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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 114





     DIMETHYLFORMAMIDE











    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

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

    First draft prepared by Dr. A. Bainova,
    Institute of Hygeine and Occupational Health, Sofia, Bulgaria

    World Health Orgnization
    Geneva, 1991


         The International Programme on Chemical Safety (IPCS) is a
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    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of
    chemicals.

    WHO Library Cataloguing in Publication Data

    Dimethylformamide.

        (Environmental health criteria ; 114)

        1.Dimethylformamide - adverse effects 2.Dimethylformamide - toxicity 
        I.Series

        ISBN 92 4 157114 4        (NLM Classification: QV 633)
        ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHYLFORMAMIDE

1. SUMMARY AND EVALUATION, CONCLUSIONS, RECOMMENDATIONS

   1.1. Summary and evaluation      
        1.1.1. General properties   
        1.1.2. Environmental transport, distribution, and transformation
        1.1.3. Environmental levels and human exposure
        1.1.4. Kinetics and metabolism      
        1.1.5. Effects on organisms in the environment
        1.1.6. Effects on experimental animals and  in vitro  test systems
        1.1.7. Effects on human beings      
   1.2. Conclusions     
   1.3. Recommendations     
        1.3.1. Safe handling    
        1.3.2. Further research     

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

   2.1. Identity        
   2.2. Physical and chemical properties    
   2.3. Organoleptic properties     
   2.4. Analytical methods      
        2.4.1. Determination of DMF in workplace air    
        2.4.2. Determination of DMF and metabolites in biological media
        2.4.3. Determination of DMF in soil, plants, and food

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

   3.1. Natural occurrence      
   3.2. Man-made sources    
        3.2.1. Production and uses      
               3.2.1.1  Production      
               3.2.1.2  Uses    

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

   4.1. Transport and distribution between media    
        4.1.1. Air      
        4.1.2. Water    
        4.1.3. Soil     
        4.1.4. Bioaccumulation      

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE      

   5.1. Environmental levels    
        5.1.1. Air      
        5.1.2. Water    
        5.1.3. Soil     
   5.2. General population exposure     


   
   5.3. Occupational exposure   
        5.3.1. Concentrations in the workplace air      
        5.3.2. Dermal exposure      

6. KINETICS AND METABOLISM      

   6.1. Animal studies      
        6.1.1. Absorption   
        6.1.2. Distribution     
        6.1.3. Metabolic transformation     
        6.1.4. Elimination and excretion    
        6.1.5. Metabolic interaction between DMF and ethanol    

   6.2. Human studies   
        6.2.1. Absorption, distribution, metabolism, excretion
        6.2.2. The influence of ethanol on DMF
               metabolism in human volunteers   
        6.2.3. Biological monitoring of workers     
               6.2.3.1  Determination of NMF in the urine   
               6.2.3.2   N,N-dimethylformamide determination in the 
                        expired air
               6.2.3.3  Appraisal   

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT      

8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

   8.1. Single exposures    
   8.2. Skin and eye irritation, sensitization      
        8.2.1. Skin irritation      
        8.2.2. Eye irritation   
        8.2.3. Sensitization    
   8.3. Repeated exposure   
   8.4. Specific organ toxicity     
        8.4.1. Liver    
        8.4.2. Gastrointestinal tract   
        8.4.3. Cardiovascular system    
        8.4.4. Kidney   
        8.4.5. Nervous system   
        8.4.6. Lungs    
        8.4.7. Haematopoietic system    
        8.4.8. Adrenals     
        8.4.9. Gonads   
   8.5. Developmental toxicity and reproduction     
        8.5.1. Developmental toxicity   
               8.5.1.1  Mouse   
               8.5.1.2  Rat     
               8.5.1.3  Rabbit      
               8.5.1.4  Appraisal   

   8.6. Mutagenicity and related end-points     
        8.6.1.  In vitro  studies     
        8.6.2.  In vivo  studies      
        8.6.3. Appraisal    

   8.7. Carcinogenicity     
   8.8. Induction of tumour cell differentiation    
   8.9. Mechanism of toxicity, mode of action   

9. EFFECTS ON HUMAN BEINGS      

   9.1. General population exposure     
   9.2. Occupational exposure   
        9.2.1. Accidental poisoning     
        9.2.2. Long-term exposure   
        9.2.3. Epidemiological studies on carcinogenicity   
        9.2.4. Alcohol intolerance      

10. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES    

REFERENCES      

RESUME ET EVALUATION, CONCLUSIONS, RECOMMANDATIONS      

RESUMEN Y EVALUACION, CONCLUSIONES, RECOMENDACIONES     

TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHYLFORMAMIDE

 Members

Dr A. Aitio, International Agency for Research on Cancer, World Health
   Organization, Lyon, France  (Chairman)

Dr A. Bainova, Institute of Hygiene and Occupational Health, Sofia,
   Bulgaria  (Co-rapporteur)

Ms J. Favilla, Office of Toxic Substances, US Environmental Protection
   Agency, Washington, USA

Dr G.L. Kennedy, Jr, Haskell Laboratory for Toxicology and Industrial
   Medicine, EI du Pont de Nemours & Co., Newark, Delaware, USA  (Co-
    rapporteur)

Professor N.P. Misra, Department of Medicine, Gandhi Medical College,
   Bhopal, India

Dr K. Morimoto, Division of Medical Chemistry, National Institute of
   Hygienic Sciences, Tokyo, Japan  (Vice-Chairman)

Dr C. Sadarangani, Petrochemical Industries Co.KSC., Ahmadi, Kuwait

Dr V. Scailteur, Procter and Gamble GMBH, Frankfurt, Federal
   Republic of Germany

Dr Yu Hui Qin, Institute of Environmental Health Monitoring, Chinese
   Academy of Preventive Medicine, Beijing, People's Republic of China

 Observers

Dr R. Jäckh, European Chemical Industries Ecology and Toxicology
   Centre, Brussels, Belgium


 Secretariat

Dr R. Hertel, Fraunhofer Institute for Toxicology and Aerosol Research,
   Hanover, Federal Republic of Germany

Dr K.W. Jager, International Programme on Chemical Safety, World
   Health Organization, Geneva, Switzerland  (Secretary)

Dr P.G. Jenkins, International Programme on Chemical Safety, World
   Health Organization, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in the criteria 
documents as accurately as possible without unduly delaying their 
publication.  In the interest of all users of the environmental health 
criteria documents, readers are kindly requested to communicate any 
errors that may have occurred to the Manager of the International 
Programme on Chemical Safety, World Health Organization, Geneva, 
Switzerland, in order that they may be included in corrigenda, which 
will appear in subsequent volumes. 



                          *    *    *



    A detailed data profile and a legal file can be obtained from the 
International Register of Potentially Toxic Chemicals, Palais des 
Nations, 1211 Geneva 10, Switzerland (Telephone no.  7988400 - 
7985850). 

ENVIRONMENTAL HEALTH CRITERIA FOR DIMETHYLFORMAMIDE

    A WHO Task Group on Environmental Health Criteria for 
Dimethylformamide, which met in Wolfsburg from 13 to 17 March 1989, 
was organized by the Fraunhofer Institute for Toxicology and Aerosol 
Research, Hanover, Federal Republic of Germany.  The meeting was 
sponsored by the Federal Government.  Dr K.W. Jager of the IPCS opened 
the meeting and welcomed the participants on behalf of the three 
cooperating organizations of the IPCS (UNEP/ILO/WHO).  The Task Group 
reviewed and revised the draft criteria document and made an 
evaluation of the risks for human health and the environment from 
exposure to dimethylformamide. 

    The first and second drafts of this document were prepared by Dr 
A. BAINOVA of the Institute of Hygiene and Occupational Health, Sofia, 
Bulgaria.  Dr K.W. JAGER of the Central Unit, International Programme 
on Chemical Safety was responsible for the scientific content of the 
document and Mrs M.O. HEAD of Oxford for the editing. 

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

1.  SUMMARY AND EVALUATION, CONCLUSIONS, RECOMMENDATIONS

1.1  Summary and evaluation

1.1.1  General properties

     N,N-dimethylformamide (dimethylformamide, DMF, CAS 68-12-2) 
is an organic solvent produced in large quantities throughout the 
world.  It is used in the chemical industry as a solvent, an 
intermediate, and an additive.  DMF is a colourless liquid with an 
unpleasant slight odour that, nevertheless, has poor warning 
properties.  It is usually stable but, when it comes in contact with 
strong oxidizers, halogens, alkylaluminium, or halogenated 
hydrocarbons (especially in combination with metals), it may cause 
fires and explosions.  DMF is completely miscible with water and most 
organic solvents.  It has a relatively low vapour pressure. 

    Gas chromatographic procedures for determining DMF are available. 

1.1.2  Environmental transport, distribution, and transformation

    DMF is stable in ambient air, but may undergo microbial and algal 
degradation in water.  Adapted microorganisms and activated sludge 
efficiently biodegrade DMF.  As a result of its complete solubility in 
water, DMF moves readily through soils and would not be expected to 
accumulate in the food chain. 

1.1.3  Environmental levels and human exposure

    DMF does not occur naturally.  There are few data concerning 
environmental levels or the exposure of the general population to DMF.  
Concentrations in the air in the range of 0.02-0.12 mg/m3 have been 
found in residential areas, near industrial sites.  DMF has rarely 
been detected in the water of heavily industrialized river basins, and 
then only at concentrations below 0.01 mg/litre. 

    Data are not available on the levels of DMF in soil, plants, 
wildlife, and food. 

    Occupational exposure occurs via skin contact with DMF liquid and 
vapour, and through the inhalation of vapour.  Concentrations of 3-86 
mg/m3 air have been detected, with peaks of up to 600 mg/m3, during 
the repair or maintenance of machines. In a few unusual situations, 
levels of up to 4500 mg/m3 have been reported.

1.1.4  Kinetics and metabolism

    Toxic amounts of DMF may be absorbed by inhalation and through the 
skin. Absorbed DMF is distributed uniformly.  The metabolic 
transformation of DMF takes place mainly in the liver, with the aid of 
microsomal enzyme systems.  In animals and human beings, the main 
product of DMF biotransformation is  N-hydroxymethyl- N-methylformamide 
(DMF-OH).  This metabolite is converted during gas chromatographic 
analysis to  N-methylformamide, which is itself (together with  N-
hydroxy methylformamide and formamide) a minor metabolite.  Thus, 

metabolic studies and biological monitoring, urinary concentrations of 
metabolites are measured and expressed as NMF, though DMF-OH is the 
major contributor to this concentration. The determination of NMF/DMF-
OH in the urine may be a suitable biological indicator of total DMF 
exposure. 

    In experimental animals, it has been demonstrated that DMF 
metabolism is saturated at high exposure levels and, at very high 
levels, DMF inhibits its own metabolism. 

    Metabolic interaction occurs between DMF and ethanol.

1.1.5  Effects on organisms in the environment

    The effects of DMF on the environment have not been well studied.  
The toxicity for aquatic organisms appears to be low. 

1.1.6  Effects on experimental animals and  in vitro test systems

    The acute toxicity of DMF in a variety of species is low (in rats, 
the oral LD50 is approximately 3000 mg/kg, the dermal LD50, 
approximately 5000 mg/kg, and the inhalational LC50, approximately 
10 000 mg/m3).  It is a slight to moderate  skin and eye irritant. 
One study on guinea-pigs indicated no sensitization potential.  DMF 
can facilitate the absorption of other chemical substances through the 
skin. 

    Exposure of experimental animals to DMF via all routes of exposure 
may cause dose-related liver injury.  Regeneration, after exposure has 
ceased, has been demonstrated.  In some studies, signs of toxicity in 
the myocardium and kidneys have also been described. 

    DMF has not been shown to be toxic to the testes or ovaries of 
rats and effects on fertility have not been demonstrated.  DMF has 
been found to be embryotoxic and a weak teratogen in rats, mice, and 
rabbits.  The rabbit was found to be the most sensitive species when 
exposed via inhalation: teratogenic effects were observed at 1350 
mg/m3 (450 ppm) and above, but not at 450 ppm (150 ppm). After dermal 
exposure, a very low incidence of embryotoxic and teratogenic effects 
was observed in some studies at dose levels of between 100 and 400 
mg/kg per day. 

    DMF was generally found to be inactive, both  in vitro  and  in
 vivo, in an extensive set of short-term tests for genetic and related
effects.
    
    No adequate long-term carcinogenicity studies on experimental 
animals have been reported. 

1.1.7  Effects on human beings

    No adverse effects of DMF on the general population have been 
clearly demonstrated. 

    Skin irritation and conjunctivitis have been reported after direct 
contact with DMF. 

    After accidental exposure to high levels of DMF, abdominal pain, 
nausea, vomiting, dizziness, and fatigue occur within 48 h.  Liver 
function may be disturbed, and blood pressure changes, tachycardia, 
and ECG abnormalities have been reported.  Recovery is usually 
complete. 

    Following long-term repeated exposure, symptoms include headache, 
loss of appetite, and fatigue.  Biochemical signs of liver dysfunction 
may be observed. Liver damage seems to occur only when the DMF 
exposure level exceeds 30 mg/m3, in the absence of skin contact.  This 
airborne level corresponds to approximately 40 mg NMF/DMF-OH/g 
creatinine in a post-shift urine sample. 

    Exposure to DMF, even at concentrations below 30 mg/m3, may cause 
alcohol intolerance.  Symptoms may include a sudden facial flush, 
tightness in the chest, and dizziness, sometimes accompanied by nausea 
and dyspnoea.  They last from 2 to 4 h and disappear without 
treatment. 

    There is limited evidence that DMF is carcinogenic for human 
beings.  An increased incidence of testicular tumours was reported in 
one study, whereas another study showed an increased incidence of 
tumours of the buccal cavity and pharynx, but not of the testes. 

    In two studies, which provide few details, an increased frequency 
of miscarriages was reported in women exposed to DMF, among other 
chemicals. 

1.2  Conclusions

    1.  In view of the present uses of DMF, general population 
        exposure is probably very low. 

    2.  DMF is readily absorbed through the skin as well as via 
        inhalation. Determination of urinary NMF/DMF-OH is a useful 
        means of estimating the total amount of DMF absorbed. 

    3.  The risk of liver damage is low, when the level of DMF in 
        ambient air is kept below 30 mg/m3 and there is no skin 
        contact.  A tentative value for the corresponding urinary 
        NMF/DMF-OH level in a post-shift sample is 40 mg/g creatinine. 
        
    4.  DMF is embryotoxic and a weak teratogen in rats, mice, and 
        rabbits. 

    5.  There is limited evidence of carcinogenicity of DMF for human 
        beings. 

    6.  Available data indicate low environmental toxicity.  It is 
        unlikely that bioaccumulation takes place. 

1.3  Recommendations

1.3.1  Safe handling

    1.  Airborne concentrations should be maintained below 30 mg/m3 
        and skin contact should be prevented. 

    2.  Urinary NMF/DMF-OH, as an index of total exposure, should be 
        monitored and maintained below 40 mg NMF/g creatinine in post-
        shift samples.  If this level is exceeded, action should be 
        taken to reduce exposure. 

1.3.2   Further research

    1.  The possible carcinogenic effects of DMF in human beings 
        should be investigated by means of studies on experimental 
        animals and human populations. 

    2.  More information is needed on the extrapolation of the 
        embryotoxicity and teratogenicity of DMF from animal studies 
        to human beings.  Comparison of the kinetics of DMF in human 
        beings and animals would be valuable. 

    3.  There is a need for more information on the mechanisms of 
        action and the relative potency of the metabolites of DMF in 
        both animals and human beings. 

    4.  The relationships should be refined between: (a) urinary 
        metabolite concentrations and atmospheric exposure levels (in 
        the absence of skin contact), and (b) total dose via all 
        routes (as indicated by post-shift urinary NMF levels) and the 
        absence of hepatotoxicity. 


2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1  Identity

     Chemical structure:           H3C        O
                                      \      //
                                       N -- C
                                      /      \
                                   H3C        H

     Chemical formula:             C3H7NO

                                   
     Common name:                  dimethylformamide

     Common synonyms:               N,N-dimethylformamide,
                                   DMF, DMFA, formdimethylamide

     CAS registry number:          68-12-2

     Relative molecular mass       73.1

     Conversion factors:           1 ppm = 3 mg/m3
        (at 20 °C)                 1 mg/m3 = 0.33 ppm

2.2  Physical and chemical properties

    Some physical properties of DMF (Eberling, 1980) are given in 
Table 1.  DMF is a colourless, organic solvent, free from suspended 
matter.  Technical DMF may contain impurities, depending on the 
manufacturing and purification processes. 

    DMF is stable.  It is hygroscopic and easily absorbs water from a 
humid atmosphere and should therefore be kept under dry nitrogen. High 
purity DMF, required for acrylic fibres, is best stored in aluminium 
tanks.  DMF does not change under light or oxygen and does not 
polymerize spontaneously.  Temperatures > 350 °C may cause 
decomposition to form dimethylamine and carbon dioxide, with pressure 
developing in closed containers (Farhi et al., 1968; US NIOSH, 1978).  
In a fire involving DMF, or at temperatures > 350 °C, the toxic gases 
and vapours consist primarily of dimethylamine and carbon monoxide. 

    DMF reacts readily with alkylaluminiums.  Contact with carbon 
tetrachloride and other halogenated hydrocarbons, particularly when in 
contact with iron, as well as contact with strong oxidizing agents 
(e.g., methylene diisocyanate, halogens, and permanganates) may cause 
fires and explosions.  In acidic solution (pH 3.8), DMF can be 
nitrosated by sodium nitrate yielding small amounts of  N-nitroso-
dimethylamine (0.04% at 37 °C and 1% at 90 °C). 

Table 1.  Physical properties of DMF
----------------------------------------------------------------------------
Property                                     Value
----------------------------------------------------------------------------
Melting point (°C)                           - 60.5

Boiling point (°C)                           153

Flash point (°C)                             58 (closed cup)
                                             67 (open cup)

Auto-ignition temperature (°C)               445

Density at 25 °C (specific gravity) (g/ml)   0.9445

Relative vapour density                      2.51

Vapour pressure (mmHg/kPa)
       at 20 °C                              2.65/0.35
       at 25 °C                              3.7/0.48
       at 60 °C                              26/3.46

Vapour concentration in saturated air at
 25 °C (mg/m3)                               14 800

Explosive limits in air at 20 °C
 (101 kPa/1 atm./%vol.)
       lower limit                           2.2 (70g/m3)
       upper limit                           16 (500 g/m3)

 n- Octanol/water partitition coefficient      0.13

Solubility in water                          Miscible in all proportions

Solubility in organic solvents               Miscible with ether, ketones,
                                             aromatic hydrocarbons,  
                                             ethanol, but not with 
                                             aliphatic hydrocarbons

Dielectric constant at 20 °C                 36.7
----------------------------------------------------------------------------

2.3  Organoleptic properties

    DMF is a colourless liquid with an unpleasant taste and an 
ammonia-like, specific odour that has poor warning properties (US 
NIOSH, 1978).  The odour threshold for the most sensitive people 
ranges from 0.12 to 0.15 mg/m3 (Odoshashvili, 1963; Lazarev & Levina, 
1976; Amster et al., 1983; Clay & Spittler, 1983).  For some people, 
the odour threshold has been reported to be as high as 60 mg/m3 
(Leonardous et al., 1965). 
 
2.4  Analytical methods

2.4.1  Determination of DMF in workplace air

    Colorimetric methods, based on the development of a red colour 
after the addition of hydroxylamine chloride as alkaline solution, are 
not specific (Farhi et al., 1968). Lauwerys et al. (1980) described a 
simple spectrophotometric method for measuring DMF vapour 
concentrations.  Gas-liquid chromatography is now the method of choice 
(Kimmerle & Eben, 1975a; US NIOSH, 1977; Muravieva & Anvaer, 1979; 
Brugnone et al., 1980a; Muravieva, 1983; Stransky, 1986).  Detector 
tubes, certified by US NIOSH, or other direct-reading devices 
calibrated to measure DMF (Krivanek et al., 1978; US NIOSH, 1978) can 
be used.  High-performance liquid chroma tographic analysis (Lipski, 
1982) can also be used.  Mass spectrometric analysis for DMF in 
expired air has been described by Wilson & Ottley (1981), with a lower 
limit of detection of 0.5 mg/m3. 
 
2.4.2  Determination of DMF and metabolites in biological media 

    Barnes & Henry (1974) developed a method for the gas 
chromatographic determination of NMF ( N-methylformamide) (thought to 
be the principal metabolite of DMF) in urine at concentrations of 
between 5 and 500 µg/litre by either direct injection of the urine or 
of urine extracts.  Methods for simultaneous gas chromatographic 
determination of DMF and NMF in the same blood sample (0.2 ml) and of 
DMF, NMF, and formamide in 1 ml 24-h urine have been published by 
Kimmerle & Eben (1975a) and Muravieva & Anvaer (1979).  Similar 
techniques were reported by Krivanek et al. (1978), Sanotsky et al.  
(1978), and Lauwerys et al. (1980), involving primarily the 
determination of NMF in the urine (Table 2). 
 
2.4.3  Determination of DMF in soil, plants, and food 

    Analytical methods for the determination of DMF in these media 
have not been described. 


Table 2.  Analytical methods for the determination of DMF, NMF (DMF-OH),
and formamide (NMF-OH) in urine, blood, and other biological tissues
-------------------------------------------------------------------------------------------------------------------
Biological   Analytical method                         Detection limits                Reference
tissue                               DMF               NMF (DMF-OH)     Formamide
                                                                        (NMF-OH)
-------------------------------------------------------------------------------------------------------------------
Urine        gas chromatography                        0.5 mg/litre                    Barnes & Henry (1974)
             gas chromatography      1.5 mg/litre      1 mg/litre       3.5 mg/litre   Kimmerle & Eben (1975a)
             gas chromatography                        0.1 mg/litre                    Krivanek et al. (1978)
             gas chromatography      1.5 mg/litre      3 mg/litre       10 mg/litre    Muravieva & Anvaer (1979)
             gas chromatography                        0.8 mg/litre                    Mráz et al. (1987)
             gas chromatography                                                        Lauwerys et al. (1980)

Blood        gas chromatography      1 mg/litre        1.5 mg/litre                    Kimmerle & Eben (1975a)
             gas chromatography      0.03 mg/litre     0.3 mg/litre     10 mg/litre    Sanotsky et al. (1978)
             gas chromatography      1.5 mg/litre      3 mg/litre                      Muravieva & Anvaer (1979)
             gas chromatography      0.4 mmol/litre                                    Lundberg et al. (1983)

Livera       gas chromatography      0.2 mmol/kg                                       Lundberg et al. (1983)

Kidney                               0.6 mmol/kg

Brain                                0.3 mmol/kg

Adrenals                             0.9 mmol/kg
-------------------------------------------------------------------------------------------------------------------
a Tissue homogenate.

3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1  Natural occurrence

    DMF does not occur naturally.

3.2  Man-made sources

3.2.1  Production and uses

3.2.1.1  Production

    DMF was first synthesized in 1893 from carbon monoxide and 
dimethylamine (Kennedy, 1986).  It is usually manufactured by a one-
stage reaction of carbon monoxide with dimethylamine: 

                     catalyst
        CO + (CH3)2NH ----> (CH3)2

or by a two-stage reaction with methylformate and dimethylamine 
(Eberling, 1980): 

                  catalyst
        CO + CH3OH ----> HCOOCH3

        HCOOCH3 + (CH3)2NH ----> HCON(CH3)2 + CH3OH

    DMF can also be manufactured from carbon dioxide, hydrogen, and 
dimethylamine, in the presence of halogen-containing transition metal 
compounds. 

    DMF is shipped in tank trucks and tank containers, and is also 
marketed in 200-kg steel drums.  The materials for DMF handling and 
storage are usually (carbon) steels, austenitic steels, and aluminium.  
Seals and pipelines should be made of polytetrafluoro-ethylene, 
polyethylene, or polypropylene of high relative molecular mass. 
Ethylene-propylene rubber can also be used. 

    The world production capacity of DMF is about 225 x 103 
tonnes/year (Eberling, 1980).  Production in the USA in 1979 was 
15 000 tonnes.  In 1980, NIOSH estimated that 69 000 US workers, in 
various occupations in 25 major industries, were exposed to DMF. 

    Data are not available on losses of DMF into the environment and 
into the ambient air during its production and use. 

    DMF can be recovered from the air by scrubbing with water and from 
aqueous solution by distillation. 

3.2.1.2  Uses

    DMF is a universal industrial solvent, because of its water 
solubility, organic nature, and high dielectric constant.  The main 
use (65-75%) of DMF is as solvent for acrylic fibres and 
polyurethanes; 15-20% is used in the production of pharmaceutical 
products (Eberling, 1980). 

    DMF is used as:

    - a spinning solvent for synthetic textiles, based on 
      polyacrylonitrile or cellulose triacetate; 

    - a resin, rubber, and polymer solvent; 

    - a solvent for dyes and pigments for use with textiles, wood, 
      leather, films, paper, and plastics; 

    - a solvent in pesticide formulations; 

    - a booster solvent in coating, printing, and adhesive 
      formulations; 

    - a chemical intermediate, catalyst, and reaction medium in 
      chemical manufacturing and the pharmaceutical industry; 

    - a solvent in the production of polyurethane and other synthetic 
      leathers, or synthetic rubber; 

    - a selective absorption and extraction solvent for recovery, 
      purification, absorption, separation, and desulfurization of 
      non-paraffinic compounds from paraffin hydrocarbons; 

    - in the manufacture of paint stripper components for the removal 
      of vinyl films, epoxy coatings, and varnish finishes; in the 
      production of wire enamels, based on polyamides, polyurethanes, 
      and other polymers; 

    - in the pigment and dye industry to improve dyeing properties; 

    - a crystallization solvent in the pharmaceutical industry; 

    - a solvent for carbonaceous deposit cleaning applications for 
      high-voltage capacitors; 

    - an oil sludge dispersing agent;

    - an anti-stall gasoline additive;

    - a laboratory solvent and as a solvent for the extraction of 
      biological material in chemical analysis. 

    DMF (itself, or as a component in consumer products) is not 
generally available to the general population (Farhi et al., 1968; 
Bainova, 1980; Lundberg, 1982; Tanaka & Utsunomiya, 1982; Barral-
Chamaillard & Rouzioux, 1983; Kennedy, 1986; US EPA, 1986). 

    Because of its hepatotoxicity, DMF is not used as a solvent in 
pharmaceutical or cosmetic products. 

    DMF has been approved by the US FDA as a component of adhesives, 
for use in the packaging, transport, or storage of food. 

    DMF is present in some registered pesticides as an inert solvent.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1  Transport and distribution between media

4.1.1  Air

    DMF is stable in air.  Concentrations in ambient air are related 
to its industrial use.  No data have been found on the rates of 
reaction of DMF with hydroxyl radicals, ozone, or other atmospheric 
pollutants.  Darnall et al. (1976) reported DMF to have a half-life of 
9.9 days in a polluted atmosphere.  In oxidizing smog-chamber studies 
(Laity et al., 1973; Farley, 1977; Sickles et al., 1980), no 
photochemical oxidation of DMF occurred.  The ultraviolet (UV) 
absorption spectrum for DMF indicated no absorption > 290 nm 
(Grasselli, 1973), showing that no photodegradation should be expected 
in the environment.  The water solubility of DMF suggests that it 
should be easily removed from air by rainfall. 

    The DMF levels in the air of working environments depend on the 
rate of usage, technology, and industrial hygiene practices (Aldyreva 
& Gafurov, 1980; Brugnone et al., 1980a; Lauwerys et al., 1980; 
Yonemoto & Suzuki, 1980; Koudela & Spazier, 1981; Taccola et al., 
1981; Paoletti & Iannaccone, 1982; Tomasini et al., 1983; Sala et al., 
1984; Kennedy, 1986; US EPA, 1986). 

4.1.2  Water

    According to Eberling (1980), aqueous solutions of DMF undergo 
slight hydrolysis at neutral pH.  After 120 h of refluxing, only 0.17% 
of a 50% solution was hydrolysed.  The hydrolysis of DMF is 
accelerated by acids and alkalis.  No data about the oxidation or 
photodegradation of DMF are available. 

    DMF is susceptible to biodegradation by activated sludges, though 
an acclimation period is usually required.  Water from the Vistula 
River was reported to biodegrade DMF, as was an unspecified bacterial 
culture isolated from soil exposed to petroleum + petroleum products 
(Chromek et al., 1983).  Dojlido (1979) reported that, in an activated 
sludge system, 100% of the 70 mg DMF/litre was degraded in 38 days.  
In a river die-away test, under light aeration conditions, 28 mg 
DMF/litre were degraded in the water with a lag time of 2 days.  The 
lag time decreased when acclimatized microorganisms were used in the 
test. 

    Chromek et al. (1983) determined the changes in respiration rate
in algal cultures of  Scenedesmus quadricauda, after treatment with
1000 mg DMF/litre.  DMF degradation via dimethylamine to ammonia 
occurred within 3 days.  The rate of DMF degradation to ammonia 
depended on the degree of adaptation of the heterotrophic mixed 
cultures (activated sludge) and varied between 35 and 70 mg/g per h.  
The dimethylamine decomposition rate was about 25 mg/g per h. 

    Gubser (1969) reported that, in a continuous-flow activated sludge 
system, DMF was reduced by 90-100% within 10 days at concentrations of 
20 and 50 mg/litre, and within 28 days at a concentration of 81 

mg/litre.  Chromek et al. (1983)  found that the alga  Scenedesmus 
 quadricauda in cultures was able to degrade DMF to dimethylamine and 
ammonia in 3 days.  The DMF concentration tested was about 1000 
mg/litre; this corresponds to values seen in industrial effluents.  
After the formation of an adaptive enzymatic system, the DMF 
concentration decreased at a constant rate of about 40 mg/g per h.  
Adaptation of the culture resulted in an enhanced rate of degradation.  
 Pseudomonas sp.,  Pseudomonas sp.II, and  Vibrio aeromonas, isolated 
from sewage effluents, degraded DMF (US EPA, 1986).  Begert (1975)  
proposed several series of aerobic bacterial systems, which eliminated 
more than 90% of the DMF in the sewage from a chemical textile plant. 

    The complete water solubility and low  n-octanol/water partition 
coefficient (Table 1) of DMF suggest that adsorption on sediments in 
water is not an important environmental process.  DMF is not expected 
to evaporate from the aquatic environment to any significant rate 
because of its volatility and high water solubility (US EPA, 1986). 

4.1.3  Soil

    Contamination of soil with DMF may occur through spillage or 
leakage during its production, transport, storage, or use.  DMF's high 
solubility in water and its low  n-octanol/water partition coefficient 
show that it can seep down into soil and potentially into ground 
water.  DMF was completely biodegraded by a bacterial culture, 
isolated from soil that had been in contact with low levels of 
petroleum and petroleum products for several years.  This culture was 
used for the purification of waste waters containing 250 mg DMF/litre 
in an aerated tank; the addition of activated sludge for 18 h resulted 
in the biodegradation of 94% of the DMF (Romadina, 1975). 
 
4.1.4  Bioaccumulation

    Sasaki (1978) found that DMF did not bioaccumulate in the carp;
the low partition coefficient was considered to be the explanation.

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1  Environmental levels

5.1.1  Air

    Air-monitoring for DMF was conducted at distances ranging from 25 
to 300 m from an artificial fibre plant in the USSR.  Odoshashvili 
(1963) found that DMF levels were only below the proposed allowable 
limit of 0.03 mg/m3 at 300 m from the plant. 

    Residents of private homes within a 0.5 mile radius of a chemical 
waste recycling site complained of unpleasant odours.  DMF was found 
to be the major atmopheric contaminant in concentrations of up to 0.12 
mg/m3, but it originated primarily from the industrial sites nearby 
and not from the soil or the waste site (Clay & Spittler, 1983).  
Amster et al. (1983) studied another abandoned chemical waste facility 
in the USA, in response to complaints from nearby residents about 
odour, with similar results, i.e., air levels of 0.024-0.15 mg DMF/m3 
originated from a neighbouring industry.

5.1.2  Water

    Very low concentrations of DMF were found in effluent waters from 
sewage-treatment plants or municipal sewage-treatment systems (US EPA, 
1986).  A concentration of 2 µg/litre was measured in a sample taken 
from a sewage-treatment plant on the western shore of Lake Michigan.  
Ewing et al. (1977) examined 204 water samples from 14 heavily 
industrialized river basins in the USA.  DMF was found in only one 
sample, at a concentration of 2 µg/litre.  Samples of 63 effluent and 
22 intake waters from various chemical manufacturers were collected in 
areas throughout the USA (Perry et al., 1979) and analysed for organic 
pollutants.  Over 570 compounds were tentatively identified, of which 
33 were important pollutants. DMF was detected once at a concentration 
< 10 µg/litre. 

    Chromek et al. (1983) reported that DMF concentrations of 
approximately 1000 mg/litre were found in effluents from the 
production of synthetic leather. 

5.1.3  Soil

    No data are available on DMF levels in soil and plants.

5.2  General population exposure

    No data are available on exposure of the general population to 
DMF. 

    However, DMF may be a component of coatings, adhesives, engine 
degreasing agents, and photographic developers for consumer use. 

    Exposure through the use of DMF in food processing, food 
packaging, and pesticides may occur, but data are not available. 

5.3  Occupational exposure

5.3.1  Concentrations in the workplace air

    DMF is not highly volatile and is manufactured in closed systems. 
Data on DMF concentrations in plants manufacturing DMF are not 
available. 

    Concentrations of DMF in the workplace air in various industrial 
applications, are listed in Table 3.  In most cases, the mean 
concentrations are less than 30 mg/m3, but certain jobs, particularly 
those involving mixing operations, result in higher concentrations. 
The cleaning of equipment or tanks that have contained DMF can involve 
exposure to levels of up to 147 mg/m3.  Kang-de & Hui-lan (1981) 
reported an unusually high DMF concentration of 4525 mg/m3 during 
repairs following an accident.  The ranges of concentration reported 
vary considerably, but the time of sampling is not generally 
specified.  The highest values have been found during repair or 
maintenance work, in accidents, and where batch sampling (opening the 
reactor system) was being conducted. 
 
5.3.2  Dermal exposure

    The relative importance of dermal exposure to liquid or vapour DMF 
(versus inhalation of vapour) was studied by Aldyreva & Gafurov 
(1980), Lauwerys et al. (1980), Bortsevich (1984), and Sala et al. 
(1984). 

    Lauwerys et al. (1980) studied 7 workers from a spinning mill in a 
polyacrylic fibre factory.  During the first week, the workers wore 
gloves and during the second week, a barrier cream was applied twice 
each day to the hands and forearms.  On the first day of the third 
week, the skin was not protected, but the workers were equipped with 
self-contained breathing equipment.  The average  N-methylformamide
(NMF) concentration in the urine at the end of the day, when there was 
no dermal protection, was about 3 times higher than that during the 
first week.  Eight hours after the start of exposure without skin 
protection, one worker reported abdominal pains; a second worker had 
to stop working 48 h later because of severe gastric pain.  Hence, 
from the second day, the workers were requested to resume wearing 
their impermeable gloves.  Urinary NMF concentrations returned to the 
values found during the first week. This convinced the workers of the 
need to avoid all contact with the DMF solution and to use protective 
gloves correctly.  The study also showed that gloves were more 
effective than silicone or glycerol barrier creams in preventing skin 
absorption of DMF. 

    In a new plant producing artificial leather, Aldyreva et al. (1980)
found DMF in nearly all washings from the operators' hands.

    According to Bortsevich (1984), the quantity of DMF absorbed 
through the skin might be twice the quantity taken up through 
inhalation.  The author reported significant DMF concentrations in the 
skin washings from the palms of hands, shoulders, back, thighs, and 
abdomen.  Part of the dermal uptake of DMF may result from its 
presence in the air and part from contaminated clothing. 


Table 3.  DMF concentrations in air in various industrial applications
----------------------------------------------------------------------------------------------------------------------------
Factory product          Job description                  Mean DMF          Range of DMF          Reference
                                                          concentrations    concentrations
                                                          (mg/m3)           (mg/m3)
----------------------------------------------------------------------------------------------------------------------------
Polyacrylic fibres       spinning line - maintenance        -                 1-46.6              Lauwerys et al. (1980)

Artificial leather       various (pre-improvement)          -                 0-60                Aldyreva & Gafurov (1980)
                         various (post-improvement)                           1/3 samples below
                                                                              detection
                         production                         5.3               1.9-8.3             Brugnone et al. (1980a)
                         production (highest in mixing)     > 30            < 150               Taccola et al. (1981)
                         production - normal                4.2-66                                Paoletti & Iannaccone
                         opening reactor                      -               < 549              (1982)
                         maintenance of rollers                               < 120
                         production - mixing                > 34                                 Tomasini et al. (1983)
                         soaking and drying                 12.1 (± 40.2)       -                 Bortsevich (1984)
                         coating and colouring              32.3 (± 98.7)       -
                         mixing resins                      22.7 and 85.2     2-117               Sala et al. (1984)
                         spreading "transfer" system        33.8              8-72
                         spreading "coagulate" system       14                2-49
                         tank cleaning                      86.3              9-147
                         machine cleaning                   24.1              12-35

Surface-treating         handlers                           0-15.4              -                 Yonemoto & Suzuki (1980)
 agents

Solvents                    -                               often > 30      peak 105-600         Lyle et al. (1979)

Synthetic rubber         repairing, accidents,                -               9.5-4525            Kang-de & Hui-lan (1981)
                         sampling with system opened,
                         extracting                         < 10 -

Unspecified chemicals    unspecified                          -               50-250              Koudela & Spazier (1981)
----------------------------------------------------------------------------------------------------------------------------
    Sala et al. (1984) reported that the total daily excretion of NMF 
(DMF-OHa and NMF) in the 24-h urine samples of a worker who usually 
cleaned the tanks in a factory where artificial polyurethane leathers 
were produced, was 95-725 mg or 35-390 mg NMF/litre. This is higher 
than would have been expected in a subject with a mean airborne 
exposure of 100 mg DMF/m3.  The worker usually operated without using 
any personal protection. 

    Penetration through various glove materials has been studied. 
Breakthrough time was > 480 min for butyl rubber, 6-66 min for 
neoprene, and 5-22 min for polyvinylchloride and polyvinyl alcohol 
(Henry & Schlatter, 1981). 

    Similarly, Sansone & Tewari (1978) showed that < 0.1% DMF passed 
through neoprene gloves, 0.1-1% through natural rubber gloves, 1-10% 
through nitrile gloves, and > 10% through poly-vinylchloride gloves, 
in half an hour. 



---------------------------------------------------------------------------
a DMF-OH =  N-hydroxymethyl- N-methylformamide.

6.  KINETICS AND METABOLISM

6.1  Animal studies

6.1.1  Absorption

    Sanotsky et al. (1978) determined DMF concentrations in the blood 
of rats, 24 h after the oral administration of 200-4000 mg DMF/kg body 
weight and found mean blood levels ranging from 40 to 1870 mg/litre.  
DMF is readily absorbed via inhalation and dermally.  Maximal blood 
and tissue concentrations were observed in rats up to 3 h after 
exposure to 438 and 6015 mg DMF/m3 (Kimmerle & Eben, 1975a) or to 1690 
and 6700 mg DMF/m3 (Lundberg et al., 1983).  According to Massmann 
(1956), at least 0.8 ml of 100% DMF was absorbed through 14 cm2 of 
exposed skin of the tails of rats in the course of 8 h, which is 
equivalent to an absorption rate of about 57 mg/cm2 per 8 h.

6.1.2  Distribution

    Twenty-four hours after an ip dose of 14C-DMF in male rats, about 
4% of the radioactivity was recovered in the blood, less than 1% in 
the brain, heart, lungs, stomach, intestines, spleen, and kidneys, and 
1-3% in the liver, adipose tissue, and muscles (Scailteur & Lauwerys, 
1984). 

    Kimmerle & Eben (1975a) studied DMF and NMF (DMF-OH)a
concentrations in the blood of rats and dogs after single and repeated 
respiratory exposure.  At the highest airborne concentration (6015 
mg/m3), DMF was still detectable in the blood of male rats up to 2 
days after the end of a 3-h exposure.  At lower concentrations, DMF 
levels in the blood decreased rapidly (Table 4).  After 3 h exposure 
to 63 mg/m3 or 6 h exposure to 87 mg/m3, similar levels of NMF were 
found in the blood at the end of the periods of exposure, but no NMF 
was detectable 3 h after the end of exposure.  Only after a 3-h 
exposure to a very high concentration (6015 mg/m3)  did NMF levels in 
blood continue to increase for the 2 days following exposure (Table 4).

    Blood concentrations of DMF in male dogs also decreased rapidly 
following a 6-h single exposure.  However, NMF could be detected in 
the blood at higher concentrations and for a longer period of time 
after exposure (Table 5). 

---------------------------------------------------------------------------
a  DMF = dimethylformamide;
   DMF-OH=  N-hydroxymethyl- N-methylformamide;
   NMF =  N-methylformamide;
   NMF-OH =  N-hydroxymethylformamide;
   F = formamide.

Table 4.  Concentrations of DMF and NMF in the blood of male rats after
a single inhalation exposure
---------------------------------------------------------------------
Hours after          Inhalation exposure to DMF (3 h)              
end of         6015 mg/m3          438 mg/m3            63mg/m3
exposure     --------------------------------------------------------
             DMF       NMF       DMF       NMF        DMF      NMF
               (mg/litre)          (mg/litre)          (mg/litre)
---------------------------------------------------------------------
0            1190      11.5      25.7       7.3      NDa       2.5
0.5          1166      12.1      21.7       6.9                1.9
1            1329      15.8      20.7      10.2                1.2
2.5          1275      20.9      10.5      11.8                0.5
4.5          1322      25.9       1.8      10.6                 ND
21            824      50.3
45             46      84.3
-----------------------------------------------------------------------
a  ND = not detectable.

    When male rats were exposed to 1050 ± 126 mg/m3, 6 h/day, for 5 
days, the levels of DMF and NMF in the blood returned to ND levels 
before each consecutive exposure.  However, when male dogs were 
exposed to 177 ± 36 mg NFM/m3, 6 h/day, for 5 days, NMF accumulated in 
the blood (10 mg/litre, 2 h after the first exposure; 30 mg/litre, 3 h 
after the fifth exposure).  In contrast, in female dogs, exposed to 69 
± 12 mg/m3, 6 h/day, for 5 days, the daily NMF concentration in the 
blood remained almost constant, returning to a low level of about 1-
1.5 mg/ml, before each new exposure. 

Table 5.  Concentrations of DMF and NMF in the blood of male dogs
after a single inhalation exposure
------------------------------------------------------------------------
Hours after              Inhalation exposure to DMF (6 h)               
end of           513 ± 114 mg/m3                   60 ± 9 mg/m3
exposure    ------------------------------------------------------------
               DMF            NMF             DMF             NMF
            (mg/litre)     (mg/litre)      (mg/litre)      (mg/litre)
------------------------------------------------------------------------
 0             51.6            9.7             7.4            10.5
 0.5           54.9           13.7             5.6            11.9
 1             47.7           14.9             4.1            12.1
 2             39.4           17.4             0.7            13.3
 3             38.7           23.6             NDa            13.3
27                                                             3.1
------------------------------------------------------------------------
a ND = not detectable.

    Finally, in male and female dogs exposed to 63 ± 9 mg/m3, 6 h/day, 
for 5 days a week over 4 weeks, DMF levels went back to ND before each 
new exposure.  There was no accumulation of NMF. The weekly average 
concentrations of NMF were slightly higher in males than in females. 

    Lundberg et al. (1983) measured DMF and NMF concentrations in 
various organs of the rat after a single 4-h inhalation exposure to 
1690 or 6700 DMF mg/m3; DMF and NMF were distributed uniformly 
throughout the tissues (Tables 6 and 7).  Blood levels of NMF (DMF-OH) 

for the first 3 h following exposure were lower after exposure to 6700 
mg/m3 than after exposure to 1690 mg/m3 (Table 6 and 7).  The authors 
suggested that high DMF doses inhibit DMF biotransformation.  This 
interpretation is supported by the results of Kimmerle & Eben (1975a), 
who reported that NMF concentrations in the blood (11-21 mg/litre) 
during the first 3 h following a 3-h exposure to 6015 mg DMF/m3 were
lower than those following a 6-h exposure to 513 mg/m3. 

6.1.3  Metabolic transformation

    After iv injection of DMF in cats, Massman (1956) found that only 
a small amount of the compound was excreted unchanged in the urine.  
He could not detect any hydrolysis of the amide to dimethylamine and 
formic acid.  Barnes & Ranta (1972) identified a urinary metabolite, 
NMF, in the urine of rats treated with sc injections of DMF. 

    After single or repeated respiratory exposure to DMF, Kimmerle & 
Eben (1975a) identified NMF and formamide in the urine of rats and 
dogs.  The authors proposed a model of successive  N-demethylations of 
DMF.

    In  in vitro  studies, Barnes & Ranta (1972) measured a low level
of formaldehyde, when rat liver homogenates were incubated with DMF in 
the presence of an NADPH-generating system.  They concluded that DMF 
was  N-demethylated in the liver with the help of microsomal enzymes.  
This was in agreement with previous  in vivo findings. 

    Later on, however, it was shown that the incubation of various rat 
tissues with DMF did not release formaldehyde  in vitro.  Furthermore, 
neither formaldehyde nor any other monocarbon derivative (CO, CH3OH, 
CH4, HCOOH) was detected, when DMF was incubated with fortified liver 
microsomes.  However, a metabolite determined by gas chromatography 
(GC) was identified as NMF. This led to speculation that DMF-OH was a 
probable metabolite of DMF that was broken down (demethylated) to form 
NMF during gas chromatographic analysis (Scailteur et al., 1984). 

    Brindley et al. (1983) indicated that a stable precursor of 
formaldehyde was present in the urine of mice treated with DMF. 

    Direct evidence that DMF-OH is a metabolite of DMF was only 
obtained by investigating urine samples of animals treated with DMF. 
DMF-OH was identified in rat urine using HPLC combined with chemical 
ionization mass spectrometry (Scailteur et al., 1984) and in mouse 
urine high-field H-NMR spectroscopy and radio thin layer 
chromatography (Kestell et al., 1986). 


Table 6.  Concentrations of DMF and NMF in rat tissues after a 4-h exposure to 6700 mg DMF/m3
------------------------------------------------------------------------------------------------------------------------
Hours after          Blood               Liver              Kidney              Brain              Adrenals
end of             (mg/litre)                              (mmol/kg)                                                    
exposure         DMF       NMF       DMF       NMF       DMF       NMF       DMF       NMF       DMF       NMF
------------------------------------------------------------------------------------------------------------------------
    0            965      < 24       9.8     < 0.3      11.0       0.8      11.4       0.4       8.6     < 1.0
    3           1089      < 24      11.7       0.5      12.8     < 0.6       2.7     < 0.3       8.8     < 1.0
    6            950        71      10.1       0.7      11.5       1.3      10.1       0.5       9.0       1.2
   20            263       295       2.6       1.9       3.1       2.3       1.5       2.1       1.9       1.9
   48           < 29      < 24     < 0.2     < 0.3     < 0.6     < 0.6     < 0.3     < 0.3     < 0.9     < 1.0
------------------------------------------------------------------------------------------------------------------------


    Table 7.  Concentrations of DMF and NMF in rat tissues after a 4-h exposure to 1690 mg DMF/m3
------------------------------------------------------------------------------------------------------------------------
Hours after          Blood               Liver              Kidney              Brain              Adrenals
end of             (mg/litre)                              (mmol/kg)                                                    
exposure         DMF       NMF       DMF       NMF       DMF       NMF       DMF       NMF       DMF       NMF
------------------------------------------------------------------------------------------------------------------------
    0            373        41       2.8       0.5       3.1       0.9       3.1      0.52        .1     < 1.0
    3            205        47       1.8       0.5       2.8       0.9       2.0       0.6       1.6     < 1.0
    6            197        47       1.8       0.6       2.0       1.2       1.9       0.7       1.5       1.0
   20           < 29      < 24     < 0.5     < 0.3     < 0.6       0.6     < 0.3     < 0.3     < 0.9     < 1.0
------------------------------------------------------------------------------------------------------------------------
    Using GC combined with mass spectrometry, Scailteur & Lauwerys 
(1984a,b) showed that besides the major metabolite, DMF-OH, a small 
amount of NMF could also be identified in the urine of DMF-treated 
rats.  This was confirmed by Kestell et al. (1986) using H-NMR 
spectroscopy.  Thus when urine samples are analysed after DMF 
administration, using gas chromatography, the combination of DMF-OH + 
NMF is determined as NMF and the combination of hydroxymethylformamide 
(NMF-OH) + formamide, as formamide (Scailteur et al., 1984).  Using 
GC/MS, Scailteur & Lauwerys (1984a,b) could not identify NMF in the 
urine of DMF-OH-treated rats.  The authors therefore suggested that 
NMF is not a product of DMF-OH biotransformation, but is directly 
formed from DMF. 

    Hepatectomy markedly reduced the  in vivo  transformation of DMF 
into DMF-OH, confirming that the liver is the main site of metabolic 
degradation (Scailteur et al., 1984). 

    In parallel with the hypothesis of Lundberg et al. (1983) that 
high doses of DMF could inhibit its biotransformation, Scailteur et 
al. (1984) showed that the urinary excretion of metabolites (DMF-OH + 
NMF, NMF-OH + F) was the same, following 2 daily ip injections of 0.5 
mg/kg body weight or 2 daily ip injections of 1 ml/kg. 

    Scailteur & Lauwerys (1984a) studied the mechanism of the  in vitro 
and  in vivo  oxidative biotransformation of DMF.  Addition of catalase 
or superoxide dismutase to liver microsomes, incubated with DMF, 
decreased the level of DMF-OH production.  in vitro  and  in vivo, DMF 
transformation was also diminished in the presence of radical 
scavengers, such as dimethylsulfoxide, tert-butyl alcohol, 
hydroquinone, and trichloroacetonitrile.  Addition of IRON/EDTAa to 
microsomes, incubated with DMF  in vitro, stimulated DMF oxidation.  
The authors concluded that the metabolic transformation of DMF to DMF-
OH involved hydroxyl radicals. 

    Metabolites, other than DMF-OH (NMF) and NMF-OH (F), appear to be 
formed from DMF. Indeed, about 20% of an ip dose was recovered in the 
urine of mice (Brindley et al., 1983) and rats (Scailteur & Lauwerys, 
1984a,b), as unidentified chemicals. 

    Kestell et al. (1986, 1987) identified low levels of methylamine
and dimethylamine in the urine of DMF-treated mice (about 4%).

    A metabolic transformation scheme is presented in Fig. 1, based on 
the above data. 


---------------------------------------------------------------------------
a EDTA = ethylene diamine tetra acetate.

FIGURE 1

6.1.4  Elimination and excretion

    The transformation and excretion of DMF in rodents is rapid. When 
14C-labelled DMF in 0.1 ml saline was injected ip at 6.8 mmol/kg body 
weight in mice, about 83% of the radioactivity was recovered in the 
urine within 24 h following injection.  Of this amount, only 5% was 
unchanged DMF and 56% was C-hydroxylated or  N-demethylated 
derivatives.  About 18% of the dose was excreted in the form of 
unknown chemicals (Brindley et al., 1983). 

    Similarly, 24 h after ip injection of 400 mg DMF/kg body weight in 
0.2 ml saline in mice, about 56% of the dose was excreted in the urine 
as DMF-OH and only 5% as unchanged DMF (Kestell et al., 1986). 

    Within 72 h of an ip administration of 1 ml 14C-DMF/kg to male
or female rats, 70% of the injected radioactivity was recovered in the
urine.  Approximately 15% was excreted as unchanged DMF, 50% as DMF-OH 
(NMF), and 5% as NMF-OH (F).  About 20% was excreted as unidentified 
metabolite(s) (Scailteur & Lauwerys, 1984a,b). 

    After oral exposure to DMF (40-2000 mg/kg), Sanotsky et al. (1978) 
determined that about 6% of the dose was excreted in 24 h. 

    The elimination of DMF, NMF (DMF-OH), and formamide (NMF-OH) was 
measured after single or repeated inhalation exposure in rats and dogs 
(Kimmerle & Eben, 1975a). Twenty-four hours after a single exposure to 
63 mg NMF/m3 for 3 h, or 87 mg/m3 for 6 h, no NMF was found in the 
urine of male rats.  Under the same conditions, exposure to 513 mg/m3 
for 6 h or to 6015 mg/m3 for 3 h led to excretion of 4 mg and 14 mg 
NMF (DMF-OH), respectively, during the 24 h following the start of 
exposure.  Only in the last case was DMF also measured in the urine.  
After repeated exposure of male rats to DMF (1050 mg/m3, 6 h/day, for 
5 days), urinary levels of NMF (DMF-OH) remained practically constant 
for the first 3 days, then slightly decreased from the fourth day of 
exposure. Excretion of F (NMF-OH) was much lower than excretion of NMF 
(DMF-OH). 

    While no accumulation of urinary NMF (DMF-OH) was observed in male 
rats, male dogs exposed to 177 mg DMF/m3 (6 h/day for 5 days) excreted 
increasing concentrations of NMF (DMF-OH) (36 mg/24 h after the first 
inhalation; 87 mg/24 h after the 4th inhalation).  Urinary excretion 
of formamide (NMF-OH) varied between 10 and 20 mg/24 h.  Excretion of 
unchanged DMF was very low (< 2 mg/24 h).  However, in female dogs 
exposed to 69 mg/m3 (6 h/day for 5 days), no urinary accumulation of 
NMF or F was observed.  When male or female rats were exposed for 4 
weeks to 63 mg/m3 (6 h/day, 5 days per week), NMF and F concentrations 
in the urine remained practically constant during the exposure period. 
Male dogs generally excreted slightly higher levels of metabolites 
than female dogs (Kimmerle & Eben, 1975a). 

    In rats treated with repeated, high, ip doses of DMF (4 daily 
injections of 1 ml/kg body weight), Scailteur et al. (1984) showed 
that females excreted higher amounts of unchanged DMF than males. The 
pattern of metabolite (NMF, F) excretion was similar in both sexes 
after single or repeated ip administration. 

6.1.5  Metabolic interaction between DMF and ethanol

    DMF and ethanol appear to interact metabolically.

    The alterations in blood metabolites depend on the dose of DMF, 
the time interval between DMF and ethanol administration, and the 
respective routes of administration. 

    The various studies performed are summarized in Table 8.  Blood 
concentrations of DMF and NMF, ethanol, and acetaldehyde were measured 
using GC methods. 

    The influence of DMF on ethanol oxidation might be explained, at 
least partially, by its inhibitory effect on the activity of alcohol 
dehydrogenase  in vitro  and  in vivo  (Sharkawi, 1979) and aldehyde 
dehydrogenase  in vivo  (Elovaara et al., 1983). 


Table 8.  Metabolic interaction between DMF and ethanol
-----------------------------------------------------------------------------------------------------------------------------------------
Species   Ethanol          Time of              DMF                 Effects on blood concentrations of:     Reference
          dose             administration       dose                                                     
          (route)                               (route)             DMF and           Ethanol and
                                                                    NMF               acetaldehyde
-----------------------------------------------------------------------------------------------------------------------------------------
Rat       .2 g/kg          immediately before   312 mg/m3           No effects on     not measured          Eben & Kimmerle (1976)
          (oral)           DMF exposure         2 h (inhalation)    DMF and NMF

Rat       2 g/kg           immediately before   261 or 627 mg/m3    DMF increased     not measured          Eben & Kimmerle (1976)
          (oral)           DMF exposure         2 h (inhalation)    NMF formation

Rat       2 g/kg per day   daily immediately    about 600 mg/m3     DMF increased     ethanol increased     Eben & Kimmerle (1976)
          for 5 days       before DMF           2 h/day 5 days      NMF formation
          (oral)           exposure             (inhalation)

Dog       2 g/kg           immediately before   about 630 mg/m3     DMF increased     not measured          Eben & Kimmerle (1976)
          (oral)           DMF exposure         2 h (inhalation)    NMF decreased

Dog       2 g/kg           immediately after    630 mg/m3           DMF increased     not measured          Eben & Kimmerle (1976)
          (oral)           DMF exposure         2 h (inhalation)    NMF decreased

Rat       2 g/kg           1 h after last       3000 mg/m3          not measured      acetaldehyde          Hanasono et al. (1977)
          (oral)           DMF exposure         4 h/day 3 days                        increased
                                                (inhalation)

Rat       2 g/kg           1 h after last       6000 mg/m3          not measured      ethanol increased     Hanasono et al. (1977)
          (oral)           DMF exposure         4 h/day 3 days                        acetaldehyde
                                                (inhalation)                          decreased

Mouse     1 g/kg           2 h after DMF        1.2 ml/kg           not measured      ethanol increased     Sharkawi (1980)
          (ip)             exposure             (ip)

Rat       2 g/kg           3 h after DMF        0.15 g/kg           not measured      ethanol increased     Hanasono et al. (1977)
          (oral)           exposure             (oral)                                acetaldehyde
                                                                                      decreased

Rat       2 g/kg           18 h after DMF       0.15 g/kg           not measured      acetaldehydea         Hanasono et al. (1977)
          (oral)           exposure             (oral)                                increased

Table 8.  (continued)
-----------------------------------------------------------------------------------------------------------------------------------------
Species   Ethanol          Time of              DMF                 Effects on blood concentrations of:     Reference
          dose             administration       dose                                                     
          (route)                               (route)             DMF and           Ethanol and
                                                                    NMF               acetaldehyde
-----------------------------------------------------------------------------------------------------------------------------------------

Rat       2 g/kg           18 h after DMF       1.5 g/kg            not measured      ethanol increased     Hanasono et al. (1977)
          (oral)           exposure             (oral)

Rat       2 g/kg           24 h after last      3000 mg/m3          not measured      acetaldehyde          Hanasono et al. (1977)
          (oral)           DMF exposure         4 h/day 3 days                        increased
                                                (inhalation)

Rat       2 g/kg           24 h after last      12 000 mg/m3        not measured      acetaldehyde          Hanasono et al. (1977)
          (oral)           DMF exposure         4 h/day 3 days                        increased
                                                (inhalation)
-----------------------------------------------------------------------------------------------------------------------------------------
a Increased acetaldehyde level observed after this dose of DMF was equivalent to that produced by an equimolar dose of disulfiram (antabuse).
6.2  Human studies

6.2.1  Absorption, distribution, metabolism, excretion

     In vitro  studies on excised human skin (Bortsevich, 1984) showed 
a relationship between the amount of DMF absorbed through the dermal 
barrier and the DMF concentrations in water, as well as the exposure 
time.  DMF enhances its own penetration.  Some of the results are 
given in Table 9.  They are of practical value, because such solutions 
are used in synthetic fibre production. 

    After respiratory exposure to DMF, lung retention in workers in an 
artificial leather factory was 72% (Brugnone, 1980a,b). 

Table 9. Quantities of DMF absorbed in  in vitro  studies on 
excised human skin
--------------------------------------------------------------
Exposure period             DMF solutions in water            
    (h)           100%         60%          30%          15%
                   % DMF absorbed through the skin (mg/cm2)
--------------------------------------------------------------
    0.5            0.046         NDa         NDa          NDa
  1-1.5            7.400       0.035        0.013        0.006
  2-2.5           20.550       0.087        0.048        0.009
  3-3.5           40.810       0.222        0.097        0.017
  4-4.5           51.730       0.300        0.160        0.069
--------------------------------------------------------------
a ND = Not detectable.

    The relative importance of skin versus inhalation for DMF 
absorption was studied in volunteers by Maxfield et al. (1975), 
Kimmerle & Eben (1975a), and Krivanek et al. (1978) (section 6.2.3.1). 

    As in animals, the major human metabolite of DMF has been reported 
to be DMF-OH and not NMF.  However, it is measured as NMF when using 
gas chromatography including the small amount of NMF excreted in the 
urine (Scailteur & Lauwerys, 1987). 

    When a male volunteer inhaled the DMF vapours that were produced 
over liquid DMF in a beaker for 6 h, Mraz & Turecek (1987) identified 
the metabolite  N-acetyl- S-( N-methylcarbamoyl) cysteine in the urine. 

    Malonova & Bardodej (1983) reported a possible increase in the 
urinary excretion of mercapturates in workers exposed to unknown 
concentrations of DMF (approximately twice the excretion in controls 
(smokers)). 

6.2.2  The influence of ethanol on DMF metabolism in human volunteers

    Eben & Kimmerle (1976) exposed 4 subjects via inhalation to DMF 
(159 mg/m3) for 2 h with, and without, ingestion of 19 g ethanol (50 
ml 38% gin), 10 min before they inhaled the DMF. No changes in DMF 
concentrations in blood were found.  The comparatively lower NMF 
concentrations in the blood of subjects with combined exposure to 
ethanol and DMF indicated that the ethanol decreased the 
biotransformation of DMF.  No significant differences in the blood 

levels of ethanol and acetaldehyde were detected in subjects with, or 
without, ethanol exposure, which differed from the effects observed in 
animal studies.  The authors suggested that this was because of the 
relatively low concentrations of DMF used in the human studies. 

6.2.3  Biological monitoring of workers

     N-Hydroxymethyl- N-methylformamide (DMF-OH) has been identified as 
the main urinary metabolite of DMF.  It is measured, using gas 
chromatography, as NMF together with the small proportion of NMF 
excreted in the urine.  Some results of studies on the correlation 
between exposure levels to DMF and NMF excretion in workers and human 
volunteers are given in Table 10. 

6.2.3.1  Determination of NMF in the urine

    NMF (DMF-OH) in the urine is a sensitive biological parameter of 
human DMF exposure.  NMF levels in the urine are usually greater at 
the end of the shift than on the morning after the exposure. Lauwerys 
et al. (1980) compared a group of 22 male workers from the spinning 
mill in a polyacrylic fibre plant with 28 controls. The workers in the 
spinning department wore gloves and long sleeves, but did not have any 
respiratory protection.  Spot urine samples were collected before, and 
after, the work shift for 5 consecutive days, to determine NMF and 
creatinine concentrations.  NMF was notdetected in the urine of 
control workers, who were not exposed to DMF. There was a poor 
correlation, on an individual basis, between the integrated DMF 
exposure and the NMF concentration in the urine collected at the end 
of the shift, or in that collected before resuming work the following 
day.  However, on a group basis, there was a good correlation between 
the intensity of exposure and NMF levels in the urine collected at the 
end of the shift. 

    In a second study in the polyacrylic fibre plant, Lauwerys et al. 
(1980) studied the NMF levels in the urine of 7 workers for 3 weeks, 
when different types of personal protective devices were used. 
Absorption of DMF vapours through the skin was more important than 
through inhalation.  In the absence of skin contact, a concentration 
of 40-50 mg NMF/g creatinine, in post-shift samples, corresponded to 
an average concentration of DMF vapour of 13 mg/m3 (45 ppm) during a 
6-h exposure period. 


Table 10.  NMF levels in urine as a test for DMF exposure
------------------------------------------------------------------------------------------------------------------
Subjects          DMF concentrations    NMF concentrations     Time of sampling           Reference
                  in the air            in the urine             
------------------------------------------------------------------------------------------------------------------
4 volunteers      78 ± 24 mg/m3a        24 mg/24 h                                        Kimmerle & Eben (1975a)
                  261 ± 75 mg/m3a       97.4 mg/24 h
                  63 ± 12 mg/m3b        30 mg/24 h

4 volunteers      159 ± 96 mg/m3a       44.8 mg/24 h                                      Eben & Kimmerle (1976)
               
4 volunteers      32.4 ± 2.1 mg/m3a,c   5 mg/24 h                                         Maxfield et al. (1975)

8 volunteers      26.4 ± 0.9 mg/m3b     2.5 mg/24 h                                       Krivanek et al. (1978)

22 workers        13 mg/m3b             20-40 mg/g             post-shift samples         Lauwerys et al. (1980)
                                        creatinine

9 workers         15.4 mg/m3b           0.4-19.6 mg/24 h                                  Yonemoto & Suzuki (1980)

85 workers        30-150 mg/m3b,c       0.104-0.224 mg/ml                                 Aldyreva et al. (1980)

23 workers        above 30 mg/m3b       20-40 mg/24 h                                     Taccola et al. (1981)

2 volunteers      30 mg/m3b             102.6 µmol/8 h                                    Wicarova & Dadak (1981)

39 workers                              217.5 µmol/24 h

30 workers        14-86.3 mg/m3b        12-188.3 mg/g          4 h after the work shift   Sala et al. (1984)
                                        creatinine             different work areas
------------------------------------------------------------------------------------------------------------------
a Single inhalation exposure to DMF (2, 4, or 6 h/day).
b Repeated inhalation exposure to DMF (6, 7, 7.5 h/day).
c Dermal absorption.
    Yonemoto & Suzuki (1980) studied the relationship between the 
individual occupational exposure to DMF and the amount of NMF in the 
urine of 9 male workers who handled polyurethane surface-treating 
agents for synthetic leather.  The time-weighted average individual 
exposures ranged from 0 to 15.4 mg DMF/m3. The amount of NMF excreted 
daily ranged from 0.4 to 19.56 mg/24 h.  The excretion rate of NMF 
(mg/h) increased from the beginning of exposure and reached a maximum 
in the urine samples collected in the evening.  The relationship 
between the total daily NMF excretion in the urine and the level of 
exposure was represented as a linear regression, indicating that the 
best biological index of DMF exposure is the determination of NMF in 
the 24-h urine (Fig. 2). At an 8-h integrated DMF exposure of 15 
mg/m3, the NMF level in the urine of the workers was less than 20 
mg/24 h. This value is higher than those obtained for volunteers 
(Kimmerle & Eben, 1975b; Krivanek et al., 1978) or for workers 
(Lauwerys et al., 1980). Yonemoto & Suzuki (1980) stated that the 
difference might be due to dermal absorption of DMF, because the 
workers did not use protective gloves or special working overalls. 

FIGURE 2

    Wicarova & Dadak (1981) studied the relationship between the 
amount of NMF in the shift urine (8 h) or the all-day urine (24 h) of 
workers and DMF concentrations in the air (0-100 mg/m3) in an 
artificial leather plant .  The relationship was linear for the shift 
urine samples.  For the 24-h urine samples, the relationship was 
linear only in the range of 0-80 mg DMF/m3 (see also Table 10).

    When Dixon et al. (1983) studied the urinary NMF excretion in a 
group of 32-37 workers who were exposed to similar air levels of DMF 
for either 8 h per shift (5 days/week) or 12 h per shift (4 
days/week), they found higher concentrations of NMF in the urine when 
the workers were working 8-h shifts.  A possible explanation was that 
a 13% reduction in urine volume was seen in workers on 8-h shifts 
during the summer months compared with higher urine outputs seen in 
the same workers on 12-h shifts during the winter months. 

    Sala et al. (1984) found a correlation between urinary NMF levels, 
4 h after workplace exposure, and the workers' exposure levels to DMF 
in 5 job categories relating to artificial leather production.  They 
reported airborne DMF concentrations of 4.5-14 mg/m3 for spreading 
"coagulate" system workers, with a mean NMF in urine of 16 mg/g 
creatinine, 9.4 mg DMF/m3 for finishing workers, with a mean NMF 
urinary value of 12 mg/g creatinine (low exposures), and 86.3 mg 
DMF/m3 in tank cleaning workers with a corresponding urinary value of 
188.3 mg NMF/g creatinine (highest exposure). 

6.2.3.2   N,N-Dimethylformamide determination in the expired air

    Airborne DMF concentrations change considerably during the work 
shift and from one workplace to another.  Brugnone et al. (1980a) 
measured the DMF concentrations in the alveolar air every hour during 
the 8-h shift of 8 workers employed in an artificial leather plant.  
The alveolar DMF concentration in 6 workers was correlated with the 
DMF concentration in the air of the respective workplaces. 

    In a second study, Brugnone et al. (1984) studied 8 exposed 
workers by determining the DMF concentrations in the environmental 
air, alveolar air, blood, and urine.   Air samples were collected at 
hourly intervals during an 8-h work shift, blood samples, at 2-h 
intervals, and urine samples, at 4-h intervals.  No DMF was found in 
the blood or urine.  A good correlation between the alveolar and 
environmental DMF concentrations was found in 6 out of the 8 workers, 
and at all subsequent hours, except for the fourth hour. 

    In practice, the alveolar air test is more difficult to perform 
and use for routine examination than measurement of NMF levels in 
urine samples, and is not recommended for biological monitoring. 

6.2.3.3  Appraisal

    The level of NMF in a post-shift urine sample is the most 
appropriate biological parameter for total DMF exposure (inhalation 
plus dermal) during the shift. 

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    The effects of DMF on organisms in the environment have been 
reviewed by Kennedy (1986) and by US EPA (1986). 

    The LC50s of DMF for various aquatic species, given in Table 11, 
indicate a low toxicity for the species tested. 

    DMF is commonly used to facilitate the solution of lipophilic 
compounds in water during aquatic toxicity tests. 

    Cardwell et al. (1978) studied the long-term toxicity of DMF for 
fathead minnow  (Pimephales promelas), brown trout  (Salvelinus 
 fontinalis), and bluegill  (Lepomis macrochirus), and found threshold 
limits of between 43 and 98 mg DMF/litre for the brook trout and 
between 5 and 10 mg/litre for the fathead minnow.  LeBlanc & 
Surprenant (1983) showed that a level of 0.1 ml DMF/litre was 
acceptable for long-term aquatic toxicity tests.  In a study by 
Tonogai et al. (1982), the 24-h and 48-h static median tolerance 
limits for the Himedaka  (Oryzias latipes) were > 1000 mg DMF/litre. 

    A no-observed-effect level (NOEL) of 7700 mg/litre was reported 
for the rainbow trout by Shubat et al. (1982). 

    Solutions of DMF of 25 g/litre (2.5%) were shown to be lethal 
within 0.5 h for eggs of sea urchins  (Lythechinus variegatus, Arbacia 
 punctulata, Lythechinus pictus), the surf clam (Spisule solidissima), 
and the annelid  (Pectinaria) (Rebhun & Sawada, 1969). 

    Hughes & Vilkas (1983) determined that the highest concentration 
that had no significant effect on the green alga  Selenastrum 
 capricornatum, was 1 ml/litre and the no-effect level was 0.5 
ml/litre. 

    Concentrations ranging from 0.085-0.340% DMF had an inhibitory 
effect on cultures of  Streptomyces aureofaciens (Welward & Halama, 
1978). 


Table 11.  Medial lethal (LC50) concentrations (mg/litre) for aquatic
organisms exposed to dimethylformamide (DMF)
----------------------------------------------------------------------------------------------------
Species                                   LC50                            Reference
                          ---------------------------------------
                              24-h        48-h          96-h
----------------------------------------------------------------------------------------------------
Guppy                         1300                                        Dojlido (1979)
 (Paecilia reticulata)

Rainbow trout                                           9800              Poirier et al. (1986)
 (Salmo gairdneri)                                       9860              Shubat et al. (1982)

Fathead minnow                                        10 600              Poirier et al. (1986)
 (Pimephales promelas)

Bluegill                                                7100              Poirier et al. (1986)
 (Lepomis macrochirus)

Midge  (Paratanytarsus                     36 200                          Poirier et al. (1986)
 parthenogeneticus)

Daphnid  (Daphnia magna)                   14 500                          Poirier et al. (1986)
                                          12 300                          LeBlanc & Surprenant
                                          (approx.)                       (1983)

Larvae  (Aedes aegypti)                    68 000                          Kramer et al. (1983)
                                          (approx.)
----------------------------------------------------------------------------------------------------
8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO  TEST SYSTEMS

8.1  Single exposures

    Data on the acute toxicity of DMF in different laboratory animals, 
when administered by different routes, have been reviewed by Kennedy 
(1986).  The acute toxicity in a number of species, following oral, 
dermal, inhalation (Table 12), or parenteral (Table 13) administration 
of DMF is relatively low, with lethal doses generally in the g/kg 
range for the oral, dermal, and parenteral routes and in the g/m3 for 
inhalation exposures.  Animals given large single doses of DMF or 
exposed to high air levels showed general depression, anaesthesia, 
loss of appetite, loss of body weight, tremors, laboured breathing, 
convulsions, haemorrage of the nose and mouth, liver injury, and coma 
immediately preceding death. 

    In mice and rats, exposed to DMF via inhalation, signs of mucous 
membrane irritation were seen (Lobanova, 1958; Lundberg et al., 1986), 
and lung damage was detected histologically (Clayton et al., 1963). 

    Where tissue pathology was included in the study, the prominent 
organ showing damage was the liver (Massmann, 1956; Sanotsky et al., 
1978; Mathew et al., 1980; Lundberg et al., 1981).  No obvious species 
differences were observed with regard to acute lethality, but young 
rats appeared more sensitive to DMF-induced lethality than older rats 
(Kimura et al., 1971). 

8.2  Skin and eye irritation, sensitization

    DMF was reported to be irritating to the eyes, mucous membranes, 
and the skin (Hamilton & Hardy, 1974; Aldyreva & Gafurov, 1980). 

8.2.1  Skin irritation

    Rat tails dipped in DMF at 40 °C for 8 h became mummified in a few 
days (Massmann, 1956). 

    A single application of 500 mg DMF/kg resulted in transient 
irritation within 2-3 h in mice, but no irritation in rats (Wiles & 
Narcisse, 1971).  DMF was slightly irritating for mice at doses of 
2500 and 5000 mg/kg.  No skin irritation was detected in rabbits with 
applications of 100, 200, or 500 mg DMF/kg.  Single applications of 
DMF on the skin of rats and guinea-pigs did not cause irritation 
(Kiss, 1979; Bainova, 1985).  Repeated 28-day treatments with 960 or 
1920 mg/kg did not induce marked local dermal effects in rats (Bainova 
et al., 1985). 


Table 12.  LD50 and LC50 values of DMF after oral, dermal, or 
inhalation exposure in various animal species
----------------------------------------------------------------------------------------------------
Species             Oral LD50   Dermal LD50  Inhalation LC50   Reference
                    (mg/kg)       (mg/kg)      (mg/m3)
----------------------------------------------------------------------------------------------------
Rat                 3000                                       Thiersch (1962)
                                5000          9432             US NIOSH (1977)
                    3920                                       Massmann (1956)
                                11 140        12 000           Schottek (1970, 1972)
                    4000                                       Sanotsky et al. (1978)
                              > 11 520                         Bainova & Antov (1980)
                                              15 000           Clayton et al. (1963)
                    4320                                       Lazarev & Levina (1976)
                                11 000a                        Stula & Krauss (1977)
                                            > 13 440           Lundberg et al. (1986)
                    3200                                       Qin & Gue (1976)
                                              14 000           Cai & Huang (1979)
                    7170                                       Bartsch et al. (1976)
                    
Mouse               3950                                       Lazarev & Levina (1976)
                    5550                                       Lazarev & Levina (1976)
                              > 5000                           Wiles & Narcisse (1971)
                    6420                                       Bartsch et al. (1976)
                    3700                      6000-9400        Lobanova (1958)
                    5400, 6200                                 Qin & Gue (1976)
                                              18 300           Cai & Huang (1979)

Rabbit            > 5000      > 500                            Wiles & Narcisse (1971)
                                1500a                          Stula & Krauss (1977)

Mongolian gerbil    3929                                       Llewellyn et al. (1974)
----------------------------------------------------------------------------------------------------
a Pregnant females.

Table 13.  LD50s (mg/kg body weight) of DMF after parenteral administration 
in various animal species
----------------------------------------------------------------------------------------------------------
Species       Intraperitoneal   Intravenous   Intramuscular  Subcutaneous     Reference
----------------------------------------------------------------------------------------------------------
Rat              1480                             4030                        Massmann (1956)
                 2500                                                         Thiersch (1962)
                 4440               2830                                      Bartsch et al. (1976)
                 4600                                                         Pham Huu Chanh et al. (1971)
                 5470                                                         Shottek (1970, 1972)

Mouse             300                                                         Massmann (1956)
                                    3500          3800           4500         US NIOSH (1977)
                  650                                                         Barral-Chamaillard
                                                                                & Rouzioux (1983)
                 1454                                                         Burgun et al. (1975)
                 2000                                                         Antoine et al. (1983)
                 3150               2800                                      Wiles & Narcisse (1971)
                 5200                                                         Pham Huu Chanh et al. (1971)
                 5850               3490                                      Bartsch et al. (1976)

Rabbit            945               1800                                      Massmann (1956)
                                    1000                                      Wiles & Narcisse (1971)
                 5000                                                         US NIOSH (1977)

Guinea-pig       1300                                                         Wahlberg & Boman (1979)
                                    1030                                      US NIOSH (1977)
                 4000                                                         Ungar et al. (1976)

Dog                                  470                                      Barral-Chamaillard
                                                                                & Rouzioux (1983)

Cat               500                                                         Massmann (1956)
----------------------------------------------------------------------------------------------------------
    After repeated application of DMF to the skin of guinea-pigs for 
21 days (Bainova, 1985), the mean irritative dose was 31% DMF (range 
17-56%). 

    Dermal irritation was not seen in rabbits treated dermally with 2 
g DMF/kg for 6 h, daily 15 times during a 4-week period (Kennedy, 
1986). 

8.2.2  Eye irritation

    A 25% (25 g/litre) solution of DMF in water, injected into the 
conjunctival sac of the rabbit, did not produce any effects; 50% was 
slightly irritating, and 75-100% produced more severe irritation 
(Massmann, 1956). Single dose DMF instillation (0.1 ml) produced 
moderate corneal damage and conjunctival redness that was most 
pronounced at 2-3 days.  By day 14, a mild degree of conjunctival 
redness, moderate corneal damage with an area of severe injury, slight 
surface distortion, and subsurface vascularization were observed 
(Kennedy & Sherman, 1986).  In another study, the same authors 
reported that, after a single DMF instillation, the eye inflammation 
subsided and disappeared by the 8th day. 

8.2.3  Sensitization

    DMF was tested, using a maximization technique, on guinea-pigs to 
determine skin sensitization; it did not induce any response (Bainova, 
1985). 

8.3  Repeated exposure

    The effects of repeated oral, dermal, or inhalation exposure to 
DMF in various animal species have been reviewed by Kennedy (1986) and 
these data, together with other new information are summarized in 
Table 14.  In all species tested, except the dog, liver damage was 
produced, the degree of damage generally being proportional to the 
dose administered.  In the two reported studies on the dog (Clayton et 
al., 1963; Kimmerle & Eben, 1975a), the inhalation exposure conditions 
appeared to be too low (60 mg/m3) to produce damage, though 1 out of 
the 4 dogs tested by Clayton did have altered liver function tests.  
Higher levels were not tested. Some evidence of recovery from the 
hepatotoxic effects of DMF was found in rats (Kennedy & Sherman, 
1986). 

    Higher, intermittent doses of DMF appeared to produce more 
pronounced effects in male rats than continuous dosing (Bainova et 
al., 1981a; Bainova, 1985).  Tanaka (1971) found more pronounced liver 
damage in rats following one rather than three weeks of exposure and 
considered that the high regenerative capacity of liver tissue was 
responsible for the observation. 
    
    Other tissues and organs that are affected, particularly by high 
doses of DMF, will be discussed in section 8.4. 

8.4  Specific organ toxicity

8.4.1  Liver

    The potency of DMF as a hepatotoxic agent has been reviewed by 
Kennedy (1986) and by Scailteur & Lauwerys (1987).  The effects of DMF 
on the liver were studied after single or repeated inhalation, dermal, 
or oral treatment of rats, mice, and rabbits (Massmann, 1956; Clayton 
et al., 1963; Shottek, 1970; Tanaka, 1971; Kimmerle & Eben, 1975a; 
Medyankin, 1975; Sanotsky et al., 1978; Germanova et al., 1979; Mathew 
et al., 1980; Bainova et al., 1981a; Lundberg et al., 1981; Lundberg, 
1982; Brondeau et al., 1983; Bainova, 1985; Kennedy & Sherman, 1986; 
Scailteur & Lauwerys, 1987).  Single oral administrations of 2250-5000 
mg DMF/kg in rats (Kennedy & Sherman, 1986) caused clay-coloured 
liver, congestion, and centrilobular necrosis of hepatocytes.  Lower 
doses resulted in deviations in liver function, such as decreased 
excretion of cholic acid in the bile, bromosulfthalein retention, 
increased serum activities of GOT, GPT, LAP, OCT, AlcP, ChE, LDH, and 
gamma-GT, and significant enhancement of cholesterol, triglyceride, 
and bilirubin contents in the serum and liver homogenates.  In rats, 
following both intraperitoneal (ip) and inhalation exposure, there 
were no increases in SDH levels at 420 and 840 mg/m3 but a lower level 
(210 mg/m3) raised the serum activity of SDH (Lundberg et al., 1986). 
Pathomorphological investigation demonstrated lipid degeneration and 
cloudy swelling of hepatocytes in the central zones of the lobules 
followed by signs of regeneration. 

    DMF at 0.6 ml/kg, administered intraperitoneally, caused mild 
changes in rat liver lobules.  Marked centrilobular necrosis and 
central phlebitis were found in the rats treated with single ip doses 
of 0.9 and 1.2 ml DMF/kg (Mathew et al., 1980).  A single ip dose of 
0.5 ml DMF/kg to hamsters caused centrilobular necrosis accompanied by 
haemosiderosis (Ungar et al., 1976).  Morphological changes were 
reported in the liver by Clayton et al. (1963), Shottek (1970), Tanaka 
(1971), and Santa Cruz & Corpino (1978) after repeated DMF exposure of 
young animals, with periodic peaks (Table 14). 


Table 14.  Effects of repeated oral, dermal, or inhalation exposure to DMF in various animal species
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
Mongolian  oral         10 000 mg/kg       30 days    no changes in body weight, liver,   Llewellyn     
gerbil                  drinking-water                or kidney                           et al. (1974) 
                                                                                                        
                        10 000 mg/kg       200 days   mortality in 25% of animals;                      
                        drinking-water                liver necrosis                                    
                                                                                                        
                        17 000 mg/kg       80 days    mortality with liver necrosis;                    
                        drinking-water                LD50 cumulative 90 206 mg/kg                      
                                                      body weight                                       
                                                                                                        
                        34 000 mg/kg       6 days     mortality with liver necrosis;                    
                        drinking-water                LD50 cumulative 3846 mg/kg body                   
                                                      weight                                            
                                                                                                        
Mouse      oral         620 or 1240        30 days    anorexia, loss of body weight       Qin & Gue      
                        mg/kg diet                                                        (1976)      
                                                                                                      
                        160, 540,          119 days   dose-related increase in relative   Becci et al.     
                        1850 mg/kg diet               and absolute liver weights; no      (1983)      
                                                      other histological or biochemical               
                                                      changes; NOEL, 246-326 mg/kg                    
                                                      diet per day                                    
                                                                                                      
Rat        oral         320 or 640         30 days    anorexia, loss of body weight       Qin & Gue        
                        mg/kg diet                                                        (1976)
                                                                                                
                        50, 500, 5000      100 days   body weight decrease; liver         Qin & Gue        
                        mg/litre                      damage at 5000 mg/litre;            (1976)
                        drinking-water                increase in liver to body weight          
                                                      ratio at 500 and 5000 mg/litre;           
                                                      structural liver changes and              
                                                      regeneration at 5000 mg/litre;            
                                                      NOEL, 50 mg/litre                         

Table 14 (continued)
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
                                                                                                
Rat        oral         102, 497, 1000     14 days    no behavioural changes at 102 or    Savolainen 
                        mg/litre           49 days    497 mg/litre for 49 days; dose-     (1981)     
                        drinking-water                related deviations in cerebral                 
                                                      and glial cell enzyme activities               
                                                                                                      
                        215, 750, 2500     104 days   dose-related increase in relative   Becci et al.
                        mg/kg diet                    and absolute liver weights,         (1983)      
                                                      considered to be physiological                  
                                                      adaptation; NOEL, 210-235 mg/kg                 
                                                      diet per day                                    

                        200, 1000, 5000    90 days    slight anaemia and leukocytosis,    Kennedy &   
                        mg/kg diet                    hypercholesterolaemia at 1000 and   Sherman (1986)
                        (equivalent to                5000 mg/kg diet; NOEL, 200 mg/kg                  
                        12, 60, 300 mg/               diet                                              
                        kg/body weight                                                                  
                        per day)                                                                        
                                                                                                        
                        0.1, 0.5, 1.0      14 days    dose-related increase in liver/     Elovaara 
                        g/litre in         49 days    body weight ratios; in liver        et al.   
                        drinking-water                and kidneys, increased values of    (1983)   
                                                      reduced glutathione, microsomal              
                                                      UDP glucuronosyl transferase,                
                                                      and ethoxycoumarin  O-demethylase             
                                                      activities; no changes in liver              
                                                      microsomal cytochrome P-450 or               
                                                      ADPH-cytochrome reductase                    
                                                      activity                                                 

Rat        dermal       470 mg/kg per      30 days    continuous dosing caused            Schottek 
                        day for 29 days               hepatoxicity and did not protect    (1970)
                        and 11 140 mg/kg              against lethality; pretreatment           
                        on the 30th day               did not enhance toxic reactions           
                                                      after application of the LD50             
                                                      in 30-day pretreated rats                 

Table 14 (continued).
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
                                                                                                
                        215, 430, 960,     30 days    dose-related changes in GOT,        Bainova &     
                        or 4800 mg/kg                 GPT, AlcP, ChE, gamma-GT, lipid     Antov (1980)  
                        per day                       fractions in serum and liver                      
                                                      homogenates; NOEL, 215 mg/kg                      
                                                                                                        
Rat        dermal       215, 320, 960,     30 days    dose-related changes (at doses      Bainova (1985)
                        or 4800 mg/kg                 > 320 mg/kg) in enzyme                           
                                                      activities per day in liver,                      
                                                      myocardium, and kidney                            
                                                      homogenates; NOEL, 215 mg/kg                      
                                                                                                        
Rat        dermal       960 mg/kg daily    28 days    functional, biochemical, and        Bainova et al.
                        or 1920 mg/kg                 pathomorphological changes in       (1981a)       
                        applied                       liver; and lipid metabolism         Bainova (1985)
                        intermittentlya               on the 4th, 8th, 14th, and 28th                   
                                                      day of the tests; changes more                    
                                                      pronounced after intermittent                     
                                                      exposure                                          
                                                                                                        
                        4-h dipping of     60 days    concentration-related changes       Medyankin        
                        tails in 60, 65,              in liver and nervous system;        (1975) 
                        70, or 80% DMF                NOEL, 60% DMF in water                     
                        in water                                                                 
                                                                                                 
                        4-h dipping of     120 days   no changes at 30% DMF contact and   Medyankin        
                        tails in                      5 mg DMF/m3 inhalation; adverse     (1975)
                        30 or 60% DMF                 effects at other concentrations           
                        and inhalation of                                                       
                        5 or 10 mg DMF/m3,                                                      
                        6 h daily                                                               

Table 14 (continued).
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
                                                                                                       
Rabbit     dermal       50, 100% water     7 days     died at 5-8 day of application      Huang et al.     
                        solution, 3                   at 100% DMF; liver biochemical      (1981)
                        times/day, 2 ml/              and histological changes                  
                        application                                                             
                                                                                                
                        2000 mg/kg per     9 days     anorexia, cyanosis, and mortality   Kennedy &      
                        day                           with liver necrosis                 Sherman (1986)
                                                                                                        
Guinea     dermal       50, 75, 100%       7 days     died 2-4 days after application of  Huang et al.     
-pig                    solution,                     75 or 100% and 4-9 days after 50%;  (1981)
                        3 times/day,                  loss of body weight; liver damage         
                        2 ml/application                                                        
                                                                                                                 
Rat        inhalation   1800 mg/m3 for     6 days     concentration-related mortality;    Schottek         
                        6 h daily                     cumulation of hepatoxic effect      (1970)
                                                                                                
                        750 and 1500       6 days                                               
                        mg/m3, 6 h daily                                                        
                                                                                                
                        30 mg/m3 for       8 days     no changes in the function of       Sanotsky &    
                        6 h daily                     the thyroid or adrenal glands       Ulanova (1975)
                                                                                                        
                        aerosol for        3 or       liver and kidney necrosis, lung     Santa Cruz &  
                        0.5 h daily        30 days    changes, arterial changes in        Corpino (1978);
                        (concentration                myocardium                          Santa Cruz &   
                        unknown)                                                          Maccioni (1978)
                                                                                                         
                        22 ± 1.6 mg/m3     18 weeks   liver changes, no other responses   Cai & Huang    
                        for 6 h daily,                                                    (1979)         
                        6 days a week                                                                    

Table 14 (continued).
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
                                                                                                         
Rat        inhalation   130 mg/m3 for      27 days    functional changes in kidneys       Germanova et al.
                        4 h daily                     and liver; arterial blood pressure  (1979)               
                                                      more pronounced after additional                    
                        300 mg/m3 in       27 days    single administration of 500 mg                     
                        5 peaks of                    DMF/kg on the 1st, 8th, and                         
                        15 min at                     27th days of the studies, and                       
                        40-min intervals              after intermittent exposure                         
                                                                                                          
                        7569 mg/m3         5 days     weakness, weight loss,              Kennedy &       
                        for 6 h daily                 dehydration, liver necrosis         Sherman (1986)  
                                                                                                          
                                                                                                          
Young rat  inhalation   600 mg/m3 for      28 days    increased serum GOT and GPT;        Tanaka (1971)   
(3-12                   8 h daily                     morphological liver changes,                        
weeks old)                                            mainly in 3-week-old rats;                          
                                                      no histological abnormalities                       
                                                      in other organs                                     
                                                                                                          
                                                                                                          
                                                                                                          
Young rat  inhalation   600 mg/m3 for      28 days    liver changes at the 1st, 2nd,      Tanaka (1971)   
(3 weeks                8 h daily and                 3rd, and 4th week of test more                           
old)                    600 mg/m3 for                 intense in the group exposed                             
                        1 h daily                     for 8 h daily; no cumulation of                          
                                                      hepatoxic effect                                         
                                                                                                               
                                                                                                               
Table 14 (continued).
________________________________________________________________________________________________________
Species    Route of     Dose               Duration   Effects                             Reference
           exposure                                                                                
________________________________________________________________________________________________________
                                                                                                               
Rat,       inhalation   450, 900, 1800,    60 days    increased serum GOT, GPT, AlcP,     Craig et al.   
mouse                   3600 mg/m3                    cholesterol, anaemia and            (1984)                     
                        for 6 h daily                 histological liver changes at                            
                                                      900 mg/m3 or more; liver weight                          
                                                      increase at 450 mg/m3;  NOEL                             
                                                      below 450 mg/m3 in both species                          
                                                                                                               
                                                                                                               
Rat, cat   inhalation   300, 690, 1350     120 days   anorexia, weight loss, liver        Massmann      
                        mg/m3, 8 h daily              degeneration, and necrosis;         (1956)                      
                                                      changes  in brain, myocardium,                           
                                                      and kidneys; no abnormalities                            
                                                      in blood tests or ECG                                    
                                                                                                               
Rabbit     inhalation   22 ± 1.6 mg/m3     18 weeks   no changes in ECG or liver          Cai & Huang    
                        for 6 h daily,                parameters                          (1979)                     
                        6 days per week                                                                        
                                                                                                               
                        317 ± 37.8 mg/m3   14 weeks   body weight changes; liver damage   Cai & Huang    
                        for 6 h daily,                functionally and structurally; by   (1979)                     
                        6 days a week                 congestion and haemorrhage                               
                                                                                                               
                                                                                                               
                        120 mg/m3 for      50 days    microscopic and electron-           Arena et al.   
                        8 h daily                     microscopic changes in the          (1982)                     
                                                      myocardium                                               
                                                                                                               
                                                                                                         
Dog        inhalation   60 mg/m3 for       107 days   reversible changes in blood         Clayton et al.             
                        6 h daily                     pressure, ECG, and in liver         (1963)               
                                                      functions                                                
                        63 mg/m3 for                                                                           
                        6 h daily           28 days   normal GOT, GPT, bilirubin, urea,   Kimmerle & Eben      
                                                      and creatinine in plasma;           (1975a)              
                                                      NOEL, 63 mg DMF/m3                                       
___________________________________________________________________________________________________________
a Two alternative intermittent regimes were used: (i) 1920 mg/kg per day for 2 days, followed by no 
  treatment for 2 days; (ii) 1920 mg/kg every second day.

    Diets supplemented with DMF at levels of 215, 750, or 2500 mg/kg 
for 104 days for rats and 160, 540, or 1850 mg/kg for 119 days for 
mice, resulted in significant dose-related increases in relative liver 
weights in all experimental animals.  No deviations were reported in 
the serum activities of GOT, GPT, AlcP, other than an increase in GPT 
activity in mice fed a diet containing 1850 mg DMF/kg.  Histo-
pathological evaluation did not reveal any hepatotoxicity (Becci et 
al., 1983).  The oral administration of a 10% water solution of DMF 
(400 mg/kg body weight) for 14 days (Leshik & Feoktistova, 1984) to 
guinea-pigs significantly decreased the ascorbic acid content and the 
concentration of cytochrome P-450 in the liver.  The daily intake of 
0.1, 0.5, or 1.0 g DMF/litre in the drinking-water for 2 or 7 weeks 
(Elovaara et al., 1983) increased the liver/body weight ratios, the 
microsomal UDP-glucuronosyl-transferase and 7-ethoxycoumarin- O-
demethylase activity, and reduced the glutathione concentration in 
liver homogenates. 

    No liver injury was seen following inhalation exposure of dogs to 
63 mg DMF/m3 (Kimmerle & Eben, 1975a).  However, in another study, 1 
out of 4 dogs exposed to 60 mg/m3 showed increased enzyme values 
(Clayton et al., 1963)).  Liver injury was also not seen: after 
inhalation exposure of rats at levels of < 450 mg/m3 (Craig et al., 
1984), after dermal exposure of rats at a level of 240 mg/kg (Bainova, 
1985), and at dietary levels of 215 mg/kg body weight per day for rats 
and 160 mg/kg for mice (Becci et al., 1983). 

8.4.2  Gastrointestinal tract

    Toxic gastroenteritis with pathomorphological deviations was 
described in the experimental animals treated at high doses or 
concentrations in studies reported in Table 14 (Massmann, 1956; 
Clayton et al., 1963; Shottek, 1970). 

8.4.3  Cardiovascular system

    Microscopic examination did not reveal any myocardial lesions in 
rats and mice after ingestion of dietary levels of 215, 750, or 2500 
mg DMF/kg for 104 days, or 160, 540, or 1850 mg DMF/kg for 119 days, 
respectively (Becci et al., 1983). 

    Clayton et al. (1963) and Germanova et al. (1979) reported 
decreases in blood pressure in dogs (not cats) following exposure to 
DMF.  The changes described were not great and, in the absence of 
confirmatory data in other test models (and in man), are of 
questionable significance.  Large iv doses (500 mg/kg) did not produce 
any changes in the contractile force of myocardial tissue in dogs 
(Pham Huu Chanh et al., 1973). 

    Santa Cruz & Maccioni (1978) described histological changes in the 
myocardium of the rat and Clayton et al. (1963) described subtle blood 
pressure changes in the dog.  The findings in the rat followed high 
exposures; the blood pressure changes in the dog were minimal and hard 
to differentiate from those in control animals. 

8.4.4  Kidney

    Swelling of the kidney tubules occurred after a single oral 
administration of 2250-5000 mg DMF/kg in rats (Kennedy & Sherman, 
1986).  Short-term feeding studies in rats and mice (Table 14) did not 
reveal any histopathological lesions in the kidneys (Becci et al., 
1983; Kennedy & Sherman, 1986). 

    A number of pathomorphological studies revealed vacuolar 
degeneration, mainly in the renal tubules (Massmann, 1956; Clayton et 
al., 1963; Santa Cruz & Corpino, 1978; Lundberg et al., 1983). Costa 
et al. (1978) observed histological, histochemical, and electron-
microscopic renal lesions in groups of rats, exposed to DMF aerosols 
(dose not stated) for 1 h/day for 15 days or for 0.5 h/day for 30 
days.  Degeneration took place in the proximal part of tubules and in 
the visceral epithelium of the glomerulus with marked mitochondrial 
changes. 

    Repeated inhalation exposure to 130 or 300 mg DMF/m3 increased the 
kidney/body weight ratio, and decreased diuresis, and the total 
protein, sodium chloride, and potassium contents in the urine of rats 
(Germanova et al., 1979). 

    Elovaara et al. (1983) reported enhanced activities of 7-ethoxy-
coumarin- O-demethylase, and UDP-glucuronosyltransferase, and a 
decrease in cytosolic formaldehyde dehydrogenase activity in rats 
orally exposed to DMF.  Bainova & Antov (1980) and Bainova et al. 
(1981b) reported that the 30-day dermal application of 960 or 4800 mg 
DMF/kg resulted in dose-related increased activities of SucDH, G-6-
PDH, and LDH in rat kidney homogenates. 

8.4.5  Nervous system

    Functional changes in the nervous system were observed after 
administration of high doses or exposure to high concentrations of DMF 
(Massmann, 1956; Clayton et al., 1963) and after prolonged treatment 
with moderate doses of DMF (Medyankin, 1975; Sanotsky et al., 1978; 
Germanova et al., 1979; Bainova, 1985) (Table 14). Doses within the 
range of lethal levels resulted in anaesthesia, depression, or coma.  
Moderate doses caused inhibition of motor activity. 

    No effects on the behaviour of rats were noted after they drank 
DMF in the drinking-water for 2 and 7 weeks at doses ranging from 1.4 
to 13.7 mmol/litre with a cumulative dose of 3200 mg/kg in the rats 
(Savolainen, 1981).  The same dose enhanced the activities of acid 
proteinase and 2,3-cyclicnucleotide-3'-phosphohydrolase in the glial 
cells. 

    Massmann (1956) and Clayton et al. (1963) observed 
pathomorphological changes in the brains of experimental animals after 
treatment with high doses of DMF (Table 14). 

8.4.6  Lungs

    Lung congestion and oedema were found in rats after single oral 
application of 2250-5000 mg DMF/kg (Kennedy & Sherman, 1986). 

    Bronchopneumonic changes were observed in experimental animals 
after inhalation of high DMF concentrations (Massmann, 1956; Clayton 
et al., 1963; Shottek, 1970; Santa Cruz & Corpino, 1978) (Table 14).  
According to the authors, the changes were related to injury of the 
small arterial vessels and, to some extent, to local irritation caused 
by DMF. 

8.4.7  Haematopoietic system

    High levels of DMF might cause some anaemia, but no other changes 
in the erythrocytes of experimental animals have been reported 
(Massmann, 1956; Clayton et al., 1963; Sanotsky et al., 1978; 
Germanova et al., 1979; Bainova & Antov, 1980) (Table 14). Depressed 
bone marrow activity was reported in rats after a single oral 
administration of 2250-5000 mg DMF/kg (Kennedy & Sherman, 1986).  Pham 
Huu Chanh et al. (1971) found leukocytosis in rats after repeated ip 
injections of DMF. 

    Pathomorphological changes were observed in the spleen after 
exposure to high doses of DMF.  They were accompanied by an increase 
in the spleen/body weight ratio (Massmann, 1956; Clayton et al., 1963; 
Bainova & Antov, 1980; Bainova, 1985).  Medyankin (1975) found 
inhibited phagocytosis activity of leukocytes and decreased glycogen 
content in the neutrophiles of rats as a result of combined dermal and 
inhalation exposure to DMF. 

8.4.8  Adrenals

    Clayton et al. (1963) observed histological changes in the adrenal 
glands after inhalation of DMF.  Decreased ascorbic acid content in 
the adrenals of rats was reported by Germanova et al. (1979), during 
intermittent and continuous inhalation exposure to DMF (Table 14). 

8.4.9  Gonads

    Male rats were exposed to 584-616 mg DMF/m3 or 49-51 mg/m3 for 4 h 
daily for 2, 4, or 8 days; female rats were exposed to 2.3 or 10.7 mg 
DMF/m3, for 4 h daily, for 30 days (Sheveleva et al., 1979).  
Examination of the sperm and the histological study of the testes and 
ovaries did not show any pathological signs. 

    Lewis et al. (1979) exposed male rats at 90 or 900 mg DMF/m3, for 
6 h daily, over 5 days.  Gross and histological examination of the 
testes did not reveal any pathological changes. 

    The histological examination of male rats, treated orally in 
short-term studies (Becci et al., 1983; Kennedy & Sherman, 1986) with 
a variety of doses (Table 14), did not result in changes in the 
testes. No lesions were noted in the male rats after a 30-day dermal 
application of DMF (Bainova, 1985).  Craig et al. (1984) did not find 
testicular or ovarian lesions in rats and mice after short-term 
inhalation exposure to DMF at concentrations of up to 3600 mg/m3
(Table 14). 

    Examination of the gonads in a large number of the acute and 
repeated-dose toxicity studies discussed earlier did not reveal them 
to be a target for DMF toxicity. 

8.5  Developmental toxicity and reproduction

    DMF was investigated for developmental toxicity in mice, rats, and 
rabbits using the oral, dermal, and inhalation routes and parenteral 
injection.  According to present-day requirements, most of the older 
studies were not adequately designed or described.  A survey is given 
in Tables 15, 16, 17. 

    No 3-generation reproduction studies were available.

8.5.1  Developmental toxicity

8.5.1.1  Mouse

    Administration by gavage of 580 or 193 µl DMF/kg per day, from day 
6 to 15 after conception, to 26 mice per dose group led to a dose-
dependent decrease in fetal weights and an increase in the number of 
retardations and variations.  At 580 µl/kg per day, 17 out of 241 
fetuses were malformed (cleft palate, exencephaly, hydro-cephalus 
internus, aplasia of presphenoid).  No maternal effects were recorded; 
the number of live fetuses remained unchanged.  At 193 µl/kg, 4 out of 
245 fetuses showed malformations.  In untreated control groups for 
each dose group, 2 out of 229 and 1 out of 310 fetuses, respectively, 
had a cleft palate (Hellwig et al., in press). 

    After an ip injection of 600 or 1100 mg DMF/kg per day, from day 1 
to 14 after conception, embryotoxic and teratogenic effects were 
registered.  The malformation rates were 18 and 75%, respectively, and 
the effects consisted of absence or retardation of posterior skull 
ossification, open eye-lids, cerebral oedema, sternal haematomas, and 
spina bifida-like defects in the thoracic region. Embryotoxic effects 
recorded were late resorptions.  Doses of 170 mg/kg per day from day 1 
to 14 after conception, and 250 mg/kg per day from day 6-14, and 
single doses of 2100 mg/kg each on days 3, 7, 9, or 11 after 
conception, did not produce any effects (Scheufler & Freye, 1975). 

    In another ip injection study on mice, 6 animals per dose group 
were treated with 0.4 or 1.0 mg DMF/kg per day from day 11 to 15 after 
conception.  Maternal body weight gain was reduced at 1.0 mg/kg per 
day, 2 out of 6 animals had abortions, 7 out of 36 fetuses showed 
exencephaly and 1 had a cleft palate.  No effects were observed at 0.4 
mg/kg (Hellwig et al., in press). 

    The studies indicate that DMF may be teratogenic for mice.


Table 15.  DMF administration to pregnant mice
----------------------------------------------------------------------------------------------------
Route          Dosea              Maternal   Embryotoxicity    Malformations          Reference
                                  toxicity
----------------------------------------------------------------------------------------------------
Gavage         control-              -            -                                   Hellwig et al.
               193 µl/kg             -       fetal weights     4 of 245 living        (in press)
               (gavage; day                  decreased         fetuses showed
               6-15 pc)                                        malformations

               580 µl/kg            NRb      fetal weights     17 of 241 living
               (gavage; day                  decreased         fetuses showed
               6-15 pc)                                        malformations

Intra-         control               -           -                   -                Scheufler &
peritoneal     170 mg/kg            NRb          -                   -                Freye (1975)
injection      (day 1-14 pc)

               250 mg/kg            NRb          -                   -
               (day 6-14 pc)

               600 mg/kg            NRb      late              malformation
               1100 mg/kg                    resorptions       rates 18 and 75%
               (day 1-14 pc)                                   respectively

Intra-         0.4 mg/kg             -           -                   -                Hellwig et al.
peritoneal     (day 11-15 pc)                                                         (in press)
injection      1.0 mg/kg             +       2/6 abortions     8/36
               (day 11-15 pc)                                  malformations
----------------------------------------------------------------------------------------------------
a pc = Post conception.
b NR = Not reported.

Table 16.  DMF administration to pregnant rats
---------------------------------------------------------------------------------------------------------
Route        Dosea                    Maternal       Embryotoxicity      Malformations     Reference
                                      toxicity
---------------------------------------------------------------------------------------------------------
Gavage       control                      -                -                -              Hellwig et al.
             (day 6-15 pc)

             533 µl/kg                    -          some embryo-        
                                                     lethality in the    
                                                     early phase,           +
                                                     reduced fetal         
                                                     weights               
                                                     + retardations        
                                                     + variations          

             1600 µl/kg               weight         63% embyro-         12% of the 85
                                      stationary     lethality in        living fetuses
                                      between        the median          were malformed
                                      day 6-15       phase

Dermal       day 6-10 and                                                                  Hellwig et al.
                  0 µl/kg                  -              -                 -
                100 µl/kg                  -              -              2.46%
                500 µl/kg                  -              -              3.05%
               1000 µl/kg                  -         slight reduced      5.46%
                                                     fetal length        (increase in rib
                                                                         and vertebral
                                                                         abnormalities)

Dermal       control                    -                -                  -              Stula &
             600 mg/kg                reduced        slight                                Krauss (1977)
             (days 9, 10 +            weight                             embryolethality
             11, 11 + 12,             gain
             12 + 13 pc)

             1200 mg/kg               reduced        slight
             (day 10 + 11 pc)         weight         embryolethality        -
                                      gain

Table 16.  (contd.)
---------------------------------------------------------------------------------------------------------
Route        Dosea                    Maternal       Embryotoxicity      Malformations     Reference
                                      toxicity
---------------------------------------------------------------------------------------------------------

Dermal       1200 mg/kg               reduced        slight
(contd.)     (day 12 + 13 pc)         weight         embryolethality        -
                                      gain

             2400 mg/kg               stationary     embryolethality        -
             (day 10 + 11 pc)         weight

             400 or 200               reduced        high embryo-           -
             mg/kg (applied           weight         lethality           
             6 times/day              gain
             days 11 + 12
             + 13 pc)

Inhalation   control                     -               -                  -              Hellwig et al.
             (day 0-1, 4-8,           weight         weights
             11-15, 18-19 pc)         gain           resorptions

             861 mg/m3 (287 ppm)      reduced        reduced fetal          -
             (day 0-3, 6-10,          weight         weights
             13-18 pc)                gain           retardations
                                                     resorptions
                                                     variations

             660 mg/m3 (220 ppm)         -           reduced                -
             (day 4-8 pc)                            weight and
                                                     length

             1560 mg/m3 (520 ppm)     reduced        embyro-                -
             (day 4-8 pc)             weight         lethality;
                                      gain           reduced weights


Table 16.  (contd.)
---------------------------------------------------------------------------------------------------------
Route        Dosea                    Maternal       Embryotoxicity      Malformations     Reference
                                      toxicity
---------------------------------------------------------------------------------------------------------

Inhalation   control                     -              -                   -              Kimmerele &
             54 mg/m3 (18 ppm)           -              -                   -              Machemer
             516 mg/m3 (172 ppm)         -           reduced fetal          -              (1975)
             (6-15 day pc)                           weights

Inhalation   control                     -                -                 -              Keller & Lewis
             903 mg/m3 (301 ppm)      reduced        ossification
             (day 6-15 pc)            weight         variations
                                      gain           slightly increased
                                                     from 60 to 75%         -

Inhalation   control                     -                -                 -              Shottek
             1200 mg/m3 (400 ppm)                    total resorp-          -              (1964)
             (4 h/day, 10-20 day pc)   NR            tions in some
                                                     animals, no
                                                     retardations

Inhalation   0.05 mg/litre ca.48 mg/m3               weight                 -              Sheveleva &
             (ca. 16 ppm)              NR            decrease                              Osina (1973)
             (day 0-20 pc)

             0.8 mg/litre ca.600 mg/m3               embryolethality;       -
             (ca. 200 ppm)             NR            weight decrease

Intravenous  control                     -               -                  -              Parkie & Webb
injection    0.5 g/kg on                                 -                  -              (1983)
             days 10, 11,              NR
             or 12 pc)
---------------------------------------------------------------------------------------------------------
a pc = Post conception.
b NR = Not reported.

Table 17.  DMF administration to pregnant rabbits
---------------------------------------------------------------------------------------------------------
Route       Dosea               Maternal         Embryotoxicity       Malformations         Reference
                                toxicity
---------------------------------------------------------------------------------------------------------
Gavage      control                -                   -                   -                Merkle &
            46.4 µl/kg             -                   -              1 hydrocephalus       Zeller (1980)
            (day 6-18 pc)

            68.1 µl/kg             -             decrease in number   3 hydrocephalus
            (day 6-18 pc)                        of implantations
                                                 and % living
                                                 implantations

            200 µl/kg           decrease in      decrease in                +
            (day 8-16 pc)       food intake,     fetal weight,        16 fetuses in
                                weight gain,     3 abortions,         7 litters were
                                and placental    placental weight     malformed:
                                weight           decrease

Dermal      control                 -                 -                     -               Stula &
            200 mg/kg                            some                       -               Krauss (1977)
            (day 8-16 pc)                        embryolethality

Dermal      control 100 mg/kg       -                -                      -               Hellwig et al.
            occlusive                                                 litter skeletal
            (day 6-28 pc)                                             anomalies; 3.3%
                                                                      agenesia of gall
                                                                      bladder

Dermal      200 mg/kg per day      -                 -                      -
            400 mg/kg per day   decrease in                           23.5% fetuses
                                body weight                           per litter sternal
                                on day 16 and                         anomalies; 2.45%
                                18                                    hernia umbilicalis,
                                                                      6.08% agenesia
                                                                      of gall bladder

Table 17 (contd.)
---------------------------------------------------------------------------------------------------------
Route       Dosea               Maternal         Embryotoxicity       Malformations         Reference
                                toxicity
---------------------------------------------------------------------------------------------------------

Inhalation  Control                -                -                       -               Hellwig et al.
            50 ppm)
            (day 7-19 pc)

            450 mg/m3           decrease in      increase in          1 hernia
            (150 ppm)           body weight      sternal              umbilicalis
                                gain             variations           (50 fetuses)

            1350 mg/m3          decrease in      decrease in          incidence of hernia
            (450 ppm)           body weight      weights,             umbilicalis
                                gain             increase in          increased;
                                                 variations           skeletal and soft
                                                 (pseudoanky-         tissue anomalies
                                                 losis)
---------------------------------------------------------------------------------------------------------
a pc = Post conception.
8.5.1.2  Rat

    In a gavage study on groups of 26 rats administered 1600 µl DMF/kg 
per day from day 6 to 15 after conception, maternal toxicity was 
observed in the form of decreased body weight.  Sixty-three percent of 
the implantations were resorbed and 12% of the surviving 85 (36.64%) 
fetuses were malformed (9 cases of diffuse anasarca, 2 cases of tail 
aplasia, 1 micrognathia, furthermore several fetuses had anomalies of 
the ribs, sternum, and vertebral column).  A dose of 533 µl DMF/kg per 
day caused some early fetal deaths, in the absence of clinical signs 
of maternal toxicity, reduced fetal weight, and also some 
malformations, as well as an increase in variations and skeletal 
retardations.  The malformations consisted of: 2 cases of tail 
aplasia, 2 cases of cleft palate, 1 atresia ani, 1 anasarca, 1 open 
eye, and several fetuses with split and aplastic vertebrae.  At 176 
µl/kg, decreased placental weights and some decreases in fetal length 
and increases in fetal weight were seen.  All other parameters were 
within the range of biological variability (Hellwig et al., in press). 

    The dermal studies on rats did not fulfil today's criteria for a 
valid study. 

    In one series of studies (Hellwig et al., in press), 0, 100, 500, 
or 1000 µl DMF/kg per day (undiluted material) were administered in an 
uncovered dermal system from day 6 to 10 and then from day 13 to 15 
after conception (26 animals per dose group; 10 in the control group).  
Under these conditions, 1000 µl/kg per day caused a slightly retarded 
weight gain among the dams and significant dermal irritation.  The 
fetuses were slightly smaller.  Malformations consisted of split 
thoracic vertebrae and anomalies of the ribs.  The rate of the 
malformations in live fetuses was 0% per litter in the controls and 
2.46%, 3.05%, and 5.46% with increasing dose level. This may indicate 
a weak dose-related teratogenic effect. 

    In another study (Stula & Krauss, 1977), rats received dermal 
doses of up to 2400 mg (undiluted DMF)/kg per day, at least every 2 
days, from day 9 to 13 after conception, under non-occlusive 
conditions.  There was clear evidence of embryolethality at 2400 mg/kg 
per day on gestation days 10 and 11 (26%, i.e., 7 rats) and at 1200 
and 2400 mg/kg per day (in 6 portions of 200 and 400 mg) on gestation 
days 11, 12, and 13 with incidences of 43 and 30%, respectively.  
Maternal weight gain and average fetal weights were also suppressed.  
Fetal abnormalities were not observed, with the exception of a few 
subcutaneous haematomas, which occurred at a rate also seen in 
historical controls at this laboratory. 

    Several inhalation studies were carried out on rats.  In one 
study, 23 animals per dose group were exposed to 54 or 516 mg DMF/m3
(18 or 172 ppm) over 6 h per day from day 6 to 15 after conception.  
There were 22 animals in the control group.  The higher exposure level 
caused a decrease in fetal weights in the absence of signs of maternal 
toxicity.  No effects were seen on the numbers of implantations, 
resorption rates, placental weights, number of fetuses weighing less 
than 3 g (runts), variations in skeletal development or malformations; 
the lower exposure level (54 mg/m3) did not cause any adverse effects 
(Kimmerle & Machemer, 1975). 

    In another rat study, exposure to 903 mg/m3 (301 ppm) for 6 h per 
day, from day 6 to 15 after conception (19 animals per group) led to a 
reduction in maternal weight gain and to a slightly increased 
incidence of skeletal (ossification) variations of from 60 to 75%. 
Exposure to 96 mg/m3 (32 ppm) did not produce any effect (Keller & 
Lewis, 1981). 

    Following 10 exposures to 1200 mg/m3 (400 ppm) for 4 h per day, 
from day 10 to 20 after conception, dead implants (54% total 
resorptions compared with 15% in the controls) occurred.  The numbers 
of animals in the treated and control groups were not reported 
(Shottek, 1964). 

    Fetal weight decreases and fetal deaths were reported in another 
study on rats after exposure to 600 mg/m3 (200 ppm) from day 0 
throughout the gestation period.  Exposure to 48 mg/m3 (16 ppm) was 
said to have caused reduced fetal weights.  However, the description 
of the study was inadequate (Sheveleva & Osina, 1973). 

    A series of inhalation studies on rats is described (Hellwig et 
al., in press) in which the exposure periods did not fully cover the 
critical period of the gestation phase (e.g., "window dosing" or non-
exposure during weekends, see Table 17).  In one set of these 
experiments, exposure to concentrations of 660 and 1560 mg/m3 (220 and 
520 ppm), for 6 h per day (days 0-3, 6-10, 11-18 after conception; 18 
animals per group) caused decreased fetal weights, retardations, and 
an increase in embryolethality.  Another exposure regimen, i.e., 861 
mg/m3 (287 ppm), for 6 h per day, was administered on days 1, 4-8, 
11-15, and 18-19 after conception to a group of 30 rats.  Twenty 
animals were subjected to caesarian section on day 20 after 
conception, the offsprings of the other 10 animals were raised until 
day 21 after birth.  Thirty rats served as untreated controls.  There 
was retarded maternal weight gain from the beginning of the treatment; 
fetal weights were decreased, and the numbers of variations and 
retardations were increased.  No malformations were found. 

    No effects were detected after single iv injections of 0.5 g/kg 
body weight between days 10, 11, or 12 after conception (Parkie & 
Webb, 1983).  Furthermore, earlier investigations on rats after single 
ip or sc injections did not give any indication of teratogenicity; 
however, such studies are of limited value for a toxicity assessment. 

    The above studies indicate that DMF is embryotoxic in the rat. 
After dermal and oral administration, teratogenicity may also occur. 

8.5.1.3  Rabbit

    DMF caused maternal toxicity and embryotoxicity, including 
teratogenicity, in rabbits after administration by gavage at 200 µl/kg 
per day from day 6-18 after conception.  All 11 animals in the dose 
group became pregnant and showed reduced food intake and weight gain.  
Placental weights were significantly lower and 3 abortions occurred.  
The fetuses showed weight reduction.  The main findings recorded on 
fetal examination were hernia umbilicalis (7 cases), hydrocephalus 
internus (6 cases), eventratio simplex (3 cases), exophthalmus (2 

cases), cleft palate (1 case), and malposition of limbs (1 case).  The 
number of implantations was not adversely influenced.  At 68.1 µl/kg 
per day, no maternal effects were observed among 16 pregnant animals 
(18 inseminated); decreased numbers of total implantations and of live 
fetuses occurred, also an increase in skeletal variations and 
retardations per litter; 3 cases of hydrocephalus internus were 
present.  At 46.4 µl/kg per day (10/12  does were pregnant) 1 case of 
hydrocephalus internus occurred; all other parameters were in the 
range of biological variability.  No malformations occurred in the 
untreated control group (22/24 animals) (Merkle & Zeller, 1980). 

    In a dermal study, 5 rabbits (4 animals in the control group) 
received 200 mg DMF/kg per day, dermally, from day 8 to day 16 after 
conception.  The test material was applied in undiluted form on the 
intact skin, apparently under non-occlusive conditions.  Embryo 
mortality was 6% compared with 3% in the controls.  The average fetal 
weight was 32.9 g in the litters of treated animals compared with 28.4 
g among controls.  Fetal abnormalities were not detected (Stula & 
Krauss, 1977). 

    In another dermal study (Hellwig et al., in press), dose levels of 
undiluted DMF of 0, 100, 200, or 400 mg/kg per day were applied for 6 
h/day, under semi-occlusive conditions (15 animals per dose group).  A 
5-6% decrease in maternal body weights occurred in the highest dose 
group, towards the end of the treatment period (days 16-18 after 
conception).  At this dose level, an increase in skeletal (sternal) 
malformations was found in 15 fetuses in 7 litters investigated 
(23.5%), and also 5 cases of missing gall bladder (in 2 litters).  No 
malformations occurred in animals in the 200 mg/kg per day group or in 
the untreated control group.  At 100 mg/kg per day, one fetus had a 
sternal anomaly, 2 fetuses had gall bladder agenesis, and one of the 
latter a hypertrophic-dilatative cardiac-aortic malformation. 

    In a recent inhalation study, exposure levels were 0, 150, 450, 
and 1350 mg/m3 (0, 50, 150, and 450 ppm) over 6 h per day from day 7 
to day 19 after conception (fifteen animals per dose group). Animals 
in the highest exposure group showed a slight retardation in body 
weight gain as a sign of maternal toxicity.  The fetal weights were 
significantly lower in this group, and there was a significant 
increase in malformations, mostly hernia umbilicalis (7 out of 86 
fetuses, in 4 out of 15 litters) and some soft-tissue malformations, 
such as missing gall bladder, without statistical significance.  In 
addition, anomalies of the sternum, an increase in split vertebrae, 
and a number of variations were also recorded.  At 450 mg/m3, maternal 
body weights were slightly retarded during the exposure period and the 
corrected body weight gain was marginally, but significantly, 
decreased.  One case of hernia umbilicalis among 75 fetuses and an 
increase in sternal variations were observed.  At 150 mg/m3, neither 
fetuses nor does showed any indications of response to treatment.  In 
summary, signs of embryotoxicity and teratogenicity were seen at the 
highest concentration (1350 mg/m3) and to a lesser degree at 450 
mg/m3.  The maternal toxicity seen at 1350 mg/m3 and 450 mg/m3 is in 
accordance with the maternal toxicity observed at 900 mg/m3 in a 
previous range-finding study (Hellwig et al., in press). 

    These studies indicate that DMF may be teratogenic for rabbits.

8.5.1.4  Appraisal

    The overall conclusion from all studies is that DMF may lead to 
embryotoxic and teratogenic effects in rats, mice, and rabbits.  An 
increase in malformations in the absence of maternal toxicity is 
clearly visible after gavage and ip administration, with a smaller 
incidence after dermal administration.  In general, the rabbit 
appeared to be more sensitive to the teratogenic effects of DMF than 
the rat.  After inhalation exposure, fetal toxicity and teratogenic 
effects appear to be confined to conditions of maternal toxicity. 

8.6  Mutagenicity and related end-points

    DMF has been tested extensively in mutagenicity and genotoxicity 
assays.  DMF was one of the 42 chemicals selected for study in the 
International Collaborative Program for the Evaluation of Short-Term 
Tests for Carcinogenicity (Serres & Ashby, 1981). 

    The genetic toxicity studies on DMF have been reviewed by Purchase 
et al. (1978), Kennedy (1986), US EPA (1986), and IARC (1989). 

8.6.1   In vitro studies

    In different  in vitro  assays, DMF did not induce mutations or 
genotoxic effects (Table 18).  Negative results were obtained with 
both in  Salmonella typhimurium and  Escherichia coli.  DMF did not 
induce unscheduled DNA synthesis, sister chromatid exchanges, 
chromosomal aberrations, or gene mutation in mammalian cells, or 
mitotic gene conversion or crossing over in yeasts (Serres & Ashby, 
1981). 


Table 18.  Short-term genotoxicity tests on DMF ( in vitro )                                           
------------------------------------------------------------------------------------------------------------
Method                     Concentration                   Condition; comment       Results  Reference
------------------------------------------------------------------------------------------------------------
Ames test                  0.65 x 10-5-1.3 x 10-3          TA 98, 100, 1535,           -     Antoine et al.
                           mol/litre                       1537, 1538,                       (1983)
                                                           with and without
                                                           liver microsome 

 B. subtilis                maximum dose 20 mg/disk         - S9, + S9 (rat, yellow     -     Serres & 
Spore rec-assay                                            tail, clam)                       Ashby (1981)

 E. coli differential       highest concentration           WP2, WP67, CM871            -     Serres & 
killing test               30 µl/plate                                                       Ashby (1981)

 E. coli rec-assay          highest concentration 1 g/ml    2921, 9239, 8471, 5519,     -     Serres & 
                                                           7623, 7689                        Ashby (1981)

DNA polymerase deficient   100 µl/ml                       + S9 and - S9               -     Serres & 
assay                                                                                        Ashby (1981)
                                                            E. coli W3110               -
                                                                   P3478

Yeast mutation                                              S. pombe                    -     Serres & 
                                                                                             Ashby (1981)
                                                            S. cerevisiae (XV185-14C)   -     Serres & 
                                                                                             Ashby (1981)
Mitotic recombination                                       S. cerevisiae (JD1)         +     Serres & 
                                                                                             Ashby (1981)
Mitotic crossing-over      10-1000 µg/ml                    S. cerevisiae (T1, T2)      -     Serres & 
assay                                                                                        Ashby (1981)

Mitotic aneuploidy         lowest effective                 S. cerevisiae (D6) - S9     +     Serres & 
                           concentration 100 µg/ml                                           Ashby (1981)

Mitotic gene conversion    5 µl/ml                          S. cerevisiae (D7) + S9     -     Serres & 
                                                                                             Ashby (1981)
Mitotic gene conversion    500 µg/ml                        S. cerevisiae (JD1)         -     Serres & 
                                                                                             Ashby (1981)
Repair test using yeast    minimum effective                S. cerevisiae (wild & rad)  +     Serres & 
strains (cell growth       concentration                                                     Ashby (1981)
inhibition)                (MEC) 300 µg/ml

Nuclear enlargement        0.01-100 µg/ml                  human fibroblasts           -     Serres & 
                           8-200 µg/ml                     HeLa cells                  +     Ashby (1981)

Table 18.  (contd.)
------------------------------------------------------------------------------------------------------------
Method                     Concentration                   Condition; comment        Results  Reference
------------------------------------------------------------------------------------------------------------
UDS test                   1.1-90 µg/ml (-S9)              human fibroblasts           -     Serres & 
                           2-30 µg/ml (+S9)                (WI - 38) -, + S9                 Ashby (1981)

                           0.032-100 µg/ml                 human fibroblasts           -     Serres & 
                                                           (from skin biopsies)              Ashby (1981)
                           0.1-100 µg/ml                   HeLa cells                  -     Serres & 
                                                                                             Ashby (1981)

Sister chromatid exchange  0.00625-0.1%                    CHO cells (-, + S9)         -     Serres & 
(SCE)                                                                                        Ashby (1981)
                           0.1-100 µg/ml                   CHO cells                   -     Serres & 
                                                                                             Ashby (1981)

RL Chromosome assay        75-300 µg/ml                    Rat liver epithelial type   -     Serres & 
                                                           cell line (RL1)                   Ashby (1981)

Mouse lymphoma             46.9-3000 µg/ml                 Mouse lymphoma cells        -     Serres & 
mutagenesis assay                                          (L5178Y)                          Ashby (1981)
                                                           -, + S9 rat liver

Human fibroblast           0.2-0.5 mg/ml                   human lung fibroblast       -     Serres & 
Diphtheria toxin                                           (HSC172)                          Ashby (1981)
Resistance test

Cell transformation test   500 µg/ml                       Baby hamster kidney cells   +     Serres & 
                                                           (BHK21C13/HRC1)                   Ashby (1981)

                                                           BHK-21 cell                 -     Serres & 
                                                                                             Ashby (1981)

Integration enhancement    0.005-0.5                       C3H2K cell                  -     Serres & 
test (MLV Test)                                                                              Ashby (1981)
               

Cytogenetic analysis       1.1 x 10-2-1.1                  human peripheral            -     Antoine et al.
                           mol/litre                       lymphocytes                       (1983)

Cytogenetic analysis       10-20%                          human peripheral            +     Koudela & 
                                                           lymphocytes                       Spazier (1979)
------------------------------------------------------------------------------------------------------------
Comment: Positive results were obtained with very high concentrations, such as 100-500 µg/ml and 10-20%.
    In one study, DMF did not induce any increase in chromosomal 
aberrations or sister chromatid exchange in human peripheral blood 
lymphocytes  in vitro  (Antoine et al., 1983).  However, in another 
study, chromosomal aberrations were reported in human peripheral 
lymphocyte cultures treated with DMF (Koudela & Spazier, 1979). The 
authors performed cytogenetic analyses of human peripheral lymphocytes 
treated with DMF (dilution from 10-7 to 10-2 mol/litre. Compared 
with the positive control, thio-TEPA, the clastogenic activity of DMF 
was 3- to 4-fold lower.  Chromosome aberrations were concentration-
related at DMF levels of 10-20%. 

    Cytogenetic analysis of peripheral lymphocytes in 40 workers 
exposed to 35-180 mg DMF/m3 was performed, first at 4-month 
intervals, and later at 6-month intervals.  Increased frequencies of 
non-specified chromosomal aberrations of 3.82 and 2.74%, respectively, 
were found (Koudela & Spazier, 1981).  In further sampling periods, 
after technological adjustments to decrease the DMF exposure to about 
30 mg/m3, the authors established lower frequencies of cell 
aberrations in most of the workers, i.e., 1.59, 1.58, and 1.49%, in 
the various periods under study.  The aberrant cells in the control 
group were 1.61-1.10% (Koudela & Spazier, 1979). 

8.6.2   In vivo studies

    In  in vivo  studies, DMF was negative in dominant lethal 
mutagenic assays, tests for chromosome aberrations and sperm 
abnormalities, and micronucleus tests, (Table 19). 

8.6.3  Appraisal

    The results obtained in the  in vitro  and  in vivo  test systems 
showed that DMF did not induce damage in genetic material. 

8.7  Carcinogenicity

    The carcinogenic activity of DMF has not been examined in 2-year 
studies on test-animals (Purchase et al., 1978; Barral-Chamaillard & 
Rouzioux, 1983; Kennedy, 1986; US EPA, 1986). However, there are some 
data concerning DMF, applied as a solvent, and for shorter periods of 
time. 

    In a study by Druckrey et al. (1967) two groups of 15 and 5 BD 
rats were treated, with 75 and 150 mg DMF/litre in the drinking-water 
for 500 and 250 days, respectively (total doses 38 000 mg/litre in 
drinking-water).  The animals were observed for up to a maximum of 750 
days, with an average survival of 532 days.  Similarly, two groups of 
12 rats each were given weekly, subcutaneous injections of 200 and 400 
mg DMF/kg (total doses 8000 and 20 000 mg/kg, respectively) and 
observed for 732 and 766 days, respectively.  No tumorigenic effects 
were reported in this small group of rats. 


Table 19.  Short-term genotoxicity tests of DMF ( in vivo )
--------------------------------------------------------------------------------------------------------------
Method                   Animal              Dose route               Results        Reference
--------------------------------------------------------------------------------------------------------------
Dominant lethal          male rat            90, 900 mg/m3               -           Lewis et al.
mutagenic bioassay                           inhalation 6 h daily                    (1979)
                                             for 5 consecutive days

Chromosome               male and            2.3-600 mg/m3               -           Sheveleva
aberrations              female rat          inhalation                              et al. (1979)

Micronucleus test        BALB/C mouse        0.2-2000 mg/kg ip           -           Antoine
                                                                                     et al. (1983)

Micronucleus test        B6C3F1 mouse        80% of LD50 ip              -           Serres & Ashby (1981)

Micronucleus test        ICR mouse           0.425-1.7 mg/kg ip          -           Serres & Ashby (1981)

Micronucleus test        CD-1 mouse          0.4-1.6 mg/kg ip            -           Serres & Ashby (1981)

Sperm morphology         (CBA x BALB/c)F1    0.1-1.5 mg/kg ip            -           Serres & Ashby (1981)
assay                    male mouse
--------------------------------------------------------------------------------------------------------------
    Kommineni (1973) reported that 9 out of 18 male, and 11 out of 19 
female rats, developed tumours in different organs following ip 
administrations of 100 mg DMF per rat, once a week, for 10 weeks. The 
incidence of tumours in male control rats was 4 out of 14 and, in 
females, 5 out of 14, also in different organs.  No specific organ or 
tumour type predominated in either the test or control group. Three 
testicular tumours were seen, a bilateral interstitial cell tumour in 
the controls, and an interstitial cell tumour and an embryonal cell 
carcinoma in the test group. 

8.8  Induction of tumour cell differentiation

    Borenfreund et al. (1975)  reported a decrease in the malignancy 
of the Friend erythroleukaemic cells and a marked increase in their 
differentiation along the erythroid pathway after their treatment with 
0.5 and 1% DMF solutions. 

    DMF induction of cell differentiation and a marked reduction of 
tumorigenicity was established by Dexter (1977) in transplantable 
murine rhabdomyosarcoma cells.  In another study, Dexter & Hager 
(1980) used 4 carcinoma cell lines derived from two specimens of 
adenosarcoma of the human sigmoid colon and showed changes in the 
carcinoma cells towards less malignant cell types.  Hager et al. 
(1980) demonstrated that a cultured human colon carcinoma cell 
responded to DMF by more differentiated development, again suggesting 
an antitumour effect. 

    Chakrabarty et al. (1984) studied the effects of DMF on AKR-2B and 
AKR-MCA cells  in vitro  and found that complete loss of anchorage 
independent growth occurred and the reduced expression of membrane 
antigens was restored. 

    The DMF induction of tumour cell differentiation has been studied 
by Kimball & Hixon (1983) in relation to the deviation of the nuclear 
protein.  Cordeiro & Savarese (1984) studied it in relation to the 
effects on cysteine/glutathione metabolism, and Levine et al. (1985) 
in relationship to the changes in receptor occupation and growth 
factor responsiveness.  Chen et al. (1986) studied the induction of 
tumour cells by DMF in relation to the rate of nucleoside transport in 
the cells. 

    A review of the studies on the effects of the induction of 
alkylformamides on terminal differentiation of tumour cells (Langdon & 
Hickman, 1987) shows that DMF should not be used for such purposes.  
The anti-neoplastic activity of DMF, determined  in vitro and  in vivo, 
does not appear to be sufficient for therapeutic use.

8.9  Mechanism of toxicity, mode of action

    Several hypotheses on the possible mechanism of DMF hepatotoxicity 
have been tested.  No experimental support for lipid peroxidation, 
lysosome labilization, or glutathione depletion has been reported.  
The critical biological effects leading to DMF hepatotoxicity have not 
been identified and still need to be elucidated (Scailteur & Lauwerys, 
1987). 

9.  EFFECTS ON HUMAN BEINGS

9.1  General population exposure

    No effects of DMF on the general population have been reported. 

9.2  Occupational exposure

    Reports of occupational poisonings with DMF have been reviewed by 
Kennedy (1986), US EPA (1986), and Scailteur & Lauwerys (1987). 

9.2.1  Accidental poisoning

    Several cases of acute accidental occupational poisoning with DMF 
have been reported (Tolot et al., 1968; Potter, 1973; Chary, 1974; 
Chivers, 1978; Aldyreva & Gafurov, 1980; Kang-de & Hui-lan, 1981; 
Shlygina & Nemolshev, 1981; Paoletti et al., 1982a,b). They were 
caused by the malfunctioning of the equipment, splashing of the 
organic solvent over the body, or working in plants without taking 
protective measures.  Over-exposure has occurred via the skin and/or 
inhalation.  Usually, the symptoms appeared from several hours up to 
several days after the accident.  The major symptoms were epigastric 
or abdominal pain, which was irradiating and progressive, accompanied 
by dizziness, nausea, anorexia, vomiting, fatigue, alcohol 
intolerance, and skin irritation.  Clinical laboratory tests showed 
liver function disturbance. Radioisotope diagnostic tests and liver 
biopsy revealed morphological changes in the liver.  No clinical 
manifestations of renal dysfunction were reported.  The patients 
recovered with symptomatic therapy in hospital for 2-3 weeks.  Liver 
function tests returned to normal.  Some of the patients, who were 
followed for several months or several years after the acute 
poisoning, had normal function tests. 

9.2.2  Long-term exposure

    After occupational exposure to DMF (intensity and length of 
exposure unspecified, no control groups), eye irritation, headache, 
anorexia, gastrointestinal disturbances, and sometimes hepatomegaly 
with biochemical signs of liver damage were reported.  Some 
haematological changes were also observed (Tolot et al., 1958; Weiss, 
1971; Dilorenzo & Grazioli, 1972).  In studies in which exposure was 
quantified, subjective complaints of headache, fatigue, and 
gastrointestinal and cardiovascular changes were reported. 
Disturbances of liver function could be measured by changes in plasma 
bilirubin levels, and increases in the serum activity of liver enzymes 
(transaminases, alkaline phosphatase, glutamyl-transpep-tidase).  
Alcohol intolerance occurred.  Haematological changes and ECG 
deviations were also observed (Table 20). 

    In a questionnaire study, for which little detail is available, 
Schottek (1972) reported 14% miscarriages in a group of women exposed 
to about 100 mg DMF/m3 compared with 10% in the control group.  No 
statistical analysis was performed.  Aldyreva & Gafurov (1980) 
reported perturbations in menstruation in 26 out of 70 women who had 
been exposed to 30-150 mg DMF/m3 for about a year.  No data are 

available on controls.  On the basis of company statistics, general 
morbidity associated with gynaecological changes appeared to be 
increased among DMF-exposed women. 

    Farquharson et al. (1983) reported miscarriages in 3 out of 9 
women, who had been exposed to DMF as well as a number of other 
chemicals. 

    Because of its effect on the stratum corneum, DMF interferes with 
the barrier function of the skin; this was demonstrated in human 
volunteers by increased water loss following DMF exposure (Baker, 
1968). 

9.2.3  Epidemiological studies on carcinogenicity

    Ducatman et al. (1986) reported three cases of testicular germ-
cell tumours in 1981-83 among 153 white men who repaired the exterior 
surfaces and electrical components of F4 Phantom jet aircraft, in the 
USA.  This finding led to surveys of two other repair shops at 
different geographical locations; in one of the shops, the same type 
of aircraft was repaired, while in the other, different types of 
aircraft were repaired.  Four out of 680 white male workers in the 
same type of repair shop had a history of testicular germ-cell cancers 
(0.95 expected) occurring in 1970-83.  No case of testicular germ-cell  
cancer  was found among the 446 white  men  employed at the facility 
where different types of aircraft were repaired.  Of the 7 cases of 
testicular germ cell tumours, 5 were seminomas and 2 were embryonal-
cell carcinomas.  All 7 men had long histories of working in aircraft 
repair.  The time from first exposure to diagnosis ranged from 4 to 19 
years.  There were many common exposures to solvents in the three 
facilities, the only exposure identified as unique to the F4 Phantom 
jet aircraft repair facilities, where the cases occurred, being to a 
solvent mixture containing 80% dimethyl-formamide (20% unspecified).  
No quantitative exposure data exist. Three of the cases had certainly 
been exposed to this mixture and 3 cases, probably exposed.  The cases 
were found through foremen and from filed death certificates, and the 
authors suggested that under-reporting was possible.  No other cases 
of cancer were investigated. 

    Levin et al. (1987) described 3 cases of embryonal-cell carcinoma 
of the testes in workers at one leather tannery in the USA, all of 
whom had worked as swabbers on the spray lines in leather finishing.  
The latency period was from 8 to 14 years.  According to the authors, 
all the tanneries surveyed used dimethylformamide, as well as a wide 
range of dyes, solvents, and other chemicals.  No quantitative 
exposure data are available.  The number of workers from which these 3 
cases arose was not given, and other cancers were not looked for. 


Table 20.  Studies on workers with long-term exposures
---------------------------------------------------------------------------------------------------------------------
Number    Number    Length    DMF exposure    Urinary   Hepato-   Alcohol   Other effects             Reference      
of        of non-   of        (mg/m3)         NMF       toxicity  intoler-                                           
exposed   exposed   exposure                                      ance                                               
subjects  controls  (years)                                                                                          
---------------------------------------------------------------------------------------------------------------------
22        28        5         1-47 (usually   20-63         -         +     NR                        Lauwerys       
                              < 30; gloves    mg/g                                                    et al. (1980) 
                              worn)           creatinine                                                             
                                                                                                                     
11         -        3         3-15            0.4-20        -      +(6)a    NR                        Yonemoto &     
                                              mg/24 h                                                 Suzuki (1980)  
                                                                                                                     
28        29        3-5       30-60           NR            -      NR       complaints of eye and     Hinkova et al. 
                                                                            respiratory tract         (1980)         
                                                                            irritation; no haemato-                  
                                                                            logical changes                          
                                                                                                                     
115       67        1-1.5     30-150 with     NR            +      NR       complaints of gastro-     Aldyreva &     
                              higher peaks +            (a few out          intestinal tract or       Gafurov (1980) 
                              skin exposure             of 29)              cardiovascular and                       
                                                                            ovarian distur-                          
                                                                            bances (29)                              
                                                                                                                     
177        -        3-5       10-30           NR            -       NR      complaints of             Aldyreva &     
                                                                            cardiovascular            Gafurov (1980) 
                                                                            disturbances (45)                        
                                                                                                                     
81        96        3.5        < 10           NR        +(10)      NR       complaints of gastro-     Kang-de &     
                              accidental                                    intestinal tract and      Hui-Lan (1981) 
                              peak levels up                                cardiovascular                           
                              to 4525 + skin                                disturbances, ECG                        
                              exposure                                      changes                                  
                                                                                                                     
23         -        2          > 30 peaks     10-40     NR         NR       No ECG changes com-       Taccola et al.
                              up to 150       mg/day                        pared with pre-exposure   (1981)         
                                                                                                                     
27        237       2         2-80 peaks      NR        +(2)       +(8)     complaints of gastro-     Paoletti &     
                              up to 549                                     intestinal tract          Iannaccone     
                                                                            disturbances (15);        (1982)         
                                                                            headache (6)                             
---------------------------------------------------------------------------------------------------------------------
                                                                                                                     

                                                                                                                     
Table 20.  (contd.)                                                                                                  
---------------------------------------------------------------------------------------------------------------------
Number    Number    Length    DMF exposure    Urinary   Hepato-    Alcohol  Other effects             Reference      
of        of non-   of        (mg/m3)         NMF       toxicity   intoler-                                          
exposed   exposed   exposure                                       ance                                              
subjects  controls  (years)                                                                                          
---------------------------------------------------------------------------------------------------------------------
13         - <       4        14-60           NR        +(2)       +(8)       complaints of gastro-     Tomasini    
                              (mean: 29)                                      intestinal tract          et al (1983) 
                                                                              disturbances (8); eye                  
                                                                              irritation (11); kidney                
                                                                              function test and                      
                                                                              haematology, normal                    
                                                                                                                     
26        54         > 5      2-5             NR         -         NR       NR                        Catenacci     
                              (mean: 3)                                                               et al.(1984)   
                                                                                                                     
28        54         > 5      12-25           NR         -         NR       NR                        Catenacci     
                              (mean: 18)                                                              et al. (1984)  
                                                                                                                     
100       100       5         8-58            NR        +          +(39)    complaints of headache,   Cirla et al.   
                              (mean: 22)                (8 versus           eye and throat            (1984)         
                                                        2 controls)         irritation, gastro-                      
                                                                            intestinal tract and                     
                                                                            cardiovascular                           
                                                                            disturbance                              
                                                                                                                     
24        29        5         10-60           NR        NR         NR       irritative dermatitis     Bainova (1985) 
                                                                                                                     
15        28        6-10      20-30           NR        NR         NR       increased coagulation     Imbriani       
                              (median 27)                                   time                      et al. (1986)  
                                                                                                                     
---------------------------------------------------------------------------------------------------------------------
a Incidence is indicated when available.
  NR = not reported
    To evaluate the significance of this cluster, an analysis of the 
New York State Cancer Registry was conducted.  Occupations were 
determined from cancer registries and from death certificates for all 
residents in Fulton County who were diagnosed as having testicular 
cancer from 1974-88.  From preliminary results, it is estimated that 
workers who are employed in the leather tanning industry are 5-6 times 
more likely to develop testicular cancer than those who are not 
leather workers.  However, the testicular cancer rates in this county 
were lower than expected within this period, and an adjacent county 
showed the same number of cases of testicular cancer, none of the 
affected individuals having ever worked in the leather industry 
(Walrath et al., 1988). 

    O'Berg et al. (1985) and Chen et al. (1988a) studied the cancer 
incidence among 2530 actively employed workers with potential exposure 
to dimethylformamide between 1956 and 1984, 1329 employees with 
exposure to dimethylformamide and acrylonitrile at an acrylic fibre 
manufacturing plant in South Carolina, USA, and 1130 controls from the 
same plant.  Cancer incidence rates for the company (1956-84) and USA 
national rates (1973-77) were used to calculate the expected number of 
cases.  For all workers exposed to DMF (alone or with acrylonitrile), 
the standardized incidence ratio (SIR), based on company rates for all 
cancers combined, was 110 [95% confidence interval (CI), 88-136]a (88 
cases); the SIR on the basis of national rates was 92.  The SIR for 
cancer of the buccal cavity and pharynx was 344 [CI, 172-615]a (11 
cases), on the basis of company rates, and 167, on the basis of US 
rates.  More cancer cases than expected from company rates (34 cases: 
SIR 134 [CI, 98-195]a) were found among employees exposed to 
dimethylformamide alone, due mainly to 8 carcinomas of the buccal 
cavity and pharynx versus 1.0 expected (SIR, 800 [CI, 345-1580]a).  
All of these cases either smoked or chewed tobacco, but no information 
was available on the smoking, tobacco chewing, or drinking habits of 
the cohort. An additional case occurred among employees exposed to 
dimethyl-formamide alone (SIR, 167); 4 of these tumours were cancers 
of the lip.  No such excess was found among the workers exposed to 
both dimethylformamide and acrylonitrile (2 observed; SIR, 125, on the 
basis of company rates).  The authors reported that there was no 
association with intensity or duration of exposure: "low" and 
"moderate" exposure SIR 420 (5 cases); "high" exposure SIR 300 (6 
cases).  "Low" exposure conditions included: no direct contact with 
liquids containing any dimethylformamide, even wearing protective 
equipment; and workplace air levels consistently below 30 mg DMF/m3 
(10 ppm) (no odour of DMF evident).  "Moderate" exposure conditions 
included: intermittent contact with liquids containing > 5% 
dimethylformamide; workplace air levels sometimes higher than 30 mg 
DMF/m3 (10 ppm) (more than once per week); DMF-laden materials 
handled, but air levels of DMF maintained at above levels.  "High" 
exposure conditions included: frequent contact with liquids containing 
> 5% dimethylformamide; workplace air levels often > 30 mg DMF/m3 
(> 10 ppm); use of breathing protection often required for periods of 
15 min-1 h;  DMF vapour levels frequently > 30 mg/m3 (> 10 ppm) 
(when handling pure dimethylformamide or dimethylformamide-containing 
 
---------------------------------------------------------------------------
a As calculated by IARC (1989).

materials). One case of testicular cancer was found among the 3859 
workers exposed to DMF (alone or with acrylonitrile) with 1.7 expected 
on the basis of company rates, and no cases of liver cancer.  The 
company rates may be more relevant for comparison, as there were only 
actively employed persons among the exposed and because the USA rates 
are based on a limited time period, 1973-77. 

    Chen et al. (1988b) analysed mortality from 1950-82 among both 
active and pensioned employees in the same cohort.  Expected numbers 
(adjusted for age and time period) were based on company rates.  For 
all workers exposed to DMF (alone or with acrylonitrile), the 
standardized mortality ratio (SMR) for lung cancer was 124 (33 cases 
[95% CI, 85-174]a).  An increased risk of lung cancer was found in the 
cohort exposed only to DMF (19 cases; SMR 141 [CI, 84-219]a), but not 
in the cohort exposed to DMF and acrylonitrile. There were 3 deaths 
from cancer of the buccal cavity and pharynx (SIR 188) in all persons 
exposed to DMF (alone or with acrylo-nitrile).  No other excess cancer 
risk was reported.  No information is given in this report on loss to 
follow-up, death certificates, or whether these deaths were included 
in the incidence study reported above. 

    Walrath et al. (1988) reported a case-control study on cancer 
among 8724 Du Pont employees with potential exposure to DMF in 4 other 
USA plants.  Summary analyses for all plants combined did not show any 
statistically significant association between ever having been exposed 
to DMF and subsequent development of cancers of the buccal cavity and 
pharynx, liver, malignant melanoma, prostate, and testes.  When odds 
ratios are examined according to plant site, prostate cancer at one 
site was significantly elevated, on the basis of 3 cases exposed out 
of 4, but no statistically significant association was observed among 
employees similarly exposed to DMF in the other 3 plants.  The recency 
of exposure to DMF, the low exposures received, and the absence of 
similar excesses at other plants argue against a causal association 
between DMF exposure and prostate cancer at the one site.  Assessment 
of highest DMF exposure rank, duration of exposure, and latent period, 
does not show any patterns suggesting an association between DMF and 
cancers of the buccal cavity and pharynx, liver, malignant melanoma, 
prostate, or testes. 

9.2.4  Alcohol intolerance

    Reviews on the synergistic action of ethanol with organic solvents 
have been published by Haguenoer et al. (1982), Hills & Venable 
(1982), and Stockley (1983). 

    Episodes of alcohol intolerance among workers exposed to DMF have 
been repeatedly described at all levels of exposure (see sections 
9.2.1 and 9.2.2, and Table 20). 

    Symptoms include flushing of the face, dizziness, nausea, 
tightness of the chest, sometimes dyspnoea, and cardiac palpitations. 
The reactions were reported within 24 h of DMF exposure and very 
shortly after alcohol ingestion.  These episodes lasted for up to 2 h 

---------------------------------------------------------------------------
a As calculated by IARC (1989).

(Chivers, 1978; Lyle et al., 1979; Yonemoto & Suzuki, 1980; Paoletti 
et al., 1982a; Cirla et al., 1984). 

    According to Loos (1979), abnormal liver function tests were 
already discovered among workers who drank only 50-70 g alcohol per 
day, but were also exposed to 45-66 mg DMF/m3, while the threshold 
consumption for functional liver changes was 80-100 g alcohol per day 
in control individuals.  It should be noted that the test group was 
also exposed to other solvents, mainly tetrahydrofuran, toluene, and 
xylene. 

10.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    The International Agency for Research on Cancer (IARC) evaluated 
the carcinogenicity of dimethylformamide in 1988 (IARC, 1989), and 
concluded that: 

    -   there is  limited evidence for the carcinogenicity of
        dimethylformamide in humans;

    -   there is  inadequate evidence for the carcinogenicity of
        dimethylformamide in experimental animals.

 Overall evaluation:     Dimethylformamide is possibly  carcinogenic
                        to humans (Group 2B).

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RESUME ET EVALUATION, CONCLUSIONS, RECOMMANDATIONS

1.  Résumé et évaluation

1.1  Propriétés générales

    Le  N,N-diméthylformamide (diméthylformamide, DMF, CSA 68-12-1) 
est un solvant organique qui est produit en grandes quantités dans 
l'ensemble du monde.  On l'utilise dans l'industrie chimique comme 
solvant, comme produit intermédiaire et comme additif.  Le DMF est un 
liquide incolore d'odeur légère mais désagréable qui, néanmoins, est 
insuffisante pour attirer l'attention.  Il est généralement stable 
mais il peut entraîner des incendies et des explosions par contact 
avec des oxydants forts, des halogènes, des dérivés alkylaluminiques 
ou des hydrocarbures halogénés (en particulier combinés à des métaux).  
Le DMF est entièrement miscible à l'eau et à la plupart des solvants 
organiques.  Sa tension de vapeur est relativement faible. 

    Du point de vue analytique, on a recours à la chromatographie
en phase gazeuse.

1.2  Transport, distribution, et transformation dans l'environnement

    Le DMF est stable dans l'air ambiant mais il peut subir une 
décomposition microbienne et algaire dans l'eau.  Les microorganismes 
adaptés et les boues activées assurent une biodégradation efficace du 
DMF.  Etant soluble dans l'eau en toutes proportions, le DMF est très 
mobile dans les sols et il ne devrait pas s'accumuler dans la chaîne 
alimentaire. 
 
1.3  Concentration dans l'environnement et exposition humaine

    Le DMF n'existe pas à l'état naturel.  On ne possède que peu de 
données sur sa concentration dans l'environnement ou sur l'exposition 
de la population générale.  Dans l'air de zones résidentielles situées 
à proximité d'installations industrielles, on a trouvé des 
concentrations allant de 0,02 à 0,12 mg/m3.  Il est rare qu'on décèle 
la présence de DMF dans l'eau des bassins fluviaux très industrialisés 
et encore, les concentrations ne dépassent pas 0,01 mg/litre. 

    On ne possède pas de données sur la concentration du DMF dans le 
sol, les végétaux, la faune sauvage et les produits alimentaires. 

    L'exposition professionnelle se produit par contact cutané avec le 
liquide ou la vapeur ou par inhalation de la vapeur.  On a décelé des 
concentrations de 3 à 86 mg/m3 dans l'air avec des maxima allant 
jusqu'à 600 mg/m3, au cours de travaux de réparation ou d'entretien de 
machines. Dans quelques cas exceptionnels, des concentrations allant 
jusqu'à 4500 mg/m3 ont été signalées. 
 
1.4  Cinétique et métabolisme

    Des quantités toxiques de DMF peuvent être absorbées par 
inhalation ou pénétration percutanée.  Une fois absorbé, le DMF se 
distribue de façon uniforme dans l'organisme.  Sa métabolisation a 
lieu principalement dans le foie sous l'action des enzymes 
microsomiales.  Chez l'animal et l'homme, le principal produit de la 
biotransformation du DMF est le  N-hydroxyméthyl- N-méthyl-formamide 
(DMF-OH).  Au cours de l'analyse par chromatographie en phase gazeuse, 
ce métabolite est transformé en  N-méthyl-formamide (NMF) qui est lui-
même (ainsi que le  N-hydroxyméthyl et le formamide) un métabolite 
mineur du DMF.  Par conséquent, lorsqu'on procède à des études 
métaboliques et que l'on effectue la surveillance biologique du DMF, 
les concentrations urinaires de métabolites sont mesurées et exprimées 
en NMF, même si le DMF-OH en est le constituant essentiel.  Le dosage 
du NMF/DMF-OH dans les urines peut donner une bonne indication 
biologique de l'exposition totale au DMF. 

    Chez l'animal d'expérience, on a montré que le mécanisme de 
métabolisation du DMF se sature lorsque l'exposition est intense, le 
DMF jouant le rôle de rétroinhibiteur de son propre métabolisme à 
concentration très élevée. 

    Il y a interaction métabolique entre le DMF et l'éthanol.

1.5  Effets sur les êtres vivant dans leur milieu naturel

    On n'a pas très bien étudié des effets du DMF sur l'environnement.  
Il semble que sa toxicité pour les organismes aquatiques soit faible. 


1.6  Effets sur les animaux d'expérience et les systèmes d'épreuve
 in vitro

    Le DMF présente pour diverses espèces une faible toxicité aiguë 
(chez le rat la DL50 par voie orale est d'environ 3000 mg/kg, la DL50 
dermique d'environ 5000 mg/kg et la CL50 par inhalation à peu près 
égale à 10 000 mg/m3).  Il est légèrement à modérément irritant pour 
la peau et les yeux.  D'après une étude sur des cobayes, il ne semble 
pas doté de pouvoir sensibilisateur.  Le DMF peut faciliter 
l'absorption percutanée d'autres substances chimiques. 

    Chez l'animal d'expérience, l'exposition au DMF, quelle que soit 
la voie de pénétration, peut provoquer des lésions hépatiques qui 
dépendent de la dose.  Lorsque l'exposition cesse, on a pu constater 
qu'il y avait régénération des tissus.  Certaines études on également 
permis d'observer des signes de toxicité au niveau du myocarde et des 
reins. 

    On n'a pas constaté de toxicité pour les testicules ou les 
ovaires, ni observé d'effets sur la fécondité chez le rat.  Chez le 
rat, la souris et le lapin, le DMF s'est révélé embryotoxique et 
faiblement tératogène.  C'est le lapin qui est l'espèce la plus 
sensible à l'exposition respiratoire:  des effets tératogènes ont été 
observés à partir de 1350 mg/m3 (450 ppm), aucun effet n'étant 

constaté à 450 mg/m3 (150ppm).  Après exposition de la peau, certaines 
études ont mis en évidence de très rares effets embryotoxiques et 
tératogènes à des doses journalières comprises entre 100 et 400 mg/kg. 

    De nombreuses épreuves à court terme à la recherche d'effets 
génétiques et anomalies de ce genre, on a montré que le DMF était en 
général inactif tant  in vitro  qu' in vivo. 

    Aucune étude convenable de cancérogénicité à long terme sur
animaux de laboratoire n'est décrite dans la littérature.

1.7  Effets sur l'homme

    Aucun effet indésirable sur la population dans son ensemble n'a
été nettement mis en évidence.

    On a fait état d'irritation cutanée et de conjonctivites après 
contact direct avec du DMF. 

    Après exposition accidentelle à de fortes concentrations de DMF, 
on note dans les 48h. des douleurs abdominales, des nausées, des 
étourdissements et de la fatigue.  La fonction hépatique peut être 
perturbée et on a signalé des modifications de la tension artérielle, 
une tachycardie et des anomalies du tracé électrocardiographique.  En 
général la récupération est totale. 

    Après des expositions réitérées sur une longue période, on observe 
des symptômes tels que céphalées, perte d'appétit et fatigue. Des 
signes biochimiques d'insuffisance hépatique peuvent également 
s'observer.  Des lésions hépatiques n'apparaissent, semble-t-il, qu'à 
partir d'une exposition de l'ordre de 30 mg/m3, en l'absence de 
contact cutané.  Cette concentration atmosphérique correspond à 
environ 40 mg de NMF/DMF-OH par gramme de créatinine dans un 
échantillon d'urine prélevé à la fin du poste de travail. 

    Même à des concentrations inférieures à 30 mg/m3, l'exposition
au DMF peut causer une intolérance à l'alcool dont les symptômes 
peuvent consister en rougeur soudaine de la face, sensation de 
constriction thoracique et étourdissements, quelques fois accompagnés 
de nausées et de dyspnée.  Ces symptômes durent de 2 à 4 heures et 
disparaissent spontanément. 

    On possède des preuves limitées d'une activité cancérogène du DMF 
pour l'homme.  C'est ainsi qu'une étude a fait état d'un accroissement 
de l'incidence des tumeurs du testicule après exposition à du DMF, 
tandis qu'une autre étude à révélé une incidence tumorale accrue au 
niveau de la cavité buccale et du pharynx, mais pas au niveau des 
testicules. 

    Deux études peu détaillées font état d'un accroissement de la 
fréquence des avortements chez des femmes exposées à du DMF, entre 
autres substances chimiques. 

2.  Conclusions

    1. Compte tenu de ses usages actuels, la population dans son 
       ensemble, n'est probablement que très peu exposée au DMF. 

    2. Le DMF est facilement résorbé au niveau de la peau et des voies 
       respiratoires.  Le dosage dans les urines du NMF/DMF-OH 
       constitue un moyen utile pour évaluer la quantité totale de DMF 
       absorbé. 

    3. Le risque de lésions hépatiques est faible si la concentration 
       du DMF dans l'air ambiant est maintenue en dessous de 30 mg/m3 
       et qu'il n'y a pas de contact cutané.  La valeur correspondante 
       de la teneur des urines en NMF/DMF-OH à la fin du poste de 
       travail a été fixée provisoirement à 40 mg/g de créatinine. 

    4. Le DMF est embryotoxique et faiblement tératogène pour le rat, 
       la souris et le lapin. 

    5. Il existe des preuves limitées d'une cancérogénicité du DMF 
       pour l'homme. 

    6. D'après les données dont on dispose, le DMF est peu toxique 
       pour l'environnement.  Il est peu probable qu'il donne lieu à 
       une bioaccumulation. 

3.  Recommandations

3.1  Précautions à prendre pour la manipulation

    1. Maintenir la concentration atmosphérique au-dessous de 30 mg/m3 
       et éviter le contact avec la peau. 

    2. Surveiller la concentration urinaire de NMF/DMF-OH qui indique 
       l'exposition totale et la maintenir en-dessous de 40 mg de 
       NMF/g de créatinine dans les échantillons prélevés à la fin du 
       poste de travail.  Si la concentration dépasse cette valeur, 
       prendre les mesures nécessaires pour réduire l'exposition. 

3.2  Recherches à effectuer

    1. Etudier les effets cancérogènes possibles du DMF chez l'homme, 
       par des études sur des populations humaines et des animaux 
       d'expérience. 

    2. Il faudrait disposer de données plus complètes sur la 
       possibilité d'extrapoler à l'homme les résultats des études 
       d'embryotoxicité et de tératogénicité effectuées sur l'animal.  
       Il serait bon d'étudier la cinétique comparée du DMF chez 
       l'homme et l'animal. 

    3. Davantage de données sont nécessaires sur le mode d'action et 
       l'activité relative des métabolites du DMF chez l'homme et 
       l'animal. 

    4. Il faudrait affiner les relations entre a) les concentrations 
       en métabolites urinaires et les taux d'exposition atmosphérique 
       (en l'absence de contact cutané), et b) la dose totale absorbée 
       par toutes les voies possibles (indiquée par la concentration 
       en NMF urinaire à la fin du poste de travail) et l'absence 
       d'hépatotoxicité. 

RESUMEN Y EVALUACION, CONCLUSIONES, RECOMENDACIONES

1.  Resumen y evaluación

1.1  Propiedades generales

    La  N,N-dimetilformamida (dimetilformamida, DMF, CAS 68-12-2) es 
un disolvente orgánico que se produce en grandes cantidades en todo el 
mundo.  Se utiliza en la industria química como disolvente, compuesto 
intermedio y aditivo.  La DMF es un líquido incoloro con un ligero 
olor desagradable que, no obstante, tiene escasas propiedades de 
alerta.  Es generalmente estable, pero cuando entra en contacto con 
oxidantes fuertes, halógenos, alquilaluminio o hidrocarburos 
halogenados (especialmente en combinación con metales), puede 
prenderse y provocar explosiones.  La DMF es totalmente miscible con 
el agua y la mayoría de los disolventes orgánicos.  Su presión de 
vapor es relativamente baja. 

    Existen procedimientos de cromatografía de gases para la
determinación de la DMF.

1.2  Transporte, distribución y transformación en el medio ambiente

    Aunque la DMF es estable en el aire, puede ser objeto en el agua 
de degradación por microbios y algas.  Los microorganismos adaptados y 
los fangos activados biodegradan la DMF de modo eficiente.  A 
consecuencia de su solubilidad total en el agua, la DMF se desplaza 
fácilmente en el suelo y no es de esperar que se acumule en la cadena 
alimentaria. 
 
1.3  Niveles medioambientales y exposición humana

    La DMF no aparece en la naturaleza.  Se dispone de pocos datos 
relativos a los niveles medioambientales o a la exposición de la 
población general a la DMF.  En zonas residenciales cercanas a centros 
industriales se han medido concentraciones atmosféricas de 0,02-0,12 
mg/m3.  Se ha detectado muy raras veces en las aguas de cuencas 
fluviales muy industrializadas, y en esos casos sólo en 
concentraciones inferiores a 0,01 mg/litro. 

    No se dispone de datos relativos a los niveles de DMF en el suelo, 
los vegetales, los animales silvestres ni los alimentos. 

    La exposición profesional se produce por contacto cutáneo con la 
DMF en forma líquida y de vapor, y por la inhalación de vapores. Se 
han detectado concentraciones de 3-86 mg/m3 de aire, con valores 
máximos de hasta 600 mg/m3, durante las operaciones de reparación o de 
mantenimiento de máquinas.  En condiciones muy especiales, se han 
registrado concentraciones de hasta 4500 mg/m3. 
 
1.4  Cinética y metabolismo

    Pueden absorberse cantidades tóxicas de DMF por inhalación y a 
través de la piel.  La DMF absorbida se distribuye uniformemente. La 
transformación metabólica de la DMF tiene lugar principalmente en el 
hígado, con el concurso de sistemas de enzimas microsómicas. En los 
animales y el ser humano, el producto principal de la 
biotransformación de la DMF es la  N-hidroximetil- N-metilformamida 
(DMF-OH).  Este metabolito principal se convierte durante el análisis 
con cromatografía de gases en  N-metilformamida, que es a su vez (junto 
con la  N-hidroximetilformamida y la formamida) uno de los metabolitos 
secundarios.  Así pues, en los estudios metabólicos y para el 
monitoreo biológico, las concentraciones de metabolitos en la orina se 
miden y expresan en forma de NMF, aunque la DMF-OH sea el 
contribuyente principal a esa concentración.  El análisis de la 
NMF/DMF-OH en la orina puede ser un indicador biológico adecuado de la 
exposición total a la DMF. 

    En los animales de experimentación, se ha demostrado que el 
metabolismo de la DMF se satura a niveles de exposición elevados y 
que, a niveles muy elevados, la DMF inhibe su propio metabolismo. 

    Se produce interacción metabólica entre la DMF y el etanol.

1.5  Efectos en los organismos del medio ambiente

    No se han estudiado bien los efectos de la DMF en el medio
ambiente. La toxicidad para los organismos acuáticos parece baja.

1.6  Efectos en los animales de experimentación y en sistemas de
ensayo  in vitro 

    La toxicidad aguda de la DMF en diversas especies es baja (en 
ratas, la DL50 es de unos 3000 mg/kg, la DL50 cutánea es de 
aproximadamente 5000 mg/kg, y la LC50 por inhalación es de unos 10 000 
mg/m3.  Su capacidad de irritación de la piel y los ojos es entre 
ligera y moderada.  En un estudio realizado con cobayas no hubo 
indicación alguna de potencial de sensibilización.  La DMF puede 
facilitar la absorción de otras sustancias químicas a través de la 
piel. 

    La exposición de animales de experimentación a la DMF por todas 
las vías de exposición puede provocar lesiones hepáticas dependientes 
de la dosis.  Se ha demostrado que se produce regeneración al cesar la 
exposición.  En algunos estudios se han descrito asimismo síntomas de 
toxicidad en el miocardio y el riñón. 

    No se ha demostrado que la DMF sea tóxica para el testículo ni 
para el ovario de la rata, ni se han observado efectos en la 
fecundidad.  Se ha descubierto que la DMF es embriotóxica y 
ligeramente teratogénica en la rata, el ratón y el conejo.  El conejo 
parece ser la especie más sensible a la exposición por inhalación:  se 
observaron efectos teratogénicos a partir de 1350 mg/m3 (450 ppm), 
pero no a 450 mg/m3 (150 ppm).  Tras la exposición cutánea, en algunos 
estudios se observó una incidencia muy baja de efectos embriotóxicos y 
teratogénicos con dosis que variaron entre 100 y 400 mg/kg al día. 

    En una amplia serie de ensayos a corto plazo en busca de efectos 
genéticos y otros afines se encontró que, en general, la DMF es 
inactiva, tanto  in vitro  como  in vivo. 

    No se han comunicado estudios suficientes sobre carcinogenicidad 
a largo plazo en animales de experimentación. 

1.7  Efectos en el ser humano

    No se ha demostrado claramente la existencia de efectos adversos 
de la DMF en la población general. 

    Se han comunicado casos de irritación cutánea y conjuntivitis tras 
el contacto directo con DMF. 

    Al cabo de 48 horas de la exposición accidental a niveles elevados 
de DMF, aparecen dolores abdominales, náuseas, vómitos, mareos y 
fatiga.  La función hepática puede alterarse y se han notificado casos 
de cambios en la tensión arterial, taquicardia y anomalías 
electroencefalográficas.  Por lo general, la recuperación es completa. 

    Después de una exposición repetida y a largo plazo, aparecen 
síntomas como dolor de cabeza, pérdida de apetito y fatiga.  Pueden 
observarse signos de disfunción hepática.  Las lesiones hepáticas 
parecen producirse sólo cuando el nivel de exposición a la DMF pasa de 
30 mg/m3, en ausencia de contacto cutáneo.  Ese nivel en el aire 
corresponde a aproximadamente 40 mg de NMF/DMF-OH/creatinina en una 
muestra de orina tomada después del turno de trabajo. 

    La exposición a la DMF, incluso en concentraciones inferiores a 30 
mg/m3, puede provocar intolerancia al alcohol.  Entre los síntomas 
pueden presentarse un acaloramiento facial repentino, opresión en el 
pecho y mareos, a veces acompañados de náuseas y disnea.  Duran entre 
2 y 4 h y desaparecen espontáneamente. 

    Existen pruebas limitadas de que la DMF es carcinogénica para el 
ser humano.  En un estudio se comunicó una incidencia mayor de tumores 
testiculares, mientras que en otro se observó una incidencia mayor de 
tumores de la cavidad oral y la faringe, pero no del testículo. 

    En dos estudios, que comunican pocos pormenores, se observó una 
frecuencia mayor de abortos espontáneos en mujeres expuestas a la DMF, 
entre otras sustancias químicas. 

2.  Conclusiones

   1.  Dados los usos actuales de la DMF, la exposición de la 
       población general es probablemente muy baja. 

   2.  La DMF se absorbe fácilmente a través de la piel además de por 
       inhalación.  La determinación de la NMF/DMF-OH en la orina es 
       un medio muy útil de estimar la cantidad total de DMF 
       absorbida. 

   3.  El riesgo de lesión hepática es reducido si el nivel de DMF en 
       el aire se mantiene por debajo de 30 mg/m3 y no hay contacto 
       cutáneo. Un valor provisional para el nivel correspondiente de 
       NMF/DMF-OH en la orina en una muestra tomada después del turno 
       de trabajo es 40 mg/g de creatinina. 

   4.  La DMF es embriotóxica y ligeramente teratogénica en la rata, 
       el ratón y el conejo. 

   5.  Existen pruebas limitadas de la carcinogenicidad de la DMF para 
       el ser humano. 

   6.  Los datos disponibles indican que tiene una baja toxicidad 
       ambiental.  Es poco probable que se produzca bioacumulación. 

3.  Recomendaciones

3.1  Manipulación sin riesgos

    1. Las concentraciones en el aire deben mantenerse por debajo de
       30 mg/m3 y debe evitarse el contacto con la piel.

    2. La NMF/DMF-OH en la orina, como índice de la exposición total, 
       debe vigilarse y mantenerse por debajo de 40 mg de NMF/g de 
       creatinina en muestras tomadas después del turno de trabajo.  
       Si se sobrepasa ese nivel, deben adoptarse medidas para 
       disminuir la exposición. 

3.2  Nuevas investigaciones

    1. Los posibles efectos carcinogénicos del DMF en el ser humano 
       deben investigarse mediante estudios en animales de 
       experimentación y poblaciones humanas. 

    2. Se necesita más información para extrapolar de los estudios en 
       animales al ser humano los datos sobre embriotoxicidad y 
       teratogenicidad de la DMF.  La comparación de la cinética de la 
       DMF en el ser humano y en los animales sería muy útil. 

    3. Se necesita más información sobre los mecanismos de acción y la 
       potencia relativa de los metabolitos de la DMF en animales y en 
       el ser humano. 

    4. Deben afinarse las relaciones entre a) las concentraciones de 
       metabolitos en la orina y los niveles de exposición en la 
       atmósfera (en ausencia de contacto cutáneo), y b) la dosis 
       total recibida por todas las vías (indicada por los niveles de 
       NMF en la orina después del trabajo) y la ausencia de 
       hepatotoxicidad. 



    See Also:
       Toxicological Abbreviations
       Dimethylformamide (HSG 43, 1990)
       Dimethylformamide  (SIDS)
       Dimethylformamide (IARC Summary & Evaluation, Volume 71, 1999)