    117 weeks for the treated animals and 109 weeks for the controls. F1
    and F2 generations were studied, the survivors being sacrificed in
    the 125th week.  Table 17 summarizes the results.  Three liver cell
    carcinomas, two lung angiosarcomas and one other, and two malignant
    gliomas were found in the group of 104 rats (F1 and F2) treated
    with morpholine.

         In a similar study using Syrian golden hamsters, only the F1
    generation was studied, the survivors being sacrificed in the 110th
    week (Shank & Newberne. 1976). With morpholine alone (1000 mg per kg),
    no liver tumours were found but the number in the group (22) was

         Morpholine oleic acid salt (MOAS), at dosage levels of 0%, 0.25%
    or 1.0%, was added to the drinking-water of B6C3F1 mice for 96
    weeks, and this was followed by normal tap water for a further 8 weeks
    (Shibata et al., 1987b). Details are given in Table 15 and section
    7.3.1. Extensive biochemical, gross pathological and histological
    studies were performed. Only the incidence of hyperplasia in
    forestomach epithelium in the males of the 1% MOAS  group was
    statistically higher than in the controls; otherwise, no significant
    increases in the incidence of non-neoplastic or neoplastic lesions
    were found.  Inhalation studies

         In a long-term inhalation study over 2 years, Sprague-Dawley rats
    (70 of each sex per group) received morpholine at mean exposure
    concentrations of 0, 0.036, 0.181 or  0.543 g/m3 (6 h/day,
    5 days/week) for up to 104 weeks (Harbison et al., 1989). Further
    details are given in section 7.3.2 and Table 15. Tissues from the
    high-dose and control groups were subjected to extensive

        Table 17.  Tumour incidence (liver and lung) in rats and hamsters after feeding morpholine, sodium nitrite or N-nitrosomorpholinea
              Dietary levels (mg/kg)                            Tumour incidence in rats (%)                  Tumour incidence in hamsters (%)
    Morpholine   Sodium      N-Nitrosomorpholine      No. of       Liver cell    Liver angio   Lung angio         No. of         Liver cell
                 nitrite                              animalsb     carcinoma     sarcoma       sarcoma            animals        carcinoma

         0           0               0                   156            0             0             0                23              4
         0        1000               0                    96            1             0             0                30              0
      1000           0               0                   104            3             0             2                22              0
      1000        1000               0                   159           97            14            23                16             31
        50        1000               0                   117           59             5             6                32              0
                     5            1000                     0          154            28            12                 8             400
      1000          50               0                   109            3             2             1                22              0
      1000           5               0                   172            1             2             1                19              0
        50          50               0                   152            2             1             1                30              0
         5           5               0                   125            1             2             2                40              0
         0           0               5                   128           58            15             9                35              0
         0           0              50                    94           93            21            20                18              6

    a  adapted from Shank & Newberne (1976)
    b  F1 and F2 generations together
    histopathological examination; in the middle- and low-dose groups,
    this examination was limited to the eye and the respiratory tract. 
    Ten males and 10 females per group were sacrificed at week 53. 
    Survival at termination in the control, low-, middle- and high-dose
    groups, respectively, was 40, 44, 33 and 32 in males and 35, 27, 32
    and 35 in females.  No significant increase in the incidence of
    tumours was seen in rats of either sex.

    7.7.2  Morpholine and nitrite  Oral studies

         Sander & Bürkle (1969) fed a group of seven female Sprague-Dawley
    rats 5 g morpholine together with 5 g nitrite/kg diet for 12 weeks.
    After 39 weeks, all of the animals developed hepato-cellular adenomas,
    six out of the seven hepatocellular carcinomas, two
    hemangioendotheliomas of the liver, one a cyst-adenocarcinoma of the
    liver and one a renal adenoma. Rats fed morpholine or nitrite alone
    did not develop tumours.

         As described in section, Shank & Newberne (1976) fed
    pregnant rats on a diet containing various concentrations of
    morpholine, sodium nitrite and NMOR.  Table 17 summarizes the dietary
    concentrations and the tumour incidences for the experimental groups. 
    Hepatocellular carcinoma and haemangio-sarcomas of the liver and
    angiosarcoma of the lungs were the most common tumours observed in the
    rats.  The neoplasms induced by nitrite and morpholine were
    morphologically similar to those induced by NMOR. High concentrations
    (1000 mg/kg) of morpholine and nitrite together were carcinogenic to
    rats. When the morpholine concentration was reduced and the nitrite
    concentration remained high, the incidence of hepatic cell carcinomas
    decreased with a linear dose-response relationship. When morpholine
    concentration remained high, with decreasing nitrite concentration,
    the number of hepatic tumours was sharply reduced. This agrees with
    the observation  in vitro that the nitrosation of morpholine depends
    on the square of the nitrite concentration (Mirvish et al., 1975).

         Groups of 40 male MRC Wistar rats were treated for 2 years with
    either 10 g morpholine/kg diet and drinking-water containing 3 g
    sodium nitrite/litre, or with drinking-water containing 0.15 g
    NMOR/litre. In both cases, one group of rats was also given sodium
    ascorbate (22.7 g/kg diet).  The results of treatment with morpholine
    plus nitrite or with NMOR were similar to those reported above.  When
    ascorbate was present, the liver tumours induced by morpholine plus
    nitrite had a longer induction period (93 versus 54 weeks) and a
    slightly lower incidence (49% versus 65%).  However, ascorbate did not
    affect liver tumour induction by preformed NMOR.  Of those treated
    with morpholine, nitrite and ascorbate, 21/39 animals developed
    forestomach tumours (Mirvish et al. 1976).

         In a similar study using Syrian hamsters (see section and
    Table 17), a high morpholine, high nitrite diet (1000 mg/kg) induced
    liver cancer in some animals. In contrast, hamsters fed NMOR in the
    diet seemed to have greater resistance to tumour induction (Shank &
    Newberne, 1976).

    7.7.3  Carcinogenicity of N-nitrosomorpholine

         NMOR has been shown to be carcinogenic in mice, rats, hamsters
    and various fish. Benign and malignant tumours of the liver and lung
    in mice, of the liver, kidney and blood vessels in rats, and of the
    liver in hamsters have been reported following oral administration of
    NMOR. After its subcutaneous injection, it produces tumours of the
    upper digestive and respiratory tract in hamsters. NMOR produces liver
    tumours following its intravenous injection in rats and liver tumours
    in various fish following its administration in tank water (IARC,

    7.8  Factors modifying toxicity; toxicity of metabolites

    7.8.1  Factors modifying toxicity

         Leaf et al. (1991) reported that rats (Sprague-Dawley, male)
    challenged with an  E. coli lipopolysaccharide (LPS; 1 mg/kg body
    weight), followed 6 and 10 h later by morpholine (80 or 100 µmol/kg
    intraperitoneally) and arginine (400 µmol/kg) treatment, showed
    significantly increased NMOR formation compared with unchallenged
    control rats. The NMOR formation was measured by monitoring the NMOR
    metabolite  N-nitroso-(2-hydroxyethyl) glycine in the urine.  Furman
    & Rubenchik (1991) showed that endogenous synthesis of NMOR in the
    stomach of adult mice administered nitrite (oral) in combination with
    morpholine (intraperitoneal or subcutaneous) was increased after
    activation of peritoneal macrophages induced by intraperitoneal
    injection of  E. coli LPS.

    7.8.2  Morpholine metabolites

         Morpholine is eliminated almost entirely in a non-metabolized
    form in the urine of the rat, mouse, hamster and rabbit (section 6.3).

          N-cyanomorpholine ( N-morpholinocarbonitrile) was formed when
    morpholine was incubated  in vitro with whole human saliva (Wishnok &
    Tannenbaum, 1976).

         Sohn et al. (1982a,b) identified a metabolite
     N-methylmorpholine- N-oxide (NMMO) in guinea-pig urine.

         Conaway et al. (1984a) reported that NMMO (0.0001-10 mg/ml) and
    other putative metabolites,  N-hydroxymorpholine (0.0001-1 mg/ml) and
    3-morpholinone (0.001-0.1 mg/ml), did not induce DNA repair at the
    non-toxic concentrations tested. The polyurethane foam catalyst,

     N-butylmorpholine (0.0001-0.1 mg/ml) was also inactive in the
    primary rat hepatocyte/DNA repair assay (Conaway et al., 1984a).

         The chemical intermediate  N-hydroxyethylmorpholine induced DNA
    repair within the dose range 1-5 mg/ml (Conaway et al., 1984a).

         The genotoxicity of substituted morpholines might be a function
    of the substituent moiety rather than morpholine itself (Conaway et
    al., 1984a).

    7.9  Mechanisms of toxicity - mode of action

         The irritating and corrosive properties of morpholine are due to
    its basicity.  The mechanism of action of its systemic effects is not

         Morpholine fungicides have been shown to act by inhibiting
    several enzymes of sterol biosynthesis (Hesselink et al. 1990; Mercer,


    8.1  General population exposure

         No data are available on the effects of short- and long-term
    exposure to morpholine on the general population.  There are no
    reports of poisonings by morpholine.

    8.1.1  Controlled human studies

         The Cosmetic Ingredient Review (1989, 1991b) reported unpublished
    studies of occlusive patch testing and in-use testing of two mascara
    products containing 1% morpholine by 320 women between the ages of 18
    and 65.  All 320 volunteer subjects underwent occlusive patch testing
    (using the Shelanski/Jordan repeat insult procedure). After 24 h, the
    patches were removed and the sites graded. This procedure was repeated
    several times for a total of 10 applications (3´ weeks). Following the
    10th application, there was a 10-day to 2-week rest period, after
    which the subjects were again patch tested, this time for 48 h, and
    then scored.  After another 10-day to 2-week rest period, the subjects
    were again patch-tested for 48 h and scored.  A final reading took
    place 24 h after this. Of the 320 subjects patch-tested with charcoal
    mascara, 314 showed no reaction, the remaining six showed varying
    reactions.  The researchers explained this irritation as being either
    non-specific or due to the occlusive patching procedure.  The same
    results were found with the blue mascara. It was concluded from this
    study that neither of the mascara products containing 1% morpholine
    was a primary irritant, nor were they contact sensitizers (Cosmetic
    Ingredient Review, 1989, 1991b).

         In the in-use testing, 50 women used charcoal mascara once daily
    for 4 weeks, and 50 women used blue mascara likewise.  A further 100
    women used once daily lash conditioner, eye make-up remover and
    mascara (50 for each colour).  In another group, 100 subjects used
    lash conditioner and eye make-up remover but no mascara. All underwent
    the above-described patch testing simultaneously.

         There were a few complaints associated with the in-use testing.
    The charcoal mascara caused a mild burning sensation in three
    subjects, some itching in a further three, and minor irritation in
    three. These findings were put down to improper use of the product,
    which resulted in the product entering the eye and causing mild
    irritation (Cosmetic Ingredient Review, 1989, 1991b).

         Shea (1939) exposed himself to 43 g morpholine/m3 (12 000 ppm)
    for 90 seconds. He experienced irritation of the nose followed by
    coughing. Pipetting of pure morpholine from the stock solution led to
    inhalation of vapour, a severe sore throat, and violently reddened
    mucous membrane.

         Shea (1939) reported that when applied to human finger tips
    undiluted morpholine caused a cracking of the eponychium and
    hyponychium about the nail and an intense stinging sensation. Diluted
    morpholine (1 to 40) was a mild irritant.  Organoleptic effects

         Hellman & Small (1974) tested the absolute and recognition
    threshold  odour index of 101 petrochemicals using a trained panel.
    During a 20-min exposure, 0.036 mg morpholine/m3 was recognized by
    50% of the panel and 0.5 mg morpholine/m3 by all of the panel
    (giving an odour index of 65.9).  It was described as an unpleasant
    fishy smell.

         The phenomenon known as blue vision, gray vision or haloes
    "glaucopsia" is a well-documented effect of amines, including
    morpholine and its derivatives, on the eyes of workers, particularly
    in the foam plastic industry (Mastromatteo, 1965; Jones & Kipling,
    1972). The vision becomes misty and haloes appear several hours after
    the subjects have been exposed to these vapours at concentrations too
    low to cause discomfort or disability during several hours of
    exposure. The disturbances lasted for 4-6 h after leaving work.  In a
    minority of the workers examined, mild conjunctival infection was
    observed; no corneal oedema or alteration in visual acuity was
    detected by inspection or by ophthalmoscopy.  The atmospheric
    concentrations of morpholine and other similar compounds were not

    8.1.2  Epidemiological studies

         No data from epidemiological studies for morpholine have been

    8.2  Occupational exposure

         Studies into the levels of morpholine and NMOR in workplace air
    are described in section 5.3.

         Katosova et al. (1991) reported a cytogenetic analysis of the
    lymphocytes in the peripheral blood of 24 workers (16 men, 8 women)
    with 3 to 10 years of exposure to morpholine during production. These
    were compared to a control group of the same size from the same town
    having no contact with chemicals at work. The morpholine workers were
    exposed to concentrations of morpholine in air of 0.54-0.93 mg/m3,
    the maximum single concentration being 0.74-2.14 mg/m3. The
    lymphocytes were cultivated for 56 h and all chromatid and chromosome
    types as well as chromosome gaps were registered. From 2561 cells
    analysed from the test group, only 2.08% had aberrations, compared to
    1.61% out of 2050 cells in the control group, showing no significant
    increase in the number of cells with chromosome aberrations.


    9.1  Laboratory experiments

         The data reported in this section refer to nominal

    9.1.1  Microorganisms  Microorganisms in water

    a)   Bacterial and cyanobacterial cultures

         In a 16-h cell multiplication inhibition test (growth parameter:
    turbidity; pH 7; 25°C), the toxicity threshold (3% reduction in
    population growth) of morpholine for  Pseudomonas putida was
    310 mg/litre (Bringmann & Kühn, 1977a).

         The effect of morpholine at neutral pH on the growth of
     Pseudomonas strains in succinate mineral salt medium has been
    reported by Knapp et al. (1982) and Emtiazi & Knapp (1994).  Both
    studies used two strains of  Pseudomonas (all four were different)
    which had not previously been exposed to morpholine and found that
    morpholine at 8.7 g/litre had no effect on the rate or extent of

         The mixed bacterial cultures studied by Mazure (1993) were able
    to degrade morpholine rapidly at 5, 10 and 20 g/litre.  The
    degradation rate was highest at 10 g/litre but was only a little less
    at 20 g/litre.  At 40 g/litre degradation was markedly inhibited.

         As reported in section 4.2.1, morpholine at up to 870 mg/litre
    does not inhibit certain strains of  Mycobacterium spp. that have
    been found to biodegrade the compound.

         In a cell multiplication inhibition test (growth parameter:
    turbidity; pH 7; 192 h) under continual lighting conditions using
     Microcystis aeruginosa, a cyanobacterium, the onset of inhibition,
    defined variously as a 1% (Bringmann, 1975) or 3% (Bringmann & Kühn,
    1978) reduction in population growth, was found to occur at a
    morpholine concentration of 1.7 mg/litre.

    b)   Activated sludge

         The effect of morpholine on the respiratory, dehydrogenase and
    nitrification activities of activated sludge was determined by
    Strotmann et al. (1993). Short-term respiration assays (pH 7.0;
    incubation time 30 min) were performed according to the OECD guideline
    209 (OECD, 1984). The dehydrogenase activity was determined by
    measuring the reduction of resazurin to resorufin. At concentrations
    of 1000 mg morpholine/litre, both respiratory and dehydrogenase

    activities were inhibited by up to 20%. A pH-dependent inhibitory
    effect on the dehydrogenase activity was not found (pH 6.0-7.5).
    Nitrification activity was determined using a specially adapted
    culture of nitrifying bacteria. Suspended biomass, previously
    inoculated with activated sludge and acclimated to a high-strength
    ammonium feed, was incubated for 30 min at pH 7.2 with different
    amounts of morpholine. The extent of inhibition was based on the
    reduction in oxygen uptake rate, compared to a control containing no
    morpholine.  Nitrification activity was inhibited by 5% at a
    morpholine concentration of 5%.

    c)   Protozoa

         The toxicity thresholds (defined as a 5% reduction in population
    growth) of morpholine for the protozoa  Entosiphon sulcatum
    (Bringmann, 1978),  Uronema parduczi and  Chilomonas paramaecium
    (Bringmann & Kühn (1980), as measured in cell multiplication
    inhibition tests under given conditions, are summarized in Table 18.  Microorganisms in soil

         No data are available concerning soil bacteria or fungi.  Pathogenic microorganisms

         Morpholine, like other amines, shows antibacterial and anti-
    mycotic action. Kubis et al. (1983) demonstrated that 0.5% morpholine
    inhibits the growth of a variety of pathogenic bacteria on agar plates
    and in liquid medium.  Application of 10% morpholine was shown to cure
    an experimental mycosis in guinea-pigs caused by  Trychophyton
     mentagrophytes var. granulosum (Kubis et al., 1981).  The pH was not

    9.1.2  Other aquatic organisms  Monocellular green algae

         Table 19 summarizes the tests carried out concerning the effect
    of morpholine on algae.

         In a 192-h test, the onset of inhibition by morpholine
    (in distilled water, pH 7.0) of cell multiplication (here defined as
    3% in population growth) in the green alga  Scenedesmus quadricauda
    in a turbidity test was noted at a concentration of 4.1 mg/litre 
    (Bringmann & Kühn, 1977a, 1978; see parallel results test with
     Microcystis aeruginosa, section

        Table 18.  Toxicity threshold (TT) of morpholine for protozoa in the cell multiplication
               inhibition test (growth factor: cell number)

    Species                  Test duration    pH      Temperature      TT        Reference
                                  (h)                     (°C)      (mg/litre)

    Entosiphon sulcatuma          72         6.9         25            12      Bringmann (1978)

    Uronema parduczia             20         6.9         25           815      Bringmann & Kühn (1980)

    Chilomonas paramaeciumb       48         6.9         20            18      Bringmann et al. (1980)

    a  bacteriovorous ciliate
    b  saprozoic flagellate

         The results of Adams et al. (1985) showed that  Selenastrum
     capricornutum grows exponentially without a lag phase in the
    presence as well as in the absence of morpholine, the growth being
    inhibited first at a concentration of 100 mg/litre. The inhibition was
    most marked after 6 days, shortly before reaching the stationary
    phase; the no-observed-effect level (NOEL) was 10 mg/litre. Using the
    same species, Calamari et al. (1980) evaluated algal growth by
    measuring  in vivo the fluorometric units at 48, 72, 96 h and 7 days.
    A 96-h EC50 of 28 mg/litre was determined.

         Millington et al. (1988) investigated the effects of varying
    growth medium composition on the toxicity of morpholine to three
    freshwater green algae:  Selenastrum capricornutum, Scenedesmus
     subspicatus and  Chlorella vulgaris. They reported that the toxic
    effect of morpholine on algae depended upon the species as well as
    upon the test medium used (see Table 19).  Invertebrates

         Table 20 summarizes the results of three investigations into the
    toxicity of morpholine, as measured by the immobilization of  Daphnia
     magna (Bringmann & Kühn, 1977b, 1982; Calamari et al., 1980). The
    test conditions were almost identical (pH 7.6-8.0; 18-22°C) and the
    resulting EC50 values (100-119 mg/litre) were in good agreement.

         Kramer et al. (1983) investigated the relative toxicity of
    organic solvents including morpholine to mosquito  (Aedes aegypti)
    larvae (2 to 3 instar) by exposing 10-20 of them to 50 ml of test
    solution in a glass container for 4 h at 22-24°C.  The test was run in
    triplicate.  An LC50 of 1000 mg/litre was reported, together with
    the observation that death was accompanied by convulsive larval
    twitching.  Vertebrates

         The acute toxicity of morpholine for fish has been tested on a
    number of fresh, sea and brackish water species (see Table 21). The
    lowest LC50 (180 mg/litre) was found for rainbow trout
     (Oncorhynchus mykiss; formerly  Salmo gairdneri) in very soft water
    (20 mg CaCO3/litre). In hard water (320 mg CaCO3/litre), the
    poisoning effect, with reference to the LC50 value, was less than
    half (Calamari et al., 1980).  Brachydanio rerio proved to be
    relatively insensitive (LC0 value > 1000 mg/litre) (Wellens, 1982).
    LC50 values for the freshwater fish  Leuciscus idus melanotus and
     Lepomis macrochirus were found to be 240-285 mg/litre (48 h) and
    350 mg/litre (96 h), respectively (Juhnke & Lüdemann, 1978; Dawson et
    al., 1977). The 96-h LC50 for the marine fish  Menidia beryllina
    was reported to be 400 mg/litre (Dawson et al., 1977). McCain & Peck
    (1976) investigated the effect of morpholine on common Hawaiian fish. 

        Table 19.  Toxicity of morpholine for algaea
    Species             Growth parameters             Test duration     pH       Temperature    Effectb/concentration  Reference
                                                          (h)                       (°C)             (mg/litre)

    Scenedesmus         inhibition of cell               192          neutral       27                TT: 4.1          Bringmann & Kühn (1978)
     quadricauda        multiplication (turbidity)

    Selenastrum         cell number after:               24           not given     22                NOEC: 100        Adams et al. (1985)
     capricornutum                                       48/72                                        NOEC: 80
                                                         96/120                                       NOEC: 50
                                                         144                                          NOEC: 10

                        area under                       24-72                                        NOEC: 80
                        growth curve                     24-96                                        NOEC: 80
                                                         24-120                                       NOEC: 80
                                                         24-144                                       NOEC: 50

                        growth rate                      24-72                                        NOEC: 80
                                                         24-96                                        NOEC: 80
                                                         24-120                                       NOEC: 80
                                                         24-144                                       NOEC: 80

    S. capricornutum    growth rate (in vivo             96           not given     24                EC0: 10c         Calamari et al. (1980)d
                        fluorescence)                                                                 EC50: 28c
                                                                                                      EC100: 80c

    S. capricornutum    area under growth                24-120       not given     22                ECL0: 100e       Millington et al. (1988)
                        curve (cell number)                                                           ECL0: 50f
                                                                                                      ECL0: 50g

    Scenedesmus         area under growth                24-120       not given     22                ECL0: 50e        Millington et al. (1988)
     subspicatus        curve (cell number)                                                           ECL0: 5f
                                                                                                      ECL0: 10g

    Table 19 (cont'd)
    Species             Growth parameters             Test duration     pH       Temperature    Effectb/concentration  Reference
                                                          (h)                       (°C)             (mg/litre)

    Chlorella vulgaris  area under growth                24-120       not given     22                ECL0: 100e       Millington et al. (1988)
                        curve (cell number)                                                           ECL0: 80f
                                                                                                      ECL0: 5g

    a  Adapted from BUA (1991)
    b  TT = toxicity threshold; NOEC = no-observed-effect concentration; EC0, EC50, EC100 = effective concentration inhibiting for the growth
       of 0, 50 and 100% of the population; ECL0 = lowest-tested concentration with significant growth inhibition
       (from 5, 10, 50, 80, 100 mg/litre)
    c  equivalent to GC-FID measured concentration ± 10%
    d  method according to Chiaudini & Vighi (1978)
    e  Bolds basal medium (BBM): rich medium; N/P-ratio 14:1
    f  OECD medium: less N than BBM; N/P-ratio 24:1
    g  EPA medium: less N than BBM; N/P-ratio 50:1

        Table 20.  Acute toxicity of morpholine for the water flea Daphnia magna
               (test duration: 24 h; effect: immobilization)a
    Test systemb   pH           Temperature   Effect/concentration    Reference
                                   (°C)           (mg/litre)
    Static         7.6-7.7      20-22         EC0: 16                 Bringmann &
                                              EC50: 100               Kühn (1977b)
                                              EC100: 500

    Static         8 ± 0.2      20            EC0: 68                 Bringmann &
                                              EC50: 101 (83-122)c     Kühn (1982)
                                              EC100: 260

    Static         7.9 ± 0.3    18-22         EC50: 119 (112-127)c    Calamari et
                                                                      al. (1980)

    a  adapted from BUA (1991)
    b  in accordance with OECD-guideline 202 part I
    c  95% confidence limits
    The 96-h LC50 (TLm) was between 100 and 180 mg/litre for white
    mullet  (Vala mugil engeli; former designation:  Chelon engeli),
    between 320 and 560 mg/litre for Gambusia affinis, and more than
    1000 mg/litre for  Tilapia sp.

    9.1.3  Terrestrial organisms  Plants

         Reynolds (1989) found that 4.4±0.9 mol morpholine/m3
    (383 mg/litre) lowers the percentage germination of lettuce seeds
     (Lactuca sativa) by 50% of the control value. The seeds were kept on
    agar for 3 days in sealed plastic containers at a temperature of 30°C.  Animals

         No data are available concerning the effects of morpholine on
    terrestrial animals.

    9.2  Field observations

         No data have been reported concerning field observations
    involving morpholine.

        Table 21. Acute toxicity of morpholine in fish static test systemsa
    Species                  Aquatic system   Test conditions                                 Test      Effect/             Reference
                                                                                              duration  concentration
                                                                                              (h)       (mg/litre)

    Rainbow trout            freshwater       hardness: 320 mg CaCO3/litre; pH 7.4;           96        LC50 380            Calamari et al.
     (Salmo gairdneri)                        15°C; > 95% O2 saturation                                 (375-460)b          (1980)

    Rainbow trout            freshwater       hardness: 20 mg CaCO3/litre; pH 7.4;            96        LC50 180            Calamari et al.
     (Salmo gairdneri)                        15°C; > 95% O2 saturation                                                     (1980)

    Golden orfe              freshwaterc      hardness: 220-320 mg CaCO3/litre; pH 8; 20°C;   48        LC50 285            Juhnke &
     (Leuciscus idus                          continual aeration (Juhnke laboratory)                    (250/340)d          Lüdemann
     melanotus)                                                                                                             (1978)

    Golden orfe              freshwaterc      hardness: 220-320 mg CaCO3/litre; pH 8; 20°C;   48        LC50 240            Juhnke &
     (L. idus melanotus)                      continual aeration (Lüdemann laboratory)                  (100/301)d          Lüdemann (1978)

    Zebra fish               freshwater       hardness: 250 mg CaCO3/litre; pH 7.5; 22°C;     96        LC50> 1000          Wellens (1982)
     (Brachydanio rerio)                      no aeration                                               (> 1000/> 1000)d

    Bluegill sunfish         freshwater       hardness: 55 mg CaCO3/litre; pH 7.6-7.9; 23°C;  96        LC50 350            Dawson et
     (Lepomis macrochirus)                    intermittent aeration 24 h after test; from                                   al. (1977)
                                              commercial hatcheries; 14 days acclimatization

    Tidewater silverside     marine           artificial seawater; 20°C; continual aeration;  96        LC50 400            Dawson et
     (Menidia beryllina)                      caught wild Horseshoe Bay (New Jersey);                                       al. (1977)
                                              40-100 mm length; 14 days acclimatization

    Mosquito fish            marinee,f        natural seawater (32% salinity); continual      96        LC0 320             McCain &
     (Gambusia affinis)                       aeration; 25.5-27.8°C; caught wild (Oahu,                 LC100 560           Peck (1976)
                                              Hawaii); 38-64 mm length; 7 days

    Table 21 (cont'd)
    Species                  Aquatic system   Test conditions                                 Test      Effect/             Reference
                                                                                              duration  concentration
                                                                                              (h)       (mg/litre)

    "Coloured perch"         marinee,f        natural seawater (32% salinity); continual      96        LC0 1000            McCain &
     (Tilapia sp.)                            aeration; 25.5-27.8°C; caught wild (Oahu,                                     Peck (1976)
                                              Hawaii); 30-65 mm length; 7 days

    White mullet             marinee          natural seawater (32% salinity); continual      96        LC0 100             McCain &
     (Chelon engeli)                          aeration; 25.5-27.8°C; caught wild (Oahu,                 LC100 320           Peck (1976)
                                              Hawaii); 91-128 mm length; 7 days

    a  adapted from BUA (1991)
    b  95% confidence limits
    c  parallel tests in two different laboratories
    d  LC0/LC100
    e  the fish were caught in rivers, presumably in the estuary area
    f  fresh or brackish water fish that were exposed to the marine system.

         The carcinogenic risks were evaluated by an International Agency
    for Research on Cancer  ad hoc Expert Group in 1988.  It was
    concluded that there is inadequate evidence for the carcinogenicity
    of morpholine in experimental animals.  No data were available from
    studies in humans on the carcinogenicity of morpholine.  The overall
    evaluation was that morpholine was not classifiable for its
    carcinogenicity to humans (IARC, 1989).

         IARC also evaluated  N-nitrosomorpholine (NMOR).  It concluded
    that there is sufficient evidence for a carcinogenic effect of NMOR in
    several experimental animal species.  No human data, case reports or
    epidemiological studies were available, nor was it possible to
    identify exposed groups.  In spite of the absence of epidemiological
    data, NMOR should be regarded for practical purposes as if it were
    carcinogenic to humans (IARC, 1978).


    Aarts AJ, Benson GB, Duchateau NL, & Davies KM (1990) Modern
    analytical techniques for the detection of rubber chemicals and their
    decomposition products in the environment. Int J Environ Anal Chem,
    38: 85-95.

    Ackermann P, Margot P, & Klotzsche, C (1989) Agricultural fungicides.
    In: Ullmann's encyclopedia of industrial chemistry, 5th ed. Weinheim,
    VCH Verlagsgesellschaft, vol A12, p 107.

    Adams N, Goulding KH, & Dobbs AJ (1985) Toxicity of eight water-
    soluble organic chemicals to  Selenastrum capricornutum: a study of
    methods for calculating toxic values using different growth
    parameters.  Arch Environ Contam Toxicol, 14: 333-345.

    Agarwala KK (1982) Study on stability of morpholine in high pressure
    boiler system. Fertil Technol, 19: 73-75.

    Air Products and Chemicals (1989) Material safety data sheet.
    Allentown, Pennsylvania, Air Products and Chemicals, Inc.

    Aitzetmüller K & Thiele E (1982) Absence of volatile N-nitrosamines in
    margarines. J Am Oil Chem Soc, 59: 387-389.

    Anderson GE (1983) Human exposure to atmospheric concentrations of
    selected chemicals. Research Triangle Park, North Carolina, US
    Environmental Protection Agency, Office of Air Quality Planning and
    Standards, pp 455-473 (Report submitted by Systems Applications, Inc.,
    San Rafael, California) (EPA No 83-265249).

    Archer MC, Tannenbaum SR, & Wishnok JS (1977) Nitrosamine formation in
    the presence of carbonyl compounds. In: Walker EA, Bogovski P, &
    Griciute L ed. Environmental  N-nitroso compounds analysis and
    formation. Lyon, International Agency for Research on Cancer,
    pp 141-145 (IARC Scientific Publications No. 14).

    Archer MC, Yang HS, & Okun JD (1979) Acceleration of nitrosamine
    formation at pH 3.5 by microorganisms. In: Walker EA, Castegnaro M,
    Griciute L, & Lyle RE ed. Environmental aspects of  N-nitroso
    compounds. Lyon, International Agency for Research on Cancer,
    pp 239-246 (IARC Scientific Publications No. 19).

    Atkinson R (1988) Estimation of gas-phase hydroxyl radical rate
    constants for organic chemicals. Environ Toxicol Chem, 7: 435-442.

    Badura R, Linde H, & Schuster RH (1989) Analysis of volatile products
    in vulcanisation fumes. In: Proceedings of the International Rubber
    Conference, Prague, 8-11 May. London, International Rubber
    Association, pp 19-38.

    BASF (1967) [Morpholine: Toxicological data.] Ludwigshafen, BASF AG,
    2 pp (Internal report) (in German).

    BASF (1987) [Data sheets: Morpholine.] Ludwigshafen, BASF AG, 8 pp
    (in German). 

    BASF (1990) [Test report: Zahn-Wellens-Test.] Ludwigshafen, BASF AG,
    12 pp (Unpublished report) (in German).

    BIA (Industries Association Institute for Work Safety) (1989)
    [Measurement of dangerous substances - BIA data sheet.] Bielefeld,
    Erich Schmidt Verlag (in German).

    Bianchi A & Muccioli G (1978) [Determination of morpholine together
    with isopropyl alcohol, toluene and xylenes (o-m-p) in the atmosphere
    by means of gas-chromatography.] Ann Ist Super Sanita, 14: 441-445
    (in Italian with English summary).

    Börzsönyi M, Török G, Surján A, Challis BC, & Bär V (1981) Protective
    effect of a new antioxidant on acute hepatotoxicity caused by
    morpholine plus nitrite in rats. Toxicol Lett, 7: 285-288.

    Bosholm J (1983) [Description of the behaviour of gaseous compounds in
    water/steam systems.] Kernenergie, 26: 198-201 (in German).

    Boyland E, Nice E, & Williams K (1971) The catalysis of nitrosation by
    thiocyanate from saliva. Food Cosmet Toxicol, 9: 639-643.

    Braun R, Schöneich J, & Ziebarth D (1977) In vivo formation of
     N-nitroso compounds and detection of their mutagenic activity in the
    host-mediated assay. Cancer Res, 37: 4572-4579.

    Bringmann G (1975) [Determination of the biological effect of water
    pollutants on blue algae  Microcystis using the cell multiplication
    inhibition test.] Gesund-Ing, 96: 238-241 (in German).

    Bringmann G (1978) [Determination of the biological effect of water
    pollutants in protozoa I Bacteriovorous flagellate protozoa (Model
    organism:  Entosiphon sulcatum Stein).] Z Wasser Abwasser Forsch,
    11: 210-215 (in German).

    Bringmann G & Kühn R (1977a) [Toxicity thresholds of water pollutants
    for bacteria  (Pseudomonas putida) and green algae  (Scenedesmus
     quadricauda) in the cell multiplication inhibition test.] Z Wasser
    Abwasser Forsch, 10: 87-98 (in German).

    Bringmann G & Kühn R (1977b) [Results of toxic action of water
    pollutants on  Daphia magna.] Z Wasser Abwasser Forsch, 10: 161-166
    (in German).

    Bringmann G & Kühn R (1978) [Toxicity thresholds of water pollutants
    for blue algae  (Microcystis aeruginosa) and green algae
     (Scenedesmus quadricauda) in the cell multiplication inhibition
    test.] Vom Wasser, 50: 45-60 (in German). 

    Bringmann G & Kühn R (1980) [Determination of the biological effect of
    water pollutants in protozoa. II.  Bacteriovorous ciliates.] Z Wasser
    Abwasser Forsch, 1: 26-31 (in German).

    Bringmann G & Kühn R (1982) [Results of the toxic action of water
    pollutants on  Daphnia magna tested by an improved standardized
    procedure system.] Z Wasser Abwasser Forsch, 15: 1-6 (in German).

    Bringmann G, Kühn R, & Winter A (1980) [Determination of the
    biological effect of water pollutants in protozoa III  Saprozoic
     flagellates.] Z Wasser Abwasser Forsch, 13: 170-173 (in German).

    Brouwer R, Marquart H, de Mik G, & van Hemmen J (1992) Risk assessment
    of dermal exposure of greenhouse workers to pesticides after re-entry.
    Arch Environ Contam Toxicol, 23: 273-280

    Brown AR (1966) Morpholine: its properties and uses. Manuf Chem
    Aerosol News, Dec 1966: 50-52.

    Brown VR & Knapp JS (1990) The effect of withdrawal of morpholine from
    the influent and its reinstatement on the performance and microbial
    ecology of a model activated sludge plant treating a morpholine-
    containing influent. J Appl Bacteriol, 69: 43-53.

    Brown VR, Knapp JS, & Heritage J (1990) Instability of the morpholine-
    degradative phenotype in mycobacteria isolated from activated sludge.
    J Appl Bacteriol, 69: 54-62.

    Brunnemann KD & Hoffmann D (1991) Decreased concentrations of
    N-nitrosodiethanolamine and N-nitrosomorpholine in commercial tobacco
    products. J Agric Food Chem, 39: 207-208.

    Brunnemann KD, Scott JC, & Hoffmann D (1982)  N-nitroso-morpholine
    and other volatile N-nitrosamines in snuff tobacco. Carcinogenesis,
    3: 693-696. 

    BUA (Society of German Chemists, Advisory Committee on Existing
    Chemicals of Environmental Relevance) (1991) [Morpholine.] Weinheim,
    VCH Verlagsgesellschaft, 181 pp (BUA Report No. 56) (in German).

    Calamari D, Da Gasso R, Galassi S, Provini A, & Vighi M (1980)
    Biodegradation and toxicity of selected amines on aquatic organisms.
    Chemosphere, 9: 753-762.

    Calmels S, Ohshima H, Vincent P, Gounot A-M, & Bartsch H (1985)
    Screening of micro-organisms for nitrosation catalysis at Ph 7 and
    kinetics studies on nitrosamines formation from secondary amines by
     E. coli strains. Carcinogenesis, 6: 911-915.

    Calmels S, Ohshima H, Crespi M, Leclerc H, Cattoen C, & Bartsch H
    (1987)  N-nitrosoamine formation by microorganisms isolated from
    human gastric juice and urine: biochemical studies on bacteria-
    catalysed nitrosation. In: Bartsch H, O`Neill IK, & Schulte-Hermann R
    ed. The relevance of  N-nitroso compounds to human cancer: Exposures
    and mechanisms. Lyon, International Agency for Research on Cancer,
    pp 391-395 (IARC Scientific Publications No. 84).

    Calmels S, Ohshima H, & Bartsch H (1988) Nitrosamine formation by
    denitrifying and non-denitrifying bacteria: Implication of nitrite
    reductase and nitrate reductase in nitrosation catalysis. J Gen
    Microbiol, 134: 221-226.

    Calmels S, Dalla Venezia N, & Bartsch H (1990) Isolation of an enzyme
    catalysing nitrosamine formation in  Pseudomonas aeruginosa and
     Neisseria mucosae. Biochem Biophys Res Commun, 171(2): 655-660.

    Calmels S, Béréziat J-C, Ohshima H, & Bartsch H (1991a) Bacterial
    formation of N-nitroso compounds in the rat stomach after omeprazole-
    induced achlorhydria. In: O'Neill IK, Chen J, & Bartsch H ed.
    Relevance to human cancer of  N-nitroso compounds, tobacco smoke and
    mycotoxins. Lyon, International Agency for Research on Cancer,
    pp 187-191 (IARC Scientific Publications No. 105).

    Calmels S, Béréziat J-C, Ohshima H, & Bartsch H (1991b) Bacterial
    formation of  N-nitroso compounds in the rat stomach after
    omeprazole-induced achlorhydria. Carcinogenesis, 12: 435-439.

    Cech JS & Chudoba J (1988) Effect of the solids retention time on the
    rate of biodegradation of organic compounds. Acta Hydrochim Hydrobiol,
    16: 313-323.

    Cech JS, Hartman P, Slosárek M, & Chudoba J (1988) Isolation and
    identification of a morpholine-degrading bacterium. Appl Environ
    Microbiol, 54: 619-621.

    Challis BC & Kyrtopoulos SA (1979) The chemistry of nitroso-compounds.
    Part 11. Nitrosation of amines by the two-phase interaction of amines
    in solution with gaseous oxides of nitrogen. J Chem Soc Perkin Trans
    I, 1979: 299-304.

    Challis BC & Outram JR (1979) The chemistry of nitroso-compounds. Part
    15. Formation of N-nitrosoamines in solution from gaseous nitric oxide
    in the presence of iodine. J Chem Soc Perkin Trans I, 1979: 2768-2775.

    Chemical Marketing Reporter (1989) Aromatics. Morpholine. Chem Mark
    Rep, July 17: 13.

    Chemical Marketing Reporter (1990) Dow to exit morpholine. Chem Mark
    Rep, May 28: 7.

    Chiaudani G & Vighi M (1978) The use of  Selenastrum capricornutum
    batch cultures in toxicity studies. Mitt Int Ver Limnol, 21: 316-329.

    Collaert B, Attström R, De Bruyn H, & Movert R (1992a) The effect of
    delmopinol rinsing on dental plaque formation and gingivitis healing.
    J Clin Periodontol, 19: 274-280.

    Collaert B, Edwardsson S, Attström R, Hase J, Aström M, & Movert R
    (1992b) Rinsing with delmopinol 0.2% and chlorhexidine 0.2%: Short-
    term effect on salivary microbiology, plaque, and gingivitis.
    J Periodontol, 63: 618-625.

    Conaway CC, Myhr BC, Rundell JO, & Brusick DJ (1982a) Evaluation of
    morpholine, piperazine and analogues in the L5178Y mouse lymphoma
    assay and Balb/3T3 transformation assay. Presented at the 13th Annual
    Meeting of the Environmental Mutagen Society, Boston, 22-28 February
    1982. New York, John Wiley and Sons, pp 1-15. 

    Conaway CC, Myhr BC, Rundell JO, & Brusick DJ (1982b) Evaluation of
    morpholine, piperazine and analogues in the L5178Y mouse lymphoma
    assay and Balb/3T3 transformation assay. Environ Mutagen, 4: 390

    Conaway CC, Tong C, & Williams GM (1984a) Evaluation of morpholine,
    3-morpholine, and N-substituted morpholines in the rat hepatocyte
    primary culture/DNA repair test. Mutat Res, 136: 153-157.

    Conaway CC, Coate WB, & Voelker RW (1984b) Subchronic inhalation
    toxicity of morpholine in rats. Fundam Appl Toxicol, 4: 465-472.

    Cooney RV & Ross PD (1987) N-nitrosation and N-nitration of morpholine
    by nitrogen dioxide in aqueous solution: effects of vanillin and
    related phenols. J Agric Food Chem, 35: 789-793.

    Cooney RV, Ross PD, Bartolini GL, & Ramseyer J (1987) N-nitrosoamine
    and N-nitroamine formation: Factors influencing the aqueous reactions
    of nitrogen dioxide with morpholine. Environ Sci Technol, 21: 77-83.

    Cooney RV, Ross PD, Hatch-Pigott V, & Ramseyer J (1992) Carcinogenic
    N-nitrosamine formation: A requirement for nitric oxide. J Environ Sci
    Health, 27(3): 789-801.

    Cosmetic Ingredient Review (1986) Scientific literature review on
    morpholine. Washington, DC, The Cosmetic, Toiletry and Fragrance
    Association, 71 pp.

    Cosmetic Ingredient Review (1989) Final report on the safety
    assessment of morpholine. J Am Colloq Toxicol, 8: 707-748.

    Cosmetic Ingredient Review (1991a) CIR annual report 1991. Washington,
    DC, The Cosmetic, Toiletry & Fragrance Association, 67 pp.

    Cosmetic Ingredient Review (1991b) Protocol: Repeated insult patch
    testing and in-use testing. Washington, DC, The Cosmetic, Toiletry &
    Fragrance Association, 16 pp (Unpublished report).

    Cusano F & Luciano S (1993) Contact dermatitis from pramoxine. Contact
    Dermatitis, 28: 39:

    Davies R, Massey RC, & McWeeny DJ (1980) The catalysis of the
    N-nitrosation of secondary amines by nitrosophenols. Food Chem,
    6: 115-122.

    Dawson GW, Jennings AL, Drozdowski D, & Rider E (1977) The acute
    toxicity of 47 industrial chemicals to fresh and saltwater fishes.
    J Hazard Mater, 1: 303-318.

    Dmitrenko GN & Gvozdyak P (1988) Detection of morpholine by
    mycobacteria. In: Proceedings of a Conference on Microbiological
    Methods for Protecting the Environment, Puschino, USSR, 5-7 April
    1988. Puschino, Scientific Centre for Biological Research of the
    Academy of Sciences, 141 pp.

    Dmitrenko GN, Udod VM, & Gvozdyak PI (1985) Destruction of morpholine
    by fixed bacteria. Khim Tekhnol Vody, 7: 71-73.

    Dmitrenko GN, Gvodzdyak PI, & Udod VM (1987) Selection of destructor
    microorganisms for heterocyclic xenobiotics. Khim Tekhnol Vody,
    9(5): 442-445.

    Dodson JJ & Bitterman ME (1989) Compound uniqueness and the
    interactive role of morpholine in fish chemoreception. Biol Behav,
    14: 13-27.

    Donath G, Heitmann HG, Messer J, & Schott M (1977) [Determination of
    the distribution coefficients of volatile alkalising agents used in
    power plants between steam and water phases and their importance for
    the corrosive behaviour of materials.] Vom Wasser, 49: 221-243
    (in German).

    Dropkin D (1985) Sampling of automobile interiors for organic
    emissions. Research Triangle Park, North Carolina, US Environmental
    Protection Agency, 20 pp (PB85-172567).

    Dynamac Corporation (1988) Information review: Morpholine (EPA
    contract No. 68-02-4251). Rockville, Maryland, Dynamac Corporation,
    pp 1-52 (IR-514) (Report prepared for TSCA Interagency Testing

    ECETOC (1991) Critical evaluation of methods for the determination of
    N-nitrosamines in personal care and household products. Brussels,
    European Chemical Industry Ecology and Toxicology Centre (Technical
    Report No. 42).

    EEC (1983) Council directive 79831 - Annex V, Part C: Methods for
    determination of ecotoxicity. 5.2 Degradation - Biotic degradation
    Manometric Respirometry. Brussels, Commission of the European Union.

    EEC (1990) Proposal for a council directive on the approximation of
    the laws of the Member States relating to cosmetic products (SEC(90)
    1985 final) (90/C 322/06). Off J Eur Communities, C/322: 29-43.

    Edwards G, Whong W-Z, & Speciner N (1979) Intrahepatic mutagenesis
    assay: a sensitive method for detecting N-nitrosomorpholine and
     in vivo nitrosation of morpholine. Mutat Res, 64: 415-423.

    Emtiazi G (1993) Microbial degradation of linear and cyclic amines.
    Leeds, University of Leeds, Department of Microbiology (Thesis).

    Emtiazi G & Knapp JS (1994) The biodegradation of piperazine and
    structurally-related linear anc cyclic amines. Biodegradation,
    5: 83-92.

    Environment Agency, Japan (1980) Annual report on chemicals in the
    environment. Tokyo, Environment Agency, pp 72-73.

    Estrin NF, Haynes CR, & Whelan JM (1982) Specifications/spectra. CTFA
    compendium of cosmetic ingredient composition. Washington, DC, The
    Cosmetic, Toiletry and Fragrance Association, Inc.

    Fadlallah S, Cooper SF, Fournier M, Drolet D, & Perrault G (1990)
    Determination of  N-nitroso compounds in the environment of a metal
    factory using metalworking fluids. Int J Environ Anal Chem,
    39: 281-288.

    Fajen JM, Carson GA, Rounbehler DP, Fan TY, Vita R, Goff UE, Wolf MH,
    Edwards GS, Fine DH, Reinhold V, & Biemann K (1979) N-nitrosamines in
    the rubber and tire industry. Science, 205: 1262-1264.

    Fan TY, Vita R, & Fine DH (1978) C-nitro compounds: a new class of
    nitrosating agents. Toxicol Lett, 2: 5-10.

    Fisher AA (1986) Contact Dermatitis. Philadelphia, Pennsylvania, Lea &

    Furman MA & Rubenchik BL (1991) Formation of carcinogenic N-nitro
    compounds after intraperitoneal administration of nitrosating
    precursors in C57BLl/6 line mice. Eksp Onkol, 13(2): 14-22.

    Gavinelli M, Fanelli R, Bonfanti M, Davoli E, & Airoldi L (1988)
    Volatile nitrosamines in foods and beverages: preliminary survey of
    the Italian market. Bull Environ Contam Toxicol, 40: 41-46.

    Gilbert R & Saheb SE (1987) Field measurement of the distribution
    coefficients of chemical additives used for corrosion control in
    steam-water cycles. Mater Perform, 26: 30-36.

    Gilbert R, Rioux R, & Saheb SE (1984) Ion chromatographic
    determination of morpholine and cyclohexylamine in aqueous solutions
    containing ammonia and hydrazine. Anal Chem, 56: 106-109.

    Glatt HR & Oesch F (1981) [Ames test for morpholine.] Ludwigshafen,
    BASF AG, 11 pp (Unpublished report submitted by the Pharmacological
    Institute, University of Mainz, Germany).

    Grant WM (1974) Morpholine. In: Toxicology of the eye, 2nd ed.
    Sringfield, Illinois, Charles C. Thomas,vol 2, pp 722-723.

    Greenblatt M, Mirvish S, & So BT (1971) Nitrosamine studies: induction
    of lung adenomas by concurrent administration of sodium nitrite and
    secondary amines in Swiss mice. J Natl Cancer Inst, 46: 1029-1034

    Griffiths MH (1968) The metabolism of N-triphenylmethylmorpholine in
    the dog and rat. Biochem J, 108: 731-740.

    Grodeckaja NS & Karamzina NM (1973) [Initial reactions by the organism
    to the effects of industrial substances in concentrations of minimal
    effect (Limac, Limch).] Toksikol Nov Prom Chim Veshchestv,
    13: 12-23 (in Russian).

    Groenen PJ, Busink E, & van Wandelen M (1987) Determination of
    volatile nitrosamines in cheese and cured meat products. Model study
    of a temperature- and pH-dependent artefact formation phenomenon in
    alkaline medium. Z Lebensm.Unters Forsch, 185: 24-30.

    Grosjean D (1991) Atmospheric chemistry of toxic contaminants.
    6. Nitrosamines: Dialkyl nitrosamines and nitrosomorpholine. J Air
    Waste Manage Assoc, 41: 306-311.

    Hamano T, Mitsuhashi Y, & Matsuki Y (1980) Improved gas
    chromatographic method for the quantitative determination of secondary
    amines as sulphonamides formed by reaction with benzene-sulphonyl
    chloride. J Chromatogr, 190: 462-465.

    Hamano T, Mitsuhashi Y, & Matsuki Y (1981) Glass capillary gas
    chromatography of secondary amines in foods with flame photometric
    detection after derivatization with benzenesulfonyl chloride. Agric
    Biol Chem, 45: 2237-2243.

    Hansen L, Akesson B, Sollenberg J, & Lundh T (1986) Determination of
    N-methylmorpholine in air samples from a polyurethane foam factory.
    Scand J Work Environ Health, 12: 66-69.

    Harbison RD, Marino DJ, Conaway CC, Rubin LF, & Gandy J (1989) Chronic
    morpholine exposure of rats. Fundam Appl Toxicol, 12: 491-507.

    Hassan SSM, Tadros FS, & Selig W (1985) Microdetermination of
    secondary aliphatic amines using a copper ion-selective electrode.
    Microchem J, 31: 1-6.

    Haworth S, Lawlor T, Mortelmans K, Speck W, & Zeiger E (1983)
    Salmonella mutagenicity test results for 250 chemicals. Environ
    Mutagen, Suppl 1: 3-142.

    Hazleton (1981) Final report: 9-day acute inhalation toxicity study in
    rats. Vienna, Virginia, Hazleton Laboratories America, Inc., 26 pp
    (Submitted to Texaco Chemical Company).

    Hecht SS & Morrison JB (1984) A sensitive method for detecting
     in vivo formation of  N-nitrosomorpholine and its application to
    rats given low doses of morpholine and sodium nitrite. Cancer Res,
    7: 2873-2877.

    Hecht SS & Young R (1981) Metabolic alpha-hydroxylation of
    N-nitrosomorpholine and 3,3,5,5-tetradeutero-N-nitrosomorpholine in
    the F344 rat. Cancer Res, 41: 5039-5043.

    Heilen G, Mercker HJ, Frank D, Reck RA, & Jäckh R (1989) [Amines,
    aliphatic.] In: [Ullmann's encyclopedia of industrial chemistry], 5th
    ed. Weinheim, VCH Verlagsgesellschaft, vol A2, pp 1-36 (in German).

    Hellman TM & Small FH (1974) Characterization of the odor properties
    of 101 petrochemicals using sensory methods. J Air Pollut Control
    Assoc, 24: 979-982.

    Hesselink PGM, Kerkenaar A, & Witholt B (1990) Inhibition of microbial
    cholesterol oxidases by dimethylmorpholines. J Steroid Biochem,
    35: 107-113.

    Hibbs JB Jr (1992) Immunology: Overview of cytotoxic mechanisms and
    defence of the intracellular environment against microbes. In: Moncada
    S, Marletta MA, Hibbs JB Jr, Higgs EA ed. The biology of nitric oxide.
    London,d Chapel Hill, Portland Press, pp 201-206.

    Hoffmann D, Brunnemann KD, Adams JD, Rivenson A, & Hecht SS (1982)
    N-nitrosamines in tobacco carcinogenesis. In: Magee PN ed.
    Nitrosamines and human cancer. Cold Spring Harbor, New York, Cold
    Spring Harbor Laboratory, pp 211-225 (Banbury Report No. 12).

    Hoffmann D, Adams JD, Lisk D, Fisenne I, & Brunnemann KD (1987) Toxic
    and carcinogenic agents in dry and moist snuff. J Natl Cancer Inst,
    79: 1281-1286.

    Hollett BA, Klemme JC, & Andjelkovich D (1982) Health hazard
    evaluation report HETA 81-045B-1216: Uniroyal, Inc., Mishawaka,
    Indiana. Cincinnati Ohio, National Institute for Occupational Safety
    and Health, 20 pp (PB84-183615).

    Hotchkiss JH & Vecchio AJ (1983) Analysis of direct contact paper and
    paperboard food packaging for N-nitrosomorpholine and morpholine. J
    Food Sci, 48: 240-242. 

    IARC (1978) N-nitrosomorpholine. In: Some  N-nitroso compounds. Lyon,
    International Agency for Research on Cancer, pp 263-280 (IARC
    Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
    Humans, Volume 17).

    IARC (1989) Morpholine. In: Some organic solvents, resin monomers and
    related compounds, pigments and occupational exposures in paint
    manufacture and painting. Lyon, International Agency for Research on
    Cancer, pp 199-213 (IARC Monographs on the Evaluation of Carcinogenic
    Risks to Humans, Volume 47).

    ILO (1991) Occupational exposure limits for airborne toxic substances,
    3rd ed. Geneva, International Labour Office, pp 282-283 (Occupational
    Safety and Health Series No. 37).

    Inui N, Nishi Y, Taketomi M, Mori M, Yamamoto M, Yamada T, & Tanimura
    A (1979) Transplacental mutagenesis of products formed in the stomach
    of golden hamsters given sodium nitrite and morpholine. Int J Cancer,
    24: 365-372.

    Iqbal ZM, Dahl K, & Epstein SE (1980) Role of nitrogen dioxide in the
    biosynthesis of nitrosamines in mice. Science, 207(4432): 1475-1476.

    Jakobi G, Löhr A, Schwuger MJ, Jung D, Fischer W, & Gloxhuber C (1983)
    [Washing agents.] In: [Ullmann's encyclopedia of industrial
    chemistry], 4th ed. Weinheim, VCH Verlagsgesellschaft, vol 24, pp 105,
    138-139 (in German).

    Japan Chemical Week (1991) Speciality chemicals handbook, 4th ed.
    Tokyo, The Chemical Daily Co., Ltd, 8 pp.

    Jones WT & Kipling MD (1972) Glaucopsia - blue-grey vision. Br J Ind
    Med, 29: 460-461. 

    Juhnke I & Lüdemann D (1978) [Results of the testing of 200 selected
    chemical compounds for acute fish toxicity with the Golden Orfe test.]
    Z Wasser Abwasser Forsch, 11: 161-164 (in German).

    Kamimura H, Enjoji Y, Sasaki H, Kawai R, Kaniwa H, Niigata K, &
    Kageyama S (1987) Disposition and metabolism of indeloxazine
    hydrochloride, a cerebral activator, in rats.  Xenobiotica,
    17(6): 645-658.

    Karweik DH & Meyers CH (1979) Spectrophotometric determination of
    secondary amines. Anal Chem, 51: 319-320.

    Katosova LD, Fomenko VN, & Davydenko LN (1991) Air pollution and
    industrial hygiene. Gig Tr Prof Zabol, 6: 35-36.

    Kleemann A & Engel J (1982) [Midodrin, Minaprin, Minocyclin;
    Trimethobenzamid, Trimethoprin, Trimetozin, Trimipramin,
    Tripelennamin.] In: [Pharmaceutical substances.] Stuttgart, New York,
    Georg Thieme Verlag, pp 602-603, 923-928 (in German).

    Knapp JS & Brown VR (1988) Morpholine biodegradation. Int Biodeterior,
    24: 299-306.

    Knapp JS & Whytell AJ (1990) The biodegradation of morpholine in river
    water and activated sludge. Environ Pollut, 68: 67-79.

    Knapp JS, Callely AG, & Mainprize J (1982) The microbial degradation
    of morpholine. J Appl Bacteriol, 52: 5-13.

    Koga M & Akiyama T (1985) Determination of trace heterocyclic amines
    in water as their 1,2,-naphthoquinone derivatives by high performance
    liquid chromatography. Anal Sci, 1: 285-288.

    Kramer VC, Schnell DJ, & Nickerson KW (1983) Relative toxicity of
    organic solvents to  Aedes aegypti larvae. J Invertebr Pathol,
    42: 285-287.

    Kubis A, Witek R, Baran E, Jadach W, Matecka K, & Zaba A (1981)
    [ In vivo antimycotic effect of topically applied morpholine.]
    Pharmazie, 36: 429-431 (in German).

    Kubis A, Witek R, & Krutul H (1983) [Investigation on antibacterial
    action of some amines.] Pharmazie, 38: 488-489 (in German).

    Lakritz L & Kimoto W (1980) N-nitrosamines - contaminants in blood-
    collection tubes. Food Cosmet Toxicol, 18: 31-34.

    Lam HF & Van Stee EW (1978) A re-evaluation of the toxicity of
    morpholine. Fed Proc, 37: 679 (Abstract).

    Lamarre C, Gilbert R, & Gendron A (1989) Liquid chromatographic
    determination of morpholine and its thermal breakdown products in
    steam-water cycles at nuclear power plants. J Chromatogr,
    467: 249-258.

    Lamb CB & Jenkins GF (1952) B.O.D. of synthetic organic chemicals. In:
    Proceedings of the 7th Industrial Waste Conference, Purdue University,
    West Lafayette, Indiana, 7-9 May 1952. Ann Arbor, Michigan, Ann Arbor
    Science Publishers, pp 326-339. 

    Lathia D & Edeler A (1989) [Influence of sulfur-containing amino acids
    on  in vitro nitrosamine formation under conditions similar to those
    found in the stomach.] Ernährungsphysiologie, 36: 21-24 (in German).

    Lathia D & Schellhöh B (1981) Inhibition of nitrosamine formation
     in vitro in presence of both ascorbic acid and sorbic acid. Recent
    Adv Clin Nutr, 1: 189-190.

    Lauharanta J (1992) Comparative efficacy and safety of amorolfine nail
    lacquer 2% versus 5% once weekly. Clin Exp Dermatol, 705: 41-43.

    Leach SA, Cook AR, Challis BC, Hill MJ, & Thompson MH (1987)
    Bacterially mediated  N-nitrosation reactions and endogenous
    formation of  N-nitroso compounds. In: Bartsch H, O`Neill IK, &
    Schulte-Hermann R ed. Relevance of  N-nitroso compounds to human
    cancer: Exposures and mechanisms. Lyon, International Agency for
    Research on Cancer, pp 396-403 (IARC Scientific Publications No. 84).

    Leach SA, Mackerness CW, Hill MJ, & Thompson MH (1991) Inhibition of
    bacterially mediated N-nitrosation by ascorbate: Therapeutic and
    mechanistic considerations. In: O`Neill IK, Chen J, & Bartsch H ed.
    Relevance to human cancer of  N-nitroso compounds, tobacco smoke and
    mycotoxins. Lyon, International Agency for Research on Cancer,
    pp 571-578 (IARC Scientific Publications No. 105).

    Leaf CD, Wishnok JS, & Tannenbaum SR (1991) Endogenous incorporation
    of nitric oxide from L-arginine into N-nitrosomorpholine stimulated by
     Escherichia coli lipopolysaccharide in the rat. Carcinogenesis,
    224: 537-539.

    Lee SA (1982) Health hazard evaluation report HETA 82-156-1231:
    Sheller-Globe Corporation, Keokuk, Iowa. Cincinnati, Ohio, National
    Institute for Occupational Safety and Health, 8 pp (PB84-172915).

    Leenheers LH, Ravensberg JC, Kerstens HJ, & Jongen MJM (1992) Gas
    chromatographic determination of the pesticide dodemorph for
    assessment of occupational exposure. J Chromatogr Sci, 132: 228-232.

    Leo A, Hansch C, & Elkins D (1971) Partition coefficients and their
    uses. Chem Rev, 71: 525, 564.

    Le Therizien L, Heymans F, Redeuilh C, Godfroid J-J, & Busch N (1980)
    Partition coefficient additivity. 1. Morpholine and
    N-(N',N'-disubstituted amino acetyl)-arylamine series. Eur J Med Chem
    Chim Ther, 15: 311-316.

    Lide DR ed. (1990) CRC handbook of chemistry and physics, 71st ed.
    Boca Raton, Florida, CRC Press, pp 8-34.

    Litton Bionetics (1979a) Evaluation of morpholine in the  in vitro
    transformation of BALB/3T3 cells assay. Kensington, Maryland, Litton
    Bionetics, Inc., 13 pp (Report submitted to Texaco Petrochemicals,
    Bellaire, Texas).

    Litton Bionetics (1979b) Evaluation of morpholine in the  in vitro
    transformation of BALB/3T3 cells assay. Kensington, Maryland, Litton
    Bionetics, Inc., 13 pp Report submitted to Texaco, Inc., Beacon, New

    Litton Bionetics (1980) Mutagenicity evaluation of morpholine in the
    sister chromatid exchange assay with chinese hamster ovary (CHO)
    cells. Kensingtn, Maryland, Litton Bionetics, Inc., 10 pp (Report
    submitted to Texaco, Inc., Beacon, New York).

    Litton Bionetics (1982) Evaluation of morpholine in the  in vitro
    transformation of Balb/3T3 cells with and without metabolic activation
    assay 80/490. Kensington, Maryland, Liotton Bionetics, Inc. 21 pp
    (Unpublished report submitted to BASF AG, Ludwigshafen).

    Liu RH, Conboy JJ, & Hotchkiss JH (1988) Nitrosation by nitro-nitroso
    derivatives of olefins: a potential mechanism for N-nitrosamine
    formation in fried bacon. J Agric Food Chem, 36: 984-987.

    Liu RH, Jacob JR, Tennant BC, & Hotchkiss JH (1992) Nitrite and
    nitrosamine synthesis by hepatocytes isolated from normal woodchucks.
    Cancer Res, 52: 4139-4143.

    Lodén M, Larsson R, Häggqvist I, & Karlsson N (1985) [The dermal
    irritancy/corrosion of 20 compounds in aqueous solutions.] Umea,
    Sweden, Försvarets Forskningsanstalt, 76 pp (FOA Report No. E/40023)
    (in Swedish with English summary). 

    Loeppky RN, Tomasik W, & Kerrick BE (1987) Nitroso transfer from
    alpha-nitrosamino aldehydes: implications for carcinogenesis.
    Carcinogenesis, 8(7): 941-946.

    London MA & Lee S (1987) Health hazard evaluation report HETA
    85-003-1834: BF Goodrich, Woodburn, Indiana. Cincinnati, Ohio,
    National Institute for Occupational Safety and Health, 27 pp

    McCain JC & Peck JM Jr (1976) The toxicity of selected chemicals used
    in power generating stations to Hawaiian fishes NOAA. Washington, DC,
    US Department of Commerce, National Technical Information Service,
    23 pp (NTIS No PB262437). 

    McGlothlin JD (1980) Health hazard evaluation report HETA 80-67-749:
    Firestone Fire and Rubber Company, Akron, Ohio. Cincinnati, Ohio,
    National Institute for Occupational Safety and Health, 18 pp

    McGlothlin J & Wilcox T (1984) Health hazard evaluation report HETA
    79-109-1538: Kelly Springfield Tire Company, Cumberland, Maryland.
    Cincinnati, Ohio, National Institute for Occupational Safety and
    Health, 50 pp (PB85-244424). 

    Mackerness CW, Leach SA, Thompson MH, & Hill MJ (1989) The inhibition
    of bacterially mediated N-nitrosation by vitamin C: relevance to the
    inhibition of endogenous N-nitrosation in the achlorhydric stomach.
    Carcinogenesis, 10(2): 397-399.

    Malaiyandi M, Thomas GH, & Meek ME (1979) Sampling and analysis of
    some corrosion inhibiting amines in steam condensates. J Environ Sci
    Health, A14: 609-627.

    Maller RK & Heidelberger C (1957) Studies on OPSPA. IV. Metabolism of
    OPSPA in the rat and human. Cancer Res, 17: 296-301.

    Mannsville Chemical Products (1981) Chemical products synopsis:
    Morpholine. Cortland, New York, Mannsville Chemical Products
    Corporation, 2 pp.

    Mastromatteo E (1965) Recent occupational health experiences in
    Ontario. J Occup Med, 702: 502-511.

    Mazure N (1993) Etude de la biodégradation de la morpholine par une
    culture pure,  Mycobacterium aurum, et des cultures mixtes
     Pseudomonas. Compiègne, France, University of Technology (Thesis).

    Meiners AF, Gadberry H, Carson BL, Owens HP, & Lapp TW (1980) Volatile
    corrosion inhibitors and boiler water additives: potential for
    nitrosamine formation. Washington, DC, US Environmental Protection
    Agency, Office of Pesticides and Toxic Substances, 99 pp (Report
    submitted by the Midwest Research Institute, Kansas City, Missouri)

    Mercer EI (1991) Morpholine antifungals and their mode of action.
    Biochem Soc Trans, 19: 788-793.

    Migukina NV (1973) [Evaluation of the danger [toxicity] of morpholine
    by chronic exposure.] Toksikol Nov Prom Chim Veshchestv, 13: 92-100
    (in Russian).

    Millington LA, Goulding KH, & Adams N (1988) The influence of growth
    medium composition on the toxicity of chemicals to algae. Water Res,
    22: 1593-1597.

    Mills EJ & Stack VT (1953) Biological oxidation of synthetic organic
    chemicals. In: Proceedings of the 8th Industrial Waste Conference,
    Purdue University, West Lafayette, Indiana, 4-6 May 1953. Ann Arbor,
    Michigan, Ann Arbor Science Publishers, Inc., pp 492-517.

    Mills EJ & Stack VT (1955) Suggested procedure for evaluation of
    biological oxidation of organic chemicals. Sewage Ind Wastes,
    27: 1061-1064.

    Mirvish SS (1975) Formation of  N-nitroso compounds: chemistry,
    kinetics, and  in vivo occurrence. Toxicol Appl Pharmacol,
    31: 325-351.

    Mirvish SS, Wallcave L, Eagen M, & Shubik P (1972) Ascorbate-nitrite
    reaction: possible means of blocking the formation of carcinogenic
     N-nitroso compounds. Science, 177: 65-68.

    Mirvish SS, Cardesa A, Wallcave L, & Shubik P (1975) Induction of
    mouse lung adenomas by amines or ureas plus nitrite and by N-nitroso
    compounds: effect of ascorbate, gallic acid, thiocyanate, and
    caffeine. J Natl Cancer Inst, 55: 633-636.

    Mirvish SS, Pelfrene AF, Garcia H, & Shubik P (1976) Effect of sodium
    ascorbate on tumor induction in rats treated with morpholine and
    sodium nitrate, and with nitrosomorpholine.  Cancer Lett, 2: 101-108.

    Mirvish SS, Ramm MD, Sams JP, & Babcock DM (1988) Nitrosamine
    formation from amines applied to the skin of mice after and before
    exposure to nitrogen dioxide. Cancer Res, 48: 1095-1099.

    Mjos K (1978) Cyclic amines. In: Kirk-Othmer encyclopedia of chemical
    technology, 3rd ed. New York, John Wiley and Sons, vol 2, pp 295-308.

    Moriyasu M, Endo M, Hashimoto Y, & Koeda T (1984) High-performance
    liquid chromatographic determination of organic substances by metal
    chelate derivatization. II. Microdetermination of methamphetamine and
    amphetamine. Chem Pharm Bull, 32: 600-608.

    Newberne PM & Shank RC (1973) Induction of liver and lung tumours in
    rats by the simultaneous administration of sodium nitrite and
    morpholine. Food Cosmet Toxicol, 11: 819-825.

    NIOSH (1977) Manual of analytical methods, 2nd ed. Cincinnati, Ohio,
    National Institute for Occupational Safety and Health, vol 3, pp

    NIOSH (1988) National occupational exposure survey as of 16.12.1988:
    Morpholine. Cincinnati, Ohio, National Institute of Occupational
    Safety and Health, 1 p. 

    Norkus EP, Boyle S, Kuenzig WA, & Mergens WJ (1984) Formation of
    N-nitrosomorpholine in mice treated with morpholine and exposed to
    nitrogen oxide. Carcinogenesis, 5: 549-554.

    Norkus EP, Kuenzig WA, Chau J, Mergens WJ, & Conney AH (1986)
    Inhibitory effect of alpha-tocopherol on the formation of
    nitrosomorpholine in mice treated with morpholine and exposed to
    nitrogen dioxide. Carcinogenesis, 7: 357-360.

    NRC (1981) Selected aliphatic amines and related compounds: an
    assessment of the biological and environmental effects. Washington,
    DC, National Research Council, Board on Toxicology and Environmental
    Health Hazards (Report prepared for the US Environmental Protection
    Agency, Washington) (NTIS/PB83-133066).

    OECD (1981a) OECD guidelines for testing of chemicals. Section 3.
    Degradation and accumulation: Ready biodegradability. 301 E - Modified
    OECD screening test. Paris, Organisation for Economic Co-operation and

    OECD (1981b) OECD guidelines for testing of chemicals. Section 3.
    Degradation and accumulation: Inherent biodegradability. 302 B -
    Modified Zahn-Wellens test. Paris, Organisation for Economic
    Co-operation and Development.

    OECD (1984) Guidelines for testing of chemicals No 202, Part I:
     Daphnia sp, acute immobilisation test. Paris, Organisation for
    Economic Co-operation and Development.

    O'Donnell CM, Edwards C, & Ware J (1988) Nitrosamine formation by
    clinical isolates of enteric bacteria. FEMS Microbiol Lett,
    51: 193-197.

    Ohnishi T (1984) [Morpholine. Studies on mutagenicity of the food
    additive morpholine (fatty acid salt).] Nippon Eiseigaku Zasski,
    39: 729-745 (in Japanese with English summary).

    Ohnishi T, Kubota M, Okada A, & Tonami K (1983) [Residual survey
    investigation and removal efficiency by washing with kitchen detergent
    of food additive morpholine.] Hokuriku Koshu Eisei Gakkaishi,
    10: 63-67 (in Japanese with English summary).

    Österdahl B-G & Slorach SA (1983) Volatile N-nitrosamines in snuff and
    chewing tobacco on the Swedish market. Food Chem Toxicol, 21: 759-762.

    Pensabene JW & Fiddler W (1988) Food additives. Determination of
    volatile N-nitrosamines in Frankfurters containing minced fish and
    surimi. J Assoc Off Anal Chem, 71: 839-843.

    Perez A, Fernandez SI, Garcia-Roche MO, De Las Cagigas A, Castillo A,
    Fonseca G, & Herrera M (1990) Mutagenicity of N-nitrosomorpholine
    biosynthesized from morpholine in the presence of nitrate and its
    inhibition by ascorbic acid. Nahrung, 34: 661-664.

    Postlethwait EM & Mustafa MG (1983) Formation of N-nitrosamine in
    isolated rat lungs during nitrogen dioxide ventilation.
    Carcinogenesis, 4: 777-778.

    Reinel D & Clarke C (1992) Comparative efficacy and safety of
    amorolfine nail lacquer 5% in onychomycosis, once-weekly versus
    twice-weekly. Clin Exp Dermatol, 705: 44-49.

    Reinhardt CF & Brittelli MR (1981) Heterocyclic and miscellaneous
    nitrogen compounds. In: Clayton GD & Clayton FE ed. Patty's industrial
    hygiene and toxicology: Vol 2A. Toxicology. New York, John Wiley and
    Sons, pp 2671-2822.

    Rekka E, Retsas S, Demopoulos VJ, & Kourounakis PN (1990)
    Lipophilicity of some substituted morpholine derivatives synthesized
    as potential antinociceptive agents. Arch Pharmacol, 323: 53-56.

    Reynolds T (1989) Comparative effects of heterocyclic compounds on
    inhibition of lettuce fruit germination. J Exp Bot, 40: 391-404.

    Rhodes C & Case DE (1977) Non-metabolite residues of ICI 58,834
    (viloxazine). Studies with (14C)morpholine, (14C)ethanolamine and
    (14C)glyoxylate. Xenobiotica, 7: 112.

    Richardson ML, Webb KS, & Gough TA (1980) The detection of some
    N-nitrosamines in the water cycle. Ecotoxicol Environ Saf, 4: 207-212.

    Ringenburg V & Fajen JM (1980) Survey for N-nitroso compounds at B.F.
    Goodrich, Woodburn, Indiana, December 12, 1979. Cincinnati, Ohio,
    National Institute for Occupational Safety and Health, 11 pp

    Rounbehler DP & Fine DH (1982) Specific detection of amines and other
    nitrogen-containing compounds with a modified TEA analyzer. In:
    Bartsch H, O'Neill IK, Castegnaro M, & Okada M ed.  N-nitroso
    compounds: Occurrence and biological effects. Lyon, International
    Agency for Research on Cancer, pp 209-219 (IARC Scientific
    Publications No. 41).

    Rounbehler DP & Fajen JM (1983) N-nitroso compounds in the factory
    environment. National Cincinnati, Ohio, National Institute for
    Occupational Safety and Health, 228 pp (PB84-145770).

    Rounbehler DP, Reisch J, & Fine DH (1980) Nitrosamines in new motor-
    cars. Food Cosmet Toxicol, 18: 147-151.

    Sander J & Bürkle G (1969) [Induction of malignant tumours in rats by
    simultaneous feeding of nitrite and secondary amines.] Z Krebsforsch,
    73: 54-66 (in German). 

    Sander J, Schweinsberg F, & Menz H-P (1968) [Studies on the formation
    of carcinogenic nitrosamines in the stomach.] Hoppe-Seyler's Z Physiol
    Chem, 349: 1691-1697 (in German).

    Savolainen H & Rosenberg C (1983) Morpholine vapour inhalation and
    interactions of simultaneous nitrite intake. Biochemical effects on
    rat spinal cord axons and skeletal muscle. Arch Toxicol, 53: 143-150.

    Schröder E, Rufer C, & Schmiechen R (1982) [Nitrofuran.] In:
    [Pharmaceutical Chemistry.] Stuttgart, New York, Georg Thieme Verlag,
    pp 858-863 (in German).

    Schuster RH, Nabholz F, & Gmünder M (1990) [The inhibition of the
    formation of N-nitrosamines: Part 1. The situation and the effect of
    alpha-tocopherol.] Kautschuk Gummi Kunstst, 43: 95-106 (in German).

    Sen NP & Baddoo PA (1986) Origin of N-nitrosomorpholine contamination
    in margarine. J Food Sci, 51: 216-217.

    Sen NP & Baddoo PA (1989) An investigation on the possible presence of
    morpholine and N-nitrosomorpholine in wax-coated apples. J Food Saf,
    9: 183-191.

    Sen NP, Seaman S, Clarkson S, Garrod F, & Lalonde P (1984) Volatile
    N-nitrosamines in baby bottle rubber nipples and pacifiers. Analysis,
    occurrence and migration. In: O'Neill IK, vn Borstel RC, Miller CT,
    Long J, & Bartsch H ed.  N-nitroso compounds: Occurrence, biological
    effects and relevance to human cancer. Lyon, International Agency for
    Research on Cancer, pp 51-57 (IARC Scientific Publications No. 57).

    Sen NP, Kushwaha SC, Seaman SW, & Clarkson SG (1985) Nitrosamines in
    baby bottle nipples and pacifiers: occurrence, migration, and effect
    of infant formulas and fruit juices on  in vitro formation of
    nitrosamines under simulated gastric conditions. J Agric Food Chem,
    33: 428-433.

    Shank RC & Newberne PM (1976) Dose-response study of the
    carcinogenicity of dietary sodium nitrite and morpholine in rats and
    hamsters. Food Cosmet Toxicol, 14: 1-8. 

    Shea TE Jr (1939) The acute and sub-acute toxicity of morpholine. J
    Ind Hyg Toxicol, 21: 236-245.

    Shenoy NR & Choughuley ASU (1989) Effect of certain plant phenolics on
    nitrosamine formation. J Agric Food Chem, 37: 721-725.

    Shenoy NR & Choughuley ASU (1992) Inhibitory effect of diet related
    sulphydryl compounds on the formation of carcinogenic nitrosamines.
    Cancer Lett, 67: 227-232.

    Shibata M-A, Kurata Y, Tamano S, Ogiso T, Fukushima S, & Ito N (1987a)
    13-week subchronic toxicity study with morpholine oleic acid salt
    administered to B6C3F1 mice. J Toxicol Environ Health, 22: 187-194.

    Shibata M-A, Kurata Y, Ogiso T, Tamano S, Fukushima S, & Ito N (1987b)
    Combined chronic toxicity and carcinogenicity studies of morpholine
    oleic acid salt in B6C3F1 mice. Food Chem Toxicol, 25: 569-574.

    Simon P & Lemacon C (1987) Determination of aliphatic primary and
    secondary amines and polyamines in air by high-performance liquid
    chromatography. Anal Chem, 59: 480-484.

    Singer GM & Lijinsky W (1976a) Naturally occurring nitrosatable
    compounds. I. Secondary amines in foodstuffs. J Agric Food Chem,
    24: 550-553.

    Singer GM & Lijinsky W (1976b) Naturally occurring nitrosatable
    amines. II Secondary amines in tobacco and cigarette smoke condensate.
    J Agric Food Chem, 24: 553-555.

    Singer SS (1980) Transnitrosation by nitrosamines and nitrosoureas.
    In: Walker EA, Griciute L, Castegnaro M, & Börzsönyi M ed.  N-nitroso
    compounds: Analysis, formation and occurrence. Lyon, International
    Agency for Research on Cancer, pp 111-117 (IARC Scientific
    Publications No. 31).

    Sittig M (1985) Handbook of toxic and hazardous chemicals and
    carcinogens, 2nd ed. Park Ridge, Noyes Publications, pp 626-627.

    Smith JH, Bomberger DC Jr, & Haynes DL (1980) Prediction of the
    volatilization rates of high-volatility chemicals from natural water
    bodies. Environ Sci Technol, 14: 1332-1337.

    Smyth HF Jr, Carpenter CP, Weil CS, & Pozzani UC (1954) Range-finding
    toxicity data. Arch Ind Hyg Occup Med, 10: 61-68.

    Sohn OS, Fiala E, Conaway CC, & Weisburger JH (1982a) Separation of
    morpholine and some of its metabolites by high-performance liquid
    chromatography. J Chromatogr, 242: 374-380.

    Sohn OS, Fiala ES, Conaway CC, & Weisburger JH (1982b) Metabolism and
    disposition of morpholine in the rat, hamster and guinea pig. Toxicol
    Appl Pharmacol, 64: 486-491. 

    Sollenberg J & Hansen L (1987) Isotachophoretic determination of
    amines from workroom air. J Chromatogr, 390: 133-140.

    Spiegelhalder B (1983) [Nitrosamines and rubber.] In: Preussmann R ed.
    [The nitrosamine problem.] Weinheim, VCH Verlagsgesellschaft,
    pp 235-244 (in German).

    Spiegelhalder B & Preussmann R (1982) Nitrosamines and rubber. In:
    Bartsch H, O'Neill IK, Castegnaro M, & Okada M ed.  N-nitroso
    compounds: Occurrence and biological effects. Lyon, International
    Agency for Research on Cancer, pp 231-2439 (IARC Scientific
    Publications No. 41).

    Spiegelhalder B & Preussmann R (1984) Contamination of toiletries and
    cosmetic products with volatile and nonvolatile N-nitroso carcinogens.
    J Cancer Res Clin Oncol, 108: 160-163.

    Spies RB, Andresen BD, & Rice DW Jr (1987) Benzthiazoles in estuarine
    sediments as indicators of street runoff. Nature (Lond), 327: 697-699.

    SRI (1990) Directory of chemical producers, Western Europe:
    Morpholine. Menlo Park, California, SRI International, vol 2, p 1563.

    Stewart BW & Farber E (1973) Strand breakage in rat liver DNA and its
    repair following administration of cyclic nitrosamines. Cancer Res,
    33: 3209-3215.

    Strotmann UJ, Weberruss U, & Bias WR (1993) Degradation of morpholine
    in several biodegradation tests and in wastewater treatment plants.
    Chemosphere, 75: 1729-1742.

    Subrahmanyam PVR, Khadakkar SN, Chakrabarti T, & Sundaresan BB (1983)
    Wastewater-treatment of a phthalate plasticizer, ethanolamine and
    morpholine manufacturing plant: a case study. Proc Ind Waste Conf,
    37: 13-20.

    Suzuki K & Mitsuoka T (1984) N-nitrosamine formation by intestinal
    bacteria. In: O'Neill IK, vn Borstel RC, Miller CT, Long J, & Bartsch
    H ed.  N-nitroso compounds: Occurrence, biological effects and
    relevance to human cancer. Lyon, International Agency for Research on
    Cancer, pp 275-281 (IARC Scientific Publications No. 57).

    Swain A, Waterhouse KV, Venables WA, Callely AG, & Lowe SE (1991)
    Biochemical studies of morpholine catabolism by an environmental
    mycobacterium. Appl Microbiol Biotechnol, 29: 110-114.

    Swope HG & Kenna M (1950) Effect of organic compounds on biochemical
    oxygen demand.  Sew Ind Wastes Eng, 21: 467-468.

    Taft RM & Stroman RE (1979) Health hazard evaluation report HETA
    78-131-586: Goodyear Tire and Rubber Company, Niagara Falls, New York.
    Cincinnati Ohio, National Institute of Occupational Safety and Health,
    Hazard Evaluations and Technical Assistance Branch, 13 pp

    Takezawa J & Lam HF (1978) Toxic effect of morpholine on rat lungs.
    Fed Proc, 37: 247 (Abstract).

    Tanaka M, Okada Z, Mihashi K, & Seiko Y (1968) Industrial waste
    treatment by activated sludge. XV. Treatment of waste from an organic
    vulcanization accelerator producing plant. Kogyo Gijutsuin Hakko
    Kenkyusho Kenkyu Hokoku, 33: 19-29.

    Tanaka A, Tokieda T, Nambaru S, Osawa M, & Yamaha T (1978) Excretion
    and distribution of morpholine salts in rats. J Food Hyg Soc,
    19: 329-334.

    Tannenbaum SR, Archer MC, Wishnok JS, & Bishop WW (1978) Nitrosamine
    formation in human saliva. J Natl Cancer Inst, 60(2): 251-253.

    Tatsumi K, Kitamura S, Yoshimura Y, Tanaka S, Hashimoto K, & Igarashi
    T (1975) The metabolism of phenyl o-(2-N-morpholinoethoxy)-phenyl
    ether hydrochloride in the rabbit and rat. Xenobiotica, 5(6): 377-388.

    Taylor R & Son PN (1982) Rubber chemicals. In: Kirk-Othmer
    encyclopedia of chemical technology, 3rd ed. New York, John Wiley and
    Sons, vol 20, pp 337-364.

    Texaco (1979a) Mutagenicity evaluation of morpholine in the Ames
    salmonella/microsome plate test. Bellaire, Texas, Texaco
    Petrochemicals, 8 pp.

    Texaco (1979b) Mutagenicity evaluation of morpholine in the mouse
    lymphoma forward mutation assay. Bellaire, Texas, Texaco
    Petrochemicals, 15 pp.

    Texaco (1986) Texaco product brochure - Morpholine. Austin, Texas,
    Texaco Chemical Company, Research and Technical Services, 29 pp.

    Tölgyessy P, Kollár M, Vanco D, & Piatrik M (1986) Bio-degradability
    of morpholine. J Radioanal Nucl Chem Lett, 107: 291-295.

    Tombropoulos EG (1979) Micromethod for the gas chromatographic
    determination of morpholine in biological tissues and fluids. J
    Chromatogr, 164: 95-99.

    Tombropoulos EG, Koo JO, Gibson W, & Hook GER (1983) Induction by
    morpholine of lysosomal alpha-mannosidase and acid phosphatase in
    rabbit alveolar macrophages  in vivo and  in vitro. Toxicol Appl
    Pharmacol, 70: 1-6.

    TRGS (1989) [Technical regulations for dangerous chemicals:
    Nitrosamine.] Cologne, Carl Heymanns Verlag KG, 13 pp (TRGS 552)
    (in German).

    Tricker AR & Preussmann R (1991) Occurrence of and exposure to
     N-nitroso compounds in tobacco. In: O'Neill IK, Chen J, & Bartsch H
    ed. Relevance to human cancer of  N-nitroso compounds, tobacco smoke
    and mycotoxins. Lyon, International Agency for Research on Cancer,
    pp 493-495 (IARC Scientific Publications No. 105).

    UBA (1990) Calculation of log POW with the Program CLOGP (data
    sheet). Berlin, Environment Office, 2 pp.

    US FDA (1984a) Code of federal regulations (April 1, 1984) - Title 21,
    Part 178.3300: Corrosion inhibitors used for steel or tinplate.
    Washington, DC, US Food and Drug Administration, p 312.

    US FDA (1984b) Code of federal regulations (April 1, 1984) - Title 21,
    Part 176.210: Defoaming agents used in the manufacture of paper and
    paperboard. Washington, DC, US Food and Drug Administration,
    pp 192-193.

    US FDA (1984c) Code of federal regulations (April 1, 1984) - Title 21,
    Part 175.105: Substances for use only as components of adhesives.
    Washington, DC, US Food and Drug Administration, pp 124-137.

    US FDA (1984d) Code of federal regulations - Title 21, Part 178.310:
    Animal glue. Washington, DC, US Food and Drug Administration, p 308.

    US FDA (1984e) Code of federal regulations - Title 21, Part 173.310:
    Boiler water additives. Washington, DC, US Food and Drug
    Administration, pp 115-118.

    US FDA (1986) Cosmetic product formulation data: Ingredients used in
    each product category. Washington, DC, US Food and Drug

    US FDA (1988) Code of federal regulations - Title 21, Part 172.235:
    Morpholine. Washington, DC, US Food and Drug Administration, pp 33-35.

    Van Stee EW, Wynns PC, & Moorman MP (1981) Distribution and
    disposition of morpholine in the rabbit. Toxicology, 20: 53-60.

    Wang X & Suskind RR (1988) Comparative studies of the sensitization
    potential of morpholine, 2-mercaptobenzothiazole and 2 of their
    derivatives in guinea pigs. Contact Dermatitis, 19: 11-15.

    Wang X & Tabor MW (1988) Studies of the reactivity of morpholine,
    2-mercaptobenzothiazole and 2 of their derivatives with selected amino
    acids. Contact Dermatitis, 19: 16-21.

    Wang H & Wu Y (1991) Inhibitory effect of Chinese tea on N-nitrosation
     in vitro and  in vivo. In: O'Neill IK, Chen J, & Bartsch H ed.
    Relevance to human cancer of  N-nitroso compounds, tobacco smoke and
    mycotoxins. Lyon, International Agency for Research on Cancer,
    pp 546-548 (IARC Scientific Publications No. 105).

    Wellens H (1982) [Comparison of the sensitivity of  Brachydanio rerio
    und  Leuciscus idus by testing the fish toxicity of chemicals and
    wastewaters.] Z Wasser Abwasser Forsch, 2: 49-52 (in German).

    Westin JB, Castegnaro MJ-J, & Friesen MD (1987) N-nitrosamines and
    nitrosatable amines, potential precursors of N-nitramines, in
    children's pacifiers and baby-bottle nipples. Environ Res,
    43: 126-134.

    Wishnok JS & Tannenbaum SE (1976) Formation of cyanamides from
    secondary amines in human saliva. Science, 191: 1179-1180.

    Wishnok JS & Tannenbaum SR (1977) An unknown salivary morpholine
    metabolite. Anal Chem, 49: 715a-716a, 718a.

    Yurchenko VA, Ilnitskii AP, Ermilow VB, Mistakopulo GM, & Nechipai AM
    (1990) [Investigation of mutagenic action of natural zeolite and
    chrysotile-asbest dusts.] Eksp Onkol, 12: 24-26 (in Russian with
    English summary).

    Zaeva GN, Timofievskaya LA, Bazarova LA, & Migukina NV (1968)
    [Comparative toxicity of a group of cyclic imino-compounds.] Toksikol
    Nov Prom Chim Veshchestv, 10: 25-35 (in Russian).

    Ziebarth D (1973) N-nitrosation of secondary amines and particularly
    of drugs, in buffer solutions and human gastric juice. In: Bogovski P
    & Walker EA ed.  N-nitroso compounds in the environment. Lyon,
    International Agency for Research on Cancer, pp 137-141 (IARC
    Scientific Publications No. 9).

    Ziebarth D. (1974) [Investigations into the nitrosation of secondary
    amines in buffer solutions and in human gastric juice.] Arch
    Geschwulstforsch, 43: 42-41 (in German).


    1.  Propriétés physiques et chimiques

         La morpholine (1-oxa-4-azacyclohexane) est un liquide incolore,
    huileux, hygroscopique et volatil qui possède l'odeur de poisson
    caractéristique des amines.  Elle est entièrement miscible à l'eau,
    ainsi qu'à de nombreux solvants organiques, mais sa solubilité est
    limitée dans les solutions aqueuses alcalines.  C'est une base, dont
    le pKa de l'acide conjugué est de 8,33.  Il s'ensuit que son
    coefficient de partage entre l'octanol et l'eau dépend du pH
    (log Pow = -2,55 à pH 7 et -0.84 à pH 10 et à 35°C).  La tension de
    vapeur des solutions aqueuses de morpholine est très proche de celle
    de l'eau.

         La morpholine peut entrer en réaction de diverses manières. 
    Chimiquement, elle se comporte comme une amine secondaire.  Dans les
    conditions environnementales et physiologiques, la
     N-nitrosomorpholine (NMOR), dont le pouvoir cancérogène chez
    l'animal est prouvé, se forme par réaction entre des solutions de
    nitrite ou des oxydes d'azote gazeux et des solutions diluées de
    morpholine.  La concentration en oxyde d'azote (NO) peut être
    importante pour la nitrosation.  Les conditions de nitrosation, en
    particulier la valeur du pH, jouent un rôle important.

    2.  Méthodes d'analyse

         On peut doser la morpholine par chromatographie en phase gazeuse
    avec des colonnes à remplissage ou des colonnes capillaires, par
    chromatographie liquide à haute performance (HPLC) et par
    chromatographie ionique.  Les détecteurs utilisés sont les détecteurs
    à ionisation de flamme, les détecteurs à photométrie de flamme, les
    détecteurs sélectifs d'azote, les détecteurs thermiques pour la
    chromatographie en phase gazeuse et, pour la chromatographie en phase
    liquide à haute performance, les détecteurs à UV et les détecteurs
    thermiques.  Pour le dosage des traces, il faut passer par un dérivé. 
    La méthode de choix sur le plan de la sensibilité semble être la
    chromatographie en phase gazeuse avec détection thermique après
    transformation de la morpholine en NMOR (limite de détection:  2 à
    3 µg/kg dans diverses matrices).  Dans l'air, de faibles
    concentrations de morpholine peuvent être mesurées par chromatographie
    en phase gazeuse avec un détecteur sélectif d'azote.

    3.  Sources d'exposition humaine et environnementale

         On estime qu'environ 25 000 tonnes de morpholine sont produites
    chaque année, toutefois on ne connaît pas dans le détail la production
    de certains pays.

         Le principal procédé de production est, semble-t-il, la réaction
    du diéthylène-glycol sur l'ammoniaque en présence d'hydrogène et de

         La morpholine est un produit chimique à tout faire mais on n'en
    connaît pas tous les usages.  Il joue un rôle important comme
    intermédiaire dans l'industrie du caoutchouc, comme inhibiteur de la
    corrosion ainsi que pour la synthèse d'éclaircissants optiques,
    d'agents pour la protection des récoltes, de colorants et de
    médicaments.  La morpholine est utilisée comme solvant pour les
    dérivés organiques les plus divers, comme par exemple les résines, les
    colorants et les cires.  On peut également l'utiliser comme
    catalyseur.  On utilise encore de la morpholine dans certains pays
    pour la confection de produits de toilette et de cosmétiques.  Dans
    d'autres, elle entre dans la composition d'additifs alimentaires, soit
    directement, soit indirectement.

         Lorsqu'il y a exposition humaine ou environnementale, elle peut
    être due soit à des émissions de gaz, soit à des décharges de
    solutions aqueuses, à moins qu'elle ne se produise directement lors de
    l'utilisation de certains produits contenant de la morpholine, comme
    par exemple des produits cosmétiques ou des cires.  Le gros des
    émissions et des décharges trouve probablement son origine dans la
    fabrication et l'utilisation de la morpholine dans l'industrie
    chimique (notamment lors de la production et de l'utilisation des
    produits destinés à l'industrie du caoutchouc) ainsi que dans
    l'application de la morpholine comme agent anti-corrosion.  On a
    trouvé de la morpholine dans des denrées alimentaires très variées
    ainsi que dans le tabac.  Il est possible que cette présence
    s'explique par la migration, dans la denrée alimentaire, de la
    morpholine incorporée à l'enduit qui recouvre les fruits ou
    l'emballage, mais dans un certain nombre de cas, on ignore d'où la
    morpholine peut provenir.

    4.  Transport, distribution et transformation dans l'environnement

         La morpholine est chimiquement stable dans la biosphère bien
    qu'elle puisse être soumise à une nitrosation chimique ou biologique
    qui la transforme en NMOR.

         La morpholine est intrinsèquement biodégradable.  On a vérifié
    cette propriété dans des conditions reproduisant celles qui règnent
    dans les usines de traitement des boues activées.  Cependant, dans des
    conditions de non adaptation, la morpholine n'est probablement pas
    décomposée en proportion importante.  Le temps de rétention moyen sur
    les matières solides présentes dans les usines de traitement des boues
    activées est d'une importance cruciale et il doit dépasser les 8 jours
    pour que l'on puisse obtenir une bonne dégradation de la morpholine.

         Les données relatives à la bioaccumulation de la morpholine par
    les organismes aquatiques et terrestres sont insuffisantes.  D'après
    la valeur du coefficient de partage entre le  n-octanol et l'eau
    (log Pow = -2,55 à pH 7), on peut s'attendre à ce qu'il n'y ait
    aucune bioaccumulation.

         Comme la morpholine est un produit chimique industriel important
    dont les applications sont variées, il faut s'attendre à retrouver ce
    composé ou ses dérivés dans un grand nombre d'effluents industriels. 
    De plus, étant donné qu'on l'utilise comme inhibiteur de la corrosion
    dans l'eau des chaudières, on va le retrouver dans les eaux usées de
    ces chaudières, et en particulier les eaux usées provenant de
    certaines centrales thermiques.  Comme la morpholine entre également
    dans la composition des additifs du caoutchouc, on va en retrouver
    également, en quantité mal définie, dans l'hydrosphère et la
    géosphère, par suite de l'usure des pneus et du rejet des pneus usés.

         La morpholine peut pénétrer dans l'environnement en se
    volatilisant à partir des encaustiques et des cirages dont elle est un
    constituant.  Elle est rapidement captée par l'humidité.  C'est donc
    principalement dans l'hydrosphère qu'elle devrait s'accumuler, mais
    les données limitées dont on dispose incitent à penser que la
    morpholine ne s'accumule pas dans ce compartiment.

         La meilleure méthode pour éliminer la morpholine concentrée est
    l'incinération, toutefois il peut être nécessaire de veiller aux
    émissions d'oxydes d'azote afin de respecter les normes de protection
    de l'environnement.  En ce qui concerne les effluents aqueux, le
    traitement des boues activées est suffisant, à la condition toutefois
    que l'usine fasse l'objet d'un contrôle rigoureux (voir ci-dessus).

    5.  Concentrations dans l'environnement et exposition humaine

         On ne dispose d'aucune donnée sur la concentration de la
    morpholine dans l'air ambiant ainsi que dans l'air intérieur des
    immeubles résidentiels ou encore dans l'eau de boisson.  Si l'on
    possède quelques données sur sa présence dans les eaux naturelles, on
    n'en a en revanche aucune sur sa présence dans le sol.

         D'après les données disponibles, c'est les denrées alimentaires
    qui constituent la principale source d'exposition à la morpholine de
    la population générale, les produits alimentaires pouvant être
    contaminés par suite d'un traitement conservateur direct des fruits à
    l'aide de cires contenant de la morpholine, lors du traitement à la
    vapeur au cours de la préparation et enfin par l'utilisation de
    matériaux d'emballage dans la composition desquels entre la
    morpholine.  Cependant on ne dispose que de données quantitatives
    limitées sur la contamination des denrées alimentaires par la
    morpholine et la NMOR.  Par exemple, dans les produits laitiers pré-
    emballés, les valeurs mesurées vont de 5 à 77 µg/kg pour la morpholine
    et jusqu'à 3,3 µg/kg pour la NMOR.  En général, les mesures effectuées

    ont montré que la teneur en morpholine de divers échantillons de
    produits alimentaires (poisson, viande, produits d'origine végétale,
    boissons) ne dépassait généralement pas 1 mg/kg.  Des valeurs plus
    élevées (jusqu'à 71 mg/kg) ont été relevées au Japon dans des agrumes. 
    Une enquête effectuée en Italie n'a pas permis de repérer la présence
    de NMOR dans diverses denrées alimentaires au seuil de détection de
    0,3 µg/kg.  Les données existantes ne permettent pas d'évaluer
    l'apport de morpholine et de NMOR par la voie alimentaire.

         On a trouvé de la morpholine dans le tabac de cigarette à la
    concentration de 0,3 mg/kg ainsi que dans le tabac à priser et à
    chiquer à des concentrations allant jusqu'à 4,0 mg/kg.  Il est arrivé
    que l'on trouve dans du tabac à priser des concentrations de
    morpholine allant jusqu'à 0,7 mg/kg.  La présence de ce produit était
    probablement la conséquence de l'utilisation de cires  à base de
    morpholine pour le conditionnement de ce tabac.

         De la NMOR a été mise en évidence dans certains produits de
    toilette et dans des cosmétiques, par exemple des shampoings, du
    rimmel ainsi que dans des articles en caoutchouc comme les sucettes
    pour bébés et les tétines pour biberon, à des concentrations allant
    jusqu'à 3,5 mg/kg.

         Il peut y avoir exposition professionnelle à la morpholine dans
    diverses industries.  On ne possède guère de données sur l'exposition
    des travailleurs à la morpholine.  Toutes les valeurs signalées sont
    inférieures à 3 mg/m3.  On a signalé des cas d'exposition
    professionnelle à la NMOR dans l'industrie du caoutchouc où des
    concentrations allant jusqu'à 250 µg/m3 ont été mesurées.

         Les données actuellement disponibles permettent de se faire une
    idée du risque d'exposition humaine mais elles ne permettent pas une
    estimation précise de l'intensité de l'exposition à la morpholine et
    la NMOR de la population générale et des diverses catégories

    6.  Cinétique et métabolisme chez les animaux de laboratoire et

         Après exposition par voie orale, cutanée ou respiratoire, il y a
    absorption de la morpholine.  Chez le rat, après administration par
    voie orale ou intraveineuse, la morpholine se répartit rapidement dans
    l'organisme, atteignant sa concentration la plus élevée dans
    l'intestin et les muscles.

         Chez le lapin, après exposition par voie intraveineuse ou
    respiratoire, la morpholine se répartit de préférence dans les reins,
    les concentrations étant plus faibles dans les poumons, le foie et le

         La morpholine ne se fixe pas de manière importante aux protéines
    plasmatiques.  Sa demi-vie dans le plasma est de 115 minutes chez le
    rat, de 120 minutes chez le hamster et de 300 minutes chez le cobaye.

         La morpholine est principalement excrétée sans modification par
    les reins chez un certain nombre d'espèces.  Un jour après
    l'administration, on a constaté que 70 à 90% de la morpholine se
    retrouvaient dans les urines.  La neutralisation en augmente la
    vitesse d'excrétion.  Une faible proportion de la morpholine est
    excrétée dans l'air expiré et dans les matières fécales.

         Les études effectuées sur des rats, des souris, des hamsters et
    des lapins indiquent que la morpholine s'élimine presque complètement
    sans métabolisation.  Chez le cobaye, il peut y avoir une
     N-méthylation suivie d'une  N-oxydation, la dose administrée
    pouvant être métabolisée jusqu'à hauteur de 20%.  En présence de
    nitrites, la morpholine peut être transformée en NMOR, tant  in vitro
    qu' in vivo.  On a constaté, en administrant de la morpholine à des
    rats avec des nitrites, que celle-ci pouvait être nitrosée dans la
    proportion de 0 à 12%, selon la dose.

         Le taux de nitrosation peut augmenter par le fait d'une immuno-
    stimulation comportant l'activation des macrophages.

    7.  Effets sur les mammifères de laboratoire et les systèmes d'épreuve
        in vitro

         Après administration de morpholine par voie orale à des rats et à
    des cobayes, on a obtenu pour la DL50 des valeurs respectives de
    1-1,9 g/kg de poids corporel et 0,9 g/kg de poids corporel, ce qui
    permet d'avoir une idée de la toxicité aiguë du produit.  Des rats qui
    avaient reçu de la morpholine neutralisée à raison de 1 g/kg de poids
    corporel ont survécu.  Après administration par voie intrapéritonéale,
    on a obtenu une DL50 de 0,4 g/kg de poids corporel chez la souris et
    de 0,1-0,4 g/kg de poids corporel chez le rat.  Après exposition par
    la voie respiratoire, la DL50 était d'environ 8 g/m3 chez le rat
    et de 5-7 g/m3 chez la souris.  La DL50 de la morpholine
    concentrée par voie percutanée était de 0,5 ml/kg chez le lapin.  La
    toxicité aiguë de la morpholine se caractérise par des hémorragies
    gastrointestinales et des diarrhées lorsqu'elle est administrée par
    voie orale et par une irritation et des hémorragies nasales, buccales,
    oculaires et pulmonaires lorsqu'elle est administrée par voie
    respiratoire.  Lors d'une étude de 30 jours au cours de laquelle des
    rats ont reçu de la morpholine par gavage à des doses de 0,16 à
    0,8 g/kg de poids corporel, on a observé des effets toxiques graves et
    une mortalité à toutes les doses.  Les mêmes observations ont été
    effectuées sur des cobayes à des doses comprises entre 0,09 et
    0,045 g/kg de poids corporel.

         Chez des rats soumis pendant une brève période à des inhalations
    de morpholine (7,2 g/m3, 4 heures par jour pendant 4 jours ou bien
    1,63 g/m3, 4 heures par jour, 5 jours par semaine pendant 30 jours),
    on a observé une altération de la fonction pulmonaire.  Le taux de
    mortalité chez d'autres rats allait de 0 à 100% selon le niveau
    d'exposition (0,36-18,1 g/m3, 6 heures par jour pendant 9 jours). 
    Par la voie respiratoire, on a constaté que la toxicité dépendait de
    la dose avec une irritation locale (yeux, bouche, nez et poumons) et
    des hémorragies de gravité variables aux niveaux d'exposition les plus
    élevés.  Dans une étude, on a observé un hyperfonctionnement de la
    glande thyroïde et dans une autre, une nécrose du foie et des tubules
    rénaux après exposition par la voie respiratoire.

         Une étude de 90 jours a montré que la morpholine administrée par
    voie orale (0.2-0,7 g quotidiennement par kg de poids corporel)
    pouvait réduire la gain de poids et entraîner une insuffisance rénale
    chez la souris.  Après 672 jours d'administration de morpholine par
    voie orale (0,28-0,5 g/kg de poids corporel quotidiennement), on a
    observé chez la souris une hyperplasie au niveau de l'épithélium de la
    portion cardiaque de l'estomac.

         Selon une étude d'inhalation de 13 semaines, la morpholine
    (administrée à la dose de 0,09-0,9 g/m3 6 heures par jour, 5 jours
    par semaine) provoque des lésions liées à la dose au niveau de la
    muqueuse nasale ainsi qu'une pneumopathie aux doses les plus élevées
    (0,36 et 0,9 mg/m3).  A la dose de 0,09 g/m3 on n'a observé aucune
    modification d'un certain nombre de paramètres qui puisse être
    imputable à ce traitement;  cette concentration peut être considérée
    comme la dose sans effets nocifs observables dans les conditions d'une
    exposition subchronique par la voie respiratoire.

         Sous sa forme concentrée et non neutralisée, la morpholine est
    extrêmement irritante pour les yeux et la peau, probablement en raison
    de sa basicité.  En la diluant et en la ramenant à un pH neutre, on
    peut sensiblement en réduire la toxicité topique.  Selon une variante
    de la méthode de Buehler, la morpholine à 2% n'a pas produit de
    sensibilisation chez le cobaye.

         La morpholine ne produit pas de mutation chez des bactéries ou
    des levures en présence ou en l'absence d'activation métabolique
    (à l'exception d'un essai effectué à très forte concentration).  Le
    passage sur hôte a également donné des résultats négatifs.

         On n'a pas non plus observé de réparation de l'ADN sous
    l'influence de la morpholine dans des cultures primaires d'hépatocytes
    de rats et ce composé n'a pas augmenté de façon sensible les échanges
    entre chromatides soeurs dans des cellules ovariennes de hamsters
    chinois.  Les résultats d'une épreuve sur cellules lymphomateuses de
    souris L5178Y ont conduit à considérer la morpholine comme faiblement
    mutagène.  Ce composé a entraîné une augmentation des foyers de type

    III lors d'une épreuve de transformation cellulaire maligne effectuée
    sur des cellules BALB/3T3, phénomène qui n'a pas été constaté avec la
    morpholine neutralisée.

         On n'a pas non plus constaté de mutation ponctuelle ni
    d'aberration chromosomique chez des embryons de hamsters exposés
     in utero à de la morpholine.

         On n'a pas constaté d'augmentation dans l'incidence des tumeurs
    chez des rats qui avaient été exposés par voie respiratoire pendant
    104 semaines à des concentrations de morpholine allant jusqu'à
    0,5 g/m3, ni chez des souris qui avaient reçu pendant 96 semaines
    dans leur eau de boisson de l'oléate de morpholine à 1%.  Une étude à
    long terme sur un groupe de 104 rats qui recevaient dans leur
    alimentation 1000 mg de morpholine par kg de nourriture, a permis de
    mettre en évidence trois carcinomes hépatocellulaires, deux
    angiosarcomes pulmonaires ainsi qu'un troisième angiosarcome de
    localisation non précisée et enfin deux gliomes malins, alors
    qu'aucune tumeur n'a été observée dans le groupe témoin comportant
    156 animaux.  Chez des hamsters exposés dans les mêmes conditions,
    aucune tumeur n'a été observée.

         Administrée en même temps qu'un nitrite, la morpholine donne un
    résultat positif à l'épreuve de passage sur hôte, qui s'explique
    probablement par la formation de NMOR.  De la morpholine administrée
    en même temps qu'un nitrite par mélange à la nourriture, a provoqué
    chez des rats des tumeurs hépatiques et pulmonaires et chez des
    hamsters des tumeurs hépatiques qui s'expliquent probablement par la
    formation endogène de NMOR.  La NMOR est mutagène pour les bactéries
    et les levures;  on a également observé avec ce composé des résultats
    faiblement positifs dans l'épreuve d'échange de chromatides soeurs sur
    des cellules CHO et lors de la recherche de mutations dans des
    cultures de cellules lymphomateuses de souris L5178Y.  La NMOR est
    cancérogène pour la souris, le rat, le hamster et divers poissons; 
    elle provoque chez la souris des tumeurs hépatiques et pulmonaires,
    chez le rats des tumeurs du foie, du rein et des vaisseaux sanguins,
    chez le hamster des tumeurs des voies digestives et respiratoires
    supérieures et enfin chez les poissons, des tumeurs hépatiques.

    8.  Effets sur l'homme

         On ne dispose d'aucun rapport faisant état de cas d'intoxication
    aiguë ou décrivant les effets d'une exposition à court ou à long terme
    à la morpholine dans la population générale.

         Un phénomène connu sous le nom de glaucopsie (vision bleutée)
    ainsi que dans certains cas une irritation de la peau et des voies
    respiratoires, ont été décrits dans des rapports d'exposition
    professionnelle à la morpholine;  toutefois, ces rapports ne précisent
    pas la concentration de la morpholine dans l'air.  On a indiqué que
    chez des ouvriers exposés pendant 3 à 10 ans à de la morpholine à des

    concentrations de 0,54-0,93 mg/m3, le nombre d'aberrations
    chromosomiques dans les lymphocytes du sang périphérique ne présentait
    pas de différence notable par rapport aux témoins.

         La morpholine concentrée est fortement irritante pour la peau; 
    en solution (à 1/40) elle se révèle encore légèrement irritante.

         On n'a pas étudié la cancérogénicité potentielle de la morpholine
    chez les populations humaines exposées.

    9.  Effets sur les autres êtres vivants au laboratoire et dans leur
        milieu naturel

         Parmi les organismes aquatiques étudiés, certaines cyanobactéries
     (Microcystis) et certaines algues bleues unicellulaires
     (Scenedesmus) se révèlent être les taxa les plus sensibles puisque
    le seuil de toxicité (critère:  inhibition de la croissance des
    populations) se situe à 1,7 mg/litre pour  Microcystis et à
    4,1 mg/litre pour  Scenedesmus (durée de l'exposition: 8 jours).

         Des bactéries aérobies telles que  Pseudomonas se sont révélées
    beaucoup plus résistantes;  le seuil de toxicité à 16 heures ainsi que
    la concentration sans effets observables sur la croissance des
    populations atteindraient respectivement 310 et 8700 mg/litre. 
    Cependant une concentration de 1000 mg/litre a inhibé la respiration
    et l'activité de la déshydrogénase (dans une proportion allant jusqu'à
    20%) chez les bactéries de boues activées provenant d'usines de
    traitement des effluents industriels.

         Chez les protozoaires aquatiques étudiés jusqu'ici, des spécimens
    des genres  Entosiphon et  Chilomonas (avec des valeursseuil
    respectivement égales à 12 et 18 mg/litre pour ce qui est de
    l'inhibition de la croissance des populations) se sont révélés être
    les plus sensibles.  Les valeurs de la CE50 à 24 heures
    (E=immobilisation) pour la daphnie se situaient dans les limites de
    100 à 120 mg/litre.  Chez les poissons, les valeurs de la CL50 à
    48 et 96 heures se sont révélées > 180 mg/litre lors d'épreuves
    effectuées en eau douce, en eau saumâtre ou en eau de mer, la truite
    arc-en-ciel étant l'espèce la plus sensible.

         On ne dispose d'aucune donnée relative aux effets à long terme de
    la morpholine sur les invertébrés et les vertébrés aquatiques. 
    L'absence d'information est également presque totale à propos de la
    toxicité de ce composé pour les organismes terricoles, puisque les
    seules données dont on dispose se limitent à la valeur de la CE à
    3 jours, égale à 400 mg/litre, en ce qui concerne l'inhibition de la
    germination des laitues.

    10.  Evaluation des risques pour la santé humaine et effets sur

    10.1  Evaluation des effets sur la santé humaine

         Les cas d'exposition de la population générale à la morpholine
    résultent principalement de la consommation de denrées alimentaires
    contaminées.  La contamination du tabac et des produits du tabac, des
    articles de toilette et des cosmétiques, de même que des articles en
    caoutchouc, peuvent contribuer à l'exposition globale.  Il peut y
    avoir exposition professionnelle à la morpholine dans de nombreuses
    industries;  ce composé peut être absorbé soit par inhalation, soit
    par la voie percutanée.  On ne dispose pas de données suffisantes pour
    déterminer le degré d'exposition de la population générale.

         Les données relatives à l'exposition professionnelle sont
    également limitées.

         La morpholine n'est pas extrêmement toxique dans les conditions
    d'une exposition aiguë.  Après administration par voie orale, la
    DL50 était de 1-1,9 g/kg de poids corporel chez le rat et de
    0,9 g/kg de poids corporel chez le cobaye.  Par ailleurs, on a trouvé,
    pour la CL50, des valeurs de 7,8 mg/m3 chez le rat et de 4,9 à
    6,9 g/m3 chez la souris.

         Dans les conditions d'une exposition à court ou à long terme par
    la voie respiratoire, c'est l'irritation des yeux et des voies
    respiratoires qui constitue l'effet critique.  Lors d'une étude de
    13 semaines au cours de laquelle des rats ont été exposés 6 heures par
    jour et 5 jours par semaine à de la morpholine, on a pu fixer à
    90 mg/m3 la concentration sans effets nocifs observables.  Lors
    d'une autre étude d'inhalation, à long terme cette fois
    (104 semaines), on a observé une augmentation de l'incidence des cas
    d'inflammation de la cornée ou d'inflammation et de nécrose des fosses
    nasales, à la dose de 540 mg/m3 chez le rat.  L'irritation des yeux
    et du nez présentait également une incidence accrue aux doses de 36 et
    180 mg/m3.

         Une forte exposition à la morpholine entraîne de graves lésions
    hépatiques et rénales chez le rat et le cobaye.  Après administration
    de morpholine à des rats, par mélange à leur nourriture (0,5 g/kg de
    poids corporel) tous les jours pendant 56 jours, on a observé une
    dégénérescence graisseuse du foie.  Des souris qui avaient reçu tous
    les jours, pendant 13 semaines, de l'oléate de morpholine mêlé à leur
    eau de boisson à la dose d'environ 0,7 g/kg de poids corporel, ont
    présenté une dégénérescence albuminoïde au niveau des tubules
    proximaux du rein (désignée également par l'expression "tuméfaction
    trouble" par certains auteurs).  Chez des souris femelles qui avaient
    reçu pendant 672 jours de la morpholine dans leur alimentation, on a
    observé aux doses comprises entre 0,05 et 0,4 g de morpholine
    administrée sous forme d'oléate, une réduction du gain de poids.

         Aux concentrations que l'on observe actuellement dans les cas
    d'exposition professionnelle ou environnementale, il ne semble pas que
    la morpholine risque véritablement d'entraîner des effets toxiques
    généraux.  Cependant lors d'une exposition accidentelle ou
    professionnelle non contrôlée à de fortes concentrations de morpholine
    présentes dans l'air, il peut y avoir des effets locaux qui prennent
    la forme d'une irritation de la muqueuse oculaire et des voies
    respiratoires;  en outre, un contact avec de la morpholine liquide
    (même diluée) peut entraîner une irritation cutanée.

         Il ne semble pas que la morpholine soit mutagène ou cancérogène
    chez l'animal.  Toutefois elle peut facilement être nitrosée pour
    donner naissance à de la NMOR qui s'est révélée, elle, mutagène et
    cancérogène chez plusieurs espèces d'animaux de laboratoire. 
    L'administration de morpholine, puis d'un nitrite, mêlés à la
    nourriture d'animaux de laboratoire a provoqué un accroissement de
    l'incidence des tumeurs, pour la plupart des carcinomes
    hépatocellulaires et des sarcomes du foie et du poumon.  Il est donc
    prudent de considérer l'exposition à la morpholine comme un facteur
    supplémentaire de risque cancérogène chez les populations exposées.

    10.2  Evaluation des effets sur l'environnement

         Comme on sait très peu de choses sur l'exposition
    environnementale et que les données relatives à l'exposition à long
    terme dans l'hydrosphère ou à court et à long terme dans le milieu
    terrestre font défaut, il est impossible, pour l'instant, de procéder
    valablement à une appréciation du risque.  On peut toutefois tirer un
    certain nombre de conclusions sur la base des propriétés observées de
    la morpholine, des données écotoxicologiques disponibles et des
    quelques renseignements dont on dispose sur les concentrations dans

         La forte solubilité dans l'eau de la morpholine et sa faible
    volatilité (dans les conditions du milieu) font que l'hydrosphère en
    constitue le principal milieu récepteur.

         La morpholine est intrinsèquement biodégradable et, bien que
    cette biodégradation soit lente, rien n'indique qu'elle s'accumule
    dans l'hydrosphère.  En outre, sa bioaccumulation est également peu

         On ne possède que relativement peu de données sur la toxicité de
    la morpholine pour les organismes vagiles.  Toutefois, il paraît
    improbable qu'au niveau actuel des émissions de morpholine, des
    dommages importants puissent être causés à l'environnement dans son
    ensemble.  Les effets locaux, dus par exemple aux émissions
    industrielles ou à la libération de morpholine dans l'environnement
    par suite de l'usure des pneumatiques, restent à évaluer.

         Il peut y avoir contamination de certains produits alimentaires
    comme le poisson, par de la morpholine, contamination qui viendrait de
    l'environnement, mais cela n'est pas certain.

         La transformation de la morpholine en NMOR est la principale
    cause d'inquiétude, en particulier en ce qui concerne les populations
    de vertébrés.  On a signalé la présence de NMOR dans des eaux
    résiduaires industrielles et dans le sol aux alentours d'une usine. 
    On peut s'inquiéter de la présence de morpholine dans de l'eau
    destinée à être traitée pour la rendre potable.

    11.  Conclusions et recommandations

         La morpholine ne présente aucun risque toxique pour l'homme au
    niveau habituel d'exposition mais il faut prendre garde à sa
    transformation en NMOR qui est cancérogène.

         Rien n'indique qu'aux nivaux actuels d'exposition, la morpholine
    constitue un risque important pour les biotes présents dans

    11.1  Recommandations en vue de la protection de la santé humaine

    a)   Il faut éviter dans la mesure du possible toute exposition
         humaine à la morpholine.

    b)   Il faut éviter la contamination des denrées alimentaires par leur
         emballage ou lors de leur transformation.

    c)   La morpholine ne doit pas entrer dans la composition d'articles
         en caoutchouc destinés en entrer en contact direct avec l'homme.

    d)   La morpholine ne doit pas entrer dans la composition de
         préparations destinées à la toilette ou à un usage cosmétique.

    e)   Les effluents industriels doivent être traités avec soin afin
         d'éviter que la morpholine ne pénètre dans l'eau destinée à la

    f)   Compte tenu de la possibilité de formation de NMOR cancérogène,
         les limites d'exposition professionnelle actuelles devront être

    11.2  Recommandations en vue de la protection de l'environnement

         Il faut éviter les déversements et les décharges massives dans
    les usines de traitement des effluents.

    11.3  Recommandations en vue de recherches ultérieures

         Des travaux doivent être entrepris dans les domaines suivants:

    a)   toxicité pour la fonction de reproduction des mammifères;

    b)   toxicité à long terme pour les mammifères;

    c)   effets sur les mammifères d'une exposition à de faibles
         concentrations de morpholine en présence ou non de nitrites et de

    d)   transnitrosation par la NMOR  in vivo et  in vitro;

    e)   biodégradation en anaérobiose, en particulier dans des conditions
         entraînant la réduction des nitrates;

    f)   catalyse microbienne de la  N-nitrosation en situation réelle;

    g)   concentrations de la morpholine dans les eaux souterraines, le
         sol et les rivières dont l'eau est utilisée pour la boisson;

    h)   concentration de morpholine aux alentours d'usines qui produisent
         ou transforment cette substance;

    i)   métabolisme et toxicocinétique chez l'homme en vue de la mise au
         point de méthodes pour la surveillance biologique de la

    j)   surveillance de la concentration de morpholine et de NMOR dans
         les denrées alimentaires, dans l'eau de boisson et l'air
         intérieur aux habitations;

    k)   collecte et diffusion de données sur l'exposition


    1.  Propiedades físicas y químicas

         La morfolina (1-oxa-4-azaciclohexano) es un líquido incoloro,
    oleoso, higroscópico y volátil que desprende un característico olor a
    amina ("a pescado").  Es totalmente miscible en agua, así como en
    numerosos disolventes orgánicos, y parcialmente soluble en soluciones
    acuosas alcalinas.  Se trata de una base, y el pKa del ácido conjugado
    es de 8,33.  En consecuencia, el coeficiente de reparto octanol/agua
    depende del pH (log Pow -2,55 a pH 7, y - 0,84 a pH 10; 35°C).  La
    presión de vapor de las soluciones acuosas de morfolina es casi como
    la del agua.

         La morfolina puede sufrir diversas reacciones.  Se comporta
    químicamente como una amina secundaria.  En condiciones ambientales y
    fisiológicas, como resultado de la reacción de las soluciones de
    nitrito o de óxidos de nitrógeno gaseosos con las soluciones diluidas
    de morfolina, se forma  N-nitrosomorfolina (NMOR), conocido
    carcinógeno para los animales.  Los niveles de óxido de nitrógeno (NO)
    pueden ser importantes en la nitrosación.  Las condiciones de
    nitrosación, en particular el pH, tienen una considerable influencia.

    2.  Métodos analíticos

         La morfolina se puede determinar mediante cromatografía de gases
    (GC) en columnas empacadas o capilares, cromatografía líquida de alta
    resolución (HPLC) y cromatografía iónica.  Entre los detectores
    utilizados cabe citar el detector de ionización por conductor, el
    detector de fotometría de llama, el detector selectivo de nitrógeno
    (NSD), y la espectrometría de masas y el analizador de energía térmica
    (TEA) para la GC, y el detector de UV y el TEA para la HPLC.  Para
    determinar cantidades ínfimas hay que recurrir a la derivatización. 
    El método de elección en lo que respecta a sensibilidad es al parecer
    la GC combinada con el TEA, previa transformación por derivatización
    en NMOR (límite de detección de 2-3 µg/kg en diversas matrices).  Las
    bajas concentraciones de morfolina en el aire se pueden determinar
    mediante GC y NSD.

    3.  Fuentes de exposición humana y ambiental

         Se estima que cada año se producen industrialmente en todo el
    mundo unas 25 000 toneladas de morfolina, pero no se conoce con
    detalle la producción de algunos países.

         El principal proceso de producción utilizado para su obtención es
    al parecer la reacción de dietilenglicol con amoniáco en presencia de
    hidrógeno y de catalizadores.

         La morfolina es una sustancia química que puede utilizarse con
    muy diversos fines, pero no se conocen todos sus posibles usos.  Es
    importante como producto intermedio en la industria del caucho, como
    inhibidor de la corrosión, y en la síntesis de abrillantadores
    ópticos, protectores de cultivos, colorantes y medicamentos.  La
    morfolina se utiliza como disolvente de una amplia variedad de
    productos orgánicos, entre ellos resinas, colorantes y ceras.  Se
    puede utilizar como catalizador.  La morfolina se usa aún en algunos
    países para elaborar productos cosméticos y de tocador.  En algunos
    países se usa también en varias aplicaciones relacionadas directa o
    indirectamente con los aditivos alimentarios.

         La exposición humana y ambiental se debe a emisiones tanto
    gaseosas como acuosas, y es también el resultado directo de alguno de
    sus usos, por ejemplo como componente de productos cosméticos y de
    ceras.  Las emisiones más importantes son resultado probablemente de
    su fabricación y de su uso en la industria química (sobre todo en la
    producción y el uso de productos químicos derivados del caucho) y como
    agente anticorrosión.  Se ha detectado morfolina en muchos tipos de
    alimento y de tabaco.  En estos casos el origen del producto podría
    ser la parafina empleada para proteger la fruta o en determinados
    envases, pero a veces no se puede establecer su procedencia.

    4.  Transporte, distribución y transformación en el medio ambiente

         La morfolina es químicamente estable en la biosfera, aunque sufre
    nitrosación química y biológica, transformándose así en NMOR.

         La morfolina es por naturaleza biodegradable.  Así es en las
    condiciones reinantes en las plantas de fangos activados que funcionan
    correctamente.  No obstante, en condiciones no idóneas probablemente
    no se produce una degradación importante.  El tiempo medio de
    retención del sólido en las plantas de fangos activados tiene una
    importancia crucial y debe ser superior a ocho días para que se
    produzca una degradación fiable de la morfolina.

         No se dispone de datos suficientes sobre la bioacumulación de
    morfolina en organismos acuáticos y terrestres.  Según el coeficiente
    de reparto  n-octanol/agua del producto (log Pow = -2,55 a pH 7),
    no debería producirse bioacumulación.

         Como es un importante producto químico industrial con una amplia
    gama de aplicaciones, es previsible la presencia de morfolina o de sus
    derivados en numerosos efluentes industriales.  Usada como inhibidor
    de la corrosión en el agua de calderas, aparece en los efluentes de
    éstas, incluidos los de las centrales eléctricas en que se utiliza
    morfolina.  Su uso en la fabricación de aditivos del caucho da lugar a
    la liberación de una cantidad indeterminada de morfolina a la
    hidrosfera y la geosfera como consecuencia del desgaste de los
    neumáticos y de la eliminación de neumáticos usados.

         Componente de parafinas y abrillantadores, la morfolina se libera
    al medio ambiente por volatilización.  Es adsorbida rápidamente por la
    humedad, y el principal compartimiento de posible acumulación de la
    morfolina es, por tanto, la hidrosfera.  No obstante, los datos
    limitados disponibles parecen indicar que el producto no se acumula en
    la hidrosfera.

         La incineración es el método preferido de eliminación de la
    morfolina no diluida, pero a veces es necesario controlar las
    emisiones de óxido de nitrógeno para respetar las reglamentaciones en
    materia de medio ambiente.  Por lo que se refiere a los efluentes
    acuosos, el tratamiento de fangos activados es suficiente, a condición
    de que la planta sea cuidadosamente controlada (véase más arriba).

    5.  Niveles ambientales y exposición humana

         No hay datos disponibles sobre los niveles de morfolina en el
    aire ambiental y de locales cerrados y en el agua de bebida.  Hay
    datos limitados sobre su presencia en aguas naturales, y se carece de
    información sobre su presencia en el suelo.

         A tenor de los datos disponibles, la fuente principal de
    exposición de la población general a la morfolina son los alimentos,
    que pueden estar contaminados como consecuencia del tratamiento
    directo de la fruta con parafinas contenedoras de morfolina a efectos
    de conservación, de los tratamientos a base de vapor empleados durante
    la elaboración de los alimentos, y del uso de material de envasado con
    morfolina.  No obstante, los datos cuantitativos disponibles acerca de
    la contaminación de los alimentos por morfolina y NMOR son limitados. 
    Por ejemplo, en productos lácteos preenvasados se han hallado valores
    comprendidos entre 5 y 77 µg/kg de morfolina y de hasta 3,3 µg/kg de
    NMOR.  La concentración de morfolina en diversas muestras de alimentos
    (pescado, carne, productos vegetales, bebidas) no rebasaba por lo
    general el valor de 1 mg/kg.  Se han detectado niveles más altos
    (hasta 71,1 mg/kg) en frutos cítricos en el Japón.  En un estudio
    realizado en Italia trabajando con un límite de detección de 0,3 µg/kg
    no se halló NMOR en una serie de alimentos.  Los datos disponibles no
    permiten hacer una estimación de la ingesta de morfolina y NMOR a
    través de los alimentos.

         Se ha detectado morfolina en tabaco de cigarrillos a una
    concentración de 0,3 mg/kg, y en tabaco en polvo y tabaco mascable a
    concentraciones de hasta 4,0 mg/kg.  En otras ocasiones se ha
    notificado el hallazgo de nitrosomorfolina a niveles de hasta
    0,7 mg/kg en el tabaco en polvo.  En estos casos el producto provenía
    probablemente de la parafina de los envases utilizados.

         Se ha detectado NMOR en algunos productos cosméticos y de
    tocador, como por ejemplo champús y maquillaje de ojos, así como en
    artículos de goma, tales como chupetes y tetillas de biberón, a
    niveles de hasta 3,5 mg/kg.

         En varias industrias puede darse una exposición ocupacional a la
    morfolina, pero se dispone de pocos datos sobre la exposición de
    trabajadores al producto.  Todos los valores notificados son
    inferiores a 3 mg/m3.  Se ha detectado la exposición ocupacional a
    NMOR en la industria del caucho, donde se han hallado concentraciones
    de hasta 250 µg/m3.

         Los datos actualmente disponibles permiten hacerse una idea del
    riesgo potencial de exposición humana, pero no estimar con exactitud
    los niveles de exposición de las poblaciones general y laboral a la
    morfolina y la NMOR.

    6.  Cinética y metabolismo en animales de laboratorio y en el hombre

         La morfolina se absorbe por vía oral, por vía cutánea y por
    inhalación.  En la rata, tras su administración oral o intravenosa, la
    morfolina se distribuye rápidamente y se concentra sobre todo en el
    intestino y el músculo.

         En el conejo, la morfolina administrada por vía intravenosa o por
    inhalación se concentra preferentemente en los riñones, y en menor
    medida en los pulmones, el hígado y la sangre.

         La morfolina no se une de forma importante a las proteínas del
    plasma.  Se han notificado semividas plasmáticas de 115 (rata),
    120 (hámster) y 300 minutos (cobayo).

         La morfolina se excreta principalmente inalterada por vía renal
    en diversas especies.  Al cabo de un día de su administración, se
    halló en la orina el 70%-90% de la morfolina.  La neutralización de la
    morfolina acelera su excreción.  Un pequeño porcentaje se excreta a
    través del aire espirado y de las heces.

         Estudios realizados en la rata, el ratón, el hámster y el conejo
    muestran que la morfolina se elimina casi enteramente en su forma no
    metabolizada.  En el cobayo, puede darse una reacción de
     N-metilación seguida de  N-oxidación, metabolizándose así hasta un
    20% de la dosis administrada.  En presencia de nitrito, la morfolina
    se puede transformar en NMOR tanto  in vitro como  in vivo.  En
    función de la dosis, entre el 0% y el 12% de la morfolina administrada
    a ratas junto con nitritos puede sufrir nitrosación.

         La inmunoestimulación, que entraña la activación de macrófagos,
    puede aumentar el grado de nitrosación.

    7.  Efectos en mamíferos de laboratorio y en sistemas de pruebas
        in vitro

         En lo que respecta a la toxicidad aguda, la DL50 de la
    morfolina administrada oralmente es de 1-1,9 g/kg de peso corporal y
    0,9 g/kg de peso corporal en la rata y el cobayo, respectivamente.

    Las ratas que recibieron morfolina neutralizada (1 g/kg de peso
    corporal) sobrevivieron.  Tras administración interperitoneal, la
    DL50 fue de 0,4 g/kg de peso corporal en el ratón y de 0,1 -
    0,4 g/kg de peso corporal en la rata.  En los experimentos de
    exposición por inhalación, la DL50 fue de aproximadamente 8 g/m3
    en la rata y de entre 5 y 7 g/m3 en el ratón.  Por vía cutánea la
    DL50 en el conejo fue de 0,5 ml/kg de morfolina no diluida.  La
    intoxicación aguda por morfolina se caracteriza por la aparición de
    hemorragia gastrointestinal y diarrea tras la exposición oral, y de
    irritación y hemorragias en la nariz, la boca, los ojos y los pulmones
    tras la inhalación.  En un estudio realizado durante 30 días con ratas
    a las que se administraron con sonda dosis de 0,16 - 0,8 g/kg de peso
    corporal, se observaron efectos tóxicos graves y mortalidad a todas
    las dosis empleadas.  En el cobayo se observó también toxicidad grave
    y mortalidad a todas las dosis en el margen de 0,09 a 0,45 g/kg de
    peso corporal.

         Se ha notificado la aparición de alteraciones de la función
    pulmonar en la rata tras la exposición a morfolina por inhalación
    durante cortos periodos (7,2 g/m3, 4 h/día, 4 días y 1,63 g/m3,
    4 h/día, 5 días/semana, 30 días).  La mortalidad en la rata osciló
    entre 0% y 100% según el nivel de exposición (0,36 - 18,1 g/m3,
    6 h/día, 9 días).  La toxicidad por inhalación dependía de la dosis,
    observándose diversos grados de irritación local (ojos, boca, nariz,
    pulmones) y hemorragias a los niveles más altos de exposición.  En un
    estudio se detectó un aumento de la función de la glándula tiroides, y
    en otro necrosis del hígado y de los túbulos renales, como resultado
    de la exposición por inhalación.

         Un estudio de 90 días de duración reveló que la morfolina
    administrada por vía oral (0,2 - 0,7 g/kg de peso corporal al día)
    durante ese espacio de tiempo puede reducir el aumento del peso
    corporal y la función renal en el ratón.  Se ha notificado la
    aparición de hiperplasia del epitelio del estómago anterior en el
    ratón como resultado de la exposición oral a morfolina
    (0,28 - 0,5 g/kg de peso corporal al día) durante 672 días.

         En un estudio de 13 semanas sobre los efectos de su inhalación,
    la morfolina (0,09 - 0,9 g/m3, 6 h/día, 5 días/semana) causó
    lesiones dosis-dependientes de la mucosa nasal y neumonía a los
    niveles de exposición más altos (0,36 y 0,9 mg/m3).  Un cierto
    número de parámetros no variaron en respuesta al tratamiento cuando se
    utilizaron 0,09 g/m3; esta concentración puede considerarse el nivel
    sin efectos adversos observados (NOAEL) en las condiciones de
    exposición por inhalación subcrónica.

         La morfolina no diluida y no neutralizada es altamente irritante
    para los ojos y la piel, probablemente a causa de sus propiedades
    alcalinas.  La dilución y la neutralización de su pH pueden reducir
    considerablemente su toxicidad tópica.  La morfolina (2%) no indujo
    sensibilidad en el cobayo al aplicar el método modificado de Buehler.

         La morfolina no indujo la aparición de mutaciones en bacterias o
    levaduras, con o sin activación metabólica (salvo en un caso a una
    concentración muy alta).  Se obtuvieron resultados negativos en el
    ensayo realizado por mediación de un huésped.

         La morfolina no indujo reparación del ADN en hepatocitos
    primarios de rata, así como tampoco un aumento importante del
    intercambio de cromátides hermanas en células ováricas de hámster
    chino.  Se consideró que la morfolina tenía efectos ligeramente
    mutagénicos en el ensayo con células L5178Y de linfoma de ratón.  El
    producto aumentó los focos de tipo III en el ensayo de transformación
    de células malignas BALB/3T3, lo que no ocurrió con la morfolina

         La morfolina no causó ni mutaciones puntuales ni aberraciones
    cromosómicas en embriones de hámster expuestos  in utero.

         No se observó ningún aumento de la incidencia de tumores en ratas
    sometidas a niveles de hasta 0,5 g/m3 de morfolina por inhalación
    durante 104 semanas, así como tampoco en ratones que ingirieron oleato
    de morfolina al 1% con el agua de bebida durante 96 semanas.  En un
    estudio de larga duración realizado con un grupo de 104 ratas que
    recibieron 1000 mg de morfolina/kg dieta, se observaron tres casos de
    carcinoma de células hepáticas, dos de pulmón y uno de angiosarcoma
    (no especificado), así como dos gliomas malignos, mientras que en un
    grupo testigo de 156 ratas no se observaron tumores.  No se detectaron
    tumores en hámsters sometidos a idénticas condiciones.

         La morfolina administrada al mismo tiempo que nitrito da lugar a
    resultados positivos en el ensayo realizado por mediación de un
    huésped, probablemente debido a la formación de NMOR.  La ingestión
    simultánea de morfolina y nitrito indujo la aparición de tumores
    hepáticos y pulmonares en la rata y de tumores hepáticos en el
    hámster, probablemente a causa de la formación endógena de NMOR.  La
    NMOR es mutágena en bacterias y levaduras; se notificaron resultados
    ligeramente positivos en lo que respecta al intercambio de cromátides
    hermanas en células CHO, así como a la aparición de mutaciones en
    células L5178Y de linfoma de ratón.  La NMOR es carcinógena en el
    ratón, la rata, el hámster y diversos peces, y produce tumores de
    hígado y de pulmón en el ratón; de hígado, riñón y vasos sanguíneos en
    la rata; de hígado y de las vías digestivas y respiratorias superiores
    en el hámster, y de hígado en peces.

    8.  Efectos en el hombre

         No se han descrito casos de intoxicación aguda o de efectos a
    corto o largo plazo de la exposición a morfolina en la población

         En informes sobre la exposición ocupacional a la morfolina se ha
    descrito el fenómeno conocido como visión azul o glaucopsia, así como
    algunos casos de irritación de la piel y del tracto respiratorio, pero
    sin hacer mención de las concentraciones atmosféricas de morfolina. 
    Se señaló que el número de aberraciones cromosómicas en los linfocitos
    de sangre periférica de trabajadores expuestos durante 3 a 10 años a
    concentraciones de morfolina de 0,54 - 0,93 mg/m3 no diferían
    significativamente del número hallado en los testigos.

         La morfolina no diluida es muy irritante para la piel; una
    solución diluida (1/40) tuvo efectos moderadamente irritantes.

         No se ha investigado el potencial carcinógeno de la morfolina en
    poblaciones humanas expuestas.

    9.  Efectos sobre otros organismos en el laboratorio y en el terreno

         Entre los microorganismos acuáticos estudiados, determinadas
    cianobacterias  (Microcystis) y algas verdes unicelulares
     (Scenedesmus) son al parecer las especies más sensibles según se
    desprende de los valores de la toxicidad liminal (empleando como
    criterio la inhibición del crecimiento de la población) notificados
    (duración de la exposición:  8 días):  1,7 mg/litro para  Microcystis,
    y 4,1 mg/litro para  Scenedesmus.

         Bacterias aerobias tales como  Pseudomonas resultaron ser mucho
    más resistentes:  la toxicidad liminal a las 16 horas y la NOEC para
    el crecimiento de la población se han cifrado, respectivamente, en
    310 y 8700 mg/litro.  No obstante, una concentración de 1000 mg/litro
    inhibía la respiración y la actividad deshidrogenasa (hasta un 20%) en
    fangos activados de plantas de tratamiento industrial.

         Entre los protozoos acuáticos analizados hasta ahora, la mayor
    sensibilidad corresponde a ejemplares de los géneros  Entosiphon y
     Chilomonas (con toxicidades liminales de 12 y 18 mg/litro,
    respectivamente, para la inhibición del crecimiento de la población). 
    En  Daphnia, la CE a las 24 horas (E = inmovilización) se ha
    establecido en valores comprendidos entre 100 y 120 mg/litro.  Los
    valores notificados para la CL50 a las 48 - 96 horas en peces
    estudiados en agua dulce, salobre o marina fueron > 180 mg/litro, y
    la especial más sensible en este sentido es la trucha arco iris.

         No se dispone de datos sobre los efectos a largo plazo en
    invertebrados y vertebrados acuáticos.  La información sobre la
    toxicidad de la morfolina en organismos silvestres del suelo es casi
    inexistente, pues se limita a una CE a los 3 días de aproximadamente
    400 mg/litro para la inhibición de la germinación en la lechuga.

    10.  Evaluación de los riesgos para la salud humana y de los efectos
         en el medio ambiente

    10.1  Evaluación de los efectos en la salud humana

         La principal vía de exposición de la población general a la
    morfolina es el consumo de alimentos contaminados.  También puede
    contribuir a la exposición general la contaminación del tabaco y de
    los productos derivados del tabaco, así como de los artículos
    cosméticos y de tocador y de los productos de goma.  En numerosas
    industrias se da una exposición ocupacional a la morfolina; el
    compuesto es absorbido por inhalación y por vía cutánea.  No hay datos
    suficientes para determinar el grado de exposición de la población
    general.  Los datos disponibles sobre la exposición ocupacional al
    producto también son limitados.

         La morfolina no es altamente tóxica en condiciones de exposición
    aguda.  La DL50 tras administración oral es de 1 a 1,9 g/kg de peso
    corporal en la rata y de 0,9 g/kg de peso corporal en el cobayo.  Se
    han notificado CL50 de 7,8 mg/m3 (rata) y 4,9 - 6,9 g/m3

         En las condiciones de exposición por inhalación de corta y larga
    duración, los efectos críticos son al parecer la irritación de los
    ojos y las vías respiratorias.  Puede considerarse que el NOAEL
    corresponde a una concentración de 90 mg/m3 en las condiciones en
    que se llevó a cabo el experimento de 13 semanas en la rata (6 h/día,
    5 días/semana).  En un estudio de larga duración (104 semanas) sobre
    los efectos de la inhalación del producto se observó una mayor
    incidencia de inflamación de la córnea y de inflamación y necrosis de
    la cavidad nasal en ratas sometidas a 540 mg/m3.  A concentraciones
    de 36 y 180 mg/m3 se observó también una mayor incidencia de
    irritación de los ojos y de la cavidad nasal.

         Las exposiciones altas a la morfolina causan lesiones graves del
    hígado y los riñones en la rata y el cobayo.  Se ha notificado la
    aparición de degeneración grasa del hígado en la rata como resultado
    de la ingestión diaria de morfolina (0,5 g/kg de peso corporal)
    durante 56 días.  En el ratón la administración de una sal de
    morfolina y ácido oleico en el agua de bebida a una dosis de
    aproximadamente 0,7 g/kg de peso corporal al día durante 13 semanas
    dio lugar a una hinchazón turbia de los túbulos proximales renales. 
    Se observó una disminución del aumento del peso corporal en los
    ratones hembra del experimento de administración prolongada (672 días)
    de una dieta con dosis comprendidas entre 0,05 y 0,4 g de morfolina
    (en forma de sal del ácido oleico).

         A los niveles que según se ha notificado alcanza actualmente la
    exposición ocupacional y ambiental, no parece que la morfolina entrañe
    ningún riesgo importante de efectos tóxicos sistémicos.  Pueden
    aparecer efectos locales (irritación) en los ojos y las vías

    respiratorias en las exposiciones ocupacionales y accidentales no
    controladas a altas concentraciones de morfolina transmitida por el
    aire, y el contacto con morfolina líquida (incluso diluida) puede
    causar irritación cutánea.

         La morfolina no parece tener efectos mutágenos o carcinógenos en
    los animales.  No obstante, fácilmente puede nitrosarse y convertirse
    en NMOR producto mutágeno y carcinógeno en varias especies de animales
    de experimentación.  En la rata, la morfolina ingerida secuencialmente
    con nitrito dio lugar a un aumento de los tumores, sobre todo de
    carcinoma hepatocelular y de sarcomas del hígado y los pulmones.  Así
    pues, por prudencia, conviene considerar que la exposición a la
    morfolina aumenta el riesgo de carcinogénesis en las poblaciones

    10.2  Evaluación de los efectos en el medio ambiente

         Habida cuenta de los muy limitados conocimientos respecto a la
    exposición ambiental, así como de la carencia de datos sobre los
    efectos de la exposición de larga duración en el agua y la exposición
    de corta y larga duración en el medio terrestre, por el momento no es
    posible hacer una evaluación rigurosa de los riesgos.  Sobre la base
    de las propiedades conocidas de la morfolina, de la información
    ecotoxicológica disponible y de los escasos datos sobre su
    concentración en el medio ambiente, es posible extraer algunas

         Debido a la alta hidrosolubilidad de la morfolina y a su baja
    volatilidad (en condiciones ambientales), su principal sumidero
    ambiental es la hidrosfera.

         La morfolina es por naturaleza biodegradable y, aunque la
    degradación es lenta, no hay datos que lleven a pensar que se acumula
    en la hidrosfera.  Su bioacumulación es improbable.

         Hay relativamente pocos datos sobre la toxicidad de la morfolina
    en organismos silvestres.  No obstante, parece improbable que los
    niveles actuales de emisión de morfolina puedan causar daños
    importantes en un radio de acción amplio.  Restan por evaluar los
    efectos locales, como por ejemplo los debidos a emisiones industriales
    o a la morfolina liberada por el desgaste de los neumáticos.

         La contaminación de algunos alimentos, como el pescado, por
    morfolina puede deberse a contaminación ambiental, pero ello no es

         La conversión de la morfolina en NMOR es la principal causa de
    inquietud, sobre todo en relación con las poblaciones de vertebrados. 
    Se ha notificado la presencia de NMOR en aguas residuales industriales

    y en el suelo próximo a una fábrica.  La presencia de morfolina en
    agua destinada a transformarse por elaboración en agua de bebida
    suscita preocupación.

    11.  Conclusiones y recomendaciones

         La morfolina no entraña riesgos de toxicidad para el hombre a los
    niveles habituales de exposición, pero hay que tener en cuenta que
    puede transformarse en el carcinógeno NMOR.

         No hay ningún indicio de que a los niveles actuales de exposición
    la morfolina entrañe un riesgo sustancial para la biota en el medio

    11.1  Recomendaciones para la protección de la salud humana

    a)   En la medida de lo posible debe evitarse la exposición humana a
         la morfolina.

    b)   Debe evitarse que los alimentos se contaminen durante su envasado
         y elaboración.

    c)   Se evitará que contengan morfolina los productos de goma con los
         que el hombre haya de tener contacto directo.

    d)   No debe emplearse morfolina en la preparación de productos
         cosméticos o de tocador.

    e)   Los efluentes industriales deben ser objeto de un riguroso
         tratamiento para evitar la contaminación por morfolina del agua
         de bebida.

    f)   Habida cuenta de la formación del carcinógeno NMOR es necesario
         replantearse los actuales límites de exposición ocupacional.

    11.2  Recomendaciones para la protección del medio ambiente

         Debe evitarse que las plantas de tratamiento de efluentes sufran
    derrames y sobrecargas.

    11.3  Recomendaciones para ulteriores investigaciones

         Deben emprenderse estudios sobre los siguientes temas:

    a)   toxicidad reproductiva en mamíferos;

    b)   toxicidad a largo plazo en mamíferos;

    c)   efecto de la exposición de mamíferos a niveles bajos de
         morfolina, con y sin nitrito y nitrato;

    d)   transnitrosación por NMOR  in vivo e  in vitro;

    e)   biodegradación en condiciones anaerobias, sobre todo en
         condiciones favorecedoras de la reducción de nitratos;

    f)   catálisis microbiana de la  N-nitrosación en condiciones

    g)   niveles ambientales de morfolina en las aguas subterráneas, el
         suelo y los ríos a partir de los cuales se obtenga agua de

    h)   niveles ambientales de morfolina en torno a las fábricas
         productoras y procesadoras de morfolina;

    i)   metabolismo y toxicocinética en el hombre, como parte del
         desarrollo de métodos para la vigilancia biológica de la

    j)   vigilancia de los niveles de morfolina y de NMOR en los
         alimentos, el agua de bebida y el aire de locales cerrados;

    k)   se deben reunir y poner a disposición datos sobre la exposición

    See Also:
       Toxicological Abbreviations
       Morpholine (HSG 92, 1995)
       Morpholine (ICSC)
       Morpholine  (IARC Summary & Evaluation, Volume 47, 1989)
       Morpholine  (IARC Summary & Evaluation, Volume 71, 1999)